Combination of Agents Including Abemaciclib and a PI3K Inhibitor and / or an mTOR Inhibitor for the Treatment of Mantle Cell Lymphoma

Abstract

Provided herein are combination therapies for use in methods for treating mantle cell lymphoma in a patient in need of such treatment.

Description

[Technical field]

[0001] The present disclosure relates to a combination of abemaciclib, or a pharmaceutically acceptable salt thereof, and a PI3K inhibitor and / or an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of mantle cell lymphoma (MCL). [Background technology]

[0002] Mantle cell lymphoma is a relatively rare and aggressive B-cell non-Hodgkin lymphoma (NHL), accounting for approximately 5-10% of all NHL diagnoses.

[0003] Non-Hodgkin's lymphoma is a type of cancer that affects lymphatic system.Mantle cell lymphoma is a rare form of NHL that arises from the malignant transformation of B-cell lymphocytes in the outer edge of lymph node follicles known as mantle zone.Mantle cell lymphoma is a recognized pathological condition in the art, and currently affects approximately 5,000 patients per year in the United States alone.

[0004] Mantle cell lymphoma is an aggressive and rapidly growing class of NHL that is associated with a poor prognosis due to limited suitable therapeutic options. Overall, the outlook is poor, with a median overall survival of approximately 6-7 years, which is significantly shorter than the median overall survival for indolent subtypes of NHL such as follicular lymphoma.

[0005] First-line therapy for MCL typically consists of intensive chemotherapy followed by autologous stem cell transplant for matched transplant-eligible patients. Patients typically eventually relapse with a progressive clinical course. No specific chemotherapy has been established as the standard of care for MCL, and practice varies from institution to institution. Some common treatment regimens for relatively well-matched patients include rituximab / dexamethasone / cytarabine / cisplatin (R-DHAP) alternating with rituximab / cyclophosphamide / doxorubicin / vincristine / prednisone (R-CHOP) (R-CHOP / R-DHAP), or rituximab / hyperfractionated cyclophosphamide / vincristine / doxorubicin / dexamethasone alternating with high-dose methotrexate and cytarabine (R-hyperCVAD). For poorly matched patients, regimens such as bendamustine / rituximab (BR) or R-CHOP are administered with or without maintenance rituximab. Following disease progression, targeted agents such as ibrutinib, lenalidomide, bortezomib, or venetoclax are often used sequentially as monotherapy. Unfortunately, treatment is typically ultimately unsuccessful, and relapse and progression are typically observed. To further complicate matters, therapies that may be successful against other forms of B-cell malignancies or NHL are often ineffective against MCL.

[0006] Furthermore, the therapeutic regimens used in attempts to treat MCL are often accompanied by significant adverse side effects. For example, common side effects associated with chemotherapy used for MCL include neutropenia, infections, leukopenia, fatigue, nausea, alopecia, stomatitis, diarrhea, anemia, rash, asthenia, thrombocytopenia, vomiting, loss of appetite, dry skin, fever, and dysgeusia. These and other side effects contribute to issues surrounding patient compliance, the need to provide additional medications to address such side effects, and the like.

[0007] Thus, there is an urgent need for new treatments for MCL that may expand the range of treatment options for patients and / or that may involve reduced side effects and / or increased patient compliance and / or that may reduce the need for additional therapy to alleviate such side effects.

[0008] Abemaciclib (LY2835219), i.e. [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzimidazol-5-yl)-pyrimidin-2-yl]-amine, is a CDK inhibitor that targets the CDK4 and CDK6 cell cycle pathways and has antitumor activity. Abemaciclib, including salt forms, and methods of making and using the compound, including for the treatment of cancer, more preferably for the treatment of breast cancer, are disclosed in WO 2010 / 075074.

[0009] Phosphoinositide 3 (PI3)-kinase (PI3K) is a group of cell membrane-associated lipid kinases. PI3K plays a role in oncogenesis as a key component of the PI3K / AKT / mTor signaling pathway and plays a key role in cell growth, proliferation, survival, and metabolism. MCL is associated with deregulation of this pathway, especially in ibrutinib-resistant MCL.

[0010] Class I PI3K consists of four isoforms: p110α, p110β, p110δ, and p110γ. Mutations in the gene encoding p110α, phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA), are common in a wide variety of cancer types, making PIK3CA the most commonly mutated oncogene.

[0011] Therefore, PI3K is considered as a therapeutic target in cancer treatment. Various PI3K inhibitors have been developed and proposed for use in the treatment of various cancers. Some known PI3K inhibitors include copanlisib (BAY80-6946), pictilisib (GDC-0941), sonolicisib (PX-866), TG100-115, CH5132799, piralalisib (XL147), ZSTK474, buparlisib (BKM-120), fimepinostat (CUDC-907), and rigosertib (ON-01910).

[0012] Moreover, certain PI3K inhibitors are inhibitors that are specific for one or more isoforms of PI3K. These include AZD8835 (PI3K delta / alpha), WX-037 (PI3K alpha), AZD8186 (PI3K beta / delta), KA2237 (PI3K beta / delta), acalisib (GS-9820 / CAL-120) (PI3K beta / delta), zandelisib (ME401 / PWT-143) (PI3K delta), AMG319 (PI3K delta), GSK2636771 (PI3K beta), palsaclisib (INCB050465) (PI3K delta), theravelisib (INK-1117) (PI3K alpha), umbralisib (TGR-1202) (PI3K delta), tenalisib (RP6530) (PI3K δ / γ), taselisib (GDC-0032)(PI3K α / δ / γ), alpelisib (BYL719)(PI3K α), duvelisib (IPI-145)(PI3K δ / γ), and idelalisib (CAL-101)(PI3K δ).

[0013] Further inhibitors of PI3K are also inhibitors of mTOR, as detailed below.

[0014] Deregulated activity of mTOR is involved in many pathophysiological conditions, including cancers such as breast, prostate, lung, liver, and kidney cancer, as well as lymphoma. Upregulation of mTOR signaling can promote tumor growth and progression through diverse mechanisms, such as promoting growth factor receptor signaling, angiogenesis, glycolysis, lipid metabolism, cancer cell migration, and suppressing autophagy. Various mTOR inhibitors have been developed and proposed for use in the treatment of various cancers, such as mantle cell lymphoma. These include rapamycins themselves (rapalogs), such as sirolimus, nab-rapamycin, temsirolimus, everolimus, and ridaforolimus, as well as ATP-competitive mTOR inhibitors, such as OSI-027, bistusertib (AZD2014), sapanisertib (MLN0128 / INK128 / TAK-228), tolquinib (PP242), ML-223, and AZD8055.

[0015] Compounds that inhibit both PI3K and mTOR are called dual PI3K / mTOR inhibitors. Examples include samotricisib (LY3023414), BGT-226, DS-7423, PF-04691502, PKI-179, omipalisib (GSK2126458 / GSK458), panulisib (P7170), SB2343 / VS-5584, dactolisib (BEZ235), paxalisib (GDC-0084), apitolisib (GDC-0980), bimiralisib (PQR309), voxtalisib (SAR245409 / XL765), SF-1126, gedatolisib (PF-05212384 / PKI-587), XH00230381967, and SN20229799306.

[0016] Certain combinations of CDK4 / 6 inhibitors and PI3K inhibitors have been disclosed in WO 2018 / 017410 and WO 2018 / 063873, which also disclose their potential use in the treatment of advanced or metastatic breast cancer and pancreatic cancer, respectively. Despite such disclosures, broadly applicable therapies for cancer, particularly mantle cell lymphoma, remain elusive, and more alternative therapies that may be effective in treating patients with mantle cell lymphoma are needed. The present invention discloses a method for treating mantle cell lymphoma using a combination of abemaciclib and a PI3K inhibitor and / or an mTOR inhibitor, which may provide patients with a new treatment option and may provide, in some patients, a superior and / or unexpected beneficial therapeutic effect than the therapeutic effect of each agent alone. Summary of the Invention

[0017] Provided herein are methods of treating mantle cell lymphoma in a patient in need of such treatment, comprising administering to the patient an effective amount of abemaciclib, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a PI3K inhibitor and / or an mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the PI3K inhibitor and / or mTOR inhibitor is a dual PI3K / mTOR inhibitor. In some embodiments, the PI3K inhibitor and / or mTOR inhibitor is a pan-PI3K inhibitor. In some embodiments, the PI3K inhibitor and / or mTOR inhibitor is a pan-PI3K inhibitor. In some embodiments, the PI3K inhibitor and / or mTOR inhibitor is copanlisib (BAY80-6946), samotricisib (LY3023414), BGT-226, DS-7423, PF-04691502, PKI-179, omipalisib (GSK2126458 / GSK458), panulisib (P7170), SB2343 / VS-5584, dactolisib (BEZ235), paxalisib (GDC-0084), apitolisib (GDC-0980), Bimiralisib (PQR309), voxtalisib (SAR245409 / XL765), SF-1126, gedatolicib (PF-05212384 / PKI-587), XH00230381967, SN20229799306, pictilisib (GDC-0941), sonolisib (PX-866), TG100-115, CH5132799, piralalisib (XL147), ZSTK474, buparlisib (BKM-120), fimepinostat (CUDC-90 7), rigosertib (ON-01910), AZD8835, WX-037, AZD8186, KA2237, acalisib (GS-9820 / CAL-120), zandelisib (ME401 / PWT-143), AMG319, GSK2636771, parsaclisib (INCB050465), selavelisib (INK-1117), umbralisib (TGR-1202), tenalisib (RP6530), taselisib (GDC-0032), alpelisib (BYL71 9), duvelisib (IPI-145), and idelalisib (CAL-101), sirolimus, nab-rapamycin, temsirolimus, everolimus, ridaforolimus, OSI-027, bistusertib (AZD2014), sapanisertib (MLN0128 / INK128 / TAK-228), tolquinib (PP242), ML-223, and AZD8055, and prodrugs, metabolites, and derivatives thereof, and pharma- ceutically acceptable salts thereof.In some embodiments, the PI3K inhibitor and / or mTOR inhibitor is copanlisib (BAY80-6946) or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the mantle cell lymphoma has acquired resistance to one or more BCL-2 inhibitors. In some embodiments, the mantle cell lymphoma has acquired resistance to venetoclax. In some embodiments, the mantle cell lymphoma has acquired resistance to ibrutinib.

[0020] In some embodiments, the mantle cell lymphoma is selected from, or characterized as, nodal mantle cell lymphoma, and leukemic non-nodal mantle cell lymphoma. In some embodiments, the mantle cell lymphoma is selected from, or characterized as, refractory mantle cell lymphoma and / or relapsed mantle cell lymphoma.

[0021] In some embodiments, the mantle cell lymphoma is associated with one or more mutations in ATM, TP53, CCND1, KMT2D, CDK2NA, BIRC3, CDKN2B, KHSC1, SMARCA4, SDHD, UBR5, NOTCH1, CARD11, SAMHD1, BCL10, MEF2B, IRS2, FGF19, FGF4, FGF3, FAT1, ROBO1, DIS3, CRLF2, CDKN2C, ARID2, ARID1A, ARID1B, NOTCH2, BCOR, TRAF2, TRAF3, MAP3K14, MYD88, BKT, PCLG2, BCL2, KMT2D, and CELSR3.

