WO2024097179A1

WO2024097179A1 - Combination therapies comprising a cdk9 inhibitor for cancer

Info

Publication number: WO2024097179A1
Application number: PCT/US2023/036397
Authority: WO
Inventors: Son Tran; Chunfen ZHANG; Ranjan MAITY; Nizar J. BAHLIS; Paola NERI; Aru NARENDRAN; Amy J. Johnson; Melanie M. FRIGAULT; Beatrix Stelte-Ludwig
Original assignee: Vincerx Pharma, Inc.
Priority date: 2022-11-02
Filing date: 2023-10-31
Publication date: 2024-05-10

Abstract

Disclosed herein are therapies comprising a CDK9 inhibitor of Formula (I), including therapies further comprising one or more additional pharmaceutically active agents, as treatments for cancer.

Description

COMBINATION THERAPIES COMPRISING A CDK9 INHIBITOR FOR CANCER

CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63/421,888 filedNovember 2, 2022; U.S. Provisional Application Serial No. 63/431,625 filed December 9, 2022; U.S. Provisional Application Serial No. 63/451,324 filed March 10, 2023; and U.S. Provisional Application Serial No. 63/459,094 filed April 13, 2023; which are each hereby incorporated by reference in their entirety.

BACKGROUND

[0002] Multiple myeloma (MM) is a hematologic malignancy affecting plasma cells. Plasma cells are a type of white blood cell that normally produces antibodies. When one tumor is present, it is called a plasmacytoma; however, when more than one such tumor is present, the disease is called multiple myeloma (MM). The cause of MM is currently unknown. At early stages of the disease, symptoms of MM are often unnoticed or undetected. Multiple myeloma is diagnosed based on blood or urine tests finding abnormal antibodies, bone marrow biopsy finding cancerous plasma cells, and medical imaging finding bone lesions. Another common finding in MM patients is high blood calcium levels. As MM progresses, bone pain, anemia, kidney dysfunction, and infections may occur. The plasma cells affected by MM can produce abnormal antibodies, which can cause kidney problems and overly thick blood. Plasma cells affected by MM can also form a mass in the bone marrow or soft tissue.

[0003] MM remains incurable, and a significant portion of patients experience disease progression or relapse, even with treatment. New treatments for newly diagnosed and relapsed MM are needed to impede disease progression and improve patient outcomes. A shift in the treatment paradigm for multiple myeloma has taken place in recent years (reviewed in Gay and Mina, Lancet Oncol. 2019, 20, 743). The upfront strategy in ASCT-eligible patients with multiple myeloma now typically includes a three-drug induction combining a proteasome inhibitor (e.g., bortezomib) and an immunomodulatory drug, followed by ASCT and lenalidomide maintenance (Gay et al., Haematologica 2018, 103, 197). In patients not eligible for ASCT, continuous lenalidomide plus dexamethasone is a standard regimen and is the backbone of several three-drug combinations assessed in clinical trials (in combination with bortezomib or daratumumab) (Larocca et al. Leukemia, 2018, 32, 1697; Larocca et al., Oncotarget. 2017, 8, 60656). Pressingly, the current recommendations for treatment of MM at relapse need to be redefined.

[0004] New combination therapies wherein one or more pharmaceutically active agents are administered to a patient in need thereof may provide a promising new method of treatment for newly-diagnosed or relapsed multiple myeloma (MM) in patients that are eligible for ASCT or are ineligible for ASCT.

[0005] Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence. The predominant histologic variants of this disease are termed embryonal (eRMS) and alveolar (aRMS), based on their appearance under light microscopy. Of the two, aRMS is associated with an more aggressive disease pattern and a higher mortality, mandating a better understanding of this cancer at the molecular level (Linardic, Cancer Lett., 2008, 270, 10). Genetic differences associated with rhabdomyosarcoma subclassification include the presence of reciprocal translocations and their associated fusions in aRMS, amplification of genes in aRMS and its fusion subsets, chromosomal losses and gains that mostly occur in eRMS, and allelic losses and mutations usually associated with eRMS. Chimeric proteins encoded from the fusion of PAX3 or PAX7 with F0X01 are expressed by most aRMS, result in a distinct pattern of downstream protein expression, and appear to be the proximate cause of the bad outcome associated with this subtype (Parham and Barr, Adv. Anat. Pathol., 2013, 20, 387).

[0006] MYCN deregulation is a feature of rhabdomyosarcoma tumorigenesis, defines groups of patients with a poor prognosis, and is a potential target for novel therapies. Increased copy number of A7 W has been found to be a feature of both the embryonal and alveolar subtypes, eRMS and aRMS respectively. The copy number and expression levels have been found to be significantly greater in the alveolar subtype, although the range of expression in both subtypes has been observed to span several orders of magnitude. In patients with alveolar rhabdomyosarcoma, overexpression (greater than median) or gain of genomic copies of MYCN were significantly associated with adverse outcome (Williamson et al., Journal of Pediatric Oncology, 2005, 23, 880).

[0007] New therapies wherein one or more pharmaceutically active agents are administered to a patient in need thereof may provide a promising new method of treatment for eRMS and aRMS, including in patients where the RMS expresses the PAX3-FOXO1 or PAX7-FOXO1 fusion protein, or the RMS displays an amplification of the MYCN gene or overexpression of MYCN protein.

[0008] Neuroblastoma is the most common extra-cranial solid tumor of childhood and the most common in the first year of life. It is a unique malignancy in that infants often present with either localized or metastatic disease that can spontaneously regress without intervention while older children can succumb to the disease after months to years of arduous therapy (Tolbert and Matthay, Cell Tissue Res., 2018, 372, 195).

[0009] Clinical presentation of neuroblastoma varies widely by age and stage. The location of the primary tumor and any metastatic sites dictates the symptomatology. In addition to the usual prognostic importance of disease stage, many biologic factors help to explain the clinical behavior in neuroblastoma, including histologic features, cytogenetic features, and the molecular changes, particularly amplification ofthe KGV oncogene. MYCN gene amplification is one of the most important markers of aggressive disease and poor prognosis in neuroblastoma (Bagatell et al. J. Clin. Oncol., 2009, 27, 365). Segmental chromosomal copy number alterations are also seen in neuroblastoma and are commonly measured by array comparative genomic hybridization. The most common of these are gain of 17q, loss of Ip and loss of 1 Iq, with multiple other segmental chromosomal alterations that are less common, but all are associated with worse outcome (Attiyeh et al., N. Engl. J. Med., 2005, 353, 2243; Bown et al., N. Engl. J. Med., 1999, 340, 1954).

[0010] New therapies wherein one or more pharmaceutically active agents are administered to a patient in need thereof may provide a promising new method of treatment for neuroblastoma, including in patients where the neuroblastoma displays an amplification of the MYCN gene or overexpression of MYCN protein, and/or where the neuroblastoma presents chromosome Ip deletion, chromosome lip deletion, and/or chromosome 17q deletion.

SUMMARY

[0011] In one aspect, the present disclosure provides methods of treating multiple myeloma in a patient in need thereof, the method comprising: administering to a patient a therapeutically effective amount of a first pharmaceutically active agent comprising 5-fluoro-4-(4-fluoro-2- methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine of Formula (I) or an enantiomer thereof or a pharmaceutically acceptable salt thereof

Formula (I); and administering to a patient a therapeutically effective amount of a second pharmaceutically active agent selected from a proteasome inhibitor, a BCL-2 inhibitor, or a modulator of E3 ubiquitin ligase activity. [0012] Provided in some embodiments herein is a method of treating multiple myeloma in a patient in need thereof, the method comprising: administering to a patient a therapeutically effective amount of a first pharmaceutically active agent comprising 5-fluoro-4-(4-fluoro-2- methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2 -amine of Formula (I) or an enantiomer thereof or a pharmaceutically acceptable salt thereof; and administering to a patient a therapeutically effective amount of a second pharmaceutically active agent selected from a proteasome inhibitor, a BCL-2 inhibitor, or a modulator of E3 ubiquitin ligase activity. In some embodiments the multiple myeloma in the patient presents one or more genetic abnormalities. In some embodiments the multiple myeloma in the patient presents one or more genetic abnormalities that independently affect one or more genes. In some embodiments the multiple myeloma in the patient overexpresses one or more biomarkers.

[0013] In some embodiments, the first pharmaceutically active agent is administered in the form of a pharmaceutical composition that comprises the first pharmaceutically active agent. In some embodiments, the second pharmaceutically active agent is administered in the form of a pharmaceutical composition that comprises the second pharmaceutically active agent.

[0014] In some embodiments, the second pharmaceutically active agent is a proteasome inhibitor. In some embodiments, the second pharmaceutically active agent is a proteasome inhibitor selected from bortezomib. In some embodiments, the second pharmaceutically active agent is a BCL-2 inhibitor. In some embodiments, the second pharmaceutically active agent is a BCL-2 inhibitor selected from venetoclax. In some embodiments, the second pharmaceutically active agent is a modulator of E3 ubiquitin ligase activity. In some embodiments, the second pharmaceutically active agent is a modulator of E3 ubiquitin ligase activity selected from lenalidomide or pomalidomide. In some embodiments, the second pharmaceutically active agent is a modulator of E3 ubiquitin ligase activity selected from lenalidomide. In some embodiments, the second pharmaceutically active agent is a modulator of E3 ubiquitin ligase activity selected from pomalidomide.

[0015] In some embodiments, the first pharmaceutically active agent is (+)-5-fluoro-4-(4- fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine of Formula (I’) or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the administration of the second pharmaceutically active agent lowers the therapeutically active amount of the first pharmaceutically active agent in comparison to the therapeutically active amount of the first pharmaceutically active agent if the second pharmaceutically active agent were not administered according to the methods described herein. In some embodiments, the administration of the first pharmaceutically active agent lowers the therapeutically active amount of the second pharmaceutically active agent in comparison to the therapeutically active amount of the second pharmaceutically active agent if the first pharmaceutically active agent were not administered according to the methods described herein.

[0017] In some embodiments, the administration of the second pharmaceutically active agent lowers the probability of occurrence or degree of severity of side effects associated with the administration of the first pharmaceutically active agent in comparison to the probability of occurrence or degree of severity of side effects associated with the administration of the first pharmaceutically active agent if the second pharmaceutically active agent were not administered according to the methods described herein. In some embodiments, the administration of the first pharmaceutically active agent lowers the probability of occurrence or degree of severity of side effects associated with the administration of the second pharmaceutically active agent in comparison to the probability of occurrence or degree of severity of side effects associated with the administration of the second pharmaceutically active agent if the first pharmaceutically active agent were not administered according to the methods described herein.

[0018] In some embodiments, the first pharmaceutically active agent is administered before the second pharmaceutically active agent. In some embodiments, the first pharmaceutically active agent is administered after the second pharmaceutically active agent. In some embodiments, the first pharmaceutically active agent and the second pharmaceutically active agent are administered simultaneously. In some embodiments, the first pharmaceutically active agent is administered with lesser frequency than is the second pharmaceutically active agent. In some embodiments, the first pharmaceutically active agent is administered with greater frequency than is the second pharmaceutically active agent. In some embodiments, the first pharmaceutically active agent is administered about once per week. In some embodiments, the second pharmaceutically active agent is administered about once per day. In some embodiments, the second pharmaceutically active agent is administered about once every three days.

[0019] In some embodiments, the first pharmaceutically active agent is administered intravenously. In some embodiments, the first pharmaceutically active agent is administered orally. In some embodiments, the second pharmaceutically active agent is administered intravenously. In some embodiments, the second pharmaceutically active agent is administered orally.

[0020] Provided in some embodiments herein is a method of treating multiple myeloma in a patient in need thereof, the method comprising: administering to a patient a therapeutically effective amount of a first pharmaceutically active agent comprising 5-fluoro-4-(4-fluoro-2- methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine of Formula (I) or an enantiomer thereof or a pharmaceutically acceptable salt thereof; and administering to a patient a therapeutically effective amount of a second pharmaceutically active agent selected from a proteasome inhibitor, a BCL-2 inhibitor, or a modulator of E3 ubiquitin ligase activity. In some embodiments, the method further comprises administering a therapeutically effective amount of an additional pharmaceutically active agent or a pharmaceutical composition thereof.

[0021] Provided in some embodiments herein is a method of treating multiple myeloma in a patient in need thereof, the method comprising: administering to a patient a therapeutically effective amount of a first pharmaceutically active agent comprising 5-fluoro-4-(4-fluoro-2- methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2 -amine of Formula (I) or an enantiomer thereof or a pharmaceutically acceptable salt thereof; and administering to a patient a therapeutically effective amount of a second pharmaceutically active agent selected from a proteasome inhibitor, a BCL-2 inhibitor, or a modulator of E3 ubiquitin ligase activity. In some embodiments, the efficacy of the treatment is predicted on the basis of the presence of one or more genetic abnormalities in the cells of the multiple myeloma in the patient. In some embodiments, the one or more genetic abnormalities comprises a translocation. In some embodiments, the one or more genetic abnormalities comprises monosomy 13. In some embodiments, the one or more genetic abnormalities comprises chromosome Iq gain. In some embodiments, the one or more genetic abnormalities comprises chromosome Ip deletion. In some embodiments, the one or more genetic abnormalities comprises chromosome 8q24 MYC gene rearrangement. In some embodiments, the one or more genetic abnormalities comprises chromosomal t (4; 14) translocation. In some embodiments, the one or more genetic abnormalities comprises chromosomal t (11 ; 14) translocation. In some embodiments, the one or more genetic abnormalities comprises chromosome 17p deletion.

[0022] In some embodiments, the efficacy of the treatment is predicted on the basis of the presence of an amplification of one or more genes in the cells of the multiple myeloma in the patient. In some embodiments, the one or more genes comprises the BCL2L11 gene. In some embodiments, the one or more genes comprises the RBI gene. In some embodiments, the one or more genes comprises the CSK1B gene. In some embodiments, the one or more genes comprises the MCL1 gene. In some embodiments, the one or more genes comprises the FAM46C gene. In some embodiments, the one or more genes comprises the CDKN2C gene. In some embodiments, the one or more genes comprises the FAF1 gene. In some embodiments, the one or more genes comprises the FC gene. In some embodiments, the one or more genes comprises the FGFR3 gene. In some embodiments, the one or more genes comprises the MEMSET gene. In some embodiments, the one or more genes comprises the CCND1 gene. In some embodiments, the one or more genes comprises the TP53 gene. In some embodiments, the one or more genes comprises the NRAS gene. In some embodiments, the one or more genes comprises the KRAS gene. In some embodiments, the one or more genes comprises the HRAS gene. In some embodiments, the one or more genes comprises the TRAF3 gene. In some embodiments, the one or more genes comprises the CDKN2A gene. In some embodiments, the one or more genes comprises the SMAD2 gene. In some embodiments, the one or more genes comprises the BRAF gene. In some embodiments, the one or more genes comprises the MSH6 gene.

[0023] In some embodiments, the efficacy of the treatment is predicted on the basis of an overexpression of one or more biomarkers in the cells of the multiple myeloma in the patient. In some embodiments, the one or more biomarkers comprises Bim (e.g., BCL-2-interacting mediator of cell death). In some embodiments, the one or more biomarkers comprises MYC. In some embodiments, the one or more biomarkers comprises MYB. In some embodiments, the one or more biomarkers comprises BCL2 Al . In some embodiments, the one or more biomarkers comprises BCL-xL. In some embodiments, the one or more biomarkers comprises Rb (e.g., retinoblastoma protein). In some embodiments, the one or more biomarkers comprises MCL1 (e.g., myeloid cell leukemia 1). In some embodiments, the one or more biomarkers comprises PARP (e.g., poly ADP-ribose polymerase). In some embodiments, the one or more biomarkers comprises pro-caspase-3. In some embodiments, the one or more biomarkers comprises RNA polymerase type-II. In some embodiments, the one or more biomarkers comprises PCNA (e.g., proliferating cell nuclear antigen).

[0024] In another aspect, the present disclosure provides methods of treating rhabdomyosarcoma or neuroblastoma in a patient in need thereof, the method comprising: administering to a patient a therapeutically effective amount of a first pharmaceutically active agent comprising 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S- methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2 -amine of Formula (I) or an enantiomer thereof or a pharmaceutically acceptable salt thereof

Formula (I).

[0025] In some embodiments, the method of treating rhabdomyosarcoma or neuroblastoma in a patient in need thereof further comprises administering to a patient a therapeutically effective amount of a second pharmaceutically active agent selected from a topoisomerase inhibitor, an exportin 1 inhibitor, a proteasome inhibitor, cyclophosphamide, or gemcitabine. [0026] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

INCORPORATION BY REFERENCE

[0027] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0029] FIG. 1 provides cell viability data of populations of multiple myeloma (MM) cell lines exposed to Formula (F) at variable concentrations for 96 hours.

[0030] FIG. 2 provides western blots carried out to monitor time-dependent and dosedependent target modulation in NCI-H929 MM and OPM-2 MM cells following exposure to Formula (F).

[0031] FIG. 3 A provides quantitative analysis of western blot data showing that exposure of NCI-H929 MM cells to Formula (F) leads to time-dependent and dose-dependent decreases in RNA Polymerase II phosphorylation.

[0032] FIG. 3B provides quantitative analysis ofwestern blot data showing that exposure of NCI-H929 MM cells to Formula (I’) leads to time-dependent and dose-dependent decreases in MYC protein levels. [0033] FIG. 4A provides quantitative analysis of western blot data showing that exposure of NCI-H929 MM cells to Formula (I’) leads to time-dependent and dose-dependent decreases in MCL1 protein levels.

[0034] FIG. 4B provides quantitative analysis of western blot data showing that exposure of NCI-H929 MM cells to Formula (F) leads to time-dependent and dose-dependent decreases in Bim protein levels.

[0035] FIG. 5A provides quantitative analysis of western blot data showing that exposure of NCI-H929 MM cells to Formula (F) leads to time-dependent and dose-dependent decreases in PCNA protein levels.

[0036] FIG. 5B provides quantitative analysis of western blot data showing that exposure of NCI-H929 MM cells to Formula (F) leads to time-dependent and dose-dependent decreases in PARP protein levels.

[0037] FIG. 6 provides quantitative analysis of western blot data showing that exposure of NCI-H929 MM cells to Formula (F) leads to time-dependent and dose-dependent decreases in pro-caspase-3 levels and time-dependent and dose-dependent increases in cleaved caspase-3 levels.

[0038] FIG. 7 provides western blots carried out to monitor target modulation in NCI-H929 MM cells and OPM-2 MM cells following exposure to Formula (F), venetoclax, and combinations of Formula (I’) and venetoclax.

[0039] FIG. 8 provides western blots carried out to monitor target modulation in OPM-2 MM cells following exposure to Formula (F), lenalidomide, and combinations of Formula (F) and lenalidomide.

[0040] FIG. 9 provides western blots carried out to monitor target modulation in OPM-2 MM cells following exposure to Formula (I’), venetoclax, and combinations of Formula (F) and venetoclax.

[0041] FIG. 10 provides data related to the tumor area of mouse tumor xenografts comprised of JJN-3 MM cells over the course of therapy with either Formula (I’) or a control. [0042] FIG. 11 provides data related to the tumor area of mouse tumor xenografts comprised of NCI-H929 MM cells over the course of therapy with either Formula (F) or a control.

[0043] FIG. 12 provides data related to the tumor area of mouse tumor xenografts comprised of OPM-2 MM cells over the course of therapy with either Formula (F), lenalidomide, both Formula (F) and lenalidomide, or a control. [0044] FIG. 13A provides data related to the time-dependent modulation of MCL1 mRNA in mouse tumor xenografts comprised of JJN-3 MM cells following administration of Formula (I’) versus a vehicle control.

[0045] FIG. 13B provides data related to the time-dependent modulation of MYC mRNA in mouse tumor xenografts comprised of JJN-3 MM cells following administration of Formula (I’) versus a vehicle control.

[0046] FIG. 13C provides data related to the time-dependent modulation of MYC protein in mouse tumor xenografts comprised of JJN-3 MM cells following administration of Formula (I’) versus a vehicle control.

[0047] FIG. 14A provides data related to the time-dependent levels of cleaved PARP in mouse tumor xenografts comprised of JJN-3 MM cells following administration of Formula (I’) versus a vehicle control.

[0048] FIG. 14B provides data related to the time-dependent levels of cleaved pro-caspase-3 in mouse tumor xenografts comprised of JJN-3 MM cells following administration of Formula (I’) versus a vehicle control.

[0049] FIG. 15A provides cell viability data of populations of rhabdomyosarcoma (RMS) cell lines exposed to Formula (I’) at variable concentrations for 96 hours.

[0050] FIG. 15B provides cell viability data of populations of neuroblastoma (NBL) cell lines exposed to Formula (I’) at variable concentrations for 96 hours.

[0051] FIG. 16 provides western blots carried out to monitor dose-dependent target modulation in Rh30 alveolar rhabdomyosarcoma cells following exposure to Formula (I’).

[0052] FIG. 17 provides flow cytometry data collected following exposure of Rh30 and Rh41 alveolar rhabdomyosarcoma cells to Formula (I’) and subsequent Annexin V/propidium iodide staining.

[0053] FIG. 18 provides bar graphs that quantify the flow cytometry data provided in FIG. 17, demonstrating the percentages of Rh30 and Rh41 alveolar rhabdomyosarcoma cells that underwent early apoptosis, late apoptosis, and/or necrosis following exposure to Formula (I¹).

[0054] FIG. 19A provides western blot data showing that exposure of Rh30 alveolar rhabdomyosarcoma cells to Formula (I¹) at various concentrations and for various times affects the levels of a variety of biomarkers in these cells.

[0055] FIG. 19B provides western blot data showing that exposure of SK-N-BE(2) neuroblastoma cells to Formula (I¹) at various concentrations and for various times affects the levels of a variety of biomarkers in these cells.

