TW201206449A - 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

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

201206449 VI. Description of the invention: [Related application] This application claims the US provisional application No. US 61/351,772 submitted on June 4, 2010 and the US (4) application submitted on May 2nd of the year. The priority rights of US 61/481, 632, each of which is incorporated herein by reference in its entirety. [Prior Art] Cancer is a complex family of diseases that affect almost every tissue in the body and is characterized by abnormal control of cell growth. The annual incidence of all cancer types is estimated to be more than 130,000 in the United States alone. Although a variety of first-line therapies have been used to treat different types of cancer with varying degrees of success, including surgical resection, radiation therapy, chemotherapy, and hormonal therapy, it is still the second leading cause of death in the United States, estimated annually. 560,000 Americans have died of cancer. Ovarian cancer is the 8th most common cancer among women worldwide, with an estimated 225,500 new diagnoses per year and an estimated 14 weeks per year, with 2 deaths. The current standard of care for first-line chemotherapy for ovarian cancer is the combination of platinum compounds (such as cisplatin, cadmium and aixaiipiatin) and taxane. Most newly diagnosed ovarian cancer patients respond to first-line chemotherapy based on paclitaxel. However, 50-80% of patients who respond to this combination therapy will eventually relapse. See, for example, Herzog, "Update on the role of topotecan in the treatment of recurrent ovarian cancer j 5 The Oncologist 7 (Supp. 5): 3-10 (2002). Women with advanced ovarian cancer relapse due to disease 156511.doc 201206449 and Has a poor long-term survival rate and mostly dies within 5 years. There is a clear need for current treatment options for improving recurrent ovarian cancer. SUMMARY OF THE INVENTION [0005] Provided herein is a method of treating platinum-resistant recurrent nested cancer in a patient, including administration An effective amount of (i) 4_iodo-3-nitr〇benzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof in the ovarian cancer patient; η) gemcitabine; and (iii) carboplatin. In some embodiments, the platinum-resistant recurrent ovarian cancer is epithelial ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is fasciola Tube (faU〇pian than ", that is, fallopian tube" cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is primary peritoneal cancer. In some embodiments, the treatment comprises at least one treatment cycle (eg, at least about 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, (7) cycles, 11 cycles, 12 cycles, 13 cycles, 14 cycles, 15 cycles, 16 cycles, π cycles, or 18 cycles), each of which (or Each of the equal periods includes the administration of an effective amount of (〇' iodo-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof; (Π) gemcitabine; and (iii) Carboplatin. In some embodiments, the treatment comprises at least about 2 (eg, from about 4 to about 12) treatment cycles, wherein each of the cycles comprises administering an effective amount of (1) 4 · iodine _ 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 two prior platinum-based Therapy. In some embodiments, the patient is 2 to 6 months after the last dose of platinum-based chemotherapy. Recurrence. In some embodiments, the 156511.doc

S -4- 201206449 The effective amount is administered over a 21-day treatment period in which (1) carboplatin is administered to the patient at 4 mg/ml Tnin (AUC 4) on the first day of the treatment cycle; (ii) gemcitabine is in the treatment The patient is administered at a dose of 1 〇〇〇 mg/m 2 on days 1 and 8 of the cycle; and (iii) 4-iodo-3-nitrobenzamide or a metabolite thereof or pharmaceutically acceptable The salt is administered to the patient twice a week at the dose of 5.6 mg/kg on Days 1, 4, 8 and 11 of the treatment cycle. In some embodiments, the effective amount produces at least one The treatment effect of the following groups is selected: ovarian tumor shrinkage, reduced metastasis, complete remission, partial remission, 'sickness of disease', overall response rate, or path 〇 complete response (path〇i〇gic 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 the patient gamma radiation. In some embodiments, the patient has platinum-resistant recurrent ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer line is selected from the group consisting of epithelial tumors, germ cell tumors, and stromal tumors. In some embodiments, the platinum-resistant recurrent ovarian cancer is metastatic. In some embodiments, the patient has platinum-resistant recurrent ovarian cancer. In some embodiments, 4_iodo-3-nitrosocarbamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof, is administered intravenously. In some embodiments, butacitabine is administered intravenously. In some embodiments, carboplatin is administered intravenously. In some embodiments, the patient has a measurable disease. In some embodiments, the treatment provides increased clinical benefit compared to treatment with gemcitabine and carboplatin but without 4-iodo-3-nitrobenzamide 156511.doc 201206449 rate. In some embodiments, an improved clinical benefit rate (CBR = CR (complete remission) + PR) compared to treatment with gemcitabine and carboplatin but without 4-iodo-3-nitrobenzamide is obtained. (partial relief) + SD (stable disease) 26 months). In some embodiments, the clinical benefit rate is increased by 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 reaction rate is greater than 20°/〇. In some embodiments, the overall reaction rate is greater than 30 〇/〇. In some embodiments, the patient has platinum-resistant recurrent ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is defective in homologous recombinant DNA repair. In some embodiments, 'homologous recombinant DNA repair-deficient platinum-resistant recurrent ovarian cancer is BRCA-deficient. In some embodiments, the BRCA-deficient platinum-resistant recurrent ovarian cancer is brcAI-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 a BRCA1 deficient and a BRCA2 deficient. Also provided herein is the use of any of the pharmaceutical compositions described herein for the manufacture of a medicament for the treatment of platinum-resistant recurrent ovarian cancer. For example, the uses provided herein are related or consistent with any of the methods described herein. Also provided herein are (i) 4-iodo-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt or solvate thereof and an antimetabolite, a pharmaceutically acceptable salt thereof or Either of the solvates and (in) a combination of any of the compounds described herein, a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture or treatment of (4) The use of drugs for the printing of nest cancer. Also provided herein are 4 winter 3 _ Shi Xiaoji Benzoylamine, 156511.doc 201206449 or its metabolite or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of an antimetabolite (such as gemcitabine) and a platinum compound. Use of a combination of (e.g., carboplatin) to treat or prevent a platinum-resistant recurrent ovarian cancer as described herein. Also provided herein is 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture or treatment of a platinum-resistant relapse in a patient described herein. Use of a medicament for ovarian cancer, wherein 4-iodo-3-nitrobenzamine, a metabolite thereof or a pharmaceutically acceptable salt or solvate thereof is intended to be an antimetabolite (such as gemcitabine) and a platinum compound ( For example, carboplatin is combined to give to the patient. Also provided herein is a synergistic composition for treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient a) 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable thereof Accepted salts or solvates, b) antimetabolites, and c) platinum compounds, wherein the antimetabolite is selected from the group consisting of citabine, capecitabine, gemcitabine ( Gemcitabine) or valopicitabine, and wherein the platinum compound is selected from the group consisting of cisplatin; cis-diamine dihydrate (II) • ion (cis-diamminediaquoplatinum (II) )-ion); chloro (diethylenetriamine)-platinum (II) chloride; dichloro(ethylenediamine)-start (11) (dichloro (ethylenediamine)-platinum (II)); diamine (1,1-cyclobutanedicarboxylated) platinum (II) (diammine (l, l-cyclobutanedicarboxylato) platinum (11)) (carboplatin); Spiroplatin; iproplatin; diamine (2-ethylmalonate) (II) (diammine(2-ethylmal) Onato)platinum (II)); lS6Sll.doc 201206449 Ethylene diamine malonate (II) (ethylenediaminemalonatoplatinum (II)); hydrated (1,2-diaminobicyclohexan) platinum sulphate (II) (aqua(l,2-diaminodicyclohexane)sulfatoplatinum (II)); hydrated (1,2-diaminodicyclohexanyl)malonate (II) (aqua(l,2-diaminodicyclohexane) malonatoplatinum (II)) (1,2-diaminocyclohexane) malonic acid (II) ((1,2-diaminocyclohexane)malonatoplatinum (II)); (4-carbyl decanoate) (1,2-diamine) (2-carboxyphthalato) (l,2-diaminocyclohexane) platinum (II)); (1,2-diaminocyclohexane)-(isocitric acid) I white (II) ((1,2-diaminocyclohexane)platinum(II)) Ormaplatin; tetraplatin; carboplatin; nedaplatin; and oxaliplatin. Also provided herein are kits for treating platinum-resistant recurrent ovarian cancer in a patient. In some embodiments, the kit comprises (a) 4-iodo-3-nitrobenzamine 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 label comprising an effective amount of (a) 4-iodo-3-nitrobenzamide or a metabolite thereof or any of its metabolites or any of the methods described herein Instructions and/or information for pharmaceutically acceptable salts or solvates, (b) antimetabolites, and (c) compounds. 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 label, Including the use of an effective amount of 4-iodo-3-nitrobenzamide or its substitution 156511.doc in accordance with any of the methods described herein.

S 201206449 Instructions for the use of a compound or a pharmaceutically acceptable salt or solvate thereof in combination with an antimetabolite (eg, gemcitabine) and a platinum compound (eg, carboplatin) to treat platinum-resistant recurrent ovarian cancer in a patient and/or Or information. In some embodiments the 'anti-metabolite is gemcitabine and the cypress compound is a card. In some embodiments, the effective amount is administered over a 21 day treatment period, wherein (1) carboplatin is administered to the patient at 4 mg/ml*min (AUC 4·) on day 1 of the treatment cycle; Π) Gemcitabine is administered to the patient at a dose of 1 mg/m on days 1 and 8 of the treatment cycle; and (1) 丨) 4-iodo-3-nitrobenzamide or a metabolite thereof Or a pharmaceutically acceptable salt is administered to the patient twice a week at a dose of 5.6 mg/kg on Days 1, 4, 8, and 11 of the treatment cycle. In some embodiments, the platinum-resistant recurrent ovarian cancer is an epithelial ovarian cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is Faye's parietal carcinoma. In some embodiments, the platinum-resistant recurrent ovarian cancer is primary peritoneal cancer. In some embodiments, the patient has relapsed within 2 to 6 months after the last dose of platinum-based chemotherapy. In some embodiments, the patient has a measurable disease. In some embodiments, the patient has not received more than two prior face-based therapies. It will be appreciated that one, some or all of the features of the various embodiments described herein may be combined to form other embodiments of the invention. These and other aspects of the invention will become apparent to those skilled in the art. All publications and patent applications mentioned in this specification are hereby incorporated by reference in their entirety in their entirety in the the the the the the Incorporate in general. 156511.doc • 9-201206449 [Embodiment] The novel features of the present invention are set forth in the appended claims. The features and advantages of the present invention will become more apparent from the <RTIgt; The term "platinum_resistant" as used herein refers to a type of ovarian cancer (e.g., recurrent ovarian cancer). The current standard of care for first-line chemotherapy for ovarian cancer is the combination of Ming compounds (such as cis, carboplatin and oxaliplatin) with taxanes. Most newly diagnosed ovarian cancer patients respond to first-line platinum-based and paclitaxel chemotherapy. However, 50-80% of patients who respond to this combination therapy will eventually relapse. See, for example, jjerzog, "Update on the role of topotecan in the treatment of recurrent ovarian cancer" 77ie W 7 (Supp. 5): 3-10 (2002). Patients who relapse within 6 months are unlikely to respond to a second round of platinum-based therapy. Therefore, if recurrence occurs more than 6 months after the last dose of platinum-based therapy, the recurrent advanced ovarian cancer tumor is classified as "platinum sensitivity"; if recurrence occurs after the last dose of platinum-based therapy Or equal to 6 months, it is classified as "platinum resistance"; if there is no reaction or disease regression during the initial platinum-based therapy, it is classified as "platinum-refractory". As used herein, "surgery" refers to any treatment or diagnostic procedure involving the action of a hand or hand and a device on the body of a human or other mammal to produce a healing, remedy or diagnostic effect. "Radiotherapy" refers to exposure of a patient to high-energy radiation, including but not limited to 156511.doc -10· 201206449 Λ x-rays, gamma rays, and neutrons. Such therapies include, but are not limited to, external beam therapy, internal radiation therapy, implantable radiation, brachytherapy, systemic radiation therapy, and radiation therapy. "Chemotherapy" refers to the use of various methods to treat pure (four) nest cancer (such as complex Patients with ovarian cancer are administered one or more anti-cancer drugs, such as anti-neoplastic chemotherapeutics, chemopreventive agents, and/or other agents, including intravenous, oral, intramuscular, intraperitoneal, intravesical, Subcutaneous, transdermal, buccal or inhalation or in the form of a suppository. "Chemotherapy" as used herein does not mean, as described herein, the administration of 4 winter 3-nitrobenzamide, antimetabolite (eg, gemcitabine), and platinum compounds (eg, carboplatin). Chemotherapy may be administered prior to surgery to reduce it prior to surgical procedures for resection of large tumors, prior to radiation therapy, or after surgery and/or radiation therapy to prevent the growth of any residual printed cancer cells in the body. Chemotherapy can also occur during the radiation therapy process. The term "effective amount" means "a pharmaceutically effective amount" means an amount of an agent sufficient to provide the desired biological, therapeutic and/or prophylactic effect. This effect may be a reduction and/or alleviation of one or more signs, symptoms or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is a) 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt or solvate thereof, b) An antimetabolite (eg, gemcitabine) or a pharmaceutically acceptable salt or solvate thereof, and c) a chain compound (eg, a cardinal) or a &amp;) 4 moth-3-nitrophenylhydrazine provided herein An amine or a metabolite thereof or a pharmaceutically acceptable salt thereof; or 156511.doc 201206449 solvate, b) an antimetabolite (such as gemcitabine) or a pharmaceutically acceptable salt or solvate thereof, and c) Compositions of platinum compounds (e.g., carboplatin) are clinically significant in reducing the amount of platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer) or slowing the progression of platinum-resistant ovarian cancer (e.g., recurrent ovarian cancer). &quot;metabolite&quot; refers to a compound produced by any in vitro or in vivo metabolic process that produces a product that is structurally distinct from the starting compound. In other words, the term "metabolite" includes a metabolite compound of 4_iodo-3-nitrobenzamide. Metabolites can include a different number or type of substituents present at any position relative to the precursor compound. In addition, the terms "metabolite" and "metabolite compound" are used interchangeably herein. "Pharmaceutically acceptable" means that a material is biologically or otherwise free of defects, that is, the material can be administered to a patient without causing any unwanted biological effects or in a detrimental manner. Any component of the composition interacts. The term "treatment" as used herein and its grammatical synonyms include the realization of therapeutic benefits and/or prophylactic benefits. The therapeutic benefit means the eradication or improvement of the underlying condition being treated. For example, in patients with #resistant nested cancer (e. g., recurrent printed cancer), therapeutic benefits include eradication or amelioration of potential Indian cancer, such as slowing the progression of the printed cancer. In addition, the therapeutic benefit is achieved by eradication or literacy of one or more of the physical symptoms of the underlying condition (eg, (4) nest cancer) such that despite the presence of the patient may still be afflicted with the underlying condition (eg, #巢癌) 'But improvements are still observed in this patient. For prophylactic benefits, patients with risk of developing I self-resistance - nest cancer (eg, recurrent or nestal cancer) or platinum-resistant ovarian cancer (eg recurrent 15651 Ldoc)

S -12- 201206449 A patient with one or more physiological symptoms of the invention of the invention performs the method of the invention or the composition of the invention, even though a diagnosis of a reversal-infected cancer (eg recurrent cancer) may not have been made Also. In some embodiments, the patient being treated has been diagnosed with a neoresistant ovarian cancer (e.g., recurrent ovarian cancer) as described herein. As used herein, a value or parameter includes (and describes) a change to the value or parameter itself. For example, the description of "about X" includes the description of "X". The singular forms "a", "","," It is to be understood that the various aspects and variations of the invention described herein include """ and/or "substantially" and "various". Treatment of ovarian cancer There are two basic types of Indian tumors: epithelial, germ cell, and stromal cell tumors. Epithelial tumors begin with cells that cover the outer surface of the ovary; most ovarian tumors are epithelial tumors. Germ cell tumors originate from the cells that produce the egg. Matrix tumors begin with the cells that make the ovaries together and produce estrogen. 'Significant risk factors for ovarian cancer include defects in homologous recombinant DNA repair, such as mutations in the BRCA1 or BRCA2 genes. These genes were originally identified in a family with multiple breast cancers, but have been linked to approximately 5% to 10,000% of ovarian cancer. Possible treatments for ovarian cancer include surgery, immunotherapy, chemotherapy, 156511.doc 201206449, therapy, radiation therapy, or a combination thereof. Surgical procedures for the treatment of ovarian cancer include debulking and unilateral or bilateral oophorectomy and/or unilateral or bilateral salpingectomy. Anticancer drugs that have also been used to treat ovarian cancer include cyclopamine, et〇p〇side, altretamine, and ifosfamide. Hormone therapy with the drug tamoxifen is also used to shrink ovarian tumors. Radiation therapy Depending on the situation, external beam radiation therapy and/or proximity therapy. In one aspect, a method of treating platinum-resistant recurrent nested cancer in a patient is provided herein, comprising administering to the patient 4. Iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable agent thereof Accepted salts, antimetabolites and platinum compounds. In some embodiments, the antimetabolite is selected from the group consisting of citabine, capecitabine, gemcitabine, or valprobine. In some embodiments the 'anti-metabolite is gemcitabine. In some embodiments, the platinum compound is selected from the group consisting of: cisplatin; cis-diamine platinum (II)-ion; chloro (diethylidene triamine)-platinum (11) vapor; Chlorine (ethylidene diamine) platinum (11); diamine (1,1-cyclobutanedicarboxylate) platinum (11) (carboplatin); spiroplatin; isopropran; diamine (2-ethyl Malonate)platinum (11); ethylidene diamine malonate platinum (11); hydrated (1,2-diaminodicyclohexane) platinumplatinum (π); hydrated (12-diamine Dicyclohexane) Platinum malonate (11); (1,2-diaminocyclohexane) Platinum malonate (Π); (4-carboxydecanoate) (1,2-diamino ring) Hexane) (11); (1,2-diaminocyclohexane)·(isocitrate)platinum (Π); (1,2-diaminocyclohexane)platinic acid platinum (Η); Platinum; tetraplatin; carboplatin; nedaplatin; and oxaliplatin, and preferably carbohydrate or oxaliplatin. In some embodiments, the platinum compound is a card face. For example, 'provides a way to treat platinum-resistant recurrent ovarian cancer in patients 156511.doc

•14·201206449 Method, including administration of an effective amount of (1)' — 峨_3_ indeed basic formamide or its shake or its pharmaceutically acceptable sleep* flying metabolism. In some embodiments, the string The string is 4 and (4). Suffering from recurrent carcinogenesis of recurrent cancer. At least a therapeutic effect was obtained in the "skin towel", which at least the effect of the tumor treatment, (4) reduction, complete remission, partial relief of pathological complete response or stable disease. 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 gamma radiation to the patient. In some embodiments, the recurrent resistant cancer cell line is selected from the group consisting of an epithelial tumor, a germ cell tumor, and a stromal cell tumor. In some embodiments, the platinum-resistant recurrent nested cancer is metastatic. In some embodiments, the primary resistant recurrent nested cancer is not metastatic. In some embodiments, the 35 resistant recurrent squamous cell carcinoma comprises an aggressive malignancy. In some embodiments, the platinum-resistant recurrent ovarian cancer does not comprise an aggressive malignancy. In one aspect, the invention provides a method of treating a platinum-resistant ovarian cancer (eg, a primary resistant recurrent ovarian cancer) in a patient, comprising administering an effective amount of a patient having ovarian cancer (eg, chain-resistant ovarian cancer) : (i) 4_iodo-3-nitrobenzoquinone or its metabolite or pharmaceutically acceptable salt; (U) gemcitabine, and (iii) card. In some embodiments, the effective amount is administered within a treatment period of 21 days, wherein (1) an effective amount of carboplatin is administered at 4 mg/m b min (AUC 4) (or about AUC4) on the first day of the treatment cycle. And the patient; (ii) effective 156511.doc •15-201206449 amount of gemcitabine administered at a dose of 10 mg/m 2 (or about 1000 mg/m 2 ) on days 1 and 8 of the treatment cycle The patient; and (out) an effective amount of 4-iodo-3-nitrobenzamine or a metabolite or pharmaceutically acceptable salt thereof on the first, fourth, eighth and first days of the treatment cycle The patient was administered twice a week at a dose of 5.6 mg/kg (or about 5.6 mg/kg). In some embodiments, the effective amount produces at least one therapeutic effect selected from the group consisting of: ovarian tumor size reduction, reduced metastasis, complete remission, partial remission, stable disease, 'total response rate, or pathological complete response . In some embodiments, an improved clinical benefit rate (CBR = CR (complete remission) + PR) is obtained as compared to treatment with gemcitabine and carboplatin but without administration of 4_iodo-1,3-phenylbenzamide. Partial relief) + SD (stable disease) ^ 6 months) In some embodiments, the clinical benefit rate is increased by about 20% or higher. In some embodiments, the therapeutic effect is an increase in overall response rate. In some embodiments, the total reaction rate is greater than 20%. « In some embodiments, the overall reaction rate is greater than 丨 5%. In some embodiments, the overall reaction 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 the patient gamma radiation. In some embodiments, the face resistant ovarian cancer (e.g., platinum resistant recurrent ovarian cancer) is selected from the group consisting of epithelial tumors, germ cell tumors, 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 transferable. In some embodiments, the platinum-resistant ovarian cancer (eg, platinum resistance -16 - 1565 ll.doc)

S 201206449 Recurrent ovarian cancer) is defective in homologous recombinant DNA repair. In some embodiments, the homologous recombinant DNA repair defective platinum-resistant ovarian cancer is BRCA-deficient. In some embodiments, the BRCA-deficient platinum-resistant ovarian cancer is BRCA1-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 a BRCA1-deficient and a BRCA2-deficient. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises a mutation in BRCA1. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises a mutation in BRCA2. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises mutations in BRCA 1 and BRCA2. In some embodiments of any of the methods described herein, platinum-resistant recurrent ovarian cancer is defective in homologous recombinant DNA repair. In some embodiments, the homologous recombinant DNA repair defective platinum-resistant recurrent ovarian cancer is of a BRCA deficient type. In some embodiments, a defect in the BRCA gene is detected in an ovarian cancer patient. In other embodiments, the defect is a genetic defect of 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 BRCAA trap type #H-I·生_巢癌&amp; is BRCA1 A trap type λ is BRCA2 deficient. In some embodiments, a method of treating platinum-resistant recurrent ovarian cancer 156511.doc -17- 201206449 (platinum-resistant recurrent ovarian cancer) comprising administering an effective amount of 4-iodo-3-nitrophenylhydrazine Indoleamine or a metabolite thereof, or a pharmaceutically acceptable salt thereof, an antimetabolite (such as gemcitabine), and a platinum compound (such as carboplatin). In some embodiments, the platinum-resistant recurrent ovarian cancer is epithelial ovarian cancer. In some embodiments, the recurrent resistant ovarian cancer is sputum pelvic carcinoma. In some embodiments, the platinum-resistant recurrent ovarian cancer is primary peritoneal cancer. For example, in some embodiments, a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering an effective amount to a patient having platinum-resistant recurrent ovarian cancer is provided: (i) 4-iodo-3-nitrate Methylbenzamide or a metabolite or pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the ovarian cancer is epithelial ovarian cancer, esculent epithelial carcinoma or primary Peritoneal cancer. In some embodiments, the platinum-resistant recurrent ovarian cancer is serous adenocarcinoma. In some embodiments, the platinum-resistant recurrent ovarian cancer is serous adenocarcinoma ovarian cancer. In some embodiments, the recurrent resistant ovarian cancer is papillary serous ovarian cancer (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 (clear cell ovarian) Cancer). In some embodiments, the patient has a measurable disease (such as a disease measurable according to RECIST 1.1). For example, the measurable disease can be defined by at least one lesion whose at least one dimension (such as the longest dimension) can be accurately measured and when by conventional techniques (eg, palpation, general X-ray, Computed Tomography or Magnetic 18-156511.doc

