Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• This invention relates to a pharmaceutical combination
• a pharmaceutical combination comprising (a) a Rat inhibitor which is the Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor, particularly ribociclib, or a pharmaceutically acceptable salt thereof.
• This invention also relates to such combinations for use in the treatment of cancer; uses of such combinations for the preparation of a medicament for the treatment of cancer; methods of treating cancer, in a subject in need thereof comprising administering to said subject a jointly therapeutically effective amount of said combinations; use of such combinations for the treatment of cancer; and pharmaceutical compositions comprising such combinations.
• This invention also relates to the Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, for use in a combination therapy with a CDK4/6 inhibitor, particularly ribociclib, or a pharmaceutically acceptable salt thereof.
• a CDK4/6 inhibitor, particularly ribociclib, or a pharmaceutically acceptable salt thereof for use in a combination therapy with the Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof.
• MAPK Mitogen Activated Protein Kinase
• RAS/RAF/CDK4/6/ERK pathway is a key signaling cascade that drives cell proliferation, differentiation, and survival. Dysregulation of this pathway underlies many instances of tumorigenesis including melanoma (Kirkwood et al, Clin Cancer Res 18(2) :555- 67, 2012).
• This pathway is comprised of the RAS small guanidine triphosphatase (GTPase), which, when activated, promotes the activation of the RAF family proteins (ARAF, BRAF and CRAF, also known as RAF1 ).
• GTPase RAS small guanidine triphosphatase
• RAF proteins lead to the phosphorylation and activation of CDK4/61/2 proteins, which subsequently phosphorylate and activate extracellular signal-regulated kinases (ERKs).
• ERKs phosphorylate a variety of substrates, including multiple transcription factors, and regulate several key cellular activities, including proliferation, differentiation, migration, survival and angiogenesis.
• ERKs phosphorylate a variety of substrates, including multiple transcription factors, and regulate several key cellular activities, including proliferation, differentiation, migration, survival and angiogenesis.
• RAS or BRAF mutations constitutively activate the Cyclin D-CDK4/6 complex, where they cooperate with CDK4 activation and lead to tumor progression (Chudnovsky Y et al 2005; Monahan KB et al 2010).
• CDK4 activation and lead to tumor progression
• RAS mutant melanoma shows aggressive behavior, with a high rate of liver and brain metastases already present at initial diagnosis (Bergamasco et al, Value in Health Journal 19 A347-A766, 2016), and, therefore, poor prognosis. Response to standard of care chemotherapy is very limited.
• discontinuation rate as a result of adverse events suspected to be related to study drug was high (20% vs. 5%), and the benefit in PFS did not transfer into improvements in overall survival (1 1.0 (95% Cl: 8.9-13.6) vs. 10.1 (7.0- 16.5) months (Dummer et al, Lancet Oncol 18(4):435-445, 2017).
• the NRAS gene is mutated in 15-20% of melanomas - a relatively common subtype of melanoma.
• melanoma the majority of activating variants in NRAS occur at codon 61 , with variants at codons 12 and 13 occurring less frequently (Gao et al, Sci Signal, 2013; van Elsas, Recent Results Cancer Res, 1995).
• the presence of NRAS mutations in melanoma causes a switch in MAPK signaling from BRAF to CRAF, initiating dysregulated cAMP signaling that allows CRAF to signal to CDK4/6 (Dumaz 2006).
• KRAS mutations are frequently found in pancreatic cancer (di Magliano MP & Logsdon CD, Gastroenterology 2013; 144(6): 1220-9).
• a study on PDAC patient samples showed that 93% of all samples had KRAS mutations (Biankin et al. Nature 2012; 491 , 399 ⁇ 05).
• KRAS has the same downstream effectors as NRAS. However, there remains a high unmet medical need in both NRAS and KRAS-mutant cancers.
• LY3009120 inhibits several other kinases, including those that have important roles in cancer such as Ephrin receptors, JNK and SRC family members, thus potentially leading to off-target toxicities.
• CDK4/6 inhibitor ribociclib in combination with a selective Raf inhibitor such as a Compound of formula (I) synergistically inhibited tumor cells in vitro.
• a selective Raf inhibitor such as a Compound of formula (I) synergistically inhibited tumor cells in vitro.
• the combination also led to significant tumor regression in patient derived melanoma xenografts, particularly NRAS mutant melanoma xenografts, and to increased median percent survival in preclinical models.
• the combination of the Compound of formula (I) and a CDK4/6 inhibitor, particularly ribociclib, or a pharmaceutically active salt thereof may achieve greater and more durable responses in patients with activated MAPK pathway, in particular, NRAS-mutant cancer, such as NRAS-mutant melanoma or KRAS-mutant cancer such as KRAS-mutant pancreatic ductal adenocarcinoma (PDAC).
• NRAS-mutant cancer such as NRAS-mutant melanoma or KRAS-mutant cancer such as KRAS-mutant pancreatic ductal adenocarcinoma (PDAC).
• PDAC pancreatic ductal adenocarcinoma
• the combination therapy may also provide fewer side- effects and/or be more tolerable for patients in need thereof.
• the Compound of formula (I), a selective Raf inhibitor, with the CDK4/6 inhibitor ribociclib may also optimize suppression of MAPK signaling in NRAS mutant melanoma.
• Compound of formula (I) and ribociclib in combination may also help to prevent the emergence of resistance to the combination of BRAF and CDK4/6 (mitogen-activated protein kinase kinase) inhibitors in NRAS mutant melanoma or KRAS mutant PDAC.
• BRAF and CDK4/6 mitogen-activated protein kinase kinase inhibitors in NRAS mutant melanoma or KRAS mutant PDAC.
• the invention therefore provides a pharmaceutical combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein the Raf inhibitor is the Compound of formula (I),
• the invention provides a pharmaceutical combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein the CDK4/6 inhibitor is ribociclib, or a pharmaceutically acceptable salt thereof.
• the invention provides a pharmaceutical combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein
• the Raf inhibitor is the Compound of formula (I), or a pharmaceutically acceptable salt thereof;
• the CDK4/6 inhibitor is ribociclib, or a pharmaceutically acceptable salt thereof.
• the invention provides these pharmaceutical combinations for use in the treatment of cancer.
• the present invention is particularly related to the combination of the invention for use in the treatment of a cancer which is characterized by activating mutations in the MAPK pathway, and in particular by one or more mutations in NRAS or KRAS.
• the combination of the invention may be useful for the treatment of melanoma, particularly, NRAS-mutant melanoma.
• the combination of the invention may be useful for the treatment of pancreatic cancer, particularly, KRAS-mutant PDAC.
• the present invention provides the Compound of formula (I) for use in treating cancer by co administration with a CDK4/6 inhibitor, for example, ribociclib, or a pharmaceutically acceptable salt thereof.
