WO2011153383A1 - Methods of treating platinum-resistant recurrent ovarian cancer with 4-iodo-3-nitrobenzamide in combination with an anti-metabolite and a platinum compound - Google Patents

Methods of treating platinum-resistant recurrent ovarian cancer with 4-iodo-3-nitrobenzamide in combination with an anti-metabolite and a platinum compound Download PDF

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Publication number
WO2011153383A1
WO2011153383A1 PCT/US2011/038975 US2011038975W WO2011153383A1 WO 2011153383 A1 WO2011153383 A1 WO 2011153383A1 US 2011038975 W US2011038975 W US 2011038975W WO 2011153383 A1 WO2011153383 A1 WO 2011153383A1
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platinum
patient
iodo
nitrobenzamide
ovarian cancer
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PCT/US2011/038975
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French (fr)
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Charles Braley
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Bipar Science, Inc.
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Priority claimed from CA 2725027 external-priority patent/CA2725027A1/en
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Publication of WO2011153383A1 publication Critical patent/WO2011153383A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • Cancer is a complex family of diseases affecting nearly every tissue in the body and characterized by aberrant control of cell growth.
  • the annual incidence of all cancer types is estimated to be in excess of 1.3 million cases in the United States alone.
  • first line therapies for the treatment of different types of cancer have been deployed with varying degrees of success, including surgical resection, radiation therapy, chemotherapy, and hormone therapy, it remains the second leading cause of death in the U.S., with an estimated 560,000 Americans dying from cancer every year.
  • Ovarian cancer is the 8th most common cancer in women worldwide with estimated 225,500 new diagnoses per year and estimated 140,200 deaths per year.
  • the current standard of care for first-line chemotherapy of ovarian cancer is a combination of a platinum compound (e.g., cisplatin, carboplatin, and oxaliplatin) with a taxane.
  • a platinum compound e.g., cisplatin, carboplatin, and oxaliplatin
  • the majority of newly-diagnosed ovarian cancer patients will respond to first-line platinum-based and paclitaxel chemotherapy. However, 50-80% of the patients who respond to this combination therapy will eventually relapse. See, e.g., Herzog, "Update on the role of topotecan in the treatment of recurrent ovarian cancer," The Oncologist 7(Suppl.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient having ovarian cancer an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin.
  • the platinum-resistant recurrent ovarian cancer is epithelial ovarian carcinoma.
  • the platinum-resistant recurrent ovarian cancer is fallopian tube cancer.
  • the platinum-resistant recurrent ovarian cancer is primary peritoneal carcinoma.
  • the treatment comprises at least 1 treatment cycle (e.g., at least about any of 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles, 12 cycles, 13 cycles, 14 cycles, 15 cycles, 16 cycles, 17 cycles, or 18 cycles), wherein each cycle (or each of the cycles) comprises administering an effective amount of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin.
  • each cycle comprises administering an effective amount of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin.
  • the treatment comprises at least about 2 (e.g., at least about 4 to about 12 or at least about 7 to about 12) treatment cycles, wherein each of the cycles comprises administering an effective amount of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin.
  • the patient has not received more than 2 prior platinum-based therapies.
  • the patient has a relapse within about 2 to about 6 months (e.g., a relapse within 2 to 6 months or a relapse within about any of 2 months, 2.5 months, 3 months, 3.5 months, 4 months, 4.5 months, 5 months, 5.5 months, or 6 months) after last dose of platinum-based chemotherapy.
  • a relapse within 2 to about 6 months e.g., a relapse within 2 to 6 months or a relapse within about any of 2 months, 2.5 months, 3 months, 3.5 months, 4 months, 4.5 months, 5 months, 5.5 months, or 6 months
  • the effective amount is administered over a 21 -day treatment cycle, wherein (i) carboplatin is administered to the patient at 4 mg/ml » minute (AUC 4) on day 1 of the treatment cycle; (ii) gemcitabine is administered to the patient at a dose of 1000 mg/m on days 1 and 8 of the treatment cycle; and (iii) 4-iodo-3-nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 5.6 mg/kg twice weekly on days 1, 4, 8, and 11 of the treatment cycle.
  • carboplatin is administered to the patient at 4 mg/ml » minute (AUC 4) on day 1 of the treatment cycle
  • gemcitabine is administered to the patient at a dose of 1000 mg/m on days 1 and 8 of the treatment cycle
  • 4-iodo-3-nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 5.6 mg/kg twice weekly on days 1, 4, 8, and 11 of the treatment
  • the effective amount produces at least one therapeutic effect selected from the group consisting of reduction in size of an ovarian tumor, reduction in metastasis, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response.
  • the method further comprises surgery, radiation therapy,
  • the method further comprises administering to the patient gamma irradiation.
  • the patient has platinum-resistant recurrent ovarian cancer.
  • the platinum-resistant recurrent ovarian cancer is selected from the group consisting of epithelial, germ cell, and stromal cell tumors.
  • the platinum-resistant recurrent ovarian cancer is metastatic.
  • 4-iodo-3- nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof is administered intravenously.
  • gemcitabine is administered
  • the platinum-resistant recurrent ovarian cancer is serous ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is serous adenocarcinoma ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is papillary serous ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is
  • the platinum-resistant recurrent ovarian cancer is clear cell ovarian cancer.
  • the platinum-resistant recurrent ovarian cancer comprises ovarian tumor of any grade, for example, any of grade 1, 2, or 3.
  • the patient has platinum compound-free interval of about any of 2 months, 3 months, 4 months, 5 months, or 6 months or at least about any of 2 months, 3 months, 4 months, 5 months, or 5.5 months.
  • the method further comprises administering granulocyte colony- stimulating factor ("G-CSF") to the patient.
  • G-CSF granulocyte colony- stimulating factor
  • the method does not further comprise administering G- CSF to the patient.
  • the treatment provides improved clinical benefit rate compared to treatment with gemcitabine and carboplatin administered without 4-iodo-3- nitrobenzamide.
  • the improvement of clinical benefit rate is about 20% or higher.
  • the therapeutic effect is an increase in overall response rate. In some embodiments, the overall response rate is greater than 15%. In some embodiments, the overall response rate is greater than 20%. In some embodiments, the overall response rate is greater than 30%.
  • the patient has platinum-resistant recurrent ovarian cancer.
  • the platinum-resistant recurrent ovarian cancer is deficient in homologous recombination DNA repair.
  • the recombination DNA repair-deficient platinum-resistant recurrent ovarian cancer is BRCA deficient.
  • the BRCA-deficient platinum-resistant recurrent ovarian cancer is BRCAl -deficient.
  • the BRCA-deficient platinum-resistant recurrent ovarian cancer is BRCA2-deficient.
  • the BRCA-deficient platinum-resistant recurrent ovarian cancer is both BRCAl -deficient and BRCA2-deficient.
  • the platinum-resistant recurrent ovarian cancer comprises at least one mutation in BRCAl. In some embodiments, the platinum-resistant recurrent ovarian cancer does not comprise a mutation in BRCAl.
  • the platinum-resistant recurrent ovarian cancer comprises at least one mutation in BRCA2. In some embodiments, the platinum-resistant recurrent ovarian cancer does not comprise a mutation in BRCA2. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises at least one mutation in BRCAl and at least one mutation in BRCA2. In some embodiments, the platinum-resistant recurrent ovarian cancer does not comprise a mutation in BRCAl or BRCA2.
  • an antimetabolite e.g., gemcitabine
  • a platinum compound e.g., carboplatin
  • pharmaceutically acceptable salt or solvate thereof is to be administered to the patient in combination with an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin).
  • an antimetabolite e.g., gemcitabine
  • a platinum compound e.g., carboplatin
  • compositions used for treating platinum- resistant recurrent ovarian cancer in a patient comprising administering to said patient a) 4- iodo-3-nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, b) an antimetabolite, and (c) a platinum compound, wherein the
  • antimetabolite is selected from the group consisting of citabine, capecitabine, gemcitabine or valopicitabine, and wherein the platinum compound is selected from the group consisting of cisplatin; cis-diamminediaquoplatinum (Il)-ion; chloro(diethylenetriamine) -platinum (II) chloride; dichloro(ethylenediamine) -platinum (II); diammine(l,l-cyclobutanedicarboxylato) platinum (II) (carboplatin); spiroplatin; iproplatin; diammine(2-ethylmalonato)platinum (II); ethylenediaminemalonatoplatinum (II); aqua(l,2-diaminodicyclohexane)sulfatoplatinum (II); aqua(l,2-diaminodicyclohexane)malonatoplatinum (II); (1,2- diaminocycl
  • kits for treating platinum-resistant recurrent ovarian cancer in a patient comprise (a) 4-iodo-3-nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, (b) an antimetabolite, and (c) a platinum compound.
  • the kits may further comprise a product or package insert or a label comprising instructions and/or information for using an effective amount of (a) 4-iodo-3-nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, (b) an antimetabolite, and (c) a platinum compound, in accordance with any of the methods described herein.
  • kits comprise 4-iodo-3-nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof and a product or package insert or a label comprising instructions and/or information for using an effective amount of 4-iodo-3-nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof in combination with an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin) for treating platinum-resistant recurrent ovarian cancer in a patient in accordance with any of the methods described herein.
  • an antimetabolite e.g., gemcitabine
  • a platinum compound e.g., carboplatin
  • the effective amount is administered over a 21 -day treatment cycle, wherein (i) carboplatin is administered to the patient at 4
  • the platinum-resistant recurrent ovarian cancer is epithelial ovarian carcinoma. In some embodiments, the platinum-resistant recurrent ovarian cancer is fallopian tube cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is primary peritoneal carcinoma.
  • the patient has a relapse within about 2 to about 6 months (e.g., a relapse within 2 to 6 months or a relapse within about any of 2 months, 2.5 months, 3 months, 3.5 months, 4 months, 4.5 months, 5 months, 5.5 months, or 6 months) after last dose of platinum-based chemotherapy.
  • the patient has measurable disease.
  • the patient has not received more than 2 prior platinum-based therapies.
  • Black square represents PD.
  • A represents no BRCA mutation.
  • M represents mutation in BRCA1 or BRCA2.
  • Black square represents PD.
  • A represents no BRCA mutation.
  • M represents mutation in BRCA1 or BRCA2.
  • PFS median progression-free survival
  • platinum-resistant refers to a type of ovarian cancer (e.g. , recurrent ovarian cancer).
  • the current standard of care for first-line chemotherapy of ovarian cancer is a combination of a platinum compound (e.g., cisplatin, carboplatin, and oxaliplatin) with a taxane.
  • a platinum compound e.g., cisplatin, carboplatin, and oxaliplatin
  • the majority of newly-diagnosed ovarian cancer patients will respond to first- line platinum-based and paclitaxel chemotherapy. However, 50-80% of the patients who respond to this combination therapy will eventually relapse.
  • surgery refers to any therapeutic or diagnostic procedure that involves methodical action of the hand or of the hand with an instrument, on the body of a human or other mammal, to produce a curative, remedial, or diagnostic effect.
  • Random therapy refers to exposing a patient to high-energy radiation, including without limitation x-rays, gamma rays, and neutrons. This type of therapy includes without limitation external-beam therapy, internal radiation therapy, implant radiation, brachytherapy, systemic radiation therapy, and radiotherapy.
  • “Chemotherapy” refers to the administration of one or more anti-cancer drugs such as, antineoplastic chemotherapeutic agents, chemopreventative agents, and/or other agents to a patient with platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer) by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical,
  • anti-cancer drugs such as, antineoplastic chemotherapeutic agents, chemopreventative agents, and/or other agents to a patient with platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer) by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical,
  • chemotherapy as used herein is not intended to refer to the administration of 4-iodo-3-nitrobenzamide, an antimetabolite (e.g., gemcitabine), and a platinum compound (e.g., carboplatin) as described herein.
  • Chemotherapy may be given prior to surgery to shrink a large tumor prior to a surgical procedure to remove it, prior to radiation therapy, or after surgery and/or radiation therapy to prevent the growth of any remaining ovarian cancer cells in the body. Chemotherapy may also occur during the course of radiation therapy.
  • phrases “effective amount” or “pharmaceutically effective amount” refer to a sufficient amount of an agent to provide the desired biological, therapeutic, and/or
  • an "effective amount" for therapeutic uses is the amount of a) 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt or solvate thereof; b) an antimetabolite (e.g. , gemcitabine), or pharmaceutically acceptable salt or solvate thereof; and c) a platinum compound (e.g., carboplatin) provided herein, or a composition comprising a) 4-iodo-3-nitrobenzamide or a metabolite thereof or a
  • a platinum compound e.g., carboplatin provided herein required to provide a clinically significant decrease in the platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer) or slowing of progression of the platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer).
  • Methodabolite refers to a compound produced through any in vitro or in vivo metabolic process which results in a product that is different in structure than that of the starting compound.
  • the term “metabolite” includes the metabolite compounds of 4-iodo-3-nitrobenzamide.
  • a metabolite can include a varying number or types of substituents that are present at any position relative to a precursor compound.
  • the terms “metabolite” and “metabolite compound” are used interchangeably herein.
  • pharmaceutically acceptable is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • treating and its grammatical equivalents as used herein include achieving a therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • therapeutic benefit includes eradication or amelioration of the underlying ovarian cancer, e.g., slowing of progression of the ovarian cancer.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder (e.g., ovarian cancer) such that an improvement is observed in the patient, notwithstanding the fact that the patient may still be afflicted with the underlying disorder (e.g., ovarian cancer).
  • a method of the invention may be performed on, or a composition of the invention administered to a patient at risk of developing platinum- resistant ovarian cancer (e.g. , recurrent ovarian cancer), or to a patient reporting one or more of the physiological symptoms of platinum-resistant ovarian cancer (e.g.
  • recurrent ovarian cancer even though a diagnosis of platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer) may not have been made.
  • the patient being treated has been diagnosed with a platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer) described herein.
  • Reference to "about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to "about X” includes description of "X”.
  • ovarian tumors There are three basic types of ovarian tumors: epithelial, germ cell, and stromal cell tumors.
  • Epithelial tumors start from the cells that cover the outer surface of the ovary; most ovarian tumors are epithelial cell tumors.
  • Germ cell tumors start from the cells that produce the eggs.
  • Stromal tumors start from cells that hold the ovary together and make the female hormones.
  • a significant risk factor for ovarian cancer includes deficiencies in DNA repair via homologous recombination, such as mutations in the BRCA1 or BRCA2 gene. Those genes were originally identified in families with multiple cases of breast cancer, but have been associated with approximately 5 to 10 percent of ovarian cancers.
  • Possible treatments for ovarian cancer include surgery, immunotherapy, and others.
  • Surgical procedures for the treatment of ovarian cancer include debulking, and a unilateral or bilateral oophorectomy and/or a unilateral or bilateral salpigectomy.
  • Anti-cancer drugs that have also been used to treat ovarian cancer include cyclophosphamide, etoposide, altretamine, and ifosfamide.
  • Hormone therapy with the drug tamoxifen is also used to shrink ovarian tumors.
  • Radiation therapy optionally includes external beam radiation therapy and/or brachytherapy.
  • kits for treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite, and a platinum compound.
  • the antimetabolite is selected from the group consisting of citabine, capecitabine, gemcitabine or valopicitabine.
  • the antimetabolite is gemcitabine.
  • the platinum compound is selected from the group consisting of cisplatin; cis-diamminediaquoplatinum (Il)-ion;
  • the platinum compound is carboplatin.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering an effective amount of (i) 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin.
  • the patient has platinum-resistant recurrent ovarian cancer.
  • At least one therapeutic effect is obtained, said at least one therapeutic effect being reduction in size of a tumor, reduction in metastasis, complete remission, partial remission, pathologic complete response, or stable disease.
  • the method further comprises surgery, radiation therapy, chemotherapy, gene therapy, viral therapy, RNA therapy, DNA therapy, adjuvant therapy, neoadjuvant therapy, immunotherapy, nanotherapy or a combination thereof.
  • the method further comprises administering to the patient gamma irradiation.
  • the platinum-resistant recurrent ovarian cancer is selected from the group consisting of epithelial, germ cell, and stromal cell tumors.
  • the platinum-resistant recurrent ovarian cancer is metastatic.
  • the platinum-resistant recurrent ovarian cancer is not metastatic.
  • the platinum-resistant recurrent ovarian cancer comprises invasive malignancy.
  • the platinum-resistant recurrent ovarian cancer does not comprise invasive malignancy.
  • the present invention provides a method of treating platinum- resistant ovarian cancer (e.g., platinum-resistant recurrent ovarian cancer) in a patient, comprising administering to the patient having ovarian cancer (e.g., platinum resistant ovarian cancer) an effective amount of: (i) 4-iodo-3-nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin.
  • platinum- resistant ovarian cancer e.g., platinum-resistant recurrent ovarian cancer
  • ovarian cancer e.g., platinum resistant ovarian cancer
  • the effective amount is administered over a 21 -day treatment cycle, wherein (i) the effective amount of carboplatin is administered to the patient at 4 mg/ml » minute (AUC 4) (or about AUC4) on day 1 of the treatment cycle; (ii) the effective amount of gemcitabine is administered to the patient at a dose of 1000 mg/m 2 (or about 1000 mg/m 2 ) on days 1 and 8 of the treatment cycle; and (iii) the effective amount of 4-iodo-3-nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 5.6 mg/kg (or about 5.6 mg/kg) twice weekly on days 1, 4, 8, and 11 of the treatment cycle.
  • AUC 4 mg/ml » minute AUC 4 mg/ml » minute
  • gemcitabine is administered to the patient at a dose of 1000 mg/m 2 (or about 1000 mg/m 2 ) on days 1 and 8 of the treatment cycle
  • the effective amount produces at least one therapeutic effect selected from the group consisting of reduction in size of an ovarian tumor, reduction in metastasis, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response.
  • the improvement of clinical benefit rate is about 20% or higher.
  • the therapeutic effect is an increase in overall response rate. In some embodiments, the overall response rate is greater than 20%.
  • the overall response rate is greater than 15%. In some embodiments, the overall response rate is greater than 30%. In some embodiments, the method further comprises surgery, radiation therapy, chemotherapy, gene therapy, viral therapy, RNA therapy, DNA therapy, adjuvant therapy, neoadjuvant therapy, immunotherapy, nanotherapy or a combination thereof. In some embodiments, the method further comprises administering to the patient gamma irradiation.
  • the platinum-resistant ovarian cancer e.g., platinum-resistant recurrent ovarian cancer
  • the platinum-resistant ovarian cancer is selected from the group consisting of epithelial, germ cell, and stromal cell tumors. In some embodiments, the platinum- resistant ovarian cancer is recurrent ovarian cancer.
  • the platinum- resistant ovarian cancer (e.g., platinum-resistant recurrent ovarian cancer) is metastatic. In some embodiments, the platinum-resistant ovarian cancer (e.g., platinum-resistant recurrent ovarian cancer) is deficient in homologous recombination DNA repair. In some
  • the homologous recombination DNA repair-deficient platinum-resistant ovarian cancer is BRCA deficient.
  • the BRCA-deficient platinum- resistant ovarian cancer is BRCA 1 -deficient.
  • the BRCA-deficient platinum-resistant ovarian cancer is BRCA2-deficient.
  • the BRCA- deficient platinum-resistant ovarian cancer is both BRCA 1 -deficient and BRCA2-deficient.
  • the platinum-resistant recurrent ovarian cancer comprises at least one mutation in BRCA1.
  • the platinum-resistant recurrent ovarian cancer does not comprise a mutation in BRCA1.
  • the platinum-resistant recurrent ovarian cancer comprises at least one mutation in BRCA2.
  • the platinum-resistant recurrent ovarian cancer does not comprise a mutation in BRCA2. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises at least one mutation in BRCA1 and at least one mutation in BRCA2. In some embodiments, the platinum-resistant recurrent ovarian cancer does not comprise a mutation in BRCA1 or BRCA2.
  • the platinum- resistant recurrent ovarian cancer is deficient in homologous recombination DNA repair.
  • the homologous recombination DNA repair-deficient platinum-resistant recurrent ovarian cancer is BRCA deficient.
  • a deficiency in a BRCA gene is detected in the ovarian cancer patient.
  • the deficiency is a genetic defect in the BRCA gene.
  • the genetic defect is a mutation, insertion, substitution, duplication or deletion of the BRCA gene.
  • the BRCA gene is BRCA 1.
  • the BRCA gene is BRCA-2.
  • the BRCA-deficient platinum-resistant recurrent ovarian cancer is BRCA1- deficient. In some embodiments, the BRCA-deficient platinum-resistant recurrent ovarian cancer is BRCA2-deficient. In some embodiments, the BRCA-deficient platinum-resistant recurrent ovarian cancer is both BRCA 1 -deficient and BRCA2-deficient.
  • a method of treating platinum-resistant recurrent ovarian cancer comprising administering an effective amount of 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (e.g., gemcitabine), and a platinum compound (e.g., carboplatin).
  • the platinum-resistant recurrent ovarian cancer is epithelial ovarian carcinoma.
  • the platinum-resistant recurrent ovarian cancer is fallopian tube cancer.
  • the platinum-resistant recurrent ovarian cancer is primary peritoneal carcinoma.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient having the platinum-resistant recurrent ovarian cancer an effective amount of: (i) 4-iodo-3-nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin.
  • the ovarian cancer described herein may be epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma.
  • the platinum-resistant recurrent ovarian cancer is serous ovarian cancer.
  • the platinum-resistant recurrent ovarian cancer is serous adenocarcinoma ovarian cancer.
  • the platinum-resistant recurrent ovarian cancer is papillary serous ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is endometrioid ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is clear cell ovarian cancer.
  • the patient has measurable disease (such as measurable disease according to RECIST 1.1).
  • the measurable disease may be defined by at least one lesion that can be accurately measured in at least one dimension (such as longest dimension), and is > 20 mm when measured by conventional techniques (e.g., palpation, plain x-ray, computed tomography, or magnetic resonance imaging) or > 10 mm when measured by spiral CT.
  • the patient has not received more than 2 prior platinum-based therapies. In some embodiments, the patient has completed only one previous course of cytotoxic therapy (which must have contained a platinum therapy and have resistance to that regimen). In some embodiments, the patient has a relapse within about 2 to about 6 months (e.g., a relapse within 2 to 6 months or a relapse within about any of 2 months, 2.5 months, 3 months, 3.5 months, 4 months, 4.5 months, 5 months, 5.5 months, or 6 months) after last dose of platinum-based chemotherapy. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises ovarian tumor of any grade, for example, any of grade 1, 2, or 3.
  • Grading of ovarian tumor may be in accordance with any of the methods known to one skilled in the art.
  • grade 0 may refer to non-invasive tumors or borderline tumors.
  • Grade 1 tumors may have cells that are well differentiated (look very similar to the normal tissue) and may be the ones with the best prognosis.
  • Grade 2 tumors may be moderately well differentiated and may be made up by cells that resemble the normal tissue.
  • Grade 3 tumors may have the worst prognosis and their cells may be abnormal, referred to as poorly differentiated.
  • the patient has not been treated with more than 2 lines of cytotoxic chemotherapy and 1 line of biologies such as anti-VEGF antibody (e.g., bevacizumab) for up to six months (hormones do not count as a line of treatment).
  • cytotoxic chemotherapy e.g., bevacizumab
  • the patient has received two cytotoxic chemotherapies, including one containing platinum and one non-platinum such as liposomal doxorubicin.
  • the patient has not received a prior chemotherapy comprising 4-iodo-3-nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof.
  • the patient has not received a prior chemotherapy comprising a PARP inhibitor (e.g., Olaparib, ABT-888 (Veliparib), AGO 14699, CEP 9722, MK 4827, KU-0059436 (AZD2281), or LT-673).
  • a PARP inhibitor e.g., Olaparib, ABT-888 (Veliparib), AGO 14699, CEP 9722, MK 4827, KU-0059436 (AZD2281), or LT-673.
  • the patient has platinum compound-free interval of about any of 2 months, 3 months, 4 months, 5 months, or 6 months or at least about any of 2 months, 3 months, 4 months, 5 months, or 5.5 months.
  • the method further comprises administering granulocyte colony- stimulating factor ("G-CSF") to the patient. In some embodiments, the method does not further administering G-CSF to the patient.
  • G-CSF granulocyte colony- stimulating factor
  • the dosing regimen for 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (e.g., gemcitabine), and a platinum compound (e.g., carboplatin) may be according to any of the dosing schedule or dosing regimen described in the Section
  • the term "patient” or “subject” refers to a human patient or subject.
  • the platinum-resistant recurrent ovarian cancer can be any stage. In some embodiments of any of the methods described herein, the platinum-resistant recurrent ovarian cancer is not metastatic. In some embodiments, the platinum-resistant recurrent ovarian cancer is metastatic. In some embodiments, the platinum-resistant recurrent ovarian cancer is any of stage 1, 2, 3 or 4. In some embodiments, the platinum-resistant recurrent ovarian cancer is any of stage la, lb, lc, 2a, 2b, 2c, 3a, 3b, 3c, or 4.
  • the staging may be according to any of the methods known to one skilled in the art. For example, the staging may be in accordance with the staging described at
  • At least one therapeutic effect is obtained, said at least one therapeutic effect being reduction in size of an ovarian tumor, reduction in metastasis, complete remission, partial remission, pathologic complete response, increase in overall response rate or stable disease.
  • the treatment provides improved clinical benefit rate compared to treatment without 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof.
  • the improvement of clinical benefit rate is at least about any of 20%, 30%, 40%, 50%, 60%, 70%, 80%, or more.
  • the therapeutic effect is an increase in overall response rate.
  • the increase in overall response rate is about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or more.
  • the methods for treating platinum-resistant recurrent ovarian cancer further comprise administering 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof in combination with an anti-tumor agent (or at least one anti-tumor agent).
  • an anti-tumor agent or at least one anti-tumor agent.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering an effective amount of (a) 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, (b) an antimetabolite (e.g.,
  • the anti-tumor agent is an antitumor alkylating agent, antitumor antimetabolite, antitumor antibiotics, plant-derived antitumor agent, antitumor platinum complex, antitumor camptothecin derivative, antitumor tyrosine kinase inhibitor, monoclonal antibody, interferon, biological response modifier, hormonal anti-tumor agent, anti-tumor viral agent, angiogenesis inhibitor, differentiating agent, or other agent that exhibits anti-tumor activities, or a pharmaceutically acceptable salt thereof.
  • the platinum complex is cisplatin, carboplatin, oxaplatin or oxaliplatin.
  • the antimetabolite is citabine, capecitabine, gemcitabine or valopicitabine.
  • the methods further comprise administering to the patient 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof in combination with more than one anti-tumor agent.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (e.g., gemcitabine), and a platinum compound (e.g., carboplatin) in combination with at least more than one anti-tumor agent.
  • an antimetabolite e.g., gemcitabine
  • a platinum compound e.g., carboplatin
  • the anti-tumor agent is administered prior to, concomitant with or subsequent to administering 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (e.g., gemcitabine), and/or a platinum complex (e.g., carboplatin).
  • the anti-tumor agent is an anti- angiogenic agent, such as Avastin or a receptor tyrosine kinase inhibitor including but not limited to Sutent, Nexavar, Recentin, ABT-869, and Axitinib.
  • the anti-tumor agent is a topoisomerase inhibitor including but not limited to irinotecan, topotecan, or camptothecin.
  • the anti-tumor agent is a taxane including but not limited to paclitaxel, docetaxel and Abraxane.
  • the anti-tumor agent is an agent targeting Her-2, Herceptin or lapatinib.
  • the antitumor agent is a hormone analog, for example, progesterone.
  • the antitumor agent is tamoxifen, a steroidal aromatase inhibitor, a non-steroidal aromatase inhibitor, or Fulvestrant.
  • the anti-tumor agent is an agent targeting a growth factor receptor.
  • such agent is an inhibitor of epidermal growth factor receptor (EGFR) including but not limited to Cetuximab and Panitumimab.
  • the agent targeting a growth factor receptor is an inhibitor of insulin-like growth factor 1 (IGF-1) receptor (IGF1R) such as CP-751871.
  • the method further comprises surgery, radiation therapy, chemotherapy, gene therapy, DNA therapy, adjuvant therapy, neoadjuvant therapy, viral therapy, RNA therapy, immunotherapy, nanotherapy or a combination thereof.
  • at least one therapeutic effect is obtained, said at least one therapeutic effect being reduction in size of a tumor, reduction in metastasis, complete remission, partial remission, pathologic complete response, or stable disease.
  • the treatment comprises a treatment cycle of at least 11 days, e.g., about 11 to about 30 days in length, wherein on from 1 to 10 separate days of the cycle, the patient receives about 1 to about 100 mg/kg of 4-iodo-3-nitrobenzamide or a molar equivalent of a metabolite thereof. In some embodiments, on from 1 to 10 separate days of the cycle, the patient receives about 1 to about 50 mg/kg of 4-iodo-3-nitrobenzamide or a molar equivalent of a metabolite thereof.
  • the patient receives about 1, 2, 3, 4, 5, 5.6, 6, 8, 10, 11.2, 12, 14, 16, 18 or 20 mg/kg of 4-iodo-3-nitrobenzamide.
  • the treatment further comprises an antimetabolite (e.g., gemcitabine), and a platinum compound (e.g., carboplatin).
  • Some embodiments described herein provide a method of treating platinum- resistant recurrent ovarian cancer in a patient (e.g., a patient having a deficiency in a BRCA gene), comprising during a 21 day treatment cycle on days 1, 4, 8 and 11 of the cycle, administering to the patient about 10 to about 100 mg/kg of 4-iodo-3-nitrobenzamide or a molar equivalent of a metabolite thereof.
  • the 4-iodo-3- nitrobenzamide is administered orally or as a parenteral injection or infusion, or inhalation.
  • the treatment further comprises an antimetabolite (e.g., gemcitabine), and a platinum compound (e.g., carboplatin).
  • Some embodiments described herein provide a method of treating platinum- resistant recurrent ovarian cancer in a patient (e.g., a patient having a deficiency in a BRCA gene), comprising: (a) establishing a treatment cycle of about 10 to about 30 days in length; (b) on from 1 to 10 separate days of the cycle, administering to the patient about 1 mg/kg to about 50 mg/kg of 4-iodo-3-nitrobenzamide, or a molar equivalent of a metabolite thereof.
  • the 4-iodo-3-nitrobenzamide is administered orally or as a parenteral injection or infusion, or inhalation.
  • the treatment further comprises an antimetabolite (e.g., gemcitabine), and a platinum compound (e.g., carboplatin).
  • Some embodiments provided herein include a method of treating ovarian cancer in a patient in need of such treatment, comprising: (a) obtaining a sample from the patient; (b) testing the sample to determine if there is a deficiency in a BRCA gene; (c) if the testing indicates that the patient has a deficiency in a BRCA gene, treating the patient with 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof; and (d) if the testing does not indicate that the patient has a deficiency in a BRCA gene, selecting a different treatment option.
  • At least one therapeutic effect is obtained, said at least one therapeutic effect being reduction in size of an ovarian tumor, reduction in metastasis, complete remission, partial remission, pathologic complete response, increase in overall response rate, or stable disease.
  • the clinical benefit rate is at least about 30%.
  • the sample is a tissue or bodily fluid sample.
  • the sample is a tumor sample, a blood sample, a blood plasma sample, a peritoneal fluid sample, an exudate or an effusion.
  • the ovarian cancer is a metastatic ovarian cancer.
  • the BRCA gene is BRCA-1. In other embodiments, the BRCA gene is BRCA-2. In some embodiments, the BRCA gene is BRCA-1 and BRCA-2. In other embodiments, the deficiency is a genetic defect in the BRCA gene. In some
  • the genetic defect is a mutation, insertion, substitution, duplication or deletion of the BRCA gene.
  • 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof may be capable of being present in a variety of physical forms— e.g., free base, salts (especially pharmaceutically acceptable salts), hydrates, polymorphs, solvates, etc. Unless otherwise qualified herein, use of a chemical name is intended to encompass all physical forms of the named chemical. For example, recitation of 4-iodo-3-nitrobenzamide, without further qualification, is intended to generically encompass the free base as well as all
  • a platinum compound e.g., carboplatin
  • a platinum compound is administered as an intravenous infusion.
  • 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered orally or as a parenteral injection or infusion, or inhalation.
  • an anti-metabolite e.g., gemcitabine
  • an intravenous infusion is administered as an intravenous infusion.
  • the method comprises treating a patient with at least three chemically distinct substances, one of which is anti-metabolite (e.g. gemcitabine), one of which is a platinum-containing complex (e.g., carboplatin or cisplatin) and 4-iodo-3-nitrobenzamide or a metabolite thereof or a
  • anti-metabolite e.g. gemcitabine
  • platinum-containing complex e.g., carboplatin or cisplatin
  • one or more of these substances may be capable of being present in a variety of physical forms— e.g., free base, salts (especially pharmaceutically acceptable salts), hydrates, polymorphs, solvates, or metabolites, etc.
  • use of a chemical name is intended to encompass all physical forms of the named chemical.
  • recitation of 4-iodo-3- nitrobenzamide, without further qualification is intended to generically encompass the free base as well as all pharmaceutically acceptable salts, polymorphs, hydrates, and metabolites thereof.
  • pharmaceutically acceptable salt or solvate thereof is to be administered to the patient in combination with an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin).
  • an antimetabolite e.g., gemcitabine
  • a platinum compound e.g., carboplatin
  • the use as provided herein is with respect to or in accordance with any of the methods described herein.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) antimetabolite such as gemcitabine; and (iii) a platinum
  • Antitumor agents that may be used in the present invention include but are not limited to antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum-complex compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors, anti-tumor viral agent, monoclonal antibodies, interferons, biological response modifiers, and other agents that exhibit anti-tumor activities, or a pharmaceutically acceptable salt thereof.
  • (i) 4-iodo-3- nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) antimetabolite such as gemcitabine; and (iii) a platinum compound such as carboplatin are used in combination with an anti-angiogenic agent.
  • (i) 4-iodo-3- nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) antimetabolite such as gemcitabine; and (iii) a platinum compound such as carboplatin are used in combination with a topoisomerase inhibitor such as irinotecan.
  • the ovarian cancer is a metastatic cancer.
  • the anti-tumor agent is an alkylating agent.
  • alkylating agent generally refers to an agent giving an alkyl group in the alkylation reaction in which a hydrogen atom of an organic compound is substituted with an alkyl group.
  • anti-tumor alkylating agents include but are not limited to nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide or carmustine.
  • the anti-tumor agent is an antimetabolite.
  • antimetabolite used herein includes, in a broad sense, substances which disturb normal metabolism and substances which inhibit the electron transfer system to prevent the production of energy-rich intermediates, due to their structural or functional similarities to metabolites that are important for living organisms (such as vitamins, coenzymes, amino acids and saccharides).
  • antimetabolites that have anti-tumor activities include but are not limited to methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-l, gemcitabine, fludarabine or pemetrexed disodium, and preferred are 5-fluorouracil, S-l, gemcitabine and the like.
  • the anti-tumor agent is an antitumor antibiotic.
  • antitumor antibiotics include but are not limited to actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimalamer, idarubicin, sirolimus or valrubicin.
  • the anti-tumor agent is a plant-derived antitumor agent.
  • plant-derived antitumor agents include but are not limited to vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel and vinorelbine, and preferred are docetaxel and paclitaxel.
  • the anti-tumor agent is a camptothecin derivative that exhibits anti-tumor activities.
  • anti-tumor camptothecin derivatives include but are not limited to camptothecin, 10- hydroxycamptothecin, topotecan, irinotecan or 9-aminocamptothecin, with camptothecin, topotecan and irinotecan being preferred.
  • irinotecan is metabolized in vivo and exhibits antitumor effect as SN-38. The action mechanism and the activity of the
  • camptothecin derivatives are believed to be virtually the same as those of camptothecin (e.g., Nitta, et al., Gan to Kagaku Ryoho, 14, 850-857 (1987)).
  • the anti-tumor agent is an organoplatinum compound or a platinum coordination compound having antitumor activity.
  • organoplatinum compound platinum compound
  • platinum complex platinum complex
  • Preferred organoplatinum compounds include but are not limited to cisplatin; cis-diamminediaquoplatinum (Il)-ion; chloro(diethylenetriamine)- platinum (II) chloride; dichloro(ethylenediamine)-platinum (II); diammine(l,l- cyclobutanedicarboxylato) platinum (II) (carboplatin); spiroplatin; iproplatin; diammine(2- ethylmalonato)platinum (II); ethylenediaminemalonatoplatinum (II); aqua(l,2- diaminodicyclohexane)sulfatoplatinum (II); aqua(l,2- diaminodicyclohexane)malonatoplatinum (II) ; ( 1 ,2-diaminocyclohexane)malonatoplatinum (II); (4-carboxyphthalato)( 1,2-di
  • tetraplatin carboplatin, nedaplatin and oxaliplatin, and preferred is carboplatin or oxaliplatin.
  • carboplatin, nedaplatin and oxaliplatin and preferred is carboplatin or oxaliplatin.
