WO2007008479A1 - Traitement de patients atteints de cancer a l'aide d'un conjugue de calicheamicine et d'anticorps en combinaison avec du zosuquidar - Google Patents
Traitement de patients atteints de cancer a l'aide d'un conjugue de calicheamicine et d'anticorps en combinaison avec du zosuquidar Download PDFInfo
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- WO2007008479A1 WO2007008479A1 PCT/US2006/025909 US2006025909W WO2007008479A1 WO 2007008479 A1 WO2007008479 A1 WO 2007008479A1 US 2006025909 W US2006025909 W US 2006025909W WO 2007008479 A1 WO2007008479 A1 WO 2007008479A1
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Classifications
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
- A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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Definitions
- the present invention relates to a method of treating patients with solid tumors, leukemiasj and other malignancies using a combination of zosuquidar and a calicheamicin-antibody conjugate, such as gemtuzumab ozogamicin (M ylotarg).
- the invention is also directed to pharmaceutical formulations comprising zosuquidar and calicheamicin-antibody conjugates.
- the formulations are particularly effective in treating relapsed Acute Myelogenous Leukemia (AML).
- oncology lies in defining the disease in molecular terms (i.e., genetics, genomics, proteomics) and tailoring therapies according to individual tumor and normal cell properties.
- This new paradigm will predetermine likely responders, assess responses earlier, and adjust treatment based on continued molecular analyses of tumors.
- Drag resistance is one of the most difficult problems that must be overcome in order to achieve successful treatment of human tumors with chemotherapy.
- drug resistance a characteristic of intrinsically resistant tumors (for example, colon, renal, and pancreas), may be evident at the onset of therapy.
- acquired drug resistance results when tumors initially respond to therapy but become refractory to subsequent treatments.
- 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
- AAC adenosine triphosphate
- P-gp is a multiple transmembrane-spanning glycoprotein. Transfection experiments with the P-gp gene (rndrl) 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.
- Dosage forms and treatment regimens for patients with solid tumors, leukemias, and other malignancies that result in increased rates of complete remission and increased cancer free survival and overall survival rates are desirable.
- Particularly desirable are dosage forms and treatment regimens for relapsed AML patients that have improved survival rates and increased complete remission rates.
- the combined use of a calicheamicin-antibody conjugate and a P-gp inhibitor such as zosuquidar enhances the therapeutic activity of the calicheamicin-antibody conjugate and can offer such advantages in the treatment of solid tumors, leukemias, and other malignancies.
- a method of treating acute myelogenous leukemia comprising administering to a patient in need thereof zosuquidar and a calicheamicin-antibody conjugate.
- the acute myelogenous leukemia is relapsed acute myelogenous leukemia.
- the step of administering to a patient in need thereof zosuquidar and a calicheamicin-antibody conjugate comprises administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg/m 2 over a period of time of from about 1 hour to about 24 hours on Day 1 of a treatment regimen; administering zosuquidar intravenously to a patient in an amount of from about 500 mg/day to about 700 mg/day over about 24 hours on Day 1 of the treatment regimen; administering the calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg/m 2 over about 1 hour to about 24 hours on Day 15 of a treatment regimen; and administering zosuquidar intravenously to a patient in an amount of 500 mg/day to about 700 mg/day over about 24 hours on Day 15 of the treatment regimen.
- the calicheamicin- antibody conjugate can be Mylotarg.
- the step of administering to a patient in need thereof zosuquidar and a calicheamicin-antibody conjugate comprises administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg/m 2 over a period of time of from about 1 hour to about 24 hours on Day 1 of a treatment regimen; administering zosuquidar intravenously to a patient in an amount of from about 500 mg/day to about 700 mg/day over about 48 hours on Days 1 and 2 of the treatment regimen; administering the calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg/m 2 over about 1 hour to about 24 hours on Day 15 of a treatment regimen; and administering zosuquidar intravenously to a patient in an amount of 500 mg/day to about 700 mg/day over about 48 hours on Days 15 and 16 of the treatment regimen.