S 201206449 Resonance Imaging) yO mm when measured or when measured by spiral CT U ^ In some examples, the patient has not previously received more than 2 platinum-based therapies, in some examples, The patient completed only one previous cytotoxic therapy regimen (which must contain platinum therapy and is resistant to the regimen). In the case of a drop, the patient relapsed within 2 to 6 months after the last dose of platinum-based chemotherapy. In some embodiments, the platinum-resistant recurrent ovarian cancer comprises any grade of ovarian tumor, such as any of grades 2, 2 or 3. The grading of ovarian tumors can be according to any method known to those skilled in the art. For example, grade 〇 can refer to a non-invasive tumor or a borderline tumor. A grade 1 tumor may have well differentiated cells (which appear to be very similar to normal tissue) and may be the tumor with the best prognosis. Grade 2 tumors may be moderately well differentiated and may be composed of cells resembling normal tissues. Grade 3 tumors may have the worst prognosis and their cells may be abnormal, called poor differentiation. In some embodiments, patients have not been treated with more than 2 lines of cytotoxic chemotherapy and 1 line of biological products (such as anti-VEGF antibodies, such as bevacizumab) for up to 6 months (hormone is not considered first line therapy). For example, patients have received two cytotoxic chemotherapy, including a platinum-containing and a non-platinum, such as the liposomal doxorubicin. In some embodiments, the patient has not received prior chemotherapy therapy comprising 4_iodo-3-nitrobenzamine or a metabolite or pharmaceutically acceptable salt thereof. In some embodiments, the patient has not received a pARp inhibitor (eg, Olaparib, ABT-888 (Veliparib), AG014699, CEP 9722, MK 4827, KU-0059436 (AZD2281) Or prior chemotherapy of LT-673). In some embodiments, the patient has a compound-free interval of about 2 months, 3 months, 4 months, 5 months, and a bite of 6 156511.doc -19-201206449 months. For example, there may be a period of about 2 months, 3 months, 5 months, or 6 months after the last platinum compound before starting any of the treatments described herein. Other features of a patient that can be treated by any of the methods provided herein are provided in the eligibility criteria of Examples 丨 and 2 of the present invention. The administration scheme of 4_iodo_3_nitrobenzamide or its metabolite or its pharmaceutically acceptable salt, antimetabolite (such as gemcitabine) and platinum compound (such as carboplatin) can be as follows Any dosing schedule or dosing schedule described in the "Formulations, Routes of Administration, and Dosing Schedules" section. In some embodiments of any of the methods described herein, the term "patient" or "individual" refers to a human patient or individual. Reversible recurrent nested cancer can be at 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 chain-resistant recurrent ovarian cancer is in any of stages 1, 2, 3 or 4. In some embodiments, the platinum-resistant recurrent ovarian cancer is in any of the stages la, lb, lc, 2a, 2b, 2c, 3a, 3b, 3c or 4 orders. The stages may be in accordance with any method known to those skilled in the art. For example, the phased approach can be phased as described at http://www.cancer.org/cancer/ 〇variancancer/detailedguide/ovarian-cancer-staging (last visit on May 30, 2011). In some embodiments of any of the methods provided herein, at least one therapeutic effect is obtained. The at least one therapeutic effect is ovarian tumor size reduction, metastasis reduction, complete remission, partial remission, pathological complete response, total response 156511.doc

S -20· 201206449 The rate is high or the disease is stable. In some embodiments, the treatment provides an increased clinical benefit rate compared to treatment without 4-iodo-3-nitrobenzamine or a metabolite thereof or a pharmaceutically acceptable salt thereof. In some embodiments, an increase in clinical benefit rate is obtained as compared to treatment without 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof (CBR=CR +PR+SD&gt;6 months). In some embodiments, the clinical benefit rate is increased by at least about 20% '30% '40%, 50% '60%, 70%, 80% or higher. In some embodiments, the therapeutic effect is an increase in the overall response rate. In some embodiments, the overall reaction rate is increased by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or higher. Any of the clinical efficacy parameters described herein can be measured in accordance with the RECIST version 1.1 standard 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. Incorporated herein. In some embodiments of any of the methods described herein, the method for treating platinum-resistant recurrent ovarian cancer further comprises administering 4-iodo-3-nitro in combination with an antineoplastic agent (or at least one antineoplastic agent) Benzylamine or a metabolite thereof or a pharmaceutically acceptable salt thereof. For example, 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 in combination with at least one other antineoplastic agent Or a pharmaceutically acceptable salt thereof, (b) an antimetabolite (eg, gemcitabine), and (c) a platinum complex (eg, carboplatin). In some embodiments, the antineoplastic agent is an anti-tumor alkylating agent, an anti-tumor antimetabolite, an anti-tumor antibiotic, a plant-derived anti-tumor 156511.doc -21 - 201206449 tumor drug, anti-tumor platinum complex, anti-tumor hi Tree test (campt〇thecin) derivatives, anti-tumor tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, hormone antineoplastic agents, anti-tumor agents, angiogenesis inhibitors, differentiation agents or other An agent exhibiting antitumor activity, or a pharmaceutically acceptable salt thereof. In some embodiments, the platinum complex is cisplatin, cyclamate, oxaplatin or oxaliplatin. In some embodiments, the anti-metabolite is citabine, capecitabine, gemcitabine or valprobine. In some embodiments, the methods further comprise administering 4_iodo-3-nitrobenzamine or a metabolite thereof or a pharmaceutically acceptable salt thereof to the patient in combination with more than one antineoplastic agent. In some embodiments, 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 in combination with at least one anti-neoplastic agent Or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (eg, gemcitabine), and a platinum compound (eg, carboplatin p. In some embodiments, the antineoplastic agent is administered 4-gorpho-3-nitrobenzene The administration of methotrexate or a metabolite thereof, or a pharmaceutically acceptable salt thereof, an antimetabolite (such as gemcitabine), and/or a platinum complex (such as carboplatin), before or after, in some embodiments, The oncology drug is a vasculogenic agent such as Avastin; or a receptor tyrosine kinase inhibitor, including but not limited to Sutent, Nexavar, Resentin, etc. , aBT 869 and Axitinib. In some embodiments, the antineoplastic agent is a topoisomerase inhibitor including, but not limited to, irinotecan, topotecan or myrtoline. In some embodiments, the antineoplastic agent is a taxane&apos; including but not limited to paclitaxel, docetaxel 156511.doc

S -22- 201206449 (docetaxel) and paclitaxel albumin particles (Abraxane). In this case, the anti-tumor drug is Herceptin or Lapatinib, which targets Her-2. In some embodiments the antineoplastic agent is a hormonal analog, such as progesterone. In some embodiments, the antineoplastic agent is tamoxifen, a steroid aromatase inhibitor, a non-steroidal aromatase inhibitor, or a Fulvestrant. In some embodiments, the antineoplastic agent is a drug that targets the growth factor receptor. In some embodiments, the agent is an epidermal growth factor receptor (EGFR) inhibitor, including but not limited to cetuximab (Cetuximab) ) and panitumimab (Panitumimab). In some embodiments, the agent of the dry growth factor receptor is an insulin-like growth factor i (1(}1?_1) receptor (IGF1R) inhibitor, such as cp_75i87b. 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, the at least one The therapeutic effect is tumor size reduction, metastasis reduction, complete remission, partial remission, pathological complete response or disease stabilization. In some embodiments of any of the methods described herein, the treatment comprises a duration of at least 11 days (eg, about Π day) a treatment cycle of up to about 30 days, wherein on the day of the 1 to 1 separate day of the cycle, the patient receives from about i to about g/kg of 4-indole-3-nitrophenyl hydrazone or molar equivalent Metabolites. In some embodiments, from 1 to 10 separate days of the cycle, the patient receives from about 1 mg/kg to about 50 mg/kg of 4-iodo-3-nitrobenzamine or moor. When I have its metabolites. In the embodiment, after i to 1 分 156511.doc •23-201206449 of the cycle, the patient accepts about 1, 2, 3, 4, 5, 5.6, ό, 8, 10, 11.2, 12, 14, 16, 18 or 20 mg/kg 4-iodo-3 nitrobenzamide The treatment further comprises an antimetabolite (such as gemcitabine) and a platinum compound (such as a card chain). Some embodiments described herein. Providing a method of treating platinum-resistant recurrent ovarian cancer in a patient, such as a patient having a BRCA gene defect, comprising during the 21-day treatment cycle, on the first, fourth, eighth, and first days of the cycle The metabolite of about 1 mg/kg to about 1 〇〇*iodo-3_nitrobenzamide or molar equivalent is administered to the patient for 11 days. In some embodiments, 4 y phenylbenzamide Oral administration, or parenteral injection or infusion, or inhalation. The treatment further includes an antimetabolite (eg, gemcitabine) and an initial compound (eg, cardinal). Some embodiments described herein provide a treatment A method of pure recurrence (four) nest cancer in a patient (eg, a patient with a BRCA gene defect), Included: (4) Establish a treatment period with a duration of about 1G to about 3G days; (7) In the 1 to 1G branch day of the cycle, the patient who is going to pay is about 丨mg/kg to about 50m:/kg4_iodine_3_nitrogen a metabolite of benzylamine or a molar equivalent. In some embodiments, 4 nitrobenzamide is administered orally, or parenterally injected or infused, or inhaled. The treatment further includes an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin). Some embodiments provided herein include a method of treating sputum cancer in a patient in need of such treatment' (4) obtaining a sample from the patient, (8) testing the sample to be defective in the BRCA-based financial, (4) if the test indicates that the patient does not have a defect in the BRCA gene, then 4 winter 3^-based phenyl 156511.doc •24· 201206449 The amine or its metabolite or a pharmaceutically acceptable salt thereof treats the patient; and (d) if the test indicates that the patient is free of defects in the BRCA gene, then different treatment options are selected. In some embodiments, at least one therapeutic effect is obtained. The at least one therapeutic effect is ovarian tumor size reduction, metastasis reduction, complete remission, partial remission, pathological complete response, elevated overall response rate, or disease stabilization. In some embodiments, an increase in clinical benefit rate is obtained compared to treatment with 4_iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof (CBR=CR +PR+SD26 months). In some embodiments, the clinical benefit rate is at least about 3%. In some embodiments, the sample is a tissue or body fluid sample. In some embodiments, the sample is a tumor sample, a blood sample, a plasma sample, a peritoneal fluid sample, an exudate, or an effluent. In some embodiments, the nested cancer is metastatic nested cancer. In some embodiments, the BRCA gene is brcaj. In other embodiments, the BRCA gene is BRCA_2e. In some embodiments, the brca gene is BRCA-1 and BRCA-2. In other embodiments, the defect is a genetic defect of the brca gene. In some embodiments, the genetic defect is a mutation, insertion, substitution, duplication or deletion of the BRCA gene. In some of the methods described herein, 4_^ schylbenzamide or a metabolite thereof, or a pharmaceutically acceptable salt thereof, can exist in a variety of physical forms such as free assays, salts (especially a pharmaceutically acceptable salt wk compound, a polymorph (polym〇rph), a solvate, etc. Unless otherwise defined herein, the body is a group of genus, and the name is intended to cover the specified chemical. ^ Rational form. For example, in the absence of other restrictions below and 4- moth ~ Shaw basic brewing fe thinking general hanged by the shaft: recognize the cover of free base and all pharmaceutically acceptable 156511.doc •25· 201206449 salt In the context of a particular physical form of a compound, the context of the reference to the compound or the scope of the patent application will be It is clear that in some embodiments of any of the methods described herein, the compound (eg, cardinal) is administered by intravenous infusion. In some embodiments, 4 nitrobenzamide or Metabolite or pharmaceutically acceptable Salt oral: with or by parenteral injection or infusion, or inhalation. In some cases, antimetabolites (such as gemcitabine) are administered by intravenous infusion in any of the methods described herein. In some embodiments, the method comprises treating the patient with at least two chemically distinct substances, one of which is an antimetabolite (eg, gemcitabine), one of which is a complex containing complex (eg, card flip or cisplatin) And 4-iodonitrobenzamide or a metabolite thereof or medicinal thereof: in some embodiments, one or more of such substances may exist in a plurality of physical forms, such as free A base, a salt (especially a pharmaceutically acceptable X') conjugate, a polymorph, a solvate or a metabolite, etc. Unless otherwise defined herein, the use of a chemical name is intended to encompass the sputum. All physical forms of the mouth. For example, without further limitation the following and 4_m succinylbenzamide are intended to cover the free test and all pharmaceutically acceptable salts, polymorphs, hydrates and metabolites thereof. Intended to make the invention or the scope of the patent In the context of a particular physical form of a compound, this will be apparent from the context of the paragraph or the scope of the patent application. (1) 4-Iodo-3-nitrobenzamide, its metabolite or 156511.doc • 26 - 201206449 Pharmaceutically acceptable salt or solvate in combination with (丨丨) an antimetabolite, a pharmaceutically acceptable salt or solvate thereof and (Hi) Use of any of the platinum compounds, pharmaceutically acceptable salts or solvates thereof for the manufacture of a medicament for the treatment or prevention of recurrent resistant ovarian cancer as described herein. Providing 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of an antimetabolite (eg, gemcitabine) and a platinum compound (eg, carboplatin) Use of a combination of drugs for treating or preventing platinum-resistant recurrent ovarian cancer as described herein. Also provided herein is 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture or treatment of a platinum-resistant relapse in a patient described herein. Use of a medicament for ovarian cancer, wherein 'iodo-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt or solvate thereof is intended to be an antimetabolite (such as gemcitabine) and a platinum compound (for example) The card is initially combined to give to the patient. Also provided herein is the use of any of the pharmaceutical compositions described herein for the manufacture of a medicament for the treatment of platinum-resistant recurrent ovarian cancer. For example, the uses provided herein are related or consistent with any of the methods described herein. Antineoplastic Agents In some embodiments, a method of treating 34 relapsed recurrent cancers in a patient's condition comprises administering to the patient an effective amount of (1) 4_m Schottky, a metabolite, or a pharmaceutically thereof thereof. An acceptable salt; (9) an antimetabolite (such as gemcitabine); and (iii) a platinum compound (such as carboplatin) and an additional antineoplastic agent. Antitumor agents which can be used in the present invention include, but are not limited to, antitumor burning agents, antitumor antimetabolites, antitumor antibiotics, plant-derived anti-156511.doc -27- 201206449 oncology drugs, anti-tumor platinum complex compounds, Anti-tumor camptothecin derivatives, anti-tumor tyrosine kinase inhibitors, anti-tumor agents, monoclonal antibodies, interferon three biological response modifiers and other agents exhibiting anti-tumor activity, or: pharmaceutically acceptable salt. In some embodiments, (1) 4-iodo-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof, (丨丨) antimetabolite (such as gemcitabine), and (iv) a compound (such as Card start) is used in combination with an anti-angiogenic agent. In other embodiments, (1) 4 quinazoline, a metabolite thereof or a pharmaceutically acceptable salt thereof, (") antimetabolite (such as gemcitabine), and (iii) a platinum compound (such as a card) Platinum) is used in combination with a topoisomerase inhibitor such as irinotecan. In other embodiments, (1) 4-moth-3-nitrobenzamine, a metabolite thereof or a pharmaceutically acceptable salt thereof , (Π) antimetabolites (such as gemcitabine), and (iii) platinum compounds (such as carboplatin) are used in combination with hormonal therapies. In other embodiments, (丨) 4-iodo-3-nitrobenzoguanamine a metabolite or a pharmaceutically acceptable salt thereof, (Η) an antimetabolite (such as gemcitabine), and (iii) a platinum compound (such as carboplatin) and a growth factor including, but not limited to, an EGFR or IGF1R inhibitor Combinations of Inhibitors In some embodiments, the ovarian cancer is a metastatic cancer. In some embodiments of any of the methods provided herein, the antineoplastic agent is an alkylating agent. The term "alkylating agent" is generally used herein. Refers to an agent that gives a burn-in in an alkylation reaction, wherein A hydrogen atom of an organic group substituted by the hospital. Examples of anti-tumor burning agents include, but are not limited to, nitrogen mustard 氧化物 oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, dibromo Mitrobronitol, carb〇qUone, thi〇tepa, 156511 .doc -28- 201206449 ramimustine, nimustine, temozolomide Temozolomide) or carmustine. In some embodiments of any of the methods provided herein, the antineoplastic agent is an antimetabolite. The term "antimetabolite" as used herein broadly includes substances that interfere with normal metabolism due to structural or functional similarities to metabolites important to living organisms such as vitamins, coenzymes, amino acids, and sugars. The electron transport system is inhibited to block the formation of energy-rich intermediates. Examples of antimetabolites having antitumor activity include, but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouridine (5-fluorouracil), tegafur, dexifluridine, carmofur, cytarabine, cytarabine Cytarabine ocfosfate), enocitabine, S-1, gemcitabine, I udarabine or pemetrexed disodium, and preferably 5-fluoropurine , S-1, gemcitabine and its analogues. In some embodiments of any of the methods provided herein, the antineoplastic agent is an anti-tumor antibiotic. Examples of anti-tumor antibiotics include, but are not limited to, actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin. , peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, net statin vinegar (zinostatin stimalamer), idarubicin, sirolimus 156511.doc •29·201206449 (sirolimus) or valrubiein. In some embodiments of any of the methods provided herein, the antineoplastic agent is a plant-derived antineoplastic agent. Examples of plant-derived antineoplastic agents include, but are not limited to, vincristine, vinbiastine, vindesine, et〇p〇side, sobuzosin (10) (10) Uniform, docetaxel, pacHtaxel & vinorelbine, and preferably docetaxel and paclitaxel. In some embodiments of any of the methods provided herein, the antineoplastic agent is a camptothecin derivative that exhibits antitumor activity. Examples of anti-tumor camptothecin derivatives include, but are not limited to, campptinthecin, 1 羟基 hydroxycamptothecin, topotecan (t〇P〇tecan), irinotecan (irin〇tecan) Or 9-aminocamptothecin, preferably camptothecin, topotecan and irinotecan. In addition, irinotecan is metabolized in vivo and exhibits an anti-tumor effect as 8 small 38. It is believed that the mechanism of action and activity of camptothecin derivatives are actually the same as those of camptothecin (eg

