WO2010004337A1 - Combinaison comprenant du n-(3-méthoxy-5-méthylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phényle)pyridine-3-sulfonamide et du pemetrexed - Google Patents

Combinaison comprenant du n-(3-méthoxy-5-méthylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phényle)pyridine-3-sulfonamide et du pemetrexed Download PDF

Info

Publication number
WO2010004337A1
WO2010004337A1 PCT/GB2009/050816 GB2009050816W WO2010004337A1 WO 2010004337 A1 WO2010004337 A1 WO 2010004337A1 GB 2009050816 W GB2009050816 W GB 2009050816W WO 2010004337 A1 WO2010004337 A1 WO 2010004337A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
pemetrexed
treatment
combination
compound
Prior art date
Application number
PCT/GB2009/050816
Other languages
English (en)
Inventor
Nicola Jane Curtis
James William Growcott
Daniel Mark Hickinson
Thomas Meredydd Morris
Della Tennant
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
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 Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Publication of WO2010004337A1 publication Critical patent/WO2010004337A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a combination comprising JV-(3-methoxy-5- methylpyrazin-2-yl)-2-(4-[l ,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulphonamide, or a pharmaceutically acceptable salt thereof, hereafter "Compound (I)" and pemetrexed, or a pharmaceutically acceptable salt thereof.
  • the combination is expected to be useful for the treatment or prophylaxis of cancer.
  • the invention also relates to a pharmaceutical composition comprising such combinations and to the use thereof in the manufacture of a medicament for use in the treatment or prophylaxis of cancer, in particular lung cancer, more particularly non-small cell lung cancer.
  • Lung cancer is one of the most commonly occurring malignancies, second to prostate cancer among men and breast cancer among women.
  • lung cancer has the highest mortality rate for all cancers among both men and women, accounting for almost one-third of all cancer deaths.
  • lung cancer mortality among men decreased by an average of 1.6% per year from 1990 to 2000, lung cancer mortality in men still surpasses that of prostate cancer and colorectal cancer.
  • Non- small cell lung cancer accounts for approximately 85% of all lung cancers.
  • the majority of patients with non- small cell lung cancer (NSCLC) present with locally advanced inoperable or metastatic disease. Those patients who are not candidates for definitive loco-regional therapy typically receive palliative treatment with a platinum-containing doublet chemotherapy regimen.
  • patients with disease progression on or after first-line therapy may be candidates for second-line chemotherapy with either docetaxel or pemetrexed.
  • docetaxel was the only approved chemotherapy agent for the second-line treatment of NSCLC and thus became the standard of care.
  • Median survival of patients that have had only one prior chemotherapy regimen for metastatic disease and received docetaxel 75 mg/m 2 administered in 3-weekly cycles was 7.2-7.9 months (Hanna et al. J. Clin. Oncol. 2004; 22:1589-97; and Ramlau et al. J. Clin. Oncol. 2006;24:2800-7).
  • docetaxel, given at this dose and schedule results in significant haematological toxicity, with many patients at risk of neutropenic fever.
  • pemetrexed 500 mg/m 2 3 -weekly has been shown to have comparable therapeutic outcomes to docetaxel with a more favourable safety profile and thus is becoming a preferred option for the second- line management of patients with advanced NSCLC.
  • median overall survival and median progression-free survival were 8.3 and 2.9 months for pemetrexed and 7.9 and 2.9 months for docetaxel, respectively (Hanna et al J. Clin. Oncol. 2004; 22:1589-97).
  • Pemetrexed is commonly used as pemetrexed disodium heptahydrate which has the chemical name L-glutamic acid, ⁇ /-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH-pyrrolo[2,3- d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, of the structural formula:
  • Pemetrexed is also known as ALIMT ATM (Trademark of Lilly) and it is an anticancer antifolate agent that disrupts folate-dependent metabolic processes involved in cell replication. Endothelin A receptor antagonists have been identified as potentially of value in the treatment of cancer (Cancer Research, 56, 663-668, February 15 th , 1996 and Nature Medicine, Volume 1, Number 9, September 1999, 944-949).
  • the endothelins are a family of endogenous 21 amino acid peptides comprising three iso forms, endothelin-1, endothelin-2 and endothelin-3.
  • the endothelins are formed by cleavage of the Trp 21 -Val 22 bond of their corresponding proendothelins by an endothelin converting enzyme.
  • the endothelins are among the most potent vasoconstrictors known. They exhibit a wide range of other activities including stimulation of cell proliferation and mitogenesis, inhibition of apoptosis, extravasation and chemotaxis, and also interact with a number of other vasoactive agents.
