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
  • 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
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • 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
  • A61K31/66—Phosphorus compounds
  • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• • 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
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

• the present invention provides methods of treating, stabilizing or lessening the severity or progression of a disease or disorder associated with Bruton's Tyrosine Kinase ("BTK").
• BTK Bruton's Tyrosine Kinase
• Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).
• protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli.
• Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H 2 0 2 ), cytokines (e.g., interleukin-1 (IL-1) and tumor necrosis factor a (TNF-a)), and growth factors (e.g., granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)).
• IL-1 interleukin-1
• TNF-a tumor necrosis factor a
• growth factors e.g., granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)
• An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.
• Chronic lymphocytic leukemia is a lymphoproliferative malignancy characterized by progressive accumulation of morphologically mature but functionally incompetent lymphocytes in the blood, bone marrow, and lymphoid tissues. It affects mainly elderly individuals with the median age at presentation of 65 to 70 years. Small lymphocytic lymphoma (SLL) and CLL are generally considered a different manifestation of the same disease. While CLL is found in the blood and bone marrow, SLL presents primarily in the lymph nodes. The clinical course of CLL/SLL ranges from indolent disease with long-term survival over 12 years to aggressive disease with median survival of 2 years. The average age of diagnosis with CLL/SLL is approximately 60 years.
• CLL/SLL remains an incurable disease and most patients eventually relapse and/or die.
• Improved and novel combination treatments for subjects with CLL/SLL requiring treatment remain an unmet medical need.
• Btk Bruton's tyrosine kinase
• BCR B-cell receptor
• Compound 1 is active in a variety of assays and therapeutic models demonstrating covalent, irreversible inhibition of BTK (in enzymatic and cellular assays).
• Compound 1 is a potent, selective, orally available, small molecule which was found to inhibit B-cell proliferation and activation. Compound 1 is therefore useful for treating one or more disorders associated with activity of BTK.
• the present invention provides methods of treating, stabilizing or lessening the severity or progression of one or more diseases and conditions associated with BTK.
• the present invention provides methods of treating, stabilizing or lessening the severity or progression of one or more diseases and conditions associated with BTK comprising administering to a patient in need thereof a pharmaceutically acceptable composition comprising N-(3-(5-fluoro-2-(4-(2- methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (1):
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of one or more diseases and conditions associated with BTK comprising administering to a patient in need thereof Compound 1 in combination with rituximab.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of one or more diseases and conditions associated with BTK comprising administering to a patient in need thereof a composition comprising Compound 1 in combination with a composition comprising rituximab.
• provided methods comprise administering to a patient in need thereof Compound 1 in combination with rituximab, wherein Compound 1 is administered once a day. In some embodiments, provided methods comprise administering to a patient in need thereof Compound 1 in combination with rituximab, wherein Compound 1 is administered twice a day. In some such embodiments, rituximab is administered once during a 28-day cycle. Accordingly, in some embodiments, provided methods comprise administering to a patient in need thereof Compound 1 in combination with rituximab, wherein Compound 1 is administered twice a day and rituximab is administered once during a 28-day cycle.
• the provided methods comprise administering to a patient in need thereof a composition comprising Compound 1 and rituximab.
• the provided methods comprise administering to a patient in need thereof Compound 1, rituximab, fludarabine and cyclophosphamide.
• the provided methods comprise administering to a patient in need thereof Compound 1, rituximab and bendamustine.
• the disease or condition associated with BTK is selected from chronic lymphocytic leukemia and small lymphocytic lymphoma.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of chronic lymphocytic leukemia (CLL), the method comprising administering to a patient in need thereof Compound 1 in combination with rituximab.
• CLL chronic lymphocytic leukemia
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of small lymphocytic lymphoma (SLL), the method comprising administering to a patient in need thereof Compound 1 in combination with rituximab.
• provided therapies comprise orally administering to a patient Compound 1 in combination with rituximab.
• each of Compound 1 and rituximab is administered in the form of a pharmaceutical formulation.
• the pharmaceutical formulation comprising Compound 1 is a capsule formulation.
• the pharmaceutical formulation comprising rituximab is an intravenous (IV) formulation.
• the present invention also provides dosing regimens and protocols for administering to patients in need thereof Compound 1 in combination with rituximab. Such methods, dosing regimens and protocols for the administration of said combination are described in further detail, below.
• Figure 1 presents the Response Assessments of patients enrolled in cohorts 1 and 2 as of October 16, 2013.
• an antibody refers to polypeptide(s) capable of binding to an epitope.
• an antibody is a full-length antibody.
• an antibody is less than full length (i.e., an antibody fragment) but includes at least one binding site.
• the binding site comprises at least one, and preferably at least two sequences with structure of antibody variable regions.
• the term "antibody” encompasses any protein having a binding domain which is homologous or largely homologous to an immunoglobulin- binding domain.
• the term "antibody” encompasses polypeptides having a binding domain that shows at least 99% identity with an immunoglobulin-binding domain.
• the antibody is any protein having a binding domain that shows at least 70%, at least 80%, at least 85%, at least 90% or at least 95% identity with an immunoglobulin-binding domain.
• Antibody polypeptides in accordance with the present invention may be prepared by any available means, including, for example, isolation from a natural source or antibody library, recombinant production in or with a host system, chemical synthesis, etc., or combinations thereof.
• an antibody is monoclonal or polyclonal.
• an antibody may be a member of any immunoglobulin class, including any of the human classes IgG, IgM, IgA, IgD and IgE. In certain embodiments, an antibody is a member of the IgG immunoglobulin class. In some embodiments, the term "antibody" refers to any derivative of an antibody that possesses the ability to bind to an epitope of interest. In some embodiments, an antibody fragment comprises multiple chains that are linked together, for example, by disulfide linkages. In some embodiments, an antibody is a human antibody. In some embodiments, an antibody is a humanized antibody.
• humanized antibodies include chimeric immunoglobulins, immunoglobulin chains or antibody fragments (Fv, Fab, Fab', F(ab') 2 or other antigen binding subsequences of antibodies) that contain minimal sequence derived from non-human immunoglobulin.
• humanized antibodies are human immunoglobulin (recipient antibody) in which residues from a complementary-determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity.
• donor antibody such as mouse, rat or rabbit having the desired specificity, affinity and capacity.
• antibodies for use in the present invention bind to particular epitopes of CD20.
• epitopes of CD20 to which anti-CD20 antibodies bind include, for example, 170 ANPS 173 (Binder et al, Blood 2006, 108(6): 1975-1978), FMC7 (Deans et al, Blood 2008, 111(4): 2492), Rp5-L and Rpl5-C (mimotopes of CD20) (Perosa et al, J. Immunol. 2009, 182:416-423), 182 YCYSI 185 (Binder et al, Blood 2006, 108(6): 1975-1978) and WEWTI (a mimic of 182 YCYSI 185 ) (Binder et al., Blood 2006, 108(6): 1975-1978).
• an anti-CD20 antibody has a binding affinity (IQ) for an epitope of CD20 of less than 12 nM, less than 11 nM, less than 10 nM, less than 9 nM, less than 8 nM, less than 7 nM, less than 6 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM or less than 1 nM.
• IQ binding affinity
• biosimilar for example, of an approved reference product/biological drug, such as a protein therapeutic, antibody, etc. refers to a biologic product that is similar to the reference product based upon data derived from (a) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including the assessment of toxicity); and/or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is approved and intended to be used and for which approval is sought (e.g., that there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product).
• the biosimilar biological product and reference product utilizes the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product.
• the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product.
• the route of administration, the dosage form, and/or the strength of the biological product are the same as those of the reference product.
• the facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent.
• the reference product may be approved in at least one of the U.S., Europe, or Japan.
• a biosimilar can be for example, a presently known antibody having the same primary amino acid sequence as a marketed antibody, but may be made in different cell types or by different production, purification or formulation methods.
• the terms “combination”, “in combination with” or “combination therapy” refer to those situations in which two or more different pharmaceutical agents are administered in overlapping regimens so that the subject is simultaneously exposed to both agents.
• such combinations refer to simultaneously administering to a subject separate dosage forms of Compound 1 and rituximab.
• such combinations refer to contemporaneously administering to a subject separate dosage forms of Compound 1 and rituximab, wherein Compound 1 is administered before, during or after administration of rituximab.
• simultaneous or contemporaneous exposure of Compound 1 and rituximab is effected via different dosage regimens appropriate for each therapeutic agent. For example, Compound 1 may be administered once or twice daily for one or more 28-day cycles, whereas rituximab may be administered once during a 28-day cycle.
• percent inhibition refers to the percent decrease of target activity in the presence of a test compound (e.g., an irreversible BTK inhibitor) relative to control target activity. It will be appreciated that percent inhibition of a target (e.g., a kinase) can be determined in numerous ways, one of which is described in Example 2, infra. In some embodiments, percent inhibition is expressed as % inhibition (e.g., 50% inhibition). In some embodiments, the percent inhibition of a kinase is an average percent inhibition.
• the term “comparable”, refers to two or more agents, entities, situations, sets of conditions, etc. that may not be identical to one another but that are sufficiently similar to permit comparison therebetween so that conclusions may reasonably be drawn based on differences or similarities observed. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable.
• the terms “comparable percent inhibition” or “comparable average percent inhibition” refer to a percent inhibition or an average percent inhibition, respectively, of a kinase that is within 10% of that observed or determined for a reference kinase inhibitor.
• an irreversible BTK inhibitor has comparable percent inhibition to a reference kinase inhibitor wherein the percent inhibition of the irreversible BTK inhibitor is within 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% inhibition of that observed or determined for a reference kinase inhibitor.
• a "disease or disorder associated with BTK” or a "BTK-mediated disorder” means any disease or other deleterious condition in which BTK, or a mutant thereof, is known or suspected to play a role. Accordingly, another embodiment of the present invention relates to preventing, treating, stabilizing or lessening the severity or progression of one or more diseases in which BTK, or a mutant thereof, is known or suspected to play a role. Specifically, the present invention relates to a method of treating or lessening the severity of a proliferative disorder, wherein said method comprises administering to a patient in need thereof Compound 1 in combination with rituximab.
• the term "irreversible” or “irreversible inhibitor” refers to an inhibitor (i.e. a compound) that is able to be covalently bonded to a target protein kinase in a substantially non-reversible manner. That is, whereas a reversible inhibitor is able to bind to (but is generally unable to form a covalent bond) the target protein kinase, and therefore can become dissociated from the target protein kinase, an irreversible inhibitor will remain substantially bound to the target protein kinase once covalent bond formation has occurred. Irreversible inhibitors usually display time dependency, whereby the degree of inhibition increases with the time with which the inhibitor is in contact with the enzyme.
• Such methods include, but are not limited to, enzyme kinetic analysis of the inhibition profile of the compound with the protein kinase target, the use of mass spectrometry of the protein drug target modified in the presence of the inhibitor compound, discontinuous exposure, also known as "washout," experiments, and the use of labeling, such as radiolabeled inhibitor, to show covalent modification of the enzyme, as well as other methods known to one of skill in the art.
• refractory CLL/SLL as used herein is defined as CLL/SLL which was treated with at least one line of prior therapy (i) without achieving at least a partial response to therapy or (ii) which progressed within 6 months of treatment.
• relapsed CLL/SLL as used herein is defined as CLL/SLL which progressed after > 6 months post-treatment after achieving partial response or complete response to therapy.
• subject means a mammal and includes human and animal subjects, such as domestic animals (e.g., horses, dogs, cats, etc.).
• domestic animals e.g., horses, dogs, cats, etc.
• a "therapeutically effective amount” means an amount of a substance ⁇ e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response.
• a therapeutically effective amount of a substance is an amount that is sufficient, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the disease, disorder, and/or condition.
• the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc.
• the effective amount of compound in a formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, disorder, and/or condition.
• a "therapeutically effective amount" is at least a minimal amount of a compound, or composition containing a compound, which is sufficient for treating one or more symptoms of a disorder or condition associated with Bruton's tyrosine kinase.
• treat refers to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and/or relieving a disorder or condition, or one or more symptoms of the disorder or condition.
• treatment refers to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and/or relieving a disorder or condition, or one or more symptoms of the disorder or condition, as described herein.
• treatment may be administered after one or more symptoms have developed.
• the term “treating” includes preventing or halting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms.
• treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
• treating includes preventing relapse or recurrence of a disease or disorder.
• unit dosage form refers to a physically discrete unit of therapeutic formulation appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
• the specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active agent employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active agent employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of one or more diseases and conditions associated with BTK comprising administering to a patient in need thereof an irreversible BTK inhibitor and rituximab.
• provided methods further comprise administering fludarabine and cyclophosphamide.
• a dose or dosing regimen of an irreversible BTK inhibitor is selected from any of the doses or dosing regimens for Compound 1 as described herein.
