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WO2006113536A2 - Utilisation de pt523 pour le traitement des cancers - Google Patents

Utilisation de pt523 pour le traitement des cancers Download PDF

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Publication number
WO2006113536A2
WO2006113536A2 PCT/US2006/014250 US2006014250W WO2006113536A2 WO 2006113536 A2 WO2006113536 A2 WO 2006113536A2 US 2006014250 W US2006014250 W US 2006014250W WO 2006113536 A2 WO2006113536 A2 WO 2006113536A2
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Prior art keywords
cancer
administered
subject
day
dose
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WO2006113536A3 (fr
Inventor
Michael Weiser
Jeff Serbin
Lindsay A. Rosenwald
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Hana Biosciences Inc
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Hana Biosciences Inc
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Publication of WO2006113536A3 publication Critical patent/WO2006113536A3/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2

Definitions

  • This application provides methods of treating or managing cancers, or symptoms thereof, including, for example, cervical cancer, non-small cell lung cancer, acute lymphocytic leukemia, and the like, using PT523 and pharmaceutical formulations thereof.
  • MTX dihydrofolate reductase (DHFR) inhibitor methotrexate
  • DHFR dihydrofolate reductase
  • MTX-resistant cancers either arising spontaneously or that acquired MTX-resistance in patients undergoing MTX therapy, typically have a reduced ability to form polyglutamated MTX.
  • MTX's toxicity to noncancerous cells prevents the administration of therapeutically effective dosages of MTX.
  • MTX-resistance may be acquired in leukemias, such as acute lymphocytic leukemia, cervical cancers, lung cancers, including non-small cell lung cancer, colorectal cancers, breast cancers, and epidermoid cancers of the head and neck.
  • leukemias such as acute lymphocytic leukemia, cervical cancers, lung cancers, including non-small cell lung cancer, colorectal cancers, breast cancers, and epidermoid cancers of the head and neck.
  • non-small cell lung cancer may recur or progress after standard first-line therapy of a platinum-based chemotherapeutic regimen (e.g., carbop latin or cisplatin), which requires a second or third line therapeutic option.
  • platinum-based chemotherapeutic regimen e.g., carbop latin or cisplatin
  • Citation or identification of any reference in this or any other section of this application shall not be construed as an admission that such reference is available as prior art to the present invention.
  • the present disclosure provides methods for the treatment or management of a cancer or a symptom thereof, hi particular, the present methods utilize PT523 or liquid pharmaceutical formulations thereof.
  • Administration of PT523 and formulations thereof can be useful therapy for delaying cancerous growth, reducing tumor sizes or cancerous cell numbers or prolonging survival of the subject afflicted with cancer.
  • the toxicology, pharmacokinetic and efficacy studies described herein the
  • PT523 formulations and methods using these formulations are likely to minimize toxic side-effects while providing beneficial therapeutic effects.
  • the present invention provides methods that comprise administering PT523 to the subject thereby treating or managing a cancer or symptom thereof.
  • the subject can be a mammal, preferably a human.
  • the PT523 to be administered is a PT523 ammonium salt, hi certain preferred embodiments, a dissolved PT523 ammonium salt is administered to the subject.
  • PT523 is administered by a parenteral route. In some embodiments, PT523 is intravenously administered.
  • an amount of PT523 effective to treat or manage a cancer or symptom thereof is administered to a subject, wherein the effective amount of
  • PT523 is tolerable by the subject.
  • 900 mg/m 2 or between about 5 mg/m 2 to about 600 mg/m 2 , or between about 30 mg/m 2 to about 400 mg/m 2 , or between about 50 mg/m 2 to about 200 mg/m 2 , or about 75.0 mg/m 2 to about 175 mg/m 2 , or between about 9 mg/m 2 to about 200 mg/m 2 , or between about
  • 9 mg/m 2 to about 160 mg/m 2 or between about 9 mg/m 2 to about 100 mg/m 2 , or between about 9 mg/m 2 to about 80 mg/m 2 of PT523 is administered.
  • the cancer to be treated or managed is an ovarian cancer, endometrial cancer, biliary cancer, esophageal cancer, mesothelioma, cervical cancer, vulvar cancer, gastric cancer, pancreatic cancer, breast cancer, prostate cancer, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia, non-small cell lung cancer, melanoma, lymphoma, renal cancer, colon cancer, soft tissue sarcoma, head and neck squamous carcinoma, or symptom thereof.
  • AML acute myelogenous leukemia
  • CML chronic myelogenous leukemia
  • ALL acute lymphocytic leukemia
  • CLL chronic lymphocytic leukemia
  • a second therapeutic agent is administered to the subject.
  • a third therapeutical agent is administered to the subject.
  • the second therapeutic agent or optional third therapeutic agent is a chemotherapeutic agent, such as, for example, cisplatin, carboplatin, paclitaxel, docetaxel, vinorebine, gemcitabine, irinotecan, topotcan, erlotinib, and the like, hi some embodiments the second therapeutic agent or third therapeutic agent is an epidermal growth factor receptor-tyrosine kinase
  • EGFR-TK EGFR-TK inhibitor
  • gefitinib or erlotinib EGFR-TK inhibitor
  • the second therapeutic agent or optional third therapeutic agent can be administered concurrently or sequentially with
  • the second therapeutic agent or third therapeutic agent is an anti-angiogenesis inhibitor, a radioisotope or a radiolabled agent.
  • PT523 is administered to the subject in a liquid formulation comprising PT523 ammonium salt, mannitol, L-arginine and 5% dextrose in water.
  • PT523 is administered to the subject in a dosing schedule or "therapeutic cycle" generally comprising about two to about five weeks in which PT523 is administered on day one of the cycle followed by a number of days in which PT523 is not administered.
  • a dosing schedule or "therapeutic cycle” generally comprising about two to about five weeks in which PT523 is administered on day one of the cycle followed by a number of days in which PT523 is not administered.
  • a dosing schedule or "therapeutic cycle” generally comprising about two to about five weeks in which PT523 is administered on day one of the cycle followed by a number of days in which PT523 is not administered.