- the step of administering to a patient in need thereof zosuquidar and a calicheamicin-antibody conjugate comprises administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of about 7 mg/m 2 over about 1 hour to about 24 hours on Day 1 of a treatment regimen; administering zosuquidar intravenously to a patient in an amount of 500 mg/day to about 700 mg/day over about 48 hours on Day 1 and Day 2 of the treatment regimen; administering the calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg/m 2 over about 1 hour to about 24 hours on Day 15 of a treatment regimen; and administering zosuquidar intravenously to a patient in an amount of 500 mg/day to about 700 mg/day over about 48 hours on Day 15 and Day 16 of the treatment regimen.
- the calicheamicin- antibody conjugate can be Mylotarg.
- the step of administering to a patient in need thereof zosuquidar and a calicheamicin-antibody conjugate comprises administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of about 9 mg/m 2 over about 1 hour to about 24 hours on Day 1 of a treatment regimen; administering zosuquidar intravenously to a patient in an amount of 500 mg/day to about 700 mg/day over about 48 hours on Day 1 and Day 2 of the treatment regimen; administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of about 7 mg/m 2 over about 1 hour to about 24 hours on Day 15 of a treatment regimen; and administering zosuquidar intravenously to a patient in an amount of 500 mg/day to about 700 mg/day about 48 hours on Day 15 and Day 16 of the treatment regimen.
- the calicheamicin- antibody conjugate can be Mylotarg.
- the step of administering to a patient in need thereof zosuquidar and a calicheamicin-antibody conjugate comprises administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of about 9 mg/m 2 over about 1 hour to about 24 hours on Day 1 of a treatment regimen; administering zosuquidar intravenously to a patient in an amount of 500 mg/day to about 700 mg/day over about 72 hours on Days 1, 2 and 3 of the treatment regimen; administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of about 9 mg/m 2 over about 1 hour to about 24 hours on Day 15 of a treatment regimen; and administering zosuquidar intravenously to a patient in an amount of 500 mg/day to about 700 mg/day over about 72 hours on Days 15, 16 and 17 of the treatment regimen.
- the calicheamicin- antibody conjugate intraven
- the step of administering to a patient in need thereof zosuquidar and a calicheamicin-antibody conjugate comprises administering a calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg/m to about 9 mg/m 2 over about 1 hour to about 24 hours on Day 1 of a treatment regimen; administering zosuquidar intravenously to a patient in an amount of about 500 mg/day to about 700 mg/day over about 24 to 72 hours starting on Day 1 of the treatment regimen; administering the calicheamicin-antibody conjugate intravenously to a patient at a rate of about 5 mg/m 2 to about 9 mg/m 2 over about 1 hour to about 24 hours on Day 15 of a treatment regimen; and administering zosuquidar intravenously to a patient in an amount of about 500 mg/day to about 700 mg/day over about 24 to 72 hours starting on Day 15 of the treatment regimen.
- a pharmaceutical kit for use in the treatment of relapsed 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 calicheamicin-antibody conjugate to treat relapsed acute myelogenous leukemia in a patient exhibiting at least one of positive efflux pump activity and positive P-gp expression or function.
- the calicheamicin-antibody conjugate is Mylotarg.
- 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 and a calicheamicin-antibody conjugate to the patient.
- the malignancy is acute myelogenous leukemia, e.g., relapsed 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.
- the calicheamicin-antibody conjugate is Mylotarg.
- 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 and a calicheamicin-antibody conjugate to the patient.
- the malignancy is acute myelogenous leukemia, e.g., relapsed acute myelogenous leukemia.
- the malignancy is a carcinoma, e.g., breast cancer or ovarian cancer.
- the malignancy is a sarcoma. In an embodiment of the fourth aspect, the malignancy is a hematologic malignancy selected from the group consisting of acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, and myelodysplasia.
- the calicheamicin-antibody conjugate is Mylotarg. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
- 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.
- AML age ⁇ 15 years. Due in part to a more resilient patient population and a more sensitive disease, the 5 year survival rates for pediatric AML is 50% (late 1990s). In contrast, due in part to multiple co-morbid conditions and a more resistant disease, the 5 year survival rates for adult AML are only 13% (late 1990s). The 5 year survival rate for patients over 65 is only 7%.
- AML patients Approximately 75% of AML patients will eventually relapse and be candidates for additional treatment. Relapsed AML patients typically require prolonged hospitalization, and their prognosis is generally poor. Of these relapsed patients, approximately 80% are P-gp positive.
