US20100189771A1 - Fixed ratio drug combination treatments for solid tumors - Google Patents

Fixed ratio drug combination treatments for solid tumors Download PDF

Info

Publication number
US20100189771A1
US20100189771A1 US12/091,738 US9173806A US2010189771A1 US 20100189771 A1 US20100189771 A1 US 20100189771A1 US 9173806 A US9173806 A US 9173806A US 2010189771 A1 US2010189771 A1 US 2010189771A1
Authority
US
United States
Prior art keywords
floxuridine
irinotecan
tumor
dose
molar ratio
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/091,738
Other languages
English (en)
Inventor
Lawrence Mayer
Christine Swenson
Andrew Janoff
John Redman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Celator Pharmaceuticals Inc
Original Assignee
Celator Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Celator Pharmaceuticals Inc filed Critical Celator Pharmaceuticals Inc
Priority to US12/091,738 priority Critical patent/US20100189771A1/en
Assigned to CELATOR PHARMACEUTICALS, INC. reassignment CELATOR PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SWENSON, CHRISTINE, JANOFF, ANDREW, MAYER, LAWRENCE
Publication of US20100189771A1 publication Critical patent/US20100189771A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to methods for improved delivery and therapeutic effectiveness of a combination of therapeutic agents. More particularly, the inventions relates to delivery of a fixed ratio combination of floxuridine and irinotecan.
  • 5-fluorouracil 5-fluorouracil
  • 5-FU 5-fluorouracil
  • Response to 5-FU appears to correlate with inhibition of thymidylate synthase activity more so than with incorporation of 5-FU into RNA.
  • Irinotecan is usually administered in two ways. In one regimen, 350 mg/m 2 irinotecan IV over 30 minutes administered every 21 days (Rougier P., et al., J. Clin. Oncol . (1997) 15:251-60). In another regimen, 125 mg/m 2 irinotecan IV over 90 minutes on days 1, 8, 15 and 22 repeated every 42 days (Pitot H. C. et al., J. Clin. Oncol .
  • FOLFIRI usually contains about irinotecan 180 mg/m 2 IV, leucovorin (LV) 100-500 mg/m 2 , and 5FU 2300-3000 mg/m 2 to be administered intravenously (IV) in 24 or 48 hour infusion or 400 mg/m 2 bolus followed by 600 mg/m 2 22 hour infusion on days 1 and 2 repeated every two weeks.
  • IFL contains irinotecan at 70 or 125 mg/m 2 , LV 20-200 mg/m 2 , and 5FU 450-500 mg/m 2 for IV bolus administration weekly for 4 weeks followed by two weeks rest. IFL is less favored because it is potentially more toxic and somewhat less active than FOLFIRI.
  • a method to treat cancer in a subject comprising administering to said subject a pharmaceutical composition comprising a fixed, non-antagonistic molar ratio of irinotecan and floxuridine, wherein said fixed, non-antagonistic molar ratio is maintained in the plasma for at least about 4 hours.
  • the fixed non-antagonistic molar ratio is maintained for at least about 8 hours, at least about 16 hours, or at least about 24 hours.
  • the irinotecan and floxuridine are stably associated with the delivery vehicle.
  • the delivery vehicle is a liposome.
  • a method to treat cancer in a subject comprising administering to said patient a pharmaceutical composition comprising a fixed, non-antagonistic molar ratio of irinotecan and floxuridine, wherein said composition is administered intravenously.
  • the pharmaceutical composition is administered in at least about 30 minutes and less than about 3 hours. In a specific embodiment, the pharmaceutical composition is administered in about 90 minutes.
  • a method to treat cancer in a subject in need thereof comprising administering to said patient a pharmaceutical composition comprising a fixed, non-antagonistic molar ratio of irinotecan and floxuridine, wherein floxuridine is administered at less than 0.001 moles/m 2 /dose.
  • the floxuridine is administered at about 0.0003 moles/m 2 /dose.
  • a method to treat cancer in a subject in need thereof comprising administering to said patient a pharmaceutical composition comprising a fixed, non-antagonistic molar ratio of irinotecan and floxuridine, wherein floxuridine is administered at less than 0.01 moles/m 2 /month.
  • the floxuridine is administered at about 0.0006 moles/m 2 /month.
  • the fixed, non-antagonist molar ratio of irinotecan and floxuridine can be between about 5:1 and about 1:5. In a specific embodiment, the fixed, non-antagonist ratio of irinotecan:floxuridine is about 1:1. Typically, the fixed, non-antagonistic ratio of irinotecan and floxuridine is encapsulated in a liposome.
  • the cancer is an advanced solid tumor.
  • the advanced solid tumor can a gastric tumor, a renal tumor, a breast tumor, a colon tumor, an esophageal tumor, a prostate tumor, a pancreatic tumor, an ovarian tumor, an osteosarcoma, or a sphenoid sinus tumor.
  • the cancer is a relapsed cancer.
  • the subject can previously have undergone at least one anti-tumor regimen.
  • the anti-tumor regimen is a multi-agent regimen.