  • the endothelins are released from a range of tissue and cell sources including vascular endothelium, vascular smooth muscle, kidney, liver, uterus, airways, intestine and leukocytes. Release can be stimulated by hypoxia, shear stress, physical injury and a wide range of hormones and cytokines. Elevated endothelin levels have been found in a number of disease states in man including cancers.
  • Endothelins exert their effects by binding via two G-protein-coupled receptors - endothelin receptor A and B (ET A and ET B ).
  • ET A and ET B appear to influence tumour progression by several mechanisms, including cell proliferation, inhibition of apoptosis, angiogenesis, matrix remodelling, and bone deposition in skeletal metastases through activation of osteoblasts (Nelson et al, Nat Rev Cancer 2003; 3: 110-116; Bagnato et al, Trends Endocrinol. Metab. 2002; 14: 44-50; and Rosano et al, Cancer Res 2001; 61 : 8340- 8346).
  • ET A endothelin-1
  • ET-I endothelin-1
  • ET A activation also induces matrix-degrading enzymes, such as matrix metalloproteinases and urokinase plasminogen activator, which have important roles in tissue remodelling and tumour metastasis (Rosano et al, Cancer Res 2001; 61 : 8340-8346).
  • matrix-degrading enzymes such as matrix metalloproteinases and urokinase plasminogen activator, which have important roles in tissue remodelling and tumour metastasis (Rosano et al, Cancer Res 2001; 61 : 8340-8346).
  • ET-1/ET A binding is involved in nociceptive effects associated with cancer bone metastasis and remodelling, and thus may be associated with bone pain in patients with bone metastasis.
  • Compound (I) is such a specific ET A receptor antagonist.
  • Compound (I) is exemplified and described in WO96/40681 as Example 36.
  • WO96/40681 claims the endothelin receptor antagonists described therein for the treatment of cardiovascular diseases.
  • the use of Compound (I) in the treatment of cancers and pain is described in WO04/018044.
  • Compound (I) has the following structure:
  • WO96/40681 discloses that the compounds described therein may be administered with a beta-adrenergic blocker (for example atenolol), a calcium channel blocker (for example nifedipine), an angiotensin converting enzyme (ACE) inhibitor (for example lisinopril), a diuretic (for example furosemide or hydrochlorothiazide), an endothelin converting enzyme (ECE) inhibitor (for example phosphoramidon), a neutral endopeptidase (NEP) inhibitor, an HMGCoA reductase inhibitor, a nitric oxide donor, an anti-oxidant, a vasodilator, a dopamine agonist, a neuroprotective agent, a steroid, a beta- agonist, an anti-coagulant, or a thrombolytic agent.
  • a beta-adrenergic blocker for example atenolol
  • a calcium channel blocker for example nifedip
  • WO2004/032922 discloses combinations on Compound (I) and a 5-HTm/m receptor agonist.
  • WO2004/035057 discloses a combination of Compound (I) with an epidermal growth factor receptor tyrosine kinase inhibitor.
  • WO2005/023264 discloses combinations of Compound (I) with an LHRH analogue and/or a bisphosphonate.
  • WO2006/056760 discloses combinations of Compound (I) with an anti-mitotic cytotoxic agent such as a taxane. None of these references disclose a combination of Compound (I) with pemetrexed.
  • the present inventors have unexpectedly found that the combination use of Compound (I) and pemetrexed may have a particular benefit in the treatment of cancer.
  • the combination is expected to exhibit at least additive or synergistic effects compared to the use of compound (I) alone or pemetrexed alone.
  • a combination comprising Compound (I) and pemetrexed, or a pharmaceutically acceptable salt thereof.
  • “combination” refers to simultaneous, separate or sequential administration.
  • “combination” refers to simultaneous administration.
  • “combination” refers to separate administration.
  • “combination” refers to sequential administration.
  • the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
  • a compound or a pharmaceutically acceptable salt thereof is referred to this refers to the compound only. In another aspect this refers to a pharmaceutically acceptable salt of the compound.
  • cancer refers to oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewing's tumour, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, brain cancer, renal cancer, malignant mesothelioma (for example malignant pleural mesothelioma), lymphoma and leukaemia. More particularly it refers to prostate cancer.
  • SCLC SCLC
  • NSCLC NSCLC
  • colorectal cancer ovarian cancer and / or breast cancer.
  • SCLC SCLC
  • NSCLC non-squamous NSCLC
  • adenocarcinoma adenocarcinoma
  • malignant pleural mesothelioma adenocarcinoma
  • colorectal cancer adenocarcinoma
  • ovarian cancer adenocarcinoma
  • ovarian cancer ovarian cancer
  • breast cancer adenocarcinoma
  • hormone receptor positive breast cancer especially to hormone receptor positive breast cancer in post-menopausal women.
  • the cancer refers to bladder cancer, oesophageal cancer, gastric cancer, melanoma, cervical cancer and / or renal cancer.
  • endometrial, liver, stomach, thyroid, rectal and / or brain cancer refers to endometrial, liver, stomach, thyroid, rectal and / or brain cancer.