- the basic treatment regimen for AML i.e. daunorubicin and idarubicin, both P-gp substrates
- Mylotarg of which the calicheamicin component is a P-gp substrate, is now approved as a treatment for relapsed AML patients.
- Mylotarg is currently only approved for use in treating relapsed AML patients, Mylotarg or other calicheamicin-antibody conjugates can also have efficacy in the treatment of other malignancies that express P-gp. Zosuquidar
- 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- 3 -[4-(10,11 -difluoromethanodibenzosuber-5-yl)piperazin- 1 -yl]-2- hydroxypropoxy)quinoline.
- PK pharmacokinetic
- Mylotarg (gemtuzumab ozogamicin) was approved in May 2000 for treatment of relapsed CD33-positive AML patients over the age of 60.
- Mylotarg from Wyeth and Celltech is based on antibody-targeted chemotherapy.
- Mylotarg's highly specific antibody recognizes a cell-surface molecule, CD33, which is abundant on AML cells in 90% of AML patients, but absent from normal blood stem cells, the seeds from which normal blood and immune cells originate.
- the antibody is linked to calicheamicin, a potent chemotherapy agent. The antibody selectively targets leukemic blast cells and delivers calicheamicin to them.
- the chemical structure of Mylotarg is provided below.
- Mylotarg is also an MDR substrate and subject to the P-gp efflux pump.
- the cytotoxic effect of Mylotarg has been shown to be inversely correlated with the amount of P-gp present.
- Two MDR modulators, valspodar and the quinolone derivative MS-209 have both been shown to reverse the resistance to Mylotarg in P-gp expressing CD33(+) leukemia cells and clinical studies are underway in combination with cyclosporine.
- CR + CRp complete remission
- P-gp substrates include, but are not limited to 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). Chemotherapeutic Regimens Utilizing Zosuquidar and Mylotarg
- zosuquidar a highly specific and safe P-gp efflux inhibitor
- the combination of zosuquidar, a highly specific and safe P-gp efflux inhibitor, in combination with the calicheamicin-antibody conjugate Mylotarg is effective for treatment of leukemias, especially AML in relapsed patients.
- Zosuquidar in combination with calicheamicin-antibody conjugates other than Mylotarg can also be effective in the treatment of solid tumors and other malignancies.
- the effective dose of zosuquidar and the timing of administration of zosuquidar and Mylotarg are critical to achieving improved complete remission rates and enhanced leukemia free and overall survival rates in the relapsed AML patient population.
- zosuquidar and Mylotarg 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).
- AML hematologic malignancies other than AML (e.g., acute lymphoblastic leukemia, chronic myeloid leukemia, plasma cell dyscrasias, lymphoma, myelodysplasia).
- a P-gp efflux inhibitor other than zosuquidar can be employed with the calicheamicin-antibody conjugate.
- Zosuquidar or certain other therapeutic agents can be administered in the form of a pharmaceutically acceptable salt, e.g., the trihydrochloride salt.
- 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 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 and/or Mylotarg 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 and/or the calicheamicin-antibody conjugate 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.
- 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 and/or the calicheamicin- antibody conjugate 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 and/or the calicheamicin-antibody conjugate 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 zosuquidar and/or the calicheamicin-antibody conjugate 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 and/or the calicheamicin-antibody conjugate 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.
- 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 and/or the calicheamicin- antibody conjugate 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. For example, 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. % or more of active ingredient(s) including zosuquidar and/or the calicheamicin-antibody conjugate, 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 and/or the calicheamicin-antibody conjugate 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 and/or the calicheamicin-antibody conjugate, 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 While in certain embodiments it can be preferred to incorporate the zosuquidar, calicheamicin-antibody conjugate, and any other therapeutic agent employed in combination therewith in a single tablet or other dosage form, in certain embodiments it can be desirable to provide the zosuquidar, the calicheamicin-antibody conjugate, and other therapeutic agents in separate dosage forms, e.g., zosuquidar in a dosage form separate from the calicheamicin-antibody conjugate. 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.
- 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. 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 and/or the calicheamicin-antibody conjugate 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 and 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 and/or the calicheamicin-antibody conjugate.
- 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 and/or the calicheamicin-antibody conjugate can also be employed.