• provided methods comprise administering an irreversible BTK inhibitor in an amount selected from any of the doses for Compound 1 as described herein.
• a dose of an irreversible BTK inhibitor is administered according to a dosing schedule selected from any of the dosing schedules described herein for Compound 1.
• a composition comprising an irreversible BTK inhibitor is any of the formulations as described herein.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of one or more diseases and conditions associated with BTK comprising administering to a patient in need thereof an irreversible BTK inhibitor and rituximab and bendamustine.
• the irreversible BTK inhibitor covalently binds to Cys 481 of BTK.
• an irreversible BTK inhibitor has activity against one or more kinases selected from the kinases recited in Table 3, infra.
• an irreversible BTK inhibitor has a percent inhibition comparable to that of a reference kinase inhibitor with respect to a kinase selected from Table 3, or combinations thereof.
• the reference kinase inhibitor is Compound 2:
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• an irreversible BTK inhibitor has a percent inhibition comparable to that of Compound 2 with respect to one or more kinases selected from Table 3, or combinations thereof, in that the irreversible kinase inhibitor has a percent inhibition within approximately 10% of that observed for Compound 2.
• an irreversible BTK inhibitor has a percent inhibition comparable to that of Compound 2 with respect to one or more kinases selected from Table 3, or combinations thereof, in that the irreversible kinase inhibitor has a percent inhibition that is within about 9%, or about 8%, or about 7%, or about 6%, or about 5%, or about 4%, or about 3%, or about 2% or about 1% inhibition of that observed for Compound 2.
• an irreversible BTK inhibitor has a percent inhibition that is greater than that observed for Compound 2 with respect to one or more kinases selected from Table 3. In some embodiments, an irreversible BTK inhibitor has a percent inhibition that is less than that observed for Compound 2 with respect to one or more kinases selected from Table 3.
• the irreversible BTK inhibitor has a percent inhibition of one or more additional kinases, wherein the percent inhibition of the kinase or kinases is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% or at least about 95%.
• the irreversible BTK inhibitor has a percent inhibition comparable to that of a reference kinase inhibitor with respect to one or more kinases selected from the group consisting of TXK, BMX/ETK, FLT3, BLK, TEC, ERBB4/HER4, Aurora B, TRKC, RET, LOK/STKIO, Aurora C, FLT4/VEGFR3, ROS/ROS1, ARK5/NUAK1, EGFR, DDR1, JAK3, LRRK2, ABL2/ARG, ITK, Aurora A, YES/YES 1, FGFR3, TNK1, BRK, FGFR2, PDGFRb, c-SRC, ACK1, FGFR1, STK16, ABL1, AXL, TYK2, ERBB2/HER2, FGR, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, PKCb2 and CLK2, or combinations thereof.
• a reference kinase inhibitor selected from
• the irreversible BTK inhibitor has a percent inhibition comparable to that of a reference kinase inhibitor with respect to the group of kinases consisting of TXK, BMX/ETK, FLT3, BLK, TEC, ERBB4/HER4, Aurora B, TRKC, RET, LOK/STKIO, Aurora C, FLT4/VEGFR3, ROS/ROS1, ARK5/NUAK1, EGFR, DDR1, JAK3, LRRK2, ABL2/ARG, ITK, Aurora A, YES/YES 1, FGFR3, TNK1, BRK, FGFR2, PDGFRb, c-SRC, ACK1, FGFR1, STK16, ABL1, AXL, TYK2, ERBB2/HER2, FGR, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11 , PKCb2 and CLK2, or combinations thereof.
• the reference kinase inhibitor consisting of TXK
• the irreversible BTK inhibitor inhibits a kinase selected from the group consisting of TXK, BMX ETK, FLT3, BLK, TEC, ERBB4/HER4, Aurora B, TRKC, RET, LOK/STKIO, Aurora C, FLT4/VEGFR3, ROS/ROS1, ARK5/NUAK1, EGFR, DDR1, JAK3, LRRK2, ABL2/ARG, ITK, Aurora A, YES/YES 1, FGFR3, TNK1, BRK, FGFR2, PDGFRb, c-SRC, ACK1, FGFR1, STK16, ABL1, AXL, TYK2, ERBB2/HER2, FGR, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11 , PKCb2 and CLK2, or combinations thereof, wherein the inhibition of the kinase or kinases is at least the percent inhibition observed for
• the irreversible BTK inhibitor has at least about 50%, at least about 55%, at least about 60%>, at least 65%>, at least about 70%>, at least about 75%>, at least about 80%, at least about 85%, at least about 90% or at least about 95% inhibition of a kinase selected from TXK, BMX/ETK, FLT3, BLK, TEC, ERBB4/HER4, Aurora B, TRKC, RET, LOK/STKIO, Aurora C, FLT4/VEGFR3, ROS/ROS1, ARK5/NUAK1, EGFR, DDR1, JAK3, LRRK2, ABL2/ARG, ITK, Aurora A, YES/YES 1, FGFR3, TNKl, BRK, FGFR2, PDGFRb, c- SRC, ACK1, FGFR1, STK16, ABLl, AXL, TYK2, ERBB2/HER2, FGR, CHK2, SIK1 , MLK
• the irreversible BTK inhibitor has a percent inhibition comparable to that of a reference kinase inhibitor with respect to one or more kinases selected from the group consisting of Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNKl, STK16, ABLl, AXL, TYK2, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11 , PKCb2 and CLK2, or combinations thereof.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition comparable to that of a reference kinase inhibitor with respect to the group of kinases consisting of Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNKl, STK16, ABLl, AXL, TYK2, CHK2, SIK1, MLK1/MAP3K9, MLK2/M AP3 K 10 , MLK3/MAP3K11, PKCb2 and CLK2, or combinations thereof.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition that is at least the percent inhibition observed for a reference kinase inhibitor with respect to one or more kinases selected from the group consisting of Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNKl, STK16, ABLl, AXL, TYK2, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11 , PKCb2 and CLK2, or combinations thereof.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has at least about 50%, at least about 55%o, at least about 60%>, at least about 65%>, at least about 70%>, at least about 75%>, at least about 80%, at least about 85%, at least about 90% or at least about 95% inhibition of a kinase selected from Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, ABL1, AXL, TYK2, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, PKCb2 and CLK2, or combinations thereof.
• a kinase selected from Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, ABL1, AXL, TYK2, CHK2, SIK1, MLK1/MAP3K9, MLK
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of CLL/SLL comprising administering to a patient in need thereof an irreversible BTK inhibitor in combination with rituximab, wherein the irreversible BTK inhibitor has not more than about 50% inhibition of a kinase selected from Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, ABL1, AXL, TYK2, CHK2, SIK1, MLK1/MAP3K9, MLK2/M AP3 K 10 , MLK3/MAP3K11, PKCb2 and CLK2, or combinations thereof
• a kinase selected from Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, ABL1, AXL, TYK2, CHK2, SIK1, MLK1/MAP3K
• the irreversible BTK inhibitor has at least about 50% inhibition of a kinase selected from Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, ABL1, AXL, TYK2, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11 and PKCb2, or combinations thereof.
• the irreversible BTK inhibitor has has at least about 50% inhibition of the group of kinases consisting of Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, ABL1, AXL, TYK2, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11 , PKCb2 and CLK2.
• the irreversible BTK inhibitor has at least about 55% inhibition of a kinase selected from Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, ABL1, CHK2, MLK1/MAP3K9, MLK2/MAP3K10 and MLK3/MAP3K11 , or combinations thereof.
• a kinase selected from Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, ABL1, CHK2, MLK1/MAP3K9, MLK2/MAP3K10 and MLK3/MAP3K11 , or combinations thereof.
• the irreversible BTK inhibitor has at least about 55% inhibition of the group of kinases consisting of Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, ABL1, CHK2, MLK1/MAP3K9, MLK2/MAP3K10 and MLK3/MAP3K11.
• the irreversible BTK inhibitor has at least about 60% inhibition of a kinase selected from Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, CHK2, MLK1/MAP3K9 and MLK3/MAP3K11, or combinations thereof.
• the irreversible BTK inhibitor has at least about 60% inhibition of the group of kinases consisting of Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, CHK2, MLK1/MAP3K9 and MLK3/MAP3K11.
• the irreversible BTK inhibitor has at least about 65% inhibition of a kinase selected from Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, TNKl, STK16, CHK2, MLK1/MAP3K9 and MLK3/MAP3K11 , or combinations thereof.
• the irreversible BTK inhibitor sh at least about 65% inhibition of the group of kinases consisting of Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, TNKl, STK16, CHK2, MLK1/MAP3K9 and MLK3/MAP3K11.
• the irreversible BTK inhibitor has at least about 70% inhibition of a kinase selected from Aurora A, Aurora B, Aurora C, ROS/ROS1, ARK5/NUAK1, TNKl, STK16, CHK2, MLK1/MAP3K9 and MLK3/MAP3K11 , or combinations thereof. In some embodiments, the irreversible BTK inhibitor at least about 70% inhibition of the group of kinases consisting of Aurora A, Aurora B, Aurora C, ROS/ROS1, ARK5/NUAK1, TNKl, STK16, CHK2, MLK1/MAP3K9 and MLK3/MAP3K11.
• the irreversible BTK inhibitor has at least about 75% inhibition of a kinase selected from Aurora A, Aurora B, ROS/ROS1, ARK5/NUAK1, TNKl, STK16 and MLK1/MAP3K9, or combinations thereof. In some embodiments, the irreversible BTK inhibitor has at least about 75% inhibition of the group of kinases consisting of Aurora A, Aurora B, ROS/ROS1, ARK5/NUAK1, TNKl, STK16 and MLK1/MAP3K9.
• the irreversible BTK inhibitor has at least about 80% inhibition of a kinase selected from Aurora A, Aurora B, ROS/ROS1, ARK5/NUAK1, TNKl and MLK1/MAP3K9, or combinations thereof. In some embodiments, the irreversible BTK inhibitor has at least about 80% inhibition of the group of kinases consisting of Aurora A, Aurora B, ROS/ROS1, ARK5/NUAK1, TNKl and MLK1/MAP3K9.
• the irreversible BTK inhibitor has at least about 85% inhibition of a kinase selected from Aurora A, Aurora B, ROS/ROS1, ARK5/NUAK1 and MLK1/MAP3K9, or combinations thereof. In some embodiments, the irreversible BTK inhibitor has at least about 85% inhibition of the group of kinases consisting of Aurora A, Aurora B, ROS/ROS1, ARK5/NUAK1 and MLK1/MAP3K9.
• the irreversible BTK inhibitor has a percent inhibition comparable to that of a reference kinase inhibitor with respect to one or more kinases selected from the group consisting of TNKl, STK16, ABL1, AXL, TYK2, CHK2, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, SIK1, PKCb2 and CLK2, or combinations thereof.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition comparable to that of a reference kinase inhibitor with respect to the group of kinases consisting of TNKl, STK16, ABLl, AXL, TYK2, CHK2, MLK1/MAP3K9, MLK2/M AP3 K 10 , MLK3/MAP3K11, SIK1, PKCb2 and CLK2, or combinations thereof.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition that is at least the percent inhibition observed for a reference kinase inhibitor with respect to one or more kinases selected from the group consisting of TNKl, STK16, ABLl, AXL, TYK2, CHK2, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11 , SIK1, PKCb2 and CLK2, or combinations thereof.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has at least about 50%, at least about 55%o, at least about 60%>, at least about 65%>, at least about 70%>, at least about 75%>, at least about 80%, at least about 85%, at least about 90% or at least about 95% inhibition of a kinase selected from TNKl, STK16, ABLl, AXL, TYK2, CHK2, MLK1/MAP3K9, MLK2/M AP3 K 10 , MLK3/MAP3K11, SIK1, PKCb2 and CLK2, or combinations thereof.
• a kinase selected from TNKl, STK16, ABLl, AXL, TYK2, CHK2, MLK1/MAP3K9, MLK2/M AP3 K 10 , MLK3/MAP3K11, SIK1, PKCb2 and CLK2, or combinations thereof.
• the irreversible BTK inhibitor has at least about 50% inhibition of a kinase selected from TNKl, STK16, ABLl, AXL, TYK2, CHK2, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11 , SIK1, PKCb2 and CLK2, or combinations thereof.
• the irreversible BTK inhibitor at least about 50% inhibition of the group of kinases consisting of TNKl, STK16, ABLl, AXL, TYK2, CHK2, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11 , SIK1, PKCb2 and CLK2.
• the irreversible BTK inhibitor has at least about 55% inhibition of a kinase selected from TNKl, STK16, ABLl, CHK2, MLK1/MAP3K9 and MLK3/MAP3K11, or combinations thereof. In some embodiments, the irreversible BTK inhibitor has at least about 55% inhibition of the group of kinases consisting of TNK1, STK16, ABL1, CHK2, MLK1/MAP3K9 and MLK3/MAP3K11, or combinations thereof.