  • a pharmaceutical composition comprising a fixed, non-antagonistic molar ratio of irinotecan and floxuridine, wherein said fixed, non-antagonistic molar ratio is maintained in the plasma for at least about 4 hours, to treat a subject with cancer as disclosed herein.
  • the disclosed pharmaceutical compositions comprising a fixed, non-antagonistic molar ratio of irinotecan and floxuridine for the preparation of a medicament to treat cancer, wherein said fixed, non-antagonistic molar ratio is maintained in the plasma for at least about 4 hours, to treat a subject with cancer as disclosed herein.
  • FIG. 1 shows the anti-tumor activity of CPX-1 in patients.
  • FIG. 2 shows the sustained fixed molar ratio of irinotecan:floxuridine in the plasma following administration of the liposomal-encapsulated irinotecan and floxuridine.
  • non-antagonistic molar ratio of irinotecan and floxuridine refers to a molar range of irinotecan:floxuridine from between about 5:1 to about 1:5. In some embodiments, the non-antagonistic molar range is about 1:1 irinotecan:floxuridine.
  • non-antagonistic molar ratios of irinotecan and floxuridine were determined in vitro using screening techniques. If these same ratios are administered separately as free drug cocktails (e.g., conventional aqueous-based pharmaceutical formulations without liposome delivery), the ratio is not maintained because the drugs are distributed and eliminated independently of one another, resulting in a continuously changing ratio.
  • free drug cocktails e.g., conventional aqueous-based pharmaceutical formulations without liposome delivery
  • the methods provided herein permit maintenance of the non-antagonistic ratio after administration for extended periods of time.
  • the liposomal formulation delivers each drug in correct proportion by controlling the individual pharmacokinetics of each drug and thereby sustaining the non-antagonistic ratio.
  • sustained delivery requires a greater amount of a drug being administered in an effort to maintain a therapeutically effective level of the drug in the plasma and ultimately in the tumor.
  • Such large doses are administered over a long period of time, often one or more days, requiring long hospital stays and/or reliance on prolonged infusion protocols that increase the risk of complications such as infection or pump malfunction.
  • Another disadvantage is toxicity with the higher doses that may prevent an optimal plasma level from being achievable.
  • Free drug cocktails are further disadvantaged when the drugs that are co-administered are only effective within a certain range of ratios of one another. For example, irinotecan and floxuridine molar can actually antagonize each other at certain irinotecan:floxuridine ratios ( ⁇ 5:1 and >1:5) depending on the tumor cell line.
  • CPX-1 is a liposomal formulation with a fixed 1:1 molar ratio of irinotecan HCl and floxuridine and has shown enhanced efficacy in cell culture and in in vivo models of colorectal carcinoma compared with the free drugs given as a cocktail and compared with individual liposomal drugs. See co-owned and co-pending U.S. Publication No. US 2004/0265368, filed Apr. 2, 2004. Any suitable source of irinotecan HCl and floxuridine can be employed.
  • the irinotecan HCl is (+)-7-ethyl-10-hydroxycamptothecine 10-(1,4′ bipiperidine)-1′-carboxylate, monohydrochloride, trihydrate and the floxuridine is 2′-deoxy-5-fluorouridine.
  • a liposomal formulation may be employed.
  • the liposomes are designed for sustained delivery of the encapsulated drugs at a fixed ratio to a tumor site.
  • irinotecan and floxuridine are stably associated with the liposomes.
  • the liposomes have a diameter of less than 300 nm, sometimes less than 200 nm. In one example, the nominal size of these liposomes is approximately 110 nm and sterilization is achieved by filtration through a 0.2 ⁇ m filter.
  • the liposome membrane is composed of distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG) and cholesterol (CHOL) in a 7:2:1:molar ratio.
  • DSPC distearoylphosphatidylcholine
  • DSPG distearoylphosphatidylglycerol
  • CHOL cholesterol
  • the liposomes are prepared by an water in oil derived liposome method and extruded liposomes are suspended in phosphate-buffered sucrose at pH 7.0. Any suitable means of encapsulating the drug combination in the liposomes can be employed.
  • irinotecan and floxuridine are encapsulated in the liposome using a copper gluconate/triethanolamine-based active loading procedure whereby irinotecan accumulates due to complexation inside pre-formed liposomes and floxuridine is passively encapsulated.
  • Cancer encompasses malignants cell with abnormal, uncontrolled growth. Such cells possess a number of characteristic properties such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain typical morphological features. Often, cancer cells will be in the form of a tumor, but such cells may also exist alone within a mammal, or may be a non-tumorigenic cancer cell, such as a leukemia cell.
