The present application relates generally to a lysine specific demethylase-1 (LSD-1) inhibitor, or a pharmaceutically acceptable salt thereof, and nivolumab, for use in methods for treating small cell lung cancer (SCLC) and/or squamous non-small cell lung cancer (sqNSCLC).

RELATED APPLICATIONS [0001] This application claims the priority benefit of U.S. provisional application 62/986,541 filed Mar. 6, 2020, the entire contents of which are incorporated herein by reference.

FIELD

[0002] The present application relates generally to methods for treating small cell lung cancer (SCLC) and/or squamous non-small cell lung cancer (sqNSCLC) with a combination of a lysine specific demethylase-1 (LSD-1) inhibitor, or a pharmaceutically acceptable salt thereof, and nivolumab.

BACKGROUND

[0003] Lung cancer is the most common cancer worldwide with approximately 1.8 million new diagnoses and 1.59 million deaths in 2012, which corresponds to the third highest incidence among cancers and the most common cancer-related mortality.

[0004] Small cell lung cancer is an aggressive high-grade neuroendocrine tumor associated with a short doubling time, a high growth fraction, and early development of widespread metastases, which contribute to the extremely poor disease prognosis. The World Health Organization (WHO) divides lung cancer into 2 major classes based on its biology, therapy, and prognosis: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).

[0005] Small cell lung cancer is an aggressive high-grade neuroendocrine tumor associated with a short doubling time, a high growth fraction, and early development of widespread metastases, which contribute to the extremely poor disease prognosis. These aspects of SCLC, as well as the limited success of current treatments, highlight the unmet medical need for the development of new therapeutics for SCLC, particularly in relapsed disease.

[0006] Non-small cell lung cancer accounts for 80% to 90% of lung cancers and includes two major types: (1) non-squamous carcinoma (including adenocarcinoma, large-cell carcinoma, other cell types); and (2) squamous cell (epidermoid) carcinoma. Squamous histology is associated with shorter survival than non-squamous histology.

[0007] Advanced squamous non-small cell lung cancer (sqNSCLC) remains a recalcitrant disease. While non-squamous NSCLC has benefited from advances in chemotherapy doublets (pemetrexed and platinum), VEGF targeted therapy (bevacizumab) and tumor profiling with actionable mutations for therapeutic interventions (ie, EGFRmut, ALK, BRAF, ROS1), the same has not occurred in the setting of sqNSCLC. Together, these factors make sqNSCLC an especially challenging disease to such that new therapies, especially ICI and combinations, could have a large impact.

[0008] Lung cancer can be asymptomatic at early stages. As such, most patients are diagnosed at an advanced stage that is not curable by surgery and have poor prognoses. Despite recent advances in targeted and immune mediated therapy, such as anti-programmed cell death 1 (PD1)/programmed death-ligand 1 (PD-L1), most patients with solid tumors do not achieve long term disease control. While cytotoxic chemotherapy remains an important disease control modality in both first and second-line treatment for patients with SCLC, long term disease control is limited. Further, while chemotherapy, targeted therapy, and/or anti-PD-1/PD-L1 therapies provide long term benefit to NSCLC patients, the majority of NSCLC patients will ultimately progress due to resistance mechanisms and succumb due to the disease.

[0009] Thus, there remains a need for more effective treatments for small cell lung cancer (SCLC) and/or squamous non-small cell lung cancer (sqNSCLC), and this disclosure satisfies this need.

SUMMARY

[0010] The present application relates generally to methods for treating small cell lung cancer (SCLC) and/or squamous non-small cell lung cancer (sqNSCLC). The methods comprise administering a combination of a lysine specific demethylase-1 (LSD-1) inhibitor, or a pharmaceutically acceptable salt thereof, with nivolumab.

[0011] The aspects and embodiments of the present disclosure provide for methods for treating subjects with small cell lung cancer (SCLC) and/or squamous non-small cell lung cancer (sqNSCLC).

[0012] Provided in one aspect is a method of treating a subject having small cell lung cancer (SCLC) and/or squamous non-small cell lung cancer (sqNSCLC) comprising: (a) administering to the subject an LSD-1 inhibitor; and (b) concomitantly or sequentially administering nivolumab; wherein the LSD-1 inhibitor is a compound having the structure:

##STR00001##

or a besylate salt thereof. In some embodiments the nivolumab is administered before the LSD-1 inhibitor, in some embodiments the nivolumab is administered after the LSD-1 inhibitor, and in some embodiments the nivolumab is administered simultaneously with the LSD-1 inhibitor.