  • a dosing schedule or "therapeutic cycle” generally comprising about two to about five weeks in which PT523 is administered on day one of the cycle followed by a number of days in which PT523 is not administered.
  • a typical 28 day therapeutic cycle PT523 is administered on days 1, 8 and 15.
  • a second cycle can be initiated
  • the methods provided herein for the treatment or management of a cancer further comprise administering folic acid or a folate binding protein binding agent to the subject before, during, and/or after the administration of PT523.
  • the methods provide for the administration of cyanocobalamin (Vitamin B 12 ) to the subject prior to, during, or after PT523 is administered.
  • the term “about 5 mg/m 2” means a range of from 4.5 mg/m 2 to 5.5 mg/m 2 .
  • “about 1 hour” means a range of from 54 minutes to 66 minutes.
  • the terms “manage,” “managing”, “management” and the like refer to the beneficial effects that a subject suffering from a cancer derives when the methods provided herein are practiced on that subject, but which do not result in a cure of the cancer.
  • a subject is administered PT523 as described herein to "manage” a cancer so as to prevent or slow the progression or worsening of the cancer.
  • a subject is administered PT523 as described herein to "manage” a cancer so as to prevent or slow tumor growth.
  • a subject is administered PT523 as described herein to "manage” a cancer so as to lengthen what would otherwise be the expected life span of the subject without being administered PT523 for the cancer.
  • compositions e.g., a carrier, diluent, excipient, vehicle or salt, approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • pharmaceutical formulation refers to composition comprising PT523, and a suitable carrier, diluent, excipient, or vehicle suitable for administration to a subject. The term includes, but is not limited to compositions for parenteral administration as described below.
  • the terms "subject” and “patient” are used interchangeably, and can refer to a mammal (e.g., a mouse, rat, guinea pig, rabbit, cow, pig, horse, donkey, goat, sheep, camel, cat, dog), more preferably a primate (e.g., a monkey, ape, gorilla, chimpanzee), and most preferably a human.
  • a mammal e.g., a mouse, rat, guinea pig, rabbit, cow, pig, horse, donkey, goat, sheep, camel, cat, dog
  • a primate e.g., a monkey, ape, gorilla, chimpanzee
  • the terms “treat”, “treatment”, “treating” and the like refer to the eradication, reduction or amelioration of a cancer or symptom thereof that results from the administration of PT523 as described herein.
  • a subject is administered PT523 as described herein to "treat” a cancer so as to result in tumor shrinkage or reduce cancer cell numbers.
  • a subject is administered PT523 as described herein to "treat” a cancer so as to prevent or halt spread of a cancer.
  • a subject is administered PT523 as described herein to "treat” a cancer so as to provide a beneficial clinical outcome, e.g., an increased subject survival time. 5.
  • Figure 1 provides body weight averages of athymic mice implanted with
  • Figure 2 provides percent changes in average body weight from Day 1 of treatment of athymic mice implanted with A549 human lung cancer cells after the treatment with PT523 alone or in combination with paclitaxel, cisplatin or TARCEV A ® .
  • Figure 3 presents tumor volumes in athymic mice implanted with A549 human lung cancer cells after the treatment with PT523 alone or in combination with paclitaxel, cisplatin or TARCEV A ® .
  • Figure 4 presents percent changes in tumor volumes in athymic mice implanted with A549 human lung cancer cells after the treatment with PT523 alone or in combination with paclitaxel, cisplatin or TARCEV A ® .
  • Figure 5 presents changes in tumor volumes in athymic mice implanted with
  • Figure 6 presents changes in tumor volumes in athymic mice implanted with
  • A549 human lung cancer cells after the treatment with PT523 alone or in combination with paclitaxel was assessed for the following effects:
  • Figure 7 presents changes in tumor volumes in athymic mice implanted with
  • Figure 8 presents changes in tumor volumes in athymic mice implanted with
  • the present invention provides methods for the treatment or management of a cancer or symptom thereof in a subject in need of such treatment or management. These methods are based, for example, on the observation of the particular toxicology, pharmacokinetic and in vivo efficacy studies of PT523 described below. Safe and effective doses for the administration of pharmaceutical formulations described herein have been determined, and the methods described herein provide a novel approach to the treatment or management of a cancer or symptom thereof in a subject. Preparation of PT523 and formulations suitable for administration to a subject, preferably a human, are described in Section 6.1.
  • the methods provided for the treatment or management of a cancer or symptom thereof in a subject in need of such treatment or management comprise administering an effect amount of a dissolved PT523 ammonium salt thereby treating or managing the cancer or symptom thereof.
  • the cancer to be treated or managed can be a metastatic or inoperable malignancy, neoplasm, carcinoma, leukemia, sarcoma, tumor, solid tumor, lymphoma, or any cancer for which there is no known curative or standard or standard palliative therapy, or for which standard therapy has failed.
  • PT523 is administered to the subject as a first line therapy for the treatment or management of a cancer or symptom thereof. In some embodiments, PT523 is administered as a second or third line therapy. [0038] hi certain embodiments, PT523 is administered to the subject in need of treatment or management of cancer, or symptom thereof, resistant to treatment or management with methotrexate, aminopterin, or pemetrexed.
  • the cancer or symptom thereof to be treated or managed is an ovarian cancer, endometrial cancer, biliary cancer, esophageal cancer, mesothelioma, cervical cancer, vulvar cancer, gastric cancer, pancreatic cancer, breast cancer, prostate cancer, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia, non-small cell lung cancer, melanoma, lymphoma, renal cancer, colon cancer, soft tissue sarcoma, head and neck squamous carcinoma, or symptom thereof.
  • AML acute myelogenous leukemia
  • CML chronic myelogenous leukemia
  • ALL acute lymphocytic leukemia
  • CLL chronic lymphocytic leukemia
  • the cancer to be treated or managed is a non-small cell lung cancer or a symptom thereof.
  • the non-small lung cancer can be histologically or cytologically confirmed prior to administration of PT523.
  • the non-small lung cancer is a recurrent disease or one for which first line therapy has failed.
  • the cancer to be treated or managed is a leukemia such as acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia, or a symptom thereof.
