EP1898916A4 - ZOSUQUIDAR, DAUNORUBICIN AND CYTARABINE FOR THE TREATMENT OF CANCER - Google Patents

ZOSUQUIDAR, DAUNORUBICIN AND CYTARABINE FOR THE TREATMENT OF CANCER

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Publication number
EP1898916A4
EP1898916A4 EP06774465A EP06774465A EP1898916A4 EP 1898916 A4 EP1898916 A4 EP 1898916A4 EP 06774465 A EP06774465 A EP 06774465A EP 06774465 A EP06774465 A EP 06774465A EP 1898916 A4 EP1898916 A4 EP 1898916A4
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EP
European Patent Office
Prior art keywords
zosuquidar
daunorubicin
cytarabine
administering
patient
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP06774465A
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German (de)
English (en)
French (fr)
Other versions
EP1898916A2 (en
Inventor
Scott Glenn
David Socks
Daniel Hoth
Branimir Sikic
Michael J Walsh
John Marcelletti
Pratik S Multani
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KANISA PHARMACEUTICALS Inc
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KANISA PHARMACEUTICALS Inc
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Priority claimed from US11/416,829 external-priority patent/US20070010478A1/en
Application filed by KANISA PHARMACEUTICALS Inc filed Critical KANISA PHARMACEUTICALS Inc
Publication of EP1898916A2 publication Critical patent/EP1898916A2/en
Publication of EP1898916A4 publication Critical patent/EP1898916A4/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P35/02—Antineoplastic agents specific for leukemia
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a method of treating patients with solid tumors, leukemias, and other malignancies using a combination of zosuquidar, daunorubicin, and cytarabine.
  • the invention is also directed to pharmaceutical formulations comprising zosuquidar, daunorubicin, and cytarabine.
  • the formulations are particularly effective in treating newly diagnosed Acute Myelogenous Leukemia (AML).
  • a tumor Once a tumor has acquired resistance to a specific chemotherapeutic agent, it is common to observe collateral resistance to other structurally similar agents.
  • the cellular mechanisms of drug resistance include apoptosis, drug uptake, DNA repair, altered drug targets, drug sequestration, detoxification, and efflux pumps (see, e.g., Dalton W.S. Semin. Oncol. 20:60, 1993).
  • Multidrug resistance the ability of cancer cells to become resistant to the agent(s) actively used for therapy as well as other drugs that are structurally and functionally unrelated, is a particularly insidious form of drug resistance.
  • This form of drug resistance is discussed in greater detail in Kuzmich et al, "Detoxification Mechanisms and Tumor Cell Resistance to Anticancer Drugs,” particularly section VII “The Multidrug-Resistant Phenotype (MDR),” Medical Research Reviews, Vol. 11, No. 2, 185-217, particularly 208-213 (1991); and in Georges et al, “Multidrug Resistance and Chemosensitization: Therapeutic Implications for Cancer Chemotherapy," Advances in Pharmacology, Vol. 21, 185-220 (1990).
  • MDR may be caused by a variety of factors, one of the most prevalent forms of MDR is the type associated with overexpression of P-glycoprotein (P-gp).
  • P-gp is a member of a superfamily of membrane proteins, termed adenosine triphosphate (ATP)-binding cassette (ABC) proteins, which behave as ATP-dependent transporters and/or ion channels for a wide variety of hydrophobic substrates.
  • ATP adenosine triphosphate
  • APC adenosine triphosphate
  • P-gp is a multiple transmembrane-spanning glycoprotein. Transfection experiments with the P-gp gene inidr ⁇ ) have conferred MDR to drug-sensitive tumor cells by providing an energy- dependent efflux pump that lowers the intracellular concentration of the cytotoxic agent, thereby allowing survival of the cell.
  • P-gp is expressed in normal biliary canaliculi of the liver, the adrenal cortex and proximal tubules of the kidney, and intestinal epithelia including the columnar cells of the large and small intestines; capillary endothelial cells of brain, testis, and placenta; and in the hematopoietic stem cells of bone marrow. It possesses excretory, protective, and barrier functions.
  • P-gp is constitutively expressed or selected in many human cancers, and confers resistance to therapeutic agents including anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone), vincas (e.g., vincristine, vinblastine, vinorelbine, vindesine), Topoisomerase-II inhibitors (e.g., etoposide, teniposide), taxanes (e.g., paclitaxel, docetaxel), and others (e.g., Gleevec, Mylotarg, dactinomycin, mithramycin).
  • anthracyclines e.g., doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone
  • vincas e.g., vincristine, vinblastine, vinorelbine, vindesine
  • chemosensitizers MDR reversal agents, modulators, or converters
  • these 'first generation' MDR drugs included compounds of diverse structure and function such as calcium channel blockers (e.g., verapamil), immunosuppressants (e.g., cyclosporin A), antibiotics (e.g., erythromycin), antimalarials (e.g., quinine), and others (e.g., biricodar, tariquidar, valspodar).
  • calcium channel blockers e.g., verapamil
  • immunosuppressants e.g., cyclosporin A
  • antibiotics e.g., erythromycin
  • antimalarials e.g., quinine
  • others e.g., biricodar, tariquidar, valspodar
  • First generation MDR drugs were not specifically developed for 'inhibiting MDR. They often had other pharmacological activities, as well as a relatively low affinity for MDR transporters and thus were limited in application.
  • P-gp has a low affinity for verapamil, thus requiring cardiotoxic levels for full modulator activity.
  • verapamil and VAD vincristine, doxorubicin, and dexamethasone.
