Classifications

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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • 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
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  • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• Btk Bruton's tyrosine kinase
• BCR cell surface B-cell receptor
• Btk is a key regulator of B-cell development, activation, signaling, and survival
• 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 (FcepsilonRI) 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
• FcepsilonRI IgE receptor
• a method for treating a hematological malignancy in an individual in need thereof comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• the hematological malignancy is CLL.
• the treating the hematological malignancy comprises managing the hematological malignancy.
• the hematological malignancy is a B-cell malignancy.
• the hematological malignancy is a leukemia
• the mobilized cells are myeloid cells or lymphoid cells.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the concentration before administration of the Btk inhibitor.
• administering the second cancer treatment regimen occurs after a subsequent decrease in peripheral blood concentration of the mobilized plurality of cells.
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a predetermined length of time.
• analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor.
• administering the second cancer treatment regimen occurs after a subsequent decrease in the number of mobilized plurality of cells in the peripheral blood.
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time. In some embodiments, analyzing the mobilized plurality of cells comprises preparing a biomarker profile for a population of cells isolated from the plurality of cells, wherein the biomarker profile indicates the expression of a biomarker, the expression level of a biomarker, mutations in a biomarker, or the presence of a biomarker. In some embodiments, the biomarker is any cytogenetic, cell surface molecular or protein or R A expression marker. In some embodiments, the biomarker is: ZAP70; t(14,18); ⁇ -2
• the method further comprises providing a second cancer treatment regimen based on the biomarker profile. In some embodiments, the method further comprises not administering based on the biomarker profile. In some embodiments, the method further comprises predicting the efficacy of a treatment regimen based on the biomarker profile.
• the hematological malignancy is a chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma.
• CLL chronic lymphocytic leukemia
• SLL small lymphocytic lymphoma
• high risk CLL or a non-CLL/SLL lymphoma.
• the hematological malignancy is follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Waldenstrom's macro globulinemia, multiple myeloma, marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, or extranodal marginal zone B cell lymphoma.
• the hematological malignancy is chronic myelogenous (or myeloid) leukemia, or acute lymphoblastic leukemia.
• the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, relapsed or refractory follicular lymphoma, relapsed or refractory CLL; relapsed or refractory SLL; relapsed or refractory multiple myeloma.
• DLBCL diffuse large B-cell lymphoma
• the Btk inhibitor forms a covalent bond with a cysteine sidechain of a Bruton's tyrosine kinase, a Bruton's tyrosine kinase homolog, or a Btk tyrosine kinase cysteine homolog.
• the irreversible Btk inhibitor is (R)- 1 -(3-(4-amino-3-(4-phenoxyphenyl)- 1 H-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop- 2-en-l-one.
• the amount of the irreversible Btk inhibitor is from 300 mg/day up to, and including, 1000 mg/day. In some embodiments, the amount of the irreversible Btk inhibitor is from 420 mg/day up to, and including, 840 mg/day. In some embodiments, the amount of the irreversible Btk inhibitor is about 420 mg/day, about 560 mg/day, or about 840 mg/day. In some embodiments, the amount of the irreversible Btk inhibitor is about 420 mg/day. In some embodiments, the AUCo-24 of the Btk inhibitor is between about 150 and about 3500 ng*h/mL.
• the AUCo-24 of the Btk inhibitor is between about 500 and about 1100 ng*h/mL.
• the Btk inhibitor is administered orally. In some embodiments, the Btk inhibitor is administered once per day, twice per day, or three times per day. In some embodiments, the Btk inhibitor is administered until disease progression, unacceptable toxicity, or individual choice. In some embodiments, the Btk inhibitor is administered daily until disease progression, unacceptable toxicity, or individual choice. In some embodiments, the Btk inhibitor is administered every other day until disease progression, unacceptable toxicity, or individual choice. In some embodiments, the Btk inhibitor is a front line therapy, second line therapy, third line therapy, fourth line therapy, fifth line therapy, or sixth line therapy.
• the Btk inhibitor treats a refractory hematological malignancy. In some embodiments, the Btk inhibitor is a maintenance therapy. In some embodiments, the second cancer treatment regimen comprises a chemotherapeutic agent, a steroid, an immunotherapeutic agent, a targeted therapy, or a combination thereof. In some embodiments, the second cancer treatment regimen comprises a B cell receptor pathway inhibitor. In some embodiments, the B cell receptor pathway inhibitor is a CD79A inhibitor, a CD79B inhibitor, a CD 19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K inhibitor, a Blnk inhibitor, a PLCy inhibitor, a PKCP inhibitor, or a combination thereof.
• the second cancer treatment regimen comprises an antibody, B cell receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor, an mTOR inhibitor, a radioimmunotherapeutic, a DNA damaging agent, a proteosome inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, an Hsp90 inhibitor, a telomerase inhibitor, a Jakl/2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a combination thereof.
• the second cancer treatment regimen comprises chlorambucil, ifosphamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL- 101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.
• the second cancer treatment regimen comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally, rituximab. In some embodiments, the second cancer treatment regimen comprises bendamustine, and rituximab. In some embodiments, the second cancer treatment regimen comprises fludarabine,
• the second cancer treatment regimen comprises cyclophosphamide, vincristine, and prednisone, and optionally, rituximab.
• the second cancer treatment regimen comprises etoposide, doxorubicin, vinristine, cyclophosphamide, prednisolone, and optionally, rituximab.
• the second cancer treatment regimen comprises dexamethasone and lenalidomide.
• the inhibitor of Bruton's tyrosine kinase is a reversible inhibitor.
• the inhibitor of Bruton's tyrosine kinase is an irreversible inhibitor. In some embodiments, the inhibitor of Bruton's tyrosine kinase forms a covalent bond with a cysteine sidechain of a Bruton's tyrosine kinase, a Bruton's tyrosine kinase homo log, or a Btk tyrosine kinase cysteine homo log. In some embodiments, the inhibitor of Bruton's tyrosine kinase has the structure of Formula (D):
• L a is CH 2 , O, NH or S
• Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl
• Y is an optionally substituted group selected from among alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
• R 7 and Rs are independently H;
• R 6 is H; and pharmaceutically active metabolites, or pharmaceutically acceptable solvates, pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs thereof.
• the Bruton's tyrosine kinase inhibitor is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one.
• La is O.
• Ar is phenyl.
• each of R 7 and Rs is H.
• Y is a 4-, 5-, 6-, or 7-membered cycloalkyl ring; or Y is a 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.
• a method for treating relapsed or refractory non-Hodgkin's lymphoma in an individual in need thereof comprising: administering to the individual a therapeutically-effective amount of (R)- 1 -(3 -(4-amino-3 -(4-phenoxyphenyl)- 1 H- pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one.
• the non- Hodgkin's lymphoma is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, or relapsed or refractory follicular lymphoma.
• the amount of (R)-l -(3 -(4-amino-3 -(4-phenoxyphenyl)- lH-pyrazolo [3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is from 300 mg/day up to, and including, 1000 mg/day.
• the amount of (R)-l -(3 -(4-amino-3 -(4-phenoxyphenyl)- 1H- pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is from 420 mg/day up to, and including, 840 mg/day.
• the amount of (R)-l-(3-(4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is about 420 mg/day, about 560 mg/day, or about 840 mg/day.
• the amount of the irreversible Btk inhibitor is about 420 mg/day.
• the AUCo-24 of the Btk inhibitor is between about 150 and about 3500 ng*h/mL. In some embodiments, the AUCo-24 of the Btk inhibitor is between about 500 and about 1100 ng*h/mL.
• (R)-l- (3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en- 1-one is administered orally.
• (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is administered once per day, twice per day, or three times per day.
• (R)-l-(3-(4-amino-3-(4- phenoxyphenyl)- 1 H-pyrazolo [3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one is administered until disease progression, unacceptable toxicity, or individual choice.
• (R)- 1 -(3 -(4-amino-3-(4-phenoxyphenyl)-l H-pyrazolo [3, 4-d]pyrimidin-l - yl)piperidin-l-yl)prop-2-en-l-one is administered until disease progression, unacceptable toxicity, or individual choice.
• (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)- 1 H-pyrazolo [3, 4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l -one is administered daily until disease progression, unacceptable toxicity, or individual choice.
• (R)-l- (3 -(4-amino-3-(4-phenoxyphenyl)-l H-pyrazolo [3, 4-d]pyrimidin-l-yl)piperi din- l-yl)prop-2-en- 1-one is administered every other day until disease progression, unacceptable toxicity, or individual choice.
• (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is a second line therapy, third line therapy, fourth line therapy, fifth line therapy, or sixth line therapy.
• the Btk inhibitor is a maintenance therapy.
• the method further comprises administering a second cancer treatment regimen.
• the second cancer treatment regimen is administered after mobilization of a plurality of lymphoid cells from the non-Hodgkin's lymphoma.
• the second cancer treatment regimen is administered after lymphocytosis of a plurality of lymphoid cells from the non-Hodgkin's lymphoma.
• the second cancer treatment regimen comprises a
• the second cancer treatment regimen comprises a B cell receptor pathway inhibitor.
• the B cell receptor pathway inhibitor is a CD79A inhibitor, a CD79B inhibitor, a CD 19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K inhibitor, a Blnk inhibitor, a PLCy inhibitor, a PKCP inhibitor, or a combination thereof.
• the second cancer treatment regimen comprises an antibody, B cell receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor, an mTOR inhibitor, a
• radioimmunotherapeutic a DNA damaging agent, a proteosome inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, an Hsp90 inhibitor, a telomerase inhibitor, a Jakl/2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a combination thereof.
• the second cancer treatment regimen comprises chlorambucil, ifosphamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.
• the second cancer treatment regimen comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally, rituximab.
• the second cancer treatment regimen comprises bendamustine, and rituximab.
• the second cancer treatment regimen comprises fludarabine, cyclophosphamide, and rituximab.
• the second cancer treatment regimen comprises cyclophosphamide, vincristine, and prednisone, and optionally, rituximab.
• the second cancer treatment regimen comprises etoposide, doxorubicin, vinristine, cyclophosphamide, prednisolone, and optionally, rituximab. In some embodiments, the second cancer treatment regimen comprises dexamethasone and lenalidomide.
• a method for treating diffuse large B-cell lymphoma, activated B cell-like subtype (ABC-DLBCL), in an individual in need thereof comprising: administering to the individual an irreversible Btk inhibitor in an amount from 300 mg/day up to, and including, 1000 mg/day.
• the method further comprises diagnosing the individual with diffuse large B-cell lymphoma, activated B cell-like subtype (ABC-DLBCL), by determining the gene sequence of one or more biomarkers in a plurality of lymphoid cells isolated from the diffuse large B-cell lymphoma.
• the irreversible Btk inhibitor is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one.
• the ABC-DLBCL is characterized by a CD79B mutation.
• the CD79B mutation is a mutation of the immunoreceptor tyrosine-based activation motif (IT AM) signaling module.
• the CD79B mutation is a missense mutation of the first immunoreceptor tyrosine- based activation motif (ITAM) tyrosine.
• the CD79B mutation increases surface BCR expression and attenuates Lyn kinase activity.
• the ABC- DLBCL is characterized by a CD79A mutation.
• the CD79A mutation is in the immunoreceptor tyrosine-based activation motif (IT AM) signaling module.
• the CD79A mutation is a splice-donor-site mutation of the immunoreceptor tyrosine-based activation motif (IT AM) signaling module.
• the CD79A mutation deletes the immunoreceptor tyrosine-based activation motif (IT AM) signaling module.
• the ABC-DLBCL is characterized by a mutation in MyD88, A20, or a combination thereof.
• the MyD88 mutation is the amino acid substitution L265P in the MYD88 Toll/IL-1 receptor (TIR) domain.
• the amount of the irreversible Btk inhibitor is from 420 mg/day up to, and including, 840 mg/day. In some embodiments, the amount of the irreversible Btk inhibitor is about 420 mg/day, about 560 mg/day, or about 840 mg/day. In some embodiments, the amount of the irreversible Btk inhibitor is about 420 mg/day.
• the AUCo-24 of the Btk inhibitor is between about 150 and about 3500 ng*h/mL. In some embodiments, the AUCo-24 of the Btk inhibitor is between about 500 and about 1100 ng*h/mL. In some embodiments, the irreversible Btk inhibitor is administered orally. In some embodiments, the irreversible Btk inhibitor is administered daily until disease progression, unacceptable toxicity, or individual choice. In some embodiments, the irreversible Btk inhibitor is administered every other day until disease progression, unacceptable toxicity, or individual choice. In some embodiments, the irreversible Btk inhibitor is a front line therapy, second line therapy, third line therapy, fourth line therapy, fifth line therapy, or sixth line therapy.
• the irreversible Btk inhibitor treats a refractory hematological malignancy. In some embodiments, the irreversible Btk inhibitor is a maintenance therapy. In some embodiments, the method further comprises administering at least one additional cancer treatment regimen. In some embodiments, the additional cancer treatment regimen comprises a chemotherapeutic agent, an immunotherapeutic agent, a steroid, radiation therapy, a targeted therapy, or a combination thereof. In some embodiments, the second cancer treatment regimen comprises an antibody, B cell receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor, an mTOR inhibitor, a
• radioimmunotherapeutic is a damaging agent, a proteosome inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, an Hsp90 inhibitor, a telomerase inhibitor, a Jakl/2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a combination thereof.
• a method of determining a cancer treatment regimen for an individual with a hematological malignancy comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; (b) analyzing the mobilized plurality of cells; and (c) selecting a cancer treatment regimen.
• the cancer treatment regimen comprises a
• the second cancer treatment regimen comprises a B cell receptor pathway inhibitor.
• the B cell receptor pathway inhibitor is a CD79A inhibitor, a CD79B inhibitor, a CD 19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K inhibitor, a Blnk inhibitor, a PLCy inhibitor, a PKCP inhibitor, or a combination thereof.
• the cancer treatment regimen comprises a B cell receptor pathway inhibitor.
• the cancer treatment regimen comprises a CD79A inhibitor, a CD79B inhibitor, a CD 19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K inhibitor, a Blnk inhibitor, a PLCy inhibitor, a PKCP inhibitor, or a combination thereof.
• the cancer treatment regimen comprises an antibody, B cell receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor, an mTOR inhibitor, a radioimmunotherapeutic, a DNA damaging agent, a proteosome inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, an Hsp90 inhibitor, a telomerase inhibitor, a Jakl/2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a combination thereof.
• the cancer treatment regimen comprises chlorambucil, ifosphamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.
• the cancer treatment regimen comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally, rituximab.
• the cancer treatment regimen comprises bendamustine, and rituximab.
• the cancer treatment regimen comprises fludarabine, cyclophosphamide, and rituximab.
• the cancer treatment regimen comprises cyclophosphamide, vincristine, and prednisone, and optionally, rituximab.
• the cancer treatment regimen comprises etoposide, doxorubicin, vinristine, cyclophosphamide, prednisolone, and optionally, rituximab. In some embodiments, the cancer treatment regimen comprises dexamethasone and lenalidomide.
• Fig. 1 depicts the role of Btk activity in a number of processes in a CLL cell that contribute to the pathogenesis of the disease
• Fig. 2 presents the absolute lyphocyte count during the course of treatment with an irreversible Btk inhibitor for an individual with CLL.
• Fig. 3 presents change in the sum of the product of the diameters of lymph node
• Fig. 4 depicts LN response in patient suffering from CLL.
• Left panel depicts LN prior to treatment with an irreversible Btk inhibitor and
• Right panel depicts LN post-treatment with an irreversible Btk inhibitor.
• Fig. 5 depicts the effect of an irreversible Btk inhibitor on LN disease burden and lymphocytosis over time in the patients suffering with CLL and/or SLL.
• Fig. 6 depicts adverse effects in patients treated with an irreversible Btk inhibitor.
• Grades 1 -4 represent severity of effects with 1 representing very mild to 4 representing extreme discomfort.
• Fig. 7 depicts the absolute lymphocyte count (ALC)/109 L vs. Cycle Day after administering a Btk inhibitor to individuals with follicular lymphoma who achieved complete or partial response (CR/PR).
• the Y Axis shows the Absolute Lymphocyte Counts (ALC) at each time point by cycle number and day in the X axis. All Patients (except Pt 32009) were treated on schedule of 4 weeks on treatment followed by one week off. Thus, dayl of each cycle follows one week off drug for these patients. Note the increases of ALC during most cycles of most patients, and the fall of ALC at the beginning of subsequent cycles. This pattern is often blunted in later cycles as patients responded to treatment. Patient 32009 received treatment without interruption and did not show this cyclic pattern, but did show an increase at Cycle 1, dayl 5, and gradual increases during Cycles 2 to 5.
• Fig. 8 depicts the absolute lymphocyte count (ALC)/109 L vs. Cycle Day after administering a Btk inhibitor to individuals with follicular lymphoma who had Stable Disease (SD) during treatment.
• the Y Axis shows the Absolute Lymphocyte Counts (ALC) at each time point by cycle number and day in the X axis. All Patients were treated on schedule of 4 weeks on treatment followed by one week off. Thus, dayl of each cycle follows one week off drug for these patients. Note the gradual increase of blood ALC mobilization of Patient 32004, who initially was stable but later had Progressive Disease (PD).
• ALC Absolute Lymphocyte Count
• Fig. 9 depicts the absolute lymphocyte count (ALC)/109 L vs. Cycle Day after administering a Btk inhibitor to PD individuals with follicular lymphoma.
• the Y Axis shows the Absolute Lymphocyte Counts (ALC) at each time point by cycle number and day in the X axis.
• All Patients except 38010 were treated on schedule of 4 weeks on treatment followed by one week off. Thus, dayl of each cycle follows one week off drug for these patients. Note lack of mobilization, especially patients 38010 and 32001.
• Patient 323001 had limited treatment before being taken off study. The lymphocyte response suggests that this patient might had responded if it had been possible to stay on treatment longer.
• Fig. 10 depicts the absolute lymphocyte count (ALC)/109 L vs. Cycle Day after administering a Btk inhibitor to PR and SD individuals with DLBCL.
• the Y Axis shows the Absolute Lymphocyte Counts (ALC) at each time point by cycle number and day in the X axis.
• Patient 38011 was treated on schedule of 4 weeks on treatment followed by one week off. Thus, dayl of each cycle follows one week off drug for this patient.
• Patients 38008 and 324001 were treated with continuous daily doses.
• Fig. 11 depicts the absolute lymphocyte count (ALC)/109 L vs. Cycle Day after administering a Btk inhibitor to PD individuals with DLBCL.
• the Y Axis shows the Absolute Lymphocyte Counts (ALC) at each time point by cycle number and day in the X axis. All Patients were treated on schedule of 4 weeks on treatment followed by one week off. Thus, dayl of each cycle follows one week off drug for these patients. Note lack of mobilization for 3 of the 4 patients. Patient 32002 received only one cycle of treatment.
• Fig. 12 depicts the absolute lymphocyte count (ALC)/109 L vs. Cycle Day after administering a Btk inhibitor to individuals with mantle cell lymphoma.
• the Y Axis shows the Absolute Lymphocyte Counts (ALC) at each time point by cycle number and day in the X axis.
• Patients 32006, 38003, and 38004 were treated on schedule of 4 weeks on treatment followed by one week off. Thus, dayl of each cycle follows one week off drug for these patients. The other patients were treated with continuous daily dosing. Note that the patient with initial PD (32014) failed to show mobilization.
• Fig. 13 depicts the absolute lymphocyte count (ALC)/109 L vs. Cycle Day for after administering a Btk inhibitor to the individuals with mantle cell lymphoma shown in Figure 12.