  • AML acute myelogenous leukemia
  • CML chronic myelogenous leukemia
  • ALL acute lymphocytic leukemia
  • CLL chronic lymphocytic leukemia
  • hairy cell leukemia or a symptom thereof.
  • the leukemia can be histologically or cytologically confirmed prior to administration of PT523.
  • the leukemia is a recurrent or refractory disease or one for which first line therapy has failed.
  • PT523 suitable for administration to a subject may be obtained by any synthetic technique known to those of skill in the art or can be obtained commercially (e.g., Nerviano Medical Sciences S.r.L, Nerviano, Italy).
  • the structure and exemplary syntheses ofPT523 are described in, for example, Rosowsky et al., 1988, J Med. Chem. 31 :1332- 1337, Rosowsky et al, 1989, Pteridines 1:91-98, and U.S. Pat. Nos. 4,767,761 and 6,989,386, which are incorporated herein by reference in their entireties for all purposes.
  • a PT523 ammonium salt, or pharmaceutical formulations thereof are administered to the subject in the methods provided herein.
  • Preparation of PT523 ammonium salts and compositions comprising PT523 ammonium salts are described, for example, in U.S. Pat. No. 6,989,386, issued January 24, 2006, and WO 2004/094427 Al, which are incorporated herein by reference in their entireties for all purposes. .
  • PT523 is a reconstituted or dissolved form of a PT523 ammonium salt.
  • PT523 can be a reconstituted or dissolved form of a monoammonium salt, diammonium salt, other incremental ammonium salt, mixtures of monoammonium salt, diammonium salt, and/or other incremental ammonium salt, and so forth, without limitation.
  • the molecular formula of PT523 is C 27 H 27 N 9 O 6 -NH 3 .
  • PT523 in an ionic form is administered to a subject for the treatment or management of a cancer or symptom thereof.
  • Counter ions to ionic PT523, or pharmaceutical formulations thereof can be, for example, inorganic cations, such as Na + , K + , Ca 2+ , Cs + , Sr + , Zn 2+ , Ba 2+ , Mg 2+ , Al 2+ , or Li + ; aliphatic amines, for example, (n-Bu) 4 N + , tetraethylammonium, tetramethylammonium, meglumine, D-glucosamine, D-galactosamine, D-glucamine, piperazine, tromethamine, choline, diethylamine, 4-phenylcyclohexylamine, benzathine, 2-aminoethanol, benethamine, adamantanamine
  • exemplary counter ions include but not limited to mono, bis and trialkyl amines like phenothiazine-propanamine, dimethylaminoethanol, imidazoleethanamine, methyl ammonium, dimethyl ammonium, trimethyl ammonium, ethyl ammonium, diethyl ammonium, triethyl ammonium, cyclohexyl ammmonium, dicyclohexyl ammonium, tricyclohexyl ammonium, benzyl ammonium, dibenzyl ammonium, tribenzyl ammonium, N-methyl-N-b enzylammonium, alpha-methylb enzylammonium, alpha-methyl- N-benzylbenzylammonium, alpha-metliyl-alpha-naplithylmetliylammonium, benzhydrylammonium, N-methylpiperazinium, N-methyl tryptammonium, N,N,-
  • the form of PT523 administered to the subject consists of no more than 4% of the D-enantiomeric form. In some embodiments, the form of PT523 administered to the subject consists of no more than 3%, 2%, 1% or 0.5% of the D-enantiomeric form.
  • PT523 or pharmaceutical formulation thereof is administered orally, parenterally or topically to the subject.
  • Liquid pharmaceutical formulations of PT523, its ammonium salts or other salts provided herein comprise PT523 in a suitable pH, osmolality, tonicity, purity and sterility to allow safe administration to a subject.
  • Liquid pharmaceutical formulations of PT523 can be prepared, for example, by dissolving, dispersing, reconstituting, solubilizing or otherwise mixing PT523 and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension.
  • Solutions or suspensions used for parenteral, oral, intradermal, subcutaneous, or topical administration of PT523 or pharmaceutical formulations thereof can include any known pharmaceutically acceptable components as exemplified by, but not limited to, the following: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, arginines, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride, sucrose or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other
  • Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
  • suitable carriers include physiological saline, phosphate buffered saline (PBS) or dextrose and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
  • Suitable PT523 pharmaceutical formulations can be dry formulations that include freeze dried or lyophilized powders for long term storage followed by reconstitution in a suitable diluent prior to administration.
  • PT523 can be supplied in containers containing about 25 mg or about 50 mg of PT523 in a lyophilized powder form.
  • a dry PT523 pharmaceutical formulation comprises PT523 in the form of an ammonium salt.
  • PT523 can be reconstituted or dissolved in sterile water or other pharmaceutically acceptable solvent prior to administration to the subject.
  • Other dry pharmaceutical formulations of PT523 include those wherein a composition comprising PT523 is compressed into tablet or pill form suitable for oral administration or compounded into a sustained release formulation.
  • the formulation be encapsulated with an enteric coating to protect the formulation and prevent premature release of PT523 therein.
  • enteric coatings are known in the art, and any suitable coating, or combinations of coatings, can be employed.
  • PT523 can be placed into any suitable dosage form. Pills and tablets represent some of such dosage forms.
  • the pharmaceutical formulations can also be encapsulated into any suitable capsule or other coating material, for example, by compression, dipping, pan coating, spray drying, etc. Suitable capsules include those made from gelatin and starch. In turn, such capsules can be coated with one or more additional materials, for example, and enteric coating, if desired.
  • PT523 or a pharmaceutical formulation thereof is administered as a pill, e.g., a capsule, tablet, caplet or the like, that is suitable for oral administration.
  • a pill e.g., a capsule, tablet, caplet or the like
  • Numerous capsule manufacturing, filling, and sealing systems are well-known in the art.
  • Preferred capsule dosage forms can be prepared from gelatin and starch. Gelatin has been the traditional material, and the dosage forms are generally produced by well known dip molding techniques. After manufacture, gelatin capsules are filled with the desired composition and then sealed. A more recently developed alternative to gelatin dosage forms are capsules produced from starch.