• a CDK4/6 inhibitor for example, ribociclib, or a pharmaceutically acceptable salt thereof.
• the present invention also provides ribocicib, or a pharmaceutically acceptable salt thereof, for use in treating cancer by co-administration with the Compound of formula (I), or a pharmaceutically acceptable salt thereof.
• the invention provides the use of the pharmaceutical combination of a Raf inhibitor which is the Compound of formula (I) and a CDK4/6 inhibitor for the preparation of a medicament for the treatment of cancer.
• the invention provides a method for treating cancer in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical combination of a Raf inhibitor which is the Compound of formula (I) and a CDK4/6 inhibitor.
• the present invention also provides a method of treating a cancer comprising
• the present invention also provides a pharmaceutical composition or combined preparation comprising a quantity of the combination of the invention, which is jointly therapeutically effective against a cancer, and optionally at least one pharmaceutically acceptable carrier.
• the present invention also provides a combined preparation comprising (a) one or more dosage units of a Raf inhibitor selected from the group consisting of (i) Compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) one or more dosage units of a CDK4/6 inhibitor, preferably ribociclib, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
• the present invention also provides a commercial package comprising as active ingredients a combination of the invention and instructions for simultaneous, separate or sequential administration of a combination of the invention to a patient in need thereof for use in the treatment of a cancer such as melanoma and in particular NRAS-mutant melanoma or pancreatic cancer such as KRAS-mutant PDAC.
• a cancer such as melanoma and in particular NRAS-mutant melanoma or pancreatic cancer such as KRAS-mutant PDAC.
• the Compound of formula (I) is also referred to herein as“LXH254” or as“NVP-LXH254”. Ribociclib is referred to herein as“LEE01 1” or as“NVP-LEE01 1
• FIGURE 1 Effect of a combination of the Compound of formula (I) and ribociclib on anti-proliferative and phopho-Rb suppression effects relative to single treatments in the SK-MEL-30 melanoma cell line
• FIGURE 1 a Shown in (FIGURE 1 a, FIGURE 1 b, FIGURE 1 c) are combination matrices for inhibition of proliferation (FIGURE 1 a), Loewe (ADD) excess inhibition (FIGURE 1 b), and Growth Inhibition (Gl) (FIGURE 1c) for ribociclib in combination with the Compound of formula (I) as measured by CyQUANT® Direct Cell Proliferation Assay in the SK-MEL-30 melanoma cell line that harbors co-incident mutations in NRAS (Q61 K) and BRAF (D287H). In all cases increasing concentrations of ribociclib are shown along the bottom row from left to right and increasing concentrations of the Compound of formula (I) along the leftmost column from bottom to top.
• the excess inhibition matrix displays the percent excess inhibition of the experimental values (left grid) over the predicted values from the Loewe dose additivity model, which predicts inhibition due to dose additivity alone (Lehar et. al., 2009). Positive numbers represent areas of increasing synergy, and negative numbers regions of antagonism.
• the Growth Inhibition (Gl) measure is based on normalizing the experimental inhibition measurements using an additional time-zero vehicle reference level (time point of drug-addition). The Gl measure results in effect values on two different linear normalization scale portions with a‘break point’ at the time-zero level (i.e.
• FIG. 1d Western blot analysis of phosphorylated RB1 , CDK4/61/2, ERK1/2 and RSK3 following either single agent or combination treatments with ribociclib and the Compound of formula (I) in SK-MEL-20 cells.
• Drug treatments including concentrations in nanomolar (nM) are noted above western blot images. The duration of drug treatment for all samples was 48 hours. The specific proteins being probed are noted to the right of each set of panels.
• FIGURE 2 The combination of the Compound of formula (I) and ribociclib
• FIGURE 2a Shown are antiproliferative effects (FIGURE 2a, FIGURE 2b, FIGURE 2c) and western analysis of key signaling protein (FIGURE 2d) in the NRAS mutant melanoma cell line IPC298 (NRASQ61 L).
• Experimental protocols and data points inFIGURE 2a, FIGURE 2b, FIGURE 2c are as described for FIGURE 1 above.
• FIGURE 3 The combination of the Compound of formula (I) and ribociclib
• FIGURE 3a Shown are antiproliferative effects (FIGURE 3a, FIGURE 3b, and FIGURE 3c) and western analysis of key signaling protein (FIGURE 3d) in the NRAS mutant melanoma cell line Meljuso (NRASQ61 L).
• Experimental protocols and data points in FIGURE 3a, FIGURE 3b, and FIGURE 3c are as described for FIGURE 1 above.
• FIGURE 4 The combination of the Compound of formula (I) and ribociclib
• FIGURE 4a Shown are antiproliferative effects (FIGURE 4a, FIGURE 4b, and FIGURE 4c) and western analysis of key signalling protein (FIGURE 4d) in the NRAS mutant melanoma cell line SK- MEL-2 (NRASQ61 R).
• Experimental protocols and data points inf FIGURE 4a, FIGURE 4b, and FIGURE 4c are as described for FIGURE 1 above.
• FIGURE 5 Anti-tumor activity of the Compound of formula (I) and ribociclib across nine patient derived NRASmut melanoma tumor xenograft models in mice.
• Each bar represents the best response achieved by each treatment (plotted as the average of 3-5 mice/treatment) in an individual patient derived xenograft (PDX) model.
• Models for each treatment are plotted left to right in the following order: FIMEX20864, FIMEX20744, HMEX4339, HMEX5727, HMEX21 124, HMEX3486, HMEX20667, HMEX20585, and HMEX2921 .
• FIGURE 6 Kaplan-Meier plot of time that tumors reached a size of 700mm 3 during daily treatment of single agents the Compound of formula (I), ribociclib or
• the present invention provides a pharmaceutical combination comprising (a) a Raf inhibitor which is a Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof and (b) a CDK4/6 inhibitor, particularly for use in the treatment of cancer.
• Raf inhibitor refers to an adenosine triphosphate (ATP)- competitive inhibitor of B-Raf protein kinase (also referred to herein as b-RAF, BRAF or b- Raf) and C-Raf protein kinase (also referred to herein as c-RAF, CRAF or c-Raf).
• ATP adenosine triphosphate
• c-RAF C-Raf protein kinase
• CRAF or c-Raf C-Raf protein kinase
• Raf inhibitor Compound of formula (I) and its pharmaceutically acceptable salts are described in WO2014/151616, which is hereby incorporated by reference in its entirety, and methods of its preparation have been described, for example, in Example 1 156 therein.
• the Compound of formula (I) is a potent and selective inhibitor targeting both BRAF and CRAF kinases with sub-nM inhibition concentration 50% (IC50) values in biochemical assays, while inhibiting the binding of only 2 (discoidin domain receptor tyrosine kinase 1 (DDR1 ) and platelet-derived growth factor receptor, beta polypeptide (R ⁇ QRRb)) of 456 kinases to a similar degree.