  • other antitumor organoplatinum compounds mentioned in the specification are known and are commercially available and/or producible by a person having ordinary skill in the art by conventional techniques.
  • the anti-tumor agent is an antitumor tyrosine kinase inhibitor.
  • tyrosine kinase inhibitor refers to a chemical substance inhibiting "tyrosine kinase” which transfers a ⁇ -phosphate group of ATP to a hydroxyl group of a specific tyrosine in protein.
  • anti-tumor tyrosine kinase inhibitors include but are not limited to gefitinib, imatinib, erlotinib, Sutent, Nexavar, Recentin, ABT-869, and Axitinib.
  • the anti-tumor agent is an antibody or a binding portion of an antibody that exhibits anti-tumor activity. In some embodiments, the anti-tumor agent is a monoclonal antibody.
  • Examples thereof include but are not limited to abciximab, adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab, daclizumab, eculizumab, efalizumab, ibritumomab, tiuxetan, infliximab, muromonab-CD3, natalizumab, omalizumab, palivizumab, panitumumab, ranibizumab, gemtuzumab ozogamicin, rituximab, tositumomab, trastuzumab, or any antibody fragments specific for antigens.
  • the anti-tumor agent is an interferon.
  • interferon has antitumor activity, and it is a glycoprotein which is produced and secreted by most animal cells upon viral infection. It has not only the effect of inhibiting viral growth but also various immune effector mechanisms including inhibition of growth of cells (in particular, tumor cells) and enhancement of the natural killer cell activity, thus being designated as one type of cytokine.
  • anti-tumor interferons include but are not limited to interferon a, interferon a -2a, interferon a- 2b, interferon ⁇ , interferon ⁇ -la and interferon ⁇ - ⁇ .
  • the anti-tumor agent is a biological response modifier. It is generally the generic term for substances or drugs for modifying the defense mechanisms of living organisms or biological responses such as survival, growth or differentiation of tissue cells in order to direct them to be useful against tumor, infection or other diseases.
  • biological response modifier include but are not limited to krestin, lentinan, sizofiran, picibanil and ubenimex.
  • the anti-tumor agents include but are not limited to mitoxantrone, L-asparaginase, procarbazine,
  • antimetabolite "antitumor antibiotic”, “plant-derived antitumor agent”, “antitumor platinum coordination compound”, “antitumor camptothecin derivative”, “antitumor tyrosine kinase inhibitor”, “monoclonal antibody”, “interferon”, “biological response modifier” and “other antitumor agent” are all known and are either commercially available or producible by a person skilled in the art by methods known per se or by well-known or conventional methods. The process for preparation of gefitinib is described, for example, in U.S. Pat. No.
  • antitumor alkylating agents are commercially available, as exemplified by the following: nitrogen mustard N-oxide from Mitsubishi Pharma Corp. as Nitrorin (tradename); cyclophosphamide from Shionogi & Co., Ltd. as Endoxan (tradename); ifosfamide from Shionogi & Co., Ltd. as Ifomide (tradename); melphalan from Mitsubishi Pharma Corp. as Nitrorin (tradename); cyclophosphamide from Shionogi & Co., Ltd. as Endoxan (tradename); ifosfamide from Shionogi & Co., Ltd. as Ifomide (tradename); melphalan from
  • GlaxoSmithKline Corp. as Alkeran (tradename); busulfan from Takeda Pharmaceutical Co., Ltd. as Mablin (tradename); mitobronitol from Kyorin Pharmaceutical Co., Ltd. as Myebrol (tradename); carboquone from Sankyo Co., Ltd. as Esquinon (tradename); thiotepa from Sumitomo Pharmaceutical Co., Ltd. as Tespamin (tradename); ranimustine from Mitsubishi Pharma Corp. as Cymerin (tradename); nimustine from Sankyo Co., Ltd. as Nidran
  • antitumor antimetabolites are commercially available, as exemplified by the following: methotrexate from Takeda Pharmaceutical Co., Ltd. as
  • Methotrexate (tradename); 6-mercaptopurine riboside from Aventis Corp. as Thioinosine (tradename); mercaptopurine from Takeda Pharmaceutical Co., Ltd. as Leukerin (tradename); 5-fluorouracil from Kyowa Hakko Kogyo Co., Ltd. as 5-FU (tradename); tegafur from Taiho Pharmaceutical Co., Ltd. as Futraful (tradename); doxyfluridine from Nippon Roche Co., Ltd. as Furutulon (tradename); carmofur from Yamanouchi Pharmaceutical Co., Ltd. as Yamafur (tradename); cytarabine from Nippon Shinyaku Co., Ltd.
  • Cylocide tradename
  • cytarabine ocfosfate from Nippon Kayaku Co., Ltd. as Strasid(tradename); enocitabine from Asahi Kasei Corp. as Sanrabin (tradename); S-1 from Taiho Pharmaceutical Co., Ltd. as TS-1 (tradename); gemcitabine from Eli Lilly & Co. as Gemzar (tradename); fludarabine from Nippon Schering Co., Ltd. as Fludara (tradename); and pemetrexed disodium from Eli Lilly & Co. as Alimta (tradename).
  • antitumor antibiotics are commercially available, as exemplified by the following: actinomycin D from Banyu Pharmaceutical Co., Ltd. as Cosmegen (tradename); doxorubicin from Kyowa Hakko Kogyo Co., Ltd. as adriamycin (tradename); daunorubicin from Meiji Seika Kaisha Ltd. as Daunomycin; neocarzino statin from Yamanouchi Pharmaceutical Co., Ltd. as Neocarzinostatin (tradename); bleomycin from Nippon Kayaku Co., Ltd. as Bleo (tradename); pepromycin from Nippon Kayaku Co, Ltd. as Pepro (tradename); mitomycin C from Kyowa Hakko Kogyo Co., Ltd. as Mitomycin (tradename); aclarubicin from Yamanouchi Pharmaceutical Co., Ltd. as Aclacinon
  • vinblastine from Kyorin Pharmaceutical Co., Ltd. as Vinblastine (tradename); vindesine from Shionogi & Co., Ltd. as Fildesin (tradename); etoposide from Nippon Kayaku Co., Ltd. as Lastet (tradename); sobuzoxane from Zenyaku Kogyo Co., Ltd. as Perazolin (tradename); docetaxel from Aventis Corp. as Taxotere (tradename); paclitaxel from Bristol- Myers Squibb Co. as Taxol (tradename); and vinorelbine from Kyowa Hakko Kogyo Co., Ltd. as Navelbine (tradename).
  • antitumor platinum coordination compounds are commercially available, as exemplified by the following: cisplatin from Nippon Kayaku Co., Ltd. as Randa (tradename); carboplatin from Bristol-Myers Squibb Co. as Paraplatin
  • camptothecin derivatives are commercially available, as exemplified by the following: irinotecan from Yakult Honsha Co., Ltd. as Campto (tradename); topotecan from GlaxoSmithKline Corp. as Hycamtin (tradename); and camptothecin from Aldrich Chemical Co., Inc., U.S.A.
  • antitumor tyrosine kinase inhibitors are commercially available, as exemplified by the following: gefitinib from AstraZeneca Corp. as Iressa (tradename); imatinib from Novartis AG as Gleevec (tradename); and erlotinib from OSI Pharmaceuticals Inc. as Tarceva (tradename).
  • interferons are commercially available, as exemplified by the following: interferon a from Sumitomo Pharmaceutical Co., Ltd. as Sumiferon
  • interferon a-2b from Schering-Plough Corp. as Intron A (tradename); interferon ⁇ from Mochida Pharmaceutical Co., Ltd. as IFN.beta. (tradename); interferon ⁇ -la from Shionogi & Co., Ltd. as Imunomax- ⁇ (tradename); and interferon ⁇ - ⁇ from Otsuka
  • krestin from Sankyo Co., Ltd. as krestin (tradename);
  • lentinan from Aventis Corp. as Lentinan (tradename); sizofiran from Kaken Seiyaku Co., Ltd. as Sonifiran (tradename); picibanil from Chugai Pharmaceutical Co., Ltd. as Picibanil (tradename); and ubenimex from Nippon Kayaku Co., Ltd. as Bestatin (tradename).
  • the above-mentioned other antitumor agents are commercially available, as exemplified by the following: mitoxantrone from Wyeth Lederle Japan, Ltd. as Novantrone (tradename); L-asparaginase from Kyowa Hakko Kogyo Co., Ltd. as Leunase (tradename); procarbazine from Nippon Roche Co., Ltd. as Natulan (tradename); dacarbazine from Kyowa Hakko Kogyo Co., Ltd. as dacarbazine (tradename); hydroxycarbamide from Bristol-Myers Squibb Co. as Hydrea (tradename); pentostatin from Kagaku Oyobi Kessei Ryoho
  • Kenkyusho as Coforin (tradename); tretinoin from Nippon Roche Co., Ltd. As Vesanoid (tradename); alefacept from Biogen plec Inc. as Amevive (tradename); darbepoetin alfa from Amgen Inc. as Aranesp (tradename); anastrozole from AstraZeneca Corp. as Arimidex (tradename); exemestane from Pfizer Inc. as Aromasin (tradename); bicalutamide from AstraZeneca Corp. as Casodex (tradename); leuprorelin from Takeda Pharmaceutical Co., Ltd. as Leuplin (tradename); flutamide from Schering-Plough Corp.
  • Eulexin tradename
  • fulvestrant from AstraZeneca Corp. as Faslodex tradename
  • pegaptanib octasodium from Gilead Sciences, Inc. as Macugen
  • denileukin diftitox from Ligand Pharmaceuticals Inc. as Ontak
  • aldesleukin from Chiron Corp. as Proleukin
  • thyrotropin alfa from Genzyme Corp. as Thyrogen
  • arsenic trioxide from Cell Therapeutics, Inc. as Trisenox tradename
  • bortezomib from Millennium
  • antitumor agent includes the above-described antitumor alkylating agent, antitumor antimetabolite, antitumor antibiotic, plant-derived antitumor agent, antitumor platinum coordination compound, antitumor camptothecin derivative, antitumor tyrosine kinase inhibitor, monoclonal antibody, interferon, biological response modifier, and other antitumor agents.
  • anti-tumor agents or anti-neoplastic agents can be used in combination with benzopyrone compounds.
  • suitable anti-tumor agents or anti-neoplastic agents include, but are not limited to, 13-cis-Retinoic Acid, 2-CdA, 2-Chlorodeoxyadenosine, 5-Azacitidine, 5-Fluorouracil, 5-FU, 6-Mercaptopurine, 6-MP, 6-TG, 6-Thioguanine, Abraxane, Accutane, Actinomycin-D, Adriamycin, Adrucil, Agrylin, Ala-Cort, Aldesleukin, Alemtuzumab, ALIMTA, Alitretinoin, Alkaban-AQ, Alkeran, All-transretinoic Acid, Alpha Interferon, Altretamine, Amethopterin, Amifostine, Aminoglutethimide, Anagrelide, Anandron,
  • Anastrozole Arabinosylcytosine, Ara-C, Aranesp, Aredia, Arimidex, Aromasin, Arranon, Arsenic Trioxide, Asparaginase, ATRA, Avastin, Azacitidine, BCG, BCNU, Bendamustine, Bevacizumab, Bexarotene, BEXXAR, Bicalutamide, BiCNU, Blenoxane, Bleomycin, Bortezomib, Busulfan, Busulfex, C225, Calcium Leucovorin, Campath, Camptosar,
  • Chlorambucil Cisplatin, Citrovorum Factor, Cladribine, Cortisone, Cosmegen, CPT-11, Cyclophosphamide, Cytadren, Cytarabine, Cytarabine Liposomal, Cytosar-U, Cytoxan, dacarbazine, Dacogen, Dactinomycin, Darbepoetin Alfa, Dasatinib, Daunomycin,
  • Daunorubicin Daunorubicin Hydrochloride, Daunorubicin Liposomal, DaunoXome, Decadron, Decitabine, Delta-Cortef, Deltasone, Denileukin Diftitox, DepoCytTM,
  • Dexamethasone Dexamethasone Acetate, Dexamethasone Sodium Phosphate, Dexasone, Dexrazoxane, DHAD, DIC, Diodex, Docetaxel, Doxil, Doxorubicin, Doxorubicin Liposomal, DroxiaTM, DTIC, DTIC-Dome, Duralone, Efudex, Eligard, Ellence, Eloxatin, Elspar, Emcyt, Epirubicin, Epoetin Alfa, Erbitux, Erlotinib, Erwinia L-asparaginase, Estramustine, Ethyol, Etopophos, Etoposide, Etoposide Phosphate, Eulexin, Evista, Exemestane, Fareston,
  • Faslodex Femara, Filgrastim, Floxuridine, Fludara, Fludarabine, Fluoroplex, Fluorouracil, Fluorouracil (cream), Fluoxymesterone, Flutamide, Folinic Acid, FUDR , Fulvestrant, G- CSF, Gefitinib, Gemcitabine, Gemtuzumab ozogamicin, Gemzar & Gemzar Side Effects - Chemotherapy Drugs, Gleevec, Gliadel Wafer, GM-CSF, Goserelin, Granulocyte - Colony Stimulating Factor, Granulocyte Macrophage Colony Stimulating Factor, Halotestin,
  • Antimetabolites are drugs that interfere with normal cellular metabolic processes. Since cancer cells are rapidly replicating, interference with cellular metabolism affects cancer cells to a greater extent than host cells.
  • An antimetabolite such as gemcitabine may be used in any one of the methods provided herein, for example, gemcitabine may be used in combination with 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) and a platinum compound such as carboplatin in treating platinum- resistant recurrent ovarian cancer in accordance with the present disclosure.
  • Gemcitabine has the following structure:
  • Gemcitabine is available, for example, as GEMZAR ® from Eli Lilly and
  • Gemcitabine used herein also includes any pharmaceutically acceptable salt form (e.g., gemcitabine HC1 or other salt forms).
  • Gemcitabine also known as 4-amino-l- [(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]pyrimidin- 2(lH)-one or 2'-deoxy-2',2'-difluorocytidine
  • the dosage of an antimetabolite such as gemcitabine may be adjusted to a particular patient.
  • the dosage of gemcitabine when used in combination with 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) and a platinum compound such as carboplatin in any of the methods provided herein, may be in the range of about 100 mg/m 2 to about 5000 mg/m 2 , about 100 mg/m 2 to about 2000 mg/m 2 , about 200 to about 4000 mg/m 2 , about 300 to about 3000 mg/m 2 , about 400 to about 2000 mg/m 2 , about 500 to about 1500 mg/m 2 , about 750 to about 1500 mg/m 2 , about 800 to about 1500 mg/m 2 , about 900 to about 1400 mg/m 2 , about 900 to about 1250 mg/m 2 , about 1000 to about 1500 mg/m 2 , about 1000 mg/m 2 , about 1050 mg/m 2 , about 1100 mg/m 2 , about 1150 mg/m 2 , about 1200 mg/m 2 , about 1250 mg/
  • the dimensions mg/m 2 refer to the amount of gemcitabine in milligrams (mg) per unit surface area of the patient in square meters (m ).
  • Gemcitabine may be administered by intravenous (IV) infusion, e.g., over a period of about 10 to about 300 minutes, about 15 to about 180 minutes, about 20 to about 60 minutes, about 10 minutes, about 20 minutes, or about 30 minutes.
  • IV intravenous
  • the term "about” in this context indicates the normal usage of approximately; and in some embodiments indicates a tolerance of + 10% or + 5%.
  • Taxanes are drugs that are derived from the twigs, needles and bark of Pacific yew tress, Taxus brevifolia.
  • paclitaxel may be derived from 10-deacetylbaccatin through known synthetic methods.
  • Taxanes such as paclitaxel and its derivative docetaxel have demonstrated antitumor activity in a variety of tumor types.
  • the taxanes interfere with normal function of microtubule growth by hyperstabilizing their structure, thereby destroying the cell's ability to use its cytoskeleton in a normal manner. Specifically, the taxanes bind to the ⁇ subunit of tubulin, which is the building block of microtubules.
  • Paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis-inhibiting protein called Bcl-2 (B-cell leukemia 2), thereby preventing Bcl-2 from inhibiting apoptosis.
  • Bcl-2 B-cell leukemia 2
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin in combination with a taxane (e.g., paclitaxel, docetaxel, or Abraxane).
  • a taxane e.g., paclitaxel, docetaxel, or Abraxane.
  • the dosage of taxane such as paclitaxel may vary depending upon the height, weight, physical condition, tumor size and progression state, etc.
  • the dosage of taxane such as paclitaxel will be in the range of about 10 to about 2000 mg/m 2 , about 10 to about 200 mg/m 2 or about 100 to about 175 mg/m 2. In some embodiments, the taxane such as paclitaxel will be administered over a period of up to about 10 hours, up to about 8 hours or up to about 6 hours.
  • the term "about” in this context indicates the normal usage of approximately; and in some embodiments indicates a tolerance of + 10% or + 5%.
  • taxanes include but are not limited to docetaxel, paclitaxel, and Abraxane.
  • Platinum complexes are pharmaceutical agents or pharmaceutical compositions used to treat cancer, which contain at least one platinum center complexed with at least one organic group. Platinum complexes include, for example, carboplatin, cisplatin, and oxaliplatin. "Platinum complex” and “platinum agent” are used interchangeably.
  • a platinum complex (or platinum compound) such as carboplatin may be used in any one of the methods provided herein, for example, carboplatin may be used in combination with 4-iodo-3- nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) and an antimetabolite such as gemcitabine in treating platinum-resistant recurrent ovarian cancer in accordance with the present disclosure.
  • Carboplatin has the following structure:
  • Carboplatin is available, for example, from Bedford Laboratories.
  • Carboplatin also known as cis-Diammine(l,l-cyclobutanedicarboxylato)platinum(II)
  • is a platinum complex (or platinum compound) which is also marketed under the brand names Paraplatin® and Paraplatin-AQ.
  • Carboplatin used herein also includes any pharmaceutically acceptable salt form. The dosage of a platinum compound such as carboplatin may be adjusted to a particular patient.
  • the dosage of a platinum compound is determined by calculating the area under the blood plasma concentration versus time curve (AUC) in mg/mL » minute by methods known to those skilled in the cancer chemotherapy art, taking into account the patient' s renal activity estimated by measuring creatinine clearance or glomerular filtration rate.
  • AUC blood plasma concentration versus time curve
  • the dosage of a platinum complex such as carboplatin used in combination with an antimetabolite (e.g., gemcitabine) and 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) is calculated to provide an AUC of about 0.1-8 mg/ml » min, about 0.1-7 mg/ml » min, about 0.1-6 mg/ml » min, about 1- 6 mg/ml » min, about 1-5 mg/ml » min, about 2-5 mg/ml » min, about 3-6 mg/ml » min, about 3-5 mg/ml » min, about 1-3 mg/ml » min, about 1.5 to about 2.5 mg/ml » min, about 1.75 to about 2.25 mg/ml » min, about 2 mg/ml » min (AUC 2, for example, is shorthand for 2 mg/ml » minute), about AUC 2.5, about AUC 3, about AUC3.5, about AUC 4, about AUC 4.5, about AUC 5, about AUC 5.5, or about
  • the dosage of platinum compound e.g., carboplatin
  • a suitable dose of carboplatin is about 10 to about 400 mg/m 2 , e.g., about 360 mg/m 2.
  • Platinum complexes, such as carboplatin are normally administered intravenously (IV) over a period of about 10 to about 300 minutes, about 30 to about 180 minutes, about 45 to about 120 minutes or about 60 minutes.
  • IV intravenously
  • the term "about” has its normal meaning of approximately. In some embodiments, about means +10% or ⁇ 5%.
  • topoisomerase inhibitors are agents designed to interfere with the action of topoisomerase enzymes (topoisomerase I and II), which are enzymes that control the changes in DNA structure by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle. Topoisomerases have become popular targets for cancer chemotherapy treatments. It is thought that topoisomerase inhibitors block the ligation step of the cell cycle, generating single and double stranded breaks that harm the integrity of the genome. Introduction of these breaks subsequently lead to apoptosis and cell death.
  • Topoisomerase inhibitors are often divided according to which type of enzyme it inhibits. Topoisomerase I, the type of topoisomerase most often found in eukaryotes, is targeted by topotecan, irinotecan, lurtotecan and exatecan, each of which is commercially available. Topotecan is available from GlaxoSmithKline under the trade name Hycamtim ® . Irinotecan is available from Pfizer under the trade name Camptosar ® . Lurtotecan may be obtained as a liposomal formulation from Gilead Sciences Inc. Topoisomerase inhibitors may be administered at an effective dose. In some embodiments an effective dose for treatment of a human will be in the range of about 0.01 to about 10 mg/m /day. The treatment may be repeated on a daily, bi-weekly, semi-weekly, weekly, or monthly basis. In some embodiments an effective dose for treatment of a human will be in the range of about 0.01 to about 10 mg/m /
  • a treatment period may be followed by a rest period of from one day to several days, or from one to several weeks.
  • (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and/or (iii) carboplatin and the topoisomerase inhibitor may be dosed on the same day or may be dosed on separate days.
  • topoisomerase poisons which target the topoisomerase-DNA complex
  • topoisomerase inhibitors which disrupt catalytic turnover.
  • Topo II poisons include but are not limited to eukaryotic type II topoisomerase inhibitors (topo II): amsacrine, etoposide, etoposide phosphate, teniposide, amrubicin and doxorubicin. These drugs are anti-cancer therapies.
  • topoisomerase inhibitors include ICRF-193. These inhibitors target the N- terminal ATPase domain of topo II and prevent topo II from turning over.
  • An angiogenesis inhibitor is a substance that inhibits angiogenesis (the growth of new blood vessels). Every solid tumor (in contrast to leukemia) needs to generate blood vessels to keep it alive once it reaches a certain size. Tumors can grow only if they form new blood vessels. Usually, blood vessels are not built elsewhere in an adult body unless tissue repair is actively in process. The angiostatic agent endostatin and related chemicals can suppress the building of blood vessels, preventing the cancer from growing indefinitely. In tests with patients, the tumor became inactive and stayed that way even after the endostatin treatment is finished. The treatment has very few side effects but appears to have very limited selectivity. Other angiostatic agents such as thalidomide and natural plant-based substances are being actively investigated.
  • VEGF vascular endothelial growth factor
  • Any of the methods provided herein may further comprise Herceptin in treating platinum-resistant recurrent ovarian cancer (e.g., HER2-positive ovarian cancer).
  • Her-2 overexpression has been found in ovarian carcinomas and HER2 overexpression and amplification is associated with advanced ovarian cancer (AOC) (Hellstrom et al., Cancer Research 61, 2420-2423, March 15, 2001).
  • Herceptin may be used for the adjuvant treatment of HER2-overexpressing ovarian cancers.
  • Herceptin can be used several different ways: as part of a treatment regimen including doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; with docetaxel and carboplatin; or as a single agent following multi-modality anthracycline-based therapy.
  • Herceptin in combination with paclitaxel is approved for the first-line treatment of HER2-overexpressing ovarian cancer.
  • Herceptin as a single agent is approved for treatment of HER2-overexpressing ovarian cancer in patients who have received one or more chemotherapy regimens for metastatic disease.
  • Lapatinib or lapatinib ditosylate is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer.
  • Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
  • Drugs used in chemotherapy, such as topotecan work in different ways to stop the growth of tumor cells, either by killing the cells or by preventing them from dividing. Giving lapatinib together with topotecan may have enhanced anti-tumor efficacy.
  • Any of the methods provided herein may further comprise a hormone therapy.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administration to the patient an effective amount of: (i) 4-iodo-3- nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, in combination with a hormone therapy.
  • Tamoxifen (marketed as Nolvadex) slows or stops the growth of cancer cells present in the body.
  • Tamoxifen is a type of drug called a selective estrogen-receptor modulator (SERM). It functions as an anti-estrogen. As tamoxifen may have stabilized rapidly advancing recurrent ovarian cancer, its role in the primary treatment of ovarian cancer in combination with cytotoxic chemotherapy should be considered.
  • SERM selective estrogen-receptor modulator
  • Any of the methods provided herein may further comprise an aromatase inhibitor (e.g., steroidal or non-steroidal aromatase inhibitor).
  • Aromatase inhibitors (AI) are a class of drugs used in the treatment of ovarian cancer in postmenopausal women that block the aromatase enzyme.
  • Aromatase inhibitors lower the amount of estrogen in post-menopausal women who have hormone-receptor-positive ovarian cancer. With less estrogen in the body, the hormone receptors receive fewer growth signals, and cancer growth can be slowed down or stopped.
  • Aromatase inhibitor medications include Arimidex (chemical name: anastrozole), Aromasin (chemical name: exemestane), and Femara (chemical name: letrozole). Each is taken by pill once a day, for up to five years. But for women with advanced (metastatic) disease, the medicine is continued as long as it is working well.
  • AIs are categorized into two types: irreversible steroidal inhibitors such as exemestane that form a permanent bond with the aromatase enzyme complex; and nonsteroidal inhibitors (such as anastrozole, letrozole) that inhibit the enzyme by reversible competition.
  • irreversible steroidal inhibitors such as exemestane that form a permanent bond with the aromatase enzyme complex
  • nonsteroidal inhibitors such as anastrozole, letrozole
  • Fulvestrant also known as ICI 182,780, and "Faslodex” is a drug treatment of hormone receptor-positive ovarian cancer in postmenopausal women with disease progression following anti-estrogen therapy. Estrogen can cause the growth of ovarian epithelial cancer cells. Fulvestrant is an estrogen receptor antagonist with no agonist effects, which works both by down-regulating and by degrading the estrogen receptor. It is administered as a once-monthly injection.
  • Any of the methods provided herein may further comprise an inhibitor targeting a growth factor receptor including but not limited to epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R).
  • EGFR epidermal growth factor receptor
  • IGF1R insulin-like growth factor 1 receptor
  • EGFR is overexpressed in the cells of certain types of human carcinomas including ovarian cancers.
  • EGFR over-expression in ovarian cancer has been associated with poor prognosis. Increased expression of EGFR may contribute to a drug resistant phenotype.
  • EGFR inhibitors include but are not limited to cetuximab, which is a chimeric monoclonal antibody given by intravenous injection for treatment of cancers including but not limited to metastatic colorectal cancer and head and neck cancer.
  • Panitumimab is another example of EGFR inhibitor. It is a humanized monoclonal antibody against EGFR. Panitumimab has been shown to be beneficial and better than supportive care when used alone in patients with advanced colon cancer and is approved by the FDA for this use.
  • IGFIR insulin-like growth factor receptor
  • CP-751871 is a human monoclonal antibody that selectively binds to IGFIR, preventing IGF1 from binding to the receptor and subsequent receptor
  • IGFIR is a receptor tyrosine kinase expressed on most tumor cells and is involved in mitogenesis, angiogenesis, and tumor cell survival.
  • Any of the methods provided herein may further comprise an inhibitor of PI3K pathway and/or an inhibitor of mTOR.
  • Phosphatidylinositol-3-kinase (PI3K) pathway deregulation is a common event in human cancer, either through inactivation of the tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 or activating mutations of pl l0-a. These hotspot mutations result in oncogenic activity of the enzyme and contribute to therapeutic resistance to the anti-HER2 antibody trastuzumab.
  • Akt and mTOR phosphorylation is also frequently detected in ovarian cancer.
  • the PI3K pathway is, therefore, an attractive target for cancer therapy.
  • NVP-BEZ235 a dual inhibitor of the PI3K and the downstream mammalian target of rapamycin (mTOR) has been shown to have antiproliferative and antitumoral activity in cancer cells with both wild-type and mutated pl l0-a (Violeta Serra, et al., Cancer Research 68, 8022-8030, October 1, 2008).
  • Hsp90 heat shock protein 90
  • Hsp90 is one of a class of chaperone proteins, whose normal job is to help other proteins acquire and maintain the shape required for those proteins to do their jobs. Chaperone proteins work by being in physical contact with other proteins. Hsp90 can also enable cancer cells to survive and even thrive despite genetic defects which would normally cause such cells to die. Thus, blocking the function of HSP90 and related chaperone proteins may cause cancer cells to die, especially if blocking chaperone function is combined with other strategies to block cancer cell survival.
  • Tubulin inhibitors target heat shock protein 90
  • any of the methods provided herein may further comprise a tubulin inhibitor.
  • Tubulins are the proteins that form microtubules, which are key components of the cellular cytoskeleton (structural network). Microtubules are necessary for cell division (mitosis), cell structure, transport, signaling and motility. Given their primary role in mitosis, microtubules have been an important target for anticancer drugs— often referred to as antimitotic drugs, tubulin inhibitors and microtubule targeting agents. These compounds bind to tubulin in microtubules and prevent cancer cell proliferation by interfering with the microtubule formation required for cell division. This interference blocks the cell cycle sequence, leading to apoptosis.
  • any of the methods provided herein may further comprise an inhibitor of apoptosis.
  • the inhibitors of apoptosis are a family of functionally- and structurally- related proteins, originally characterized in Baculovirus, which serve as endogenous inhibitors of apoptosis.
  • the human IAP family consists of at least 6 members, and IAP homologs have been identified in numerous organisms.
  • 10058-F4 is a c-Myc inhibitor that induces cell-cycle arrest and apoptosis. It is a cell-permeable thiazolidinone that specifically inhibits the c-Myc-Max interaction and prevents transactivation of c-Myc target gene expression.
  • GNF-2 belongs to a new class of Bcr-abl inhibitors. GNF-2 appears to bind to the myristoyl binding pocket, an allosteric site distant from the active site, stabilizing the inactive form of the kinase. It inhibits Bcr-abl phosphorylation with an IC 50 of 267 nM, but does not inhibit a panel of 63 other kinases, including native c-Abl, and shows complete lack of toxicity towards cells not expressing Bcr- Abl.
  • GNF-2 shows great potential for a new class of inhibitor to study Bcr-abl activity and to treat resistant Chronic myelogenous leukemia (CML), which is caused the Bcr- Abl oncoprotein.
  • Pifithrin-a is a reversible inhibitor of p53-mediated apoptosis and p53- dependent gene transcription such as cyclin G, p21/wafl, and mdm2 expression.
  • Pifithrin-a enhances cell survival after genotoxic stress such as UV irradiation and treatment with cytotoxic compounds including doxorubicin, etopoxide, paclitaxel, and cytosine-P-D- arabinofuranoside.
  • Pifithrin- ⁇ protects mice from lethal whole body ⁇ -irradiation without an increase in cancer incidence. 4-iodo-3-nitrobenzamide
  • 4-iodo-3-nitrobenzamide is a small molecule that acts on tumor cells without exerting toxic effects in normal cells.
  • 4-iodo-3-nitrobenzamide is very lipophilic and distributes rapidly and widely into tissues, including the brain and cerebrospinal fluid (CSF). It is active against a broad range of cancer cells in vitro, including against drug resistant cell lines.
  • CSF cerebrospinal fluid
  • 4-iodo-3-nitrobenzamide may be administered in any pharmaceutically acceptable form, e.g., as a pharmaceutically acceptable salt, solvate, or complex. Additionally, as 4-iodo-3-nitrobenzamide is capable of
  • 4-iodo-3-nitrobenzamide is intended to be embraced by the term BA (or the equivalent 4-iodo-3-nitrobenzamide), along with the salts, solvates or complexes.
  • 4-iodo-3-nitrobenzamide may be administered in combination with a cyclodextrin, such as hydroxypropylbetacyclodextrin.
  • a cyclodextrin such as hydroxypropylbetacyclodextrin.
  • other active and inactive agents may be combined with 4- iodo-3-nitrobenzamide; and recitation of 4-iodo-3-nitrobenzamide will, unless otherwise stated, include all pharmaceutically acceptable forms thereof.
  • the dosage of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof may vary depending upon the patient's age, height, weight, overall health, etc.
  • the dosage of 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) is in the range of any one of about 0.1 mg/kg to about 50 mg/kg, about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 50 mg/kg, about 1 mg/kg to about 25 mg/kg, about 2 to about 70 mg/kg, about 2 mg/kg to about 50 mg/kg, about 2 mg/kg to about 40 mg/kg, about 3 mg/kg to about 30 mg/kg, about 4 to about 100 mg, about 4 to about 25 mg/kg, about 4 to about 20 mg/kg, about 4 to about 15 mg/kg, about 5 to about 20 mg/kg, about 5 to about 15 mg/kg, about 50 to about 100 mg/kg or about 25
  • 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) is administered at about 1 mg/kg, about 2 mg/kg, about 4 mg/kg, about 5 mg/kg, about 5.6 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 11.2 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 75 mg/kg, or about 90 mg/kg.
  • 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) is administered at a dose of at least any of about 2 mg/kg, about 4 mg/kg, about 5 mg/kg, about 5.6 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 11.2 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 75 mg/kg, or about 90 mg/kg.
  • 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) may be administered intravenously, e.g., by IV infusion over about 10 to about 300 minutes, about 30 to about 180 minutes, about 45 to about 120 minutes or about 60 minutes (i.e., about 1 hour).
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein 4- iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof is intravenously administered to the patient at about 5 to about 20 mg/kg or about 5 mg/kg to about 15 mg/kg.
  • 4-iodo-3-nitrobenzamide may alternatively be administered orally.
  • the term "about" has its normal meaning of
  • about means +20%, +10%, or +5%.
  • 4-iodo-3-nitrobenzamide is described in United States Patent No. 5,464,871, which is incorporated herein by reference in its entirety.
  • 4-iodo-3-nitrobenzamide may be prepared in concentrations of 10 mg/mL and may be packaged in a convenient form, e.g., in 10 mL vials.
  • BA means 4-iodo-3-nitrobenzamide
  • BNO means 4-iodo-3- nitrosobenzamide
  • BNHOH means 4-iodo-3-hydroxyaminobenzamide.
  • Precursor compounds useful in the present invention are of Formula (la)
  • R 1 ; R 2 , R 3 , R 4 , and R5 are, independently selected from the group consisting of hydrogen, hydroxy, amino, nitro, iodo, (C -C 6 ) alkyl, (C -C 6 ) alkoxy, (C 3 -C 7 ) cycloalkyl, and phenyl, wherein at least two of the five R 1 ; R 2 , R 3 , R4, and R5 substituents are always hydrogen, at least one of the five substituents are always nitro, and at least one substituent positioned adjacent to a nitro is always iodo, and pharmaceutically acceptable salts, solvates, isomers, tautomers, metabolites, analogs, or pro-drugs thereof.
  • R 1 ; R 2 , R 3 , R 4 , and R5 can also be a halide such as chloro, fluoro, or bromo substituents.
  • at least one of the R 1 ; R 2 , R , R ⁇ , and R5 substituents is always nitro or nitroso and at least one substituent positioned adjacent to the nitro or nitroso is always iodo.
  • the compound of formula la is a compound of formula IA or a metabolite or pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof.
  • the compound of formula la is a compound of formula IA or pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof.
  • 4-iodo-3-nitrobenazmide also known as iniparib or "BA” has the formula:
  • 4-iodo-3-nitrobenzamide may be prepared in concentrations of 10 mg/mL and may be packaged in a convenient form, e.g., in 10 mL vials.
  • 4-iodo-3- nitrobenazmide or a pharmaceutically acceptable salt thereof is administered.
  • a metabolite of 4-iodo-3-nitrobenazmide e.g., BNO
  • pharmaceutically acceptable salt thereof is administered.
  • the compounds of (2) are such that the iodo group is always adjacent to a R 1; R 2 , R 3 , R4 or R5 group that is a nitroso, hydroxyamino, hydroxy or amino group. In some embodiments, the compounds of (2) are such that the iodo group is always adjacent to a R 1; R 2 , R 3 , R* or R 5 group that is a nitroso, hydroxyamino, or amino group.
  • any of the compounds with structure formula la or Ila may be used for the treatment of platinum-resistant recurrent ovarian cancer.
  • an effective amount of a compound with structure formula la or Ila in combination with gemcitabine and carboplatin is administered to a patient with platinum-resistant recurrent ovarian cancer.
  • the compound with structure formula la or Ila is 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof.
  • R 6 is selected from the group consisting of hydrogen, alkyl (C r C 8 ), alkoxy (C r C 8 ), isoquinolinones, indoles, thiazole, oxazole, oxadiazole, thiophene, or phenyl.
  • IABA 4-iodo-3-aminobenzoic acid
  • 4-iodo-3-aminobenzamide examples include, for example, 4-iodo-3-aminobenzoic acid (“IABA”), 4-iodo-3-aminobenzamide
  • 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered.
  • 4-iodo-3-nitrobenzamide or a pharmaceutically acceptable salt thereof is administered.
  • a metabolite of 4-iodo-3- nitrobenzamide is administered.
  • the metabolite of 4-iodo-3- nitrobenzamide is 4-iodo-3-aminobenzoic acid or 4-iodo-3-aminobenzamide.
  • nitrobenzamide metabolite compounds have selective cytotoxicity upon malignant cancer cells but not upon non-malignant cancer cells. See Rice et at., Proc. Natl. Acad. Sci. USA 89:7703-7707 (1992), incorporated herein in it entirety.
  • the nitrobenzamide metabolite compounds utilized in the methods of the present invention may exhibit more selective toxicity towards tumor cells than non-tumor cells.