  • Starch capsules (typically made from potato starch) afford several advantages compared to gelatin capsules, including pH-independent dissolution, better suitability for enteric coating, water in the dosage form is tightly bound to the starch (and is thus less likely to migrate into the composition encapsulated in the dosage form), and the absence of animal-derived ingredients (which may be antigenic or contaminated with pathogens). Starch capsules are odorless and rigid, and exhibit similar dissolution properties as compared to gelatin capsules.
  • Containers of dry or liquid pharmaceutical formulations can be labeled to identify to identify the formulation contained therein and other info useful to health care providers and subjects in the treatment of cancers or symptoms thereof including, but not limited to, instructions for use, dose, dosing interval, duration, indication, contraindications, warnings, precautions, handling and storage instructions and the like. 6.2. Doses and Dosing Schedules
  • the amount of PT523 to be administered to a subject in the methods provided can be determined based on subject's body surface area (BSA). For example, in calculating BSA, actual heights and weights of the subject can be used, with no adjustment to "ideal" body weight. For instance, BSA (m 2 ) can be calculated as follows:
  • the dose administered can be between about 0.2 mg/m 2 to about
  • 900 mg/m 2 or between about 5 mg/m 2 to about 600 mg/m 2 , or between about 30 mg/m 2 to about 400 mg/m 2 , or between about 50 mg/m 2 to about 200 mg/m 2 , or about 75.0 mg/m 2 to about 175 mg/m 2 , or between about 9 mg/m 2 to about 200 mg/m 2 , or between about
  • 9 mg/m 2 to about 160 mg/m 2 or between about 9 mg/m 2 to about 100 mg/m 2 , or between about 9 mg/m 2 to about 80 mg/m 2 .
  • PT523 is administered in an amount effective to treat or manage the cancer of symptom thereof wherein the amount of PT523 administered is tolerable by the subject.
  • tolerable it is meant that the side effects of PT523 are reversible (e.g., nonlethal) and relatively short-lasting (i.e., the subject should be free of side effects within minutes or by 6-15 days).
  • doses of PT523 are tolerable if at some time after PT523 administration, the subject's absolute neutrophil count (ANC) is equal to or exceeds 1000/mm 3 , platelet count is equal to or exceeds 50,000/mm 3 and/or serum creatinine concentration is equal to or less than 1.5 mg/dL.
  • ANC absolute neutrophil count
  • a dose of PT523 or pharmacological formulations thereof can be administered at once to a subject, or may be divided into a number of smaller doses to be administered at intervals of time.
  • PT523 is administered once per day for at least one day. In some embodiments, PT523 is administered to the subject once per day for two, three, four, five or more consecutive days.
  • PT523 is administered to the subject once a week.
  • PT523 can administered to the subject about once per week for at least about two consecutive weeks, about three consecutive weeks, about four consecutive weeks, about five consecutive weeks or more consecutive weeks.
  • PT523 is administered in a dosing schedule or
  • PT523 is administered on day 1 of the cycle and the cycle concludes with one or more days of no PT523 administration.
  • PT523 can be administered.
  • PT523 can be administered to the subject on days 1, 8 and 15 followed by 13 days of no PT523 administration, to constitute one cycle.
  • PT523 can be administered about once per week for two weeks (for instance on day 1 and on day 8 or day 15) followed by at least a week of no administration, to constitute one cycle.
  • PT523 or a pharmaceutical formulation thereof is administered to the subject in one, two, three, four or five infusions over a therapeutic cycle of 21 days.
  • PT523 or a pharmaceutical formulation thereof can, for example, be administered on days 1 and 8 of a 21 day cycle.
  • PT523 or a pharmaceutical formulation can be administered from dayl to day 5 followed by sixteen days of no administration in a 21 day cycle.
  • PT523 or a pharmaceutical formulation thereof is administered to the subject for five days, followed by a period of no administration of
  • PT523 or a pharmaceutical formulation thereof.
  • PT523 or a pharmaceutical formulation thereof is administered to the subject in two to four infusions over a therapeutic cycle of about two to about six weeks.
  • the duration of a therapeutic cycle is about three weeks, about four weeks, about five weeks or about seven weeks.
  • the dose of PT523 to be administered represents the total dose administered to the subject in the cycle.
  • 30 mg/m 2 PT523 administered on days 1, 8 and 15 in a 28-day cycle means that 10 mg/m 2 PT523 is administered on days 1, 8 and 15.
  • Methods of treatment or management of a cancer or a symptom thereof in a subject can comprise any number of therapeutic cycles.
  • PT523 is administered in two or more therapeutic cycles.
  • Therapeutic cycles can begin one after the other or may be separated by one and up to four days.
  • PT523 the following criteria should be observed in the subject before a second or later dose of PT523 is administered to the subject: absolute neutrophil count (ANC) ⁇ lOOO/mm 3 ; platelets >50,000/mm 3 ; and serum creatinine ⁇ 1.5 mg/dL.
  • ANC absolute neutrophil count
  • platelets >50,000/mm 3
  • serum creatinine ⁇ 1.5 mg/dL.
  • a second or later dose of PT523 can be administered to a subject in which their values for ANC, platelet count and serum creatinine concentration exceed these numbers.
  • Changes in only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the RECIST criteria. Measurements are made with conventional techniques (CT, MRI, X-ray, spiral CT scan), or if superficial lesions are to be observed, e.g., skin lesions or nodules apparent beneath skin, or palpable lymph nodes, these may be measured directly, for example, using a ruler.
  • PT523 or pharmaceutical formulations thereof can be parenterally, intradermally, or topically administered. In certain embodiments, PT523 or a pharmaceutical formulation thereof is administered parenterally.
  • the te ⁇ n parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intraarterial injection, or infusion techniques.
  • PT523 or a pharmaceutical formulation thereof is administered intravenously to the subject.
  • continuous intravenous infusions can be administered with the aid of an i.v. drip, infusion pump or device.
  • PT523 can be administered in a combination of continuous intravenous infusions and intravenous push infusion ("bolus doses").
  • PT523 is delivered through a free running peripheral intravenous or central venous catheter, without the use of an inline filter, using an infusion pump or delivered via either gravity drip or i.v. push.
  • PT523 can be administered in an about five minute infusion.
  • PT523 can administered into a single arm of the subject.