• the irreversible BTK inhibitor has at least about 60%, at least about 65% or at least about 70% inhibition of a kinase selected from TNK1, STK16, CHK2, MLK1/MAP3K9 and MLK3/MAP3K11, or combinations thereof. In some embodiments, the irreversible BTK inhibitor has at least about 60%, at least about 65% or at least about 70% inhibition of the group of kinases consisting of CHK2, MLK1/MAP3K9 and MLK3/MAP3K11.
• the irreversible BTK inhibitor has at least about 75% inhibition of a kinase selected from TNK1, STK16 and MLK1/MAP3K9, or combinations thereof. In some embodiments, the irreversible BTK inhibitor has at least about 75% inhibition of the the group of kinases consisting of TNK1, STK16 and MLK1/MAP3K9.
• an irreversible BTK inhibitor for use in the present invention has a percent inhibition comparable to that of a reference kinase inhibitor with respect to one or more kinases selected from the group consisting of c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or combinations thereof.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition comparable to that of a reference kinase inhibitor with respect to the group of kinases consisting of c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or combinations thereof.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition that is not more than the percent inhibition observed for a reference kinase inhibitor with respect to one or more kinases selected from the group consisting of c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or combinations thereof.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has not more than about 50%, not more than about 45%, not more than about 40%, not more than about 35%, not more than about 30%, not more than about 25%, not more than about 20%, not more than about 15%, not more than about 10% or not more than about 5% inhibition of a kinase selected from c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BPvAF, ARAF and SRMS, or combinations thereof.
• a kinase selected from c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BPvAF, ARAF and SRMS, or combinations thereof.
• the irreversible BTK inhibitor has not more than about 50%, not more than about 45%, not more than about 40%, not more than about 35%, not more than about 30%, not more than about 25%, not more than about 20%, not more than about 15%, not more than about 10% or not more than about 5% inhibition of a kinase selected from RIPK2, HCK, LYN, CSK, LCK, LYN B and FYN, or combinations thereof.
• the irreversible BTK inhibitor has not more than about 50%, not more than about 45%, not more than about 40%, not more than about 35%, not more than about 30%, not more than about 25%, not more than about 20%, not more than about 15%, not more than about 10% or not more than about 5% inhibition of a kinase selected from EPHA6, LYN B, FRK/PTK5, RIPK3, BRAF, ARAF and SRMS, or combinations thereof.
• a kinase selected from EPHA6, LYN B, FRK/PTK5, RIPK3, BRAF, ARAF and SRMS, or combinations thereof.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of CLL/SLL comprising administering to a patient in need thereof an irreversible BTK inhibitor in combination with rituximab, wherein the irreversible BTK inhibitor has at least about 50% inhibition of a kinase selected from c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK PTK5, FYN, BRAF, RIPK3, ARAF and SRMS, or combinations thereof.
• a kinase selected from c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK PTK5, FYN, BRAF, RIPK3, ARAF and SRMS, or combinations thereof.
• the irreversible BTK inhibitor has not more than about 50% inhibition of a kinase selected from c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or combinations thereof.
• a kinase selected from c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or combinations thereof.
• the irreversible BTK inhibitor has not more than about 50% inhibition of the group of kinases consisting of c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS.
• group of kinases consisting of c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS.
• the irreversible BTK inhibitor has not more than about 45% inhibition of a kinase selected from c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or combinations thereof.
• a kinase selected from c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or combinations thereof.
• the irreversible BTK inhibitor has not more than about 45% inhibition of the group of kinases consisting of c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK PTK5, FYN, RIPK3, BRAF, ARAF and SRMS.
• the irreversible BTK inhibitor has not more than about 40% inhibition of a kinase selected from c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or combinations thereof.
• a kinase selected from c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or combinations thereof.
• the irreversible BTK inhibitor has not more than about 40% inhibition of the group of kinases consisting of c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS.
• group of kinases consisting of c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS.
• the irreversible BTK inhibitor has not more than about 35% inhibition of a kinase selected from c-Kit, RIPK2, HCK, EPHA6, LYN, CSK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or combinations thereof.
• the irreversible BTK inhibitor has not more than about 35% inhibition of the group of kinases consisting of c-Kit, RIPK2, HCK, EPHA6, LYN, CSK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS.
• the irreversible BTK inhibitor has not more than about 30% inhibition of a kinase selected from c-Kit, RIPK2, HCK, EPHA6, LYN, CSK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or combinations thereof.
• the irreversible BTK inhibitor has not more than about 30% inhibition of the group of kinases consisting of c-Kit, RIPK2, HCK, EPHA6, LYN, CSK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS.
• the irreversible BTK inhibitor has not more than about 25% inhibition of a kinase selected from c-Kit, RIPK2, EPHA6, CSK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or combinations thereof. In some embodiments, the irreversible BTK inhibitor has not more than about 25% inhibition of the group of kinases consisting of c-Kit, IPK2, EPHA6, CSK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS.
• the irreversible BTK inhibitor has not more than about 20% inhibition of a kinase selected from EPHA6, CSK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or combinations thereof. In some embodiments, the irreversible BTK inhibitor has not more than about 20% inhibition of the group of kinases consisting of EPHA6, CSK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS.
• the irreversible BTK inhibitor has not more than about 15% inhibition of a kinase selected from EPHA6, LYN B, FRK/PTK5, RIPK3, BRAF, ARAF and SRMS, or combinations thereof. In some embodiments, the irreversible BTK inhibitor has not more than about 15% inhibition of the group of kinases consisting of EPHA6, LYN B, FRK/PTK5, RIPK3, BRAF, ARAF and SRMS.
• the irreversible BTK inhibitor has not more than about 10% inhibition of a kinase selected from EPHA6, LYN B, FRK/PTK5, RIPK3, BRAF, ARAF and SRMS, or combinations thereof. In some embodiments, the irreversible BTK inhibitor has not more than about 10% inhibition of the group of kinases consisting of EPHA6, LYN B, FRK/PTK5, RIPK3, BRAF, ARAF and SRMS.
• the irreversible BTK inhibitor has not more than about 5% inhibition of a kinase selected from EPHA6, FRK/PTK5, RIPK3, BRAF, ARAF and SRMS, or combinations thereof. In some embodiments, the irreversible BTK inhibitor has not more than about 5% inhibition of the group of kinases consisting of EPHA6, FRK/PTK5, RIPK3, BRAF, ARAF and SRMS.
• the irreversible BTK inhibitor has a percent inhibition of LYN comparable to that of a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN that is not more than that observed for a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN that is about 20-30%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN that is about 25-30%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN that is about 25-28%.
• the irreversible BTK inhibitor has a percent inhibition of LYN that is not more than about 25%, not more than about 26%, not more than about 27%, not more than about 28%, not more than about 29%, not more than about 30%, not more than about 31%, not more than about 32% or not more than about 33%.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition of c-Kit comparable to that of a reference kinase inhibitor.
• the irreversible BTK inhibitor has a percent inhibition of c-Kit that is not more than that observed for a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of c-Kit that is about 15-25%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of c-Kit that is about 20-25%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of c-Kit that is about 20-23%.
• the irreversible BTK inhibitor has a percent inhibition of c-Kit that is not more than about 15%, not more than about 16%, not more than about 17%, not more than about 18%, not more than about 19%, not more than about 20%, not more than about 21%, not more than about 22%, not more than about 23%, not more than about 24% or not more than about 25%.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition of PDGFRa comparable to that of a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of PDGFRa that is not more than that observed for a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of PDGFRa that is about 30-40%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of PDGFRa that is about 35-40%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of PDGFRa that is about 35-38%.
• the irreversible BTK inhibitor has a percent inhibition of PDGFRa that is not more than about 30%, not more than about 31%, not more than about 32%, not more than about 33%, not more than about 34%, not more than about 35%, not more than about 36%, not more than about 37%, not more than about 38%, not more than about 39% or not more than about 40%.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition of RIPK2 comparable to that of a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of RIPK2 that is not more than that observed for a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of RIPK2 that is about 20-30%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of RIPK2 that is about 20-25%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of RIPK2 that is about 22-25%.
• the irreversible BTK inhibitor has a percent inhibition of RIPK2 that is not more than about 18%, not more than about 19%, not more than about 20%, not more than about 21%, not more than about 22%, not more than about 23%, not more than about 24%, not more than about 25%, not more than about 26% or not more than about 27%.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition of HCK comparable to that of a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of HCK that is not more than that observed for a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of HCK that is about 25-35%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of HCK that is about 27-32%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of HCK that is about 28-31%.
• the irreversible BTK inhibitor has a percent inhibition of HCK that is not more than about 26%, not more than about 27%, not more than about 28%, not more than about 29%, not more than about 30%, not more than about 31%, not more than about 32%, not more than about 33% or not more than about 34%.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition of EPHA6 comparable to that of a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of EPHA6 that is not more than that observed for a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of EPHA6 that is about 0-10%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of EPHA6 that is about 0-5%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of EPHA6 that is about 0-3%.
• the irreversible BTK inhibitor has a percent inhibition of EPHA6 that is not more than about 0.5%, not more than about 0.6%, not more than about 0.7%, not more than about 0.8%, not more than about 0.9%, not more than about 1%, not more than about 2%, not more than about 3% or not more than about 4%.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition of CSK comparable to that of a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of CSK that is not more than that observed for a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of CSK that is about 10-20%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of CSK that is about 15-20%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of CSK that is about 16-19%.
• the irreversible BTK inhibitor has a percent inhibition of CSK that is not more than about 15%, not more than about 16%, not more than about 17%, not more than about 18%, not more than about 19%, not more than about 20%, not more than about 21%, not more than about 22% or not more than about 23%.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition of LCK comparable to that of a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LCK that is not more than that observed for a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LCK that is about 30-40%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LCK that is about 32-37%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LCK that is about 34-37%.
• the irreversible BTK inhibitor has a percent inhibition of LCK that is not more than about 34%, not more than about 35%, not more than about 36%, not more than about 37%, not more than about 38%, not more than about 39%, not more than about 40%, not more than about 41% or not more than about 42%.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition of ZAK/MLTK comparable to that of a reference kinase inhibitor.
• the irreversible BTK inhibitor has a percent inhibition of ZAK/MLTK that is not more than that observed for a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of ZAK MLTK that is about 10-20%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of ZAK/MLTK that is about 12-17%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of ZAK/MLTK that is about 14-17%.
• the irreversible BTK inhibitor has a percent inhibition of ZAK/MLTK that is not more than about 12%, not more than about 13%, not more than about 14%, not more than about 15%, not more than about 16%, not more than about 17%, not more than about 18%, not more than about 19% or not more than about 20%.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition of LYN B comparable to that of a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN B that is not more than that observed for a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN B that is about 0-10%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN B that is about 3-8%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN B that is about 4-7%.
• the irreversible BTK inhibitor has a percent inhibition of LYN B that is not more than about 1%, not more than about 2%, not more than about 3%, not more than about 4%, not more than about 5%, not more than about 6%, not more than about 7%, not more than about 8%, not more than about 9% or not more than about 10%.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition of FRK/PTK5 comparable to that of a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FRK/PTK5 that is not more than that observed for a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FRK/PTK5 that is about 0-10%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FRK/PTK5 that is about 0-5%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FRK/PTK5 that is about 0-3%.
• the irreversible BTK inhibitor has a percent inhibition of FRK/PTK5 that is not more than about 0.5%, not more than about 0.6%, not more than about 0.7%, not more than about 0.8%, not more than about 0.9%, not more than about 1%, not more than about 1.5%, not more than about 2%, not more than about 3% or not more than about 4%.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition of FYN comparable to that of a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FYN that is not more than that observed for a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FYN that is about 15-25%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FYN that is about 15-20%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FYN that is about 17-20%.
• the irreversible BTK inhibitor has a percent inhibition of FYN that is not more than about 15%, not more than about 16%, not more than about 17%, not more than about 18%, not more than about 19%, not more than about 20%, not more than about 21%, not more than about 22% or not more than about 23%.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• the irreversible BTK inhibitor has a percent inhibition of BPvAF comparable to that of a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of BRAF that is not more than that observed for a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of BRAF that is about 0-10%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of BRAF that is about 0.1-5%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of BRAF that is about 0.2-3%.
• the irreversible BTK inhibitor has a percent inhibition of BRAF that is not more than about 0.1%, not more than about 0.2%, not more than about 0.3%, not more than about 0.4%, not more than about 0.5%, not more than about 0.6%, not more than about 0.7%, not more than about 0.8%, not more than about 0.9%, not more than about 1%, not more than about 2%, not more than about 3%, not more than about 4% or not more than about 5%.
• the reference kinase inhibitor is Compound 2.
• the percent inhibition of the reference kinase inhibitor is that shown for Compound 2 in Example 2.