[0013] In some embodiments, the subject has any one of the following: (a) a complete response (CR) as assessed by Response Evaluation Criteria in Solid Tumor (RECIST), Version 1.1; (b) the disappearance of all target lesions; and/or (c) the reduction of target and/or non-target pathological lymph nodes in short axis to less than about 10 mm.

[0014] In some embodiments, the subject has any one of the following: (a) a partial response (PR) as assessed by Response Evaluation Criteria In Solid Tumor (RECIST), Version 1.1; and/or (b) at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameter.

[0015] In some embodiments, the subject has a duration of response as defined by a time from the first occurrence of a documented objective response to a time of a first objectively documented progression, as determined by Response Evaluation Criteria In Solid Tumor (RECIST), Version 1.1, or death from any cause, whichever comes first, wherein the duration of the response is: (a) about 1, about 2, about 5, about 10, about 52, or greater weeks; (b) at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 12 weeks, at least about 18 weeks, at least about 24 weeks, at least about 30 weeks, at least about 36 weeks, at least about 42 weeks, at least about 48 weeks, or at least about 54 weeks; and/or (c) about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 12 weeks, about 18 weeks, about 24 weeks, about 30 weeks, about 36 weeks, about 42 weeks, about 48 weeks, or about 54 weeks.

[0016] In some embodiments, the subject has a progression-free survival as defined by from first dose of study treatment to the date of the first objectively documented tumor progression as determined by Response Evaluation Criteria In Solid Tumor (RECIST), Version 1.1, or death from any cause, whichever comes first, wherein the duration of the progression-free survival is: (a) about 1, about 2, about 5, about 10, about 52, or greater weeks; (b) at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 12 weeks, at least about 18 weeks, at least about 24 weeks, at least about 30 weeks, at least about 36 weeks, at least about 42 weeks, at least about 48 weeks, or at least about 54 weeks; and/or (c) about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 12 weeks, about 18 weeks, about 24 weeks, about 30 weeks, about 36 weeks, about 42 weeks, about 48 weeks, or about 54 weeks.

[0017] In some embodiments, the method further comprises any one of the following: (a) the LSD-1 inhibitor is administered orally; (b) the LSD-1 inhibitor is administered in the form of a tablet or capsule; (c) the LSD-1 inhibitor is administered once a week; and/or (d) the LSD-1 inhibitor is administered at a dose of about 20 mg, about 40 mg, or about 60 mg.

[0018] In some embodiments, (a) the LSD-1 inhibitor is administered at about 40 mg orally once a week in a 28-day period; and/or (b) the LSD-1 inhibitor is administered on Days 1, 8, 15, and 22 in a 28-day period; and/or (c) the 28 day period is repeated for as long as the subject has a complete response (CR) or partial response (PR) as assessed by Response Evaluation Criteria In Solid Tumor (RECIST), Version 1.1.

[0019] In some embodiments, (a) the LSD-1 inhibitor is administered at about 60 mg orally once a week in a 28-day period; and/or (b) the LSD-1 inhibitor is administered on Days 1, 8, 15, and 22 in a 28-day period; and/or (c) the 28 day period is repeated for as long as the subject has a complete response (CR) or partial response (PR) as assessed by Response Evaluation Criteria In Solid Tumor (RECIST), Version 1.1.

[0020] In some embodiments, (a) the nivolumab is administered intravenously; and/or (b) the nivolumab is administered in the form of an injection; and/or (c) the nivolumab is administered once every two weeks or every 4 weeks; and/or (d) the nivolumab is administered at a dose of at least about 240 mg or about 480 mg; and/or (e) the nivolumab is administered at a dose of about 240 mg or about 480 mg.

[0021] In some embodiments, (a) the nivolumab is administered at about 480 mg intravenously once a week in a 28-day period; and/or (b) the nivolumab is administered on Day 1 in a 28-day period; and/or (c) the 28 day period is repeated for as long as the subject has a complete response (CR) or partial response (PR) as assessed by Response Evaluation Criteria In Solid Tumor (RECIST), Version 1.1.