• DDR1 discoidin domain receptor tyrosine kinase 1
• R ⁇ QRRb beta polypeptide
• the Compound of formula (I) has demonstrated efficacy in a wide range of MAPK pathway-driven human cancer cell lines and in vivo tumor xenografts including models harboring activating lesions in the KRAS, NRAS, and BRAF oncogenes.
• the compound of formula (I) exhibits activity in the low uM range on human pancreatic cancer cell lines that express mutations in KRAS (see WO/2018/203219 A1 , Example 1 B, Table 2).
• compositions of the present invention further comprise a CDK4/6 inhibitor.
• the D-cyclin- CDK4/6 - RB1 axis is a major effector pathway downstream of MAPK signaling that controls the transition of cells from the G1 -to-S phase of the cell cycle.
• Suitable CDK4/6 inhibitors for use in the present invention include ribociclib, or a
• a CDK4/6 inhibitor useful in the pharmaceutical combinations of the invention include ribociclib or palbociclib.
• Ribociclib (Kisqali®) is an orally bioavailable and highly selective small molecule inhibitor with highly specific inhibitory activity against CDK4/cyclin-D1 and CDK6/cyclin-D3 enzyme complexes.
• a particularly useful salt of ribociclib is the succinate salt thereof.
• the present invention further relates to a pharmaceutical combination
• a pharmaceutical combination comprising (a) a Raf inhibitor which is the Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor, particularly for simultaneous, separate or sequential use in the treatment of cancer.
• the term“combination of the invention” refers to the pharmaceutical combination of (a) a Raf inhibitor which is the Compound of formula (I), or a
• the term“combination of the invention” also refers to the co-administration or combined administration (of (a) a Raf inhibitor which is the Compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor, preferably ribociclib, or a pharmaceutically acceptable salt thereof.
• a Raf inhibitor which is the Compound of formula (I), or a pharmaceutically acceptable salt thereof
• a CDK4/6 inhibitor preferably ribociclib, or a pharmaceutically acceptable salt thereof.
• the Compound of formula (I), or a pharmaceutically acceptable salt thereof, and the CDK4/6 inhibitor, preferably ribociclib, or a pharmaceutically acceptable salt thereof may be employed in combination in accordance with the invention by administration simultaneously in a unitary pharmaceutical composition including both compounds.
• the combination may be administered separately in separate pharmaceutical compositions, each including the Raf inhibitor and a CDK4/6 inhibitor in a sequential manner wherein, for example, the Raf inhibitor or a CDK4/6 inhibitor is administered first and the other second.
• Such sequential administration may be close in time ( e.g simultaneously) or remote in time.
• the actual dosage can vary by up to 10% (preferably by up to 5%) from the stated amount: this usage recognizes that the precise amount in a given dosage form may differ slightly from an intended amount for various reasons without materially affecting the in vivo effect of the administered compound.
• a therapeutic agent in these combinations can be administered concurrently with, prior to, or subsequent to, one or more other additional therapies or therapeutic agents.
• the therapeutic agents can be administered in any order. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. It will further be appreciated that the additional therapeutic agent utilized in this combination may be administered together in a single composition or administered separately in different compositions. In general, it is expected that additional therapeutic agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized as single-agent therapeutics.
• the combinations of the invention have therapeutic or protective functions or both.
• these molecules may be administered to a human subject, to treat and/or prevent a variety of disorders, such as cancers as described herein.
• “combination”,“therapeutic combination” or“pharmaceutical combination” as used herein refer to either a fixed combination in one dosage unit form, or non-fixed combination, or a kit of parts for the combined administration (co-administration) where two or more therapeutic agents may be administered together, independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g., synergistic, effect.
• composition therapy refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure.
• Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single formulation having a fixed ratio of active ingredients or in separate formulations ⁇ e.g., capsules and/or intravenous formulations) for each active ingredient.
• administration and co-administration also encompass use of each type of therapeutic agent in a sequential or separate manner, either at approximately the same time or at different times.
• the active ingredients are administered as a single formulation or in separate formulations
• the drugs are administered to the same patient as part of the same course of therapy.
• the treatment regimen will provide beneficial effects in treating the conditions or disorders described herein.
• simultaneous therapeutic use within the meaning of the present invention is meant an administration of at least two active ingredients by the same route and at the same time or at substantially the same time.
• sequential therapeutic use is meant administration of at least two active ingredients at different times, the administration route being identical or different. More particularly by an administration method is meant according to which the whole administration of one of the active ingredients is carried out before administration of the other or others commences.
• the terms“fixed combination”,“fixed dose” and“single formulation” as used herein refers to a single carrier or vehicle or dosage form formulated to deliver an amount, which is jointly therapeutically effective for the treatment of cancer, of both therapeutic agents to a patient.
• the single vehicle is designed to deliver an amount of each of the agents along with any pharmaceutically acceptable carriers or excipients.
• the vehicle is a tablet, capsule, pill, or a patch. In other embodiments, the vehicle is a solution or a suspension.
• non-fixed combination or“kit of parts” means that the therapeutic agents of the combination of the invention are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of a subject in need thereof.
• cocktail therapy e.g., the administration of three or more active ingredients.
• pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues of a subject, e.g., a mammal or human, without excessive toxicity, irritation, allergic response and other problems or complications commensurate with a reasonable benefit/risk ratio.
• the term“pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives ⁇ e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art. Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
• pharmaceutical composition refers to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human, in order or treat a particular disease or condition affecting the subject.
• the present pharmaceutical combinations can be formulated in suitable pharmaceutical compositions for enteral or parenteral administration, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, direct compression, granulating, sugar-coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art.
• the pharmaceutical composition may contain, from about 0.1 % to about 99.9%, preferably from about 1 % to about 60 %, of the therapeutic agent(s).
• One of ordinary skill in the art may select one or more of the aforementioned carriers with respect to the particular desired properties of the dosage form by routine experimentation and without any undue burden.
• the amount of each carriers used may vary within ranges conventional in the art.
• These optional additional conventional carriers may be incorporated into the oral dosage form either by incorporating the one or more conventional carriers into the initial mixture before or during granulation or by combining one or more conventional carriers with granules comprising the combination of agents or individual agents of the combination of agents in the oral dosage form.
• the combined mixture may be further blended, e.g., through a V-blender, and subsequently compressed or molded into a tablet, for example a monolithic tablet, encapsulated by a capsule, or filled into a sachet.
• compositions may be presented in unit dose forms containing a
• the unit dose includes one or more vehicles such that each vehicle includes an effective amount of at least one of the therapeutic agents along with pharmaceutically acceptable carriers and excipients.
• the unit dose is one or more tablets, capsules, pills, injections, infusions, patches, or the like, administered to the patient at the same time.
