WO2016164336A1 - Traitement du carcinome hépatocellulaire à l'aide d'une combinaison de cc 122 et de sorafenib - Google Patents

Traitement du carcinome hépatocellulaire à l'aide d'une combinaison de cc 122 et de sorafenib Download PDF

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Publication number
WO2016164336A1
WO2016164336A1 PCT/US2016/025986 US2016025986W WO2016164336A1 WO 2016164336 A1 WO2016164336 A1 WO 2016164336A1 US 2016025986 W US2016025986 W US 2016025986W WO 2016164336 A1 WO2016164336 A1 WO 2016164336A1
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compound
solvate
acceptable salt
pharmaceutically acceptable
administered
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PCT/US2016/025986
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English (en)
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Michael POURDEHNAD
Anita GANDHI
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Celgene Corporation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives 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
    • A61K31/70—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
    • A61K31/7072—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 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Hepatocellular carcinoma also known as malignant hepatoma, is the most common primary malignancy of the liver and accounts for 80-90% of primary liver tumors. HCC is one of the most common and devastating malignant diseases worldwide, responsible for more than 1 million deaths annually in the world (Parkin et al, CA Cancer J. Clin. 1999, 49, 33-64; Bruix et al, Cancer Cell 2004, 5, 215-219).
  • HCC hepatitis B or C viral infection
  • alcoholic liver disease Rustgi, Gastroenterol. Clin. North Am. 1987, 16, 545-551; Bosch et al, Semin. Liver Dis. 1999, 19, 271-285; Bosch et al,
  • HCC hepatitis B virus
  • HCV hepatitis C virus
  • HCC is associated with HBV infection in about 50% of cases (Liaw, Semin. Liver Dis. 2005, 25, 40-47). HCV infection is the cause of 70% of the cases of HCC in Japan (Hasan, et al, Hepatology, 1990, 12:589-591; El-Serag et al, N. Engl. J. Med. 1999, 340, 745-750). The HCC incidence has been increasing in Western countries in recent years due to the spread of hepatitis C virus (HCV) infection (El- Serag, Hepatology 2002, 36, S74-83; Trevisani et al, Carcinogenesis 2008, 29, 1299- 1305).
  • HCV hepatitis C virus
  • HCC human cancer
  • Five-year survival rates for advanced stage disease are only 3% to 5% worldwide.
  • HCC that is diagnosed at an advanced stage or with progression after locoregional therapy has dismal prognosis, owing to the underlying liver disease and the lack of effective treatment option.
  • the risk of recurrence is approximately 70% at 5 years after resection and prognosis after recurrence is poor.
  • Patients with HCC of Stage B and C have a median survival ranging from 10 to 14 months following appropriate treatments.
  • HCC hepatocellular carcinoma
  • compositions, dosage forms, dosing regimen in connection with the above-described methods.
  • HCC hepatocellular carcinoma
  • HCC hepatocellular carcinoma
  • administering to a patient in need thereof a therapeutically or prophylactically effective amount of Compound A of following formula, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: in combination with a therapeutically or prophylactically effective amount of sorafenib, or a pharmaceutically acceptable salt or solvate thereof.
  • HCC is unresectable HCC.
  • compositions are provided herein.
  • dosage forms are provided herein.
  • Figure 1 is a schematic illustration of overall design for clinical study of combination therapy for hepatocellular carcinoma.
  • Figure 2 is a table summarizing the list of events during clinical study.
  • Figure 3 shows the effects of Compound A concentration on colony formation of JHH4 cell line.
  • Figure 4 shows the enhanced inhibition effects of combination of Compound A with sorafenib on colony formation of JHH4 cell line.
  • Figure 5 shows the enhanced inhibition effects of combination of sorafenib with Compound A on colony formation of JHH4 cell line.
  • Figure 6 shows the effects of combination of Compound A with sorafenib on IL-2 secretion in 72 hour anti-CD3 -stimulated CD3+ T-cell assay.
  • Figure 7A shows the enhanced effects of combination of Compound A with sorafenib or Compound A with DC-101 on tumor volume.
  • Figures 7B and 7C show enhancement of tumor cell apoptosis and vascular normalization by the combination treatment, while tumor cell proliferation is significantly decreased.
  • Figure 7D shows enhanced effects of combination of Compound A with sorafenib on animal survival.
  • treat refers to alleviating or abrogating a disease, e.g., hepatocellular carcinoma, or one or more of the symptoms associated with the disease; or alleviating or eradicating the cause(s) of the disease itself.
  • the term “preventing” refers to the treatment with or administration of a compound provided herein, with or without other additional active compound, prior to the onset of symptoms, particularly to patients at risk of cancer and/or other disorders described herein.