  • VAD vincristine, doxorubicin, and dexamethasone
  • Four of the responders had elevated P-gp expression and function.
  • verapamil has demonstrated some clinical utility in overcoming drug resistance.
  • Cyclosporin A alters the pharmacokinetics of coadministered cytotoxic agents, resulting in significantly increased exposure to the oncolytic, thus confounding the interpretation of clinical trials.
  • valspodar was studied in a Phase III study in elderly patients with acute myelogenous leukemia. Enrollment in the valspodar arm was halted due to excessive early mortality, most likely due to the PK interactions.
  • a second generation MDR modulator with activity against both P-gp and MRPl was biricodar.
  • Vertex studied the agent in multiple Phase II studies of soft tissue sarcomas, ovarian cancer, small cell lung cancer, and others.
  • biricodar and valspodar are both substrates for the P450 isoenzyme 3A4.
  • Competition between cytotoxic agents and the P-gp inhibitors for cytochrome P450 3A4 resulted in unpredictable PK interactions and resulted in increased serum concentrations of cytoxics and, therefore, greater toxicity to the patient.
  • a common response of clinical researchers has been to reduce the dose of the cytotoxic agents.
  • the PK interactions are unpredictable and cannot be determined in advance.
  • cytotoxic serum levels were either too high resulting in excessive toxicity or too low resulting in decreased efficacy.
  • many of the second generation modulators function as substrates for other transporters, particularly the ABC family, inhibition of which could lessen the ability of normal, healthy cells to protect themselves from the cytotoxic agents.
  • a P-gp inhibitor such as zosuquidar and chemotherapeutic agents such as daunorubicin and cytarabine enhances the therapeutic activity of the chemotherapeutics and can offer such advantages in the treatment of solid tumors, leukemias, and other malignancies. Accordingly, in a first aspect a method of treating a malignancy is provided, the method comprising administering to a patient in need thereof zosuquidar, daunorubicin, and cytarabine.
  • the malignancy is acute myelogenous leukemia. In an embodiment of the first aspect, the malignancy is newly diagnosed acute myelogenous leukemia.
  • the step of administering to a patient in need thereof zosuquidar, daunorubicin, and cytarabine comprises the steps of administering zosuquidar intravenously to a patient in an amount of from about 300 mg to about 800 mg administered continuously over from about 6 hours to about 24 hours on about 3 days; administering daunorubicin intravenously to a patient at a rate of from about 20 mg/m /day to about 100 mg/m /day for about 3 days, wherein administering daunorubicin is initiated from about 1 hour to about 5 hours after initiating administering zosuquidar; and administering cytarabine intravenously to a patient in an amount of from about 50 mg/m 2 /day to about 150 mg/m 2 /day continuously for about 7 days.
  • the step of administering to a patient in need thereof zosuquidar, daunorubicin, and cytarabine comprises the steps of administering zosuquidar intravenously to a patient in an amount of from about 500 mg to about 700 mg administered continuously over from about 6 hours to about 24 hours on about 3 days; administering daunorubicin intravenously to a patient at a rate of from about 40 mg/m 2 /day to about 50 mg/m 2 /day for about 3 days, wherein administering daunorubicin is initiated from about 1 hour to about 4 hours after initiating administering zosuquidar; and administering cytarabine intravenously to a patient in an amount of from about 90 mg/m 2 /day to about 110 mg/m 2 /day continuously for about 7 days.
  • the step of administering to a patient in need thereof zosuquidar, daunorubicin, and cytarabine comprises the steps of administering zosuquidar intravenously to a patient in an amount of from about 500 mg to about 700 mg administered continuously over from about 6 hours to about 24 hours on about 3 days; administering daunorubicin intravenously to a patient at a rate of about 45 mg/m 2 /day for about 3 days, wherein administering daunorubicin is initiated from about 1 hour to about 4 hours after initiating administering zosuquidar; and administering cytarabine intravenously to a patient in an amount of about 100 mg/m 2 /day continuously for about 7 days.
  • the step of administering to a patient in need thereof zosuquidar, daunorubicin, and cytarabine comprises the steps of administering zosuquidar intravenously to a patient in an amount of from about 500 mg to about 700 mg administered continuously over from about 6 hours to about 24 hours on about 3 days; administering daunorubicin intravenously to a patient at a rate of about 45 mg/m 2 /day for about 3 days, wherein administering daunorubicin is initiated from about 1 hour to about 4 hours after initiating administering zosuquidar; and administering cytarabine intravenously to a patient in an amount of about 100 mg/m /day continuously for about 7 days.
  • the step of administering to a patient in need thereof zosuquidar, daunorubicin, and cytarabine comprises the steps of administering zosuquidar intravenously to a patient in an amount of from about 500 mg to about 700 mg administered continuously over about 6 hours on about 3 days; administering daunorubicin intravenously to a patient at a rate of about 45 mg/m /day for about 3 days, wherein administering daunorubicin is initiated from about 1 hour to about 4 hours after initiating administering zosuquidar; and administering cytarabine intravenously to a patient in an amount of about 100 mg/m /day continuously for about 7 days.
  • the step of administering to a patient in need thereof zosuquidar, daunorubicin, and cytarabine comprises the steps of administering zosuquidar intravenously to a patient in an amount of from about 550 mg administered continuously over about 6 hours on about 3 days; administering daunorubicin intravenously to a patient at a rate of about 45 mg/m 2 /day for about 3 days, wherein administering daunorubicin is initiated about 1 hour after initiating administering zosuquidar; and administering cytarabine intravenously to a patient in an amount of about 100 mg/m 2 /day continuously for about 7 days.