• the axis has been changed, as compared to Fig. 12, to demonstrate low amplitude fluctuations. Note that all responding patients showed some degree of mobilization.
• Fig. 14 demonstrates that lymphocyte mobilization, specifically B Cell type, consistent with lymphoma cells, decreases as disease responds.
• Patient 32007, Cohort 4 had follicular lymphoma, grade 3, which gradually regressed from SD to CR.
• the changes of ALC in this case are not dramatic, the B cell fraction is undergoing characteristic cyclic increases in response to treatment with a Btk inhibitor.
• Fig. 15 demonstrates that there is increased B Cell mobilization with disease progression.
• Patient 32004, Cohort 2 had follicular lymphoma, grade 1, which progressed from SD initially to PD following Cycle 6.
• Fig. 16 depicts early mobilization and eventual decrease of a CD45 DIM B cell subpopulation in responding mantle cell lymphoma patient 200-005.
• This subpopulation has a typical MCL immunophenotype (CD45 DIM ) and is different than that of normal lymphocytes.
• Fig. 17 depicts abnormal high light scatter CD19 + cells mobilizing and then regressing in CR DLBCL Pt 324001. These CD45 + cells with light scatter (SSC-H) in the upper panels were gated upon and their CD3 vs CD 19 staining displayed in the lower panels. Here the putative malignant cells were "hidden" in the large MNC window normally defining monocytes.
• Figure 18 presents the responses for a clinical trial involving administering a Btk inhibitor to elderly patients with CLL or SLL, who are naive for drug intervention. Individuals were administered 420 mg/day of a Btk inhibitor.
• Figure 19 presents the responses for a clinical trial involving administering a Btk inhibitor to R/R patients with CLL or SLL. Individuals were administered 420 mg/day of a Btk inhibitor.
• Figure 20 presents the responses for a clinical trial involving administering a Btk inhibitor to individuals with high risk CLL.
• Figure 21 presents the response over time for a clinical trial involving
• Figure 22 presents the best responses for all patients in a clinical trial involving administering a Btk inhibitor to individuals with CLL or SLL.
• Figure 23 presents the best responses for abstract patients in a clinical trial involving administering a Btk inhibitor to individuals with CLL or SLL.
• Figure 24 presents the best response by prognostic factor in CLL or SLL patients involved in a clinical trial involving administering a Btk inhibitor.
• Figure 25 presents initial (Cycle 2) response assessment and best response
• Figure 26 presents initial (Cycle 2) response assessment by dose in
• Figure 27 presents improvements in hematological parameters in CLL or SLL patients involved in a clinical trial involving administering a Btk inhibitor.
• Figure 28 present data showing the results of a combination of a Btk inhibitor and
• Figure 29 present data showing the results of a combination of a Btk inhibitor and
• Figure 30 present data showing the results of a combination of a Btk inhibitor and
• Temsirolimus or R406 in DoHH2 cells Temsirolimus or R406 in DoHH2 cells.
• Figure 31 present data showing the results of a combination of a Btk inhibitor and Gemcitabine or Doxorubicin in DoHH2 cells.
• Figure 32 present data showing the results of a combination of a Btk inhibitor and
• Figure 33 present data showing the results of a combination of a Btk inhibitor and
• Figure 34 present data showing the results of a combination of a Btk inhibitor and vincristine in TMD8 cells.
• Figure 35 present data showing the results of a combination of a Btk inhibitor and doxorubicin in TMD8 cells.
• Figure 36 present data showing the results of a combination of a Btk inhibitor and lenolidomide in TMD8 cells.
• Figure 37 present data showing the results of a combination of a Btk inhibitor and velcade in TMD8 cells.
• Figure 38 present data showing the results of a combination of a Btk inhibitor and
• Figure 39 present data showing the results of a combination of a Btk inhibitor and taxol in TMD8 cells.
• a method for treating a hematological malignancy in an individual in need thereof comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• a method for treating diffuse large B-cell lymphoma, activated B cell-like subtype (ABC-DLBCL), in an individual in need thereof comprising: administering to the individual an irreversible Btk inhibitor in an amount from 300 mg/day up to, and including, 1000 mg/day.
• a method for treating relapsed or refractory non-Hodgkin's lymphoma in an individual in need thereof comprising:
• Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection).
• Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein.
• the foregoing techniques and procedures can be generally performed of conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification.
• alkyl refers to an aliphatic hydrocarbon group.
• the alkyl moiety may be a "saturated alkyl” group, which means that it does not contain any alkene or alkyne moieties.
• the alkyl moiety may also be an "unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety.
• An "alkene” moiety refers to a group that has at least one carbon- carbon double bond
• an “alkyne” moiety refers to a group that has at least one carbon- carbon triple bond.
• the alkyl moiety, whether saturated or unsaturated may be branched, straight chain, or cyclic. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group). The alkyl group could also be a "lower alkyl” having 1 to 6 carbon atoms.
• Ci-C x includes Ci-C 2 , C 1 -C3 . . Ci-C x .
• the "alkyl” moiety may have 1 to 10 carbon atoms (whenever it appears herein, a numerical range such as “1 to 10" refers to each integer in the given range; e.g., "1 to 10 carbon atoms” means that the alkyl group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
• the alkyl group of the compounds described herein may be designated as "C 1 -C 4 alkyl" or similar designations.
• C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, and t-butyl.
• C 1 -C 4 alkyl includes Ci-C 2 alkyl and Ci-C 3 alkyl.
• Alkyl groups can be substituted or unsubstituted.
• Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
• non-cyclic alkyl refers to an alkyl that is not cyclic (i.e., a straight or branched chain containing at least one carbon atom).
• Non-cyclic alkyls can be fully saturated or can contain non-cyclic alkenes and/or alkynes.
• Non-cyclic alkyls can be optionally substituted.
• the alkenyl moiety may be branched, straight chain, or cyclic (in which case, it would also be known as a "cycloalkenyl” group).
• an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group).
• Alkenyl groups can be optionally substituted.
• Alkenyl groups could have 2 to 10 carbons.
• the alkenyl group could also be a "lower alkenyl" having 2 to 6 carbon atoms.
• alkynyl refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, an alkynyl group begins with the atoms -C ⁇ C-R, wherein R refers to the remaining portions of the alkynyl group, which may be the same or different.
• R refers to the remaining portions of the alkynyl group, which may be the same or different.
• the "R" portion of the alkynyl moiety may be branched, straight chain, or cyclic.
• an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).
• Alkynyl groups can be optionally substituted.
• Non-limiting examples of an alkynyl group include, but are not limited to, -C ⁇ CH, -C ⁇ CCH 3 , -C ⁇ CCH 2 CH 3 , -C ⁇ C-, and - C ⁇ CCH 2 -.
• Alkynyl groups can have 2 to 10 carbons.
• the alkynyl group could also be a "lower alkynyl" having 2 to 6 carbon atoms.
• alkoxy refers to a (alkyl)O- group, where alkyl is as defined herein.
• Hydroxyalkyl refers to an alkyl radical, as defined herein, substituted with at least one hydroxy group.
• Non-limiting examples of a hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)- 2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl,
• Alkoxyalkyl refers to an alkyl radical, as defined herein, substituted with an alkoxy group, as defined herein.
• alkenyloxy refers to a (alkenyl)O- group, where alkenyl is as defined herein.
• x 2
• the alkyl groups, taken together with the N atom to which they are attached, can optionally form a cyclic ring system.
• Alkylaminoalkyl refers to an alkyl radical, as defined herein, substituted with an alkylamine, as defined herein.
• An "amide” is a chemical moiety with the formula -C(0)NHR or -NHC(0)R, where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
• An amide moiety may form a linkage between an amino acid or a peptide molecule and a compound described herein, thereby forming a prodrug. Any amine, or carboxyl side chain on the compounds described herein can be amidified.
• esters refers to a chemical moiety with formula -COOR, where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and
• Rings refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non- aromatic heterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings can be optionally substituted. Rings can be monocyclic or polycyclic.
• ring system refers to one, or more than one ring.
• membered ring can embrace any cyclic structure.
• membered is meant to denote the number of skeletal atoms that constitute the ring.
• cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, and thiophene are 5-membered rings.
• fused refers to structures in which two or more rings share one or more bonds.
• Carbocyclic or “carbocycle” refers to a ring wherein each of the atoms forming the ring is a carbon atom.
• Carbocycle includes aryl and cycloalkyl. The term thus distinguishes carbocycle from heterocycle ("heterocyclic") in which the ring backbone contains at least one atom which is different from carbon (i.e a heteroatom).
• Heterocycle includes heteroaryl and heterocycloalkyl. Carbocycles and heterocycles can be optionally substituted.
• aromatic refers to a planar ring having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted.
• aromatic includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “hetero aromatic") groups (e.g., pyridine).
• the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
• aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
• Aryl rings can be formed by five, six, seven, eight, nine, or more than nine carbon atoms.
• Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl.
• an aryl group can be a monoradical or a diradical (i.e., an arylene group).
• aryloxy refers to an (aryl)O- group, where aryl is as defined herein.
• Aralkyl means an alkyl radical, as defined herein, substituted with an aryl group.
• Non- limiting aralkyl groups include, benzyl, phenethyl, and the like.
• alkenyl means an alkenyl radical, as defined herein, substituted with an aryl group, as defined herein.
• cycloalkyl refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, partially unsaturated, or fully unsaturated.
• Cycloalkyl groups include groups having from 3 to 10 ring atoms.
• Illustrative examples of cycloalkyl groups include the following moieties:
• a cycloalkyl group can be a monoradical or a diradical (e.g., an cycloalkylene group).
• the cycloalkyl group could also be a "lower cycloalkyl" having 3 to 8 carbon atoms.
• Cycloalkylalkyl means an alkyl radical, as defined herein, substituted with a cycloalkyl group.
• Non- limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
• heterocycle refers to heteroaromatic and heteroalicyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4 to 10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
• a heterocycle e.g., Ci-C 6 heterocycle
• the heteroatom must be present in the ring.
• Designations such as "Ci-C 6 heterocycle” refer only to the number of carbon atoms in the ring and do not refer to the total number of atoms in the ring.
• heterocylic ring can have additional heteroatoms in the ring.
• Designations such as "4-6 membered heterocycle” refer to the total number of atoms that are contained in the ring (i.e., a four, five, or six membered ring, in which at least one atom is a carbon atom, at least one atom is a heteroatom and the remaining two to four atoms are either carbon atoms or heteroatoms).
• 4-6 membered heterocycle refer to the total number of atoms that are contained in the ring (i.e., a four, five, or six membered ring, in which at least one atom is a carbon atom, at least one atom is a heteroatom and the remaining two to four atoms are either carbon atoms or heteroatoms).
• heterocycles that have two or more heteroatoms those two or more
• heteroatoms can be the same or different from one another.
• Heterocycles can be optionally substituted. Binding to a heterocycle can be at a heteroatom or via a carbon atom.
• Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
• the heterocyclic groups include benzo-fused ring systems.
• An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine).
• An example of a 5-membered heterocyclic group is thiazolyl.
• An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl.
• Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolin
• aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
• a group derived from pyrrole may be pyrrol-l-yl (N-attached) or pyrrol-3-yl (C- attached).
• a group derived from imidazole may be imidazol-l-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
• a heterocycle group can be a monoradical or a diradical (i.e., a heterocyclene group).
• heteroaryl or, alternatively, “hetero aromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
• An N- containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
• heteroaryl groups include the following moieties:
• a heteroaryl group can be a monoradical or a diradical (i.e., a heteroarylene group).
• non-aromatic heterocycle As used herein, the term "non-aromatic heterocycle”, “heterocycloalkyl” or
• hetero alicyclic refers to a non-aromatic ring wherein one or more atoms forming the ring is a heteroatom.
• a “non-aromatic heterocycle” or “heterocycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl. Heterocycloalkyl rings can be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heterocycloalkyl rings can be optionally substituted.
• non-aromatic heterocycles contain one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups.
• heterocycloalkyls include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4- oxathiin, 1 ,4-oxathiane, tetrahydro-l,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-l,3,5-triazine, tetrahydrothio
• heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
• a heterocycloalkyl group can be a monoradical or a diradical (i.e., a
• halo or, alternatively, "halogen” or “halide” means fluoro, chloro, bromo and iodo.
• haloalkyl include alkyl, alkenyl, alkynyl and alkoxy structures in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another. In other embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as one another.
• fluoroalkyl refers to alkyl group in which at least one hydrogen is replaced with a fluorine atom.
• fluoroalkyl groups include, but are not limited to, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -CH 2 CH 2 CF 3 and the like.
• heteroalkyl “heteroalkenyl” and “heteroalkynyl” include optionally substituted alkyl, alkenyl and alkynyl radicals in which one or more skeletal chain atoms is a heteroatom, e.g., oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof.
• the heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the heteroalkyl group is attached to the remainder of the molecule.
• up to two heteroatoms may be consecutive, such as, by way of example, -CH 2 -NH-
• heteroatom refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from among oxygen, sulfur, nitrogen, silicon and phosphorus, but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms can all be the same as one another, or some or all of the two or more heteroatoms can each be different from the others.
• bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
• An "isocyanato" group refers to a -NCO group.
• An "isothiocyanato" group refers to a -NCS group.
• moiety refers to a specific segment or functional group of a molecule.
• Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
• a "thioalkoxy” or “alkylthio” group refers to a -S-alkyl group.
• alkylthioalkyl refers to an alkyl group substituted with a -S-alkyl group.
• Carboxy means a -C(0)OH radical.
• cyano refers to a group of formula -CN.
• Cyanoalkyl means an alkyl radical, as defined herein, substituted with at least one cyano group.
• O-carbamyl refers to a group of formula -
• N-carbamyl refers to a group of formula
• O-thiocarbamyl refers to a group of formula -
• N-thiocarbamyl refers to a group of formula
• Aminocarbonyl refers to a -CONH2 radical.
• substituent "R” appearing by itself and without a number designation refers to a substituent selected from among from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon).
• the term "optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, acyl, nitro, haloalkyl, fluoroalkyl, amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
• Michael acceptor moiety refers to a functional group that can participate in a Michael reaction, wherein a new covalent bond is formed between a portion of the Michael acceptor moiety and the donor moiety.
• the Michael acceptor moiety is an electrophile and the "donor moiety” is a nucleophile.
• nucleophile refers to an electron rich compound, or moiety thereof.
• An example of a nucleophile includes, but in no way is limted to, a cysteine residue of a molecule, such as, for example Cys 481 of Btk.
• electrophile refers to an electron poor or electron deficient molecule, or moiety thereof. Examples of electrophiles include, but in no way are limited to, Micheal acceptor moieties.
• BCLD B-cell lymphoproliferative disorders
• Tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
• Neoplastic refers to any form of dysregulated or unregulated cell growth, whether malignant or benign, resulting in abnormal tissue growth.
• neoplastic cells include malignant and benign cells having dysregulated or unregulated cell growth.
• cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
• examples of cancer include, but are not limited to, B-cell lymphoproliferative disorders (BCLDs), such as lymphoma and leukemia, and solid tumors.
• B cell-related cancer or “cancer of B-cell lineage” is intended any type of cancer in which the dysregulated or unregulated cell growth is associated with B cells.
• refractory in the context of a cancer is intended the particular cancer is resistant to, or non-responsive to, therapy with a particular therapeutic agent.
• a cancer can be refractory to therapy with a particular therapeutic agent either from the onset of treatment with the particular therapeutic agent (i.e., non-responsive to initial exposure to the therapeutic agent), or as a result of developing resistance to the therapeutic agent, either over the course of a first treatment period with the therapeutic agent or during a subsequent treatment period with the therapeutic agent.
• agonist activity is intended that a substance functions as an agonist.
• An agonist combines with a receptor on a cell and initiates a reaction or activity that is similar to or the same as that initiated by the receptor's natural ligand.
• antagonist activity is intended that the substance functions as an antagonist.
• An antagonist of Btk prevents or reduces induction of any of the responses meidated by Btk.
• significant an agonist activity of at least 30%
• "significant" agonist activity is an agonist activity that is at least 2-fold greater or at least 3 -fold greater than the agonist activity induced by a neutral substance or negative control as measured in an assay of a B cell response.
• "significant" agonist activity would be induction of a level of B cell proliferation that is at least 2-fold greater or at least 3-fold greater than the level of B cell proliferation induced by a neutral substance or negative control.
• a substance "free of significant agonist activity” would exhibit an agonist activity of not more than about 25% greater than the agonist activity induced by a neutral substance or negative control, preferably not more than about 20% greater, 15% greater, 10% greater, 5% greater, 1% greater, 0.5% greater, or even not more than about 0.1% greater than the agonist activity induced by a neutral substance or negative control as measured in an assay of a B cell response.
• the Btk inhibitor therapeutic agent is an antagonist anti-
• Btk antibody Such antibodies are free of significant agonist activity as noted above when bound to a Btk antigen in a human cell.
• the antagonist anti-Btk antibody is free of significant agonist activity in one cellular response.
• the antagonist anti-Btk antibody is free of significant agonist activity in assays of more than one cellular response (e.g., proliferation and differentiation, or proliferation, differentiation, and, for B cells, antibody production).
• Btk-mediated signaling it is intended any of the biological activities that are dependent on, either directly or indirection, the activity of Btk.
• Btk-mediated signaling are signals that lead to proliferation and survival of Btk-expressing cells, and stimulation of one or more Btk- signaling pathways within Btk-expressing cells.
• a Btk "signaling pathway” or “signal transduction pathway” is intended to mean at least one biochemical reaction, or a group of biochemical reactions, that results from the activity of Btk, and which generates a signal that, when transmitted through the signal pathway, leads to activation of one or more downstream molecules in the signaling cascade.
• Signal transduction pathways involve a number of signal transduction molecules that lead to
• Btk signal transduction pathways which ultimately regulate (either enahnce or inhibit) the activation of NF-KB via the NF- ⁇ signaling pathway.
• the methods of the present invention are directed to methods for treating cancer that, in certain embodiments, utilize antibodies for determining the expression or presence of certain BCLD biomarkers in these methods.
• the following terms and definitions apply to such antibodies.
• Antibodies and "immunoglobulins” are glycoproteins having the same structural characteristics. The terms are used synonymously. In some instances the antigen specificity of the immunoglobulin may be known.
• antibody is used in the broadest sense and covers fully assembled antibodies, antibody fragments that can bind antigen (e.g., Fab, F(ab') 2 , Fv, single chain antibodies, diabodies, antibody chimeras, hybrid antibodies, bispecific antibodies, humanized antibodies, and the like), and recombinant peptides comprising the forgoing.
• antigen e.g., Fab, F(ab') 2 , Fv, single chain antibodies, diabodies, antibody chimeras, hybrid antibodies, bispecific antibodies, humanized antibodies, and the like
• recombinant peptides comprising the forgoing.
• the terms "monoclonal antibody” and "mAb” as used herein refer to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts.
• Native antibodies and "native immunoglobulins" are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (V R ) followed by a number of constant domains.
• V R variable domain
• Each light chain has a variable domain at one end (V L ) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light and heavy-chain variable domains.
• variable refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies. Variable regions confer antigen-binding specificity. However, the variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in three segments called complementarity determining regions (CDRs) or hypervariable regions, both in the light chain and the heavy-chain variable domains. The more highly conserved portions of variable domains are celled in the framework (FR) regions.
• CDRs complementarity determining regions
• FR framework
• the variable domains of native heavy and light chains each comprise four FR regions, largely adopting a ⁇ -pleated-sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the ⁇ -pleated-sheet structure.