  • the term “prevention” includes the inhibition or reduction of a symptom of the particular disease. Patients with familial history of a disease in particular are candidates for preventive regimens in certain embodiments. In addition, patients who have a history of recurring symptoms are also potential candidates for the prevention. In this regard, the term “prevention” may be interchangeably used with the term “prophylactic treatment.”
  • “managing” and “management” refer to preventing or slowing the progression, spread or worsening of a disease or disorder, or of one or more symptoms thereof. In certain cases, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disease or disorder.
  • the term "therapeutically effective amount" of a compound refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of a disease, e.g., hepatocellular carcinoma, being treated.
  • the term also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • a therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of a disease, e.g., hepatocellular carcinoma.
  • the term encompasses an amount that improves overall therapy, reduces, or avoids symptoms or causes of a disease, e.g., hepatocellular carcinoma, or enhances the therapeutic efficacy of another therapeutic agent.
  • a prophylactically effective amount of a compound is an amount sufficient to inhibit or reduce a symptom of a disease or to prevent recurrence of a disease.
  • a prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the inhibition or reduction of a symptom of a disease or recurrence of a disease.
  • the term "prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • the term "pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
  • suitable non-toxic acids include inorganic and organic acids such as, but not limited to, acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucuronic, galacturonic, glycidic, hydrobromic,
  • suitable are hydrochloric, hydrobromic, phosphoric, and sulfuric acids.
  • solvate means a compound that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
  • stereoisomer encompasses all enantiomerically/stereomerically pure
  • stereomerically pure means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound.
  • a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20%) by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10%> by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, greater than about 98% by weight of one stereoisomer of the compound and less than about 2% by weight of the other stereoisomers of the compound or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound.
  • stereomerically enriched means a composition that comprises greater than about 55% by weight of one stereoisomer of a compound, greater than about 60% by weight of one stereoisomer of a compound, greater than about 70% by weight, or greater than about 80% by weight of one stereoisomer of a compound.
  • enantiomerically pure means a stereomerically pure composition of a compound having one chiral center.
  • enantiomerically enriched means a stereomerically enriched composition of a compound having one chiral center.
  • “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about” or
  • the compound suitable for use in the methods provided herein is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6- (Compound A) having the structure of the following formula:
  • Compound A can be prepared according to the methods described in the Examples provided herein or as described in U.S. Pat. No. 7,635,700, the disclosure of which is incorporated herein by reference in its entirety.
  • the compound can be also synthesized according to other methods apparent to those of skill in the art based upon the teaching herein.
  • TNF-a is
  • TNF-a inflammatory cytokine produced by macrophages and monocytes during acute inflammation.
  • TNF-a is responsible for a diverse range of signaling events within cells. TNF-a may play a pathological role in cancer. Without being limited by theory, one of the biological effects exerted by Compound A is the reduction of synthesis of TNF-a. Compound A enhances the degradation of TNF-a mRNA. Compound A also potently inhibits IL-1 ⁇ , IL-2, upregulates interferon, and stimulates IL-10 under these conditions.
  • Compound A is a potent co- stimulator of T cells and increase cell proliferation in a dose dependent manner under appropriate conditions.
  • the biological effects exerted by Compound A include, but not limited to, anti-angiogenic and immune modulating effects.
  • Compound A is a solid. In certain embodiments, Compound A is hydrated. In certain embodiments, Compound A is solvated. In certain embodiments, Compound A is anhydrous. In certain embodiments, Compound A is nonhygroscopic.
  • Compound A is amorphous.
  • Compound A is crystalline. In certain embodiments, Compound A is in a crystalline form described in U.S. Publication No. 2012/0232100-A1, which is incorporated herein by reference in its entirety.
  • the solid forms of Compound A can be prepared according to the methods described in the disclosure of U.S. Publication No. 2012/0232100-A1.
  • the solid forms can be also prepared according to other methods apparent to those of skill in the art.
  • Compound A is a hydrochloride salt of 3-(5-amino- 2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
  • the hydrochloride salt is a solid.
  • the hydrochloride salt is anhydrous.
  • the hydrochloride salt is nonhygroscopic.
  • the hydrochloride salt is amorphous.
  • the hydrochloride salt is crystalline.
  • the hydrochloride salt is in crystalline Form A.
  • hydrochloride salt of Compound A and solid forms thereof can be prepared according to the methods described in the disclosure of U.S. Publication No. 2012/0232100-A1.
  • the hydrochloride salt the solid forms thereof can be also prepared according to other methods apparent to those of skill in the art.
  • Compound A provided herein contains one chiral center, and can exist as a mixture of enantiomers, e.g., a racemic mixture.