  • the metabolites according to the invention may thus be administered to a patient in need of such treatment in conjunction with chemotherapy with at least one an antimetabolite (e.g., gemcitabine) in addition to the at least one platinum complex (e.g., carboplatin, cisplatin, etc.)
  • the dosage range for any of the metabolites described herein used for treating platinum-resistant recurrent ovarian cancer may be in the range of about 0.0004 to about 0.5 mmol/kg (millimoles of metabolite per kilogram of patient body weight), which dosage corresponds, on a molar basis, to a range of about 0.1 to about 100 mg/kg of 4-iodo-3- nitrobenzamide.
  • Other effective ranges of dosages for metabolites are 0.0024-0.5 mmol/kg and 0.0048-0.25 mmol/kg.
  • Such doses may be administered on a daily, every-other-daily, twice-weekly, weekly, bi-weekly, monthly or other suitable schedule.
  • Essentially the same modes of administration may be employed for the metabolites as for 4-iodo-3- nitrobenzamide— e.g., oral, i.v., i.p., etc.
  • 4-iodo-3-nitrobenzamide or a pharmaceutically acceptable salt thereof is administered.
  • a metabolite of 4-iodo-3-nitrobenzamide or a pharmaceutically acceptable salt of a metabolite of 4-iodo-3-nitrobenzamide is administered.
  • pharmaceutically acceptable salt means those salts which retain the biological effectiveness and properties of the compounds used herein, and which are not biologically or otherwise undesirable. For example, a pharmaceutically acceptable salt does not interfere with the beneficial effect of the compound described herein in treating platinum- resistant recurrent ovarian cancer.
  • Typical salts are those of the inorganic ions, such as, for example, sodium, potassium, calcium and magnesium ions.
  • Such salts include salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid.
  • suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexyl-amine, ethanolamine, diethanolamine and triethanolamine.
  • 4-iodo-3-nitrobenzamide is formulated in 25% (w/v) hydroxypropyl- ⁇ - cyclodextrin and 10 mM phosphate buffer for intravenous administration as described in U.S. Patent Application Publication No. 2010/0160442, which is incorporated herein by reference.
  • Any of the methods described herein may further comprise another anti-cancer therapy including but not limited to surgery, radiation therapy (e.g. , X rays), gene therapy, DNA therapy, adjuvant therapy, neoadjuvant therapy, viral therapy, immunotherapy, RNA therapy, or nanotherapy.
  • radiation therapy e.g. , X rays
  • gene therapy e.g. , DNA therapy, adjuvant therapy, neoadjuvant therapy, viral therapy, immunotherapy, RNA therapy, or nanotherapy.
  • the non- drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, by a significant period of time.
  • the conjugate and the other pharmacologically active agent may be administered to a patient simultaneously, sequentially or in combination. It will be appreciated that when using a combination of the invention, the compound of the invention and the other pharmacologically active agent may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously.
  • the term "combination" further refers to the case where the compounds are provided in separate dosage forms and are administered sequentially.
  • Radiotherapy is the medical use of ionizing radiation as part of cancer treatment to control malignant cells. Radiotherapy may be used for curative or adjuvant cancer treatment. It is used as palliative treatment (where cure is not possible and the aim is for local disease control or symptomatic relief) or as therapeutic treatment (where the therapy has survival benefit and it can be curative). Radiotherapy is used for the treatment of malignant tumors and may be used as the primary therapy. It is also common to combine radiotherapy with surgery, chemotherapy, hormone therapy or some mixture of the three. Most common cancer types can be treated with radiotherapy in some way. The precise treatment intent (curative, adjuvant, neoadjuvant, therapeutic, or palliative) will depend on the tumour type, location, and stage, as well as the general health of the patient.
  • Radiation therapy is commonly applied to the cancerous tumor.
  • the radiation fields may also include the draining lymph nodes if they are clinically or radiologically involved with tumor, or if there is thought to be a risk of subclinical malignant spread. It is necessary to include a margin of normal tissue around the tumor to allow for uncertainties in daily set-up and internal tumor motion.
  • Radiation therapy works by damaging the DNA of cells.
  • the damage is caused by a photon, electron, proton, neutron, or ion beam directly or indirectly ionizing the atoms which make up the DNA chain. Indirect ionization happens as a result of the ionization of water, forming free radicals, notably hydroxyl radicals, which then damage the DNA.
  • free radicals notably hydroxyl radicals
  • most of the radiation effect is through free radicals.
  • cells have mechanisms for repairing DNA damage, breaking the DNA on both strands proves to be the most significant technique in modifying cell characteristics.
  • cancer cells generally are undifferentiated and stem cell-like, they reproduce more, and have a diminished ability to repair sub-lethal damage compared to most healthy differentiated cells.
  • the DNA damage is inherited through cell division, accumulating damage to the cancer cells, causing them to die or reproduce more slowly.
  • Proton radiotherapy works by sending protons with varying kinetic energy to precisely stop at the tumor.
  • Gamma rays may be used to treat any of the ovarian cancers described herein.
  • multiple concentrated beams of gamma rays are directed on the growth in order to kill the cancerous cells.
  • the beams are aimed from different angles to focus the radiation on the growth while minimizing damage to the surrounding tissues.
  • Radiosensitizers are known to increase the sensitivity of cancerous cells to the toxic effects of electromagnetic radiation. Many cancer treatment protocols currently employ radiosensitizers activated by the electromagnetic radiation of x-rays. Examples of x-ray activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5- iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives of the same.
  • metronidazole misonidazole
  • desmethylmisonidazole pimonidazole
  • Photodynamic therapy (PDT) of cancers employs visible light as the radiation activator of the sensitizing agent.
  • photodynamic radiosensitizers include the following, but are not limited to: hematoporphyrin derivatives, photofrin, benzoporphyrin derivatives, NPe6, tin etioporphyrin SnET2, pheoborbide-alpha, bacteriochlorophyll-alpha, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives of the same.
  • Gene therapy agents insert copies of genes into a specific set of a patient' s cells, and can target both cancer and non-cancer cells.
  • the goal of gene therapy can be to replace altered genes with functional genes, to stimulate a patient's immune response to cancer, to make cancer cells more sensitive to chemotherapy, to place "suicide" genes into cancer cells, or to inhibit angiogenesis.
  • Genes may be delivered to target cells using viruses, liposomes, or other carriers or vectors. This may be done by injecting the gene-carrier composition into the patient directly, or ex vivo, with infected cells being introduced back into a patient. Such compositions are suitable for use in the present invention.
  • Adjuvant therapy includes a treatment given after the primary treatment to increase the chances of a cure.
  • Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, or biological therapy.
  • the method further comprises administering granulocyte colony- stimulating factor ("G- CSF"). In some embodiments, the method does not further comprise administering G-CSF.
  • G- CSF granulocyte colony- stimulating factor
  • adjuvant therapy Because the principal purpose of adjuvant therapy is to kill any cancer cells that may have spread, treatment is usually systemic (uses substances that travel through the bloodstream, reaching and affecting cancer cells all over the body). For example, adjuvant therapy for ovarian cancer involves chemotherapy or hormone therapy, either alone or in combination.
  • Adjuvant chemotherapy is the use of drugs to kill cancer cells.
  • Adjuvant chemotherapy is usually a combination of anticancer drugs, which has been shown to be more effective than a single anticancer drug.
  • Radiation therapy is sometimes used as a local adjuvant treatment. Radiation therapy is considered adjuvant treatment when it is given before or after surgical treatment, e.g., a mastectomy. Such treatment is intended to destroy cancer cells that have spread to nearby parts of the body, such as the chest wall or lymph nodes.
  • Various therapies including but not limited to hormone therapy, e.g., tamoxifen, or gonadotropin-releasing hormone (GnRH) analogues, and radioactive monoclonal antibody therapy have been used to treat ovarian cancer.
  • hormone therapy e.g., tamoxifen, or gonadotropin-releasing hormone (GnRH) analogues
  • GnRH gonadotropin-releasing hormone
  • radioactive monoclonal antibody therapy have been used to treat ovarian cancer.
  • Neoadjuvant therapy refers to a treatment given before the primary treatment.
  • examples of neoadjuvant therapy include chemotherapy, radiation therapy, and hormone therapy.
  • Neoadjuvant chemotherapy in gynecological cancers is an approach that is shown to have positive effects on survival. It increases the rate of resectability in ovarian and cervical cancers and thus contributes to survival (Ayhan A. et. al. European journal of gynaecological oncology. 2006, vol. 27).
  • Viral therapy for cancer utilizes a type of viruses called oncolytic viruses.
  • An oncolytic virus is a virus that is able to infect and lyse cancer cells, while leaving normal cells unharmed, making them potentially useful in cancer therapy. Replication of oncolytic viruses both facilitates tumor cell destruction and also produces dose amplification at the tumor site. They may also act as vectors for anticancer genes, allowing them to be specifically delivered to the tumor site.
  • Transductional targeting involves modifying the specificity of viral coat protein, thus increasing entry into target cells while reducing entry to non-target cells.
  • Non-transductional targeting involves altering the genome of the virus so it can only replicate in cancer cells. This can be done by either transcription targeting, where genes essential for viral replication are placed under the control of a tumor- specific promoter, or by attenuation, which involves introducing deletions into the viral genome that eliminate functions that are dispensable in cancer cells, but not in normal cells. There are also other, slightly more obscure methods.
  • Viral agents administered intravenously can be particularly effective against metastatic cancers, which are especially difficult to treat conventionally.
  • bloodborne viruses can be deactivated by antibodies and cleared from the blood stream quickly e.g., by Kupffer cells (extremely active phagocytic cells in the liver, which are responsible for adenovirus clearance). Avoidance of the immune system until the tumour is destroyed could be the biggest obstacle to the success of oncolytic virus therapy. To date, no technique used to evade the immune system is entirely satisfactory. It is in conjunction with conventional cancer therapies that oncolytic viruses show the most promise, since combined therapies operate synergistically with no apparent negative effects.
  • oncolytic viruses have the potential to treat a wide range of cancers including ovarian cancer with minimal side effects.
  • Oncolytic viruses have the potential to solve the problem of selectively killing cancer cells.
  • Nanometer- sized particles have novel optical, electronic, and structural properties that are not available from either individual molecules or bulk solids. When linked with tumor- targeting moieties, such as tumor- specific ligands or monoclonal antibodies, these nanoparticles can be used to target cancer- specific receptors, tumor antigens (biomarkers), and tumor vasculatures with high affinity and precision.
  • tumor- targeting moieties such as tumor-specific ligands or monoclonal antibodies
  • tumor antigens biomarkers
  • the formulation and manufacturing process for cancer nanotherapy is disclosed in patent US7179484, and article M. N. Khalid, P. Simard, D. Hoarau, A. Dragomir, J. Leroux, Long Circulating Poly(Ethylene
  • RNA including but not limited to siRNA, shRNA, microRNA may be used to modulate gene expression and treat cancers.
  • Double stranded oligonucleotides are formed by the assembly of two distinct oligonucleotide sequences where the oligonucleotide sequence of one strand is complementary to the oligonucleotide sequence of the second strand; such double stranded oligonucleotides are generally assembled from two separate oligonucleotides (e.g., siRNA), or from a single molecule that folds on itself to form a double stranded structure (e.g., shRNA or short hairpin RNA).
  • each strand of the duplex has a distinct nucleotide sequence, wherein only one nucleotide sequence region (guide sequence or the antisense sequence) has complementarity to a target nucleic acid sequence and the other strand (sense sequence) comprises nucleotide sequence that is homologous to the target nucleic acid sequence.
  • MicroRNAs are single- stranded RNA molecules of about 21-23 nucleotides in length, which regulate gene expression. miRNAs are encoded by genes that are transcribed from DNA but not translated into protein (non-coding RNA); instead they are processed from primary transcripts known as pri-miRNA to short stem-loop structures called pre-miRNA and finally to functional miRNA. Mature miRNA molecules are partially complementary to one or more messenger RNA (mRNA) molecules, and their main function is to downregulate gene expression.
  • mRNA messenger RNA
  • RNA inhibiting agents may be utilized to inhibit the expression or translation of messenger RNA (“mRNA”) that is associated with a cancer phenotype.
  • mRNA messenger RNA
  • RNA inhibiting agents suitable for use herein include, but are not limited to, Cand5, Sirna- 027, fomivirsen, and angiozyme.
  • Certain small molecule therapeutic agents are able to target the tyrosine kinase enzymatic activity or downstream signal transduction signals of certain cell receptors such as epidermal growth factor receptor ("EGFR") or vascular endothelial growth factor receptor (“VEGFR”). Such targeting by small molecule therapeutics can result in anti-cancer effects.
  • EGFR epidermal growth factor receptor
  • VEGFR vascular endothelial growth factor receptor
  • agents suitable for use herein include, but are not limited to, imatinib, gefitinib, erlotinib, lapatinib, canertinib, ZD6474, sorafenib (BAY 43-9006), ERB-569, and their analogues and derivatives.
  • cancer metastasis The process whereby cancer cells spread from the site of the original tumor to other locations around the body is termed cancer metastasis.
  • Certain agents have anti- metastatic properties, designed to inhibit the spread of cancer cells. Examples of such agents suitable for use herein include, but are not limited to, marimastat, bevacizumab, trastuzumab, rituximab, erlotinib, MMI- 166, GRN163L, hunter-killer peptides, tissue inhibitors of metalloproteinases (TIMPs), their analogues, derivatives and variants.
  • marimastat marimastat
  • bevacizumab trastuzumab
  • rituximab rituximab
  • erlotinib MMI- 166
  • GRN163L hunter-killer peptides
  • TRIPs tissue inhibitors of metalloproteinases
  • Certain pharmaceutical agents such as chemopreventative agents may be used in combination with any of the methods provided herein. These agents can be used to prevent initial occurrences of cancer, or to prevent recurrence or metastasis. Administration with such chemopreventative agents in combination with any one of the treatments described herein can act to both treat and prevent the recurrence of cancer. Examples of
  • chemopreventative agents suitable for use herein include, but are not limited to, tamoxifen, raloxifene, tibolone, bisphosphonate, ibandronate, estrogen receptor modulators, aromatase inhibitors (letrozole, anastrozole), luteinizing hormone-releasing hormone agonists, goserelin, vitamin A, retinal, retinoic acid, fenretinide, 9-cis-retinoid acid, 13-cis-retinoid acid, all-trans- retinoic acid, isotretinoin, tretinoid, vitamin B6, vitamin B 12, vitamin C, vitamin D, vitamin E, cyclooxygenase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, ibuprofen, celecoxib, polyphenols, polyphenol E, green tea extract, folic acid, glucaric acid, interferon-alpha, anethole dithiolethione, zinc, pyr
  • chemopreventative agents suitable for use in the present invention is cancer vaccines. These can be created through immunizing a patient with all or part of a cancer cell type that is targeted by the vaccination process.
  • Clinical efficacy may be measured by any of the methods known in the art.
  • clinical efficacy of the therapeutic treatments described herein may be determined by measuring the clinical benefit rate (CBR).
  • CBR clinical benefit rate
  • the clinical benefit rate is measured by determining the sum of the percentage of patients who are in complete remission (CR), the number of patients who are in partial remission (PR) and the number of patients having stable disease (SD) at a time point at least 6 months out from the end of therapy.
  • an antimetabolite e.g. , gemcitabine
  • a platinum compound e.g.
  • CBR G EM/CARBO/BA 4-iodo-3-nitrobenzamide
  • an antimetabolite e.g. , gemcitabine
  • a platinum compound e.g., carboplatin
  • CBR G EM/CARBO is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or more. In some embodiments, the CBR is at least about 30%, at least about 40%, or at least about 50%.
  • At least one therapeutic effect is obtained, said at least one therapeutic effect being reduction in size of an ovarian tumor, reduction in metastasis, complete remission, partial remission, pathologic partial response, pathologic complete response, increase in overall response rate or objective response rate, or stable disease.
  • the improvement of clinical benefit rate is at least about any of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%.
  • the administration of 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) in combination with gemcitabine and carboplatin results in a complete response, partial response, or stable disease.
  • the patient has measurable disease.
  • Measurable disease may be determined by RECIST version 1.1 criteria, which is described in Eisenhauer EA et al. 2009, Eur J Cancer., 45(2):228-47, the disclosure of which is incorporated by reference in its entirety.
  • Measurable disease may also be defined by at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded), and is > 20 mm when measured by conventional techniques (palpation, plain x-ray, computed tomography (CT), or magnetic resonance imaging (MRI)) or > 10 mm when measured by spiral CT.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • Response rates may be determined according to RECIST version 1.1 criteria.
  • complete response may be defined as disappearance of all target lesions; any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to ⁇ 10 mm.
  • partial response may be defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters (baseline sum diameters may be a sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions).
  • progressive disease may be defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum may also demonstrate an absolute increase of at least 5 mm.
  • stable disease may be defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (taking as reference the smallest sum diameters while on study).
  • non-target lesion CR may be disappearance of all non-target lesions and normalization of tumour marker level (all lymph nodes may be non-pathological in size ( ⁇ 10mm short axis)).
  • non-CR/non-PD may be persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits.
  • progressive disease PD
  • PD may be unequivocal progression of existing non-target lesions. The appearance of one or more new lesions may be considered progression.
  • Overall response may be determined according to Eisenhauer EA et al. 2009, Eur J Cancer., 45(2):228-47 such as Tables 1-3, the disclosure of which is incorporated by reference in its entirety.
  • Efficacy parameters may be determined by any of methods known to one skilled in the art. For example, they may be determined according to RECIST version 1.1 criteria.
  • Progression-free survival may be defined as the time from the date of starting treatment (or date of initiation of study treatment or date of randomization) until the date of first observation of disease progression or the date of death.
  • Overall survival may be defined as the time from the date of starting treatment (or date of initiation of study treatment or date of randomization) until the date of death.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) an antimetabolite such as gemcitabine; and (iii) a platinum compound such as carboplatin, wherein the treatment results in reduction in size of an ovarian tumor in the patient.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in reduction in metastasis of ovarian cancer in the patient.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (i) 4- iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in complete response in the patient.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in pathological complete response in the patient.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in partial response in the patient.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (i) 4- iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in stable disease in the patient.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in reduction in metastasis of ovarian cancer in the patient.
  • metastasis is inhibited (e.g., compared to metastasis before the administration of (i) 4- iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin).
  • any of the methods is used to inhibit metastasis to lymph node.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in reduction in size of an ovarian tumor in the patient.
  • the tumor size is reduced by at least about 10% (including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%) (e.g. , compared to tumor size before the administration of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin).
  • the administration of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof, the administration of gemcitabine, and/or the administration of carboplatin have a synergistic effect.
  • a lower amount of each pharmaceutically active compound is used as part of a combination therapy compared to the amount generally used for individual therapy.
  • the same or greater therapeutic benefit is achieved using a combination therapy than by using any of the individual compounds alone.
  • the same or greater therapeutic benefit is achieved using a smaller amount (e.g. , a lower dose or a less frequent dosing schedule) of a pharmaceutically active compound in a combination therapy than the amount generally used for individual therapy.
  • the use of a small amount of pharmaceutically active compound may result in a reduction in the number, severity, frequency, or duration of one or more side-effects associated with the compound.
  • formulations e.g., pharmaceutical formulations
  • 4-iodo-3-nitrobenzamide or a metabolite thereof, or a
  • the formulations may include optical isomers, diastereomers, carriers, or pharmaceutically acceptable salts of the compounds disclosed herein.
  • the carrier is a cyclodextrin, or a derivative thereof, e.g., hydroxypropyl-B-cyclodextrin (HPBCD).
  • the formulations are formulated for intravenous
  • compositions of the present invention may be provided as a prodrug and/or may be allowed to interconvert to 4-iodo-3-nitrobenzamide form in vivo after administration. That is, either 4-iodo-3-nitrobenzamide or metabolites thereof or
  • 4-iodo-3-nitrobenzamide (or a metabolite thereof), an antimetabolite (e.g. , gemcitabine) and a platinum compound (e.g. , carboplatin) provided herein may be formulated in separate formulations or in the same formulation.
  • 4-iodo-3-nitrobenzamide (or a metabolite thereof), an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g. , carboplatin) provided herein may be administered through different administration route or using same administration routes.
  • synergistic compositions used for treating platinum- resistant recurrent ovarian cancer in a patient comprising (i) 4-iodo-3-nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt thereof, (ii) gemcitabine, and (iii) carboplatin.
  • a formulation may comprise both the 4-iodo-3-nitrobenzamide compound and acid forms in particular proportions, depending on the relative potencies of each and the intended indication.
  • the two forms may be formulated together or in different formulations. They may be in the same dosage unit e.g. in one cream, suppository, tablet, capsule, or packet of powder to be dissolved in a beverage; or each form may be formulated in a separate unit, e.g., two creams, two suppositories, two tablets, two capsules, a tablet and a liquid for dissolving the tablet, a packet of powder and a liquid for dissolving the powder, etc.
  • 4-iodo-3-nitrobenzamide (or a metabolite thereof), an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin) provided herein may be coadministered to the patient.
  • Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound), such as described herein.
  • 4-iodo-3-nitrobenzamide (or a metabolite thereof), an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin) provided herein may be coadministered to the patient.
  • Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound), such as described herein.
  • 4-iodo-3-nitrobenzamide (or a metabolite thereof), an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin) provided herein
  • antimetabolite e.g. , gemcitabine
  • a platinum compound e.g. , carboplatin
  • “Not continuously” means that the compound or composition provided herein is not administered to the patient over a period of time, e.g., there is a resting period when the patient does not receive the compound or composition. It may be that one compound is administered continuously administered to a patient while the second compound is not administered continuously administered to the patient.
  • antimetabolite e.g. , gemcitabine
  • a platinum compound e.g., carboplatin
  • the three compounds and/or forms of a compound may be formulated together, in the same dosage unit e.g., in one cream, suppository, tablet, capsule, or packet of powder to be dissolved in a beverage; or each form may be formulated in separate units, e.g., three creams, three suppositories, three tablets, three capsules, a tablet and a liquid for dissolving the tablet, a packet of powder and a liquid for dissolving the powder, etc.
  • pharmaceutically acceptable salt means those salts which retain the biological effectiveness and properties of the compounds used in the present invention, and which are not biologically or otherwise undesirable.
  • a pharmaceutically acceptable salt does not interfere with the beneficial effect of a compound provided herein in treating platinum-resistant recurrent ovarian cancer.
  • Typical salts are those of the inorganic ions, such as, for example, sodium, potassium, calcium and magnesium ions.
  • Such salts include salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid.
  • suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexyl-amine, ethanolamine, diethanolamine and triethanolamine.
  • compositions may be formulated for administration in aqueous solutions, preferably in physiologically compatible buffers such as phosphate buffers, Hank's solution, or Ringer's solution.
  • physiologically compatible buffers such as phosphate buffers, Hank's solution, or Ringer's solution.
  • Such compositions may also include one or more excipients, for example, preservatives, solubilizers, fillers, lubricants, stabilizers, albumin, and the like.
  • Formulations of 4-iodo-3-nitrobenzamide are described in US Pat. Publ. No. 2008/0176946 Al, which is incorporated by reference in its entirety, particularly with reference to intravenous (e.g., hydroxypropyl-P-cyclodextrin, etc.) and oral (e.g., sodium lauryl sulfate, etc.) formulations.
  • 4-iodo-3-nitrobenzamide is formulated in 25% (w/v) hydroxypropyl-P-cyclodext
  • the formulation has 10 mg/mL 4- iodo-3-nitrobenzamide, 25% (w/v) hydroxypropyl-P-cyclodextrin, and 10 mM phosphate buffer, pH 7.4.
  • compositions described herein may also be formulated for transmucosal administration, buccal administration, for administration by inhalation, for parental administration, for transdermal administration, and rectal administration.
  • compositions suitable for use as described herein include compositions wherein the active ingredients are present in an effective amount, i.e., in an amount effective to achieve therapeutic and/or prophylactic benefit in at least one of the platinum-resistant ovarian cancers ⁇ e.g., recurrent ovarian cancer) described herein.
  • the actual amount effective for a particular administration will depend on the platinum-resistant recurrent ovarian cancer ⁇ e.g., recurrent ovarian cancer) being treated, the condition of the subject, the formulation, and the route of administration, as well as other factors known to those of skill in the art in view of the specific teaching provided herein.
  • optimization of an effective amount of 4-iodo-3-nitrobenzamide, antimetabolite ⁇ e.g., gemcitabine), and/or platinum compound ⁇ e.g., carboplatin) provided herein, within the ranges specified, may be determined.
  • the composition or formulation is administered in unit dosage form.
  • the unit dosage form is adapted for oral or parenteral administration.
  • at least one therapeutic effect is obtained, said at least one therapeutic effect being reduction in size of a tumor, reduction in metastasis, complete remission, partial remission, pathologic complete response, increase in overall response rate, or stable disease.
  • the improvement of clinical benefit rate is at least about 20%.
  • the improvement of clinical benefit rate is at least about any of 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more.
  • the amount of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof, the amount of gemcitabine, and/or the amount of carboplatin is an amount sufficient to decrease the size of a tumor, decrease the number of cancer cells, or decrease the growth rate of a tumor (including decrease in metastasis) by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% compared to the corresponding tumor size, number of cancer cells, or tumor growth rate in the same patient at the time of starting treatment or compared to the corresponding activity in other patients not receiving the treatment. Standard methods can be used to measure the magnitude of this effect.
  • the amount of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof, the amount of gemcitabine, and/or the amount of carboplatin is below the level that induces a toxicological effect (e.g. , an effect above a clinically acceptable level of toxicity) or is at a level where a potential side effect can be controlled or tolerated.
  • the amount of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof, the amount of gemcitabine, and/or the amount of carboplatin is close to a maximum tolerated dose (MTD). In some embodiments, the amount is at least about any of 80%, 90%, 95%, or 98% of the MTD.
  • compositions or compounds described herein may be administered to a patient through appropriate route, such as, but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, intraarterial, subcutaneous, intranasal, epidural, and oral routes.
  • the composition or compound(s) provided herein is administered by the parenteral route, e.g., intravenously, intraperitoneally, subcutaneously, intradermally, or intramuscularly.
  • compositions or compounds described herein may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered in combination with other biologically active agents, e.g., such as described herein. Administration can be systemic or local.
  • the dosage of 4-iodo-3-nitrobenzamide is in the range of any one of about 0.1 mg/kg to about 50 mg/kg, about 1 mg/kg to about 100 mg/kg, 2 mg/kg to about 50 mg/kg, about 2 mg/kg to about 10 mg/kg, about 4 mg/kg to about 8 mg/kg, about 5 mg/kg to about 7 mg/kg, about 1 mg/kg to about 50 mg/kg, about 1 mg/kg to about 25 mg/kg, about 2 to about 70 mg/kg, about 2 mg/kg to about 50 mg/kg, about 2 mg/kg to about 40 mg/kg, about 3 mg/kg to about 30 mg/kg, about 4 to about 100 mg/kg, about 4 to about 25 mg/kg, about 4 to about 20 mg/kg, about 4 to about 15 mg/kg, about 5 to about 20 mg/kg,
  • the dosage of 4-iodo-3-nitrobenzamide is about any of 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 5.6 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 11.2 mg/kg, 12.5 mg/kg, 15 mg/kg, 20 mg/kg, 30 mg/kg, 50 mg/kg, 75 mg/kg, or 100 mg/kg.
  • 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) is administered at a dose of at least any of about lmg/kg, 2 mg/kg, about 4 mg/kg, about 5 mg/kg, about 5.6 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 11.2 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 75 mg/kg, or about 90 mg/kg.
  • 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) may be administered intravenously, e.g., by IV infusion over about 10 to about 300 minutes, about 30 to about 180 minutes, about 45 to about 120 minutes or about 60 minutes (i.e., about 1 hour).
  • 4-iodo-3-nitrobenzamide or its metabolite or its pharmaceutically acceptable salt thereof may be administered weekly, twice every week, once every three weeks, twice every three weeks, three times out of four weeks, four times out of three weeks, four times out of five weeks, or five times out of six weeks.
  • 4-iodo-3- nitrobenzamide or its metabolite or its pharmaceutically acceptable salt thereof may be administered on 2 days or 4 days of a treatment cycle, e.g., on days 1 and 8 (with the dosage of about 11.2 mg/kg) or days 1, 4, 8, and 11 (with the dosage of about 5.6 mg/kg) of a 21-day treatment cycle.
  • a method of treating platinum- resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein 4-iodo-3- nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof is intravenously administered to the patient at about 5 to about 20 mg/kg or about 5 mg/kg to about 15 mg/kg.
  • 4-iodo-3-nitrobenzamide may alternatively be administered orally.
  • the dosage of an antimetabolite provided herein may vary depending upon the patient's age, height, weight, overall health, etc. In some embodiments, the dosage of the antimetabolite
  • a gemcitabine e.g., gemcitabine
  • the antimetabolite e.g., gemcitabine
  • An antimetabolite e.g., gemcitabine
  • 2 2 2 may be administered at a dose of at least about any of 50 mg/m", 75 mg/m", 100 mg/m", 125 mg/m 2 , 150 mg/m 2 , 175 mg/m 2 , 200 mg/m 2 , 250 mg/m 2 , 300 mg/m 2 , 400 mg/m 2 , 450 mg/m 2 , 500 mg/m 2 , 550 mg/m 2 , 600 mg/m 2 , 650 mg/m 2 , 700 mg/m 2 , 750 mg/m 2 , 800 mg/m 2 , 850 mg/m 2 , 900 mg/m 2 , 1000 mg/m 2 , 1050 mg/m 2 , 1100 mg/m 2 , 1150 mg/m 2 , 1200 mg/m 2 , 1250 mg/m 2 , 1300 mg/m 2 , 1350 mg/m 2 , 1400 mg/m 2 , 1450 mg/m 2 , 1500 mg/m 2 , 1550 mg/m 2 , 1600 mg
  • An antimetabolite provided herein may be administered weekly, once every three weeks, twice every week, twice every three weeks, three times out of four weeks, four times out of three weeks, four times out of five weeks, or five times out of six weeks.
  • an antimetabolite provided herein e.g., gemcitabine
  • An antimetabolite e.g., gemcitabine
  • An antimetabolite may be administered intravenously, e.g., by IV infusion over about 10 to about 500 minutes, about 10 to about 300 minutes, about 15 to about 180 minutes, about 30 to about 180 minutes, about 30 to about 60 minutes, about 45 to about 120 minutes, about 20 to about 60 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 60 minutes (i.e. about 1 hour) or about 30 minutes.
  • An antimetabolite e.g., gemcitabine
  • the dosage of a platinum compound provided herein may vary depending upon the patient' s age, height, weight, overall health, etc.
  • the dosage of a platinum compound, e.g., carboplatin is determined by calculating the area under the blood plasma concentration versus time curve (AUC) in mg/mL » minute by methods known to those skilled in the cancer chemotherapy art, taking into account the patient' s renal activity estimated by measuring creatinine clearance or glomerular filtration rate.
  • the dosage of a platinum compound provided herein (e.g., carboplatin) used in combination with an antimetabolite (e.g., gemcitabine) and 4-iodo-3-nitrobenzamide is calculated to provide an AUC of about 0.1 to about 8 mg/ml » min, about 0.1 to about 7 mg/ml » min, about 0.1 to about 6 mg/ml » min, about 1 to about 6 mg/ml » min, about 1 to about 5 mg/ml » min, about 2 to about 5 mg/ml » min, about 3 to about 6 mg/ml » min, about 3 to about 5 mg/ml » min, about 1 to about 3 mg/ml » min, about 1.5 to about 2.5 mg/ml » min, about 1.75 to about 2.25 mg/ml » min, about 2 mg/ml » min (or AUC 2 ("AUC 2" is shorthand for 2 mg/ml « minute)), about AUC 2.5, about AUC 3, about AUC 3.5, about AUC 4, about AUC 4, about AUC 2
  • a platinum compound provided herein (e.g., carboplatin) is about 10 to about 400 mg/m , e.g., about 360 mg/m .
  • a platinum compound provided herein may be administered weekly, twice every week, once every three weeks, twice every three weeks, three times out of four weeks, four times out of three weeks, four times out of five weeks, or five times out of six weeks.
  • carboplatin may be administered on 1 day of a treatment cycle, e.g., on day 1 (with the dosage of about AUC 4) of a 21 -day treatment cycle.
  • Platinum complexes platinum compound (e.g. , carboplatin) are normally administered intravenously (IV) over a period of about 10 to about 500 minutes, about 10 to about 300 minutes, about 30 to about 180 minutes, about 45 to about 120 minutes or about 60 minutes.
  • IV intravenously
  • about has its normal meaning of approximately. In some embodiments, about means +20%, +10%, or +5%.
  • a beneficial effect is achieved when the administration of the antimetabolite (e.g. , gemcitabine) and the platinum compound (e.g., carboplatin) is temporally removed from the administration of the 4-iodo-3-nitrobenazmide (or
  • a significant period of time e.g., about 12 hours, about 24 hours, about 36 hours, about 48 hours, etc.
  • administration may be on different days of a treatment cycle, such as the treatment cycles described herein.
  • the interval between administration of the 4-iodo-3-nitrobenzamide, the antimetabolite (e.g. , gemcitabine), and the platinum compound e.g.
  • carboplatin may vary within a treatment cycle (e.g., administration is not always spaced apart by 1 day, but may be at intervals of 1 day followed by an interval of 3 days, etc.).
  • the 4-iodo-3-nitrobenzamide, the antimetabolite (e.g. , gemcitabine), and the platinum compound (e.g. , carboplatin) may be administered at the same time, and at other points during the treatment administered at different times.
  • the treatment includes 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles, 12 cycles, 13 cycles, 14 cycles, 15 cycles, 16 cycles, 17 cycles, 18 cycles, 19 cycles, or 20 cycles.
  • the term "cycle” means "treatment cycle.”
  • the method comprises at least one treatment cycle (e.g., one cycle, two cycles, three cycles, four cycles, five cycles, six cycles, seven cycles, eight cycles, nine cycles, or ten cycles, or at least any one of one cycle, two cycles, three cycles, four cycles, five cycles, six cycles, seven cycles, eight cycles, nine cycles, ten cycles, twelve cycles, fourteen cycles, sixteen cycles, or twenty cycles) comprising the administration of an effective amount of (a) 4-iodo-3-nitrobenzamide or a metabolite thereof or a
  • the treatment includes at most any of 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, or 10 cycles.
  • the cycle e.g., the treatment cycle
  • the cycle is a period of about any of 1 week, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks.
  • the cycle is a period of at least about any of 1 week, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks.
  • the cycle (e.g., the treatment cycle) is a period of no more than about any of 1 week, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks.
  • the treatment comprises a treatment cycle of at least about any of 1 week, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 12 weeks, or 15 weeks.
  • any of the methods provided herein may comprise at least one treatment cycle (e.g., 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles, 12 cycles, 13 cycles, 14 cycles, or 15 cycles), wherein the cycle is a period of 3 weeks, wherein the cycle comprises the administration of (a) 4-iodo- 3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, (b) gemcitabine, and (c) carboplatin.
  • at least one treatment cycle e.g., 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles, 12 cycles, 13 cycles, 14 cycles, or 15 cycles
  • the cycle is a period of 3 weeks
  • the cycle comprises the administration of (a) 4-iodo- 3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, (b) gemcitabine, and (c) carboplatin.
  • 4-iodo-3-nitrobenzamide may be administered every day of the treatment cycle, or administered every day of the treatment cycle, or on certain days but not on every day of the treatment cycle.
  • 4-iodo-3-nitrobenzamide is administered daily, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, once 10 days, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks.
  • 4-iodo-3-nitrobenzamide may be administered on the selected days of each treatment cycle, for example, 4-iodo-3- nitrobenzamide is administered daily for the period of 1 (or 2, 3, 4, 5, 6, 7, 8, 9, 10) days of the treatment cycle, and 4-iodo-3-nitrobenzamide is not administered on other days of the treatment cycle.
  • the intervals between each administration of 4-iodo- 3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof are less than about any of 6 months, 3 months, 1 month, 20 days, 15, days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day.
  • the interval between each administration is no more than about any of 3 weeks, 2 weeks, or 1 week. In some embodiments, the interval between each administration is about a week, about two weeks, or about three weeks.
  • 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) may be administered (e.g. , at about 5.6 mg/kg) on 4 days of a treatment cycle, e.g. , on days 1, 4, 8, 11 of a 21-day treatment cycle.
  • 4-iodo-3- nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) may be administered (e.g.
  • An antimetabolite (e.g., gemcitabine) provided herein may be administered daily, e.g., every day of the treatment cycle, or administered on certain days but not on every day of the treatment cycle.
  • the antimetabolite (e.g., gemcitabine) provided herein is administered daily, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, once every 10 days, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks.
  • An antimetabolite (e.g., gemcitabine) provided herein may be administered on the selected days of each treatment cycle, for example, the antimetabolite (e.g.
  • gemcitabine is administered daily for the period of 1 (or 2, 3, 4, 5, 6, 7, 8, 9, 10) days of the treatment cycle, and the antimetabolite (e.g., gemcitabine) is not administered on other days of the treatment cycle.