• the CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, Kabat et al. (1991) NIH PubL. No. 91-3242, Vol. I, pages 647-669).
• the constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as Fc receptor (FcR) binding, participation of the antibody in antibody-dependent cellular toxicity, initiation of complement dependent cytotoxicity, and mast cell degranulation.
• FcR Fc receptor
• hypervariable region refers to the amino acid residues of an antibody that are responsible for antigen-binding.
• the hypervariable region comprises amino acid residues from a "complementarily determining region” or "CDR" (i.e., residues 24-34 (LI), 50-56 (L2), and 89-97 (L3) in the light-chain variable domain and 31-35 (HI), 50-65 (H2), and 95-102 (H3) in the heavy-chain variable domain; Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed.
• CDR complementarily determining region
• Antibody fragments comprise a portion of an intact antibody, preferably the antigen-binding or variable region of the intact antibody.
• antibody fragments include Fab, Fab, F(ab')2, and Fv fragments; diabodies; linear antibodies (Zapata et al. (1995) Protein Eng. 10: 1057-1062); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
• Papain digestion of antibodies produces two identical antigen- binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual "Fc” fragment, whose name reflects its ability to crystallize readily.
• Pepsin treatment yields an F(ab')2 fragment that has two antigen-combining sites and is still capable of cross- linking antigen.
• Fv is the minimum antibody fragment that contains a complete antigen recognition and binding site. This region consists of a dimer of one heavy- and one light-chain variable domain in tight, non-covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the V R -V L dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
• the Fab fragment also contains the constant domain of the light chain and the first constant domain (C H I) of the heavy chain.
• Fab fragments differ from Fab' fragments by the addition of a few residues at the carboxy terminus of the heavy chain C H I domain including one or more cysteines from the antibody hinge region.
• Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group.
• Fab' fragments are produced by reducing the F(ab')2 fragment's heavy chain disulfide bridge. Other chemical couplings of antibody fragments are also known.
• the "light chains" of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa ( ⁇ ) and lambda ( ⁇ ), based on the amino acid sequences of their constant domains.
• immunoglobulins can be assigned to different classes. There are five major classes of human immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.
• the heavy- chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively.
• the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known. Different isotypes have different effector functions. For example, human IgGl and IgG3 isotypes have ADCC (antibody dependent cell-mediated cytotoxicity) activity.
• ADCC antibody dependent cell-mediated cytotoxicity
• label when used herein refers to a detectable compound or composition that is conjugated directly or indirectly to the antibody so as to generate a "labeled" antibody.
• the label may be detectable by itself (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition that is detectable.
• agonist refers to a compound, the presence of which results in a biological activity of a protein that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the protein, such as, for example, Btk.
• partial agonist refers to a compound the presence of which results in a biological activity of a protein that is of the same type as that resulting from the presence of a naturally occurring ligand for the protein, but of a lower magnitude.
• the term "antagonist” refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of a protein.
• the presence of an antagonist results in complete inhibition of a biological activity of a protein, such as, for example, Btk.
• an antagonist is an inhibitor.
• Bruton's tyrosine kinase (Btk), refers to Bruton's tyrosine kinase from Homo sapiens, as disclosed in, e.g., U.S. Patent No. 6,326,469 (GenBank Accession No. NP_000052).
• Bruton's tyrosine kinase homolog refers to orthologs of Bruton's tyrosine kinase, e.g., the orthologs from mouse (GenBank Accession No.
• NP 001007799 chicken (GenBank Accession No. NP 989564), or zebra fish (GenBank Accession No. XP 6981 17), and fusion proteins of any of the foregoing that exhibit kinase activity towards one or more substrates of Bruton's tyrosine kinase (e.g. a peptide substrate having the amino acid sequence "AVLESEEELYSSARQ").
• co -administration or “combination therapy” and the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
• an "effective amount" for diagnostic and/or prognostic uses is the amount of the composition including a compound as disclosed herein required to provide a clinically significant decrease an increase or appearance in the blood of a subpopulation of lymphocytes without undue adverse side effects.
• An appropriate "effective amount” in any individual case may be determined using techniques, such as a dose escalation study.
• terapéuticaally effective amount refers to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms s B-cell lymphoproliferative disorder (BCLD). The result can be reduction and/or alleviation of the signs, symptoms, or causes of BCLD, or any other desired alteration of a biological system.
• therapeutically effective amount includes, for example, a prophylactically effective amount.
• An "effective amount" of a compound disclosed herein is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects.
• an effect amount or "a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of the compound of any of Formula (A), Formula (B), Formula (C), or Formula (D), age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.
• therapeutically effective amounts may be determined by routine experimentation, including but not limited to a dose escalation clinical trial.
• the terms “enhance” or “enhancing” means to increase or prolong either in potency or duration a desired effect.
• “enhancing” the effect of therapeutic agents refers to the ability to increase or prolong, either in potency or duration, the effect of therapeutic agents on during treatment of a disease, disorder or condition.
• An “enhancing- effective amount,” as used herein, refers to an amount adequate to enhance the effect of a therapeutic agent in the treatment of a disease, disorder or condition. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
• cysteine 482 is the homologous cysteine of the rat ortholog of Bruton's tyrosine kinase
• cysteine 479 is the homologous cysteine of the chicken ortholog
• cysteine 481 is the homologous cysteine in the zebra fish ortholog.
• the homologous cysteine of TXK is Cys 350. See also the sequence alignments of tyrosine kinases (TK) published on the world wide web at kinase.com/human/kinome/phylogeny.html.
• TK tyrosine kinases
• substantially identical refers to two or more sequences which have a percentage of sequential units which are the same when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using comparison algorithms or by manual alignment and visual inspection.
• two or more sequences may be “substantially identical” if the sequential units are about 60% identical, about 65% identical, about 70%> identical, about 75%o identical, about 80%> identical, about 85% identical, about 90%> identical, or about 95% identical over a specified region. Such percentages to describe the "percent identity" of two or more sequences.
• the identity of a sequence can exist over a region that is at least about 75-100 sequential units in length, over a region that is about 50 sequential units in length, or, where not specified, across the entire sequence.
• This definition also refers to the complement of a test sequence.
• two or more polypeptide sequences are identical when the amino acid residues are the same, while two or more polypeptide sequences are "substantially identical" if the amino acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80%> identical, about 85% identical, about 90% identical, or about 95% identical over a specified region.
• the identity can exist over a region that is at least about 75-100 amino acids in length, over a region that is about 50 amino acids in length, or, where not specified, across the entire sequence of a polypeptide sequence.
• two or more polynucleotide sequences are identical when the nucleic acid residues are the same, while two or more polynucleotide sequences are "substantially identical" if the nucleic acid residues are about 60% identical, about 65% identical, about 70% identical, about 75%) identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a specified region.
• the identity can exist over a region that is at least about 75-100 nucleic acids in length, over a region that is about 50 nucleic acids in length, or, where not specified, across the entire sequence of a polynucleotide sequence.
• inhibitors refer to inhibition of enzymatic phosphotransferase activity.
• the term "irreversible inhibitor,” as used herein, refers to a compound that, upon contact with a target protein (e.g., a kinase) causes the formation of a new covalent bond with or within the protein, whereby one or more of the target protein's biological activities (e.g., phosphotransferase activity) is diminished or abolished notwithstanding the subsequent presence or absence of the irreversible inhibitor.
• a target protein e.g., a kinase
• biological activities e.g., phosphotransferase activity
• the irreversible inhibitor of Btk can form a covalent bond with a Cys residue of Btk; in particular embodiments, the irreversible inhibitor can form a covalent bond with a Cys 481 residue (or a homolog thereof) of Btk or a cysteine residue in the homologous corresponding position of another tyrosine kinase.
• isolated refers to separating and removing a component of interest from components not of interest. Isolated substances can be in either a dry or semi-dry state, or in solution, including but not limited to an aqueous solution.
• the isolated component can be in a homogeneous state or the isolated component can be a part of a pharmaceutical composition that comprises additional pharmaceutically acceptable carriers and/or excipients.
• nucleic acids or proteins are “isolated” when such nucleic acids or proteins are free of at least some of the cellular components with which it is associated in the natural state, or that the nucleic acid or protein has been concentrated to a level greater than the concentration of its in vivo or in vitro production.
• a gene is isolated when separated from open reading frames which flank the gene and encode a protein other than the gene of interest.
• a "metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
• active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
• metabolism refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes, such as, oxidation reactions) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
• cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyl transferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. Both methods are well known in the art. In some embodiments, metabolites of a compound are formed by oxidative processes and correspond to the corresponding hydroxy-containing compound. In some embodiments, a compound is metabolized to pharmacologically active metabolites.
• module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
• a modulator refers to a compound that alters an activity of a molecule.
• a modulator can cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator.
• a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule.
• an inhibitor completely prevents one or more activities of a molecule.
• a modulator is an activator, which increases the magnitude of at least one activity of a molecule.
• the presence of a modulator results in an activity that does not occur in the absence of the modulator.
• selective binding compound refers to a compound that selectively binds to any portion of one or more target proteins.
• selective binds refers to the ability of a selective binding compound to bind to a target protein, such as, for example, Btk, with greater affinity than it binds to a non-target protein.
• specific binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, 1000 or more times greater than the affinity for a non-target.
• selective modulator refers to a compound that selectively modulates a target activity relative to a non-target activity.
• specific modulator refers to modulating a target activity at least 10, 50, 100, 250, 500, 1000 times more than a non-target activity.
• substantially purified refers to a component of interest that may be substantially or essentially free of other components which normally accompany or interact with the component of interest prior to purification.
• a component of interest may be “substantially purified” when the preparation of the component of interest contains less than about 30%, less than about 25%, less than about 20%>, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%), less than about 2%, or less than about 1% (by dry weight) of contaminating components.
• a “substantially purified” component of interest may have a purity level of about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%o, about 99% or greater.
• subject refers to an animal which is the object of treatment, observation or experiment.
• a subject may be, but is not limited to, a mammal including, but not limited to, a human.
• target activity refers to a biological activity capable of being modulated by a selective modulator.
• Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, effects on particular biomarkers related to B-cell lymphoproliferative disorder pathology.
• target protein refers to a molecule or a portion of a protein capable of being bound by a selective binding compound.
• a target protein is Btk.
• treat include alleviating, abating or ameliorating a disease or condition, or symptoms thereof; managing a disease or condition, or symptoms thereof; preventing additional symptoms; ameliorating or preventing the underlying metabolic causes of symptoms; inhibiting the disease or condition, e.g., arresting the development of the disease or condition; relieving the disease or condition; causing regression of the disease or condition, relieving a condition caused by the disease or condition; or stopping the symptoms of the disease or condition.
• the terms “treat,” “treating” or “treatment” include, but are not limited to, prophylactic and/or therapeutic treatments.
• the IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as inhibition of Btk, in an assay that measures such response.
• EC50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50%> of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
• hematological malignancy in an individual in need thereof, comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• the hematological malignancy is CLL.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the
• administering the second cancer treatment regimen occurs after a subsequent decrease in peripheral blood concentration of the mobilized plurality of cells.
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the concentration before administration of the Btk inhibitor.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a predetermined length of time.
• analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood. In some embodiments, the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in the number of mobilized plurality of cells in the peripheral blood. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before administration of the Btk inhibitor.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• the hematological malignancy is a chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma.
• the hematological malignancy is follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Waldenstrom's macro globulinemia, multiple myeloma, marginal zone lymphoma, Burkitt's lymphoma, non- Burkitt high grade B cell lymphoma, or extranodal marginal zone B cell lymphoma.
• the hematological malignancy is acute or chronic myelogenous (or myeloid) leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia.
• the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, relapsed or refractory follicular lymphoma, relapsed or refractory CLL; relapsed or refractory SLL; relapsed or refractory multiple myeloma.
• the hematological malignancy is a hematological malignancy that is classified as high-risk.
• the hematological malignancy is high risk CLL or high risk SLL.
• BCLDs B-cell lymphoproliferative disorders
• BCLDs can originate either in the lymphatic tissues (as in the case of lymphoma) or in the bone marrow (as in the case of leukemia and myeloma), and they all are involved with the uncontrolled growth of lymphocytes or white blood cells.
• There are many subtypes of BCLD e.g., chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).
• CLL chronic lymphocytic leukemia
• NHL non-Hodgkin lymphoma
• Malignant lymphomas are neoplastic transformations of cells that reside predominantly within lymphoid tissues.
• Two groups of malignant lymphomas are Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL). Both types of lymphomas infiltrate reticuloendothelial tissues. However, they differ in the neoplastic cell of origin, site of disease, presence of systemic symptoms, and response to treatment (Freedman et al., "Non-Hodgkin's Lymphomas" Chapter 134, Cancer Medicine, (an approved publication of the American Cancer Society, B.C. Decker Inc., Hamilton, Ontario, 2003).
• Hodgkin's lymphoma in an individual in need thereof comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• the hematological malignancy is CLL.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the concentration before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a predetermined length of time. In some embodiments, analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in the number of mobilized plurality of cells in the peripheral blood. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• a method for treating relapsed or refractory non-Hodgkin's lymphoma in an individual in need thereof comprising: administering to the individual a therapeutically-effective amount of (R)-l-(3-(4-amino-3-(4- phenoxyphenyl)- 1 H-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one.
• the non-Hodgkin's lymphoma is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, or relapsed or refractory follicular lymphoma.
• DLBCL diffuse large B-cell lymphoma
• Non-Hodgkin lymphomas are a diverse group of malignancies that are predominately of B-cell origin. NHL may develop in any organs associated with lymphatic system such as spleen, lymph nodes or tonsils and can occur at any age. NHL is often marked by enlarged lymph nodes, fever, and weight loss. NHL is classified as either B-cell or T-cell NHL. Lymphomas related to lymphoproliferative disorders following bone marrow or stem cell transplantation are usually B-cell NHL.
• NHL has been divided into low-, intermediate-, and high-grade categories by virtue of their natural histories (see “The Non-Hodgkin's Lymphoma Pathologic Classification Project," Cancer 49(1982):2112-2135).
• the low-grade lymphomas are indolent, with a median survival of 5 to 10 years (Horning and Rosenberg (1984) N. Engl. J. Med. 311 : 1471-1475).
• B-cell NHL includes Burkitt's lymphoma (e.g., TbT), TbT, TbT, TbT, Tb
• DLBCL Diffuse Mixed Small and Large Cell Lympoma
• Diffuse Small Cleaved Cell Diffuse Small Lymphocytic Lymphoma
• Extranodal Marginal Zone B-cell lymphoma follicular lymphoma, Follicular Small Cleaved Cell (Grade 1), Follicular Mixed Small Cleaved and Large Cell (Grade 2), Follicular Large Cell (Grade 3), Intravascular Large B-Cell Lymphoma, Intravascular Lymphomatosis, Large Cell Immunoblastic Lymphoma, Large Cell Lymphoma (LCL), Lymphoblastic Lymphoma, MALT Lymphoma, Mantle Cell Lymphoma (MCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), extranodal marginal zone B-cell lympho
• lymphoplasmocytic lymphoma hairy cell leukemia, Waldenstrom's Macroglobulinemia, and primary central nervous system (CNS) lymphoma. Additional non-Hodgkin's lymphomas are contemplated within the scope of the present invention and apparent to those of ordinary skill in the art.
• a method for treating a DLCBL in an individual in need thereof comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the
• administering the second cancer treatment regimen occurs after a subsequent decrease in peripheral blood concentration of the mobilized plurality of cells.
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the concentration before administration of the Btk inhibitor.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a predetermined length of time.
• analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood. In some embodiments, the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in the number of mobilized plurality of cells in the peripheral blood. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• DLBCL Diffuse large B-cell lymphoma
• DLBCLs represent approximately 30% of all lymphomas and may present with several morphological variants including the centroblastic, immunoblastic, T- cell/histiocyte rich, anaplastic and plasmoblastic subtypes. Genetic tests have shown that there are different subtypes of DLBCL. These subtypes seem to have different outlooks (prognoses) and responses to treatment. DLBCL can affect any age group but occurs mostly in older people (the average age is mid-60s).
• B-cell lymphoma, activated B cell-like subtype (ABC-DLBCL), in an individual in need thereof, comprising: administering to the individual an irreversible Btk inhibitor in an amount from 300 mg/day up to, and including, 1000 mg/day.
• the ABC subtype of diffuse large B-cell lymphoma (ABC-DLBCL) is thought to arise from post germinal center B cells that are arrested during plasmatic differentiation.
• the ABC subtype of DLBCL (ABC-DLBCL) accounts for approximately 30% total DLBCL diagnoses. It is considered the least curable of the DLBCL molecular subtypes and, as such, patients diagnosed with the ABC-DLBCL typically display significantly reduced survival rates compared with individuals with other types of DLCBL.
• ABC-DLBCL is most commonly associated with chromosomal translocations deregulating the germinal center master regulator BCL6 and with mutations inactivating the PRDMl gene, which encodes a transcriptional repressor required for plasma cell differentiation.
• a particularly relevant signaling pathway in the pathogenesis of ABC-DLBCL is the one mediated by the nuclear factor (NF)-KB transcription complex.
• the NF- ⁇ family comprises 5 members (p50, p52, p65, c-rel and RelB) that form homo- and heterodimers and function as transcriptional factors to mediate a variety of proliferation, apoptosis, inflammatory and immune responses and are critical for normal B-cell development and survival.
• NF- ⁇ is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival.
• many different types of human tumors have misregulated NF- ⁇ : that is, NF- KB is constitutively active. Active NF- ⁇ turns on the expression of genes that keep the cell proliferating and protect the cell from conditions that would otherwise cause it to die via apoptosis.
• somatic mutations of the coiled-coil domain of CARD 11 in DLBCL render this signaling scaffold protein able to spontaneously nucleate protein-protein interaction with MALT1 and BCL10, causing IKK activity and NF-kB activation.
• Constitutive activity of the B cell receptor signaling pathway has been implicated in the activation of NF-kB in ABC DLBCLs with wild type CARD11, and this is associated with mutations within the cytoplasmic tails of the B cell receptor subunits CD79A and CD79B.
• Oncogenic activating mutations in the signaling adapter MYD88 activate NF-kB and synergize with B cell receptor signaling in sustaining the survival of ABC DLBCL cells.
• inactivating mutations in a negative regulator of the NF-kB pathway, A20 occur almost exclusively in ABC DLBCL.
• DLBCL cells of the ABC subtype have chronic active BCR signalling and are very sensitive to the Btk inhibitors described herein.
• induction of apoptosis as shown by capsase activation, Annexin-V flow cytometry and increase in sub-GO fraction is observed in OCILylO.
• Both sensitive and resistant cells express Btk at similar levels, and the active site of Btk is fully occupied by the inhibitor in both as shown using a fluorescently labeled affinity probe.
• OCI-LylO cells are shown to have chronically active BCR signalling to NF-kB which is dose dependently inhibited by the Btk inhibitors described herein.
• the activity of Btk inhibitors in the cell lines studied herein are also characterized by comparing signal transduction profiles (Btk, PLCy, ERK, NF-kB, AKT), cytokine secretion profiles and mRNA expression profiles, both with and without BCR stimulation, and observed significant differences in these profiles that lead to clinical biomarkers that identify the most sensitive patient populations to Btk inhibitor treatment. See U.S. Patent No. 7,711,492 and Staudt et al., Nature, Vol. 463, Jan. 7, 2010, pp. 88-92, the contents of which are incorporated by reference in their entirety.