  • This disclosure encompasses the use of stereomerically pure forms of such a compound, as well as the use of mixtures of those forms.
  • mixtures comprising equal or unequal amounts of the enantiomers of Compound A provided herein may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents.
  • Compound A can contain unnatural proportions of atomic isotopes at one or more of the atoms.
  • the compound may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (1251), sulfur 35 (35S), or carbon-14 (14C), or may be isotopically enriched, such as with deuterium (2H), carbon-13 (13C), or nitrogen-15 (15N).
  • an “isotopologue” is an isotopically enriched compound.
  • the term “isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom.
  • isotopically enriched may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.
  • isotopic composition refers to the amount of each isotope present for a given atom.
  • Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of Compound A, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein.
  • isotopologues of Compound A for example, the isotopologues are deuterium, carbon- 13, or nitrogen-15 enriched Compound A.
  • a compound that can be used in connection with methods provided herein is sorafenib, or a pharmaceutically acceptable salt or solvate thereof.
  • Sorafenib is chemically known as 4-(4-(3-(4-chloro-3-
  • Sorafenib is commercially available under the trade name Nexavar®.
  • the compound can also be synthesized using the synthetic methods substantially similar to those described in U.S. Patent No. 7,235,576, the entirety of which is incorporated herein by reference.
  • Sorafenib is a multikinase inhibitor that blocks tumor cell proliferation by targeting the Raf/mitogen-activated protein kinase/extracellular signal regulated kinase (Raf/MEK/ERK) signaling pathway and exerts an anti angiogenic effect by targeting the tyrosine kinases (TKs) VEGF receptor 2 (VEGFR-2),VEGFR-3, and platelet-derived growth factor receptor b (PDGFR-b) (Wilhelm, 2004).
  • TKs tyrosine kinases
  • VEGFR-2 VEGF receptor 2
  • VDGFR-3 platelet-derived growth factor receptor b
  • PDGFR-b platelet-derived growth factor receptor b
  • Sorafenib exhibited growth-inhibitory effects, induction of apoptosis, and down-regulation of the antiapoptotic protein Mcl-1 through a Raf/MEK/ERK-independent mechanism. Sorafenib also acts as an immunomodulator. It was reported sub-pharmacological concentrations of sorafenib activates T cells from HCC patients as measured by cytokine IL-2 production, increased proliferation and upregulation of CD25 cell surface expression while blocking Treg function. In addition, sorafenib triggers pro-inflammatory activity of tumor associated macrophages and subsequently induces antitumor natural killer (NK) cell responses in a cytokine-dependent manner.
  • the compound is a pharmaceutically acceptable salt of sorafenib. In some embodiment, the compound is a tosylate salt of sorafenib.
  • isotopologues of sorafenib for example, the isotopologues are deuterium, carbon-13, or nitrogen-15 enriched sorafenib.
  • HCC hepatocellular carcinoma
  • sorafenib in combination with a therapeutically or prophylactically effective amount of sorafenib, or a pharmaceutically acceptable salt or solvate thereof.
  • HCC is unresectable HCC.
  • the patient has received one or more prior systemic therapies for HCC. In another embodiment, the patient has received no prior systemic therapy for HCC.
  • Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.
  • Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is orally administered.
  • Compound A or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered at an amount of about 0.01 mg to about 100 mg per day, about 0.1 mg to about 75 mg per day, about 0.5 mg to about 50 mg per day, about 0.1 mg to about 25 mg per day, about 1 mg to about 25 mg per day, about 0.5 mg to about 10 mg per day, about 1 mg to about 10 mg per day, about 0.5 mg to about 5 mg per day, about 1 mg to about 5 mg per day, about 1 mg to about 3 mg per day, or about 2 mg to about 5 mg per day.
  • Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered at an amount of about 1 mg to about 5 mg per day. In one embodiment, Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered at an amount of about 1 mg per day. In one embodiment, Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered at an amount of about 2 mg per day. In one embodiment, Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered at an amount of about 3 mg per day. In one embodiment, Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered at an amount of about 4 mg per day.
  • Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered once daily for 28 consecutive days in a 28 days cycle. In one embodiment, Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered once daily for 5 consecutive days followed by 2 days of no administration in a 28 days cycle. In one embodiment, Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered once daily for 21 consecutive days followed by 7 days of no administration in a 28 days cycle.
  • sorafenib, or a pharmaceutically acceptable salt or solvate thereof is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.
  • sorafenib, or a pharmaceutically acceptable salt or solvate thereof is orally administered.