  • the cancer is not melanoma.
  • the cancer is in a non-metastatic state.
  • the cancer is locally advanced (cancer has spread to tissues close to the site of the primary tumour).
  • the cancer is in a metastatic state.
  • the cancer is in a metastatic state, and more particularly the cancer produces metastases to the bone.
  • the cancer is in a metastatic state, and more particularly the cancer produces skin metastases.
  • particularly the cancer is in a metastatic state, and more particularly the cancer produces lymphatic metastases.
  • the cancer is metastatic or locally advanced non-squamous NSCLC.
  • the cancer is metastatic non-squamous NSCLC.
  • non-squamous this refers to NSCLC that is determined by histology or cytology to be predominantly cancer of non-squamous cells.
  • tumours Such histology and cytology methods are well known and will be carried out on a sample of the tumour obtained for example by biopsy, sputum or bronchial lavage. Where the analysis reveals more than one form of malignancy, the tumour is considered to be predominantly non-squamous if 50% or more of the malignant cells are non-squamous. Where the treatment of cancer is referred to particularly this is the treatment of cancerous tumours expressing endothelin A.
  • This treatment is in terms of one or more of the extent of the response (for example reduced tumour volume or reduced tumour burden), the response rate, the clinical benefit rate (the sum of complete response, partial response and stable disease), the time to disease progression, objective disease progression (measured using Response Evaluation Criteria In Solid Tumours (RECIST)), and the survival rate (for example progression- free survival, the overall survival rate or the time to death).
  • Such clinical trial endpoints are well known and are described in for example the FDA publication "Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologies" May 2007 (www.fda.gov/CbER/gdlns/clintrialend.htm).
  • the combinations according to the invention are expected to provide an anti- tumour effect, for example one or more of inhibition of tumour growth, tumour growth delay, regression of tumour, shrinkage of tumour, increased time to re-growth of tumour on cessation of treatment or slowing of disease progression.
  • Compound (I) and pemetrexed, or a pharmaceutically acceptable salt thereof may also have a beneficial effect in preventing the onset of cancer in warm-blooded animals, such as man.
  • a combination comprising Compound (I) and pemetrexed, or a pharmaceutically acceptable salt thereof for use as a medicament.
  • a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of pemetrexed, or a pharmaceutically acceptable salt thereof.
  • NSCLC non-small cell lung cancer
  • NSCLC non-squamous non-small cell lung cancer
  • NSCLC locally advanced or metastatic non-squamous non- small cell lung cancer
  • the treatment of cancer also refers to the prevention of metastases and the treatment of metastases, i.e. cancer spread. Therefore the combination of the present invention could be used to treat a patient who has no metastases to stop them occurring, or to lengthen the time period before they occur, and to a patient who already has metastases to treat the metastases themselves.
  • the treatment of cancer also refers to treatment of an established primary tumour or tumours and developing primary tumour or tumours.
  • the treatment of cancer relates to the prevention of metastases.
  • the treatment of cancer relates to the treatment of metastases.
  • the treatment of cancer relates to treatment of an established primary tumour or tumours or developing primary tumour or tumours.
  • the treatment of cancer also refers to the production of an anti-angiogenic effect in a warm blooded animal.
  • the treatment of cancer relates to an adjuvant treatment.
  • the treatment of cancer refers to the neo-adjuvant treatment of cancer.
  • adjuvant therapy refers to a treatment given in addition to the primary therapy used to remove or kill the tumour.
  • the adjuvant therapy is used to kill any cancer cells that may have spread from the primary tumour.
  • the primary therapy may be for example, surgery and/or radiotherapy.
  • noneo-adjuvant therapy refers to a treatment given prior to a primary therapy such as surgery or radiotherapy.
  • the treatment of the cancer refers to the first- line treatment of the cancer.
  • the treatment of the cancer refers to the second- line treatment of the cancer (a treatment administered following failure of the first- line treatment of the cancer).
  • the treatment of cancer also refers to the prevention of cancer per se.
  • the effect of a method of treatment of the present invention is expected to be at least equivalent to the addition of the effects of each of the components of said treatment used alone, that is, of each of Compound (I) and the pemetrexed used alone.
  • the effect of a method of treatment of the present invention is expected to be greater than the addition of the effects of each of the components of said treatment used alone, that is, of each of Compound (I) and the pemetrexed used alone.