Nitta et al, Gan to Kagaku Ryoho, 14, 850-857 (1987)) » In some embodiments of any of the methods provided herein, the antineoplastic agent is an organoplatinum compound or a platinum coordination compound having antitumor activity. The term "organoplatinum compound", "platinum compound" or "platinum complex J and the like as used herein, refers to a platinum-containing compound that provides platinum in ionic form. Preferred organoplatinum compounds include, but are not limited to, cisplatin; Cis-diamine dihydrate di(Π)-ion; gas (diethylidene triamine)_platinum (11) vapor; digas (extended ethylenediamine)-platinum (II); diamine (U- Cyclobutane dicarboxylate)platinum (11) (carboplatin); spiroplatinum; isopropaplatin; diamine (2-ethylmalonate) platinum (11); ethylidene diamine malonate Π); hydrated (1,2-diaminodicyclohexane) platinum (II) sulfate; water 156511.doc • 30-201206449 (1,2-diaminodicyclohexane)platinum malonate ( II); (1,2-diaminocyclohexane)platinum(II) malonate; (4-carboxydecanoic acid) (1,2-diaminocyclohexane)platinum (II); (1, 2-diaminocyclohexane)-(isocitrate)platinum(II); (1,2-diaminocyclohexane)platinic acid platinum (II); omalimin; tetraplatinum; carboplatin; Nida Platinum; and oxaliplatin, and preferably carboplatin or oxaliplatin. In addition, other anti-tumor mentioned in the specification has Platinum compounds are known and commercially available and/or can be produced by those skilled in the art by conventional techniques. In some embodiments of any of the methods provided herein, the antineoplastic agent is an anti-tumor tyrosine kinase Inhibitor. The term "tyrosine kinase inhibitor" as used herein refers to a chemical that inhibits "tyrosine kinase," which transfers the λ-phosphate group of ATP to the hydroxyl group of a particular tyrosine in a protein. Examples of anti-tumor tyrosine kinase inhibitors include, but are not limited to, gefitinib, imatinib, erlotinib, suttan, leisawa, leisentin, ABT- 869 and Axitinib. In some embodiments of any of the methods provided herein, the antineoplastic agent is a binding moiety of an antibody or antibody that exhibits anti-tumor activity. In some embodiments, the antineoplastic agent is a monoclonal antibody. Examples include, but are not limited to, abciximab, adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab. Mabximab, daclizumab, eculizumab, efalizumab, ibritumomab tiuxetan, infliximab , morozumab-CD3 (muromonab-CD3), natalizumab (natalizumab), omalizumab (omalizumab), paley 156511.doc -31 - 201206449 benzumab (palivizumab), Pani Antibiotic (panitumumab), ranibizumab, gemtuzumab ozogamicin, rituximab, tositumomab, trastuzumab Or any antibody fragment specific for an antigen. In some embodiments of any of the methods provided herein, the antineoplastic agent is an interferon. Such interferons have antitumor activity and are glycoproteins which are produced and secreted by most animal cells upon infection with a virus. It not only has the effect of inhibiting the growth of the virus, but also has various immune effect mechanisms, including inhibiting the growth of cells (especially tumor cells) and enhancing the activity of natural killer cells, and is therefore called a type of cytokine. Examples of anti-tumor interferons include, but are not limited to, interferon alpha, interferon alpha 2a, interferon alpha 2b, interferon beta, interferon gamma-la, and interferon gamma-nι. In some embodiments of any of the methods provided herein, the antineoplastic agent is a biologic response modifier. It is generally a generic term for a substance or drug used to alter the defense mechanism or biological response of a living organism, such as the survival, growth or differentiation of tissue cells, to make it useful for tumors, infections or other diseases. Examples of biological response modifiers include, but are not limited to, krestin, lentinan, sizofiran, picibanil, and ubenimex. In some embodiments of any of the methods, the antineoplastic agent includes, but is not limited to, mitox xantrone, L-asparaginase, procarbazine, dacarbazine ), hydroxycarbamide, pentastatin 156511.doc -32- 201206449 (pentostatin), retinoic acid (tretinoin), afefacept (aiefacept), darbepoetin alfa, anaqu Azostroz〇le, exemestane, bicalutamide, leuprorelin, flutamide, fuivestrant, 11 chenta Pegaptanib octasodium, denileukin diftitox, aidesieukin, thyrotropin alfa, arsenic trioxide, bortezomib Capecitabine and goserelin. The above terms "anti-tumor alkylating agent", "anti-tumor and anti-metabolite", "anti-tumor antibiotic", "plant-derived anti-tumor drug", "anti-tumor platinum coordination compound", "anti-tumor "Anti-tumor tyrosine kinase inhibitors", "monoclonal antibodies", "interferons", "biological response modifiers" and "other anti-tumor drugs" are well known and commercially available or may be familiar with this item. The skilled person produces it by methods known per se or by well-known or conventional methods. A method for preparing gefitinib is described, for example, in U.S. Patent No. 5,77,599; a method for preparing cetuximab is described, for example, in w〇96/4〇21〇; for preparing a bevacate The method of the monoclonal antibody is described, for example, in WO 94/10202; the method for preparing oxaliplatin is described, for example, in U.S. Patent Nos. 5,42,3,19 and 5,959,133, the method for preparing gemcitabine, for example, described in the United States. Patent Nos. 5,434,254 and 5,223,6-8; methods for preparing a Hibiscus test are described, for example, in U.S. Patent Nos. 5,162,532, 5,247, q89, 5'191'082, 5'200,524, No. 5, 243, 050 and No. 321, 140, the method for the preparation of irinotecan is described, for example, in U.S. Patent No. 5, 561, 511, pp. A method for preparing temozolomide is described, for example, in JP-B No. 4-5029; and a method for preparing rituximab is described, for example, in JP-W No. 2-503143. The above antitumor alkylating agent is commercially available, for example, the following: nitrogen mustard N-oxide, Nitrorin (trade name) from Mitsubishi Pharma Corp.; cyclohexylamine as Endoxan (trade name) from Shionogi &amp; Co ·, Ltd.; Isocyclic guanamine, as Ifomide (trade name) from Shionogi &amp; Co., Ltd.; US law, as Alkeran (trade name) from GlaxoSmithKline Corp.; busulfan, as Mablin (commodity Name) from Takeda Pharmaceutical Co., Ltd.; Ermomannitol, as Myebrol (trade name) from Kyorin Pharmaceutical Co., Ltd.; Kappo, as Esquinon (trade name) from Sankyo Co., Ltd.; As a Tespamin (trade name) from Sumitomo Pharmaceutical Co., Ltd.; Ramustine, as Cymerin (trade name) from Mitsubishi Pharma Corp.; Nemo, as Nidran (trade name) from Sankyo Co. , Ltd.; Temo beta octaamine, as Temodar (trade name) from Schering Corp.; and Carmose, Ding, as Gliadel Wafer (trade name) from Guilford Pharmaceuticals Inc. The above antitumor antimetabolite is commercially available, for example, the following: indole pterin, as Methotrexate (trade name) from Takeda Pharmaceutical Co., Ltd.; 6_ thiopurine nucleoside, as Thiioinosine (trade name) derived from Aventis Corp.; 巯基嗓吟, as Leukerin (trade name) from Takeda Pharmaceutical Co., Ltd.; 5-fluorouric acid, as 5-34-156511.doc

S 201206449 FU (trade name) from Kyowa Hakko Kogyo Co., Ltd.; Ming | L bite, Futraful (trade name) from Taiho Pharmaceutical Co., Ltd.; Deoxyfluorouridine, as Furutulon (trade name) from Nippon Roche Co., Ltd.; Carmofur, as Yamafur (trade name) from Yamanouchi Pharmaceutical Co., Ltd.; cytarabine, as Cylocide (trade name) from Nippon Shinyaku Co., Ltd.; Pu Shi 18th base acid salt, as Strasid (trade name) from Nippon Kayaku Co., Ltd.; Enochaline, as Sanrabin (trade name) from Asahi Kasei Corp.; S-1, as TS-1 ( Trade name) from Taiho Pharmaceutical Co., Ltd.; Gemcitabine, as Gemzar (trade name) from Eli Lilly &amp;Co·; talabin, as Fludara (trade name) from Nippon Schering Co., Ltd.; Metrozine disodium, as Alimta (trade name) from Eli Lilly &amp; Co. The above antitumor antibiotic is commercially available, for example, as follows: Actinomycin D, as Cosmegen (trade name) from Banyu Pharmaceutical Co., Ltd.; Doxorubicin, as Adriamycin (trade name) from Kyowa Hakko Kogyo Co., Ltd.; daunorubicin, as Daunomycin from Meiji Seika Kaisha Ltd.; new carotenoid, as Neocarzinostatin (trade name) from Yamanouchi Pharmaceutical Co., Ltd.; Latomycin, as Bleo (trade name) from Nippon Kayaku Co., Ltd.; Ilomycin, Pepro (trade name) from Nippon Kayaku Co, Ltd.; mitomycin C, as Mitomycin (trade name) From Kyowa Hakko Kogyo Co" Ltd.; Arubicin, as Aclacinon (trade name) from Yamanouchi 156511.doc -35- 201206449

Pharmaceutical Co., Ltd.;. Bibibine, as Pinorubicin (trade name) from Nippon Kayaku Co., Ltd.; epirubicin, as Pharmorubicin (trade name) from Pharmacia Corp.; net statin ester, as Smancs (trade name) from Yamanouchi Pharmaceutical Co., Ltd.; Idarubicin, as Idamycin (trade name) from Pharmacia Corp.; sirolimus, as Rapamune (trade name) from Wyeth Corp.; and valrubicin, as Valstar (trade name) ) from Anthra Pharmaceuticals Inc. 〇 The above plant-derived anti-tumor drugs are commercially available, for example, the following: Changchun New Test, from Oncovin (trade name), Shionogi &amp; Co., Ltd.; Changchun test, as Vinblastine ( Trade name) from Kyorin Pharmaceutical Co., Ltd.; Vindesine, as Fildesin (trade name) from Shionogi &amp; Co., Ltd.; Etopo, as Lastet (trade name) from Nippon Kayaku Co., Ltd. Sobzozo, as Perazolin (trade name) from Zenyaku Kogyo Co., Ltd.; Docetaxel, as Taxotere (trade name) from Aventis Corp.; Pacific paclitaxel, as Taxol (trade name) From Bristol-Myers Squibb Co ·; and vinorelbine, as Navelbine (trade name) from Kyowa Hakko Kogyo Co., Ltd .. The above antitumor platinum coordination compound is commercially available, for example, as follows: cisplatin, as Randa (trade name) from Nippon Kayaku Co., Ltd.; card in white, as Paraplatin (trade name) from Bristol-Myers Squibb Co_ Nida flip, as Aqupla (trade name) from Shionogi &amp; Co., Ltd.; and Osali, as Eloxatin (trade name) from Sanofi-Synthelabo Co. 156511.doc -36- 201206449 The above anti-tumor eucalyptus derivative is commercially available, for example, the following: irinotecan, as Campto (trade name) from Yakult Honsha Co., Ltd.; topotecan, as Hycamtin (trade name) from GlaxoSmithKline Corp.; and Hi-tree test, from Aldrich Chemical Co., Inc., USA. The above antitumor tyrosine kinase inhibitor is commercially available, for example, as follows: gefitinib, Iressa (trade name) from AstraZeneca Corp.; imatinib, as Gleevec (trade name) from Novartis AG; and erlotinib, as Tarceva (trade name) from 〇SI Pharmaceuticals Inc. ° The above monoclonal antibodies are commercially available, for example, the following: cetuximab, as Erbitux (trade name) from Bristol- Myers Squibb Co.; bevacizumab' as Avastin (trade name) from Genentech, Inc.; rituximab, as Rituxan (trade name) from Biogen Idee Inc.; alemtuzumab, as Campa Campath (trade name) from Berlex Inc.; and trastuzumab 'as Hershey; Ding (trade name) from Chugai Pharmaceutical Co., Ltd. The above interferon is commercially available, for example, the following: interferon alpha, as * Sumiferon (trade name) from Sumitomo Pharmaceutical Co.,

Ltd.; interferon a-2a' as canferon-A (trade name) from Takeda Pharmaceutical Co., Ltd.; interferon a-2b, as Intron A (trade name) from Schering-Pl〇Ugh corp.; interferon β, as IFN·β·(trade name) from Mochida pharmaceutical Co., Ltd.; interferon γ-ία' as Imimomax-γ (trade name) from shi〇n〇gi &amp; c〇. , Ltd.; 156511 .doc -37-201206449 and interferon γ-nl, as Ogamma (trade name) from Otsuka Pharmaceutical Co" Ltd. ° The above biological reaction modifiers are commercially available, for example, the following: Yunzhi polysaccharide, as Krestin (trade name) ) from Sankyo Co., Ltd.; Xiangyi polysaccharide, as Lentinan (trade name) from Aventis Corp.; Nishi Shout, as Sonifiran (trade name) from Kaken Seiyaku Co., Ltd.; Bisibani, as Picibanil (trade name) from Chugai Pharmaceutical Co., Ltd.; and umbrel, as Bestatin (trade name) from Nippon Kayaku Co., Ltd. The above other antitumor drugs are commercially available, for example, the following: Oh, as Novantrone (trade name) from Wyeth Lede Rle Japan, Ltd. ; L-aspartame, as Leunase (trade name) from Kyowa Hakko Kogyo Co., Ltd.; procarbazine, as Natulan (trade name) from Nippon Roche Co., Ltd.; Kabbah ° Qin, as Dacarbazine (trade name) from Kyowa Hakko Kogyo Co., Ltd.; hydroxyurea, as Hydrea (trade name) from Bristol-Myers Squibb Co.; pentastatin, as Coforin (trade name) from Kagaku Oyobi Kessei Ryoho Kenkyusho; retinoic acid, as Vesanoid (trade name) from Nippon Roche Co., Ltd.; Afaset, as Amevive (trade name) from Biogen Idee Inc.; darbepoetin alpha, as Alane ( Aranesp) (trade name) from Amgen Inc.; anastrozole, as Arimidex (trade name) from AstraZeneca Corp.; exemestane, as Aromasin (trade name) from pnzer Inc. Bicalutamide, as Casodex (trade name) from AstraZeneca Corp.; leuprolide, -38 * 156511.doc δ 201206449 as Leuplin (trade name) from Takeda Pharmaceutical Co., Ltd.; Oreamine, as Eulexin (trade name) from Schering-Plough Corp.; fulvestrant, for Faslodex (trade name) from AstraZeneca Corp.; Patagonian VIII, as Macugen (trade name) from Gilead Sciences, Inc.; Interleukin toxin conjugate, as Ontak (trade name) from Ligand Pharmaceuticals Inc.; aldileukin, as Proleukin (trade name) from Chiron Corp.; thyrotropin alpha, as Thyrogen (trade name) from Genzyme Corp.; Dioxin, as Trisenox (trade name) from Cell Therapeutics, Inc.; shedezomib, as Velcade (trade name) from Millennium Pharmaceuticals, Inc.; capecitabine, as Xeloda (trade name) from Hoffmann-La Roche , Ltd.; and Goserelin, as Zoladex (trade name) from AstraZeneca Corp. The term "antineoplastic agent" as used in the present specification includes the above antitumor alkylating agent, antitumor antimetabolite, antitumor antibiotic, plant-derived antitumor drug, antitumor platinum coordination compound, and antitumor camptothecin derivative. , anti-tumor tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers and other antineoplastic agents. Other antineoplastic or antibiotic agents can be used in combination with the benzopyrone compound. Such suitable antineoplastic or antibiotic agents include, but are not limited to, 13-cis retinoic acid, 2-CdA, 2-deoxyadenosine, 5-azacytidine, 5-fluorouridine, 5- FU, 6-mercaptopurine, 6-MP, 6-TG, 6-thioguanine, paclitaxel albumin microparticles, isotretinoin (Accutane), actinomycin-D, doxorubicin, Adrucil (Adrucil ), Agrylin, Ala-Cort, Aldileucil, Alemtuzumab, ALIMTA, Alitretinoin, 156511.doc -39- 201206449 Aikaban-AQ (Alkaban-AQ), Love Alkeran, all-trans retinoic acid, alpha interferon 'hexamethylene melamine, Amethopterin, Amifostine, Aminoglutethimide, Anagrelide ), Anandron, Anas, Sit, Arabinose, Ara-C, Alane, Aredia, Reining, Arnold, Arranon, Arc Dioxide , aspartate, ATRA, Avastin, azacytidine, BCG, BCNU, bendamustine, bevacizumab, bexarotene, BEXXAR, ratio Lumamine, BiCNU, Blenoxane, bleomycin, bortezomib, busulfan, Busulfex, C225, Calcium Leucovorin, Campas, Camptosar, Hibiscus test-11, capecitabine, Carac, carboplatin, carmustine, carmustine glutinous rice paper, Constance, (:(:- 5013, CCI-779, CCNU, CDDP, CeeNU, Cerubidine, cetuximab, Chlorambucil, C. cerevisiae, Cetrovorum factor, cladribine (Cladribine), Cortisone, Cosmegen, CPT-11, cyclopamine, Cytadren, cytarabine, cytarabine liposomes, Saida - U (Cytosar-U), Cytoxan, Dacaba 桊, Dacogen, Dactinomycin, darbepoetin alpha, Dasatinib, Daunol Neomycin, daunorubicin, daunorubicin hydrochloride, daunorubicin liposomes, daunoXome, decadron, decitabine , Delta-Cortef, Deltasson 156511.doc -40- 201206449 (Deltasone), Dini interleukin toxin, DepoCytTM, Dexamethasone, Dexamethasone acetate, Dexamethasone, Desasone, Dexrazoxane, DHAD, DIC, Diodex, Docetaxel, Doxil, Doxorubicin, Doxorubicin liposomes, DroxiaTM, DTIC, DTIC-Dome, Duralone, Efudex, Eligard, Ellence, Elosa; Ding Eloxatin), Elspar, Emcyt, epirubicin, Epoetin Alfa, Erbitux, Erlotinib, Erwinia L-aspartate indolease, estramustine, Ethyol, Etopophos, etopox, basal acid, euthene, Evista , Exemestane, Fareston, Faslodex, Femara, Filgrastim, Floxuridi Ne), Fludara, Fludarabine, Fluoroplex, Fluoride β-Bite, Fluoride Cancer Bite (cream), Fluoxymesterone, Flutamide, Folin , FUDR, gas vistas, G-CSF, gefitinib, gemcitabine, gemuzumab ozogamicin, Gemzar &amp; Gemzar side effects - chemotherapeutic drugs, Glivi, Gliadel glutinous rice paper pouch Agent, GM-CSF, goserelin, granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, Halotestin, Herceptin, Hexadrol, Hexalen ), hexamethylene melamine, HMM, and Hycamtin, Hydrea, Hydrocort Acetate, hydrocortisone, sodium hydrocortisone, hydrocortisone Sodium sulphate, citrate 156511.doc • 41 - 201206449 Hydrocorter Phosphate, basal gland, Ibritumomab, Ibritumomab Tiuxetan, Idamycin , idarubicin, Ifex, IFN-α, ifosfamide, IL-11, IL-2, Imatinib sulfonate, imidazole carboxamide, interferon alpha, interferon a-2b (PEG conjugate), interleukin-2, interleukin-11, Intron A (interferon a-2b), Iressa , Irinotecan, isotretinoin, Ixabepilone, Ixempra, Kidrolase (t), Lanacort, Lapatinib, L- Aspartate, LCR, Lenalidomide, lysine, Leucovorin, Leukeran, Leukine, Leuprolide , Changchun new test (Leurocristine), leustatin (Leustatin), liposome Ara-C, liquid Pred, Lomustine, L-PAM, L-sarcoma, Lupron, Lu Lupron Depot, Matulane, Maxidex, Mechlorethamine, Dichloroethylguanamine Hydrochloride, Medralone, Rice Medrol, Megace, Megestrol, Megestrol acetate, Methadine, Keji, Mesna, Misnas (Mesnex), methotrexate, methotrexate sodium, Methylprednisolone, Meticorten, mitomycin, mitomycin-C, mitoxantrone, M-splash M-Prednisol, MTC, MTX, Mustargen, Mustine, Mutamycin, Myleran, Mylocel, and Melotag Mylotarg), Navelbine, Nelarabine, Neosar, Nepal

156Sll.doc -42- S 201206449 Neulasta, Neumega, Neupogen, Lysawa, Nilandron, Nilutamide, Niebu Nipent, fenfen, Novaldex, Novantone, Octreotide, octreotide acetate, Oncospar, Oncovin, Otto Ontak), Onxal, Oprevelkin, Orapred, Orasone, Oxaliplatin, Pacific Paclitaxel, Pacific Paclitaxel (Protein Binator), Pami Pamidronate, panitumumab, Panretin, Paraplatin, Pediapred, PEG interferon, PEG aspartate, PEG filgrastim , PEG-INTRON, PEG-L-aspartate, pemetrexed, pentastatin, amphetamine, palatinol, palatinib-AQ, prednisolone Prednisolone), Prednisone, Prelone, Procarba, PROCRIT, Proleukin, Puli 13⁄4: Prolifeprospan 20 and Carmustine Implants, Purinethol, Raloxifene, Revlimid, Rheumatrex, Rituxan, Lee Toximab, Roferon-A (interferon a-2a), Rubex, Rubidomycin hydrochloride, good definite, good LAR, Sargramostim, Solu-Cortef, Solu-Medrol, Sorafenib, SPRYCEL, STI-571, Streptozocin, SU11248, Sunitinib, Sotan, Tamoxifen, Tarceva, Targretin, Taxol, and his 156511.doc -43 - 201206449 (Taxotere), Temodar, Temo. Oleamine, Temsirolimus, Teniposide, TESPA, Thalidomide, Thalomid, TheraCys, Sulphur吟, thioindigo tablets, thiophosphonates, Thioplex, thiotepa, TICE, Toposar, Topotecan, Toremifene, Tolise (Torisel), tositumomab, trastuzumab, retinoic acid, TrexallTM, Trisenox, TSPA, TYKERB, VCR, Vectibix, Vitibbi, Velban , Velcade, VePesid, Vesanoid, Viadur, Vidaza, Changchun, Changchun Sulfuric Acid, Vikasa Pfs ( Vincasar Pfs), Vincristine, Vinorelbine, Vinorelbine Tartrate, VLB, VM-26, Vorinostat, VP-16, Vumon, Xeloda, Zano Zanosar, Zevalin, Zinecard, Zoladex, lysine, Zolinza, Zami Zometa). Antimetabolites Antimetabolites are drugs that interfere with the metabolic processes of normal cells. Due to the rapid replication of cancer cells, interfering with cellular metabolism affects cancer cells to a greater extent than host cells. An antimetabolite such as gemcitabine can be used in any of the methods provided herein, for example, gemcitabine can be used in accordance with the present invention with 4-iodo-3-nitrobenzamine (or a metabolite thereof or a pharmaceutically acceptable salt thereof) And a platinum compound (such as carboplatin) in combination for the treatment of platinum-resistant recurrent ovarian cancer. Gemcitabine has the following structure: 156511.doc • 44· 201206449

Gemcitabine Gemcitabine is available, for example as GEMZAR® from Eli Lilly and Company. Gemcitabine as used herein also includes any pharmaceutically acceptable salt form (e.g., gemcitabine HC1 or other salt forms). Gemcitabine (also known as 4-amino-1-[(211,411,511)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]pyrimidine-2 (1 H) The ketone or 2,-deoxy-2,2,-difluorocyte is a nucleoside analog that interferes with cell division, for example by blocking DNA synthesis, thus causing cell death. The dose of antimetabolite (such as gemcitabine) can be adjusted depending on the particular patient. In the adult, gemcitabine is used in combination with 4-A-3-3-nitrobenzamine (or a metabolite thereof or a pharmaceutically acceptable salt thereof) and a platinum compound (such as carboplatin). The dosage of any method may range from about 1 mg/m2 to about 5000 mg/m2, from about 1 mg/m to about 2000 mg/m2, from about 200 to about 4000 mg/m2, from about 300 to about 3000 mg. /m2, from about 400 to about 2000 mg/m2, from about 500 to about 15 mg/m2, from about 750 to about 1500 mg/m2, from about 800 to about 1500 mg/m2, from about 900 to about 1400 mg/m2. From about 900 to about 1250 mg/m2, from about 1000 to about 1500 mg/m2, about 1〇00 mg/m2, about 1〇5〇mg/m2, about 1100 mg/m2, about 1150 mg/m2 About 1200 mg/m2, 156511.doc • 45· 201206449 About 1250 mg/m2, about 1300 mg/m2, about 1350 mg/m2, about 1400 mg/m2, about 1450 mg/m2 or about 1500 mg/m2. The dimension mg/m2 refers to the amount of gemcitabine (mg/mg) per unit of patient surface area (m2/m2). Gemcitabine can be administered by intravenous (IV) injection, for example, at about 1 to about 3 minutes, about 15 to about 180 minutes, about 20 to about 60 minutes, about 1 minute, about 20 minutes, or about 30 minutes. In the time period. In this context, the term "abnormal usage" is also approximate; and in some embodiments, the tolerance of 10% or ± 5% of soil. Taxanes Taxus is a drug derived from the twigs, needles and bark of the yew tree of the Pacific yew tree. In particular, Pacific paclitaxel can be derived from 1 〇-deacetyl berry gibberellin by known synthetic methods. Taxanes, such as paclitaxel and its derivative docetaxel, have exhibited antitumor activity in a variety of tumor types. Taxanes interfere with the normal function of microtubule growth by ultra-stabilizing their structure, thereby disrupting the ability of cells to use their cytoskeleton in a normal manner. Specifically, the taxane binds to the beta subunit of tubulin, which is the building block of the microtubule. The resulting taxane/tubulin complex does not decompose, which results in abnormal cell function and eventual cell death. "Paclitaxel inhibits proteins in cancer cells by binding to a protein called BA 2 (B cell leukemia 2), thereby preventing Μ〗 〖Suppression> Weekly death to induce progressive cell death (> weeks of death). Thus, paclitaxel has been shown to be an effective therapeutic agent for a variety of cancers because it down-regulates cell division by disrupting normal cytoskeletal rearrangement during cell division and induces apoptosis via an anti-two mechanism. 156511.doc -46· 201206449 In some embodiments, a method of treating a patient's initial resistance to recurrent ovarian cancer comprising administering an effective amount of (i) 4-iodo-3-nitrobenzoquinone to the patient is provided An amine, a metabolite thereof or a pharmaceutically acceptable salt thereof, (ii) gemcitabine and (iii) carboplatin in combination with a taxane (e.g., paclitaxel, docetaxel or paclitaxel albumin microparticles). The dose of the taxane (such as paclitaxel) may vary depending on height, weight, physical condition, tumor size, and progression. In some embodiments, the dosage of the taxane (such as paclitaxel) will range from about 10 to about 2000 mg/m2, from about 1 to about 200 mg/m2, or from about 1 to about 175 mg/m2. . In some embodiments, the taxane (such as Pacific paclitaxel) will be administered over a period of up to about 10 hours, up to about 8 hours, or up to about 6 hours. In this context, the term "about" means normal use, i.e., about; and in some embodiments, a tolerance of ±1% or ±5%. Examples of taxanes include, but are not limited to, docetaxel, paclitaxel, and paclitaxel albumin microparticles. Ming Complex The complex is a pharmaceutical or pharmaceutical composition for treating cancer and containing 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" are used interchangeably. An intrinsic complex (or a compound), such as a cardinal, can be used in any of the methods provided herein, for example, a card flip can be used in accordance with the present invention with 4 winter 3 nitrobenzamide (or its metabolite or its medicinal Acceptable tread) and = thank you (such as gemcitabine) combination poetry _ resistance recurrence; nest 156511.doc •47· 201206449 carboplatin has the following structure: 〇