• Compound 1 is an irreversible BTK inhibitor
• Btk Bruton's tyrosine kinase
• BCR B-cell receptor
• Compound 1 is active in a variety of assays and therapeutic models demonstrating covalent, irreversible inhibition of BTK (in enzymatic and cellular assays).
• Compound 1 inhibits Btk activity by binding with high affinity to the adenosine triphosphate (ATP) binding site of Btk and forming a targeted covalent bond with the Btk protein, providing rapid, complete, and prolonged inhibition of Btk activity, both in vitro and in vivo.
• ATP adenosine triphosphate
• Compound 1 In single dose studies in healthy subjects, Compound 1 evidenced adequate safety, predictable pharmacokinetics (PK), and, at doses greater than 0.5 mg/kg, 80%> to 100%) occupancy of the Btk receptor target in normal human peripheral blood B-cells.
• PK pharmacokinetics
• a phase I dose escalation study of a single agent of Compound 1 is currently being conducted in different hematologic malignancies, including CLL/SLL.
• Anti-CD20 Antibodies Anti-CD20 Antibodies
• CD20 the first B-cell specific antigen defined by the monoclonal antibody tositumomab, plays a critical role in B-cell development.
• Human CD20 is a 297 amino acid (30- to 35-kDa) phosphoprotein with four transmembrane domains encoded by the gene MS4A1 located on chromosome l lql2.2.
• CD20 plays a critical role in B-cell development and is a biomarker for immunotherapies targeting B-cell derived diseases.
• CD20 is an integral membrane protein expressed by B lymphocytes in early stages of differentiation and by most B cell lymphomas, but not by differentiated plasma cells. CD20 remains on the membrane of B cells without dissociation or internalization upon antibody binding.
• CD20 functions though binding to the Src family of tyrosine kinases, such as Lyn, Fyn and Lck, and believed to be involved as a result in the phosphorylation cascade of intracellular proteins.
• Anti-CD20 antibodies are broadly classified into type I and type II antibodies. Both types of anti-CD 20 antibodies exhibit equal ability in activating Fc-FcyR interactions such as antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis.
• Type I anti-CD20 antibodies redistribute CD20 into membrane lipid rafts and potently activate complement-dependent cytotoxicity (CDC).
• Type II anti-CD20 antibodies weakly activate CDC but more potently induce direct programmed cell death.
• the present invention encompasses the recognition that the combination of a BTK inhibitor, i.e. Compound 1, in combination with an anti-CD20 antibody is useful in treating BTK-mediated diseases or disorders.
• the present invention comprises a method of treating a BTK-mediated disease or disorder, the method comprising administering to a patient in need thereof Compound 1 in combination with an anti-CD20 antibody.
• a BTK inhibitor i.e. Compound 1
• the present invention comprises a method of treating a BTK-mediated disease or disorder, the method comprising administering to a patient in need thereof Compound 1 in combination with an anti-CD20 antibody.
• a person of ordinary skill in the art can readily identify and select additional anti-CD20 antibodies that are useful in the present invention. For example, in some embodiments, such antibodies are described, for example, in U.S. Patent Nos.
• an anti-CD20 antibody for use in the present invention is a type I antibody. In some embodiments, an anti-CD20 for use in the present invention is a type II antibody. [00110] In some embodiments, an anti-CD20 antibody is an antibody that binds to a CD20 epitope selected from 170 ANPS 173 and 182 YCYSI 185 .
• an anti-CD20 antibody has a binding affinity (Ka) for an epitope of CD20 of less than 12 nM, less than 11 nM, less than 10 nM, less than 9 nM, less than 8 nM, less than 7 nM, less than 6 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM or less than 1 nM.
• Ka binding affinity
• an anti-CD20 antibody for use in the present invention includes, for example, rituximab (Rituxan® or MabThera®), Gazyva® (i.e., obinutuzumab) and Arzerra® (ofatumumab).
• rituximab Rostuximab
• Gazyva® i.e., obinutuzumab
• Arzerra® ofatumumab
• rituximab all references to rituximab, or a biosimilar thereof, are to be read by a person skilled in the art to encompass the class of anti-CD20 antibodies.
• anti-CD20 antibodies ofatumumab Arzerra®
• obinutuzumab Gazyva®
• provided methods comprise administering Compound 1 and ofatumumab.
• ofatumumab is administered in 12 doses according to the following schedule: 300 mg initial dose, followed 1 week later by 2000 mg dose weekly for 7 doses, followed 4 weeks later by 2000 mg every 4 weeks for 4 doses.
• provided methods comprise administering Compound 1 and obinutuzumab.
• obinutuzumab is administered for six 28-day cycles as follows: 100 mg on day 1, cycle 1; 900 mg on day 2 cycle 1; 1000 mg on days 8 and 15 of cycle 1; and 1000 mg on day 1 of cycles 2-6.
• the term "rituximab” encompasses all corresponding anti-CD20 antibodies that fulfill the requirements necessary for obtaining a marketing authorization as an identical or biosimilar product in a country or territory selected from the group of countries consisting of the USA, Europe and Japan.
• an anti-CD20 antibody has the same or similar activity as rituximab, or a biosimilar thereof. In some embodiments, an anti-CD20 antibody binds to the same or similar region or epitope as rituximab or a fragment thereof. In some embodiments, an anti-CD20 antibody competes with the binding of rituximab or a fragment thereof to CD20. In some embodiments, an anti-CD20 antibody is bioequivalent to rituximab or a fragment thereof. In some embodiments, an anti-CD20 antibody is a biosimilar of rituximab or a fragment thereof. In some embodiments, an anti-CD20 antibody is a variant or derivative of rituximab, including functional fragments, derivatives, or antibody conjugates.
• Rituximab (Rituxan® or MabThera®) is a genetically engineered cytolytic, chimeric murine/human monoclonal IgGi kappa antibody directed against the CD20 cell-surface molecule present in normal B lymphocytes and B-cell CLL and in most forms of non-Hodgkin's B-cell lymphomas.
• Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM.
• Rituximab can induce complement-dependent cellular cytotoxicity (CDC) and anti-body- dependent cellular cytotoxicity (ADCC), leading to its clinical activity against lymphoma cells.
• CDC complement-dependent cellular cytotoxicity
• ADCC anti-body- dependent cellular cytotoxicity
• Rituximab can also lead to apoptosis of B cells upon binding to CD20, thereby leading to direct inhibition of cellular growth.
• Rituximab is produced by mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product.
• Rituximab is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous administration.
• Rituximab is supplied at a concentration of 10 mg/mL in either 100 mg/lOmL or 500 mg/50mL single -use vials.
• Rituximab is formulated in polysorbate 80 (0.7 mg/mL), sodium citrate dihydrate (7.35 mg/mL), sodium chloride (9 mg/mL) and water for injection.
• the pH of Rituxan® (or MabThera®) is 6.5
• Rituximab has been investigated in clinical studies and approved for treatment of patients with CLL in combination with fludarabine and cyclophosphamide, as well as patients with rheumatoid arthritis in combination with methotrexate.
• Rituximab is also approved for treatment of non-Hodgkin's lymphoma, Wegener's Granulomatosis and Microscopic Polyangiitis.
• provided methods comprise administering to a patient in need thereof a combination of Compound 1 and rituximab, wherein the patient is further treated with fludarabine and cyclophosphamide in accordance with the approved indications.
• provided methods comprise administering Compound 1 and an anti-CD20 antibody (e.g., rituximab, ofatumumab, obinutuzumab, etc.) to a patient in need thereof.
• Such methods optionally further comprise administering either (i) fludarabine and cyclophosphamide or (ii) bendamustine.
• each of the therapeutic agents can be administered simultaneously or sequentially (e.g., Compound 1 can be administered before, during or after an anti-CD20 antibody and/or either (i) fludarabine and cyclophosphamide or (ii) bendamustine and vice versa) as part of a dosing regimen.
• Compound 1 may be administered one or more hours, days or weeks before administration of an anti-CD20 antibody.
• Compound 1 and an anti-CD20 antibody may be administered one or more hours, days or weeks before administration of either (i) fludarabine and cyclophosphamide or (ii) bendamustine.
• the present invention provides methods for treating, stabilizing or lessening the severity or progression of one or more diseases or conditions associated with BTK. In some embodiments, the present invention provides methods for preventing the progression of a disease or disorder associated with BTK. In some embodiments, the disease or disorder associated with BTK is selected from chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
• CLL chronic lymphocytic leukemia
• SLL small lymphocytic lymphoma
• the disease or disorder associated with BTK is refractory CLL. In some embodiments, the disease or disorder associated with BTK is relapsed CLL. In some embodiments, the disease or disorder associated with BTK is refractory SLL. In some embodiments, the disease or disorder associated with BTK is relapsed SLL.
• provided methods comprise administering to a patient in need thereof Compound 1 in combination with rituximab.
• each of Compound 1 and rituximab is administered as a composition further comprising one or more pharmaceutically acceptable excipients.
• provided methods comprise administering each of Compound 1, rituximab, fludarabine and cyclophosphamide.
• each of Compound 1, rituximab, fludarabine and cyclophosphamide is administered as a composition further comprising one or more pharmaceutically acceptable excipients.
• provided methods comprise administering each of Compound 1, rituximab and bendamustine.
• each of Compound 1, rituximab and bendamustine is administered as a composition further comprising one or more pharmaceutically acceptable excipients.
• provided methods comprise administering to a patient in need thereof a therapeutically effective amount of Compound 1 in combination with a therapeutically effective amount of rituximab.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of one or more diseases associated with BTK, the method comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1 in combination with a therapeutically effective amount of rituximab.
• provided methods comprise administering to a patient in need thereof therapeutically effective amounts of each of Compound 1, rituximab, fludarabine and cyclophosphamide.
• provided methods comprise administering to a patient in need thereof therapeutically effective amounts of each of Compound 1, rituximab and bendamustine.
• provided methods comprise administering Compound 1 in combination with rituximab, wherein Compound 1 is administered once daily (“QD”). In some embodiments, provided methods comprise administering Compound 1 in combination with rituximab, wherein Compound 1 is administered twice daily (“BID"). For purposes of clarity, administration of a 375 mg dose of Compound 1 "BID" means that the patient is administered two separate doses of 375 mg in one day. In some embodiments, provided methods comprise administering each of Compound 1, rituximab, fludarabine and cyclophosphamide, wherein Compound 1 is administered twice daily (“BID”). In some embodiments, provided methods comprise administering each of Compound 1, rituximab and bendamustine, wherein Compound 1 is administered twice daily (“BID").
• provided methods comprise administering Compound 1 in combination with rituximab, wherein rituximab is administered once during a 28-day cycle. In some embodiments, provided methods comprise administering Compound 1 in combination with rituximab, wherein rituximab is administered on cycle 1 day 1 or day 2. In some embodiments, provided methods comprise administering Compound 1 in combination with rituximab, wherein rituximab is administered on day 1 of a 28-day cycle. In some such embodiments, rituximab is administered on day 1 of cycles 2-6. In some embodiments, rituximab is administered on day 1 of cycles 2-5.
• rituximab is administered on day 1 of cycles 2-4. In some embodiments, rituximab is administered on day 1 of cycles 2-3. In some embodiments, provided methods comprise administering each of Compound 1, rituximab, fludarabine and cyclophosphamide, wherein rituximab is administered once during a 28-day cycle. In some such embodiments, rituximab is administered on day 1 or day 2 of a 28-day cycle.
• provided methods comprise administering each of Compound 1, rituximab and bendamustine, wherein rituximab is administered once during a 28-day cycle. In some such embodiments, rituximab is administered on day 1 or day 2 of a 28-day cycle.
• provided methods comprise administering Compound 1 in combination with rituximab, wherein Compound 1 is administered twice daily and rituximab is administered once during a 28-day cycle. In some embodiments, provided methods comprise administering Compound 1 in combination with rituximab, wherein Compound 1 is administered twice daily and rituximab is administered on cycle 1 day 1 or day 2. In some embodiments, provided methods comprise administering Compound 1 in combination with rituximab, wherein Compound 1 is administered twice daily and rituximab is administered on day 1 of a 28-day cycle. In some such embodiments, rituximab is administered on day 1 of cycles 2-6.
• provided methods comprise administering each of Compound 1, rituximab, fludarabine and cyclophosphamide, wherein Compound 1 is administered twice daily and rituximab is administered once during a 28-day cycle. In some such embodiments, rituximab is administered on day 1 or day 2 of a 28-day cycle.
• provided methods comprise administering each of Compound 1, rituximab and bendamustine, wherein Compound 1 is administered twice daily and rituximab is administered once during a 28-day cycle. In some such embodiments, rituximab is administered on day 1 or day 2 of a 28-day cycle.
• each of Compound 1 and rituximab is administered as pharmaceutically acceptable compositions.
• a pharmaceutically acceptable composition comprising Compound 1 is formulated as an oral dosage form. In some embodiments, such oral dosage forms are capsules.