  • the effect of a method of treatment of the present invention is expected to be a synergistic effect.
  • a combination treatment is defined as affording a synergistic effect if the effect of the combination is therapeutically superior, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, to that achievable on dosing one or other of the components of the combination treatment at its conventional dose.
  • the effect of the combination treatment is synergistic if the effect is therapeutically superior to the effect achievable with Compound (I) or the pemetrexed alone.
  • the effect of the combination treatment is synergistic if a beneficial effect is obtained in a group of patients that does not respond (or responds poorly) to Compound (I) or the pemetrexed alone.
  • the effect of the combination treatment is defined as affording a synergistic effect if one of the components is dosed at its conventional dose and the other component(s) is/are dosed at a reduced dose and the therapeutic effect, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, is equivalent to that achievable on dosing conventional amounts of the components of the combination treatment.
  • synergy is deemed to be present if the conventional dose of Compound (I) or the pemetrexed may be reduced without detriment to one or more of the extent of the response, the response rate, the time to disease progression and survival data, in particular without detriment to the duration of the response, but with fewer and/or less troublesome side-effects than those that occur when conventional doses of each component are used.
  • a kit comprising Compound (I) and pemetrexed, or a pharmaceutically acceptable salt thereof; optionally with instructions for use.
  • kits comprising: a) Compound (I), in a first unit dosage form; b) pemetrexed, or a pharmaceutically acceptable salt thereof; in a second unit dosage form; and c) container means for containing said first and second dosage forms; and optionally d) with instructions for use.
  • kits comprising: a) Compound (I), together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) pemetrexed, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier in a second unit dosage form; and c) container means for containing said first and second dosage forms; and optionally d) with instructions for use.
  • a combination comprising Compound (I) and pemetrexed, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
  • a combination comprising Compound (I) and pemetrexed, or a pharmaceutically acceptable salt thereof, for use in the treatment of NSCLC.
  • a combination comprising Compound (I) and pemetrexed, or a pharmaceutically acceptable salt thereof, for use in the treatment of non-squamous NSCLC.
  • a combination comprising Compound (I) and pemetrexed, or a pharmaceutically acceptable salt thereof, for use in the treatment of locally advanced or malignant non-squamous NSCLC.
  • a combination comprising Compound (I) and pemetrexed, or a pharmaceutically acceptable salt thereof, for use in the treatment of malignant pleural mesothelioma.
  • Compound (I) and the pemetrexed may be used as a single composition containing Compound (I) and pemetrexed.
  • a further aspect of the invention provides a pharmaceutical composition which comprises Compound (I) and pemetrexed, or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition which comprises Compound (I) and pemetrexed, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • Suitable cancers are as hereinbefore described.
  • Compound (I) and the pemetrexed may be used as two individual compositions, one containing Compound (I) and one containing pemetrexed, wherein the two compositions are administered simultaneously, separately or sequentially.
  • a further aspect of the invention provides a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises pemetrexed, or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises pemetrexed, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises pemetrexed, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier, for use in the treatment of NSCLC.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises pemetrexed, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier, for use in the treatment of non-squamous NSCLC.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises pemetrexed, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier, for use in the treatment of locally advanced or metastatic non-squamous NSCLC.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises pemetrexed, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier, for use in the treatment of malignant pleural mesothelioma.
  • a combination treatment comprising the administration of an effective amount of Compound (I), optionally together with a pharmaceutically acceptable diluent or carrier, in combination with an effective amount of pemetrexed, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment for use in the treatment of cancer.
  • a warm-blooded animal such as man in need of such therapeutic treatment for use in the treatment of cancer.