• the amount of active ingredient per dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient.
• Preferred unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient.
• such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.
• compositions of the invention may include a“therapeutically effective amount” or“effective amount” of a compound of the invention.
• the term“pharmaceutically effective amount”,“therapeutically effective amount” or“clinically effective amount” of a combination of therapeutic agents is an amount sufficient, at dosages and for periods of time necessary, to provide an observable or clinically significant improvement over the baseline of clinically observable signs and symptoms of the disorders treated with the combination.
• a therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual.
• a therapeutically effective amount is also one in which any toxic or detrimental effects of the therapeutic agents are outweighed by therapeutically beneficial effects.
• a "therapeutically effective dosage” preferably modulates a measurable parameter, such as tumor growth rate or disease progression in a desired manner.
• a measurable parameter such as tumor growth rate or disease progression
• the ability of a compound to modulate a measurable parameter can be evaluated in an animal model system predictive of efficacy in human tumors to help establish suitable dosing levels and schedules. Alternatively, this property of a composition can be evaluated by examining the ability of the compound to modulate an undesired parameter by using in vitro assays known to the skilled practitioner.
• jointly therapeutically active or“joint therapeutic effect” as used herein means that the therapeutic agents can be given jointly, separately or sequentially in such time intervals that they prefer such that the subject, especially human, to be treated, still show an (preferably synergistic) interaction (joint therapeutic effect). Whether this is the case can, inter alia, be determined by following the blood levels of the compounds, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals.
• an“agent” is understood to mean a substance that produces a desired effect in a tissue, system, animal, mammal, human, or other subject. It is also to be understood that an“agent” may be a single compound or a combination or composition of two or more compounds.
• cancer is preferably a cancer.
• cancer refers to a disease characterized by the undesired and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body.
• cancer or“tumor” includes premalignant, as well as malignant cancers and tumors.
• the term“cancer” is used herein to mean a broad spectrum of tumors, including all solid and hematological malignancies.
• proliferative disease or “proliferative disorder” also refer to cancer in general or to a cancer as defined herein.
• An“oral dosage form” includes a unit dosage form prescribed or intended for oral administration.
• the terms“treat”,“treatment” and“treating” refer to the reduction or amelioration of the progression, severity and/or duration of a disorder, e.g., a proliferative disorder, or the amelioration of one or more symptoms, suitably of one or more discernible symptoms, of the disorder resulting from the administration of one or more therapies.
• the terms“treat”,“treatment” and“treating” refer to the amelioration of at least one measurable physical parameter of a proliferative disorder, such as growth of a tumor, not necessarily discernible by the patient.
• the terms“treat”, “treatment” and“treating” refer to the inhibition of the progression of a proliferative disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments the terms“treat”, “treatment” and“treating” refer to the reduction or stabilization of tumor size or cancerous cell count.
• the terms“treat”,“treatment” and“treating” include the reduction of the incidence and severity of adverse events (AEs) and serious AEs (SAEs) including changes in laboratory values, vital signs and Electrocardiograms (ECGs) in a patient or a patient population.
• the terms“treat”,“treatment” and“treating” include an improvement of the overall response rate (ORR), Disease control rate (DCR), Duration of response (DOR), Progression Free Survival (PFS), e.g., as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 , in a patient or a patient population.
• the term“treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
• the term“protect” is used herein to mean prevent, delay, or treat, or all, as appropriate, development, continuance or aggravation of a disease in a subject, e.g., a mammal or human.
• subject or“patient” as used herein is intended to include animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer.
• subjects include mammals, e.g., humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
• the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from a cancer, such as cancer.
• inhibitortion includes a reduction in a certain parameter, e.g., an activity, of a given molecule or pathway.
• a certain parameter e.g., an activity, of a given molecule or pathway.
• inhibition of an activity of a targeted kinase (Raf or CDK4/6) by 5%, 10%, 20%, 30%, 40% or more is included by this term.
• inhibition may be, but need not be, 100%.
• salts can be present alone or in mixture with free compounds of the combination of the invention, e.g., Raf inhibitor Compound with formula (I) or or CDK4/6 inhibitor, preferably ribociclib, and are preferably pharmaceutically acceptable salts.
• Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of the combination of the invention with a basic nitrogen atom, especially the pharmaceutically acceptable salts.
• pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compound and which typically are not biologically or otherwise undesirable. The compound may be capable of forming acid addition salts by virtue of the presence of an amino group.
• any reference to the free compounds is to be understood as referring also to the corresponding salts, as appropriate and expedient.
• the salts of compounds used in the combination of the invention are preferably pharmaceutically acceptable salts; suitable counter-ions forming pharmaceutically acceptable salts are known in the field.
• reference to therapeutic agents useful in the pharmaceutical combination provided herein includes both the free base of the compounds, and all pharmaceutically acceptable salts of the
• the term“synergistic effect” as used herein, refers to action of two agents such as, for example, Raf inhibitor Compound with formula (I), or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor, preferably ribociclib, or a pharmaceutically acceptable salt thereof, to produce an effect, for example, slowing the symptomatic progression of cancer or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves.
• the combination of the invention comprises (a) a Raf inhibitor which is the Compound of formula (I)
• the combination of the invention comprises (a) a Raf inhibitor
• CDK4/6 inhibitor selected from ribociclib and palbociclib, and pharmaceutically acceptable salts thereof.
• the CDK4/6 inhibitor is preferably ribociclib, or a pharmaceutically acceptable salt thereof.
• Combinations of the invention demonstrated increased depth and durability of tumor response compared to either single-agent therapy in cell lines and human xenograft models, (see Examples), and may therefore be effective for the treatment of a cancer. Accordingly, the invention provides compositions and methods using a Raf inhibitor which is the
• MAPK pathway alterations e.g. NRAS-mutant cancers and KRAS-mutant cancers.
• these therapeutic agents are administered at therapeutically effective dosages which, when combined, provide a beneficial effect.
• the present invention particularly pertains to a combination of the invention useful for separate, simultaneous or sequential administration to a subject in need thereof for treating a cancer.
• the present invention particularly pertains to a combination of the invention for use in the treatment of a cancer.
• combination of therapeutic agents having different modes of action does not necessarily lead to combinations with advantageous effects and does not necessarily translate into clinical benefit for patients suffering from certain cancers.
• the administration of the combination of the invention is expected to result in a more beneficial effect, e.g., a synergistic or improved anti-proliferative effect, e.g., with regard to the delay of progression or inhibiting the cancer or its symptoms, and may also provide further beneficial effects such as any one or more of the following: fewer side- effects such as skin-related toxicity (e.g. rash) and gastro-intestitinal-toxicity (e.g. diarrhea), improved tolerability, higher quality of life and decreased morbidity, as compared to any therapy in the prior art or to monotherapy with any one of the combination partners.