- the zosuquidar and/or the calicheamicin-antibody conjugate are delivered to the lungs while inhaling and traverse 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 and/or the calicheamicin-antibody conjugate.
- 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, calicheamicin-antibody conjugate, 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 and/or the calicheamicin-antibody conjugate 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.
- Pharmaceutical formulations suitable for use with a nebulizer, either jet or ultrasonic typically comprise the zosuquidar and/or the calicheamicin-antibody conjugate dissolved or suspended in water at a concentration of about 0.01 mg or less to 100 mg or more of each of zosuquidar and the calicheamicin-antibody conjugate 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., for protein stabilization and regulation of osmotic pressure).
- the nebulizer formulation can also contain a surfactant to reduce or prevent surface induced aggregation of the zosuquidar and/or the calicheamicin-antibody conjugate 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 and/or the calicheamicin- antibody conjugate, 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 and/or the calicheamicin-antibody conjugate 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.
- 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 of skill in the art. 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,
- the zosuquidar and/or the calicheamicin-antibody conjugate 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 and/or the calicheamicin-antibody conjugate 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 and/or the calicheamicin-antibody conjugate 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 and/or the calicheamicin-antibody conjugate in combination with one or more additional therapeutic agents can be provided, or separate pharmaceutical compositions containing zosuquidar, the calicheamicin-antibody conjugate, and additional therapeutic agents can be provided.
- the kit can also contain separate doses of zosuquidar and/or the calicheamicin-antibody conjugate 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 and/or the calicheamicin-antibody conjugate 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 includes both zosuquidar and the calicheamicin-antibody conjugate and instructions for administering each.
- a kit for the treatment of AML includes zosuquidar and one or more diagnostics or instructions for conducting one or more diagnostics for determining P-gp expression and/or efflux pump activity.
- the kit can also include instructions, an assay, and/or a diagnostic for determining if a patient has AML.
- the zosuquidar and the calicheamicin-antibody conjugate can be administered to a patient having a leukemia, a solid tumor, or other malignancy.
- 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
- the zosuquidar and the calicheamicin-antibody conjugate can be administered to patients suffering from leukemia, solid tumors, or other malignancies prior to confirmation of the P-gp expression or function, or to AML patients other than relapse AML patients.
- therapy is preferably administered to newly diagnosed patients or in combination with or sequentially after chemotherapy in 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 previously untreated AML patient, and severity of the condition.
- Contemplated amounts of the calicheamicin-antibody conjugate for intravenous administration to treat relapsed AML are from about 10 mg/day or less to about 1000 mg/day or more administered on one, two, or more separate days.
- the dosage is preferably administered intravenously at a rate of about 1 mg/m 2 or less to about 10 mg/m 2 or more continuously over the course of about 2, 3, or 4 hours to about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours, more preferably over the course of about 2 hours to about 6 hours; however, administration at a rate of 5 mg/m 2 , 7 mg/m 2 , or 9 mg/m 2 over about 2 hours is particularly preferred.
- doses of the calicheamicin-antibody conjugate are administered on Day 1 and Day 15 of the treatment regimen.
- the second dose can be administered on Day 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, or 22, or another day of the treatment regimen.
- Other dosing regimens include administering three doses total over a week.
- the calicheamicin-antibody conjugate is Mylotarg.
- Other calicheamicin-antibody conjugates include conjugates of calicheamicin with any suitable P-gp substrate, as discussed above.
- Contemplated amounts of zosuquidar for intravenous administration to treat relapsed AML are from about 400 mg/day or less to about 1,600 mg/day or more, preferably from about 500 or 600 mg/day to about 700, 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 mg/day, and most preferably from about 500 mg/day to about 800 mg/day. It is generally preferred to start the infusion of zosuquidar from about 1 hours or less to about 6 hours or more prior to the administration of the calicheamicin-antibody conjugate. In the course of a treatment regimen, the zosuquidar is preferably administered on two, three, four, or five separate days.
- the dosage is preferably administered in intravenously continuously over the course of about 6 to 90 hours, more preferably over the course of 6, 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.
- Table 1 provides various dosing regimes that can be used in treating relapsed AML. Table 1.
- Tables 2 and 3 provide alternative dosing regimes that can be used in treating relapsed AML.