  • Suitable cancers in this embodiment are as hereinbefore described.
  • the use of Compound (I), in combination with pemetrexed, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of cancer, in a warm-blooded animal, such as man.
  • Compound (I) in combination with pemetrexed, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of locally advanced or metastatic non-squamous NSCLC, in a warm-blooded animal, such as man.
  • Suitable pharmaceutically-acceptable salts include, for example, salts with alkali metal (such as sodium, potassium or lithium), alkaline earth metals (such as calcium or magnesium), ammonium salts, and salts with organic bases affording physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine and morpholine.
  • suitable pharmaceutically-acceptable salts include, pharmaceutically-acceptable acid-addition salts with hydrogen halides, sulphuric acid, phosphoric acid and with organic acids such as citric acid, maleic acid, methanesulphonic acid and p-toluenesulphonic acid.
  • the compounds may exist in zwitterionic form.
  • Compound (I) is used in the free base form, particularly crystalline Compound (I) Form 1 described in WO2007/010235 and the Cambridge crystallographic database [N-(3-Methoxy-5-methylpyrazin-2-yl)-2-[4-(l,3,4-oxadiazol-2- yl)phenyl]pyridine-3-sulfonamide (ZD4054 Form 1). Acta Crystallographica, Section E: Structure Reports Online (2004), E60(10), ol817-ol819].
  • the pemetrexed is suitably used in the form of a salt with an alkaline metal, for example the disodium salt, heptahydrate mentioned hereinbefore.
  • compositions and unit dosage forms described herein may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • sterile solution, suspension or emulsion for topical administration as an ointment or cream or for rectal administration as a suppository.
  • topical administration as an ointment or cream
  • rectal administration as a suppository.
  • the above compositions may be prepared in a conventional manner using conventional excipients.
  • Compound (I) can be formulated as a tablet using the following excipients: Compound (I);
  • Lactose monohydrate filler
  • Croscarmellose sodium disintegrant
  • Povidone binder
  • Magnesium stearate lubricant
  • Hypromellose film coat component
  • Polyethylene glycol 300 (film coat component); and Titanium dioxide (film coat component).
  • Compound (I) can be formulated as a tablet comprising Compound (I), mannitol and microcrystalline cellulose.
  • a tablet containing lOmg of Compound (I) shown in Table 1 a tablet containing lOmg of Compound (I) shown in Table 1 :
  • Pemetrexed is suitably formulated for parenteral, particularly intravenous administration.
  • Such formulations are well known.
  • the pemetrexed may be used as a lyophilised powder which is dissolved in a suitable liquid medium, such as saline solution, prior to intravenous administration to a patient.
  • Compound (I) or a pharmaceutically acceptable salt thereof, administered would be that sufficient to provide the desired pharmaceutical effect.
  • Compound (I) could be administered to a warm-blooded animal orally, at a unit dose less than Ig daily but more than 2.5mg.
  • Particularly Compound (I) could be administered to a warm-blooded animal, at a unit dose of less than 250 mg per day.
  • Compound (I) could be administered to a warm-blooded animal, at a unit dose of less than 130 mg per day.
  • Compound (I) could be administered to a warm-blooded animal, at a unit dose of less than 50 mg per day.
  • Particularly Compound (I) could be administered to a warm-blooded animal, at a unit dose of 10 mg per day. In another aspect of the invention, particularly Compound (I) could be administered to a warm-blooded animal, at a unit dose of 15 mg per day.
  • Pemetrexed may be administered according to known clinical practice. For example, in the treatment of NSCLC or malignant pleural mesothelioma the recommended dose of pemetrexed is 500mg/m 2 given by 10 minute intravenous infusion administered on the first day of each 21 -day cycle.
  • the patient may be treated with a suitable premedication regime prior to administration of the pemetrexed.
  • Such pre -treatments are well known and include for example a steroid and/or vitamin supplements.
  • patients may be pre -treated with a corticosteroid, folic acid and vitamin B 12 prior to receiving the pemetrexed.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • the dosage of each of the drugs and their proportions have to be composed so that the best possible treatment effects, as defined by national and international guidelines (which are periodically reviewed and re-defined), will be met.
  • the scheduling of the dosing of Compound (I) and the pemetrexed can be varied. As mentioned herein before the drugs of the combination may be administered simultaneously, sequentially or separately. In one embodiment Compound (I) is administered daily at a suitable dose (for example 10 to 15mg) and the pemetrexed is administered as a short (for example 10 minute) intravenous infusion once every 21 days. Administration of Compound (I) prior to administration of the pemetrexed may be of particular benefit. Therefore, in one embodiment of the invention Compound (I) is administered before the pemetrexed infusion (for example 1 hour, 2 hours, 4 hours, 6 hours 8 hours or 1 day before the pemetrexed).