• a method for treating a follicular lymphoma in an individual in need thereof comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in peripheral blood concentration of the mobilized plurality of cells. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a predetermined length of time.
• analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor.
• administering the second cancer treatment regimen occurs after a subsequent decrease in the number of mobilized plurality of cells in the peripheral blood.
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• follicular lymphoma refers to any of several types of non-Hodgkin's lymphoma in which the lymphomatous cells are clustered into nodules or follicles.
• the term follicular is used because the cells tend to grow in a circular, or nodular, pattern in lymph nodes. The average age for people with this lymphoma is about 60.
• CLL/SLL [00187] Disclosed herein, in certain embodiments, is a method for treating a CLL or SLL in an individual in need thereof, comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the CLL or SLL is high-risk.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in peripheral blood concentration of the mobilized plurality of cells. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the concentration before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a
• analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor.
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• CLL/SLL Chronic lymphocytic leukemia and small lymphocytic lymphoma
• SLL small lymphocytic lymphoma
• CLL and SLL are slow-growing diseases, although CLL, which is much more common, tends to grow slower.
• CLL and SLL are treated the same way. They are usually not considered curable with standard treatments, but depending on the stage and growth rate of the disease, most patients live longer than 10 years. Occasionally over time, these slow-growing lymphomas may transform into a more aggressive type of lymphoma.
• CLL Chronic lymphoid leukemia
• chemotherapy chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation.
• Symptoms are sometimes treated surgically (splenectomy removal of enlarged spleen) or by radiation therapy ("de-bulking" swollen lymph nodes).
• CLL progresses slowly in most cases, it is considered generally incurable. Certain CLLs are classified as high- risk.
• high risk CLL means CLL characterized by at least one of the following 1) 17pl3-; 2) 1 lq22-; 3) unmutated IgVH together with ZAP-70+ and/or CD38+; or 4) trisomy 12.
• CLL treatment is typically administered when the patient's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the patient's quality of life.
• Small lymphocytic leukemia is very similar to CLL described supra, and is also a cancer of B-cells. In SLL the abnormal lymphocytes mainly affect the lymph nodes.
• SLL non-Hodgkin lymphoma
• SLL indolent lymphoma
• a method for treating a Mantle cell lymphoma in an individual in need thereof comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in peripheral blood concentration of the mobilized plurality of cells. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a predetermined length of time.
• analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor.
• administering the second cancer treatment regimen occurs after a subsequent decrease in the number of mobilized plurality of cells in the peripheral blood.
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• Mantle cell lymphoma refers to a subtype of B-cell lymphoma, due to CD5 positive antigen-naive pregerminal center B-cell within the mantle zone that surrounds normal germinal center follicles. MCL cells generally over-express cyclin Dl due to a t(l 1 : 14) chromosomal translocation in the DNA. More specifically, the translocation is at t(l I;14)(ql3;q32). Only about 5% of lymphomas are of this type. The cells are small to medium in size. Men are affected most often. The average age of patients is in the early 60s. The lymphoma is usually widespread when it is diagnosed, involving lymph nodes, bone marrow, and, very often, the spleen. Mantle cell lymphoma is not a very fast growing lymphoma, but is difficult to treat.
• a method for treating a marginal zone B-cell lymphoma in an individual in need thereof comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in peripheral blood concentration of the mobilized plurality of cells. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a predetermined length of time.
• analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor.
• administering the second cancer treatment regimen occurs after a subsequent decrease in the number of mobilized plurality of cells in the peripheral blood.
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• marginal zone B-cell lymphoma refers to a group of related B-cell neoplasms that involve the lymphoid tissues in the marginal zone, the patchy area outside the follicular mantle zone.
• Marginal zone lymphomas account for about 5% to 10% of lymphomas. The cells in these lymphomas look small under the microscope.
• There are 3 main types of marginal zone lymphomas including extranodal marginal zone B-cell lymphomas, nodal marginal zone B-cell lymphoma, and splenic marginal zone lymphoma.
• a method for treating a MALT in an individual in need thereof comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the concentration before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a predetermined length of time. In some embodiments, analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in the number of mobilized plurality of cells in the peripheral blood. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• MALT lymphoma refers to extranodal manifestations of marginal-zone lymphomas. Most MALT lymphoma are a low grade, although a minority either manifest initially as intermediate-grade non-Hodgkin lymphoma (NHL) or evolve from the low-grade form. Most of the MALT lymphoma occur in the stomach, and roughly 70% of gastric MALT lymphoma are associated with Helicobacter pylori infection. Several cytogenetic abnormalities have been identified, the most common being trisomy 3 or t(l 1;18). Many of these other MALT lymphoma have also been linked to infections with bacteria or viruses. The average age of patients with MALT lymphoma is about 60.
• a method for treating a nodal marginal zone B-cell lymphoma in an individual in need thereof comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in peripheral blood concentration of the mobilized plurality of cells. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the concentration before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a
• analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor.
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• nodal marginal zone B-cell lymphoma refers to an indolent B-cell lymphoma that is found mostly in the lymph nodes.
• the disease is rare and only accounts for 1% of all Non-Hodgkin's Lymphomas (NHL). It is most commonly diagnosed in older patients, with women more susceptible than men.
• the disease is classified as a marginal zone lymphoma because the mutation occurs in the marginal zone of the B-cells. Due to its confinement in the lymph nodes, this disease is also classified as nodal.
• a method for treating a splenic marginal zone B-cell lymphoma in an individual in need thereof comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in peripheral blood concentration of the mobilized plurality of cells. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the concentration before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a
• analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor.
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• splenic marginal zone B-cell lymphoma refers to specific low-grade small B-cell lymphoma that is incorporated in the World Health Organization classification. Characteristic features are splenomegaly, moderate lymphocytosis with villous morphology, intrasinusoidal pattern of involvement of various organs, especially bone marrow, and relative indolent course. Tumor progression with increase of blastic forms and aggressive behavior are observed in a minority of patients. Molecular and cytogenetic studies have shown heterogeneous results probably because of the lack of standardized diagnostic criteria.
• Burkitt Lymphoma Disclosed herein, in certain embodiments, is a method for treating a Burkitt lymphoma in an individual in need thereof, comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in peripheral blood concentration of the mobilized plurality of cells. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a predetermined length of time.
• analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor.
• administering the second cancer treatment regimen occurs after a subsequent decrease in the number of mobilized plurality of cells in the peripheral blood.
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• Burkitt lymphoma refers to a type of Non-Hodgkin Lymphoma
• Burkitt's lymphoma that commonly affects children. It is a highly aggressive type of B-cell lymphoma that often starts and involves body parts other than lymph nodes. In spite of its fast-growing nature, Burkitt's lymphoma is often curable with modern intensive therapies. There are two broad types of Burkitt's lymphoma - the sporadic and the endemic varieties:
• EBV Epstein Barr Virus
• Sporadic Burkitt's lymphoma The type of Burkitt's lymphoma that affects the rest of the world, including Europe and the Americas is the sporadic type. Here too, it's mainly a disease in children.
• Epstein Barr Virus (EBV) is not as strong as with the endemic variety, though direct evidence of EBV infection is present in one out of five patients. More than the involvement of lymph nodes, it is the abdomen that is notably affected in more than 90% of the children. Bone marrow involvement is more common than in the sporadic variety.
• a method for treating a Waldenstrom macroglobulinemia in an individual in need thereof comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in peripheral blood concentration of the mobilized plurality of cells. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a predetermined length of time.
• analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor.
• administering the second cancer treatment regimen occurs after a subsequent decrease in the number of mobilized plurality of cells in the peripheral blood.
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• lymphoplasmacytic lymphoma cancer involving a subtype of white blood cells called lymphocytes. It is characterized by an uncontrolled clonal proliferation of terminally differentiated B lymphocytes. It is also characterized by the lymphoma cells making an antibody called immunoglobulin M (IgM).
• IgM immunoglobulin M
• the IgM antibodies circulate in the blood in large amounts, and cause the liquid part of the blood to thicken, like syrup. This can lead to decreased blood flow to many organs, which can cause problems with vision (because of poor circulation in blood vessels in the back of the eyes) and neurological problems (such as headache, dizziness, and confusion) caused by poor blood flow within the brain.
• a method for treating a myeloma in an individual in need thereof comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the concentration before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a predetermined length of time. In some embodiments, analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in the number of mobilized plurality of cells in the peripheral blood. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• a method for treating a multiple myeloma in an individual in need thereof comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in peripheral blood concentration of the mobilized plurality of cells. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a predetermined length of time.
• analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor.
• administering the second cancer treatment regimen occurs after a subsequent decrease in the number of mobilized plurality of cells in the peripheral blood.
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• myeloma also known as MM, myeloma, plasma cell myeloma, or as Kahler's disease (after Otto Kahler) is a cancer of the white blood cells known as plasma cells.
• a type of B cell, plasma cells are a crucial part of the immune system responsible for the production of antibodies in humans and other vertebrates. They are produced in the bone marrow and are transported through the lymphatic system.
• a method for treating a leukemia in an individual in need thereof comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in peripheral blood concentration of the mobilized plurality of cells. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the concentration before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a predetermined length of time.
• analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood. In some embodiments, the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the concentration before administration of the Btk inhibitor. In some embodiments, administering the second cancer treatment regimen occurs after a subsequent decrease in the number of mobilized plurality of cells in the peripheral blood. In some embodiments, analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before administration of the Btk inhibitor. In some embodiments, the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase of blood cells, usually leukocytes (white blood cells).
• Leukemia is a broad term covering a spectrum of diseases. The first division is between its acute and chronic forms: (i) acute leukemia is characterized by the rapid increase of immature blood cells. This crowding makes the bone marrow unable to produce healthy blood cells. Immediate treatment is required in acute leukemia due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. Acute forms of leukemia are the most common forms of leukemia in children; (ii) chronic leukemia is distinguished by the excessive build up of relatively mature, but still abnormal, white blood cells.
• the cells are produced at a much higher rate than normal cells, resulting in many abnormal white blood cells in the blood.
• Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group. Additionally, the diseases are subdivided according to which kind of blood cell is affected.
• lymphoblastic or lymphocytic leukemias the cancerous change takes place in a type of marrow cell that normally goes on to form lymphocytes, which are infection-fighting immune system cells;
• myeloid or myelogenous leukemias the cancerous change takes place in a type of marrow cell that normally goes on to form red blood cells, some other types of white cells, and platelets.
• ALL Acute lymphoblastic leukemia
• AML Acute myelogenous leukemia
• CML Chronic myelogenous leukemia
• HCL Hairy cell leukemia
• a BCLD a dosing regimen of a Btk inhibitor.
• definitions of referred-to standard chemistry terms may be found in reference works (if not otherwise defined herein), including Carey and Sundberg "Advanced Organic Chemistry 4th Ed.” Vols. A (2000) and B (2001), Plenum Press, New York.
• conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology within the ordinary skill of the art are employed.
• nucleic acid and amino acid sequences for Btk are known in the art as disclosed in, e.g., U.S. Patent No. 6,326,469. Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.
• the Btk inhibitor compounds described herein are selective for Btk and kinases having a cysteine residue in an amino acid sequence position of the tyrosine kinase that is homologous to the amino acid sequence position of cysteine 481 in Btk.
• an irreversible inhibitor compound of Btk used in the methods described herein is identified or characterized in an in vitro assay, e.g., an acellular biochemical assay or a cellular functional assay. Such assays are useful to determine an in vitro IC 50 for an irreversible Btk inhibitor compound.
• an acellular kinase assay can be used to determine Btk activity after incubation of the kinase in the absence or presence of a range of concentrations of a candidate irreversible Btk inhibitor compound. If the candidate compound is in fact an irreversible Btk inhibitor, Btk kinase activity will not be recovered by repeat washing with inhibitor-free medium. See, e.g., J. B. Smaill, et al. (1999), J. Med. Chem, 42(10): 1803-1815.
• covalent complex formation between Btk and a candidate irreversible Btk inhibitor is a useful indicator of irreversible inhibition of Btk that can be readily determined by a number of methods known in the art (e.g., mass spectrometry).
• some irreversible Btk-inhibitor compounds can form a covalent bond with Cys 481 of Btk (e.g., via a Michael reaction).
• Cellular functional assays for Btk inhibition include measuring one or more cellular endpoints in response to stimulating a Btk-mediated pathway in a cell line (e.g., BCR activation in Ramos cells) in the absence or presence of a range of concentrations of a candidate irreversible Btk inhibitor compound.
• Useful endpoints for determining a response to BCR activation include, e.g., autophosphorylation of Btk, phosphorylation of a Btk target protein (e.g., PLC- ⁇ ), and cytoplasmic calcium flux.
• High throughput assays for many acellular biochemical assays e.g., kinase assays
• cellular functional assays e.g., calcium flux
• high throughput screening systems are commercially available (see, e.g., Zymark Corp., Hopkinton, MA; Air Technical Industries, Mentor, OH; Beckman
• the Btk inhibitor is selected from the group consisting of a small organic molecule, a macromolecule, a peptide or a non-peptide.
• the Btk inhibitor provided herein is a reversible or irreversible inhibitor. In certain embodiments, the Btk inhibitor is an irreversible inhibitor.
• the irreversible Btk inhibitor forms a covalent bond with a cysteine sidechain of a Bruton's tyrosine kinase, a Bruton's tyrosine kinase homo log, or a Btk tyrosine kinase cysteine homolog.
• Irreversible Btk inhibitor compounds can use for the manufacture of a medicament for treating any of the foregoing conditions (e.g., autoimmune diseases, inflammatory diseases, allergy disorders, B-cell proliferative disorders, or thromboembolic disorders).
• any of the foregoing conditions e.g., autoimmune diseases, inflammatory diseases, allergy disorders, B-cell proliferative disorders, or thromboembolic disorders.
• the irreversible Btk inhibitor compound used for the methods described herein inhibits Btk or a Btk homo log kinase activity with an in vitro IC 50 of less than 10 ⁇ .
• an in vitro IC 50 of less than 10 ⁇ .
• the irreversible Btk inhibitor compound selectively and irreversibly inhibits an activated form of its target tyrosine kinase (e.g., a phosphorylated form of the tyrosine kinase).
• activated Btk is transphosphorylated at tyrosine 551.
• the irreversible Btk inhibitor inhibits the target kinase in cells only once the target kinase is activated by the signaling events.
• the Btk inhibitor used in the methods describe herein has the structure of any of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E), or Formula (F).
• pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs of such compounds are provided.
• Pharmaceutical compositions that include at least one such compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically active metabolite or pharmaceutically acceptable prodrug of such compound are provided.
• when compounds disclosed herein contain an oxidizable nitrogen atom the nitrogen atom can be converted to an N-oxide by methods well known in the art.
• isomers and chemically protected forms of compounds having a structure represented by any of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E), or Formula (F), are also provided.
• A is independently selected from N or CR 5 ;
• R 2 and R3 are independently selected from H, lower alkyl and substituted lower alkyl
• R 4 is L3-X-L4-G, wherein,
• L3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;
• L 4 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;
• R 6 , R7 and Rs are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower
• R 5 is H, halogen, -L 6 -(substituted or unsubstituted C 1 -C3 alkyl), -L 6 -(substituted or
• each R 9 is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;
• each Rio is independently H, substituted or unsubstituted lower alkyl, or substituted or
• two Rio groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;
• R 9 and Rio can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring
• A is independently selected from N or CR 5 ;
• R 2 and R 3 are independently selected from H, lower alkyl and substituted lower alkyl
• R 4 is L 3 -X-L 4 -G, wherein,
• L 3 is optional, and when present is a bond, or an optionally substituted group selected from alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, or
• L 4 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;
• R 7 and Rs are H
• R 6 is H, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 heteroalkyl, Ci-Csalkylaminoalkyl, Ci-Cshydroxyalkylaminoalkyl, Ci- Csalkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted Ci-CsalkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, Ci-C 4 alkyl(aryl), Ci-C 4 alkyl(heteroaryl), Ci- Csalkylethers, Ci-Csalkylamides, or Ci-C 4 alkyl(C 2 -C 8 heterocycloalkyl);
• R 6 and Rs are H
• R 7 is H, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 heteroalkyl, Ci-Csalkylaminoalkyl, Ci-Cshydroxyalkylaminoalkyl, Ci- Csalkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted Ci-CsalkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, Ci-C 4 alkyl(aryl), Ci-C 4 alkyl(heteroaryl), Ci- Csalkylethers, Ci-Csalkylamides, or Ci-C 4 alkyl(C 2 -C 8 heterocycloalkyl); or R 6 and Rs
• each R is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;
• each Rio is independently H, substituted or unsubstituted lower alkyl, or substituted or
• two Rio groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;
• R and Rio can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring
• salts of compounds of Formula (Al) are provided pharmaceutically acceptable salts of compounds of Formula (Al).
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid.
• Further salts include those in which the counterion is an anion, such as adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate,
• Formula (Al) including those in which the ester group is selected from a formate, acetate, propionate, butyrate, acrylate and ethylsuccinate.
• N-acyl groups include N-acetyl and N- ethoxycarbonyl groups.
• the compound of Formula (A) has the following structure of Formula (B):
• Y is alkyl or substituted alkyl, or a 4-, 5-, or 6-membered cycloalkyl ring;
• each R a is independently H, halogen, -CF 3 , -CN, -N0 2 , OH, NH 2 , -L a -(substituted or
• R 6 , R 7 and Rs are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;
• Ri 2 is H or lower alkyl; or Y and Ri2 taken together form a 4-, 5-, or 6-membered heterocyclic ring; and pharmaceutically acceptable active metabolites, pharmaceutically acceptable solvates,
• G is selected from among and 0 / O . In further embodiments, is selected from among
• the compound of Formula (Al) has the following structure of Formula (Bl):
• Y is an optionally substituted group selected from among alkylene, heteroalkylene, arylene, heteroarylene, alkylenearylene, alkyleneheteroarylene, and alkyleneheterocycloalkylene; each R a is independently H, halogen, -CF 3 , -CN, -N0 2 , OH, NH 2 , -L a -(substituted or
• R 7 and Rs are H
• R 6 is H, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 heteroalkyl, Ci-Csalkylaminoalkyl, Ci-Cshydroxyalkylaminoalkyl, Ci-
• R 6 and Rs are H
• R 7 is H, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 heteroalkyl, Ci-Csalkylaminoalkyl, Ci-Cshydroxyalkylaminoalkyl, Ci- Csalkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted Ci-C 8 alkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, Ci- C 4 alkyl(aryl), Ci-C 4 alkyl(heteroaryl), Ci-Csalkylethers, Ci-Csalkylamides, or Ci- C 4 alkyl(C 2 -C 8 heterocycloalkyl); or
• R 7 is H, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-
• Ci-Csalkylaminoalkyl Ci-Cshydroxyalkylaminoalkyl, Ci- Csalkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted Ci-C 8 alkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, Ci- C 4 alkyl(aryl), Ci-C 4 alkyl(heteroaryl), Ci-Csalkylethers, Ci-Csalkylamides, or Ci-
• Ri 2 is H or lower alkyl
• Y and Ri 2 taken together form a 4-, 5-, or 6-membered heterocyclic ring
• G is selected from among
• R is H, alkyl, alkylhydroxy, heterocycloalkyl, heteroaryl, alkylalkoxy, alkylalkoxyalkyl.