[0022] In some embodiments, the mantle cell lymphoma is associated with cyclin D1 overexpression, t(11;14) and / or t(11;14)(q13;q32) translocation, Ki67 overexpression, lactate dehydrogenase overexpression, and / or beta-2 microglobulin overexpression.

[0023] In some embodiments, the mantle cell lymphoma is retinoblastoma protein (Rb) proficient.

[0024] In some embodiments, the method further comprises administering to the patient an effective amount of a BTK inhibitor. In some embodiments, the method further comprises administering to the patient an effective amount of one or more additional agents selected from fulvestrant or a pharma- ceutically acceptable salt thereof, an aromatase inhibitor or a pharma- ceutically acceptable salt thereof, an AR inhibitor, an immune checkpoint inhibitor such as a PD-L1 inhibitor or a PD-1 inhibitor, a CDK4 / 6 inhibitor, an AKT inhibitor, a cyclin E / CDK2 inhibitor, an autophagy inhibitor, an anti-EGFR inhibitor, and a PARP inhibitor.

[0025] Also provided herein is a combination of abemaciclib or a pharmaceutically acceptable salt thereof with a PI3K inhibitor and / or an mTOR inhibitor or a pharmaceutically acceptable salt thereof for use in treating mantle cell lymphoma in a patient in need of such treatment. Also provided is abemaciclib or a pharmaceutically acceptable salt thereof for use in treating mantle cell lymphoma in a patient in need of such treatment, comprising administering to the patient the abemaciclib or a pharmaceutically acceptable salt thereof in combination with a PI3K inhibitor and / or an mTOR inhibitor or a pharmaceutically acceptable salt thereof. Further provided is a PI3K inhibitor and / or an mTOR inhibitor or a pharmaceutically acceptable salt thereof for use in treating mantle cell lymphoma in a patient in need of such treatment, comprising administering to the patient the PI3K inhibitor and / or the mTOR inhibitor or a pharmaceutically acceptable salt thereof in combination with abemaciclib or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the use comprises administering to the patient simultaneously, separately or sequentially the abemaciclib, or a pharmaceutically acceptable salt thereof, and the PI3K inhibitor and / or the mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the PI3K inhibitor and / or mTOR inhibitor is a dual PI3K / mTOR inhibitor. In some embodiments, the PI3K inhibitor and / or mTOR inhibitor is a pan-PI3K inhibitor. In some embodiments, the PI3K inhibitor and / or mTOR inhibitor is a pan-PI3K inhibitor. In some embodiments, the PI3K inhibitor and / or mTOR inhibitor is copanlisib (BAY80-6946), samotricisib (LY3023414), BGT-226, DS-7423, PF-04691502, PKI-179, omipalisib (GSK2126458 / GSK458), panulisib (P7170), SB2343 / VS-5584, dactolisib (BEZ235), paxalisib (GDC-0084), apitolisib (GDC-0980), Bimiralisib (PQR309), voxtalisib (SAR245409 / XL765), SF-1126, gedatolicib (PF-05212384 / PKI-587), XH00230381967, SN20229799306, pictilisib (GDC-0941), sonolisib (PX-866), TG100-115, CH5132799, piralalisib (XL147), ZSTK474, buparlisib (BKM-120), fimepinostat (CUDC-90 7), rigosertib (ON-01910), AZD8835, WX-037, AZD8186, KA2237, acalisib (GS-9820 / CAL-120), zandelisib (ME401 / PWT-143), AMG319, GSK2636771, parsaclisib (INCB050465), selavelisib (INK-1117), umbralisib (TGR-1202), tenalisib (RP6530), taselisib (GDC-0032), alpelisib (BYL71 9), duvelisib (IPI-145), and idelalisib (CAL-101), sirolimus, nab-rapamycin, temsirolimus, everolimus, ridaforolimus, OSI-027, bistusertib (AZD2014), sapanisertib (MLN0128 / INK128 / TAK-228), tolquinib (PP242), ML-223, and AZD8055, and prodrugs, metabolites, and derivatives thereof, and pharma- ceutically acceptable salts thereof.In some embodiments, the PI3K inhibitor and / or mTOR inhibitor is copanlisib (BAY80-6946) or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the mantle cell lymphoma has acquired resistance to a BCL-2 inhibitor. In some embodiments, the mantle cell lymphoma has acquired resistance to venetoclax. In some embodiments, the mantle cell lymphoma has acquired resistance to ibrutinib.

[0029] In some embodiments, the mantle cell lymphoma is selected from, or characterized as, nodal mantle cell lymphoma, and leukemic non-nodal mantle cell lymphoma. In some embodiments, the mantle cell lymphoma is selected from, or characterized as, refractory mantle cell lymphoma and / or relapsed mantle cell lymphoma.

[0030] In some embodiments, the mantle cell lymphoma is associated with one or more mutations in ATM, TP53, CCND1, KMT2D, CDK2NA, BIRC3, CDKN2B, KHSC1, SMARCA4, SDHD, UBR5, NOTCH1, CARD11, SAMHD1, BCL10, MEF2B, IRS2, FGF19, FGF4, FGF3, FAT1, ROBO1, DIS3, CRLF2, CDKN2C, ARID2, ARID1A, ARID1B, NOTCH2, BCOR, TRAF2, TRAF3, MAP3K14, MYD88, BKT, PCLG2, BCL2, KMT2D, and CELSR3.

[0031] In some embodiments, the mantle cell lymphoma is associated with cyclin D1 overexpression, t(11;14) and / or t(11;14)(q13;q32) translocation, Ki67 overexpression, lactate dehydrogenase overexpression, and / or beta-2 microglobulin overexpression. In some embodiments, the mantle cell lymphoma is retinoblastoma protein (Rb) functional.

[0032] In some embodiments, the use comprises further administering to the patient an effective amount of a BTK inhibitor, hi some embodiments, the use comprises further administering to the patient an effective amount of one or more additional agents selected from fulvestrant or a pharma- ceutically acceptable salt thereof, an aromatase inhibitor or a pharma- ceutically acceptable salt thereof, an AR inhibitor, an immune checkpoint inhibitor such as a PD-L1 inhibitor or a PD-1 inhibitor, a CDK4 / 6 inhibitor, an AKT inhibitor, a cyclin E / CDK2 inhibitor, an autophagy inhibitor, an anti-EGFR inhibitor, and a PARP inhibitor.

[0033] Further provided herein is the use of a combination of abemaciclib or a pharmaceutically acceptable salt thereof and a PI3K inhibitor and / or an mTOR inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of mantle cell lymphoma in a patient in need of such treatment.Also provided is the use of abemaciclib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of mantle cell lymphoma in a patient in need of such treatment by administering abemaciclib or a pharmaceutically acceptable salt thereof in combination with a PI3K inhibitor and / or an mTOR inhibitor or a pharmaceutically acceptable salt thereof to the patient in need of such treatment.Also provided is the PI3K inhibitor and / or the mTOR inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of mantle cell lymphoma in a patient in need of such treatment by administering a PI3K inhibitor and / or an mTOR inhibitor or a pharmaceutically acceptable salt thereof in combination with abemaciclib or a pharmaceutically acceptable salt thereof to the patient in need of such treatment. Typically, the PI3K inhibitor and / or mTOR inhibitor, mantle cell lymphoma, treatment and / or the patient are as defined herein. [Brief description of the drawings]

[0034] [Figure 1-1]Abemaciclib induces cytotoxicity and leads to cell cycle arrest in the G1 phase of MCL cell lines. A. Immunoblot evaluation of cell cycle regulators highly expressed in primary MCL patients and MCL cell lines. [Figure 1-2] Abemaciclib induces cytotoxicity and results in cell cycle arrest in G1 phase in MCL cell lines. B. Abemaciclib can inhibit cell growth in MCL cell lines after exposure to different concentrations of Abemaciclib for 72 hours (0.2E6 / ml). IC50 values ​​are shown in the table on the right. [Figure 1-3] Abemaciclib induces cytotoxicity and results in cell cycle arrest in G1 phase of MCL cell lines. C. Abemaciclib causes cell cycle arrest in G1 phase after 24 hours exposure of MCL cell lines to Abemaciclib. Results are shown for three biological replicates. [Figure 2-1] Abemaciclib in combination with copanlisib can synergistically inhibit MCL cells. A. The combination of abemaciclib and copanlisib can induce greater cytotoxicity than either agent alone after 72 hours of treatment. [Figure 2-2] Abemaciclib in combination with copanlisib can synergistically inhibit MCL cells. B. In the venetoclax-resistant MCL cell line JeKo-1, the combination down-regulated p-mTOR and phospho-p70S6K. Furthermore, the combination can down-regulate Bcl-xL. [Figure 3-1] The combination of abemaciclib and copanlisib shows strong antitumor effects in Mino-venetoclax-resistant derived xenograft models. A. Mino-venetoclax-resistant tumors were treated with venetoclax (5 mg / kg daily, orally), abemaciclib (25 mg / kg daily, orally), copanlisib (5 mg / kg IP, three times weekly), and the combination of abemaciclib and copanlisib. Tumor burden was calculated by measuring tumor volume (n=5, p<0.0001). B. Tumor weight was calculated. [Figure 3-2]The combination of abemaciclib and copanlisib shows strong antitumor effects in a Mino-venetoclax resistance-derived xenograft model. C. Tumor size was shown at the end of the experiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] The present invention will be described with respect to certain embodiments and with reference to certain drawings, but the present invention is not limited thereto, but only by the claims. Any reference signs in the claims should not be interpreted as limiting the scope. Of course, it should be understood that not all aspects or advantages can be realized in accordance with any particular embodiment of the present invention. Thus, for example, a person skilled in the art will recognize that the present invention can be embodied or performed in a manner that realizes or optimizes one or a group of advantages as taught herein, without necessarily realizing other aspects or advantages as may be taught or suggested herein.

[0036] Additionally, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0037] All publications, patents, and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

[0038] definition The following terms or definitions are provided solely to aid in the understanding of the present invention. Unless specifically defined herein, all terms used herein have the same meaning as they would have to one of ordinary skill in the art of the present invention. For definitions and terminology of practitioners, see, inter alia, Remington: The Science and Practice of Pharmacy, LV Allen, Editor, 22 ndEdition, Pharmaceutical Press, 2012. The definitions provided herein should not be construed to have a scope narrower than understood by a person of ordinary skill in the art.

[0039] As used herein, "about" when referring to a measurable value, such as an amount, duration, and the like, is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and even more preferably ±0.1% from the particular value, where such variations are appropriate for performing the disclosed methods.