〇 H3N 〇

XPtX H3N〆\〇 Carboplatin is available, for example, from Bedford Laboratories. Carboplatin, also known as cis-monoamine (1,1-cyclobutanedicarboxylate)platinum (11), is a platinum complex (or platinum compound) which is also sold under the tradenames paraplatin 8 and Paraplatin AQ. The carboplatin used herein also includes any pharmaceutically acceptable salt form. The dose of the platinum compound (such as carboplatin) can be adjusted depending on the particular patient. The dose of the platinum compound (e.g., carboplatin) is determined by calculating the area under the plasma concentration versus time curve (AUC, mg/mL*min), which is considered by methods known to those skilled in the art of cancer chemotherapy. The renal activity of the patient was assessed by measuring creatinine clearance or glomerular filtration rate. In some embodiments, a platinum complex (such as carboplatin) and an antimetabolite (such as gemcitabine) and 4-indole-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) The dose used in combination is calculated to provide about 0. U mg / mpmin, about 0.1-7 mg / ml * min, about 0.1 - 6 mg / m, min, about 1-6

Mg/m b min, about 1-5 mg/m b min, about 2-5 mg/m b min, about 3-6 mg/m b min, about 3-5 mg/ml*min, about 1-3 Mg/ml*min, about 1.5 to about 2.5 mg/rrd.min, about 1.75 to about 2.25 mg/m b min, about 2 mg/ml*min (AUC 2, for example, 2 mg/ml*min abbreviation ), 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 of about 6 AUC. Alternatively, ]565H.doc •48· 201206449 Calculate the dose of a platinum compound (eg, carboplatin) based on the body surface area of the patient. In some embodiments, a suitable dose of carboplatin is from about 1 〇 to about 4 〇〇 mg/m 2 , for example about 360 mg/m \ platinum complex (such as carboplatin), typically administered intravenously (IV) about 1 The crucible is about 300 minutes, about 3 to about 18 minutes, and is about 120 minutes or about 60 minutes. In these contexts, the term "about" has its normal meaning', that is, approximately. Be careful at the same time.. ^ ^ You insisted that the term "about" means ±10〇/〇 or ±5%. Topoisomerase Inhibitors Any of the methods provided herein may further comprise a topoisomerase inhibitor. Topoisomerase inhibitors are agents designed to interfere with the activity of enzyme topoisomerases (topoisomerases and (1). Topoisomerases are catalyzed by the cleavage of the DNA diphosphate backbone during the normal cell cycle. And re-ligating enzymes that control changes in DNA structure. Topoisomerases have become a popular target for cancer chemotherapy treatment. It is believed that topoisomerase inhibitors block the cell cycle junction step 'forming a single strand that compromises genome integrity and Double strand breaks. The introduction of such breaks subsequently leads to cell death and cell death. Topoisomerase inhibitors are often classified according to the type of enzyme they inhibit. Topotecan, irinotecan, letoticon ( Lurtotecan) and exenotecan (which are all commercially available) can target topoisomerases, the most common type of topoisomerases in eukaryotic organisms. Topotecan is commercially available. Hycamtim® is available from GlaxoSmithKline. Irinotecan is available under the trade name CamptQsar@. Letoticon is available as a s...

Inc. Topoisomerase inhibitors can be administered in an effective amount. In some embodiments, an effective dose for treating a human will range from about 1 to about 10 mg/m2 / 156511.doc -49 to 201206449 days. The treatment can be daily, every two weeks, every half. Repeat weekly, weekly or monthly. In some embodiments, the treatment period may be a day of rest to several days, or a rest period of one week to several weeks. In some embodiments, (丨) 4-androst-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof, (ii) gemcitabine and/or (iii) carboplatin and topologically different The enzyme inhibitor can be administered on the same day or can be administered on separate days. Dividing compounds of Π-type topoisomerase into two broad categories: topoisomerase poisons targeting topoisomerase-DNA complexes and topoisomerase inhibitors that disrupt catalytic turnover ^ Topo Η poisons include but are not limited to true Nuclear type 11 topoisomeric % inhibitor (t〇p〇II): amsacrine, etoposide, etoposide phosphate, teniposide, amrubicin and doxorubicin star. These drugs are anti-cancer therapies. Examples of topoisomerase inhibitors include ICRF-193» These inhibitors target the n-terminal ATp enzyme domain of t〇p〇 π and prevent topo π turnover. Classen (pr〇ceedings Nati〇nal

The Academy of Science, 2004) has resolved the structure of this compound that binds to the ATp enzyme domain, showing that the drug binds in a non-competitive manner and locks down the ATPase domain dimerization. Anti-Angiogenesis Agents Any of the methods provided herein can further comprise an anti-angiogenic agent. An angiogenesis inhibitor is a substance that inhibits angiogenesis (new blood vessel growth). Once it reaches a certain size 'Every solid tumor (unlike leukemia) needs to generate blood: to keep it alive. Tumors only grow when they form new blood vessels. Pass: 'The other parts of the adult do not construct blood vessels' unless the tissue repair is actively carried out. Angiostatin pharmaceutical endothelin (_(10) heart) 156511.doc •50· 201206449 and related chemicals can inhibit the structure of blood vessels and prevent the cancer from growing indefinitely. In tests performed on patients, the tumor became inactive and remained as it was after the endothelin treatment. This treatment has few side effects but exhibits a very limited selectivity. Other vascular inhibitors (such as thalidomide) and natural plant-based substances are in active research. Inhibitors are known to include the drug bevacizumab (Avastin), which binds to vascular endothelial growth factor (VEGF), thereby inhibiting its binding to receptors that promote angiogenesis. Other anti-angiogenic agents include, but are not limited to, carboxyamidotriazole, TNF-470, CM101, lFN-α, IL-12, platelet factor-4, suramin, SU5416, thrombospondin (thrombospondin), vasopressive steroid + heparin, cartilage-derived angiogenesis inhibitory factor, matrix metalloproteinase inhibitor, angiostatin, endostatin, 2-decyloxyestradiol, tecocaine ( Tecogalan), thrombospondin, prolactin (pr〇Uctin), alpha+ inhibitor, and linomide.

Her-2 Orientation Therapy Any of the methods provided herein can further include Herceptin in the treatment of platinum-resistant recurrent ovarian cancer (e.g., HER2-positive ovarian cancer). Her-2 overexpression has been found in ovarian cancer, and HER2 overexpression and expansion are associated with late stage nest cancer (AOC) (Hellstrdm et al, παβαπ/ί 61, 2420-2423, March 15, 2001). Herceptin can be used as adjunctive therapy for HER2 overexpressing ovarian cancer. Herceptin can be used in several different ways: as part of a treatment regimen including either doxorubicin, cyclophosphamide, and paclitaxel or docetaxel, with docetaxel and card Or as a single agent following multimodal modal anthracycline-based therapy as 156511.doc -51- 201206449. Herceptin in combination with Pacific Paclitaxel was approved for one-line treatment of HER2 overexpressing ovarian cancer. Herbine, a single-agent, is approved for the treatment of cerebral cancer in patients who have received one or more chemotherapy regimens for metastatic disease. Lapatinib or lapatinib dibenzoate is an oral active chemotherapeutic drug for solid tumors such as breast cancer. During development, it is called the small molecule GW572016. Lapatinib can stop tumor cell growth by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as topotecan, act in different ways to stop tumor cell growth by killing the cells or by preventing their division. Administration of lapatinib with topotecan has enhanced anti-tumor efficacy. Hormone Therapy Any of the methods provided herein can further comprise hormonal therapy. For example, a method of treating platinum-resistant recurrent ovarian cancer in a patient is provided, comprising administering to the patient an effective amount: (1) benzylamine, a metabolite thereof or a pharmaceutically acceptable salt thereof, (ii) gemcitabine and ( Iii) Carboplatin and hormone therapy. Tamoxifen-hormone antagonist Any of the methods provided herein may further comprise tamoxifen. Tamoxifen (sold as Nolvadex) slows or stops the growth of cancer cells present in the body. Tamoxifen is a class of drugs called selective estrogen receptor modulators (SERM). It functions as an anti-estrogen. Because tamoxifen is a stable and rapidly progressing recurrent ovarian cancer, it should be considered 156511.d〇c -52- 201206449 to consider its combination with cytotoxic chemotherapy in the main treatment of ovarian cancer. Any of the methods provided herein may further comprise an aromatase inhibitor (e.g., a steroid or a non-steroidal aromatase inhibitor). Aromatase inhibitors (Αι) are a class of drugs for the treatment of ovarian cancer in postmenopausal women, which block the enzyme aromatase. Aromatase inhibitors reduce the amount of estrogen in postmenopausal women with hormone receptor-positive ovarian cancer. When there are fewer estrogens in the body, hormone receptors receive less growth signals and cancer growth can be slowed or terminated. Aromatase inhibitors include Reynolds (chemical name anastrozole), Arnold (chemical name: exemestane) and Furlong (chemical name: letrozole) each taken once a day with pills. It lasts for up to five years. But for women with advanced (metastatic) disease, as long as they work well, continue to take the drug. 0 AI is divided into two categories: irreversible steroid inhibitors that form permanent bonds with the enzyme aromatase complex (such as Exemestane; and non-steroidal inhibitors (such as anastrozole, letrozole) that inhibit enzymes by reversible competition. 'Vistos are also called 1 (:1 182,78〇 and "heart 1〇"仏", for the treatment of hormone receptor-positive Indian cancer in postmenopausal women who have disease progression after hormonal therapy. Estrogen can induce (4) nest epithelial cancer cells to produce chaos Estrogen receptor antagonism without agonist effects works by down-regulating and by degrading both hormone receptors. The pot is administered as a monthly injection. ', provided by sputum therapy Any method can further comprise targeted growth Factor Receptor I565IJ.doc •53·201206449 (including but not limited to inhibitors of epidermal growth factor receptor (egfr) and the elegans growth factor 1 receptor (IGF1R)) EGFR in certain types of human cancer ( Overexpression in cells including Insect Cancer. EGFR overexpression in Indian cancer has been linked to poor prognosis. Ascending EGFR expression can contribute to a drug resistance phenotype. Examples of EGFR^p preparations include but are not limited to Cetuximab, a chimeric monoclonal antibody, is administered by intravenous injection for the treatment of cancer, including but not limited to metastatic colorectal cancer and head and neck cancer. Panitumumab is an EGFR inhibitor Another example is a humanized monoclonal antibody against EGFR. Panitumumab has been shown to be beneficial and better than supportive medical measures when used alone in patients with advanced colon cancer and get 1?1) Approved for this purpose. Activated type I 姨-like growth factor receptor (IGF1R) promotes proliferation and inhibits apoptosis in a variety of cell types. An example of an IGF1R inhibitor is cp_751871. CP-751871 is a selective binding IGF1R, resistance IGF1 binds to the human monoclonal antibody that is autophosphorylated by this receptor and subsequent receptors. Inhibition of IGF 1R autoantibodies can result in decreased expression of receptors on tumor cells expressing igf 1R and decreased anti-apoptotic effect of IGF. And inhibiting tumor growth. IGF 1R is a receptor glycosyl kinase that is expressed on most tumor cells and is involved in mitosis, angiogenesis, and tumor cell survival. PI3K/mTOR pathway Any of the methods provided herein may further comprise PI3K pathway inhibition Agent and/or mTOR inhibitor. Phospholipid inositol-3-kinase (PI3K) pathway dysregulation is a common event in human cancer due to inactivation of tumor suppressor gene constituting enzyme and tensin of chromosome 10 deletion Homolog or ριι〇_α 156511.doc -54· 201206449

/ Activation is sudden. These hotspot mutations result in the carcinogenic activity of the enzyme and contribute to the therapeutic resistance of the chiral mAb. Frequency of mTOR phosphorylation is also frequently detected in ovarian cancer. Therefore, the PI3K pathway is an attractive target for cancer therapy. NVP-BEZ235 (a dual inhibitor of PI3K and a downstream mammalian target of rapamycin (mTOR)) has been shown to have anti-proliferative and anti-tumor properties in cancer cells with both wild-type and mutant ρΐ 10-α Activity (Violeta Serra et al, Cancer Research 68, 8022-8030, January 1st, 2008).

Hsp90 Inhibitors Any of the methods provided herein can further comprise an inhibitor. These drugs target heat shock protein 9 (hsP90). Hsp90 is one of a class of accompanying proteins that work normally to help other proteins acquire and maintain the shape of their proteins for their work. 1 The protein works by contacting other protein entities. Despite the genetic defects that can cause cancer cell death under normal conditions, HsP90 can also enable such cells to survive and, and the function of the associated protein can cause the death of the protein to cause the accompanying protein function. This is especially true for other strategies to block cancer cell survival. Tubulin Inhibitors Any of the methods provided herein may further comprise tubulin inhibiting the inclusion of tubulin as a key component of the microtubule-forming protein f, which is a structural network of cells. Microtubules are divided into cells (,, · structure - transport, signal transmission and movement are necessary: there are two; cracked in) have: the main role in the cell knot, microtubules have been ... η complicated in its mitosis has become An important dry substance of anticancer music (often referred to as anti-filament 156511.doc -55-201206449 cleavage drug, tubulin inhibitor and microtubule targeting agent). These compounds bind to tubulin in microtubules and prevent cancer cell proliferation by interfering with the formation of microtubules required for cell division. Such interference blocks cell cycle sequences leading to apoptosis. Apoptosis inhibitors Any of the methods provided herein may further comprise an inhibitor of apoptosis. Apoptosis inhibitors (IAPs) are a group of functionally and structurally related proteins that were originally characterized in baculovirus and act as endogenous inhibitors of apoptosis. The human IAP family consists of at least six members and has been identified in numerous organisms for IAP homologs. i〇〇58-F4 is a c-Myc inhibitor that induces cell cycle arrest and apoptosis. It is a cell-permeable thiazolidine that specifically inhibits c-Myc-Max interaction and prevents transactivation of c_Myc target gene expression. 10058-F4 inhibits tumor cell growth in vitro and in vivo in a PCT-dependent manner. BI 6C9 is a sputum inhibitor and anti-apoptosis. GNF-2 belongs to a new class of Bcr_aM inhibitors. In combination with the nutmeg-binding bag (a ectopic site away from the active site), the inactive form of the kinase is stabilized. It inhibits Bcr_abl phosphorylation 1 (:5〇 is 267 nM, but does not inhibit a group of 63 species Other kinases, including natural c Abi, and no το total lack of toxicity against cells that do not express Bcr Abi. GNF 2 shows no significant use as a new class of inhibitors for studying activity and treatment by Bcr-Abl oncoproteins The potential of drug-resistant chronic myeloid leukemia (CML). Plflthrin 〇^p53 is a reversible inhibitor of apoptosis and dependent gene transcription (such as cyclin G, called / (4) and melon (5)). Plfithdn_a Increase (iv) transmission of toxic I (such as uv light shot 1565Il.doc -56- 201206449 and use of cytotoxic compounds (including doxorubicin, etoposide (etopurine), paclitaxel and cytosine-β-D - arabinofuranoside) treatment After the survival of the cells, Pifithrin-α prevents the mice from being affected by lethal systemic γ-radiation, and the incidence of cancer is not elevated. 4-iodo-3-nitrobenzamide 4_iodine_3_synthesis benzene f Indoleamine (ΒΑ) is a small molecule that acts on tumor cells and does not exert toxic effects in normal cells. 4_Iodine_3_nitrobenzamide is very lipophilic and fast &amp; Each group, including the brain and cerebrospinal fluid (CSF), is active in a wide range of cancer cells in vitro, including active against drug-resistant cell lines. Those skilled in the art will recognize that 4_fill_3 -Nitrobenzamide can be administered in any pharmaceutically acceptable form, for example as a pharmaceutically acceptable salt, solvate or complex. In addition, because 4 moth nitro stupid amine can be) The tautomerism in the liquid, so the term BA (or the synonym 4 winter 3 · Benzene Benzamine) is intended to cover the tautomeric form of the heart woven · % nitrobenzoguanamine and the salt, solvate or complex In some embodiments, '4_iodo-3-nitrobenzamide can be combined with a cyclodextrin, such as propyl beta cyclodextrin. However, those skilled in the art will recognize that other active and inactive agents can be combined with 4Winter 3_nitrobenzamide; and unless otherwise stated, 4-iron-3- Nitrobenzamide will include all of its pharmaceutically acceptable forms. The dose of 4-Moth-3'-based carbamide, its metabolite or its pharmaceutically acceptable salt may vary with the age and height of the patient. , weight, overall health, etc., in some embodiments, the dose of m-based benzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) is from about 1 mg/kg to about 5 Torr. 156511.doc -57·201206449 mg/kg, from about 1 mg/kg to about 100 mg/kg, from about 1 mg/kg to about 50 mg/kg, from about 1 mg/kg to about 25 mg/kg, about 2 to About 70 mg/kg, from about 2 mg/kg to about 50 mg/kg, from about 2 mg/kg to about 40 mg/kg, from about 3 mg/kg to about 30 mg/kg, from about 4 to about 100 mg, about 4 to about 25 mg/kg, from about 4 to about 20 mg/kg, from about 4 to about 15 mg/kg, from about 5 to about 20 mg/kg, from about 5 to about 15 mg/kg, from about 50 to about 100 mg Within the range of /kg, or from about 25 to about 75 mg/kg. In some embodiments, 4 - moth-3 - benzylbenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) is 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 for administration. In some embodiments, 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) is at least 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' 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 Any dose of mg/kg is administered. 4-androst-3-succinylbenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) can be administered intravenously, for example, by IV infusion, at about 1 〇 To about 3 minutes, about 3 to about 180 minutes, about 45 to about 12 minutes or about 60 minutes (ie about hours). In some embodiments, a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering an effective amount to the patient: (i) 4_iodo_3_nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof; (Η) gemcitabine; and (iii) carboplatin, wherein 4-iodo-3-nitrostamine is a metabolite or a pharmaceutically acceptable salt thereof of about 5 The patient is administered intravenously to about 20 mg/kg or from about 5 mg/kg to about 15 mg/kg. In some embodiments &apos; 4-iodo-3-nitrobenzamide may be administered orally. In this context, the term "about" has its normal meaning, that is, approximately. In some embodiments, approximately means 20 〇/〇, ±10%, or ±5%. The synthesis of 4-magnetic-3-stone succinylamine is described in U.S. Patent No. 5,464,871, the disclosure of which is incorporated herein in its entirety. 4-iodo-3-nitroindole Amine can be prepared at a concentration of 10 mg/mL and can be packaged in a convenient form, such as in a 10 mL vial. 4-iodo-3-nitrobenzamide (BA) metabolite As used herein, "BA" means 4-iodo-3-nitrobenzamide; "BNO" means 4-峨-3 - nitrosobenzamine; "BNHOH" means 4-iodo-3-hydroxyaminophenylguanamine. Useful precursor compounds in the present invention have the formula (la): 156511.doc • 59- 201206449

Wherein Ri, R2, R_3, R·4 and R·5 are independently selected from the group consisting of hydrogen, hydroxy, amine, nitro, iodo, (CVC: 6) alkyl, ((VC6) burned) Oxyl, (C3-C7)cycloalkyl and phenyl, wherein at least two of the five substituents r, r2, r3, 4 and &amp; always are hydrogen, among the five substituents At least one substituent which is always nitro' and at least one ortho to the nitro group is always iodine' and its pharmaceutically acceptable salts, solvates, isomers, tautomers, metabolites, Analogs or prodrugs. R1, R2, R4 and R5 may also be halides such as gas, fluorine or bromine substituents. In some embodiments, such R!, R2, R3, R4 and Rs substituents There are at least one substituent which is always a nitro or nitroso group and at least one of which is ortho to the nitro group or nitroso is always iodine. In some embodiments, the compound of formula Ia is a compound of the formula or a metabolite thereof or a pharmaceutically acceptable salt, solvate, isomer or tautomer. In some embodiments, the Ri, R2, R3, R4 and Rs substituents are a substituent which is always a nitro or nitroso group and at least one ortho to the nitro or nitroso group is always iodine. In some embodiments, the compound of formula la is a compound of formula VIII or a pharmaceutically acceptable compound thereof Accepted salts, solvates, isomers or tautomers. 4-indole-3-nitrophenyl f-amine, also known as inipari or "BA", having the formula: 15651I. Doc 201206449 Ο

II c-νη2 ^V^no2 4-iodo-3-nitrobenzoin (BA) A process for preparing 4-iodo-3-nitrobenzamine is known in the art, such as The method disclosed in U.S. Patent No. 5,464,871, the disclosure of which is incorporated herein by reference in its entirety in its entirety in the the the the the the the It can be packaged in a convenient form, for example in a 10 mL vial. &quot; In some embodiments of any of the methods provided herein, 4_iodine·3 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ In some embodiments, it is a metabolite (e.g., hydrazine) or a pharmaceutically acceptable salt of 4-nitrobenzamide. Metabolites of formula (Ila) are also provided herein:

II C-NH2 (Ila)