  • a pharmaceutical kit for use in the treatment of newly diagnosed acute myelogenous leukemia comprising at least one dose of zosuquidar; directions for conducting at least one diagnostic for determining whether a patient exhibits at least one of positive efflux pump activity and positive P-gp expression or function; and directions for administering the zosuquidar in combination with a daunorubicin and cytarabine to treat newly dosed acute myelogenous leukemia in a patient exhibiting at least one of positive efflux pump activity and positive P-gp expression or function.
  • a method of treating a malignancy in a patient comprising the steps of conducting a diagnostic test, whereby it is determined that the malignancy expresses or selects P-glycoprotein; and administering zosuquidar, daunorubicin, and cytarabine to the patient.
  • the malignancy is acute myelogenous leukemia.
  • the malignancy is newly diagnosed acute myelogenous leukemia.
  • the malignancy is a carcinoma, e.g., breast cancer or ovarian cancer.
  • the malignancy is a sarcoma.
  • the malignancy is a hematologic malignancy selected from the group consisting of acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, and myelodysplasia.
  • a method of treating a malignancy in a patient comprising the steps of conducting a diagnostic test, whereby it is determined that the malignancy exhibits positive efflux pump activity; and administering zosuquidar, daunorubicin, and cytarabine to the patient.
  • the malignancy is acute myelogenous leukemia.
  • the malignancy is newly diagnosed acute myelogenous leukemia.
  • the malignancy is a carcinoma, e.g., breast cancer or ovarian cancer. In an embodiment of the fourth aspect, the malignancy is a sarcoma.
  • the malignancy is a hematologic malignancy selected from the group consisting of acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, and myelodysplasia.
  • a method of treating a malignancy in a patient comprising the steps of conducting a diagnostic test, whereby it is determined that the malignancy expresses or selects P-glycoprotein or exhibits positive efflux pump activity; and administering zosuquidar and a chemotherapeutic agent that is a substrate for P-glycoprotein to the patient.
  • the malignancy is acute myelogenous leukemia.
  • the malignancy is a carcinoma, e.g., breast cancer or ovarian cancer. In an embodiment of the fifth aspect, the malignancy is a sarcoma.
  • the malignancy is a hematologic malignancy, e.g., acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, or myelodysplasia.
  • a hematologic malignancy e.g., acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, or myelodysplasia.
  • the chemotherapeutic agent is an anthracycline, e.g., doxorubicin, daunorubicin, epirubicin, idarubicin, or mitoxantrone.
  • anthracycline e.g., doxorubicin, daunorubicin, epirubicin, idarubicin, or mitoxantrone.
  • the chemotherapeutic agent is a Topoisomerase-II inhibitor, e.g., etoposide or teniposide.
  • the chemotherapeutic agent is a vinca, e.g., vincristine, vinblastine, vinorelbine, or vindesine.
  • the chemotherapeutic agent is a taxane, e.g., paclitaxel or docetaxel.
  • the chemotherapeutic agent is Gleevec, dactinomycin, mitomycin, mithramycin, or Mylotarg.
  • cancer express P-gp, and thus can benefit from the administration of a P-gp efflux pump inhibitor when treated with a chemotherapeutic agent that is a substrate for P-gp efflux.
  • a chemotherapeutic agent that is a substrate for P-gp efflux.
  • most solid tumors, lymphomas, bladder cancer, pancreatic cancer, ovarian cancer, liver cancer, myeloma, and sarcoma are all cancers with a P-gp expression of greater than 50%.
  • Lymphocytic leukemia also has a P-gp expression of greater than 50%.
  • the P-gp expression of breast cancers is about 30%.
  • 63% express P-gp.
  • the methods and formulations of preferred embodiments are particularly efficacious in the treatment of any malignancy exhibiting some degree of P-gp expression or function, or in patients who are P-gp positive.
  • MDS advanced myelodysplastic syndrome
  • AML patients Standard induction therapy in the U.S. for newly diagnosed, or de novo, AML patients is cytarabine with either idarubicin or daunorubicin (both P-gp substrates).
  • idarubicin or daunorubicin both P-gp substrates.
  • 71% of AML patients greater than 60 years of age expressed moderate to high levels of P-gp.
  • the expression was associated with a reduction in the complete remission (CR) rate.
  • the CR rate for P-gp negative AML patients was 67% compared to 34% for P- gp positive patients.
  • This combination of high levels of P-gp expression with the nearly universal use of drugs that are P-gp substrates provides a ready opportunity for the coadministration of a P-gp inhibitor in patients with AML.
  • U.S. Pat. Nos. 5,643,909 and 5,654,304 disclose a series of 10,11- methanobenzosuberane derivatives useful in enhancing the efficacy of existing cancer chemotherapeutics and for treating multidrug resistance.
  • One such derivative having good activity, oral bioavailability, and stability, is zosuquidar, a compound of formula (2R)-anti-5-
  • Zosuquidar Given the limitations of previous generations of MDR modulators, three preclinical critical success factors were identified and met for zosuquidar: 1) it is a potent inhibitor of P-glycoprotein; T) it is selective for P-glycoprotein; and 3) no pharmacokinetic interaction with co-administered chemotherapy is observed.