  • the intervals between each administration of gemcitabine are less than about any of 6 months, 3 months, 1 month, 21 days, 20 days, 15, days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day.
  • the interval between each administration is no more than about any of 3 weeks, 2 weeks, or 1 week. In some embodiments, the interval between each administration is about a week, about two weeks, or about three weeks.
  • Gemcitabine may be administered (e.g. , at about 1000 mg/m ) on 2 days of a treatment cycle, e.g., on days 1 and 8 of a 21 -day treatment cycle.
  • a platinum compound (e.g., carboplatin) provided herein may be administered daily, e.g., every day of the treatment cycle, or administered on certain days but not on every day of the treatment cycle.
  • the platinum compound (e.g., carboplatin) provided herein is administered daily, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, once every 10 days, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks.
  • a platinum compound (e.g., carboplatin) provided herein may be administered on the selected days of each treatment cycle, for example, the platinum compound (e.g., carboplatin) is administered daily for the period of 1 (or 2, 3, 4, 5, 6, 7, 8, 9, 10) days of the treatment cycle, and the platinum compound (e.g., carboplatin) is not administered on other days of the treatment cycle.
  • the intervals between each administration of carboplatin are less than about any of 6 months, 3 months, 1 month, 21 days, 20 days, 15, days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day.
  • the interval between each administration is no more than about any of 3 weeks, 2 weeks, or 1 week. In some embodiments, the interval between each administration is about a week, about two weeks, or about three weeks.
  • Carboplatin may be administered (e.g. , at about AUC4) on 1 day of a treatment cycle, e.g., on day 1 of a 21-day treatment cycle.
  • the method comprises 15, 12, 10, 9, 8, 7, 6 or fewer dosing cycles, wherein each cycle contains a period of 21 days.
  • 4- iodo-3-nitrobenzamide or the pharmaceutically acceptable salt thereof is administered at about 5.1 mg/kg to about 8.6 mg/kg on days 1, 4, 8, and 11 of each cycle, the antimetabolite
  • the platinum compound e.g., carboplatin
  • AUC 4 mg/ml » minute
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising at least one treatment cycle comprising administering (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin to the patient, wherein (i) carboplatin is administered to the patient at about AUC3 to about AUC5 (e.g., AUC4) once over the treatment cycle (e.g. , on day 1 of a treatment cycle such as a 21-day cycle), wherein
  • gemcitabine is administered to the patient at about 500 to about 1500 mg/m (e.g., 1000 mg/m ) twice over the treatment cycle (e.g. , on days 1 and 8 of a treatment cycle such as a 21-day cycle), and wherein (iii) 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered to the patient at about 5 mg/kg to about 20 mg/kg (or about 5 mg/kg to about 15 mg/kg) (e.g., 5.6 mg/kg) once, twice, three times, or four times over the treatment cycle (e.g.
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising at least one treatment cycle comprising administering (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin to the patient, wherein (i) carboplatin is administered to the patient at about AUC4 once over the treatment cycle (e.g., on day 1 of a treatment cycle such as a 21 -day cycle), wherein (ii) gemcitabine is administered to the patient at about 1000 mg/m twice over the treatment cycle (e.g., on days 1 and 8 of a treatment cycle such as a 21 -day cycle), wherein 4-iodo-3-nitrobenzamide or a metabolite
  • a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising at least one treatment cycle comprising administering (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin to the patient, wherein (i) carboplatin is administered to the patient at about AUC4 once over the treatment cycle (e.g., on day 1 of a treatment cycle such as a 21 -day cycle), wherein (ii) gemcitabine is administered to the patient at about 1000 mg/m twice over the treatment cycle (e.g.
  • kits and articles of manufacture for administration of 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, a antimetabolite such as gemcitabine and a platinum compound such as carboplatin as provided herein.
  • the kits or articles of manufacture comprise (i) 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, (ii) an antimetabolite (e.g., gemcitabine), and (iii) a platinum compound (e.g., carboplatin) for treating platinum-resistant recurrent ovarian cancer in a patient.
  • kits described herein may further comprise instructions (e.g., on a product insert, a package insert or a label) for using (i) 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, (ii) gemcitabine, and (iii) carboplatin in accordance with any of the methods provided herein.
  • kits comprise 4-iodo-3-nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof and a product or package insert or a label comprising instructions and/or information for using 4-iodo-3- nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof in combination with gemcitabine and carboplatin in accordance with any of the methods described herein for treating platinum-resistant recurrent ovarian cancer in a patient.
  • the kit may comprise instructions for treating platinum-resistant recurrent ovarian cancer in a patient, comprising at least one treatment cycle comprising administering (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin to the patient, wherein (i) carboplatin is administered to the patient at about AUC3 to about AUC5 once over the treatment cycle (e.g., on day 1 of a treatment cycle such as a 21 -day cycle), wherein (ii) gemcitabine is administered to the patient at about 500 to about 1500 mg/m twice over the treatment cycle (e.g., on days 1 and 8 of a treatment cycle such as a 21 -day cycle), and wherein (iii) 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered to the patient at about 5 mg/kg to about 20 mg/kg (or about 5
  • the treatment comprises a 21 -day treatment cycle, wherein (i) carboplatin is administered to the patient at 4 mg/ml » minute (AUC 4) on day 1 of the treatment cycle; (ii) gemcitabine is administered to the patient at a dose of 1000 mg/m on days 1 and 8 of the treatment cycle; and (iii) 4-iodo-3- nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 5.6 mg/kg twice weekly on days 1, 4, 8, and 11 of the treatment cycle.
  • the platinum-resistant recurrent ovarian cancer is epithelial ovarian carcinoma.
  • the platinum-resistant recurrent ovarian cancer is fallopian tube cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is primary peritoneal carcinoma. In some embodiments, the patient has a relapse within about 2 to about 6 months (e.g., a relapse within 2 to 6 months or a relapse within about any of 2 months, 2.5 months, 3 months, 3.5 months, 4 months, 4.5 months, 5 months, 5.5 months, or 6 months) after last dose of platinum-based chemotherapy. In some embodiments, the patient has measurable disease. In some embodiments, the patient has not received more than 2 prior platinum-based therapies.
  • kits may include a dosage amount of at least one composition as disclosed herein. Kits may further comprise suitable packaging and/or instructions for use of the formulation. Kits may also comprise a means for the delivery of the formulation thereof.
  • kits may include other pharmaceutical agents (such as the side-effect limiting agents, chemotherapy agents, gene therapy agents, DNA therapy agents, RNA therapy agents, viral therapy agents, nanotherapy agents, small molecule enzymatic inhibitors, anti-metastatic agents, etc.), for use in conjunction with 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (e.g. , gemcitabine) provided herein, and a platinum compound (e.g. , carboplatin) provided herein.
  • pharmaceutical agents such as the side-effect limiting agents, chemotherapy agents, gene therapy agents, DNA therapy agents, RNA therapy agents, viral therapy agents, nanotherapy agents, small molecule enzymatic inhibitors, anti-metastatic agents, etc.
  • agents may be provided in a separate form, or mixed with 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (e.g., gemcitabine) provided herein, and a platinum compound (e.g. , carboplatin) provided herein, provided such mixing does not reduce the effectiveness of 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof), an antimetabolite (e.g. , gemcitabine) provided herein or a platinum compound (e.g., carboplatin) provided herein, and is compatible with the route of administration.
  • the kits may include additional agents for adjunctive therapy or other agents known to the skilled artisan as effective in the treatment or prevention of platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer) described herein.
  • kits may optionally include appropriate instructions for preparation and administration of the composition, side effects of the composition, and any other relevant information.
  • the instructions may be in any suitable format, including, but not limited to, printed matter, videotape, computer readable disk, optical disc or directions to internet-based instructions.
  • kits for treating a patient who suffers from or is susceptible to the platinum-resistant ovarian cancer (e.g. , recurrent ovarian cancer) described herein comprising a first container comprising a dosage amount of a formulation as disclosed herein, and instructions for use.
  • the container may be any of those known in the art and appropriate for storage and delivery of intravenous formulation.
  • the kit further comprises a second container comprising a pharmaceutically acceptable carrier, diluent, adjuvant, etc. for preparation of the composition to be administered to the patient.
  • Kits may also be provided that contain sufficient dosages of 4-iodo-3- nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof (including formulation thereof) as disclosed herein to provide effective treatment for a patient for an extended period, such as 1-3 days, 1-5 days, a week, 2 weeks, 3, weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or more.
  • Kits may also include multiple doses of any of the compounds described herein and instructions for use and packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.
  • kits may include the compounds as described herein packaged in either a unit dosage form or in a multi-use form.
  • the kits may also include multiple units of the unit dose form.
  • the compositions may be provided in a multi-dose form (e.g., a blister pack, etc.).
  • Example 1 Phase II study of 4-iodo-3-nitrobenzamide in combination with gemcitabine and carboplatin in platinum-resistant recurrent ovarian cancer.
  • Inclusion Criteria (1) At least 18 years of age; (2) Histological diagnosis of epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma; (3) Completion of only one previous course of chemotherapy which contained a platinum therapy, with resistance to that regimen.
  • Platinum-resistance is defined by a relapse within 2 to 6 months after termination of platinum-based chemotherapy; (4) Measurable disease, defined by at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded), and is > 20 mm when measured by conventional techniques (palpation, plain x-ray, computed tomography [CT], or magnetic resonance imaging [MRI]) or > 10 mm when measured by spiral CT; (5) Adequate organ function defined as: absolute neutrophil count (ANC) > l,500/mm3, platelets > 100,000/mm3, creatinine clearance > 50mL/min, alanine aminotransferase (ALT) and aspartate
  • ANC absolute neutrophil count
  • ALT alanine aminotransferase
  • AST aminotransferase
  • UPN upper limit of normal
  • ECOG Eastern Cooperative Oncology Group
  • IRB Institutional review board
  • Concurrent invasive malignancy not including: (i) Non- melanomatous skin cancer; (ii) In situ malignancies; (iii) Concurrent superficial endometrial carcinoma, if their endometrial carcinoma is superficial or invades less than 50% the thickness of the myometrium); (iv) Low risk breast cancer (localized, non-inflammatory) treated with curative intent; (v) Lesions identifiable only by positron emission tomography (PET); (vi) Prior treatment with poly (ADP-ribose) polymerase (PARP) inhibitors, including 4-iodo-3-nitrobenzamide; (vii) Major medical conditions that might affect study participation (i.e., uncontrolled pulmonary, renal, or hepatic dysfunction, uncontrolled infection); (viii) Other significant co-morbid condition which the investigator feels might compromise effective and safe participation in the study, including a history of congestive cardiac failure or an electrocardiogram (ECG) suggesting significant conduction defect or myocardial ischemia; (ECG)
  • a maximum of 48 patients with platinum-resistant recurrent ovarian cancer will be treated in this study using a Simon two-stage design.
  • the primary endpoint is an improved overall response rate compared to patients receiving treatment with gemcitabine and carboplatin alone determined using historical data from a previous trial.
  • the secondary endpoints are improved progression-free survival and patient safety.
  • the exploratory endpoints are BRCA status and translational medicine.
  • Example 2 Phase II study of 4-iodo-3-nitrobenzamide in combination with gemcitabine and carboplatin in platinum-resistant recurrent ovarian cancer.
  • the primary objective of this study is to evaluate the objective response rate (ORR) of gemcitabine/carboplatin in combination with 4-iodo-3-nitrobenzamide.
  • the secondary objectives of this study are (1) to determine the nature and degree of toxicity of
  • the exploratory objectives may include relationship of BRCA status with response.
  • Eligible subjects must meet the following criteria to be enrolled in the study (inclusion criteria): 1) At least 18 years of age; 2) Histological diagnosis of epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma; 3) Completion of only one previous course of cytotoxic chemotherapy which must have contained a platinum therapy, with resistance to that regimen.
  • Platinum resistance is defined by a relapse within 2 to 6 months after last dose of platinum-based chemotherapy; 4) Measurable disease, defined by at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded), and is > 20 mm when measured by conventional techniques (palpation, plain x-ray, computed tomography (CT), or magnetic resonance imaging (MRI)) or > 10 mm when measured by spiral CT; 5) Adequate organ function defined as: absolute neutrophil count
  • ANC ANC
  • ANC 1,500/mm 3
  • platelets > 100,000/mm 3
  • creatinine clearance > 50mL/min
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • total bilirubin ⁇ 1.5 mg/dL
  • ECOG Eastern Cooperative Oncology Group
  • IRS Institutional review board
  • Eligible subjects must not have any of the following to be enrolled in the study (exclusion criteria): 1) Concurrent invasive malignancy, not including: (a) non-melanomatous skin cancer; (b) in situ malignancies; (c) concurrent superficial endometrial carcinoma, if their endometrial carcinoma is superficial or invades less than 50% the thickness of the myometrium); (d) low risk breast cancer (localized, non-inflammatory) treated with curative intent; 2) Lesions identifiable only by positron emission tomography (PET); 3) Been treated with more than 2 lines of cytotoxic chemotherapy (i.e. one containing platinum and one non- platinum such as liposomal doxorubicin) and 1 line of biologies such as avastin for up to six months (hormones do not count as a line of treatment); 4) Treatment with
  • investigational device or drug study, or current treatment with other investigational agents 9) Concurrent radiation therapy to treat primary disease throughout the course of the study; 10) Inability to comply with the requirements of the study; 11) Pregnancy or lactation; 12) Leptomeningeal disease or brain metastases requiring steroids or other therapeutic intervention.
  • Treatment continues for at least 6 cycles in the absence of disease progression or unacceptable toxicity. Subjects can continue for an additional 4 cycles, up to a possible 10 cycles, at physician's discretion. 4-iodo-3-nitrobenzamide can be continued beyond 10 cycles, as maintenance at physician discretion, until progressive disease (PD). Subjects that discontinue treatment before PD will undergo regular staging evaluation for objective response rate every 90 ( ⁇ 10) days until PD or death.
  • the first scheduled tumor response measurement for measurable disease is performed after every other cycle or approximately every 6 weeks, in addition to initial staging at baseline. Tumor response according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) is used to establish disease progression by CT or MRI (the same technique used during screening must be used).
  • RECIST modified Response Evaluation Criteria in Solid Tumors
  • Example 3 Phase II study of 4-iodo-3-nitrobenzamide in combination with gemcitabine and carboplatin ("GC”) in platinum-resistant recurrent ovarian cancer.
  • Example 4 Chemosensitizing properties of 4-iodo-3-nitrobenzamide in combination with gemcitabine (“G”) and carboplatin (“C”) in OVCAR-3 ovarian adenocarcinoma
  • Example 5 Phase II study of 4-iodo-3-nitrobenzamide in combination with gemcitabine and carboplatin ("GC”) in platinum-resistant recurrent ovarian cancer.
  • AUC 4 intravenous
  • IV gemcitabine
  • 4-iodo-3-nitrobenzamide 5.6 mg/kg; IV; days 1, 4, 8, and 11
  • Eligible patients were >18 years with epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma and demonstration of platinum-resistant disease, defined as relapse with in 2-6 months after last dose of platinum-based chemotherapy.
  • Eligible patients had measurable disease. Patients had at least 1 but not more than 2 prior therapies (platinum-based). Patients with or without BRCA mutations were eligible. Eligible patients had ECOG PS 0-2.
  • the primary endpoint was objective response rate ("ORR") based on patients who received at least 1 dose of study drug and had 2 post-baseline assessments or
  • the second endpoints were (i) progression free survival ("PFS") based on patients who received at least 1 dose of study drug and had 1 post -baseline assessment or progression/death within 60 days of last assessment and (ii) safety based on all patients who received at least 1 dose of study drug (NCTCTCAE v3.0).
  • the exploratory endpoint was relationship between BRCA status and response.
  • the BRCA status for the response evaluable patients shown in Figure 2 is shown in Figures 3 and 4.
  • thrombocytopenia thrombocytopenia, anemia, small intestinal obstruction, and nausea were most common.
  • SAEs were considered related to study drug, which included the following Grade 3/4 events: thrombocytopenia, anemia, nausea, vomiting, small intestinal obstruction, fatigue, dehydration, and hypokalemia.

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Abstract

The present invention provides a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient an effective amount of 4- iodo-3-nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof; gemcitabine; and carboplatin.

Description

METHODS OF TREATING PLATINUM-RESISTANT RECURRENT OVARIAN CANCER WITH 4-IODO-3-NITROBENZAMIDE IN COMBINATION WITH AN
ANTI-METABOLITE AND A PLATINUM COMPOUND
RELATED APPLICATIONS
[0001] This application claims the priority benefit of U.S. provisional applications U.S. Serial No. 61/351,772, filed June 4, 2010, and U.S. Serial No. 61/481,632, filed May 2, 2011, Canadian Patent Application No. 2725027, filed December 10, 2010, and Australian Patent Application No. 2010249298, filed December 13, 2010, all of which are incorporated herein by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] Cancer is a complex family of diseases affecting nearly every tissue in the body and characterized by aberrant control of cell growth. The annual incidence of all cancer types is estimated to be in excess of 1.3 million cases in the United States alone. While a number of first line therapies for the treatment of different types of cancer have been deployed with varying degrees of success, including surgical resection, radiation therapy, chemotherapy, and hormone therapy, it remains the second leading cause of death in the U.S., with an estimated 560,000 Americans dying from cancer every year.
[0003] Ovarian cancer is the 8th most common cancer in women worldwide with estimated 225,500 new diagnoses per year and estimated 140,200 deaths per year. The current standard of care for first-line chemotherapy of ovarian cancer is a combination of a platinum compound (e.g., cisplatin, carboplatin, and oxaliplatin) with a taxane. The majority of newly-diagnosed ovarian cancer patients will respond to first-line platinum-based and paclitaxel chemotherapy. However, 50-80% of the patients who respond to this combination therapy will eventually relapse. See, e.g., Herzog, "Update on the role of topotecan in the treatment of recurrent ovarian cancer," The Oncologist 7(Suppl. 5):3-10 (2002). Women with advanced ovarian cancer have poor long-term survival due to disease recurrence and most die within 5 years. There is clearly a need to improve the current treatment options for recurrent ovarian cancer. BRIEF SUMMARY OF THE INVENTION
[0004] Provided herein is a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient having ovarian cancer an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin. In some embodiments, the platinum-resistant recurrent ovarian cancer is epithelial ovarian carcinoma. In some embodiments, the platinum-resistant recurrent ovarian cancer is fallopian tube cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is primary peritoneal carcinoma. In some embodiments, the treatment comprises at least 1 treatment cycle (e.g., at least about any of 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles, 12 cycles, 13 cycles, 14 cycles, 15 cycles, 16 cycles, 17 cycles, or 18 cycles), wherein each cycle (or each of the cycles) comprises administering an effective amount of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin. In some embodiments, the treatment comprises at least about 2 (e.g., at least about 4 to about 12 or at least about 7 to about 12) treatment cycles, wherein each of the cycles comprises administering an effective amount of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin. In some embodiments, the patient has not received more than 2 prior platinum-based therapies. In some embodiments, the patient has a relapse within about 2 to about 6 months (e.g., a relapse within 2 to 6 months or a relapse within about any of 2 months, 2.5 months, 3 months, 3.5 months, 4 months, 4.5 months, 5 months, 5.5 months, or 6 months) after last dose of platinum-based chemotherapy. In some embodiments, the effective amount is administered over a 21 -day treatment cycle, wherein (i) carboplatin is administered to the patient at 4 mg/ml»minute (AUC 4) on day 1 of the treatment cycle; (ii) gemcitabine is administered to the patient at a dose of 1000 mg/m on days 1 and 8 of the treatment cycle; and (iii) 4-iodo-3-nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 5.6 mg/kg twice weekly on days 1, 4, 8, and 11 of the treatment cycle. In some embodiments, the effective amount produces at least one therapeutic effect selected from the group consisting of reduction in size of an ovarian tumor, reduction in metastasis, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response. In some embodiments, the method further comprises surgery, radiation therapy,
chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, adjuvant therapy, neoadjuvant therapy, immunotherapy, nanotherapy or a combination thereof. In some embodiments, the method further comprises administering to the patient gamma irradiation. In some embodiments, the patient has platinum-resistant recurrent ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is selected from the group consisting of epithelial, germ cell, and stromal cell tumors. In some embodiments, the platinum-resistant recurrent ovarian cancer is metastatic. In some embodiments, 4-iodo-3- nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof is administered intravenously. In some embodiments, gemcitabine is administered
intravenously. In some embodiments, carboplatin is administered intravenously. In some embodiments, the patient has measurable disease. In some embodiments, the platinum- resistant recurrent ovarian cancer is serous ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is serous adenocarcinoma ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is papillary serous ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is
endometrioid ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is clear cell ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises ovarian tumor of any grade, for example, any of grade 1, 2, or 3. In some embodiments, the patient has platinum compound-free interval of about any of 2 months, 3 months, 4 months, 5 months, or 6 months or at least about any of 2 months, 3 months, 4 months, 5 months, or 5.5 months. For example, prior to the initiation of any of the treatments described herein, there has been a period of about any of 2 months, 3 months, 4 months, 5 months, or 6 months or at least about any of 2 months, 3 months, 4 months, 5 months, or 5.5 months after the last dose of a platinum compound. In some embodiments, the method further comprises administering granulocyte colony- stimulating factor ("G-CSF") to the patient. In some embodiments, the method does not further comprise administering G- CSF to the patient.
[0005] In some embodiments, the treatment provides improved clinical benefit rate compared to treatment with gemcitabine and carboplatin administered without 4-iodo-3- nitrobenzamide. In some embodiments, an improved clinical benefit rate (CBR = CR (complete remission) + PR (partial remission) + SD (stable disease) > 6 months) is obtained compared to treatment with gemcitabine and carboplatin administered without 4-iodo-3- nitrobenzamide. In some embodiments, the improvement of clinical benefit rate is about 20% or higher. In some embodiments, the therapeutic effect is an increase in overall response rate. In some embodiments, the overall response rate is greater than 15%. In some embodiments, the overall response rate is greater than 20%. In some embodiments, the overall response rate is greater than 30%.
[0006] In some embodiments, the patient has platinum-resistant recurrent ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is deficient in homologous recombination DNA repair. In some embodiments, the homologous
recombination DNA repair-deficient platinum-resistant recurrent ovarian cancer is BRCA deficient. In some embodiments, the BRCA-deficient platinum-resistant recurrent ovarian cancer is BRCAl -deficient. In some embodiments, the BRCA-deficient platinum-resistant recurrent ovarian cancer is BRCA2-deficient. In some embodiments, the BRCA-deficient platinum-resistant recurrent ovarian cancer is both BRCAl -deficient and BRCA2-deficient. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises at least one mutation in BRCAl. In some embodiments, the platinum-resistant recurrent ovarian cancer does not comprise a mutation in BRCAl. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises at least one mutation in BRCA2. In some embodiments, the platinum-resistant recurrent ovarian cancer does not comprise a mutation in BRCA2. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises at least one mutation in BRCAl and at least one mutation in BRCA2. In some embodiments, the platinum-resistant recurrent ovarian cancer does not comprise a mutation in BRCAl or BRCA2.
[0007] Also provided herein are uses of any of the pharmaceutical compositions described herein for the manufacture of a medicament for treating platinum-resistant recurrent ovarian cancer. For example, the use as provided herein is with respect to or in accordance with any of the methods described herein.
[0008] Also provided herein are uses of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, in combination with (ii) any one of the antimetabolites, a pharmaceutically acceptable salt or solvate thereof and with (iii) any one of the platinum compounds described herein, a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment or prevention of platinum-resistant recurrent ovarian cancer as described herein. Also provided herein are uses of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prevention of platinum-resistant recurrent ovarian cancer as described herein in combination with an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin). Also provided herein are uses of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prevention of platinum-resistant recurrent ovarian cancer in a patient as described herein, wherein 4-iodo-3-nitrobenzamide, a metabolite thereof, or a
pharmaceutically acceptable salt or solvate thereof is to be administered to the patient in combination with an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin).
[0009] Also provided herein are synergistic compositions used for treating platinum- resistant recurrent ovarian cancer in a patient comprising administering to said patient a) 4- iodo-3-nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, b) an antimetabolite, and (c) a platinum compound, wherein the
antimetabolite is selected from the group consisting of citabine, capecitabine, gemcitabine or valopicitabine, and wherein the platinum compound is selected from the group consisting of cisplatin; cis-diamminediaquoplatinum (Il)-ion; chloro(diethylenetriamine) -platinum (II) chloride; dichloro(ethylenediamine) -platinum (II); diammine(l,l-cyclobutanedicarboxylato) platinum (II) (carboplatin); spiroplatin; iproplatin; diammine(2-ethylmalonato)platinum (II); ethylenediaminemalonatoplatinum (II); aqua(l,2-diaminodicyclohexane)sulfatoplatinum (II); aqua(l,2-diaminodicyclohexane)malonatoplatinum (II); (1,2- diaminocyclohexane)malonatoplatinum (II) ; (4-carboxyphthalato)( 1 ,2-diaminocyclohexane) platinum (II); (l,2-diaminocyclohexane)-(isocitrato)platinum (II); (1,2- diaminocyclohexane)oxalatoplatinum (II); ormaplatin; tetraplatin; carboplatin, nedaplatin and oxaliplatin.
[0010] Also provided herein are kits for treating platinum-resistant recurrent ovarian cancer in a patient. In some embodiments, the kits comprise (a) 4-iodo-3-nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, (b) an antimetabolite, and (c) a platinum compound. The kits may further comprise a product or package insert or a label comprising instructions and/or information for using an effective amount of (a) 4-iodo-3-nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, (b) an antimetabolite, and (c) a platinum compound, in accordance with any of the methods described herein. In some embodiments, the kits comprise 4-iodo-3-nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof and a product or package insert or a label comprising instructions and/or information for using an effective amount of 4-iodo-3-nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof in combination with an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin) for treating platinum-resistant recurrent ovarian cancer in a patient in accordance with any of the methods described herein. In some embodiments, the antimetabolite is gemcitabine, and the platinum compound is carboplatin. In some embodiments, the effective amount is administered over a 21 -day treatment cycle, wherein (i) carboplatin is administered to the patient at 4
mg/ml»minute (AUC 4) on day 1 of the treatment cycle; (ii) gemcitabine is administered to the patient at a dose of 1000 mg/m on days 1 and 8 of the treatment cycle; and (iii) 4-iodo-3- nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 5.6 mg/kg twice weekly on days 1, 4, 8, and 11 of the treatment cycle. In some embodiments, the platinum-resistant recurrent ovarian cancer is epithelial ovarian carcinoma. In some embodiments, the platinum-resistant recurrent ovarian cancer is fallopian tube cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is primary peritoneal carcinoma. In some embodiments, the patient has a relapse within about 2 to about 6 months (e.g., a relapse within 2 to 6 months or a relapse within about any of 2 months, 2.5 months, 3 months, 3.5 months, 4 months, 4.5 months, 5 months, 5.5 months, or 6 months) after last dose of platinum-based chemotherapy. In some embodiments, the patient has measurable disease. In some embodiments, the patient has not received more than 2 prior platinum-based therapies.
[0011] It is to be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the invention will become apparent to one of skill in the art.
INCORPORATION BY REFERENCE
[0012] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application is specifically and individually indicated to be incorporated by reference.
BRIEF DESCRIPTION OF THE FIGURES
[0013] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings. [0014] FIGURE 1 shows study design and treatment schedule of a multi-center, single arm phase 2 study using 4-iodo-3-nitrobenzamide (also known as "iniparib") in combination with carboplatin and gemcitabine (Simon two-stage design, N=48). Preliminary analysis was based on the first 34 patients enrolled. "GO" refers to gemcitabine, carboplatin, and iniparib. "PD" refers to progressive disease.
[0015] FIGURE 2 shows platinum-free interval and best target lesion response shown as percent change from baseline calculated at the lowest post-baseline tumor burden of target lesions for response evaluable patients (N=32). Bars were patterned according to the
Investigator's assessment of confirmed response. Square with broken line pattern represents confirmed complete response ("CR") (n=0) and partial response ("PR") (n=8). Square with solid line pattern represents unconfirmed PR (n=2) and stable disease ("SD") (n=16). Black square represents progressive disease ("PD") (n= 5).
[0016] FIGURE 3 shows platinum-free interval and percent change from baseline calculated at the lowest post-baseline tumor burden of target lesions for response evaluable patients (N=32) with BRCA mutation status shown for the patients. Bars were patterned according to the Investigator's assessment of confirmed response. Square with broken line pattern represents confirmed CR and PR. Square with solid line pattern represents
unconfirmed PR and SD. Black square represents PD. "A" represents no BRCA mutation. "M" represents mutation in BRCA1 or BRCA2.
[0017] FIGURE 4 shows platinum-free interval and percent change from baseline calculated at the lowest post-baseline tumor burden of target lesions for response evaluable patients (N=32) with BRCA mutation status shown for the patients. Bars were patterned according to the Investigator's assessment of confirmed response. Square with broken line pattern represents confirmed CR and PR. Square with solid line pattern represents
unconfirmed PR and SD. Black square represents PD. "A" represents no BRCA mutation. "M" represents mutation in BRCA1 or BRCA2.
[0018] FIGURE 5 shows median progression-free survival ("PFS") 6.44 months for PFS evaluable patients (N=32). 95% CI: 5.39-7.86; Censored: 46.9%; Progression events: 15 (46.9%).
DETAILED DESCRIPTION
[0019] As used herein, the term "platinum-resistant" refers to a type of ovarian cancer (e.g. , recurrent ovarian cancer). The current standard of care for first-line chemotherapy of ovarian cancer is a combination of a platinum compound (e.g., cisplatin, carboplatin, and oxaliplatin) with a taxane. The majority of newly-diagnosed ovarian cancer patients will respond to first- line platinum-based and paclitaxel chemotherapy. However, 50-80% of the patients who respond to this combination therapy will eventually relapse. See, e.g., Herzog, "Update on the role of topotecan in the treatment of recurrent ovarian cancer," The Oncologist 7(Suppl. 5):3-10 (2002). Patients who relapse within six months are less likely to respond to a second round of platinum-based therapy. Therefore, advanced ovarian cancer tumors that have recurred are classified as being "platinum- sensitive" if relapse occurs more than six months after the last dose of platinum-based therapy, "platinum-resistant" if relapse occurs less than or equal to six months after the last dose of platinum-based therapy, and "platinum- refractory" if no response or disease regression occurs during initial platinum-based therapy.
[0020] As used herein "surgery" refers to any therapeutic or diagnostic procedure that involves methodical action of the hand or of the hand with an instrument, on the body of a human or other mammal, to produce a curative, remedial, or diagnostic effect.
[0021] "Radiation therapy" refers to exposing a patient to high-energy radiation, including without limitation x-rays, gamma rays, and neutrons. This type of therapy includes without limitation external-beam therapy, internal radiation therapy, implant radiation, brachytherapy, systemic radiation therapy, and radiotherapy.
[0022] "Chemotherapy" refers to the administration of one or more anti-cancer drugs such as, antineoplastic chemotherapeutic agents, chemopreventative agents, and/or other agents to a patient with platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer) by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical,
subcutaneous, transdermal, buccal, or inhalation or in the form of a suppository. Unless clearly dictated otherwise by context, "chemotherapy" as used herein is not intended to refer to the administration of 4-iodo-3-nitrobenzamide, an antimetabolite (e.g., gemcitabine), and a platinum compound (e.g., carboplatin) as described herein. Chemotherapy may be given prior to surgery to shrink a large tumor prior to a surgical procedure to remove it, prior to radiation therapy, or after surgery and/or radiation therapy to prevent the growth of any remaining ovarian cancer cells in the body. Chemotherapy may also occur during the course of radiation therapy.
[0023] The terms "effective amount" or "pharmaceutically effective amount" refer to a sufficient amount of an agent to provide the desired biological, therapeutic, and/or
prophylactic result. That result can be reduction and/or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a) 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt or solvate thereof; b) an antimetabolite (e.g. , gemcitabine), or pharmaceutically acceptable salt or solvate thereof; and c) a platinum compound (e.g., carboplatin) provided herein, or a composition comprising a) 4-iodo-3-nitrobenzamide or a metabolite thereof or a
pharmaceutically acceptable salt or solvate thereof; b) an antimetabolite (e.g., gemcitabine), or pharmaceutically acceptable salt or solvate thereof; and c) a platinum compound (e.g., carboplatin) provided herein required to provide a clinically significant decrease in the platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer) or slowing of progression of the platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer).
[0024] "Metabolite" refers to a compound produced through any in vitro or in vivo metabolic process which results in a product that is different in structure than that of the starting compound. In other words, the term "metabolite" includes the metabolite compounds of 4-iodo-3-nitrobenzamide. A metabolite can include a varying number or types of substituents that are present at any position relative to a precursor compound. In addition, the terms "metabolite" and "metabolite compound" are used interchangeably herein.
[0025] By "pharmaceutically acceptable" is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
[0026] The term "treating" and its grammatical equivalents as used herein include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. For example, in a patient having platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer), therapeutic benefit includes eradication or amelioration of the underlying ovarian cancer, e.g., slowing of progression of the ovarian cancer. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder (e.g., ovarian cancer) such that an improvement is observed in the patient, notwithstanding the fact that the patient may still be afflicted with the underlying disorder (e.g., ovarian cancer). For prophylactic benefit, a method of the invention may be performed on, or a composition of the invention administered to a patient at risk of developing platinum- resistant ovarian cancer (e.g. , recurrent ovarian cancer), or to a patient reporting one or more of the physiological symptoms of platinum-resistant ovarian cancer (e.g. , recurrent ovarian cancer), even though a diagnosis of platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer) may not have been made. In some embodiments, the patient being treated has been diagnosed with a platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer) described herein.
[0027] Reference to "about" a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X".
[0028] As used herein and in the appended claims, the singular forms "a," "or," and "the" include plural referents unless the context clearly dictates otherwise. It is understood that aspects and variations of the invention described herein include "consisting" and/or
"consisting essentially of aspects and variations.
Treatment of Ovarian Cancer
[0029] There are three basic types of ovarian tumors: epithelial, germ cell, and stromal cell tumors. Epithelial tumors start from the cells that cover the outer surface of the ovary; most ovarian tumors are epithelial cell tumors. Germ cell tumors start from the cells that produce the eggs. Stromal tumors start from cells that hold the ovary together and make the female hormones.
[0030] A significant risk factor for ovarian cancer includes deficiencies in DNA repair via homologous recombination, such as mutations in the BRCA1 or BRCA2 gene. Those genes were originally identified in families with multiple cases of breast cancer, but have been associated with approximately 5 to 10 percent of ovarian cancers.
[0031] Possible treatments for ovarian cancer include surgery, immunotherapy,
chemotherapy, hormone therapy, radiation therapy, or a combination thereof. Surgical procedures for the treatment of ovarian cancer include debulking, and a unilateral or bilateral oophorectomy and/or a unilateral or bilateral salpigectomy. Anti-cancer drugs that have also been used to treat ovarian cancer include cyclophosphamide, etoposide, altretamine, and ifosfamide. Hormone therapy with the drug tamoxifen is also used to shrink ovarian tumors. Radiation therapy optionally includes external beam radiation therapy and/or brachytherapy.
[0032] In one aspect, provided herein are methods of treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite, and a platinum compound. In some embodiments, the antimetabolite is selected from the group consisting of citabine, capecitabine, gemcitabine or valopicitabine. In some embodiments, the antimetabolite is gemcitabine. In some embodiments, the platinum compound is selected from the group consisting of cisplatin; cis-diamminediaquoplatinum (Il)-ion;
chloro(diethylenetriamine)-platinum (II) chloride; dichloro(ethylenediamine) -platinum (II); diammine(l,l-cyclobutanedicarboxylato) platinum (II) (carboplatin); spiroplatin; iproplatin; diammine(2-ethylmalonato)platinum (II); ethylenediaminemalonatoplatinum (II); aqua(l,2- diaminodicyclohexane)sulfatoplatinum (II); aqua(l,2- diaminodicyclohexane)malonatoplatinum (II) ; ( 1 ,2-diaminocyclohexane)malonatoplatinum (II); (4-carboxyphthalato)(l,2-diaminocyclohexane) platinum (II); (1,2-diaminocyclohexane)- (isocitrato)platinum (II); (l,2-diaminocyclohexane)oxalatoplatinum (II); ormaplatin;
tetraplatin; carboplatin, nedaplatin and oxaliplatin, and preferred is carboplatin or oxaliplatin. In some embodiments, the platinum compound is carboplatin. For example, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering an effective amount of (i) 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin. In some embodiments, the patient has platinum-resistant recurrent ovarian cancer. In some
embodiments, at least one therapeutic effect is obtained, said at least one therapeutic effect being reduction in size of a tumor, reduction in metastasis, complete remission, partial remission, pathologic complete response, or stable disease.