  • sorafenib, or a pharmaceutically acceptable salt or solvate thereof is administered at an amount of about 50 mg per day, about 100 mg per day, about 150 mg per day, about 200 mg per day, about 250 mg per day, about 300 mg per day, about 350 mg per day, about 400 mg per day, about 450 mg per day, about 500 mg per day, about 550 mg per day, about 600 mg per day, about 650 mg per day, about 700 mg per day, about 750 mg per day, or about 800 mg per day.
  • sorafenib or a pharmaceutically acceptable salt or solvate thereof, is administered at an amount of about 400 mg per day.
  • sorafenib or a pharmaceutically acceptable salt or solvate thereof, is administered twice daily for 28 consecutive days in a 28 days cycle.
  • Compound A or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is orally administered at an amount of about 1 mg to about 5 mg per day, and sorafenib, or a pharmaceutically acceptable salt or solvate thereof, is orally administered at an amount of about 400 mg per day.
  • Compound A or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered once daily for 28 consecutive days, and sorafenib, or a pharmaceutically acceptable salt or solvate thereof, is administered twice daily for 28 consecutive days.
  • Compound A or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered once daily for 5 consecutive days followed by 2 days of no administration in a 28 days cycle, and sorafenib, or a pharmaceutically acceptable salt or solvate thereof, is administered twice daily for 28 consecutive days.
  • Compound A or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered once daily for 21 consecutive days followed by 7 days of no administration in a 28 days cycle, and sorafenib, or a pharmaceutically acceptable salt or solvate thereof, is administered twice daily for 28 consecutive days.
  • Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and sorafenib, or a pharmaceutically acceptable salt or solvate thereof may be administered using the same route or via different routes.
  • Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and sorafenib, or a pharmaceutically acceptable salt or solvate thereof may be administered simultaneously or sequentially.
  • Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and sorafenib, or a pharmaceutically acceptable salt or solvate thereof may be administered in one pharmaceutical composition or in separate compositions.
  • compounds provided herein can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID).
  • the administration can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug).
  • Compound A or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and sorafenib, or a pharmaceutically acceptable salt or solvate thereof, may be administered in combination with one or more additional active agents.
  • adozelesin aldesleukin; altretamine; ambomycin; ametantrone acetate; amrubicin;
  • amsacrine amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;
  • azotomycin batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;
  • cactinomycin cactinomycin
  • calusterone caracemide
  • carbetimer carboplatin
  • carmustine carubicin hydrochloride
  • carzelesin cedefingol
  • celecoxib celecoxib (COX-2 inhibitor); chlorambucil
  • cirolemycin cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate;
  • estramustine estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; trasrabine; fenretinide; floxuridine;
  • fludarabine phosphate fluorouracil; flurocitabine; fosquidone; fostriecin sodium;
  • gemcitabine gemcitabine hydrochloride; herceptin; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; lapatinib; letrozole; leuprolide acetate; liarozole hydrochloride;
  • romidepsin safingol; safingol hydrochloride; semustine; pumprazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; stem cell treatments such as PDA-001; streptonigrin; streptozocin; sulofenur; talisomycin;
  • vinepidine sulfate vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;
  • vinrosidine sulfate vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.
  • Other examples include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin;
  • aldesleukin ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine;
  • aminolevulinic acid aminolevulinic acid
  • amrubicin amsacrine
  • anagrelide anastrozole
  • andrographolide angiogenesis inhibitors
  • antagonist D antagonist G
  • antarelix anti-dorsalizing morphogenetic protein- 1
  • antiandrogen prostatic carcinoma
  • antiestrogen ;
  • antineoplaston antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;
  • BCR/ABL antagonists benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; b-FGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine;
  • budotitane buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS);
  • cicaprost cis-porphyrin
  • cladribine clomifene analogues
  • clotrimazole collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;
  • cyclopentanthraquinones cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
  • dexamethasone dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin;
  • diphenyl spiromustine diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;
  • edrecolomab eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; trasrabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;
  • galocitabine ganirelix
  • gelatinase inhibitors gemcitabine
  • glutathione inhibitors glutathione inhibitors
  • hepsulfam hexamethylene bisacetamide; hypericin; ibandronic acid;
  • idarubicin idoxifene; idramantone; ilmofosine; ilomastat; imatinib (e.g., GLEEVEC®), imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone
  • loxoribine lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine;
  • mannostatin A marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth
  • factor-saporin mitoxantrone; mofarotene; molgramostim;Erbitux, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol;
  • myriaporone N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;
  • naloxone+pentazocine napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; oblimersen (GENASENSE ® ); 0 6 -benzylguanine; octreotide; okicenone;
  • oligonucleotides onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;
  • paclitaxel derivatives palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol;
  • phenazinomycin phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors;
  • sargramostim Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; tallimustine; tamoxifen methiodide;
  • tauromustine tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; translation inhibitors;
  • tretinoin triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
  • compositions and dosage forms which comprise: (1) Compound A, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; (2) and sorafenib, or a pharmaceutically acceptable salt or solvate thereof; or (3) a mixture thereof.