• the pharmaceutically acceptable composition comprising rituximab is formulated as an intravenous composition. In some embodiments, fludarabine, cyclophosphamide and bendamustine are formulated as intravenous compositions.
• a pharmaceutically acceptable composition comprising Compound 1 comprises from about 5% to about 60% of Compound 1, or a pharmaceutically acceptable salt thereof, based upon total weight of the composition.
• a pharmaceutically acceptable composition comprising Compound 1 comprises from about 5% to about 15%) or about 7%> to about 15% or about 7% to about 10%> or about 9% to about 12% of Compound 1, based upon total weight of the composition.
• provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 25% to about 75% or about 30% to about 60% or about 40% to about 50%) or about 40% to about 45% of Compound 1, based upon total weight of the formulation.
• provided regimens comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 20%, about 30%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 50%, about 60%, about 70%), or about 75% of Compound 1, based upon total weight of given composition or formulation.
• Rituximab is commercially available as a lOmg/mL solution comprising sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid and water.
• Commercially available vials comprise either lOOmg/lOmL or 500mg/50mL.
• a pharmaceutically acceptable composition comprises from about 1 mg/mL to about 4 mg/mL rituximab. In some embodiments, a pharmaceutically acceptable composition comprises from about 1 mg/mL, about 2 mg/mL, about 3 mg/mL or about 4 mg/mL rituximab. In some embodiments, a pharmaceutically acceptable composition comprises 10 mg/mL.
• Fludarabine (Fludara®) is commercially available as a vial of sterile lyophilized solid cake containing 50 mg of fludarabine phosphate, 50 mg of mannitol and sodium hydroxide to adjust pH to 7.7. The pH range for the final solution is 7.2-8.2. The solid cake is reconstituted with 2 mL of Sterile Water for Injection USP, which results in a solution containing 25 mg/mL of fludarabine phosphate intended for intravenous administration.
• Cyclophosphamide (Cytoxan®) is commercially available as a sterile powder which may be prepared for parenteral use by infusion by reconstituting, for example, in 0.9% sterile sodium chloride (5 mL per 100 mg anhydrous powder). Alternative solutions for reconstitution may be found, for example, in the package insert.
• Bendamustine (Treanda®) is commercially available as a single-use vial containing 100 mg of bendamustine hydrochloride as a lyophilized powder.
• the powder is reconstituted with 20 mL of Sterile Water for Injection USP to a final concentration of 5 mg/mL.
• the 5 mg/mL reconstituted solution is transferred to a 500 mL infusion bag containing 0.9% Sodium Chloride Injection USP.
• the 5 mg/mL reconstituted solution may be transferred to a 500 mL infusion bag containing 2.5% Dextrose/0.45% Sodium Chloride Injection USP.
• the final concentration of bendamustine hydrochloride in the infusion bag should be about 0.2-0.6 mg/mL.
• provided methods comprise administering Compound 1 in combination with rituximab daily for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days.
• a treatment regimen comprises at least one 28-day cycle.
• 28-day cycle means that provided treatment regimens are administered to a patient in need thereof for 28 consecutive days.
• the combination of Compound 1 and rituximab is administered for at least two, at least three, at least four, at least five or at least six 28-day cycles.
• the combination of Compound 1 and rituximab is administered for at least seven, at least eight, at least nine, at least ten, at least eleven or at least twelve 28-day cycles. In some embodiments, the combination of Compound 1 and rituximab is administered for at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen or at least twenty 28-day cycles. In some embodiments, the combination of Compound 1 and rituximab is administered to a patient for the duration of the patient's life.
• provided methods comprise administering to a patient in need thereof each of Compound 1, rituximab, fludarabine and cyclophosphamide, wherein each of rituximab, fludarabine and cyclophosphamide is administered for at least one, two, at least three, at least four, at least five or at least six 28-day cycles.
• the combination of Compound 1 and rituximab is administered for at least six 28-day cycles, and Compound 1 is administered for at least one additional 28-day cycle. In some embodiments, the combination of Compound 1 and rituximab is administered for at least six 28-day cycles, and Compound 1 is administered for an additional two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen 28-day cycles. In some embodiments, the combination of Compound 1 and rituximab is administered for at least six 28- day cycles, and Compound 1 is administered for the duration of the patient's life.
• Compound 1 is administered on days 1 through 28 (for example, one dose each day or two doses each day) of one or more 28-day cycles and rituximab is administered on day 1 of a 28-day cycle. In some embodiments, Compound 1 is administered on days 1 through 28 of one or more 28-day cycles and rituximab is administered on day 1 or day 2 of a 28-day cycle.
• two adjacent 28-day cycles may be separated by a rest period.
• a rest period may be one, two, three, four, five, six, seven or more days during which the patient is not administered either or both Compound 1 and rituximab.
• two adjacent 28-day cycles are continuous.
• provided methods comprise administering to a patient in need thereof Compound 1 in combination with rituximab, wherein the patient has failed at least one prior therapy. In some embodiments, provided methods comprise administering to a patient in need thereof Compound 1, rituximab, fludarabine and cyclophosphamide, wherein the patient has failed at least one prior therapy. In some embodiments, provided methods comprise administering to a patient in need thereof Compound 1, rituximab and benmustine, wherein the patient has failed at least one prior therapy.
• compositions for use in the present invention may be prepared as a unit dosage form.
• the unit dosage forms described herein refer to an amount of a component in its free base form.
• the amount of the salt form present in the composition is an amount that is equivalent to a unit dose of the free base of the component (i.e., of Compound 1).
• a pharmaceutical composition comprising a besylate salt of Compound 1 would contain 34.97 mg of the besylate salt form necessary to deliver an equivalent 25 mg unit dose of the free base of Compound 1.
• provided methods comprise administering to a patient in need thereof a therapeutically effective amount of Compound 1, wherein the therapeutically effective amount of Compound 1 is about 250 mg to about 1250 mg.
• the therapeutically effective amount of Compound 1 is administered as one or more discreet doses.
• a therapeutically effective amount of Compound 1 is 250 mg, wherein the therapeutically effective amount is administered as 125 mg twice daily (BID).
• a therapeutically effective amount of Compound 1 is 500 mg, wherein the therapeutically effective amount is administered as 250 mg twice daily (BID).
• a therapeutically effective amount of Compound 1 is 750 mg, wherein the therapeutically effective amount is administered as 375 mg twice daily (BID). In some embodiments, a therapeutically effective amount of Compound 1 is 1000 mg, wherein the therapeutically effective amount is administered as 500 mg twice daily (BID).
• provided methods comprise administering to a patient in need thereof a therapeutically effective amount of Compound 1, wherein the therapeutically effective amount of Compound 1 is about 125 mg to about 1250 mg, or about 125 mg to about 1125 mg, or about 125 mg to about 1000 mg, or about 125 mg to about 875 mg, or about 125 mg to about 750 mg, or about 125 mg to about 625 mg, or about 125 mg to about 500 mg, or about 125 mg to about 375 mg, or about 125 mg to about 250 mg, or about 250 mg to about 1250 mg, or about 250 mg to about 1125 mg, or about 250 mg to about 1000 mg, or about 250 mg to about 875 mg, or about 250 mg to about 750 mg, or about 250 mg to about 625 mg, or about 250 mg to about 500 mg, or about 250 mg to about 375 mg, or about 375 mg to about 1250 mg, or about 375 mg to about 1125 mg, or about 375 mg to about 1000 mg, or about 375 mg to about 1000 mg, or about 375 mg
• provided methods comprise administering to a patient in need thereof a therapeutically effective amount of Compound 1, wherein the therapeutically effective amount of Compound 1 is about 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg 165 mg 170 mg 175 mg 180 mg 185 mg 190 mg 195 mg 200 mg 205 mg 210 mg
• provided methods comprise administering to a patient in need thereof a pharmaceutical composition comprising a unit dose of Compound 1 in combination with rituximab.
• the unit dose of Compound 1 is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg or about 250 mg.
• provided methods comprise administering to a patient in need thereof a pharmaceutical composition comprising rituximab, wherein rituximab is administered as an infusion at a rate of 50 mg/hr.
• the infusion rate of rituximab is increased by 50 mg/hr every 30 minutes, to a maximum of 400 mg/hr.
• the infusion rate of rituximab is increased by 100 mg/hr every 30 minutes, to a maximum of 400 mg/hr.
• the infusion rate of rituximab is 100 mg/hr.
• the infusion rate of rituximab is 150 mg/hr.
• the infusion rate of rituximab is 200 mg/hr. In some embodiments, the infusion rate of rituximab is 250 mg/hr. In some embodiments, the infusion rate of rituximab is 300 mg/hr. In some embodiments, the infusion rate of rituximab is 350 mg/hr. In some embodiments, the infusion rate of rituximab is 400 mg/hr.
• Compound 1 and compositions described herein are generally useful for the inhibition of protein kinase activity of one or more enzymes.
• kinases that are inhibited by Compound 1 and compositions described herein and against which the methods described herein are useful include BTK and other TEC-kinases, including ITK, TEC, BMX and RLK, or a mutant thereof.
• BTK Bruton's tyrosine kinase
• BCR cell surface B-cell receptor
• BTK is a key regulator of B-cell development, activation, signaling, and survival (Kurosaki, Curr. Op. Imm., 2000, 276-281; Schaeffer and Schwartzberg, Curr. Op. Imm. 2000, 282-288).
• BTK plays a role in a number of other hematopoietic cell signaling pathways, e.g., Toll like receptor (TLR) and cytokine receptor-mediated TNF-a production in macrophages, IgE receptor (Fc epsilon RI) signaling in mast cells, inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation.
• TLR Toll like receptor
• Fc epsilon RI IgE receptor
• BTK also plays a crucial role in mast cell activation through the high-affinity IgE receptor (Fc epsilon RI). BTK deficient murine mast cells have reduced degranulation and decreased production of proinflammatory cytokines following Fc epsilon RI cross-linking (Kawakami et al. Journal of Leukocyte Biology 65: 286-290).
• Compound 1 is an inhibitor of BTK and therefore useful for treating one or more disorders associated with activity of BTK.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of a BTK- mediated disorder comprising the step of administering to a patient in need thereof Compound 1 in combination with rituximab.
• CLL chronic lymphocytic leukemia
• SLL small lymphocytic lymphoma
• CLL is a lymphoproliferative malignancy characterized by progressive accumulation of morphologically mature but functionally incompetent lymphocytes in the blood, bone marrow, and lymphoid tissues. It affects mainly elderly individuals with the median age at presentation of 65 to 70 years. The clinical course of CLL ranges from indolent disease with long-term survival over 12 years to aggressive disease with median survival of 2 years.
• Chronic lymphocytic leukemia is the most common leukemia in the U.S. and is typically characterized immunophenotypically as CD5+, CD23+, CD 10-, CD 19+, CD20 dim, sig dim, and cyclin Dl- (the latter point a distinguishing feature from mantle cell lymphoma).
• Chronic lymphocytic leukemia must also be distinguished from monoclonal B lymphocytosis (absolute monoclonal B-cell count ⁇ 5000/ ⁇ and absence of adenopathy or other clinical features of lymphoproliferative disorder).
• monoclonal B lymphocytosis absolute monoclonal B-cell count ⁇ 5000/ ⁇ and absence of adenopathy or other clinical features of lymphoproliferative disorder.
• Btk The cellular expression of Btk is restricted and largely limited to B-lymphocytes, monocytes, and mast cells or basophils. Investigation has revealed that some B-cell lymphomas and CLL/SLL depend on BCR signaling, suggesting that interruption of such signaling could be a promising therapeutic opportunity Recently it has been reported that half of all CLL retain BCR signaling in vitro and that immunoglobulin heavy gene somatic mutation (IgVH) is an important determinant of BCR responsiveness. Indeed, the mutational status of the BCR in CLL is one of the strongest predictors of disease progression, as aggressive disease typically displays BCR encoded by unmutated immunoglobulin variable heavy chains.
• IgVH immunoglobulin heavy gene somatic mutation
• Allogeneic stem cell transplant is the only potentially curative treatment for CLL, but 70% of affected patients are > 65 years of age at the time of diagnosis, have co-morbid conditions limiting eligibility for such therapy, and may exhibit a prolonged natural history with or without specific treatment.
• the actual prognosis of CLL is variable and dependent principally on clinical stage and certain genetic and molecular features. Both the Rai and Binet clinical staging systems are able to distinguish patient prognostic groups with median OSs ranging from 19 months in the most advanced stage (thrombocytopenia) to > 150 months in the earliest stage (blood and marrow lymphocytosis without adenopathy, organomegaly, or defined anemia/thrombocytopenia).