  • a cell is identified as cancer by any of a number of ways, including, but not limited to, detecting the presence of a tumor or tumors (e.g., by clinical or radiological means), examining cells within a tumor or from another biological sample (e.g., from a tissue biopsy), measuring blood markers indicative of cancer (e.g., CA125, PAP, PSA, CEA, and the like), and/or detecting a genotype indicative of a cancer (e.g., TP53, ATM, and the like).
  • solid tumors refers to tumors other than leukemias or lymphomas (i.e., cancers of the blood) that form solid masses of cancer cells.
  • the term “advanced solid tumors” refers to a malignant tumor that is metastatic or locally advanced and inoperable. Solid tumors can be of any origin including, but not limited to cancer of the adrenal gland, bladder, bone, brain, breast, cervix, colon, esophagus, gall bladder, ganglia, gastrointestinal tract, head and neck, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, prostate, rectum, salivary glands, sinus, skin, soft tissue, spleen, testis, thymus, thyroid, or uterus.
  • the methods disclosed herein provide for a sustained delivery of a non-antagonistic molar ratio of irinotecan and floxuridine.
  • the non-antagonistic molar ratio for irinotecan:floxuridine in the plasma is maintained for up to at least about 24, hours, at least about 16 hours, at least about 12 hours, at least about 8 hours, and often at least about 4 hours following a single administration of the drug combination.
  • the sustained concentration of the liposomal encapsulated-drug combination in the plasma is greater than the drug concentration of the free cocktail drug combination in the plasma.
  • the methods also facilitate the administration of floxuridine at a significantly lower dose intensity than previously reported while maintaining its therapeutic effect. See Tables 1 and 2.
  • the FOLFIRI regimen of a 5-FU and irinotecan requires a fluoropyrimidine (in this case 5-FU) dose intensity of 0.0246 moles/m 2 /dose or 0.0492 moles/m 2 /month.
  • 5-FU and floxuridine are fluoropyrimidines that induce tumor cell death via the same active intermediate and have been shown to be equivalent clinically when administered at doses that are similar on a molar basis.
  • the IFL regimen of 5FU, irinotecan and LV requires a fluoropyrimidine dose intensity of 0.0038 moles/m 2 /day or 0.0154 moles/m 2 /month.
  • the fluoropyrimidine (floxuridine in this case) dose intensity used during the administration of CPX-1 can be less than about 0.0035 moles/m 2 /dose, less than about 0.0025 moles/m 2 /dose, 0.0010 moles/m 2 /dose, or 0.005 moles/m 2 /dose of the irinotecan:floxuridine drug combination while maintaining therapeutic efficacy. Typically, only one dose is administered in a day. In a specific embodiment, the fluoropyrimidine dose intensity is about 0.0003 moles/m 2 /dose of the irinotecan:floxuridine drug combination.
  • the fluoropyrimidine dose intensity is less than about 0.0150 moles/m 2 /month, less than about 0.0100 moles/m 2 /month, less than about 0.0050 moles/m 2 /month, or less than about 0.0020 moles/m 2 /month. In a specific embodiment, the fluoropyrimidine dose intensity is about 0.0006 moles/m 2 /month of the irinotecan:floxuridine drug combination.
  • a fluoropyrimidine e.g., floxuridine
  • a fluoropyrimidine is administered at doses that are less than when the drugs are administered individually in a conventional non-liposomal aqueous-based formulation while maintaining therapeutic efficacy.
  • the disclosed methods also provide a means of rapidly delivering a therapeutically effective dose of the drug combination irinotecan:floxuridine at a fixed molar ratio.
  • the liposomal formulation of CPX-1 has the additional advantage of requiring a shorter (and thus more rapid) intravenous administration time than the current therapies.
  • the liposome-encapsulated irinotecan:floxuridine drug combination can be administered to a patient by IV in at least about 30 minutes and less than about three hours.
  • the liposome-encapsulated irinotecan:floxuridine drug combination is administered IV over about 90 minutes.
  • other regimens employing free drug cocktails of irinotecan and floxuridine required at least 24 hours (Douillard J.
  • a “relapsed cancer” refers to a cancer that has recurred following prior complete or partial remission in response to a prior treatment. Recurrence can be defined in any way, including a reappearance or re-growth of a tumor as detected by clinical, radiological, or biochemical assays, or by an increased level of a cancer marker.
  • Prior treatments can include, but are not limited to chemotherapy, biological therapies, radiation therapy, and bone marrow transplantation.
  • the patients treated with the methods provided herein are those that have previously been treated, failed or are resistant to other therapies.
  • patients can be treated with the methods provided herein after receiving or becoming resistant to any chemotherapy or biological therapy.
  • the patient have previously received a platinum-containing regimen.
  • the patient has previously received, FOLFIRI, FOLFOX (5-FU and oxaliplatin), or IFL.