[0033] In some embodiments of any of the methods described herein, the method further comprises surgery, radiation therapy, chemotherapy, gene therapy, viral therapy, RNA therapy, DNA therapy, adjuvant therapy, neoadjuvant therapy, immunotherapy, nanotherapy or a combination thereof. In some embodiments, the method further comprises administering to the patient gamma irradiation. In some embodiments, the platinum-resistant recurrent ovarian cancer is selected from the group consisting of epithelial, germ cell, and stromal cell tumors. In some embodiments, the platinum-resistant recurrent ovarian cancer is metastatic. In some embodiments, the platinum-resistant recurrent ovarian cancer is not metastatic. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises invasive malignancy. In some embodiments, the platinum-resistant recurrent ovarian cancer does not comprise invasive malignancy.
[0034] In one aspect, the present invention provides a method of treating platinum- resistant ovarian cancer (e.g., platinum-resistant recurrent ovarian cancer) in a patient, comprising administering to the patient having ovarian cancer (e.g., platinum resistant ovarian cancer) an effective amount of: (i) 4-iodo-3-nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin. In some embodiments, the effective amount is administered over a 21 -day treatment cycle, wherein (i) the effective amount of carboplatin is administered to the patient at 4 mg/ml»minute (AUC 4) (or about AUC4) on day 1 of the treatment cycle; (ii) the effective amount of gemcitabine is administered to the patient at a dose of 1000 mg/m 2 (or about 1000 mg/m 2 ) on days 1 and 8 of the treatment cycle; and (iii) the effective amount of 4-iodo-3-nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 5.6 mg/kg (or about 5.6 mg/kg) twice weekly on days 1, 4, 8, and 11 of the treatment cycle. In some embodiments, the effective amount produces at least one therapeutic effect selected from the group consisting of reduction in size of an ovarian tumor, reduction in metastasis, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response. In some embodiments, an improved clinical benefit rate (CBR = CR (complete remission) + PR (partial remission) + SD (stable disease) > 6 months) is obtained compared to treatment with gemcitabine and carboplatin administered without 4-iodo-3-nitrobenzamide. In some embodiments, the improvement of clinical benefit rate is about 20% or higher. In some embodiments, the therapeutic effect is an increase in overall response rate. In some embodiments, the overall response rate is greater than 20%. In some embodiments, the overall response rate is greater than 15%. In some embodiments, the overall response rate is greater than 30%. In some embodiments, the method further comprises surgery, radiation therapy, chemotherapy, gene therapy, viral therapy, RNA therapy, DNA therapy, adjuvant therapy, neoadjuvant therapy, immunotherapy, nanotherapy or a combination thereof. In some embodiments, the method further comprises administering to the patient gamma irradiation. In some embodiments, the platinum-resistant ovarian cancer (e.g., platinum-resistant recurrent ovarian cancer) is selected from the group consisting of epithelial, germ cell, and stromal cell tumors. In some embodiments, the platinum- resistant ovarian cancer is recurrent ovarian cancer. In some embodiments, the platinum- resistant ovarian cancer (e.g., platinum-resistant recurrent ovarian cancer) is metastatic. In some embodiments, the platinum-resistant ovarian cancer (e.g., platinum-resistant recurrent ovarian cancer) is deficient in homologous recombination DNA repair. In some
embodiments, the homologous recombination DNA repair-deficient platinum-resistant ovarian cancer is BRCA deficient. In some embodiments, the BRCA-deficient platinum- resistant ovarian cancer is BRCA 1 -deficient. In some embodiments, the BRCA-deficient platinum-resistant ovarian cancer is BRCA2-deficient. In some embodiments, the BRCA- deficient platinum-resistant ovarian cancer is both BRCA 1 -deficient and BRCA2-deficient. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises at least one mutation in BRCA1. In some embodiments, the platinum-resistant recurrent ovarian cancer does not comprise a mutation in BRCA1. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises at least one mutation in BRCA2. In some embodiments, the platinum-resistant recurrent ovarian cancer does not comprise a mutation in BRCA2. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises at least one mutation in BRCA1 and at least one mutation in BRCA2. In some embodiments, the platinum-resistant recurrent ovarian cancer does not comprise a mutation in BRCA1 or BRCA2.
[0035] In some embodiments of any of the methods described herein, the platinum- resistant recurrent ovarian cancer is deficient in homologous recombination DNA repair. In some embodiments, the homologous recombination DNA repair-deficient platinum-resistant recurrent ovarian cancer is BRCA deficient. In some embodiments, a deficiency in a BRCA gene is detected in the ovarian cancer patient. In other embodiments, the deficiency is a genetic defect in the BRCA gene. In some embodiments, the genetic defect is a mutation, insertion, substitution, duplication or deletion of the BRCA gene. In some embodiments, the BRCA gene is BRCA 1. In other embodiments, the BRCA gene is BRCA-2. In some embodiments, the BRCA-deficient platinum-resistant recurrent ovarian cancer is BRCA1- deficient. In some embodiments, the BRCA-deficient platinum-resistant recurrent ovarian cancer is BRCA2-deficient. In some embodiments, the BRCA-deficient platinum-resistant recurrent ovarian cancer is both BRCA 1 -deficient and BRCA2-deficient.
[0036] In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer comprising administering an effective amount of 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (e.g., gemcitabine), and a platinum compound (e.g., carboplatin). In some embodiments, the platinum-resistant recurrent ovarian cancer is epithelial ovarian carcinoma. In some embodiments, the platinum-resistant recurrent ovarian cancer is fallopian tube cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is primary peritoneal carcinoma. For example, in some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient having the platinum-resistant recurrent ovarian cancer an effective amount of: (i) 4-iodo-3-nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin. The ovarian cancer described herein may be epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma. In some embodiments, the platinum-resistant recurrent ovarian cancer is serous ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is serous adenocarcinoma ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is papillary serous ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is endometrioid ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is clear cell ovarian cancer. In some embodiments, the patient has measurable disease (such as measurable disease according to RECIST 1.1). For example, the measurable disease may be defined by at least one lesion that can be accurately measured in at least one dimension (such as longest dimension), and is > 20 mm when measured by conventional techniques (e.g., palpation, plain x-ray, computed tomography, or magnetic resonance imaging) or > 10 mm when measured by spiral CT. In some embodiments, the patient has not received more than 2 prior platinum-based therapies. In some embodiments, the patient has completed only one previous course of cytotoxic therapy (which must have contained a platinum therapy and have resistance to that regimen). In some embodiments, the patient has a relapse within about 2 to about 6 months (e.g., a relapse within 2 to 6 months or a relapse within about any of 2 months, 2.5 months, 3 months, 3.5 months, 4 months, 4.5 months, 5 months, 5.5 months, or 6 months) after last dose of platinum-based chemotherapy. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises ovarian tumor of any grade, for example, any of grade 1, 2, or 3. Grading of ovarian tumor may be in accordance with any of the methods known to one skilled in the art. For example, grade 0 may refer to non-invasive tumors or borderline tumors. Grade 1 tumors may have cells that are well differentiated (look very similar to the normal tissue) and may be the ones with the best prognosis. Grade 2 tumors may be moderately well differentiated and may be made up by cells that resemble the normal tissue. Grade 3 tumors may have the worst prognosis and their cells may be abnormal, referred to as poorly differentiated. In some embodiments, the patient has not been treated with more than 2 lines of cytotoxic chemotherapy and 1 line of biologies such as anti-VEGF antibody (e.g., bevacizumab) for up to six months (hormones do not count as a line of treatment). For example, the patient has received two cytotoxic chemotherapies, including one containing platinum and one non-platinum such as liposomal doxorubicin. In some embodiments, the patient has not received a prior chemotherapy comprising 4-iodo-3-nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has not received a prior chemotherapy comprising a PARP inhibitor (e.g., Olaparib, ABT-888 (Veliparib), AGO 14699, CEP 9722, MK 4827, KU-0059436 (AZD2281), or LT-673). In some embodiments, the patient has platinum compound-free interval of about any of 2 months, 3 months, 4 months, 5 months, or 6 months or at least about any of 2 months, 3 months, 4 months, 5 months, or 5.5 months. For example, prior to the initiation of any of the treatments described herein, there has been a period of about any of 2 months, 3 months, 4 months, 5 months, or 6 months or at least about any of 2 months, 3 months, 4 months, 5 months, or 5.5 months after the last dose of a platinum compound. Other characteristics of patients that can be treated with any one of the methods provided herein are provided in the eligibility criteria in Examples 1 and 2 of the present disclosure. In some embodiments, the method further comprises administering granulocyte colony- stimulating factor ("G-CSF") to the patient. In some embodiments, the method does not further administering G-CSF to the patient. The dosing regimen for 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (e.g., gemcitabine), and a platinum compound (e.g., carboplatin) may be according to any of the dosing schedule or dosing regimen described in the Section
"Formulations, Routes of administration, and Dosing Regimen" described below.
[0037] In some embodiments of any of the methods described herein, the term "patient" or "subject" refers to a human patient or subject.
[0038] The platinum-resistant recurrent ovarian cancer can be any stage. In some embodiments of any of the methods described herein, the platinum-resistant recurrent ovarian cancer is not metastatic. In some embodiments, the platinum-resistant recurrent ovarian cancer is metastatic. In some embodiments, the platinum-resistant recurrent ovarian cancer is any of stage 1, 2, 3 or 4. In some embodiments, the platinum-resistant recurrent ovarian cancer is any of stage la, lb, lc, 2a, 2b, 2c, 3a, 3b, 3c, or 4. The staging may be according to any of the methods known to one skilled in the art. For example, the staging may be in accordance with the staging described at
http://www.cancer.org/cancer/ovariancancer/detailedguide/ovarian-cancer-staging (last accessed May 30, 2011).
[0039] In some embodiments of any of the methods provided herein, at least one therapeutic effect is obtained, said at least one therapeutic effect being reduction in size of an ovarian tumor, reduction in metastasis, complete remission, partial remission, pathologic complete response, increase in overall response rate or stable disease. In some embodiments, the treatment provides improved clinical benefit rate compared to treatment without 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof. In some embodiments, an improvement of clinical benefit rate (CBR = CR + PR + SD > 6 months) is obtained as compared to treatment without 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement of clinical benefit rate is at least about any of 20%, 30%, 40%, 50%, 60%, 70%, 80%, or more. In some embodiments, the therapeutic effect is an increase in overall response rate. In some embodiments, the increase in overall response rate is about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or more.
[0040] Any of the clinical efficacy parameters described herein may be measured according to RECIST version 1.1 criteria, which is described in Eisenhauer EA et al. 2009, Eur J Cancer., 45(2):228-47, the disclosure of which is incorporated by reference in its entirety.
[0041] In some embodiments of any of the methods described herein, the methods for treating platinum-resistant recurrent ovarian cancer further comprise administering 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof in combination with an anti-tumor agent (or at least one anti-tumor agent). For example, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering an effective amount of (a) 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, (b) an antimetabolite (e.g.,
gemcitabine), and (c) a platinum complex (e.g., carboplatin) in combination with at least one additional anti-tumor agent. In some embodiments, the anti-tumor agent is an antitumor alkylating agent, antitumor antimetabolite, antitumor antibiotics, plant-derived antitumor agent, antitumor platinum complex, antitumor camptothecin derivative, antitumor tyrosine kinase inhibitor, monoclonal antibody, interferon, biological response modifier, hormonal anti-tumor agent, anti-tumor viral agent, angiogenesis inhibitor, differentiating agent, or other agent that exhibits anti-tumor activities, or a pharmaceutically acceptable salt thereof. In some embodiments, the platinum complex is cisplatin, carboplatin, oxaplatin or oxaliplatin. In some embodiments, the antimetabolite is citabine, capecitabine, gemcitabine or valopicitabine. In some embodiments, the methods further comprise administering to the patient 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof in combination with more than one anti-tumor agent. In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (e.g., gemcitabine), and a platinum compound (e.g., carboplatin) in combination with at least more than one anti-tumor agent. In some embodiments, the anti-tumor agent is administered prior to, concomitant with or subsequent to administering 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (e.g., gemcitabine), and/or a platinum complex (e.g., carboplatin). In some embodiments, the anti-tumor agent is an anti- angiogenic agent, such as Avastin or a receptor tyrosine kinase inhibitor including but not limited to Sutent, Nexavar, Recentin, ABT-869, and Axitinib. In some embodiments, the anti-tumor agent is a topoisomerase inhibitor including but not limited to irinotecan, topotecan, or camptothecin. In some embodiments, the anti-tumor agent is a taxane including but not limited to paclitaxel, docetaxel and Abraxane. In some embodiments, the anti-tumor agent is an agent targeting Her-2, Herceptin or lapatinib. In some embodiments, the antitumor agent is a hormone analog, for example, progesterone. In some embodiments, the antitumor agent is tamoxifen, a steroidal aromatase inhibitor, a non-steroidal aromatase inhibitor, or Fulvestrant. In some embodiments, the anti-tumor agent is an agent targeting a growth factor receptor. In some embodiments, such agent is an inhibitor of epidermal growth factor receptor (EGFR) including but not limited to Cetuximab and Panitumimab. In some embodiments, the agent targeting a growth factor receptor is an inhibitor of insulin-like growth factor 1 (IGF-1) receptor (IGF1R) such as CP-751871. In other embodiments, the method further comprises surgery, radiation therapy, chemotherapy, gene therapy, DNA therapy, adjuvant therapy, neoadjuvant therapy, viral therapy, RNA therapy, immunotherapy, nanotherapy or a combination thereof. In some embodiments, at least one therapeutic effect is obtained, said at least one therapeutic effect being reduction in size of a tumor, reduction in metastasis, complete remission, partial remission, pathologic complete response, or stable disease.
[0042] In some embodiments of any of the methods described herein, the treatment comprises a treatment cycle of at least 11 days, e.g., about 11 to about 30 days in length, wherein on from 1 to 10 separate days of the cycle, the patient receives about 1 to about 100 mg/kg of 4-iodo-3-nitrobenzamide or a molar equivalent of a metabolite thereof. In some embodiments, on from 1 to 10 separate days of the cycle, the patient receives about 1 to about 50 mg/kg of 4-iodo-3-nitrobenzamide or a molar equivalent of a metabolite thereof. In some embodiments, on from 1 to 10 separate days of the cycle, the patient receives about 1, 2, 3, 4, 5, 5.6, 6, 8, 10, 11.2, 12, 14, 16, 18 or 20 mg/kg of 4-iodo-3-nitrobenzamide. The treatment further comprises an antimetabolite (e.g., gemcitabine), and a platinum compound (e.g., carboplatin).
[0043] Some embodiments described herein provide a method of treating platinum- resistant recurrent ovarian cancer in a patient (e.g., a patient having a deficiency in a BRCA gene), comprising during a 21 day treatment cycle on days 1, 4, 8 and 11 of the cycle, administering to the patient about 10 to about 100 mg/kg of 4-iodo-3-nitrobenzamide or a molar equivalent of a metabolite thereof. In some embodiments, the 4-iodo-3- nitrobenzamide is administered orally or as a parenteral injection or infusion, or inhalation. The treatment further comprises an antimetabolite (e.g., gemcitabine), and a platinum compound (e.g., carboplatin).
[0044] Some embodiments described herein provide a method of treating platinum- resistant recurrent ovarian cancer in a patient (e.g., a patient having a deficiency in a BRCA gene), comprising: (a) establishing a treatment cycle of about 10 to about 30 days in length; (b) on from 1 to 10 separate days of the cycle, administering to the patient about 1 mg/kg to about 50 mg/kg of 4-iodo-3-nitrobenzamide, or a molar equivalent of a metabolite thereof. In some embodiments, the 4-iodo-3-nitrobenzamide is administered orally or as a parenteral injection or infusion, or inhalation. The treatment further comprises an antimetabolite (e.g., gemcitabine), and a platinum compound (e.g., carboplatin).
[0045] Some embodiments provided herein include a method of treating ovarian cancer in a patient in need of such treatment, comprising: (a) obtaining a sample from the patient; (b) testing the sample to determine if there is a deficiency in a BRCA gene; (c) if the testing indicates that the patient has a deficiency in a BRCA gene, treating the patient with 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof; and (d) if the testing does not indicate that the patient has a deficiency in a BRCA gene, selecting a different treatment option. In some embodiments, at least one therapeutic effect is obtained, said at least one therapeutic effect being reduction in size of an ovarian tumor, reduction in metastasis, complete remission, partial remission, pathologic complete response, increase in overall response rate, or stable disease. In some embodiments, an improvement of clinical benefit rate (CBR = CR + PR + SD > 6 months) is obtained as compared to treatment without 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the clinical benefit rate is at least about 30%. In some embodiments, the sample is a tissue or bodily fluid sample. In some embodiments, the sample is a tumor sample, a blood sample, a blood plasma sample, a peritoneal fluid sample, an exudate or an effusion. In some embodiments, the ovarian cancer is a metastatic ovarian cancer. In some embodiments, the BRCA gene is BRCA-1. In other embodiments, the BRCA gene is BRCA-2. In some embodiments, the BRCA gene is BRCA-1 and BRCA-2. In other embodiments, the deficiency is a genetic defect in the BRCA gene. In some
embodiments, the genetic defect is a mutation, insertion, substitution, duplication or deletion of the BRCA gene. [0046] In some embodiments of any of the methods described herein, 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof may be capable of being present in a variety of physical forms— e.g., free base, salts (especially pharmaceutically acceptable salts), hydrates, polymorphs, solvates, etc. Unless otherwise qualified herein, use of a chemical name is intended to encompass all physical forms of the named chemical. For example, recitation of 4-iodo-3-nitrobenzamide, without further qualification, is intended to generically encompass the free base as well as all
pharmaceutically acceptable salts, polymorphs, hydrates, etc. Where it is intended to limit the disclosure or claims to a particular physical form of a compound, this will be clear from the context of the passage or claim in which the reference to the compound appears.
[0047] In some embodiments of any of the methods described herein, a platinum compound (e.g., carboplatin) is administered as an intravenous infusion. In some
embodiments, 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered orally or as a parenteral injection or infusion, or inhalation. In some embodiments, an anti-metabolite (e.g., gemcitabine) is administered as an intravenous infusion.
[0048] In some embodiments of any of the methods described herein, the method comprises treating a patient with at least three chemically distinct substances, one of which is anti-metabolite (e.g. gemcitabine), one of which is a platinum-containing complex (e.g., carboplatin or cisplatin) and 4-iodo-3-nitrobenzamide or a metabolite thereof or a
pharmaceutically acceptable salt thereof. In some embodiments, one or more of these substances may be capable of being present in a variety of physical forms— e.g., free base, salts (especially pharmaceutically acceptable salts), hydrates, polymorphs, solvates, or metabolites, etc. Unless otherwise qualified herein, use of a chemical name is intended to encompass all physical forms of the named chemical. For example, recitation of 4-iodo-3- nitrobenzamide, without further qualification, is intended to generically encompass the free base as well as all pharmaceutically acceptable salts, polymorphs, hydrates, and metabolites thereof. Where it is intended to limit the disclosure or claims to a particular physical form of a compound, this will be clear from the context of the passage or claim in which the reference to the compound appears.
[0049] Also provided herein are uses of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, in combination with (ii) any one of the antimetabolites, a pharmaceutically acceptable salt or solvate thereof and with (iii) any one of the platinum compounds described herein, a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment or prevention of platinum-resistant recurrent ovarian cancer as described herein. Also provided herein are uses of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prevention of platinum-resistant recurrent ovarian cancer as described herein in combination with an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin). Also provided herein are uses of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a
pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prevention of platinum-resistant recurrent ovarian cancer in a patient as described herein, wherein 4-iodo-3-nitrobenzamide, a metabolite thereof, or a
pharmaceutically acceptable salt or solvate thereof is to be administered to the patient in combination with an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin).
[0050] Also provided herein are uses of any of the pharmaceutical compositions described herein for the manufacture of a medicament for treating platinum-resistant recurrent ovarian cancer. For example, the use as provided herein is with respect to or in accordance with any of the methods described herein.
Anti-tumor agents
[0051] In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) antimetabolite such as gemcitabine; and (iii) a platinum
compound such as carboplatin, in combination with an additional anti-tumor agent. Antitumor agents that may be used in the present invention include but are not limited to antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum-complex compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors, anti-tumor viral agent, monoclonal antibodies, interferons, biological response modifiers, and other agents that exhibit anti-tumor activities, or a pharmaceutically acceptable salt thereof. In some embodiments, (i) 4-iodo-3- nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) antimetabolite such as gemcitabine; and (iii) a platinum compound such as carboplatin are used in combination with an anti-angiogenic agent. In still other embodiments, (i) 4-iodo-3- nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) antimetabolite such as gemcitabine; and (iii) a platinum compound such as carboplatin are used in combination with a topoisomerase inhibitor such as irinotecan. In other
embodiments, (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) antimetabolite such as gemcitabine; and (iii) a platinum
compound such as carboplatin are used in combination with hormone therapy. In still other embodiments, (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) antimetabolite such as gemcitabine; and (iii) a platinum
compound such as carboplatin are used in combination with a growth factor receptor inhibitor including but not limited to EGFR or IGF1R inhibitor. In some embodiments, the ovarian cancer is a metastatic cancer.
[0052] In some embodiments of any of the methods provided herein, the anti-tumor agent is an alkylating agent. The term "alkylating agent" herein generally refers to an agent giving an alkyl group in the alkylation reaction in which a hydrogen atom of an organic compound is substituted with an alkyl group. Examples of anti-tumor alkylating agents include but are not limited to nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide or carmustine.
[0053] In some embodiments of any of the methods provided herein, the anti-tumor agent is an antimetabolite. The term "antimetabolite" used herein includes, in a broad sense, substances which disturb normal metabolism and substances which inhibit the electron transfer system to prevent the production of energy-rich intermediates, due to their structural or functional similarities to metabolites that are important for living organisms (such as vitamins, coenzymes, amino acids and saccharides). Examples of antimetabolites that have anti-tumor activities include but are not limited to methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-l, gemcitabine, fludarabine or pemetrexed disodium, and preferred are 5-fluorouracil, S-l, gemcitabine and the like.
[0054] In some embodiments of any of the methods provided herein, the anti-tumor agent is an antitumor antibiotic. Examples of antitumor antibiotics include but are not limited to actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimalamer, idarubicin, sirolimus or valrubicin.
[0055] In some embodiments of any of the methods provided herein, the anti-tumor agent is a plant-derived antitumor agent. Examples of plant-derived antitumor agents include but are not limited to vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel and vinorelbine, and preferred are docetaxel and paclitaxel.
[0056] In some embodiments of any of the methods provided herein, the anti-tumor agent is a camptothecin derivative that exhibits anti-tumor activities. Examples of anti-tumor camptothecin derivatives include but are not limited to camptothecin, 10- hydroxycamptothecin, topotecan, irinotecan or 9-aminocamptothecin, with camptothecin, topotecan and irinotecan being preferred. Further, irinotecan is metabolized in vivo and exhibits antitumor effect as SN-38. The action mechanism and the activity of the
camptothecin derivatives are believed to be virtually the same as those of camptothecin (e.g., Nitta, et al., Gan to Kagaku Ryoho, 14, 850-857 (1987)).
[0057] In some embodiments of any of the methods provided herein, the anti-tumor agent is an organoplatinum compound or a platinum coordination compound having antitumor activity. The terms "organoplatinum compound," "platinum compound," or "platinum complex" and the like as used herein refer to a platinum-containing compound which provides platinum in ion form. Preferred organoplatinum compounds include but are not limited to cisplatin; cis-diamminediaquoplatinum (Il)-ion; chloro(diethylenetriamine)- platinum (II) chloride; dichloro(ethylenediamine)-platinum (II); diammine(l,l- cyclobutanedicarboxylato) platinum (II) (carboplatin); spiroplatin; iproplatin; diammine(2- ethylmalonato)platinum (II); ethylenediaminemalonatoplatinum (II); aqua(l,2- diaminodicyclohexane)sulfatoplatinum (II); aqua(l,2- diaminodicyclohexane)malonatoplatinum (II) ; ( 1 ,2-diaminocyclohexane)malonatoplatinum (II); (4-carboxyphthalato)( 1,2-diaminocyclohexane) platinum (II); (1,2-diaminocyclohexane)- (isocitrato)platinum (II); (l,2-diaminocyclohexane)oxalatoplatinum (II); ormaplatin;
tetraplatin; carboplatin, nedaplatin and oxaliplatin, and preferred is carboplatin or oxaliplatin. Further, other antitumor organoplatinum compounds mentioned in the specification are known and are commercially available and/or producible by a person having ordinary skill in the art by conventional techniques.
[0058] In some embodiments of any of the methods provided herein, the anti-tumor agent is an antitumor tyrosine kinase inhibitor. The term "tyrosine kinase inhibitor" herein refers to a chemical substance inhibiting "tyrosine kinase" which transfers a λ-phosphate group of ATP to a hydroxyl group of a specific tyrosine in protein. Examples of anti-tumor tyrosine kinase inhibitors include but are not limited to gefitinib, imatinib, erlotinib, Sutent, Nexavar, Recentin, ABT-869, and Axitinib. [0059] In some embodiments of any of the methods provided herein, the anti-tumor agent is an antibody or a binding portion of an antibody that exhibits anti-tumor activity. In some embodiments, the anti-tumor agent is a monoclonal antibody. Examples thereof include but are not limited to abciximab, adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab, daclizumab, eculizumab, efalizumab, ibritumomab, tiuxetan, infliximab, muromonab-CD3, natalizumab, omalizumab, palivizumab, panitumumab, ranibizumab, gemtuzumab ozogamicin, rituximab, tositumomab, trastuzumab, or any antibody fragments specific for antigens.
[0060] In some embodiments of any of the methods provided herein, the anti-tumor agent is an interferon. Such interferon has antitumor activity, and it is a glycoprotein which is produced and secreted by most animal cells upon viral infection. It has not only the effect of inhibiting viral growth but also various immune effector mechanisms including inhibition of growth of cells (in particular, tumor cells) and enhancement of the natural killer cell activity, thus being designated as one type of cytokine. Examples of anti-tumor interferons include but are not limited to interferon a, interferon a -2a, interferon a- 2b, interferon β, interferon γ-la and interferon γ-ηΐ.
[0061] In some embodiments of any of the methods provided herein, the anti-tumor agent is a biological response modifier. It is generally the generic term for substances or drugs for modifying the defense mechanisms of living organisms or biological responses such as survival, growth or differentiation of tissue cells in order to direct them to be useful against tumor, infection or other diseases. Examples of the biological response modifier include but are not limited to krestin, lentinan, sizofiran, picibanil and ubenimex.
[0062] In some embodiments of any of the methods provided herein, the anti-tumor agents include but are not limited to mitoxantrone, L-asparaginase, procarbazine,
dacarbazine, hydroxycarbamide, pentostatin, tretinoin, alefacept, darbepoetin alfa, anastrozole, exemestane, bicalutamide, leuprorelin, flutamide, fulvestrant, pegaptanib octasodium, denileukin diftitox, aldesleukin, thyrotropin alfa, arsenic trioxide, bortezomib, capecitabine, and goserelin.
[0063] The above-described terms "antitumor alkylating agent", "antitumor
antimetabolite", "antitumor antibiotic", "plant-derived antitumor agent", "antitumor platinum coordination compound", "antitumor camptothecin derivative", "antitumor tyrosine kinase inhibitor", "monoclonal antibody", "interferon", "biological response modifier" and "other antitumor agent" are all known and are either commercially available or producible by a person skilled in the art by methods known per se or by well-known or conventional methods. The process for preparation of gefitinib is described, for example, in U.S. Pat. No. 5,770,599; the process for preparation of cetuximab is described, for example, in WO 96/40210; the process for preparation of bevacizumab is described, for example, in WO 94/10202; the process for preparation of oxaliplatin is described, for example, in U.S. Pat. Nos. 5,420,319 and 5,959,133; the process for preparation of gemcitabine is described, for example, in U.S. Pat. Nos. 5,434,254 and 5,223,608; and the process for preparation of camptothecin is described in U.S. Pat. Nos. 5,162,532, 5,247,089, 5,191,082, 5,200,524, 5,243,050 and 5,321,140; the process for preparation of irinotecan is described, for example, in U.S. Pat. No. 4,604,463; the process for preparation of topotecan is described, for example, in U.S. Pat. No. 5,734,056; the process for preparation of temozolomide is described, for example, in JP- B No. 4-5029; and the process for preparation of rituximab is described, for example, in JP- W No. 2-503143.
[0064] The above-mentioned antitumor alkylating agents are commercially available, as exemplified by the following: nitrogen mustard N-oxide from Mitsubishi Pharma Corp. as Nitrorin (tradename); cyclophosphamide from Shionogi & Co., Ltd. as Endoxan (tradename); ifosfamide from Shionogi & Co., Ltd. as Ifomide (tradename); melphalan from
GlaxoSmithKline Corp. as Alkeran (tradename); busulfan from Takeda Pharmaceutical Co., Ltd. as Mablin (tradename); mitobronitol from Kyorin Pharmaceutical Co., Ltd. as Myebrol (tradename); carboquone from Sankyo Co., Ltd. as Esquinon (tradename); thiotepa from Sumitomo Pharmaceutical Co., Ltd. as Tespamin (tradename); ranimustine from Mitsubishi Pharma Corp. as Cymerin (tradename); nimustine from Sankyo Co., Ltd. as Nidran
(tradename); temozolomide from Schering Corp. as Temodar (tradename); and carmustine from Guilford Pharmaceuticals Inc. as Gliadel Wafer (tradename).
[0065] The above-mentioned antitumor antimetabolites are commercially available, as exemplified by the following: methotrexate from Takeda Pharmaceutical Co., Ltd. as
Methotrexate (tradename); 6-mercaptopurine riboside from Aventis Corp. as Thioinosine (tradename); mercaptopurine from Takeda Pharmaceutical Co., Ltd. as Leukerin (tradename); 5-fluorouracil from Kyowa Hakko Kogyo Co., Ltd. as 5-FU (tradename); tegafur from Taiho Pharmaceutical Co., Ltd. as Futraful (tradename); doxyfluridine from Nippon Roche Co., Ltd. as Furutulon (tradename); carmofur from Yamanouchi Pharmaceutical Co., Ltd. as Yamafur (tradename); cytarabine from Nippon Shinyaku Co., Ltd. as Cylocide (tradename); cytarabine ocfosfate from Nippon Kayaku Co., Ltd. as Strasid(tradename); enocitabine from Asahi Kasei Corp. as Sanrabin (tradename); S-1 from Taiho Pharmaceutical Co., Ltd. as TS-1 (tradename); gemcitabine from Eli Lilly & Co. as Gemzar (tradename); fludarabine from Nippon Schering Co., Ltd. as Fludara (tradename); and pemetrexed disodium from Eli Lilly & Co. as Alimta (tradename).
[0066] The above-mentioned antitumor antibiotics are commercially available, as exemplified by the following: actinomycin D from Banyu Pharmaceutical Co., Ltd. as Cosmegen (tradename); doxorubicin from Kyowa Hakko Kogyo Co., Ltd. as adriamycin (tradename); daunorubicin from Meiji Seika Kaisha Ltd. as Daunomycin; neocarzino statin from Yamanouchi Pharmaceutical Co., Ltd. as Neocarzinostatin (tradename); bleomycin from Nippon Kayaku Co., Ltd. as Bleo (tradename); pepromycin from Nippon Kayaku Co, Ltd. as Pepro (tradename); mitomycin C from Kyowa Hakko Kogyo Co., Ltd. as Mitomycin (tradename); aclarubicin from Yamanouchi Pharmaceutical Co., Ltd. as Aclacinon
(tradename); pirarubicin from Nippon Kayaku Co., Ltd. as Pinorubicin (tradename);
epirubicin from Pharmacia Corp. as Pharmorubicin (tradename); zinostatin stimalamer from Yamanouchi Pharmaceutical Co., Ltd. as Smancs (tradename); idarubicin from Pharmacia Corp. as Idamycin (tradename); sirolimus from Wyeth Corp. as Rapamune (tradename); and valrubicin from Anthra Pharmaceuticals Inc. as Valstar (tradename).
[0067] The above-mentioned plant-derived antitumor agents are commercially available, as exemplified by the following: vincristine from Shionogi & Co., Ltd. as Oncovin
(tradename); vinblastine from Kyorin Pharmaceutical Co., Ltd. as Vinblastine (tradename); vindesine from Shionogi & Co., Ltd. as Fildesin (tradename); etoposide from Nippon Kayaku Co., Ltd. as Lastet (tradename); sobuzoxane from Zenyaku Kogyo Co., Ltd. as Perazolin (tradename); docetaxel from Aventis Corp. as Taxotere (tradename); paclitaxel from Bristol- Myers Squibb Co. as Taxol (tradename); and vinorelbine from Kyowa Hakko Kogyo Co., Ltd. as Navelbine (tradename).
[0068] The above-mentioned antitumor platinum coordination compounds are commercially available, as exemplified by the following: cisplatin from Nippon Kayaku Co., Ltd. as Randa (tradename); carboplatin from Bristol-Myers Squibb Co. as Paraplatin
(tradename); nedaplatin from Shionogi & Co., Ltd. as Aqupla (tradename); and oxaliplatin from Sanofi-Synthelabo Co. as Eloxatin (tradename).
[0069] The above-mentioned antitumor camptothecin derivatives are commercially available, as exemplified by the following: irinotecan from Yakult Honsha Co., Ltd. as Campto (tradename); topotecan from GlaxoSmithKline Corp. as Hycamtin (tradename); and camptothecin from Aldrich Chemical Co., Inc., U.S.A.
[0070] The above-mentioned antitumor tyrosine kinase inhibitors are commercially available, as exemplified by the following: gefitinib from AstraZeneca Corp. as Iressa (tradename); imatinib from Novartis AG as Gleevec (tradename); and erlotinib from OSI Pharmaceuticals Inc. as Tarceva (tradename).
[0071] The above-mentioned monoclonal antibodies are commercially available, as exemplified by the following: cetuximab from Bristol-Myers Squibb Co. as Erbitux
(tradename); bevacizumab from Genentech, Inc. as Avastin (tradename); rituximab from Biogen Idee Inc. as Rituxan (tradename); alemtuzumab from Berlex Inc. as Campath
(tradename); and trastuzumab from Chugai Pharmaceutical Co., Ltd. as Herceptin
(tradename).
[0072] The above-mentioned interferons are commercially available, as exemplified by the following: interferon a from Sumitomo Pharmaceutical Co., Ltd. as Sumiferon
(tradename); interferon a-2a from Takeda Pharmaceutical Co., Ltd. as Canferon-A
(tradename); interferon a-2b from Schering-Plough Corp. as Intron A (tradename); interferon β from Mochida Pharmaceutical Co., Ltd. as IFN.beta. (tradename); interferon γ-la from Shionogi & Co., Ltd. as Imunomax-γ (tradename); and interferon γ-ηΐ from Otsuka
Pharmaceutical Co., Ltd. as Ogamma (tradename).
[0073] The above-mentioned biological response modifiers are commercially available, as exemplified by the following: krestin from Sankyo Co., Ltd. as krestin (tradename);
lentinan from Aventis Corp. as Lentinan (tradename); sizofiran from Kaken Seiyaku Co., Ltd. as Sonifiran (tradename); picibanil from Chugai Pharmaceutical Co., Ltd. as Picibanil (tradename); and ubenimex from Nippon Kayaku Co., Ltd. as Bestatin (tradename).
[0074] The above-mentioned other antitumor agents are commercially available, as exemplified by the following: mitoxantrone from Wyeth Lederle Japan, Ltd. as Novantrone (tradename); L-asparaginase from Kyowa Hakko Kogyo Co., Ltd. as Leunase (tradename); procarbazine from Nippon Roche Co., Ltd. as Natulan (tradename); dacarbazine from Kyowa Hakko Kogyo Co., Ltd. as Dacarbazine (tradename); hydroxycarbamide from Bristol-Myers Squibb Co. as Hydrea (tradename); pentostatin from Kagaku Oyobi Kessei Ryoho
Kenkyusho as Coforin (tradename); tretinoin from Nippon Roche Co., Ltd. As Vesanoid (tradename); alefacept from Biogen Idee Inc. as Amevive (tradename); darbepoetin alfa from Amgen Inc. as Aranesp (tradename); anastrozole from AstraZeneca Corp. as Arimidex (tradename); exemestane from Pfizer Inc. as Aromasin (tradename); bicalutamide from AstraZeneca Corp. as Casodex (tradename); leuprorelin from Takeda Pharmaceutical Co., Ltd. as Leuplin (tradename); flutamide from Schering-Plough Corp. as Eulexin (tradename); fulvestrant from AstraZeneca Corp. as Faslodex (tradename); pegaptanib octasodium from Gilead Sciences, Inc. as Macugen (tradename); denileukin diftitox from Ligand Pharmaceuticals Inc. as Ontak (tradename); aldesleukin from Chiron Corp. as Proleukin (tradename); thyrotropin alfa from Genzyme Corp. as Thyrogen (tradename); arsenic trioxide from Cell Therapeutics, Inc. as Trisenox (tradename); bortezomib from Millennium
Pharmaceuticals, Inc. as Velcade (tradename); capecitabine from Hoffmann-La Roche, Ltd. as Xeloda (tradename); and goserelin from AstraZeneca Corp. as Zoladex (tradename). The term "antitumor agent" as used in the specification includes the above-described antitumor alkylating agent, antitumor antimetabolite, antitumor antibiotic, plant-derived antitumor agent, antitumor platinum coordination compound, antitumor camptothecin derivative, antitumor tyrosine kinase inhibitor, monoclonal antibody, interferon, biological response modifier, and other antitumor agents.