R2 wherein η ^ 1 Κ 2 ' at least one of the substituents R3, R4 and R5 is always a 3 sulfur substituent ' and the remaining substituents of R1, I, r3, r4a r5 are independently selected from the group consisting of hydrogen, Meramide, amine group, acetyl group, arginine, odor fluoride, chlorine, (C1-C6) alkyl, (c^-Ce) alkoxy, (c3-c7) cycloalkyl 156511.doc • 61- 201206449 and a phenyl group, wherein at least two of the five substituents of Ri, R2, and 4 and 1 are always hydrogen; or (2) at least one of h, R2, I, and a cardiac and cardiac substituent is not included a sulfur substituent and at least one of the five substituents &amp;, &amp;, R4 and R5 is always iodine, and wherein the iodine is always in the form of a nitro group, a nitroso group, a hydroxylamine group, a hydroxyl group or an amine group Ortho-position of the Ri, R2, R4 or R5 group; and a pharmaceutically acceptable salt, solvate, isomer, tautomer, metabolite, analog or prodrug thereof. In some embodiments, the (2) compound is such that the iodine group is ortho to the R1, R2, core or group of the nitroso, hydroxylamine, hydroxyl or amine group. In some embodiments, the (2) compound is such that the iodine group is ortho to the &amp;, R2, R4 or R5 group as a nitroso, hydroxylamine or amine group. Any compound having the structural formula la or Ila can be used to treat recurrent resistant ovarian cancer. In some embodiments, an effective amount of a compound of formula la or Ila is administered to a platinum-resistant recurrent nude-sex cancer string and gemcitabine and carboplatin are used. In some embodiments, the compound having the structural formula la or Ila is stilbene 3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof. ^ Metabolite compounds are provided herein, each represented by the following chemical formula. • 62· 156511.doc

201206449

H2N

MS328 R6 is selected from the group consisting of hydrogen, alkyl (cvc8), alkoxy (C!-c8), isoindolinone, 丨 朵 、, sold out, noisy, σ 嗤, sold Phenol or benzene

156511.doc -63- 201206449

Although not limited to any particular mechanism, an example of MS292 metabolism achieved by a nitroreductase or glutathione binding mechanism is provided below: Nitroreductase mechanism

156511.doc -64- S 201206449

ΝΗ2

Ηη2 η2ο -► NADPH/H+ NADP+ ^ν^Ν02

4-iodo-3-nitrobenzamide glutathione binding and metabolism:

Indole-acetyltransferase

HSCoA CH3COSC0A

Molecular weight: 285.28 -65-156511.doc 201206449 Any of the above-described nitrophenylguanamine metabolite compounds are provided herein for use in treating the ovarian cancer according to any of the methods provided herein (eg, treating ovarian cancer with a genetic defect in the bRCA gene) the use of. Any of the metabolites of 4-iodo-3-nitrobenzamide described herein can be used in any of the methods provided herein. Metabolites of 4-iodo-3-nitrobenzamide include, for example, 4- Iodo-3-aminobenzoic acid ("ΙΑΒΑ"), 4_iodine·3_aminobenzamide (“ΙΑΒΜ”), 4-iodo-3-nitrosobenzamide (“ΒΝ〇” ") and 'E-3-aminobenzamide ("βνηΟΗ"). Metabolites and methods of making the metabolites are disclosed in U.S. Publication No. 2008/0103,104, and U.S. Patent No. 5,877,1, the entire disclosure of each of The method of things. In some embodiments of any of the methods provided herein, 4_峨_石肖基苯胺amine or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered. In a differential embodiment, 4-iodo-3-nitrobenzamine 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-bromo-3-aminobenzoic acid or 4-iodo-3-aminobenzamide. Nitrobenzamide metabolite compounds have been reported to have selective cytotoxicity against malignant cancer cells but not for non-malignant cancer cells. See Rice et al.

Proc. Natl. Acad. Sci. USA 89: 7703-7707 (1992), which is incorporated herein by reference in its entirety. In one embodiment, the nitrobenzamide metabolite compound utilized in the methods of the invention exhibits a selective toxicity to tumor cells that is higher than non-tumor cells. Thus compatible with at least one antimetabolite (eg, gemcitabine) and at least one platinum complex (eg, carboplatin, cisplatin • 66-156511.doc)

The chemotherapy of 201206449, etc., combines the metabolites of the present invention with patients in need of such treatment. The dosage of any of the metabolites described herein for treating platinum-resistant recurrent stocal carcinoma can range from about 0.0004 to about 0.5 mmol/kg (mole of metabolite per kg of patient body weight), The molar meter corresponds to a range of from about mg to about 100 mg/kg of 4-iodo-3·nitrobenzamine. Other effective doses of metabolites range from 0.0024-0.5 mmol/kg and 0.0048-0.25 mmol/kg. Such doses can be administered daily, every other day, twice a week, every week, every two weeks, every month, or other suitable schedule. The metabolite of 4_iodo-3 nitrobenzamide can be used in substantially the same mode of administration, for example, orally, intravenously, intraperitoneally, and the like. In some embodiments, 4-iodonitrophenylguanamine or a pharmaceutically acceptable salt thereof is administered. In some embodiments, a pharmaceutically acceptable salt of a metabolite of 4_Moth-3. Shisaki Benzene Amine or a metabolite of 4 Winter 3. Nitrobenzamide is administered. The term "pharmaceutically acceptable salts" means 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 benefit of the compounds described herein in the treatment of (4) resistant recurrent ovarian cancer. ', the type of salt is the step of inorganic ions (such as sodium, potassium, feed and town ions). The t-type salt includes and inorganic or organic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid 'diacid: sulfuric acid 1 sulfonic acid, p-toluene acid, acetic acid, fumaric acid, horn: oleic acid, almond acid, frequency fruit Acid, citric acid, tartaric acid or maleic acid). Further, in the case where the compound contains a few groups or other acidic groups, J 565II. -67. 201206449 can be converted into a pharmaceutically acceptable addition salt by an inorganic or organic base. Examples of suitable bases include sodium hydroxide 'potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine. In some embodiments, 4-iodo-3-nitrobenzamide is formulated for intravenous administration in 25% (w/v) hydroxypropyl-β-cyclodextrin and 1 mM mM phosphate buffer. And, as described in US Patent Application Publication No. 2010/0160442, which is incorporated herein by reference. Combination therapy

Any of the methods described herein may further include additional anti-cancer therapies including, but not limited to, surgery, radiation therapy (eg, X-ray), gene therapy, DNA therapy' adjuvant therapy, neoadjuvant therapy, viral therapy, immunotherapy, RNA therapy or nanotherapy. The non-pharmacological treatment can be carried out at any suitable time when the combination therapy further includes non-pharmacological treatment, as long as the co-action of the therapeutic agent and the non-drug treatment group achieves a beneficial effect. For example, where appropriate:: Since the administration of the therapeutic agent temporarily removes the non-pharmacological treatment, it still has a beneficial effect. Conjugates and other-medicine two: two: order or combination of patients. It will be understood that 'in the use of the present invention, the compound of the present invention and another pharmaceutically active agent may be in the same carrier as the drug, and thus simultaneously administered to the carrier, such as a conventional oral dose. Form, two: The "combination" of the medicine also refers to the situation in which the two administrations are provided in separate dosage forms. "Alpha-substance and sequential radiation therapy 156511.doc -68-201206449 Radiation therapy (or radiation therapy) refers to ions Radiation is part of cancer treatment to control the treatment of malignant cells (4). Radiation therapy can be used to treat or assist with cancer treatment. It is used as a palliative treatment (in cases where it is not possible to cure and is intended for local disease control or symptom relief) or as a therapeutic treatment (in the case where the therapy has a survival benefit and it can be curative). Radiation therapy is used to treat malignant tumors and can be used as a primary therapy. It is also common to combine radiation therapy with surgery, chemotherapy, hormone therapy, or a mixture of these three. The most common type of cancer can be treated with radiation therapy in some aspects. A clear indication of treatment (healing, assisting, neoadjuvant, treatment, or palliative) will depend on the type, location, stage/period, and general health of the patient. Radiation therapy is often used for cancerous tumors. If the radiation field is clinically or radiologically involved in a tumor, or if a subclinical malignancy (4) is considered, the radiation field may also include a draining lymph node. It is necessary to include the edges of normal tissue around the tumor to allow for uncertainty in daily settings and internal tumor movement. Radiation therapy is performed by damaging cellular DNA. Damage is caused by photons, electrons, protons, neutrons, or ion beams that ionize the atoms that make up the DNA strand, either directly or indirectly. Indirect ionization occurs due to ionization of water 'forming free radicals&amp;, especially via radicals&amp;, which can then damage DNA. In the most common forms of radiation therapy, most (four) effects are achieved by free radicals. Because cells have a mechanism to repair DNA damage, breaking DNA on both strands proves to be the most important technique for altering cellular characteristics. Because cancer cells are generally undifferentiated and stem cell-like, they multiply more than most healthy differentiated cells and have a reduced ability to repair sublethal damage. DNA damage is inherited through cell division, accumulating damage 156511.doc -69 - 201206449 to cancer cells' causing it to die or to multiply more slowly. Proton radiation therapy is performed by sending protons with different (4) to stop in the stagnation. Gamma rays can be used to treat any of the cancers described herein. In a procedure called gamma surgery, a plurality of concentrated ray rays are directed to the growth to kill the cancerous cells. These beams are from different angles to focus the radiation on the growth while minimizing damage to surrounding tissue. Radiation sensitizers are known to increase the sensitivity of cancerous cells to the toxic effects of electromagnetic radiation. Various cancer treatment regimens currently employ radiation sensitizers activated by X-ray electromagnetic radiation. Examples of X-ray activated radiation sensitizers include, but are not limited to, the following: metronidazole (metr〇nidaz〇le), miso Misonidazole, demethylmethoxazole, pim〇nidaz〇le, etanidazole, nimoraz〇ie, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-deoxyuridine (iudR), desertoxypeptone, fluorodeoxyuridine (FudR), hydroxyurea , cisplatin, and therapeutically effective analogs and derivatives thereof. Photodynamic Therapy for Cancer (PDT) uses visible light as a light activator for sensitizers. Examples of the photodynamic radiation sensitizer include, but are not limited to, the following: hematoporphyrin derivative, photoporphyrin, benzoporphyrin derivative, NPe6, tin porphyrin SnET2, non-Pabidob-α (pheoborbide-α) ), bacteriochlorophyll-α, naphthalocyanine, phthalocyanine, zinc phthalocyanine, and therapeutically effective analogs and derivatives thereof. Gene Therapy Agents 156511.doc •70· 201206449 Gene Therapy Agents insert gene copies into specific groups of patient cells and target both cancer cells and non-cancer cells. The purpose of gene therapy can be to replace the altered gene with a functional gene, stimulate the patient's immune response to cancer, make the cancer cell more sensitive to chemotherapy, place the "suicide" gene into the cancer cell, or inhibit angiogenesis. The gene can be delivered to the target cell using a virus, liposome or other carrier or carrier. This can be done by injecting the gene-carrier composition directly or ex vivo into the patient, wherein the infected cells are directed back into the patient. Such compositions are suitable for use in the present invention. 0 Adjuvant Therapy Any of the methods provided herein may further comprise adjuvant therapy. Adjuvant therapy includes treatment that is given after the main treatment to increase the chance of cure. Adjunctive therapy can include chemotherapy, radiation therapy, hormone therapy, or biological therapy. In some embodiments of any of the methods described herein, the method further comprises administering a granulocyte colony stimulating factor (rG_CSF). In some embodiments, the method does not further include administration because the primary purpose of the adjuvant therapy is to kill Death of any cancer cells that may have spread - so treatment is usually systemic (using substances that are transported through the bloodstream to 胄 and affect the body's cancer cells). For example, adjuvant therapy for ovarian cancer. involves chemotherapy or hormone therapy 'It can be used alone or in combination. Auxiliary chemotherapy refers to the use of drugs to kill cancer cells. Auxiliary 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 topical Adjuvant therapy. When radiotherapy is given before or after surgery 1565Il.doc -71 - 201206449 (eg mastectomy), it is considered adjuvant therapy. Such treatment is intended to eliminate parts that have spread to the vicinity of the body (such as the chest wall or Cancer cells of lymph nodes. Xiage therapy has been used to treat ovarian cancer, including but not limited to hormone therapy For example, tamoxifen, or gonadotropin releasing hormone (GnRH) analogs, and radioactive monoclonal antibody therapy. Neoadjuvant therapy Neoadjuvant therapy refers to treatment given prior to primary treatment. Examples of neoadjuvant therapy include chemotherapy, Radiation Therapy and Hormone Therapy. Neoadjuvant chemotherapy for gynaecological cancer t is a way to show positive effects on survival. It improves resectability in ovarian and cervical cancer and thus contributes to survival (Ayhan A. et al. , European j〇urnai 〇f gynaec〇i〇gicai oncology. 2006, Vol. 27). Oncolytic virus therapy The viral therapy of cancer uses a class of viruses called oncolytic viruses, which are capable of infecting and lysing cancer cells. At the same time, it does not damage the virus of normal cells, making it potentially useful in cancer therapy. The replication of oncolytic virus not only promotes tumor cell destruction but also produces dose amplification at the tumor site. It can also act as a carrier of anti-cancer genes, allowing its specificity. Sexual delivery to the tumor site. There are two main ways to produce ± tumor selectivity: angiography and non-transduction targeting. The specificity involved in modifying the coat protein of the virus, thereby increasing the probability of entering the stem cells while reducing the chance of entering the non-stem cells. The non-transduced stem direction involves changing the genome of the virus so that it can only replicate in cancer cells. By transcriptional stem (which will be critical for viral replication, 1565ll.doc.72·201206449 genes are placed in tumor-specific initiation early in the control) or by attenuating (this involves

The deletion is introduced into the viral genome, straight, 'accounting for 1$·A. In addition to the unnecessary functions in cancer cells but necessary functions in normal cells. There are other ways that are slightly more difficult.

Chen et al. (2001) used CV706'-prostate-specific adenovirus in combination with prostate cancer in mice. This combination treatment results in a synergistic increase in cell death and a significant increase in the amount of virus released (the number of viral particles released from each cell breakdown). ONYX-015 has been tested in combination with chemotherapy. This combination treatment gave a greater response than either-alone treatment, but the results were not completely conclusive. ONYX-015 has shown promise in combination with radiation therapy. 4 doses of intravenous administration of the disease can be particularly effective in the treatment of metastasis. However, blood-borne viruses can be inactivated by antibodies and rapidly cleared from the bloodstream by, for example, Kupffer cells (very active phagocytic cells in the liver, which are cleared by negative adenovirus). Avoiding the immune system until the tumor is eliminated may be the biggest obstacle to the success of oncolytic therapy. To date, none of the techniques used to circumvent the immune system is entirely satisfactory. It is in combination with conventional cancer therapies that oncolytic viruses have been shown to be the most promising because combination therapies work together and have no significant negative effects. The specificity and flexibility of oncolytic viruses means their potential to treat a variety of cancers, including ovarian cancer, with minimal side effects. Oncolytic viruses have the potential to address the problem of selective killing of cancer cells. Nanotherapy Nano-sized particles are not available from molecular individuals or bulk solids. 156511.doc -73· 201206449 New optical, electrical and structural properties. When linked to a tumor targeting moiety, such as a tumor-specific ligand or a monoclonal antibody, these nanoparticles can be used to target cancer-specific receptors, tumor antigens (biomarkers) with high affinity and precision. Tumor vasculature. The formulation and manufacturing process of cancer nanotherapy is disclosed in the patent US7179484 and the paper 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, which is incorporated herein by reference in its entirety. RNA Therapy RNA (including but not limited to siRNA, shRNA, microRNA) can be used to regulate gene expression and treat cancer. A double-stranded oligonucleotide is formed by assembling two different oligonucleotide sequences, wherein one oligonucleotide sequence is complementary to the second strand oligonucleotide sequence; such double-stranded oligonucleotides are generally from two A separate oligonucleotide (eg, siRNA) or assembled from a single molecule that folds to form a double-stranded structure (eg, shRNA or short hairpin RNA). All of the double-stranded oligonucleotides known in the art have a common feature, that is, each strand of the duplex has a different nucleotide sequence, wherein there is only one nucleotide sequence region (guide sequence or The antisense sequence) is complementary to the target nucleic acid sequence and the other strand (sense sequence) comprises a nucleotide sequence homologous to the target nucleic acid sequence. MicroRNAs (miRNAs) are single-stranded RNA molecules of approximately 21-23 nucleotides in length that regulate gene expression. A miRNA is encoded by a gene that is transcribed from DNA but not translated into a protein (non-coding RNA); alternatively, it is called -74-156511.doc