  • pharmaceutical compositions and dosage forms further comprise one or more excipients.
  • compositions and dosage forms provided herein also comprise one or more additional active ingredients. Examples of optional second, or additional, active ingredients are disclosed herein elsewhere.
  • Single unit dosage forms provided herein are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal, or transcutaneous administration to a patient.
  • parenteral e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial
  • topical e.g., eye drops or other ophthalmic preparations
  • transdermal e.g., transcutaneous administration to a patient.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions;
  • suppositories powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in- oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
  • suspensions e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in- oil liquid emulsions
  • solutions elixirs
  • liquid dosage forms suitable for parenteral administration to a patient eye drops
  • composition, shape, and type of dosage forms provided herein may vary depending on their use.
  • a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients than a dosage form used in the chronic treatment of the same disease.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients than an oral dosage form used to treat the same disease. See, e.g., Remington's
  • compositions or dosage form provided herein depends on a variety of factors, including, but not limited to, the route of administration.
  • oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms.
  • the suitability of a particular excipient may also depend on the specific active ingredients in the dosage form.
  • the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition. Consequently, encompassed herein are pharmaceutical compositions and dosage forms that contain little, if any, lactose.
  • lactose-free means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
  • Lactose-free compositions provided herein can comprise excipients that are listed, for example, in the U.S. Pharmacopeia (USP) 25 F20 (2002).
  • lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • lactose-free dosage forms comprise active ingredients,
  • microcrystalline cellulose pre-gelatinized starch, and magnesium stearate.
  • anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
  • water can facilitate the degradation of some compounds.
  • water e.g., 5%
  • water is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80.
  • water and heat accelerate the decomposition of some compounds.
  • the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
  • Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, in certain embodiments, provided herein are anhydrous compositions packaged using materials to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients.
  • the dosage forms provided herein comprise
  • the dosage forms provided herein comprise Compound A, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in an amount of about 0.1, about 1, about 2, about 3, about 4, about 5, about 7.5, about 10, about 12.5, about 15, about 17.5, about 20, about 25, about 50, about 100, about 150, or about 200 mg.
  • the dosage forms provided herein comprise sorafenib, or a pharmaceutically acceptable salt or solvate thereof, in an amount ranging from about 1 to about 1000 mg, from about 10 to about 800 mg, from about 50 to about 600 mg, from about 100 to about 700 mg, from about 100 to about 500 mg, from about 300 to about 500 mg, from about 200 to about 400 mg, or from about 350 to about 450 mg.
  • the dosage forms provided herein comprise Compound A, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in an amount of about 50, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, or about 1000 mg.
  • compositions provided herein that are suitable for oral administration are formulated as discrete dosage forms, examples of which include, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients and may be prepared by some known methods of pharmacy. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
  • the oral dosage forms provided herein are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed.
  • tablets can be coated by standard aqueous or nonaqueous techniques.
  • dosage forms may be prepared by some known methods of pharmacy.
  • pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet is prepared by compression or molding.
  • compressed tablets are be prepared by compressing in a suitable machine the active ingredients in a free-flowing form, e.g., powder or granules, optionally mixed with an excipient.
  • molded tablets are made by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
  • Suitable forms of microcrystalline cellulose include, but are not limited to, AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (FMC
  • An specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose (e.g., AVICEL RC-581).
  • Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103TM and Starch 1500 LM.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions provided herein is present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Disintegrants are used in the compositions provided herein to provide tablets the ability to disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms provided herein. The amount of disintegrant used varies based upon the type of formulation. In certain embodiments, the pharmaceutical compositions provided herein comprise from about 0.5 to about 15 weight percent or from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that are suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that are suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, but are not limited to, a syloid silica gel
  • lubricants are used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated. 4.5.2 Delayed release dosage form
  • the active ingredients provided herein are administered by controlled release means or by delivery devices.
  • controlled release means include, but are not limited to, those described in U.S. Patent Nos. : 3,845,770; 3,916,899; 3,536,809; 3,598, 123; 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5, 120,548, 5,073,543,
  • dosage forms are be used to provide slow or controlled-release of one or more active ingredients using, for example,
  • hydropropylmethyl cellulose other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • single unit dosage forms suitable for oral administration including, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
  • controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
  • Controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • drug active ingredient
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms provided herein include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles such as,
  • Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms provided herein.