  • a suitable dose for example 10 to 15mg
  • the pemetrexed is administered as a short (for example 10 minute) intravenous infusion once every 21 days.
  • Administration of Compound (I) prior to administration of the pemetrexed may be of particular benefit. Therefore, in one embodiment of the invention Compound (I) is
  • a unit dose of Compound (I) is administered daily for between 1 and 14 days (for example 1, 2, 3, 4, 5, 6, or 7 days, and particularly for 7 days) before the pemetrexed infusion is administered. Following administration of the pemtrexed, Compound (I) may continue to be administered on a daily basis. Suitable unit doses for daily dosing of Compound (I) are as hereinbefore defined, for example 10 to 15mg of Compound (I) daily. In another embodiment Compound (I) is administered after the pemetrexed infusion (for example 1 to 14 days after the pemetrexed infusion).
  • Compound (I) is administered substantially simultaneously with the pemetrexed infusion, for example Compound (I) and the pemetrexed are administered within a time period of less than 1 hour, 2 hours, 4 hours, 6 hours, 8 hours or 1 day of one another.
  • Figure 1 shows the dosing schedules used in an in- vitro study on the effect of Compound (I) and pemetrexed alone and in combination on NCI-H 1975 adenocarcinoma cells.
  • NT refers to no treatment
  • PEM refers to pemetrexed
  • ZD4054 refers to Compound (I).
  • Figures 2 and 3 show the results of 2 individual experiments illustrating the effect of Compound (I), pemetrexed used alone and in combination on the apoptosis of NCI- HI 975 adenocarcinoma cells.
  • the y-axis shows the % mean number of cells which stained positive for the activated form of the pro-apoptotic BAK protein. Accordingly in Figures 2 and 3 high levels of BAK indicate a high degree of apoptosis in the cells.
  • Pemetrexed is commercially available as Alimta (pemetrexed disodium salt, heptahydrate).
  • NCI-H1975 non-small-cell lung cancer cells
  • the NCI-H1975 cells were derived from a human female non-smoker with adenocarcinoma of the lung (Phelps RM et al J Cell Biochem Suppl. 1996;24:32-91).
  • the NCI-H 1975 ((adenocarcinoma, non- small cell lung carcinoma) cell line was routinely cultured in DMEM (phenol red free) + 10% Foetal Calf Serum (FCS) + 1% glutamine. Cell culture media and FCS were obtained from Sigma.
  • the NCI-H 1975 cells were kept in a humidified atmosphere of 37°C at 5% CO 2 NCI-H 1975 cells were plated in 96 well plates in DMEM (phenol red free) + 2.5% Charcoal/Dextran treated FCS (Hyclone, cat # SH30068) + 1% glutamine. After 4 hours incubation cells were treated according to the following sequences:
  • Example 2 A Phase II, Double-blind, Placebo-controlled, Randomised Study to Assess the
  • the phase II trial described below has been proposed to demonstrate the effects of Compound (I) used in combination with pemetrexed in the treatment of NSCLC.
  • the proposed study will evaluate Compound (I) in combination with pemetrexed as second line treatment in patients with non-small cell lung cancer (NSCLC) and predominantly non- squamous histology, a common disease that often presents at an advanced stage and is associated with a poor prognosis.
  • NSCLC non-small cell lung cancer
  • the primary objective of this study will be to demonstrate an improvement in survival for the combination of Compound (I) plus pemetrexed compared to pemetrexed alone in patients with locally advanced or metastatic NSCLC without predominantly squamous histology after failure of first line anti-cancer therapy.
  • RECIST Response Evaluation Criteria In Solid Tumours
  • MTAV Mandatory Tumour Assessment Visit
  • Folic acid will be taken daily starting 5-7 days prior to first dose of pemetrexed and continued for 21 days after the last dose of pemetrexed.
  • An intramuscular injection of vitamin Bi 2 will be received during the 7 days prior to the first dose of pemetrexed and subsequently once every 3 cycles.
  • Subsequent vitamin Bi 2 injections may be given the same day as pemetrexed.
  • a corticosteroid will be given the day prior, on the day of and the day after each pemetrexed administration.
  • Folic acid, vitamin Bi 2 and corticosteroid should all be started prior to randomisation at Visit 2.
  • DCO data cut-off
  • MTAV disease progression estimated to be 3 months after the last patient is randomised.
  • SAEs serious adverse events
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • ALP alkaline phosphatase
  • CYP450 eg, phenytoin, rifampicin, carbamazepine, phenobarbitone, St John's Wort
  • Dexamethasone a known inducer of CYP2D6 and CYP3A4, may be used as premedication for pemetrexed.
  • Compound (I) 10 mg or pemetrexed 500 mg/m 2 with placebo matching Compound (I).
  • Compound (I) and matching placebo are to be given orally once daily.