  • the patient has previously been treated with irinotecan.
  • the methods disclosed herein can also be employed as a first line therapy for cancers that have not previously been treated.
  • Responses to the disclosed therapeutic methods include any clinically evident, positive change in tumor disease state. Such responses can include increases in overall survival and increases in progression-free survival. Disease responses are assessed by any suitable means. In one embodiment, disease is assessed using RECIST (Response Evaluation Criteria in Solid Tumors) criteria (Therasse, P., et al., J. Natl Cancer Inst . (2000) 92:205-16). Best response on study will be classified as outlined below: Complete Response (CR): disappearance of all clinical and radiological evidence of tumor. Partial Response (PR): at least a 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum of the longest diameters. Stable Disease (SD): steady state of disease.
  • CR Complete Response
  • PR Partial Response
  • SD Stable Disease
  • Progressive Disease at least a 20% increase in the sum of the longest diameters of measured lesions taking as references the smallest sum of longest diameters recorded since the treatment started. Appearance of new lesions will also constitute progressive disease. In exceptional circumstances unequivocal progression of a non-measured lesion may be accepted as evidence of disease progression.
  • compositions provided herein are administered to any suitable subjects, preferably human subjects with cancer.
  • the pharmaceutical compositions of the present invention are administered intravenously. Dosage for the delivery vehicle formulations will depend on the ratio of drug to lipid and the administrating physician's opinion based on age, weight, and condition of the patient.
  • compositions comprising delivery vehicles of the invention are prepared according to standard techniques and may comprise water, buffered water, 0.9% saline, 0.3% glycine, 5% dextrose and the like, including glycoproteins for enhanced stability, such as albumin, lipoprotein, globulin, and the like. These compositions may be sterilized by conventional, well-known sterilization techniques. The resulting aqueous solutions may be packaged for use or filtered under aseptic conditions and lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration.
  • compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, and the like.
  • the delivery vehicle suspension may include lipid-protective agents which protect lipids against free-radical and lipid-peroxidative damages on storage. Lipophilic free-radical quenchers, such as alpha-tocopherol and water-soluble iron-specific chelators, such as ferrioxamine, are suitable.
  • Leucovorin may also be administered with compositions of the invention through standard techniques to enhance the life span of administered fluoropyrimidines.
  • the concentration of delivery vehicles in the pharmaceutical formulations can vary widely, such as from less than about 0.05%, usually at or at least about 2-5% to as much as 10 to 30% by weight and will be selected primarily by fluid volumes, viscosities, and the like, in accordance with the particular mode of administration selected. For example, the concentration may be increased to lower the fluid load associated with treatment. Alternatively, delivery vehicles composed of irritating lipids may be diluted to low concentrations to lessen inflammation at the site of administration. For diagnosis, the amount of delivery vehicles administered will depend upon the particular label used, the disease state being diagnosed and the judgment of the clinician.
  • CPX-1 (Irinotecan HCl:Floxuridine) liposome injection was based on 1) defining a non-antagonistic ratio of the two active moieties, irinotecan HCl and floxuridine, using cell-based screening assays and 2) designing a liposomal drug carrier to maintain this ratio after intravenous administration.
  • This ratio was not based on the empirically-derived regimens currently used for irinotecan HCl and fluoropyrimidines. Rather the ratio dependency of the antitumor effects of irinotecan and fluoropyrimidines provided the rationale for fixing these drugs in a carrier to improve on the therapeutic activity currently achieved with these combinations.
  • CPX-1 would provide an enhanced therapeutic effect in cancers that were sensitive to irinotecan and fluoropyrimidines.
  • Preclinical data in human gastrointestinal tumor cell lines in vitro and in murine colorectal cancer models in vivo demonstrated the rationale for the chosen drug to drug ratio.
  • the primary objective of this study was to determine the recommended phase II dose of CPX-1 (defined as maximum tolerated dose (MTD) in this protocol) that can be given to patients with advanced solid tumors as an infusion on an every two week schedule.
  • MTD maximum tolerated dose
  • This study also evaluated the safety and dose-limiting toxicities (DLT) of CPX-1 and the pharmacokinetic parameters of CPX-1 administered in this schedule as well as determining preliminary efficacy information of CPX-1 administered in this schedule in patients with advanced solid tumors.