  • Another significant attribute of zosuquidar as an MDR modulator is the minimal pharmacokinetic (PK) interactions with several oncolytics tested in preclinical models. Such minimal PK interaction permits normal doses of oncolytics to be administered and also a more straightforward interpretation of the clinical results. Daunorubicin
  • Daunorubicin is an antibiotic chemotherapy treatment that is widely used to treat acute myeloid leukemia and acute lymphocytic leukemia. It is produced by the bacteria Streptomyces coeruleorubidis and was approved by the FDA as a first line therapy treatment for leukemia in 1998. Daunorubicin is typically administered intravenously. It is marketed under the brand names Cerubidine, DaunoXome, and Liposomal daunorubicin. Daunorubicin has the following structure:
  • Cytarabine is a deoxycytidine analogue, cytosine arabinoside (ara-C), which is metabolically activated to the triphosphate nucleotide (ara-CTP), which acts as a competitive inhibitor of DNA polymerase and produces S phase-specific cytotoxicity. It is used as an antineoplastic, generally as part of a combination chemotherapy regimen, in the treatment of acute lymphocytic and acute myelogenous leukemia, the blast phase of chronic myelogenous leukemia, erythroleukemia, and non-Hodgkin's lymphoma. It is typically administered intravenously and subcutaneously, and for the prophylaxis and treatment of meningeal leukemia, administered intrathecally. Cytarabine has the following structure:
  • zosuquidar a highly specific and safe P-gp efflux inhibitor
  • the antibiotic chemotherapeutic daunorubicin and the antineoplastic cytarabine is effective for treatment of leukemias, especially newly diagnosed AML.
  • the formulations and dosing regimens employing zosuquidar, daunorubicin, and cytarabine can be employed in treating AML patients other than newly diagnosed AML patients, or for treatment of other types of leukemia, lymphomas or lymphocytic leukemia.
  • the effective dose of zosuquidar and the timing of administration of zosuquidar, daunorubicin, and cytarabine are critical to achieving improved complete remission rates and enhanced leukemia free survival rates in the newly diagnosed AML patient population.
  • zosuquidar, daunorubicin, and cytarabine can be administered according to the disclosed dosing regimens, or slightly modified dosing regimens, for treatment of other types of leukemia or other cancers that express P-gp and/or exhibit P-gp function, e.g., many solid tumors, bladder cancer, pancreatic cancer, liver cancer, myeloma, carcinomas (e.g., breast cancer and ovarian cancer), sarcomas, and hematologic malignancies other than AML (e.g., acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, myelodysplasia).
  • hematologic malignancies e.g., acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, myelodysplasia.
  • Zosuquidar, daunorubicin, and cytarabine or certain other therapeutic agents can be administered in the form of a pharmaceutically acceptable ; salt, e.g., the trihydrochloride salt.
  • pharmaceutically acceptable salts and “a pharmaceutically acceptable salt thereof as used herein are broad terms and are used in their ordinary sense, including, without limitation, to refer to salts prepared from pharmaceutically acceptable, non-toxic acids or bases.
  • Suitable pharmaceutically acceptable salts include metallic salts, e.g., salts of aluminum, zinc, alkali metal salts such as lithium, sodium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts; organic salts, e.g., salts of lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine), procaine, and tris; salts of free acids and bases; inorganic salts, e.g., sulfate, hydrochloride, and hydrobromide; and other salts which are currently in widespread pharmaceutical use and are listed in sources well known to those of skill in the art, such as, for example, The Merck Index.
  • metallic salts e.g., salts of aluminum, zinc, alkali metal salts such as lithium, sodium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts
  • Any suitable constituent can be selected to make a salt of zosuquidar, daunorubicin, or cytarabine or other therapeutic agents discussed herein, provided that it is non-toxic and does not substantially interfere with the desired activity.
  • pharmaceutically acceptable precursors and derivatives of the compounds can be employed.
  • Pharmaceutically acceptable amides, lower alkyl esters, and protected derivatives can also be suitable for use in compositions and methods of preferred embodiments.
  • Also suitable for administration are selected therapeutic agents in hydrated form, selected enantiomeric forms of certain therapeutic agents, racemic mixtures of certain therapeutic agents, and the like.
  • Contemplated routes of administration include topical, oral, subcutaneous, parenteral, intradermal, intramuscular, intraperitoneal, and intravenous. However, it is particularly preferred to administer zosuquidar, daunorubicin, and/or cytarabine in intravenous form.
  • the combination or individual components can be in any suitable solid or liquid form.
  • a particularly preferred form comprises a lyophilized form that is reconstituted for intravenous administration.
  • Zosuquidar, daunorubicin, and/or cytarabine can be formulated into liquid preparations for, e.g., oral, nasal, anal, rectal, buccal, vaginal, peroral, intragastric, mucosal, perlingual, alveolar, gingival, olfactory, or respiratory mucosa administration. Suitable forms for such administration include suspensions, syrups, and elixirs. If nasal or respiratory (mucosal) administration is desired ⁇ e.g., aerosol inhalation or insufflation), compositions may be in a form and dispensed by a squeeze spray dispenser, pump dispenser or aerosol dispenser. Aerosols are usually under pressure by means of a hydrocarbon. Pump dispensers can preferably dispense a metered dose or a dose having a particular particle size.
  • compositions containing zosuquidar, daunorubicin, and/or cytarabine are preferably isotonic with the blood or other body fluid of the patient.
  • the isotonicity of the compositions can be attained using sodium tartrate, propylene glycol or other inorganic or organic solutes.
  • Sodium chloride is particularly preferred.
  • Buffering agents can be employed, such as acetic acid and salts thereof, citric acid and salts thereof, boric acid and salts thereof, and phosphoric acid and salts thereof.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, and fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like.