• the compound of Formula (B) has the following structure of Formula (C):
• Y is alkyl or substituted alkyl, or a 4-, 5-, or 6-membered cycloalkyl ring;
• Ri 2 is H or lower alkyl
• Y and Ri 2 taken together form a 4-, 5-, or 6-membered heterocyclic ring;
• R 6 , R 7 and Rs are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl; and pharmaceutically acceptable active metabolites, pharmaceutically acceptable solvates, pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs thereof.
• the compound of Formula (Bl) has the following structure of Formula (CI):
• Y is an optionally substituted group selected from among alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, and alkylheterocycloalkyl;
• Ri 2 is H or lower alkyl
• Y and Ri 2 taken together form a 4-, 5-, or 6-membered heterocyclic ring;
• R 7 and Rs are H
• R 6 is H, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 heteroalkyl, Ci-Csalkylaminoalkyl, Ci-Cshydroxyalkylaminoalkyl, Ci- Csalkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted Ci-CsalkylCs-Cecycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, Ci- C 4 alkyl(aryl), Ci-C 4 alkyl(heteroaryl), Ci-Csalkylethers, Ci-Csalkylamides, or Ci- C 4 alkyl(C 2 -C 8 heterocycloalkyl);
• R 6 and Rs are H
• R 7 is H, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 heteroalkyl, Ci-Csalkylaminoalkyl, Ci-Cshydroxyalkylaminoalkyl, Ci- Csalkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted Ci-CsalkylCs-Cecycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, Ci- C 4 alkyl(aryl), Ci-C 4 alkyl(heteroaryl), Ci-Csalkylethers, Ci-Csalkylamides, or Ci- C 4 alkyl(C 2 -C 8 heterocycloalkyl); or
• R 7 is H, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 heteroalkyl, Ci-Csalkylaminoalkyl, Ci-Cshydroxyalkylaminoalkyl, Ci- Csalkoxyalkylaminoalkyl, substituted or unsubstituted C3-C 6 cycloalkyl, substituted or unsubstituted Ci-CsalkylCs-Cecycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, Ci- C 4 alkyl(aryl), Ci-C 4 alkyl(heteroaryl), Ci-Csalkylethers, Ci-Csalkylamides, or Ci- C 4 alkyl(C 2 -C 8 heterocycloalkyl); and
• Formula (Bl), or Formula (CI) is any group that is used to tailor the physical and biological properties of the molecule. Such tailoring/modifications are achieved using groups which modulate Michael acceptor chemical reactivity, acidity, basicity, lipophilicity, solubility and other physical properties of the molecule.
• the physical and biological properties modulated by such modifications to G include, by way of example only, enhancing chemical reactivity of Michael acceptor group, solubility, in vivo absorption, and in vivo metabolism.
• in vivo metabolism includes, by way of example only, controlling in vivo PK properties, off-target activities, potential toxicities associated with cypP450 interactions, drug-drug interactions, and the like.
• modifications to G allow for the tailoring of the in vivo efficacy of the compound through the modulation of, by way of example, specific and non-specific protein binding to plasma proteins and lipids and tissue distribution in vivo.
• L a is CH 2 , O, NH or S
• Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl
• Y is an optionally substituted group selected from among alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
• R 6 , R 7 , and Rs are each independently selected from among H, substituted or
• Ci-C 4 alkyl substituted or unsubstituted Ci-C 4 heteroalkyl, substituted or unsubstituted C3-C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, Ci-C 6 alkoxyalkyl, Ci-Csalkylaminoalkyl, substituted or unsubstituted C 3 - Cecycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Ci-C 4 alkyl(aryl), substituted or unsubstituted Ci-C 4 alkyl(heteroaryl), substituted or unsubstituted Ci-C 4 alkyl(C 3 -Cscycloalkyl), or substituted or unsubstituted Ci-C 4 alkyl(C 2 -C 8 heterocycloalkyl); or
• L a is CH 2 , O, NH or S
• Ar is an optionally substituted aromatic carbocycle or an aromatic heterocycle
• Y is an optionally substituted group selected from among alkylene, heteroalkylene, arylene, heteroarylene, alkylenearylene, alkyleneheteroarylene, and alkyleneheterocycloalkylene, or combination thereof;
• R 7 and Rs are H
• R 6 is H, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 heteroalkyl, Ci-Csalkylaminoalkyl, Ci-Cshydroxyalkylaminoalkyl, Ci- Csalkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted Ci-CsalkylCs-Cecycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, Ci- C 4 alkyl(aryl), Ci-C 4 alkyl(heteroaryl), Ci-Csalkylethers, Ci-Csalkylamides, or Ci- C 4 alkyl(C 2 -C 8 heterocycloalkyl);
• R 6 and Rs are H
• R 7 is H, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 heteroalkyl, Ci-Csalkylaminoalkyl, Ci-Cshydroxyalkylaminoalkyl, Ci- Csalkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted Ci-CsalkylCs-Cecycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, Ci- C 4 alkyl(aryl), Ci-C 4 alkyl(heteroaryl), Ci-Csalkylethers, Ci-Csalkylamides, or Ci- C 4 alkyl(C 2 -C 8 heterocycloalkyl); or
• R 7 is H, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 heteroalkyl, Ci-Csalkylaminoalkyl, Ci-Cshydroxyalkylaminoalkyl, Ci- Csalkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted Ci-CsalkylCs-Cecycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, Ci- C 4 alkyl(aryl), Ci-C 4 alkyl(heteroaryl), Ci-Csalkylethers, Ci-Csalkylamides, or Ci- C 4 alkyl(C 2 -C 8 heterocycloalkyl);
• compositions of Formula (Dl) are provided pharmaceutically acceptable salts of compounds of Formula (Dl).
• salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid.
• Further salts include those in which the counterion is an anion, such as adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate,
• Formula (Dl) including those in which the ester group is selected from a formate, acetate, propionate, butyrate, acrylate and ethylsuccinate.
• N-acyl groups include N-acetyl and N- ethoxycarbonyl groups.
• L a is O.
• Ar is phenyl
• each of R ls R 2 , and R 3 is H.
• R 6 , R 7 , and Rs are all H.
• R 6 , R 7 , and Rs are not all H.
• substituents can be selected from among from a subset of the listed alternatives.
• L a is CH 2 , O, or NH.
• L a is O or NH. In yet other embodiments, L a is O.
• Ar is a substituted or unsubstituted aryl. In yet other embodiments, Ar is a 6-membered aryl. In some other embodiments, Ar is phenyl.
• R 7 and Rs are independently selected from among H, unsubstituted C 1 -C 4 alkyl, substituted Ci-C 4 alkyl, unsubstituted Ci-C 4 heteroalkyl, and substituted Ci-C 4 heteroalkyl; or R 7 and Rs taken together form a bond.
• each of R 7 and Rs is H; or R 7 and Rs taken together form a bond.
• R 6 is H, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 heteroalkyl, Ci-Cealkoxyalkyl, Ci-C 2 alkyl-N(Ci-C 3 alkyl) 2 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, Ci-C 4 alkyl(aryl), Ci- C 4 alkyl(heteroaryl), Ci-C 4 alkyl(C 3 -Cscycloalkyl), or Ci-C 4 alkyl(C 2 -Csheterocycloalkyl).
• R 6 is H, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 heteroalkyl, Ci-C 6 alkoxyalkyl, Ci-C 2 alkyl-N(Ci-C 3 alkyl) 2 , Ci-C 4 alkyl(aryl), Ci-C 4 alkyl(heteroaryl), Ci-C 4 alkyl(C 3 -Cscycloalkyl), or Ci-C 4 alkyl(C 2 -Csheterocycloalkyl).
• R 6 is H, substituted or unsubstituted Ci-C 4 alkyl, -CH 2 -0-(Ci-C3alkyl), - CH 2 -N(Ci-C3alkyl) 2 , Ci-C 4 alkyl(phenyl), or Ci-C 4 alkyl(5- or 6-membered heteroaryl).
• R 6 is H, substituted or unsubstituted Ci-C 4 alkyl, -CH 2 -0-(Ci-C 3 alkyl), -CH 2 - N(Ci-C 3 alkyl) 2 , Ci-C 4 alkyl (phenyl), or Ci-C 4 alkyl(5- or 6-membered heteroaryl containing 1 or 2 N atoms), or Ci-C 4 alkyl(5- or 6-membered heterocycloalkyl containing 1 or 2 N atoms).
• Y is an optionally substituted group selected from among alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl. In other embodiments, Y is an optionally substituted group selected from among Ci-Cealkyl, Ci-Ceheteroalkyl, 4-, 5-, 6- or 7-membered cycloalkyl, and 4-, 5-, 6- or 7-membered heterocycloalkyl.
• Y is an optionally substituted group selected from among Ci-C 6 alkyl, Ci-Ceheteroalkyl, 5-, or 6- membered cycloalkyl, and 5-, or 6-membered heterocycloalkyl containing 1 or 2 N atoms. In some other embodiments, Y is a 5-, or 6-membered cycloalkyl, or a 5-, or 6-membered heterocycloalkyl containing 1 or 2 N atoms.
• the irreversible inhibitor of a kinase has the structure of
• kinase wherein is a moiety that binds to the active site of a kinase, including a
• tyrosine kinase further including a Btk kinase cysteine homolog
• Y is an optionally substituted group selected from among alkylene, heteroalkylene,
• R 6 , R 7 , and Rs are each independently selected from among H, substituted or
• Ci-C 4 alkyl substituted or unsubstituted Ci-C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, Ci-C 6 alkoxyalkyl, Ci-Csalkylaminoalkyl, substituted or unsubstituted C 3 - C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Ci-C 4 alkyl(aryl), substituted or unsubstituted Ci-C 4 alkyl(heteroaryl), substituted or unsubstituted Ci-C 4 alkyl(C 3 -C 8 cycloalkyl), or substituted or unsubstituted Ci-C 4 alkyl(C 2 -C 8 heterocycloalkyl); or
• Formula (F) is as follows:
• L a is CH 2 , O, NH or S
• Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; and either
• Y is an optionally substituted group selected from among alkylene, heteroalkylene, arylene, heteroarylene, alkylenearylene, alkyleneheteroarylene, alkylenecycloalkylene and alkyleneheterocycloalkylene;
• R 6 , R 7 , and Rs are each independently selected from among H, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, Ci- Cealkoxyalkyl, Ci-Csalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or un
• R 7 is H, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 heteroalkyl, Ci-Csalkylaminoalkyl, Ci-Cs hydroxyalkylaminoalkyl, Ci-Cs
• alkoxyalkylaminoalkyl substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted Ci-C 8 alkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, Ci- C 4 alkyl(aryl), Ci-C 4 alkyl(heteroaryl), Ci-Csalkylethers, Ci-Csalkylamides, or Ci- C 4 alkyl(C 2 -C 8 heterocycloalkyl); or
• R 6 is selected from among H, substituted or unsubstituted Ci-C 4 alkyl, substituted or
• Ci-C 4 heteroalkyl substituted or unsubstituted Ci-C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, Ci-C 6 alkoxyalkyl, Ci-Csalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Ci-C 4 alkyl(aryl), substituted or unsubstituted Ci-C 4 alkyl(heteroaryl), substituted or unsubstituted Ci- C 4 alkyl(C 3 -C 8 cycloalkyl), or substituted or unsubstituted Ci-C 4 alkyl(C 2 - Csheterocycloalkyl) or
• Y is an optionally substituted group selected from cycloalkylene or heterocycloalkylene;
• R 6 is substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 heteroalkyl, Ci-Csalkylaminoalkyl, Ci-Cs hydroxyalkylaminoalkyl, Ci-Cs alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted Ci-CsalkylCs- C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 - Csheterocycloalkyl, substituted or unsubstituted heteroaryl, Ci-C 4 alkyl(aryl), Ci- C 4 alkyl(heteroaryl), Ci-Csalkylethers, Ci-Csalkylamides, or Ci-C 4 alkyl(C 2 - Csheterocycloalkyl);
• R 7 is substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 heteroalkyl, Ci-C 8 alkylaminoalkyl, Ci-Cs hydroxyalkylaminoalkyl, Ci-Cs alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted Ci-CsalkylC 3 - C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 - Csheterocycloalkyl, substituted or unsubstituted heteroaryl, Ci-C 4 alkyl(aryl), Ci- C 4 alkyl(heteroaryl), Ci-Csalkylethers, Ci-Csalkylamides, or Ci-C 4 alkyl(C 2 - Csheterocycloalkyl); or
• R 6 is substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 heteroalkyl, C l -Csalkylaminoalkyl, C i -Cshydroxyalkylaminoalkyl, C i -Csalkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted Ci-CsalkylC 3 - C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 - Csheterocycloalkyl, substituted or unsubstituted heteroaryl, Ci-C 4 alkyl(aryl), Ci- C 4 alkyl(heteroaryl), Ci-Csalkylethers, Ci-Csalkylamides, or Ci-C 4 alkyl(C 2 - Cshetero
• Formula (D) include, but are not limited to, compounds selected from the group consisting of:
• compounds provided herein are selected from [00263]
• the Btk inhibitor is (R)-l-(3-(4-amino-3-(4- phenoxyphenyl)- 1 H-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one.
• the Btk inhibitor is a-cyano-P-hydroxy- ⁇ - methyl-N-(2,5- dibromophenyl)propenamide (LFM-A13), AVL-101, 4-tert-butyl-N-(3-(8- (phenylamino)imidazo [ 1 ,2-a]pyrazin-6-yl)phenyl)benzamide, 5 -(3 -amino-2-methylphenyl)- 1 - methyl-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazin-2(lH)-one, N-(2-methyl-3-(4- methyl-6-(4-(morpholine-4-carbonyl)phenylamino)-5-oxo-4,5-dihydropyrazin-2- yl)phenyl)acetamide, 4-tert-butyl-N-(2-methyl-3-(4-methyl-6-(4-(morpholine-4-(morpholine-4-carbony
• any of the Btk inhibitors and/or the second agent provided herein for the invention methods is included in a pharmaceutical composition comprising: i) a physiologically acceptable carrier, diluent, and/or excipient.
• the Btk inhibitor of the invention methods is administered at a dose of from about 1.25 mg/kg/day to about 12.5 mg/kg/day. In certain embodiments, the Btk inhibitor is administered at a dose selected from the group consisting of about 1.25 mg/kg/day, about 2.5 mg/kg/day, about 5 mg/kg/day, about 8.3 mg/kg/day, or about 12.5 mg/kg/day.
• biomarkers in accordance with the practice of the present invention is selected from ZAP-70, CD5, t(14;18), CD38, ⁇ -2 microglobulin, p53 mutational status, ATM mutational status, chromosome 17p deletion, chromosome 1 lq deletion, surface or cytoplasmic immunoglobulin, CD138, CD25, 6q deletion, CD19, CD20, CD22, CD1 lc, CD 103, chromosome 7q deletion, and V H mutational status.
• determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes is of a combination of biomarkers.
• the combination of biomarkers is CD 19 and CD5 or CD20 and CD5.
• the second agent is administered at a dose of from about
• the second agent is administered at a dose selected from the group consisting of about 1.25 mg/kg/day, about 2.5 mg/kg/day, about 5 mg/kg/day, about 8.3 mg/kg/day, or about 12.5 mg/kg/day.
• the dosage of the second agent is based on the determined expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes. A person skilled in the art such as a physician can readily determine the suitable regimen (e.g. dosage of the second agent) based on the diagnostic results.
• the present invention provides methods for treating a cancer comprising determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes in a subject that has received a dose of a Btk inhibitor; and administering a second agent based on the determined expression profile.
• the present invention also provides methods for treating a cancer comprising administering a Btk inhibitor sufficient to result in an increase or appearance in the blood of a subpopulation of lymphocytes defined by immunophenotyping; and
• the subject is a human.
• the Btk inhibitors are orally administered.
• any of the aforementioned aspects are further embodiments in which administration is enteral, parenteral, or both, and wherein (a) the effective amount of the Btk inhibitor is systemically administered to the mammal; (b) the effective amount of the Btk inhibitor is administered orally to the mammal; (c) the effective amount of the Btk inhibitor is intravenously administered to the mammal; (d) the effective amount of the Btk inhibitor administered by inhalation; (e) the effective amount of the Btk inhibitor is administered by nasal administration; or (f) the effective amount of the Btk inhibitor is administered by injection to the mammal; (g) the effective amount of the Btk inhibitor is administered topically (dermal) to the mammal; (h) the effective amount of the Btk inhibitor is administered by ophthalmic
• any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the Btk inhibitor, including further embodiments in which (i) the Btk inhibitor is administered once; (ii) the Btk inhibitor is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously.
• any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the Btk inhibitor, including further embodiments in which (i) the Btk inhibitor is administered in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the Btk inhibitor is administered to the mammal every 8 hours.
• the method comprises a drug holiday, wherein the administration of the Btk inhibitor is temporarily suspended or the dose of the Btk inhibitor being administered is temporarily reduced; at the end of the drug holiday, dosing of the Btk inhibitor is resumed.
• the length of the drug holiday can vary from 2 days to 1 year.
• any of the aforementioned aspects are further embodiments in which administration is enteral, parenteral, or both, and wherein (a) the effective amount of the second agent is systemically administered to the mammal; (b) the effective amount of the second agent is administered orally to the mammal; (c) the effective amount of the second agent is
• the effective amount of the second agent administered by inhalation is administered by nasal administration; or (f) the effective amount of the second agent is administered by injection to the mammal; (g) the effective amount of the second agent is administered topically (dermal) to the mammal; (h) the effective amount of the second agent is administered by ophthalmic administration; or (i) the effective amount of the second agent is administered rectally to the mammal.
• any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of second agent, including further embodiments in which (i) the second agent is administered once; (ii) the second agent is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously.
• any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the second agent, including further embodiments in which (i) the second agent is administered in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the second agent is administered to the mammal every 8 hours.
• the method comprises a drug holiday, wherein the administration of the second agent is temporarily suspended or the dose of the second agent being administered is temporarily reduced; at the end of the drug holiday, dosing of the second agent is resumed.
• the length of the drug holiday can vary from 2 days to 1 year.
• the second agent is selected from the group consisting of alemtuzumab, arsenic trioxide, asparaginase (pegylated or non-), bevacizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine,
• Compounds of Formula D may be synthesized using standard synthetic techniques known to those of skill in the art or using methods known in the art in combination with methods described herein. In additions, solvents, temperatures and other reaction conditions presented herein may vary according to those of skill in the art. As a further guide the following synthetic methods may also be utilized. [00284] The reactions can be employed in a linear sequence to provide the compounds described herein or they may be used to synthesize fragments which are subsequently joined by the methods described herein and/or known in the art.
• Carboxamides carboxylic acids amines/anilines
• esters carboxylic acids Alcohols hydrazines Hydrazides carboxylic acids
• N-acylureas or Anhydrides carbodiimides carboxylic acids
• Vinyl sulfide Propargyl amide thiol of Protecting Groups [00286] In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Protecting groups are used to block some or all reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In one embodiment, each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. Protective groups can be removed by acid, base, and hydrogenolysis.
• Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
• Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
• Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc.
• Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.
• Allyl blocking groups are useful in then presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts.
• an allyl-b locked carboxylic acid can be deprotected with a Pd°-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
• Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
• blocking/protecting groups may be selected from:
• the compounds described herein may possess one or more stereocenters and each center may exist in the R or S configuration.
• the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
• Stereoisomers may be obtained, if desired, by methods known in the art as, for example, the separation of stereoisomers by chiral chromatographic columns.
• Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known, for example, by
• enantiomers can be separated by chiral chromatographic columns.
• enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers, and mixtures thereof are considered as part of the compositions described herein.