[0075] Other anti-tumor agents or anti-neoplastic agents can be used in combination with benzopyrone compounds. Such suitable anti-tumor agents or anti-neoplastic agents include, but are not limited to, 13-cis-Retinoic Acid, 2-CdA, 2-Chlorodeoxyadenosine, 5-Azacitidine, 5-Fluorouracil, 5-FU, 6-Mercaptopurine, 6-MP, 6-TG, 6-Thioguanine, Abraxane, Accutane, Actinomycin-D, Adriamycin, Adrucil, Agrylin, Ala-Cort, Aldesleukin, Alemtuzumab, ALIMTA, Alitretinoin, Alkaban-AQ, Alkeran, All-transretinoic Acid, Alpha Interferon, Altretamine, Amethopterin, Amifostine, Aminoglutethimide, Anagrelide, Anandron,
Anastrozole, Arabinosylcytosine, Ara-C, Aranesp, Aredia, Arimidex, Aromasin, Arranon, Arsenic Trioxide, Asparaginase, ATRA, Avastin, Azacitidine, BCG, BCNU, Bendamustine, Bevacizumab, Bexarotene, BEXXAR, Bicalutamide, BiCNU, Blenoxane, Bleomycin, Bortezomib, Busulfan, Busulfex, C225, Calcium Leucovorin, Campath, Camptosar,
Camptothecin- 11, Capecitabine, Carac, Carboplatin, Carmustine, Carmustine Wafer,
Casodex, CC-5013, CCI-779, CCNU, CDDP, CeeNU, Cerubidine, Cetuximab,
Chlorambucil, Cisplatin, Citrovorum Factor, Cladribine, Cortisone, Cosmegen, CPT-11, Cyclophosphamide, Cytadren, Cytarabine, Cytarabine Liposomal, Cytosar-U, Cytoxan, Dacarbazine, Dacogen, Dactinomycin, Darbepoetin Alfa, Dasatinib, Daunomycin,
Daunorubicin, Daunorubicin Hydrochloride, Daunorubicin Liposomal, DaunoXome, Decadron, Decitabine, Delta-Cortef, Deltasone, Denileukin Diftitox, DepoCyt™,
Dexamethasone, Dexamethasone Acetate, Dexamethasone Sodium Phosphate, Dexasone, Dexrazoxane, DHAD, DIC, Diodex, Docetaxel, Doxil, Doxorubicin, Doxorubicin Liposomal, Droxia™, DTIC, DTIC-Dome, Duralone, Efudex, Eligard, Ellence, Eloxatin, Elspar, Emcyt, Epirubicin, Epoetin Alfa, Erbitux, Erlotinib, Erwinia L-asparaginase, Estramustine, Ethyol, Etopophos, Etoposide, Etoposide Phosphate, Eulexin, Evista, Exemestane, Fareston,
Faslodex, Femara, Filgrastim, Floxuridine, Fludara, Fludarabine, Fluoroplex, Fluorouracil, Fluorouracil (cream), Fluoxymesterone, Flutamide, Folinic Acid, FUDR , Fulvestrant, G- CSF, Gefitinib, Gemcitabine, Gemtuzumab ozogamicin, Gemzar & Gemzar Side Effects - Chemotherapy Drugs, Gleevec, Gliadel Wafer, GM-CSF, Goserelin, Granulocyte - Colony Stimulating Factor, Granulocyte Macrophage Colony Stimulating Factor, Halotestin,
Herceptin, Hexadrol, Hexalen, Hexamethylmelamine, HMM, Hycamtin, Hydrea, Hydrocort Acetate, Hydrocortisone, Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium
Succinate, Hydrocortone Phosphate, Hydroxyurea, Ibritumomab, Ibritumomab Tiuxetan, Idamycin, Idarubicin, Ifex , IFN-alpha, Ifosfamide, IL-11, IL-2, Imatinib mesylate, Imidazole Carboxamide, Interferon alfa, Interferon Alfa-2b (PEG Conjugate), Interleukin - 2,
Interleukin-11, Intron A (interferon alfa-2b), Iressa, Irinotecan, Isotretinoin, Ixabepilone, Ixempra, Kidrolase (t), Lanacort, Lapatinib, L-asparaginase, LCR, Lenalidomide, Letrozole, Leucovorin, Leukeran, Leukine, Leuprolide, Leurocristine, Leustatin, Liposomal Ara-C, Liquid Pred, Lomustine, L-PAM, L-Sarcolysin, Lupron, Lupron Depot, Matulane, Maxidex, Mechlorethamine, Mechlorethamine Hydrochloride, Medralone, Medrol, Megace, Megestrol, Megestrol Acetate, Melphalan, Mercaptopurine, Mesna, Mesnex, Methotrexate, Methotrexate Sodium, Methylprednisolone, Meticorten, Mitomycin, Mitomycin-C, Mitoxantrone, M- Prednisol, MTC, MTX, Mustargen, Mustine, Mutamycin, Myleran, Mylocel, Mylotarg, Navelbine, Nelarabine, Neosar, Neulasta, Neumega, Neupogen, Nexavar, Nilandron,
Nilutamide, Nipent, Nitrogen Mustard, Novaldex, Novantrone, Octreotide, Octreotide acetate, Oncospar, Oncovin, Ontak, Onxal, Oprevelkin, Orapred, Orasone, Oxaliplatin, Paclitaxel, Paclitaxel Protein-bound, Pamidronate, Panitumumab, Panretin, Paraplatin, Pediapred, PEG Interferon, Pegaspargase, Pegfilgrastim, PEG-INTRON, PEG-L- asparaginase, PEMETREXED, Pentostatin, Phenylalanine Mustard, Platinol, Platinol-AQ, Prednisolone, Prednisone, Prelone, Procarbazine, PROCRIT, Proleukin, Prolifeprospan 20 with Carmustine Implant, Purinethol, Raloxifene, Revlimid, Rheumatrex, Rituxan,
Rituximab, Roferon-A (Interferon Alfa-2a), Rubex, Rubidomycin hydrochloride, Sandostatin, Sandostatin LAR, Sargramostim, Solu-Cortef, Solu-Medrol, Sorafenib, SPRYCEL, STI-571, Streptozocin, SU11248, Sunitinib, Sutent, Tamoxifen, Tarceva, Targretin, Taxol, Taxotere, Temodar, Temozolomide, Temsirolimus, Teniposide, TESPA, Thalidomide, Thalomid, TheraCys, Thioguanine, Thioguanine Tabloid, Thiophosphoamide, Thioplex, Thiotepa, TICE, Toposar, Topotecan, Toremifene, Torisel, Tositumomab, Trastuzumab, Tretinoin, Trexall™, Trisenox, TSPA, TYKERB, VCR, Vectibix, Vectibix, Velban, Velcade, VePesid, Vesanoid, Viadur, Vidaza, Vinblastine, Vinblastine Sulfate, Vincasar Pfs, Vincristine, Vinorelbine, Vinorelbine tartrate, VLB, VM-26, Vorinostat, VP- 16, Vumon, Xeloda, Zanosar, Zevalin, Zinecard, Zoladex, Zoledronic acid, Zolinza, Zometa.
Antimetabolites
[0076] Antimetabolites are drugs that interfere with normal cellular metabolic processes. Since cancer cells are rapidly replicating, interference with cellular metabolism affects cancer cells to a greater extent than host cells. An antimetabolite such as gemcitabine may be used in any one of the methods provided herein, for example, gemcitabine may be used in combination with 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) and a platinum compound such as carboplatin in treating platinum- resistant recurrent ovarian cancer in accordance with the present disclosure.
[0077] Gemcitabine has the following structure:
Figure imgf000030_0001
Gemcitabine
[0078] Gemcitabine is available, for example, as GEMZAR® from Eli Lilly and
Company. Gemcitabine used herein also includes any pharmaceutically acceptable salt form (e.g., gemcitabine HC1 or other salt forms). Gemcitabine (also known as 4-amino-l- [(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]pyrimidin- 2(lH)-one or 2'-deoxy-2',2'-difluorocytidine) is a nucleoside analog, which, for example, interferes with cellular division by blocking DNA synthesis, thus resulting in cell death. The dosage of an antimetabolite such as gemcitabine may be adjusted to a particular patient. In adults, the dosage of gemcitabine, when used in combination with 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) and a platinum compound such as carboplatin in any of the methods provided herein, may be in the range of about 100 mg/m2 to about 5000 mg/m2, about 100 mg/m2 to about 2000 mg/m2, about 200 to about 4000 mg/m2, about 300 to about 3000 mg/m2, about 400 to about 2000 mg/m2, about 500 to about 1500 mg/m2, about 750 to about 1500 mg/m2, about 800 to about 1500 mg/m2, about 900 to about 1400 mg/m2, about 900 to about 1250 mg/m2, about 1000 to about 1500 mg/m 2 , about 1000 mg/m 2 , about 1050 mg/m 2 , about 1100 mg/m 2 , about 1150 mg/m 2 , about 1200 mg/m2, about 1250 mg/m2, about 1300 mg/m2, about 1350 mg/m2, about 1400 mg/m2, about 1450 mg/m 2 , or about 1500 mg/m 2. The dimensions mg/m 2 refer to the amount of gemcitabine in milligrams (mg) per unit surface area of the patient in square meters (m ). Gemcitabine may be administered by intravenous (IV) infusion, e.g., over a period of about 10 to about 300 minutes, about 15 to about 180 minutes, about 20 to about 60 minutes, about 10 minutes, about 20 minutes, or about 30 minutes. The term "about" in this context indicates the normal usage of approximately; and in some embodiments indicates a tolerance of + 10% or + 5%.
Taxanes
[0079] Taxanes are drugs that are derived from the twigs, needles and bark of Pacific yew tress, Taxus brevifolia. In particular paclitaxel may be derived from 10-deacetylbaccatin through known synthetic methods. Taxanes such as paclitaxel and its derivative docetaxel have demonstrated antitumor activity in a variety of tumor types. The taxanes interfere with normal function of microtubule growth by hyperstabilizing their structure, thereby destroying the cell's ability to use its cytoskeleton in a normal manner. Specifically, the taxanes bind to the β subunit of tubulin, which is the building block of microtubules. The resulting taxane/tubulin complex cannot disassemble, which results in aberrant cell function and eventual cell death. Paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis-inhibiting protein called Bcl-2 (B-cell leukemia 2), thereby preventing Bcl-2 from inhibiting apoptosis. Thus paclitaxel has proven to be an effective treatment for various cancers, as it down-regulates cell division by interrupting normal cytoskeletal rearrangement during cell division and it induces apoptosis via the anti-Bcl-2 mechanism.
[0080] In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin in combination with a taxane (e.g., paclitaxel, docetaxel, or Abraxane). The dosage of taxane such as paclitaxel may vary depending upon the height, weight, physical condition, tumor size and progression state, etc. In some embodiments, the dosage of taxane such as paclitaxel will be in the range of about 10 to about 2000 mg/m 2 , about 10 to about 200 mg/m 2 or about 100 to about 175 mg/m 2. In some embodiments, the taxane such as paclitaxel will be administered over a period of up to about 10 hours, up to about 8 hours or up to about 6 hours. The term "about" in this context indicates the normal usage of approximately; and in some embodiments indicates a tolerance of + 10% or + 5%.
[0081] Examples of taxanes include but are not limited to docetaxel, paclitaxel, and Abraxane.
Platinum complexes
[0082] Platinum complexes are pharmaceutical agents or pharmaceutical compositions used to treat cancer, which contain at least one platinum center complexed with at least one organic group. Platinum complexes include, for example, carboplatin, cisplatin, and oxaliplatin. "Platinum complex" and "platinum agent" are used interchangeably. A platinum complex (or platinum compound) such as carboplatin may be used in any one of the methods provided herein, for example, carboplatin may be used in combination with 4-iodo-3- nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) and an antimetabolite such as gemcitabine in treating platinum-resistant recurrent ovarian cancer in accordance with the present disclosure.
[0083] Carboplatin has the following structure:
0
Figure imgf000032_0001
[0084] Carboplatin is available, for example, from Bedford Laboratories. Carboplatin, also known as cis-Diammine(l,l-cyclobutanedicarboxylato)platinum(II), is a platinum complex (or platinum compound), which is also marketed under the brand names Paraplatin® and Paraplatin-AQ. Carboplatin used herein also includes any pharmaceutically acceptable salt form. The dosage of a platinum compound such as carboplatin may be adjusted to a particular patient. The dosage of a platinum compound, e.g., carboplatin, is determined by calculating the area under the blood plasma concentration versus time curve (AUC) in mg/mL»minute by methods known to those skilled in the cancer chemotherapy art, taking into account the patient' s renal activity estimated by measuring creatinine clearance or glomerular filtration rate. In some embodiments, the dosage of a platinum complex such as carboplatin used in combination with an antimetabolite (e.g., gemcitabine) and 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) is calculated to provide an AUC of about 0.1-8 mg/ml»min, about 0.1-7 mg/ml»min, about 0.1-6 mg/ml»min, about 1- 6 mg/ml»min, about 1-5 mg/ml»min, about 2-5 mg/ml»min, about 3-6 mg/ml»min, about 3-5 mg/ml»min, about 1-3 mg/ml»min, about 1.5 to about 2.5 mg/ml»min, about 1.75 to about 2.25 mg/ml»min, about 2 mg/ml»min (AUC 2, for example, is shorthand for 2 mg/ml»minute), about AUC 2.5, about AUC 3, about AUC3.5, about AUC 4, about AUC 4.5, about AUC 5, about AUC 5.5, or about AUC 6. Alternatively, the dosage of platinum compound, e.g., carboplatin, is calculated based on the patient's body surface area. In some embodiments, a suitable dose of carboplatin is about 10 to about 400 mg/m 2 , e.g., about 360 mg/m 2. Platinum complexes, such as carboplatin, are normally administered intravenously (IV) over a period of about 10 to about 300 minutes, about 30 to about 180 minutes, about 45 to about 120 minutes or about 60 minutes. In this context, the term "about" has its normal meaning of approximately. In some embodiments, about means +10% or ±5%.
Topoisomerase inhibitors
[0085] Any of the methods provided herein may further comprise a topoisomerase inhibitor. Topoisomerase inhibitors are agents designed to interfere with the action of topoisomerase enzymes (topoisomerase I and II), which are enzymes that control the changes in DNA structure by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle. Topoisomerases have become popular targets for cancer chemotherapy treatments. It is thought that topoisomerase inhibitors block the ligation step of the cell cycle, generating single and double stranded breaks that harm the integrity of the genome. Introduction of these breaks subsequently lead to apoptosis and cell death.
Topoisomerase inhibitors are often divided according to which type of enzyme it inhibits. Topoisomerase I, the type of topoisomerase most often found in eukaryotes, is targeted by topotecan, irinotecan, lurtotecan and exatecan, each of which is commercially available. Topotecan is available from GlaxoSmithKline under the trade name Hycamtim®. Irinotecan is available from Pfizer under the trade name Camptosar®. Lurtotecan may be obtained as a liposomal formulation from Gilead Sciences Inc. Topoisomerase inhibitors may be administered at an effective dose. In some embodiments an effective dose for treatment of a human will be in the range of about 0.01 to about 10 mg/m /day. The treatment may be repeated on a daily, bi-weekly, semi-weekly, weekly, or monthly basis. In some
embodiments, a treatment period may be followed by a rest period of from one day to several days, or from one to several weeks. In some embodiments, (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and/or (iii) carboplatin and the topoisomerase inhibitor may be dosed on the same day or may be dosed on separate days.
[0086] Compounds that target type II topoisomerase are split into two main classes: topoisomerase poisons, which target the topoisomerase-DNA complex, and topoisomerase inhibitors, which disrupt catalytic turnover. Topo II poisons include but are not limited to eukaryotic type II topoisomerase inhibitors (topo II): amsacrine, etoposide, etoposide phosphate, teniposide, amrubicin and doxorubicin. These drugs are anti-cancer therapies. Examples of topoisomerase inhibitors include ICRF-193. These inhibitors target the N- terminal ATPase domain of topo II and prevent topo II from turning over. The structure of this compound bound to the ATPase domain has been solved by Classen (Proceedings of the National Academy of Science, 2004) showing that the drug binds in a non-competitive manner and locks down the dimerization of the ATPase domain.
Anti-angiogenic agents
[0087] Any of the methods provided herein may further comprise an anti-angiogenic agent. An angiogenesis inhibitor is a substance that inhibits angiogenesis (the growth of new blood vessels). Every solid tumor (in contrast to leukemia) needs to generate blood vessels to keep it alive once it reaches a certain size. Tumors can grow only if they form new blood vessels. Usually, blood vessels are not built elsewhere in an adult body unless tissue repair is actively in process. The angiostatic agent endostatin and related chemicals can suppress the building of blood vessels, preventing the cancer from growing indefinitely. In tests with patients, the tumor became inactive and stayed that way even after the endostatin treatment is finished. The treatment has very few side effects but appears to have very limited selectivity. Other angiostatic agents such as thalidomide and natural plant-based substances are being actively investigated.
[0088] Known inhibitors include the drug bevacizumab (Avastin), which binds vascular endothelial growth factor (VEGF), inhibiting its binding to the receptors that promote angiogenesis. Other anti-angiogenic agents include but are not limited to
carboxyamidotriazole, TNF-470, CM101, IFN-alpha, IL-12, platelet factor-4, suramin, SU5416, thrombospondin, angiostatic steroids + heparin, cartilage-derived angiogenesis inhibitory factor, matrix metalloproteinase inhibitors, angiostatin, endostatin, 2- methoxyestradiol, tecogalan, thrombospondin, prolactin, αγβ3 inhibitors and linomide. Her-2 targeted therapy
[0089] Any of the methods provided herein may further comprise Herceptin in treating platinum-resistant recurrent ovarian cancer (e.g., HER2-positive ovarian cancer). Her-2 overexpression has been found in ovarian carcinomas and HER2 overexpression and amplification is associated with advanced ovarian cancer (AOC) (Hellstrom et al., Cancer Research 61, 2420-2423, March 15, 2001). Herceptin may be used for the adjuvant treatment of HER2-overexpressing ovarian cancers. Herceptin can be used several different ways: as part of a treatment regimen including doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; with docetaxel and carboplatin; or as a single agent following multi-modality anthracycline-based therapy. Herceptin in combination with paclitaxel is approved for the first-line treatment of HER2-overexpressing ovarian cancer. Herceptin as a single agent is approved for treatment of HER2-overexpressing ovarian cancer in patients who have received one or more chemotherapy regimens for metastatic disease.
[0090] Lapatinib or lapatinib ditosylate is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer. During development it was known as small molecule GW572016. Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as topotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by preventing them from dividing. Giving lapatinib together with topotecan may have enhanced anti-tumor efficacy.
Hormone therapy
[0091] Any of the methods provided herein may further comprise a hormone therapy. For example, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administration to the patient an effective amount of: (i) 4-iodo-3- nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, in combination with a hormone therapy.
Tamoxifen-Hormone antagonist
[0092] Any of the methods provided herein may further comprise tamoxifen. Tamoxifen (marketed as Nolvadex) slows or stops the growth of cancer cells present in the body.
Tamoxifen is a type of drug called a selective estrogen-receptor modulator (SERM). It functions as an anti-estrogen. As tamoxifen may have stabilized rapidly advancing recurrent ovarian cancer, its role in the primary treatment of ovarian cancer in combination with cytotoxic chemotherapy should be considered. [0093] Any of the methods provided herein may further comprise an aromatase inhibitor (e.g., steroidal or non-steroidal aromatase inhibitor). Aromatase inhibitors (AI) are a class of drugs used in the treatment of ovarian cancer in postmenopausal women that block the aromatase enzyme. Aromatase inhibitors lower the amount of estrogen in post-menopausal women who have hormone-receptor-positive ovarian cancer. With less estrogen in the body, the hormone receptors receive fewer growth signals, and cancer growth can be slowed down or stopped.
[0094] Aromatase inhibitor medications include Arimidex (chemical name: anastrozole), Aromasin (chemical name: exemestane), and Femara (chemical name: letrozole). Each is taken by pill once a day, for up to five years. But for women with advanced (metastatic) disease, the medicine is continued as long as it is working well.
[0095] AIs are categorized into two types: irreversible steroidal inhibitors such as exemestane that form a permanent bond with the aromatase enzyme complex; and nonsteroidal inhibitors (such as anastrozole, letrozole) that inhibit the enzyme by reversible competition.
[0096] Fulvestrant, also known as ICI 182,780, and "Faslodex" is a drug treatment of hormone receptor-positive ovarian cancer in postmenopausal women with disease progression following anti-estrogen therapy. Estrogen can cause the growth of ovarian epithelial cancer cells. Fulvestrant is an estrogen receptor antagonist with no agonist effects, which works both by down-regulating and by degrading the estrogen receptor. It is administered as a once-monthly injection.
Targeted therapy
[0097] Any of the methods provided herein may further comprise an inhibitor targeting a growth factor receptor including but not limited to epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R).
[0098] EGFR is overexpressed in the cells of certain types of human carcinomas including ovarian cancers. EGFR over-expression in ovarian cancer has been associated with poor prognosis. Increased expression of EGFR may contribute to a drug resistant phenotype. Examples of EGFR inhibitors include but are not limited to cetuximab, which is a chimeric monoclonal antibody given by intravenous injection for treatment of cancers including but not limited to metastatic colorectal cancer and head and neck cancer. Panitumimab is another example of EGFR inhibitor. It is a humanized monoclonal antibody against EGFR. Panitumimab has been shown to be beneficial and better than supportive care when used alone in patients with advanced colon cancer and is approved by the FDA for this use.
[0099] Activation of the type 1 insulin-like growth factor receptor (IGFIR) promotes proliferation and inhibits apoptosis in a variety of cell types. One example of an IGFIR inhibitor is CP-751871. CP-751871 is a human monoclonal antibody that selectively binds to IGFIR, preventing IGF1 from binding to the receptor and subsequent receptor
autophosphorylation. Inhibition of IGFIR autophosphorylation may result in a reduction in receptor expression on tumor cells that express IGFIR, a reduction in the anti-apoptotic effect of IGF, and inhibition of tumor growth. IGFIR is a receptor tyrosine kinase expressed on most tumor cells and is involved in mitogenesis, angiogenesis, and tumor cell survival.
PI3K/mTOR pathway
[0100] Any of the methods provided herein may further comprise an inhibitor of PI3K pathway and/or an inhibitor of mTOR. Phosphatidylinositol-3-kinase (PI3K) pathway deregulation is a common event in human cancer, either through inactivation of the tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 or activating mutations of pl l0-a. These hotspot mutations result in oncogenic activity of the enzyme and contribute to therapeutic resistance to the anti-HER2 antibody trastuzumab. Akt and mTOR phosphorylation is also frequently detected in ovarian cancer. The PI3K pathway is, therefore, an attractive target for cancer therapy. NVP-BEZ235, a dual inhibitor of the PI3K and the downstream mammalian target of rapamycin (mTOR) has been shown to have antiproliferative and antitumoral activity in cancer cells with both wild-type and mutated pl l0-a (Violeta Serra, et al., Cancer Research 68, 8022-8030, October 1, 2008).
Hsp90 inhibitors
[0101] Any of the methods provided herein may further comprise an Hsp90 inhibitor. These drugs target heat shock protein 90 (hsp90). Hsp90 is one of a class of chaperone proteins, whose normal job is to help other proteins acquire and maintain the shape required for those proteins to do their jobs. Chaperone proteins work by being in physical contact with other proteins. Hsp90 can also enable cancer cells to survive and even thrive despite genetic defects which would normally cause such cells to die. Thus, blocking the function of HSP90 and related chaperone proteins may cause cancer cells to die, especially if blocking chaperone function is combined with other strategies to block cancer cell survival. Tubulin inhibitors
[0102] Any of the methods provided herein may further comprise a tubulin inhibitor. Tubulins are the proteins that form microtubules, which are key components of the cellular cytoskeleton (structural network). Microtubules are necessary for cell division (mitosis), cell structure, transport, signaling and motility. Given their primary role in mitosis, microtubules have been an important target for anticancer drugs— often referred to as antimitotic drugs, tubulin inhibitors and microtubule targeting agents. These compounds bind to tubulin in microtubules and prevent cancer cell proliferation by interfering with the microtubule formation required for cell division. This interference blocks the cell cycle sequence, leading to apoptosis.
Apoptosis inhibitors
[0103] Any of the methods provided herein may further comprise an inhibitor of apoptosis. The inhibitors of apoptosis (IAP) are a family of functionally- and structurally- related proteins, originally characterized in Baculovirus, which serve as endogenous inhibitors of apoptosis. The human IAP family consists of at least 6 members, and IAP homologs have been identified in numerous organisms. 10058-F4 is a c-Myc inhibitor that induces cell-cycle arrest and apoptosis. It is a cell-permeable thiazolidinone that specifically inhibits the c-Myc-Max interaction and prevents transactivation of c-Myc target gene expression. 10058-F4 inhibits tumor cell growth in a c-Myc-dependent manner both in vitro and in vivo. BI-6C9 is a tBid inhibitor and antiapoptotic. GNF-2 belongs to a new class of Bcr-abl inhibitors. GNF-2 appears to bind to the myristoyl binding pocket, an allosteric site distant from the active site, stabilizing the inactive form of the kinase. It inhibits Bcr-abl phosphorylation with an IC50 of 267 nM, but does not inhibit a panel of 63 other kinases, including native c-Abl, and shows complete lack of toxicity towards cells not expressing Bcr- Abl. GNF-2 shows great potential for a new class of inhibitor to study Bcr-abl activity and to treat resistant Chronic myelogenous leukemia (CML), which is caused the Bcr- Abl oncoprotein. Pifithrin-a is a reversible inhibitor of p53-mediated apoptosis and p53- dependent gene transcription such as cyclin G, p21/wafl, and mdm2 expression. Pifithrin-a enhances cell survival after genotoxic stress such as UV irradiation and treatment with cytotoxic compounds including doxorubicin, etopoxide, paclitaxel, and cytosine-P-D- arabinofuranoside. Pifithrin-α protects mice from lethal whole body γ-irradiation without an increase in cancer incidence. 4-iodo-3-nitrobenzamide
[0104] 4-iodo-3-nitrobenzamide (BA) is a small molecule that acts on tumor cells without exerting toxic effects in normal cells. 4-iodo-3-nitrobenzamide is very lipophilic and distributes rapidly and widely into tissues, including the brain and cerebrospinal fluid (CSF). It is active against a broad range of cancer cells in vitro, including against drug resistant cell lines. The person skilled in the art will recognize that 4-iodo-3-nitrobenzamide may be administered in any pharmaceutically acceptable form, e.g., as a pharmaceutically acceptable salt, solvate, or complex. Additionally, as 4-iodo-3-nitrobenzamide is capable of
tautomerizing in solution, the tautomeric form of 4-iodo-3-nitrobenzamide is intended to be embraced by the term BA (or the equivalent 4-iodo-3-nitrobenzamide), along with the salts, solvates or complexes. In some embodiments, 4-iodo-3-nitrobenzamide may be administered in combination with a cyclodextrin, such as hydroxypropylbetacyclodextrin. However, one skilled in the art will recognize that other active and inactive agents may be combined with 4- iodo-3-nitrobenzamide; and recitation of 4-iodo-3-nitrobenzamide will, unless otherwise stated, include all pharmaceutically acceptable forms thereof.
[0105] The dosage of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof may vary depending upon the patient's age, height, weight, overall health, etc. In some embodiments, the dosage of 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) is in the range of any one of about 0.1 mg/kg to about 50 mg/kg, about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 50 mg/kg, about 1 mg/kg to about 25 mg/kg, about 2 to about 70 mg/kg, about 2 mg/kg to about 50 mg/kg, about 2 mg/kg to about 40 mg/kg, about 3 mg/kg to about 30 mg/kg, about 4 to about 100 mg, about 4 to about 25 mg/kg, about 4 to about 20 mg/kg, about 4 to about 15 mg/kg, about 5 to about 20 mg/kg, about 5 to about 15 mg/kg, about 50 to about 100 mg/kg or about 25 to about 75 mg/kg. In some embodiments, 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) is administered at about 1 mg/kg, about 2 mg/kg, about 4 mg/kg, about 5 mg/kg, about 5.6 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 11.2 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 75 mg/kg, or about 90 mg/kg. In some embodiments, 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) is administered at a dose of at least any of about 2 mg/kg, about 4 mg/kg, about 5 mg/kg, about 5.6 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 11.2 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 75 mg/kg, or about 90 mg/kg. 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) may be administered intravenously, e.g., by IV infusion over about 10 to about 300 minutes, about 30 to about 180 minutes, about 45 to about 120 minutes or about 60 minutes (i.e., about 1 hour). In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein 4- iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof is intravenously administered to the patient at about 5 to about 20 mg/kg or about 5 mg/kg to about 15 mg/kg. In some embodiments, 4-iodo-3-nitrobenzamide may alternatively be administered orally. In this context, the term "about" has its normal meaning of
approximately. In some embodiments, about means +20%, +10%, or +5%.
[0106] The synthesis of 4-iodo-3-nitrobenzamide is described in United States Patent No. 5,464,871, which is incorporated herein by reference in its entirety. 4-iodo-3-nitrobenzamide may be prepared in concentrations of 10 mg/mL and may be packaged in a convenient form, e.g., in 10 mL vials.
4-iodo-3-nitrobenzamide (BA) Metabolites
[0107] As used herein "BA" means 4-iodo-3-nitrobenzamide; "BNO" means 4-iodo-3- nitrosobenzamide; "BNHOH" means 4-iodo-3-hydroxyaminobenzamide.
[0108] Precursor compounds useful in the present invention are of Formula (la)
Figure imgf000040_0001
wherein R1 ; R2, R3, R4, and R5 are, independently selected from the group consisting of hydrogen, hydroxy, amino, nitro, iodo, (C -C6) alkyl, (C -C6) alkoxy, (C3 -C7) cycloalkyl, and phenyl, wherein at least two of the five R1 ; R2, R3, R4, and R5 substituents are always hydrogen, at least one of the five substituents are always nitro, and at least one substituent positioned adjacent to a nitro is always iodo, and pharmaceutically acceptable salts, solvates, isomers, tautomers, metabolites, analogs, or pro-drugs thereof. R1 ; R2, R3, R4, and R5 can also be a halide such as chloro, fluoro, or bromo substituents. In some embodiments, at least one of the R1 ; R2, R , R^, and R5 substituents is always nitro or nitroso and at least one substituent positioned adjacent to the nitro or nitroso is always iodo. In some embodiments, the compound of formula la is a compound of formula IA or a metabolite or pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof. In some embodiments, at least one of the R1 ; R2, R , Rj, and R5 substituents is always nitro or nitroso and at least one substituent positioned adjacent to the nitro or nitroso is always iodo. In some embodiments, the compound of formula la is a compound of formula IA or pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof.
[0109] 4-iodo-3-nitrobenazmide, also known as iniparib or "BA," has the formula:
Figure imgf000041_0001
4-iodo-3-nitrobenzamide
(BA)
[0110] Methods of making 4-iodo-3-nitrobenzamide are known to the field, such as the methods disclosed in U.S. Patent No. 5,464,871, which is hereby incorporated by reference in its entirety, particularly with respect to the synthetic methods disclosed therein. 4-iodo-3- nitrobenzamide may be prepared in concentrations of 10 mg/mL and may be packaged in a convenient form, e.g., in 10 mL vials.
[0111] In some embodiments of any one of the methods provided herein, 4-iodo-3- nitrobenazmide or a pharmaceutically acceptable salt thereof is administered. In some embodiments, a metabolite of 4-iodo-3-nitrobenazmide (e.g., BNO), or pharmaceutically acceptable salt thereof is administered.
[0112] Also provided herein are metabolites with the Formula (Ila):
Figure imgf000042_0001
wherein either: (1) at least one of R1; R2, R3, R4, and R5 substituent is always a sulfur- containing substituent, and the remaining substituents R1; R2, R3, Rj, and R5 are
independently selected from the group consisting of hydrogen, hydroxy, amino, nitro, iodo, bromo, fluoro, chloro, (Ci -C6) alkyl, (Ci -C6) alkoxy, (C3 -C7) cycloalkyl, and phenyl, wherein at least two of the five R1; R2, R3, R4, and R5 substituents are always hydrogen; or (2) at least one of R1; R2, R3, R4, and R5 substituents is not a sulfur-containing substituent and at least one of the five substituents R1; R2, R3, Rj, and R5 is always iodo, and wherein said iodo is always adjacent to a R1; R2, R3, R4, or R5 group that is either a nitro, a nitroso, a
hydroxyamino, hydroxy or an amino group; and pharmaceutically acceptable salts, solvates, isomers, tautomers, metabolites, analogs, or pro-drugs thereof. In some embodiments, the compounds of (2) are such that the iodo group is always adjacent to a R1; R2, R3, R4 or R5 group that is a nitroso, hydroxyamino, hydroxy or amino group. In some embodiments, the compounds of (2) are such that the iodo group is always adjacent to a R1; R2, R3, R* or R5 group that is a nitroso, hydroxyamino, or amino group.
[0113] Any of the compounds with structure formula la or Ila may be used for the treatment of platinum-resistant recurrent ovarian cancer. In some embodiments, an effective amount of a compound with structure formula la or Ila in combination with gemcitabine and carboplatin is administered to a patient with platinum-resistant recurrent ovarian cancer. In some embodiments, the compound with structure formula la or Ila is 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof.
[0114] Provided herein are metabolite compounds, each represented by a chemical formula:
Figure imgf000043_0001
R6 is selected from the group consisting of hydrogen, alkyl (CrC8), alkoxy (CrC8), isoquinolinones, indoles, thiazole, oxazole, oxadiazole, thiophene, or phenyl.
Figure imgf000043_0002
Figure imgf000044_0001
MS263 MS276 MS278
Figure imgf000044_0002
Figure imgf000044_0003
[0115] While not being limited to any one particular mechanism, the following provides an example for MS292 metabolism via a nitroreductase or glutathione conjugation mechanism: Nitroreductase mechanism
Figure imgf000045_0001
-iodo-3-nitrobenzamide glutathione conjugation and metabolism:
Molecular Weight:
Figure imgf000046_0001
Molecular Weight: 327.31 Molecular Weight: 285.28
[0117] Provided herein are uses of any of the aforesaid nitrobenzamide metabolite
compounds for the treatment of ovarian cancer (e.g., treating ovarian cancer with a genetic defect in a BRCA gene) described in accordance with any of the methods provided herein.
[0118] Any one of the metabolites of 4-iodo-3-nitrobenzamide described herein may be used in any one of the methods provided herein. Metabolites of 4-iodo-3-nitrobenzamide
include, for example, 4-iodo-3-aminobenzoic acid ("IABA"), 4-iodo-3-aminobenzamide
("IABM"), 4-iodo-3-nitrosobenzamide ("BNO"), and 4-iodo-3-hydroxyaminobenzamide
("BNHOH"). Metabolites and methods of making metabolites are disclosed in U.S.
Publication No. 2008/0103104 and U.S. Patent No. 5,877,185, which are hereby incorporated by reference in their entirety, and in particular with respect to the metabolites and methods of making metabolites.
[0119] In some embodiments of any of the methods provided herein, 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered. In some embodiments, 4-iodo-3-nitrobenzamide or a pharmaceutically acceptable salt thereof is administered. In some embodiments, a metabolite of 4-iodo-3- nitrobenzamide is administered. In some embodiments, the metabolite of 4-iodo-3- nitrobenzamide is 4-iodo-3-aminobenzoic acid or 4-iodo-3-aminobenzamide.
[0120] It has been reported that nitrobenzamide metabolite compounds have selective cytotoxicity upon malignant cancer cells but not upon non-malignant cancer cells. See Rice et at., Proc. Natl. Acad. Sci. USA 89:7703-7707 (1992), incorporated herein in it entirety. In one embodiment, the nitrobenzamide metabolite compounds utilized in the methods of the present invention may exhibit more selective toxicity towards tumor cells than non-tumor cells. The metabolites according to the invention may thus be administered to a patient in need of such treatment in conjunction with chemotherapy with at least one an antimetabolite (e.g., gemcitabine) in addition to the at least one platinum complex (e.g., carboplatin, cisplatin, etc.)
[0121] The dosage range for any of the metabolites described herein used for treating platinum-resistant recurrent ovarian cancer may be in the range of about 0.0004 to about 0.5 mmol/kg (millimoles of metabolite per kilogram of patient body weight), which dosage corresponds, on a molar basis, to a range of about 0.1 to about 100 mg/kg of 4-iodo-3- nitrobenzamide. Other effective ranges of dosages for metabolites are 0.0024-0.5 mmol/kg and 0.0048-0.25 mmol/kg. Such doses may be administered on a daily, every-other-daily, twice-weekly, weekly, bi-weekly, monthly or other suitable schedule. Essentially the same modes of administration may be employed for the metabolites as for 4-iodo-3- nitrobenzamide— e.g., oral, i.v., i.p., etc.