  • CPX-1 (Irinotecan HCl:Floxuridine) Liposome Injection was a liposomal formulation of a fixed combination of the antineoplastic drugs irinotecan HCL trihydrate ((+)-7-ethyl-10-hydroxycamptothecine 10-(1,4′ bipiperidine)-1′-carboxylate, monohydrochloride, trihydrate) and floxuridine (2′-deoxy-5-fluorouridine) for intravenous infusion.
  • the two drugs were contained within the liposome in a 1:1 molar ratio shown to have non-antagonistic activity in preclinical studies.
  • the liposome membrane was composed of distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG) and cholesterol (CHOL) in a 7:2:1:molar ratio.
  • CPX-1 was intended for intravenous administration by slow infusion.
  • CPX-1 (Irinotecan HCl:Floxuridine) Liposome Injection was provided as a sterile, pyrogen-free, pale blue-green, opaque dispersion in single-use vials.
  • CPX-1 was stored frozen ( ⁇ 20° C.) and was thawed at room temperature for 60 minutes prior to dilution and administration. This dispersion was diluted in normal saline or dextrose for injection before intravenous administration to the patient.
  • Each single-use vial of CPX-1 (Irinotecan HCl:Floxuridine) Liposome Injection provided 25 mg of irinotecan HCl trihydrate and 9.1 mg of floxuridine.
  • Each milliliter of the thawed drug product contained the ingredients as shown in the Table below.
  • CPX-1 All doses of CPX-1 described referred to the irinotecan HCl trihydrate and the floxuridine content delivered in the CPX-1 injections.
  • CPX-1 doses can also be referred to as units of CPX-1.
  • One unit of CPX-1 contains 1 mg of irinotecan HCl trihydrate and 0.36 mg of floxuridine.
  • cytotoxic antineoplastic agents For cytotoxic antineoplastic agents, the usual starting dose for the first trial in humans was calculated on the basis of body surface area (mg/m 2 ) and was generally given as 1/10th the LD 10 in rodents (if this dose was not severely toxic in non-rodents) or 1 ⁇ 3rd the “Toxic Dose Low” (the lowest dose which produced drug-induced pathologic alterations in hematologic, chemical, clinical or morphologic parameters) in the most sensitive species if double this dose was not lethal and did not cause severe, irreversible toxicity.
  • An LD 10 for rodents was not identified for CPX-1 (Irinotecan HCl:Floxuridine) Liposome Injection.
  • CPX-1 (Irinotecan HCl:Floxuridine) Liposome Injection was 5 mg/kg irinotecan HCl (+1.8 mg/kg floxuridine) equivalent to 100 mg/m 2 irinotecan HCl. Double this dose was not lethal. From the toxicology information, the starting dose level for this phase I study was calculated to be CPX-1 33:12 mg/m 2 . Arbitrarily, for dosing convenience, the starting dose was CPX-1 30:10.9 mg/m 2 . In the study, one unit of CPX-1 contained 1 mg irinotecan and 0.36 mg floxuridine.
  • the dosing schedule of every 14 days was chosen based on (1) precedent for irinotecan (and fluoropyrimidines), (2) animal pharmacokinetics for CPX-1, and (3) desire to avoid cumulative toxicities.
  • Irinotecan schedules approved for use included irinotecan 125 mg/m 2 weekly ⁇ 4, with two weeks rest and the “European schedule” of irinotecan 300-350 mg/m 2 every three weeks (the 300 mg/m 2 dose is suggested for age >70 years or performance status of 2).
  • the FOLFIRI regimen (Tournigand, C., et al., J. Clin. Oncol . (2004): 22:229-237), another frequently used irinotecan/5-FU/leucovorin regimen, was given every two weeks with an irinotecan dose of 180 mg/m 2 .
  • Acute infusion-associated reactions e.g., flushing, shortness of breath, headache, chills, back pain, tightness in the chest and/or hypotension
  • liposomal chemotherapeutic agents Doxil®, Ortho Biotech Produces L.P. (2001), and DaunoXome®, Gilead Sciences, Inc. (2002) package inserts.
  • these reactions resolve over several hours to one day once the infusion is terminated.
  • the reaction resolves by slowing the infusion rate.
  • the following table compares the amount of lipid in several liposome products and in CPX-1. A 90 minute infusion time was chosen based on this information.
  • Lipid Usual drug Lipid Infusion infusion dose dose time rate Agent (mg/kg) (mg/kg) (hours) (mg/kg/hr) DaunoXome ® (40 mg/m 2 ) 1.03 19.23 1 19.23 Doxil ® (50 mg/m 2 ) 1.28 10.26 1 10.26 Myocet ® (60 mg/m 2 ) 1.54 5.71 1 5.71 CPX-1 3.21 25.55 1.5 16.86 Assumptions: Doxil ® recommended to start at an infusion rate of 1 mg/min and then, if tolerated, the rate is increased to infuse over one hour. Calculations are based on a 70 kg, 1.8 m 2 BSA patient. CPX-1 dose assumed above would be the 125:45.5 mg/m 2 dose.
  • Dose levels The doses of CPX-1 were not escalated in individual patients. Dose were escalated in successive cohorts according to the following dose escalation scheme, based on toxicity.
  • CPX-1 (Irinotecan HCl:Floxuridine) Liposome Injection was a liposomal formulation of a fixed ratio combination of the antineoplastic drugs irinotecan HCL trihydrate and floxuridine. The two drugs were present inside the liposome in a fixed 1:1 molar ratio.