• a synergistic or improved anti-proliferative effect e.g., with regard to the delay of progression or inhibiting the cancer or its symptoms
• further beneficial effects such as any one or more of the following: fewer side- effects such as skin-related toxicity (e.g. rash) and gastro-intestitinal-toxicity (e.g. diarrhea), improved tolerability, higher quality of life and decreased mor
• the therapeutic agents of the combination of the invention may be separately,
• the combination of the invention is for use in the treatment of cancer, particularly a cancer as described herein.
• cancer is used herein to mean a broad spectrum of tumors, including all solid and hematological malignancies.
• the cancer may be at an early, intermediate or late stage.
• the cancer may be locally advanced or metastatic.
• the cancer to be treated by the combination therapy described herein may have progressed following standard of care or for whom no effective standard therapy exists.
• the cancer is melanoma.
• the combination of the invention is particularly useful for the treatment of a cancer such as a cancer that harbors one or more Mitogen-activated protein kinase (MAPK) pathway alterations, such as an NRAS-mutant tumor, and in particular, a tumor expressing at least one gain-of-function mutation of Ras, as described herein, and/or at least one gain-of- function mutation of Raf, as described herein.
• a cancer such as a cancer that harbors one or more Mitogen-activated protein kinase (MAPK) pathway alterations, such as an NRAS-mutant tumor, and in particular, a tumor expressing at least one gain-of-function mutation of Ras, as described herein, and/or at least one gain-of- function mutation of Raf, as described herein.
• MPK Mitogen-activated protein kinase
• NRAS mutant cancers or tumors include any NRAS mutations of interest.
• NRAS mutations of interest may be selected from G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61 R, Q61 L, Q61 K, Q61 H, Q61 P and Q61 E.
• the term“NRAS-mutant” tumor or cancer includes any tumor that exhibits a mutated NRAS protein, in particular gain of function NRAS-mutation; especially any G13R, Q61 K, Q61 L, Q61 R, NRAS-mutant tumor.
• NRAS-mutant melanoma includes melanoma having at least one NRAS mutation corresponding to Q61 K, Q61 L or Q61 R.
• the cancer may be NRAS QG13R-mutant melanoma. Included are also KRAS mutant cancers or tumors. KRAS mutations of interest may be selected from G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61 R, Q61 L, Q61 K, Q61 H, Q61 P and Q61 E.
• the term“KRAS-mutant” tumor or cancer includes any tumor that exhibits a mutated KRAS protein.
• the cancer may be at an early, intermediate or late stage.
• the cancer may be locally advanced or metastatic.
• the cancer is resistant or refractory to standard of care. In another embodiment, the cancer is resistant or refractory to standard of care with dacarzabine.
• the cancer is resistant or refractory to treatment with a MEK inhibitor.
• thecancer is resistant or refractory to treatment with immunotherapy treatment including therapy with one or more immune checkpoint inhibitors.
• the cancer is resistant or refractory to treatment with a cytotoxic agent such as a nitrosurea and/or mitomycin C.
• a cytotoxic agent such as a nitrosurea and/or mitomycin C.
• the cancer is characterized by at least one mutation selected from the group comprising NRAS proteins.
• the cancer is characterized by an NRAS mutation.
• the combination of the invention relates to a method for treating a cancer, particularly a melanoma.
• the combination of the invention may be especially useful in treating NRAS-mutant melanoma.
• the cancer is characterized by at least one mutation selected from the group comprising KRAS proteins.
• the cancer is characterized by an KRAS mutation.
• the combination of the invention relates to a method for treating a cancer, particularly a pancreatic cancer.
• the combination of the invention may be especially useful in treating KRAS-mutant PDAC.
• a method for treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a pharmaceutical combination of the invention comprising (a) a Raf inhibitor which is the Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor.
• a pharmaceutical combination of the invention comprising (a) a Raf inhibitor which is the Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor.
• the CDK4/6 inhibitor is ribociclib, or a pharmaceutically acceptable salt thereof.
• a method for treating cancer in a subject in need thereof comprising administering simultaneously, separately or sequentially to a subject in need thereof a combination of the invention in a quantity which is jointly therapeutically effective against said cancer wherein the combination of the invention comprises (a) a Raf inhibitor which is the Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof and (b) a CDK4/6 inhibitor.
• the CDK4/6 inhibitor is ribociclib, or a pharmaceutically acceptable salt thereof.
• the present invention is particularly related to a method of treating a cancer harboring one or more Mitogen-activated protein kinase (MAPK) pathway alterations.
• the present invention is related to a method of treating a cancer, which is characterized by at least one mutation in NRAS.
• the present invention is related to a method of treating a cancer, which is characterized by at least one mutation in KRAS.
• the present invention relates to the use of the combination of the invention for the preparation of a medicament for the treatment of cancer, particularly a cancer as described herein.
• the combination of the invention is for use in the preparation of a medicament for the treatment of cancer.
• the present invention relates to the use of the combination of the invention for the preparation of a medicament for the treatment of a cancer characterized by gain-of-function mutation in the MAPK pathway.
• the combination or composition, or both, provided herein display a synergistic effect.
• the invention may provide a method of enhancing the efficacy of an anticancer compound by using it in combination with another anticancer compound, particularly a method using a Raf inhibitor which is the Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, together with a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt, thereof to provide enhanced efficacy which is not achievable by administering similar doses of either the Compound of formula (I), or a pharmaceutically acceptable salt thereof, or the CDK4/6 inhibitor as a single agent (monotherapy).
• a Raf inhibitor which is the Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof
• a further benefit provided by the invention may be that lower doses of the therapeutic agents of the combination of the invention can be used, for example, such that the dosages may not only often be smaller, but also may be applied less frequently, or can be used in order to diminish the incidence of side-effects observed with one of the combination partners alone.
• the pharmaceutically acceptable salt thereof, and/or the CDK4/6 inhibitor, preferably ribociclib, or a pharmaceutically acceptable salt thereof may be administered at a therapeutic or lower- than therapeutic dose relative to a single-agent dose level.
• the concentration or dosage of the one therapeutic agent that is required to achieve inhibition, e.g., growth inhibition or tumor shrinkage is lower when the other therapeutic agent is used or administered in combination with the first therapeutic agent than when each therapeutic agent is administered individually.
• the concentration or dosage of one therapeutic agent that is required to achieve inhibition is lower than the therapeutic dose as a monotherapy, e.g., 10-20%, 20- 30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower.
• the optimum range for the effect and absolute dose ranges of each component for the effect may be definitively measured by administration of the components over different w/w ratio ranges and doses to patients in need of treatment.
• the complexity and cost of carrying out clinical studies on patients may render the use of this form of testing as a primary model for synergy impractical.
• the observation of synergy in certain experiments can be predictive of the effect in other species, and animal models exist may be used to further quantify a synergistic effect.