  • cyclodextrin and its derivatives can be used to increase the solubility of a compound provided herein. See, e.g., U.S. Patent No. 5,134, 127, the disclosure of which is incorporated herein by reference in its entirety.
  • Topical and mucosal dosage forms provided herein include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
  • excipients e.g., carriers and diluents
  • other materials that can be used to provide topical and mucosal dosage forms encompassed herein depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied.
  • the excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3- diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable.
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Additional examples of such ingredients can be found, e.g., in Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990).
  • the pH of a pharmaceutical composition or dosage form may also be adjusted to improve delivery of one or more active ingredients.
  • the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
  • stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
  • stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery- enhancing or penetration-enhancing agent.
  • Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting
  • compounds provided herein are not administered to a patient at the same time or by the same route of administration. Therefore,
  • kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a patient.
  • kits provided herein comprises a dosage form of a compound provided herein.
  • the kit provided herein further comprises additional active ingredients. Examples of the additional active ingredients include, but are not limited to, those disclosed herein elsewhere.
  • the kit provided herein further comprises a device that is used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.
  • the kit provided herein further comprises cells or blood for transplantation as well as pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
  • the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and nonaqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles such as, but not limited to, ethyl alcohol,
  • a Phase lb dose escalation and expansion clinical study of Compound A in combination with sorafenib in subjects with unresectable HCC who have received no prior systemic therapy for HCC is conducted.
  • the dose escalation part of the study initially explores 3 dose levels of Compound A in combination with a fixed dose of sorafenib using a rolling-six dose escalation design, followed by an expansion part.
  • Compound A is initially administered orally continuously once daily (QD) on Days 1 to 28 of each 28-day cycle.
  • the investigated daily doses of Compound A 1.0 mg, 2.0 mg, and 3.0 mg QD.
  • MTD maximum tolerated dose
  • further dose escalation on an intermittent schedule of Compound A either on 5 consequent days out of a week (5 days on/2 days off weekly) or on 21 consequent days out of a 28-day cycle (21 days on/7 days off every 28 days)] starting at a comparable cycle dose intensity, a 4.0 mg
  • Compound A dose QD may be explored at the discretion of the Safety review
  • Compound A dose-levels is fixed at 400 mg BID on Days 1 to 28 of each 28-day cycle.
  • a rolling-six dose escalation design is used to identify the initial toxicity of each combination. Up to six subjects are concurrently enrolled onto a dose level.
  • a subject evaluable for DLT is defined as one who: (1) Received at least 75% of the planned doses of Compound A during Cycle 1 without experiencing a DLT, and (2) Received at least 50% of the planned dose of sorafenib during Cycle 1 without experiencing a DLT, or experienced a DLT after receiving at least one dose of either study drug.
  • a dose is considered the normalized total dose (NTD) when 2 or more out of up to 6 evaluable subjects in a cohort experience a DLT in Cycle 1.
  • the MTD is defined as the last dose level(s) below the NTD with 0 or 1 out of 6 evaluable subjects experiencing a DLT during Cycle 1. If 2 or more DLTs out of up to 6 evaluable subjects are observed at any dose level of the combination given continuously, an intermittent dose of Compound A or intermittent schedule (e.g., 5 days on/2 days off weekly or 21 days on 11 days off every 28 days) may be explored at the discretion of the SRC.
  • An intermediate dose of study drugs (one between the NTD and the last dose level before the NTD) may be evaluated to more precisely determine the MTD of the combination.
  • the dose may be escalated in the next cohort. If one DLT occurs in a given cohort, the cohort must be expanded to enroll a total of 6 evaluable subjects. Once expanded to 6, if 1 DLT occurs out of 6 evaluable subjects the dose may be escalated. If 2 or more subjects out of up to 6 evaluable subjects in a given cohort experience a DLT at any time during enrollment, the NTD will have been met and the last dose level(s) below the NTD with 0 or 1 out of up to 6 evaluable subjects experiencing a DLT during Cycle 1 will be declared the MTD.
  • Non-evaluable subjects without experiencing a DLT will be replaced based on rolling-six rules. Additional subjects within any dose cohort may be enrolled at the discretion of the SRC.
  • the screening period lasts approximately 28 days. Subjects may remain on treatment until clinically significant disease progression, unacceptable toxicity, subject or physician decision, withdrawal of consent, or death. If treatment is discontinued for reason other than disease progression, subjects will continue to be followed until progression. Subjects continue to be followed for survival status until death or until the last subject enrolled completes 24 months of study therapy.
  • Enrollment is expected to take approximately 27 months to complete (18 months for dose escalation, and 6-9 months for expansion). Completion of active treatment and post-treatment follow-up is expected to take an additional 12 to 15 months. The entire study is expected to last approximately 4 years.