  • the liposome membrane was composed of distearylphosphatidylcholine (DSPC), distearylphosphatidylglycerol (DSPG) and cholesterol (CHOL) in a 7:2:1 molar ratio.
  • DSPC distearylphosphatidylcholine
  • DSPG distearylphosphatidylglycerol
  • cholesterol CHOL
  • CPX-1 was provided as a sterile, pyrogen-free, pale blue-green, opaque dispersion of 5 ml in amber glass, single-use vials. Doses of CPX-1 were referred to by the Irinotecan HCl trihydrate and the Floxuridine content delivered in the CPX-1 injections. For example, a dose of 50:18 mg/m 2 CPX-1 refers to 50 mg/m 2 of irinotecan HCl trihydrate plus 18 mg/m 2 floxuridine delivered as CPX-1.
  • CPX-1 (Irinotecan HCl:Floxuridine) Liposome Injection was administered by 90 minute intravenous infusion.
  • the rationale for the length of infusion is outlined above.
  • the infusion of CPX-1 (Irinotecan HCl:Floxuridine) Liposome Injection was performed through either a peripheral or central venous catheter, using an infusion pump to ensure that the drug was infused over the specified time period.
  • Non-PVC containing administration sets, such as those that are polyethylene-lined were used. An in-line filter was not used.
  • DLT Dose Limiting Toxicity
  • Dose limiting hematologic toxicity was defined as absolute neutrophil count (ANC) ⁇ 0.5 ⁇ 10 9 /L for >7 days, febrile neutropenia (defined as ANC ⁇ 500 ⁇ 10 9 /L together with either fever >38.5 C or hospitalization for febrile neutropenia), platelet count ⁇ 25 ⁇ 10 9 /L (with or without bleeding) or grade 3 thrombocytopenia (platelets ⁇ 50 ⁇ 10 9 /L and >25 ⁇ 10 9 /L) associated with bleeding.
  • ANC absolute neutrophil count
  • MTD Maximum Tolerated Dose definition: The maximum tolerated dose (MTD) was defined as the dose at which there were fewer than one third of patients who experience a DLT, and this was the next lower dose from a cohort where a third or more experience a DLT.
  • Descriptive statistics (mean, SD, CV %, median, min, and max) were used to summarize the plasma concentration and the PK parameters for each treatment cohort.
  • Results 26 subjects (16M:10F), median age 54.5y (21-72), all with prior therapy, enrolled in 6 cohorts with the 5th cohort expanded to 6 subjects. Diagnoses: 8 colorectal, 3 pancreatic, 3 ovarian, 2 breast, 2 gastric, 2 esophageal, 2 sarcomas, 1 renal cell, 1 prostate, 1 NSCLC and 1 sphenoid sinus. Seven patients (4M:3F), median age 58Y (50-79), all with prior therapy and colorectal cancer enrolled in the extension phase of the study. See FIG. 1 .
  • the first patient was a person with colon cancer whose response lasted 4.5 months.
  • This subject presented with metastatic disease and was treated with surgical resection of the primary tumor, followed by irinotecan+oxaliplatin with shrinkage of liver metastases, attempted resection of residual liver lesions with discovery of persistent lymph node disease, and finally with capecitabine, all administered before entry into the Phase I study.
  • This patient responded in spite of prior exposure to fluoropyrimidine and irinotecan.
  • the second patient had non-small cell lung cancer and responded for 3.0 months.
  • This patient had received prior docetaxel, cisplatin, etoposide, and gefitinib.
  • This type of cancer is traditionally not treated with fluoropyrimidines but may respond to irinotecan.
  • DLTs were observed at the 6th dose level: 4 subjects with DLTs: 3 diarrhea (one resulting in death due to dehydration/ARF) and one neutropenia. Other possibly related grade 3 and 4 events included one each of: grade 3 diarrhea, grade 3 vomiting, grade 3 neutropenia, grade 3 fatigue, grade 3 compression fracture and arthralgia and pulmonary embolism grade 4.
  • PK The pharmacokinetic analysis is shown in FIG. 2 . In all 26 subjects analyzed to date, the 1:1 molar ratio of IRI to FLOX was maintained for 24 hours and metabolites 5-FU and SN-38 were present in the plasma. Below the results from the clinical trial were compared with published data from previous clinical trials.
  • CPX1 represents a new approach to developing drug combinations in which drug ratios were pre-selected in vitro based on optimal antitumor activity and maintained systemically throughout pharmacokinetic control. Phase 2 studies are planned with a recommended dose of 210 units(U)/m 2 of CPX-1.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
US12/091,738 2005-10-25 2006-10-25 Fixed ratio drug combination treatments for solid tumors Abandoned US20100189771A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/091,738 US20100189771A1 (en) 2005-10-25 2006-10-25 Fixed ratio drug combination treatments for solid tumors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US73019905P 2005-10-25 2005-10-25
US75922506P 2006-01-12 2006-01-12
US12/091,738 US20100189771A1 (en) 2005-10-25 2006-10-25 Fixed ratio drug combination treatments for solid tumors
PCT/US2006/041832 WO2007050784A2 (fr) 2005-10-25 2006-10-25 Traitement a base de combinaisons de medicaments a rapport fixe pour le traitement de tumeurs solides