  • any suitable vessel can be used for infusion, including peripheral vessels such as the vessels in the antecubital fossa of the arm or a central line into the chest.
  • the composition is infused into the cephalic or median cubital vessel at the antecubital fossa in the arm of the subject.
  • folic acid In certain embodiments of the methods provided wherein PT523 is administered to a subject, folic acid, a folate binding protein binding agent, and/or cyanocobalamin (vitamin B 12 ) is administered prior to, during, and/or after PT523 administration to the subject.
  • cyanocobalamin vitamin B 12
  • administration of folic acid or folate binding protein binding agent and cyanocobalamin reduce toxicities without affecting the efficacy of PT523 administered to a subject.
  • folic acid, a folate binding protein binding agent or cyanocobalamin are administered to the subject one, two, three, four, five, six, seven or eight days before PT523 is administered to the subject.
  • folic acid, a folate binding protein binding agent or cyanocobalamin are administered to the subject on the same day on which PT523 is administered to the subject.
  • folic acid, a folate binding protein binding agent or cyanocobalamin are administered to the subject between one day to one week, or between one week to three weeks after PT523 is administered to the subject.
  • Folic acid, a folate binding protein binding agent or cyanocobalamin can be administered to the subject in weekly intervals or in daily intervals.
  • folic acid typically, about 350 ⁇ g to about 1000 ⁇ g folic acid (or an equivalent amount of a folate binding protein binding agent) can be administered daily to the subject before, during and/or after PT523 administration.
  • Folic acid is generally taken orally.
  • Cyanocobalamin can be orally administered daily to the subject in, for example, about
  • folic acid, folate binding protein binding agent and/or cyanocobalamin are administered by parenteral, subcutaneous, or intramuscular delivery.
  • subjects to whom PT523 is administered in the methods provided can be given blood and platelet transfusions, narcotics or standard anti-emetic therapy as appropriate.
  • a second therapeutic agent is administered to the subject.
  • combination therapy does not limit the order in which agents or treatments are administered to a subject in the methods provided.
  • the agents of the combination therapy can be administered concurrently, sequentially in any order or cyclically to a subject.
  • two components of a combination therapy are administered concurrently to a subject.
  • Components of combination therapy can be administered to a subject in the same pharmaceutical composition.
  • components of combination therapies can be administered to a subject in separate pharmaceutical compositions, and these separate compositions may be administered by the same or by different routes of administration, including, for example, oral, parenteral, or topical.
  • the second therapeutic agent, and/or optional third therapeutic agent are administered to subject according to their respective standard or art-recognized doses and dosing schedules.
  • a second therapeutic agent, and/or optional third therapeutic agent is selected for its additive effects with PT523 on the treatment or management of a cancer or symptom thereof.
  • a second therapeutic agent, and/or optional third therapeutic agent is selected for its synergistic effects with PT523 on the treatment or management of a cancer or symptom thereof.
  • chemotherapeutic agents and toxins examples include chemotherapeutic agents and toxins.
  • a second therapeutic agent or therapeutic agent can be abrin, anthramycin (AMC), asparaginase, auristatin E, 5-azacytidine, azathioprine, bleomycin, busulfan, buthionine sulfoximine, camptothecin, carboplatin, carmustine (BSNU), CC- 1065, chlorambucil, cisplatin, colchicine, cyclophosphamide, cytarabine, cytidine arabinoside, cytochalasin B, dacarbazine, dactinomycin, daunorubicin, decarbazine, docetaxel, doxorubicin, an estrogen, 5-fluorodeoxyuridine, fluosol, 5-fluorouracil, gramicidin D,
  • a second therapeutic agent or optional third therapeutic agent is selected from the agents consisting of cisplatin, carboplatin, cetuximab, cyclosphamide, docetaxel, doxorubicin, erlotinib (TARCEV A ® ), etopside, gefitinib, gemcitabine hydrochloride, ifosfamide, irinotecan, lomustine, paclitaxel, topotecan, and vinorelbine tartrate.
  • the second therapeutic agent or optional third therapeutic agent is selected from the agents consisting of cisplatin, carboplatin, cyclosphosphamide (CYTOXAN ® ), docetaxel, doxorubicin, etopside, erlotinib (TARCEV A ® ), gemcitabine hydrochloride, ifosfamide, irinotecan, lomustine (CEENU ® ), paclitaxel, topotecan (HYCAMTINTM), and vinorelbine tartrate.
  • the second therapeutic agent or optional third therapeutic agent is an epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitor.
  • EGFR-TK epidermal growth factor receptor-tyrosine kinase
  • the EGFR-TK inhibitor is gefitinib, erlotinib, or cetuximab.
  • the second therapeutic agent or and/or optional third therapeutic agent is a radioisotope or radiolabled agent.
  • the second therapeutic agent or and/or optional third therapeutic agent is an anti-angiogenic agent, such as, for example, bevacizumab
  • PT523 When administered daily for five days as a 54 mg/kg intraperitoneal injection starting on Day 9, PT523 produced a 97% reduction in size of the AS283 xenograft on Day 26 as compared with controls, with one of six mice found to be tumor-free on Day 40. When the dose was increased to 80 mg/kg (qd x 5), three out of six mice died of drug toxicity and there were no Day 40 survivors. Essentially complete suppression of growth of the AS283 xenograft was observed when the 54 mg/kg (qd x 5) dose of PT523 was administered intravenously, and there were no toxic deaths. Another group of six mice received 80 mg/kg on this schedule and in this group there was one toxic death and one 40 day survivor.
  • PC-3 prostate carcinoma cells were implanted subcutaneously in athymic nude mice on Day 0, and treatment was begun on Day 13.
  • PT523 was injected daily in 0.05 M Tris buffer (0.1 mL/10 g body weight).
  • the PC-3 tumor caused approximately 20% weight loss in mice not treated with drug or vehicle.
  • the vehicle itself did not inhibit tumor growth.
  • Intraperitoneal PT523 injections of 54 and 80 mg/kg produced growth inhibition of the tumor xenograft of 60% (Day 29) and 63% (Day 22), respectively.
  • the 54 mg/kg dose resulted in a 40% reduction in tumor size.