[0122] In some embodiments, 4-iodo-3-nitrobenzamide or a pharmaceutically acceptable salt thereof is administered. In some embodiments, a metabolite of 4-iodo-3-nitrobenzamide or a pharmaceutically acceptable salt of a metabolite of 4-iodo-3-nitrobenzamide is administered. The term "pharmaceutically acceptable salt" means those salts which retain the biological effectiveness and properties of the compounds used herein, and which are not biologically or otherwise undesirable. For example, a pharmaceutically acceptable salt does not interfere with the beneficial effect of the compound described herein in treating platinum- resistant recurrent ovarian cancer.
[0123] Typical salts are those of the inorganic ions, such as, for example, sodium, potassium, calcium and magnesium ions. Such salts include salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid. In addition, where compounds contain a carboxy group or other acidic group, it may be converted into a pharmaceutically acceptable addition salt with inorganic or organic bases. Examples of suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexyl-amine, ethanolamine, diethanolamine and triethanolamine. In some
embodiments, 4-iodo-3-nitrobenzamide is formulated in 25% (w/v) hydroxypropyl-β- cyclodextrin and 10 mM phosphate buffer for intravenous administration as described in U.S. Patent Application Publication No. 2010/0160442, which is incorporated herein by reference.
Combination Therapy
[0124] Any of the methods described herein may further comprise another anti-cancer therapy including but not limited to surgery, radiation therapy (e.g. , X rays), gene therapy, DNA therapy, adjuvant therapy, neoadjuvant therapy, viral therapy, immunotherapy, RNA therapy, or nanotherapy.
[0125] Where the combination therapy further comprises a non-drug treatment, the non- drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, by a significant period of time. The conjugate and the other pharmacologically active agent may be administered to a patient simultaneously, sequentially or in combination. It will be appreciated that when using a combination of the invention, the compound of the invention and the other pharmacologically active agent may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term "combination" further refers to the case where the compounds are provided in separate dosage forms and are administered sequentially.
Radiation Therapy
[0126] Radiation therapy (or radiotherapy) is the medical use of ionizing radiation as part of cancer treatment to control malignant cells. Radiotherapy may be used for curative or adjuvant cancer treatment. It is used as palliative treatment (where cure is not possible and the aim is for local disease control or symptomatic relief) or as therapeutic treatment (where the therapy has survival benefit and it can be curative). Radiotherapy is used for the treatment of malignant tumors and may be used as the primary therapy. It is also common to combine radiotherapy with surgery, chemotherapy, hormone therapy or some mixture of the three. Most common cancer types can be treated with radiotherapy in some way. The precise treatment intent (curative, adjuvant, neoadjuvant, therapeutic, or palliative) will depend on the tumour type, location, and stage, as well as the general health of the patient.
[0127] Radiation therapy is commonly applied to the cancerous tumor. The radiation fields may also include the draining lymph nodes if they are clinically or radiologically involved with tumor, or if there is thought to be a risk of subclinical malignant spread. It is necessary to include a margin of normal tissue around the tumor to allow for uncertainties in daily set-up and internal tumor motion.
[0128] Radiation therapy works by damaging the DNA of cells. The damage is caused by a photon, electron, proton, neutron, or ion beam directly or indirectly ionizing the atoms which make up the DNA chain. Indirect ionization happens as a result of the ionization of water, forming free radicals, notably hydroxyl radicals, which then damage the DNA. In the most common forms of radiation therapy, most of the radiation effect is through free radicals. Because cells have mechanisms for repairing DNA damage, breaking the DNA on both strands proves to be the most significant technique in modifying cell characteristics. Because cancer cells generally are undifferentiated and stem cell-like, they reproduce more, and have a diminished ability to repair sub-lethal damage compared to most healthy differentiated cells. The DNA damage is inherited through cell division, accumulating damage to the cancer cells, causing them to die or reproduce more slowly. Proton radiotherapy works by sending protons with varying kinetic energy to precisely stop at the tumor.
[0129] Gamma rays may be used to treat any of the ovarian cancers described herein. In the procedure called gamma-knife surgery, multiple concentrated beams of gamma rays are directed on the growth in order to kill the cancerous cells. The beams are aimed from different angles to focus the radiation on the growth while minimizing damage to the surrounding tissues.
[0130] Radiosensitizers are known to increase the sensitivity of cancerous cells to the toxic effects of electromagnetic radiation. Many cancer treatment protocols currently employ radiosensitizers activated by the electromagnetic radiation of x-rays. Examples of x-ray activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5- iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives of the same. [0131] Photodynamic therapy (PDT) of cancers employs visible light as the radiation activator of the sensitizing agent. Examples of photodynamic radiosensitizers include the following, but are not limited to: hematoporphyrin derivatives, photofrin, benzoporphyrin derivatives, NPe6, tin etioporphyrin SnET2, pheoborbide-alpha, bacteriochlorophyll-alpha, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives of the same.
Gene Therapy Agents
[0132] Gene therapy agents insert copies of genes into a specific set of a patient' s cells, and can target both cancer and non-cancer cells. The goal of gene therapy can be to replace altered genes with functional genes, to stimulate a patient's immune response to cancer, to make cancer cells more sensitive to chemotherapy, to place "suicide" genes into cancer cells, or to inhibit angiogenesis. Genes may be delivered to target cells using viruses, liposomes, or other carriers or vectors. This may be done by injecting the gene-carrier composition into the patient directly, or ex vivo, with infected cells being introduced back into a patient. Such compositions are suitable for use in the present invention.
Adjuvant therapy
[0133] Any of the methods provided herein may further comprise an adjuvant therapy. Adjuvant therapy includes a treatment given after the primary treatment to increase the chances of a cure. Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, or biological therapy. In some embodiments of any of the methods described herein, the method further comprises administering granulocyte colony- stimulating factor ("G- CSF"). In some embodiments, the method does not further comprise administering G-CSF.
[0134] Because the principal purpose of adjuvant therapy is to kill any cancer cells that may have spread, treatment is usually systemic (uses substances that travel through the bloodstream, reaching and affecting cancer cells all over the body). For example, adjuvant therapy for ovarian cancer involves chemotherapy or hormone therapy, either alone or in combination.
[0135] Adjuvant chemotherapy is the use of drugs to kill cancer cells. Adjuvant chemotherapy is usually a combination of anticancer drugs, which has been shown to be more effective than a single anticancer drug.
[0136] Radiation therapy is sometimes used as a local adjuvant treatment. Radiation therapy is considered adjuvant treatment when it is given before or after surgical treatment, e.g., a mastectomy. Such treatment is intended to destroy cancer cells that have spread to nearby parts of the body, such as the chest wall or lymph nodes.
[0137] Various therapies including but not limited to hormone therapy, e.g., tamoxifen, or gonadotropin-releasing hormone (GnRH) analogues, and radioactive monoclonal antibody therapy have been used to treat ovarian cancer.
Neoadjuvant therapy
[0138] Neoadjuvant therapy refers to a treatment given before the primary treatment. Examples of neoadjuvant therapy include chemotherapy, radiation therapy, and hormone therapy. Neoadjuvant chemotherapy in gynecological cancers is an approach that is shown to have positive effects on survival. It increases the rate of resectability in ovarian and cervical cancers and thus contributes to survival (Ayhan A. et. al. European journal of gynaecological oncology. 2006, vol. 27).
Oncolytic viral therapy
[0139] Viral therapy for cancer utilizes a type of viruses called oncolytic viruses. An oncolytic virus is a virus that is able to infect and lyse cancer cells, while leaving normal cells unharmed, making them potentially useful in cancer therapy. Replication of oncolytic viruses both facilitates tumor cell destruction and also produces dose amplification at the tumor site. They may also act as vectors for anticancer genes, allowing them to be specifically delivered to the tumor site.
[0140] There are two main approaches for generating tumor selectivity: transductional and non-transductional targeting. Transductional targeting involves modifying the specificity of viral coat protein, thus increasing entry into target cells while reducing entry to non-target cells. Non-transductional targeting involves altering the genome of the virus so it can only replicate in cancer cells. This can be done by either transcription targeting, where genes essential for viral replication are placed under the control of a tumor- specific promoter, or by attenuation, which involves introducing deletions into the viral genome that eliminate functions that are dispensable in cancer cells, but not in normal cells. There are also other, slightly more obscure methods.
[0141] Chen et al (2001 ) used CV706, a pro state- specific adenovirus, in conjunction with radiotherapy on prostate cancer in mice. The combined treatment results in a synergistic increase in cell death, as well as a significant increase in viral burst size (the number of virus particles released from each cell lysis). [0142] ONYX-015 has undergone trials in conjunction with chemotherapy. The combined treatment gives a greater response than either treatment alone, but the results have not been entirely conclusive. ONYX-015 has shown promise in conjunction with
radiotherapy.
[0143] Viral agents administered intravenously can be particularly effective against metastatic cancers, which are especially difficult to treat conventionally. However, bloodborne viruses can be deactivated by antibodies and cleared from the blood stream quickly e.g., by Kupffer cells (extremely active phagocytic cells in the liver, which are responsible for adenovirus clearance). Avoidance of the immune system until the tumour is destroyed could be the biggest obstacle to the success of oncolytic virus therapy. To date, no technique used to evade the immune system is entirely satisfactory. It is in conjunction with conventional cancer therapies that oncolytic viruses show the most promise, since combined therapies operate synergistically with no apparent negative effects.
[0144] The specificity and flexibility of oncolytic viruses means they have the potential to treat a wide range of cancers including ovarian cancer with minimal side effects. Oncolytic viruses have the potential to solve the problem of selectively killing cancer cells.
Nanotherapy
[0145] Nanometer- sized particles have novel optical, electronic, and structural properties that are not available from either individual molecules or bulk solids. When linked with tumor- targeting moieties, such as tumor- specific ligands or monoclonal antibodies, these nanoparticles can be used to target cancer- specific receptors, tumor antigens (biomarkers), and tumor vasculatures with high affinity and precision. The formulation and manufacturing process for cancer nanotherapy is disclosed in patent US7179484, and article M. N. Khalid, P. Simard, D. Hoarau, A. Dragomir, J. Leroux, Long Circulating Poly(Ethylene
Glycol)Decorated Lipid Nanocapsules Deliver Docetaxel to Solid Tumors, Pharmaceutical Research, 23(4), 2006, all of which are herein incorporated by reference in their entireties.
RNA therapy
[0146] RNA including but not limited to siRNA, shRNA, microRNA may be used to modulate gene expression and treat cancers. Double stranded oligonucleotides are formed by the assembly of two distinct oligonucleotide sequences where the oligonucleotide sequence of one strand is complementary to the oligonucleotide sequence of the second strand; such double stranded oligonucleotides are generally assembled from two separate oligonucleotides (e.g., siRNA), or from a single molecule that folds on itself to form a double stranded structure (e.g., shRNA or short hairpin RNA). These double stranded oligonucleotides known in the art all have a common feature in that each strand of the duplex has a distinct nucleotide sequence, wherein only one nucleotide sequence region (guide sequence or the antisense sequence) has complementarity to a target nucleic acid sequence and the other strand (sense sequence) comprises nucleotide sequence that is homologous to the target nucleic acid sequence.
[0147] MicroRNAs (miRNA) are single- stranded RNA molecules of about 21-23 nucleotides in length, which regulate gene expression. miRNAs are encoded by genes that are transcribed from DNA but not translated into protein (non-coding RNA); instead they are processed from primary transcripts known as pri-miRNA to short stem-loop structures called pre-miRNA and finally to functional miRNA. Mature miRNA molecules are partially complementary to one or more messenger RNA (mRNA) molecules, and their main function is to downregulate gene expression.
[0148] Certain RNA inhibiting agents may be utilized to inhibit the expression or translation of messenger RNA ("mRNA") that is associated with a cancer phenotype.
Examples of such agents suitable for use herein include, but are not limited to, short interfering RNA ("siRNA"), ribozymes, and antisense oligonucleotides. Specific examples of RNA inhibiting agents suitable for use herein include, but are not limited to, Cand5, Sirna- 027, fomivirsen, and angiozyme.
Small Molecule Enzymatic Inhibitors
[0149] Certain small molecule therapeutic agents are able to target the tyrosine kinase enzymatic activity or downstream signal transduction signals of certain cell receptors such as epidermal growth factor receptor ("EGFR") or vascular endothelial growth factor receptor ("VEGFR"). Such targeting by small molecule therapeutics can result in anti-cancer effects. Examples of such agents suitable for use herein include, but are not limited to, imatinib, gefitinib, erlotinib, lapatinib, canertinib, ZD6474, sorafenib (BAY 43-9006), ERB-569, and their analogues and derivatives.
Anti-Metastatic Agents
[0150] The process whereby cancer cells spread from the site of the original tumor to other locations around the body is termed cancer metastasis. Certain agents have anti- metastatic properties, designed to inhibit the spread of cancer cells. Examples of such agents suitable for use herein include, but are not limited to, marimastat, bevacizumab, trastuzumab, rituximab, erlotinib, MMI- 166, GRN163L, hunter-killer peptides, tissue inhibitors of metalloproteinases (TIMPs), their analogues, derivatives and variants.
Chemopreventative agents
[0151] Certain pharmaceutical agents such as chemopreventative agents may be used in combination with any of the methods provided herein. These agents can be used to prevent initial occurrences of cancer, or to prevent recurrence or metastasis. Administration with such chemopreventative agents in combination with any one of the treatments described herein can act to both treat and prevent the recurrence of cancer. Examples of
chemopreventative agents suitable for use herein include, but are not limited to, tamoxifen, raloxifene, tibolone, bisphosphonate, ibandronate, estrogen receptor modulators, aromatase inhibitors (letrozole, anastrozole), luteinizing hormone-releasing hormone agonists, goserelin, vitamin A, retinal, retinoic acid, fenretinide, 9-cis-retinoid acid, 13-cis-retinoid acid, all-trans- retinoic acid, isotretinoin, tretinoid, vitamin B6, vitamin B 12, vitamin C, vitamin D, vitamin E, cyclooxygenase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, ibuprofen, celecoxib, polyphenols, polyphenol E, green tea extract, folic acid, glucaric acid, interferon-alpha, anethole dithiolethione, zinc, pyridoxine, finasteride, doxazosin, selenium, indole-3-carbinal, alpha-difluoromethylornithine, carotenoids, beta-carotene, lycopene, antioxidants, coenzyme Q10, flavonoids, quercetin, curcumin, catechins, epigallocatechin gallate, N-acetylcysteine, indole-3-carbinol, inositol hexaphosphate, isoflavones, glucanic acid, rosemary, soy, saw palmetto, and calcium. An additional example of
chemopreventative agents suitable for use in the present invention is cancer vaccines. These can be created through immunizing a patient with all or part of a cancer cell type that is targeted by the vaccination process.
Clinical Efficacy
[0152] Clinical efficacy may be measured by any of the methods known in the art. In some embodiments, clinical efficacy of the therapeutic treatments described herein may be determined by measuring the clinical benefit rate (CBR). The clinical benefit rate is measured by determining the sum of the percentage of patients who are in complete remission (CR), the number of patients who are in partial remission (PR) and the number of patients having stable disease (SD) at a time point at least 6 months out from the end of therapy. The shorthand for this formula is CBR = CR + PR + SD > 6 months. Similarly, the CBR for combination therapy with an antimetabolite (e.g. , gemcitabine), a platinum compound (e.g. , carboplatin), and 4-iodo-3-nitrobenzamide (CBRGEM/CARBO/BA) may be compared to that of the double combination therapy with an antimetabolite (e.g. , gemcitabine) and a platinum compound (e.g., carboplatin) (CBRGEM/CARBO)- In some embodiments, CBRGEM/CARBO/BA is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or more. In some embodiments, the CBR is at least about 30%, at least about 40%, or at least about 50%.
[0153] In some embodiments of any one of the methods provided herein, at least one therapeutic effect is obtained, said at least one therapeutic effect being reduction in size of an ovarian tumor, reduction in metastasis, complete remission, partial remission, pathologic partial response, pathologic complete response, increase in overall response rate or objective response rate, or stable disease. In some embodiments, a comparable clinical benefit rate (CBR = CR + PR + SD > 6 months) is obtained with treatment of the 4-iodo-3- nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) in combination with gemcitabine and carboplatin as compared to treatment with gemcitabine and carboplatin without 4-iodo-3-nitrobenzamide (or a metabolite thereof or a
pharmaceutically acceptable salt thereof). In some embodiments, the improvement of clinical benefit rate is at least about any of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the administration of 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) in combination with gemcitabine and carboplatin results in a complete response, partial response, or stable disease.
[0154] In some embodiments of any one of the methods provided herein, the patient has measurable disease. Measurable disease may be determined by RECIST version 1.1 criteria, which is described in Eisenhauer EA et al. 2009, Eur J Cancer., 45(2):228-47, the disclosure of which is incorporated by reference in its entirety. Measurable disease may also be defined by at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded), and is > 20 mm when measured by conventional techniques (palpation, plain x-ray, computed tomography (CT), or magnetic resonance imaging (MRI)) or > 10 mm when measured by spiral CT.
[0155] Response rates may be determined according to RECIST version 1.1 criteria. For example, regarding target lesion, complete response (CR) may be defined as disappearance of all target lesions; any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. Regarding target lesion, partial response (PR) may be defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters (baseline sum diameters may be a sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions). Regarding target lesion, progressive disease (PD) may be defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum may also demonstrate an absolute increase of at least 5 mm. Regarding target lesion, stable disease (SD) may be defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (taking as reference the smallest sum diameters while on study). Regarding non-target lesion, CR may be disappearance of all non-target lesions and normalization of tumour marker level (all lymph nodes may be non-pathological in size (<10mm short axis)). Regarding non-target lesion, non-CR/non-PD may be persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits. Regarding non-target lesion, progressive disease (PD) may be unequivocal progression of existing non-target lesions. The appearance of one or more new lesions may be considered progression.
[0156] Overall response may be determined according to Eisenhauer EA et al. 2009, Eur J Cancer., 45(2):228-47 such as Tables 1-3, the disclosure of which is incorporated by reference in its entirety. Efficacy parameters may be determined by any of methods known to one skilled in the art. For example, they may be determined according to RECIST version 1.1 criteria. For example, objective response rate or overall response rate may be defined as the proportion of patients with an overall response or a best overall response of complete response or partial response (for example, overall response rate may be defined as complete response rate plus partial response rate, or ORR = CR + PR). Progression-free survival may be defined as the time from the date of starting treatment (or date of initiation of study treatment or date of randomization) until the date of first observation of disease progression or the date of death. Overall survival may be defined as the time from the date of starting treatment (or date of initiation of study treatment or date of randomization) until the date of death.
[0157] In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) an antimetabolite such as gemcitabine; and (iii) a platinum compound such as carboplatin, wherein the treatment results in reduction in size of an ovarian tumor in the patient. In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in reduction in metastasis of ovarian cancer in the patient. In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient an effective amount of: (i) 4- iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in complete response in the patient. In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in pathological complete response in the patient. In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in partial response in the patient. In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient an effective amount of: (i) 4- iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in stable disease in the patient.
[0158] In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in reduction in metastasis of ovarian cancer in the patient. In some embodiments, at least about 10% (including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%) metastasis is inhibited (e.g., compared to metastasis before the administration of (i) 4- iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin). In some embodiments, any of the methods is used to inhibit metastasis to lymph node.
[0159] In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in reduction in size of an ovarian tumor in the patient. In some embodiments, the tumor size is reduced by at least about 10% (including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%) (e.g. , compared to tumor size before the administration of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin).
[0160] In some embodiments, the administration of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof, the administration of gemcitabine, and/or the administration of carboplatin have a synergistic effect. In some embodiments, a lower amount of each pharmaceutically active compound is used as part of a combination therapy compared to the amount generally used for individual therapy. In some embodiments, the same or greater therapeutic benefit is achieved using a combination therapy than by using any of the individual compounds alone. In some embodiments, the same or greater therapeutic benefit is achieved using a smaller amount (e.g. , a lower dose or a less frequent dosing schedule) of a pharmaceutically active compound in a combination therapy than the amount generally used for individual therapy. For example, the use of a small amount of pharmaceutically active compound may result in a reduction in the number, severity, frequency, or duration of one or more side-effects associated with the compound.
Formulations, Routes of Administration, and Dosing Regimen
[0161] In some embodiments, there are provided formulations (e.g., pharmaceutical formulations) comprising 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a
pharmaceutically acceptable salt or solvate thereof), an antimetabolite (e.g. , gemcitabine) and/or a platinum compound (e.g., carboplatin), and/or a carrier, such as a pharmaceutically acceptable carrier. The formulations may include optical isomers, diastereomers, carriers, or pharmaceutically acceptable salts of the compounds disclosed herein. In some embodiments, the carrier is a cyclodextrin, or a derivative thereof, e.g., hydroxypropyl-B-cyclodextrin (HPBCD). In some embodiments, the formulations are formulated for intravenous
administration.
[0162] The pharmaceutical compositions of the present invention may be provided as a prodrug and/or may be allowed to interconvert to 4-iodo-3-nitrobenzamide form in vivo after administration. That is, either 4-iodo-3-nitrobenzamide or metabolites thereof or
pharmaceutically acceptable salts may be used in developing a formulation for use in the present invention. 4-iodo-3-nitrobenzamide (or a metabolite thereof), an antimetabolite (e.g. , gemcitabine) and a platinum compound (e.g. , carboplatin) provided herein may be formulated in separate formulations or in the same formulation. 4-iodo-3-nitrobenzamide (or a metabolite thereof), an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g. , carboplatin) provided herein may be administered through different administration route or using same administration routes.
[0163] Also provided herein are synergistic compositions used for treating platinum- resistant recurrent ovarian cancer in a patient comprising (i) 4-iodo-3-nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt thereof, (ii) gemcitabine, and (iii) carboplatin.
[0164] A formulation may comprise both the 4-iodo-3-nitrobenzamide compound and acid forms in particular proportions, depending on the relative potencies of each and the intended indication. The two forms may be formulated together or in different formulations. They may be in the same dosage unit e.g. in one cream, suppository, tablet, capsule, or packet of powder to be dissolved in a beverage; or each form may be formulated in a separate unit, e.g., two creams, two suppositories, two tablets, two capsules, a tablet and a liquid for dissolving the tablet, a packet of powder and a liquid for dissolving the powder, etc.
[0165] 4-iodo-3-nitrobenzamide (or a metabolite thereof), an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin) provided herein may be coadministered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound), such as described herein. 4-iodo-3-nitrobenzamide (or a metabolite thereof), an
antimetabolite (e.g. , gemcitabine) and/or a platinum compound (e.g. , carboplatin) provided herein may be continuously or not continuously given to a patient. "Not continuously" means that the compound or composition provided herein is not administered to the patient over a period of time, e.g., there is a resting period when the patient does not receive the compound or composition. It may be that one compound is administered continuously administered to a patient while the second compound is not administered continuously administered to the patient.
[0166] The pharmaceutical compositions of the 4-iodo-3-nitrobenzamide, an
antimetabolite (e.g. , gemcitabine) and a platinum compound (e.g., carboplatin) can be combined with other active ingredients, such as other chemotherapeutic agents as described herein. The three compounds and/or forms of a compound may be formulated together, in the same dosage unit e.g., in one cream, suppository, tablet, capsule, or packet of powder to be dissolved in a beverage; or each form may be formulated in separate units, e.g., three creams, three suppositories, three tablets, three capsules, a tablet and a liquid for dissolving the tablet, a packet of powder and a liquid for dissolving the powder, etc.
[0167] The term "pharmaceutically acceptable salt" means those salts which retain the biological effectiveness and properties of the compounds used in the present invention, and which are not biologically or otherwise undesirable. For example, a pharmaceutically acceptable salt does not interfere with the beneficial effect of a compound provided herein in treating platinum-resistant recurrent ovarian cancer.
[0168] Typical salts are those of the inorganic ions, such as, for example, sodium, potassium, calcium and magnesium ions. Such salts include salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid. In addition, where compounds contain a carboxy group or other acidic group, it may be converted into a pharmaceutically acceptable addition salt with inorganic or organic bases. Examples of suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexyl-amine, ethanolamine, diethanolamine and triethanolamine.
[0169] For injection, 4-iodo-3-nitrobenzamide or a metabolite thereof or a
pharmaceutically acceptable salt thereof may be formulated for administration in aqueous solutions, preferably in physiologically compatible buffers such as phosphate buffers, Hank's solution, or Ringer's solution. Such compositions may also include one or more excipients, for example, preservatives, solubilizers, fillers, lubricants, stabilizers, albumin, and the like. Formulations of 4-iodo-3-nitrobenzamide are described in US Pat. Publ. No. 2008/0176946 Al, which is incorporated by reference in its entirety, particularly with reference to intravenous (e.g., hydroxypropyl-P-cyclodextrin, etc.) and oral (e.g., sodium lauryl sulfate, etc.) formulations. In some embodiments, 4-iodo-3-nitrobenzamide is formulated in 25% (w/v) hydroxypropyl-P-cyclodextrin and 10 mM phosphate buffer for intravenous
administration as described in U.S. Patent Application Publication No. 2010/0160442, which is incorporated herein by reference. In some embodiments, the formulation has 10 mg/mL 4- iodo-3-nitrobenzamide, 25% (w/v) hydroxypropyl-P-cyclodextrin, and 10 mM phosphate buffer, pH 7.4.
[0170] Additional methods of formulation, such as for the antimetabolite (e.g. , gemcitabine) and the platinum compound (e.g., carboplatin) described herein, are known in the art, for example, as disclosed in Remington' s Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton, PA. Compositions described herein may also be formulated for transmucosal administration, buccal administration, for administration by inhalation, for parental administration, for transdermal administration, and rectal administration.
[0171] Pharmaceutical compositions suitable for use as described herein include compositions wherein the active ingredients are present in an effective amount, i.e., in an amount effective to achieve therapeutic and/or prophylactic benefit in at least one of the platinum-resistant ovarian cancers {e.g., recurrent ovarian cancer) described herein. The actual amount effective for a particular administration will depend on the platinum-resistant recurrent ovarian cancer {e.g., recurrent ovarian cancer) being treated, the condition of the subject, the formulation, and the route of administration, as well as other factors known to those of skill in the art in view of the specific teaching provided herein. In light of the disclosure herein, optimization of an effective amount of 4-iodo-3-nitrobenzamide, antimetabolite {e.g., gemcitabine), and/or platinum compound {e.g., carboplatin) provided herein, within the ranges specified, may be determined.
[0172] In some embodiments of any of the compositions or formulations provided herein, the composition or formulation is administered in unit dosage form. In some embodiments, the unit dosage form is adapted for oral or parenteral administration. In some embodiments, upon administration of the composition or formulation, at least one therapeutic effect is obtained, said at least one therapeutic effect being reduction in size of a tumor, reduction in metastasis, complete remission, partial remission, pathologic complete response, increase in overall response rate, or stable disease. In some embodiments, upon administration of the composition or formulation, an improvement of clinical benefit rate (CBR = CR + PR + SD > 6 months) is obtained as compared to treatment with the antimetabolite {e.g., gemcitabine) and the platinum compound {e.g., carboplatin) but without 4-iodo-3-nitrobenzamide or the metabolite thereof or the pharmaceutically acceptable salt thereof. In some embodiments, the improvement of clinical benefit rate is at least about 20%. In some embodiments, the improvement of clinical benefit rate is at least about any of 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more.
[0173] In some embodiments of any one of the methods provided herein, the amount of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof, the amount of gemcitabine, and/or the amount of carboplatin is an amount sufficient to decrease the size of a tumor, decrease the number of cancer cells, or decrease the growth rate of a tumor (including decrease in metastasis) by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% compared to the corresponding tumor size, number of cancer cells, or tumor growth rate in the same patient at the time of starting treatment or compared to the corresponding activity in other patients not receiving the treatment. Standard methods can be used to measure the magnitude of this effect.
[0174] In some embodiments, the amount of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof, the amount of gemcitabine, and/or the amount of carboplatin is below the level that induces a toxicological effect (e.g. , an effect above a clinically acceptable level of toxicity) or is at a level where a potential side effect can be controlled or tolerated.
[0175] In some embodiments, the amount of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof, the amount of gemcitabine, and/or the amount of carboplatin is close to a maximum tolerated dose (MTD). In some embodiments, the amount is at least about any of 80%, 90%, 95%, or 98% of the MTD.
[0176] Any of the compositions or compounds described herein may be administered to a patient through appropriate route, such as, but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, intraarterial, subcutaneous, intranasal, epidural, and oral routes. In some embodiments, the composition or compound(s) provided herein is administered by the parenteral route, e.g., intravenously, intraperitoneally, subcutaneously, intradermally, or intramuscularly.
[0177] Any of the compositions or compounds described herein may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered in combination with other biologically active agents, e.g., such as described herein. Administration can be systemic or local. In addition, it may be desirable to introduce the pharmaceutical compositions of the invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
[0178] The dosage of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a
pharmaceutically acceptable salt thereof may vary depending upon the patient's age, height, weight, overall health, etc. In some embodiments, the dosage of 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) is in the range of any one of about 0.1 mg/kg to about 50 mg/kg, about 1 mg/kg to about 100 mg/kg, 2 mg/kg to about 50 mg/kg, about 2 mg/kg to about 10 mg/kg, about 4 mg/kg to about 8 mg/kg, about 5 mg/kg to about 7 mg/kg, about 1 mg/kg to about 50 mg/kg, about 1 mg/kg to about 25 mg/kg, about 2 to about 70 mg/kg, about 2 mg/kg to about 50 mg/kg, about 2 mg/kg to about 40 mg/kg, about 3 mg/kg to about 30 mg/kg, about 4 to about 100 mg/kg, about 4 to about 25 mg/kg, about 4 to about 20 mg/kg, about 4 to about 15 mg/kg, about 5 to about 20 mg/kg, about 5 to about 15 mg/kg, about 50 to about 100 mg/kg or about 25 to about 75 mg/kg, about 2 mg/kg, about 4 mg/kg, about 5 mg/kg, about 5.6 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 11.2 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 75 mg/kg, or about 90 mg/kg. In some embodiments, the dosage of 4-iodo-3-nitrobenzamide is about any of 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 5.6 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 11.2 mg/kg, 12.5 mg/kg, 15 mg/kg, 20 mg/kg, 30 mg/kg, 50 mg/kg, 75 mg/kg, or 100 mg/kg. In some embodiments, 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) is administered at a dose of at least any of about lmg/kg, 2 mg/kg, about 4 mg/kg, about 5 mg/kg, about 5.6 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 11.2 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 75 mg/kg, or about 90 mg/kg. 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) may be administered intravenously, e.g., by IV infusion over about 10 to about 300 minutes, about 30 to about 180 minutes, about 45 to about 120 minutes or about 60 minutes (i.e., about 1 hour). 4-iodo-3-nitrobenzamide or its metabolite or its pharmaceutically acceptable salt thereof may be administered weekly, twice every week, once every three weeks, twice every three weeks, three times out of four weeks, four times out of three weeks, four times out of five weeks, or five times out of six weeks. For example, 4-iodo-3- nitrobenzamide or its metabolite or its pharmaceutically acceptable salt thereof may be administered on 2 days or 4 days of a treatment cycle, e.g., on days 1 and 8 (with the dosage of about 11.2 mg/kg) or days 1, 4, 8, and 11 (with the dosage of about 5.6 mg/kg) of a 21-day treatment cycle. In some embodiments, there is provided a method of treating platinum- resistant recurrent ovarian cancer in a patient, comprising administering to the patient an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein 4-iodo-3- nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof is intravenously administered to the patient at about 5 to about 20 mg/kg or about 5 mg/kg to about 15 mg/kg. In some embodiments, 4-iodo-3-nitrobenzamide may alternatively be administered orally.
[0179] The dosage of an antimetabolite provided herein (e.g., gemcitabine) that may be used in any of the methods provided herein may vary depending upon the patient's age, height, weight, overall health, etc. In some embodiments, the dosage of the antimetabolite
2 2
(e.g., gemcitabine) provided herein is in the range of about 100 mg/m to about 5000 mg/m , about 100 mg/m2 to about 2000 mg/m2, about 200 to about 4000 mg/m2, about 300 to about 3000 mg/m2, about 400 to about 2000 mg/m2, about 500 to about 1500 mg/m2, about 750 to about 1500 mg/m2, about 800 to about 1500 mg/m2, about 900 to about 1400 mg/m2, about 900 to about 1250 mg/m2, about 1000 to about 1500 mg/m2, about 10 mg/m2 to about 1000
2 2 2 2 2
mg/m , about 25mg/m to about 500 mg/m , about 50 mg/m to about 200 mg/m , or about 75
2 2
mg/m to about 200 mg/m . In some embodiments, the antimetabolite (e.g., gemcitabine) is
2 2 2 2 2 administered at about any of 50 mg/m", 75 mg/m", 100 mg/m", 125 mg/m", 150 mg/m", 175 mg/m2, 200 mg/m2, 250 mg/m2, 300 mg/m2, 400 mg/m2, 450 mg/m2, 500 mg/m2, 550 mg/m2, 600 mg/m2, 650 mg/m2, 700 mg/m2, 750 mg/m2, 800 mg/m2, 850 mg/m2, 900 mg/m2, 1000 mg/m2, 1050 mg/m2, 1100 mg/m2, 1150 mg/m2, 1200 mg/m2, 1250 mg/m2, 1300 mg/m2, 1350 mg/m2, 1400 mg/m2, 1450 mg/m2, 1500 mg/m2, 1550 mg/m2, 1600 mg/m2, 1700
2 2 2 2
mg/m , 1800 mg/m , 1900 mg/m , or 2000 mg/m . An antimetabolite (e.g., gemcitabine)
2 2 2 may be administered at a dose of at least about any of 50 mg/m", 75 mg/m", 100 mg/m", 125 mg/m2, 150 mg/m2, 175 mg/m2, 200 mg/m2, 250 mg/m2, 300 mg/m2, 400 mg/m2, 450 mg/m2, 500 mg/m2, 550 mg/m2, 600 mg/m2, 650 mg/m2, 700 mg/m2, 750 mg/m2, 800 mg/m2, 850 mg/m2, 900 mg/m2, 1000 mg/m2, 1050 mg/m2, 1100 mg/m2, 1150 mg/m2, 1200 mg/m2, 1250 mg/m2, 1300 mg/m2, 1350 mg/m2, 1400 mg/m2, 1450 mg/m2, 1500 mg/m2, 1550 mg/m2, 1600 mg/m2, 1700 mg/m2, 1800 mg/m2, 1900 mg/m2, or 2000 mg/m2. An antimetabolite provided herein (e.g., gemcitabine) may be administered weekly, once every three weeks, twice every week, twice every three weeks, three times out of four weeks, four times out of three weeks, four times out of five weeks, or five times out of six weeks. For example, an antimetabolite provided herein (e.g., gemcitabine) may be administered on 2 days of a treatment cycle, e.g., on days 1 and 8 (with the dosage of about 1000 mg/m ) of a 21-day treatment cycle. An antimetabolite (e.g., gemcitabine) provided herein may be administered intravenously, e.g., by IV infusion over about 10 to about 500 minutes, about 10 to about 300 minutes, about 15 to about 180 minutes, about 30 to about 180 minutes, about 30 to about 60 minutes, about 45 to about 120 minutes, about 20 to about 60 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 60 minutes (i.e. about 1 hour) or about 30 minutes. An antimetabolite (e.g., gemcitabine) may alternatively be administered orally.
[0180] The dosage of a platinum compound provided herein (e.g., carboplatin) that may be used in any of the methods provided herein may vary depending upon the patient' s age, height, weight, overall health, etc. The dosage of a platinum compound, e.g., carboplatin, is determined by calculating the area under the blood plasma concentration versus time curve (AUC) in mg/mL»minute by methods known to those skilled in the cancer chemotherapy art, taking into account the patient' s renal activity estimated by measuring creatinine clearance or glomerular filtration rate. In some embodiments, the dosage of a platinum compound provided herein (e.g., carboplatin) used in combination with an antimetabolite (e.g., gemcitabine) and 4-iodo-3-nitrobenzamide is calculated to provide an AUC of about 0.1 to about 8 mg/ml»min, about 0.1 to about 7 mg/ml»min, about 0.1 to about 6 mg/ml»min, about 1 to about 6 mg/ml»min, about 1 to about 5 mg/ml»min, about 2 to about 5 mg/ml»min, about 3 to about 6 mg/ml»min, about 3 to about 5 mg/ml»min, about 1 to about 3 mg/ml»min, about 1.5 to about 2.5 mg/ml»min, about 1.75 to about 2.25 mg/ml»min, about 2 mg/ml»min (or AUC 2 ("AUC 2" is shorthand for 2 mg/ml«minute)), about AUC 2.5, about AUC 3, about AUC 3.5, about AUC 4, about AUC 4.5, about AUC 5, about AUC 5.5, or about AUC 6. Alternatively, the dosage of platinum compound (e.g., carboplatin) is calculated based on the patient's body surface area. In some embodiments, a suitable dose of platinum compound
2 2
(e.g., carboplatin) is about 10 to about 400 mg/m , e.g., about 360 mg/m . A platinum compound provided herein (e.g., carboplatin) may be administered weekly, twice every week, once every three weeks, twice every three weeks, three times out of four weeks, four times out of three weeks, four times out of five weeks, or five times out of six weeks. For example, carboplatin may be administered on 1 day of a treatment cycle, e.g., on day 1 (with the dosage of about AUC 4) of a 21 -day treatment cycle. Platinum complexes platinum compound (e.g. , carboplatin) are normally administered intravenously (IV) over a period of about 10 to about 500 minutes, about 10 to about 300 minutes, about 30 to about 180 minutes, about 45 to about 120 minutes or about 60 minutes. In this context, the term
"about" has its normal meaning of approximately. In some embodiments, about means +20%, +10%, or +5%.