[0056] FIG. 20 provides bar graphs illustrating the Bliss synergy score of two- and three- agent combinations of Formula (I¹) (at 50-100 nM concentrations), irinotecan (at 1-2 pM concentrations), and temozolomide (at 2.5-5 pM concentrations) for inducing cell death in Rh30 and Rh41 alveolar rhabdomyosarcoma cells following 96 hours of exposure of the cells to the specified combination. Bliss synergy scores were obtained using experimental cell viability data.

DETAILED DESCRIPTION

[0057] In the following detailed description, reference is made to the accompanying figures, which form a part hereof. In the figures, similar symbols typically identify similar components, unless context dictates otherwise. The illustrative embodiments described in the detailed description, figures, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure, as generally described herein, and illustrated in the figures, canbe arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein.

[0058] Although certain embodiments and examples are disclosed below, inventive subject matter extends beyond the specifically disclosed embodiments to other alternative embodiments and/or uses, and to modifications and equivalents thereof. Thus, the scope of the claims appended hereto is not limited by any of the particular embodiments described below. For example, in any method or process disclosed herein, the acts or operations of the method or process may be performed in any suitable sequence and are not necessarily limited to any particular disclosed sequence. Various operations may be described as multiple discrete operations in turn, in a manner that may be helpful in understanding certain embodiments, however, the order of description should not be construed to imply that these operations are order dependent. Additionally, the structures, systems, and/or devices described herein may be embodied as integrated components or as separate components.

[0059] For purposes of comparing various embodiments, certain aspects and advantages of these embodiments are described. Not necessarily all such aspects or advantages are achieved by any particular embodiment. Thus, for example, various embodiments may be carried out in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other aspects or advantages as may also be taught or suggested herein.

[0060] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described or preclude the combination of the subject matter of the disclosure under any one section heading with any other subject matter of the disclosure under any other section heading or any other subject matter of the disclosure. Embodiments described herein with any one or more features may be readily combined with the features of any embodiments described further herein. Embodiments described herein are not limiting so as to wholly describe all embodiments of the disclosure.

DEFINITIONS

[0061] Unless defined otherwise, all terms of art, notations, and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[0062] Throughout this application, various embodiments may be presented in a range of formats. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, a description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0063] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unlessthe context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including combinations thereof.

[0064] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative, or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of’ can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

[0065] The term “about” or “approximately” as used herein when referring to a measurable value such as an amount or concentration and the like, is meant to encompass variations of 20 %, 10 %, 5 %, 1 %, 0.5 %, or even 0.1 % of the specified amount. For example, “about” can mean plus or minus 10 %, per the practice in the art. Alternatively, “about” can mean a range of plus or minus 20 %, plus or minus 10 %, plus or minus 5 %, or plus or minus 1 % of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, up to 5-fold, or up to 2-fold, of a value. Where particular values can be describedin the application and claims, unless otherwise stated the term “about” may be assumed to encompass the acceptable error range for the particular value. Also, where ranges, subranges, or both, of values, can be provided, the ranges or subranges can include the endpoints of the ranges or subranges.

[0066] Where values are described as ranges, it may be understood that such disclosure includes the disclosure of all possible sub-ranges within such ranges, as well as specific numerical values that fall within such ranges irrespective of whether a specific numerical value or specific sub -range is expressly stated.

[0067] The terms “comprise,” “have,” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes,” and “including,” are also open-ended. For example, any method that “comprises,” “has,” or “includes” one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps.

[0068] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0069] As used herein, the term “therapeutic” or “pharmaceutically active” means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a subject. In some embodiments, a pharmaceutically active agent such as a Formula (I) is directed to the treatment and/or the amelioration of cancers, including multiple myeloma (MM).

[0070] A “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology). [0071] The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to therapeutic treatment, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. A prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition, stabilization of a condition, or decreasing the likelihood of occurrence of a condition.

[0072] The term “animal” as used herein includes, but is not limited to, humans and nonhuman vertebrates such as wild, domestic and farm animals. As used herein, the terms “patient,” “subject” and “individual” are intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the subject is a primate. In certain embodiments, the primate or subject is a human. In certain instances, the human is an adult. In certain instances, the human is child. In further instances, the human is under the age of 12 years. In certain instances, the human is elderly. In other instances, the human is 60 years of age or older. Other examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The experimental animal can be an animal model for a disorder, e.g., a transgenic mouse with hypertensive pathology. A subject can be a patient. A patient can be a subject.

[0073] “Administering” when usedin conjunction with a therapeutic means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a subject whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering”, when used in conjunction with a composition described herein, can include, but is not limited to, providing a composition into or onto the target tissue; providing a composition systemically to a subject by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells. “Administering” a composition may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other techniques in the art. [0074] The family of cyclin-dependent kinase (CDK) proteins consists of members that are key regulators of the cell division cycle (cell cycle CDK's), that are involved in regulation of gene transcription (transcriptional CDK's), and of members with other functions. CDKs require for activation the association with a regulatory cyclin subunit. The cell cycle CDKs CDKl/cyclin B, CDK2/cyclin A, CDK2/cyclinE, CDK4/cyclinD, and CDK6/cyclinD get activated in a sequential order to drive a cell into and through the cell division cycle. The transcriptional CDKs CDK9/cyclin T and CDK7/cyclin H regulate the activity of RNA polymerase II via phosphorylation of the carb oxy -terminal domain (CTD). Positive transcription factorb (P-TEFb) is a heterodimer of CDK9 and one of four cyclin partners, cyclin Tl, cyclin K, cyclin T2a or T2b.

[0075] Whereas CDK9 (NCBI GenBank Gene ID 1025) is exclusively involved in transcriptional regulation, CDK7 in addition participates in cell cycle regulation as CDK- activating kinase (CAK).

[0076] Transcription of genes by RNA polymerase II is initiated by assembly of the preinitiation complex at the promoter region and phosphorylation of Ser 5 and Ser 7 of the CTD by CDK7/cyclin H. For a major fraction of genes RNA polymerase II stops mRNA transcription after it moved 20-40 nucleotides along the DNA template. This promoter-proximal pausing of RNA polymerase II is mediated by negative elongation factors and is recognized as a major control mechanism to regulate expression of rapidly induced genes in response to a variety of stimuli (Cho et al., Cell Cycle 2010, 9, 1697). P-TEFb is crucially involved in overcoming promoter-proximal pausing of RNA polymerase II and transition into a productive elongation state by phosphorylation of Ser 2 of the CTD as well as by phosphorylation and inactivation of negative elongation factors.

[0077] Activity of P-TEFb itself is regulated by several mechanisms. About half of cellular P-TEFb exists in an inactive complex with 7SK small nuclear RNA (7SK snRNA), La-related protein 7 (LARP7/PIP7S) and hexamethylene bis-acetamide inducible proteins 1/2 (HEXIM1/2, He et al., Mol. Cell 2008, 29, 588). The remaining half of P-TEFb exists in an active complex containing the bromodomain protein Brd4 (Yang et al., Mol. Cell 2005, 19, 535). Brd4 recruits P-TEFb through interaction with acetylated histones to chromatin areas primed for gene transcription. Through alternately interacting with its positive and negative regulators, P-TEFb is maintained in a functional equilibrium: P-TEFb bound to the 7SK snRNA complex represents a reservoir from which active P-TEFb can be released on demand of cellular transcription and cell proliferation (Zhou& Yik, Microbiol. Mol. Biol. Rev. 2006, 70, 646). Furthermore, the activity of P-TEFb is regulated by posttranslation al modifications including phosphorylation/de- phosphorylation, ubiquitination, and acetylation (reviewed in Cho et al., Cell Cycle 2010, 9, 1697).

[0078] Deregulated CDK9 kinase activity of the P-TEFb heterodimer is associated with a variety of human pathological settings such as hyper-proliferative diseases (e.g. cancer such as chronic lymphocytic leukemia (CLL)), virally induced infectious diseases or cardiovascular diseases. Cancer is regarded as a hyper-proliferative disorder mediated by a disbalance of proliferation and cell death (apoptosis). High levels of anti-apoptotic BCL-2-family proteins are found in various human tumors and account for prolonged survival of tumor cells and therapy resistance. Inhibition of P-TEFb kinase activity was shown to reduce transcriptional activity of RNA polymerase II leading to a decline of short-lived anti-apoptotic proteins, especially MCL-1 and XIAP, reinstalling the ability of tumour cells to undergo apoptosis. A number of other proteins associated with the transformed tumour phenotype (such as MYC, NF-kB responsive gene transcripts, mitotic kinases) are either short-lived proteins or are encoded by short-lived transcripts which are sensitive to reduced RNA polymerase II activity mediated by P-TEFb inhibition (reviewed in Wang & Fischer, Trends Pharmacol. Sci. 2008, 29, 302).

[0079] In summary, multiple lines of evidence suggest that selective inhibition of the CDK9 kinase activity of the P-TEFb heterodimer (= CDK9 and one of four cyclin partners, cyclin Tl, cyclin K, cyclin T2a or T2b) represents an innovative approach for the treatment of diseases such as cancer, viral diseases, and/or diseases of the heart. CDK9 belongs to a family of at least 13 closely related kinases of which the subgroup of the cell cycle CDK's fulfils multiple roles in regulation of cell proliferation. Thus, co-inhibition of cell cycle CDK's (e.g. CDKl/cyclin B, CDK2/cyclin A, CDK2/cyclinE, CDK4/cyclinD, CDK6/cyclinD) and of CDK9 is expected to impact normal proliferating tissues such as intestinal mucosa, lymphatic and hematopoietic organs, and reproductive organs. To maximize the therapeutic margin of CDK9 kinase inhibitors, molecules with high selectivity towards CDK9 are therefore required.

[0080] The proteasome is a central component of the protein degradation machinery in eukaryotic cells. Both transformed and normal cells depend on the function of the proteasome to control the expression of proteins linked to cell survival and proliferation. Cancer cells produce proteins that promote both cell survival and proliferation, and/or inhibit mechanisms of cell death. This notion set the stage for preclinical testing of proteasome inhibitors as a means to shift this fine equilibrium towards cell death. Clinical trials using proteasome inhibitors in myeloma, mantle-cell lymphoma (MCL) and amyloidosis have transformed the treatment of these diseases by establishing new standards of care (reviewed in Manasanch & Orlowski, Nature Reviews Clinical Oncology 2017, 14, 417). Three proteasome inhibitors have received regulatory approval and are used routinely in clinical settings, including bortezomib, carfilzomib and ixazomib. Primary resistance to proteasome inhibitors remains a challenge in patients with solid tumours; in addition, acquired resistance can be developed in myeloma and MCL even after initial responses.

[0081] B-cell lymphoma 2 (BCL-2) is a key protein regulator of apoptosis. It is variably highly expressed in many hematological malignancies, providing protection from cell death induced by oncogenic and external stresses. Avoidance of apoptosis is a prominent feature of many hematological malignancies. Venetoclax is the first selective BCL-2 inhibitor, and the first of a new class of anticancer drug (BH3 -mimetics) to be approved for routine clinical practice, currently in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) (reviewed in Roberts, Hematology Am. Soc. Hematol. Educ. Program 2020, 1, 1). Venetoclax has shown clinically meaningful single agent activity in multiple myeloma (Kumar et al. Blood 2017, 130, 2401).

[0082] Lenalidomide (Revlimid®) is an immunomodulatory drug structurally related to thalidomide, with improved efficacy and tolerability. Lenalidomide has become one of the most commonly used drugs in treatment of patients with newly diagnosed multiple myeloma (Cejalvo & de la Rubia, Future Oncol. 2015, 11, 1643). Lenalidomide has been used in treatments of multiple myeloma, often in combination with dexamethasone, in patients that have undergone autologous stem cell transplantation (ASCT) (Syed, Drugs 2017, 77, 1473) or are ineligible for ASCT (Zagouri et al., Expert Opin. Pharmacother. 2015, 16, 1865). Lenalidomide acts by a novel drug mechanism — modulation of the substrate specificity of the CRL4^CRBN E3 ubiquitin ligase. In multiple myeloma, lenalidomide induces the ubiquitination of IKZF1 and IKZF3 by CRL4^CRBN (Fink & Ebert, Blood 2015, 126, 2366). Sub sequent proteasomal degradation of these transcription factors kills multiple myeloma cells.

[0083] Pomalidomide (Imnovid; Pomalyst®), an analogue of thalidomide, is an immunomodulatory agent, with several mechanisms of action (both direct and indirect) thought to be involved in its anti-myeloma activity. The key therapeutic mechanisms of action of pomalidomide reside in its immunomodulatory, antiproliferative and anti-angiogenic effects (Scott, Drugs 2014, 74, 549). Pomalidomide is a modulator of E3 ubiquitin ligase activity. Oral pomalidomide is available in several countries for use in combination with low-dose dexamethasone in adults with relapsed and refractory multiple myeloma (Hoy, Drugs 2017, 77, 1897).

[0084] In some embodiments, methods for treating multiple myeloma (MM) in patients in need thereof may comprise administration of a first pharmaceutically active agent and administration of a second pharmaceutically active agent. In some embodiments, the methods disclosed herein comprise combination therapies. In some embodiments, the methods comprise administering a therapeutically effective dose of a first pharmaceutically active agent and administering a therapeutically effective dose of a second pharmaceutically active agent. In some embodiments, a first pharmaceutically active agent comprises a CDK9 inhibitor. In some embodiments, a first pharmaceutically active agent comprises a CDK9 inhibitor of Formula (I), or an enantiomer thereof, or a pharmaceutically-acceptable salt thereof. In some embodiments, a therapeutically effective dose of a first pharmaceutically active agent may be administered in the form of a pharmaceutical composition that comprises the first pharmaceutically active agent. In some embodiments, a therapeutically effective dose of a second pharmaceutically active agent may be administered in the form of a pharmaceutical composition that comprises the second pharmaceutically active agent.

CDK9 Inhibitors

[0085] Disclosed herein are methods of use of a first pharmaceutically active agent that is a CDK9 inhibitor with one or more pharmaceutically active agents for treating cancer in a patient in need thereof. In some embodiments, a CDK9 inhibitor may comprise a selective CDK9 inhibitor. In some embodiments, the selective CDK9 inhibitor is Formula (I) or Formula (F). In some embodiments the selective CDK9 inhibitor is a compound of Formula (I), an enantiomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the selective CDK9 inhibitor is a compound of Formula (F), an enantiomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments the selective CDK9 inhibitor is 5-fluoro-4-(4- fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2 -amine, an enantiomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments the selective CDK9 inhibitor is (+)-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S- methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the selective CDK9 inhibitor is 5-fluoro-4-(4-fluoro-2- methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine:

enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the selective CDK9 inhibitor is (+)-5-fluoro-4-(4-fluoro-2- methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2 -amine:

enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0088] The CDK9 inhibitor may be used to treat cancer in a patient in need thereof. In some embodiments, the cancer is multiple myeloma (MM), rhabdomyosarcoma (RMS), or neuroblastoma (NBL). In some embodiments, the CDK9 inhibitor may be administered with one or more pharmaceutically active agents.

Additional Therapeutic Agents

[0089] Disclosed herein are methods of use of a CDK9 inhibitor and one or more pharmaceutically active agents for treating a cancer in a patient in need thereof. In some embodiments, the CDK9 inhibitor and one or more pharmaceutically active agents is used in treating a cancer that is multiple myeloma (MM), rhabdomyosarcoma (RMS), or neuroblastoma (NBL).

[0090] In some embodiments, the second pharmaceutically active agent is a proteasome inhibitor. In some embodiments, the proteasome inhibitor is a 26S protease inhibitor. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the proteasome inhibitor is bortezomib. In some embodiments, the proteasome inhibitor is Velcade®. In some embodiments, the proteasome inhibitor is B-[(lR)-3 -methyl- 1 -[[(25)- l-oxo-3 -phenyl-2-[(2- pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic acid. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the proteasome inhibitor is ixazomib. In some embodiments, the proteasome inhibitor is selected from lactacystin, disulfiram, marizomib, oprozomib, epoxomicin, or combinations thereof.

[0091] In some embodiments, the second pharmaceutically active agent is a BCL-2 inhibitor. In some embodiments, the BCL-2 inhibitor is venetoclax. In some embodiments, the BCL-2 inhibitor is 4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-l-cyclohexen-l-yl]methyl}-l- piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(lH- pyrrolo[2,3-b]pyridin-5-yloxy)benzamide. In some embodiments, the BCL-2 inhibitor is navitoclax. In some embodiments, the BCL-2 inhibitor is obatoclax. In some embodiments, the BCL-2 inhibitor is oblimersen. In some embodiments, the BCL-2 inhibitor is gossypol.

[0092] In some embodiments, the second pharmaceutically active agent is a modulator of E3 ubiquitin ligase activity. In some embodiments, the modulator of E3 ubiquitin ligase activity is lenalidomide. In some embodiments, the modulator of E3 ubiquitin ligase activity is 3-(4-amino- 1-oxo-l,3-dihydro-2H-isoindol-2-yl)-2,6-piperidinedione. In some embodiments, the modulator of E3 ubiquitin ligase activity is pomalidomide. In some embodiments, the modulator of E3 ubiquitin ligase activity is 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-l, 3-dione. In some embodiments, the modulator of E3 ubiquitin ligase activity is Revlimid. In some embodiments, the modulator of E3 ubiquitin ligase activity is Pomalyst®.

[0093] In some embodiments, the second pharmaceutically active agent is a topoisomerase inhibitor. In some embodiments, the topoisomerase inhibitor is a topoisomerase I inhibitor. In some embodiments, the topoisomerase inhibitor is a topoisomerase II inhibitor. In some embodiments, the topoisomerase inhibitor is topotecan. In some embodiments, the topoisomerase inhibitor is (5)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-l/7- pyrano[3',4':6,7]indolizino[l,2-Z>]quinoline-3, 14(4/7, 12J7)-dione. In some embodiments, the topoisomerase inhibitor is etoposide. In some embodiments, the topoisomerase inhibitor is 4'- demethyl-epipodophyllotoxin 9-[4,6-O-(/?)-ethylidene-Z>eta-D-glucopyranoside]. In some embodiments, the topoisomerase inhibitor is irinotecan. In some embodiments, the topoisomerase inhibitor is (S)-4, 11 -diethyl-3, 4,12, 14-tetrahydro-4-hydroxy- 3,14-dioxolH- pyrano[3',4':6,7]-indolizino[l,2-b]quinolin- 9-yl-[l,4'bipiperidine]-r-carboxylate.

[0094] In some embodiments, the second pharmaceutically active agent is an exportin 1 inhibitor. In some embodiments, the exportin 1 inhibitor is Selinexor. In some embodiments, the exportin 1 inhibitor is (2Z)-3-{3-[3,5-Bis(trifluoromethyl)phenyl]-l,2,4-triazol-l-yl}-7V''-pyrazin-

2-ylprop-2-enehydrazide.

[0095] In some embodiments, the second pharmaceutically active agent is cyclophosphamide. In some embodiments, the second pharmaceutically active agent is N,N- bis(2-chloroethyl)-l,3,2-oxazaphosphinan-2-amine 2-oxide.

[0096] In some embodiments, the second pharmaceutically active agent is gemcitabine. In some embodiments, the second pharmaceutically active agent is 4-amino-l-(2-deoxy-2,2- difhioro-P-D-er tAro-pentofuranosyl)pyrimidin-2(177)-on.

[0097] In some embodiments, the second pharmaceutically active agent is temozolomide. In some embodiments, the second pharmaceutically active agent is 4-methyl-5-oxo-2,3,4,6,8- pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide.

[0098] In some embodiments, the combinations disclosed herein further comprise temozolomide. In some embodiments, the uses of combinations disclosed herein further comprise use of temozolomide. In some embodiments, the methods of treatment disclosed herein further comprise administrating a therapeutically effective dose of temozolomide to a subject. [0099] In some embodiments, the second pharmaceutically active agent is administered in the form of a pharmaceutically acceptable salt of the second pharmaceutically active agent.

[00100] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising alkylating agents, antimetabolites, plant-derived anti -tumor agents, hormonal therapy agents, topoisomerase inhibitors, camptothecin derivatives, kinase inhibitors, targeted drugs, immunologicals, antibodies, interferons and/or biological response modifiers, anti-angiogenic compounds, and other antitumor drugs in practice of the methods disclosed herein. In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure are used in fixed or separate combination with other pharmaceutically active agents comprising alkylating agents, anti -metabolites, plant-derived anti-tumor agents, hormonal therapy agents, topoisomerase inhibitors, camptothecin derivatives, kinase inhibitors, targeted drugs, immunologicals, antibodies, interferons and/or biological response modifiers, anti- angiogenic compounds, and other anti-tumor drugs in practice of the methods disclosed herein. [00101] In some embodiments, alkylating agents comprise nitrogen mustard 7V-oxide, cyclophosphamide, ifosfamide, thiotepa, ranimustine, nimustine, temozolomide, altretamine, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, mafosfamide, bendamustin, and mitolactol; platinum-coordinated alkylating compounds include, but are not limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin, and satraplatin.

[00102] In some embodiments, anti-metabolites comprise methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5 -fluorouracil alone or in combination with leucovorin, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, gemcitabine, fludarabin, 5 -azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflomithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, melphalan, nelarabine, nolatrexed, ocfosfite, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, and vinorelbine.

[00103] In some embodiments, hormonal therapy agents comprise exemestane, Lupron, anastrozole, doxercalciferol, fadrozole, formestane, 11-beta hydroxy steroid dehydrogenase 1 inhibitors, 17-alpha hydroxylase/17,20 lyase inhibitors such as abiraterone acetate, 5 -alpha reductase inhibitors such as finasteride and epristeride, anti-estrogens such as tamoxifen citrate and fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene, letrozole, anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex, and anti-progesterones and combinations thereof. [00104] In some embodiments, plant-derived anti-tumor substances comprise those selected from mitotic inhibitors, for example epothilones such as sagopilone, ixabepilone and epothilone B, vinblastine, vinflunine, docetaxel, and paclitaxel.

[00105] In some embodiments, topoisomerase inhibitors comprise aclarubicin, doxorubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan, topotecan, edotecarin, epimbicin, etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirambicin, pixantrone, rubitecan, sobuzoxane, tafluposide, and combinations thereof.

[00106] In some embodiments, immunologicals comprise interferons such as interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-la and interferon gamma-nl, and other immune enhancing agents such as L19-IL2 and other IL2 derivatives, filgrastim, lentinan, sizofilan, TheraCys, ubenimex, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab, ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim, sargramostim, tasonermin, tecleukin, thymalasin, tositumomab, Vimlizin, epratuzumab, mitumomab, oregovomab, pemtumomab, and Provenge; Merial melanoma vaccine.

[00107] In some embodiments, biological response modifiers comprise agents that modify defense mechanisms of living organisms or biological responses such as survival, growth or differentiation of tissue cells to direct them to have anti-tumor activity; such agents include, e.g., krestin, lentinan, sizofiran, picibanil, ProMune, and ubenimex.

[00108] In some embodiments, anti-angiogenic compounds comprise acitretin, aflibercept, angiostatin, aplidine, asentar, axitinib, recentin, bevacizumab, brivanib alaninat, cilengtide, combretastatin, DAST, endostatin, fenretinide, halofuginone, pazopanib, ranibizumab, rebimastat, removab, sorafenib, vatalanib, squalamine, sunitinib, telatinib, thalidomide, ukrain, and vitaxin;

[00109] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising antibodies such as trastuzumab, cetuximab, bevacizumab, rituximab, ticilimumab, ipilimumab, lumiliximab, catumaxomab, atacicept, oregovomab, and alemtuzumab.

[00110] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising VEGF inhibitors such as, e.g., sorafenib, DAST, bevacizumab, sunitinib, recentin, axitinib, aflibercept, telatinib, brivanib alaninate, vatalanib, pazopanib, and ranibizumab; Palladia. [00111] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising EGFR (HER1) inhibitors such as, e.g., cetuximab, panitumumab, vectibix, gefitinib, erlotinib, and Zactima.

[00112] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising HER2 inhibitors such as, e.g., lapatinib, tratuzumab, and pertuzumab.

[00113] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising mTOR inhibitors such as, e.g., temsirolimus, sirolimus/Rapamycin, and everolimus.

[00114] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising c-Met inhibitors.

[00115] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising PI3K and AKT inhibitors.

[00116] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising CDK inhibitors such as roscovitine and flavopiridol.

[00117] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising spindle assembly checkpoints inhibitors and targeted anti-mitotic agents such as PLK inhibitors, Aurora inhibitors (e.g. Hesperadin), checkpoint kinase inhibitors, and KSP inhibitors.

[00118] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising HD AC inhibitors such as, e.g, panobinostat, vorinostat, MS275, belinostat, and LBH589.

[00119] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising HSP90 and HSP70 inhibitors. [00120] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising proteasome inhibitors such as carfilzomib.

[00121] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising serine/threonine kinase inhibitors including MEK inhibitors (such as e.g. RDEA 119) and Raf inhibitors such as sorafenib.

[00122] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising famesyl transferase inhibitors such as, e.g., tipifarnib.

[00123] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising tyrosine kinase inhibitors including, e.g., dasatinib, nilotibib, DAST, bosutinib, sorafenib, bevacizumab, sunitinib, AZD2171, axitinib, aflibercept, telatinib, imatinib mesylate, brivanib alaninate, pazopanib, ranibizumab, vatalanib, cetuximab, panitumumab, vectibix, gefitinib, erlotinib, lapatinib, tratuzumab, pertuzumab, and c-Kit inhibitors; Palladia, masitinib.

[00124] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising vitamin D receptor agonists. [00125] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising cluster of differentiation 20 receptor antagonists such as, e.g., rituximab.

[00126] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising ribonucleotide reductase inhibitors such as, e.g., gemcitabine.

[00127] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising tumor necrosis apoptosis inducing ligand receptor 1 agonists such as, e.g., mapatumumab. [00128] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising 5-hydroxytryptamine receptor antagonists such as, e.g., rEV598, xaliprode, palonosetron hydrochloride, granisetron, Zindol, and AB- 1001.

[00129] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising integrin inhibitors including alpha5-betal integrin inhibitors such as, e.g., E7820, JSM 6425, volociximab, and endostatin. [00130] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising androgen receptor antagonists including, e.g., nandrolone decanoate, fluoxymesterone, Android, Prost-aid, andromustine,bicalutamide, flutamide, apo-cyproterone, apo-flutamide, chlormadinone acetate, Androcur, Tabi, cyproterone acetate, and nilutamide.

[00131] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising aromatase inhibitors such as, e.g., anastrozole, letrozole, testolactone, exemestane, aminoglutethimide, and formestane.

[00132] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising matrix metalloproteinase inhibitors.

[00133] In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in fixed or separate combination with other pharmaceutically active agents comprising anti-cancer agents including, e.g., alitretinoin, ampligen, atrasentan bexarotene, bosentan, calcitriol, exisulind, fotemustine, ibandronic acid, miltefosine, mitoxantrone, I-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazaroten, gallium nitrate, canfosfamide, darinaparsin, and tretinoin.

[00134] In some embodiments the methods of the present disclosure may also be employed in cancer treatment in conjunction with radiation therapy and/or surgical intervention. In some embodiments, the first pharmaceutically active agent and second pharmaceutically active agent of the present disclosure may be used in conjunction with radiation therapy and/or surgical intervention. Pharmaceutical Compositions

[00135] Disclosed herein are methods of treating cancer in a patient in need thereof using a pharmaceutical composition. In some embodiments, the cancer is multiple myeloma (MM), rhabdomyosarcoma (RMS), or neuroblastoma (NBL). In some embodiments, the rhabdomyosarcoma is embryonal rhabdomyosarcoma (eRMS). In some embodiments, the rhabdomyosarcoma is alveolar rhabdomyosarcoma (aRMS). In some embodiments, the pharmaceutical composition comprises a first pharmaceutically active agent and/or a second pharmaceutically active agent.

In some embodiments, the methods comprise administering a therapeutically effective dose of a first pharmaceutically active agent. In some embodiments, the methods comprise administering a therapeutically effective dose of a first pharmaceutically active agent and administering a therapeutically effective dose of a second pharmaceutically active agent. In some embodiments, a first pharmaceutically active agent comprises a CDK9 inhibitor. In some embodiments, a first pharmaceutically active agent comprises a CDK9 inhibitor of Formula (I), or an enantiomer thereof, or a pharmaceutically-acceptable salt thereof. In some embodiments, a therapeutically effective dose of a first pharmaceutically active agent may be administered in the form of a pharmaceutical composition that comprises the first pharmaceutically active agent. In some embodiments, a therapeutically effective dose of a second pharmaceutically active agent may be administered in the form of a pharmaceutical composition that comprises the second pharmaceutically active agent.

[00136] In some embodiments, a second pharmaceutically active agent may comprise a proteasome inhibitor, a BCL2 inhibitor, or a modulator of E3 ubiquitin ligase activity. In some embodiments, a second pharmaceutically active agent may comprise bortezomib, venetoclax, lenalidomide, or pomalidomide.

[00137] In some embodiments, a second pharmaceutically active agent may comprise a topoisomerase inhibitor, an exportin 1 inhibitor, a proteasome inhibitor, cyclophosphamide, or gemcitabine. In some embodiments, a second pharmaceutically active agent may comprise bortezomib, carfilzomib, Selinexor, topotecan, etoposide, cyclophosphamide, or gemcitabine. In some embodiments, the second pharmaceutically active agent comprises a topoisomerase inhibitor, an exportin 1 inhibitor, a proteasome inhibitor, cyclophosphamide, or gemcitabine. In some embodiments, the second pharmaceutically active agent comprises bortezomib, carfilzomib, Selinexor, topotecan, etoposide, cyclophosphamide, or gemcitabine.

[00138] Pharmaceutical compositions may comprise at least a compound, enantiomer, or salt of Formula (I) or (I’) described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersing agents, suspending agents, and/or thickening agents. Pharmaceutical compositions may comprise at least a second pharmaceutically active agent described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersing agents, suspending agents, and/or thickening agents.

[00139] Pharmaceutical compositions comprising the first pharmaceutical agent or the second pharmaceutical agent may be formulated using one or more physiologically-acceptable carriers comprising excipients and auxiliaries. Formulation may be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising the first pharmaceutical agent or the second pharmaceutical agent may be manufactured, for example, by lyophilizing, mixing, dissolving, emulsifying, encapsulating or entrapping the first pharmaceutical agent or the second pharmaceutical agent. The pharmaceutical compositions may also include the first pharmaceutical agent or the second pharmaceutical agent in a free-base form or a pharmaceutically -acceptable salt form.

[00140] Methods for formulation of the first pharmaceutical agent or the second pharmaceutical agent may include formulating any of the first pharmaceutical agent or the second pharmaceutical agent with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions may include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. Alternatively, the first pharmaceutical agent or the second pharmaceutical agent may be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[00141] Pharmaceutical compositions comprising the first pharmaceutical agent or the second pharmaceutical agent may comprise at least one active ingredient (e.g., a compound, salt or conjugate and other agents). The active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.

[00142] The pharmaceutical compositions and formulations may be sterilized. Sterilization may be accomplished by filtration through sterile filtration.

[00143] The pharmaceutical compositions described herein are administered to a subject by appropriate administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical compositions 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.

[00144] The pharmaceutical compositions comprising the first pharmaceutical agent or the second pharmaceutical agent may be formulated for administration as an injection. Non-limiting examples of formulations for injection may include a sterile suspension, solution or emulsion in oily or aqueous vehicles. Suitable oily vehicles may include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity or tonicity of the solution or suspension. The solution or suspension may also contain suitable stabilizers. Injections may be formulated for bolus injection or continuous infusion. Alternatively, the pharmaceutical compositions may be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[00145] For parenteral administration, the first pharmaceutical agent or the second pharmaceutical agent may be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles may be inherently non-toxic, andnon-therapeutic. Vehicles may be water, saline, Ringer’s solution, dextrose solution, organic solvents (e.g., ethanol, DMF, DMSO) and 5% human serum albumin; and combinations thereof. Non-aqueous vehicles such as fixed oils and ethyl oleate may also be used. Liposomes may be used as carriers. The vehicle may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[00146] In some embodiments, the disclosure relates to methods and pharmaceutical compositions of the first pharmaceutical agent or the second pharmaceutical agent formulated or formulated into a pharmaceutical composition suitable for injection into the body including intramuscular, subcutaneous, or intravenous, intratympanic, intraocular, epidural injection. In one aspect, formulations suitable for injection intramuscular, subcutaneous, or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, complexing agents (e.g., cyclodextrins) or vehicles include water, ethanol, polyols (propylene glycol, polyethylene-glycol, glycerol, cremophor and the like), vegetable oils and organic esters, such as ethyl oleate. In some aspects of the disclosure, formulations suitable for subcutaneous injection contain additives such as preserving, wetting, emulsifying, and dispensing agents. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin. [00147] For intravenous injections, the first pharmaceutical agent or the second pharmaceutical agent described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.

[00148] Parenteral injections may involve bolus injection or continuous infusion.

Formulations for injection may be presentedin unit dosage form, e.g., in ampoules or in multidose containers, with an added preservative. The pharmaceutical compositions described herein may be in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In one aspect, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[00149] In certain aspects of the disclosure, delivery systems for pharmaceutically active agents may be employed, such as, for example, liposomes and emulsions. In certain aspects of the disclosure, pharmaceutical compositions provided herein can also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

[00150] In some embodiments, the disclosure relates to methods and compositions of the first pharmaceutical agent or the second pharmaceutical agent formulated for oral delivery to a subject in need. In some embodiments, pharmaceutical compositions maybe formulated so as to deliver one or more pharmaceutically active agents to a subject through a mucosa layer in the mouth or esophagus. In some embodiments, pharmaceutical compositions may be formulated to deliver one or more pharmaceutically active agents to a subject through a mucosa layer in the stomach and/or intestines.

[00151] In some embodiments, pharmaceutical compositions of the first pharmaceutical agent or the second pharmaceutical agent are provided in modified release dosage forms. Suitable modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof. In some embodiments, the pharmaceutical compositions may also comprise non-release controlling excipients.

[00152] In some embodiments, pharmaceutical compositions comprising the first pharmaceutical agent or the second pharmaceutical agent are provided in enteric coated dosage forms. These enteric coated dosage forms can also comprise non-release controlling excipients. In some embodiments, the pharmaceutical compositions are in the form of enteric-coated granules, as controlled-release capsules for oral administration. The pharmaceutical compositions can further comprise cellulose, cyclodextrins, disodium hydrogen phosphate, hydroxypropyl cellulose, pyridazine, lactose, mannitol, or sodium lauryl sulfate. In some embodiments the pharmaceutical compositions may be in the form of enteric-coated pellets, as controlled-release capsules for oral administration. The pharmaceutical compositions can further comprise cyclodextrins, glycerol monostearate 40-50, hydroxypropyl cellulose, pyridazine, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, or triethyl citrate.

[00153] In some embodiments, the pharmaceutical compositions comprising the first pharmaceutical agent or the second pharmaceutical agent are enteric-coated controlled-release tablets for oral administration. The pharmaceutical compositions can further comprise carnauba wax, crospovidone, cyclodextrins, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, pyridazine phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, or yellow ferric oxide.

[00154] In some embodiments, sustained-release preparations comprising the first pharmaceutical agent or the second pharmaceutical agent may also be prepared. Examples of sustained-release preparations may include semipermeable matrices of solid hydrophobic polymers that may contain the compound, salt or conjugate, and these matrices may be in the form of shaped articles (e.g., films or microcapsules). Examples of sustained-release matrices may include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid andy ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTM (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3 -hydroxybutyric acid.

[00155] Pharmaceutical formulations comprising the first pharmaceutical agent or the second pharmaceutical agent may be prepared for storage by mixing the first pharmaceutical agent or the second pharmaceutical agent with a pharmaceutically acceptable carrier, excipient, and/or a stabilizer. This formulation may be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, and/or stabilizers may be nontoxic to recipients at the dosages and concentrations used. Acceptable carriers, excipients, and/or stabilizers may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and/or nonionic surfactants or polyethylene glycol.

[00156] In some embodiments, the pharmaceutical compositions comprising the first pharmaceutical agent or the second pharmaceutical agent may further comprise calcium stearate, crospovidone, cyclodextrins, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

[00157] In some embodiments, pharmaceutical compositions comprising the first pharmaceutical agent or the second pharmaceutical agent are provided in effervescent dosage forms. These effervescent dosage forms can also comprise non-release controlling excipients. [00158] In some embodiments, pharmaceutical compositions comprising the first pharmaceutical agent or the second pharmaceutical agent may be provided in a dosage form that has at least one component that can facilitate the immediate release of the pharmaceutically active agent, and at least one component that can facilitate the controlled release of the pharmaceutically active agent. In some embodiments, the dosage form can be capable of giving a discontinuous release of the compound in the form of at least two consecutive pulses separated in time from 0.1 up to 24 hours. In some embodiments, the pharmaceutical compositions comprising the first pharmaceutical agent or the second pharmaceutical agent may further comprise one or more release controlling and non-release controlling excipients, such as those excipients suitable for a disruptable semi-permeable membrane and as swellable substances. [00159] In some embodiments, pharmaceutical compositions comprising the first pharmaceutical agent or the second pharmaceutical agent may be provided in a dosage form for oral administration to a subject, which further comprise one or more pharmaceutically acceptable excipients or carriers, enclosed in an intermediate reactive layer comprising a gastric juice-resistant polymeric layered material partially neutralized with alkali and having cation exchange capacity and a gastric juice-resistant outer layer.

[00160] In some embodiments, the pharmaceutical compositions comprising the first pharmaceutical agent or the second pharmaceutical agent provided herein can be in unit-dosage forms or multiple-dosage forms. Unit-dosage forms, as used herein, refer to physically discrete units suitable for administration to human or non-human animal subjects and packaged individually. Each unit-dose can contain a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. In some embodiments, unit-dosage forms may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container, which can be administered in segregated unit-dosage form. Examples of multiple-dosage forms include, but are not limited to, vials, bottles of tablets or capsules, or bottles of pints or gallons. In other embodiments the multiple dosage forms may comprise different pharmaceutically active agents.

[00161] In some embodiments, the pharmaceutical compositions comprising Formula (I) or (I’) may also be formulated as a modified release dosage form, including immediate-, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, extended, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to a variety methods and techniques (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc. : New York, N.Y., 2002; Vol. 126, which are herein incorporated by reference in their entirety).

Combination Therapies

[00162] Disclosed herein are methods of treating cancer in a patient in need thereof using a combination therapy. In some embodiments, the cancer is multiple myeloma (MM), rhabdomyosarcoma (RMS), or neuroblastoma (NBL). In some embodiments, the rhabdomyosarcoma is embryonal rhabdomyosarcoma (eRMS). In some embodiments, the rhabdomyosarcoma is alveolar rhabdomyosarcoma (aRMS).

[00163] In some embodiments, the methods comprise administration of a first pharmaceutically active agent and administration of a second pharmaceutically active agent. In some embodiments, the methods comprise administering a therapeutically effective dose of a first pharmaceutically active agent and administering a therapeutically effective dose of a second pharmaceutically active agent. In some embodiments, the methods of treatment disclosed herein comprise administering a first pharmaceutically active agent to a patient according to a first administration schedule or treatment cycle and administering a second pharmaceutically active agent to a patient according to a second administration schedule or treatment cycle. In some embodiments, the method comprises administering a therapeutically effective dose of a first pharmaceutically active agent, administering a therapeutically effective dose of a second pharmaceutically active agent, and administering a therapeutically effective dose of an additional pharmaceutically active agent. In some embodiments, an additional pharmaceutically active agent may be any pharmaceutically active agent named, identified, or described herein. [00164] In some embodiments, the methods disclosed herein are combination therapies. In some embodiments, combination therapies may comprise administering a therapeutically effective dose of a first pharmaceutically active agent and administering a therapeutically effective dose of a second pharmaceutically active agent. In some embodiments, combination therapies may comprise administering a first pharmaceutically active agent to a patient according to a first administration schedule or treatment cycle and administering a second pharmaceutically active agent to a patient according to a second administration schedule or treatment cycle. In some embodiments, combination therapies may comprise administering a therapeutically effective dose of a first pharmaceutically active agent, administering a therapeutically effective dose of a second pharmaceutically active agent, and administering a therapeutically effective dose of an additional pharmaceutically active agent. In some embodiments, an additional pharmaceutically active agent may be any pharmaceutically active agent named, identified, or described herein. In some embodiments, combination therapies comprise administering a first pharmaceutically active agent to a patient according to a first administration schedule or treatment cycle and administering a second pharmaceutically active agent to a patient according to a second administration schedule or treatment cycle. In some embodiments, combination therapies comprise administering a therapeutically effective dose of a first pharmaceutically active agent, administering a therapeutically effective dose of a second pharmaceutically active agent, and administering a therapeutically effective dose of an additional pharmaceutically active agent. In some embodiments, an additional pharmaceutically active agent is selected from any pharmaceutically active agent named, identified, or described herein.

[00165] In some embodiments, combination therapies according to the methods disclosed herein may comprise the administration of a therapeutically effective amount of a compound of Formula (I) or (I’) to a patient, wherein Formula (I) or (F) are CDK9 inhibitors. In some embodiments, combination therapies according to the methods disclosed herein may comprise the administration of a therapeutically effective amount of a compound of Formula (I) or (F) to a patient, and administration of a therapeutically effective amount of a second pharmaceutical agent.

[00166] In some embodiments, combination therapies according to the methods disclosed herein comprise the administration of a therapeutically effective amount of a compound of Formula (I) or (F) to a patient, wherein Formula (I) or (F) are CDK9 inhibitors. In some embodiments, combination therapies according to the methods disclosed herein comprise the administration of a therapeutically effective amount of a compound of Formula (I) or (F) to a patient, and administration of a therapeutically effective amount of a second pharmaceutical agent.

[00167] In some embodiments, the methods described herein comprise administering to the subject a pharmaceutical composition. In some embodiments, the pharmaceutical composition may comprise a pharmaceutically active agent as described herein. In some embodiments, the pharmaceutical composition may comprise a first pharmaceutically active agent. In some embodiments, the pharmaceutical composition may comprise a second pharmaceutically active agent. In some embodiments, the pharmaceutical composition may comprise a first pharmaceutically active agent and a second pharmaceutically active agent. In some embodiments, a pharmaceutical composition may comprise a cyclin-dependent kinase 9 (CDK9) inhibitor. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a CDK9 inhibitor, or an enantiomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient. In some embodiments, the CDK9 inhibitor is a selective CDK9 inhibitor. In some embodiments, the CDK9 inhibitor is a CDK9 inhibitor described herein, such as herein above.

[00168] In some embodiments, methods of treating multiple myeloma (MM) in patients in need thereof comprise administering a first pharmaceutically active agent that is a CDK9 inhibitor.

[00169] In some embodiments, methods of treating rhabdomyosarcoma (RMS) or neuroblastoma (NBL) in patients in need thereof comprise administering a first pharmaceutically active agent that is a CDK9 inhibitor. In some embodiments, methods of treating rhabdomyosarcoma (RMS) in patients in need thereof comprise administering a first pharmaceutically active agent that is a CDK9 inhibitor. In some embodiments, the rhabdomyosarcoma is embryonal rhabdomyosarcoma (eRMS). In some embodiments, the rhabdomyosarcoma is alveolar rhabdomyosarcoma (aRMS). In some embodiments, methods of treating neuroblastoma (NBL) in patients in need thereof comprise administering a first pharmaceutically active agent that is a CDK9 inhibitor.

[00170] In some embodiments, a CDK9 inhibitor may comprise a selective CDK9 inhibitor. In some embodiments, the selective CDK9 inhibitor is Formula (I) or Formula (I’). In some embodiments the CDK9 inhibitor is a compound of Formula (I), an enantiomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments the selective CDK9 inhibitor is a compound of Formula (I’), an enantiomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments the selective CDK9 inhibitor is 5-fluoro-4-(4-fluoro-2-methoxyphenyl)- N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine, an enantiomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments the selective CDK9 inhibitor is (+)-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2- yl}pyridin-2 -amine, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[00171] In some embodiments, a CDK9 inhibitor is 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-

N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2 -amine:

enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[00172] In some embodiments, a CDK9 inhibitor is (+)-5-fluoro-4-(4-fluoro-2- methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2 -amine:

enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[00173] In some embodiments, the compounds described herein may be considered useful as pharmaceutical compositions for administration to a subject in need thereof. In some embodiments, pharmaceutical compositions may comprise at least a compound, enantiomer, or salt of Formula (I) or (I’) described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersing agents, suspending agents, and/or thickening agents. In some embodiments, pharmaceutical compositions comprise at least a compound, enantiomer, or salt of Formula (I) or (F) described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersing agents, suspending agents, and/or thickening agents.

[00174] In some embodiments, a pharmaceutical composition may comprise a first pharmaceutically active agent. In some embodiments, a first pharmaceutically active agent may comprise a compound, enantiomer, or salt of Formula (I) or (F). In some embodiments, a pharmaceutical composition may comprise a second pharmaceutically active agent. In some embodiments, a second pharmaceutically active agent may comprise a proteasome inhibitor, a BCL-2 inhibitor, or a modulator of E3 ubiquitin ligase activity. In some embodiments, a second pharmaceutically active agent may comprise bortezomib, venetoclax, lenalidomide, or pomalidomide. In some embodiments, a second pharmaceutically active agent may comprise a topoisomerase inhibitor, an exportin 1 inhibitor, a proteasome inhibitor, cyclophosphamide, or gemcitabine. In some embodiments, a second pharmaceutically active agent may comprise topotecan, etoposide, Selinexor, carfilzomib, cyclophosphamide, bortezomib, or gemcitabine. In some embodiments, a pharmaceutical composition may comprise a first pharmaceutically active agent and a second pharmaceutically active agent. In some embodiments, a pharmaceutical composition comprising a first pharmaceutically active agent may be administered in the same course of treatment as a pharmaceutical composition comprising a second pharmaceutically active agent. In some embodiments, practice of the methods of treatment disclosed herein comprise administering a pharmaceutical composition comprising a first pharmaceutically active agent to a patient according to a first administration schedule or treatment and administering a pharmaceutical composition comprising a second pharmaceutically active agent to a patient according to a second administration schedule or treatment cycle.

[00175] In some embodiments, pharmaceutical compositions comprising a compound, enantiomer, or salt of Formula (I) or (I’) may be formulated using one or more physiologically - acceptable carriers comprising excipients and auxiliaries. Formulation may be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound, salt or conjugate may be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions may also include the compounds, salts or conjugates in a free- base form or pharmaceutically -acceptable salt form.

[00176] In some embodiments, methods for formulation of a compound, enantiomer, or salt of Formula (I) or (F) may include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions may include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. Alternatively, the compounds, salts or conjugates may be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[00177] In some embodiments, pharmaceutical compositions comprising a compound, enantiomer, or salt of Formula (I) or (F) may comprise at least one active ingredient (e.g., a compound, salt or conjugate and other agents). The active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly- (methylmethacylate) microcapsules, respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.

[00178] In some embodiments, pharmaceutical compositions and formulations may be sterilized. Sterilization may be accomplished by filtration through sterile filtration.

[00179] In some embodiments, the pharmaceutical compositions described herein may be administered to a subject by appropriate administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical compositions 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.

[00180] In some embodiments, the pharmaceutical compositions comprising a compound, enantiomer, or salt of Formula (I) or (I’) may be formulated for administration as an injection. Non-limiting examples of formulations for injection may include a sterile suspension, solution or emulsion in oily or aqueous vehicles. Suitable oily vehicles may include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity or tonicity of the solution or suspension. The solution or suspension may also contain suitable stabilizers. Injections may be formulated for bolus injection or continuous infusion. Alternatively, the pharmaceutical compositions may be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[00181] In some embodiments, the methods disclosed herein are combination therapies. In some embodiments, combination therapies according to the methods disclosed herein may comprise the administration of a therapeutically effective amount of a compound of Formula (I) or (F) to a patient, wherein Formula (I) or (F) are CDK9 inhibitors. In some embodiments, a compound of Formula (I) or (F) may comprise a pharmaceutically acceptable salt of Formula (I) or (F). In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered to the subject and a level of the CDK9 inhibitor is maintained in the subject over a period of time, such as a period of time (e.g., an extended period of time) described herein (e.g., at least about 30 minutes (e.g., about 30 minutes or more, about 1 hour or more, about 2 hours or more, about 3 hours or more, about 4 hours or more, about 5 hours or more, or about 6 hours or more)). In some embodiments, the level of the CDK9 inhibitor maintained in the subject is at or above a minimum therapeutically effective threshold. In some embodiments, the level of the CDK9 inhibitor maintained in the subject is below atoxic threshold. In some embodiments, the level of the CDK9 inhibitor maintained in the subject is below a threshold that produces a toxic event. In some embodiments, the toxic event occurs after the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered to the subject. In some embodiments, the toxic event occurs days after the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered to the subject. In some embodiments, the toxic event occurs weeks after the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered to the subject. In some embodiments, the toxic event occurs months after the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered to the subject. In some embodiments, the toxic event is neutropenia.

[00182] In some embodiments, the methods disclosed herein are combination therapies. In some embodiments, combination therapies according to the methods disclosed herein may comprise the administration of a therapeutically effective amount of a compound of Formula (I) or (I’) to a patient, wherein Formula (I) or (F) are CDK9 inhibitors. In some embodiments, a compound of Formula (I) or (F) may comprise a pharmaceutically acceptable salt of Formula (I) or(F). In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose sufficient to provide a maximum plasma concentration (C_max) of the CDK9 inhibitor below a toxic effective threshold of the CDK9 inhibitor in the subject. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose sufficient to provide a minimum plasma concentration (Cmin) of the CDK9 inhibitor of at least the therapeutically effective threshold of the CDK9 inhibitor in the subject. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose sufficient to provide a maximum plasma concentration (C_max) of the CDK9 inhibitor below a toxic effective threshold of the CDK9 inhibitor and a minimum plasma concentration (C_min) of the CDK9 inhibitor of at least the therapeutically effective threshold of the CDK9 inhibitor in the subject. In some embodiments, the level of the CDK9 inhibitor is maintained in the subject above the therapeutically effective threshold. In some embodiments, the level of the CDK9 inhibitor is maintained in the subject below the toxic effective threshold of the CDK9 inhibitor. In some embodiments, the level of the CDK9 inhibitor is maintained in the subject above the therapeutically effective threshold and below the toxic effective threshold of the CDK9 inhibitor. In some embodiments, the level of the CDK9 inhibitor is maintained in a biological sample (e.g., serum, plasma, or whole blood) of the subject above the therapeutically effective threshold and below the toxic effective threshold of the CDK9 inhibitor. In some embodiments, the toxic threshold is below a threshold that produces a toxic event. In some embodiments, the toxic threshold is below a threshold that produces a toxic event occurring after (days after, weeks after, months after, etc.) the CDK9 inhibitor is administered to the subject.

[00183] In some embodiments, the level of the CDK9 inhibitor is measured in a biological sample of the subject. In some embodiments, the level of the CDK9 inhibitor is measured in serum, plasma, and/or whole blood of the subject.

[00184] In some embodiments, the methods disclosed herein are combination therapies. In some embodiments, combination therapies according to the methods disclosed herein may comprise the administration of a therapeutically effective amount of a compound of Formula (I) or (I’) to a patient, wherein Formula (I) or (F) are CDK9 inhibitors. In some embodiments, a compound of Formula (I) or (F) may comprise a pharmaceutically acceptable salt of Formula (I) or (F). In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered to the subject a first time. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered to the subject a second time. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered to the subject the first time over an extended period of time, such as an extended period of time of time described herein (e.g., at least about 30 minutes (e.g., about 30 minutes or more, about 1 hour or more, about 2 hours or more, about 3 hours or more, about 4 hours or more, about 5 hours or more, or about 6 hours or more)). In some embodiments, the first time is over a period of time that is at least about 30 minutes. In some embodiments, the first time is over a period of time that is about 3 or 4 hours. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered to the subject the second time over an extended period of time, such as an extended period of time of time described herein (e.g., at least about 30 minutes (e.g., about 30 minutes or more, about 1 hour or more, about 2 hours or more, about 3 hours or more, about 4 hours or more, about 5 hours or more, or about 6 hours or more)). In some embodiments, the second time is over a period of time that is at least about 30 minutes. In some embodiments, the second time is over a period of time that is about 3 or 4 hours. In some embodiments, the second time is about 7 days after the first time. In some embodiments, the second time is a week or less after the first time. In some embodiments, the second time is no more than a week after the first time. In some embodiments, the second time is a week or more after the first time. In some embodiments, the second time is no less than a week after the first time. In some embodiments, the second time is about a week after the first time. In some embodiments, the second time is about a week after the first time with optional intervening administration of a therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the second time is about a week after the first time with optional subsequent administration of a therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the second time is about a week after the first time with optional intervening and/or subsequent administration of a therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof.

[00185] In some embodiments, the methods disclosed herein are combination therapies. In some embodiments, combination therapies according to the methods disclosed herein may comprise the administration of a therapeutically effective amount of a compound of Formula (I) or (I’) to a patient, wherein Formula (I) or (F) are CDK9 inhibitors. In some embodiments, a compound of Formula (I) or (F) may comprise a pharmaceutically acceptable salt of Formula (I) or (F). In some embodiments, the therapeutically effective amount of a CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered a first time and a second time with intervening and/or subsequent administration of the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of a CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered a first time and a second time with intervening administration of the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of a CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered a first time and a second time with subsequent administration of the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of a CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered another time, such as another time after the first time and/or the second time. In some embodiments, the therapeutically effective amount of a CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered at least a third time. In some embodiments, the therapeutically effective amount of a CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject a third time, a fourth time, a fifth time, or more times. In some embodiments, the therapeutically effective amount of a CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject one or more times after the second time. In some embodiments, the therapeutically effective amount of a CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject at weekly intervals, such that the second time is a week after the first time, the third time is a week after the second time, the fourth time is a week after the third time, and so on. In some embodiments, the therapeutically effective amount of a CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered (e.g., weekly) to the subject until one or more (e.g., cancer) biomarker described herein is (e.g., significantly) reduced. In some embodiments, the therapeutically effective amount of a CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered (e.g., weekly) to the subject until the proliferative disease or disorder (e.g., cancer) is treated in the subject. In some embodiments, the therapeutically effective amount of a CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered (e.g., weekly) to the subject until one or more endpoints is met.

[00186] Provided in some embodiments herein is a method of treating MM in a subject in need thereof. Provided in some embodiments herein is a method of treating RMS or NBL in a subject in need thereof. Provided in some embodiments herein is a method of treating RMS in a subject in need thereof. Provided in some embodiments herein is a method of treating NBL in a subject in need thereof. In some embodiments, the methods disclosed herein are combination therapies. In some embodiments, combination therapies according to the methods disclosed herein may comprise the administration of a therapeutically effective amount of a compound of Formula (I) or (I’) to a patient, wherein Formula (I) or (I’) are CDK9 inhibitors. In some embodiments, a compound of Formula (I) or (I’) may comprise a pharmaceutically acceptable salt of Formula (I) or (I’). In some embodiments, the method comprises administering to the subject in need thereof a therapeutically effective amount of a CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, according to a dosing regimen. In some embodiments, the dosing regimen is a prolonged dosing regimen. In some embodiments, the (e.g., prolonged) dosing regimen comprises administering the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, at a reduced C_max level, such as in the peripheral blood of the subject. In some embodiments, the reduced C_max level is lower than a Cmax level provided when the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered over a shorter period of time. In some embodiments, the reduced C_max level is about half as low as a C_max level provided when the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered over a shorter period of time. In some embodiments, such as when administered over the shorter period of time, the therapeutically effective amount of a CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject is administered via an intravenous (IV) drip. In some embodiments, such as when administered over a longer period of time, the therapeutically effective amount of a CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject is administered via an intravenous (IV) pump. [00187] In some embodiments, the methods disclosed herein are combination therapies. In some embodiments, combination therapies according to the methods disclosed herein may comprise the administration of a therapeutically effective amount of a compound of Formula (I) or (I’) to a patient, wherein Formula (I) or (F) are CDK9 inhibitors. In some embodiments, a compound of Formula (I) or (F) may comprise a pharmaceutically acceptable salt of Formula (I) or (F). In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject at a C_max (level) described herein. In some embodiments, the C_max (level) is no more than about 1 ,000 ng/mL. In some embodiments, the C_max (level) is about 1,000 ng/mL or less, 900 ng/mL or less, 800 ng/mL or less, 700 ng/mL or less, 600 ng/mL or less, 500 ng/mL or less, 400 ng/mL or less, 300 ng/mL or less, 200 ng/mL or less, or 100 ng/mL or less. In some embodiments, the C_max (level) is about 500 ng/mL or less. In some embodiments, the C_max (level) is about 400 ng/mL or less. In some embodiments, the C_max (level) is about 300 ng/mL or less. In some embodiments, the C_max (level) is about 200 ng/mL or less. In some embodiments, the C_max (level) is about 100 ng/mL or less. In some embodiments, the C_max (level) is no less than about 10 ng/mL. In some embodiments, the C_max (level) is about 10 ng/mL or more, 100 ng/mL or more, 200 ng/mL or more, 300 ng/mL or more, 400 ng/mL or more, 500 ng/mL or more, 600 ng/mL or more, 700 ng/mL or more, 800 ng/mL or more, or about 900 ng/mL or more. In some embodiments, the Cmax (level) is about 10 ng/mL or more. In some embodiments, the C_max (level) is about 100 ng/mL or more. In some embodiments, the C_max (level) is about 200 ng/mL or more. In some embodiments, the C_max (level) is about 300 ng/mL or more. In some embodiments, the C_max (level) is about 400 ng/mL or more. In some embodiments, the C_max (level) is about 500 ng/mL or more. In some embodiments, the C_max (level) is about 500 ng/mL to about 50 ng/mL. In some embodiments, the C_max (level) is about 500 ng/mL to about 100 ng/mL. In some embodiments, the Cmax (level) is about 250 ng/mL to about 100 ng/mL. In some embodiments, the C_max (level) is about 500 ng/mL. In some embodiments, the C_max (level) is about 250 ng/mL. In some embodiments, the C_max (level) is about 125 ng/mL.

[00188] In some embodiments, the methods disclosed herein are combination therapies. In some embodiments, combination therapies according to the methods disclosed herein may comprise the administration of a therapeutically effective amount of a compound of Formula (I) or (I’) to a patient, wherein Formula (I) or (F) are CDK9 inhibitors. In some embodiments, a therapeutically effective amount of a compound of Formula (I) or (F) may be formulated into a pharmaceutical composition suitable for administration to a patient in need thereof. In some embodiments, a therapeutically effective amount of a second pharmaceutically active agent may be formulated into a pharmaceutical composition suitable for administration to a patient in need thereof. In some embodiments, the pharmaceutical composition (e.g., the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof) herein is administered to the subject for at least 30 minutes. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 30 minutesor more, about 1 hour or more, about 2 hours or more, about 3 hours or more, about 4 hours or more, about 5 hours or more, or about 6 hours or more. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 30 minutes or more. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 1 hour or more. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 2 hours or more. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 3 hours or more. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 4 hours or more. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 5 hours or more. In some embodiments, the pharmaceutical composition herein is administered to the subjectfor about 6 hours or more. In some embodiments, the pharmaceutical composition herein is administered to the subject for at most 6 hours. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 6 hours or less, about 5 hours or less, about 4 hours or less, about 3 hours or less, about 2 hours or less, about 1 hour or less, or about 30 minutes or less. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 6 hours or less. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 5 hours or less. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 4 hours or less. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 3 hours or less. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 2 hours or less. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 1 hour or less. In some embodiments, the pharmaceutical composition herein is administered to the subjectfor about 30 minutes or less. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 30 minutes to about 6 hours. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 30 minutes to about 5 hours. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 30 minutes to about 4 hours. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 1 hour to about 4 hours. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 2 hours to about 4 hours. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 3 hours to about 4 hours. In some embodiments, the pharmaceutical composition herein is administered to the subject for about 4 hours.

[00189] In some embodiments, the methods disclosed herein are combination therapies. In some embodiments, combination therapies according to the methods disclosed herein may comprise the administration of a therapeutically effective amount of a compound of Formula (I) or (I’) to a patient, wherein Formula (I) or (F) are CDK9 inhibitors. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject for about 1 hour at a C_max (level) that is about 500 ng/mL or less. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject for about 2 hours at a Cmax (level) that is about 500 ng/mL or less. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject for about 3 hours at a C_max (level) that is about 500 ng/mL or less. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject for about 4 hours at a C_max (level) that is about 500 ng/mL or less. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject for about 1 hour to about 4 hours at a C_max (level) that is about 500 ng/mL to about 50 ng/mL. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject for about 1 hour to about 4 hours at a C_max (level) that is about 500 ng/mL to about 100 ng/mL. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject for about 1 hour to about 4 hours at a C_max (level) that is about 250 ng/mL to about 100 ng/mL. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subjectfor about 1 hour at a C_max (level) that is about 500 ng/mL. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subjectfor about 2 hours at a C_max (level) that is about 250 ng/mL. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject for about 4 hours at a Cmax (level) that is about 125 ng/mL.

[00190] In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof three times a week, two times a week, once a week, bi-weekly, or monthly. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof at least once a week. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof three times a week, two times a week, or once a week. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof about once a week. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof once a week.

[00191] In some embodiments, the pharmaceutical composition described herein is administered to the subject orally.

[00192] In some embodiments, a level of at least one biomarker is reduced in the subject. In some embodiments, the methods disclosed herein may reduce the level of at least one biomarker in the cells of the MM in the patient in need of treatment. In some embodiments, the methods disclosed herein may reduce the level of at least one biomarker in the cells of the RMS or NBL in the patient in need of treatment. In some embodiments, the methods disclosed herein may reduce the level of at least one biomarker in the cells of the RMS in the patient in need of treatment. In some embodiments, the methods disclosed herein may reduce the level of at least one biomarker in the cells of the NBL in the patient in need of treatment. In some embodiments, target modulation comprises the reduction of the level of at least one biomarker. In some embodiments, a level of at least one biomarker is reduced after the CDK9 inhibitor is administered to the subject. In some embodiments, a level of at least one biomarker is reduced days after the CDK9 inhibitor is administered to the subject. In some embodiments, a level of at least one biomarker is reduced weeks after the CDK9 inhibitor is administered to the subject. In some embodiments, a level of at least one biomarker is reduced months after the CDK9 inhibitor is administered to the subject. In some embodiments, a level of at least one biomarker is reduced in the subject (e.g., for any period of time described herein) after the subject undergoes any dosing regimen described herein. In some embodiments, a level of at least one biomarker is reduced in the subject indefinitely after the subject undergoes any dosing regimen described herein. In some embodiments, the level of the at least one biomarker is reduced more when the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject at a (relatively) low C_max, such as over a (relatively) longer period of time, than at a (relatively) high C_max, such as over a (relatively) shorter period of time. In some embodiments, the amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is the same when administered at the (relatively) low C_max for the (relatively) long time and the (relatively) high C_max over the (relatively) short period of time. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is the same when administered at the (relatively) low C_max for the (relatively) long time and the (relatively) high C_max over the (relatively) short period of time.

[00193] In some embodiments, a level of at least one biomarker is reduced after the combination therapy is administered to the subject. In some embodiments, a level of at least one biomarker is reduced days after the combination therapy is administered to the subject. In some embodiments, a level of at least one biomarker is reduced weeks after the combination therapy is administered to the subject. In some embodiments, a level of at least one biomarker is reduced months after the combination therapy is administered to the subject.

[00194] In some embodiments, the at least one biomarker is a cancer (i.e., oncogenic) biomarker. In some embodiments, the at least one (e.g., cancer) biomarker is a (e.g., cancer) biomarker described herein, such as in any FIG. or Example provided herein. In some embodiments, the at least one (e.g., cancer) biomarker is selected from the group comprising MYC, MYB, BCL2A1, BCL-xL, Rb, MCL1, Bim, PARP, pro-caspase-3, RNA polymerase type II, and PCNA. In some embodiments, the biomarker is MYC. In some embodiments, the biomarker is MYB. In some embodiments, the biomarker is BCL2A1. In some embodiments, the biomarker is BCL-xL. In some embodiments, the biomarker is retinoblastoma protein (Rb). In some embodiments, the biomarker is MCL1 . In some embodiments, the biomarker is Bim. In some embodiments, the biomarker is PARP. In some embodiments, the biomarker is pro- caspase-3. In some embodiments, the biomarker is RNA polymerase type II. In some embodiments, the biomarker is PCNA. In some embodiments, the biomarker is MYCN. In some embodiments, the biomarker is PLK1. In some embodiments, the biomarker is PAX3-FOXO1. In some embodiments, the biomarker is PAX7-FOXO1.

[00195] In some embodiments, the efficacy of the method may be predicted on the basis of the presence of one or more genetic abnormalities in the cells of the MM for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of a genetic abnormality in the cells of the MM for treatment.

[00196] In some embodiments, the efficacy of the method may be predicted on the basis of the presence of one or more genetic abnormalities in the cells of the RMS or NBL for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of a genetic abnormality in the cells of the RMS or NBL for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of one or more genetic abnormalities in the cells of the RMS for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of a genetic abnormality in the cells of the RMS for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of one or more genetic abnormalities in the cells of the NBL for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of a genetic abnormality in the cells of the NBL for treatment.

[00197] In some embodiments, the efficacy of the method may be predicted on the basis of the presence of one or more gene amplifications in the cells of the MM for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of a gene amplification in the cells of the MM for treatment.

[00198] In some embodiments, the efficacy of the method may be predicted on the basis of the presence of one or more gene amplifications in the cells of the RMS or NBL for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of a gene amplification in the cells of the RMS or NBL for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of one or more gene amplifications in the cells of the RMS for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of a gene amplification in the cells of the RMS for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of one or more gene amplifications in the cells of the NBL for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of a gene amplification in the cells of the NBL for treatment.

[00199] In some embodiments, the RMS or NBL for treatment may present an amplification of the MYCN gene. In some embodiments, the RMS for treatment may present an amplification of the MYCN gene. In some embodiments, the NBL for treatment may present an amplification of the MYCN gene.

[00200] In some embodiments, the efficacy of the method may be predicted on the basis of the presence of one or more increased gene copy numbers in the cells of the RMS or NBL for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of an increased gene copy number in the cells of the RMS or NBL for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of one or more increased gene copy numbers in the cells of the RMS for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of an increased gene copy number in the cells of the RMS for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of one or more increased gene copy numbers in the cells of the NBL for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of an increased gene copy number in the cells of the NBL for treatment. [00201] In some embodiments, the RMS or NBL for treatment may present an increased gene copy number of the MYCN gene. In some embodiments, the RMS for treatment may present an increased gene copy number of the MYCN gene. In some embodiments, the NBL for treatment may present an increased gene copy number of the MYCN gene.

[00202] In some embodiments, the efficacy of the method may be predicted on the basis of the presence of overexpression of one or more biomarkers in the cells of the MM for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of overexpression of a biomarker in the cells of the MM for treatment.

[00203] In some embodiments, the efficacy of the method may be predicted on the basis of the presence of overexpression of one or more biomarkers in the cells of the RMS or NBL for treatment. In some embodiments, the efficacy of the method maybe predicted on the basis of the presence of overexpression of a biomarker in the cells of the RMS or NBL for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of overexpression of one or more biomarkers in the cells of the RMS for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of overexpression of a biomarker in the cells of the RMS for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of overexpression of one or more biomarkers in the cells of the NBL for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of overexpression of a biomarker in the cells of the NBL for treatment.

[00204] In some embodiments, the efficacy of the method may be predicted on the basis of the presence of one or more biomarkers in the cells of the RMS or NBL for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of a biomarker in the cells of the RMS or NBL for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of one or more biomarkers in the cells of the RMS for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of a biomarker in the cells of the RMS for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of one or more biomarkers in the cells of the NBL for treatment. In some embodiments, the efficacy of the method may be predicted on the basis of the presence of a biomarker in the cells of the NBL for treatment.

[00205] In some embodiments, the pharmaceutical compositions described herein are used in the methods of treatment described herein. In some embodiments, the pharmaceutical compositions described herein are used in combination therapies. In some embodiments, a method for treating multiple myeloma in a subject in need of such treatment may comprise administration of pharmaceutical compositions in therapeutically effective amounts to said subject.

[00206] Dosages of compounds or pharmaceutical compositions described herein can be determined by any suitable method. Maximum tolerated doses (MTD) and maximum response doses (MRD) for Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof, can be determined via established animal and human experimental protocols as well as in the examples described herein. For example, toxicity and therapeutic efficacy of Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD₅₀ and ED₅₀. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED₅₀ with minimal toxicity. The dosage may vary within this range dependingupon the dosage form employed and the route of administration utilized. Additional relative dosages, represented as a percent of maximal response or of maximum tolerated dose, are readily obtained via the protocols.

[00207] In some embodiments, the amount of a given formulation comprising Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof, that corresponds to such an amount varies depending upon factors such as the particular salt or form, disease condition and its severity, the identity (e.g., age, weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the liquid formulation type, the condition being treated, and the subject or host being treated.

[00208] Administration of the selective CDK9 inhibitor (e.g., Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof), may be at a dosage described herein or at other dose levels and compositions determined and contemplated by a medical practitioner. In certain embodiments, the selective CDK9 inhibitor (e.g., Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof), may be administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the selective CDK9 inhibitor (e.g., Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof), is administered to a subject already suffering from a disease in an amount sufficient to cure the disease or at least partially arrest or ameliorate the symptoms. Amounts effective for this use depend on the age of the subject, severity of the disease, previous therapy, the subject's health status, weight, and response to the pharmaceutical compositions, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial.

[00209] In prophylactic applications, the pharmaceutical compositions described herein are administered to a subject susceptible to or otherwise at risk of a particular disease, e.g., cancer. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the subject's age, state of health, weight, and the like. When used in a subject, effective amounts for this use will depend on the risk or susceptibility of developingthe particular disease, previous therapy, the subject's health status and response to the pharmaceutical compositions, and the judgment of the treating physician.

[00210] In certain embodiments wherein the subject’s condition does not improve, upon the doctor’s discretion the administration of a composition described herein are administered chronically, that is, for an extended period of time, including throughout the duration of the subject’s life in orderto ameliorate or otherwise control or limit the symptoms of the subject’s disease. In other embodiments, administration of a composition continues until complete or partial response of a disease.

[00211] In some embodiments, a first pharmaceutically active agent comprises a compound of Formula (I) or (I’). In some embodiments, the selective CDK9 inhibitor (e.g., Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof), may be administered orally. In some embodiments, the selective CDK9 inhibitor (e.g., Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof), is administered intravenously.

[00212] In some embodiments, a first pharmaceutically active agent comprises a compound of Formula (I) or (F). In some embodiments, the selective CDK9 inhibitor (e.g., Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof), is administered to a subject who is in a fasted state. A fasted state refers to a subject who has gone without food or fasted for a certain period of time. General fasting periods include at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours and at least 16 hours without food. In some embodiments, the selective CDK9 inhibitor (e.g., Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof), is administered to a subject who is in a fasted state for at least 8 hours. In other embodiments, Formula (I), or a pharmaceutically acceptable saltthereof, is administered to a subject who is in a fasted state for at least 10 hours. In yet other embodiments, the selective CDK9 inhibitor (e.g., Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof), is administered to a subject who is in a fasted state for at least 12 hours. In other embodiments, the selective CDK9 inhibitor (e.g., Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof), is administered to a subject who has fasted overnight.

[00213] In some embodiments, a first pharmaceutically active agent comprises a compound of Formula (I) or (F). In some embodiments, the selective CDK9 inhibitor (e.g., Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof), is administered to a subject who is in a fed state. A fed state refers to a subject who has taken food or has had a meal. In certain embodiments, a composition is administered to a subject in a fed state 5 minutes post-meal, 10 minutes post-meal, 15 minutes post-meal, 20 minutes post-meal, 30 minutes postmeal, 40 minutes post-meal, 50 minutes post-meal, 1 hour post-meal, or 2 hours post-meal. In certain instances, the selective CDK9 inhibitor (e.g., Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof), is administered to a subject in a fed state 30 minutes post-meal. In other instances, the selective CDK9 inhibitor (e.g., Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof), is administered to a subject in a fed state 1 hour post-meal. In yet further embodiments, Formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt or solvate thereof, is administered to a subject with food.

[00214] The length of a treatment cycle depends on the treatment being given. In some embodiments, the length of a treatment cycle ranges from two to six weeks. In some embodiments, the length of a treatment cycle ranges from three to six weeks. In some embodiments, the length of a treatment cycle ranges from three to four weeks. In some embodiments, the length of a treatment cycle is three weeks (or 21 days). In some embodiments, the length of a treatment cycle is four weeks (28 days). In some embodiments, the length of a treatment cycle is five weeks (35 days). In some embodiments, the length of a treatment cycle is 56 days. In some embodiments, a treatment cycle lasts one, two, three, four, or five weeks. In some embodiments, a treatment cycle lasts three weeks. In some embodiments, a treatment cycle lasts four weeks. In some embodiments, a treatment cycle lasts five weeks. The number of treatment doses scheduled within each cycle also varies depending on the drugs being given. [00215] In some embodiments, the methods of treating multiple myeloma (MM) in patients in need thereof disclosed herein may comprise one or more synergistic effects. In some embodiments, the methods of treating rhabdomyosarcoma (RMS) or neuroblastoma (NBL) in patients in need thereof disclosed herein may comprise one or more synergistic effects. In some embodiments, the methods of treating rhabdomyosarcoma (RMS) in patients in need thereof disclosed herein may comprise one or more synergistic effects. In some embodiments, the methods of treating neuroblastoma (NBL) in patients in need thereof disclosed herein may comprise one or more synergistic effects. In some embodiments, the combination therapies disclosed herein may comprise one or more synergistic effects. In some embodiments, the combination therapies disclosed herein may comprise one or more synergistic effects. In some embodiments, a synergistic effect may comprise a lowering of a therapeutically effective dose of a pharmaceutically active agent when an additional pharmaceutically active agent is administered in the practice of a method of treatment as described herein, as compared to the therapeutically effective dose of a pharmaceutically active agent when the additional pharmaceutically active agent is not administered. In some embodiments, a synergistic effect may comprise a lowering of a rate of occurrence of one or more side effects associated with a pharmaceutically active agent when the pharmaceutically active agent is administered with an additional pharmaceutically active agent in the practice of a method of treatment as described herein, as compared to the rate of occurrence of one or more side effects associated with a pharmaceutically active agent when the additional pharmaceutically active agent is not administered. In some embodiments, a synergistic effect may comprise a lowering of a degree of severity of one or more side effects associated with a pharmaceutically active agent when the pharmaceutically active agent is administered with an additional pharmaceutically active agent in the practice of a method of treatment as described herein, as compared to the degree of severity of one or more side effects associated with a pharmaceutically active agent when the additional pharmaceutically active agent is not administered. In some embodiments, a synergistic effect may comprise an increase in efficacy of a pharmaceutically active agent when the pharmaceutically active agent is administered with an additional pharmaceutically active agent in the practice of a method of treatment as described herein, as compared to the efficacy of a pharmaceutically active agent when the additional pharmaceutically active agent is not administered. In some embodiments, an increase in efficacy of a pharmaceutically active agent may comprise increasing the efficacy of a chemotherapeutic drug against MM, wherein the MM is resistant to the chemotherapeutic drug. In some embodiments, resistance of MM to a chemotherapeutic drug implies that the chemotherapeutic drug may only comprise a therapeutically effective therapy for the treatment of the MM when the chemotherapeutic drug is administered in combination with an additional pharmaceutically active agent in practice of a method of treatment as described herein. In some embodiments, an increase in efficacy of a pharmaceutically active agent may comprise increasing the efficacy of a chemotherapeutic drug against RMS, wherein the RMS is resistant to the chemotherapeutic drug. In some embodiments, resistance of RMS to a chemotherapeutic drug implies that the chemotherapeutic drug may only comprise a therapeutically effective therapy for the treatment of the RMS when the chemotherapeutic drug is administered in combination with an additional pharmaceutically active agent in practice of a method of treatment as described herein. In some embodiments, an increase in efficacy of a pharmaceutically active agent may comprise increasing the efficacy of a chemotherapeutic drug against NBL, wherein the NBL is resistant to the chemotherapeutic drug In some embodiments, resistance of NBL to a chemotherapeutic drug implies that the chemotherapeutic drug may only comprise a therapeutically effective therapy for the treatment of the NBL when the chemotherapeutic drug is administered in combination with an additional pharmaceutically active agent in practice of a method of treatment as described herein.

[00216] In some embodiments, a pharmaceutically active agent may be a first pharmaceutically active agent as described herein. In some embodiments, a pharmaceutically active agent may be a second pharmaceutically active agent as described herein. In some embodiments, another pharmaceutically active agent may be a first pharmaceutically active agent as described herein. In some embodiments, another pharmaceutically active agent may be a second pharmaceutically active agent as described herein.

[00217] In some embodiments, a pharmaceutically active agent may be administered orally. In some embodiments, a pharmaceutically active agent may be administered intravenously. In some embodiments, a pharmaceutically active agent may be administered as a suppository. In some embodiments, a pharmaceutically active agent may be administered topically.

[00218] In some embodiments, the methods of treatment disclosed herein comprise the administration of a therapeutically effective dose of a pharmaceutically active agent to a patient in need thereof. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be in the inclusive range of 0.01 mg/kgto 1000 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be in the inclusive range of 0.1 mg/kg to 100 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be in the inclusive range of 1 mg/kg to 100 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be in the inclusive range of 1 mg/kgto 10 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be in the inclusive range of 10 mg/kg to 100 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be in the inclusive range of 10 mg/kg to 50 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be about 0.01 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be about 0.05 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be about 0.1 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be about 1 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be about 5 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be about 10 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be about 15 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be about 25 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be about 50 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be about 100 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be about 150 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be about 250 mg/kg. In some embodiments, a therapeutically effective dose of a pharmaceutically active agent may be about 500 mg/kg.

[00219] In some embodiments, the methods of treating multiple myeloma (MM) disclosed herein may comprise administering a first pharmaceutically active agent to a patient and administering a second pharmaceutically active agent to a patient. In some embodiments, the methods of treating rhabdomyosarcoma (RMS) disclosed herein may comprise administering a first pharmaceutically active agent to a patient and administering a second pharmaceutically active agent to a patient. In some embodiments, the methods of treating neuroblastoma (NBL) disclosed herein may comprise administering a first pharmaceutically active agent to a patient and administering a second pharmaceutically active agent to a patient. In some embodiments, the first pharmaceutically active agent is administered before the second pharmaceutically active agent is administered. In some embodiments, the first pharmaceutically active agent is administered after the second pharmaceutically active agent is administered. In some embodiments, the first pharmaceutically active agent and the second pharmaceutically active agent are administered simultaneously. In some embodiments, simultaneous administration comprises the administration of a pharmaceutical composition that comprises multiple pharmaceutically active agents. In some embodiments, simultaneous administration comprises an administration procedure wherein one or more pharmaceutically active agents are administered in a manner intended to result in the one or more pharmaceutically active agents modulating or inhibiting their respective biological targets at the same time. In some embodiments, the first pharmaceutically active agent is administered with greater frequency than with which the second pharmaceutically active agent is administered. In some embodiments, the first pharmaceutically active agent is administered with lesser frequency than with which the second pharmaceutically active agent is administered. In some embodiments, the first pharmaceutically active agent is administered about monthly. In some embodiments, the first pharmaceutically active agent is administered about biweekly. In some embodiments, the first pharmaceutically active agent is administered about weekly. In some embodiments, the first pharmaceutically active agent is administered about semiweekly. In some embodiments, the first pharmaceutically active agent is administered about daily. In some embodiments, the first pharmaceutically active agent is administered about twice per day. In some embodiments, the first pharmaceutically active agent is administered about three times per day. In some embodiments, the second pharmaceutically active agent is administered about monthly. In some embodiments, the second pharmaceutically active agentis administered about biweekly. In some embodiments, the second pharmaceutically active agent is administered about weekly. In some embodiments, the second pharmaceutically active agent is administered about semiweekly. In some embodiments, the second pharmaceutically active agent is administered about daily. In some embodiments, the second pharmaceutically active agent is administered about twice per day. In some embodiments, the second pharmaceutically active agent is administered about three times per day.

[00220] In some embodiments, the patient in need of treatment has previously undergone other treatments for cancer. In some embodiments, the patient in need of treatment has previously undergone other treatments for MM. In some embodiments, the patient in need of treatment has previously been administered dexamethasone as a treatment for MM. In some embodiments, the patient in need of treatment has previously been administered a treatment for MM comprising dexamethasone. In some embodiments, the patient in need of treatment has previously been administered a treatment for MM comprising dexamethasone and a second pharmaceutically active agent.

[00221] In some embodiments the MM for treatment by the methods disclosed herein is newly -diagnosed. In some embodiments the MM for treatment by the methods disclosed herein is relapsed. In some embodiments the MM for treatment by the methods disclosed herein is refractory. In some embodiments the MM for treatment by the methods disclosed herein is resistant to chemotherapy. In some embodiments the MM for treatment by the methods disclosed herein has previously been subject to one course of treatment. In some embodiments the MM for treatment by the methods disclosed herein has previously been subject to multiple courses of treatment. In some embodiments, a course of treatment may comprise chemotherapy. In some embodiments, chemotherapy may comprise a chemotherapeutic drug or pharmaceutically active agent as described herein. In some embodiments, a course of treatment may comprise radiation therapy.

[00222] In some embodiments the MM for treatment by the methods disclosed herein presents one or more genetic abnormalities. In some embodiments the MM for treatment by the methods disclosed herein presents one genetic abnormality. In some embodiments the MM for treatment by the methods disclosed herein presents two genetic abnormalities. In some embodiments the MM for treatment by the methods disclosed herein presents three genetic abnormalities. In some embodiments the MM for treatment by the methods disclosed herein presents four genetic abnormalities. In some embodiments the MM for treatment by the methods disclosed herein presents five genetic abnormalities.

[00223] In some embodiments, the patient in need of treatment has previously undergone other treatments for cancer. In some embodiments, the patient in need of treatment has previously undergone other treatments for RMS. In some embodiments, the patient in need of treatment has previously been administered dexamethasone as a treatment for RMS. In some embodiments, the patient in need of treatment has previously been administered a treatment for RMS comprising dexamethasone. In some embodiments, the patient in need of treatment has previously been administered a treatment for RMS comprising dexamethasone and a second pharmaceutically active agent.

[00224] In some embodiments the RMS for treatment by the methods disclosed herein is newly -diagnosed. In some embodiments the RMS for treatment by the methods disclosed herein is relapsed. In some embodiments the RMS for treatment by the methods disclosed herein is refractory. In some embodiments the RMS for treatment by the methods disclosed herein is resistant to chemotherapy. In some embodiments the RMS for treatment by the methods disclosed herein has previously been subject to one course of treatment. In some embodiments the RMS for treatment by the methods disclosed herein has previously been subject to multiple courses of treatment. In some embodiments, a course of treatment may comprise chemotherapy. In some embodiments, chemotherapy may comprise a chemotherapeutic drug or pharmaceutically active agent as described herein. In some embodiments, a course of treatment may comprise radiation therapy.

[00225] In some embodiments the RMS for treatment by the methods disclosed herein presents one or more genetic abnormalities. In some embodiments the RMS for treatment by the methods disclosed herein presents one genetic abnormality. In some embodiments the RMS for treatment by the methods disclosed herein presents two genetic abnormalities. In some embodiments the RMS for treatment by the methods disclosed herein presents three genetic abnormalities. In some embodiments the RMS for treatment by the methods disclosed herein presents four genetic abnormalities. In some embodiments the RMS for treatment by the methods disclosed herein presents five genetic abnormalities.

[00226] In some embodiments, the patient in need of treatment has previously undergone other treatments for cancer. In some embodiments, the patient in need of treatment has previously undergone other treatments for NBL. In some embodiments, the patient in need of treatment has previously been administered dexamethasone as a treatment for NBL. In some embodiments, the patient in need of treatment has previously been administered a treatment for NBL comprising dexamethasone. In some embodiments, the patient in need of treatment has previously been administered a treatment for NBL comprising dexamethasone and a second pharmaceutically active agent.

[00227] In some embodiments the NBL for treatment by the methods disclosed herein is newly -diagnosed. In some embodiments the NBL for treatment by the methods disclosed herein is relapsed. In some embodiments the NBL for treatment by the methods disclosed herein is refractory. In some embodiments the NBL for treatment by the methods disclosed herein is resistant to chemotherapy. In some embodiments the NBL for treatment by the methods disclosed herein has previously been subject to one course of treatment. In some embodiments the NBL for treatment by the methods disclosed herein has previously been subject to multiple courses of treatment. In some embodiments, a course of treatment may comprise chemotherapy. In some embodiments, chemotherapy may comprise a chemotherapeutic drug or pharmaceutically active agent as described herein. In some embodiments, a course of treatment may comprise radiation therapy.

[00228] In some embodiments the NBL for treatment by the methods disclosed herein presents one or more genetic abnormalities. In some embodiments the NBL for treatment by the methods disclosed herein presents one genetic abnormality. In some embodiments the NBL for treatment by the methods disclosed herein presents two genetic abnormalities. In some embodiments the NBL for treatment by the methods disclosed herein presents three genetic abnormalities. In some embodiments the NBL for treatment by the methods disclosed herein presents four genetic abnormalities. In some embodiments the NBL for treatment by the methods disclosed herein presents five genetic abnormalities.

[00229] In some embodiments, a genetic abnormality may affect one or more genes. In some embodiments, a gene affected by a genetic abnormality may present homozygous deletion (HOMDEL). In some embodiments, a gene affected by a genetic abnormality may present amplification (AMP). In some embodiments, a gene affected by a genetic abnormality may present an abnormality, error, or dysfunction in transcription and/or expression of the gene as genetic material (e.g. DNA, RNA) and/or as proteins. In some embodiments, a gene affected by a genetic abnormality may present an abnormality, error, or dysfunction in transcription of the gene as genetic material (e.g. DNA, RNA). In some embodiments, a gene affected by a genetic abnormality may present an abnormality, error, or dysfunction in expression of the gene as genetic material (e.g. DNA, RNA). In some embodiments, a gene affected by a genetic abnormality may present an abnormality, error, or dysfunction in transcription of the gene as proteins. In some embodiments, a gene affected by a genetic abnormality may present an abnormality, error, or dysfunction in expression of the gene as proteins. [00230] In some embodiments, a genetic abnormality may comprise one or more mutations. In some embodiments, a genetic abnormality may comprise a single mutation. In some embodiments, a genetic abnormality may comprise one or more translocations. In some embodiments, a genetic abnormality may comprise a translocation. In some embodiments, a genetic abnormality may be associated with the amplification of one or more genes. In some embodiments, a genetic abnormality may be associated with the amplification of a gene. In some embodiments, a genetic abnormality may be associated with the overexpression of a biomarker. In some embodiments, a genetic abnormality may be associated with the overexpression of one or more biomarkers.

[00231] In some embodiments, one or more genetic abnormalities may comprise monosomy 13, chromosome Iq gain (Iq gain), chromosome Ip deletion (Ip del), chromosome 8q24 MYC gene rearrangement (MYC 8q24), chromosomal t (4; 14) translocation, chromosomal t (11 ; 14) translocation, chromosome 17p deletion (17p del), chromosome 17q gain, chromosome l ip deletion, t(l ; 13)(p36;q 14) chromosomal translocation, t(2;13)(q35;ql4) chromosomal translocation or combinations thereof. In some embodiments, a genetic abnormality may comprise monosomy 13. In some embodiments, a genetic abnormality may comprise chromosome Iq gain (Iq gain). In some embodiments, a genetic abnormality may comprise chromosome Ip deletion (Ip del). In some embodiments, a genetic abnormality may comprise chromosome 8q24 MYC gene rearrangement (MYC 8q24). In some embodiments, a genetic abnormality may comprise chromosomal t (4; 14) translocation. In some embodiments, a genetic abnormality may comprise chromosomal t (11 ;14) translocation. In some embodiments, a genetic abnormality may comprise chromosome 17p deletion (17p del). In some embodiments, a genetic abnormality may comprise t(2;13)(q35;ql4) chromosomal translocation. In some embodiments, a genetic abnormality may comprise t(l ; 13)(p36;ql 4) chromosomal translocation. In some embodiments, a genetic abnormality may comprise chromosome 17q gain. In some embodiments, a genetic abnormality may comprise chromosome l ip deletion.

[00232] In some embodiments, a genetic abnormality may lead to expression of the PAX3- FOXO1 fusion protein. In some embodiments, a genetic abnormality may lead to expression of the PAX7-FOXO1 fusion protein.

[00233] In some embodiments, a genetic abnormality may affect the MYCN gene. In some embodiments, a genetic abnormality may affect the PLK1 gene. In some embodiments, a genetic abnormality may affect the PAX3 gene. In some embodiments, a genetic abnormality may affect the PAX7 gene. In some embodiments, a genetic abnormality may affect the FOXO1 gene. In some embodiments, a genetic abnormality may affect the RBI gene. In some embodiments, a genetic abnormality may affect the CSK1B gene. In some embodiments, a genetic abnormality may affect the MCL1 gene. In some embodiments, a genetic abnormality may affect the FAM46C gene. In some embodiments, a genetic abnormality may affect the CDKN2C gene. In some embodiments, a genetic abnormality may affect the FAF1 gene. In some embodiments, a genetic abnormality may affect the MYC gene. In some embodiments, a genetic abnormality may affect the FGFR3 gene. In some embodiments, a genetic abnormality may affect the MEMSET gene. In some embodiments, a genetic abnormality may affect the CCND1 gene. In some embodiments, a genetic abnormality may affect the TP53 gene. In some embodiments, a genetic abnormality may affect the NRAS gene. In some embodiments, a genetic abnormality may affect the KRAS gene. In some embodiments, a genetic abnormality may affect the HRAS gene. In some embodiments, a genetic abnormality may affect the TRAF3 gene. In some embodiments, a genetic abnormality may affect the CDKN2A gene. In some embodiments, a genetic abnormality may affect the SMAD2 gene. In some embodiments, a genetic abnormality may affect the BRAF gene. In some embodiments, a genetic abnormality may affect the MSH6 gene. In some embodiments, a genetic abnormality may affect the BCL2L11 gene. In some embodiments, a genetic abnormality may affect the BCL2L11 gene, wherein the BCL2L11 gene encodes the Bim protein biomarker. In some embodiments, the BCL2L11 gene encodes the Bim protein biomarker.

[00234] In some embodiments, the presence of a genetic abnormality in the MM for treatment by the methods described herein may render the MM more susceptible to treatment by the methods described herein as compared to MM that does not present the same genetic abnormality. In some embodiments, the presence of a genetic abnormality in the MM for treatment by the combination therapies described herein may render the MM more susceptible to treatment by the combination therapies described herein as compared to MM that does not present the same genetic abnormality.

[00235] In some embodiments, the MM for treatment presents an amplification of one or more genes. In some embodiments, the MM for treatment presents an amplification of a gene. In some embodiments, the amplification of a gene affected by a genetic abnormality in the MM for treatment by the methods described herein may render the MM more susceptible to treatment by the methods described herein as compared to MM that does not present the same gene affected by a genetic abnormality. In some embodiments, the amplification of a gene affected by a genetic abnormality in the MM for treatment by the combination therapies described herein may render the MM more susceptible to treatment by the combination therapies described herein as compared to MM that does not present the same gene affected by a genetic abnormality. In some embodiments, the amplification of a gene in the MM for treatment by the methods described herein may render the MM more susceptible to treatment by the methods described herein as compared to MM that does not present the same gene amplification.

[00236] In some embodiments, the MM for treatment overexpresses one or more biomarkers. In some embodiments, the MM for treatment overexpresses a biomarker. In some embodiments, the overexpression of one or more biomarkers in the MM for treatment by the methods described herein may render the MM more susceptible to treatment by the methods described herein as compared to MM that does not present the same overexpression of one or more biomarkers. In some embodiments, the overexpression of a biomarker in the MM for treatment by the combination therapies described herein may render the MM more susceptible to treatment by the combination therapies described herein as compared to MM that does not present the same overexpression of a biomarker.

[00237] In some embodiments, the presence of a genetic abnormality in the RMS for treatment by the methods described herein may render the RMS more susceptible to treatment by the methods described herein as compared to RMS that does not present the same genetic abnormality. In some embodiments, the presence of a genetic abnormality in the RMS for treatment by the combination therapies described herein may render the RMS more susceptible to treatment by the combination therapies described herein as compared to RMS that does not present the same genetic abnormality.

[00238] In some embodiments, the RMS for treatment presents an amplification of one or more genes. In some embodiments, the RMS for treatment presents an amplification of a gene. In some embodiments, the amplification of a gene affected by a genetic abnormality in the RMS for treatment by the methods described herein may render the RMS more susceptible to treatment by the methods described herein as compared to RMS that does not present the same gene affected by a genetic abnormality. In some embodiments, the amplification of a gene affected by a genetic abnormality in the RMS for treatment by the combination therapies described herein may render the RMS more susceptible to treatment by the combination therapies described herein as compared to RMS that does not present the same gene affected by a genetic abnormality. In some embodiments, the amplification of a gene in the RMS for treatment by the methods described herein may render the RMS more susceptible to treatment by the methods described herein as compared to RMS that does not present the same gene amplification.

[00239] In some embodiments, the RMS for treatment overexpresses one or more biomarkers. In some embodiments, the RMS for treatment overexpresses a biomarker. In some embodiments, the overexpression of one or more biomarkers in the RMS for treatment by the methods described herein may render the RMS more susceptible to treatment by the methods described herein as compared to RMS that does not present the same overexpression of one or more biomarkers. In some embodiments, the overexpression of a biomarker in the RMS for treatment by the combination therapies described herein may render the RMS more susceptible to treatment by the combination therapies described herein as compared to RMS that does not present the same overexpression of a biomarker.

[00240] In some embodiments, the presence of a genetic abnormality in the NBL for treatment by the methods described herein may render the NBL more susceptible to treatment by the methods described herein as compared to NBL that does not present the same genetic abnormality. In some embodiments, the presence of a genetic abnormality in the NBL for treatment by the combination therapies described herein may render the NBL more susceptible to treatment by the combination therapies described herein as compared to NBL that does not present the same genetic abnormality.

[00241] In some embodiments, the NBL for treatment presents an amplification of one or more genes. In some embodiments, the NBL for treatment presents an amplification of a gene. In some embodiments, the amplification of a gene affected by a genetic abnormality in the NBL for treatment by the methods described herein may render the NBL more susceptible to treatment by the methods described herein as compared to NBL that does not present the same gene affected by a genetic abnormality. In some embodiments, the amplification of a gene affected by a genetic abnormality in the NBL for treatment by the combination therapies described herein may render the NBL more susceptible to treatment by the combination therapies described herein as compared to NBL that does not present the same gene affected by a genetic abnormality. In some embodiments, the amplification of a gene in the NBL for treatment by the methods described herein may render the NBL more susceptible to treatment by the methods described herein as compared to NBL that does not present the same gene amplification.

[00242] In some embodiments, the NBL for treatment overexpresses one or more biomarkers. In some embodiments, the NBL for treatment overexpresses a biomarker. In some embodiments, the overexpression of one or more biomarkers in the NBL for treatment by the methods described herein may render the NBL more susceptible to treatment by the methods described herein as compared to NBL that does not present the same overexpression of one or more biomarkers. In some embodiments, the overexpression of a biomarker in the NBL for treatment by the combination therapies described herein may render the NBL more susceptible to treatment by the combination therapies described herein as compared to NBL that does not present the same overexpression of a biomarker. [00243] In some embodiments, the present disclosure comprises a method of treating or managing a proliferative disease or disorder (e.g., cancer) in a subject in need thereof. In some embodiments, the proliferative disease or disorder is a disease or disorder described herein, such as cancer. In some embodiments, the proliferative disease or disorder is cancer. In some embodiments, the proliferative disease or disorder is multiple myeloma (MM). In some embodiments, the proliferative disease or disorder is rhabdomyosarcoma (RMS). In some embodiments, the proliferative disease or disorder is neuroblastoma (NBL). In some embodiments, the proliferative disease or disorder is a solid tumor. In some embodiments, the cancer is multiple myeloma (MM). In some embodiments, the cancer is rhabdomyosarcoma (RMS). In some embodiments, the cancer is neuroblastoma (NBL).

[00244] In some embodiments, the method described herein is a method of treating or managing cancer in a subject in need thereof. In some embodiments, the method described herein is a method of treating or managing multiple myeloma in a subject in need thereof. In some embodiments, the method described herein is a method of treating or managing a solid tumor in a subject in need thereof.

[00245] In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or the enantiomer thereof, or the pharmaceutically acceptable salt thereof, is provided to the subject in an amount insufficient to provide an adverse effect (AE). In some embodiments, the adverse event is a toxic event. In some embodiments, the adverse effect (e.g., the toxic event) is neutropenia. In some embodiments, an adverse effect is a side effect.

[00246] In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered to the subject over an extended period of time. In some embodiments, the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose that is the same over the extended period of time (e.g., 2 hours, 3 hours, or 4 hours) and a shorter period of time (e.g., 30 minutes or less). In some embodiments, the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject at a maximum plasma concentration (C_max) that achieves (substantially) the same area under the curve (AUC) when the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered the extended period of time and the shorter period of time. In some embodiments, the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject at a C_max that is lower than when the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered over the shorter period of time. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered to the subject for at least 30 minutes or more (e.g., about 30 minutes or more, about 1 hour or more, about 2 hours or more, about 3 hours or more, about 4 hours or more, about 5 hours or more, or about 6 hours or more). In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered intravenously (e.g., via intravenous (IV) infusion (e.g., via an IV infusion pump)) over an extended period of time, such as for at least 30 minutes (e.g., about 30 minutes or more, about 1 hour or more, about 2 hours or more, about 3 hours or more, about 4 hours or more, about 5 hours or more, or about 6 hours or more). In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered continuously over the extended period of time.

[00247] In some embodiments, the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof at a C_max that is less than when the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered over a shorter period of time. In some embodiments, the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject atthe same dose over the extended period of time and the shorter period of time. In some embodiments, the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject atthe same dose over the extended period of time and the shorter period of time such that the area under the curve (AUC) for the shorter administration time is (substantially) the same as the extended administration time.

[00248] Unless stated otherwise herein, the first time and the first administration are used interchangeably herein. Unless stated otherwise herein, the second time and the second administration are used interchangeably herein.

[00249] In some embodiments, the second administration of the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is substantially the same as the first administration of the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the second administration of the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is about the same as the first administration of the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the second administration of the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is the same as the first administration of the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the second dose (e.g., administered the second time) of the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is the same as the first dose (e.g., administered the first time) of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered to the subject the second time for about the same period of time as the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered to the subject the first period of time, such as any period of time described herein.

[00250] In some embodiments, the second administration of the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is different from the first administration of the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the second dose (e.g., administered the second time) of the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is different from the first dose (e.g., administered the first time) of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered to the subject the second time for a different period of time than the therapeutically effective amount of the CDK9 inhibitor, or the pharmaceutically acceptable salt thereof, is administered to the subject the first period of time, such as any period of time described herein.

[00251] In some embodiments, the proliferative disease or disorder treated according to any method described herein is cancer. In some embodiments, the proliferative disease or disorder treated according to any method described herein is a liquid tumor or a solid tumor. In some embodiments, the proliferative disease or disorder treated according to any method described herein is a liquid tumor. In some embodiments, the proliferative disease or disorder treated according to any method described herein is multiple myeloma (MM). In some embodiments, the proliferative disease or disorder treated according to any method described herein is rhabdomyosarcoma (RMS) or neuroblastoma (NBL). In some embodiments, the proliferative disease or disorder treated according to any method described herein is rhabdomyosarcoma (RMS). In some embodiments, the proliferative disease or disorder treated according to any method described herein is neuroblastoma (NBL). In some embodiments, the proliferative disease or disorder treated according to any method described herein is leukemia or lymphoma. In some embodiments, the proliferative disease or disorder treated according to any method described herein is leukemia. In some embodiments, the proliferative disease or disorder treated accordingto any method described herein is lymphoma. In some embodiments, the proliferative disease or disorder treated according to any method described herein is non-Hodgkin’s lymphoma. In some embodiments, the proliferative disease or disorder treated according to any method described herein is diffused large B-cell lymphoma (DLBCL). In some embodiments, the proliferative disease or disorder treated according to any method described herein is a solid tumor. In some embodiments, the proliferative disease or disorder treated according to any method described herein is selected from the group consisting of colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, thyroid cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, thyroid cancer, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, non-small cell lung cancer, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin's disease and nonHodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease. In some embodiments, the proliferative disease or disorder treated according to any method described herein is a refractory cancer. In some embodiments, the proliferative disease or disorder treated according to any method described herein is a relapsed cancer. In some embodiments, the subject has received prior treatment.

[00252] In some embodiments, the cancer described herein is a liquid tumor or a solid tumor. In some embodiments, the cancer described herein is a solid tumor. In some embodiments, the cancer described herein is a liquid tumor. In some embodiments, the liquid tumor is leukemia or lymphoma. In some embodiments, the liquid tumor is leukemia. In some embodiments, the liquid tumor is lymphoma. In some embodiments, the lymphoma is a non-Hodgkin’s lymphoma. In some embodiments, the non-Hodgkin’s lymphoma is diffuse large B-cell lymphoma (DLBCL).

[00253] In some embodiments, the cancer described herein is selected from the group consisting of colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, thyroid cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, thyroid cancer, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, non-small cell lung cancer, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease.

[00254] In some embodiments, the cancer described herein is refractory. In some embodiments, the cancer described herein is relapsed. In some embodiments, the subject has received a prior treatment.

[00255] In some embodiments, the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is administered parenterally.

[00256] In some embodiments, the method described herein comprises administering to the subject a pharmaceutical composition. In some embodiments, the pharmaceutical composition may comprise a pharmaceutically active agent as described herein. In some embodiments, the pharmaceutical composition may comprise a first pharmaceutically active agent. In some embodiments, the pharmaceutical composition may comprise a second pharmaceutically active agent. In some embodiments, the pharmaceutical composition described herein is administered to the subject intravenously. In some embodiments, the pharmaceutical composition described herein is administered to the subject intravenously via a pump. In some embodiments, the pharmaceutical composition described herein is administered to the subject via IV infusion. In some embodiments, the pharmaceutical composition described herein is administered to the subject via an IV infusion pump. In some embodiments, the pharmaceutical composition may be suitable for parenteral administration. In some embodiments, the pharmaceutical composition may be suitable for intravenous administration. In some embodiments, the pharmaceutical composition may be suitable for intraperitoneal administration. In some embodiments, the pharmaceutical composition may be suitable for administration via infusion. In some embodiments, the pharmaceutical composition may be suitable for administration via an infusion pump. [00257] In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is no more than about 100 mg. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is about 100 mg or less, 90 mg or less, 80 mg or less, 70 mg or less, 60 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, or 10 mg or less. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is about 50 mg or less. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is about 40 mg or less. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is about 30 mg or less. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is about 20 mg or less. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is about 10 mg or less. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is no less than about 10 mg. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is about 10 mg ormore, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 60 mg or more, 70 mg or more, 80 mg or more, 90 mg or more, or 100 mg or more. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is about 10 mg or more. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is about 20 mg or more. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is about 30 mg or more. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is about 40 mg or more. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is about 50 mg or more. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable saltthereof, is about 100 mgto about 10 mg. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is about 50 mg to about 10 mg. In some embodiments, the therapeutically effective amount of the CDK9 inhibitor, or a pharmaceutically acceptable salt thereof, is about 30 mg.

Some Embodiments of the Disclosure

[00258] Below are provided some non-limiting Embodiments of the present disclosure. [00259] Embodiment 1 : A method of treating rhabdomyosarcoma or neuroblastoma in a patient in need thereof, the method comprising: administering to a patient a therapeutically effective amount of a first pharmaceutically active agent comprising 5-fluoro-4-(4-fluoro-2- methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2 -amine of Formula (I) or an enantiomer thereof or a pharmaceutically acceptable salt thereof.

[00260] Embodiment 2: The method of Embodiment 1 wherein the cells of the rhabdomyosarcoma or neuroblastoma in the patient present one or more genetic abnormalities. [00261] Embodiment 3 : The method of Embodiment 1 or Embodiment 2, wherein the cells of the rhabdomyosarcoma or neuroblastoma in the patient present one or more genetic abnormalities that independently affect one or more genes.

[00262] Embodiment 4: The method of any one of Embodiments 1 to 3, wherein the cells of the rhabdomyosarcoma or neuroblastoma in the patient present an amplification of one or more genes affected by a genetic abnormality.

[00263] Embodiment 5 : The method of any one of Embodiments 1 to 4, wherein the cells of the rhabdomyosarcoma or neuroblastoma overexpress one or more biomarkers.

[00264] Embodiment 6: The method of any one of Embodiments 1 to 5, wherein the first pharmaceutically active agent is administered in the form of a pharmaceutical composition that comprises the first pharmaceutically active agent.

[00265] Embodiment?: The method of any one of Embodiments 1 to 6, further comprising administering to a patient a therapeutically effective amount of a second pharmaceutically active agent selected from a topoisomerase inhibitor, an exportin 1 inhibitor, a proteasome inhibitor, cyclophosphamide, or gemcitabine.

[00266] Embodiment 8 : The method of Embodiment 7, wherein the second pharmaceutically active agent is administered in the form of a pharmaceutical composition that comprises the second pharmaceutically active agent.

[00267] Embodiment 9: The method of Embodiment 7 or Embodiment 8, wherein the second pharmaceutically active agent is a topoisomerase inhibitor.

[00268] Embodiment 10: The method of any one of Embodiments 7 to 9, wherein the second pharmaceutically active agent is a topoisomerase inhibitor selected from topotecan.

[00269] Embodiment 11 : The method of any one of Embodiments 7 to 9, wherein the second pharmaceutically active agent is a topoisomerase inhibitor selected from etoposide.

[00270] Embodiment 12: The method of Embodiment 7 or Embodiment 8, wherein the second pharmaceutically active agent is an exportin 1 inhibitor.

[00271] Embodiment 13 : The method of any one of Embodiments 7, 8, or 12, wherein the second pharmaceutically active agent is an exportin 1 inhibitor selected from Selinexor. [00272] Embodiment 14: The method of Embodiment 7 or Embodiment 8, wherein the second pharmaceutically active agent is a proteasome inhibitor.

[00273] Embodiment 15 : The method of any one of Embodiments 7, 8, or 14, wherein the second pharmaceutically active agent is a proteasome inhibitor selected from carfilzomib.

[00274] Embodiment 16: The method of any one of Embodiments 7, 8, or 14, wherein the second pharmaceutically active agent is a proteasome inhibitor selected from bortezomib. [00275] Embodiment 17: The method of Embodiment 7 or Embodiment 8, wherein the second pharmaceutically active agent is cyclophosphamide.

[00276] Embodiment 18: The method of Embodiment 7 or Embodiment 8, wherein the second pharmaceutically active agent is gemcitabine.

[00277] Embodiment 19: The method of any one of Embodiments 1 to 18, wherein the first pharmaceutically active agent is (+)-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S- methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine of Formula (I’) or a pharmaceutically acceptable salt thereof.

[00278] Embodiment 20: The method of any one of Embodiments 7 to 19, wherein the administration of the second pharmaceutically active agent lowers the therapeutically active amount of the first pharmaceutically active agent in comparison to the therapeutically active amount of the first pharmaceutically active agent when the second pharmaceutically active agent is not administered.

[00279] Embodiment 21 : The method of any one of Embodiments 7 to 20, wherein the administration of the first pharmaceutically active agent lowers the therapeutically active amount of the second pharmaceutically active agent in comparison to the therapeutically active amount of the second pharmaceutically active agent when the first pharmaceutically active agent is not administered.

[00280] Embodiment 22: The method of any one of Embodiments 7 to 21, wherein the administration of the second pharmaceutically active agent lowers the probability of occurrence or degree of severity of side effects associated with the administration of the first pharmaceutically active agent.

[00281] Embodiment 23 : The method of any one of Embodiments 7 to 22, wherein the administration of the first pharmaceutically active agent lowers the probability of occurrence or degree of severity of side effects associated with the administration of the second pharmaceutically active agent.

[00282] Embodiment 24: The method of any one of Embodiments 7 to 23, wherein the first pharmaceutically active agent is administered before the second pharmaceutically active agent. [00283] Embodiment 25: The method of any one of Embodiments 7 to 23, wherein the first pharmaceutically active agent is administered after the second pharmaceutically active agent. [00284] Embodiment 26: The method of any one of Embodiments 7 to 23, wherein the first pharmaceutically active agent and the second pharmaceutically active agent are administered simultaneously.

[00285] Embodiment 27: The method of any one of Embodiments 7 to 23, wherein the first pharmaceutically active agent is administered with lesser frequency than is the second pharmaceutically active agent.

[00286] Embodiment 28: The method of any one of Embodiments 7 to 23, wherein the first pharmaceutically active agent is administered with greater frequency than is the second pharmaceutically active agent.

[00287] Embodiment 29: The method of any one of Embodiments 1 to 28, wherein the first pharmaceutically active agent is administered about once per week.

[00288] Embodiment 30: The method of any one of Embodiments 7 to 29, wherein the second pharmaceutically active agent is administered about once per day.

[00289] Embodiment 31 : The method of any one of Embodiments 7 to 29, wherein the second pharmaceutically active agent is administered about once every three days.

[00290] Embodiment32: The method of any one of Embodiments 1 to 31, wherein the first pharmaceutically active agent is administered intravenously.

[00291] Embodiment 33 : The method of any one of Embodiments 1 to 31, wherein the first pharmaceutically active agent is administered orally.

[00292] Embodiment 34: The method of any one of Embodiments 7 to 33, wherein the second pharmaceutically active agent is administered intravenously.

[00293] Embodiment 35: The method of any one of Embodiments 7 to 33, wherein the second pharmaceutically active agent is administered orally.

[00294] Embodiment 36: The method of any one of Embodiments 1 to 35, wherein the method further comprises administering a therapeutically effective amount of an additional pharmaceutically active agent or a pharmaceutical composition thereof.

[00295] Embodiment 37: The method of any one of Embodiments 1 to 36, wherein the efficacy of the treatment is predicted on the basis of the presence of one or more genetic abnormalities in the cells of the rhabdomyosarcoma or neuroblastoma in the patient.

[00296] Embodiment 38: The method of any one of Embodiments 1 to 37, wherein the rhabdomyosarcoma or neuroblastoma comprises at least one cell that comprises one or more genetic abnormalities. [00297] Embodiment 39: The method of Embodiment 37 or Embodiment 38, wherein the one or more genetic abnormalities comprises a translocation.

[00298] Embodiment40: The method of any one of Embodiments 37 to 39, wherein the one or more genetic abnormalities comprises a t(2;13)(q35;ql4) chromosomal translocation.

[00299] Embodiment 41 : The method of any one of Embodiments 37 to 40, wherein the one or more genetic abnormalities leads to expression of the PAX3-FOXO1 fusion protein.

[00300] Embodiment 42: The method of any one of Embodiments 37 to 41, wherein the one or more genetic abnormalities comprises a t(l ; 13)(p36;q 14) chromosomal translocation.

[00301] Embodiment 43 : The method of any one of Embodiments 37 to 42, wherein the one or more genetic abnormalities comprises chromosome 17q gain.

[00302] Embodiment 44: The method of any one of Embodiments 37 to 43, wherein the one or more genetic abnormalities comprises chromosome Ip deletion.

[00303] Embodiment 45 : The method of any one of Embodiments 37 to 44, wherein the one or more genetic abnormalities comprises chromosome l ip deletion.

[00304] Embodiment46: The method of any one of Embodiments 37 to 45, wherein the one or more genetic abnormalities leads to expression of the PAX7-FOXO1 fusion protein.

[00305] Embodiment 47: The method of any one of Embodiments 1 to 46, wherein the efficacy of the treatment is predicted on the basis of the presence of an amplification of one or more genes in the cells of the rhabdomyosarcoma or neuroblastoma in the patient.

[00306] Embodiment 48: The method of any one of Embodiments 1 to 47, wherein the rhabdomyosarcoma or neuroblastoma comprises at least one cell that comprises an amplification of one or more genes.

[00307] Embodiment 49: The method of Embodiment 47 or Embodiment 48, wherein the one or more genes comprises the MYCN gene.

[00308] Embodiment 50: The method of any one of Embodiments 1 to 49, wherein the efficacy of the treatment is predicted on the basis of an overexpression of one or more biomarkers in the cells of the rhabdomyosarcoma or neuroblastoma in the patient.

[00309] Embodiment 51 : The method of any one of Embodiments 1 to 50, wherein the rhabdomyosarcoma or neuroblastoma comprises at least one cell that comprises an overexpression of one or more biomarkers.

[00310] Embodiment 52: The method of Embodiment 50 or Embodiment 51, wherein the one or more biomarkers comprises MYCN.

[00311] Embodiment 53 : The method of any one of Embodiments 50 to 52, wherein the one or more biomarkers comprises PLK1 . [00312] Embodiment 54: The method of any one of Embodiments 50 to 53, wherein the one or more biomarkers comprises PAX3-FOXO1.

[00313] Embodiment 55: The method of any one of Embodiments 50 to 54, wherein the one or more biomarkers comprises PAX7-FOXO1.

[00314] Embodiment 56: The method of any one of Embodiments 1 to 6, further comprising administering to the patient a therapeutically effective amount of a second pharmaceutically active agent selected from temozolomide.

[00315] Embodiment 57: The method of any one of Embodiments 7 to 9, wherein the second pharmaceutically active agent is a topoisomerase inhibitor selected from irinotecan.

[00316] Embodiment 58: The method of any one of Embodiments 1 to 55 or 57, wherein the method further comprises administering to the patient a therapeutically effective amount of temozolomide.

[00317] Embodiment 59: A method of treating multiple myeloma in a patient in need thereof, the method comprising: administering to a patient a therapeutically effective amount of a first pharmaceutically active agent comprising 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S- methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine of Formula (I) or an enantiomer thereof or a pharmaceutically acceptable salt thereof

Formula (I); and administering to a patient a therapeutically effective amount of a second pharmaceutically active agent selected from a proteasome inhibitor, a BCL-2 inhibitor, or a modulator of E3 ubiquitin ligase activity.

[00318] Embodiment 60: The method of Embodiment 59, wherein the cells of the multiple myeloma in the patient present one or more genetic abnormalities.

[00319] Embodiment 61 : The method of Embodiment 59 or 60, wherein the cells of the multiple myeloma in the patient present one or more genetic abnormalities that independently affect one or more genes.

[00320] Embodiment 62: The method of any one of Embodiments 59to 61, wherein the cells of the multiple myeloma in the patient present an amplification of one or more genes affected by a genetic abnormality. [00321] Embodiment 63 : The method of any one of Embodiments 59 to 62, wherein the cells of the multiple myeloma overexpress one or more biomarkers.

[00322] Embodiment 64: The method of any one of Embodiments 59 to 63, wherein the first pharmaceutically active agent is administered in the form of a pharmaceutical composition that comprises the first pharmaceutically active agent.

[00323] Embodiment 65: The method of any one of Embodiments 59 to 64, wherein the second pharmaceutically active agent is administered in the form of a pharmaceutical composition that comprises the second pharmaceutically active agent.

[00324] Embodiment 66: The method of any one of Embodiments 59 to 65, wherein the second pharmaceutically active agent is a proteasome inhibitor.

[00325] Embodiment 67: The method of any one of Embodiments 59 to 66, wherein the second pharmaceutically active agent is a proteasome inhibitor selected from bortezomib.

[00326] Embodiment 68: The method of any one of Embodiments 59 to 65, wherein the second pharmaceutically active agent is a BCL-2 inhibitor.

[00327] Embodiment 69: The method of any one of Embodiments 59-65 or 68, wherein the second pharmaceutically active agent is a BCL-2 inhibitor selected from venetoclax.

[00328] Embodiment 70: The method of any one of Embodiments 59 to 65, wherein the second pharmaceutically active agent is a modulator of E3 ubiquitin ligase activity.

[00329] Embodiment 71 : The method of any one of Embodiments 59-65 or 70, wherein the second pharmaceutically active agent is a modulator of E3 ubiquitin ligase activity selected from lenalidomide or pomalidomide.

[00330] Embodiment 72: The method of Embodiment 71, wherein the modulator of E3 ubiquitin ligase activity is lenalidomide.

[00331] Embodiment 73 : The method of Embodiment 71, wherein the modulator of E3 ubiquitin ligase activity is pomalidomide.

[00332] Embodiment 74: The method of any one of Embodiments 59 to 73, wherein the first pharmaceutically active agent is (+)-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S- methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2 -amine of Formula (T) or a pharmaceutically acceptable salt thereof.

[00333] Embodiment 75: The method of any one of Embodiments 59 to 74, wherein the administration of the second pharmaceutically active agent of step (b) lowers the therapeutically active amount of the first pharmaceutically active agent necessary to complete step (a) in comparison to the therapeutically active amount of the first pharmaceutically active agent necessary to complete step (a) if step (b) is not conducted. [00334] Embodiment 76: The method of any one of Embodiments 59 to 74, wherein the administration of the first pharmaceutically active agent of step (a) lowers the therapeutically active amount of the second pharmaceutically active agent necessary to complete step (b) in comparison to the therapeutically active amount of the second pharmaceutically active agent necessary to complete step (b) if step (a) is not conducted.

[00335] Embodiment 77: The method of any one of Embodiments 59 to 76, wherein the administration of the second pharmaceutically active agent of step (b) lowers the probability of occurrence or degree of severity of side effects associated with the administration of the first pharmaceutically active agent of step (a).

[00336] Embodiment 78: The method of any one of Embodiments 59 to 76, wherein the administration of the first pharmaceutically active agent of step (a) lowers the probability of occurrence or degree of severity of side effects associated with the administration of the second pharmaceutically active agent of step (b).

[00337] Embodiment 79: The method of any one of Embodiments 59 to 78, wherein the first pharmaceutically active agent is administered before the second pharmaceutically active agent. [00338] Embodiment 80: The method of any one of Embodiments 59 to 78, wherein the first pharmaceutically active agent is administered after the second pharmaceutically active agent. [00339] Embodiment 81 : The method of any one of Embodiments 59 to 78, wherein the first pharmaceutically active agent and the second pharmaceutically active agent are administered simultaneously.

[00340] Embodiment 82: The method of any one of Embodiments 59 to 78, wherein the first pharmaceutically active agent is administered with lesser frequency than is the second pharmaceutically active agent.

[00341] Embodiment 83 : The method of any one of Embodiments 59 to 78, wherein the first pharmaceutically active agent is administered with greater frequency than is the second pharmaceutically active agent.

[00342] Embodiment 84: The method of any one of Embodiments 59 to 83, wherein the first pharmaceutically active agent is administered about once per week.

[00343] Embodiment 85: The method of any one of Embodiments 59 to 84, wherein the second pharmaceutically active agent is administered about once per day.

[00344] Embodiment 86: The method of any one of Embodiments 59 to 84, wherein the second pharmaceutically active agent is administered about once every three days.

[00345] Embodiment 87 : The method of any one of Embodiments 59 to 86, wherein the first pharmaceutically active agent is administered intravenously. [00346] Embodiment 88: The method of any one of Embodiments 59 to 86, wherein the first pharmaceutically active agent is administered orally.

[00347] Embodiment 89: The method of any one of Embodiments 59 to 88, wherein the second pharmaceutically active agent is administered intravenously.

[00348] Embodiment 90: The method of any one of Embodiments 59 to 88, wherein the second pharmaceutically active agent is administered orally.

[00349] Embodiment 91 : The method of any one of Embodiments 59 to 90, wherein the method further comprises administering a therapeutically effective amount of an additional pharmaceutically active agent or a pharmaceutical composition thereof.

[00350] Embodiment 92: The method of any one of Embodiments 59 to 91, wherein the efficacy of the treatment is predicted on the basis of the presence of one or more genetic abnormalities in the cells of the multiple myeloma in the patient.

[00351] Embodiment 93 : The method of any one of Embodiments 59 to 92, wherein the multiple myeloma comprises at least one cell that comprises one or more genetic abnormalities.

[00352] Embodiment 94: The method of Embodiment 92 or 93, wherein the one or more genetic abnormalities comprises a translocation.

[00353] Embodiment 95: The method of Embodiment 92 or 93, wherein the one or more genetic abnormalities comprises monosomy 13.

[00354] Embodiment 96: The method of Embodiment 92 or 93, wherein the one or more genetic abnormalities comprises chromosome Iq gain.

[00355] Embodiment 97: The method of Embodiment 92 or 93, wherein the one or more genetic abnormalities comprises chromosome Ip deletion.

[00356] Embodiment 98: The method of Embodiment 92 or 93, wherein the one or more genetic abnormalities comprises chromosome 8q24 MYC gene rearrangement.

[00357] Embodiment 99: The method of Embodiment 92 or 93, wherein the one or more genetic abnormalities comprises chromosomal t (4; 14) translocation.

[00358] Embodiment 100: The method of Embodiment 92 or 93, wherein the one or more genetic abnormalities comprises chromosomal t (11 ;14) translocation.

[00359] Embodiment 101 : The method of Embodiment 92 or 93, wherein the one or more genetic abnormalities comprises chromosome 17p deletion.

[00360] Embodiment 102: The method of any one of Embodiments 59 to 101, wherein the efficacy of the treatment is predicted on the basis of the presence of an amplification of one or more genes in the cells of the multiple myeloma in the patient. [00361] Embodiment 103: The method of any one of Embodiments 59 to 102, wherein the multiple myeloma comprises at least one cell that comprises an amplification of one or more genes.

[00362] Embodiment 104: The method of Embodiment 102 or 103, wherein the one or more genes comprises the BCL2L11 gene.

[00363] Embodiment 105: The method of Embodiment 102 or 103, wherein the one or more genes comprises the RBI gene.

[00364] Embodiment 106: The method of Embodiment 102 or 103, wherein the one or more genes comprises the CSK1B gene.

[00365] Embodiment 107: The method of Embodiment 102 or 103, wherein the one or more genes comprises the MCL1 gene.

[00366] Embodiment 108: The method of Embodiment 102 or 103, wherein the one or more genes comprises the FAM46C gene.

[00367] Embodiment 109: The method of Embodiment 102 or 103, wherein the one or more genes comprises the CDKN2C gene.

[00368] Embodiment 110: The method of Embodiment 102 or 103, wherein the one or more genes comprises the FAF1 gene.

[00369] Embodiment 111 : The method of Embodiment 102 or 103, wherein the one or more genes comprises the MYC gene.

[00370] Embodiment 112: The method of Embodiment 102 or 103, wherein the one or more genes comprises the FGFR3 gene.

[00371] Embodiment 113 : The method of Embodiment 102 or 103, wherein the one or more genes comprises the MEMSET gene.

[00372] Embodiment 114: The method of Embodiment 102 or 103, wherein the one or more genes comprises the CCND1 gene.

[00373] Embodiment 115: The method of Embodiment 102 or 103, wherein the one or more genes comprises the TP53 gene.

[00374] Embodiment 116: The method of Embodiment 102 or 103, wherein the one or more genes comprises the NRAS gene.

[00375] Embodiment 117: The method of Embodiment 102 or 103, wherein the one or more genes comprises the KRAS gene.

[00376] Embodiment 118: The method of Embodiment 102 or 103, wherein the one or more genes comprises the HRAS gene.

[00377] Embodiment 119: The method of Embodiment 102 or 103, wherein the one or more genes comprises the TRAF3 gene. [00378] Embodiment 120: The method of Embodiment 102 or 103, wherein the one or more genes comprises the CDKN2A gene.

[00379] Embodiment 121 : The method of Embodiment 102 or 103, wherein the one or more genes comprises the SMAD2 gene.

[00380] Embodiment 122: The method of Embodiment 102 or 103, wherein the one or more genes comprises the BRAF gene.

[00381] Embodiment 123 : The method of Embodiment 102 or 103, wherein the one or more genes comprises the MSH6 gene.

[00382] Embodiment 124: The method of any one of Embodiments 59 to 123, wherein the efficacy of the treatment is predicted on the basis of an overexpression of one or more biomarkers in the cells of the multiple myeloma in the patient.

[00383] Embodiment 125: The method of any one of Embodiments 59 to 124, wherein the multiple myeloma comprises at least one cell that comprises an overexpression of one or more biomarkers.

[00384] Embodiment 126: The method of Embodiment 124 or 125, wherein the one or more biomarkers comprises Bim.

[00385] Embodiment 127: The method of Embodiment 124 or 125, wherein the one or more biomarkers comprises MYC.

[00386] Embodiment 128: The method of Embodiment 124 or 125, wherein the one or more biomarkers comprises MYB.

[00387] Embodiment 129: The method of Embodiment 124 or 125, wherein the one or more biomarkers comprises BCL2A1.

[00388] Embodiment 130: The method of Embodiment 124 or 125, wherein the one or more biomarkers comprises BCL-xL.

[00389] Embodiment 131 : The method of Embodiment 124 or 125, wherein the one or more biomarkers comprises Rb.

[00390] Embodiment 132: The method of Embodiment 124 or 125, wherein the one or more biomarkers comprises MCL1.

[00391] Embodiment 133 : The method of Embodiment 124 or 125, wherein the one or more biomarkers comprises PARP.

[00392] Embodiment 134: The method of Embodiment 124 or 125, wherein the one or more biomarkers comprises pro-caspase-3.

[00393] Embodiment 135: The method ofEmbodiment 124 or 125, wherein the one or more biomarkers comprises RNA polymerase type II. [00394] Embodiment 136: The method of Embodiment 124 or 125, wherein the one or more biomarkers comprises PCNA.

EXAMPLES

[00395] The following example are included for illustrative purposes only and are not intended to limit the scope of the disclosure.

Example 1: Evaluation of Formula (I’) and Combinations Comprising Formula (I’) Against Multiple Myeloma Cell Lines

[00396] Several multiple myeloma cell lines were selected for in vitro and in vivo studies. The MM cell lines employed included MM. I S, HCI-H929, OPM-2, U266B1, and JJN-3. The properties and genetic abnormalities associated with each of these cell lines was compiled in Table 1. In Table 1, HOMDEL is an abbreviation for homozygous deletion. In Table 1, AMP is an abbreviation for amplification.

Table 1

[00397] The efficacy of (+)-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S- methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine [Formula (I’)] as a single agent for inducing apoptosis in multiple myeloma (MM) cells was assessed in vitro. MM cells were exposed to variable concentrations of Formula (F) for 96 hours, and MM cell viability was then determined by an alamarBlue™ assay. A plot of cell viability as a function of concentration of Formula (F) employed for each of the MM cell lines is presented in FIG. 1. Based on the cell viability data, the IC50 of Formula (I’) as a single agent against MM cell lines was found to range from 36-78 nM. The IC₅₀ values of Formula (F) against each of the MM cell lines employed were compiled in Table 2.

Table 2

[00398] Some impacts of Formula (F) on MM cells were observed in target modulation studies. Populations of NCI-H929 MM cells were separately exposed to 500 nM or 1000 nM concentrations of Formula (F). Aliquots of the NCI-H929 cell populations were removed at various time points (1 hour, 2 hours, 6 hours, 12 hours, and 24 hours) and subsequently assayed using western blots. The western blots obtained from these studies are presented in FIG. 2. The results of the western blot assays were quantified to provide conclusions regarding timedependent and dose-dependent target modulation in MM cells upon exposure to Formula (I’). Formula (F) was found to affect the levels of biomarkers in MM cells, as depicted in the Figures and descriptions thereof as provided herein.

[00399] As depicted in the graph of FIG. 3A, Formula (I’) was found to decrease the phosphorylation of RNA Polymerase II in MM cells in a time-dependent and dose-dependent manner. As depicted in the graph of FIG. 3B, Formula (F) was found to decrease levels of MYC protein in MM cells in a time-dependent and dose-dependent manner. As depicted in the graph of FIG. 4A, Formula (F) was found to decrease the levels ofMCLl protein in MM cells a time-dependent and dose-dependent manner. As depicted in the graph of FIG. 4B, Formula (F) was found to decrease the levels of Bim protein in MM cells a time-dependent and dosedependent manner. As depicted in the graph of FIG. 5A, Formula (F) was found to decrease levels of PCNA protein in MM cells in a time-dependent and dose-dependent manner. As depicted in the graph of FIG. 5B, Formula (F) was found to decrease levels PARP in MM cells in a time-dependent and dose-dependent manner. Apoptotic pathways may comprise cleavage of PARP. As depicted in the graph of FIG. 6, Formula (F) was found to decrease levels of pro- caspase-3 in MM cells in a time-dependent and dose-dependent manner, and to increase levels of cleaved caspase-3 in MM cells in a time-dependent and dose-dependent manner. Apoptotic pathways may comprise cleavage of pro-caspase-3.

[00400] Cell viability assays were conducted with Formula (I’) at variable concentrations in combination with variable concentrations of a second pharmaceutically active agent selected from bortezomib, lenalidomide, pomalidomide, or venetoclax. MM cells were exposed to variable concentrations of Formula (F) combined with variable concentrations of the second pharmaceutically active agent for 96 hours, and MM cell viability was then determined by an alamarBlue™ assay. All two agent combinations of Formula (F) with bortezomib, lenalidomide, pomalidomide, or venetoclax were assayed against MM. IS, HCI-H929, OPM-2, and U266B1 MM cells. Tables 3 -6 show cell viability data of MM.1 S MM cells exposed to Formula (F) combined with bortezomib, lenalidomide, pomalidomide, and venetoclax, respectively. Tables 7-10 show cell viability data of NCI-H929 MM cells exposed to Formula (F) combined with bortezomib, lenalidomide, pomalidomide, and venetoclax, respectively. Tables 11-14 show cell viability data of OPM-2 MM cells exposed to Formula (F) combined with bortezomib, lenalidomide, pomalidomide, and venetoclax, respectively. Tables 15-18 show cell viability data of U266B1 MM cells exposed to Formula (I’) combined with bortezomib, lenalidomide, pomalidomide, and venetoclax, respectively. Cell viability values are percentages determined relative to DMSO controls.

Table 3 (MM. IS)

Table 4 (MM. IS)

Lenalidomide (nM)

Table 5 (MM. IS)

Pomalidomide (nM)

Table 6 (MM. IS)

Table 7 (NCI-H929)

Bortezomib (nM)

Table 8 (NCI-H929)

Lenalidomide (nM)

Table 9 (NCI-H929)

Pomalidomide (nM)

Table 10 (NCI-H929)

Table 11 (OPM-2)

Bortezomib (nM)

Table 12 (OPM-2)

Lenalidomide (nM)

Table 13 (OPM-2)

Pomalidomide (nM)

Table 14 (OPM-2)

Table 15 (U266B1)

Table 16 (U266B1)

Lenalidomide (nM)

Table 17 (U266B1)

Pomalidomide (nM)

Table 18 (U266B1)

Example 2: Target Modulation in MM Cells by Formula (I’) in Combination with Venetoclax or Lenalidomide

[00401] Some impacts of combinations of Formula (I’) and venetoclax on MM cells were observed in target modulation studies. Target modulation studies may involve monitoring the levels of biomarkers or cancer biomarkers in a cell population following exposure of the cell population to a pharmaceutically active agent. Populations of NCI-H929 MM cells and OPM2 MM cells were separately exposed to 50 nM or 100 nM concentrations of Formula (I’). Populations of NCI-H929 MM cells and OPM2 MM cells were separately exposed to venetoclax. Populations of NCI-H929 MM cells and OPM2 MM cells were separately exposed to venetoclax and 50 nM or 100 nM concentrations of Formula (I’). After 24 hours, the MM cell populations were assayed using western blots, depicted in FIG. 7. The western blot data suggested venetoclax and Formula (I’) used in combination had greater impacts in MM cells than did venetoclax or Formula (I’) used as single agents. Greater impacts observed included greater PARP cleavage and greater caspase-3 cleavage in MM cells exposed to combinations of venetoclax and Formula (I’) compared to the levels of PARP cleavage and caspase-3 cleavage in MM cells exposed to only venetoclax or only Formula (I’).

[00402] Populations of OPM-2 MM cells were exposed to various concentrations of lenalidomide (0, 1, 2.5, and 5 pM), Formula (I’) (0, 100, 250, and 500 nM), and combinations of lenalidomide and Formula (I’). Combinations of lenalidomide and Formula (I’) were evaluated such that the concentration of each pharmaceutically active agent within the concentrations could be directly compared to data obtained from experiments using solely Formula (I’) or solely lenalidomide. After exposure of OPM-2 MM cells to the specified pharmaceutically active agent(s) for 2 hours, the lysates of the OPM-2 cells were evaluated by Western blots as depicted in FIG. 8.

[00403] Populations of OPM-2 MM cells were exposed to various concentrations of venetoclax (0, 100, 250, and 500 nM), Formula (I’) (0, 100, 250, and 500 nM), and combinations of venetoclax and Formula (F). Combinations of venetoclax and Formula (F) were evaluated such that the concentration of each pharmaceutically active agent within the concentrations could be directly compared to data obtained from experiments using solely Formula (F) or solely venetoclax. After exposure of OPM-2 MM cells to the specified pharmaceutically active agent(s) for 2 hours, the lysates of the OPM-2 cells were evaluated by Western blots as depicted in FIG. 9.

Example 3: Effects of Formula (I’) with and without Co-Administration of Lenalidomide in Mouse MM Tumor Xenograft Models

[00404] The in vivo effects of Formula (F), and combination therapies comprising Formula (I’), against MM tumors were assessed using SCID/Beige mouse xenograft models. Separate SCID/Beige mouse xenograft models with JJN-3, NCI-H929, and OPM-2 MM cells were employed. Control mice were given daily oral 10 mL/kg doses of 80% polyethylene glycol 400 (PEG400).

[00405] In SCID/Beige mouse xenograft models with JJN-3 cells, weekly 15 mg/kg doses of Formula (F) were administered intravenously, leading to tumor regression and increased median survival compared to control. Tumor regression was determined by observing at day 20 after the start of treatment, tumor volumes were reduced to 1 -4% of that of tumors of control mice as depicted in FIG. 10.

[00406] In SCID/Beige mouse xenograft models with JJN-3 cells orNCI-H929 cells, weekly 15 mg/kg doses of Formula (F) were administered intravenously, leading to tumor regression and increased median survival. In these models, increased median survival of 10.5 days was observed in mice provided treatment with Formula (F) as compared to control mice. A profile of tumor area over the course of treatment of mouse xenograft models NCI-H929 cells is depicted in FIG. 11

[00407] In SCID/Beige mouse xenograft models with OPM-2 MM cells, a first cohort of mice received weekly 15 mg/kg doses of Formula (F) intravenously, a second cohort of mice received daily 50 mg/kg doses of lenalidomide orally, and a third cohort of mice received both weekly 15 mg/kg doses of Formula (F) intravenously and daily 50 mg/kg doses of lenalidomide orally. All courses of treatment led to tumor regression compared to control. The efficacy of Formula (F), including its duration of efficacy over the course of the treatment, was enhanced in its combination with lenalidomide. Profiles of tumor size over these courses of treatment in OPM-2 MM mouse xenograft models are depicted in FIG. 12.

[00408] Target modulation studies were conducted in mice tumor xenograft models of JJN-3 cells following administration of 15 mg/kg intravenous doses of Formula (I’). The levels of MCL1 mRNA and MYC mRNA were monitored over 24 hours following administration of Formula (I’). As depicted in FIG. 13A and FIG. 13B, both MCL1 mRNA and MYC mRNA levels decreased within 1 hour of administration of Formula (F), and continued to decrease for several additional hours. After 24 hours, the levels of both MCL1 mRNA and MYC mRNA returned to approximately pre-administration levels. The levels of MYC protein were monitored over 24 hours following administration of Formula (F). As depicted in FIG. 13C, MYC protein levels decreased within 1 hour of administration of Formula (F), and continued to decrease for several additional hours. After 24 hours, the levels of MYC protein remained low compared to pre-administration levels. The levels of cleaved PARP and cleaved pro-caspase-3 were monitored over 24 hours following administration of Formula (F). As depicted in FIG. 14A and FIG. 14B, both cleaved PARP and cleaved pro-caspase-3 levels increased within 1 hour of administration of Formula (F), and continued to increase. After 24 hours, the levels cleaved PARP remained high compared to pre-administration levels. After 24 hours, the levels of cleaved pro-caspase-3 returned to approximately pre-administration levels.

Example 4: Effects of Formula (I’) on Rhabdomyosarcoma and Neuroblastoma Cell Lines [00409] Several rhabdomyosarcoma (RMS) and neuroblastoma (NBL) cell lines were selected for in vitro studies. The RMS cell lines employed included RD, Rh30, and Rh41. The NBL cell lines employed included LAN1, SK-N-AS, SK-N-BE(2), SK-N-MC. Notable genetic features of these cell lines were summarized in Table 19. The antitumor activity of Formula (I’) against these cell lines was determined by alamarBlue™ cell viability assay after 96 h of treatment at 9 dose levels (2 mM to 8 nM) with corresponding DMSO treatments as controls. The IC₅₀ of Formula (I’) against these cell lines were calculated and summarized in Table 19. FIG. 15A and FIG. 15B depict the dose-dependent cell viability data of Formula (I’) against RMS and NBL cell lines, respectively. The data obtained in these studies collectively supported the concept that Formula (I’) may comprise an effective monotherapy for RMS and/or NBL. Table 19

[00410] Some impacts of Formula (I’) on Rh30 aRMS cells and SK-N-BE(2)NBL cells were observed in target modulation studies.

[00411] In one set of target modulation studies, Rh30 aRMS cells were treated with either 50 nM or 100 nM of Formula (F) for 24 hours, and then total cell lysates obtained from the Rh30 aRMS cells were analyzed by Western blotting. The biomarker levels evaluated in these experiments comprised the levels of PARP, RNA polymerase II, caspase-3, PAX3-FOXO1, MYCN (i.e., N-Myc), and PLK1. Western blots normalized to beta-actin, as depicted in FIG. 16, demonstrated that Formula (F) exposure reduced the levels of oncogenic biomarkers PAX3- FOXO1, MYCN, and PLK1 in alveolar rhabdomyosarcoma (aRMS) cells as compared to control.

[00412] In another set of target modulation studies, Rh30 aRMS cells and SK-N-BE(2) NBL cells were separately treated with either 50 nM or 100 nM of Formula (I’) for 4 hours or 24 hours, and then total cell lysates obtained from the Rh30 aRMS cells and SK-N-BE(2) NBL cells were separately analyzed by Western blotting. Beta-actin was used as a loading control. DMSO was used as a vehicle control to compare against samples treated with Formula (F). The biomarker levels evaluated in these experiments comprised the levels of PARP (including cleaved PARP), RNA polymerase II, caspase-3 (including cleaved caspase-3), PAX3-FOXO1, MYCN (i.e., N-Myc), MCL-1, and PLK1. Western blots normalized to beta-actin, as depicted in FIG. 19A, demonstrated that Formula (F) exposure reduced the levels of biomarkers PAX3- FOXO1, MYC, MCL-1, caspase-3, and PLK1 in alveolar rhabdomyosarcoma (aRMS) cells as compared to control. Western blots normalized to beta-actin, as depicted in FIG. 19B, demonstrated that Formula (I’) exposure reduced the levels of biomarkers RNA polymerase II, PARP, MYCN, MCL-1, and caspase-3 in neuroblastoma (NBL) cells as compared to control. [00413] The dose-dependent induction of apoptosis in Rh30 and Rh41 aRMS cells upon exposure to Formula (F) was evaluated. Populations ofRh30 andRh41 were separately exposed to 25 nM or 50 nM of Formula (I’) for 24 hours, and the fraction of late apoptotic (Q2) cells were then determined by Annexin V/propidium iodide staining and flow cytometry. The flow cytometry data obtained were aggregated in FIG. 17, and these data also provide the basis for the graphs provided in FIG. 18. The data suggested that exposure of Rh41 aRMS cells to Formula (F) led to a dose-dependent increase in apoptotic and necrotic cells.

Example 5: Evaluation of Combination Therapies for Alveolar Rhabdosarcoma Comprising Formula (I’)

[00414] Cell viability assays of Formula (I’) in combination with one of several second pharmaceutically active agents against Rh41 and Rh30 aRMS cells were conducted. The second pharmaceutically active agents employed included bortezomib, carfilzomib, cisplatin, etoposide, gemcitabine, irinotecan, selinexor, temozolomide, SN-38 and topotecan. Populations of Rh41 aRMS cells were exposed to combinations of Formula (F) and a second pharmaceutically active agent at constant dilution ratios of the two agents for 96 hours, followed by determination of cell viability using an alamarBlue™ assay. The cell viability obtained from several of these experiments were collected into Tables 20-26. The values in Tables 20-26 correspond to the percentage of viable Rh41 aRMS cells remaining following exposure to the specified concentrations of Formula (F) and the specified second pharmaceutically active agent. Cell viability data obtained in these studies was used to obtain Bliss synergy scores for the combinations comprising Formula (I¹). Bliss synergy scores of some combinations against Rh41 and Rh30 aRMS cells are provided in FIG. 20.

Table 20

Topotecan (nM)

Table 21

Etoposide (nM)

Table 22

Selinexor (nM)

Table 23

Table 24

Cyc ophosphamide (SN-38) (nM)

Table 25

Gemcitabine (nM)

Table 26

[00415] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Itis notintended thatthe disclosure be limited by the specific examples provided within the specification. While the disclosure has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. Furthermore, it shall be understood that all aspects of the disclosure are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is therefore contemplated that the disclosure shall also cover any such alternatives, modifications, variations or equivalents.

Claims

WHAT IS CLAIMED IS:

1. A method of treating multiple myeloma in a patient in need thereof, the method comprising:

(a) administering to the patient a therapeutically effective amount of a first pharmaceutically active agent comprising 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S- methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine of Formula (I) or an enantiomer thereof or a pharmaceutically acceptable salt thereof

Formula (I); and

(b) administering to the patient a therapeutically effective amount of a second pharmaceutically active agent selected from a proteasome inhibitor, a BCL-2 inhibitor, or a modulator of E3 ubiquitin ligase activity.

2. The method of claim 1 , wherein the first pharmaceutically active agent is administered in the form of a pharmaceutical composition that comprises the first pharmaceutically active agent and a pharmaceutically acceptable excipient.

3. The method of claim 1 or 2, wherein the second pharmaceutically active agent is administered in the form of a pharmaceutical composition that comprises the second pharmaceutically active agent and a pharmaceutically acceptable excipient.

4. The method of any one of claims 1 to 3, wherein the second pharmaceutically active agent is a proteasome inhibitor.

5. The method of any one of claims 1 to 3 , wherein the second pharmaceutically active agent is a proteasome inhibitor selected from bortezomib.

6. The method of any one of claims 1 to 3, wherein the second pharmaceutically active agent is a BCL-2 inhibitor. The method of any one of claims 1 to 3, wherein the second pharmaceutically active agent is a BCL-2 inhibitor selected from venetoclax. The method of any one of claims 1 to 3, wherein the second pharmaceutically active agent is a modulator of E3 ubiquitin ligase activity. The method of any one of claims 1 to 3, wherein the second pharmaceutically active agent is a modulator of E3 ubiquitin ligase activity selected from lenalidomide or pomalidomide. The method of any one of claims 1 to 9, wherein the first pharmaceutically active agent is (+)-5-fluoro-4-(4-fluoro-2 -meth oxyp henyl)-N-{4-[(S-methylsulfonimidoy l)methyl]pyridin- 2-yl}pyridin-2 -amine of Formula (T) or a pharmaceutically acceptable salt thereof. The method of any one of claims 1 to 10, wherein the first pharmaceutically active agent is administered with lesser frequency than is the second pharmaceutically active agent. The method of any one of claims 1 to 10, wherein the first pharmaceutically active agent is administered with greater frequency than is the second pharmaceutically active agent. The method of any one of claims 1 to 12, wherein the first pharmaceutically active agent is administered about once per week. The method of any one of claims 1 to 12, wherein the second pharmaceutically active agent is administered about once per day. The method of any one of claims 1 to 14, wherein the first pharmaceutically active agent is administered intravenously. The method of any one of claims 1 to 15, wherein the second pharmaceutically active agent is administered intravenously. The method of any one of claims 1 to 15, wherein the second pharmaceutically active agent is administered orally. The method of any one of claims 1 to 17, wherein the multiple myeloma comprises at least one cell that comprises one or more genetic abnormalities. The method of claim 18, wherein the one or more genetic abnormalities comprises a translocation. The method of claim 18, wherein the one or more genetic abnormalities comprises monosomy 13, chromosome Iq gain, chromosome Ip deletion, chromosome 8q24 MYC gene rearrangement, chromosomal t (4; 14) translocation, chromosomal t (11 ;14) translocation, or chromosome 17p deletion. The method of any one of claims 1 to 20, wherein the multiple myeloma comprises at least one cell that comprises an amplification of one or more genes. The method of claim 21, wherein the one or more genes comprises the BCL2L11 gene, the RBI gene, the CSK1B gene, the MCL1 gene, the FAM46C gene, the CDKN2C gene, the FAF1 gene, the MYC gene, the FGFR3 gene, the MEMSET gene, the CCND1 gene, the TP53 gene, the NRAS gene, the KRAS gene, the HRAS gene, the TRAF3 gene, the CDKN2A gene, the SMAD2 gene, the BRAF gene, the MSH6 gene, or a combination thereof. The method of any one of claims 1 to 22, wherein the multiple myeloma comprises at least one cell that comprises an overexpression of one or more biomarkers. The method of claim 23, wherein the one or more biomarkers comprises Bim, MYC, MYB, BCL2A1, BCL-xL, Rb, MCL1, PARP, PCNA, or a combination thereof. A method of treating rhabdomyosarcoma or neuroblastoma in a patient in need thereof, the method comprising: administering to the patient a therapeutically effective amount of a first pharmaceutically active agent comprising 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S- methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2 -amine of Formula (I):

Formula (I); or an enantiomer thereof or a pharmaceutically acceptable salt thereof. The method of claim 25, wherein the method is a method of treating rhabdomyosarcoma in a patient in need thereof. The method of claim 25, wherein the method is a method of treating neuroblastoma in a patient in need thereof. The method of any one of claims 25 to 27, wherein the first pharmaceutically active agent is administered in the form of a pharmaceutical composition that comprises the first pharmaceutically active agent and a pharmaceutically acceptable excipient. The method of any one of claims 25 to 28, further comprising administering to the patient a therapeutically effective amount of a second pharmaceutically active agent selected from temozolomide. The method of any one of claims 25 to 28, further comprising administering to a patient a therapeutically effective amount of a second pharmaceutically active agent selected from a topoisomerase inhibitor, an exportin 1 inhibitor, a proteasome inhibitor, cyclophosphamide, or gemcitabine. The method of claim 29 or 30, wherein the second pharmaceutically active agent is administered in the form of a pharmaceutical composition that comprises the second pharmaceutically active agent and a pharmaceutically acceptable excipient. The method of claim 30 or 31, wherein the second pharmaceutically active agent is a topoisomerase inhibitor. The method of claim 30 or 31, wherein the second pharmaceutically active agent is a topoisomerase inhibitor selected from topotecan. The method of claim 30 or 31, wherein the second pharmaceutically active agent is a topoisomerase inhibitor selected from etoposide. The method of claim 30 or 31, wherein the second pharmaceutically active agent is a topoisomerase inhibitor selected from irinotecan. The method of claim 30 or 31, wherein the second pharmaceutically active agent is an exportin 1 inhibitor. The method of claim 30 or 31, wherein the second pharmaceutically active agent is an exportin 1 inhibitor selected from Selinexor. The method of claim 30 or 31, wherein the second pharmaceutically active agent is a proteasome inhibitor.

9. The method of claim 30 or 31, wherein the second pharmaceutically active agent is a proteasome inhibitor selected from carfilzomib. 0. The method of claim 30 or 31, wherein the second pharmaceutically active agent is a proteasome inhibitor selected from bortezomib. 1. The method of claim 30 or 31, wherein the second pharmaceutically active agent is cyclophosphamide. . The method of claim 30 or 31, wherein the second pharmaceutically active agent is gemcitabine. 3. The method of any one of claims 25 to 42, wherein the first pharmaceutically active agent is (+)-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin- 2-yl}pyridin-2-amine of Formula (T) or a pharmaceutically acceptable salt thereof. . The method of any one of claims 29 to 43, wherein the first pharmaceutically active agent is administered with lesser frequency than is the second pharmaceutically active agent. 5. The method of any one of claims 29 to 43, wherein the first pharmaceutically active agent is administered with greater frequency than is the second pharmaceutically active agent. 6. The method of any one of claims 25 to 45, wherein the first pharmaceutically active agent is administered about once per week. 7. The method of any one of claims 29 to 45, wherein the second pharmaceutically active agent is administered about once per day. 8. The method of any one of claims 25 to 47, wherein the first pharmaceutically active agent is administered orally. 9. The method of any one of claims 29 to 48, wherein the second pharmaceutically active agent is administered intravenously. 0. The method of any one of claims 29 to 48, wherein the second pharmaceutically active agent is administered orally. 1 . The method of any one of claims 25 to 50, wherein the rhabdomyosarcoma or neuroblastoma comprises at least one cell that comprises one or more genetic abnormalities. The method of claim 51, wherein the one or more genetic abnormalities comprises a translocation. The method of claim 51 or 52, wherein the one or more genetic abnormalities comprises a t(2;13)(q35;ql4) chromosomal translocation, expression of the PAX3-F0X01 fusion protein, a t(l ; 13)(p36;ql 4) chromosomal translocation, chromosome 17q gain, chromosome Ip deletion, chromosome 1 Ip deletion, expression of the PAX7-FOXO1 fusion protein, or a combination thereof. The method of any one of claims 25 to 53, wherein the rhabdomyosarcoma or neuroblastoma comprises at least one cell that comprises an amplification of one or more genes. The method of claim 54, wherein the one or more genes comprises the MYCN gene. The method of any one of claims 25 to 55, wherein the rhabdomyosarcoma or neuroblastoma comprises at least one cell that comprises an overexpression of one or more biomarkers. The method of claim 56, wherein the one or more biomarkers comprises MYCN, PLK1, PAX3-F0X01, PAX7-F0X01, or a combination thereof.