• synergy in one species can be predictive of the effect in other species and using animal models, as described herein, a synergistic effect can be measured and the results of such studies can also be used to predict effective dose ratio ranges and the absolute doses and plasma concentrations required in other species by the application of pharmacokinetic/pharmacodynamic (PK/PD) methods.
• PK/PD pharmacokinetic/pharmacodynamic
• Established correlations between tumor models and effects seen in man suggest that synergy in animals may be demonstrated, for example, by xenograft models or in appropriate cell lines. It can be shown by established test models that a combination of the invention results in the beneficial effects described herein. The person skilled in the art is fully enabled to select a relevant test model to prove such beneficial effects.
• the pharmacological activity of the combination of the invention may, for example, be demonstrated in a clinical study or in an in vivo or in vitro test procedure as essentially described herein.
• Administration of the combination includes administration of the combination in a single formulation or unit dosage form, administration of the individual agents of the combination concurrently but separately, or administration of the individual agents of the combination sequentially by any suitable route.
• the individual combination partners of the combination of the invention may be administered separately at different times during the course of therapy, or sequentially in any order or concurrently in divided or single combination forms, e.g., simultaneously or in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g., in daily or intermittent (i.e., not daily) dosages corresponding to the amounts described herein.
• the Compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the methods, treatments, combinations and compositions disclosed herein is a potent inhibitor of BRAF and CRAF.
• the Compound of formula (I), or a pharmaceutically acceptable salt thereof is administered orally.
• the Compound of formula (I), or a pharmaceutically acceptable salt thereof is administered at a total daily dose of about 200-1200 mg, about 300-1000 mg, about 400-800 mg, or about 500-600 mg (e.g., once per day).
• the Compound of formula (I), or a pharmaceutically acceptable salt thereof can be administered at a total daily dose of about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1 100 mg, about 1 150 mg or about 1200 mg.
• the Compound of formula (I), or a pharmaceutically acceptable salt thereof may be administered at a total daily dose selected from about 200 mg, 400 mg, 600 mg, 800 mg and 1200 mg.
• the total dose of the Compound of formula (I), or a pharmaceutically acceptable salt thereof may be administered once daily, or may be divided into two and each dose of the Compound of formula (I) administered twice daily, with the actual dosage and timing of administration determined by criteria such as the patient’s age, weight, and gender; the extent and severity of the cancer to be treated; and the judgment of a treating physician.
• the total dose of the Compound of formula (I) is administered once daily.
• the total dose of the Compound of formula (I) is administered twice daily.
• the CDK4/6 inhibitor as part of the combination according to the present invention is administered to a subject in need thereof in a therapeutically effective amount.
• the total daily dose of CDK4/6 inhibitor ribociclib or a
• pharmaceutically acceptable salt thereof administered daily as part of the combination according to the present invention in a subject in need thereof will be an amount selected from about 100 mg to about 600 mg per day; suitably, the amount will be selected from about 200 mg to about 400 mg per day.
• ribociclib, or a pharmaceutically acceptable salt thereof is administered at daily dose selected from about 100, about 200 mg, about 400 mg and about 600 mg.
• the total dose may be divided in two doses, which are administered twice daily.
• 600 mg 100 mg, 200 mg, 400 mg, 600 mg, or 900 mg
• the amount referred to refers to the amount of the therapeutic agent.
• the tablet will contain ribociclib succinate equivalent to 200 mg ribociclib.
• ribociclib or a pharmaceutically acceptable salt thereof is administered orally.
• ribociclib is prepared for administration via oral delivery, and may be used in the salt form, e.g. the succinate salt form.
• the compound is prepared in tablet form for oral administration.
• the tablets can be produced in a variety of dosages for flexible administration.
• the dose of ribociclib, or a pharmaceutically acceptable salt thereof may be administered once daily, or twice daily, or three times daily, or four times daily.
• the total daily dose of ribociclib, or a pharmaceutically acceptable salt thereof, may be administered once or twice a day.
• the Compound of formula (I), or a pharmaceutically acceptable salt thereof may be administered at a total daily dose of about 200 mg, about 400 mg, about 600 mg, about 800 mg or about 1200 mg and ribociclib, e.g. in the succinate salt form, may be administered in a total daily dose selected from about 100 mg, about 200 mg, about 400 mg and about 600 mg.
• the daily dose of the Compound of formula (1 ) may be administered once or twice per day.
• a dose of about 200 mg of the Compound of formula (I) may be administered twice per day and (total daily dose about 400 mg) and a dose of about 100 mg or about 200 mg of ribociclib may be administered once per day.
• a dose of about 200 mg of the Compound of formula (I) may be administered twice per day and (total daily dose about 400 mg) and a dose of about 100 mg or about 200 mg of ribociclib may be administered twice per day.
• the Compound of formula (I) may be administered 600 mg twice a day (b.i.d or BID) and ribociclib administered at 600 mg once a day.
• the Compound of formula (I) may be also be administered 400 mg twice a day (BID) and ribociclib administered at 200 mg once a day.
• the Compound of formula (I) is preferably administered continuously, i.e. without a drug holiday period.
• the CDK4/6 inhibitor may be administered either continuously i.e. without a break during the treatment period, or with a drug holiday period.
• the CDK4/6 inhibitor e.g. ribociclib or a pharmaceutically acceptable salt thereof
• the following regimens may be used according to the present invention
• the Compound of formula (I) may be given without a drug holiday period once or twice a day and the CDK4/6 inhibitor (e.g. ribociclib, or a pharmaceutically acceptable salt thereof) may be administered three weeks on and one week off.
• the CDK4/6 inhibitor e.g. ribociclib, or a pharmaceutically acceptable salt thereof
• the total daily doses of the Compound of formula (I) and of the CDK4/6 inhibitor are as described above and throughout the description.
• a dose of 400 mg or 600 mg of the Compound of formula (I) may be given once or twice a day, preferably twice a day, and a dose of 200 mg of ribociclib may be given once a day, three weeks on and one week off.
• a dose of 600 mg of the Compound of formula (I) may be given once or twice a day, preferably twice a day, and a dose of 600 mg of ribociclib may be given once a day, three weeks on and one week off.
• the Compound of formula (I), or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor, preferably ribociclib, or a pharmaceutically acceptable salt thereof can be used together according to methods disclosed herein.
• the two compounds can be administered together or separately, depending on the intended dosage amount and frequency of administration, since it is contemplated that the treatments of the invention may be continued for 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more than 4 weeks as deemed appropriate to the treating physician, and further as guided using methods described herein to determine a suitable dosage and administration frequency. Frequency of dosage may vary depending on the compound used and the particular condition to be treated.
• the use of the minimum dosage that is sufficient to provide effective therapy is preferred and may be determined by criteria such as the patient’s age, weight, and gender; the extent and severity of the cancer to be treated; and the judgment of a treating physician.