[0181] In some cases, a beneficial effect is achieved when the administration of the antimetabolite (e.g. , gemcitabine) and the platinum compound (e.g., carboplatin) is temporally removed from the administration of the 4-iodo-3-nitrobenazmide (or
pharmaceutically acceptable salt or solvate thereof, or metabolite thereof) by a significant period of time (e.g., about 12 hours, about 24 hours, about 36 hours, about 48 hours, etc.), or, for example, when administration is spaced apart by at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, etc.). For example, administration may be on different days of a treatment cycle, such as the treatment cycles described herein. The interval between administration of the 4-iodo-3-nitrobenzamide, the antimetabolite (e.g. , gemcitabine), and the platinum compound (e.g. , carboplatin) may vary within a treatment cycle (e.g., administration is not always spaced apart by 1 day, but may be at intervals of 1 day followed by an interval of 3 days, etc.). Similarly, at certain times during the treatment cycle, the 4-iodo-3-nitrobenzamide, the antimetabolite (e.g. , gemcitabine), and the platinum compound (e.g. , carboplatin) may be administered at the same time, and at other points during the treatment administered at different times.
[0182] In some embodiments of any of the methods provided herein, the treatment includes 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles, 12 cycles, 13 cycles, 14 cycles, 15 cycles, 16 cycles, 17 cycles, 18 cycles, 19 cycles, or 20 cycles. As used here, the term "cycle" means "treatment cycle." In some embodiments, the method comprises at least one treatment cycle (e.g., one cycle, two cycles, three cycles, four cycles, five cycles, six cycles, seven cycles, eight cycles, nine cycles, or ten cycles, or at least any one of one cycle, two cycles, three cycles, four cycles, five cycles, six cycles, seven cycles, eight cycles, nine cycles, ten cycles, twelve cycles, fourteen cycles, sixteen cycles, or twenty cycles) comprising the administration of an effective amount of (a) 4-iodo-3-nitrobenzamide or a metabolite thereof or a
pharmaceutically acceptable salt thereof, (b) gemcitabine, and (c) carboplatin. In some embodiments, the treatment includes at most any of 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, or 10 cycles. In some embodiments, the cycle (e.g., the treatment cycle) is a period of about any of 1 week, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks. In some embodiments, the cycle (e.g., the treatment cycle) is a period of at least about any of 1 week, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks. In some embodiments, the cycle (e.g., the treatment cycle) is a period of no more than about any of 1 week, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks. In some embodiments, the treatment comprises a treatment cycle of at least about any of 1 week, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 12 weeks, or 15 weeks. Any of the methods provided herein may comprise at least one treatment cycle (e.g., 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles, 12 cycles, 13 cycles, 14 cycles, or 15 cycles), wherein the cycle is a period of 3 weeks, wherein the cycle comprises the administration of (a) 4-iodo- 3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, (b) gemcitabine, and (c) carboplatin.
[0183] 4-iodo-3-nitrobenzamide may be administered every day of the treatment cycle, or administered every day of the treatment cycle, or on certain days but not on every day of the treatment cycle. In some embodiments, 4-iodo-3-nitrobenzamide is administered daily, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, once 10 days, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks. 4-iodo-3-nitrobenzamide may be administered on the selected days of each treatment cycle, for example, 4-iodo-3- nitrobenzamide is administered daily for the period of 1 (or 2, 3, 4, 5, 6, 7, 8, 9, 10) days of the treatment cycle, and 4-iodo-3-nitrobenzamide is not administered on other days of the treatment cycle. In some embodiments, the intervals between each administration of 4-iodo- 3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof are less than about any of 6 months, 3 months, 1 month, 20 days, 15, days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, there is no break in the dosing schedule. In some embodiments, the interval between each administration is no more than about any of 3 weeks, 2 weeks, or 1 week. In some embodiments, the interval between each administration is about a week, about two weeks, or about three weeks. 4-iodo-3-nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) may be administered (e.g. , at about 5.6 mg/kg) on 4 days of a treatment cycle, e.g. , on days 1, 4, 8, 11 of a 21-day treatment cycle. 4-iodo-3- nitrobenzamide (or a metabolite thereof, or a pharmaceutically acceptable salt thereof) may be administered (e.g. , at about any one of 11.2 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, or 20 mg/kg) on 2 days of a treatment cycle, e.g. , on days 1 and 8 of a 21 -day treatment cycle.
[0184] An antimetabolite (e.g., gemcitabine) provided herein may be administered daily, e.g., every day of the treatment cycle, or administered on certain days but not on every day of the treatment cycle. In some embodiments, the antimetabolite (e.g., gemcitabine) provided herein is administered daily, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, once every 10 days, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks. An antimetabolite (e.g., gemcitabine) provided herein may be administered on the selected days of each treatment cycle, for example, the antimetabolite (e.g. , gemcitabine) is administered daily for the period of 1 (or 2, 3, 4, 5, 6, 7, 8, 9, 10) days of the treatment cycle, and the antimetabolite (e.g., gemcitabine) is not administered on other days of the treatment cycle. In some embodiments, the intervals between each administration of gemcitabine are less than about any of 6 months, 3 months, 1 month, 21 days, 20 days, 15, days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, there is no break in the dosing schedule. In some
embodiments, the interval between each administration is no more than about any of 3 weeks, 2 weeks, or 1 week. In some embodiments, the interval between each administration is about a week, about two weeks, or about three weeks. Gemcitabine may be administered (e.g. , at about 1000 mg/m ) on 2 days of a treatment cycle, e.g., on days 1 and 8 of a 21 -day treatment cycle.
[0185] A platinum compound (e.g., carboplatin) provided herein may be administered daily, e.g., every day of the treatment cycle, or administered on certain days but not on every day of the treatment cycle. In some embodiments, the platinum compound (e.g., carboplatin) provided herein is administered daily, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, once every 10 days, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks. A platinum compound (e.g., carboplatin) provided herein may be administered on the selected days of each treatment cycle, for example, the platinum compound (e.g., carboplatin) is administered daily for the period of 1 (or 2, 3, 4, 5, 6, 7, 8, 9, 10) days of the treatment cycle, and the platinum compound (e.g., carboplatin) is not administered on other days of the treatment cycle. In some embodiments, the intervals between each administration of carboplatin are less than about any of 6 months, 3 months, 1 month, 21 days, 20 days, 15, days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, there is no break in the dosing schedule. In some embodiments, the interval between each administration is no more than about any of 3 weeks, 2 weeks, or 1 week. In some embodiments, the interval between each administration is about a week, about two weeks, or about three weeks. Carboplatin may be administered (e.g. , at about AUC4) on 1 day of a treatment cycle, e.g., on day 1 of a 21-day treatment cycle.
[0186] In some embodiments of any one of the methods for treating platinum-resistant recurrent ovarian cancer provided herein, the method comprises 15, 12, 10, 9, 8, 7, 6 or fewer dosing cycles, wherein each cycle contains a period of 21 days. In some embodiments, 4- iodo-3-nitrobenzamide or the pharmaceutically acceptable salt thereof is administered at about 5.1 mg/kg to about 8.6 mg/kg on days 1, 4, 8, and 11 of each cycle, the antimetabolite
(e.g., gemcitabine is administered at 1000 mg/m daily on days 1 and 8 of each cycle, and the platinum compound (e.g., carboplatin) is administered at 4 mg/ml»minute (AUC 4) on day 1 of each cycle.
[0187] In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising at least one treatment cycle comprising administering (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin to the patient, wherein (i) carboplatin is administered to the patient at about AUC3 to about AUC5 (e.g., AUC4) once over the treatment cycle (e.g. , on day 1 of a treatment cycle such as a 21-day cycle), wherein
(ii) gemcitabine is administered to the patient at about 500 to about 1500 mg/m (e.g., 1000 mg/m ) twice over the treatment cycle (e.g. , on days 1 and 8 of a treatment cycle such as a 21-day cycle), and wherein (iii) 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered to the patient at about 5 mg/kg to about 20 mg/kg (or about 5 mg/kg to about 15 mg/kg) (e.g., 5.6 mg/kg) once, twice, three times, or four times over the treatment cycle (e.g. , on days 1 and 8 of a treatment cycle such as a 21 -day cycle, or on days 1, 4, 8, and 11 of a treatment cycle such as a 21 -day cycle). In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising at least one treatment cycle comprising administering (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin to the patient, wherein (i) carboplatin is administered to the patient at about AUC4 once over the treatment cycle (e.g., on day 1 of a treatment cycle such as a 21 -day cycle), wherein (ii) gemcitabine is administered to the patient at about 1000 mg/m twice over the treatment cycle (e.g., on days 1 and 8 of a treatment cycle such as a 21 -day cycle), wherein 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered to the patient at about 5.6 mg/kg four times over the treatment cycle (e.g. , on days 1, 4, 8, and 11 of a treatment cycle such as a 21 -day cycle). In some embodiments, there is provided a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising at least one treatment cycle comprising administering (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin to the patient, wherein (i) carboplatin is administered to the patient at about AUC4 once over the treatment cycle (e.g., on day 1 of a treatment cycle such as a 21 -day cycle), wherein (ii) gemcitabine is administered to the patient at about 1000 mg/m twice over the treatment cycle (e.g. , on days 1 and 8 of a treatment cycle such as a 21-day cycle), wherein 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered to the patient at about 11.2 mg/kg twice over the treatment cycle (e.g. , on days 1 and 8 of a treatment cycle such as a 21 -day cycle).
Kits, articles of manufacture, and uses
[0188] Also provided are kits and articles of manufacture for administration of 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, a antimetabolite such as gemcitabine and a platinum compound such as carboplatin as provided herein. In some embodiments, the kits or articles of manufacture comprise (i) 4-iodo-3- nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, (ii) an antimetabolite (e.g., gemcitabine), and (iii) a platinum compound (e.g., carboplatin) for treating platinum-resistant recurrent ovarian cancer in a patient. Any of the kits described herein may further comprise instructions (e.g., on a product insert, a package insert or a label) for using (i) 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, (ii) gemcitabine, and (iii) carboplatin in accordance with any of the methods provided herein. In some embodiments, the kits comprise 4-iodo-3-nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof and a product or package insert or a label comprising instructions and/or information for using 4-iodo-3- nitrobenzamide, or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof in combination with gemcitabine and carboplatin in accordance with any of the methods described herein for treating platinum-resistant recurrent ovarian cancer in a patient.
[0189] For example, the kit may comprise instructions for treating platinum-resistant recurrent ovarian cancer in a patient, comprising at least one treatment cycle comprising administering (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin to the patient, wherein (i) carboplatin is administered to the patient at about AUC3 to about AUC5 once over the treatment cycle (e.g., on day 1 of a treatment cycle such as a 21 -day cycle), wherein (ii) gemcitabine is administered to the patient at about 500 to about 1500 mg/m twice over the treatment cycle (e.g., on days 1 and 8 of a treatment cycle such as a 21 -day cycle), and wherein (iii) 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered to the patient at about 5 mg/kg to about 20 mg/kg (or about 5 mg/kg to about 15 mg/kg) once, twice, three times, or four times over the treatment cycle (e.g., on days 1 and 8 of a treatment cycle such as a 21 -day cycle, or on days 1, 4, 8, and 11 of a treatment cycle such as a 21 -day cycle). In some embodiments, the treatment comprises a 21 -day treatment cycle, wherein (i) carboplatin is administered to the patient at 4 mg/ml»minute (AUC 4) on day 1 of the treatment cycle; (ii) gemcitabine is administered to the patient at a dose of 1000 mg/m on days 1 and 8 of the treatment cycle; and (iii) 4-iodo-3- nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 5.6 mg/kg twice weekly on days 1, 4, 8, and 11 of the treatment cycle. In some embodiments, the platinum-resistant recurrent ovarian cancer is epithelial ovarian carcinoma. In some embodiments, the platinum-resistant recurrent ovarian cancer is fallopian tube cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is primary peritoneal carcinoma. In some embodiments, the patient has a relapse within about 2 to about 6 months (e.g., a relapse within 2 to 6 months or a relapse within about any of 2 months, 2.5 months, 3 months, 3.5 months, 4 months, 4.5 months, 5 months, 5.5 months, or 6 months) after last dose of platinum-based chemotherapy. In some embodiments, the patient has measurable disease. In some embodiments, the patient has not received more than 2 prior platinum-based therapies.
[0190] In certain embodiments, the kits may include a dosage amount of at least one composition as disclosed herein. Kits may further comprise suitable packaging and/or instructions for use of the formulation. Kits may also comprise a means for the delivery of the formulation thereof.
[0191] The kits may include other pharmaceutical agents (such as the side-effect limiting agents, chemotherapy agents, gene therapy agents, DNA therapy agents, RNA therapy agents, viral therapy agents, nanotherapy agents, small molecule enzymatic inhibitors, anti-metastatic agents, etc.), for use in conjunction with 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (e.g. , gemcitabine) provided herein, and a platinum compound (e.g. , carboplatin) provided herein. These agents may be provided in a separate form, or mixed with 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (e.g., gemcitabine) provided herein, and a platinum compound (e.g. , carboplatin) provided herein, provided such mixing does not reduce the effectiveness of 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof), an antimetabolite (e.g. , gemcitabine) provided herein or a platinum compound (e.g., carboplatin) provided herein, and is compatible with the route of administration. Similarly, the kits may include additional agents for adjunctive therapy or other agents known to the skilled artisan as effective in the treatment or prevention of platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer) described herein.
[0192] The kits may optionally include appropriate instructions for preparation and administration of the composition, side effects of the composition, and any other relevant information. The instructions may be in any suitable format, including, but not limited to, printed matter, videotape, computer readable disk, optical disc or directions to internet-based instructions.
[0193] In another aspect, provided are kits for treating a patient who suffers from or is susceptible to the platinum-resistant ovarian cancer (e.g. , recurrent ovarian cancer) described herein, comprising a first container comprising a dosage amount of a formulation as disclosed herein, and instructions for use. The container may be any of those known in the art and appropriate for storage and delivery of intravenous formulation. In certain embodiments, the kit further comprises a second container comprising a pharmaceutically acceptable carrier, diluent, adjuvant, etc. for preparation of the composition to be administered to the patient.
[0194] Kits may also be provided that contain sufficient dosages of 4-iodo-3- nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof (including formulation thereof) as disclosed herein to provide effective treatment for a patient for an extended period, such as 1-3 days, 1-5 days, a week, 2 weeks, 3, weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or more.
[0195] Kits may also include multiple doses of any of the compounds described herein and instructions for use and packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.
[0196] The kits may include the compounds as described herein packaged in either a unit dosage form or in a multi-use form. The kits may also include multiple units of the unit dose form. In certain embodiments, provided are the compound described herein in a unit dose form. In other embodiments the compositions may be provided in a multi-dose form (e.g., a blister pack, etc.).
[0197] The examples below are intended to be purely exemplary of the invention and should therefore not be considered to limit the invention in any way. The following examples and detailed description are offered by way of illustration and not by way of limitation. Additional examples can be found in U.S. Patent Publication No. US 2009/0123419 Al, which is incorporated herein by reference.
EXAMPLES Example 1: Phase II study of 4-iodo-3-nitrobenzamide in combination with gemcitabine and carboplatin in platinum-resistant recurrent ovarian cancer.
[0198] A Phase II trial to evaluate the efficacy of 4-iodo-3-nitrobenzamide (BA) in combination with gemcitabine and carboplatin in the treatment of platinum-resistant recurrent ovarian cancer is conducted. Platinum-resistance is defined by relapse or recurrence of ovarian cancer two to six months after receiving the last dose of a platinum-based
chemotherapeutic.
[0199] Primary Endpoint: To evaluate the objective response rate (ORR) of
gemcitabine/carboplatin in combination with 4-iodo-3-nitrobenzamide [ Time Frame: Until progressive disease or death ] .
[0200] Secondary Endpoints: (1) To determine the nature and degree of toxicity of gemcitabine/carboplatin in combination with 4-iodo-3-nitrobenzamide [ Time Frame: 30 days after last 4-iodo-3-nitrobenzamide exposure ]; (2) To evaluate progression-free survival (PFS) of gemcitabine/carboplatin in combination with 4-iodo-3-nitrobenzamide
[ Time Frame: until progressive disease or death ].
[0201] Inclusion Criteria: (1) At least 18 years of age; (2) Histological diagnosis of epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma; (3) Completion of only one previous course of chemotherapy which contained a platinum therapy, with resistance to that regimen. "Platinum-resistance" is defined by a relapse within 2 to 6 months after termination of platinum-based chemotherapy; (4) Measurable disease, defined by at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded), and is > 20 mm when measured by conventional techniques (palpation, plain x-ray, computed tomography [CT], or magnetic resonance imaging [MRI]) or > 10 mm when measured by spiral CT; (5) Adequate organ function defined as: absolute neutrophil count (ANC) > l,500/mm3, platelets > 100,000/mm3, creatinine clearance > 50mL/min, alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) < 2.5 x upper limit of normal (ULN; or < 5 x ULN in case of liver metastases); total bilirubin < 1.5 mg/dL; (6) For women of child bearing potential, documented negative pregnancy test within two weeks of study entry and agreement to acceptable birth control during the duration of the study therapy; (7) Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2; and (8) Signed, institutional review board (IRB) approved written informed consent. [0202] Exclusion Criteria: (1) Concurrent invasive malignancy, not including: (i) Non- melanomatous skin cancer; (ii) In situ malignancies; (iii) Concurrent superficial endometrial carcinoma, if their endometrial carcinoma is superficial or invades less than 50% the thickness of the myometrium); (iv) Low risk breast cancer (localized, non-inflammatory) treated with curative intent; (v) Lesions identifiable only by positron emission tomography (PET); (vi) Prior treatment with poly (ADP-ribose) polymerase (PARP) inhibitors, including 4-iodo-3-nitrobenzamide; (vii) Major medical conditions that might affect study participation (i.e., uncontrolled pulmonary, renal, or hepatic dysfunction, uncontrolled infection); (viii) Other significant co-morbid condition which the investigator feels might compromise effective and safe participation in the study, including a history of congestive cardiac failure or an electrocardiogram (ECG) suggesting significant conduction defect or myocardial ischemia; (ix) Enrollment in another investigational device or drug study, or current treatment with other investigational agents; (x) Concurrent radiation therapy to treat primary disease throughout the course of the study; (xi) Inability to comply with the requirements of the study; (xii) Pregnancy or lactation; and (xiii) Leptomeningeal disease or brain metastases requiring steroids or other therapeutic intervention. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
[0203] A maximum of 48 patients with platinum-resistant recurrent ovarian cancer will be treated in this study using a Simon two-stage design. The primary endpoint is an improved overall response rate compared to patients receiving treatment with gemcitabine and carboplatin alone determined using historical data from a previous trial. The secondary endpoints are improved progression-free survival and patient safety. The exploratory endpoints are BRCA status and translational medicine.
[0204] During the first stage, study participants (n=23) received 4-iodo-3-nitrobenzamide intravenously at a dose of 5.6 mg/kg on days 1, 4, 8, and 11 of each cycle, gemcitabine at a dose of 1000 mg/m on days 1 and 8 of each cycle, and carboplatin at AUC 4 (i.e., at 4 mg/ml»minute) on day 1 of each cycle.
[0205] Fourteen patients have been enrolled in this trial to date. The combination therapy was well-tolerated, with low grade nausea the most common side effect. After a minimum of four cycles/twelve weeks, the overall response rate was 21%, with 8 of 14 patients having stable disease and 3 of 14 in either complete or partial remission. Median follow-up will be performed at twelve weeks. Patients will continue with additional cycles of treatment as long as they have stable or responding disease (per RECIST criteria) and wish to remain on study. A minimum of 4 responses at the first stage of the trial are required before proceeding to the second stage (n=25).
Example 2: Phase II study of 4-iodo-3-nitrobenzamide in combination with gemcitabine and carboplatin in platinum-resistant recurrent ovarian cancer.
[0206] A Phase 2, multi-center, single-arm, safety and efficacy study in which up to 48 subjects are enrolled using a Simon two-stage design (n = 23 in Stage 1, and n = 25 in Stage 2) is conducted. Same treatment regimen is administered at each stage.
[0207] The primary objective of this study is to evaluate the objective response rate (ORR) of gemcitabine/carboplatin in combination with 4-iodo-3-nitrobenzamide. The secondary objectives of this study are (1) to determine the nature and degree of toxicity of
gemcitabine/carboplatin in combination with 4-iodo-3-nitrobenzamide and (2) to evaluate progression-free survival (PFS). The exploratory objectives may include relationship of BRCA status with response.
[0208] All dosing regimens are repeated on a 21 -day cycle: carboplatin (AUC 4; 60-minute intravenous ("IV") infusion) on Day 1, gemcitabine (1000 mg/m ; 30-minute IV infusion) on Days 1 and 8, and 4-iodo-3-nitrobenzamide (5.6 mg/kg; 60-minute IV infusion) on Days 1, 4, 8, and 11 of each 21 -day cycle.
[0209] Eligible subjects must meet the following criteria to be enrolled in the study (inclusion criteria): 1) At least 18 years of age; 2) Histological diagnosis of epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma; 3) Completion of only one previous course of cytotoxic chemotherapy which must have contained a platinum therapy, with resistance to that regimen. "Platinum resistance" is defined by a relapse within 2 to 6 months after last dose of platinum-based chemotherapy; 4) Measurable disease, defined by at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded), and is > 20 mm when measured by conventional techniques (palpation, plain x-ray, computed tomography (CT), or magnetic resonance imaging (MRI)) or > 10 mm when measured by spiral CT; 5) Adequate organ function defined as: absolute neutrophil count
(ANC) > 1,500/mm 3 , platelets > 100,000/mm 3 , creatinine clearance > 50mL/min, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN; or < 5 x ULN in case of liver metastases); total bilirubin < 1.5 mg/dL; 6) For women of child bearing potential, documented negative pregnancy test within two weeks of study entry and agreement to acceptable birth control during the duration of the study therapy; 7) Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2; 8) Signed, institutional review board (IRB) approved written informed consent.
[0210] Eligible subjects must not have any of the following to be enrolled in the study (exclusion criteria): 1) Concurrent invasive malignancy, not including: (a) non-melanomatous skin cancer; (b) in situ malignancies; (c) concurrent superficial endometrial carcinoma, if their endometrial carcinoma is superficial or invades less than 50% the thickness of the myometrium); (d) low risk breast cancer (localized, non-inflammatory) treated with curative intent; 2) Lesions identifiable only by positron emission tomography (PET); 3) Been treated with more than 2 lines of cytotoxic chemotherapy (i.e. one containing platinum and one non- platinum such as liposomal doxorubicin) and 1 line of biologies such as avastin for up to six months (hormones do not count as a line of treatment); 4) Treatment with
chemotherapy/biologic agent within 3 weeks of enrollment; 5) Prior treatment with 4-iodo-3- nitrobenzamide or poly (ADP-ribose) polymerase (PARP) inhibitors; 6) Major medical conditions that might affect study participation (i.e., uncontrolled pulmonary, renal, or hepatic dysfunction, uncontrolled infection); 7) Other significant co-morbid condition which the investigator feels might compromise effective and safe participation in the study, including a history of congestive cardiac failure or an electrocardiogram ECG) suggesting significant conduction defect or myocardial ischemia; 8) Enrollment in another
investigational device or drug study, or current treatment with other investigational agents; 9) Concurrent radiation therapy to treat primary disease throughout the course of the study; 10) Inability to comply with the requirements of the study; 11) Pregnancy or lactation; 12) Leptomeningeal disease or brain metastases requiring steroids or other therapeutic intervention.
[0211] Treatment continues for at least 6 cycles in the absence of disease progression or unacceptable toxicity. Subjects can continue for an additional 4 cycles, up to a possible 10 cycles, at physician's discretion. 4-iodo-3-nitrobenzamide can be continued beyond 10 cycles, as maintenance at physician discretion, until progressive disease (PD). Subjects that discontinue treatment before PD will undergo regular staging evaluation for objective response rate every 90 (±10) days until PD or death.
[0212] The first scheduled tumor response measurement for measurable disease is performed after every other cycle or approximately every 6 weeks, in addition to initial staging at baseline. Tumor response according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) is used to establish disease progression by CT or MRI (the same technique used during screening must be used). Example 3: Phase II study of 4-iodo-3-nitrobenzamide in combination with gemcitabine and carboplatin ("GC") in platinum-resistant recurrent ovarian cancer.
[0213] Methods: This multicenter, single-arm phase 2 study used a Simon two-stage design (Stage I n=25; total N=48). Eligible patients were >18 years with a histological diagnosis of epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma and had platinum-resistant disease, defined as relapse 2 to 6 months following primary treatment termination. Carboplatin (AUC 4; intravenous ("IV"); days 1), gemcitabine (1000 mg/m ; IV; days 1 and 8), and 4-iodo-3-nitrobenzamide (5.6 mg/kg; IV; days 1, 4, 8, and 11) were given on a 21 -day cycle. The primary endpoint was overall response rate ("ORR"; RECIST 1.0); secondary endpoints were safety and progression-free survival ("PFS").
[0214] Results: Analysis from the first 19 patients demonstrated an ORR of 31.6%, consisting of 6 confirmed responses. Early analysis showed a median PFS of 5.9 months (95% CI, 3.0-NE). Safety profiles were consistent with those observed in previous clinical studies of 4-iodo-3-nitrobenzamide in combination with gemcitabine and carboplatin.
[0215] Conclusions: 4-iodo-3-nitrobenzamide in combination with gemcitabine and carboplatin demonstrated activity in patients with platinum-resistant recurrent ovarian cancer, with promising evidence of response (ORR=31.6%) and substantial increase in median PFS (5.9 months) compared with a previous study of pegylated lioposomal doxorubicin in platinum-resistant recurrent ovarian cancer (ORR=11.7%; median PFS=3.1 months; Mutch et ah, J Clin Oncol 2007, 25:2811-2818). No unexpected toxicities were reported.
Example 4: Chemosensitizing properties of 4-iodo-3-nitrobenzamide in combination with gemcitabine ("G") and carboplatin ("C") in OVCAR-3 ovarian adenocarcinoma
[0216] Methods: The chemosensitizing properties of a single dose of 4-iodo-3- nitrobenzamide were evaluated in combination with gemcitabine and carboplatin against OVCAR-3 ovarian adenocarcinoma 72 hours after treatment. Cell proliferation was evaluated with FACS-based cell cycle analysis, including DNA staining and bromodeoxyuridine (BrdU) incorporation. Apoptotic cells were quantified by TUNEL staining.
[0217] Results: FACS analysis showed that 4-iodo-3-nitrobenzamide potentiated apoptosis induced by gemcitabine or carboplatin in OVCAR-3 cells (Table 1). Combination of 4-iodo- 3-nitrobenzamide with gemcitabine + carboplatin enhanced apoptosis and induced S-phase cell cycle arrest in OVCAR-3 cells. Table 1:
Figure imgf000078_0001
- data represent % cells from total population of viable cells
[0218] Conclusions: These data demonstrate the potentiation of the antiproliferative and pro-apoptopic activities of carboplatin and gemcitabine by 4-iodo-3-nitrobenzamide in OVCAR-3 cells. They support the clinical investigation of 4-iodo-3-nitrobenzamide in combination with these DNA-damaging agents.
Example 5: Phase II study of 4-iodo-3-nitrobenzamide in combination with gemcitabine and carboplatin ("GC") in platinum-resistant recurrent ovarian cancer.
[0219] This multicenter, single-arm phase 2 study used a Simon two-stage design (N=48). The preliminary analysis was based on the first 34 patients enrolled. The study design and treatment schedule are shown in Figure 1. Carboplatin (AUC 4; intravenous ("IV"); day 1), gemcitabine (1000 mg/m ; IV; days 1 and 8), and 4-iodo-3-nitrobenzamide (5.6 mg/kg; IV; days 1, 4, 8, and 11) were given on a 21-day cycle.
[0220] Eligible patients were >18 years with epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma and demonstration of platinum-resistant disease, defined as relapse with in 2-6 months after last dose of platinum-based chemotherapy.
Eligible patients had measurable disease. Patients had at least 1 but not more than 2 prior therapies (platinum-based). Patients with or without BRCA mutations were eligible. Eligible patients had ECOG PS 0-2.
[0221] The primary endpoint was objective response rate ("ORR") based on patients who received at least 1 dose of study drug and had 2 post-baseline assessments or
progression/death with in 60 days of last assessment. The second endpoints were (i) progression free survival ("PFS") based on patients who received at least 1 dose of study drug and had 1 post -baseline assessment or progression/death within 60 days of last assessment and (ii) safety based on all patients who received at least 1 dose of study drug (NCTCTCAE v3.0). The exploratory endpoint was relationship between BRCA status and response.
[0222] This study used Simon two- stage design which was designed to detect an improvement in ORR from 15% to 30%. An estimated historical control ORR of 11.7% (Mutch et al. J Clin Oncol 2007, 19: 2811-2818) was assumed in this platinum-resistant patient population. 34 of 48 patients were enrolled and the trial was ongoing when the data included in this Example were collected. The patient characteristics are shown in Table 2. TABLE 2 Baseline Patient Characteristics
Figure imgf000079_0001
0/1/2 9 (27) / 23 (70)/ 1 (3)
Tumor grade, %
Grade 1/2/3 0/9/91
Histology, n (%)
Serous 22 (65)
Endometrioid 2(6)
Clear Cell 2(6)
Other 7(22)
[0223] BRCA status for the patients is shown in Table 3.
TABLE 3 BRCA Status
Figure imgf000080_0001
*Percentages based on the number of patients with BRCA tested.
[0224] The efficacy data based on efficacy population (n=32) are shown in Table 4. TABLE 4 Response - Efficacy Population
Figure imgf000080_0002
Tumor response measured ~ after every other cycle according to RECIST 1.1.
[0225] The response data based on BRCA 1/2 mutation status are shown in Table 5.
TABLE 5 Response by Mutation Status - Efficacy Population
Figure imgf000080_0003
not known 1 (12.5) 0 0 0
ORR† 50% - 17% 19%
CBR† 75% 100% 83% 81%
Response Evaluable (n= 32); Tumor response measured ~ a ter every other cycle according to
RECIST 1.1.
[0226] Figure 2 shows best target lesion response for response evaluable patients (n=32). The BRCA status for the response evaluable patients shown in Figure 2 is shown in Figures 3 and 4. The median progress-free survival ("PFS") for PFS evaluable patients (n=32) was 6.44 months. See Figure 5.
[0227] The treatment emergent adverse events ("AEs") are shown in Table 6.
TABLE 6 All Treatment Emergent Adverse Events* (>10%)
Figure imgf000081_0001
* Regardless of relationship; Safety population
[0228] The dosing information for patients (n=33) is shown in Table 7.
Table 7 Dosing
Figure imgf000081_0002
[0229] There were no deaths on study or within 60 days of the last dose of study drug. 15 patients (43%) experienced a serious treatment emergent adverse event (SAEs)
(thrombocytopenia, anemia, small intestinal obstruction, and nausea were most common). For 26% (9 patients), the SAEs were considered related to study drug, which included the following Grade 3/4 events: thrombocytopenia, anemia, nausea, vomiting, small intestinal obstruction, fatigue, dehydration, and hypokalemia.
[0230] In summary, based on this preliminary analysis, treatment using 4-iodo-3- nitrobenzamide in combination with gemcitabine and carboplatin demonstrated activity in patients with platinum-resistant recurrent ovarian cancer. For the 32 patients evaluable for response, ORR was 25% (8/32) and CBR was 81% (26/32). Responses were observed in both BRCA mutant and wild type patients. The safety profiles were consistent with those observed in prior clinical studies with gemcitabine and carboplatin. Further randomized studies were warranted with this combination.
[0231] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS WHAT IS CLAIMED IS:
1. A method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient having the platinum-resistant recurrent ovarian cancer an effective amount of: (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a
pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin.
2. The method of claim 1, wherein the patient has a relapse within 2 to 6 months after last dose of platinum-based chemotherapy.
3. The method of claim 1 or 2, wherein the treatment comprises at least about 2 treatment cycles, wherein each of the cycles comprises administering (i) 4-iodo-3- nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin.
4. The method of any one of claims 1-3, wherein the platinum-resistant recurrent ovarian cancer is epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma.
5. The method of any one of claims 1-4, wherein the patient has not received more than 2 prior platinum-based therapies.
6. The method of any one of claims 1-5, wherein the patient has measurable disease.
7. The method of any one of claims 1-6, wherein the effective amount produces at least one therapeutic effect selected from the group consisting of reduction in size of an ovarian tumor, reduction in metastasis, complete remission, partial remission, stable disease, and a pathologic complete response.
8. The method of any one of claims 1-7, further comprising surgery, radiation therapy, chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, adjuvant therapy, neoadjuvant therapy, immunotherapy, nanotherapy or a combination thereof.
9. The method of any one of claims 1-8, further comprising administering to the patient gamma irradiation.
10. The method of any one of claims 1-9, wherein the platinum-resistant recurrent ovarian cancer is selected from the group consisting of epithelial, germ cell, and stromal cell tumors.
11. The method of any one of claims 1-10, wherein the platinum-resistant recurrent ovarian cancer is metastatic.
12. The method of any one of claims 1-11, wherein 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof is administered
intravenously.
13. The method of any one of claims 1-12, wherein gemcitabine is administered intravenously.
14. The method of any one of claims 1-13, wherein carboplatin is administered intravenously.
15. The method of claim 14, wherein the effective amount is administered over a 21 -day treatment cycle, wherein (i) carboplatin is administered to the patient at 4
mg/ml»minute (AUC 4) on day 1 of the treatment cycle; (ii) gemcitabine is administered to the patient at a dose of 1000 mg/m on days 1 and 8 of the treatment cycle; and (iii) 4-iodo-3- nitrobenzamide is administered to the patient at a dose of 5.6 mg/kg twice weekly on days 1, 4, 8, and 11 of the treatment cycle.
16. A kit for treating platinum-resistant recurrent ovarian cancer in a patient comprising (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin.
17. The kit of claim 16 further comprising instructions for using an effective amount of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin to treat platinum-resistant recurrent ovarian cancer in the patient.
18. The kit of claim 17, wherein the effective amount is administered over a 21- day treatment cycle, wherein (i) carboplatin is administered to the patient at 4 mg/ml»minute (AUC 4) on day 1 of the treatment cycle; (ii) gemcitabine is administered to the patient at a dose of 1000 mg/m on days 1 and 8 of the treatment cycle; and (iii) 4-iodo-3-nitrobenzamide is administered to the patient at a dose of 5.6 mg/kg twice weekly on days 1, 4, 8, and 11 of the treatment cycle.
19. A kit comprising (i) 4-iodo-3-nitrobenzamide, a metabolite or a
pharmaceutically acceptable salt thereof and (ii) instructions for using an effective amount of 4-iodo-3-nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof in combination with gemcitabine and carboplatin for treating platinum-resistant recurrent ovarian cancer in a patient.
20. The kit of claim 19, wherein the effective amount is administered over a 21- day treatment cycle, wherein (i) carboplatin is administered to the patient at 4 mg/ml»minute (AUC 4) on day 1 of the treatment cycle; (ii) gemcitabine is administered to the patient at a dose of 1000 mg/m on days 1 and 8 of the treatment cycle; and (iii) 4-iodo-3-nitrobenzamide is administered to the patient at a dose of 5.6 mg/kg twice weekly on days 1, 4, 8, and 11 of the treatment cycle.
21. The kit of any one of claims 16-20, wherein the platinum-resistant recurrent ovarian cancer is epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma.
22. The kit of any one of claims 16-21, wherein the patient has a relapse within 2 to 6 months after last dose of platinum-based chemotherapy.
23. The kit of any one of claims 16-22, wherein the patient has measurable disease.
24. The kit of any one of claims 16-23, wherein the patient has not received more than 2 prior platinum-based therapies.
25. The kit of any one of claims 17-24, wherein the effective amount produces at least one therapeutic effect selected from the group consisting of reduction in size of an ovarian tumor, reduction in metastasis, complete remission, partial remission, stable disease, and a pathologic complete response.
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