[0040] As used herein, a "PI3K inhibitor" is a compound that directly or indirectly reduces the enzymatic activity of one or more classes of PI3K, such as class I PI3K, class II PI3K, and / or class III PI3K. A PI3K inhibitor may be capable of directly or indirectly reducing the enzymatic activity of one or more isoforms of PI3K, such as PI3Kα, PI3Kβ, PI3Kγ, and / or PI3Kδ. A "pan-PI3K inhibitor" typically can inhibit all of PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ. For example, it is routine for a person skilled in the art to determine whether a given compound is a PI3K inhibitor by testing the effectiveness of the compound in a commercially available PI3K activity assay kit (e.g., PI3K-Glo™ Class I Profiling Kit available from Promega).

[0041] As used herein, "mTOR inhibitor" refers to a compound that directly or indirectly reduces the enzymatic activity of mTOR.For example, it is routine for those skilled in the art to determine whether a given compound is an mTOR inhibitor by testing the effectiveness of the compound in a commercially available mTOR activity assay kit (for example, the K-LISA™ mTOR activity assay kit available from Merck Millipore).

[0042] As used herein, a "BTK inhibitor" is a compound that directly or indirectly reduces the enzymatic activity of mTOR. For example, it is routine for a person skilled in the art to determine whether a given compound is a BTK inhibitor by testing the effectiveness of the compound in a commercially available BTK activity assay kit (e.g., the BTK assay kit available from BPSBioscience).

[0043] As used herein, the term "kit" refers to a package containing at least two separate agents. Typically, the first agent is abemaciclib, or a pharmaceutically acceptable salt thereof, and the second agent is a PI3K inhibitor and / or an mTOR inhibitor, or a pharmaceutically acceptable salt thereof. Optionally, a third agent may be included in the kit. For example, the third agent may be a BTK inhibitor, or a pharmaceutically acceptable salt thereof. The kit may include any additional active agent as defined herein. The "kit" may also include instructions for administering all or some of these agents to a cancer patient, preferably a mantle cell lymphoma patient. The mantle cell lymphoma referred to in this context is preferably a mantle cell lymphoma as defined herein.

[0044] As used herein, the terms "treat," "to treat," or "treatment" refer to inhibiting, slowing, halting, alleviating, contracting, maintaining a stable condition, or reversing the progression or severity of an existing symptom, disorder, condition, or disease.

[0045] As used herein, the term "patient" refers to a mammal, preferably a human, more preferably a human female. Preferably, the patient is a male or female, about 18 to about 90 years of age (such as about 20 to about 85 years of age), for example about 30 to about 80 years of age (such as about 50 to about 70 years of age). As used herein, the terms "subject" and "patient" are used interchangeably unless otherwise required by context.

[0046] As used herein, the terms "cancer" and "cancerous" refer to or describe a physiological condition in a patient that is typically characterized by unregulated cell proliferation. This definition includes benign and malignant cancers. Typically, in the present invention, the cancer is mantle cell lymphoma. Cancers can be evaluated according to classifications commonly used in the art, such as the American Joint Committee on Cancer (AJCC) TNM system.

[0047] The term "mantle cell lymphoma" refers to lymphoma characterized as an aggressive, usually diffuse non-Hodgkin's lymphoma composed of small to medium-sized B lymphocytes (centrocytes). Most patients present with advanced stage disease with lymphadenopathy, hepatosplenomegaly, and bone marrow involvement. The diagnosis and determination of mantle cell lymphoma is easily determined by those skilled in the art, for example, according to currently accepted guidelines. For example, the guidelines set forth by the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) are widely accepted. Markers of mantle cell lymphoma include B cell surface markers (e.g., CD20), overexpression of cyclin D1, and (11;14) translocation.

[0048] The term "effective amount" as used herein refers to an amount or dosage of abemaciclib or a pharma- ceutically acceptable salt thereof, and an amount or dosage of a PI3K inhibitor and / or an mTOR inhibitor that provides an effective response in a patient under diagnosis or treatment. In some embodiments of the invention involving administration of additional active agents to a subject, an "effective amount" of such agents is that amount or dosage that, when administered in combination with an effective amount of abemaciclib or a pharma- ceutically acceptable salt thereof, as described herein, provides an effective response in such a patient.

[0049] As used herein, the term "effective response" of a patient or "responsiveness" of a patient to treatment with a combination of agents refers to the clinical or therapeutic benefit conferred to a patient upon administration of abemaciclib or a pharma- ceutically acceptable salt thereof, and a PI3K inhibitor and / or an mTOR inhibitor or a pharma- ceutically acceptable salt thereof, and any additional active agents, if any.

[0050] As used herein, the term "in combination with" refers to administration of abemaciclib or a pharma- ceutically acceptable salt thereof, and a PI3K inhibitor and / or an mTOR inhibitor or a pharma- ceutically acceptable salt thereof, either simultaneously or sequentially in any order, e.g., at repeated intervals, such as during a standard course of treatment for a single cycle or one or more cycles, such that one agent can be administered before, simultaneously, or after administration of the other agent, or in any combination thereof. In some embodiments of the invention that include administration of an additional active agent, such as a BTK inhibitor or a pharma- ceutically acceptable salt thereof, such administration of the additional agent can be either simultaneously or sequentially in any order with either or both of abemaciclib or a pharma- ceutically acceptable salt thereof, and a PI3K inhibitor and / or an mTOR inhibitor or a pharma- ceutically acceptable salt thereof.

[0051] The main advantage of the combination treatment of the present invention is its ability to produce significant anti-cancer effects in patients without causing significant toxicity or adverse events, so that patients benefit from the comprehensive combination treatment approach. The efficacy of the combination treatment of the present invention can be measured by various endpoints commonly used in the evaluation of cancer treatment, including, but not limited to, tumor regression, shrinkage of tumor weight or size, time to progression, overall survival, progression-free survival, overall response rate, duration of response, and quality of life. The therapeutic agents used in the present invention may cause inhibition of local progressive or metastatic spread without shrinkage of the primary tumor, may induce shrinkage of the primary tumor, or may simply exert a tumor suppressive effect. Since the present invention is directed to the use of combinations of anti-tumor agents, novel approaches for determining the efficacy of any particular combination treatment of the present invention can be optionally used, including, for example, measuring plasma or urinary markers of angiogenesis and / or cell cycle activity, measuring tissue-based biomarkers for angiogenesis and / or cell cycle activity, and measuring response by radiographic imaging.

[0052] In the present specification, the reference herein to a compound or combination for use in treating a particular condition can be used interchangeably with the reference herein to a compound or combination for use in a method for treating a condition.Thus, for example, the present specification provides a combination of abemaciclib or its pharmaceutically acceptable salt with a PI3K inhibitor and / or an mTOR inhibitor or its pharmaceutically acceptable salt for use in treating mantle cell lymphoma in a patient in need of such treatment, and thus, the present specification also provides a combination of abemaciclib or its pharmaceutically acceptable salt with a PI3K inhibitor and / or an mTOR inhibitor or its pharmaceutically acceptable salt for use in a method for treating mantle cell lymphoma in a patient in need of such treatment. Similarly, provided herein is abemaciclib, or a pharmaceutically acceptable salt thereof, for use in treating mantle cell lymphoma in a patient in need thereof, said use comprising administering to said patient said abemaciclib, or a pharmaceutically acceptable salt thereof, in combination with a PI3K inhibitor and / or an mTOR inhibitor, or a pharmaceutically acceptable salt thereof; thus, also provided herein is abemaciclib, or a pharmaceutically acceptable salt thereof, for use in a method of treating mantle cell lymphoma in a patient in need thereof, said use comprising administering to said patient said abemaciclib, or a pharmaceutically acceptable salt thereof, in combination with a PI3K inhibitor and / or an mTOR inhibitor, or a pharmaceutically acceptable salt thereof.Similarly, provided herein is a PI3K inhibitor and / or an mTOR inhibitor, or a pharma- ceutically acceptable salt thereof, for use in the treatment of mantle cell lymphoma in a patient in need thereof, said use comprising administering to said patient said PI3K inhibitor and / or an mTOR inhibitor, or a pharma- ceutically acceptable salt thereof, in combination with abemaciclib or a pharma- ceutically acceptable salt thereof; thus similarly, provided herein is a PI3K inhibitor and / or an mTOR inhibitor, or a pharma- ceutically acceptable salt thereof, for use in a method of treating mantle cell lymphoma in a patient in need thereof, said use comprising administering to said patient said PI3K inhibitor and / or an mTOR inhibitor, or a pharma- ceutically acceptable salt thereof, in combination with abemaciclib or a pharma- ceutically acceptable salt thereof.

[0053] Reference herein to mantle cell lymphoma selected from, associated with, or characterized by one of a number of options should be understood to encompass situations in which the mantle cell lymphoma is selected from, associated with, or characterized by more than one of the recited features (e.g., two or more of the recited features).

[0054] Those skilled in the art will understand that the compounds described herein can be used as free bases. Similarly, the compounds can be reacted with any of a number of inorganic and organic acids to form pharma-ceutically acceptable salts. Such pharma-ceutically acceptable salts and the general methods for their preparation are well known in the art. See, for example, P.Stahl, et al, Handbook of Pharmaceutical Salts: Properties, Selection and Use (VCHA / Wiley-VCH, 2002); LDBighley, et al., Encyclopedia of Pharmaceutical Technology, 453-499 (1995); S.M.Berge, et al., Journal of Pharmaceutical Sciences, 66, 1, (1977). Hydrochloride and mesylate are preferred salts for abemaciclib. Mesylate is a particularly preferred salt for abemaciclib.

[0055] Abemaciclib Abemaciclib is described above. Preferably, abemaciclib or a pharma- ceutically acceptable salt thereof is formulated for oral administration. Preferably, abemaciclib or a pharma- ceutically acceptable salt thereof is formulated into a tablet or capsule. Preferably, abemaciclib or a pharma- ceutically acceptable salt thereof is formulated into a tablet. Also, preferably, abemaciclib or a pharma- ceutically acceptable salt thereof is formulated into a capsule. Preferably, abemaciclib or a pharma- ceutically acceptable salt thereof is formulated into a tablet or capsule containing about 50 mg to about 200 mg of abemaciclib. Preferably, abemaciclib or a pharma- ceutically acceptable salt thereof is formulated into a tablet or capsule containing about 50 mg, about 100 mg, about 150 mg, or about 200 mg of abemaciclib. Preferably, abemaciclib or a pharma- ceutically acceptable salt thereof is formulated into a tablet or capsule containing 50 mg of abemaciclib. Also preferably, abemaciclib or a pharma- ceutically acceptable salt thereof is formulated into a tablet or capsule containing 100 mg of abemaciclib. Also preferably, abemaciclib or a pharma- ceutically acceptable salt thereof is formulated into a tablet or capsule containing 150 mg of abemaciclib. Also preferably, abemaciclib or a pharma- ceutically acceptable salt thereof is formulated into a tablet or capsule containing 200 mg of abemaciclib.

[0056] Preferably, abemaciclib is formulated with one or more pharma- ceutically acceptable excipients.Suitable excipients include microcrystalline cellulose (e.g., microcrystalline cellulose 102, microcrystalline cellulose 101), lactose monohydrate, croscarmellose sodium, sodium stearyl fumarate, silicon dioxide (e.g., colloidal hydrated silica), and the like.