• the methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity.
• compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
• the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
• Compounds of Formula D in unoxidized form can be prepared from N-oxides of compounds of Formula D by treating with a reducing agent, such as, but not limited to, sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like in a suitable inert organic solvent, such as, but not limited to, acetonitrile, ethanol, aqueous dioxane, or the like at 0 to 80°C.
• a reducing agent such as, but not limited to, sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
• a suitable inert organic solvent such as, but not limited to, acetonitrile, ethanol, aqueous dioxane, or the like at 0 to 80°C.
• prodrugs refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
• prodrug an example, without limitation, of a prodrug would be a compound described herein, which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
• prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
• a prodrug upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
• a prodrug is
• a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vivo administration.
• the prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
• Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.
• Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al, Am. J. Physiol, 269:G210-218 (1995); McLoed et al, Gastroenterol, 106:405-413 (1994); Hochhaus et al, Biomed.
• Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulas and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F, 36 C1, respectively.
• isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Further, substitution with isotopes such as deuterium, i.e., H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half- life or reduced dosage requirements.
• the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
• Compounds described herein may be formed as, and/or used as, pharmaceutically acceptable salts.
• the type of pharmaceutical acceptable salts include, but are not limited to: (1) acid addition salts, formed ) by reacting the free base form of the compound with a
• inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2- naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]
• organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
• Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
• the corresponding counterions of the pharmaceutically acceptable salts may be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.
• the salts are recovered by using at least one of the following techniques:
• a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs.
• Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be
• the compounds provided herein can exist in unsolvated as well as solvated forms.
• the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
• a reference to a salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs.
• Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
• Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
• Compounds described herein may be in various forms, including but not limited to, amorphous forms, milled forms and nano-particulate forms.
• compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound.
• Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility.
• the screening and characterization of the pharmaceutically acceptable salts, polymorphs and/or solvates may be accomplished using a variety of techniques including, but not limited to, thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy.
• Thermal analysis methods address thermo chemical degradation or thermo physical processes including, but not limited to, polymorphic transitions, and such methods are used to analyze the relationships between polymorphic forms, determine weight loss, to find the glass transition temperature, or for excipient compatibility studies.
• Such methods include, but are not limited to, Differential scanning calorimetry (DSC), Modulated Differential Scanning Calorimetry
• X-ray diffraction methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources.
• the various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state).
• the various microscopy techniques include, but are not limited to, polarized light microscopy, Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis (EDX), Environmental Scanning Electron Microscopy with EDX (in gas or water vapor atmosphere), IR microscopy, and Raman microscopy.
• a method for treating a hematological malignancy in an individual in need thereof comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• analyzing the mobilized plurality of cells comprises measuring the peripheral blood concentration of the mobilized plurality of cells.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells increases as compared to the
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the peripheral blood concentration of the mobilized plurality of cells as compared to the concentration before administration of the Btk inhibitor.
• the method further comprises administering a second cancer treatment regimen after the peripheral blood concentration of the mobilized plurality of cells has increased for a predetermined length of time.
• analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the number before
• administering the second cancer treatment regimen occurs after a subsequent decrease in the number of mobilized plurality of cells in the peripheral blood.
• analyzing the mobilized plurality of cells comprises measuring the duration of an increase in the number of mobilized plurality of cells in the peripheral blood as compared to the number before administration of the Btk inhibitor.
• the method further comprises administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood has increased for a predetermined length of time.
• administering a Btk inhibitor before a second cancer treatment regimen reduces immune-mediated reactions to the second cancer treatment regimen.
• administering a Btk inhibitor before ofatumumab reduces immune- mediated reactions to ofatumumab.
• the second cancer treatment regimen comprises a chemotherapeutic agent, a steroid, an immunotherapeutic agent, a targeted therapy, or a combination thereof.
• the second cancer treatment regimen comprises a B cell receptor pathway inhibitor.
• the B cell receptor pathway inhibitor is a CD79A inhibitor, a CD79B inhibitor, a CD 19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K inhibitor, a Blnk inhibitor, a PLCy inhibitor, a PKCP inhibitor, or a combination thereof.
• the second cancer treatment regimen comprises an antibody, B cell receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor, an mTOR inhibitor, a radioimmunotherapeutic, a DNA damaging agent, a proteosome inhibitor, a histone deacytlase inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, an Hsp90 inhibitor, a telomerase inhibitor, a Jakl/2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a combination thereof.
• the second cancer treatment regimen comprises chlorambucil, ifosphamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab,
• dexamethasone prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.
• the second cancer treatment regimen comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally, rituximab.
• the second cancer treatment regimen comprises bendamustine, and rituximab.
• the second cancer treatment regimen comprises fludarabine, cyclophosphamide, and rituximab.
• the second cancer treatment regimen comprises cyclophosphamide, vincristine, and prednisone, and optionally, rituximab.
• the second cancer treatment regimen comprises etoposide, doxorubicin, vinristine, cyclophosphamide, prednisolone, and optionally, rituximab.
• the second cancer treatment regimen comprises dexamethasone and lenalidomide.
• Additional cancer treatment regimens include Nitrogen Mustards such as for example, bendamustine, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, prednimustine, trofosfamide; Alkyl Sulfonates like busulfan, mannosulfan, treosulfan; Ethylene Imines like carboquone, thiotepa, triaziquone; Nitrosoureas like carmustine, fotemustine, lomustine, nimustine, ranimustine, semustine, streptozocin; Epoxides such as for example, etoglucid; Other Alkylating Agents such as for example dacarbazine, mitobronitol, pipobroman, temozolomide; Folic Acid Analogues such as for example methotrexate, permetrexed, pralatrexate, raltitrexed; Purine Ana
• Alkaloids such as for example vinblastine, vincristine, vindesine, vinflunine, vinorelbine;
• Podophyllotoxin Derivatives such as for example etoposide, teniposide; Colchicine derivatives such as for example demecolcine; Taxanes such as for example docetaxel, paclitaxel, paclitaxel poliglumex; Other Plant Alkaloids and Natural Products such as for example trabectedin;
• Actinomycines such as for example dactinomycin
• Antracyclines such as for example aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pirarubicin, valrubicin, zorubincin
• Other Cytotoxic Antibiotics such as for example bleomycin, ixabepilone, mitomycin, plicamycin
• Platinum Compounds such as for example carboplatin, cisplatin, oxaliplatin, satraplatin
• Methylhydrazines such as for example procarbazine
• Sensitizers such as for example aminolevulinic acid, efaproxiral, methyl aminolevulinate, porfimer sodium, temoporfm
• Protein Kinase Inhibitors such as for example dasatinib, erlotinib, everolimus, gefitinib,
• Additional cancer treatment regimens include interferons, interleukins, Tumor
• Additional cancer treatment regimens include Immunostimulants such as for example ancestim, filgrastim, lenograstim, molgramostim, pegfilgrastim, sargramostim;
• Interferons such as for example interferon alfa natural, interferon alfa-2a, interferon alfa-2b, interferon alfacon-1, interferon alfa-nl, interferon beta natural, interferon beta-la, interferon beta-lb, interferon gamma, peginterferon alfa-2a, peginterferon alfa-2b; Interleukins such as for example aldesleukin, oprelvekin; Other Immunostimulants such as for example BCG vaccine, glatiramer acetate, histamine dihydrochloride, immunocyanin, lentinan, melanoma vaccine, mifamurtide, pegademase, pidotimod, plerixafor, poly I:C, poly ICLC, roquinimex, tasonermin, thymopentin; Immunosuppressants such as for example abatacept, abetimus,
• Additional cancer treatment regimens include Adalimumab, Alemtuzumab,
• Efalizumab Efalizumab, Gemtuzumab, Ibritumomab tiuxetan, Infliximab, Muromonab-CD3, Natalizumab, Panitumumab, Ranibizumab, Rituximab, Tositumomab, Trastuzumab, or the like, or a combination thereof.
• Additional cancer treatment regimens include Monoclonal Antibodies such as for example alemtuzumab, bevacizumab, catumaxomab, cetuximab, edrecolomab, gemtuzumab, ofatumumab, panitumumab, rituximab, trastuzumab, , Immunosuppressants, eculizumab, efalizumab, muromab-CD3, natalizumab; TNF alpha Inhibitors such as for example
• adalimumab afelimomab, certolizumab pegol, golimumab, infliximab, , Interleukin Inhibitors, basiliximab, canakinumab, daclizumab, mepolizumab, tocilizumab, ustekinumab, ,
• Radiopharmaceuticals ibritumomab tiuxetan, tositumomab; Others Monoclonal Antibodies such as for example abagovomab, adecatumumab, alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET monoclonal antibody MetMab, apolizumab, apomab, arcitumomab, basiliximab, bispecific antibody 2B1, blinatumomab, brentuximab vedotin, capromab pendetide, cixutumumab, claudiximab, conatumumab, dacetuzumab, denosumab, eculizumab,
• epratuzumab epratuzumab, epratuzumab, ertumaxomab, etaracizumab, figitumumab, fresolimumab, galiximab, ganitumab, gemtuzumab ozogamicin, glembatumumab, ibritumomab, inotuzumab ozogamicin, ipilimumab, lexatumumab, lintuzumab, lintuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, monoclonal antibody CC49, necitumumab, nimotuzumab, ofatumumab, oregovomab, pertuzumab, ramacurimab, ranibizumab, siplizumab, sonepcizumab,
• Additional cancer treatment regimens include agents that affect the tumor micro- enviroment such as cellular signaling network (e.g. phosphatidylinositol 3-kinase (PI3K) signaling pathway, signaling from the B-cell receptor and the IgE receptor).
• cellular signaling network e.g. phosphatidylinositol 3-kinase (PI3K) signaling pathway, signaling from the B-cell receptor and the IgE receptor.
• PI3K phosphatidylinositol 3-kinase
• the second agent is a PI3K signaling inhibitor or a syc kinase inhibitor.
• the syk inhibitor is R788.
• a PKCy inhibitor such as by way of example only, enzastaurin.
• agents that affect the tumor micro-environment include PI3K signaling inhibitor, syc kinase inhibitor, Protein Kinase Inhibitors such as for example dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazonanib, sorafenib, sunitinib, temsirolimus; Other Angiogenesis Inhibitors such as for example GT-111, JI-101, R1530; Other Kinase Inhibitors such as for example AC220, AC480, ACE-041, AMG 900, AP24534, Arry- 614, AT7519, AT9283, AV-951, axitinib, AZD1 152, AZD7762, AZD8055, AZD8931, bafetinib, BAY 73-4506, BGJ398, BGT226, BI 811283
• anti-cancer agents for use in combination with a Btk inhibitor compound include inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43- 9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).
• mitogen-activated protein kinase signaling e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43- 9006, wortmannin, or LY294002
• Syk inhibitors e.g., mTOR inhibitors
• mTOR inhibitors e.g., rituxan
• anti-cancer agents that can be employed in combination with a Btk inhibitor compound include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carb
• carmustine carubicin hydrochloride
• carzelesin cedefingol
• chlorambucil cirolemycin
• cladribine crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;
• estramustine estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; cambine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine
• interferon alfa-2a including recombinant interleukin II, or rlL2
• interferon alfa-2a interferon alfa-2b
• interferon alfa-nl interferon alfa-n3
• interferon beta-1 a interferon gamma-1 b
• iproplatin irinotecan hydrochloride
• lanreotide acetate letrozole
• leuprolide acetate liarozole hydrochloride
• lometrexol sodium lomustine; losoxantrone hydrochloride; masoprocol; maytansine;
• mechlorethamine hydrochloride megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran;
• pegaspargase peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
• piposulfan piroxantrone hydrochloride
• plicamycin plicamycin
• plomestane porfimer sodium
• porfiromycin prednimustine; procarbazine hydrochloride; puromycin; puromycin
• hydrochloride pyrazofurin; riboprine; rogletimide; safmgol; safmgol hydrochloride; semustine; pumprazene; sparfosate sodium; sparsomycin; spiro germanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur;
• teloxantrone hydrochloride temoporfm
• teniposide teroxirone
• testolactone thiamiprine
• anti-cancer agents that can be employed in combination with a Btk inhibitor compound include: 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide;
• anastrozole andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen;
• antineoplaston antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;
• bizelesin breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole;
• carboxyamidotriazole CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole;
• collismycin A collismycin B; combretastatin A4; combretastatin analogue; conagenin;
• crambescidin 816 crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;
• cyclopentanthraquinones cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
• cytostatin cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone;
• dexifosfamide dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron;
• edrecolomab eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane;
• fadrozole fadrozole; trasrabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors;
• gemcitabine glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide;
• hypericin ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;
• imidazoacridones imiquimod
• immunostimulant peptides insulin-such as for example growth factor- 1 receptor inhibitor
• interferon agonists interferons
• interleukins interleukins
• iobenguane interleukins
• iododoxorubicin ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
• lenograstim lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds;
• loxoribine lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin
• A marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol;
• mitomycin analogues mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin;
• oligonucleotides onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer;
• ormaplatin osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol;
• phenazinomycin phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins;
• pyrazoloacridine pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;
• raltitrexed ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl ; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparf
• spicamycin D spiromustine; splenopentin; spongistatin 1; squalamine
• stem cell inhibitor stem- cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;
• tellurapyrylium tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide;
• tetrachlorodecaoxide tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
• urogenital sinus-derived growth inhibitory factor urokinase receptor antagonists
• vapreotide variolin B
• vector system erythrocyte gene therapy
• velaresol veramine; verdins; verteporfm; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
• nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.
• alkyl sulfonates e.g., busulfan
• nitrosoureas e.g., carmustine, lomusitne, ete.
• triazenes e.g., triazenes
• antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g.,
• alkylating agents that can be employed in combination a Btk inhibitor compound include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, ete.).
• nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan, etc.
• ethylenimine and methylmelamines e.g., hexamethlymelamine, thiotepa
• antimetabolites include, but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.
• folic acid analog e.g., methotrexate
• pyrimidine analogs e.g., fluorouracil, floxouridine, Cytarabine
• purine analogs e.g., mercaptopurine, thioguanine, pentostatin.
• anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules and which can be used in combination with a Btk inhibitor compound include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2,
• Epothilones such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B ), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N- oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21- hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26
• Epothilones such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB
• hematological malignancy in an individual in need thereof, comprising: (a) administering to the individual an amount of an irreversible Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and (b) analyzing the mobilized plurality of cells.
• the amount of the irreversible Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
• analyzing the mobilized plurality of cells comprises preparing a biomarker profile for a population of cells isolated from the plurality of cells.
• the biomarker expression profile is used to diagnose, determine a prognosis, or create a predictive profile of a hematological malignancy.
• the biomarker profile indicates the expression of a biomarker, the expression level of a biomarker, mutations in a biomarker, or the presence of a biomarker.
• the biomarker is any cytogenetic, cell surface molecular or protein or RNA expression marker.
• the biomarker is: ZAP70; t(14,18); ⁇ -2 microglobulin; p53 mutational status; ATM mutational status; del(17)p; del(l l)q; del(6)q; CD5; CDl lc; CD19; CD20; CD22; CD25; CD38; CD 103; CD 138; secreted, surface or cytoplasmic immunoglobulin expression; V H mutational status; or a combination thereof.
• the method further comprises providing a second cancer treatment regimen based on the biomarker profile.
• the method further comprises not administering based on the biomarker profile.
• the method further comprises predicting the efficacy of a treatment regimen based on the biomarker profile.
• the methods comprise diagnosing, determining a prognosis, or creating a predictive profile of a hematological maligancy maligancy based upon the expression or presence of certain biomarkers.
• the methods further comprise stratefying patient populations based upon the expression or presence of certain biomarkers in the affected lymphocytes.
• the methods further comprise determining a therapeutic regimen for the subject based upon the expression or presence of certain biomarkers in the affected lymphocytes.
• the methods further comprise predicting a response to therapy in a subject based upon the expression or presence of certain biomarkers in the affected lymphocytes.
• kits for diagnosing, determining a prognosis, or creating a predictive profile of a hematological maligancy in a subject comprising: (a) administering a Btk inhibitor to the subject sufficient to result in an increase or appearance in the blood of a subpopulation of lymphocytes; and (b) determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes; wherein the expression or presence of one or more biomarkers is used to diagnose the hematological maligancy, determine the prognosis of the hematological maligancy, or create a predictive profile of the hematological maligancy.
• the increase or appearance in the blood of a subpopulation of lymphocytes is determined by immunophenotyping. In another embodiment, the increase or appearance in the blood of a subpopulation of lymphocytes is determined by fluorescent activated cell sorting (FACS).
• FACS fluorescent activated cell sorting
• methods of stratifying a patient population having a hematological maligancy comprising: (a) administering a Btk inhibitor to the subject sufficient to result in an increase or appearance in the blood of a subpopulation of lymphocytes; and (b) determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes; wherein the expression or presence of one or more biomarkers is used to stratify patients for treatment of the hematological maligancy.
• the increase or appearance in the blood of a subpopulation of lymphocytes is determined by immunophenotyping.
• the increase or appearance in the blood of a subpopulation of lymphocytes is determined by fluorescent activated cell sorting (FACS).
• kits for determining a therapeutic regimen in a subject having a hematological maligancy comprising: (a) administering a Btk inhibitor to the subject sufficient to result in an increase or appearance in the blood of a subpopulation of lymphocytes; and (b) determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes; wherein the expression or presence of one or more biomarkers is used to determine the therapeutic regimen for the treatment of the hematological maligancy.
• the increase or appearance in the blood of a subpopulation of lymphocytes is determined by immunophenotyping.
• the increase or appearance in the blood of a subpopulation of lymphocytes is determined by fluorescent activated cell sorting (FACS).
• kits for predicting a response to therapy in a subject having a hematological maligancy comprising: (a) administering a Btk inhibitor to the subject sufficient to result in an increase or appearance in the blood of a subpopulation of lymphocytes; and (b) determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes; wherein the expression or presence of one or more biomarkers is used to predict the subject's response to therapy for the
• the increase or appearance in the blood of a subpopulation of lymphocytes is determined by immunophenotyping. In another embodiment, the increase or appearance in the blood of a subpopulation of lymphocytes is determined by fluorescent activated cell sorting (FACS).
• FACS fluorescent activated cell sorting
• kits for diagnosing, determining a prognosis, or creating a predictive profile of a hematological maligancy in a subject comprising determining the expression or presence of one or more biomarkers from one or more
• the dose of Btk inhibitor is sufficient to result in an increase or appearance in the blood of a subpopulation of lymphocytes defined by immunophenotyping.
• the determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes further comprises isolating, detecting or measuring one or more type of lymphocyte.
• the Btk inhibitor is a reversible or irreversible inhibitor.
• methods of stratifying a patient population having a hematological maligancy comprising determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes in a subject that has received a dose of a Btk inhibitor wherein the expression or presence of one or more biomarkers is used to stratify patients for treatment of the hematological maligancy.
• the dose of Btk inhibitor is sufficient to result in an increase or appearance in the blood of a subpopulation of lymphocytes defined by immunophenotyping.
• the determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes further comprises isolating, detecting or measuring one or more type of
• the Btk inhibitor is a reversible or irreversible inhibitor.
• kits for determining the therapeutic regimen in a subject having a hematological maligancy comprising determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes in a subject that has received a dose of a Btk inhibitor wherein the expression or presence of one or more biomarkers is used to determine the therapeutic regimen for the treatment of the hematological maligancy.
