WO2015134548A1 - Méthodes pour déterminer la réponse maximale susceptible d'être atteinte pour un agent de traitement du cancer - Google Patents

Méthodes pour déterminer la réponse maximale susceptible d'être atteinte pour un agent de traitement du cancer Download PDF

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WO2015134548A1
WO2015134548A1 PCT/US2015/018551 US2015018551W WO2015134548A1 WO 2015134548 A1 WO2015134548 A1 WO 2015134548A1 US 2015018551 W US2015018551 W US 2015018551W WO 2015134548 A1 WO2015134548 A1 WO 2015134548A1
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cycles
dose
paclitaxel
cancer
response rate
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PCT/US2015/018551
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Vuong Trieu
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Sorrento Therapeutics, Inc.
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to methods for determining the maximum achievable response for cancer treatment agents.
  • Taxanes are highly active chemotherapeutic agents in the treatment of breast cancer. Being hydrophobic, taxanes require solvents (Cremphor EL or polysorbate) to enable parenteral administration. These solvents contribute to the main toxicities seen with taxanes (hypersensitivity, peripheral neuropathy, and myelo-suppression). Cremophor EL can also leach plasticizers from polyvinyl chloride tubing, which can result in severe, sometimes fatal, anaphylactic reactions. To prevent or limit the onset of hypersensitivity reactions, corticosteroids and antihistamines are standard premedication with taxanes.
  • Cremophor EL entraps paclitaxel into circulating micelles, which reduces its availability and delivery into tumors.
  • Micelle formation with solvent-based paclitaxel results in nonlinear kinetics and the absence of a dose-response relationship: increasing the dose increases toxicity without an accompanying enhancement in efficacy.
  • Abraxane is the drug of choice in first and second line of treatment in metastatic breast cancer and is approved in majority of markets. Dose-limiting side effects of Abraxane include dose-dependent bone marrow suppression (primarily neutropenia). In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC) and 47% of patients with non-small cell lung cancer (NSCLC). Abraxane also requires tedious reconstitution which may cause foaming or clumping of the reconstituted lyophilized powder.
  • MBC metastatic breast cancer
  • NSCLC non-small cell lung cancer
  • cytotoxic drug compositions that are useful in the treatment of various cancers there exists a need for methods of treatment and drug administration that reduce side effects, have improved drug stability and/or increase the efficacy of the treatment regimen.
  • cytotoxic drug compositions that can be administered at higher doses and with increased activity, especially for cancers that are resistant to current treatment regimens.
  • the present invention relates to compositions comprising cancer drugs in a micelle or nanoparticle wherein the composition is stable in protein-free medium, and less stable or unstable in a protein containing medium and where the composition does not contain albumin.
  • the present invention relates to paclitaxel compositions wherein the paclitaxel is contained within a micelle or nanoparticle which is stable in protein-free medium and unstable in a protein containing medium.
  • the present invention also relates to methods of treating cancer patients such that the dosage, treatment schedule and number of cycles of the treatment schedule provide an overall response rate greater than at least 40%, or at least 50% or at least 60%.
  • the present invention relates to methods for determining the maximum achievable response for an anticancer agent.
  • the methods of the present invention include administer to cancer patients a cancer treatment agent utilizing a specific treatment regimen where the regimen is repeated for a predetermined number of cycles and then the overall response rate for the patients is measured and the results of the overall response rate is plotted versus the number of cycles of the treatment regimen. Once plotted it is possible to determine the point at which the overall response rate plateaus thus determining the maximum achievable response rate for a given cancer treatment agent.
  • the determination of the maximum achievable response rate for a given cancer treatment agent enables optimization of dosing, treatment regimen and cycles of treatment regimen.
  • the methods of the present invention enabled the unexpected finding of maximum achievable response for paclitaxel beyond which no further increase in dose or frequency of dosing can improve on the response.
  • the method was applied to micellar nanoparticle containing paclitaxel.
  • the methods of the present invention indicate that the maximum achievable response for paclitaxel is at 60%-80% and can be shown by plotting response versus cycle treated.
  • the methods of the present invention that treatment regimens resulting in responses lower than 60-80% can be optimized improved by using dose dense regimen that is, more frequent (weekly) dosing or by increasing the dose of the cancer treatment agent.
  • the methods of the present invention provide for doses between 50mg/m 2 to about 1000 mg/m 2 .
  • the methods of the present invention provide dosing schedules that include but are not limited to 21-day 24-hour continuous intravenous (c.i.v.), 3-day i.v. bolus, weekly 72-hour c.i.v., weekly 24-hour c.i.v., and weekly bolus i.v. regimens.
  • the present invention relates to methods of treating cancer where the paclitaxel containing micelles are administered from 2 cycles to 100 cycles of the treatment regimen.
  • FIG. 1 Plot of Overall Response Rate (ORR) of phase 3 data for IG-001 (interim), Abraxane, and Tocosol.
  • ORR Overall Response Rate
  • FIG. 3 Plot of preclinical demonstration of maximum achievable response for Abraxane and Tocosol.
  • MDA-MB-435 tumor xenograft were treated with Abraxane or Tocosol on Q3Dx5 schedule. Both Tocosol and Abraxane were equally effective.
  • Significant antitumor activity was observed at 20 mg/kg dose.
  • Significant gain in activity was observed when the dose was increased to 30 mg/kg.
  • no further gain was observed going from 30 mg/kg to 40 mg/kg. 05.
  • Figure 4A Plot of overall response rate (ORR) versus cycles of treatment for IG-002/Tocosol-Pac.
  • Figure 4B Plot of overall response rate (ORR) versus cycles of treatment for Taxol/Crem-Pac.
  • Figure 4C Plot of overall response rate (ORR) versus cycles of treatment for IG-001.
  • the present invention relates to compositions comprising cancer drugs in a micelle or nanoparticle wherein the composition is stable in protein-free medium, and less stable or unstable in a protein containing medium and where the composition does not contain albumin.
  • the present invention relates to paclitaxel compositions wherein the paclitaxel is contained within a micelle or nanoparticle which is stable in protein-free medium and unstable in a protein containing medium.
  • the present invention relates to methods for determining the maximum achievable response for an anticancer agent.
  • the methods of the present invention include administer to cancer patients a cancer treatment agent utilizing a specific treatment regimen where the regimen is repeated for a predetermined number of cycles and then the overall response rate for the patients is measured and the results of the overall response rate is plotted versus the number of cycles of the treatment regimen. Once plotted it is possible to determine the point at which the overall response rate plateaus thus determining the maximum achievable response rate for a given cancer treatment agent.
  • a specific cancer treatment agent such as paclitaxel, may be selected for determination of the maximum achievable response.
  • the composition of the paclitaxel to be delivered eg.
  • the dose of paclitaxel to be delivered e.g. 300 mg/m 2
  • the treatment regimen of paclitaxel delivery to patients weekly
  • the cycles of the treatment regimen e.g. 5, 10, 15 and 20 cycles
  • the patients are treated with the paclitaxel in the predetermined manner and the overall response rate is determined for the patient population.
  • the overall response rate is plotted against the cycles of treatment and the maximum achievable response for the paclitaxel can be determined as the overall response rate at the point the plot curve plateaus. If the curve does not plateau then the maximum achievable response has not been achieved for this set of parameters.
  • the determination of the maximum achievable response rate for a given cancer treatment agent enables optimization of dosing, treatment regimen and cycles of treatment regimen.
  • the methods of the present invention enabled the unexpected finding of maximum achievable response for paclitaxel beyond which no further increase in dose or frequency of dosing can improve on the response.
  • the method was applied to micellar nanoparticle containing paclitaxel.
  • the methods of the present invention indicate that the maximum achievable response for paclitaxel is at 60%-80% and can be shown by plotting response versus cycle treated.
  • the methods of the present invention that treatment regimens resulting in responses lower than 60-80% can be optimized improved by using dose dense regimen that is, more frequent (weekly) dosing or by increasing the dose of the cancer treatment agent.
  • Cancer treatment agent used in the compositions and formulations and methods of the present include but are not limited to paclitaxel, docetaxel, 7-epipaclitaxel, t-acetyl paclitaxel, 10-desacetyl- paclitaxel, 10-desacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, 10-desacetyl-7-glutarylpaclitaxel, 7-N,N- dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel carboplatin, cisplatin, cyclophosphamide, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, methotrexate, topotecan, vincristine and vinblastine.
  • compositions and methods of the present invention may be used in conjunction with the treatment of a variety of cancer including but not limited to breast, ovarian, pancreatic, liver, bladder, prostate, esophageal, lung and melanoma cancers.
  • the present invention relates to method of treating cancer wherein the amount of cancer treating agent administered is from about 50mg/m 2 to about 1000 mg/m 2 , or from about 50mg/m 2 to about 900 mg/m 2 , or from about 50 mg/m 2 to about 800 mg/m 2 , or from about 50mg/m 2 to about 700 mg/m , or from about 50 mg/m to about 600 mg/m , from about 50mg/m to about 500 mg/m , or
  • 75mg/m to about 500 mg/m or 75mg/m to about 400 mg/m or from about 75mg/m to about 300 mg/m or from about 75mg/m to about 200 mg/m or from about 75mg/m to about 100 mg/m or from about 100 mg/m 2 to about 1000 mg/m 2 , or from about 100mg/m 2 to about 900 mg/m 2 , or from about 100 mg/m 2 to about 800 mg/m 2 , or from about 100mg/m 2 to about 700 mg/m 2 , or from about 100 mg/m to about 600 mg/m , from about lOOmg/m to about 500 mg/m , or from about lOOmg/m to about 400 mg/m 2 or from about 100mg/m 2 to about 300 mg/m 2 or from about 100mg/m 2 to about 200 mg/m or from about 150mg/m to about 1000 mg/m or from about 150mg/m to about 900 mg/m , or from about 150mg
  • 250mg/m to about 500 mg/m or 250mg/m to about 400 mg/m or from about 250mg/m to about 300 mg/m 2 or from about 300mg/m 2 to about 1000 mg/m 2 or from about 300mg/m 2 to about 900 mg/m or from about 300mg/m to about 800 mg/m , or from about 300mg/m to about 700 mg/m , or from about 300 mg/m to about 600 mg/m , from about 300mg/m to about 500 mg/m , or 300mg/m to about 400 mg/m 2 or from about 400mg/m 2 to about 1000 mg/m 2 or from about 400mg/m 2 to about
  • the present invention relates to method of treating cancer wherein the amount of paclitaxel administered is at least 190mg/m 2 or at least 220 mg/m 2 or at least 260mg/m 2 or at least 300 mg/m 2 .
  • the present invention relates to method of treating cancer wherein the amount of paclitaxel administered is from about
  • the present invention relates to methods of treating cancer by administering cancer treating agents utilizing dosing schedules including but not limited to the 21-day 24-hour continuous intravenous (c.i.v.), the 3-day i.v. bolus, the weekly 72-hour c.i.v., the weekly 24-hour c.i.v., and the weekly bolus i.v. regimens.
  • dosing schedules including but not limited to the 21-day 24-hour continuous intravenous (c.i.v.), the 3-day i.v. bolus, the weekly 72-hour c.i.v., the weekly 24-hour c.i.v., and the weekly bolus i.v. regimens.
  • the present invention relates to methods of treating cancer where the paclitaxel containing micelles are administered in at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 7, or at least 8, or at least 9, or at least 10, or at least 15, or at least 20, or at least 25, or at least 30 cycles, or at least 40, or at least 50 cycles of the dosing schedule.
  • the present invention relates to methods of treating cancer where the cancer treating agents are administered from 2 cycles to 100 cycles, or from 2 to 90 cycles, or from 2 to 80 cycles, or from 2 to 70 cycles, or from 2 to 60 cycles, from 2 to 50 cycles, or from 2 to 40 cycles, or from 2 to 30 cycles, or from 2 to 20 cycles, or from 2 to 10 cycles, or from 3 cycles to 100 cycles, or from 3 to 90 cycles, or from 3 to 80 cycles, or from 3 to 70 cycles, or from 3 to 60 cycles, from 3 to 50 cycles, or from 3 to 40 cycles, or from 3 to 30 cycles, or from 3 to 20 cycles, or from 3 to 10 cycles or from 4 cycles to 100 cycles, or from 4 to 90 cycles, or from 4 to 80 cycles, or from 4 to 70 cycles, or from 4 to 60 cycles, from 4 to 50 cycles, or from 4 to 40 cycles, or from 4 to 30 cycles, or from 4 to 20 cycles, or from 4 to 10 cycles, or from 5 cycles to 100 cycles, or from 5 to 90 cycles, or from 5 to 80 cycles, or from 5 to 70 cycles,
  • the present invention relates to methods of treating cancer where the paclitaxel containing micelles are administered from 3 cycles to 15 cycles.
  • the present invention relates to method of treating cancer where the paclitaxel containing micelles are administered from 3 cycles to 10 cycles.
  • the present invention relates to method of treating cancer where the paclitaxel containing micelles are administered from 5 cycles to 10 cycles.
  • the present invention relates to method of treating cancer where the overall response rate is greater than 20% or greater than 30% or greater than 40% or greater than 50% or from between about 20% to about 90% or from about 25% to about 75% or from about 30% to about 60% or from 30% to about 50% or from about 30% to about 40%.
  • the present invention relates to method of treating cancer by administering paclitaxel containing micelles to the patient at least twice such that there is a first dose and a second dose.
  • the present invention relates to method of treating cancer by administering paclitaxel containing micelles to the patient at least twice such that there is a first dose and a second dose where the first dose is about the same as the second dose, or where the first dose and the second dose comprise differing amounts of paclitaxel.
  • the present invention relates to method of treating patients with cancer comprising administering paclitaxel containing micelles to the patient comprising administering a dose of paclitaxel containing micelles containing about 300 mg/m 2 to about 435 mg/m 2 pacitaxel for at least one cycle.
  • the present invention also relates to methods of treating patients with cancer comprising administering a one or more doses of paclitaxel containing micelles and other cancer treatment agents.
  • Other cancer treating agent include but are not limited to gemcitabine, cisplatin, carboplatin, erlotinib, and capecitabine or combinations thereof.
  • the methods of the present invention relates to methods of treating patients with cancer comprising administering a one or more doses of paclitaxel containing micelles and other cancer treating agents including gemcitabine wherein the amount of paclitaxel administered is at least 200 mg/m 2 and the amount of gemcitabine is about 1250 mg/m 2 .
  • the methods of the present invention relates to methods of treating patients with cancer comprising administering a one or more doses of paclitaxel containing micelles and gemcitabine wherein the amount of paclitaxel administered is between about 220 mg/m 2 to about 300 mg/m 2 and the amount of gemcitabine is from about 800 mg/m 2 to about 1400 mg/m 2 , or from about 900 mg/m 2 to about 1400 mg/m 2 , or from about 1000 mg/m 2 to about 1400 mg/m 2 ,or from about 1100 mg/m 2 to about 1400 mg/m 2 , or from about 1200 mg/m 2 to about 1400 mg/m 2 , or from about 1300 mg/m 2 to about 1400 mg/m 2 .
  • the amount of gemcitabine is administered per dose is about 1250 mg/m 2 .
  • the cancer treatment agent used in conjunction with the paclitaxel micelles may be administered in the same or different regimen as the paclitaxel containing micelles.
  • the cancer treatment agent, such as gemcitabine may be administered weekly or at any other dosing interval that is appropriate.
  • the invention relates to method of defining the maximum achievable response by plotting the response versus cycle and determining the plateau as maximum responses.
  • the invention also relates to methods to increase the ORR to achieve the maximum response by either increasing the dose or by increasing the frequency of the dose.
  • the micelle compositions of the present invention include amphiphilic block copolymers which may contain a hydrophilic block (A) and a hydrophobic block (B) linked with each other in the form of an A-B, A-B-A, or B-A-B structure.
  • the amphiphilic block copolymer may form core-shell type polymeric micelles in its aqueous solution state, wherein the hydrophobic block forms the core and the hydrophilic block forms the shell.
  • the hydrophilic block (A) of the amphiphilic copolymer may be polyethylene glycol (PEG) or monomethoxypolyethylene glycol (MPEG).
  • the hydrophilic block (A) may have an average molecular weight of about 500-20,000 daltons, or between about 1,000 to about 5,000 daltons or about 1,000-2,500 daltons.
  • the hydrophobic block (B) of the amphiphilic copolymer may be a water-insoluble, biodegradable polymer.
  • the hydrophobic block (B) of the amphiphilic copolymer may be polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA).
  • the hydrophobic block (B) may have an average molecular weight of about 500-20,000 daltons, or between about 1,000 to about 5,000 daltons or about 1,000-2,500 daltons. Hydroxyl end groups of the hydrophobic block (B) may be protected by fatty acid groups including but not limited to acetate, propionate, butyrate, stearate, palmitate groups and the like.
  • the amphiphilic block copolymer comprising the hydrophilic block (A) and the hydrophobic block (B) may be present in the composition in an amount of about 20-98 wt%, or from about 65-98 wt% or from about 80-98 wt% based on the total dry weight of the composition.
  • the amphiphilic block copolymer comprising the hydrophilic block (A) and the hydrophobic block (B) may be composed such that the hydrophilic block (A) comprises about 40-70% of the block copolymer. In other embodiments the hydrophilic block (A) comprises about 50-60% of the block copolymer.
  • the hydrophilic block (A) When the hydrophilic block (A) is present in a proportion less than 40% of the block copolymer the polymer has undesirably low solubility in water, resulting in difficult formation of micelles. When the hydrophilic block (A) is present in a proportion greater than 70% of the block copolymer the polymer becomes too hydrophilic to form stable polymeric micelles and thus a less effective composition for solubilizing less soluble active drug compounds such as taxane.
  • a preferred paclitaxel formulation is IG-001 (also referred to as Genexol-PM and CynviloqTM) which is a Cremphor-free, polymeric micelle formulation of paclitaxel which utilizes a biodegradable block co-polymer comprised of methoxy poly (ethylene glycol) poly lactide to form nanoparticles with a paclitaxel containing hydrophobic core and a hydrophilic shell.
  • the micellar composition may be made by dissolving an amphipathic co-polymer, monomethoxypolyethylene glycol-polylactide with an average molecular weight of 1766-2000 dalton at 80°C in ethanol.
  • Paclitaxel is added to the dissolved copolymer and the solution cooled to about 50°C where room temperature water is added. Anhydrous lactose may be added and dissolved. The solution may then be filtered and lyophilized.
  • IG-002 Another paclitaxel formulation is IG-002
  • IG-002/Tocosof-Paclitaxel is a Cremophor-free, vitamin E- based paclitaxel emulsion incorporating a P-glycoprotein (Pgp) inhibitor and particle size-based tumor targeting.
  • Pgp P-glycoprotein
  • IG-002 was developed to overcome a number of the limitations of the commercially available formulation of paclitaxel. Potential advantages as a result of elimination of the Cremophor/ethanol delivery vehicle include the ability to bolus dose the emulsion in 15 minutes or less and passive tumor targeting as a result of 200 nm emulsion particles being preferentially deposited in the tumor by the enhanced permeability and retention effect.
  • the nanoparticle contains three components:
  • the inner core consists of lipophilic material; d, l-alpha tocopherol.
  • d lipophilic material
  • d l-alpha tocopherol
  • TPGS alphatocopherol polyethylene glycol succinate
  • compositions of the present invention can be administered alone or as admixtures with conventional excipients, for example, pharmaceutically, or physiologically, acceptable organic, or inorganic carrier substances suitable for enteral or parenteral application which do not deleteriously react with the composition.
  • suitable pharmaceutically acceptable carriers indue water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, and polyvinyl pyrolidine.
  • compositions administered to the human can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring and/or aromatic substances and the like which do not deleteriously react with the compositions administered to the human.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring and/or aromatic substances and the like which do not deleteriously react with the compositions administered to the human.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring and/or aromatic substances and the like which do not deleteriously react with the compositions administered to the human.
  • the composition of the invention can be in any suitable dosage form or formulation, (
  • Pharmaceutically acceptable salts of the agents discussed herein include metal salts, such as sodium salt, potassium salt, cesium salt, and the like; alkaline earth metals, such as calcium salt, magnesium salt, and the like; organic amine salts, such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, ⁇ , ⁇ '-dibenzylethylenediamine salt, and the like; inorganic acid salts, such as hyd rochloride, hydrobromide, sulfate, phosphate, and the like; organic acid salts, such as formate, acetate, trifluoroacetate, maleate, tartrate, and the like; sulfonates, such as methanesulfonate, benzenesu lfonate, p-toluenesulfonate, and the like; amino acid salts, such as arginate, asparginate, glutamate
  • a Phase I II, multicenter, randomized comparison of the safety and efficacy of weekly TOCOSOL ® Paclitaxel (100 mg/m 2 ) vs. weekly Paclitaxel Injection (80 mg/m 2 ) in the treatment of metastatic breast cancer (M BC) was conducted.
  • the primary endpoint was to compare the objective response rates (ORR) as assessed by RECIST in patients with M BC treated with weekly TOCOSOL Paclitaxel or weekly Taxol as first-line or second-line therapy.
  • M BC patients (1050) were screened and a total of 821 were randomized to receive either IG-002 (100 mg/m 2 weekly, IV) or Crem-Pac (80 mg/m 2 weekly, IV) u ntil disease progression.
  • IG-001 phase 4 trial and two phase 2 trials in M BC were used as benchmark for q3w dosing (300 mg/m 2 q3w, IV). There were a total of 243 patients in the IG-001 group. Best overall response rates (ORR) were compared vs. cycle and used to assess clinical effectiveness. Diagnosis and main exclusion criteria included female patients with histologic diagnosis of metastatic (stage IV [M l] ) breast cancer, with no more than one cytotoxic chemotherapy regimen for treatment of M BC.
  • stage IV [M l] stage IV
  • a chemotherapy regimen was defined as a minimu m of two consecutive cycles of chemotherapy, preferably with a regimen that included an anthracycline (number of patients randomized who had not been exposed to anthracycline therapy was targeted to not exceed 25% of randomized patients).
  • Tocosol-Pac Taxol Total was defined as a minimu m of two consecutive cycles of chemotherapy, preferably with a regimen that included an anthracycline (number of patients randomized who had not been exposed to anthracycline therapy was targeted to not exceed 25% of randomized patients).
  • ORR The primary endpoint of adjudicated ORR was 44.7% for Crem-Pac and 37.4 % for IG-002.
  • cycle of treatment significantly correlated with ORR.
  • ORR steadily increased with cycle number reaching maximum median at 40% for IG-001-Pac and 60% for IG-002 and Crem-Pac.
  • the IG-001 results are similar to the reported phase 3 nab-Pac registration trial conducted in MBC against Crem-Pac on q3w dosing, where nab-Pac was found to be more effective.
  • the IG-002 results are similar to a recent trial comparing nab-Pac vs. Crem-Pac on weekly schedule where nab-Pac was found to be no better than Crem-Pac.
  • the discordance of the two trials was reflected in the IG-001 and IG-002 data and can be explained by the underlying improved efficacy of the weekly schedule vs. the q3w schedule. Therefore, the more frequent dose regimen is more effective.
  • ORR did not hit its maximum; therefore increasing the dose did result in a therapeutic gain as shown by a doubling of ORR.
  • ORR was already at maximum and therefore increasing the dose did not result in a therapeutic gain. Therefore for paclitaxel treatment that did not achieved maximum responses, the dosing can be increased to achieve an improved response
  • any indication that a feature is optional is intended provide adequate support (e.g., under 35 U.S.C. 112 or Art. 83 and 84 of EPC) for claims that include closed or exclusive or negative language with reference to the optional feature.
  • Exclusive language specifically excludes the particular recited feature from including any additional subject matter. For example, if it is indicated that A can be drug X, such language is intended to provide support for a claim that explicitly specifies that A consists of X alone, or that A does not include any other drugs besides X.
  • Non-limiting examples of exclusive or negative terms include “only,” “solely,” “consisting of,” “consisting essentially of,” “alone,” “without”, “in the absence of (e.g., other items of the same type, structure and/or function)" "excluding,” “not including", “not", “cannot,” or any combination and/or variation of such language.
  • a dog is intended to include support for one dog, no more than one dog, at least one dog, a plurality of dogs, etc.
  • qualifying terms that indicate singularity include “a single”, “one,” “alone”, “only one,” “not more than one”, etc.
  • qualifying terms that indicate (potential or actual) plurality include “at least one,” “one or more,” “more than one,” “two or more,” “a multiplicity,” “a plurality,” “any combination of,” “any permutation of,” “any one or more of,” etc.

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Abstract

La présente invention concerne des méthodes permettant de déterminer la réponse maximale susceptible d'être atteinte pour des agents de traitement du cancer.
PCT/US2015/018551 2014-03-05 2015-03-03 Méthodes pour déterminer la réponse maximale susceptible d'être atteinte pour un agent de traitement du cancer WO2015134548A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010018919A1 (en) * 1999-07-06 2001-09-06 Kutzko John D. Method, apparatus and system for use in treating patient with a drug having an antineoplastic effect to optimize therapy and prevent an adverse drug response
EP2036988A1 (fr) * 2007-09-12 2009-03-18 Siemens Healthcare Diagnostics GmbH Procédé de prédiction d'une réponse à une tumeur chez un patient souffrant ou risquant de développer un cancer gynécologique récurrent vers un agent chimiothérapique
US20100317001A1 (en) * 2007-09-05 2010-12-16 Laurentian University Method of using tumour rna integrity to measure response to chemotherapy in cancer patients
US20120252748A1 (en) * 2011-03-28 2012-10-04 New York University Methods and compositions for determining the responsiveness of cancer therapeutics
US20130281312A1 (en) * 2010-08-24 2013-10-24 Dana-Farber Cancer Institute, Inc. Methods for predicting anti-cancer response

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010018919A1 (en) * 1999-07-06 2001-09-06 Kutzko John D. Method, apparatus and system for use in treating patient with a drug having an antineoplastic effect to optimize therapy and prevent an adverse drug response
US20100317001A1 (en) * 2007-09-05 2010-12-16 Laurentian University Method of using tumour rna integrity to measure response to chemotherapy in cancer patients
EP2036988A1 (fr) * 2007-09-12 2009-03-18 Siemens Healthcare Diagnostics GmbH Procédé de prédiction d'une réponse à une tumeur chez un patient souffrant ou risquant de développer un cancer gynécologique récurrent vers un agent chimiothérapique
US20130281312A1 (en) * 2010-08-24 2013-10-24 Dana-Farber Cancer Institute, Inc. Methods for predicting anti-cancer response
US20120252748A1 (en) * 2011-03-28 2012-10-04 New York University Methods and compositions for determining the responsiveness of cancer therapeutics

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