[0057] PI3K inhibitors and mTOR inhibitors Any suitable PI3K inhibitor and / or mTOR inhibitor can be used according to the present disclosure. The PI3K inhibitor and / or mTOR inhibitor disclosed herein are commercially available (e.g., from Selleck Chemicals, US, MedChemExpress US, Sigma Aldrich, etc.) or are otherwise available to those skilled in the art (e.g., by conventional organic synthesis using methods disclosed in March's Advanced Organic Chemistry, Wiley).

[0058] Preferably, the PI3K inhibitor and / or mTOR inhibitor is an inhibitor of one or more of class I PI3K, class II PI3K, and class III PI3K. Preferably, the PI3K inhibitor and / or mTOR inhibitor is an inhibitor of two or more of class I PI3K, class II PI3K, and class III PI3K. Preferably, the PI3K inhibitor and / or mTOR inhibitor is an inhibitor of all of class I PI3K, class II PI3K, and class III PI3K. Most preferably, the PI3K inhibitor and / or mTOR inhibitor is an inhibitor of class I PI3K.

[0059] Preferably, the PI3K inhibitor and / or mTOR inhibitor is one or more inhibitors of PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ. Preferably, the PI3K inhibitor and / or mTOR inhibitor is two or more inhibitors of PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ. Preferably, the PI3K inhibitor and / or mTOR inhibitor is three or more inhibitors of PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ. Preferably, the PI3K inhibitor and / or mTOR inhibitor is all inhibitors of PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ. As used herein, a compound that inhibits all of PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ is also called a pan-PI3K inhibitor.

[0060] Preferably, the PI3K inhibitor and / or mTOR inhibitor is a competitive mTOR inhibitor. Competitive mTOR inhibitors bind to the mTOR ATP binding site and prevent phosphorylation. Competitive mTOR inhibitors include OSI-027, bistusertib (AZD2014), sapanisertib (MLN0128 / INK128 / TAK-228), tolquinib (PP242), ML-223, and AZD8055.

[0061] Alternatively, and preferably, the mTOR inhibitor is a rapamycin analogue, including sirolimus, nab-rapamycin, temsirolimus, everolimus, and ridaforolimus.

[0062] Most preferably, the PI3K inhibitor and / or mTOR inhibitor is a dual PI3K and mTOR inhibitor. Examples of dual PI3K and mTOR inhibitors include samotricisib (LY3023414), BGT-226, DS-7423, PF-04691502, PKI-179, omipalisib (GSK2126458 / GSK458), panulisib (P7170), SB2343 / VS-5584, dactolisib (BEZ235 ... These include xalisib (GDC-0084), apitolisib (GDC-0980), bimiralisib (PQR309), voxtalisib (SAR245409 / XL765), SF-1126, gedatolisib (PF-05212384 / PKI-587), XH00230381967, and SN20229799306.

[0063] Preferably, the PI3K inhibitor and / or mTOR inhibitor is a competitive PI3K inhibitor, which binds to the PI3K active site and prevents phosphorylation.

[0064] PI3K and / or mTOR inhibitors include PI3K inhibitors but not mTOR inhibitors, such as copanlisib (BAY80-6946), pictilisib (GDC-0941), sonolisib (PX-866), TG100-115, CH5132799, piralalisib (XL147), ZSTK474, buparlisib (BKM-120), fimepinostat (CUDC-907), rigosertib (ON-01910), AZD8835, WX-037, AZD8186, and KA223. 7, acalisib (GS-9820 / CAL-120), zandelisib (ME401 / PWT-143), AMG319, GSK2636771, palsaclisib (INCB050465), selavelisib (INK-1117), umbralisib (TGR-1202), tenalisib (RP6530), taselisib (GDC-0032), alpelisib (BYL719), duvelisib (IPI-145), and idelalisib (CAL-101).

[0065] PI3K inhibitors include the following compounds:

[0066] Pictilisib (GDC-0941), 4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine, is a potent inhibitor of PI3K with a nanomolar IC50 against PI3Kα / δ in cell-free assays and moderate selectivity against p110β (11-fold) and p110γ (25-fold).

[0067] Sonolisib (PX-866), [(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5-h]isochromen-10-yl]acetate, is a potent inhibitor of PI3K with a nanomolar IC50 against PI3Kα / γ / δ.

[0068] TG100-115, 3-[2,4-diamino-7-(3-hydroxyphenyl)pteridin-6-yl]phenol, is an inhibitor of PI3K with a nanomolar IC50 against PI3Kγ / δ. TG100-115 has the following structure: [ka]

[0069] CH5132799, 5-(7-(methylsulfonyl)-2-morpholino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-2-amine, is a selective class I PI3K inhibitor with a nanomolar IC50 against class I PI3Ks, particularly PI3Kα. CH5132799 has the following structure: [ka]

[0070] Piralalisib (XL147), 2-amino-N-[3-[[3-(2-chloro-5-methoxyanilino)quinoxalin-2-yl]sulfamoyl]phenyl]-2-methylpropanamide, is a potent and highly selective inhibitor of PI3K with nanomolar IC50 against PI3Kα / β / γ / δ.

[0071] ZSTK474, 4,4'-(6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)dimorpholine, is an ATP-competitive pan-class I PI3K inhibitor with nanomolar IC50 against PI3Kα / β / γ / δ. ZSTK474 has the following structure: [ka]

[0072] Buparlisib (BKM-120), 5-(2,6-dimorpholin-4-ylpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine, is a pan-class I PI3K inhibitor with a nanomolar IC50 against PI3Kα / β / γ / δ.

[0073] Copanlisib (BAY80-6946), 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro-1H-imidazo[1,2-c]quinazolin-5-ylidene]pyrimidine-5-carboxamide, is a potent, selective and ATP-competitive pan-class I PI3K inhibitor with nanomolar IC50 against PI3Kα / β / γ / δ.

[0074] Fimepinostat (CUDC-907), N-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl-methylamino]pyrimidine-5-carboxamide, is a potent inhibitor of class I PI3K with a nanomolar IC50 against PI3Kα / β / δ.

[0075] Rigosertib (ON-01910), 2-[2-methoxy-5-[[(E)-2-(2,4,6-trimethoxyphenyl)ethenyl]sulfonylmethyl]anilino]acetic acid, is a PI3K inhibitor.

[0076] AZD8835, 1-[4-[5-[5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-1-ethyl-1,2,4-triazol-3-yl]piperidin-1-yl]-3-hydroxypropan-1-one, is a potent and selective PI3K inhibitor with a nanomolar IC50 against PI3Kα / δ. AZD8835 has the following structure: [ka]

[0077] AZD8186, 8-[(1R)-1-(3,5-difluoroanilino)ethyl]-N,N-dimethyl-2-morpholin-4-yl-4-oxochromene-6-carboxamide, is a PI3K inhibitor with a nanomolar IC50 for PI3Kβ / δ and selectivity over PI3Kα / γ. AZD8186 has the following structure: [ka]

[0078] Acalisib (GS-9820 / CAL-120), 6-fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)ethyl]quinazolin-4-one, is a potent and selective PI3Kδ inhibitor with a nanomolar IC50.

[0079] Zandelisib (ME401 / PWT-143), 4-[2-(difluoromethyl)benzimidazol-1-yl]-N-[2-methyl-1-[2-(1-methylpiperidin-4-yl)phenyl]propan-2-yl]-6-morpholin-4-yl-1,3,5-triazin-2-amine, is a potent and selective PI3Kδ inhibitor with a nanomolar IC50.

[0080] AMG319, N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine, is a potent and selective PI3Kδ inhibitor with a nanomolar IC50. AMG319 has the following structure: [ka]

[0081] GSK2636771, 2-methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-morpholin-4-ylbenzimidazole-4-carboxylic acid, is a potent and selective PI3Kβ inhibitor with a nanomolar IC50. GSK2636771 has the following structure: [ka]

[0082] Parsaclisib (INCB050465), (4R)-4-[3-[(1S)-1-(4-amino-3-methylpyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl]pyrrolidin-2-one, is a potent and selective PI3Kδ inhibitor with a nanomolar IC50.

[0083] Serravelisib (INK-1117), i.e., [6-(2-amino-1,3-benzoxazol-5-yl)imidazo[1,2-a]pyridin-3-yl]-morpholin-4-ylmethanone, is a potent and selective PI3Kα inhibitor with a nanomolar IC50. Serravelisib has the following structure: [ka]

[0084] Umbralisib (TGR-1202), 2-[(1S)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one, is a potent and selective PI3Kδ inhibitor with a nanomolar IC50. Umbralisib has the following structure: [ka]

[0085] Tenalisib (RP6530), 3-(3-fluorophenyl)-2-[(1S)-1-(7H-purin-6-ylamino)propyl]chromen-4-one, is a potent and selective PI3K inhibitor with a nanomolar IC50 against PI3Kγ / δ. Tenalisib has the following structure: [ka]

[0086] Taselisib (GDC-0032), 2-methyl-2-[4-[2-(5-methyl-2-propan-2-yl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]propanamide, is a potent PI3K inhibitor with nanomolar IC50 against PI3Kα / β / γ / δ. Taselisib has the following structure: [ka]

[0087] Alpelisib (BYL719), (2S)-1-N-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl]pyrrolidine-1,2-dicarboxamide, is a potent and selective PI3K inhibitor with nanomolar IC50 against PI3Kα / β / γ / δ. Alpelisib has the following structure: [ka]

[0088] Duvelisib (IPI-145), 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]isoquinolin-1-one, is a potent and selective PI3K inhibitor with a nanomolar IC50 against PI3Kδ. Duvelisib has the following structure: [ka]

[0089] Idelalisib (CAL-101), 5-fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]quinazolin-4-one, is a potent and selective PI3K inhibitor with a nanomolar IC50 against PI3Kδ. Idelalisib has the following structure: [ka]

[0090] Other PI3K inhibitors include WX-037 and KA2237.

[0091] mTOR inhibitors include the following compounds:

[0092] Sirolimus, rapamycin, i.e. (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone, is a potent and selective mTOR inhibitor with a nanomolar IC50.

[0093] Nab-rapamycin is a nanoparticle albumin-bound rapamycin.

[0094] Temsirolimus, i.e., [(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaerythro- Antioxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl]3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate is a potent inhibitor of mTOR with a micromolar IC50.

[0095] Everolimus, or (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone, is a rapamycin derivative and a potent, selective and orally active mTOR1 inhibitor.

[0096] Ridaforolimus, or (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-12-[(2R)-1-[(1S,3R,4R)-4-dimethylphosphoryloxy-3-methoxycyclohexyl]propan-2-yl]-1,18-hydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone, is a rapamycin derivative and a potent, selective and orally active mTOR1 inhibitor.

[0097] OSI-027, 4-[4-amino-5-(7-methoxy-1H-indol-2-yl)imidazo[5,1-f][1,2,4]triazin-7-yl]cyclohexane-1-carboxylic acid, is a potent and selective mTOR inhibitor with a nanomolar IC50. OSI-027 has the following structure: [ka]

[0098] Bistusertib (AZD2014), 3-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-N-methylbenzamide, is a potent and selective mTOR inhibitor with a nanomolar IC50.