S 201206449 The primary transcript of pri-miRNA is engineered into a short stem-loop structure called pre-miRNA and finally processed into a functional miRNA. A mature miRNA molecule is partially complementary to one or more messenger RNA (mRNA) molecules and its primary function is to down-regulate gene expression. Certain RNA inhibitors can be used to inhibit the expression or translation of messenger RNA ("mRNA") 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 inhibitors suitable for use herein include, but are not limited to, Cand5, Sirna-027, fomivirsen, and angiozyme. Small molecule enzyme inhibitors Some small molecule therapeutics are capable of targeting tyrosine kinase activity of certain cellular receptors, such as epidermal growth factor receptor ("EGFR") or vascular endothelial growth factor receptor ("VEGFR"). Or downstream signal transduction signals. Such targeting of small molecule therapeutics can produce an anti-cancer effect. Examples of such agents suitable for use herein include, but are not limited to, imatinib, gefitinib, erlotinib, lapatinib, carartinib, ZD6474, sorafenib (BAY 43-9006) ), ERB-5 69, and its analogs and derivatives. Anti-metastatic agents The process by which cancer cells spread from the initial tumor site to other locations around the body is called cancer metastasis. Certain agents have anti-metastatic properties and are 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 Hunting 156511.doc -75- 201206449 hunter-killer peptide, tissue inhibitor of metalloproteinase (TIMP), analogs, derivatives and variants thereof. Chemopreventive Agents Certain pharmaceutical agents, such as chemopreventive agents, can be used in combination with any of the methods provided herein. These agents can be used to prevent the onset of cancer or to prevent recurrence or metastasis. Administration of such chemopreventive agents in combination with any of the treatments described herein can serve to treat and prevent cancer recurrence. Examples of chemopreventive agents suitable for use herein include, but are not limited to, tamoxifen, raixixifen, tibolone (tib〇i〇ne), bisphosphonates ( Bisphosphonate, ibandronate, estrogen receptor modulating agent, galangin inhibitor (ie tr〇zole, anastrozole), luteinizing hormone releasing hormone Agent, goserelin, vitamin A, retinal, retinoic acid, fenretinide, 9-cis-retinoic acid, 13-cis-retinoic acid, all_ Trans _ retinoic acid, isotretinoin, tretinoid, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, cyclooxygenase inhibitor, non-steroidal anti-inflammatory drug (NSAID), aspirin (aspirin), ibuprofen, celecoxib, polyphenols, polyphenols e, chlorophyll extract, folic acid, glucaric acid, interferon alpha, bacteriophage Anethole dithiolethione, rhein, pyridoxine, phenazone (Hnasteride), and more sand. Kyu. Qin (doxazosin), 砸, 〇 卜 -3- -3- carbonitrile (carbinal), α- dioxin methyl ornithine, carotenoids, beta carotene, lycopene, antioxidants, coenzyme Q10, Flavonoids, quercetin, curcumin, catechins, 156511.doc • 76· 201206449 Acidic epigallocatechin (epigallocatechin gallate), N-ethylcysteine, 丨°° Carbinol, hexainoic acid inositol, isoflavones, glucanic acid, rosemary, soy, sabah brown, and calcium. Another example of a chemopreventive agent suitable for use in the present invention is a cancer vaccine. These can be created by immunizing the patient with all or part of the cancer cell type targeted by the vaccination process. Clinical Efficacy Clinical efficacy can be measured by any method known in the art. In some embodiments, the clinical efficacy of the therapeutic treatments described herein can be determined by measuring the clinical benefit rate (CBR). By determining the sum of the number of patients in a complete regression (CR) state, the number of patients in a partial regression (PR) state, and the number of patients with stable disease (SD) at a time point at least 6 months from the end of treatment To measure the clinical benefit rate. The abbreviation for this formula is CBR=CR+PR+SD for 26 months. Similarly, a combination of an antimetabolite (eg, gemcitabine), a platinum compound (eg, carboplatin), and 4-iodo-3-nitrobenzamine, CBR (CBRgem/carbo/ba) and an antimetabolite ( CBR (CBRgem/carb0) comparison of dual combination therapies such as gemcitabine and platinum compounds such as carboplatin. 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%. In some embodiments of any of the methods provided herein, at least one therapeutic effect is obtained, the at least one therapeutic effect being ovarian tumor size reduction, metastasis reduction, complete regression, partial regression, pathological partial response, 156511.doc - 77- 201206449 Pathological complete response, elevated overall response rate or objective response rate or stable disease. In some embodiments, treatment with gemcitabine and carboplatin is achieved with 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) and treatment with gemcitabine and carboplatin. The clinical benefit rate of treatment without 4-iodo-3-nitrobenzamide (or its metabolite or its pharmaceutically acceptable salt) (CBR=CR+PR+SD>6 months ). In some embodiments, the clinical benefit rate is increased by at least about 20%, 30%, 40%, 50%, 60%, 70°/. , 80%, 90% or 95%. In some embodiments, 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) is administered and a complete, partial or stable disease is produced with gemcitabine and carboplatin. In some embodiments of any of the methods provided herein, the patient has a measurable disease. The measurable disease can be determined according to the ruler: (:: 131' 1·ι version of the standard', which is described in Eisenhauer EA et al., 2009, Eur J Cancer., 45(2): 228-47, the disclosure of which The disease measurable by β can also be defined by at least one of the following lesions, at least one of which (the longest dimension to be recorded) can be accurately measured, and by conventional techniques ( Palpation, general X-ray, computed tomography (CT) or magnetic resonance imaging (MRI) measurement when measuring &gt;20 mni or when measuring by spiral CT 210 mm ° response rate according to RECIST 1 · 1 For example, the complete response (CR) for dry lesions can be defined as the disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must be reduced to &lt; i 〇 mm on the short axis. Lesion, partial response (pR) can be defined as the diameter of the target lesion 156511.doc •78· 201206449 The sum of the baseline diameters of the salt j to / 3G/e α is used as a reference (the sum of the baseline diameters is the diameter of all dry lesions (non-nodular) Lesion (10) is the longest (4), nodular lesion (n〇 Dal lesion) is the sum of the short axes). For dry lesions, &amp; disease (PD) can be used to increase the sum of the diameters of the target lesions at least, to study the minimum of 9 o'clock and as a reference (this includes the baseline) And, if it is minimal at the time of the study), except for the relative increase of (4), the sum can also show an absolute increase of at least 5: A. Regarding the lesion, the disease stability (sd) can be defined as both Reduction to achieve the PR state is not sufficiently increased to reach the state (based on the sum of the smallest diameters at the time of the study as a reference for non-dry lesions, CR can be the disappearance of all non-target lesions and the normalization of tumor markers (all lymph nodes in size) May be non-pathological (short axis &lt; 10 mm). For non-dry lesions, non-CR/non-PD may be - or multiple non-dry lesions persist and/or tumor target levels maintained above normal limits. Non-dry lesions, progressive disease (PD) may be a clear progression of existing non-stem lesions... or the presence of multiple new lesions may be considered progression. The overall response may be in accordance with EiSenhauer EA et al., 2〇〇9, Eur j —, 45(7) :228_47 (such as Table 3) to determine, it is revealed The contents are hereby incorporated by reference in their entirety. The efficacy parameters can be determined by any method known to those skilled in the art. For example, it can be determined according to the recist n standard. For example, the objective response rate or the total response rate can be defined. The proportion of patients who have a complete response or a partial response to the overall response or the best overall response (eg, the overall response rate can be defined as the complete response rate plus the part = response rate, or 〇RR = CR + PR). Progression free survival can be Defined as the date from the start of treatment (or the date of initiation of the (four) treatment or randomization) to the first observation of the disease 156511.doc •79-201206449 The date of progression or the date of death ^ Overall survival can be defined as the beginning The date of treatment (or the date of initiation of the study or treatment or the date of randomization) to the date of death. In some embodiments, a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (i) 4_峨_3 nitrophenyl hydrazine, a metabolite thereof, or a pharmaceutically acceptable salt; (ii) an antimetabolite (such as gemcitabine); and (iii) a platinum compound (such as carboplatin), wherein the treatment results in a reduction in the size of the ovarian tumor of the patient. In some embodiments, a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering an effective amount to the patient: (i) 4-E-3-nitrobenzamine, a metabolite thereof, or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) a card flip wherein the treatment results in a reduction in ovarian cancer metastasis in the patient. In some embodiments, 'k is a method for treating a patient's resistance to recurrent ovarian cancer, including the effective amount of the patient: (i) 4-moth-3-nitrobenzamine, a metabolite thereof Or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) a carbo wherein the treatment results in complete response of the patient. In some embodiments, 'providing a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (i) 4-trans-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iH) card initiation wherein the treatment results in a pathologically complete response in the patient. In some embodiments, a method for treating a patient with recurrent resistant ovarian cancer comprises administering to the patient an effective amount: (i) 4_iodo-3-nitrobenzamine, its metabolism Or a pharmaceutically acceptable salt thereof; (丨丨) gemcitabine; and (iii) carboplatin, wherein the treatment causes a partial response in the patient. In a method of treating a patient with relapsed ovarian cancer, a method comprising administering an effective amount to the patient: (i) 4_iodonitrobenzene Indoleamine, a metabolite thereof or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) a card face, wherein the treatment stabilizes the disease in the patient. In some embodiments, 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; (Η) gemcitabine; and (iii) carboplatin, wherein the treatment results in a reduction in ovarian cancer metastasis in the patient. In some embodiments, at least about 10% (including, for example, at least about 20%, 30%/〇, 40%, 〇%, 〇%, 8%, 9%, or 〇〇%) The transfer of one) is inhibited (for example, with administration of (1) 4-iodo-3-nitrostamine, a metabolite thereof or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (ι) carboplatin Compared to the previous transfer). In some embodiments, any method is used to inhibit metastasis to lymph nodes. In some embodiments, a method of treating platinum-resistant recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (i) 4 iodine-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in a reduction in the size of the patient's ovarian tumor. In some embodiments, the tumor size is reduced by at least about 10% (including, for example, at least about 20%, 3〇〇/0, 40%, 60%, 70%, 80%, 90〇/〇, or 100/〇) Either (for example, with (i) 4-iodo-3·nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) a card Compared to previous tumor size). In some embodiments, administration of 4_iodo-3-nitrobenzamide, its metabolite 156511.doc •81 - 201206449 or a pharmaceutically acceptable salt thereof, administration of gemcitabine and/or a card Platinum has a synergistic effect. In some embodiments, a small amount of each pharmaceutically active compound is used as part of the combination therapy 2 as compared to the amount used in the individual therapy. In some embodiments, combination therapy is used to achieve the same or greater therapeutic benefit as compared to the use of any individual compound alone. In some embodiments, a pharmaceutically active compound that achieves the same or greater therapeutic benefit in combination therapy with a small amount (eg, a lower dose or a lower frequency dosing schedule) than the amount typically used in the individual therapy. . For example, the use of a small amount of a pharmaceutically active compound can reduce/reduce/short the number, severity, frequency or duration of one or more of the effects associated with the compound. 'Formulations, routes of administration, and dosing schedules, in some embodiments, provide 4-iodo-3-nitrobenzene-f-amine (or a metabolite thereof or a pharmaceutically acceptable salt or solvate thereof) Formulations of antimetabolites (eg, gemcitabine) and/or platinum compounds (eg, carboplatin) and/or carriers (such as pharmaceutically acceptable carriers) (eg, pharmaceutical formulation formulations may include the compounds disclosed herein) Optical isomer, diastereomer, carrier or pharmaceutically acceptable salt. In some embodiments, the carrier is a cyclodextrin or a derivative thereof, such as hydroxypropyl-β-cyclodextrin Fine (HpBCD). In some embodiments, the formulation is formulated for intravenous administration. The pharmaceutical composition of the present invention can be provided as a prodrug and/or can be converted to 4-iodine in vivo after administration. In the form of -3-nitrobenzamide, i.e., iodine-3-nitrobenzamide or a metabolite or pharmaceutically acceptable salt thereof may be used in the development of a formulation for use in the present invention. 4_Iodine_3_Nitrate 15651 ] .doc • 82 - 201206449 Benzobenzamide (or its metabolite) An antimetabolite (eg, gemcitabine) and a platinum compound (eg, carboplatin) may be formulated in separate formulations or in the same formulation. 4-Iodo-3-nitrobenzamide provided herein (or Metabolites, antimetabolites (eg, gemcitabine), and platinum compounds (eg, carboplatin) can be administered via different routes of administration or using the same route of administration. Also provided herein are platinum-resistant recurrent ovarian cancers for treating patients. a synergistic composition comprising (i) 4_iodo-3-nitrobenzamine or a metabolite thereof or a pharmaceutically acceptable salt thereof, (ii) gemcitabine, and (ni) carboplatin. A specific ratio of both 4-iodo-3-nitrobenzamine compound and the acid form, depending on the respective relative potency and the intended indication. These two forms may be formulated together or in different formulations. In one unit of the same dose, for example in a cream, suppository, lozenge, capsule or powder package to be dissolved in a beverage; or each form can be formulated in separate units 'eg two creams, two Suppository, two kinds of tablets, two kinds of glue Agent, a tablet and a liquid for dissolving the tablet, a powder package and a liquid for dissolving the powder, etc. 4-Iodo-3-nitrobenzamide provided herein (or its metabolism) , an antimetabolite (eg, gemcitabine), and a platinum compound (eg, carboplatin) can be co-administered to the patient. Co-administration is intended to include the simultaneous or sequential administration of the compounds, either alone or in combination (more than one compound), such as described herein. The 4_峨_3-nitrobenzamide (or its metabolite), antimetabolite (such as gemcitabine), and/or the compound (such as Carmen) provided herein may be continuously or not The patient is continuously administered. "Discontinuously" means that the compound or composition provided herein is not administered to the patient for a period of time, such as a rest period, during which the patient does not accept the patient at 156511.doc • 83-201206449 A compound or composition. It can be as follows: one compound is administered to the patient continuously, and the second compound is administered to the patient discontinuously. Pharmaceutical compositions of 4-iodo-3-nitrobenzamide, antimetabolites (e.g., gemcitabine), and an initial compound (e.g., carboplatin) can be combined with other active ingredients, such as other chemotherapeutic agents described herein. The three compounds and/or compound forms may be formulated in the same dosage unit, for example, in a cream, suppository, lozenge, capsule, or powder package to be dissolved in a beverage; or each form may be in separate units Formulated in, for example, three creams, three suppositories, three kinds of tablets, three capsules, a tablet and a liquid for dissolving the tablet, a powder package and a liquid for dissolving the powder. The term "pharmaceutically acceptable salts" means 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 effects of the compounds provided herein in the treatment of platinum-resistant recurrent ovarian cancer. Typical salts are salts of inorganic ions such as sodium, potassium, calcium and magnesium ions. Such salts include with inorganic or organic acids (such as hydrochloric acid, hydrogen desert acid, phosphoric acid, sulfonium I sulfur &amp; L, phthalic acid, p-toluene acid, acetic acid, fumaric acid, prapa lactic acid, almond acid, Malate, malic acid, tartaric acid or maleic acid) can be converted into a pharmaceutically acceptable addition salt by inorganic or organic testing in the case where the compound contains a carboxyl group or other acidic group. Examples of suitable bases include sodium hydroxide 'potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine. 156511.doc δ • 84 · 201206449 For injection, 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof may be formulated for use in an aqueous solution, preferably physiologically A compatible buffer such as phosphate buffer, Hank's solution or Ringer's solution (Ringer, ss〇丨uti〇n) is administered. Such compositions may also include one or more excipients such as preservatives, solubilizers' fillers, lubricants, stabilizers, albumin, and the like. Formulations of 4-iodonitrostanoin are described in U.S. Patent Publication No. 2008/0176946 A1, which is incorporated herein in its entirety by reference in its entirety in particular in particular in the s s Fine, etc.) and oral (such as sodium lauryl sulfate, etc.) formulations. In some embodiments, 4-iodo-3-nitrobenzamide is formulated for intravenous administration in 25% (w/v) hydroxypropyl-beta-cyclodextrin and 10 mM phosphate buffer. , as described in U.S. Patent Application Publication No. 201 0/0160442, which is incorporated herein by reference. In some embodiments, the formulation had 10 mg/mL 4-indole-3-nitrobenzamide, 25°/. (w/v) Hydroxypropyl-β·cyclodextrin and mM phosphate buffer (ρΗ 7.4). Other methods of formulation, such as those for use with the antimetabolites described herein (e.g., gemcitabine) and platinum compounds (e.g., carboplatin) are known in the art, for example, as disclosed in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing. Co., Easton, PA. The compositions described herein may also be formulated for transmucosal administration, buccal administration, administration by inhalation, parenteral administration, transdermal administration, and rectal administration. A pharmaceutical composition suitable for use as described herein includes a composition comprising an effective amount of the active ingredient therein, i.e., the effective amount is effective in at least one of the platinum-resistant ovarian cancers (e.g., recurrent ovarian cancer) described herein. Achieve treatment 156511.doc -85 - 201206449 and / or the amount of preventive benefit. The actual effective amount for a particular administration will depend on the platinum-resistant recurrent ovarian cancer (eg, recurrent ovarian cancer) being treated, the individual's condition, the formulation, and the route of administration, as well as those skilled in the art in view of the specifics provided herein. Teach other factors known. According to the disclosure herein, the optimal range can be determined within the specified range of 4-iodo-3-nitrobenzamide, antimetabolite (eg, gemcitabine), and/or platinum compound (eg, carboplatin) provided herein. In some embodiments of any of the compositions or formulations provided herein, the compositions or formulations are administered in unit dosage form. In some embodiments, the unit dosage form is suitable for oral or parenteral administration. In some embodiments, after administration of the composition or formulation, at least one therapeutic effect is obtained, the at least one therapeutic effect being tumor size reduction, metastasis reduction, complete regression, partial regression, pathological complete response, total response rate increase High or stable disease. In some embodiments, after administration of the composition or formulation, with an antimetabolite (eg, gemcitabine) and a platinum compound (eg, carboplatin) but without 4_iodo-3.nitrobenzamide or its metabolism The clinical benefit rate (CBR = CR + pR + SE ^ 6 months) was improved compared to the treatment of the substance or its pharmaceutically acceptable salt. In some embodiments, the clinical benefit rate is increased by at least about. In some embodiments, 'increasing the clinical benefit rate by at least about 25%, 3〇%, 35%, 40%, 45〇/〇, 50%, 55%, 60%, 65%, 7〇%, 75〇/ 〇 or higher order. In some embodiments of any of the methods provided herein, the amount of 4-iodo-3-nitrobenzamine, a metabolite thereof or a pharmaceutically acceptable salt thereof, the amount of gemcitabine, and/or a card The amount of platinum is the activity corresponding to the tumor size, cancer cell number or tumor growth rate in the same patient at the beginning of treatment 156511.doc δ • 86 - 201206449 or in other patients who do not receive the treatment. In comparison, it is sufficient to reduce tumor size, reduce the number of cancer cells or reduce the tumor growth rate (including reducing metastasis) by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80°/ The amount of 〇, 90°/〇, 95% or 100%. Standard methods can be used to measure the extent of this effect. 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 carboplatin is lower than the induced toxicology The level of effects (eg, effects that exceed clinically acceptable levels of toxicity) or levels at which potential side effects can be controlled or tolerated. In some embodiments, the amount of 4-iodo-3-nitrobenzamine, its metabolite or its pharmaceutically acceptable salt, the amount of gemcitabine, and/or carboplatin is near the maximum dose. (MTD). In some embodiments, the amount is at least about any of 80%, 90%, 95%, or 98% of the MTD. Any of the compositions or compounds described herein can be administered to a patient via a suitable route such as, but not limited to, intradermal, intramuscular, intraperitoneal, intravenous, intraarterial, subcutaneous, intranasal, epidural, and oral routes. In some embodiments, the compositions or compounds provided herein are administered by parenteral routes, such as intravenous, intraperitoneal, subcutaneous, intradermal or intramuscular. Any of the compositions or compounds described herein can be administered by any convenient route, such as by infusion or bolus injection, by absorption through epithelial or mucosal skin linings (eg, oral mucosa, rectal and intestinal mucosa, etc.), and Administration with other biologically active agents, such as, for example, as described herein. Administration can be 156511.doc -87· 201206449 for whole body or partial. In addition, it may be desirable to introduce the pharmaceutical composition of the present invention into the central nervous system by any suitable route, including intraluminal and intrathecal injection; indoor injection may be by an internal catheter (eg, attached to a reservoir, such as an Ommaya reservoir) ) to promote. The dose of 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof may vary depending on the age, height, weight, overall health, and the like of the patient. In some embodiments, the dose of 4-iodo-3-nitrobenzamine (or a metabolite thereof or a pharmaceutically acceptable salt thereof) is from about 0.1 mg/kg to about 50 mg/kg, about 1 From mg/kg to about 100 mg/kg, from 2 mg/kg to about 50 mg/kg, from about 2 mg/kg to about 10 mg/kg, from about 4 mg/kg to about 8 mg/kg, about 5 mg/kg To about 7 mg/kg, from about 1 mg/kg to about 50 mg/kg, from about 1 mg/kg to about 25 mg/kg, from about 2 to about 70 mg/kg, from about 2 mg/kg to about 50 mg/ Kg, from about 2 mg/kg to about 40 mg/kg, from about 3 mg/kg to about 30 mg/kg, from about 4 to about 100 mg/kg, from about 4 to about 25 mg/kg, from about 4 to about 20 mg /kg, from about 4 to about 15 mg/kg, from about 5 to about 20 mg/kg, from about 5 to about 15 mg/kg, from about 50 to about 100 mg/kg, or from about 25 to about 75 mg/kg. In the range of 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, approximately 17 mg/kg, approximately 18 mg/kg, approximately 19 mg/kg, approximately 20 mg/kg, approximately 25 mg/kg, approximately 30 mg/kg, approximately 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-A-3-stone Schiffkibenzene-88-156511.doc

S 201206449 The dosage of the brewing amine is about 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, &quot;.2 mg/kg, 12 5 mg/kg, 15 mg/kg, 20 mg/kg, 30 mg/kg, Any of 50 mg/kg, 75 mg/kg or 1 〇〇mg/kg. In some embodiments, 4_峨_3_nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) is at least about 1 mg/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, approximately 12 mg/kg, approximately 13 mg/kg, approximately 14 mg/kg, approximately 15 mg/kg, approximately 16 mg/kg, approximately 17 mg/kg, approximately 18 mg/kg, approximately 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 a dose of about 90 mg/kg. 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) may be in the range of from about 10 to about 3 minutes, from about 3 to about 18 minutes, and about 45 minutes. It is administered intravenously, for example by IV infusion, to about 120 minutes or about 60 minutes (i.e., about 1 hour). 4-A-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof can be administered once a week, once every three weeks, twice a week, three times a week, three weeks Four, five, four or six Fridays. For example, 4·iodo_3_nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof may be administered within 2 or 4 days of the treatment cycle, for example, on the first day of the 21-day treatment cycle and Day 8 (at a dose of about 112 mg/kg) or on Day 1, Day 4, Day 8, and Day 11 (at a dose of about 5.6 mg/kg). In some embodiments, a method of treating platinum-resistant 156511.doc-89-201206449 recurrent ovarian cancer in a patient, iodide-3-nitrobenzamide, comprising administering an effective amount to the patient: i) 4-

The patient is administered intravenously from mg/kg to about 15 mg/kg. In some embodiments, 4-iodo-3-nitrobenzamide may be administered orally. The dosage of an antimetabolite (e.g., gemcitabine) provided herein for use in any of the methods provided herein can vary with the age, height, weight, overall health, and the like of the patient. In some embodiments, the dosage of an antimetabolite (eg, gemcitabine) provided herein is from about 1 mg/m2 to about 5000 mg/m2, from about 1 mg/m2 to about 2000 mg/m2, about 200. Up to about 4000 mg/m2, from about 300 to about 3000 mg/m2, from about 400 to about 2000 mg/m2, from about 500 to about 1500 mg/m2, from about 750 to about 1500 mg/m2, from about 800 to about 1500 mg/ M2, from about 900 to about 1400 mg/m2, from about 900 to about 1250 mg/m2, from about 1 to about 1500 mg/m2, from about 10 mg/m2 to about 1000 mg/m2, from about 25 mg/m2 to about 500 mg/m2, from about 50 mg/m2 to about 200 mg/m2, or from about 75 mg/m2 to about 200 mg/m2. In some embodiments, the antimetabolite (eg, gemcitabine) is about 50 mg/m2, 75 mg/m2, 100 mg/m2, 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/m , 1000 mg/m , 1050 mg/m 2 ' 1100 mg/m 2 ' 1150 mg/m 2 ' 1200 mg/m, 1250 -90- 156511.doc s 201206449 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 is administered. Antimetabolites (eg, gemcitabine) can be at least about 50 mg/m2, 75 mg/m2, 100 mg/m2, 125 mg/m2, 150 mg/m2, 175 mg/m2' 200 mg/m2, 250 mg/m2 300 mg/m2, 4〇〇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 One dose is administered. The antimetabolites (eg, gemcitabine) provided herein may be administered weekly, every three weeks, twice a week, twice every three weeks, three times a week, three times a week, five weeks, four weeks, or six weeks. . For example, an antimetabolite (eg, gemcitabine) provided herein can be administered during 2 days of the treatment cycle, for example, on days 1 and 8 of the 21-day treatment cycle (at a dose of about 1 mg/m2). versus. An antimetabolite (eg, gemcitabine) provided herein can be from about 1 to about 500 minutes, from about 10 to about 300 minutes, from about 15 to about 180 minutes, from about 30 to about 180 minutes, from about 30 to about 60 minutes, about 45 to about 120 minutes, about 20 to about 60 minutes, about 10 minutes, about 2 minutes, about 30 minutes, about 6 minutes (ie about 1 hour) or about 30 minutes intravenously, for example by... Infusion to vote. Antimetabolites (eg, gemcitabine) may be administered orally. 156511.doc -91· 201206449 The dosage of the initial compound (e.g., carboplatin) provided herein for use in any of the methods provided herein can vary with the age, height, weight, overall health, and the like of the patient. The dose of the platinum compound (e.g., carboplatin) is determined by calculating the area under the plasma concentration-time curve (AUC, mg/mL, min), which is considered by methods known to those skilled in the art of cancer chemotherapy. The renal activity of the patient was assessed by measuring creatinine clearance or glomerular filtration rate. In some embodiments, a platinum compound (eg, carboplatin) provided herein is used in combination with an antimetabolite (eg, gemcitabine) and 4-iodo-3-nitrobenzamine in an amount of about ten 〇 _; [to about 8 mg / ml ^ min, about 〇. 1 to about 7 mg / ml. min, about 〇 · 1 to about 6 mg / m b min, about 1 to about 6 mg / ml * min, From about 1 to about 5 mg/m b min, from about 2 to about 5 mg/ml*min, from about 3 to about 6 mg/ml.min, from about 3 to about 5 mg/ml.min, from about 1 to about 3 Mg/ml, min, about 1.5 to about 2.5 mg/m b min, about 1.75 to about 2.25 mg/m b min, about 2 mg/ml.min (or AUC 2 ("AUC 2" is 2 mg/m b Abbreviation of min)), 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 of about AUC » or based on the body surface area of the patient A dose of a platinum compound (e.g., carboplatin). In some embodiments, a suitable dose of a platinum compound (e.g., carboplatin) is from about 10 to about 400 mg/m2, such as about 360 mg/m2. The starting compounds (eg, Kaming) provided in this article may be administered weekly, twice weekly, once every three weeks, every three weeks, three times three times, three times four times, five weeks four times, or six weeks. . For example, carboplatin can be administered during the first day of the treatment cycle, for example, on the first day of the 21-day treatment cycle (at a dose of about AUC 4). The platinum complex platinum compound (e.g., carboplatin) typically ranges from about 1 Torr to about 500 minutes, from about 10 to about 300 15651 l.doc 92-