  • Viscosity of the pharmaceutical compositions can be maintained at a selected level using a pharmaceutically acceptable thickening agent.
  • Methylcellulose is preferred because it is readily and economically available and is easy to work with.
  • Other suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, and the like.
  • the preferred concentration of the thickener can depend upon the thickening agent selected. An amount is preferably used that can achieve the selected viscosity. Viscous compositions are normally prepared from solutions by the addition of such thickening agents.
  • a pharmaceutically acceptable preservative can be employed to increase the shelf life of the pharmaceutical compositions.
  • Benzyl alcohol can be suitable, although a variety of preservatives including, for example, parabens, thimerosal, chlorobutanol, and benzalkonium chloride can also be employed.
  • a suitable concentration of the preservative is typically from about 0.02% to about 2% based on the total weight of the composition, although larger or smaller amounts can be desirable depending upon the agent selected.
  • the zosuquidar, daunorubicin, and/or cytarabine can be in admixture with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose, and the like, and can contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired. See, e.g., standard texts such as "Remington: The Science and Practice of Pharmacy", Lippincott Williams & Wilkins; 20th edition (June 1, 2003) and “Remington's Pharmaceutical Sciences,” Mack Pub.
  • Such preparations can include complexing agents, metal ions, polymeric compounds such as polyacetic acid, polyglycolic acid, hydrogels, dextran, and the like, liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts or spheroblasts.
  • Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. The presence of such additional components can influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance, and are thus chosen according to the intended application, such that the characteristics of the carrier are tailored to the selected route of administration.
  • the zosuquidar, daunorubicin, and/or cytarabine can be provided as a tablet, aqueous or oil suspension, dispersible powder or granule, emulsion, hard or soft capsule, syrup, or elixir.
  • Compositions intended for oral administration can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and can include one or more of the following agents: sweeteners, flavoring agents, coloring agents and preservatives.
  • Aqueous suspensions can contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • Formulations for oral administration can also be provided as hard gelatin capsules, wherein the zosuquidar, daunorubicin, and/or cytarabine are mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules.
  • an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin
  • the active ingredients can be dissolved or suspended in suitable liquids, such as water or an oil medium, such as peanut oil, olive oil, fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • suitable liquids such as water or an oil medium, such as peanut oil, olive oil, fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • Stabilizers and microspheres formulated for oral administration can also be used.
  • Capsules can include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the zosuquidar, daunorubicin, and/or cytarabine in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc and magnesium stearate and, optionally, stabilizers.
  • Tablets can be uncoated or coated by known methods to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time.
  • a time delay material such as glyceryl monostearate can be used.
  • the solid form When administered in solid form, such as tablet form, the solid form typically comprises from about 0.001 wt. % or less to about 50 wt.
  • active ingredient(s) including zosuquidar, daunorubicin, and/or cytarabine preferably from about 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 wt. % to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45 wt. %.
  • Tablets can contain the zosuquidar, daunorubicin, and/or cytarabine in admixture with non-toxic pharmaceutically acceptable excipients including inert materials.
  • a tablet can be prepared by compression or molding, optionally, with one or more additional ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet or capsule contains from about 10 mg or less to about 1,000 mg or more of each of zosuquidar, daunorubicin, and/or cytarabine, more preferably from about 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg to about 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, or 900 mg.
  • tablets or capsules are provided in a range of dosages to permit divided dosages to be administered. A dosage appropriate to the patient and the number of doses to be administered daily can thus be conveniently selected.
  • zosuquidar, daunorubicin, cytarabine, and any other therapeutic agent employed in combination therewith in a single tablet or other dosage form
  • it can be desirable to provide the zosuquidar, daunorubicin, cytarabine, and other therapeutic agents in separate dosage forms e.g., each of zosuquidar, daunorubicin, and cytarabine in separate dosage forms, or daunorubicin and cytarabine in one dosage form and zosuquidar alone in another.
  • Combinations of dosage forms can also be employed, e.g., oral and intravenous.
  • Suitable inert materials include diluents, such as carbohydrates, mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextrans, starch, and the like, and inorganic salts such as calcium triphosphate, calcium phosphate, sodium phosphate, calcium carbonate, sodium carbonate, magnesium carbonate, and sodium chloride.
  • diluents such as carbohydrates, mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextrans, starch, and the like
  • inorganic salts such as calcium triphosphate, calcium phosphate, sodium phosphate, calcium carbonate, sodium carbonate, magnesium carbonate, and sodium chloride.
  • Disintegrants or granulating agents can be included in the formulation, for example, starches such as corn starch, alginic acid, sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite, insoluble cationic exchange resins, powdered gums such as agar, karaya, and tragacanth, and alginic acid and salts thereof. Binders can be used to form a hard tablet.
  • starches such as corn starch, alginic acid, sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite, insoluble cationic exchange resins, powdered gums such as agar, karaya, and tragacanth, and alginic acid and salts thereof. Binders can be used to form a
  • Binders include materials from natural products such as acacia, tragacanth, starch, gelatin, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, and the like.
  • Lubricants such as stearic acid and magnesium or calcium salts thereof, polytetrafluoroethylene, liquid paraffin, vegetable oils, waxes, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol, starch, talc, pyrogenic silica, hydrated silicoaluminate, and the like can be included in tablet formulations.
  • Surfactants can also be employed, for example, anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate, cationic detergents such as benzalkonium chloride and benzethonium chloride, and/or nonionic detergents such as polyoxyethylene hydrogenated castor oil, glycerol monostearate, polysorbates, sucrose fatty acid ester, methyl cellulose, and carboxymethyl cellulose.
  • anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate
  • cationic detergents such as benzalkonium chloride and benzethonium chloride
  • nonionic detergents such as polyoxyethylene hydrogenated castor oil, glycerol monostearate, polysorbates, sucrose fatty acid ester, methyl cellulose, and
  • Controlled-release formulations can be employed wherein the zosuquidar, daunorubicin, and/or cytarabine are incorporated into an inert matrix that permits release by either diffusion or leaching mechanisms. Slowly degenerating matrices can also be incorporated into the formulation.
  • Other delivery systems can include timed release, delayed release, or sustained release delivery systems. Nanoparticulate systems or nanoparticulate forms of the active ingredients can advantageously be employed in certain embodiments.
  • Coatings can be used, for example, nonenteric materials such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methylhydroxy-ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl-methyl cellulose, sodium carboxy-methyl cellulose, providone, polyethylene glycols, and enteric materials such as phthalic acid esters.
  • Dyestuffs and pigments can be added for identification or to characterize different combinations of active compound doses
  • a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils can be added to the zosuquidar, daunorubicin, and/or cytarabine.
  • Physiological saline solution, dextrose, other saccharide solutions, and glycols such as ethylene glycol, propylene glycol, and polyethylene glycol are also suitable liquid carriers.
  • the pharmaceutical compositions can also be in the form of oil-in-water emulsions.
  • the oily phase can be a vegetable oil, such as olive or arachis oil, a mineral oil such as liquid paraffin, or a mixture thereof.
  • Suitable emulsifying agents include naturally-occurring gums such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate.
  • the emulsions can also contain sweetening and flavoring agents.
  • Pulmonary delivery of zosuquidar, daunorubicin, and/or cytarabine can also be employed.
  • the zosuquidar, daunorubicin, and/or cytarabine are delivered to the lungs while inhaling and traverses across the lung epithelial lining to the blood stream.
  • a wide range of mechanical devices designed for pulmonary delivery of therapeutic products can be employed, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.
  • These devices employ formulations suitable for the dispensing of zosuquidar, daunorubicin, and/or cytarabine.
  • each formulation is specific to the type of device employed and can involve the use of an appropriate propellant material, in addition to diluents, adjuvants, and/or carriers useful in therapy.
  • the zosuquidar, daunorubicin, cytarabine, and/or other optional active ingredients are advantageously prepared for pulmonary delivery in particulate form with an average particle size of from 0.1 ⁇ m or less to 10 ⁇ m or more, more preferably from about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 ⁇ m to about 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, or 9.5 ⁇ m.
  • Pharmaceutically acceptable carriers for pulmonary delivery of zosuquidar, daunorubicin, and/or cytarabine include carbohydrates such as trehalose, mannitol, xylitol, sucrose, lactose, and sorbitol.
  • Other ingredients for use in formulations can include dipalmitoylphosphatidylcholine (DPPC), 1,2-sn- dioleoylphosphatidylcholine (DOPE), disteroylphosphatidylcholine (DSPC), and dioleoylphosphatidyl-choline (DOPC).
  • Natural or synthetic surfactants can be used, including polyethylene glycol and dextrans, such as cyclodextran.
  • Bile salts and other related enhancers, as well as cellulose and cellulose derivatives, and amino acids can also be used. Liposomes, microcapsules, microspheres, inclusion complexes, and other types of carriers can also be employed.
  • compositions suitable for use with a nebulizer typically comprise the zosuquidar, daunorubicin, and/or cytarabine dissolved or suspended in water at a concentration of about 0.01 mg or less to 100 mg or more of ( each of zosuquidar, daunorubicin, and/or cytarabine per mL of solution, preferably from about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg per mL of solution to about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 mg per mL of solution.
  • the formulation can also include a buffer and a simple sugar (e.g.
  • the nebulizer formulation can also contain a surfactant to reduce or prevent surface induced aggregation of the zosuquidar, daunorubicin, and/or cytarabine caused by atomization of the solution in forming the aerosol.
  • Formulations for use with a metered-dose inhaler device generally comprise a finely divided powder containing the active ingredients suspended in a propellant with the aid of a surfactant.
  • the propellant can include conventional propellants, such as chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons, and hydrocarbons.
  • Preferred propellants include trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, 1,1,1,2-tetrafluoroethane, and combinations thereof.
  • Suitable surfactants include sorbitan trioleate, soya lecithin, and oleic acid.
  • Formulations suitable for dispensing from a powder inhaler device typically comprise a finely divided dry powder containing zosuquidar, daunorubicin, and/or cytarabine, optionally including a bulking agent, such as lactose, sorbitol, sucrose, mannitol, trehalose, or xylitol, in an amount that facilitates dispersal of the powder from the device, typically from about 1 wt. % or less to 99 wt. % or more of the formulation, preferably from about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 wt. % to about 55, 60, 65, 70, 75, 80, 85, or 90 wt. % of the formulation.
  • a bulking agent such as lactose, sorbitol, sucrose, mannitol, trehalose, or xylitol
  • zosuquidar, daunorubicin, and/or cytarabine are administered by intravenous, cutaneous, subcutaneous, parenteral, or other injection, they are preferably in the form of pyrogen-free, parenterally acceptable aqueous solutions or oleaginous suspensions.
  • Suspensions can be formulated according to methods well known in the art using suitable dispersing or wetting agents and suspending agents. The preparation of acceptable aqueous solutions with suitable pH, isotonicity, stability, and the like, is within the skill in the art.