• Patients may generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated, which will be familiar to those of ordinary skill in the art.
• combination partners of the combination of the invention i.e., Compound of formula (I), or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof, that yield efficacy without toxicity are based on the kinetics of the therapeutic agents’ availability to target sites and a variety of factors, including, but not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking.
• Optimal dosages may be established using routine testing and procedures that are well known in the art.
• a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
• the therapeutic agents of the combination of the invention may be administered by any appropriate route. It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the location of the cancer to be treated.
• each of the therapeutic agents may be administered by the same or different routes and that the therapeutic agents, e.g., the Compound of formula (I), or a pharmaceutically acceptable salt thereof, and the CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof, may be compounded together in a
• the Compound of formula (I), or a pharmaceutically acceptable salt thereof, and the CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof, can be used together as disclosed herein.
• the two therapeutic agents of the combination of the invention can be administered together (simultaneously), sequentially or separately.
• the compounds are administered in the same dosage form, e.g., one compound may be administered topically and the other compound may be administered orally.
• both therapeutic agents are administered orally.
• the compounds can be can be administered in the same or different dosage form.
• one or more doses of the Compound of formula (I), or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially or separately with one or more doses of a CDK4/6 inhibitor, suitably ribociclib, or a
• multiple doses of the Compound of formula (I), or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially or separately with multiple doses of a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof.
• multiple doses of the Compound of formula (I), or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially or separately with one dose of a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof.
• one dose of the Compound of formula (I), or a pharmaceutically acceptable salt thereof is administered simultaneously, sequentially or separately with multiple doses of a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof.
• one dose of the Compound of formula (I), or a pharmaceutically acceptable salt thereof is administered simultaneously, sequentially or separately with one dose of a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof.
• the Compound of formula (I), or a pharmaceutically acceptable salt thereof may be administered first or the CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof may be administered first.
• a pharmaceutical composition comprising (a) the Compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof for use in the methods of the invention.
• the pharmaceutical composition further comprises one or more pharmaceutically acceptable diluents, excipients or carriers.
• the carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof.
• Such elements of the pharmaceutical compositions utilized may be presented in separate pharmaceutical combinations or formulated together in one pharmaceutical composition.
• compositions or dosage forms as described can be administered together in a single composition or administered separately in two or more different compositions, e.g., compositions or dosage forms as described and the components may be administered as the same formulation, or as separate formulations, alone, e.g., as indicated above, or in combination with one or more pharmaceutically acceptable carriers by any suitable route.
• Dosage unit forms as used herein refer to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound (e.g., the Compound of formula (I), or a pharmaceutically acceptable salt thereof, or the CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof, calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
• the unit dosage form may also be a fixed combination.
• packaged pharmaceutical products may contain one or more dosage forms that contain the combination of compounds, and one or more dosage forms that contain one of the therapeutic agents of the combination of the invention, but not the other therapeutic agent of the combination of the invention.
• the combination partners which are employed in the combination of the invention, are applied in the form as marketed as single drug, their dosage and mode of administration can be in accordance with the information provided on the package insert of the respective marketed drug, if not mentioned otherwise.
• packaged pharmaceutical products can contain one or more dosage forms that contain the combination of agents, and one or more dosage forms that contain one of the therapeutic agents of the combination, but not the other therapeutic agent of the combination.
• a combination kit comprising, as therapeutic agents, the combination of the invention for simultaneous, separate or sequential administration as described herein, together with one or more other elements: instructions for use; other reagents for use with the combination of the invention; devices or other materials for preparing the compound for administration, such as a mixing container; pharmaceutically acceptable carriers; and devices or other materials for administration to a subject, such as a syringe.
• kits or“kit of parts” as used herein is meant the pharmaceutical composition or compositions that are used according to the invention.
• the combination kit can contain the Compound of formula (I), or a pharmaceutically acceptable salt thereof, and the CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof and the CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions.
• the Compound of formula (I), or a pharmaceutically acceptable salt thereof, and the CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof and the CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof are not
• the combination kit will contain the Compound of formula (I), or a pharmaceutically acceptable salt thereof, and the CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof in separate pharmaceutical compositions either in a single package or in separate pharmaceutical compositions in separate packages.
• the kit of parts comprising the following components: (a) a Raf inhibitor compound selected from the group consisting of (i) the Compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with pharmaceutically acceptable excipients, diluents and/or carriers, and (b) a CDK4/6 inhibitor, preferably ribociclib, or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipients, diluents or carrier, wherein the components are provided in a form which is suitable for sequential, separate and/or simultaneous
• the combination kit can also be provided with instructions, such as dosage and administration instructions.
• dosage and administration instructions can be of the kinds that are provided to a doctor, for example by a drug product label, or they can be of the kinds that are provided by a doctor, such as instructions to a patient.
• EXAMPLE 1 Enhanced combination effects of RAF inhibition with CDK4/CDK6 inhibition in NRAS mutant melanoma cell lines
• SK-MEL-2 cells were purchased from American Type Culture Collection (ATCC), MEL-JUSO cells were purchased from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ), MM415 cells were purchased from Cell Bank Australia, and IPC-298 and SK-MEL-30 cells were acquired from GNF. IPC-298, MEL-JUSO, MM415, and SK-MEL-30 cells were cultured in RPMI medium (ATCC) and the SK-MEL-2 cells were cultured in EMEM medium (ATCC) both supplemented with 10% fetal bovine serum (Gibco) and incubated at 37°C/5% C02.
• ATCC American Type Culture Collection
• MEL-JUSO cells were purchased from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ)
• MM415 cells were purchased from Cell Bank Australia
• IPC-298 and SK-MEL-30 cells were acquired from GNF. IPC-298, MEL-JUSO, MM415, and SK-M
• CyQUANT® Direct (Thermo #C3501 1 ) according to the manufacturer’s protocol.
• Combination data analysis was performed using the internal Novartis software, Combination Analysis Module.
• the application utilized the Loewe dose additivity model to calculate a weighted synergy score across each dose matrix that adjusts for dose sampling and coverage, and weights to favor combination effects at high inhibition levels (Lehar et al., 2009).
• the combination of the Compound of formula (I) and ribociclib demonstrated improved anti proliferative and phopho-Rb suppression effects relative to single treatments in the SK-MEL- 30 melanoma cell line (FIGURE 1 ).
• the SK-MEL-30 melanoma cell line harbors co-incident mutations in NR AS (Q61 K) and BRAF (D287H).
• the combination of the Compound of formula (I) and ribociclib demonstrated improved anti proliferative and phopho-Rb suppression effects relative to single treatments in the IPC-298 melanoma cell line (FIGURE 2).
• the IPC-298 melanoma cell line harbors a NRAS mutation (NRASQ61 L).