  • Dosing starts at Dose Level 1. Each dose level must be cleared by SRC based on all available clinical, safety, PK, PD and laboratory data before initiating the next higher dose level. [00121] If 2 or more DLTs out of up to 6 evaluable subjects are observed at any dose level of the combination given continuously, an intermittent schedule of Compound A (5 days on/2 days off weekly or 21 days on 11 days off every 28 days) may be explored at the discretion of the SRC. An intermediate dose of Compound A (one between the NTD and the last dose level before the NTD, e.g., 1.5 or 2.5 mg daily) as well as an intermittent dosing schedule may be evaluated to more precisely accurately determine the MTD of the combination.
  • the decision to either evaluate a higher dose level, an intermittent dose schedule, or declare an NTD, MTD, or RP2D is determined by the SRC, based on their review of all available clinical PK, PD and laboratory safety data for a given dose cohort.
  • Intra-subject dose escalation of study drugs is not permitted during Cycle 1 but may be permitted in later cycles if approved by the SRC.
  • Study treatment may be discontinued if there is evidence of clinically significant disease progression, unacceptable toxicity or subject/physician decision to withdraw. Subjects may continue to receive study drugs beyond disease progression at the discretion of the Investigator.
  • the estimated total number of subjects to be enrolled during dose escalation is approximately 20 to 40, depending on cohort size. Approximately 30 additional subjects are evaluated for safety, PK, PD, and preliminary anti-tumor effects in the expansion cohort.
  • the End of Trial is defined as either the date of the last visit of the last subject to complete the study, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as pre- specified in the protocol and/or the Statistical Analysis Plan (SAP), whichever is the later date.
  • SAP Statistical Analysis Plan
  • Tumor assessments are performed at screening (up to 28 days before the start of study drugs), every 2 cycles (8 weeks ⁇ 7 days) through cycle 6, thereafter every 3 cycles (12 weeks ⁇ 7 days). Tumor assessments are also performed at any time, if clinically indicated. Tumor assessments continue at the defined schedule until progression, beyond the end of treatment if necessary.
  • New anticancer therapies are also collected at the same schedule.
  • New anticancer therapy includes (but is not limited to) any systemic or locoregional medication, surgery, radiation, or any other therapy intended to treat the subject's cancer.
  • Response assessments include computed tomography (CT) scan or MRI.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • the regions to be imaged are the chest and abdomen/pelvis, as well as any other sites required for tumor imaging.
  • the same mode of imaging for lesion evaluation at screening must be used consistently throughout the study.
  • the CT imaging includes contrast unless medically contraindicated.
  • Mesurable diseases include tumor legions and malignant lymph nodes.
  • Tumor legions must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:
  • a malignant lymph node must be > 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed.
  • All other lesions including small lesions (longest diameter ⁇ 10 mm or pathological lymph nodes with > 10 to ⁇ 15 mm short axis) as well as truly non- measurable lesions are considered non-mesurable disease. Lesions considered truly non- measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques.
  • Nodes that have a short axis ⁇ 10 mm are considered non-pathological and are not recorded or followed.
  • the sum of the target lesions (longest diameter of tumor lesions plus short axis of lymph nodes: overall maximum of 5) is to be recorded.
  • Target lesions are assessed as follows:
  • pathological lymph nodes (whether target or non-target) must have reduction in short axis to ⁇ 10 mm;
  • Non-target lesions will be assessed as follows:
  • CR Complete Response
  • Additional scans including brain scans, MRI of the head, or nuclear medicine bone scan are performed if clinically indicated (e.g., symptoms of brain metastasis) at the discretion of the investigator. 5.2.3 Assessment based on immune-related response criteria (irRC)
  • Percentage changes in tumor burden per assessment time point describe the size and growth kinetics of both conventional and new, measurable lesions as they appear.
  • the response in index and new, measurable lesions is defined based on the change in tumor burden (after ruling out irPD). Decreases in tumor burden must be assessed relative to baseline measurements (i.e., the SPD of all index lesions at screening).
  • the irRC were derived from WHO criteria and, therefore, the thresholds of response remain the same.
  • the overall response according to the irRC is derived from time-point response assessments (based on tumor burden) as follows:
  • irCR complete disappearance of all lesions (whether measurable or not, and no new lesions) - confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented
  • irPR decrease in tumor burden >50%relative to baseline - confirmed by a consecutive assessment at least 4 weeks after first documentation
  • irSD not meeting criteria for irCR or irPR, in absence of irPD
  • irPD increase in tumor burden > 25% relative to nadir (minimum recorded tumor burden) - confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented.