  • a preferred pharmaceutical composition for injection preferably contains an isotonic vehicle such as 1,3-butanediol, water, isotonic sodium chloride solution, Ringer's solution, dextrose solution, dextrose and sodium chloride solution, lactated Ringer's solution, or other vehicles as are known in the art.
  • an isotonic vehicle such as 1,3-butanediol, water, isotonic sodium chloride solution, Ringer's solution, dextrose solution, dextrose and sodium chloride solution, lactated Ringer's solution, or other vehicles as are known in the art.
  • sterile fixed oils can be employed conventionally as a solvent or suspending medium.
  • any bland fixed oil can be employed, including synthetic monoglycerides and diglycerides.
  • fatty acids such as oleic acid can likewise be used in the formation of injectable preparations.
  • the pharmaceutical compositions can also contain stabilizers, preservatives, buffers, antioxidants, and other additives known to those
  • the duration of the injection can be adjusted depending upon various factors, and can comprise a single injection administered over the course of a few seconds or less to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, 54, 60, 66, 72, 78, 84, 90, or 96 hours or more of continuous intravenous administration.
  • the injection can be administered over the course of up to 5, 6, 7, 8, 9, 10, or more days.
  • the zosuquidar, daunorubicin, and/or cytarabine can be administered systemically or locally, via a liquid or gel, or as an implant or device.
  • compositions of the preferred embodiments can additionally employ adjunct components conventionally found in pharmaceutical compositions in their art-established fashion and at their art-established levels.
  • the compositions can contain additional compatible pharmaceutically active materials for combination therapy (such as supplemental P-gp inhibitors, chemotherapeutic agents, and the like), or can contain materials useful in physically formulating various dosage forms of the preferred embodiments, such as excipients, dyes, perfumes, thickening agents, stabilizers, preservatives and antioxidants.
  • the zosuquidar, daunorubicin, and/or cytarabine can be provided to an administering physician or other health care professional in the form of a kit.
  • the kit is a package which houses one or more containers which contain zosuquidar, daunorubicin, and/or cytarabine in suitable form and instructions for administering the pharmaceutical composition to a subject.
  • the kit can optionally also contain one or more additional therapeutic agents.
  • the kit can optionally contain one or more diagnostic tools and instructions for use, e.g., a diagnostic to measure efflux pump activity or P-gp expression or function.
  • kits containing a single composition comprising zosuquidar, daunorubicin, and/or cytarabine in combination with one or more additional therapeutic agents can be provided, or separate pharmaceutical compositions containing zosuquidar, daunorubicin, and/or cytarabine, and additional therapeutic agents can be provided.
  • the kit can also contain separate doses of zosuquidar, daunorubicin, and/or cytarabine for serial or sequential administration.
  • the kit can contain suitable delivery devices, e.g., syringes, inhalation devices, and the like, along with instructions for administrating zosuquidar, daunorubicin, and/or cytarabine and any other therapeutic agent.
  • the kit can optionally contain instructions for storage, reconstitution (if applicable), and administration of any or all therapeutic agents included.
  • the kits can include a plurality of containers reflecting the number of administrations to be given to a subject.
  • kits for the treatment of AML, especially newly diagnosed AML includes zosuquidar, daunorubicin, and cytarabine and instructions for administering each.
  • a kit for the treatment of newly diagnosed AML includes zosuquidar, daunorubicin, and/or cytarabine and one or more diagnostics or instructions for conducting one or more diagnostics for determining P-gp expression and/or efflux pump activity (function).
  • the kit can also include instructions, an assay, and/or a diagnostic for determining if a patient has AML.
  • the combination of zosuquidar, daunorubicin, and cytarabine can be administered to a patient having a leukemia, a solid tumor, or other malignancy. It is particularly preferred to administer the combination when P-gp expression is positive, or to use the combination in the treatment of a malignancy exhibiting P-gp expression or function. Cancer targets exhibiting a P-gp expression > 50% of patients are particularly preferred for treatment by the combinations of the preferred embodiments.
  • Dosage regimes as described below for AML can also be suitable for the treatment of other leukemias, solid tumors, bladder cancer, pancreatic cancer, liver cancer, myeloma, carcinomas (e.g., breast cancer and ovarian cancer), sarcomas, and other hematologic malignancies (e.g., acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, myelodysplasia).
  • Treatment of Acute Myelogenous Leukemia e.g., acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, myelodysplasia.
  • the combination of zosuquidar, daunorubicin, and cytarabine are most preferably administered to newly diagnosed AML patients.
  • the combination can also be administered prophylactically to patients believed to be suffering from AML prior to confirmation of the diagnosis, or to AML patients other than newly diagnosed AML patients (e.g., relapsed AML patients).
  • the administration route, amount administered, and frequency of administration can vary depending on the age of the patient, status as relapsed or newly diagnosed AML patient, and severity of the condition.
  • Contemplated amounts of zosuquidar for intravenous administration to treat newly diagnosed AML are from about 400 mg/day or less to about 1,600 mg/day or more, preferably from about 500, 600, or 700 mg/day to about 900, 1000, 1100, 1200, 1300, 1400, or 1500 mg/day, and most preferably 700 mg/day.
  • the zosuquidar is preferably administered on two, three, or four separate days.
  • the dosage is preferably administered in intravenously continuously over the course of about 6 to about 90 hours, more preferably over the course of about 12, 18, 24, 30, 36, or 42 hours to about 54, 60, 66, 72, 78, or 84 hours, most preferably over about 24 hours, 48 hours, or 72 hours, depending upon the treatment regimen.