  • Doses of 80 mg/kg resulted in toxic deaths in three of six animals.
  • untreated PC-3 mice also experienced considerable weight loss, and suggesting that the weight loss in the drug- treated group was probably due to the tumor rather than the drug.
  • PT523 was prepared daily in sterile deionized water. Paclitaxel was dissolved in a mixture of DMSO/Cremophore E1/H 2 O (10:18 :72). Cisplatin was dissolved in DMSO first and diluted to final volume with sterile H 2 O and kept DMSO concentration at 2 %. TARCEV A ® tablets were purchased from a commercial vendor. For dosing, the tablets were grinded to a powder form and dissolved in 0.5% hydroxypropylcellulose in sterile saline. PT523, paclitaxel, and cisplatin were administered via i.v. injection once weekly and TARCEV A ® was given orally daily via gavaging. The total treatment period was 4 weeks. Dosing regimen is described in Table 3 below.
  • Tumor volumes were measured every 3-4 days and body weights once a week for 30 days. Animals were observed daily for adverse clinical signs related to the treatment received. Unscheduled sacrifices were performed when tumor volumes reached > 1,500 mm3, or loss of > 25% of the original body weight, or tumors developed ulceration, or animals became moribund.
  • PT523 at 15 mg/kg or 35 mg/kg in combination with 5 mg/kg of cisplatin significantly inhibited the tumor growth with the P values ⁇ 0.01 and 0.05 respectively. See Figure 7.
  • PT523 at 15 and 25 mg/kg in combination with 50 mg/kg of TARCEV A ® inhibited tumor growth with the P values ⁇ 0.05 and 0.01 respectively.
  • PT523 at the high dose level (35 mg/kg) in combination with 50 mg/kg of TARCEV A ® did not show significant inhibition of tumor growth likely due to the large variation of tumor volumes in this group. See Figure 8. [00112] Throughout the entire study, no obvious toxic effect was seen in the treatment groups as indicated by the body weight measurements.
  • LS/MS/MS (“LS/MS/MS”) technique for detecting and quantifying PT523 was developed and validated for mouse, rat, dog, and human plasma.
  • the technique provided the required sensitivity, selectivity, and accuracy for the analysis of PT523 in these biological fluids.
  • the mean percentage accuracy of the method over the concentration range of PT523 of 1 to 500 ng/mL ranged between 94% and 104%.
  • the percent coefficient of variation for concentrations above 2.5 ng/mL was less than 10%.
  • the percent coefficient of variation for the lowest concentration (1 ng/mL) ranged from 1.4 to 17%.
  • the stability of PT523 was assessed in 1.4% NaHCO 3 (an isotonic concentration), NaOH/saline (prepared by dilution of 0.
  • PT523 was found to be stable at concentrations ranging from 1 to 10 mg/mL in 1.4% NaHCO 3 for at least 72 hours at both 4 0 C and at room temperature (longer time points were not assessed). PT523 was found to be stable in NaOH/saline at a concentration of 10 mg/mL of PT-523 for at least 168 hours at -20 0 C, 4 0 C, or 37 0 C maintained under dark conditions (all temperatures tested), reduced lights (room temperature), or ordinary fluorescent lighting (room temperature).
  • PT523 was found to be stable in 3.4% tromethamine at a concentration of 10 mg/mL of PT523 for at least 168 hours at -2O 0 C, 4 0 C, or 37°C maintained under dark conditions (all temperatures tested), reduced lights (room temperature), or ordinary fluorescent lighting (room temperature).
  • PT523 was observed to degrade rapidly when exposed to sunlight.
  • Plasma protein binding was determined for mouse, rat, dog, and human plasma. Each species of plasma was mixed with PT523 at a final concentration of 0.1, 1, or iuu ⁇ g/nij./. Aiier preparation, each mixture was incubated for approximately 15 minutes at 37 0 C. Aliquots of each plasma mixture were centrifuged, and the filtrate was analyzed by LC/MS/MS for PT523 concentration. Results are shown in Table 5.
  • a PBS phosphate buffered saline (pH 7.4)
  • Tables 6 and 7 summarize the pharmacokinetic data with PT523 in various species.
  • mice The pharmacokinetics of PT523 were characterized in mice by giving CD 2 Fl mice a single i.v. (tail vein) dose of 5 or 15 mg/kg of PT523 at an injection volume of 0.1 mL/lOg body weight. At various times after post-dosing, three mice per dose group were sacrificed and blood was collected from the brachial artery of mice anesthetized with isoflurane. In addition, for each dose group, urine and feces were collected from 5 mice maintained in a single metabolism cage at 0-6 hours and 6-24 hours post-dosing.
  • PT523 was formulated by dissolving PT523 in 0.1N NaOH, and diluting the solution to the appropriate volume with 0.9% saline. The solution was filtered through a 0.45 ⁇ m syringe filter. The concentration and homogeneity of the dosing formulations was also assessed. The formulations were determined to be within 95% of target. Plasma, urine and feces samples were subsequently analyzed for concentrations of PT523 and its 7-hydroxy metabolite concentrations.
  • the calculated AUC value was 791 ⁇ g-min/mL, which was approximately three-fold higher than the value determined following administration of the three-fold lower dose of 5 mg/kg.
  • Computed half-lives for PT523 were 6.6, 22.0, and 478 minutes.
  • the clearance and Vd ss were similar to those determined after administration of the lower i.v. dose, and were 19.0 mL/min/kg and 556 mL/kg, respectively.
  • mice administered 15 mg/kg i.v. 18% of the dose was eliminated in urine as unmetabolized PT523 within 24 hours of dosing, and 34% was eliminated in feces; thus the total 24-hour recovery of PT-523 represented 52% of the dose (Table 6).
  • the amount eliminated in urine and feces as 7-hydroxy-PT523 during this same interval accounted for 0.5% of the dose.
  • the urinary clearance of PT523 was estimated to be 4 mL/min/kg after administration of an i.v. dose of 5 or 15 mg/kg.
  • the fecal clearance of PT523 was slightly higher, and was 6 or 7 mL/min/kg after a dose of 5 or 15 mg/kg, respectively.