  • Plasma samples are collected to assay plasma concentrations of stereoisomers of Compound A and sorafenib (Compound A is indirectly measured from the
  • Intensive PK sampling is performed in a minimum of 3 subjects at the first dose level at the following time points:
  • a PK sample is collected at or near the time of biopsy in all subjects. In the escalation part, the biopsy is collected on Cycle 2, Day 1 - 15 at 3 to 6 ( ⁇ 1) hours post- dose.
  • Cycle 1 Day 1 - Predose (0 hr) (within 90 minutes prior to dosing) Cycle 1, Day 15 - Predose (0 hr) (within 90 minutes prior to dosing), 1.5
  • Collection is mandatory during dose escalation and dose expansion.
  • the sample is retrieved and sent after subject eligibility is confirmed (Screening), preferably before the end of Cycle 1. If archival tumor tissue is not available or is insufficient for submission, an on screening biopsy is required.
  • Sample may be collected on Day 1-15 of Cycle 2. The sample must be collected at 3 to 6
  • Sample may be collected on Day 15-28 of Cycle 1. The sample must be collected at 3 to 6 ( ⁇ 1) hours post-dose.
  • the tumor biopsy For subjects on intermittent schedule(s), the tumor biopsy must be collected on a day that Compound A is administered per the intermittent schedule (preferably after at least 3 continuous days of administration).
  • sorafenib (1 ⁇ ) resulted in a 36%> decrease compared to DMSO. 79%> and 86%) decreased colony volume was observed for the combination of sorafenib (1 ⁇ ) with 1 and 5 ⁇ Compound A, respectively.
  • the orthotopic HCC liver cancer model was developed by injecting about 2xl0 5 BNL-IMEA cells (from American Type Culture Collection, ATCC) into the subcapsular area of the left liver lobe of male BALB/c or SCID mice at age of 6-7 weeks. Mice were randomized to different treatment groups on day 6 after tumor implantation. Sorafenib (Bayer Schering Pharma) was given by gavage or intra-peritoneal injection. In some examples, Compound A was administered in addition to sorafenib. In some examples, Compound A was administered in addition to anti-VEGFR (vascular endothelial growth factor receptor) antibody DC-101.
  • BNL-IMEA cells from American Type Culture Collection, ATCC
  • Sorafenib (Bayer Schering Pharma) was given by gavage or intra-peritoneal injection.
  • Compound A was administered in addition to sorafenib.
  • Compound A was administered in addition to anti-VEGFR (vascular endothelial growth factor receptor) antibody
  • Compound A was combined with sorafenib. In other examples Compound A was combined with anti-VEGFR (vascular endothelial growth factor receptor) antibody DC-101.
  • VEGFR vascular endothelial growth factor receptor
  • VNI vascular normalization index

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Abstract

La présente invention concerne des méthodes de traitement, de prévention et/ou de prise en charge d'un carcinome hépatocellulaire à l'aide d'une polythérapie.
PCT/US2016/025986 2015-04-06 2016-04-05 Traitement du carcinome hépatocellulaire à l'aide d'une combinaison de cc 122 et de sorafenib WO2016164336A1 (fr)

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US9682952B2 (en) 2012-09-04 2017-06-20 Celgene Corporation Isotopologues of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl) piperidine-2-6-dione and methods of preparation thereof
US9732064B2 (en) 2006-09-26 2017-08-15 Celgene Corporation 5-substituted quinazolinone derivatives and compositions comprising and methods of using the same
US9751853B2 (en) 2011-03-11 2017-09-05 Celgene Corporation Solid forms of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses
WO2018165142A1 (fr) * 2017-03-07 2018-09-13 Celgene Corporation Formes solides de 3-(5-amino-2-méthyl-4-oxo-4h-quinazolin-3-yl)-pipéridine-2,6-dione, leurs compositions pharmaceutiques et leurs utilisations

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9732064B2 (en) 2006-09-26 2017-08-15 Celgene Corporation 5-substituted quinazolinone derivatives and compositions comprising and methods of using the same
US9751853B2 (en) 2011-03-11 2017-09-05 Celgene Corporation Solid forms of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses
US9969713B2 (en) 2011-03-11 2018-05-15 Celgene Corporation Solid forms of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses
US9682952B2 (en) 2012-09-04 2017-06-20 Celgene Corporation Isotopologues of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl) piperidine-2-6-dione and methods of preparation thereof
WO2018165142A1 (fr) * 2017-03-07 2018-09-13 Celgene Corporation Formes solides de 3-(5-amino-2-méthyl-4-oxo-4h-quinazolin-3-yl)-pipéridine-2,6-dione, leurs compositions pharmaceutiques et leurs utilisations

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