• the CLL treatment algorithm is complex and requires first the decision to treat (e.g., presence of symptoms such as fatigue or night sweats; bulky adenopathy/organomegaly; progressive anemia/thrombocytopenia); and second, choice of the treatment regimen, usually involving one or more: purine nucleosides (fludarabine), alkylating agents (cyclophosphamide, chlorambucil, bendamustine), corticosteroids, anti-CD20 monoclonal antibodies (rituximab/ofatumumab), or anti-CD52 monoclonal antibodies (alemtuzumab).
• purine nucleosides fludarabine
• alkylating agents cyclophosphamide, chlorambucil, bendamustine
• corticosteroids anti-CD20 monoclonal antibodies
• anti-CD20 monoclonal antibodies rituximab/ofatumumab
• anti-CD52 monoclonal antibodies alemtu
• Spleen tyrosine kinase is a kinase in the BCR signaling pathway proximal to Btk. Inhibition of Syk with the orally available Syk inhibitor fostamatinib disodium produced clinical responses in DLBCL, CLL, and mantle cell lymphoma.
• Btk inhibitor PCI-32765 which have reported objective anti-tumor responses in patients with DLBCL; mantle cell, marginal zone/ mucosa-associated lymphoid tissue (MALT), and follicular lymphoma (FL), WM, and CLL/SLL, with good tolerability.
• Compound 1 is generally well tolerated as a single agent at up to 750 mg PO QD and the maximum tolerated dose (MTD) has not yet been reached. Studies are ongoing and additional dose levels currently being investigated include: 1000 mg QD, 1250 mg QD, 375 mg BID and 500 mg BID.
• Rituximab has also been shown to exhibit good activity against relapsed/refractory CLL patients.
• rituximab in combination with fludarabine/cyclophosphamide, was evaluated in 408 patients with CLL and showed an 86% response rate, as compared to the 73% response rate observed for fludarabine/cyclophosphamide alone.
• the median progression-free survival was 39.8 months, as compared to 31.5 months observed for fludarabine/cyclophosphamide alone.
• the present invention encompasses the recognition that a BTK inhibitor such as Compound 1 in combination with rituximab is useful in the treatment of CLL and SLL.
• Compound 1 either as a single agent or in combination, may be found to be efficacious in CLL patients, including but not limited to those who had expressed one or more of the following prognostic/genetic markers and cytogenetic risk factors: deletions of chromosome 1 lq, 17p or 13q, or Trisomy 12 and 14q, zeta-chain-associated protein kinase 70 (ZAP 70) or immunoglobulin heavy chain variable region (IgVH) un-mutated.
• prognostic/genetic markers and cytogenetic risk factors deletions of chromosome 1 lq, 17p or 13q, or Trisomy 12 and 14q, zeta-chain-associated protein kinase 70 (ZAP 70) or immunoglobulin heavy chain variable region (IgVH) un-mutated.
• ZAP 70 zeta-chain-associated protein kinase 70
• IgVH immunoglobulin heavy chain variable region
• the present invention provides methods of treating, stabilizing or lessening the severity or progression of one or more diseases and conditions associated with BTK comprising administering to a patient in need thereof Compound 1 in combination with rituximab.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising administering to a patient in need thereof Compound 1 in combination with rituximab.
• provided methods comprise administering to a patient in need thereof each of Compound 1, rituximab, fludarabine and cyclophosphamide.
• provided methods comprise administering to a patient in need thereof each of Compound 1, rituximab and bendamustine.
• provided methods comprise administering to a patient in need thereof a composition comprising Compound 1 in combination with a composition comprising rituximab.
• the composition comprising Compound 1 further comprises one or more pharmaceutically acceptable excipients.
• the composition comprising Compound 1 is formulated as an oral dosage form.
• the oral dosage form is a capsule.
• provided methods comprise administering to a patient in need thereof compositions comprising each of Compound 1, rituximab, fludarabine and cyclophosphamide.
• provided methods comprise administering to a patient in need thereof compositions comprising each of Compound 1, rituximab and bendamustine.
• the composition comprising rituximab further comprises one or more pharmaceutically acceptable excipients.
• the composition comprising rituximab is formulated as an intravenous dosage form.
• provided methods comprise administering to a patient in need thereof a unit dose of Compound 1 in combination with a unit dose of rituximab.
• the unit dose of Compound 1 is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg or about 250 mg.
• provided methods comprise administering to a patient in need thereof a pharmaceutical composition comprising rituximab, wherein rituximab is administered as an infusion at a rate of 50 mg/hr.
• the infusion rate of rituximab is increased by 50 mg/hr every 30 minutes, to a maximum of 400 mg/hr.
• the infusion rate of rituximab is increased by 100 mg/hr every 30 minutes, to a maximum of 400 mg/hr.
• the infusion rate of rituximab is 100 mg/hr.
• the infusion rate of rituximab is 150 mg/hr.
• the infusion rate of rituximab is 200 mg/hr. In some embodiments, the infusion rate of rituximab is 250 mg/hr. In some embodiments, the infusion rate of rituximab is 300 mg/hr. In some embodiments, the infusion rate of rituximab is 350 mg/hr. In some embodiments, the infusion rate of rituximab is 400 mg/hr.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising administering to a patient in need thereof Compound 1 in combination with rituximab, wherein the patient has failed at least one prior therapy.
• provided methods comprise administering to a patient in need thereof Compound 1, rituximab, fludarabine and bendamustine, wherein the patient has failed at least one prior therapy.
• provided methods comprise administering to a patient in need thereof Compound 1, rituximab and bendamustine, wherein the patient has failed at least one prior therapy.
• provided methods comprise administering to a patient in need thereof about 500 mg to about 1250 mg Compound 1 in combination with about 375 mg/m 2 to about 500 mg/m 2 rituximab. In some embodiments, provided methods comprise administering to a patient in need thereof about 750 mg to about 1000 mg Compound 1 and about 375 mg/m 2 to about 500 mg/m 2 rituximab. In some embodiments, provided methods comprise administering to a patient in need thereof about 500 mg to about 1250 mg Compound 1, about 375 mg/m 2 to about 500 mg/m 2 rituximab, about 25 mg/m 2 fludarabine and about 250 mg/m 2 cyclophosphamide. In some embodiments, provided methods comprise administering to a patient in need thereof about 750 mg to about 1000 mg Compound 1, about 375 mg/m 2 to about 500 mg/m 2 rituximab and about 70 mg/m 2 bendamustine.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising administering to a patient in need thereof about 375 mg BID to about 500 mg BID Compound 1 in combination with about 375 mg/m 2 to about 500 mg/m 2 rituximab.
• rituximab is administered once during a 28-day cycle.
• provided methods comprise administering to a patient in need thereof about 250 mg to about 500 mg BID Compound 1, about 375 mg/m 2 to about 500 mg/m 2 rituximab, about 25 mg/m 2 fludarabine and about 250 mg/m 2 cyclophosphamide, wherein rituximab is administered on day 1 of a 28-day cycle.
• each of fludarabine and cyclophosphamide is administered on days 1-3 of a 28-day cycle.
• provided methods comprise administering to a patient in need thereof about 750 mg to about 1000 mg Compound 1, about 375 mg/m 2 to about 500 mg/m 2 rituximab and about 70 mg/m 2 bendamustine, wherein rituximab is administered on day 1 of a 28-day cycle.
• bendamustine is administered on days 1 and 2 of a 28-day cycle.
• provided methods comprise administering to a patient in need thereof about 125 mg BID Compound 1 and about 375 mg/m 2 rituximab. In some such embodiments, provided methods further comprise administering about 25 mg/m 2 fludarabine and about 250 mg/m 2 cyclophosphamide. In some embodiments, provided methods comprise administering to a patient in need thereof about 125 mg BID Compound 1, about 375 mg/m 2 rituximab and about 70 mg/m 2 bendamustine.
• provided methods comprise administering to a patient in need thereof about 125 mg BID Compound 1 and about 500 mg/m 2 rituximab. In some such embodiments, provided methods further comprise administering about 25 mg/m 2 fludarabine and about 250 mg/m 2 cyclophosphamide. In some embodiments, provided methods comprise administering to a patient in need thereof about 125 mg BID Compound 1, about 500 mg/m 2 rituximab and about 70 mg/m 2 bendamustine.
• provided methods comprise administering to a patient in need thereof about 250 mg BID Compound 1 and about 375 mg/m 2 rituximab. In some such embodiments, provided methods further comprise administering about 25 mg/m 2 fludarabine and about 250 mg/m 2 cyclophosphamide. In some embodiments, provided methods comprise administering to a patient in need thereof about 250 mg BID Compound 1, about 375 mg/m 2 rituximab and about 70 mg/m 2 bendamustine.
• provided methods comprise administering to a patient in need thereof about 250 mg BID Compound 1 and about 500 mg/m 2 rituximab. In some such embodiments, provided methods further comprise administering about 25 mg/m 2 fludarabine and about 250 mg/m 2 cyclophosphamide. In some embodiments, provided methods comprise administering to a patient in need thereof about 250 mg BID Compound 1, about 500 mg/m 2 rituximab and about 70 mg/m 2 bendamustine.
• provided methods comprise administering to a patient in need thereof about 375 mg BID Compound 1 and about 375 mg/m 2 rituximab. In some such embodiments, provided methods further comprise administering about 25 mg/m 2 fludarabine and about 250 mg/m 2 cyclophosphamide. In some embodiments, provided methods comprise administering to a patient in need thereof about 375 mg BID Compound 1, about 375 mg/m 2 rituximab and about 70 mg/m 2 bendamustine.
• provided methods comprise administering to a patient in need thereof about 375 mg BID Compound 1 and about 500 mg/m 2 rituximab. In some such embodiments, provided methods further comprise administering about 25 mg/m 2 fludarabine and about 250 mg/m 2 cyclophosphamide. In some embodiments, provided methods comprise administering to a patient in need thereof about 375 mg BID Compound 1, about 500 mg/m 2 rituximab and about 70 mg/m 2 bendamustine.
• provided methods comprise administering to a patient in need thereof about 500 mg BID Compound 1 and about 375 mg/m 2 rituximab. In some such embodiments, provided methods further comprise administering about 25 mg/m 2 fludarabine and about 250 mg/m 2 cyclophosphamide. In some embodiments, provided methods comprise administering to a patient in need thereof about 500 mg BID Compound 1, about 375 mg/m 2 rituximab and about 70 mg/m 2 bendamustine.
• provided methods comprise administering to a patient in need thereof about 500 mg BID Compound 1 and about 500 mg/m 2 rituximab. In some such embodiments, provided methods further comprise administering about 25 mg/m 2 fludarabine and about 250 mg/m 2 cyclophosphamide. In some embodiments, provided methods comprise administering to a patient in need thereof about 500 mg BID Compound 1, about 500 mg/m 2 rituximab and about 70 mg/m 2 bendamustine.
• rituximab is administered once during a 28-day cycle. In some embodiments, rituximab is administered on cycle 1 day 1 or day 2. In some embodiments, rituximab is administered on day 1 of a 28-day cycle. In some embodiments, rituximab is administered on cycle 2 day 1. In some embodiments, rituximab is administered on cycle 3 day
• rituximab is administered on cycle 4 day 1. In some embodiments, rituximab is administered on cycle 5 day 1. In some embodiments, rituximab is administered on cycle 6 day 1. In some embodiments, rituximab is administered on each of cycle 1 day 1 or day
• cycle 2 day 1 cycle 3 day 1
• cycle 4 day cycle 5 day 1 and cycle 6 day 1.
• 375 mg/m 2 rituximab is administered on cycle 1 day 1 or day 2, and 500 mg/m 2 rituximab is administered on cycle 2 day 1.
• 375 mg/m 2 rituximab is administered on cycle 1 day 1 or day 2
• 500 mg/m 2 rituximab is administered on each of cycle 2 day 1 and cycle 3 day 1.
• 375 mg/m 2 rituximab is administered on cycle 1 day 1 or day 2
• 500 mg/m 2 rituximab is administered on each of cycle 2 day 1, cycle 3 day 1 and cycle 4 day 1.
• 375 mg/m 2 rituximab is administered on cycle 1 day 1 or day 2, and 500 mg/m 2 rituximab is administered on each of cycle 2 day 1 , cycle 3 day 1, cycle 4 day 1 and cycle 5 day 1. In some embodiments, 375 mg/m 2 rituximab is administered on cycle 1 day 1 or day 2, and 500 mg/m 2 rituximab is administered on each of cycle 2 day 1 , cycle 3 day 1 , cycle 4 day 1 , cycle 5 day 1 and cycle 6 day 1.
• 25 mg/m 2 fludarabine is administered on days 1-3 of cycles 1, 2, 3, 4, 5 and/or 6.
• 250 mg/m 2 cyclophosphamide is administered on days 1-3 1 of cycles 1, 2, 3, 4, 5 and/or 6.
• 70 mg/m 2 bendamustine is administered on days 1 and 2 of cycles 1, 2, 3, 4, 5 and/or 6.