Publications (1)

Publication Number Publication Date
US20100189771A1 true US20100189771A1 (en) 2010-07-29

Family

ID=37882130

Family Applications (2)

Application Number Title Priority Date Filing Date
US12/091,738 Abandoned US20100189771A1 (en) 2005-10-25 2006-10-25 Fixed ratio drug combination treatments for solid tumors
US11/586,215 Active 2029-03-31 US7842676B2 (en) 2005-10-25 2006-10-25 Fixed ratio drug combination treatments for solid tumors

Family Applications After (1)

Application Number Title Priority Date Filing Date
US11/586,215 Active 2029-03-31 US7842676B2 (en) 2005-10-25 2006-10-25 Fixed ratio drug combination treatments for solid tumors

Country Status (7)

Country Link
US (2) US20100189771A1 (fr)
EP (1) EP1951239A2 (fr)
JP (1) JP5687411B2 (fr)
AU (1) AU2006306108B2 (fr)
CA (1) CA2628015C (fr)
IL (1) IL191040A (fr)
WO (1) WO2007050784A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10907214B2 (en) 2016-12-30 2021-02-02 Oncology Venture ApS Methods for predicting drug responsiveness in cancer patients
US11173178B2 (en) 2008-05-23 2021-11-16 Liplasome Pharma Aps Liposomes for drug delivery and methods for preparation thereof
US11207269B2 (en) * 2009-09-17 2021-12-28 Bio-Bedst Aps Medical use of sPLA2 hydrolysable liposomes

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101376895B1 (ko) 2004-05-03 2014-03-25 헤르메스 바이오사이언스, 인코포레이티드 약물 전달에 유용한 리포좀
WO2012088414A1 (fr) 2010-12-23 2012-06-28 Ludwig Institute For Cancer Research Ltd. Formulation liposomale de céramides non-glycosidiques et leurs utilisations
BR112014009305B1 (pt) 2011-10-21 2023-01-24 Celator Pharmaceuticals Inc. Composição lipossomal de fase gel liofilizada
US9717724B2 (en) 2012-06-13 2017-08-01 Ipsen Biopharm Ltd. Methods for treating pancreatic cancer using combination therapies
AU2013202947B2 (en) 2012-06-13 2016-06-02 Ipsen Biopharm Ltd. Methods for treating pancreatic cancer using combination therapies comprising liposomal irinotecan
EP3028933A1 (fr) * 2014-12-05 2016-06-08 Öhlins Racing Ab Unité de ressort
US11318131B2 (en) 2015-05-18 2022-05-03 Ipsen Biopharm Ltd. Nanoliposomal irinotecan for use in treating small cell lung cancer
CA2992789A1 (fr) 2015-08-20 2017-02-23 Ipsen Biopharm Ltd. Traitement combine utilisant l'irinotecan liposomal et un inhibiteur de parp pour un traitement anticancereux
EP3791876A1 (fr) 2015-08-21 2021-03-17 Ipsen Biopharm Ltd. Méthodes permettant de traiter le cancer du pancréas métastatique au moyen de traitements d'association comprenant de l'irinotécan liposomal et de l'oxaliplatine
MX2018004328A (es) 2015-10-16 2018-08-01 Ipsen Biopharm Ltd Composiciones farmaceuticas estabilizantes de camptotecina.
CN107281102A (zh) * 2016-04-11 2017-10-24 江苏竞诺择生物医药科技有限公司 一种用于结直肠肿瘤治疗的药物微粒组合物
US11986451B1 (en) 2016-07-22 2024-05-21 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11602512B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11602513B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
UY37341A (es) 2016-07-22 2017-11-30 Flamel Ireland Ltd Formulaciones de gamma-hidroxibutirato de liberación modificada con farmacocinética mejorada
US11504347B1 (en) 2016-07-22 2022-11-22 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
SG11201903615WA (en) 2016-11-02 2019-05-30 Ipsen Biopharm Ltd Treating gastric cancer using combination therapies comprising liposomal irinotecan, oxaliplatin, 5-fluoruracil (and leucovorin)
CN113473980A (zh) 2019-03-01 2021-10-01 弗拉梅尔爱尔兰有限公司 在进食状态下具有改善的药代动力学的γ-羟基丁酸酯组合物
US11980636B2 (en) 2020-11-18 2024-05-14 Jazz Pharmaceuticals Ireland Limited Treatment of hematological disorders
US11779557B1 (en) 2022-02-07 2023-10-10 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11583510B1 (en) 2022-02-07 2023-02-21 Flamel Ireland Limited Methods of administering gamma hydroxybutyrate formulations after a high-fat meal