  • the zosuquidar is administered on Day 1 of the treatment regimen.
  • additional zosuquidar is administered on Day 2, on Days 2 and 3, or on Days 2, 15, and 16.
  • one, two, or three or more additional doses can be administered on other days of the treatment regimen.
  • Contemplated amounts of daunorubicin for intravenous administration to treat newly diagnosed AML are from about 10 mg/m 2 /day or less to about 100 mg/m 2 /day or more administered at initiation of zosuquidar infusion or up to about 1, 2, 3, 4, 5, or 6 or more hours after initiation of zosuquidar infusion.
  • the dosage is preferably administered intravenously at a rate of about 25 mg/m 2 /day or less to about 90 mg/m 2 /day or more, preferably about 30, 35, or 40 mg/m 2 /day or less to about 50, 55, 60, 65, 70, 75, 80, or 85 mg/m 2 /day, and most preferably about 45 mg/m 2 /day continuously over the course of about 2 or 2.5 days to about 3.5 or 4 days, preferably about 3 days.
  • Contemplated amounts of cytarabine for intravenous administration to treat newly diagnosed AML patients are from about 10 mg/day or less to about 3,000 mg/day or more administered at initiation of zosuquidar infusion or after initiation of zosuquidar infusion.
  • the dosage is preferably administered intravenously at a rate of about 50 mg/m 2 /day or less to about 200 mg/m 2 /day or more, preferably 60, 70, 80, or 90 mg/m 2 /day or less to about 110, 120, 130, 140, 150, 160, 170, 180, or 190 mg/m 2 /day, and most preferably about 100 mg/m 2 /day continuously over the course of about 1, 2, 3, 4, 5, or 6 days up to about 8, 9, or 10 days or more, preferably over about 7 days.
  • a particularly preferred dosing regimen for newly diagnosed AML includes continuous intravenous administration of 550 mg of zosuquidar over 6 hours (3 days), continuous intravenous administration of cytarabine at a rate of 100 mg/m 2 /day (7 days), and intravenous administration of daunorubicin at a dose of 45 mg/m 2 /day (3 days), wherein infusion of daunorubicin is started 1 hour after initiation of zosuquidar infusion.
  • Another particularly preferred dosing regimen includes continuous intravenous administration (preferably about 1 to 24 hours in duration, more preferably about 6 to 24 hours in duration, most preferably about 24 hours in duration) of 500 to 700 mg/day of zosuquidar (3 days), continuous intravenous administration of cytarabine at a rate of 100 mg/m 2 /day (7 days), and intravenous administration of daunorubicin at a dose of 45 mg/m 2 /day (3 days), wherein infusion of daunorubicin is started 1 to 4 hours after initiation of zosuquidar infusion.
  • infusion of daunorubicin is started after a specified time period has lapsed after initiation of zosuquidar infusion
  • other start times can be preferred, e.g., immediately after or during initiation of zosuquidar infusion up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more hours after initiation of zosuquidar infusion.
  • the above-described dosing regimens for treatment of newly diagnosed AML can also be adapted to the treatment of relapsed AML as well as metastatic breast cancer or other carcinomas.
  • Figure 1 presents the relationships between plasma zosuquidar levels and inhibition of P-gp function. Means of 3 patients for each time point are shown. Peak zosuquidar levels were achieved by 24 hours post-initiation of drug infusion. The levels of zosuquidar remained relative stable at 180-207 ng/ml for the remainder of the infusion period. After the 72 hour time point when zosuquidar infusion had been halted, plasma zosuquidar levels rapidly decreased to approximately 50-60 ng/ml at the 80-96 hour time point.
  • P-gp function for both NK cells and leukemic blasts was potently inhibited within 2 hours after the start of zosuquidar infusion. Inhibition of P-gp function can be attributed to zosuquidar since treatment with daunorubicin and cytarabine were initiated after the 4 hour time point. Inhibition of P-gp functional activity was maintained throughout the infusion period, and continued for at least 12 hours after zosuquidar infusion was halted. These results indicate that it is possible give a relatively short infusion of zosuquidar allowing for continued inhibition of leukemia cell P-gp function after the infusion has been halted and lessening the occurrence of adverse events such as central nervous system toxicities.

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EP06774465A 2005-07-06 2006-06-30 ZOSUQUIDAR, DAUNORUBICIN AND CYTARABINE FOR THE TREATMENT OF CANCER Withdrawn EP1898916A4 (en)

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US11/416,829 US20070010478A1 (en) 2005-07-06 2006-05-03 Zosuquidar, daunorubicin, and cytarabine for the treatment of cancer
US11/416,571 US20070010465A1 (en) 2005-07-06 2006-05-03 Zosuquidar, daunorubicin, and cytarabine for the treatment of cancer
US11/416,832 US20070010466A1 (en) 2005-07-06 2006-05-03 Zosuquidar, daunorubicin, and cytarabine for the treatment of cancer
PCT/US2006/025993 WO2007008490A2 (en) 2005-07-06 2006-06-30 Zosuquidar, daunorubicin, and cytarabine for the treatment of cancer

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US9757385B2 (en) * 2013-11-27 2017-09-12 Merck Sharp & Dohme Corp. Method of treating leukemia using pharmaceutical formulation containing thienotriazolodiazepine compounds
CN109475542A (zh) * 2016-07-27 2019-03-15 弗吉尼亚大学专利基金会 用于治疗癌症的组合疗法
WO2023144830A1 (en) 2022-01-30 2023-08-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Zika m protein blockers as anti-zika virus agents

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See also references of WO2007008490A2 *

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