• the combination of Compound 1 and rituximab is administered over a period of 28 consecutive days ("a 28-day cycle").
• the combination of Compound 1 and rituximab is administered for two, three, four, five or six 28-day cycles.
• the combination of Compound 1 and rituximab is administered for one, two, three, four, five or six 28-day cycles, and Compound 1 is administered for an additional one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen 28-day cycles.
• the combination of Compound 1 and rituximab is administered to a patient for one, two, three, four, five or six 28-day cycles, and Compound 1 is administered for the duration of the patient's life.
• the combination of Compound 1 and rituximab is administered to a patient for one, two, three, four, five or six 28-day cycles, and either of Compound 1 or rituximab is further administered to the patient for one or more additional 28-day cycles. In some embodiments, the combination of Compound 1 and rituximab is administered to a patient for the duration of the patient's life.
• each of Compound 1, rituximab, fludarabine and cyclophosphamide is administered for one, two, three, four, five or six 28-day cycles, and Compound 1 is administered for an additional one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen 28-day cycles.
• each of Compound 1, rituximab and bendamustine is administered for one, two, three, four, five or six 28-day cycles, and Compound 1 is administered for an additional one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen 28-day cycles.
• two adjacent 28-day cycles may be separated by a rest period.
• a rest period may be one, two, three, four, five, six, seven or more days during which the patient is not administered either or both Compound 1 and rituximab.
• two adjacent 28-day cycles are continuous.
• provided methods comprise administering to a patient in need thereof Compound 1 in combination with rituximab, wherein the patient has failed at least one prior therapy.
• provided methods comprise administering to a patient in need thereof each of Compound 1, rituximab, fludarabine and cyclophosphamide, wherein the patient has failed at least one prior therapy.
• provided methods comprise administering to a patient in need thereof each of Compound 1, rituximab and bendamustine, wherein the patient has failed at least one prior therapy.
• the present invention provides a system for treating, stabilizing or lessening the severity of one or more diseases or conditions associated with BTK, the system comprising Compound 1 and rituximab.
• the system is a kit.
• the kit comprises a pharmaceutical composition comprising Compound 1 and a pharmaceutical composition comprising rituximab.
• the kit comprises twenty-eight (28) daily doses of Compound 1 and one 10 mg/mL vial of rituximab. In some embodiments, the kit comprises twenty-eight (28) daily doses of Compound 1 and one lOOmg/lOmL vial of rituximab. In some embodiments, the kit comprises twenty-eight (28) daily doses of Compound 1 and one 500mg/50mL vial of rituximab.
• the kit comprises fifty-six (56) 375 mg doses of Compound 1 and one 10 mg/mL vial of rituximab. In some embodiments, the kit comprises fifty-six (56) 375 mg doses of Compound 1 and one lOOmg/lOmL vial of rituximab. In some embodiments, the kit comprises fifty-six (56) 375 mg doses of Compound 1 and one 500mg/50mL vial of rituximab.
• the kit comprises two 375 mg doses of Compound 1 and one 10 mg/mL vial of rituximab. In some embodiments, the kit comprises two 375 mg doses of Compound 1 and one 100 mg/lOmL vial of rituximab. In some embodiments, the kit comprises two 375 mg doses of Compound 1 and one 500 mg/50mL vial of rituximab. In some embodiments, the kit comprises two 500 mg doses of Compound 1 and one 10 mg/mL dose of rituximab. In some embodiments, the kit comprises two 500 mg doses of Compound 1 and one lOOmg/lOmL vial of rituximab. . In some embodiments, the kit comprises two 500 mg doses of Compound 1 and one 500mg/50mL vial of rituximab.
• provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising Compound 1, wherein the pharmaceutically acceptable composition is an oral dosage form.
• the pharmaceutically acceptable composition is formulated as a capsule.
• provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition which comprises Compound 1, and one or more pharmaceutically acceptable excipients, such as, for example, binders, film coatings, diluents, disintegrants, surfactants (wetting agents), lubricants and glidants (adsorbents), or combinations thereof.
• the category under which a particular component is listed is not intended to be limiting; in some cases a particular component might appropriately fit in more than one category. Also, as will be appreciated, the same component can sometimes perform different functions, or can perform more than one function, in the context of a particular formulation, for example depending upon the amount of the ingredient and/or the presence of other ingredients and/or active compound(s).
• the pharmaceutically acceptable composition is a blended powder. i. Binders and Diluents
• compositions for use in the present invention may comprise one or more binders. Binders are used in the formulation of solid oral dosage forms to hold the active pharmaceutical ingredient and inactive ingredients together in a cohesive mix. In some embodiments, pharmaceutical compositions of the present invention comprise about 5% to about 50% (w/w) of one or more binders and/or diluents. In some embodiments, pharmaceutical compositions of the present invention comprise about 20% (w/w) of one or more binders and/or diluents. Suitable binders and/or diluents (also referred to as "fillers”) are known in the art.
• binders and/or diluents include, but are not limited to, starches such as celluloses (low molecular weight HPC (hydroxypropyl cellulose), microcrystalline cellulose (e.g., Avicel ® ), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxymethyl cellulose, ethylcellulose), sugars such as lactose (i.e. lactose monohydrate), sucrose, dextrose, fructose, maltose, glucose, and polyols such as sorbitol, mannitol, lactitol, malitol and xylitol, or a combination thereof.
• a provided composition comprises a binder of microcrystalline cellulose and/or lactose monohydrate.
• compositions for use in the present invention may further comprise one or more disintegrants.
• Suitable disintegrants are known in the art and include, but are not limited to, agar, calcium carbonate, sodium carbonate, sodium bicarbonate, cross-linked sodium carboxymethyl cellulose (croscarmellose sodium), sodium carboxymethyl starch (sodium starch glycolate), microcrystalline cellulose, or a combination thereof.
• provided formulations comprise from about 1%, to about 25% disintegrant, based upon total weight of the formulation.
• Surfactants also referred to as bioavailability enhancers, are well known in the art and typically facilitate drug release and absorption by enhancing the solubility of poorly-soluble drugs.
• Representative surfactants include, but are not limited to, poloxamers, polyoxyethylene ethers, polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polysorbates, and combinations thereof.
• the surfactant is a poloxamer.
• the poloxamer is poloxamer 407.
• compositions for use in the present invention comprise from about 1% to about 30%> by weight of surfactant, based upon total weight of the blended powder. iv. Lubricants
• compositions of the present invention may further comprise one or more lubricants.
• Lubricants are agents added in small quantities to formulations to improve certain processing characteristics. Lubricants prevent the formulation mixture from sticking to the compression machinery and enhance product flow by reducing interparticulate friction.
• Representative lubricants include, but are not limited to, magnesium stearate, glyceryl behenate, sodium stearyl fumarate and fatty acids (i.e. palmitic and stearic acids).
• a lubricant is magnesium stearate.
• provided formulations comprise from about 0.2% to about 3% lubricant, based upon total weight of given formulation. v. Glidants
• compositions of the present invention may further comprise one or more glidants.
• Representative glidants include, but are not limited to, silicas (i.e. fumed silica), microcrystalline celluloses, starches (i.e. corn starch) and carbonates (i.e. calcium carbonate and magnesium carbonate).
• provided formulations comprise from about 0.2% to about 3%) glidant, based upon total weight of given formulation.
• the present invention provides a method of treating a disease or disorder selected from chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising administering to a patient in need thereof Compound 1 in combination with rituximab.
• the besylate salt of Compound 1 N-(3-(5-fluoro-2-(4-(2- methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide benzenesulfonic acid salt, has recently been identified and is currently in clinical trials as monotherapy in subjects with relapsed or refractory B-cell non-Hodgkin's lymphoma (B-NHL), chronic lymphocytic leukemia (CLL) and Waldenstrom's macroglobulinemia (WM).
• B-NHL B-cell non-Hodgkin's lymphoma
• CLL chronic lymphocytic leukemia
• WM Waldenstrom's macroglobulinemia
• provided methods comprise administering to a patient in need thereof a besylate salt of Compound 1.
• provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 5% to about 60% of the besylate salt of Compound 1, based upon total weight of the formulation. In some embodiments, provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 5% to about 15% or about 7% to about 15% or about 7% to about 10% or about 9% to about 12% of the besylate salt of Compound 1, based upon total weight of the composition.
• provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 25 %> to about 75 %> or about 30%> to about 60%> or about 40%> to about 50%) or about 40%> to about 45 %> of the besylate salt of Compound 1, based upon total weight of the formulation.
• provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 20%, about 30%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 50%, about 60%, about 70%, or about 75 %> of the besylate salt of Compound 1, based upon total weight of given composition or formulation.
• provided methods comprise administering to a patient in need thereof a pharmaceutical composition comprising a unit dose of Compound 1, wherein Compound 1 is in the form of a besylate salt.
• the unit dose is an amount sufficient to provide about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg or about 250 mg of the free base of Compound 1.
• the pharmaceutical composition comprising the besylate salt of Compound 1 is a solid oral dosage form.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising administering to a patient in need thereof Compound 1 in combination with rituximab, wherein Compound 1 is administered as the besylate salt.
• the besylate salt of Compound 1 is administered in the form of a composition comprising one or more pharmaceutically acceptable excipients selected from binders, film coatings, diluents, disintegrants, surfactants, lubricants and glidants.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising administering to a patient in need thereof each of Compound 1, rituximab, fludarabine and cyclophosphamide, wherein Compound 1 is administered as the besylate salt.
• the besylate salt of Compound 1 is administered in the form of a composition comprising one or more pharmaceutically acceptable excipients selected from binders, film coatings, diluents, disintegrants, surfactants, lubricants and glidants.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising administering to a patient in need thereof each of Compound 1, rituximab and bendamustine, wherein Compound 1 is administered as the besylate salt.
• the besylate salt of Compound 1 is administered in the form of a composition comprising one or more pharmaceutically acceptable excipients selected from binders, film coatings, diluents, disintegrants, surfactants, lubricants and glidants.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising the besylate salt of Compound 1 in combination with rituximab, wherein the amount of besylate salt of Compound 1 is sufficient to deliver about 125 mg, about 250 mg, about 325 mg, about 375 mg, about 400 mg, about 500 mg, about 625 mg, about 750 mg, about 1000 mg or about 1250 mg of the free base of Compound 1.
• the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients selected from binders, film coating, diluents, disintegrants, surfactants, lubricants and glidants.
• the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients selected from microcrystalline cellulose, lactose monohydrate, sodium starch, poloxamer 407, fumed silica and magnesium stearate.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising administering to a patient in need thereof a pharmaceutical compositions comprising each of the besylate salt of Compound 1 (i.e., Compoundl besylate), rituximab, fludarabine and cyclophosphamide, wherein the amount of besylate salt of Compound 1 is sufficient to deliver about 125 mg, about 250 mg, about 325 mg, about 375 mg, about 400 mg, about 500 mg, about 625 mg, about 750 mg, about 1000 mg or about 1250 mg of the free base of Compound 1.
• Compound 1 i.e., Compoundl besylate
• rituximab rituximab
• fludarabine cyclophosphamide
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising administering to a patient in need thereof a pharmaceutical compositions comprising each of the besylate salt of Compound 1 (i.e., Compoundl besylate), rituximab and bendamustine, wherein the amount of besylate salt of Compound 1 is sufficient to deliver about 125 mg, about 250 mg, about 325 mg, about 375 mg, about 400 mg, about 500 mg, about 625 mg, about 750 mg, about 1000 mg or about 1250 mg of the free base of Compound 1.
• a pharmaceutical compositions comprising each of the besylate salt of Compound 1 (i.e., Compoundl besylate), rituximab and bendamustine, wherein the amount of besylate salt of Compound 1 is sufficient to deliver about 125 mg
• An intragranular portion of sieved magnesium stearate (2.0%, per Table 1, below) is added to the blender and the formulation blended.
• This blended formulation is then roller compacted, milled, and then blended.
• the blended formulation is additionally roller compacted, milled and then blended.
• the remainder or extragranular portion of the magnesium stearate (0.5%, per Table 1, below) is added and the final formulation is blended.
• Capsules are either mechanically filled or manually filled via the flood fill method.
• N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4- ylamino)phenyl)acrylamide besylate is a chemically synthesized small molecule substituted pyrimidine developed as the benzenesulfonic acid salt and is a white to off-white crystalline powder.
• N-(3 -(5 -fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4- ylamino)phenyl)acrylamide besylate is an oral, potent (IC 50 ⁇ 0.5nM) and selective small molecule inhibitor of Btk.
• N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4- ylamino)phenyl)acrylamide besylate exhibits solubility of approximately 0.16 mg/mL in water and a maximum aqueous solubility of 0.40 mg/mL at approximately pH 3.0.