  • the tablets should be swallowed whole with water, and should be taken at the same time ⁇ 2 hours in the morning. Patients should not take a late dose if there are less than 12 hours before their next scheduled dose, thereby missing a dose. Missed doses are to be recorded.
  • Pemetrexed is to be given by intravenous infusion over 10 minutes every 21 days according to the manufacturer's guidelines.
  • Patients should take folic acid (approximately 400 ⁇ g) daily starting 5-7 days prior to the first dose of pemetrexed and continuing for 21 days after the last dose of pemetrexed.
  • Patients should also receive an intramuscular injection of vitamin Bi 2 (1000 ⁇ g) during the 7 days prior to the first dose of pemetrexed and subsequently once every 3 cycles. Subsequent vitamin Bi 2 injections may be given on the same day as pemetrexed.
  • a corticosteroid should be given the day prior, on the day and the day after each pemetrexed administration. The corticosteroid should be equivalent to 4 mg of dexamethasone administered orally twice a day.
  • the folic acid, vitamin Bi 2 and corticosteroid should all be started prior to randomisation at Visit 2.
  • Time to death will be calculated (in days) as the interval from date of randomisation to date of patient death of any cause. Patients who have not died at the time of the final analysis (data cut-off for survival) will be censored at the last date the patient was known to be alive.
  • a disease progression event on or before the MTAV defined as:
  • Objective disease progression is defined as at least 20% increase in the sum of longest diameters of measurable lesions, presence of new lesions or unequivocal progression of non-measurable lesions. Lesions in previously irradiated areas will be considered evaluable for progression.
  • Clinical disease progression is defined as a global deterioration of health status requiring discontinuation of treatment and making an objective tumour assessment by scan impossible as a result of the underlying disease and not due to intercurrent illness or adverse effects from therapy.
  • BNP b-type natriuretic peptide
  • the primary objective is to assess the efficacy of Compound (I) in combination with pemetrexed versus pemetrexed alone in the treatment of patients with NSCLC without predominantly squamous histology by the assessment of overall survival. This will be done by comparison of TTD between the 2 treatment groups on an ITT basis.
  • the secondary objectives of the study are:
  • ITT Intention-to-treat
  • EFS Evaluable for safety
  • the primary objective of assessing efficacy of Compound (I) in combination with pemetrexed versus pemetrexed alone for the treatment of patients with NSCLC will be achieved by comparing TTD between treatment groups.
  • Time to death will be calculated from the date of randomisation to date of patient death from any cause. Patients who have not died at the time of the DCO will be censored at the last date the patient was known to be alive.
  • the analysis for survival will be performed using a Cox proportional hazards regression model on an ITT basis.
  • the estimated hazard ratio (HR) will be reported together with appropriate confidence intervals (CIs) and p-value.
  • Time to death will also be summarised using the Kaplan-Meier method.
  • the secondary efficacy objective of the study is to assess the efficacy of Compound (I) in combination with pemetrexed versus pemetrexed alone by assessment of disease progression.
  • the number of patients with progression events occurring on or before the intermediate MTAV will be compared between the treatment groups using a logistic regression model with a complementary log-log function and including a factor for treatment group. The results can be approximated as a HR.
  • the intermediate MTAV will be defined to be approximately 3 months after completion of randomisation of all patients.
  • the estimated HR of a progression event for the combination therapy compared to pemetrexed alone will be reported together with the corresponding appropriate CIs and p- value.
  • An additional analysis taking account of the timing of a progression event may also be performed in support of the progression event count analysis.
  • the probability that the population HR is of a certain value will be quantified based on the observed HR to assess the evidence for further development of Compound (I). Analyses will be performed on an ITT basis using the ITT analysis set.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur une combinaison comprenant du N-(3-méthoxy-5-méthylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phényle)pyridine-3-sulfonamide ou un sel pharmaceutiquement acceptable de celui-ci et du pemetrexed ou un sel pharmaceutiquement acceptable de celui-ci. On pense que la combinaison peut être utile dans le traitement d'un cancer, en particulier un cancer des poumons.
PCT/GB2009/050816 2008-07-10 2009-07-09 Combinaison comprenant du n-(3-méthoxy-5-méthylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phényle)pyridine-3-sulfonamide et du pemetrexed WO2010004337A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7954108P 2008-07-10 2008-07-10
US61/079,541 2008-07-10