S 201206449 minutes, about 30 to about 180 minutes, about 45 to about 120 minutes, or about 60 minutes, administered intravenously (IV). In this context, the term "about" has its normal meaning 'that is, about. In some embodiments, about means ±20%, ±1%, or ±5〇/〇. In some cases, temporary release of antimetabolites (eg, gemcitabine) from the administration of 4-iodo-3-nitrobenzamide (or its pharmaceutically acceptable salt or solvate or its metabolite) And administration of a platinum compound (e.g., carboplatin) for a significant period of time (e.g., about 12 hours, about 24 hours, about 36 hours, about 48 hours, etc.) or, for example, at least 1 day, 2 days apart from administration. , 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 1 day, etc.), still achieved beneficial effects. For example, it can be administered on different days of a treatment cycle, such as the treatment cycle described herein. The interval between administration of 4_iododonitrobenzamide, antimetabolite (eg, gemcitabine), and a platinum compound (eg, carboplatin) may vary during the treatment cycle (eg, administration is not always a day apart, However, it can be separated by 1 day, followed by 3 days, and similarly, 4_iodine-3 nitrobenzamide, antimetabolite (such as gemcitabine) and initial compound (such as card start) can be used during the treatment cycle. Some times are administered at the same time and are administered at different times during other times during the treatment. In some embodiments of any of the methods provided herein, the treatment comprises ^ cycles, 2 cycles, 3 cycles , cycle, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 1 cycle, &quot; cycles, 12 cycles, 13 cycles, 14 cycles, 15 cycles, 16 cycles, 17 cycles, 18 cycles, 19 cycles, or a paste cycle. The term "cycle" as used herein means "treatment cycle." In this embodiment 156511.doc • 93· 201206449, the method Includes at least one treatment cycle, three cycles , four cycles, five cycles, two cycles, eight cycles, nine cycles or ten:, six cycles, seven phases, two cycles, three cycles, = period, or at least four weeks Cycle, five cycles, &gt; = seven: _, eight cycles 'nine cycles, ten cycles two cycles: fourteen cycles, sixteen cycles, or twenty cycles, 6 The treatment cycle includes administration of (a) 4_iodo-3-nitrobenzamide: its metabolite or its pharmaceutically acceptable salt, (b) Kyrgyzstan and (4) card start. In some embodiments, the treatment comprises any of up to 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, or 10 cycles. . In some embodiments, the period (eg, treatment cycle) is about! A time period of any of weeks, 1 day, 2 weeks, 3 weeks, , , $ weeks/weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks. In some embodiments, the period (eg, treatment cycle) is at least (1) weeks, days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 1 week k. In some implementations, the cycle (eg, treatment cycle) is no more than about 1 week, 1 day, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks '9 weeks or 10 weeks The time of the person - the person. In some embodiments the treatment comprises at least about 1, 10, 2, 3, 4, 5, 6, 7, 7, 8, 9, 10, 12, or 5 weeks The treatment cycle of either. Any method provided herein may include at least one treatment cycle (eg, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 1 cycle) , u cycles, 12 cycles, 13 cycles, 14 cycles, or 15 cycles), where the cycle is a period of 3 weeks, and the T cycle of 156511.doc -94 - 201206449 includes casting (a) 4_ Iodine_3_nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, (8) gemcitabine and (4) card turnover. 4-iodo-3-nitrobenzamine can be administered every day of the treatment cycle, or every day of the treatment cycle, or during the treatment cycle, rather than every technique and in some embodiments. Medium, 4-indole-3-nitrostamine daily, = once a week, twice a week, three times a week, four times a week, one Friday, - Saturday, every 10 days, every two weeks Once, every three weeks, every four weeks, every six weeks - once or every eight weeks. It can be administered in the treatment cycle of each treatment cycle, for example, 4 winter 3 确 笨 醯 醯 醯 在 在 在 在 在 在 丨 丨 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或7, 8, $, 10) Daily doses of 'and 4_iodine_3_nitrobenzamide are not administered on other days of the treatment cycle. In some embodiments, the interval between each administration of 4 ginseng 3-nitrobenzamide, its metabolite or its pharmaceutically acceptable salt is less than about 6 months, 3 months, 1 Any of months, 20 days, 15 days, 14 days, 13 days, 12 days, u days, 1 day, 8 days, 7 days, 6 days, 5 2: 2, 2, 2, or 1 day By. In some embodiments, there is no discontinuity in the (7) music schedule. In some embodiments, the interval between each administration is no more than about 3 weeks, 2 weeks, or 1 week. In some embodiments, the interval between each administration is about whistle 'about 2 weeks or: 3 weeks. 4-iodo-3-nitrobenzamide (or its salt) can be used in the 4th day of treatment (4), for example, = 1 夭, 笛j as in the 4th of the 21st treatment cycle Days, Day 8, Day U administration (eg, at about 5.6 mg/kg) 〇4: at 3: benzylamine (or its metabolite or its pharmaceutically acceptable salt) ~ treatment cycle In 2 days, for example, on the first day of the 21-day treatment cycle and on the 15th day of the 156511.doc -95-201206449 (for example, at about 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). The antimetabolites (e. g., gemcitabine) provided herein can be administered daily, for example, every day of the treatment cycle, or during some of the treatment cycles, rather than every day. In some embodiments, the antimetabolite (eg, gemcitabine) provided herein is daily, once a week, twice a week, three times a week, four times a week, one Friday, one Saturday, once every day, Once every two weeks, every three weeks, every four weeks, every six weeks, or once every eight weeks. The antimetabolites (eg, gemcitabine) provided herein can be administered on selected days of each treatment cycle, eg, an antimetabolite (eg, gemcitabine) at 1 (or 2, 3, 4, 5, 6, 7, 8, 9, 1 〇) administered daily during the day, and antimetabolites (such as gemcitabine) are not administered in other lice during the treatment cycle. In some embodiments, the interval between each administration of gemcitabine is less than about 6 months, 3 months, i months, 21 days '2 days, 15 days, 14 days, 13 days, 12 days, U Any of 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 are no discontinuities in the dosing schedule. In some embodiments, the interval between each administration does not exceed any of about 3 weeks, 2 weeks, or weeks. In some embodiments, the interval between each administration is about [weeks, about 2 weeks, or about 3 weeks. Gemcitabine can be administered during 2 days of the treatment cycle, for example, on days 1 and 8 of the ^day treatment cycle (e.g., at about 1 mg/m2). The platinum compounds (e.g., carboplatin) provided herein can be administered daily, for example, every day of the treatment cycle, or on certain days of the treatment cycle rather than every day 156511.doc -96.201206449. In the second embodiment of this sound &quot;fafe, in this paper, platinum-plated carboplatin is provided), and one A is adjusted daily (for example, weekly-time, twice a week, three times a week, once, one Friday, one tone) Thursday,: people, mothers 10 days - times, every two weeks - times, every two weeks, every four adjustments can be mentioned in this article ^ 4 'persons, mothers six weeks - times or per person per week - to vote. Compounds (eg, carboplatin) can be administered on each selected day, for example, the force N is the parental chemotherapy cycle and, for example, the compound (eg, Kaming) is in the treatment cycle 1 (^2, 3, 4, 5, α, λ 6, 7, 8, 9, 1 〇) days of 投 daily administration of the composition (for example, card (f) is not administered on other days of the treatment cycle. In one embodiment, 'per-time contribution The interval between the cards # is less than about 6 months, 3 months, 1 month, 21 days, 2G days, 15 days, 14 days, 13 days, 12 days, π days, 1 day, 9 days, Days, 5 days, 4 days, 3 days, 2 days, or 1 day of the cup. In some embodiments, there is no interruption in the dosing schedule. In some embodiments, each - the interval between sub-investments is not exceeded = ” Any of 3 weeks, 2 weeks, or ! weeks. In some embodiments, the interval between each administration is about, about 2 weeks, or about 3 weeks. The card face can be in the first day of the treatment cycle. For example, administered over a 21 day treatment cycle (eg, at about AUC4). In some embodiments of any of the methods for treating platinum-resistant recurrent ovarian cancer, methods, including 15, 12 1, 〇, 9, 8, 7, 6 $ less dosing cycles, each period of # contains a period of 21 days. In some embodiments, 4_iodo-3-nitrobenzamide or The pharmaceutically acceptable salt is administered from 3 mg/kg to about 8.6 mg/kg on the third, fourth, eighth and u day of each cycle, with an antimetabolite (eg gemcitabine) at On day 1 and day 8 of each cycle, 1 〇〇〇mg/m2 is administered daily, and platinum 156511.doc -97. 201206449 compound (such as carboplatin) is 4 on the third day of each cycle. Mg/ml, min (Auc 4) Administration In some embodiments, a method of treating platinum-resistant recurrent ovarian cancer in a patient is provided, comprising at least one treatment cycle comprising administering the patient (i) 4-iodo-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof; (Π) gemcitabine; and (ni) carboplatin (1) carboplatin once during the treatment cycle ( For example, on the third day of the treatment cycle (such as the 2nd day cycle), the patient is administered at about AUC3 to about AUC5 (eg, AUC4), wherein (ii) gemcitabine is administered twice during the treatment cycle (eg, during a treatment cycle (such as The patient is administered from about 500 to about 15 mg/m2 (eg, 1 mg/m) on day 1 and day 8 of the 21 day cycle, and wherein 4_iodine-3 nitrobenzoic acid Indamine or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered once, twice, twice or four times during the treatment cycle (eg, on days ith and day 8 of a treatment cycle (such as a 21-day cycle), or On the third, fourth, eighth and third days of the treatment cycle (such as the 21-day cycle), from about 5 mg/kg to about 2 mg/kg (or from about 5 mg/kg to about 15 mg) /kg) (eg 5.6 mg/kg) is administered to the patient. In some embodiments, a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising at least one treatment cycle comprising administering to the patient (i) 4-iodo-3-nitrobenzamide a metabolite or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein (1) carboplatin is administered once per treatment cycle (eg, on day j of a treatment cycle (such as a 21-day cycle) The patient is administered at about AUC4, wherein (u) gemcitabine is administered twice during the treatment cycle (eg, on days 1 and 8 of the treatment cycle (such as the 21-day cycle) at about 1 mg/m) With β Hai patients' which is 4-ancillary-3-*shawylbenzamide or its metabolite-98·156511.doc

S 201206449 or a pharmaceutically acceptable salt thereof is administered four times during the treatment cycle (eg, on day 1, day 4, day 8, and day of the treatment cycle (such as a 21-day cycle) at about 5.6 mg/ Kg is administered to the patient. In some embodiments, a method of treating platinum-resistant recurrent ovarian cancer in a patient, comprising at least one treatment cycle comprising administering to the patient (i) iodo-nitrobenzamide, metabolism thereof Or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein (1) carboplatin is administered once during the treatment cycle (eg, on the first day of a treatment cycle (such as a 21-day cycle)) AUC4 is administered to the patient, wherein (η) gemcitabine is administered twice at the treatment cycle (eg, on days 1 and 8 of the treatment cycle (such as the 2 i-day cycle) at about 1 〇〇〇 mg/m2 a patient wherein 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered twice during the treatment cycle (eg, on the first day of a treatment cycle (such as a 21-day cycle) and Day 8) The patient was administered at approximately 11.2 mg/kg. The kit, article of manufacture and use are also provided for administration of a 4-indolyl-3-benzyl benzoate or a metabolite thereof, or a pharmaceutically acceptable salt thereof, an antimetabolite (such as gemcitabine) as provided herein. Sets and products of Ming compounds (such as card flips). In some embodiments, the kit or article comprises (i) 4-iodo-3-nitrobenzamine or a metabolite thereof or a pharmaceutically acceptable thereof for treating platinum-resistant recurrent ovarian cancer in a patient Acceptable salts, (ii) antimetabolites (eg, gemcitabine), and (iH) platinum compounds (eg, carboplatin). Any of the kits described herein may further comprise (i) 4-iodo-3-nitrobenzamine or a metabolite thereof, or a pharmaceutically acceptable salt thereof, according to any of the methods provided herein, (Π Instructions for the start of gemcitabine and (Ui) cards (eg on product inserts, package inserts or labels). In some embodiments, the kit comprises 4_iodo-3-nitrobenzamide or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, or a product thereof, or Package insert or label 'comprising for the use of 4·iodo-3-nitrobenzamine or a metabolite thereof or a pharmaceutically acceptable salt or solvent thereof in combination with gemcitabine and carboplatin according to any of the methods described herein Instructions and/or information on the treatment of patients with relapsed infective cancer. For example, the kit can include instructions for treating the patient's initial resistance to recurrent ovarian cancer, including at least one treatment cycle comprising administering to the patient (i) 4-iodo-3-nitrobenzamide a metabolite or a pharmaceutically acceptable salt thereof; (11) gemcitabine; and (iii) carboplatin, wherein (1) carboplatin is administered once during the treatment cycle (eg, on the ith day of the treatment cycle (such as a 21-day cycle) The patient is administered from about AUC3 to about AUC5, wherein (u) gemcitabine is administered twice in the treatment cycle (eg, on days 1 and 8 of the treatment cycle (such as a 21-day cycle) from about 500 to about 1500 mg) /m2 is administered to the patient, and wherein (1) 丨) 4_iodo-3-nitrobenzamine or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered once, twice, three times or four times in the /alpha treatment cycle Times (for example, on days 1 and 8 of a treatment cycle (such as a 21-day cycle), or on the first day, the fourth day 'the 8th day and the second day of the treatment cycle (such as a 21-day cycle) The patient is administered from 5 mg/kg to about 2 mg/kg (or from about 5 mg/kg to about 15 mg/kg). In some embodiments, the treatment comprises a 21-day treatment period, wherein (1) carboplatin is administered to the patient at 4 mg/ml.min (AUC4) on the first day of the treatment cycle; (Η) gemcitabine is in the treatment cycle On the 1st and 8th day, the patient was administered at a dose of 1〇〇〇mg/m2, and (iii) 4-bromo-3-nitrobenzamide or its metabolite or pharmaceutically acceptable to the party The salt was administered to the patient at a dose of 5.6 mg/kg twice a week on days 1, 4, 8, and 156 511511.doc δ • 100 · 201206449 of the treatment cycle. In some embodiments t&apos; sets may include a dose of at least one of the compositions disclosed herein. The kit may include suitable packaging and/or instructions for using the formulation. The kit may also include components for delivering the formulation. The kit may include other pharmaceutical agents (such as side effect limiting agents, chemotherapeutic agents, gene therapy agents, DNA therapy agents, RNA therapy agents, viral therapy agents, nanotherapeutics, small molecule enzyme inhibitors, anti-metastatic agents, etc.), For use with 4-moth-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite provided herein (eg, gemcitabine) ^ a platinum compound (eg, a card provided herein) Platinum) is used in combination. Such agents may be provided in the form of a knife, or with 4_iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite such as gemcitabine provided herein. And the platinum compound (e.g., carboplatin) provided herein provides that such mixing does not reduce 4-iodo-3-nitrobenzamine (or its metabolite or pharmaceutically acceptable salt thereof) The antimetabolite (eg, gemcitabine) provided herein or the platinum compound (eg, carboplatin) provided herein is governmental and compatible with the route of administration. Similarly, the kit may include other agents for adjuvant therapy or other agents known to those skilled in the art to be effective in treating or preventing a face resistant ovarian cancer (e.g., recurrent ovarian cancer) as described herein. The kit may optionally include instructions for the preparation and administration of the composition, the action of the composition, and any other relevant information. These usage statements may be in any suitable format, including but not limited to print-based, video-based

156511, &lt;J〇Q 201206449 Instructions for use with a computer-readable disk, CD-ROM, or Internet instructions. In another aspect, a kit for treating a patient suffering from or susceptible to a platinum-resistant imprinted cancer (eg, recurrent printed cancer) described herein is provided, including a dose-containing as herein The first container of the disclosed formulation and instructions for use. The container can be any container known in the art and suitable for storing and delivering intravenous formulations. In certain embodiments, the kit further includes a second container containing a pharmaceutically acceptable carrier, diluent, adjuvant, and the like for preparing a composition to be administered to a patient. A kit comprising a sufficient amount of 4_iodo-3-nitrobenzamide as disclosed herein, a metabolite thereof, or a pharmaceutically acceptable salt thereof, including a formulation thereof, may also be provided to provide a patient Provide longer periods (such as 13 days, i days, 1 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 longer) effective treatment. The kit may also include multiple doses of any of the compounds described herein and instructions for use, and packaged in an amount sufficient to be stored and used in a pharmacy, such as a hospital pharmacy and a pharmaceutical pharmacy. Kits can include the compounds described herein, packaged in unit dosage form or in multiple use. A kit can also include unit dose forms for multiple units. In certain embodiments, a compound described herein is provided in unit dosage form. In other embodiments, the composition can be provided in a multi-use form (e.g., blister pack, etc.). The following examples are intended to illustrate the invention only and therefore should not be construed as limiting the invention in any way. The following examples and detailed descriptions are provided as examples, but not 1565 丨 l.doc •102- 201206449 is restrictive. Other examples can be found in U.S. Patent Publication No. 2009/0123419 A1, which is incorporated herein by reference. EXAMPLES Example 1 · Phase I of 4-iodo-3-nitrobenzamide combined with gemcitabine and carboplatin in platinum-resistant recurrent ovarian cancer A phase II trial was performed to evaluate 4-A-3- The efficacy of nitrophenylamine (BA) in combination with gemcitabine and carboplatin in the treatment of platinum-resistant recurrent, nested cancer. Platinum-resistance is defined as recurrence or recurrence of ovarian cancer two to six months after receiving the last dose of platinum-based chemotherapeutic agent. Primary endpoint: Assessment of objective response rate (ORR) of gemcitabine/carboplatin with 4-iodo-3-nitrobenzamide [time range: until progressive disease or death]. Secondary endpoints: (1) Determination of the toxicity and extent of gemcitabine/carboplatin and 4_iodo-3-nitrobenzamide combination [Time range: last 4 iodine _3_nitrobenzoguanamine exposure After 30 days]; and (2) evaluation of progression-free survival (pFS) of gemcitabine/carboplatin in combination with 4-iodo-3-nitrobenzamide [time range: until progressive disease or death]. Inclusion criteria: (1) at least 18 years of age; (2) histological diagnosis of epithelial squamous cell carcinoma or primary peritoneal cancer; (3) completion of at least one previous chemotherapy with platinum therapy The course of treatment is sensitive to the program. "Board resistance" is defined as recurrence within _ month after the end of the chemotherapeutic chemistry; W measurable disease is defined by at least one of the following lesions, at least one size of the lesion (the longest size to be recorded) Accurately measured and measured by conventional techniques (palpation, common χ-ray, computed tomography 1565Jl.doc 201206449 [CT] or magnetic resonance imaging [MRI]) 220 mm or when by spiral CT measurement &gt; 10 mm; (5) Appropriate organ function, defined as: absolute neutrophil count (ANC) 2l, 500/mm3, platelet 2100,000/mm3, creatinine clearance &gt; 50mL/min , alanine aminotransferase (ALT) and aspartate aminotransferase (AST) &lt; 2.5 times normal upper limit (ULN; or in the case of liver metastasis 1 ί7 &lt; 5 times ULN); total bilirubin (1.5) For women who are likely to have a pregnancy, record the negative pregnancy test within two weeks of the study and agree to the fertility control acceptable for the duration of the study therapy; (7) Eastern Cooperative Oncology Group ( Eastern Cooperative Oncology Group ; ECOG) performance status 0, 1 or 2; and (8) Written by institutional review board (IRB) approval of the informed consent. Exclusion criteria: (1) concurrent invasive malignancies, excluding: (i) | melanoma skin cancer; (ii) in situ malignancy; (iii) concurrent superficial uterine cancer, if in the uterus Membrane cancer is located in superficial or invasive less than 50% of the thick layer of the myometrium; (iv) low-risk breast cancer treated with healing intentions (limited, with sputum); (v) can only be emitted by positrons Tomography (ρΕτ) to identify lesions; (10) Previous treatment with poly(ADP_ribose) polymerase (pARp) inhibitors including 4'·3_@-benzamide; (νΗ) may affect research participation Major medical condition (ie uncontrolled lung, kidney or liver dysfunction, uncontrolled infection); (Viii) other significant commonalities that the investigator believes may compromise the effective and safe participation of the research order. _ U _ Vortex conditions, including history of congestive heart failure or electrocardiogram (ECG) showing significant defects such as conduction deficits or myocardial ischemia; (ix) participation in another sputum keying device or music study, or currently using other Investigative treatment of the drug; (χ) the entire mouth of the payment! * Nine processes simultaneously Radiation 15651I.doc •104· 201206449 Therapy to treat primary disease; (Xi) does not meet the research requirements; (xii) maternal or breastfeeding, and (xiii) soft meningeal disease requiring steroids or other therapeutic interventions (Leptomeningeal disease) or brain metastasis. The above information is not intended to include all considerations related to the potential involvement of patients in clinical trials. A two-stage design using Simon will treat up to 48 patients with platinum-resistant recurrent ovarian cancer in this study. The primary end point was the improved overall response rate compared to patients receiving gemcitabine and carboplatin alone, using historical data from a prior trial to determine. The secondary endpoint was improved progression-free survival and patient safety. The exploratory endpoint is the Brca state and translational medicine. During the first phase, study participants (n=23) received an intravenous dose of 5- 6 mg/kg 4-iodine on Days 1, 4, 8 and 11 of each cycle. 3-Nitrobenzamide received a dose of 1000 mg/m2 of gemcitabine on the third and eighth day of each cycle and received AUC4 on the first day of each cycle (ie 4 mg/m b min) The card begins. To date, 14 patients have participated in the trial. The combination therapy can be better and 乂 轻 'mild ° nausea as the most common side effect β after a minimum of four cycles / twelve weeks, the total response rate is 21%, 8 of the 14 patients with stable disease, And 3 of the 14 patients were either in a completely regressed state or in a partially resolved state. The median follow-up will be performed at 12 weeks and the patient will continue with an additional treatment cycle as long as the disease is stable or responsive (according to rECIST quasi-Beibei) and wishes to continue the study. A minimum of 4 reactions were required during the first phase of the trial prior to the second phase (11 = 25). Example 2 ··· 4-Moth-3-nitrobenzamide combined with gemcitabine and carboplatin in platinum 156511.doc -105· 201206449 Reactive recurrent ovarian cancer in the ιι phase study using Simon two-stage design Phase 2, multicenter, one-arm, safety, and efficacy studies involving up to 48 individuals (stage i, n=23, and stage 2, n=25). The same treatment regimen is administered at each stage. The primary objective of this study was to evaluate the objective response rate (〇rR) of the combination of gemcitabine/carboplatin with 4_iodo-3-nitrobenzamide. The secondary objectives of this study were (1) determination of the toxicity and extent of gemcitabine/carboplatin in combination with 4-iodo-3-nitrobenzamide and (2) assessment of progression-free survival (PFS). Exploratory purposes can include the correlation of BRCA status and response. All dosing regimens were repeated in a 21-day cycle: each 21-day cycle, on day 1 carboplatin (AUC 4; 60 minutes intravenous (iv) infusion), on day 1 and day 8 gemcitabine (1000 mg/m2) ; 30 minutes IV infusion), and in the first! Days, Day 4, Day 8, and Day 11 4-iodo-3-nitrobenzamide (5 6 mg/kg; 6〇 min IV infusion). Qualified individuals must meet the following criteria in order to participate in the study (inclusion criteria). 1) at least 18 years of age; 2) histological diagnosis of epithelial ovarian cancer, esculent epithelial carcinoma or primary peritoneal cancer; 3) Only one previous cytotoxic chemotherapy regimen that must contain initial therapy is resistant to this regimen. "Reverse resistance" is defined as recurrence within 2 to 6 months after the last dose of platinum-based chemotherapy; 4) measurable disease (defined as at least one size that can be accurately measured for at least one lesion) (the longest size recorded)) when measured by conventional techniques (palatometry, general X-ray, computed tomography (CT) or magnetic resonance imaging (MRI)) 2〇mm or when Spiral ct measurement &gt; i 〇mm ; 5) Appropriate organ function, defined as: absolute neutrophil count 156511.doc -106 - 201206449 (ANC)U,500/mm3, platelet u〇〇〇〇 〇/mm3, creatinine clearance > 50 mL/min, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) &lt; 2.5 times normal upper limit (ULN; or in the case of liver metastases) <ULN); total bilirubin <1.5 mg/dL; 6) For women who are likely to have a pregnancy, the test record of the surname mother is negative within two weeks of the study and agrees to accept acceptable birth during the study period. Control; 7) Eastern Cooperative Oncology Group (ECOG) physical status 〇, 1 or 2; 8) Signed by the System Review Board (IRB) Written informed consent. Eligible individuals must not have any of the following to participate in the study (exclusion criteria 1) concurrent invasive malignancies, excluding: (phantom non-melanoma skin cancer; (b) in situ malignancy; (c) concurrent Superficial endometrial cancer, if its endometrial cancer is superficial or invasive to less than 50% of the thickness of the myometrium; (d) Low-risk breast cancer treated with curative intentions (limited, non-inflammatory) ), 2) lesions that can only be identified by positron emission tomography (pET); 3) more than 2 lines of cytotoxic chemotherapy (ie, one containing platinum and one non-platinum, such as liposome doxorubicin) Star) and 1 line of biological products (such as Avastin) for up to six months (hormone is not considered first-line treatment); 4) use of chemotherapy / biologic treatment within 3 weeks of participation; 5) previously used 4 · Treatment with iodine·nitrobenzoin or poly(ADP-ribose) polymerase (PARp) inhibitors; ^ 6) Major medical conditions that may affect the study participation (ie uncontrolled lung, kidney or liver dysfunction) , uncontrolled infection); 7) Researchers believe that it may damage research Other major common rickets that are effective and safe to participate in, including history of congestive heart failure or electrocardiogram (ECG) showing significant conduction defects or cardiac ischemia; 8) Participation in another investigative device or drug study, 156511 .doc •107- 201206449 or current treatment with other investigative agents; 9) throughout the study (iv) radiation therapy to treat primary disease; 1) cannot meet research requirements; 11) (iv) or money; 12 ) requires steroids for other therapeutic interventions in pia mater disease or brain metastases. Treatment continued to &gt; 6 cycles without disease progression or unacceptable toxicity. At the discretion of the physician, the individual can continue for up to * cycles of up to 10 cycles. According to the judgment of the physician, as a maintenance, 4-iodo-3-nitrobenzamine can last for more than one cycle until progressive disease (PD). Individuals who discontinued treatment prior to PD will undergo a periodic, phased assessment of the objective response rate every 9 〇 (±1 〇) days until pD or death. The first scheduled tumor response measurement was performed on the measurable disease every other cycle or approximately every 6 weeks, except for the initial stage at baseline. The progression of the disease is confirmed by CT or MRI (the same technique used during screening must be used) using a tumor response consistent with the improved Resap〇nse Evaluati〇n Criteria in Solid Tumors (RECIST). Example 3: Combination of 4-iodo-3-nitrobenzamide with gemcitabine and carboplatin in the treatment of recurrent ovarian cancer: a multicenter, one-arm, phase 2 study using Sim〇 n Two-stage design (phase I ' n = 25; total N = 48). Qualified patients are > 18 years old, have histological diagnosis of epithelial ovarian cancer, sputum epithelial carcinoma or primary peritoneal cancer and have a disease of reversal disease defined as recurrence 2 to 6 months after the end of primary treatment . Card surface (AUC 4; intravenous (IV); day 1), gemcitabine (1000 mg/m2; IV; days 1 and 8) and 4-e-3-nitrobenzamine (5.6 mg) /kg; IV; Day 1, Day 4, Day 8, and Day 11) were given by a 21-day cycle of 156511.doc •108-201206449. The primary endpoint was the overall response rate (""; RECIsT 1 〇); the secondary endpoint was safety and progression-free survival (r PFS). RESULTS: Analysis of 19 patients showed 3 1.6% of 〇rr, consisting of 6 s-threshold responses. Early analysis showed a median pFS of 5 9 months (95 〇 / 〇