• the combination of the Compound of formula (I) and ribociclib demonstrated improved anti proliferative and phopho-Rb suppression effects relative to single treatments in the Meljuso melanoma cell line (FIGURE 3).
• the Meljuso melanoma cell line harbors a NRAS mutation (NRASQ61 L).
• EXAMPLE 2 Combination efficacy of the Compound of formula (I) and ribociclib in NRAS mutant melanoma patient derived xenografts
• mice Female mice (Athymic Nude- nu”) (Charles River, Indianapolis) were allowed to acclimate in the Novartis NIBR animal facility with access to food and water ad libitum for minimum of 3 days prior to manipulation (Table 1 ).
• Test compound and formulations the Compound of formula (I) (free base form) was dosed p.o. (orally) in MEPC4 vehicle (45% Cremophor RH40 + 27% PEG400 + 18% Corn Oil Glycerides + 10% ethanol). The Compound of formula (I) was formulated at 5 mg/mL.
• Ribociclib succinate salt was dosed p.o. (orally) in a vehicle of 0.5% methyl cellulose;
• ribociclib was formulated at 7.5 mg/mL.
• HMEX4339, HMEX20744, and HMEX21 124 patient-derived tumor xenografts (PDX) were propagated by serial passage of tumor slurry in nude mice. Briefly, fragments of fresh tumor from a previous passage were homogenized using gentle MACS Dissociator (MACS).
• PD pharmacodynamics
• Body Weight The percent change in body weight was calculated as ( BW CU rrent -
• V tumor volume of the drug-treated (or untreated) group on a given day of the study
• the antitumor efficacy of the Compound of formula (I) when combined with ribociclib was determined using nine NRAS mutant patient derived melanoma xenograft models in nude mice: HMEX5727 (NRASQ61 K), HMEX3486 (NRASQ61 K), HMEX20667 (NRASQ61 R), HMEX2921 (NRASQ61 R), HMEX20585 (NRASQ61 R), HMEX20864 (NRASQ61 R),
• HMEX21 124 (NRASQ61 H), HMEX20744 (NRASQ61 K), and HMEX4339 (NRASQ61 R).
• Table 3 Anti-tumor efficacy and tolerability of the Compound of formula (I) and ribociclib in nine patient derived NRAS mutant melanoma tumor xenograft models in mice
• the purpose of the study is to characterize the safety and the tolerability of the dual combination the Compound of formula (I) and ribociclib in patients with NRAS mutant melanoma and identify a recommended dose.
• Inclusion criteria Adult (18 years or older) melanoma patients with diagnosis of locally advanced or metastatic NRAS-mutated melanoma who have progressed following standard of care or for whom no effective standard therapy exists, is tolerated, appropriate or is considered equivalent to study treatment will be eligible to participate in this study. Presence of NRAS mutation in tumor tissue is prior to study treatment as determined by a local laboratory or a Novartis designated central laboratory, or written documentation of KRAS, BRAF or NRAS mutation. ECOG (Eastern Cooperative Oncology Group) performance status is £ 2. Patients must have a site of disease amenable to biopsy and must be willing to undergo a new tumor biopsy at baseline and during treatment according to treating institution’s own guidelines and requirements for such procedure. Presence of at least one measurable lesion according to RECIST v1 .1 is required.
• CDK4/6 inhibitor or CDK4/6 inhibitor.
• RVO retinal vein occlusion
• current risk factors for RVO e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes.
• inhibitors and/or inducers of CYP3A and CYP2C8 inhibitor or inducers of UGT2B7; substrates and inhibitors of UGT1 A1 ; substrates of CYP2C8, CYP2C9, and CYP3A with a narrow therapeutic index; and sensitive substrates of CYP3A, herb medicines known to cause liver toxicity, which cannot be discontinued 7 days prior to the start study treatment and for the duration of the study.
• Exceptions to this exclusion criterion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers; and completely resected carcinoma in situ of any type.
• the dose escalation for each tested regimen will be guided by a Bayesian logistic regression model (BLRM) based on the first cycle DLT data.
• BLRM Bayesian logistic regression model
• BLRM/BHLRM is a well-established method to estimate the MTD in cancer patients.
• the adaptive BLRM/BHLRM will be guided by the escalation with overdose control (EWOC) principle to control the risk of DLT in future patients on study.
• EWOC overdose control
• Bayesian response adaptive models for small datasets has been accepted by EMEA (“Guideline on clinical trials in small populations”, February 13, 2007) and endorsed by numerous publications (Babb et al 1998, Neuenschwander et al 2008, Neuenschwander et al 2010), and its development and appropriate use is one aspect of the FDA’s Critical Path Initiative.
• the safety (including the dose-DLT relationship) and tolerability of the combination will be assessed; dose(s) and regimen(s) will be identified for use in the dose expansion based on the review of these data.
• the recommended dose for expansion will also be guided by available information on PK, PD, and preliminary anti-tumor activity.
• the study treatment will be administered in 28-day dosing cycles in fasted condition.
• Tablet and capsule for oral use dose as assigned, daily dose for 28 day cycles.
• the investigator or responsible site personnel should instruct the patient to take the study drug exactly as prescribed to promote compliance.
• Patients should inform the investigational site staff of any missed or delayed doses. Patients may be discontinued from study treatment earlier due to unacceptable toxicity, progressive disease, if treatment is discontinued at the discretion of the investigator or the patient and/or if the patient withdraws consent.
• the following table describes the starting doses and the provisional dose levels of the individual investigational drugs (not the combination) that may be evaluated during this trial.
• * lt is possible for additional and/or intermediate dose levels to be added during the course of the study, including doses outside the range of provisional doses shown in this table and not exceeding the recommended dose (RD) for both single agents. Cohorts may be added at any dose level below the maximum tolerated dose (MTD) of the combination in order to better understand safety, PK or PD.
• MTD maximum tolerated dose
• ** DL -1 represent treatment doses for patients requiring a dose reduction from the starting dose level and/or the potential starting dose depending on the safety information from FIH studies.
• the MTD(s) for any combination is defined as the highest dose combination for that combination that is unlikely ( ⁇ 25% posterior probability) to cause DLTs in 33% or more of the treated patients in the first cycle of the Compound of formula (I) and ribociclib treatment during the escalation part of the study.
• the RD will be a dose that is less than or equal to MTD and has, in the view of Investigators and Novartis study personnel, the most appropriate benefit-risk assessment based on the review of safety and tolerability, PK, PD and activity information. Note that it is possible that the MTD may not be reached in some situations.
• the CDK4/6 inhibitor may be administered either continuously i.e. without a break during the treatment period, or with a holiday period.
• the CDK4/6 inhibitor e.g. ribociclib or a pharmaceutically acceptable salt thereof
• the following regimens may be used according to the present invention

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