Publications (1)

Publication Number Publication Date
WO2010004337A1 true WO2010004337A1 (fr) 2010-01-14

Family

ID=41036767

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2009/050816 WO2010004337A1 (fr) 2008-07-10 2009-07-09 Combinaison comprenant du n-(3-méthoxy-5-méthylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phényle)pyridine-3-sulfonamide et du pemetrexed

Country Status (1)

Country Link
WO (1) WO2010004337A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004018044A2 (fr) * 2002-08-23 2004-03-04 Astrazeneca Ab Usage therapeutique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004018044A2 (fr) * 2002-08-23 2004-03-04 Astrazeneca Ab Usage therapeutique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VILLELA LETICIA R ET AL: "Pemetrexed, a novel antifolate therapeutic alternative for cancer chemotherapy", PHARMACOTHERAPY, vol. 26, no. 5, May 2006 (2006-05-01), pages 641 - 654, XP009122546, ISSN: 0277-0008 *

Similar Documents

Publication Publication Date Title
US20220160707A1 (en) Pharmaceutical combination comprising tno155 and ribociclib
NZ529145A (en) Combination comprising N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)- 2pyrimidine-amine and a chemotherapeutic agent
US11872211B2 (en) Treatments with nirogacestat
US11951096B2 (en) Treatments with nirogacestat
US20230019186A1 (en) Dosing regimens for use in treating myelofibrosis and mpn-related disorders with navitoclax
US20230038138A1 (en) Combination therapy for treating cancer
US20220409582A1 (en) Combination therapies comprising panobinostat for the treatment of cholangiocarcinoma
WO2010004337A1 (fr) Combinaison comprenant du n-(3-méthoxy-5-méthylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phényle)pyridine-3-sulfonamide et du pemetrexed
WO2021048419A1 (fr) Polythérapies comprenant du tramétinib pour le traitement du cholangiocarcinome
US20230089371A1 (en) Combination comprising alpelisib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid
TW202329946A (zh) 用於治療癌症之方法及包含cdk2抑制劑之給藥方案
US12036207B2 (en) Treatments with nirogacestat
US20090062246A1 (en) Therapeutic treatment-014
WO2023170065A1 (fr) Méthodes de traitement du cancer du poumon à petites cellules
TW202339753A (zh) 用於與抗癌藥物共同投與之包含酞嗪酮衍生物之醫藥組合物
TW202332431A (zh) 用於治療癌症之方法及包含cdk2抑制劑及cdk4抑制劑之給藥方案
AU2014264318B2 (en) Combination of a PI3 kinase inhibitor with paclitaxel for use in the treatment or prevention of a cancer of the head and neck
WO2023194530A1 (fr) Polythérapie pour le traitement du cancer
TW202342044A (zh) Cdk4及6抑制劑及氟維司群用於治療先前以cdk4及6抑制劑治療的患者之荷爾蒙受體陽性、人類表皮生長因子受體2陰性之晚期或轉移性乳癌
WO2022101255A1 (fr) Combinaisons de lurbinectédine et d'irinotécan
EP3458048A1 (fr) Polythérapies utilisant des dérivés d'indazolylbenzamide pour le traitement du cancer
AU2005246965A1 (en) Combination comprising N-{5-[4(4-methyl-piperazino-methyl)-bezoylamido]-2-methylphenyl}-4-(3-pyridyl)-2pyrimidine-amine and a chemotherapeutic agent

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09785295

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09785295

Country of ref document: EP

Kind code of ref document: A1