Cl, 3.0-NE). The safety profile is consistent with their observations in previous clinical studies of 4_iodo_3_nitrostamine in combination with gemcitabine and carboplatin. Conclusion: 4-iodo-3-nitrobenzamide combined with gemcitabine and carboplatin showed activity in patients with platinum-resistant recurrent ovarian cancer, with promising signs of reaction (ORR=31.6%) and medium Value PFS (5.9 months) versus a previous PEGylated liposome doxorubicin in platinum-resistant recurrent ovarian cancer (〇RR=11.7%; median PFsy) months; Mutch et al, CHn

Oncol 2007, 25: 2811-2818) has a substantial extension. According to reports, no unexpected toxicity. Example 4: 4-iodo-3-nitrobenzamide combined with gemcitabine ("G") and carboplatin (C") in OVCAR-3 imprinted adenocarcinoma Chemical sensitization characteristics method: The chemical sensitization characteristics of a single dose of 4-iodo-3-nitrobenzamide in combination with gemcitabine and carboplatin were evaluated for 0VCAR_3 ovarian adenocarcinoma 72 hours after treatment. Cell proliferation was assessed by FACS-based cell cycle analysis, which included DNA staining and bromodeoxyuridine (BrdU) incorporation. Apoptotic cells were quantified by TUNEL staining. RESULTS: FACS analysis showed that 4-A-3-nitrobenzamide enhanced the apoptosis induced by gemcitabine or carboplatin in 〇vcar_3 cells (Table υ4•iodine_3_nitro156511.doc-109· 201206449 Combination of benzoguanamine and gemcitabine + carboplatin enhances apoptosis and induces S phase cell cycle arrest in OVCAR-3 cells. Table 1: Treatment of Sub-Gl* Gl* BrdU(-) S* S* G2/M * TUNEL(+) vehicle (control) 3.42 48.34 2.85 31.11 14.29 5.5 4-Moth-3-nitrobenzamide (0 uM)+C (0 uM) +G (0 nM) 3.42 48.24 2.70 31.43 14.21 5.5 +G (1 nM) 4.28 43.38 2.85 38.70 10.79 7.4 +G (2 nM) 6.47 27.81 3.24 54.80 7.68 9.2 4-A-3-nitrobenzamine (0 uM)+C (5 uM) +G (0 nM) 11.87 15.07 6.30 34.37 32.40 14.3 +G (1 nM) 9.47 13.48 5.66 39.20 32.20 13.1 +G (2 nM) 9.11 11.26 5.53 40.12 33.98 12.0 4-Moth-3-nitrobenzamide (0 uM)+C (10 uM) +G (0 nM) 17.06 16.55 9.35 31.45 25.59 14.8 +G (1 nM) 16.44 16.86 12.41 32.26 22.03 17.7 +G (2 nM) 20.43 21.98 11.46 26.73 19.40 18.8 4-block-3-nitrobenzene Guanamine (50 uM) + C (0 uM) + G (0 nM) 4.7 5 42.31 4.23 32.30 16.41 14.2 +G(1 nM) 5.51 32.96 4.59 44.18 12.76 17.2 +G (2 _ 7.84 21.38 5.09 54.58 11.10 25.1 4-Moth-3-nitrobenzamide (50 uM) + C (5 uM ) +G (0 nM) 11.07 13.52 11.37 30.02 34.02 39.2 +G (1 nM) 11.78 14.34 12.70 34.94 26.23 41.0 +G (2 nM) 11.09 13.76 10.68 36.76 27.72 42.5 4-Moth-3-nitrobenzamide ( 50 uM)+C (10 uM) +G (0 nM) 14.01 16.16 14.52 30.67 24.64 49.5 156511.doc · 110·

S 201206449 +G (1 nM) 15.87 19.94 17.90 28.59 17.70 53.3 +G (2 nM) 12.60 17.99 14.43 34.04 20.93 50.3 *-Data means cell % relative to the total population of living cells Conclusion: These data demonstrate OVCAR-3 cells Enhancement of the antiproliferative and pro-apoptotic activities of carboplatin and gemcitabine by 4-iodo-3-nitrobenzamide. It supports a clinical investigation of the combination of 4-iodo-3-nitrobenzamide with these DNA damaging agents. Example 5: Phase II study of 4-iodo-3·nitrobenzamide combined with gemcitabine and carboplatin (“GC”) in platinum-resistant recurrent ovarian cancer This multicenter, one-arm, phase 2 study was used. Simon two-stage design (N=48). The preliminary analysis was based on the top 34 patients involved. Research design

The I and treatment schedule are shown in Figure 1. Carboplatin (AUC 4; intravenous (IV); day 1), gemcitabine (1000 mg/m2; IV; days 1 and 8) and 4-iodo-3-nitrobenzamine (5.6 mg) /kg; IV; Day 1, Day 4, Day 8, and Day 11) were administered over a 21 day period. Qualified patients aged 8 years with epithelial ovarian cancer, French squamous cell carcinoma or primary peritoneal cancer and showing platinum-resistant disease are defined as within 2-6 months after the last dose of #based chemotherapy relapse. Qualified patients have measurable diseases. The patient has at least 1 but no more than 2 prior treatments (platinum based). Patients with or without BRCA mutations were eligible. Qualified patients have ECOG PS 0-1. The primary end point was the objective response rate ("ORR") based on patients who received at least a barium study drug and had 2 post-baseline assessments or had progression/death within 60 days of the last assessment. The second endpoint was (1) based on progression-free survival ("PFS") based on patients who received at least [Pharmaceutical Research 156511.doc -111 - 201206449 and had a post-baseline assessment or had progression/death within 60 days of the last assessment and (ii) Safety based on all patients receiving at least one dose of study drug (NCI-CTCAE version 3.0). The exploratory endpoint is the correlation between BRCA status and response. This study used Simon's two-stage design, which was designed to detect an improvement in ORR from 15% to 30%. The estimated historical control ORR was assumed to be 11.7% in this platinum resistant patient population (Mutch et al, J Clin Oncol 2007, 19: 2811-2818). Patient characteristics are shown in Table 2. Table 2: Baseline patient characteristics participation/drug/evaluable number, N 341/33/32 age, age, median (range) 61 (37 - 85) no initial interval, month, median (range) 4.6 (2 - 6) ECOG PS,n(%) 0/1/2 9 (27)/23 (70)/1 (3) Tumor grade, % Grade 1/2/3 0/9/91 Histology, n (% Serum 22 (65) Endometrioid 2 (6) Clear cells 2 (6) Other 7 (22) The BRCA status of the patients is shown in Table 3. Table 3: BRCA status n (%) Patients who have been tested for BRCA: 16 (49) BRCA11 8 (50) BRCA21 2 (13) No mutation 1 6 (38) BRCA test pending patients 17 (52) 156511.doc - 112- 1 Based on the percentage of patients who have tested BRCA. 201206449 Efficacy data based on the efficacy population (n=32) is shown in Table 4. Table 4: Reaction-Efficacy Population Optimal Response Evaluable Response (n=32) n(%) CR 0 PR 8(25) PR (unconfirmed) 2(6) SD 16(50) PD 5(15) Unknown 1 (3) ORR (CR + PR) 25% Clinical benefit rate (CBR) (CR + PR + SD) 81% Measure tumor response ~ every other cycle, according to RECIST 1.1. Table 5 shows the reaction data based on the BRCA1/2 mutation state. Table 5: Reaction in the mutant state - efficacy population optimal response BRCA mutation status * BRCA1 BRCA2 no mutation pending (n = 8) (η = 2) (η = 6) (η = 16) η (%) η ( %) η (%) η(%) CR 0 0 0 0 PR 4(50) 0 1 (16.7) 3 (18.8) PR (unconfirmed) 1 (12.5) 0 1 (16.7) 0 SD 1 (12.5) 2 (100) 3(50) 10(62.5) PD 1 (12.5) 0 1 (16.7) 3(18.8) Unknown 1 (12.5) 0 0 0 ORRf 50% • 17% 19% CBRf 75% 100% 83% 81 % * evaluable response (n = 32); measurement of tumor response ~ every other cycle, 'l56511.doc - 113- 201206449 according to RECIST 1.1. Figure 2 shows the optimal target lesion response in patients (n = 32) who can be evaluated for response. Figures 3 and 4 show the BRCA status of the patient in the evaluable response shown in Figure 2. Progression-free survival ("PFS") was assessed in patients (n = 32) with a median PFS of 6.44 months. See Figure 5. Treatment emergency adverse events ("AE") are shown in Table 6. Table 6: All treatments for emergency adverse events 1 (&gt;10%) All grades of toxicity, % Grade 3/4, % Fatigue 71 6 0 Nausea 63 14 Anemia 54 14 Neutrophil reduction 54 46 Constipation 46 0 Thrombocytopenia 43 26 » Area spit 37 6 Diarrhea 29 3 Abdominal pain 20 9 Drug allergy 20 3 Low magnesium blood 20 0 Peripheral neuropathy 17 0 Fever 17 3 Back pain 17 0 Small bowel obstruction 14 11 Headache 14 0 Dyspnea 14 3 Dizziness 11 0 156511.doc -114- 1 Not related to relevance; security group. Information on administration of patients (n=33) is shown in Table 7. 201206449 Table 7: Administration η=33 η(%) Reduced medication 28 (85) Delayed medication 9 (27) Reduced or delayed medication due to sputum 30 (91) Stopping due to sputum 0 Number of cycles completed per patient 0 -3 7(21) 4-6 12 (36) 7-12 14 (42) Number of patients receiving G-CSF 19 (58) There were no deaths during the study or within 60 days of the last study drug. Fifteen patients (43%) experienced severe treatment for emergency adverse events (SAE) (platelet reduction, anemia, intestinal obstruction, and nausea were the most common). For 26% (9 patients), SAE was considered to be related to the study drug, including the following 3/4 events: thrombocytopenia, anemia, nausea, alpha vomiting, intestinal obstruction, fatigue, dehydration, and hypokalemia . In summary, based on this preliminary analysis, treatment with 4-iodo-3-nitrobenzamide in combination with gemcitabine and carboplatin exhibited activity in patients with platinum-resistant recurrent nested cancer. For 32 patients with evaluable responses, the ORR was 25% (8/32) and the CBR was 81°/. (26/32). Responses were observed in both BRCA mutant and wild type patients. The safety profile is consistent with their previous observations in clinical studies with gemcitabine and carboplatin. Further randomization studies are permitted under this combination. Although the preferred embodiment of the invention has been shown and described herein, it will be apparent to those skilled in the art that these embodiments are only provided as examples of 156511.doc -115-201206449. Those skilled in the art will now be able to devise numerous variations, changes and substitutions without departing from the invention. It will be appreciated that various alternatives to the embodiments of the invention described herein may be employed in the practice of the invention. It is intended that the scope of the invention be defined by the appended claims [Simplified Schematic] Figure 1 shows a multi-center, one-arm, phase 2 study using 4-A-3-nitrobenzamide (also known as "enipa") with carboplatin and gemcitabine. Design and treatment schedule (Simon two-stage design, n=48). The preliminary analysis was based on the top 34 patients involved. "GCI" means gemcitabine, carboplatin and inipa. "PD" refers to progressive disease (pr〇gressive disease); Figure 2 shows platinum-free interval and best target lesion response in patients with measurable response (N=32) 'The latter is shown as a percentage change from baseline calculated at the lowest tumor burden after baseline for dry lesions. A bar chart was formed based on the researchers' assessment of the confirmed response. A square with a dotted pattern indicates a confirmed complete response ("CR") (n = 0) and a partial reaction ("PR") (n = 8). Squares with solid lines indicate unproven PR (n=2) and stable disease ("SD") (n=16). Black squares indicate progressive disease ("pd") (n=5); Figure 3 shows the relative platinum-free interval between patients with evaluable response (N=32) and the relative tumor load after baseline of target lesions. The percentage change from baseline and shows the patient's BRCA mutation status. A bar chart was formed based on the researchers' assessment of the confirmed response. Square table with dotted pattern 156511.doc - Π6 -

S 201206449 Confirmed CR and PR. Squares with solid lines indicate unproven PR and SD. A black square indicates that PD ° "A" indicates no BRCA mutation. "M" indicates a mutation in BRCA1 or BRCA2; Figure 4 shows the percentage of change in the platinum-free interval between patients with evaluable response (N=32) and the baseline at the lowest tumor burden after the baseline of the target lesion, and The patient's BRCA mutation status is shown. A bar chart was formed based on the researchers' assessment of the confirmed response. Squares with a dotted pattern indicate confirmed CR and PR. Squares with solid lines indicate unproven PR and SD. The black square indicates the PD. "A" indicates no BRCA mutation. "M" indicates a mutation in BRCA1 or BRCA2; and Figure 5 shows progression-free survival ("PFS"). The median PFS of patients (N=32) was 6.44 months. 95% Cl: 5.39-7.86; examiner: 46.9%; progress event: 15 cases (46.9%). 156511.doc 117-

Claims (1)

201206449 VII. Patent Application Range: 1 · A method for treating platinum-resistant recurrent ovarian cancer in a patient, comprising administering to the patient having the face-resistant recurrent ovarian cancer an effective amount: (i) 4-breaking- 3-Acetylbenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof' (ii) gemcitabine; and (iii) carboplatin. 2. The method of claim 1, wherein the patient has relapsed within 2 to 6 months after the last dose of platinum-based chemotherapy. 3. The method of claim 1 or 2, wherein the treatment comprises at least about 2 treatment weeks 'months, wherein each of the 5 meta-equal periods comprises administration of (i) 4-broken-3-stone benzyl decyl amide , a metabolite thereof or a pharmaceutically acceptable salt thereof; (Η) gemcitabine; and (iii) carboplatin. 4. The method according to any one of items 1 to 3, wherein the platinum-resistant recurrent ovarian cancer is epithelial ovarian cancer, sputum epithelial cancer (faU〇pUncentralized cancer) or primary peritoneum cancer. 5. The method of any of claims 1 to 41, wherein the patient has not previously received more than 2 face-based therapies. The method of any one of the items 1 to 5, wherein the patient has a measurable disease, wherein the effective amount produces at least one selected from the group consisting of The therapeutic effects of the following groups: ovarian tumor size reduction, metastasis reduction, complete regression, partial regression, stable disease, and pathological complete response. Further, including surgery, radiation, DNA therapy, viral therapy, 8. method therapy according to any one of claims 1 to 7, chemotherapy, gene therapy 156511.doc 201206449 A therapy, adjuvant therapy, neoadjuvant therapy or combination.佾 不木疗 9. The method of claim 1 to 8 φ &amp; τε., further comprising administering the bone gamma radiation. The method of any one of items 1 to 9, wherein the platinum-resistant recurrent ovarian cancer is selected from the group consisting of an epithelial tumor, a germ cell tumor, and a stromal cell tumor. 11. The method of claim 1 or claim 1 wherein the platinum-resistant recurrent ovarian cancer is metastatic. 12. A method according to any one of the claims, wherein 4 iodine-3 nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof is administered intravenously. 13. The method of any one of claims 12 to wherein the gemcitabine is administered intravenously. 14. The method of any one of claims 13 to 13, wherein the carboplatin is administered intravenously. 15. The method of claim 14, wherein the effective amount is administered within 21 days of treatment cycle wherein: (1) carboplatin is administered to the patient at 4 mg/m b min (AUC 4) on the first day of the treatment cycle (ii) gemcitabine was administered to the patient at a dose of 1 〇〇〇 mg/m 2 on days 1 and 8 of the treatment cycle; and (丨丨丨) 4_ moth -3- 3-nitrobenzamide The patient was administered on the first, fourth, eighth, and eleventh days of the treatment cycle at a dose of 5.6 mg/kg twice a week. 16. A kit for treating platinum-resistant recurrent ovarian cancer in a patient comprising (i) 4-deficiency-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable -2- 156511.doc S 201206449 Salt accepted; (ϋ) gemcitabine; and (iii) carboplatin. 17. The kit of claim 16, further comprising the use of an effective amount of (1) 4-iodo-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof, (π) gemcitabine and (iii) Instructions for the use of carboplatin to treat platinum-resistant recurrent ovarian cancer in this patient. 18. In the case of a request for π, where the effective sputum is administered within a 21-day treatment period with 'where (1) the card is turned over at the first day of the treatment cycle at 4 mg/m b min (AUC 4) The patient; (ii) gemcitabine was administered to the patient at a dose of 1 mg/m 2 on days 1 and 8 of the treatment cycle; and 4 iodine-3-phenylbenzamide was in the treatment cycle On the 1st, 3rd, 8th, and 11th day, the patient was administered at a dose of 5.6 mg/kg twice a week. 19. A kit comprising 4_iodo-3-nitrobenzamine, a metabolite or pharmaceutically acceptable salt thereof and (ii) for the use of an effective amount of 4 iodine-3 nitrobenzamide Or a metabolite or a pharmaceutically acceptable salt and the use of gemcitabine and carbaryl to treat platinum-resistant recurrent ovarian cancer in a patient. 20. The kit of claim 19, wherein the effective amount is again in the 21-day treatment period with 'where (i) the card surface is 4 mg/ml.min (AUC 4) on the first day of the treatment cycle. Administering the patient; (ii) gemcitabine was administered to the patient at a dose of 1 mg/m 2 on days 1 and 8 of the treatment cycle; and 4-iodo-3-nitrobenzamine was The patient was administered on the 1st, 4th, 8th, and 11th day of the treatment cycle at a dose of 5.0 mg/kg twice a week. 21. The kit of any one of claims 16 to 20, wherein the platinum-resistant recurrent nested cancer is epithelial ovarian cancer, sputum epithelial carcinoma or primary peritoneal 156511.doc 201206449 cancer. The kit of any one of claims 16 to 21, wherein the patient has relapsed within 2 to 6 months after the last dose of platinum-based chemotherapy. 23. The kit of any of claims 16 to 22, wherein the patient has a measurable disease. 24. The kit of any one of claims 16 to 23 wherein the patient has not previously received more than 2 methods based on the treatment. 25. The kit of any one of claims 17 to 24, wherein the effective amount produces at least one therapeutic effect selected from the group consisting of ovarian tumor size reduction, metastasis reduction, complete regression, partial regression, stable disease And pathologically complete response. 156511.doc