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Abstract
Priority Applications (4)
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JP2008520323A JP2009500416A (ja) | 2005-07-06 | 2006-06-30 | カリケアマイシン−抗体複合体をゾスキダルと組み合わせて用いる癌患者の処置 |
CA002614321A CA2614321A1 (fr) | 2005-07-06 | 2006-06-30 | Traitement de patients atteints de cancer a l'aide d'un conjugue de calicheamicine et d'anticorps en combinaison avec du zosuquidar |
EP06774444A EP1898946A1 (fr) | 2005-07-06 | 2006-06-30 | Traitement de patients atteints de cancer à l'aide d'un conjugué de calicheamicine et d'anticorps en combinaison avec du zosuquidar |
AU2006269481A AU2006269481A1 (en) | 2005-07-06 | 2006-06-30 | Treatment of patients with cancer using a calicheamicin-antibody conjugate in combination with zosuquidar |
Applications Claiming Priority (6)
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US69675605P | 2005-07-06 | 2005-07-06 | |
US60/696,756 | 2005-07-06 | ||
US11/416,992 | 2006-05-03 | ||
US11/416,833 US20070009531A1 (en) | 2005-07-06 | 2006-05-03 | Treatment of patients with cancer using a calicheamicin-antibody conjugate in combination with zosuquidar |
US11/416,833 | 2006-05-03 | ||
US11/416,992 US20070009532A1 (en) | 2005-07-06 | 2006-05-03 | Treatment of patients with cancer using a calicheamicin-antibody conjugate in combination with zosuquidar |
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WO2007008479A1 true WO2007008479A1 (fr) | 2007-01-18 |
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PCT/US2006/025909 WO2007008479A1 (fr) | 2005-07-06 | 2006-06-30 | Traitement de patients atteints de cancer a l'aide d'un conjugue de calicheamicine et d'anticorps en combinaison avec du zosuquidar |
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EP (1) | EP1898946A1 (fr) |
JP (1) | JP2009500416A (fr) |
KR (1) | KR20080030659A (fr) |
AU (1) | AU2006269481A1 (fr) |
CA (1) | CA2614321A1 (fr) |
WO (1) | WO2007008479A1 (fr) |
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WO2004043461A1 (fr) * | 2002-11-06 | 2004-05-27 | Wyeth | Therapie combinee de traitement de la leucemie aigue et du syndrome myelodysplasique |
-
2006
- 2006-06-30 AU AU2006269481A patent/AU2006269481A1/en not_active Abandoned
- 2006-06-30 EP EP06774444A patent/EP1898946A1/fr not_active Withdrawn
- 2006-06-30 JP JP2008520323A patent/JP2009500416A/ja active Pending
- 2006-06-30 WO PCT/US2006/025909 patent/WO2007008479A1/fr active Application Filing
- 2006-06-30 CA CA002614321A patent/CA2614321A1/fr not_active Abandoned
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WO2004043461A1 (fr) * | 2002-11-06 | 2004-05-27 | Wyeth | Therapie combinee de traitement de la leucemie aigue et du syndrome myelodysplasique |
Non-Patent Citations (4)
Title |
---|
HAMANN ET AL.: "An anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia", CHOICE OF LINKER. BIOCONJUGATE CHEMISTRY, vol. 13, 2002, pages 40 - 46, XP008060232 * |
PICCALUGA ET AL.: "First experience with gentuzuman ozogamicin plus cytarbine as continuous infusion of elderly acute amyloid leukemia patients", LEUKEMIA RESEARCH, vol. 28, April 2004 (2004-04-01), pages 987 - 990, XP003005930 * |
SHEPARD ET AL.: "Modulation of P-glycoprotein but not MRP1- or BCRP mediated drug resistance by LY335979", INTERNATIONAL JOURNAL OF CANCER, vol. 103, 2003, pages 121 - 125, XP003005929 * |
SPERR ET AL.: "CD33 as a target of therapy in acute myeloid leukemia: current status and future perspectives", LEUKEMIA AND LYMPHOMA, vol. 46, no. 8, August 2005 (2005-08-01), pages 1115 - 1120, XP008075688 * |
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EP1898946A1 (fr) | 2008-03-19 |
AU2006269481A1 (en) | 2007-01-18 |
KR20080030659A (ko) | 2008-04-04 |
JP2009500416A (ja) | 2009-01-08 |
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