  • the urinary and fecal clearances of 7-hydroxy-PT523 were higher than those for PT523, and ranged between 10 and 22 mL/min/kg.
  • Calculated AUC values were 438,789 and 1,160,677 ng-min/mL for the 5 and 15 mg/kg doses, respectively (Table 6).
  • Estimated half-lives for 5 mg/kg were 3.2, 15.6, and 45.0 minutes; for 15 mg/kg, the half-lives were 4.6, 22.8, and 183 minutes. Values for clearance after 5 or 15 mg/kg were 11.4 and 12.9 mL/min/kg, respectively.
  • the Vd ss was estimated to be 240 mL/kg for the 5 mg/kg dose and 299 mL/min for the 15 mg/kg dose.
  • the urinary clearance of PT523 was estimated to be 3 mL/min/kg in rats.
  • the fecal clearance of PT523 was 6 and 4 mL/min/kg after 5 and 15 mg/kg, respectively.
  • the urinary and fecal clearance of 7-hydroxy-PT523 could not be calculated for 5 mg/kg, but for 15 mg/kg, the urinary and fecal clearance of 7-hydroxy-PT523 was very high, estimated at 143 and 58 mL/min/kg, respectively.
  • AUC increased proportionally to dose.
  • the estimated half-lives for the three phases of elimination of PT523 were similar among dogs in each dose group, and were 1.8-5.9 minutes, 70.6-90.3 minutes, and 194-514 minutes for the a phase, ⁇ phase, and 7 phase, respectively.
  • the clearance and volume of distribution at steady state (Vd ss ) of PT-523 were also independent of the dose level and ranged from 2.5- 4.1 mL/min/kg and 317-553 mL/kg, respectively. There was no evidence of saturation of elimination or metabolism of PT523.
  • the long terminal phase of elimination (up to 514 minutes) was considered to be possibly related to high plasma protein binding.
  • Plasma concentrations of PT523 on Study Day 1 at 0.02 mg/kg/day ranged from 108 to 211 ng/niL at 2 minutes post-dosing. Thereafter, plasma drug concentrations declined biphasically, and were between 3.93 and 6.02 ng/mL at 3 hours post-dosing. On Day 5, plasma concentrations of PT523 at 2 minutes post-dosing were approximately 2-fold higher than on Day 1, and ranged from 237 to 475 ng/mL. No 7-hydroxy PT-523 was detectable at any timepoint.
  • the PT523 concentration in plasma decreased in a polyexponential manner and the terminal log-linear phase was achieved 4-6 h after dosing, hi the 7 patients receiving doses of 16 mg/m 2 , the mean peak drug concentration in plasma (C max ) was 5,650 ⁇ 300 ng/mL and the median plasma concentration 48 h after dosing was 1.7 ng/mL ⁇ range, " i7(f- ' 23.4 ng/mL).
  • the apparent biological half-life (t 1/2jZ ), total body clearance (CL) and apparent volume of distribution at steady-state (V ss ) were all independent of the dose.
  • PT523 The toxicological assessment of PT523 was performed in Fisher 344 rats and beagle dogs. Administration of PT523 as a single i.v. injection and a repeated dosing schedule involving an i.v. injection given on 5 consecutive days was evaluated in both species. Animals were examined for clinical signs of toxicity, clinical pathology parameters (i.e., complete blood counts and serum chemistries) and gross and microscopic histopathological changes. Objectives included determination of the target organ toxicity and its reversibility following administration of PT523.
  • PT523 prepared in Tris base/saline was administered to male rats as a single i.v. (tail vein) bolus administration using a slow push. Doses of PT523 ranged from 5 mg/kg to 380 mg/kg.
  • Hematology assessments were made on Days 4, 5, 8 and/or 16.
  • Drug related changes in hematologic parameters observed on days 4, 5 or 8 included decreased mean neutrophil count at doses >20 mg/kg; decreased reticulocyte count at doses >30 mg/kg; decreased RBC, hematocrit and hemoglobin at doses >140 mg/kg; Decreased platelet counts on Days 4 or 8 at 180 to 380 mg/kg, with minimum values ranging from 7% (380 mg/kg) to 70% (200 mg/kg) of controls; decreased WBC at 180, 240, 280, 300, 340, and 380 mg/kg, with minimum group mean WBC values observed at Day 8, respectively, of 59%, 29%, 29%, 35%, 15%, and 31% of the group mean values in controls.
  • the maximum tolerated dose (MTD) of PT-523 was considered to be 200 mg/kg.
  • a summary of some toxicology results in rats is shown in Table 8.
  • PT523 ammonium salt dissolved in Tris base/saline was administered in a single i.v. dose (see Table 8 for doses) using a dosing volume of 1 mL/kg to groups of one male and one female beagle dogs.
  • Drug-induced toxicity was characterized by gastrointestinal symptoms, body weight loss, decreased leukocyte, neutrophil and lymphocyte counts, increased fibrinogen concentration, and histopathologic changes (lymphoid depletion in the lymph nodes, thymus, tonsil and spleen; bone marrow depletion; mucosal necrosis in the stomach and intestines). Results of this study are summarized in Table 8.
  • Treatment-related effects on hematological parameters included the following changes. Decreases in WBC counts at 5 mg/kg (male, Day 4), 7.5 mg/kg (female, Days 4 and 8), and 15 mg/kg. The WBC counts were 19% to 54% of the corresponding baseline values. Decreases in neutrophil counts at 2 mg/kg (male, Day 8), 7.5 mg/kg (female, Day 8), and 15 mg/kg (male Day 4, female, Days 4 and 6). The decreased neutrophil values ranged from 18% to 52% of the corresponding baseline values.
  • NOEL no-observable effect-level
  • Treatment- related toxicity was observed at 0.05 mg/kg/day and above characterized by gastrointestinal toxicity (emesis/bloody emesis and diarrhea/bloody diarrhea), body weight loss, clinical pathological changes (including decreased leukocytes, neutrophils, and lymphocytes, increases in RBC, HGB, AHCT ⁇ BUN, creatinine, globulin, ALT, ALP, total bilirubin, and fibrinogen, decreased glucose, total protein, and albumin), and histopathological changes in the lymph tissue, small and large intestines and stomach.