• the dose of Btk inhibitor is sufficient to result in an increase or appearance in the blood of a subpopulation of lymphocytes defined by
• the determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes further comprises isolating, detecting or measuring one or more type of lymphocyte.
• the Btk inhibitor is a reversible or irreversible inhibitor.
• kits for predicting a response to therapy in a subject having a hematological maligancy comprising determining the expression or presence of one or more biomarkers from one or more circulating lymphocytes in a subject that has received a dose of a Btk inhibitor wherein the expression or presence of one or more biomarkers is used to predict the subject's response to therapy for the hematological maligancy.
• the dose of Btk inhibitor is sufficient to result in an increase or appearance in the blood of a subpopulation of lymphocytes defined by immunophenotyping.
• the determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes further comprises isolating, detecting or measuring one or more type of lymphocyte.
• the Btk inhibitor is a reversible or irreversible inhibitor.
• any biomarker related to hematological maligancies are in some embodiments utilized in the present methods. These biomarkers include any biological molecule (found either in blood, other body fluids, or tissues) or any chromosomal abnormality that is a sign of a hematological maligancy.
• the biomarkers include, but are not limited to, TdT, CD5, CD1 lc, CD19, CD20, CD22, CD79a, CD15, CD30, CD38, CD138, CD103, CD25, ZAP-70, p53 mutational status, ATM mutational status, mutational status of IgV H , chromosome 17 deletions (del 17p), chromosome 6 deletions (del 6q), chromosome 7 deletions (del 7q), chromosome 11 deletions (del 1 lq), trisomy 12, chromosome 13 deletions (del 13 q), t(l 1 : 14) chromosomal translocation, t(14: 18) chromosomal
• the biomarkers include ZAP-70, CD5, t(14;18), CD38, ⁇ -2 microglobulin, p53 mutational status, ATM mutational status, chromosome 17p deletion, chromosome 1 lq deletion, surface or cytoplasmic immunoglobulin, CD 138, CD25, 6q deletion, CD 19, CD20, CD22, CD1 lc, CD 103, chromosome 7q deletion, V H mutational status, or a combination thereof.
• subpopulations of patients having a hematological maligancy cancer or pre- that would benefit from a known treatment regimen are identified by screening candidate subjects for one or more clinically useful biomarkers known in the art. Any clinically useful prognostic marker known to those of skill in the art can be used.
• the subpopulation includes patients having chronic lymphocytic leukemia (CLL), and the clinically useful prognostic markers of particular interest include, but are not limited to, ZAP-70, CD38, .beta.2 microglobulin, and cytogenetic markers, for example, p53 mutational status, ATM mutational status, chromosome deletions, such as the chromosome 17p deletion and the chromosome 1 lq deletion, all of which are clinically useful prognostic markers for this disease.
• CLL chronic lymphocytic leukemia
• ZAP-70 is a tyrosine kinase that associates with the zeta subunit of the T cell antigen receptor (TCR) and plays a pivotal role in T cell activation and development (Chan et al. (1992) Cell 71 :649-662). ZAP-70 undergoes tyrosine phosphorylation and is essential in mediating signal transduction following TCR stimulation. Overexpression or constitutive activation of tyrosine kinases has been demonstrated to be involved in a number of malignancies including leukemias and several types of solid tumors.
• TCR T cell antigen receptor
• ZAP-70 RNA expression levels are a prognostic marker of chronic lymphocytic leukemia (CLL) (Rosenwald et al. (2001) J. Exp. Med. 194: 1639-1647).
• CLL chronic lymphocytic leukemia
• ZAP-70 is expressed in T-cells and natural killer cells, but is not known to be expressed in normal B-cells.
• ZAP-70 is expressed at high levels in the B-cells of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients, and more particularly in the subset of CLL patients who tend to have the more aggressive clinical course that is found in CLL/SLL patients with unmutated Ig genes (Wiestner et al. (2003) Blood 101 : 4944-4951; U.S. Patent Application Publication No. 20030203416).
• CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma
• ZAP- 70 can be used as a prognostic indicator to identify those patients likely to have severe disease (high ZAP-70, unmutated Ig genes), and who are therefore candidates for aggressive therapy.
• CD38 is a signal transduction molecule as well as an ectoenzyme catalyzing the synthesis and degradation of cyclic ADP ribose (cADPR).
• CD38 expression is present at high levels in bone marrow precursor B cells, is down-regulated in resting normal B cells, and then is re-expressed in terminally differentiated plasma cells (Campana et al. (2000) Chem. Immunol. 75: 169-188).
• CD38 is a reliable prognostic indicator in B-CLL, with the expression of CD38 generally indicating a less favorable outcome (D'Arena et al. (2001) Leuk. Lymphoma 42: 109; Del Poeta et al.
• CD38 expression has been associated with include an advanced stage of disease, poor responsiveness to chemotherapy, a shorter time before initial treatment is required, and a shorter survival time (Deaglio et al. (2003) Blood 102:2146-2155).
• a strong correlation between CD38 expression and IgV gene mutation was observed, with patients having unmutated V genes displaying higher percentages of CD38.sup.+ B-CLL cells than those with mutated V genes (Damle et al.
• p53 is a nuclear phosphoprotein that acts as a tumor suppressor. Wild-type p53 is involved in regulating cell growth and division. p53 binds to DNA, stimulating the production of a protein (p21) that interacts with a cell division-stimulating protein (cdk2). When p21 is bound to cdk2, the cell is blocked from entering the next stage of cell division. Mutant p53 is incapable of binding DNA effectively, thus preventing p21 from acting as the stop signal for cell division, resulting in uncontrolled cell division, and tumor formation. p53 also regulates the induction of programmed cell death (apoptosis) in response to DNA damage, cell stress or the aberrant expression of some oncogenes. Expression of wild type p53 in some cancer cell lines has been shown to restore growth suppression control (Casey et al. ( 1991 ) Oncogene 6: 1791-1797;
• B-2-microglobulin is an extracellular protein that is noncovalently associated with the .alpha, chain of the class I major histocompatibility complex (MHC). It is detectable in the serum, and is an adverse prognostic indicator in CLL (Keating et al. (1998) Blood 86:606a) and Hodgkin's lymphoma (Chronowski et al. (2002) Cancer 95:2534-2538). It is clinically used for lymphoproliferative diseases including leukemia, lymphoma, and multiple myeloma, where serum ⁇ -2-microglobulin levels are related to tumor cell load, prognosis, and disease activity (Bataille et al. (1983) Br. J. Haematol. 55:439-447; Aviles et al. (1992) Rev. Invest. Clin.
• P2 microglobulin is also useful in staging myeloma patients (Pasqualetti et al. (1991) Eur. J. Cancer 27: 1123-1126).
• Cytogenetic aberrations may also be used as markers to create a predictive profile of a hematological maligancy. For example, chromosome abnormalities are found in a large percentage of CLL patients and are helpful in predicting the course of CLL. For example, a 17p deletion is indicative of aggressive disease progression.
• CLL patients with a chromosome 17p deletion or mutation in p53, or both, are known to respond poorly to chemotherapeutics and rituximab.
• Allelic loss on chromosome 17p may be also be a useful prognostic marker in colorectal cancer, where patients with a 17p deletion are associated with an increased tendency of disease dissemination in colorectal cancer (Khine et al. (1994) Cancer 73:28-35).
• ATA4 The ataxia telangiectasia mutated (ATA4) gene is a tumor suppressor gene that is involved in cell cycle arrest, apoptosis, and repair of DNA double-strand breaks. It is found on chromosome 11. ATMmutations are associated with increased risk for breast cancer among women with a family history of breast cancer (Chenevix -Trench et al. (2002) J. Natl. Cancer Inst. 94:205-215; Thorstenson et al. (2003) Cancer Res. 63:3325-3333) and/or early-onset breast cancers (Izatt et al. (1999) Genes Chromosomes Cancer 26:286-294; Teraoka et al. (2001)
• the biomarkers that are evaluated in the methods described herein include the cell survival and apoptotic proteins described supra, and proteins involved in hematological maligancy-related signaling pathways. Determining the expression or presence can be at the protein or nucleic acid level. Thus, the biomarkers include these proteins and the genes encoding these proteins. Where detection is at the protein level, the biomarker protein comprises the full- length polypeptide or any detectable fragment thereof, and can include variants of these protein sequences.
• the biomarker nucleic acid includes DNA comprising the full-length coding sequence, a fragment of the full-length coding sequence, variants of these sequences, for example naturally occurring variants or splice- variants, or the complement of such a sequence.
• Biomarker nucleic acids also include RNA, for example, mRNA, comprising the full-length sequence encoding the biomarker protein of interest, a fragment of the full-length RNA sequence of interest, or variants of these sequences.
• Biomarker proteins and biomarker nucleic acids also include variants of these sequences.
• fragment is intended a portion of the polynucleotide or a portion of the amino acid sequence and hence protein encoded thereby.
• Polynucleotides that are fragments of a biomarker nucleotide sequence generally comprise at least 10, 15, 20, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, or 1,400 contiguous nucleotides, or up to the number of nucleotides present in a full-length biomarker polynucleotide disclosed herein.
• a fragment of a biomarker polynucleotide will generally encode at least 15, 25, 30, 50, 100, 150, 200, or 250 contiguous amino acids, or up to the total number of amino acids present in a full-length biomarker protein of the invention.
• "Variant” is intended to mean substantially similar sequences. Generally, variants of a particular biomarker of the invention will have at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to that biomarker as determined by sequence alignment programs known in the art.
• Circulating levels of biomarkers in a blood sample obtained from a candidate subject can be measured, for example, by ELISA, radioimmunoassay (RIA), electrochemiluminescence (ECL), Western blot, multiplexing technologies, or other similar methods.
• Cell surface expression of biomarkers can be measured, for example, by flow cytometry, immunohistochemistry, Western Blot, immunoprecipitation, magnetic bead selection, and quantification of cells expressing either of these cell surface markers.
• Biomarker RNA expression levels could be measured by RT-PCR, Qt-PCR, microarray, Northern blot, or other similar technologies.
• determining the expression or presence of the biomarker of interest at the protein or nucleotide level can be accomplished using any detection method known to those of skill in the art.
• detecting expression or “detecting the level of is intended determining the expression level or presence of a biomarker protein or gene in the biological sample.
• detecting expression encompasses instances where a biomarker is determined not to be expressed, not to be detectably expressed, expressed at a low level, expressed at a normal level, or overexpressed.
• the one or more subpopulation of lymphocytes are isolated, detected or measured. In certain embodiments, the one or more subpopulation of lymphocytes are isolated, detected or measured using immunophenotyping techniques. In other embodiments, the one or more subpopulation of lymphocytes are isolated, detected or measured using fluorescence activated cell sorting (FACS) techniques.
• FACS fluorescence activated cell sorting
• the one or more biomarkers comprises ZAP-70, CD5, t(14;18), CD38, ⁇ -2 microglobulin, p53 mutational status, ATM mutational status, chromosome 17p deletion, chromosome 1 lq deletion, surface or cytoplasmic immunoglobulin, CD138, CD25, 6q deletion, CD19, CD20, CD22, CDl lc, CD 103, chromosome 7q deletion, VH mutational status, or a combination thereof.
• the determining step requires determining the expression or presence of a combination of biomarkers.
• the combination of biomarkers is CD 19 and CD5 or CD20 and CD5.
• the expresssion or presence of these various biomarkers and any clinically useful prognostic markers in a biological sample can be detected at the protein or nucleic acid level, using, for example, immunohistochemistry techniques or nucleic acid-based techniques such as in situ hybridization and RT-PCR.
• the expression or presence of one or more biomarkers is carried out by a means for nucleic acid amplification, a means for nucleic acid sequencing, a means utilizing a nucleic acid microarray (DNA and RNA), or a means for in situ hybridization using specifically labeled probes.
• the determining the expression or presence of one or more biomarkers is carried out through gel electrophoresis. In one embodiment, the determination is carried out through transfer to a membrane and hybridization with a specific probe.
• the determining the expression or presence of one or more biomarkers carried out by a diagnostic imaging technique In other embodiments, the determining the expression or presence of one or more biomarkers carried out by a detectable solid substrate. In one embodiment, the detectable solid substrate is paramagnetic nanoparticles functionalized with antibodies.
• kits for detecting or measuring residual lymphoma following a course of treatment in order to guide continuing or discontinuing treatment or changing from one therapeutic regimen to another comprising determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes in a subject wherein the course of treatment is treatment with a Btk inhibitor.
• Methods for detecting expression of the biomarkers described herein, and optionally cytokine markers, within the test and control biological samples comprise any methods that determine the quantity or the presence of these markers either at the nucleic acid or protein level. Such methods are well known in the art and include but are not limited to western blots, northern blots, ELISA, immunoprecipitation, immunofluorescence, flow cytometry, immunohistochemistry, nucleic acid hybridization techniques, nucleic acid reverse transcription methods, and nucleic acid amplification methods.
• expression of a biomarker is detected on a protein level using, for example, antibodies that are directed against specific biomarker proteins. These antibodies can be used in various methods such as Western blot, ELISA, multiplexing technologies, immunoprecipitation, or immunohistochemistry techniques.
• detection of cytokine markers is accomplished by
• ECL electrochemiluminescence
• biomarker for example, biomarker, a biomarker of cell survival or proliferation, a biomarker of apoptosis, a biomarker of a Btk-mediated signaling pathway
• expression level of a biomarker protein of interest in a biological sample is detected by means of a binding protein capable of interacting specifically with that biomarker protein or a biologically active variant thereof.
• a binding protein capable of interacting specifically with that biomarker protein or a biologically active variant thereof.
• labeled antibodies, binding portions thereof, or other binding partners may be used.
• the word "label” when used herein refers to a detectable compound or composition that is conjugated directly or indirectly to the antibody so as to generate a "labeled" antibody.
• the label may be detectable by itself (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition that is detectable.
• the antibodies for detection of a biomarker protein may be monoclonal or polyclonal in origin, or may be synthetically or recombinantly produced.
• the amount of complexed protein for example, the amount of biomarker protein associated with the binding protein, for example, an antibody that specifically binds to the biomarker protein, is determined using standard protein detection methodologies known to those of skill in the art.
• a detailed review of immunological assay design, theory and protocols can be found in numerous texts in the art (see, for example, Ausubel et al, eds. (1995) Current Protocols in Molecular Biology) (Greene Publishing and Wiley-Interscience, NY)); Coligan et al, eds. (1994) Current Protocols in Immunology (John Wiley & Sons, Inc., New York, N.Y.).
• the choice of marker used to label the antibodies will vary depending upon the application. However, the choice of the marker is readily determinable to one skilled in the art.
• These labeled antibodies may be used in immunoassays as well as in histological applications to detect the presence of any biomarker or protein of interest.
• the labeled antibodies may be polyclonal or monoclonal.
• the antibodies for use in detecting a protein of interest may be labeled with a radioactive atom, an enzyme, a chromophoric or fluorescent moiety, or a colorimetric tag as described elsewhere herein.
• the choice of tagging label also will depend on the detection limitations desired. Enzyme assays (ELISAs) typically allow detection of a colored product formed by interaction of the enzyme -tagged complex with an enzyme substrate.
• Radionuclides that can serve as detectable labels include, for example, 1-131, 1-123, 1-125, Y-90, Re-188, Re-186, At-211, Cu-67, Bi-212, and Pd-109.
• enzymes that can serve as detectable labels include, but are not limited to, horseradish peroxidase, alkaline phosphatase, beta-galactosidase, and glucose-6-phosphate dehydrogenase.
• Chromophoric moieties include, but are not limited to, fluorescein and rhodamine.
• the antibodies may be conjugated to these labels by methods known in the art.
• enzymes and chromophoric molecules may be conjugated to the antibodies by means of coupling agents, such as dialdehydes, carbodiimides, dimaleimides, and the like.
• conjugation may occur through a ligand-receptor pair.
• suitable ligand-receptor pairs are biotin-avidin or biotin-streptavidin, and antibody- antigen.
• expression or presence of one or more biomarkers or other proteins of interest within a biological sample is determined by radioimmunoassays or enzyme-linked immunoassays (ELISAs), competitive binding enzyme-linked immunoassays, dot blot (see, for example, Promega Protocols and Applications Guide (2 nd ed.; Promega Corporation (1991), Western blot (see, for example, Sambrook et al. (1989) Molecular Cloning, A Laboratory Manual, Vol. 3, Chapter 18 (Cold Spring Harbor Laboratory Press, Plainview, N.Y.), chromatography, preferably high performance liquid chromatography (HPLC), or other assays known in the art.
• the detection assays can involve steps such as, but not limited to, immunoblotting,
• the methods of the invention are useful for identifying and treating hematological maligancys, including those listed above, that are refractory to (i.e., resistant to, or have become resistant to) first-line oncotherapeutic treatments.
• the expression or presence of one or more of the biomarkers described herein may also be determined at the nucleic acid level.
• Nucleic acid-based techniques for assessing expression are well known in the art and include, for example, determining the level of biomarker mRNA in a biological sample.
• Many expression detection methods use isolated RNA. Any RNA isolation technique that does not select against the isolation of mRNA can be utilized for the purification of RNA (see, e.g., Ausubel et al, ed. (1987-1999) Current Protocols in Molecular Biology (John Wiley & Sons, New York). Additionally, large numbers of tissue samples can readily be processed using techniques well known to those of skill in the art, such as, for example, the single-step RNA isolation process disclosed in U.S. Pat. No. 4,843,155.
• nucleic acid probe refers to any molecule that is capable of selectively binding to a specifically intended target nucleic acid molecule, for example, a nucleotide transcript. Probes can be synthesized by one of skill in the art, or derived from appropriate biological preparations. Probes may be specifically designed to be labeled, for example, with a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags that are discussed above or that are known in the art. Examples of molecules that can be utilized as probes include, but are not limited to, RNA and DNA.
• isolated mRNA can be used in hybridization or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction analyses and probe arrays.
• One method for the detection of mRNA levels involves contacting the isolated mRNA with a nucleic acid molecule (probe) that can hybridize to the mRNA encoded by the gene being detected.
• the nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least 7, 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to an mRNA or genomic DNA encoding a biomarker, biomarker described herein above. Hybridization of an mRNA with the probe indicates that the biomarker or other target protein of interest is being expressed.
• the mRNA is immobilized on a solid surface and contacted with a probe, for example by running the isolated mRNA on an agarose gel and transferring the mRNA from the gel to a membrane, such as nitrocellulose.
• the probe(s) are immobilized on a solid surface and the mRNA is contacted with the probe(s), for example, in a gene chip array.
• a skilled artisan can readily adapt known mRNA detection methods for use in detecting the level of mRNA encoding the biomarkers or other proteins of interest.
• An alternative method for determining the level of a mRNA of interest in a sample involves the process of nucleic acid amplification, e.g., by RT-PCR (see, for example, U.S. Pat. No. 4,683,202), ligase chain reaction (Barany (1991) Proc. Natl. Acad. Sci. USA 88: 189-193), self-sustained sequence replication (Guatelli et al. (1990) Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (Kwoh et al. (1989) Proc. Natl. Acad. Sci.
• biomarker expression is assessed by quantitative fluorogenic RT-PCR (i.e., the TaqMan® System).
• RNA of interest may be monitored using a membrane blot (such as used in hybridization analysis such as Northern, dot, and the like), or microwells, sample tubes, gels, beads or fibers (or any solid support comprising bound nucleic acids). See U.S. Pat. Nos. 5,770,722, 5,874,219, 5,744,305, 5,677,195 and 5,445,934, which are
• the detection of expression may also comprise using nucleic acid probes in solution.