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4778679B2 (ja) * 2001-10-03 2011-09-21 セレーター ファーマシューティカルズ インコーポレイテッド 併用薬剤を送達するための組成物
US20040265368A1 (en) * 2003-04-02 2004-12-30 Lawrence Mayer Combination compositions of camptothecins and fluoropyrimidines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Cancer Classification" [retrieved on 11 December 2008] [online] Retrieved from *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11173178B2 (en) 2008-05-23 2021-11-16 Liplasome Pharma Aps Liposomes for drug delivery and methods for preparation thereof
US11207269B2 (en) * 2009-09-17 2021-12-28 Bio-Bedst Aps Medical use of sPLA2 hydrolysable liposomes
US10907214B2 (en) 2016-12-30 2021-02-02 Oncology Venture ApS Methods for predicting drug responsiveness in cancer patients

Also Published As

Publication number Publication date
WO2007050784A2 (fr) 2007-05-03
CA2628015A1 (fr) 2007-05-03
AU2006306108A1 (en) 2007-05-03
EP1951239A2 (fr) 2008-08-06
US7842676B2 (en) 2010-11-30
IL191040A0 (en) 2009-08-03
JP5687411B2 (ja) 2015-03-18
AU2006306108B2 (en) 2012-10-04
WO2007050784A3 (fr) 2007-06-14
CA2628015C (fr) 2016-02-23
JP2009513662A (ja) 2009-04-02
IL191040A (en) 2012-06-28
US20090023680A1 (en) 2009-01-22

Similar Documents

Publication Publication Date Title
US7842676B2 (en) Fixed ratio drug combination treatments for solid tumors
JP6857210B2 (ja) リポソームイリノテカンを含む併用療法を用いた、膵臓癌を治療するための方法
Ardizzoni et al. Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group.
AU2017354903B2 (en) Treating gastric cancer using combination therapies comprising liposomal irinotecan, oxaliplatin, 5-fluoruracil (and leucovorin)
US20180271787A1 (en) Combination methods and compositions
KR101434009B1 (ko) 4-아닐리노-3-사이아노퀴놀린과 카페시타빈의 항신생물성 조합물
US20110052580A1 (en) Use of picoplatin and bevacizumab to treat colorectal cancer
TW201701880A (zh) 改善持續釋放藥物治療之藥物動力學及治療指數之方法
Gelmon et al. A phase 1 study of OSI-211 given as an intravenous infusion days 1, 2, and 3 every three weeks in patients with solid cancers
US8168661B2 (en) Use of picoplatin to treat colorectal cancer
US20130338129A1 (en) Method of treating refractory cancer
US8168662B1 (en) Use of picoplatin to treat colorectal cancer
US20200390702A1 (en) Liposomal taxanes for treatment of sclc
KR20100042549A (ko) 병용 방법 및 조성물
AU2022326184A1 (en) Combination therapy for the treatment of pan-kras mutated cancers
RU2808427C2 (ru) Способы лечения рака поджелудочной железы с применением комбинированной терапии, включающей липосомальный иринотекан
CA3240993A1 (fr) Inhibiteur de cdk4 pour le traitement du cancer
KR20050116166A (ko) 이리노테칸의 저항성 유방암 치료용 용도
KR20160017660A (ko) 병용 방법 및 조성물
CN101330917A (zh) 固定比率的联合用药治疗实体瘤
US20120156199A1 (en) Use of picoplatin to treat colorectal cancer

Legal Events

Date Code Title Description
AS Assignment

Owner name: CELATOR PHARMACEUTICALS, INC., NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:JANOFF, ANDREW;MAYER, LAWRENCE;SWENSON, CHRISTINE;SIGNING DATES FROM 20091005 TO 20091022;REEL/FRAME:023490/0111

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION