US20160256529A1 - Combination therapy - Google Patents

Combination therapy Download PDF

Info

Publication number
US20160256529A1
US20160256529A1 US15/063,227 US201615063227A US2016256529A1 US 20160256529 A1 US20160256529 A1 US 20160256529A1 US 201615063227 A US201615063227 A US 201615063227A US 2016256529 A1 US2016256529 A1 US 2016256529A1
Authority
US
United States
Prior art keywords
compound
bid
peginterferon alfa
group
day
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
US15/063,227
Inventor
Kapil Dhingra
Brian Higgins
Kenneth Kolinsky
Richard J. Lee
Brian Lestini
Kathryn Packman
Fei Su
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.)
Hoffmann La Roche Inc
Original Assignee
Hoffmann La Roche 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 Hoffmann La Roche Inc filed Critical Hoffmann La Roche Inc
Priority to US15/063,227 priority Critical patent/US20160256529A1/en
Publication of US20160256529A1 publication Critical patent/US20160256529A1/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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • 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
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a combination therapy for treating a patient suffering from a proliferative disorder, in particular a solid tumor, for example, colorectal cancer, melanoma, and thyroid cancer, comprising administering to the patient propane-1-sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-1H-pyrrolo [2,3-b] pyridine-3-carbonyl]-2,4-difluoro-phenyl ⁇ -amide and an interferon.
  • a proliferative disorder in particular a solid tumor, for example, colorectal cancer, melanoma, and thyroid cancer
  • b-Raf Normally functioning b-Raf is a kinase which is involved in the relay of signals from the cell membrane to the nucleus and is active only when it is needed to relay such signals. Mutant b-Raf containing a V600E mutation, however, is constantly active and thus plays a role in tumor development. Such mutant b-Raf has been implicated in various tumors, for example, colorectal cancer, melanoma, and thyroid cancer.
  • Propane-1-sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-1H-pyrrolo [2,3-b] pyridine-3-carbonyl]-2,4-difluoro-phenyl ⁇ -amide (hereafter also referred to as “Compound I”) is a b-raf kinase inhibitor that specifically targets mutant b-Raf containing the V600E mutation.
  • This compound is described in WO 2007/002325. Accordingly, such an inhibitor is used in the inhibition of tumors, particularly solid tumors, for example, colorectal cancer, melanoma, and thyroid cancer, which comprise b-Raf having the V600E mutation.
  • Interferons are naturally occurring proteins that have antiviral, antiproliferative, and immunoregulatory activity.
  • the IFN ⁇ family represents the predominant class of IFNs produced by stimulated peripheral blood leukocytes and lymphoblastoid and myeloblastoid cell lines. Interferons downregulate the expression of bFGF.
  • Interferon shall refer also to modified interferons and/or recombinantly produced interferons such as peginterferon alfa-2a.
  • Peginterferon alfa-2a (sold as Pegasys® by Genentech, South San Francisco, USA) is a covalent conjugate of recombinant alfa-2a interferon (having an approximate molecular weight of 20,000 daltons) with a single branched bis-monomethoxy polyethylene glycol (PEG) chain (having an approximate molecular weight of 40,000 daltons).
  • the PEG moiety is linked at a single site to the interferon alfa moiety via a stable amide bond to lysine.
  • Peginterferon alfa-2a has an approximate molecular weight of 60,000 daltons.
  • the advantage of peginterferon alfa-2a over interferons that do not contain the PEG moiety is that peginterferon alfa-2a exhibits a longer half-life, requiring less frequent dosing.
  • the present invention relates to a method of treating a patient suffering from a proliferative disorder, comprising administering to the patient: (A) a first component which comprises, as an active agent, Compound I, or a pharmaceutically-acceptable salt thereof; and (B) a second component which comprises, as an active agent, an interferon; the amounts of said active agents being such that the combination thereof is therapeutically-effective in the treatment of said proliferative disorder.
  • the present invention also relates to a kit comprising: (A) a first component which comprises, as an active agent, Compound I, or a pharmaceutically-acceptable salt thereof; and (B) a second component which comprises, as an active agent, an interferon.
  • the present invention further relates to a composition
  • a composition comprising: (A) a first component which comprises, as an active agent, Compound I, or a pharmaceutically-acceptable salt thereof; and (B) a second component which comprises, as an active agent, an interferon.
  • the present invention relates to the use of Compound I, or a pharmaceutically-acceptable salt thereof, and an interferon for the treatment of a proliferative disorder.
  • a yet further aspect of the present invention is the use of Compound I, or a pharmaceutically-acceptable salt thereof, and an interferon for the preparation of a medicament for the treatment of a proliferative disorder.
  • FIG. 1 illustrates the tolerability, as demonstrated by % body weight change, of Compound I 75 mg/kg bid monotherapy, peginterferon alfa-2a 900 ⁇ g 1 ⁇ /wk monotherapy, and Compound I 75 mg/kg bid/peginterferon alfa-2a 900 ⁇ g 1 ⁇ /wk combination therapy.
  • FIG. 2 illustrates the antitumor activity, as demonstrated by tumor volume, of Compound I 75 mg/kg bid monotherapy, peginterferon alfa-2a 900 ⁇ g 1 ⁇ /wk monotherapy, and Compound I 75 mg/kg bid/peginterferon alfa-2a 900 ⁇ g 1 ⁇ /wk combination therapy.
  • FIG. 3 illustrates the effect on survival, as demonstrated by percentage of surviving mice over time, of Compound I 75 mg/kg bid monotherapy, peginterferon alfa-2a 900 ⁇ g 1 ⁇ /wk monotherapy, and Compound I 75 mg/kg bid/peginterferon alfa-2a 900 ⁇ g 1 ⁇ /wk combination therapy.
  • FIG. 4 illustrates the tolerability, as demonstrated by % body weight change, of Compound I 25 mg/kg bid monotherapy, peginterferon alfa-2a 450 ⁇ g 1 ⁇ /wk monotherapy, and Compound I 25 mg/kg bid/peginterferon alfa-2a 450 ⁇ g 1 ⁇ /wk combination therapy.
  • FIG. 5 illustrates the antitumor activity, as demonstrated by tumor volume, of Compound I 25 mg/kg bid monotherapy, peginterferon alfa-2a 450 ⁇ g 1 ⁇ /wk monotherapy, and Compound I 25 mg/kg bid/peginterferon alfa-2a 450 ⁇ g 1 ⁇ /wk combination therapy.
  • FIG. 6 illustrates the effect on survival, as demonstrated by percentage of surviving mice over time, of Compound I 25 mg/kg bid monotherapy, peginterferon alfa-2a 450 ⁇ g 1 ⁇ /wk monotherapy, and Compound I 25 mg/kg bid/peginterferon alfa-2a 450 ⁇ g 1 ⁇ /wk combination therapy.
  • Compound I shall herein refer to propane-1-sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-1H-pyrrolo [2,3-b] pyridine-3-carbonyl-2,4-difluoro-phenyl]-amide ⁇ . This is a compound having the following structure.
  • Compound I is a b-Raf kinase inhibitor that specifically targets the V600E mutation of b-Raf.
  • V600E mutation of b-Raf refers to a mutation in the b-Raf protein wherein the valine residue at residue position 600 of b-Raf is replaced by glutamic acid.
  • the term “pharmaceutically acceptable carrier” indicates that the indicated carrier does not have properties that would cause a reasonably prudent medical practitioner to avoid administration thereof to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration.
  • the term “pharmaceutically acceptable salt” of a compound refers to any conventional salt or base addition salt that retains the biological effectiveness and properties of the compound and which is formed from a suitable non-toxic organic or inorganic acid or organic or inorganic base.
  • the term “therapeutically effective” means an amount of drug, or combination or composition, which is effective for producing a desired therapeutic effect upon administration to a patient, for example, to stem the growth, or result in the shrinkage, of a cancerous tumor or to increase the patient's life span.
  • cell proliferative disorder and “proliferative disorder” refer to disorders that are associated with some degree of abnormal cell proliferation.
  • the proliferative disorder is cancer.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth/proliferation.
  • examples of cancer include, but are not limited to, colorectal cancer, melanoma, and thyroid cancer.
  • colon tumor or “colorectal cancer” refers to any tumor or cancer of the large bowel, which includes the colon (the large intestine from the cecum to the rectum) and the rectum, including, e.g., adenocarcinomas and less prevalent forms, such as lymphomas and squamous cell carcinomas.
  • “Inhibiting cell growth or proliferation” means decreasing a cell's growth or proliferation by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%, and includes inducing cell death.
  • substantially reduced refers to a sufficiently high degree of difference between two numeric values (generally one associated with a molecule and the other associated with a reference/comparator molecule) such that one of skill in the art would consider the difference between the two values to be of statistical significance within the context of the biological characteristic measured by said values.
  • tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre
  • “Regression” of a tumor is said to occur following treatment when the volume of said tumor is reduced. If the tumor remains present (tumor volume >0 mm 3 ) but its volume is reduced from what it was at the initiation of treatment, “partial regression” (PR) is said to have occurred. If the tumor is palpably absent following treatment, “complete regression” (CR) is said to have occurred.
  • the present invention relates to a method of treating a patient suffering from a proliferative disorder, comprising administering to the patient: (A) a first component which comprises, as an active agent, Compound I, or a pharmaceutically-acceptable salt thereof; and (B) a second component which comprises, as an active agent, an interferon; the amount of said active agents being such that the combination thereof is therapeutically-effective in the treatment of said proliferative disorder.
  • Treatment of a proliferative disorder shall be understood to include maintaining or decreasing tumor size, inducing tumor regression (either partial or complete), inhibiting tumor growth, and/or increasing the life span of a patient suffering from said disorder.
  • the present invention also relates to a kit or a composition
  • a kit or a composition comprising: (A) a first component which comprises, as an active agent, Compound I, or a pharmaceutically-acceptable salt thereof; and (B) a second component which comprises, as an active agent, an interferon.
  • the kit or composition may be used, for example, in the treatment of a poliferative disorder.
  • the present invention provides the use of Compound I, or a pharmaceutically-acceptable salt thereof, and an interferon for the treatment of a proliferative disorder.
  • the invention further provides the use of Compound I, or a pharmaceutically-acceptable salt thereof, and an interferon for the preparation of a medicament for the treatment of a proliferative disorder.
  • the patient is a human.
  • the proliferative disorder is a solid tumor.
  • the proliferative disorder is a tumor containing the V600E b-Raf mutation.
  • the tumor is a solid tumor is selected from the group consisting of: colorectal cancer, melanoma, and thyroid cancer and the cancer involves a tumor comprising b-Raf having the V600E mutation.
  • the proliferative disorder is a solid tumor comprising b-Raf having the V600E mutation.
  • the tumor is a solid tumor containing the V600E b-Raf mutation and said tumor is selected from the group consisting of: colorectal cancer, melanoma, and thyroid cancer.
  • the tumor is melanoma.
  • the tumor is melanoma containing the V600E b-Raf mutation.
  • the interferon is selected from the group consisting of: peginterferon alfa-2a, interferon alfa-2a, peginterferon alfa-2b, and interferon alfa-2b.
  • the interferon is peginterferon alfa-2a.
  • the interferon is interferon alfa-2b.
  • the present invention relates to a method of treating a patient suffering from melanoma containing the V600E b-Raf mutation, comprising administering to the patient: (A) a first component which comprises, as an active agent, Compound I, or a pharmaceutically-acceptable salt thereof, and (B) a second component which comprises, as an active agent, peginterferon alfa-2a; the amount of said active agents being such that the combination thereof is therapeutically-effective in the treatment of said melanoma.
  • the amount of each component administered according to the present method may, but does not have to be therapeutically effective by itself. That is, this invention specifically contemplates combinations wherein the amount of Compound I, or a pharmaceutically-acceptable salt thereof, and/or the amount of interferon, in the combination may be less than the amount that is therapeutically-effective for each active agent when said agent is administered in monotherapy.
  • Compound I may, for example, be administered orally.
  • Peginterferon alfa-2a may, for example, be administered subcutaneously.
  • the first component and the second component of the present invention are administered in any amount and for any duration that the combined amounts thereof are therapeutically effective in treating a proliferative disorder.
  • Compound I is administered daily at a dosage amount of from about 200 mg/day to about 3000 mg/day, from about 800 mg/day to about 2500 mg/day, from about 1400 mg/day to about 2100 mg/day, about 960 mg/day, about 1440 mg/day, or about 1920 mg/day.
  • the foregoing amounts of Compound I may be administered as a single dose daily or divided, for example into equal doses (though this is not required), and administered twice daily (bid).
  • Compound I may be administered daily in a dosage amount of from about 100 mg to about 1500 mg bid, from about 400 mg to about 1250 mg bid, from about 700 mg to about 1050 mg bid, about 480 mg bid, about 720 mg bid, or about 960 mg bid.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof occurs until disease progression or unacceptable toxicity.
  • peginterferon alfa-2a is administered at a dosage of from about 1 ⁇ g/week to about 1,000 ⁇ g/week, from about 50 ⁇ g/week to about 800 g/week, or from about 90 ⁇ g/week to about 630 ⁇ g/week. In yet another embodiment, the dosage amount is about 180 ⁇ g/week.
  • the administration of peginterferon alfa-2a occurs until disease relapse, disease progression or unacceptable toxicity.
  • the peginterferon alfa-2a is administered at the dosage amounts described above for a period of up to 12 months, up to 24 months, up to 36 months, or up to 60 months.
  • the present invention also provides a method of treating a patient suffering from a proliferative disorder, comprising administering to the patient: (A) a first component which comprises, as an active agent, Compound I in an amount of from about 200 mg/day to about 3000 mg/day, from about 800 mg/day to about 2500 mg/day, from about 1400 mg/day to about 2100 mg/day, about 960 mg/day, about 1440 mg/day, or about 1920 mg/day; and (B) a second component which comprises, as an active agent, peginterferon alfa-2a in an amount of from about 1 ⁇ g/week to about 1,000 ⁇ g/week, from about 50 ⁇ g/week to about 800 ⁇ g/week, from about 90 ⁇ g/week to about 630 g/week, or about 180 ⁇ g/week.
  • A a first component which comprises, as an active agent, Compound I in an amount of from about 200 mg/day to about 3000 mg/day, from about 800 mg/day to about 2500 mg
  • the proliferative disorder is a solid tumor, in particular the disorder is selected from the group consisting of: colorectal cancer, melanoma, and thyroid cancer.
  • the proliferative disorder involves a tumor comprising b-Raf having the V600E mutation.
  • the proliferative disorder is melanoma comprising b-Raf having the V600E mutation.
  • the components herein described above are administered in conjunction with radiotherapy and/or in conjunction with another active agent.
  • Compound I exists in its natural state in a crystalline form.
  • the amorphous form of the compound has greater solubility in water as compared with the crystalline form and thus has an improved dissolution rate and, therefore, improved bioavailability as compared to the crystalline form.
  • the amorphous form of the compound is preferred.
  • Compound I is in substantially amorphous form and, more preferably, in amorphous form.
  • substantially amorphous material embraces material which has no more than about 10% crystallinity; and “amorphous” material embraces material which has no more than about 2% crystallinity.
  • Compound I is contained in a solid molecular complex formed with hydroxypropyl methyl cellulose acetate succinate (HPMC-AS).
  • solid molecular complex means a composition wherein Compound I is randomly distributed (“molecularly dispersed”) within a matrix formed by HPMC-AS.
  • Compound I is present in the polymer in a final state of subdivision.
  • Compound I is molecularly dispersed within the HPMC-AS matrix such that it is immobilized in its amorphous form.
  • immobilized it is meant that the molecules of Compound I interact with molecules of HPMC-AS in such a way that they are held in the aforementioned matrix and prevented from crystal nucleation due to lack of mobility.
  • the polymer may prevent intramolecular hydrogen bonding or weak dispersion forces between two or more molecules of Compound I.
  • the ratio of the amount by weight of Compound I within the solid molecular complex to the amount by weight of HPMC-AS therein is from about 1:9 to about 5:5. In an embodiment, said ratio is from about 2:8 to about 4:6. In another embodiment, said ratio is about 3:7.
  • the first component comprises the aforementioned solid molecular complex of Compound I and HPMC-AS blended with colloidal silicon dioxide.
  • the blend is at least 0.5% by weight silicon dioxide. In an embodiment of the present invention, the blend is about 97% complex and about 3% silicon dioxide.
  • the first component includes a composition comprising the aforementioned solid molecular complex, either blended or not blended with silicon dioxide as described above, and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier is hydroxypropylcellulose (HPC).
  • HPC hydroxypropylcellulose
  • the vehicle contains about 2% by weight HPC.
  • Each component may also contain additional agents such as preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents and antioxidants.
  • additional agents such as preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents and antioxidants.
  • the first component may comprise a solid molecular complex of Compound I and HPMC-AS blended with colloidal silicon dioxide, hydroxypropylcellulose, Crospovidone (a disintegrating agent), magnesium stearate (a lubricant that may be used in tablet and capsulation operations), and/or croscarmellose sodium (a disintegrating agent).
  • colloidal silicon dioxide hydroxypropylcellulose
  • Crospovidone a disintegrating agent
  • magnesium stearate a lubricant that may be used in tablet and capsulation operations
  • croscarmellose sodium a disintegrating agent
  • the first component is a hard gelatin capsule comprising a solid molecular complex of Compound I and HPMC-AS blended with colloidal silicon dioxide, hydroxypropylcellulose, magnesium stearate, and croscarmellose sodium.
  • the first component is a tablet comprising Compound I, or a pharmaceutically acceptable salt thereof.
  • the tablet comprises a solid molecular complex of Compound I, or a pharmaceutically acceptable salt thereof, and HPMC-AS.
  • the complex may, for example, be blended with colloidal silicon dioxide, hydroxypropylcellulose, magnesium stearate, and croscarmellose sodium.
  • the tablet may, for example, be coated with a film coating.
  • the film coating may, for example, comprise polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, and iron oxide red.
  • the second component may comprise peginterferon alfa-2a as an injectable solution.
  • Pegasys® is available as an injectable solution in vials and prefilled syringes. Each 180 ⁇ g/1.0 ml vial contains approximately 1.2 ml of solution to deliver 1.0 ml of drug product. Subcutaneous (sc) administration of 1.0 ml delivers 180 g of drug product (expressed as the amount of interferon alfa-2a), 8.0 mg sodium chloride, 0.05 mg polysorbate 80, 10.0 mg benzyl alcohol, 2.62 mg sodium acetate trihydrate, and 0.0462 mg acetic acid. The solution is colorless to light yellow and the pH is 6.0 ⁇ 0.5. Each 180 ⁇ g/0.5 ml prefilled syringe contains 0.6 ml of solution to deliver 0.5 ml of drug product.
  • Subcutaneous (sc) administration of 0.5 ml delivers 180 ⁇ g of drug product (expressed as the amount of interferon alfa-2a), 4.0 mg sodium chloride, 0.025 mg polysorbate 80, 5.0 mg benzyl alcohol, 1.3085 mg sodium acetate trihydrate, and 0.0231 mg acetic acid.
  • the solution is colorless to light yellow and the pH is 6.0 ⁇ 0.5.
  • mice containing a human melanoma xenograft have conducted studies using mice containing a human melanoma xenograft.
  • This example describes the formation of a suspension comprising Compound 1.
  • a solid molecular complex comprising Compound I and hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) was first formed.
  • the co-precipitate was then washed with water to remove DMA, filtered, dried to ⁇ 2% moisture content and passed through a #30 mesh screen prior to evaluation.
  • the resulting solid molecular complex was 30% by weight Compound I and 70% by weight HPMC.
  • the complex was then blended with colloidal silicon dioxide (available as Aerosil® 200 from Evonik Industries AG, Essen, Germany) such that, per 100 g of the blend, 97 g was the complex and 3 g was colloidal silicon dioxide.
  • colloidal silicon dioxide available as Aerosil® 200 from Evonik Industries AG, Essen, Germany
  • aqueous vehicle containing 2% hydroxypropylcellulose available as Klucel® LF from Aqualon, Wilmington, Del., USA
  • 1N HCL at Qs to pH4 for the purpose of pH adjustment was then prepared.
  • 23.2 mL of the vehicle was equilibrated to room temperature and slowly transferred into 773.2 mg of the aforementioned blend.
  • the resulting preparation was then slowly mixed until a homogenous suspension was obtained.
  • the suspension was stored at 2-8° C. and protected from light.
  • the suspension contained 9.375 mg/mL of Compound I.
  • This example describes an injectable solution of peginterferon alfa-2a.
  • mice were implanted with human LOX-IMVI melanoma cell xenografts. The mice, cell line used, and implantation are described below.
  • mice Female athymic Crl:NU-Foxn1nu mice were used for efficacy testing (Charles River, Wilmington, Mass., USA). Mice were 10-12 weeks of age and weighed 23-25 grams. The health of the mice was assessed daily by observation and analysis of blood samples taken from sentinel animals on shared shelf racks. All animals were allowed to acclimate and recover from shipping-related stress for one week. Autoclaved water and irradiated food (5058-ms Pico Lab mouse chow, Purina Mills, Richmond, Ind., USA) were provided ad libitum, and the animals were kept in a 12 hour light and dark cycle. Cages, bedding and water bottles were autoclaved before use and changed weekly. All animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals, local regulations, and protocols approved by the Roche Animal Care and Use Committee in our AAALAC accredited facility.
  • LOX-IMVI cells (aka LOX, National Cancer Institute—Bethesda, Md.) were grown in RPMI-1640 medium supplemented with 10% Fetal Bovine Serum (FBS) and 1% of 200 nM L-glutamine, scaled up, harvested, and prepared so that each mouse received 2 ⁇ 10 6 cells/0.2 ml calcium and magnesium free phosphate-buffered saline (PBS). Cells were implanted in the subcutaneous right flank of each mouse.
  • FBS Fetal Bovine Serum
  • PBS calcium and magnesium free phosphate-buffered saline
  • mice implanted with human xenografts were randomized into eight groups of 10 mice each according to tumor volume so that all groups had similar starting mean tumor volumes.
  • the approximate starting mean tumor volume for this study was 130 mm 3 .
  • Compound I was formulated as a suspension as described in example 1.
  • Peginterferon alfa-2a was formulated as an injectable solution as described in example 2.
  • mice Treatment began on day 5 post-cell implant and ended at day 18 post-cell implant.
  • the Compound I suspension and its corresponding vehicle were dosed using a sterile 1 cc syringe and 18-gauge gavage needle (0.2 ml/animal) twice daily.
  • the peginterferon alfa-2a solution and its corresponding vehicle were dosed using a sterile 1 cc syringe and 26-gauge needle (0.2 ml/animal) once weekly on days 5 and 12 post-cell implant for a total of two injections.
  • Weight loss was graphically represented as percent change in mean group body weight, using the formula: ((W ⁇ W 0 )/W 0 ) ⁇ 100, where ‘W’ represents mean body weight of the treated group at a particular day, and ‘W 0 ’ represents mean body weight of the same treated group at initiation of treatment. Maximum weight loss was also represented using the above formula, and indicated the maximum percent body weight loss that was observed at any time during the entire experiment for a particular group.
  • Efficacy data was graphically represented as the mean tumor volume ⁇ standard error of the mean (SEM).
  • tumor volumes of treated groups were presented as percentages of tumor volumes of the control groups (% T/C), using the formula: 100 ⁇ ((T ⁇ T 0 )/(C ⁇ C 0 )), where T represented mean tumor volume of a treated group on a specific day during the experiment, T 0 represented mean tumor volume of the same treated group on the first day of treatment; C represented mean tumor volume of a control group on the specific day during the experiment, and C 0 represented mean tumor volume of the same treated group on the first day of treatment.
  • Tumor volume (in cubic millimeters) was calculated using the ellipsoid formula: (D ⁇ (d 2 ))/2, where “D” represents the large diameter of the tumor and “d” represents the small diameter.
  • tumor regression and/or percent change in tumor volume was calculated using the formula: ((T ⁇ T 0 )/T 0 ) ⁇ 100, where ‘T’ represents mean tumor volume of the treated group at a particular day, and ‘T 0 ’ represents mean tumor volume of the same treated group at initiation of treatment.
  • the percent of increased life space was calculated as: 100 ⁇ [(median survival day of treated group ⁇ median survival day of control group)/median survival day of control group].
  • Median survival was determined utilizing Kaplan Meier survival analysis. Survival in treated groups was statistically compared with the vehicle group and survival comparisons were done between groups using the log-rank test (Graph Pad Prism, La Jolla, Calif., USA). Differences between groups were considered significant when the probability value (p) was ⁇ 0.05.
  • TGI Tumor Growth Inhibition
  • the group receiving Compound I monotherapy at 75 mg/kg bid exhibited greater than 100% TGI with 10 out of 10 complete regressions (CRs).
  • the group receiving peginterferon alfa-2a monotherapy at 900 ⁇ g 1 ⁇ /wk exhibited 98% TGI, 2 partial regressions (PRs) and 3 CRs out of 10.
  • the group receiving combination therapy of Compound I at 75 mg/kg bid and peginterferon alfa-2a at 900 ⁇ g 1 ⁇ /wk exhibited greater than 100% TGI with 10 out of 10 CRs. See Tables 2 and 3 and FIG. 2 .
  • the group receiving Compound I monotherapy at 75 mg/kg bid exhibited 3500% increased life span (ILS).
  • the group receiving peginterferon alfa-2a monotherapy at 900 ⁇ g 1 ⁇ /wk exhibited 143% ILS.
  • the group receiving combination therapy of Compound I at 75 mg/kg bid and peginterferon alfa-2a at 900 ⁇ g 1 ⁇ /wk exhibited 3400% ILS. See Table 4 and FIG. 3 .
  • the % TGI in the Compound I 75 mg/kg bid/peginterferon alfa-2a 900 ⁇ g 1 ⁇ /wk combination therapy group was statistically superior to that of the peginterferon alfa-2a 900 ⁇ g 1 ⁇ /wk monotherapy group but equivalent to that of the Compound I 75 mg/kg bid monotherapy group.
  • the % ILS in the Compound I 75 mg/kg bid/peginterferon alfa-2a 900 ⁇ g 1 ⁇ /wk combination therapy group was statistically superior to that of the peginterferon alfa-2a 900 ⁇ g 1 ⁇ /wk monotherapy group but equivalent to that of the Compound I 75 mg/kg bid monotherapy group. See Table 5.
  • Compound I was formulated as a suspension as described in example 1.
  • the Compound I vehicle was 2.0 grams of Klucel LF in Peginterferon alfa-2a was formulated as an injectable solution as described in example 2.
  • the Compound I suspension and its corresponding vehicle were dosed using a sterile 1 cc syringe and 18-gauge gavage needle (0.2 ml/animal) twice daily.
  • the peginterferon alfa-2a solution and its corresponding vehicle were dosed using a sterile 1 cc syringe and 26-gauge needle (0.2 ml/animal) once weekly on days 6 and 13 post-cell implant for a total of two injections.
  • Weight loss was graphically represented as percent change in mean group body weight, using the formula: ((W ⁇ W 0 )/W 0 ) ⁇ 100, where ‘W’ represents mean body weight of the treated group at a particular day, and ‘W 0 ’ represents mean body weight of the same treated group at initiation of treatment. Maximum weight loss was also represented using the above formula, and indicated the maximum percent body weight loss that was observed at any time during the entire experiment for a particular group.
  • Efficacy data was graphically represented as the mean tumor volume ⁇ standard error of the mean (SEM).
  • tumor volumes of treated groups were presented as percentages of tumor volumes of the control groups (% T/C), using the formula: 100 ⁇ ((T ⁇ T 0 )/(C ⁇ C 0 )), where T represented mean tumor volume of a treated group on a specific day during the experiment, T 0 represented mean tumor volume of the same treated group on the first day of treatment; C represented mean tumor volume of a control group on the specific day during the experiment, and C 0 represented mean tumor volume of the same treated group on the first day of treatment.
  • Tumor volume (in cubic millimeters) was calculated using the ellipsoid formula: (D ⁇ (d2))/2, where “D” represents the large diameter of the tumor and “d” represents the small diameter.
  • tumor regression and/or percent change in tumor volume was calculated using the formula: ((T ⁇ T 0 )/T 0 ) ⁇ 100, where ‘T’ represents mean tumor volume of the treated group at a particular day, and ‘T 0 ’ represents mean tumor volume of the same treated group at initiation of treatment.
  • the percent of increased life space was calculated as: 100 ⁇ [(median survival day of treated group ⁇ median survival day of control group)/median survival day of control group].
  • Median survival was determined utilizing Kaplan Meier survival analysis. Survival in treated groups was statistically compared with the vehicle group and survival comparisons were done between groups using the log-rank test (Graph Pad Prism, La Jolla, Calif., USA). Differences between groups were considered significant when the probability value (p) was ⁇ 0.05.
  • TGI Tumor Growth Inhibition
  • the group receiving Compound I monotherapy at 25 mg/kg bid exhibited greater than 100% TGI with 10 out of 10 CRs.
  • the group receiving peginterferon alfa-2a monotherapy at 450 ⁇ g 1 ⁇ /wk exhibited greater than 100% TGI, 6 PRs and 1 CR out of 10.
  • the group receiving combination therapy of Compound I at 25 mg/kg bid and peginterferon alfa-2a at 450 ⁇ g 1 ⁇ /wk exhibited greater than 100% TGI with 10 out of 10 complete regressions (CRs). See Tables 7 and 8 and FIG. 5 .
  • the group receiving Compound I monotherapy at 25 mg/kg bid exhibited 321% increased life span (ILS).
  • the group receiving peginterferon alfa-2a monotherapy at 450 ⁇ g 1 ⁇ /wk exhibited 114% ILS.
  • the group receiving combination therapy of Compound I at 25 mg/kg bid and peginterferon alfa-2a at 450 ⁇ g 1 ⁇ /wk exhibited 2843% ILS. See Table 9 and FIG. 6 .
  • the % TGI in the Compound I 25 mg/kg bid/peginterferon alfa-2a 450 ⁇ g 1 ⁇ /wk combination therapy group was statistically superior to that of the peginterferon alfa-2a 450 ⁇ g 1 ⁇ /wk monotherapy group but equivalent to that of the Compound I 25 mg/kg bid monotherapy group.
  • the % ILS in the Compound I 25 mg/kg bid/peginterferon alfa-2a 450 ⁇ g 1 ⁇ /wk combination therapy group was statistically superior to that each monotherapy group. See Table 10.

Abstract

The present invention relates to a combination therapy of propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo [2,3-b] pyridine-3-carbonyl-2,4-difluoro-phenyl]-amide}, or a pharmaceutically acceptable salt thereof, and an interferon for treating a patient suffering from a proliferative disorder, in particular a solid tumor, for example, colorectal cancer, melanoma, and thyroid cancer. In particular, the present invention relates to such a therapy wherein the interferon is peginterferon alfa-2a and the disorder is melanoma containing the V600E b-Raf mutation.

Description

    PRIORITY TO RELATED APPLICATIONS
  • This application claims the benefit of U.S. Provisional Application No. 61/422,690, filed Dec. 14, 2010, which is hereby incorporated by reference in its entirety.
    • FIELD OF THE INVENTION
  • The present invention relates to a combination therapy for treating a patient suffering from a proliferative disorder, in particular a solid tumor, for example, colorectal cancer, melanoma, and thyroid cancer, comprising administering to the patient propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo [2,3-b] pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide and an interferon.
    • BACKGROUND OF THE INVENTION
  • Normally functioning b-Raf is a kinase which is involved in the relay of signals from the cell membrane to the nucleus and is active only when it is needed to relay such signals. Mutant b-Raf containing a V600E mutation, however, is constantly active and thus plays a role in tumor development. Such mutant b-Raf has been implicated in various tumors, for example, colorectal cancer, melanoma, and thyroid cancer.
  • Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo [2,3-b] pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (hereafter also referred to as “Compound I”) is a b-raf kinase inhibitor that specifically targets mutant b-Raf containing the V600E mutation. This compound is described in WO 2007/002325. Accordingly, such an inhibitor is used in the inhibition of tumors, particularly solid tumors, for example, colorectal cancer, melanoma, and thyroid cancer, which comprise b-Raf having the V600E mutation.
  • Interferons (IFNs) are naturally occurring proteins that have antiviral, antiproliferative, and immunoregulatory activity. The IFNα family represents the predominant class of IFNs produced by stimulated peripheral blood leukocytes and lymphoblastoid and myeloblastoid cell lines. Interferons downregulate the expression of bFGF. These drugs can be self administered by patients via subcutaneous injection with resultant good pharmacokinetics. For the purpose of the present specification, the term “interferon” shall refer also to modified interferons and/or recombinantly produced interferons such as peginterferon alfa-2a.
  • Peginterferon alfa-2a (sold as Pegasys® by Genentech, South San Francisco, USA) is a covalent conjugate of recombinant alfa-2a interferon (having an approximate molecular weight of 20,000 daltons) with a single branched bis-monomethoxy polyethylene glycol (PEG) chain (having an approximate molecular weight of 40,000 daltons). The PEG moiety is linked at a single site to the interferon alfa moiety via a stable amide bond to lysine. Peginterferon alfa-2a has an approximate molecular weight of 60,000 daltons. The advantage of peginterferon alfa-2a over interferons that do not contain the PEG moiety is that peginterferon alfa-2a exhibits a longer half-life, requiring less frequent dosing.
    • SUMMARY OF THE INVENTION
  • The present invention relates to a method of treating a patient suffering from a proliferative disorder, comprising administering to the patient: (A) a first component which comprises, as an active agent, Compound I, or a pharmaceutically-acceptable salt thereof; and (B) a second component which comprises, as an active agent, an interferon; the amounts of said active agents being such that the combination thereof is therapeutically-effective in the treatment of said proliferative disorder.
  • The present invention also relates to a kit comprising: (A) a first component which comprises, as an active agent, Compound I, or a pharmaceutically-acceptable salt thereof; and (B) a second component which comprises, as an active agent, an interferon.
  • The present invention further relates to a composition comprising: (A) a first component which comprises, as an active agent, Compound I, or a pharmaceutically-acceptable salt thereof; and (B) a second component which comprises, as an active agent, an interferon.
  • In addition, the present invention relates to the use of Compound I, or a pharmaceutically-acceptable salt thereof, and an interferon for the treatment of a proliferative disorder.
  • A yet further aspect of the present invention is the use of Compound I, or a pharmaceutically-acceptable salt thereof, and an interferon for the preparation of a medicament for the treatment of a proliferative disorder.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 illustrates the tolerability, as demonstrated by % body weight change, of Compound I 75 mg/kg bid monotherapy, peginterferon alfa-2a 900 μg 1×/wk monotherapy, and Compound I 75 mg/kg bid/peginterferon alfa-2a 900 μg 1×/wk combination therapy.
  • FIG. 2 illustrates the antitumor activity, as demonstrated by tumor volume, of Compound I 75 mg/kg bid monotherapy, peginterferon alfa-2a 900 μg 1×/wk monotherapy, and Compound I 75 mg/kg bid/peginterferon alfa-2a 900 μg 1×/wk combination therapy.
  • FIG. 3 illustrates the effect on survival, as demonstrated by percentage of surviving mice over time, of Compound I 75 mg/kg bid monotherapy, peginterferon alfa-2a 900 μg 1×/wk monotherapy, and Compound I 75 mg/kg bid/peginterferon alfa-2a 900 μg 1×/wk combination therapy.
  • FIG. 4 illustrates the tolerability, as demonstrated by % body weight change, of Compound I 25 mg/kg bid monotherapy, peginterferon alfa-2a 450 μg 1×/wk monotherapy, and Compound I 25 mg/kg bid/peginterferon alfa-2a 450 μg 1×/wk combination therapy.
  • FIG. 5 illustrates the antitumor activity, as demonstrated by tumor volume, of Compound I 25 mg/kg bid monotherapy, peginterferon alfa-2a 450 μg 1×/wk monotherapy, and Compound I 25 mg/kg bid/peginterferon alfa-2a 450 μg 1×/wk combination therapy.
  • FIG. 6 illustrates the effect on survival, as demonstrated by percentage of surviving mice over time, of Compound I 25 mg/kg bid monotherapy, peginterferon alfa-2a 450 μg 1×/wk monotherapy, and Compound I 25 mg/kg bid/peginterferon alfa-2a 450 μg 1×/wk combination therapy.
    •  DETAILED DESCRIPTION OF THE INVENTION
  • As stated above, “Compound I” shall herein refer to propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo [2,3-b] pyridine-3-carbonyl-2,4-difluoro-phenyl]-amide}. This is a compound having the following structure.
  • Figure US20160256529A1-20160908-C00001
  • Compound I is a b-Raf kinase inhibitor that specifically targets the V600E mutation of b-Raf.
  • The “V600E” mutation of b-Raf, as used herein, refers to a mutation in the b-Raf protein wherein the valine residue at residue position 600 of b-Raf is replaced by glutamic acid.
  • As used herein, the term “pharmaceutically acceptable carrier” indicates that the indicated carrier does not have properties that would cause a reasonably prudent medical practitioner to avoid administration thereof to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration.
  • As used herein, the term “pharmaceutically acceptable salt” of a compound refers to any conventional salt or base addition salt that retains the biological effectiveness and properties of the compound and which is formed from a suitable non-toxic organic or inorganic acid or organic or inorganic base.
  • As used herein, the term “therapeutically effective” means an amount of drug, or combination or composition, which is effective for producing a desired therapeutic effect upon administration to a patient, for example, to stem the growth, or result in the shrinkage, of a cancerous tumor or to increase the patient's life span.
  • The terms “cell proliferative disorder” and “proliferative disorder” refer to disorders that are associated with some degree of abnormal cell proliferation. In one embodiment, the proliferative disorder is cancer.
  • The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth/proliferation. Examples of cancer include, but are not limited to, colorectal cancer, melanoma, and thyroid cancer.
  • The term “colorectal tumor” or “colorectal cancer” refers to any tumor or cancer of the large bowel, which includes the colon (the large intestine from the cecum to the rectum) and the rectum, including, e.g., adenocarcinomas and less prevalent forms, such as lymphomas and squamous cell carcinomas.
  • “Inhibiting cell growth or proliferation” means decreasing a cell's growth or proliferation by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%, and includes inducing cell death.
  • The phrase “substantially reduced” or “substantially different,” as used herein, refers to a sufficiently high degree of difference between two numeric values (generally one associated with a molecule and the other associated with a reference/comparator molecule) such that one of skill in the art would consider the difference between the two values to be of statistical significance within the context of the biological characteristic measured by said values.
  • The term “tumor” refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” “cell proliferative disorder,” “proliferative disorder,” and “tumor” are not mutually exclusive as referred to herein.
  • “Regression” of a tumor is said to occur following treatment when the volume of said tumor is reduced. If the tumor remains present (tumor volume >0 mm3) but its volume is reduced from what it was at the initiation of treatment, “partial regression” (PR) is said to have occurred. If the tumor is palpably absent following treatment, “complete regression” (CR) is said to have occurred.
  • The present invention relates to a method of treating a patient suffering from a proliferative disorder, comprising administering to the patient: (A) a first component which comprises, as an active agent, Compound I, or a pharmaceutically-acceptable salt thereof; and (B) a second component which comprises, as an active agent, an interferon; the amount of said active agents being such that the combination thereof is therapeutically-effective in the treatment of said proliferative disorder.
  • Treatment of a proliferative disorder shall be understood to include maintaining or decreasing tumor size, inducing tumor regression (either partial or complete), inhibiting tumor growth, and/or increasing the life span of a patient suffering from said disorder.
  • The present invention also relates to a kit or a composition comprising: (A) a first component which comprises, as an active agent, Compound I, or a pharmaceutically-acceptable salt thereof; and (B) a second component which comprises, as an active agent, an interferon. The kit or composition may be used, for example, in the treatment of a poliferative disorder.
  • In addition, the present invention provides the use of Compound I, or a pharmaceutically-acceptable salt thereof, and an interferon for the treatment of a proliferative disorder.
  • The invention further provides the use of Compound I, or a pharmaceutically-acceptable salt thereof, and an interferon for the preparation of a medicament for the treatment of a proliferative disorder.
  • In an embodiment of the present invention, the patient is a human.
  • In an embodiment of the invention, the proliferative disorder is a solid tumor.
  • In another embodiment of the invention, the proliferative disorder is a tumor containing the V600E b-Raf mutation.
  • In a further embodiment of the invention, the tumor is a solid tumor is selected from the group consisting of: colorectal cancer, melanoma, and thyroid cancer and the cancer involves a tumor comprising b-Raf having the V600E mutation.
  • In yet a further embodiment of the invention, the proliferative disorder is a solid tumor comprising b-Raf having the V600E mutation.
  • In yet a further embodiment of the invention, the tumor is a solid tumor containing the V600E b-Raf mutation and said tumor is selected from the group consisting of: colorectal cancer, melanoma, and thyroid cancer.
  • In yet a further embodiment of the invention, the tumor is melanoma.
  • In yet a further embodiment of the invention, the tumor is melanoma containing the V600E b-Raf mutation.
  • In yet a further embodiment of the invention, the interferon is selected from the group consisting of: peginterferon alfa-2a, interferon alfa-2a, peginterferon alfa-2b, and interferon alfa-2b.
  • In yet a further embodiment of the invention, the interferon is peginterferon alfa-2a.
  • In yet a further embodiment of the invention, the interferon is interferon alfa-2b.
  • In yet a further embodiment of the invention, the present invention relates to a method of treating a patient suffering from melanoma containing the V600E b-Raf mutation, comprising administering to the patient: (A) a first component which comprises, as an active agent, Compound I, or a pharmaceutically-acceptable salt thereof, and (B) a second component which comprises, as an active agent, peginterferon alfa-2a; the amount of said active agents being such that the combination thereof is therapeutically-effective in the treatment of said melanoma.
  • The amount of each component administered according to the present method may, but does not have to be therapeutically effective by itself. That is, this invention specifically contemplates combinations wherein the amount of Compound I, or a pharmaceutically-acceptable salt thereof, and/or the amount of interferon, in the combination may be less than the amount that is therapeutically-effective for each active agent when said agent is administered in monotherapy.
  • Compound I, or a pharmaceutically-acceptable salt thereof, may, for example, be administered orally. Peginterferon alfa-2a may, for example, be administered subcutaneously. The first component and the second component of the present invention are administered in any amount and for any duration that the combined amounts thereof are therapeutically effective in treating a proliferative disorder.
  • In embodiments of the present invention, Compound I is administered daily at a dosage amount of from about 200 mg/day to about 3000 mg/day, from about 800 mg/day to about 2500 mg/day, from about 1400 mg/day to about 2100 mg/day, about 960 mg/day, about 1440 mg/day, or about 1920 mg/day.
  • In an embodiment of the present invention, the foregoing amounts of Compound I may be administered as a single dose daily or divided, for example into equal doses (though this is not required), and administered twice daily (bid). For example, Compound I may be administered daily in a dosage amount of from about 100 mg to about 1500 mg bid, from about 400 mg to about 1250 mg bid, from about 700 mg to about 1050 mg bid, about 480 mg bid, about 720 mg bid, or about 960 mg bid.
  • In an embodiment of the present invention, the administration of Compound I, or a pharmaceutically acceptable salt thereof, occurs until disease progression or unacceptable toxicity.
  • In an embodiment of the present invention, peginterferon alfa-2a is administered at a dosage of from about 1 μg/week to about 1,000 μg/week, from about 50 μg/week to about 800 g/week, or from about 90 μg/week to about 630 μg/week. In yet another embodiment, the dosage amount is about 180 μg/week.
  • In an embodiment of the present invention, the administration of peginterferon alfa-2a occurs until disease relapse, disease progression or unacceptable toxicity. In another embodiment, the peginterferon alfa-2a is administered at the dosage amounts described above for a period of up to 12 months, up to 24 months, up to 36 months, or up to 60 months.
  • The present invention also provides a method of treating a patient suffering from a proliferative disorder, comprising administering to the patient: (A) a first component which comprises, as an active agent, Compound I in an amount of from about 200 mg/day to about 3000 mg/day, from about 800 mg/day to about 2500 mg/day, from about 1400 mg/day to about 2100 mg/day, about 960 mg/day, about 1440 mg/day, or about 1920 mg/day; and (B) a second component which comprises, as an active agent, peginterferon alfa-2a in an amount of from about 1 μg/week to about 1,000 μg/week, from about 50 μg/week to about 800 μg/week, from about 90 μg/week to about 630 g/week, or about 180 μg/week. In an embodiment of this invention, the proliferative disorder is a solid tumor, in particular the disorder is selected from the group consisting of: colorectal cancer, melanoma, and thyroid cancer. In another embodiment of this invention, the proliferative disorder involves a tumor comprising b-Raf having the V600E mutation. In a particular embodiment of this invention, the proliferative disorder is melanoma comprising b-Raf having the V600E mutation.
  • In another aspect of this invention, the components herein described above are administered in conjunction with radiotherapy and/or in conjunction with another active agent.
  • Compound I exists in its natural state in a crystalline form. However, the amorphous form of the compound has greater solubility in water as compared with the crystalline form and thus has an improved dissolution rate and, therefore, improved bioavailability as compared to the crystalline form. As such, the amorphous form of the compound is preferred. Accordingly, in preferred embodiments of the present invention, Compound I is in substantially amorphous form and, more preferably, in amorphous form. As used herein, the term “substantially amorphous” material embraces material which has no more than about 10% crystallinity; and “amorphous” material embraces material which has no more than about 2% crystallinity.
  • In an embodiment of the present invention, Compound I is contained in a solid molecular complex formed with hydroxypropyl methyl cellulose acetate succinate (HPMC-AS). As used herein, the term “solid molecular complex” means a composition wherein Compound I is randomly distributed (“molecularly dispersed”) within a matrix formed by HPMC-AS. In certain embodiments Compound I is present in the polymer in a final state of subdivision. In certain embodiments, Compound I is molecularly dispersed within the HPMC-AS matrix such that it is immobilized in its amorphous form. By “immobilized”, it is meant that the molecules of Compound I interact with molecules of HPMC-AS in such a way that they are held in the aforementioned matrix and prevented from crystal nucleation due to lack of mobility. In some embodiments the polymer may prevent intramolecular hydrogen bonding or weak dispersion forces between two or more molecules of Compound I.
  • In some embodiments the ratio of the amount by weight of Compound I within the solid molecular complex to the amount by weight of HPMC-AS therein is from about 1:9 to about 5:5. In an embodiment, said ratio is from about 2:8 to about 4:6. In another embodiment, said ratio is about 3:7.
  • In certain embodiments of the method and kit of the present invention, the first component comprises the aforementioned solid molecular complex of Compound I and HPMC-AS blended with colloidal silicon dioxide. In certain embodiments, the blend is at least 0.5% by weight silicon dioxide. In an embodiment of the present invention, the blend is about 97% complex and about 3% silicon dioxide.
  • In another embodiment, the first component includes a composition comprising the aforementioned solid molecular complex, either blended or not blended with silicon dioxide as described above, and a pharmaceutically acceptable carrier. In certain embodiments, the aforementioned complex or blend comprising the same is suspended in the carrier. An example of a carrier is hydroxypropylcellulose (HPC). In an embodiment, the vehicle contains about 2% by weight HPC.
  • Each component may also contain additional agents such as preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents and antioxidants.
  • In certain embodiments, the first component may comprise a solid molecular complex of Compound I and HPMC-AS blended with colloidal silicon dioxide, hydroxypropylcellulose, Crospovidone (a disintegrating agent), magnesium stearate (a lubricant that may be used in tablet and capsulation operations), and/or croscarmellose sodium (a disintegrating agent).
  • In an embodiment, the first component is a hard gelatin capsule comprising a solid molecular complex of Compound I and HPMC-AS blended with colloidal silicon dioxide, hydroxypropylcellulose, magnesium stearate, and croscarmellose sodium.
  • In an embodiment, the first component is a tablet comprising Compound I, or a pharmaceutically acceptable salt thereof. In an embodiment, the tablet comprises a solid molecular complex of Compound I, or a pharmaceutically acceptable salt thereof, and HPMC-AS. The complex may, for example, be blended with colloidal silicon dioxide, hydroxypropylcellulose, magnesium stearate, and croscarmellose sodium. The tablet may, for example, be coated with a film coating. The film coating may, for example, comprise polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, and iron oxide red.
  • In certain embodiments, the second component may comprise peginterferon alfa-2a as an injectable solution.
  • Pegasys® is available as an injectable solution in vials and prefilled syringes. Each 180 μg/1.0 ml vial contains approximately 1.2 ml of solution to deliver 1.0 ml of drug product. Subcutaneous (sc) administration of 1.0 ml delivers 180 g of drug product (expressed as the amount of interferon alfa-2a), 8.0 mg sodium chloride, 0.05 mg polysorbate 80, 10.0 mg benzyl alcohol, 2.62 mg sodium acetate trihydrate, and 0.0462 mg acetic acid. The solution is colorless to light yellow and the pH is 6.0±0.5. Each 180 μg/0.5 ml prefilled syringe contains 0.6 ml of solution to deliver 0.5 ml of drug product. Subcutaneous (sc) administration of 0.5 ml delivers 180 μg of drug product (expressed as the amount of interferon alfa-2a), 4.0 mg sodium chloride, 0.025 mg polysorbate 80, 5.0 mg benzyl alcohol, 1.3085 mg sodium acetate trihydrate, and 0.0231 mg acetic acid. The solution is colorless to light yellow and the pH is 6.0±0.5.
  • Applicants have conducted studies using mice containing a human melanoma xenograft.
  • Applicants found that, while the combination of Compound I at 75 mg/kg bid and peginterferon alfa-2a at 900 μg 1×/wk produced significantly increased life span (ILS) in mice in comparison to what was achieved with 900 μg 1×/wk peginterferon alfa-2a monotherapy, the ILS results were statistically equivalent to what was achieved with Compound I 75 mg/kg bid monotherapy.
  • In order to unmask the effect of combination therapy, applicants conducted studies in which Compound I was administered at 25 mg/kg bid and peginterferon alfa-2a was administered at 450 μg 1×/wk. In mice, 25 mg/kg bid Compound I achieved 321% increased life span (ILS) and 450 μg 1×/wk peginterferon alfa-2a achieved 114% ILS. By contrast, when a combined therapy of 25 mg/kg bid Compound I and 450 μg 1×/wk peginterferon alfa-2a was administered to mice, 2843% ILS was achieved. As such, ILS achieved by the combination therapy is significantly better than correlative monotherapy results at p<0.05.
  • It is important to note that no increased toxicity was seen in the combination groups and there was no antagonism between the two agents.
  • These studies indicate that treating patients with a combination of Compound I and peginterferon alfa-2a is superior to treatment with either agent alone, and that combining the two agents allows for reduction in the dose of either agent needed to obtain equivalent or better results.
    • EXAMPLES
  • The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.
  • Abbreviations used herein are as follows:
  • q.s. as much as needed
    x times
    po orally
    sc subcutaneously
    bid twice daily
    wk week
    BWL body weight loss
    • Example 1
  • This example describes the formation of a suspension comprising Compound 1.
  • A solid molecular complex comprising Compound I and hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) was first formed.
  • Compound I and HPMC-AS in a ratio of approximately 3:7, respectively, were dissolved in dimethylacetamide (DMA). The resulting solution was then added with stirring to very cold dilute hydrochloric acid resulting in the co-precipitation of Compound I and HPMC-AS as a solid molecular complex wherein Compound I was present in a nanoparticulate size range. The ratio of DMA to acid was in the range of 1:5 to 1:10.
  • The co-precipitate was then washed with water to remove DMA, filtered, dried to <2% moisture content and passed through a #30 mesh screen prior to evaluation. The resulting solid molecular complex was 30% by weight Compound I and 70% by weight HPMC.
  • The complex was then blended with colloidal silicon dioxide (available as Aerosil® 200 from Evonik Industries AG, Essen, Germany) such that, per 100 g of the blend, 97 g was the complex and 3 g was colloidal silicon dioxide.
  • An aqueous vehicle containing 2% hydroxypropylcellulose (available as Klucel® LF from Aqualon, Wilmington, Del., USA) and 1N HCL at Qs to pH4 for the purpose of pH adjustment was then prepared. 23.2 mL of the vehicle was equilibrated to room temperature and slowly transferred into 773.2 mg of the aforementioned blend. The resulting preparation was then slowly mixed until a homogenous suspension was obtained. The suspension was stored at 2-8° C. and protected from light.
  • The suspension contained 9.375 mg/mL of Compound I.
    • Example 2
  • This example describes an injectable solution of peginterferon alfa-2a.
  • Component Amount
    Peginterferon alfa-2a 4.5 mg
    Benzyl alcohol 10.0 mg
    Sodium chloride 8.00 mg
    Sodium acetate trihydrate 2.617 mg
    Acetic acid, glacial 0.0462 mg
    Polysorbate
    80 0.05 mg
    Sodium acetate trihydrate, 10% w/v q.s. pH 6.0
    Acetic acid, 10% w/v q.s., pH 6.0
    Water for injection q.s. to 1.0 ml

    The solution was stored at 2 to 8° C.
    • Example 3
  • Mice were implanted with human LOX-IMVI melanoma cell xenografts. The mice, cell line used, and implantation are described below.
  • Female athymic Crl:NU-Foxn1nu mice were used for efficacy testing (Charles River, Wilmington, Mass., USA). Mice were 10-12 weeks of age and weighed 23-25 grams. The health of the mice was assessed daily by observation and analysis of blood samples taken from sentinel animals on shared shelf racks. All animals were allowed to acclimate and recover from shipping-related stress for one week. Autoclaved water and irradiated food (5058-ms Pico Lab mouse chow, Purina Mills, Richmond, Ind., USA) were provided ad libitum, and the animals were kept in a 12 hour light and dark cycle. Cages, bedding and water bottles were autoclaved before use and changed weekly. All animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals, local regulations, and protocols approved by the Roche Animal Care and Use Committee in our AAALAC accredited facility.
  • LOX-IMVI cells (aka LOX, National Cancer Institute—Bethesda, Md.) were grown in RPMI-1640 medium supplemented with 10% Fetal Bovine Serum (FBS) and 1% of 200 nM L-glutamine, scaled up, harvested, and prepared so that each mouse received 2×106 cells/0.2 ml calcium and magnesium free phosphate-buffered saline (PBS). Cells were implanted in the subcutaneous right flank of each mouse.
  • Mice implanted with human xenografts were randomized into eight groups of 10 mice each according to tumor volume so that all groups had similar starting mean tumor volumes. The approximate starting mean tumor volume for this study was 130 mm3.
    • Example 4
  • Compound I was formulated as a suspension as described in example 1. Peginterferon alfa-2a was formulated as an injectable solution as described in example 2.
  • Treatment began on day 5 post-cell implant and ended at day 18 post-cell implant. Four groups of mice developed in example 3 were used. Each group was subjected to a different therapy as follows:
  • (1) mice receiving Compound I vehicle bid po and peginterferon alfa-2a vehicle 1×/wk sc;
    (2) mice receiving Compound I at 75 mg/kg bid bid po;
    (3) mice receiving peginterferon alfa-2a at 900 μg 1×/wk sc; and
    (4) mice receiving Compound I at 75 mg/kg bid bid po and peginterferon alfa-2a at 900 μg 1×/wk sc.
  • The Compound I suspension and its corresponding vehicle were dosed using a sterile 1 cc syringe and 18-gauge gavage needle (0.2 ml/animal) twice daily. The peginterferon alfa-2a solution and its corresponding vehicle were dosed using a sterile 1 cc syringe and 26-gauge needle (0.2 ml/animal) once weekly on days 5 and 12 post-cell implant for a total of two injections.
  • Tumor measurements were taken once or twice per week. All animals were individually followed throughout the experiment.
  • Weight loss was graphically represented as percent change in mean group body weight, using the formula: ((W−W0)/W0)×100, where ‘W’ represents mean body weight of the treated group at a particular day, and ‘W0’ represents mean body weight of the same treated group at initiation of treatment. Maximum weight loss was also represented using the above formula, and indicated the maximum percent body weight loss that was observed at any time during the entire experiment for a particular group.
  • Efficacy data was graphically represented as the mean tumor volume±standard error of the mean (SEM). In addition, tumor volumes of treated groups were presented as percentages of tumor volumes of the control groups (% T/C), using the formula: 100×((T−T0)/(C−C0)), where T represented mean tumor volume of a treated group on a specific day during the experiment, T0 represented mean tumor volume of the same treated group on the first day of treatment; C represented mean tumor volume of a control group on the specific day during the experiment, and C0 represented mean tumor volume of the same treated group on the first day of treatment.
  • Tumor volume (in cubic millimeters) was calculated using the ellipsoid formula: (D×(d2))/2, where “D” represents the large diameter of the tumor and “d” represents the small diameter.
  • Also, tumor regression and/or percent change in tumor volume was calculated using the formula: ((T−T0)/T0)×100, where ‘T’ represents mean tumor volume of the treated group at a particular day, and ‘T0’ represents mean tumor volume of the same treated group at initiation of treatment.
  • Statistical analysis was determined by the rank sum test and One Way Anova and a post-hoc Bonferroni t-test (SigmaStat, version 2.0, Jandel Scientific, San Francisco, Calif., USA). Differences between groups were considered to be significant when the probability value (p) was ≦0.05.
  • For survival assessment, the percent of increased life space (ILS) was calculated as: 100×[(median survival day of treated group−median survival day of control group)/median survival day of control group]. Median survival was determined utilizing Kaplan Meier survival analysis. Survival in treated groups was statistically compared with the vehicle group and survival comparisons were done between groups using the log-rank test (Graph Pad Prism, La Jolla, Calif., USA). Differences between groups were considered significant when the probability value (p) was ≦0.05.
    • Toxicity
  • No signs of toxicity were noted in any dose group in any of the studies described as assessed by measuring changes in body weight and gross observation of individual animals. These results are depicted in Table 1 and FIG. 1.
  • TABLE 1
    % Change in
    Body Weight at Max % Max %
    end of Study Weight Weight # animals ≧20%
    Group Frequency Route Day 18 Loss Gain BWL Mortality
    Combo bid, 1x/wk po, sc 13.5 5.3 13.5 0 0
    Vehicle
    Compound I bid po −7.0 −7.0 −3.6 0 0
    75 mg/kg
    Peginterferon 1x/wk sc 2.7 0.7 2.7 0 0
    alfa-2a 900 μg
    Compound I bid, 1x/wk po, sc −1.1 −1.1 0.5 0 0
    75 mg/kg +
    Peginterferon
    alfa-2a 900 μg
    • Tumor Growth Inhibition (TGI)
  • The group receiving Compound I monotherapy at 75 mg/kg bid exhibited greater than 100% TGI with 10 out of 10 complete regressions (CRs). The group receiving peginterferon alfa-2a monotherapy at 900 μg 1×/wk exhibited 98% TGI, 2 partial regressions (PRs) and 3 CRs out of 10. The group receiving combination therapy of Compound I at 75 mg/kg bid and peginterferon alfa-2a at 900 μg 1×/wk exhibited greater than 100% TGI with 10 out of 10 CRs. See Tables 2 and 3 and FIG. 2.
  • TABLE 2
    Mean Tumor Mean Tumor
    Volume (mm3) Volume (mm3)
    Start Study End Study
    Group Frequency Route DAY: 5 SEM SD DAY: 18 SD SEM
    Combo Vehicle bid, 1x/wk po, sc 132.83 ±2.65 ±8.38 3918.69 ±914.15 ±289.08
    Compound I bid po 134.36 ±2.52 ±7.98 0.00 ±0.00 ±0.00
    75 mg/kg
    Peginterferon 1x/wk sc 131.77 ±2.84 ±8.98 193.98 ±220.41 ±69.70
    alfa-2a 900 μg
    Compound I bid, 1x/wk po, sc 131.79 ±1.68 ±5.32 0.00 ±0.00 ±0.00
    75 mg/kg +
    Peginterferon
    alfa-2a 900 μg
  • TABLE 3
    % T/C % Inhibition end P value Average
    end of study of study End of study % Regression per Partial Complete Animals per % Tumor Growth
    Group Day: 18 Day: 18 Day: 18 Group Regression Regression Group Inhibition
    Combo Vehicle — — — — 0 0 10 —
    Compound I −4 regression <0.001 100 0 10 10 >100
    75 mg/kg bid
    Peginterferon alfa- 2 98 <0.001 — 2 3 10 98
    2a 900 μg 1x/wk
    Compound I −3 regression <0.001 100 0 10 10 >100
    75 mg/kg bid +
    Peginterferon alfa-
    2a 900 μg 1x/wk
    • Assessment of Survival
  • The group receiving Compound I monotherapy at 75 mg/kg bid exhibited 3500% increased life span (ILS). The group receiving peginterferon alfa-2a monotherapy at 900 μg 1×/wk exhibited 143% ILS. The group receiving combination therapy of Compound I at 75 mg/kg bid and peginterferon alfa-2a at 900 μg 1×/wk exhibited 3400% ILS. See Table 4 and FIG. 3.
  • TABLE 4
    ILS Calculations
    50% 50%
    Treatment Vehicle % P
    Group Days Days ILS value
    Combo Vehicle — — — —
    Compound I 504 14 3500 <0.0001
    75 mg/kg bid
    Peginterferon alfa-2a 34 14 143 <0.0001
    900 μg 1x/wk
    Compound I 490 14 3400 <0.0001
    75 mg/kg bid +
    Peginterferon alfa-2a
    900 μg 1x/wk
    • Statistical Analysis
  • The % TGI in the Compound I 75 mg/kg bid/peginterferon alfa-2a 900 μg 1×/wk combination therapy group was statistically superior to that of the peginterferon alfa-2a 900 μg 1×/wk monotherapy group but equivalent to that of the Compound I 75 mg/kg bid monotherapy group. The % ILS in the Compound I 75 mg/kg bid/peginterferon alfa-2a 900 μg 1×/wk combination therapy group was statistically superior to that of the peginterferon alfa-2a 900 μg 1×/wk monotherapy group but equivalent to that of the Compound I 75 mg/kg bid monotherapy group. See Table 5.
  • TABLE 5
    TGI ILS
    Treatment versus Treatment p value* p value **
    Compound I Peginterferon alfa-2a <0.05 <0.0001
    75 mg/kg bid 900 μg 1x/wk
    Compound I Compound I >0.05 0.1343
    75 mg/kg bid 75 mg/kg bid +
    Peginterferon alfa-2a
    900 μg 1x/wk
    Peginterferon Compound I <0.05 <0.0001
    alfa-2a 75 mg/kg bid +
    900 μg 1x/wk Peginterferon alfa-2a
    900 μg 1x/wk
    *One-Way ANOVA, post-hoc Bonferroni
    ** Breslow-Gehan-Wilcoxon
    • Example 5
  • Compound I was formulated as a suspension as described in example 1. The Compound I vehicle was 2.0 grams of Klucel LF in Peginterferon alfa-2a was formulated as an injectable solution as described in example 2.
  • Treatment began on day 6 post-cell implant and ended at day 19 post-cell implant. Four groups of mice developed in example 3 were used. The treatment groups were as follows:
  • (1) mice receiving Compound I vehicle bid po and peginterferon alfa-2a vehicle 1×/wk sc;
    (2) mice receiving Compound I at 25 mg/kg bid po;
    (3) mice receiving peginterferon alfa-2a at 450 μg 1×/wk sc; and
    (4) mice receiving Compound I at 25 mg/kg bid and peginterferon alfa-2a at 450 μg 1×/wk.
  • The Compound I suspension and its corresponding vehicle were dosed using a sterile 1 cc syringe and 18-gauge gavage needle (0.2 ml/animal) twice daily. The peginterferon alfa-2a solution and its corresponding vehicle were dosed using a sterile 1 cc syringe and 26-gauge needle (0.2 ml/animal) once weekly on days 6 and 13 post-cell implant for a total of two injections.
  • Tumor measurements were taken once or twice per week. All animals were individually followed throughout the experiment.
  • Weight loss was graphically represented as percent change in mean group body weight, using the formula: ((W−W0)/W0)×100, where ‘W’ represents mean body weight of the treated group at a particular day, and ‘W0’ represents mean body weight of the same treated group at initiation of treatment. Maximum weight loss was also represented using the above formula, and indicated the maximum percent body weight loss that was observed at any time during the entire experiment for a particular group.
  • Efficacy data was graphically represented as the mean tumor volume±standard error of the mean (SEM). In addition, tumor volumes of treated groups were presented as percentages of tumor volumes of the control groups (% T/C), using the formula: 100×((T−T0)/(C−C0)), where T represented mean tumor volume of a treated group on a specific day during the experiment, T0 represented mean tumor volume of the same treated group on the first day of treatment; C represented mean tumor volume of a control group on the specific day during the experiment, and C0 represented mean tumor volume of the same treated group on the first day of treatment.
  • Tumor volume (in cubic millimeters) was calculated using the ellipsoid formula: (D×(d2))/2, where “D” represents the large diameter of the tumor and “d” represents the small diameter.
  • Also, tumor regression and/or percent change in tumor volume was calculated using the formula: ((T−T0)/T0)×100, where ‘T’ represents mean tumor volume of the treated group at a particular day, and ‘T0’ represents mean tumor volume of the same treated group at initiation of treatment.
  • Statistical analysis was determined by the rank sum test and One Way Anova and a post-hoc Bonferroni t-test (SigmaStat, version 2.0, Jandel Scientific, San Francisco, Calif., USA). Differences between groups were considered to be significant when the probability value (p) was <0.05.
  • For survival assessment, the percent of increased life space (ILS) was calculated as: 100×[(median survival day of treated group−median survival day of control group)/median survival day of control group]. Median survival was determined utilizing Kaplan Meier survival analysis. Survival in treated groups was statistically compared with the vehicle group and survival comparisons were done between groups using the log-rank test (Graph Pad Prism, La Jolla, Calif., USA). Differences between groups were considered significant when the probability value (p) was ≦0.05.
    • Toxicity
  • No signs of toxicity were noted in any dose group in any of the studies described as assessed by measuring changes in body weight and gross observation of individual animals. These results are depicted in Table 6 and FIG. 4.
  • TABLE 6
    % Change in
    Body Weight at Max % Max %
    end of Study Weight Weight # animals ≧20%
    Group Frequency Route Day 19 Loss Gain BWL Mortality
    Combo bid, 1x/wk po, sc 15.1 3.3 15.1 0 0
    Vehicle
    Compound I bid po 1.3 −1.0 1.3 0 0
    25 mg/kg
    Peginterferon 1x/wk sc 8.1 3.7 8.1 0 0
    alfa-2a 450 μg
    Compound I bid, 1x/wk po, sc 2.1 0.1 2.1 0 0
    25 mg/kg +
    Peginterferon
    alfa-2a 450 μg
    • Tumor Growth Inhibition (TGI)
  • The group receiving Compound I monotherapy at 25 mg/kg bid exhibited greater than 100% TGI with 10 out of 10 CRs. The group receiving peginterferon alfa-2a monotherapy at 450 μg 1×/wk exhibited greater than 100% TGI, 6 PRs and 1 CR out of 10. The group receiving combination therapy of Compound I at 25 mg/kg bid and peginterferon alfa-2a at 450 μg 1×/wk exhibited greater than 100% TGI with 10 out of 10 complete regressions (CRs). See Tables 7 and 8 and FIG. 5.
  • TABLE 7
    Mean Tumor Mean Tumor
    Volume (mm3) Volume (mm3)
    Start Study End Study
    Group Frequency Route DAY: 6 SEM SD DAY: 19 SD SEM
    Combo Vehicle bid, 1x/wk po, sc 130.71 ±1.46 ±4.63 2906.48 ±463.14 ±146.46
    Compound I bid po 131.02 ±2.06 ±6.52 0.00 ±0.00 ±0.00
    25 mg/kg
    Peginterferon 1x/wk sc 131.12 ±1.19 ±3.77 122.93 ±117.57 ±37.18
    alfa-2a 450 μg
    Compound I bid, 1x/wk po, sc 132.29 ±1.53 ±4.84 0.00 ±0.00 ±0.00
    25 mg/kg +
    Peginterferon
    alfa-2a 450 μg
  • TABLE 8
    % T/C % Inhibition end P value Average
    end of study of study End of study % Regression per Partial Complete Animals per % Tumor Growth
    Group Day: 19 Day: 19 Day: 19 Group Regression Regression Group Inhibition
    Combo Vehicle — — — — 0 0 10 —
    Compound I −5 regression <0.001 100 0 10 10 >100
    25 mg/kg bid
    Peginterferon alfa- 0 regression <0.001 6 6 1 10 >100
    2a 450 μg 1x/wk
    Compound I −5 regression <0.001 100 0 10 10 >100
    25 mg/kg bid +
    Peginterferon alfa-
    2a 450 ug 1x/wk
    • Assessment of Survival
  • The group receiving Compound I monotherapy at 25 mg/kg bid exhibited 321% increased life span (ILS). The group receiving peginterferon alfa-2a monotherapy at 450 μg 1×/wk exhibited 114% ILS. The group receiving combination therapy of Compound I at 25 mg/kg bid and peginterferon alfa-2a at 450 μg 1×/wk exhibited 2843% ILS. See Table 9 and FIG. 6.
  • TABLE 9
    ILS Calculations
    50% 50%
    Treatment Vehicle % P
    Group Days Days ILS value
    Combo Vehicle — — — —
    Compound I 59 14 321 <0.0001
    25 mg/kg bid
    Peginterferon alfa-2a 30 14 114 <0.0001
    450 μg 1x/wk
    Compound I 412 14 2843 <0.0001
    25 mg/kg bid +
    Peginterferon alfa-2a
    450 μg 1x/wk
  • The % TGI in the Compound I 25 mg/kg bid/peginterferon alfa-2a 450 μg 1×/wk combination therapy group was statistically superior to that of the peginterferon alfa-2a 450 μg 1×/wk monotherapy group but equivalent to that of the Compound I 25 mg/kg bid monotherapy group. The % ILS in the Compound I 25 mg/kg bid/peginterferon alfa-2a 450 μg 1×/wk combination therapy group was statistically superior to that each monotherapy group. See Table 10.
  • TABLE 10
    TGI ILS
    Treatment versus Treatment p value* p value **
    Compound I Peginterferon alfa-2a <0.05 <0.0001
    25 mg/kg bid 450 μg 1x/wk
    Compound I Compound I >0.05 0.0464
    25 mg/kg bid 125 mg/kg bid +
    Peginterferon alfa-2a
    450 μg 1x/wk
    Peginterferon Compound I <0.05 <0.0001
    alfa-2a 25 mg/kg bid +
    450 μg 1x/wk Peginterferon alfa-2a
    450 μg 1x/wk
    *One-Way ANOVA, post-hoc Bonferroni
    ** Breslow-Gehan-Wilcoxon

Claims (6)

1-17. (canceled)
18: A kit comprising: (A) a first component which comprises, as an active agent, propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo [2,3-b] pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide, or a pharmaceutically-acceptable salt thereof; and (B) a second component which comprises, as an active agent, an interferon.
19: A kit according to claim 18, for use in the treatment of a proliferative disorder.
20: A composition comprising: (A) a first component which comprises, as an active agent, propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo [2,3-b] pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide, or a pharmaceutically-acceptable salt thereof; and (B) a second component which comprises, as an active agent, an interferon.
21: A composition according to claim 20, for use in the treatment of a proliferative disorder.
22-23. (canceled)
US15/063,227 2010-12-14 2016-03-07 Combination therapy Abandoned US20160256529A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US15/063,227 US20160256529A1 (en) 2010-12-14 2016-03-07 Combination therapy

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US42269010P 2010-12-14 2010-12-14
US13/313,042 US9295669B2 (en) 2010-12-14 2011-12-07 Combination therapy for proliferative disorders
US15/063,227 US20160256529A1 (en) 2010-12-14 2016-03-07 Combination therapy

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US13/313,042 Division US9295669B2 (en) 2010-12-14 2011-12-07 Combination therapy for proliferative disorders

Publications (1)

Publication Number Publication Date
US20160256529A1 true US20160256529A1 (en) 2016-09-08

Family

ID=45370460

Family Applications (2)

Application Number Title Priority Date Filing Date
US13/313,042 Expired - Fee Related US9295669B2 (en) 2010-12-14 2011-12-07 Combination therapy for proliferative disorders
US15/063,227 Abandoned US20160256529A1 (en) 2010-12-14 2016-03-07 Combination therapy

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US13/313,042 Expired - Fee Related US9295669B2 (en) 2010-12-14 2011-12-07 Combination therapy for proliferative disorders

Country Status (13)

Country Link
US (2) US9295669B2 (en)
EP (1) EP2651414A1 (en)
JP (1) JP5757544B2 (en)
KR (2) KR101628448B1 (en)
CN (1) CN103370066B (en)
AR (1) AR084233A1 (en)
BR (1) BR112013014642A2 (en)
CA (1) CA2819426A1 (en)
HK (1) HK1185808A1 (en)
MX (1) MX2013006362A (en)
RU (1) RU2592983C2 (en)
TW (1) TWI468161B (en)
WO (1) WO2012080151A1 (en)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8709419B2 (en) 2010-08-17 2014-04-29 Hoffmann-La Roche, Inc. Combination therapy
US9216170B2 (en) 2012-03-19 2015-12-22 Hoffmann-La Roche Inc. Combination therapy for proliferative disorders
BR112015003418A2 (en) 2012-08-17 2017-07-04 Hoffmann La Roche pharmaceutical, combined, methods for extending the duration of treatment response, delaying or preventing the development of treatment resistance, selecting a therapy, and optimizing therapeutic efficacy.
PL3072529T3 (en) * 2015-03-26 2018-04-30 Ratiopharm Gmbh Composition comprising vemurafenib and hpmc-as
WO2017004421A1 (en) * 2015-06-30 2017-01-05 The Trustees Of The University Of Pennsylvania Resiquimod topical and injectable compositions for the treatment of neoplastic skin conditions
EP3571200B8 (en) 2017-01-17 2022-08-03 HepaRegeniX GmbH Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
CN112245570A (en) * 2019-07-22 2021-01-22 厦门特宝生物工程股份有限公司 Interferon-based disease treatment method
EP4282427A1 (en) * 2021-01-21 2023-11-29 Xiamen Amoytop Biotech Co., Ltd. Interferon-based cancer treatment method, and pharmaceutical combination

Family Cites Families (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5516807A (en) 1994-10-25 1996-05-14 Warner-Lambert Company Method for treating vascular proliferative disorders following balloon angioplasty
AU2001236529A1 (en) 2000-01-26 2001-08-07 Schering Corporation Combination therapy for cancer
US6545010B2 (en) 2000-03-17 2003-04-08 Aventis Pharma S.A. Composition comprising camptothecin or a camptothecin derivative and a platin derivative for the treatment of cancer
CA2408710C (en) 2000-05-15 2010-01-26 Celgene Corp. Compositions and methods for the treatment of colorectal cancer
KR20030063360A (en) 2000-10-13 2003-07-28 비온 퍼마슈티컬즈 인코포레이티드 Modified prodrug forms of AP/AMP
RU2179859C1 (en) 2001-05-22 2002-02-27 Центральный научно-исследовательский рентгено-радиологический институт Method for treating the cases of renal cell carcinoma
GB0123400D0 (en) 2001-09-28 2001-11-21 Novartis Ag Organic compounds
CA2383259A1 (en) 2002-04-23 2003-10-23 Celator Technologies Inc. Synergistic compositions
US20080193445A1 (en) 2002-01-18 2008-08-14 Liliane Goetsch Novel anti-IGF-IR antibodies and uses thereof
JP2005534623A (en) 2002-04-08 2005-11-17 スミスクライン ビーチャム コーポレーション ERB family inhibitors and methods of treating cancer comprising administering RAF and / or RAS inhibitors
EA009668B1 (en) 2003-03-19 2008-02-28 Арес Трейдинг С.А. Ifn-beta alone or in combination with other medicaments for treating alzheimer's disease and demens disorders
JP2006523655A (en) 2003-04-17 2006-10-19 アレス トレーディング ソシエテ アノニム Interferon beta in severe acute respiratory syndrome (SARS)
US8007826B2 (en) * 2003-12-11 2011-08-30 Acorda Therapeutics, Inc. Sustained release aminopyridine composition
SI1696920T1 (en) 2003-12-19 2015-02-27 Plexxikon Inc. Compounds and methods for development of ret modulators
US20070281041A1 (en) 2004-03-02 2007-12-06 Introgen Therapeutics, Inc. Compositions and Methods Involving MDA-7 for the Treatment of Cancer
TW200533339A (en) 2004-03-16 2005-10-16 Bristol Myers Squibb Co Therapeutic synergy of anti-cancer compounds
RU2006146625A (en) 2004-06-03 2008-07-20 Ф.Хоффманн-Ля Рош Аг (Ch) TREATMENT WITH IRINOTEKAN (SRT-11) AND AN EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITOR (EGFR)
KR100851271B1 (en) 2004-06-03 2008-08-08 에프. 호프만-라 로슈 아게 Treatment with irinotecan cpt-11 and an egfr-inhibitor
EP1785484B1 (en) 2004-06-30 2011-06-01 Japan Science and Technology Agency Oligonucleotide inhibiting tumor cell proliferation and method therefor
JP2008535508A (en) 2005-04-14 2008-09-04 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング Anti-EGFR antibody therapy based on increased copy number EGFR gene in tumor tissue
WO2006119395A2 (en) 2005-05-03 2006-11-09 Biopolymer Engineering, Inc. Combination of a beta-glucan and an egf receptor antagonist for the treatment of cancer and infection
US20060257400A1 (en) 2005-05-13 2006-11-16 Bristol-Myers Squibb Company Combination therapy
PE20070100A1 (en) 2005-06-22 2007-03-10 Plexxikon Inc PIRROLO [2,3-b] PYRIDINE DERIVATIVES AS KINE MODULATORS
EP2130822A1 (en) 2005-12-01 2009-12-09 F. Hoffmann-La Roche AG 2,4,5-triphenyl imidazoline derivatives as inhibitors of the interaction between p53 and mdm2 proteins for use as anticancer agents
JP2009535372A (en) 2006-05-03 2009-10-01 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト Combination of anti-EDB fibronectin domain antibody L19-SIP and anti-EGFR-antibody
US20100004253A1 (en) 2006-09-19 2010-01-07 Novartis Ag Biomarkers of target modulation, efficacy, diagnosis and/or prognosis for raf inhibitors
JPWO2008111441A1 (en) 2007-03-05 2010-06-24 協和発酵キリン株式会社 Pharmaceutical composition
CN105177014B (en) 2007-08-01 2018-04-06 艾德拉药物股份有限公司 TLR9 synthetic activator
US8354444B2 (en) 2008-09-18 2013-01-15 Hoffmann-La Roche Inc. Substituted pyrrolidine-2-carboxamides
MX2011008303A (en) 2009-04-03 2011-11-29 Plexxikon Inc Propane- i-sulfonic acid {3- [5- (4 -chloro-phenyl) -1h-pyrrolo [2, 3-b] pyridine-3-carbonyl] -2, 4-difluoro-pheny l } -amide compositions and uses thereof.
WO2010120759A1 (en) 2009-04-14 2010-10-21 Schering Corporation Interferon-alfa sensitivity biomarkers
CN102459647B (en) 2009-05-21 2015-05-06 默沙东公司 Genetic markers associated with interferon-alpha response
BR112012003926A2 (en) 2009-08-24 2020-08-11 Genentech Inc method for identifying a patient unresponsive to treatment with a b-raf inhibitor, method for determining whether a tumor will respond to treatment with a b-raf inhibitor, method for predicting whether a patient will be unresponsive to treatment with a b-raf inhibitor specific braf, kit, method for classifying a breast, lung, colon, ovary, thyroid, melanoma, or pancreatic tumor and method for identifying a tumor unresponsive to treatment with a b-raf inhibitor
US8709419B2 (en) 2010-08-17 2014-04-29 Hoffmann-La Roche, Inc. Combination therapy
US20120045433A1 (en) 2010-08-17 2012-02-23 Kapil Dhingra Combination therapy
NZ608630A (en) 2010-10-01 2015-03-27 Biogen Idec Inc Interferon-beta for use as monotherapy or in combination with other cancer therapies
US9216170B2 (en) 2012-03-19 2015-12-22 Hoffmann-La Roche Inc. Combination therapy for proliferative disorders

Also Published As

Publication number Publication date
KR101628448B1 (en) 2016-06-08
TWI468161B (en) 2015-01-11
EP2651414A1 (en) 2013-10-23
US20120148533A1 (en) 2012-06-14
WO2012080151A1 (en) 2012-06-21
JP5757544B2 (en) 2015-07-29
AR084233A1 (en) 2013-05-02
RU2592983C2 (en) 2016-07-27
US9295669B2 (en) 2016-03-29
RU2013130926A (en) 2015-01-20
MX2013006362A (en) 2013-07-30
CN103370066B (en) 2015-09-09
CA2819426A1 (en) 2012-06-21
TW201300107A (en) 2013-01-01
HK1185808A1 (en) 2014-02-28
JP2013545772A (en) 2013-12-26
BR112013014642A2 (en) 2020-08-11
CN103370066A (en) 2013-10-23
KR20130092617A (en) 2013-08-20
KR20160031039A (en) 2016-03-21

Similar Documents

Publication Publication Date Title
US20160256529A1 (en) Combination therapy
US9486445B2 (en) Combination therapy for proliferative disorders
US8709419B2 (en) Combination therapy
US20120045433A1 (en) Combination therapy
CN117355297A (en) Methods and compositions for inducing brown adipogenesis

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

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