[0099] Sapanisertib (MLN0128 / INK128 / TAK-228), 5-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1,3-benzoxazol-2-amine, is a potent and selective mTOR inhibitor with a nanomolar IC50. Sapanisertib has the following structure: [ka]

[0100] Tolquinib (PP242), 2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol, is a potent and selective mTOR inhibitor with a nanomolar IC50.

[0101] AZD8055, [5-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxyphenyl]methanol, is a potent and selective mTOR inhibitor with a nanomolar IC50. AZD8055 has the following structure: [ka]

[0102] Other mTOR inhibitors include ML-223.

[0103] Dual PI3K and mTOR inhibitors include the following compounds:

[0104] Samotricisib (LY3023414), 8-[5-(2-hydroxypropan-2-yl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methylimidazo[4,5-c]quinolin-2-one, potently and selectively inhibits the class I PI3K isoforms DNA-PK and mTOR1 / 2 with IC values ​​of 6.07 nM, 77.6 nM, 38 nM, 23.8 nM, 4.24 nM, and 165 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, DNA-PK, and mTOR, respectively. 50 Samotricisib potently inhibits mTORC1 / 2 at low nanomolar concentrations.

[0105] BGT-226, 8-(6-methoxypyridin-3-yl)-3-methyl-1-[4-piperazin-1-yl-3-(trifluoromethyl)phenyl]imidazo[4,5-c]quinolin-2-one, is a potent dual PI3K and mTOR inhibitor with nanomolar IC50 against PI3Kα / β / γ / δ and mTOR. BGT-226 has the following structure: [ka]

[0106] PF-04691502, 2-amino-8-[4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7-one, is a potent dual PI3K and mTOR inhibitor with nanomolar IC50 against PI3Kα / β / γ / δ and mTOR. PF-04691502 has the following structure: [ka]

[0107] PKI-179, 1-[4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]phenyl]-3-pyridin-4-yl urea, is a potent dual PI3K and mTOR inhibitor with nanomolar IC50 against PI3Kα / β / γ / δ and mTOR. PKI-179 has the following structure: [ka]

[0108] Omipalisib (GSK2126458 / GSK458), 2,4-difluoro-N-[2-methoxy-5-(4-pyridazin-4-ylquinolin-6-yl)pyridin-3-yl]benzenesulfonamide, is a potent dual PI3K and mTOR inhibitor with nanomolar IC50 against PI3Kα / β / γ / δ and mTOR.

[0109] Panulisib (P7170), [8-[6-amino-5-(trifluoromethyl)pyridin-3-yl]-1-[6-(2-cyanopropan-2-yl)pyridin-3-yl]-3-methylimidazo[4,5-c]quinolin-2-ylidene]cyanamide, is a potent dual PI3K and mTOR inhibitor.

[0110] SB2343 / VS-5584, 5-(8-methyl-2-morpholin-4-yl-9-propan-2-ylpurin-6-yl)pyrimidin-2-amine, is a potent dual PI3K and mTOR inhibitor with nanomolar IC50 against PI3Kα / β / γ / δ and mTOR. SB2343 has the following structure: [ka]

[0111] Dactolisib (BEZ235), 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-ylimidazo[4,5-c]quinolin-1-yl)phenyl]propanenitrile, is a potent dual PI3K and mTOR inhibitor with nanomolar IC50 against PI3Kα / β / γ / δ and mTOR.

[0112] Paxalisib (GDC-0084), 5-(6,6-dimethyl-4-morpholin-4-yl-8,9-dihydropurino[8,9-c][1,4]oxazin-2-yl)pyrimidin-2-amine, is a potent dual PI3K and mTOR inhibitor with nanomolar IC50 against PI3Kα / β / γ / δ and mTOR.

[0113] Apitolisib (GDC-0980), (2S)-1-[4-[[2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl]piperazin-1-yl]-2-hydroxypropan-1-one, is a potent dual PI3K and mTOR inhibitor with nanomolar IC50 against PI3K α / β / γ / δ and mTOR.

[0114] Bimiralisib (PQR309), 5-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, is a potent dual PI3K and mTOR inhibitor with nanomolar IC50 against PI3K α / β / γ / δ and mTOR.

[0115] Voxtalisib (SAR245409 / XL765), 2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7-one, is a potent dual PI3K and mTOR inhibitor with nanomolar IC50 against PI3K α / β / γ / δ and mTOR.

[0116] SF-1126, (2S)-2-[[(2S)-3-carboxy-2-[[2-[[(2S)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yl]methoxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]-3-hydroxypropanoate, is a potent dual PI3K and mTOR inhibitor. SF-1126 has the following structure: [ka]

[0117] Getatricib (PF-05212384 / PKI-587), 1-[4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl]-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl], is a potent dual PI3K and mTOR inhibitor with nanomolar IC50 against PI3Kα / γ and mTOR.

[0118] Other dual PI3K and mTOR inhibitors include DS-7423, XH00230381967, and SN20229799306.

[0119] In a preferred embodiment of the invention, the PI3K inhibitor and / or mTOR inhibitor is copanlisib or a pharma- ceutically acceptable salt thereof.

[0120] subject In some embodiments, the patient is a human subject. In some embodiments, the patient is a female human subject. In some embodiments, the patient is a male human subject.

[0121] In some embodiments, the patient is about 18 to about 80 years old (such as about 20 to about 75 years old), e.g., about 25 to about 60 years old (such as about 30 to about 50 years old). Often, the patient is under 60 years old (such as under 55 years old), e.g., under 50 years old (such as under 45 years old), e.g., under 40 years old.

[0122] Mantle cell lymphoma may be characterized according to the Mantle Cell International Prognostic Index (MIPI). Patients may be assigned according to the following table: [Table 1] ECOG PS, Eastern Cooperative Oncology Group Performance Status; LDH (ULN), lactate dehydrogenase (upper limit of normal); WBC, leukocyte count. Total score: 0-3, low risk; 4-5, intermediate risk; 6-11, high risk.

[0123] In some embodiments, the subject may have stage 1 mantle cell lymphoma. Stage 1 mantle cell lymphoma is typically associated with lymphoma detected in one lymph node region or a single organ. In some embodiments, the subject may have stage 2 mantle cell lymphoma. Stage 2 mantle cell lymphoma is typically associated with lymphoma detected in two or more lymph node regions on the same side of the diaphragm. In some embodiments, the subject may have stage 3 mantle cell lymphoma. Stage 3 mantle cell lymphoma is typically associated with lymphoma detected in two or more lymph node regions above and below the diaphragm. In some embodiments, the subject may have stage 4 mantle cell lymphoma. Stage 4 mantle cell lymphoma is typically associated with widespread disease in lymph nodes and / or other parts of the body. The stage of mantle cell lymphoma can be easily assessed by one of skill in the art.

[0124] In some embodiments, the patient may have cancer that has metastasized to one or more sites selected from lung / pleura, liver, bone, breast / chest wall, soft tissue, distal lymph nodes, regional lymph nodes, central nervous system / brain, bone marrow, bloodstream, and gut.

[0125] In some embodiments, the patient has one or more mutations associated with mantle cell lymphoma. In some embodiments, the patient has one or more mutations in one or more of ATM, TP53, CCND1, KMT2D, CDK2NA, BIRC3, CDKN2B, KHSC1, SMARCA4, SDHD, UBR5, NOTCH1, CARD11, SAMHD1, BCL10, MEF2B, IRS2, FGF19, FGF4, FGF3, FAT1, ROBO1, DIS3, CRLF2, CDKN2C, ARID2, ARID1A, ARID1B, NOTCH2, and BCOR. The patient may have one or more mutations in one or more of TRAF2, TRAF3, MAP3K14, MYD88, BKT, PCLG2, BCL2, KMT2D, and CELSR3.

[0126] In some embodiments, the patient has one or more mutations in one or more of ATM, TP53, CCND1, KMT2D, and CDKN2A.

[0127] In some embodiments, the patient has one or more mutations in ATM. In some embodiments, the patient has one or more mutations in TP53. In some embodiments, the patient has one or more mutations in CCND1. In some embodiments, the patient has one or more mutations in KMT2D. In some embodiments, the patient has one or more mutations in CDKN2A. Mutations in such genes can be detected using techniques available to those skilled in the art, for example, by DNA sequencing of a biological sample (e.g., a blood sample) from the patient, with optional PCR to amplify the DNA encoding the gene to be evaluated.

[0128] In some embodiments, the patient has mantle cell lymphoma that is resistant to treatment with a BCL-2 inhibitor, such as venetoclax or navitoclax. The patient may have mantle cell lymphoma that has acquired resistance to a BCL-2 inhibitor. Resistance to a BCL-2 inhibitor can be determined by failure to treat the mantle cell lymphoma with a BCL-2 inhibitor (e.g., by administering an inhibitor to a patient and the mantle cell lymphoma progresses during or after such treatment) or by determining that the mantle cell lymphoma is associated with a genetic profile known to be resistant to BCL-2 inhibitors.

[0129] One of skill in the art will appreciate that treating mantle cell lymphoma that has acquired resistance to an inhibitor, such as a BCL-2 inhibitor, is a different challenge than treating mantle cell lymphoma that has an inherent, i.e., primary, resistance to the inhibitor. Treatment of mantle cell lymphoma that has acquired resistance to an inhibitor is provided by the therapies provided herein.

[0130] For example, in some embodiments, the patient has mantle cell lymphoma that is resistant to treatment with venetoclax. The patient may have mantle cell lymphoma that has acquired resistance to venetoclax. Resistance to venetoclax can be determined by failure to treat the mantle cell lymphoma with venetoclax (e.g., by administering venetoclax to the patient and progression of the mantle cell lymphoma during or after such treatment), or by determining that the mantle cell lymphoma is associated with a genetic profile with known resistance to venetoclax. For example, mutations associated with venetoclax resistance can include one or more mutations in one or more of TRAF2, TRAF3, MAP3K14, CARD11, MYD88, CCND1, BKT, and PCLG2.

[0131] In some embodiments, the patient has mantle cell lymphoma that is resistant to treatment with ibrutinib. The patient may have mantle cell lymphoma that has acquired resistance to ibrutinib. Resistance to ibrutinib can be determined by failure to treat mantle cell lymphoma with ibrutinib (e.g., by administering ibrutinib to the patient and progression of mantle cell lymphoma during or after such treatment), or by determining that the mantle cell lymphoma is associated with a genetic profile that is known to be resistant to ibrutinib. For example, the mutation associated with ibrutinib resistance can include one or more mutations in one or more of SMARCA4, BCL2, TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2, and ATM.

[0132] In some embodiments, the patient has mantle cell lymphoma characterized by or associated with one or more of cyclin D1 overexpression, t(11;14) and / or t(11;14)(q13;q32) translocation, Ki67 overexpression, lactate dehydrogenase overexpression, and / or beta-2 microglobulin overexpression.

[0133] In some embodiments, the patient has mantle cell lymphoma characterized by or associated with cyclin D1 overexpression. The patient may have mantle cell lymphoma characterized by or associated with cyclin D1, D2 and / or D3 overexpression. Cyclin overexpression can be readily determined by one of skill in the art.

[0134] In some embodiments, the patient has mantle cell lymphoma characterized by or associated with a t(11);14) translocation. In some embodiments, the patient has mantle cell lymphoma characterized by or associated with a t(11);14)(q13;q32) translocation. In t(11;14), the result is the juxtaposition of the immunoglobulin heavy chain (IgH) locus and the cyclin D1 gene (CCND1, PRAD1, BCL1). Without being bound by theory, it is believed that this translocation overexpresses cyclin D1 due to the juxtaposition of a transcriptional enhancer from the IgH locus (14q32) next to the CCND1 gene (11q13). Cyclin D1 is a nuclear protein that promotes the entry of cells from the G1 phase into the S phase of the cell cycle. Detection of such translocations is routine for those skilled in the art. For example, the t(11;14) translocation can be detected using cytogenetics, Southern blot, polymerase chain reaction (PCR) analysis, or interphase fluorescent in situ hybridization.

[0135] In some embodiments, the patient has mantle cell lymphoma characterized by or associated with Ki67 overexpression, lactate dehydrogenase overexpression, and / or beta-2 microglobulin overexpression. In some embodiments, the patient has mantle cell lymphoma characterized by or associated with Ki67 overexpression. In some embodiments, the patient has mantle cell lymphoma characterized by or associated with lactate dehydrogenase overexpression. In some embodiments, the patient has mantle cell lymphoma characterized by or associated with beta-2 microglobulin overexpression. Determining such overexpression is routine for those skilled in the art.

[0136] In some embodiments, the patient has refractory and / or relapsed mantle cell lymphoma. As used herein, the term "refractory" refers to mantle cell lymphoma that does not respond to treatment or where the response is short-lived. The term "relapsed" refers to mantle cell lymphoma that recurs or regrows after a period of remission.

[0137] In some embodiments, the patient has mantle cell lymphoma selected from, or characterized as, one of, nodal mantle cell lymphoma and leukemic non-nodal mantle cell lymphoma. Nodal mantle cell lymphoma affects lymph nodes, but often metastasizes to other parts of the body, such as bone marrow, bloodstream, intestine, and liver. In some embodiments, the nodal mantle cell lymphoma is selected from, or characterized as, one of, blastic mantle cell lymphoma and pleomorphic mantle cell lymphoma.

[0138] Retinoblastoma (Rb) is a protein that exerts tumor suppressor functions. Deregulation of Rb is associated with various cancer types. Lymphoma cells can be Rb functional (also called Rb positive, Rb+) or Rb deficient (also called Rb negative, Rb-). Rb status has been shown to be independent of sensitivity to many chemotherapeutic agents, such as cisplatin (CDDP), 5-fluorouracil, idarubicin, epirubicin, PRIMA-1met, fludarabine, and PD-0332991.

[0139] In some embodiments provided herein, the patient has an Rb-negative mantle cell lymphoma. Thus, in some embodiments, the patient has an Rb-deficient mantle cell lymphoma. In some embodiments provided herein, the patient has an Rb-positive mantle cell lymphoma. Thus, in some embodiments, the patient has an Rb-functional mantle cell lymphoma.

[0140] The therapy provided herein is useful for treating both Rb-positive and Rb-negative mantle cell lymphoma. However, without being bound by theory in any way, it is believed that the therapy provided herein may be particularly beneficial in treating Rb-functional mantle cell lymphoma. Without being bound by theory in any way, it is believed that in Rb-functional mantle cell lymphoma, mTOR (mechanistic target of rapamycin) deregulation may promote cell growth and proliferation. It is believed that mTOR forms two structurally and functionally distinct complexes, mTORC1 and mTORC2. It is believed that phosphorylated Rb interacts with the mTORC2 complex to suppress AKT activation, and as a result, inhibition of CDK4 / 6 by abemaciclib reduces Rb phosphorylation, thus weakening Rb inhibition on mTORC2 activation and boosting AKT phosphorylation and activation, providing a biological rationale for treating Rb+ mantle cell lymphoma in combination with abemaciclib and a PI3K inhibitor and / or an mTOR inhibitor.

[0141] As described herein, mantle cell lymphomas may, in some embodiments, be characterized by the expression of androgen receptor (AR) (e.g., in LAR mantle cell lymphomas).Androgen receptor (AR) is a steroid hormone receptor that links transcription factors that control specific genes involved in different, sometimes opposing, cellular processes, and can stimulate or inhibit both cell proliferation and apoptosis depending on the parallel signaling pathways that are activated.AR is expressed in some, but not all, mantle cell lymphomas.

[0142] Thus, in some embodiments, the subject has a mantle cell lymphoma that is AR positive (AR functional), however, in other embodiments, the subject has a mantle cell lymphoma that is AR negative (AR deficient).

[0143] In some embodiments, for example, in embodiments where the subject has mantle cell lymphoma that is AR positive, the subject may be administered an anti-AR therapy. In embodiments where an anti-AR therapy is administered to the subject, any suitable anti-AR therapy may be used. The preferred anti-AR therapy may be determined according to various parameters, in particular the severity and histology of the mantle cell lymphoma, the age, weight and condition of the subject to be treated, the route of administration, and the required regimen. A physician can determine the preferred anti-AR therapy to use, as well as the route of administration and dosage required for any particular subject. Preferably, the anti-AR therapy may be selected from AR inhibitors such as bicalutamide (Casodex), enzalutamide (Xtandi), and abiraterone acetate (Zytiga). For example, bicalutamide may be administered at a dose of about 50 mg per day. Enzalutamide may be administered at a dose of about 160 mg per day. Abiraterone acetate may be administered at a dose of about 1000 mg once a day.

[0144] Mantle cell lymphoma may, in some embodiments, be characterized by expression of PD-L1. PD-L1 (programmed cell death ligand 1) is a ligand for PD-1 (programmed cell death protein 1), an immune checkpoint receptor that limits T cell effector function in tissues. PD-L1 expression may be driven, for example, by loss of PTEN expression or function due to mutations.

[0145] Thus, in some embodiments, the subject has mantle cell lymphoma that expresses PD-L1 (PD-L1 positive), however, in other embodiments, the subject has mantle cell lymphoma that does not express PD-L1 (PD-L1 negative).

[0146] In some embodiments, for example, in embodiments where the subject has mantle cell lymphoma that is PD-L1 positive, the subject may be administered a PD-1 or PD-L1 inhibitor. In embodiments where a PD-1 or PD-L1 inhibitor is administered to the subject, any suitable PD-1 or PD-L1 inhibitor may be used. The preferred PD-1 or PD-L1 inhibitor may be determined according to various parameters, in particular the severity and histology of the mantle cell lymphoma, the age, weight and condition of the subject to be treated, the route of administration, and the required regimen. A physician can determine the preferred PD-1 or PD-L1 inhibitor to use, as well as the route of administration and dosage required for any particular subject. Preferably, the PD-1 or PD-L1 inhibitor may be selected from pembrolizumab (Keytruda), nivolumab (Opdivo), cemiplimab (Libtayo), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi). For example, pembrolizumab may be administered at a dose of about 200 mg every 3 weeks. Nivolumab may be administered at a dose of about 240 mg every 2 weeks or 480 mg every 4 weeks. Cemiplimab may be administered at a dose of about 350 mg once every 3 weeks. Atezolizumab may be administered at a dose of about 840 mg every 2 weeks, or 1200 mg every 3 weeks, or 1680 mg every 4 weeks. Avelumab may be administered at a dose of about 800 mg every 2 weeks. Durvalumab may be administered at a dose of about 10 mg / kg every 2 weeks, or 1500 mg every 3 or 4 weeks.

[0147] Further embodiments Also provided herein is a product that is a combination of abemaciclib or a pharma- ceutically acceptable salt thereof and a PI3K inhibitor and / or an mTOR inhibitor as described herein. The product may include one or more pharma- ceutically acceptable components, such as any one of the excipients, diluents, or adjuvants as described herein. The product may include one or more additional active agents as described herein. The product may be formulated as a dosage form, for example, as an oral dosage form, or as a dosage form for injection or infusion as described herein. The product may be provided as a kit as described herein.

[0148] Further Aspects The following are further numbered aspects of the present invention:

[0149] 1. Use of abemaciclib, or a pharmaceutically acceptable salt thereof, in combination with a PI3K inhibitor and / or an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of mantle cell lymphoma in a patient in need of such treatment.

[0150] 2. Use of abemaciclib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of mantle cell lymphoma in a patient in need of such treatment by administering said abemaciclib or a pharmaceutically acceptable salt thereof in combination with a PI3K inhibitor and / or an mTOR inhibitor or a pharmaceutically acceptable salt thereof.

[0151] 3. Use of a PI3K inhibitor and / or an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of mantle cell lymphoma in a patient in need of such treatment, by administering said PI3K inhibitor and / or an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, in combination with abemaciclib or a pharmaceutically acceptable salt thereof.

[0152] 4. The use of a combination, abemaciclib, or a PI3K inhibitor and / or an mTOR inhibitor as defined in any one of aspects 1-3, wherein said medicaments are for the treatment of mantle cell lymphoma in said patient by simultaneously, separately or sequentially administering to said patient said abemaciclib or a pharmaceutically acceptable salt thereof, and said PI3K inhibitor and / or said mTOR inhibitor or a pharmaceutically acceptable salt thereof.

[0153] 5. The use of a combination, abemaciclib, or a PI3K inhibitor and / or an mTOR inhibitor according to any one of aspects 1 to 4, wherein the PI3K inhibitor and / or mTOR inhibitor is a dual PI3K / mTOR inhibitor.

[0154] 6. The use of a combination, abemaciclib, or a PI3K inhibitor and / or an mTOR inhibitor according to any one of aspects 1 to 5, wherein the PI3K inhibitor and / or mTOR inhibitor is a pan-PI3K inhibitor.

[0155] 7. PI3K inhibitors and / or mTOR inhibitors include copanlisib (BAY80-6946), samotricisib (LY3023414), BGT-226, DS-7423, PF-04691502, PKI-179, omipalisib (GSK2126458 / GSK458), panulisib (P7170), SB2343 / VS-5584, dactolisib (BEZ235), paxalisib (GDC-0084), apitolisib (GDC-09 80), bimiralisib (PQR309), voxtalisib (SAR245409 / XL765), SF-1126, gedatolisib (PF-05212384 / PKI-587), XH00230381967, SN20229799306, pictilisib (GDC-0941), sonolisib (PX-866), TG100-115, CH5132799, piralalisib (XL147), ZSTK474, buparlisib (BKM-120) , fimepinostat (CUDC-907), rigosertib (ON-01910), AZD8835, WX-037, AZD8186, KA2237, acalisib (GS-9820 / CAL-120), zandelisib (ME401 / PWT-143), AMG319, GSK2636771, parsaclisib (INCB050465), theravelisib (INK-1117), umbralisib (TGR-1202), tenalisib (RP65 30), taselisib (GDC-0032), alpelisib (BYL719), duvelisib (IPI-145), and idelalisib (CAL-101), sirolimus, nab-rapamycin, temsirolimus, everolimus, ridaforolimus, OSI-027, bistusertib (AZD2014), sapanisertib (MLN0128 / INK128 / TAK-228), tolquinib (PP242), ML-223, and AZD8055. and prodrugs, metabolites, and derivatives thereof, and pharma- ceutically acceptable salts thereof, and the use of abemaciclib, or a PI3K inhibitor and / or an mTOR inhibitor according to any one of aspects 1 to 6.

[0156] 8. The use of a combination, abemaciclib, or a PI3K inhibitor and / or an mTOR inhibitor according to any one of aspects 1-7, wherein the PI3K inhibitor and / or mTOR inhibitor is copanlisib (BAY80-6946) or a pharma- ceutically acceptable salt thereof.

[0157] 9. The use of a combination, abemaciclib, or a PI3K inhibitor and / or an mTOR inhibitor according to any one of aspects 1-8, wherein the mantle cell lymphoma has acquired resistance to one or more BCL-2 inhibitors.

[0158] 10. The use of a combination according to any one of aspects 1 to 9, abemaciclib, or a PI3K inhibitor and / or an mTOR inhibitor, wherein the mantle cell lymphoma has acquired resistance to venetoclax.

[0159] 11. The use of a combination according to any one of aspects 1 to 10, abemaciclib, or a PI3K inhibitor and / or an mTOR inhibitor, wherein the mantle cell lymphoma has acquired resistance to ibrutinib.

[0160] 12. The use of a combination, abemaciclib, or a PI3K inhibitor and / or an mTOR inhibitor according to any one of aspects 1-11, wherein the mantle cell lymphoma is selected from or characterized as one of: nodal mantle cell lymphoma, and leukemic non-nodal mantle cell lymphoma.

[0161] 13. The use of a combination, abemaciclib, or a PI3K inhibitor and / or an mTOR inhibitor according to any one of aspects 1-12, wherein the mantle cell lymphoma is selected from or characterized as refractory mantle cell lymphoma and / or relapsed mantle cell lymphoma.

[0162] 14. The use of a combination, abemaciclib, or a PI3K inhibitor and / or an mTOR inhibitor according to any one of aspects 1-13, wherein the mantle cell lymphoma is associated with one or more mutations in TP53, CCND1, KMT2D, CDK2NA, BIRC3, CDKN2B, KHSC1, SMARCA4, SDHD, UBR5, NOTCH1, CARD11, SAMHD1, BCL10, MEF2B, IRS2, FGF19, FGF4, FGF3, FAT1, ROBO1, DIS3, CRLF2, CDKN2C, ARID2, ARID1A, ARID1B, NOTCH2, BCOR, TRAF2, TRAF3, MAP3K14, MYD88, BKT, PCLG2, BCL2, KMT2D, and CELSR3.

[0163] 15. The use of a combination, abemaciclib, or a PI3K inhibitor and / or an mTOR inhibitor according to any one of aspects 1-14, wherein said mantle cell lymphoma is associated with cyclin D1 overexpression, t(11;14) and / or t(11;14)(q13;q32) translocation, Ki67 overexpression, lactate dehydrogenase overexpression, and / or beta-2 microglobulin overexpression.

[0164] 16. The use of a combination, abemaciclib, or a PI3K inhibitor and / or an mTOR inhibitor according to any one of aspects 1-15, wherein said mantle cell lymphoma is retinoblastoma protein (Rb) functional.

[0165] 17. The use of the combination, abemaciclib, or a PI3K inhibitor and / or an mTOR inhibitor according to any one of aspects 1 to 16, wherein the medicament is for the treatment of mantle cell lymphoma by further administering to the patient an effective amount of a BTK inhibitor.

[0166] 18. The use of the combination, abemaciclib, or a PI3K inhibitor and / or mTOR inhibitor according to any one of aspects 1 to 17, for the treatment of mantle cell lymphoma by further administering to the patient an effective amount of one or more additional agents selected from fulvestrant or a pharma- ceutically acceptable salt thereof, an aromatase inhibitor or a pharma-ceutically acceptable salt thereof, an AR inhibitor, an immune checkpoint inhibitor such as PD-L1 or PD-1 inhibitor, a CDK4 / 6 inhibitor, an AKT inhibitor, a cyclin E / CDK2 inhibitor, an autophagy inhibitor, an anti-EGFR inhibitor, and a PARP inhibitor.

[0167] The following examples are provided solely to illustrate the invention and are non-limiting. In particular, there are many assays available to demonstrate the anticancer efficacy and potential synergistic effects of pharma- ceutically acceptable drug combinations, and therefore a negative result in any one assay is not definitive. EXAMPLES

[0168] These examples illustrate the utility of the claimed therapies in the treatment of mantle cell lymphoma.

[0169] Abstract Novel therapeutic strategies, such as BTK inhibitors and Bcl-2 inhibitors, have dramatically improved the prognosis of MCL patients, but resistance to these treatments is inevitable.

[0170] The tumor suppressor gene CDKN2A is commonly deleted in ibrutinib-resistant tumors, resulting in upregulation of CDK4 / 6 signaling, among other hallmarks, the mTOR / PI3K pathway, the Myc pathway, and the OXPHOS pathway.

[0171] Therefore, we attempt to utilize joint targeting of the CDK4 / 6 and PI3K pathways to overcome therapeutic resistance using in vitro and PDX models.

[0172] method This preclinical study used ibrutinib- or venetoclax-sensitive and resistant MCL cell lines.

[0173] 1 x 10 per well 4 Cells were seeded in 96-well plates and treated in triplicate with abemaciclib monotherapy or in combination with copanlisib (a PI3K inhibitor) for 72 hours, then mixed with CellTiter-Glo Luminescent Cell viability Assay Reagent.

[0174] For cell cycle assay, cells were seeded in 6-well plates and treated with vehicle or abemaciclib for 24 h. Cells were fixed in 70% pre-chilled ethanol and stained with propidium iodide. Cell cycle stages were quantified by Novocyte Flow Cytometer.

[0175] The molecular events at the protein level after treatment were determined by immunoblotting.

[0176] For in vivo experiments, the combination of abemaciclib (25 mg / kg, orally, daily) and copanlisib (5 mg / kg, IP, three times weekly) was evaluated in a Mino-venetoclax-resistant xenograft model.

[0177] IC50 values ​​were calculated using GraphPad Prism 8 for each cell line. Student's t-test was performed to compare the differences between vehicle and treatment groups. Two-way analysis of variance (ANOVA) was performed to analyze tumor growth in vivo experiments. P values ​​less than 0.05 were considered statistically significant.

[0178] result Our previous studies identified a subset of MCL cells that were resistant to venetoclax (JeKo-1) or ibrutinib treatment (Maver-1 and Z-138).

[0179] To overcome resistance, we first treated MCL cell lines with abemaciclib, and the results showed that abemaciclib as a single agent exhibited potent anti-MCL activity in a subset of MCL cell lines, including venetoclax-sensitive (Mino, Rec-1, Maver-1, and Z138) and transiently resistant MCL cells (JeKo-1) (Ic 50 =70~952nM). (Figure 1)

[0180] However, the cell lines Mino-ven-R and Rec-ven-R that have acquired resistance to venetoclax are highly resistant to abemaciclib treatment (Ic 50 =6.0 and 4.4 μM). The PI3K / ATK pathway has been reported to be highly upregulated in Mino-ven-R and Rec-ven-R cells compared to their parental cells. To further increase the efficacy of targeted therapy, we treated resistant MCL cells with a combination of abemaciclib and copanlisib, and the results showed synergistically enhanced cytotoxicity in venetoclax or ibrutinib resistant MCL cell lines. Consistent with the function of CDK4 / 6 in cell cycle progression, inhibition of CDK4 / 6 by abemaciclib resulted in cell cycle arrest in the G1 phase of MCL cell lines. (Figure 2)

[0181] To verify whether abemaciclib in combination with copanlisib can overcome venetoclax resistance in vivo, we evaluated the anticancer effect of abemaciclib in combination with copanlisib using a venetoclax-resistant xenograft model derived from Mino-ven-R cell line in immunodeficient NSG mice (Figure 3). As a result, abemaciclib (25 mg / kg, orally, daily) significantly reduced tumor volume compared to vehicle control (n=5, p<0.0001), but venetoclax (5 mg / kg, orally, daily) or copanlisib (5 mg / kg, IP, 3 times weekly) did not.

[0182] Of note, the combination of abemaciclib and copanlisib also demonstrated significant in vivo synergy compared with monotherapy (p<0.0001).

[0183] Notably, the combination did not result in significant loss of body weight.

[0184] Taken together, these results suggest that combination therapy may be effective in overcoming venetoclax resistance in MCL.

[0185] conclusion Clinically, synergistic drug combinations allow each drug to be administered at a lower dose to achieve comparable therapeutic efficacy. Reduction in drug dosage may alleviate dose-limiting toxicity, a major factor responsible for treatment cessation in patients.

[0186] The results presented herein demonstrate the importance of the combination of abemaciclib with a PI3K inhibitor, such as copanlisib, and / or an mTOR inhibitor in the treatment of MCL. In particular, the data presented herein support that the combination treatment of abemaciclib with a PI3K inhibitor, such as copanlisib, and / or an mTOR inhibitor exerts robust anti-lymphoma effects in both in vitro and in vivo models. Such data indicate that such a combination can achieve clinically actionable effects through overcoming venetoclax resistance in MCL and may become an effective treatment regimen for refractory / relapsed MCL patients in the future.

[0187] References Wang,ML,et al.,Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma.N Engl J Med,2013.369(6):p.507-16 Tam,CS,et al.,Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma.N Engl J Med,2018.378(13):p.1211-1223 Morschhauser,F.,et al.,Clinical activity of abemaciclib in patients with relapsed or refractory mantle cell lymphoma-a phase II study.Haematologica,2021.106(3):p.859-862。 Bea,S.and E.Campo,Secondary genomic alterations in non-Hodgkin’s lymphomas:tumor-specific profiles with impact on clinical behavior.Haematologica,2008.93(5):p.641-5。 Jares,P.,D.Colomer,and E.Campo,Genetic and molecular pathogenesis of mantle cell lymphoma:perspectives for new targeted therapeutics.Nat Rev Cancer,2007.7(10):p.750-62。

Claims

1. 1. A method of treating mantle cell lymphoma in a patient in need of such treatment, the method comprising administering to the patient an effective amount of abemaciclib, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a PI3K inhibitor and / or an mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the PI3K inhibitor and / or the mTOR inhibitor is a dual PI3K / mTOR inhibitor.

3. The method of claim 1 , wherein the PI3K inhibitor and / or the mTOR inhibitor is a pan-PI3K inhibitor.

4. The PI3K inhibitor and / or the mTOR inhibitor is copanlisib, samotricisib, BGT-226, DS-7423, PF-04691502, PKI-179, omipalisib, panulisib, SB2343 / VS-5584, dactolisib, paxalisib Apitolisib, bimiralisib (PQR309), voxtalisib, SF-1126, getatricisib, XH00230381967, SN20229799306, pictilisib, sonolisib, TG100-115, CH5132799, piralalisib, ZSTK474, buparlisib, fimepinostat, rigosertib, AZD8835, WX-037, AZD8186, KA2237, acalisib, zanderisib , AMG319, GSK2636771, palsaclisib, ceravelisib, umbralisib, tenalisib, taselisib, alpelisib, duvelisib, and idelalisib, sirolimus, nab-rapamycin, temsirolimus, everolimus, ridaforolimus, OSI-027, bistusertib, sapanisertib (MLN0128 / INK128 / TAK-228), tolquinib, ML-223, and AZD8055, and their prodrugs, metabolites, and derivatives, and pharma- ceutically acceptable salts thereof.

5. 2. The method of claim 1, wherein the PI3K inhibitor and / or the mTOR inhibitor is copanlisib or a pharma- ceutically acceptable salt thereof.

6. The method of claim 1, wherein the mantle cell lymphoma has acquired resistance to one or more BCL-2 inhibitors.

7. 2. The method of claim 1, wherein the mantle cell lymphoma has acquired resistance to venetoclax.

8. 2. The method of claim 1, wherein the mantle cell lymphoma has acquired resistance to ibrutinib.

9. 2. The method of claim 1, wherein the mantle cell lymphoma is selected from or characterized as one of: nodal mantle cell lymphoma, and leukemic non-nodal mantle cell lymphoma.

10. 2. The method of claim 1, wherein the mantle cell lymphoma is selected from or characterized as refractory mantle cell lymphoma and / or relapsed mantle cell lymphoma.

11. 2. The method of claim 1, wherein the mantle cell lymphoma is associated with one or more mutations in ATM, TP53, CCND1, KMT2D, CDK2NA, BIRC3, CDKN2B, KHSCl, SMARCA4, SDHD, UBR5, NOTCH1, CARD11, SAMHD1, BCL10, MEF2B, IRS2, FGF19, FGF4, FGF3, FAT1, ROBO1, DIS3, CRLF2, CDKN2C, ARID2, ARID1A, ARID1B, NOTCH2, BCOR, TRAF2, TRAF3, MAP3K14, MYD88, BKT, PCLG2, BCL2, KMT2D, and CELSR3.

12. 2. The method of claim 1, wherein the mantle cell lymphoma is associated with cyclin D1 overexpression, t(11;14) and / or t(11;14)(q13;q32) translocation, Ki67 overexpression, lactate dehydrogenase overexpression, and / or beta-2 microglobulin overexpression.

13. 2. The method of claim 1, wherein the mantle cell lymphoma is retinoblastoma protein (Rb) functional.

14. 10. The method of claim 1, further comprising administering to the patient an effective amount of a BTK inhibitor.

15. 2. The method of claim 1, further comprising administering to the patient an effective amount of one or more additional agents selected from fulvestrant or a pharma- ceutically acceptable salt thereof, an aromatase inhibitor or a pharma- ceutically acceptable salt thereof, an AR inhibitor, an immune checkpoint inhibitor such as a PD-L1 inhibitor or a PD-1 inhibitor, a CDK4 / 6 inhibitor, an AKT inhibitor, a cyclin E / CDK2 inhibitor, an autophagy inhibitor, an anti-EGFR inhibitor, and a PARP inhibitor.

16. A combination of abemaciclib, or a pharma- ceutically acceptable salt thereof, and a PI3K inhibitor and / or an mTOR inhibitor, or a pharma- ceutically acceptable salt thereof, for use in the treatment of mantle cell lymphoma in a patient in need of such treatment.

17. 1. Abemaciclib, or a pharmaceutically acceptable salt thereof, for use in the treatment of mantle cell lymphoma in a patient in need of such treatment, said use comprising administering to said patient said abemaciclib, or a pharmaceutically acceptable salt thereof, in combination with a PI3K inhibitor and / or an mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

18. A PI3K inhibitor and / or an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of mantle cell lymphoma in a patient in need of such treatment, said use comprising administering to said patient said PI3K inhibitor and / or said mTOR inhibitor, or a pharmaceutically acceptable salt thereof, in combination with abemaciclib or a pharmaceutically acceptable salt thereof.

19. The combination for use, abemaciclib for use, or a PI3K inhibitor and / or an mTOR inhibitor for use according to any one of claims 16 to 18, wherein said use comprises simultaneously, separately or sequentially administering to said patient said abemaciclib or a pharmaceutically acceptable salt thereof, and said PI3K inhibitor and / or said mTOR inhibitor or a pharmaceutically acceptable salt thereof.

20. The combination for use, abemaciclib for use, or a PI3K inhibitor and / or an mTOR inhibitor for use according to any one of claims 16 to 19, wherein the PI3K inhibitor and / or the mTOR inhibitor is a dual PI3K / mTOR inhibitor.

21. The combination for use, abemaciclib for use, or a PI3K inhibitor and / or mTOR inhibitor for use according to any one of claims 16 to 20, wherein the PI3K inhibitor and / or the mTOR inhibitor is a pan-PI3K inhibitor.

22. The PI3K inhibitor and / or the mTOR inhibitor is copanlisib, samotricisib, BGT-226, DS-7423, PF-04691502, PKI-179, omipalisib, panulisib, SB2343 / VS-5584, dactolisib, paxalisib Apitolisib, bimiralisib (PQR309), voxtalisib, SF-1126, getatricisib, XH00230381967, SN20229799306, pictilisib, sonolisib, TG100-115, CH5132799, piralalisib, ZSTK474, buparlisib, fimepinostat, rigosertib, AZD8835, WX-037, AZD8186, KA2237, acalisib, zanderisib , AMG319, GSK2636771, palsaclisib, ceravelisib, umbralisib, tenalisib, taselisib, alpelisib, duvelisib, and idelalisib, sirolimus, nab-rapamycin, temsirolimus, everolimus, ridaforolimus, OSI-027, bistusertib, sapanisertib (MLN0128 / INK128 / TAK-228), tolquinib, ML-223, and AZD8055, and their prodrugs, metabolites, and derivatives, and pharma- ceutically acceptable salts thereof.

23. 23. The combination for use, abemaciclib for use, or a PI3K inhibitor and / or mTOR inhibitor for use according to any one of claims 16 to 22, wherein the PI3K inhibitor and / or the mTOR inhibitor is copanlisib or a pharma- ceutically acceptable salt thereof.

24. 24. The combination for use, abemaciclib for use, or a PI3K inhibitor and / or mTOR inhibitor for use according to any one of claims 16 to 23, wherein the mantle cell lymphoma has acquired resistance to one or more BCL-2 inhibitors.

25. 25. The combination for use, abemaciclib for use, or a PI3K inhibitor and / or mTOR inhibitor for use according to any one of claims 16 to 24, wherein the mantle cell lymphoma has acquired resistance to venetoclax.

26. 26. The combination for use, abemaciclib for use, or a PI3K inhibitor and / or mTOR inhibitor for use according to any one of claims 16 to 25, wherein the mantle cell lymphoma has acquired resistance to ibrutinib.

27. 27. The combination for use, abemaciclib for use, or a PI3K inhibitor and / or mTOR inhibitor for use according to any one of claims 16 to 26, wherein the mantle cell lymphoma is selected from or characterized as one of nodal mantle cell lymphoma, and leukemic non-nodal mantle cell lymphoma.

28. 28. The combination for use, abemaciclib for use, or a PI3K inhibitor and / or an mTOR inhibitor for use according to any one of claims 16 to 27, wherein the mantle cell lymphoma is selected from or characterized as refractory mantle cell lymphoma and / or relapsed mantle cell lymphoma.

29. The mantle cell lymphoma is selected from the group consisting of ATM, TP53, CCND1, KMT2D, CDK2NA, BIRC3, CDKN2B, KHSC1, SMARCA4, SDHD, UBR5, NOTCH1, CARD11, SAMHD1, BCL10, MEF2B, IRS2, FGF19, FGF4, FGF3, FAT1, ROBO1, DIS3, CRLF2, CDKN2C, ARID2, ARI 29. The combination for use, abemaciclib for use, or a PI3K inhibitor and / or mTOR inhibitor for use according to any one of claims 16 to 28, associated with one or more mutations in D1A, ARID1B, NOTCH2, BCOR, TRAF2, TRAF3, MAP3K14, MYD88, BKT, PCLG2, BCL2, KMT2D, and CELSR3.

30. 30. The combination for use, abemaciclib for use, or a PI3K inhibitor and / or mTOR inhibitor for use according to any one of claims 16 to 29, wherein the mantle cell lymphoma is associated with cyclin D1 overexpression, t(11;14) and / or t(11;14)(q13;q32) translocation, Ki67 overexpression, lactate dehydrogenase overexpression, and / or beta-2 microglobulin overexpression.

31. The combination for use, abemaciclib for use, or a PI3K inhibitor and / or mTOR inhibitor for use according to any one of claims 16 to 30, wherein the mantle cell lymphoma is retinoblastoma protein (Rb) functional.

32. 32. The combination for use, abemaciclib for use, or a PI3K inhibitor and / or an mTOR inhibitor for use according to any one of claims 16 to 31, wherein said use comprises further administering to said patient an effective amount of a BTK inhibitor.

33. 33. The combination for use according to any one of claims 16 to 32, abemaciclib for use, or a PI3K inhibitor and / or mTOR inhibitor for use, wherein said use comprises further administering to the patient an effective amount of one or more additional agents selected from fulvestrant or a pharma- ceutically acceptable salt thereof, an aromatase inhibitor or a pharma- ceutically acceptable salt thereof, an AR inhibitor, an immune checkpoint inhibitor such as a PD-L1 inhibitor or a PD-1 inhibitor, a CDK4 / 6 inhibitor, an AKT inhibitor, a cyclin E / CDK2 inhibitor, an autophagy inhibitor, an anti-EGFR inhibitor, and a PARP inhibitor.

34. Use of abemaciclib, or a pharma- ceutically acceptable salt thereof, in combination with a PI3K inhibitor and / or an mTOR inhibitor, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of mantle cell lymphoma in a patient in need of such treatment.

35. 1. Use of abemaciclib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of mantle cell lymphoma in a patient in need of such treatment, by administering abemaciclib, or a pharmaceutically acceptable salt thereof, in combination with a PI3K and / or mTOR inhibitor, or a pharmaceutically acceptable salt thereof, to said patient.

36. Use of a PI3K and / or mTOR inhibitor, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of mantle cell lymphoma in a patient in need of such treatment, by administering said PI3K and / or mTOR inhibitor, or a pharma- ceutically acceptable salt thereof, in combination with abemaciclib or a pharma- ceutically acceptable salt thereof.

37. - the PI3K inhibitor and / or the mTOR inhibitor is as defined in any one of claims 20 to 23, - the medicament is for treating mantle cell lymphoma as defined in any one of claims 24 to 31, and / or - the treatment is as defined in any one of claims 19 or 32-33, Use of a combination as defined in any one of claims 34 to 36, abemaciclib, or a PI3K inhibitor and / or an mTOR inhibitor.

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