• N-(3-(5-fluoro-2-(4-(2- methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide besylate exhibits no environmental instabilities (i.e. heat, acid, base) that require special handling.
• N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4- ylamino)phenyl)acrylamide besylate was formulated into capsules containing the components and quantities listed in Table 1 to obtain the study drug.
• the capsules listed in Table 1 will be administered during the dose escalation and expansion cohort studies.
• Rituximab is provided to the physician/investigator in lOmg/mL vials comprising lOOmg/lOmL or 500mg/50mL. Prior to administration, rituximab is diluted to a dose of 1 mg/mL, 2 mg/mL, 3 mg/mL or 4 mg/mL with either 5% dextrose in water or 0.9% sodium chloride. Rituximab is thereafter administered as a 1 mg/mL to 4 mg/mL infusion according to the dosages set forth in Table 2, below. Study Design
• NTD Not Tolerated Dose
• OBE Optimal Biologic Effect dose
• MTD Maximum Tolerated Dose
• Study treatment was administered in 28-day cycles at specified dose levels as scheduled until disease progression, unacceptable toxicity, or discontinuation for any other reason. Subjects will continue on the starting dose until the preliminary recommended Phase 2 dose (RP2D) is determined, at which point they can be switched to the preliminary RP2D.
• RP2D Phase 2 dose
• treatment duration refers to the time a patient is enrolled in the study, inclusive of all rest periods, until treatment is discontinued.
• Rituximab was administered as a single intravenous (IV) infusion.
• the initial infusion during cycle 1 was administered at 375 mg/m 2 ; subsequent infusions during cycles 2 through 6 were administered at 500 mg/m 2 .
• Administration of rituximab began on day 2 of cycle
• rituximab will be discontinued. Subjects may continue on treatment with N-(3-(5-fluoro-2-(4-(2- methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide besylate if appropriate.
• the first infusion of rituximab was at a rate of 50 mg/hr. In the absence of infusion toxicity, the infusion rate will be increased by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. Each subsequent infusion will be initiated at 100 mg/hr. In the absence of infusion toxicity, the infusion rate will be increased by 100 mg/hr increments at 30 minute intervals to a maximum of 400 mg/hr.
• the dose level at which a patient is enrolled will be based on which cohort is open at the time of enrollment. Dose escalation, via enrollment in the next higher dose, is allowed only if none (0) of the first three (3) subjects enrolled in any cohort experience dose limiting toxicity (DLT). If one (1) of the first three (3) subjects dosed in any cohort experiences a DLT in cycle 1, three (3) more subjects will be enrolled in that dose cohort. A dose level will be considered to be below the NTD if ⁇ 1 of 3 DLT evaluable subjects enrolled experiences a DLT during the first
• a dose will be considered a NTD when at least two (2) of six (6) DLT-evaluable subjects in that cohort experience a DLT.
• a MTD will be declared when at least six (6) subjects have been enrolled and safely complete cycle 1 at that dose level. The MTD is defined as the last dose below the NTD with zero (0) or one (1) DLT-evaluable subject experiencing DLT during the first two 28-day cycles.
• OBE dose is defined as follows:
• PR Partial Response
• LN lymph node
• ANC 1500/uL or Hgb > 11.0 g/dL
• a status of PR is the investigator's assessment based on a physical exam evaluation of lymph nodes, spleen and liver and laboratory values of blood counts. Confirmed PR also includes imaging of tumor lesions by CT scan.
• Figure 1 summarizes the enrollment and response assessment of patients. All three patients in Cohort 1 have been assessed as having a partial response to study treatment. In all three cases the investigators' assessment of PR as of cycle 3 has been confirmed by CT scans showing a greater than 50 % reduction in the size of lymph nodes compared to pre-treatment baseline values. The first subject enrolled is currently being treated in cycle 9 and continues to maintain a partial response. The other two patients in cohorts 1 have continued with treatment into cycle 8 and also maintain a partial response to treatment. Of the six subjects treated in cohort 2, two subjects have achieved a partial response by the start of cycle 3 according to the investigator assessment by examination. One subject has exhibited a partial response by cycle 5 as per investigator assessment. Response assessments for the additional 3 subjects enrolled in cohort 2 is pending.
• rituximab will be administered according to the schedule set forth in the dose escalation cohorts.
• Rituximab will be administered as a single intravenous (IV) infusion.
• the initial infusion during cycle 1 will be administered at 375 mg/m 2 ; subsequent infusions during cycles 2 through 6 will be administered at 500 mg/m 2 .
• Administration of rituximab will begin on day 2 of cycle 1 and on day 1 of each cycle thereafter. Following the cycle 6 infusion, rituximab will be discontinued.
• the physician-investigator may elect to rest a patient during the study, during which time the patient does not receive treatment.
• the physician- investigator may elect to rest a patient due to occurrence or recurrence of adverse events.
• a patient who has been rested is still enrolled in the study until the physician- investigator determines that the patient should not continue treatment, at which time such patients are discontinued from further treatment.
• treatment duration refers to the time a patient is enrolled in the study, inclusive of all rest periods, until treatment is discontinued.
• DLTs dose limiting toxicities
• AEs adverse events
• Hematologic DLTs include Grade 4 anemia (hemoglobin decrease) or thrombocytopenia by NCI-CTCAE (v. 4.03) or by IWCLL criteria, whichever results in the lower blood threshold; Grade 4 neutropenia greater than 5 days despite granulocyte colony-stimulating factor (G-CSF) support; and Grade 3 or higher febrile neutropenia.
• Lymphocytosis may be observed as a consequence of disease progression but has also been described as a redistribution (lymphocytle migration and trafficking) phenomenon in subjects receiving another BTK inhibitor even as lymph node disease responds to treatment. Therefore, lymphocytosis will not be rated for DLT. Reduction of malignant lymphocytosis is an intended therapeutic effect of treatment and will not be considered for DLT.
• Non-hematologic DLTs include Grade 4 or higher non-hematologic AEs of any duration; Grade 3 total bilirubin elevation, whether symptomatic or asymptomatic; and any Grade 3 non-hematologic toxicity except nausea, vomiting and diarrhea lasting less than 24 hours following medical therapy; tumor lysis syndrome which does not progress to Grade 4 and resolves in less than 7 days with medical management is not considered a DLT; and transient, and Grade 3 non-hematologic laboratory anomaly that is asymptomatic and rapidly reversible (returns to baseline or ⁇ Grade 1 within 7 days) will not be considered a DLT.
• Subjects without disease progression and without DLT at the end of the first two 28- day treatment cycles are eligible to continue receiving N-(3-(5-fluoro-2-(4-(2- methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide besylate in combination with rituximab for additional 28-day cycles until (i) the patient experiences unacceptable toxicity, (ii) the underlying malignancy progresses, (iii) the patient withdraws consent, or (iv) the treating physician-investigator otherwise determines that the patient should not continue treatment.
• Subjects experiencing a DLT may remain on study treatment if the treating investigator determines that the subject is receiving a clinical benefit from the study treatment.
• Rituximab will only be administered for the first 6 cycles; however patients continuing to benefit from N-(3 -(5 -fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4- ylamino)phenyl)acrylamide besylate can remain on treatment.
• One subject in cohort 1 experienced herpetic esophagitis during cycle 2 and two SAEs during cycle 5; an incidence of atrial fibrillation and pneumonia and an incidence of hypotension, altered mental status and pneumonia, both reports which were considered unrelated to the study drugs. All 3 of these SAE reports required brief hospitalizations and drug interruptions, however following re-challenged with drug this subject has subsequently achieved further improvement in disease status.
• cohort 2 In cohort 2, one subject experienced scrotal abscess during cycle 2, which was deemed unrelated to the study drugs. Another cohort 2 subject experienced a Grade 3 fatigue during cycle 2 which was declared a DLT; however, the AE was not reported as serious. This patient remains on study treatment at a reduced dose of N-(3-(5- fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide besylate. One additional subject in cohort 2 experienced visual disturbance during cycle 2, which was present at baseline. Two subjects, one from each cohort, reported Grade 3 neutropenia.
• the binding assay system for profiling kinase activity were based upon HotSpot technology (Reaction Biology Corp.; Malvern, PA, USA) and utilized radio-isotope-based P81 filtration.
• Compound 2 was dissolved in pure DMSO to make a lOmM stock solution and serial dilutions were performed to a final 3 ⁇ test concentration.
• Substrates for the various kinases tested against Compound 2 were prepared fresh daily in Reaction Buffer. Any required cofactors were then added to the substrate solution. The identification and selection of the appropriate cofactor for each kinase is within the ability of a person skilled in the art.
• Table 3 sets forth the average percent inhibition for Compound 2 against various kinases:
• Rituximab is provided to the physician/investigator in lOmg/mL vials comprising lOOmg/lOmL or 500mg/50mL. Prior to administration, rituximab is diluted to a dose of 1 mg/mL, 2 mg/mL, 3 mg/mL or 4 mg/mL with either 5% dextrose in water or 0.9% sodium chloride. Rituximab is thereafter administered as a 1 mg/mL to 4 mg/mL infusion according to the dosages set forth in Table 4, below.
• Fludarabine is approved as Fludara® and is commercially available in a vial containing a sterile lyophilized solid cake which contains 50 mg of fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide.
• the solid cake is reconstituted with 2 mL of Sterile Water for Injection USP, resulting in a 25 mg/mL solution.
• Cyclophosphamide is approved as Cytoxan® and is commerically available as a sterile powder which con be reconstituted according to the package insert.
• Bendamustine is approved as Treanda® and is commercially available as as a single- use vial containing 100 mg of bendamustine hydrochloride as a lyophilized powder.
• the powder is reconstituted with 20 mL of Sterile Water for Injection USP, resulting in a 5 mg/mL solution, which is further diluted with 0.9% Sodium Chloride Injection, USP or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP immediately prior to injection (final concentration of 0.2-0.6 mg/mL).
• Compound 1 besylate, rituximab, fludarabine and cyclophosphamide will be administered according to the cohorts for Arm A of the study, listed in Table 4:
• Compound 1 besylate, rituximab and bendamustine will be administered according to the cohorts for Arm B of the study, listed in Table 5 :
• Rituximab will be administered as a single intravenous (IV) infusion.
• the initial infusion during cycle 1 will be administered at 375 mg/m 2 ; subsequent infusions during cycles 2 through 6 will be administered at 500 mg/m 2 .
• Administration of rituximab will begin on day 1 of cycle 1 and on day 1 of each cycle thereafter. Following the cycle 6 infusion, rituximab will be discontinued. Subjects may continue on treatment with Compound 1 besylate if appropriate.
• the first infusion of rituximab will be at a rate of 50 mg/hr. In the absence of infusion toxicity, the infusion rate will be increased by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. Each subsequent infusion will be initiated at 100 mg/hr. In the absence of infusion toxicity, the infusion rate will be increased by 100 mg/hr increments at 30 minute intervals to a maximum of 400 mg/hr.
• Fludarabine will be administered as a 25 mg/mL (Sterile Water USP) intravenous infusion of 25 mg/m 2 over 20-30 minutes on days 1-3 for cycles 1-6.
• Cyclophosphamide will be administered as a 100mg/5mL intravenous infusion of 250 mg/m 2 over 10-30 minutes on days 1- 3 for cycles 1-6.
• Bendamustine will be diluted to 5 mg/mL concentration with Sterile Water for Injection. Immediately prior to use, the bendamustine solution will be transferred to a 500mL infusion bag of 0.9% Sodium Chloride Injection USP. The bendamustine infusion solution will then be administered as an intravenous infusion of 70 mg/m 2 over 30-60 minutes on days 1 and 2 for cycles 1-6.
• each dose of ofatumumab is prepared in lOOOmL 0.9% Sodium Chloride Injection, USP solutions.
• the dilution of ofatumumab is as follows:
• NTD Not Tolerated Dose
• OBE Optimal Biologic Effect dose
• MTD Maximum Tolerated Dose
• Study treatment will be administered in 28-day cycles at specified dose levels as scheduled until disease progression, unacceptable toxicity, or discontinuation for any other reason. Subjects will continue on the starting dose until the preliminary recommended Phase 2 dose (RP2D) is determined, at which point they can be switched to the preliminary RP2D.
• RP2D Phase 2 dose
• Compound 1 besylate and ofatumumab will be administered according to the cohorts for the study, listed in Table 6:
• Ofatumumab will be administered as a single intravenous (IV) infusion.
• the initial infusion during the first dose will be at a rate of 3.6 mg/hour (12 mL/hour).
• the infustion rate of dose 2 will be at a rate of 24 mg/hour (12 mL/hour).
• Subsequent infusion rates will be at 50 mg/hour (25 mL/hour).
• the rate of infustion may be increased every 30 minutes as described in Table 7:
• Dose 1 300 mg (0.3 mg/mL)
• Doses 2 and 3-12 2000 mg (2 mg/mL)

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