• microarrays are used to determine expression or presence of one or more biomarkers.
• Microarrays are particularly well suited for this purpose because of the reproducibility between different experiments.
• DNA microarrays provide one method for the simultaneous measurement of the expression levels of large numbers of genes. Each array consists of a reproducible pattern of capture probes attached to a solid support. Labeled RNA or DNA is hybridized to complementary probes on the array and then detected by laser scanning. Hybridization intensities for each probe on the array are determined and converted to a quantitative value representing relative gene expression levels. See, U.S. Pat. Nos.
• High-density oligonucleotide arrays are particularly useful for determining the gene expression profile for a large number of R A's in a sample.
• arrays may be peptides or nucleic acids on beads, gels, polymeric surfaces, fibers such as fiber optics, glass or any other appropriate substrate, see U.S. Pat. Nos. 5,770,358, 5,789,162, 5,708,153, 6,040,193 and 5,800,992, each of which is hereby incorporated in its entirety for all purposes.
• Arrays may be packaged in such a manner as to allow for diagnostics or other manipulation of an all-inclusive device. See, for example, U.S. Pat. Nos. 5,856,174 and 5,922,591, herein incorporated by reference.
• compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used
• a pharmaceutical composition refers to a mixture of a compound described herein, such as, for example, compounds of Formula D or the second agent, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
• the pharmaceutical composition facilitates administration of the compound to an organism.
• therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated.
• the mammal is a human.
• a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
• the compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
• compositions may also include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
• acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids
• bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane
• buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
• acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
• compositions may also include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
• salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
• the term "pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
• the term "fixed combination” means that the active ingredients, e.g. a compound described herein and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
• the term “non-fixed combination” means that the active ingredients, e.g. a compound described herein and a co- agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
• cocktail therapy e.g. the administration of three or more active ingredients.
• the pharmaceutical formulations described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
• the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
• compositions including a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
• Antifoaming agents reduce foaming during processing which can result in coagulation of aqueous dispersions, bubbles in the finished film, or generally impair processing.
• Exemplary anti-foaming agents include silicon emulsions or sorbitan sesquoleate.
• Antioxidants include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. In certain embodiments, antioxidants enhance chemical stability where required.
• BHT butylated hydroxytoluene
• antioxidants enhance chemical stability where required.
• compositions provided herein may also include one or more preservatives to inhibit microbial activity.
• Suitable preservatives include mercury- containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
• Formulations described herein may benefit from antioxidants, metal chelating agents, thiol containing compounds and other general stabilizing agents.
• stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1%) to about 1% w/v methionine, (c) about 0.1 % to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.
• polysorbate 20 (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.
• Binders impart cohesive qualities and include, e.g., alginic acid and salts thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel ® ), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel ® ), ethylcellulose (e.g., Ethocel ® ), and micro crystalline cellulose (e.g., Avicel ® ); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonites; gelatin; polyvinylpyrrolidone/vinyl acetate copolymer; crosspovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac ® ), glucose, dextrose, molasses, mannitol, sorb
• a “carrier” or “carrier materials” include any commonly used excipients in pharmaceutics and should be selected on the basis of compatibility with compounds disclosed herein, such as, compounds of any of Formula D and the second agent, and the release profile properties of the desired dosage form.
• Exemplary carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like.
• “Pharmaceutically compatible carrier materials” may include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate,
• PVP polyvinylpyrrollidone
• cholesterol cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid, phosphotidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like.
• PVP polyvinylpyrrollidone
• Disposing agents include materials that control the diffusion and homogeneity of a drug through liquid media or a granulation method or blend method. In some embodiments, these agents also facilitate the effectiveness of a coating or eroding matrix.
• Exemplary diffusion facilitators/dispersing agents include, e.g., hydrophilic polymers, electrolytes, Tween ® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone ® ), and the carbohydrate-based dispersing agents such as, for example, hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
• HPMCAS noncrystalline cellulose, magnesium aluminum silicate, triethanolamine
• polyvinyl alcohol PVA
• vinyl pyrrolidone/vinyl acetate copolymer S630
• 4-(l,l,3,3-tetramethylbutyl)- phenol polymer with ethylene oxide and formaldehyde also known as tyloxapol
• poloxamers e.g., Pluronics F68 ® , F88 ® , and F108 ® , which are block copolymers of ethylene oxide and propylene oxide
• poloxamines e.g., Tetronic 908 ® , also known as Poloxamine 908 ® , which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)
• polyvinylpyrrolidone K12 polyvinylpyrrolidone K17
• polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, polysorbate-80, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium
• carboxymethylcellulose methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates, chitosans and combinations thereof.
• Plasticizcers such as cellulose or triethyl cellulose can also be used as dispersing agents.
• Dispersing agents particularly useful in liposomal dispersions and self-emulsifying dispersions are dimyristoyl phosphatidyl choline, natural phosphatidyl choline from eggs, natural phosphatidyl glycerol from eggs, cholesterol and isopropyl myristate.
• Combinations of one or more erosion facilitator with one or more diffusion facilitator can also be used in the present compositions.
• diluent refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution. In certain embodiments, diluents increase bulk of the composition to facilitate compression or create sufficient bulk for homogenous blend for capsule filling.
• Such compounds include e.g., lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel ® ; dibasic calcium phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugar, such as Di-Pac ® (Amstar); mannitol,
• hydroxypropylmethylcellulose hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents, confectioner's sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the like.
• disintegrate includes both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluid.
• disintegration agents or disintegrants facilitate the breakup or disintegration of a substance.
• disintegration agents include a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel ® , or sodium starch glycolate such as Promogel ® or Explotab ® , a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel ® , Avicel ® PH101, Avicel ® PH102, Avicel ® PH105, Elcema ® P100, Emcocel ® , Vivacel ® , Ming Tia ® , and Solka- Floe ® , methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carb
• Drug absorption typically refers to the process of movement of drug from site of administration of a drug across a barrier into a blood vessel or the site of action, e.g., a drug moving from the gastrointestinal tract into the portal vein or lymphatic system.
• enteric coating is a substance that remains substantially intact in the stomach but dissolves and releases the drug in the small intestine or colon.
• the enteric coating comprises a polymeric material that prevents release in the low pH environment of the stomach but that ionizes at a higher pH, typically a pH of 6 to 7, and thus dissolves sufficiently in the small intestine or colon to release the active agent therein.
• Erosion facilitators include materials that control the erosion of a particular material in gastrointestinal fluid. Erosion facilitators are generally known to those of ordinary skill in the art. Exemplary erosion facilitators include, e.g., hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.
• Filling agents include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
• “Flavoring agents” and/or “sweeteners” useful in the formulations described herein include, e.g., acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet ® ), maltol, mannitol, maple,
• Lubricants and “glidants” are compounds that prevent, reduce or inhibit adhesion or friction of materials.
• exemplary lubricants include, e.g., stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex ® ), higher fatty acids and their alkali- metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet ® , boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol (e.g., PEG-4000) or a methoxypolyethylene glycol such as CarbowaxTM, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl
• a "measurable serum concentration” or “measurable plasma concentration” describes the blood serum or blood plasma concentration, typically measured in mg, ⁇ g, or ng of therapeutic agent per ml, dl, or 1 of blood serum, absorbed into the bloodstream after administration. As used herein, measurable plasma concentrations are typically measured in ng/ml or Dg/ml.
• "Pharmacodynamics” refers to the factors which determine the biologic response observed relative to the concentration of drug at a site of action.
• Pharmacokinetics refers to the factors which determine the attainment and maintenance of the appropriate concentration of drug at a site of action.
• Plasticizers are compounds used to soften the microencapsulation material or film coatings to make them less brittle.
• Suitable plasticizers include, e.g., polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, triethyl cellulose and triacetin.
• plasticizers can also function as dispersing agents or wetting agents.
• Solubilizers include compounds such as triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide and the like.
• Stabilizers include compounds such as any antioxidation agents, buffers, acids, preservatives and the like.
• Step state is when the amount of drug administered is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant plasma drug exposure.
• Suspending agents include compounds such as polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or
• polyvinylpyrrolidone K30 vinyl pyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol
• the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,
• “Surfactants” include compounds such as sodium lauryl sulfate, sodium docusate,
• Tween 60 or 80 triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic ® (BASF), and the like.
• Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g. , polyoxyethylene (60)
• surfactants may be included to enhance physical stability or for other purposes.
• Viscosity enhancing agents include, e.g., methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
• hydroxypropylmethyl cellulose acetate stearate hydroxypropylmethyl cellulose phthalate, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.
• Weight agents include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate, sodium doccusate, triacetin, Tween 80, vitamin E TPGS, ammonium salts and the like.
• compositions described herein can be formulated for administration to a subject via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal or transdermal administration routes.
• parenteral e.g., intravenous, subcutaneous, or intramuscular
• buccal e.g., intranasal, rectal or transdermal administration routes.
• compositions described herein which include a compound of any of Formula D or the second agent can be formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a patient to be treated, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent
• compositions lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
• Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
• Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium
• carboxymethylcellulose or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
• PVP polyvinylpyrrolidone
• disintegrating agents may be added, such as the cross-linked
• croscarmellose sodium polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
• Dragee cores are provided with suitable coatings.
• suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc,
• polyvinylpyrrolidone carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different
• compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
• the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
• stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
• the solid dosage forms disclosed herein may be in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol.
• a tablet including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet
• a pill including a sterile
• the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a fast-melt tablet. Additionally, pharmaceutical formulations described herein may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets.
• solid dosage forms e.g., tablets, effervescent tablets, and capsules
• solid dosage forms are prepared by mixing particles of a compound of any of Formula (A1-A6), Formula (B1-B6), Formula (C1-C6), or Formula (D1-D6), with one or more pharmaceutical excipients to form a bulk blend composition.
• a bulk blend composition e.g., tablets, effervescent tablets, and capsules
• Formula (B1-B6), Formula (C1-C6), or Formula (D1-D6) are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.
• the individual unit dosages may also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent. These formulations can be manufactured by conventional pharmacological techniques.
• Conventional pharmacological techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al, The Theory and Practice of
• the pharmaceutical solid dosage forms described herein can include a compound described herein and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.
• a compatible carrier such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.
• a film coating is provided around the formulation of the compound of any of Formula (A1-A6), Formula (B1-B6), Formula (C1-C6), or Formula (D1-D6).
• some or all of the particles of the compound of any of Formula (A1-A6), Formula (B1-B6), Formula (C1-C6), or Formula (D1-D6) are coated.
• some or all of the particles of the compound of any of Formula (A1-A6), Formula (B1-B6), Formula (C1-C6), or Formula (D1-D6) are microencapsulated.
• the particles of the compound of any of Formula (A1-A6), Formula (B1-B6), Formula (C1-C6), or Formula (D1-D6) are not microencapsulated and are uncoated.
• Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose,
• hydroxypropylmethylcellulose acetate stearate sucrose, micro crystalline cellulose, lactose, mannitol and the like.
• Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC),
• HPLC HPLC
• sucrose sucrose
• xylitol lactitol
• mannitol sorbitol
• sodium chloride polyethylene glycol, and the like.
• Formula (C1-C6), or Formula (D1-D6) from a solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage forms are compressed with binder. Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form.
• Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel ® , or sodium starch glycolate such as Promogel ® or Explotab ® , a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel ® , Avicel ® PH101, Avicel ® PH102, Avicel ® PH105, Elcema ® PI 00, Emcocel ® , Vivacel ® , Ming Tia ® , and Solka-Floc ® , methylcellulose,
• croscarmellose or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol ® ), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross- linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum ® HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like.
• Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step.
• Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to,
• carboxymethylcellulose methylcellulose (e.g., Methocel ® ), hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel ® ), ethylcellulose (e.g., Ethocel ® ), and microcrystalline cellulose (e.g., Avicel ® ), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin,
• polyvinylpyrrolidone/vinyl acetate copolymer crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac ® ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab ® ), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone ® CL, Kollidon ® CL, Polyplasdone ® XL- 10, and Povidone ® K-12), larch arabogalactan, Veegum ® , polyethylene glycol, waxes, sodium alginate, and the like.
• sucrose
• binder levels of 20-70% are used in powder- filled gelatin capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binder. Formulators skilled in art can determine the binder level for the formulations, but binder usage level of up to 70% in tablet formulations is common.
• Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet ® , boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as CarbowaxTM, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.
• stearic acid calcium hydroxide, talc
• Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like.
• non water-soluble diluent represents compounds typically used in the formulation of pharmaceuticals, such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose, and microcellulose (e.g., having a density of about 0.45 g/cm , e.g. Avicel, powdered cellulose), and talc.
• Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10 ® ), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like.
• quaternary ammonium compounds e.g., Polyquat 10 ®
• sodium oleate sodium lauryl sulfate
• magnesium stearate sodium docusate
• triacetin vitamin E TPGS and the like.
• Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic ® (BASF), and the like.
• Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30,
• polyethylene glycol e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium
• carboxymethylcellulose hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.
• Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
• BHT butylated hydroxytoluene
• sodium ascorbate sodium ascorbate
• tocopherol sodium ascorbate
• additives used in the solid dosage forms described herein there is considerable overlap between additives used in the solid dosage forms described herein.
• the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms described herein.
• the amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.
• one or more layers of the pharmaceutical formulation are plasticized.
• a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol,
• polyethylene glycol triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
• Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulations described above.
• compressed tablets which are designed to dissolve in the mouth will include one or more flavoring agents.
• the compressed tablets will include a film surrounding the final compressed tablet.
• the film coating can provide a delayed release of the compound of of any of Formula D or the second agent, from the formulation.
• the film coating aids in patient compliance (e.g., Opadry ® coatings or sugar coating). Film coatings including Opadry ® typically range from about 1% to about 3% of the tablet weight.
• the compressed tablets include one or more excipients.
• a capsule may be prepared, for example, by placing the bulk blend of the formulation of the compound of any of Formula D or the second agent, described above, inside of a capsule.
• the formulations non-aqueous suspensions and solutions
• the formulations are placed in a soft gelatin capsule.
• the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC.
• the formulation is placed in a sprinkle capsule, wherein the capsule may be swallowed whole or the capsule may be opened and the contents sprinkled on food prior to eating.
• the therapeutic dose is split into multiple (e.g., two, three, or four) capsules.
• the entire dose of the formulation is delivered in a capsule form.
• the particles of the compound of any of Formula D or the second agent, and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the formulation into the gastrointestinal fluid.
• dosage forms may include microencapsulated formulations.
• one or more other compatible materials are present in the formulations.
• microencapsulation material examples include, but are not limited to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.
• Materials useful for the microencapsulation described herein include materials compatible with compounds of any of Formula D or the secodn agent, which sufficiently isolate the compound of any of Formula D or the secodn agent, from other non-compatible excipients.
• Materials compatible with compounds of any of Formula D or the secodn agent are those that delay the release of the compounds of of any of Formula D or the secodn agent, in vivo.
• microencapsulation materials useful for delaying the release of the formulations including compounds described herein include, but are not limited to,
• HPC hydroxypropyl cellulose ethers
• L-HPC low-substituted hydroxypropyl cellulose ethers
• HPMC hydroxypropyl methyl cellulose ethers
• Seppifilm-LC Pharmacoat ® , Metolose SR, Methocel ® -E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel ® -A,
• hydroxypropylmethylcellulose acetate stearate Aqoat HF-LS, HF-LG,HF-MS
• Metolose ® Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel ® , Aqualon ® -EC, Surelease ® , Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such as Natrosol ® , carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aqualon ® -CMC, polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR ® , monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit ® EPO, Eudragit ® L30D- 55, Eudragit ® FS 30D Eudragit ®
• plasticizers such as polyethylene glycols, e.g., PEG
• microencapsulation material 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material.
• compositions is from the USP or the National Formulary (NF).
• the microencapsulation material is Klucel.
• the microencapsulation material is methocel.
• Microencapsulated compounds of any of Formula D or the secodn agent may be formulated by methods known by one of ordinary skill in the art. Such known methods include, e.g., spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath.
• several chemical techniques e.g., complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, in-liquid drying, and desolvation in liquid media could also be used.
• other methods such as roller compaction, extrusion/spheronization, coacervation, or nanoparticle coating may also be used.
• the particles of compounds of any of Formula D or the secodn agent are microencapsulated prior to being formulated into one of the above forms.
• some or most of the particles are coated prior to being further formulated by using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).
• Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
• a powder including the formulations with a compound of any of Formula D or the secodn agent, described herein may be formulated to include one or more pharmaceutical excipients and flavors.
• Such a powder may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend
• effervescent powders are also prepared in accordance with the present disclosure.
• Effervescent salts have been used to disperse medicines in water for oral administration.
• Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid.
• effervescent salts include, e.g., the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and/or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6.0 or higher.
• the solid dosage forms described herein can be formulated as enteric coated delayed release oral dosage forms, i.e., as an oral dosage form of a
• the enteric coated dosage form may be a compressed or molded or extruded tablet/mold (coated or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated.
• the enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.
• delayed release refers to the delivery so that the release can be accomplished at some generally predictable location in the intestinal tract more distal to that which would have been accomplished if there had been no delayed release alterations.
• the method for delay of release is coating. Any coatings should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract.
• the polymers described herein are anionic carboxylic polymers.
• the polymers and compatible mixtures thereof, and some of their properties include, but are not limited to:
• Shellac also called purified lac, a refined product obtained from the resinous
• Acrylic polymers The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers.
• the Eudragit series E, L, S, RL, RS and NE are available as solubilized in organic solvent, aqueous dispersion, or dry powders.
• the Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for colonic targeting.
• the Eudragit series E dissolve in the stomach.
• the Eudragit series L, L-30D and S are insoluble in stomach and dissolve in the intestine;
• cellulose derivatives are: ethyl cellulose; reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance can vary based on the degree and type of substitution.
• Cellulose acetate phthalate (CAP) dissolves in pH >6.
• Aquateric (FMC) is an aqueous based system and is a spray dried CAP psuedolatex with particles ⁇ 1 ⁇ .
• Other components in Aquateric can include pluronics, Tweens, and acetylated monoglycerides.
• suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman);
• methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and
• hydroxypropylmethylcellulose acetate succinate e.g., AQOAT (Shin Etsu)
• HPMCP such as, HP-50, HP-55, HP-55S, HP-55F grades are suitable.
• suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.
• AS-LG LF
• AS-MG MF
• HF AS-HG
• PVAP Poly Vinyl Acetate Phthalate
• PVAP dissolves in pH >5, and it is much less permeable to water vapor and gastric fluids.
• the coating can, and usually does, contain a plasticizer and possibly other coating excipients such as colorants, talc, and/or magnesium stearate, which are well known in the art.
• Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin
• anionic carboxylic acrylic polymers usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate,
• polyethylene glycol triethyl citrate and triacetin.
• Conventional coating techniques such as spray or pan coating are employed to apply coatings.
• the coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is reached.
• Colorants e.g., carnuba wax or PEG may be added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product.
• lubricants e.g., carnuba wax or PEG
• the formulations described herein which include compounds of Formula D or the secodn agent, are delivered using a pulsatile dosage form.
• a pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites.
• Many other types of controlled release systems known to those of ordinary skill in the art and are suitable for use with the formulations described herein. Examples of such delivery systems include, e.g., polymer-based systems, such as polylactic and polyglycolic acid, plyanhydrides and
• polycaprolactone porous matrices, nonpolymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like.
• lipids including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides
• hydrogel release systems silastic systems
• peptide-based systems wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like.

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