  • the no observable effect level of PT-523 on a qd x 5 dose schedule was 0.01 mg/kg/day.
  • the maximum tolerated dose of PT-523 was not determined in this study, but appears to be between 0.01 and 0.05 mg/kg/day. Gastrointestinal toxicity was dose limiting.
  • Toxicology analyses were also performed on the dogs that received five daily doses of 0.02 or 0.002 mg/kg/day of PT523 as described in Paragraphs [00133] to [00136] above. No adverse clinical signs were observed in any dogs in the 0 or 0.002 mg/kg/day dose groups. There were no treatment-related changes in body temperature. Clinical chemistry results did not indicate any treatment-related changes.
  • PT523 was administered as a 5-minute infusion on days 1 and 8 on a 21 -day therapeutic cycle to patients with relapsed or refractory non-small lung cancer.
  • Patient population Fifteen patients with histologically or cytologically confirmed NSCLC stage III / IV or recurrent / refractory disease, that failed two or more lines of therapy other than PT523 were enrolled. Patients were within grades 0-2 of the Eastern Cooperative Oncology Group (ECOG) Performance Status grades (for information regarding grades on ECOG Performance Status, see the ECOG web site at http://www.ecog.org/general/perf_stat.html) and had signed informed consent documents.
  • ECOG Eastern Cooperative Oncology Group
  • Results Patients completed a median of 3 cycles (ranging from 1 cycle to 8 cycles). Four patients (27% of patients) completed four or more cycles. Thirteen patients (87% of patients) completed two or more cycles. Antitumor activity is provided in Table 10.
  • Table 11 Characteristics of Patients with Disease Control
  • PT523 was administered as a 5-minute infusion on days 1 and 8 on a 21-day therapeutic cycle using the same dose escalation design (27-270 mg/m 2 /cycle) as described above. All patients received folic acid and vitamin B 12 . Safety assessments were performed by standard laboratory and clinical DLT definitions. Responses were assessed based on RECIST criteria. Plasma PT523 concentrations were analyzed by a LC/MS/MS method. Concentration-time profiles of PT523 were analyzed by noncompartmental methods using WINNONLIN ® software.
  • PT523 exhibited linear pharmacokinetics profile across the 5 dose levels evaluated. Pharmacokinetics data for sixteen patients showed that C max and AUCo- ⁇ exhibited linear PK and Overall mean values ( ⁇ SD) for CL was 1.31 ⁇ 0.31 L/hr/m 2 ; for
  • Ti / 2 z was 6.5 ⁇ 1.4 h, for V ss was 8.9 ⁇ 2.5 L/m 2 .
  • the following exemplifies a method for the treatment/management of a non-small lung cancer in a patient on a 28-Day therapeutic cycle (PT523 administered on Days 1 and 8) using a 40 mg/m 2 PT523 dosage.
  • PT523 monoammonium salt is prepared in a sterile lyophilized powder for injection in vials containing 25 mg of PT523, 50 mg of mannitol, United States Pharmacopoeia (USP), and 28 mg of L-arginine, USP.
  • the powder is packaged in 20 cc amber molded vials, with 20 mm lyo stoppers and red, flip-off aluminum seals. Vials of the sterile lyophilized powder for injection can be kept refrigerated (2-8°C).
  • Dosage Determination The patient's body surface area (BSA) is determined using actual heights and weights with no adjustment to "ideal" weight.
  • the appropriate volume of reconstituted PT523 to be administered is calculated using the patient's BSA and the reconstituted concentration of PT523 to result in 20 mg/m 2 of reconstituted PT523 per single infusion ⁇ e.g., on Day 1 or Day 8).
  • Injection is reconstituted with 5 mL of Water for Injection, USP to yield a clear, yellow solution with a drug concentration of 5 mg/mL and a pH of 9.1 to 9.6.
  • the reconstituted vials are stored refrigerated for up to 7 days, or at room temperature for up to 24 hours, if necessary.
  • the appropriate amount of reconstituted PT523 for Injection is diluted in 50 mL of 5% Dextrose Injection, USP for intravenous administration, which is used within 8 hours. [00178] On Days 1 and 8, each dose of PT523 is administered by i.v. infusion over
  • the drug is delivered through a free running peripheral intravenous catheter or central venous catheter, without the use of an inline filter, using an infusion pump. All materials in the fluid path of the medication bag and infusion set are constructed from medical grade PVC.
  • the delay should be no more than one day.
  • the patient is administered folic acid (1 mg PO qd) and cyanocobalamin
  • a second cycle or third cycle is initiated if the following parameters are observed in the patient: ANC > 1000/mm 3 ; platelets > 50,000/mm 3 ; serum creatinine ⁇ 1.5 mg/dL.
  • PT523 was administered as a 5-minute infusion on days 1-5 on a 21-day therapeutic cycle to patients with relapsed or refractory leukemia or myolodysplastic syndrome.
  • Patient population Fourteen patients including seven patients with acute myelogenous leukemia, five patients with acute lymphocytic leukemia, one patient with chromic lymphocytic leukemia in the blastic phase, and one patient with hair cell leukemia were enrolled. These patients had been treated with several therapies and no standard therapies had resulted in a durable remission.
  • Dose escalation was as follows: 0.2 mg/m 2 (1 mg/m 2 per cycle); 0.4 mg/m 2 (2 mg/m 2 per cycle); 0.6 mg/m 2 (3 mg/m 2 per cycle); 0.8 mg/m 2 (4 mg/m 2 per cycle) using a standard design. Intrapatient dose escalation was made if no toxicity greater than grade 2 was observed, no evidence of disease progression as defined by the RECIST criteria was observed, and other eligibility criteria.
  • Results Patients completed a median of one cycle (ranging from 1 cycle to

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Abstract

L'invention concerne des méthodes de traitement ou de prise en charge thérapeutique d'un cancer ou des symptômes de celui-ci, comprenant l'administration de PT523 et de formulations pharmaceutiques de celui-ci.
PCT/US2006/014250 2005-04-14 2006-04-13 Utilisation de pt523 pour le traitement des cancers Ceased WO2006113536A2 (fr)

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