[0022] In some embodiments, the subject exhibits one or more of the following specific levels of baseline characteristics: (a) gene expression in peripheral blood (LSD1-regulated genes in PBMCs) and/or in tumor samples (such as SOX-2, Notch1/2, ASCL1, POU2F2, YAP, NeuroD1, CgA, GRP, REST, HES1, HEY1); and/or (b) molecular features in tumor samples, such as amplification of Sox-2 (c) secreted proteins in blood selected from pro-gastrin-releasing peptide (pro-GRP) and chromogranin A (CgA) and midkine; and/or (d) localization and/or density of T cells, MDSCs and other immune cells in tumor tissues; and/or (e) expression of programmed cell death protein 1 (PD-1) and/or programmed death-ligand 1 (PD-L1) in tumor tissues; and/or (f) expression of lysine-specific histone demethylase 1A (LSD1) and/or an LSD1-associated molecular signature in tumor tissue; and/or (g) protein markers in tumor tissues and/or in circulating tumor cells (CTCs); and/or (h) amount and molecular features of circulating tumor DNA (ctDNA) in the blood.

[0023] In some embodiments, the subject exhibits one or more of the following changes from baseline: (a) gene expression in peripheral blood (LSD1-regulated genes in PBMCs) and/or in tumor samples (such as SOX-2, Notch1, ASCL1, IGFBP2/5, REST, Hes1, Hey1, MDK, CgA, GRP); and/or (b) secreted proteins in blood selected from pro-gastrin-releasing peptide (pro-GRP) and chromogranin A (CgA) and midkine; and/or (c) localization and/or density of T cells, MDSCs and other immune cells in tumor tissues; and/or (d) expression of programmed cell death protein 1 (PD-1) and/or programmed death-ligand 1 (PD-L1) in tumor tissues; and/or (e) expression of lysine-specific histone demethylase 1A (LSD1) and/or an LSD1-associated molecular signature in tumor tissue; and/or (f) protein markers in tumor tissues (such as CXCL9, MCSF, Notch1/2, chromagraninA) and/or in circulating tumor cells (CTCs); and/or (g) amount and molecular features of circulating tumor DNA (ctDNA) in the blood. In some embodiments, the gene expression in tumor samples is the gene expression of sex determining region Y-box 2 (SOX2).

[0024] In some embodiments, the protein marker in tumor tissues is one or more of AC124319.1, ADAR, APOL6, ARID5B, ARL4A, ASCL1, AUTS2, B2M, BANK1, BATF2, BPGM, BST2, BTG1, C1R, C1S, CASP1, CASP3, CASP4, CASP7, CASP8, CHGA, CCL2, CCL5, CCL7, CD274 (PDL1), CD3, CD38, CD4, CD40, CD69, CD74, CD8, CD86, CDH2, CDKN1A, CFB, CFH, CIITA, CMKLR1, CMPK2, CMTR1, CSF2RB, CXCL10, CXCL11, CXCL9, DDX58, DDX60, DHX58, DLL1, DLL3, EIF2AK2, EIF4E3, EPSTI1, FAS, FCGR1A, FGFR1, FGFR13, FGL2, FPR1, GBP4, GBP6, GCH1, GPR18, GRP, GZMA, HELZ2, HERC6, HEY1, HES1, HIF1A, HLA-A, HLA-B, HLA-DMA, HLA-DQA1, HLA-DRB1, HLA-G, ICAM1, IDOL IFI27, IFI30, IF135, IF144, IFI44L, IFIH1, IFIT1, IFIT2, IFIT3, IFITM2, IFITM3, IFNAR2, IFL10RA, IGFBP2, IGFBP5, IL15, IL15RA, IL18BP, IL2RB, IL4R, IL6, IL7, IRF1, IRF2, IRF4, IRF5, IRF7, IRF8, IRF9, ISG15, ISG20, ISOC1, ITGAB, ITGB7, JAG1, JAK2, KAT2B, KLRK1, LAP3, LATS2, LCP2, LGALS3BP, LYSE, LYSMD2, MAGEC2, 1-MAR, MCSF, MDK, METTL7B, MT2A, MEHFD2, MVP, MX1, MX2, MYD88, M-CSF, NAMPT, NCOA3, NEUROD1, NFKB1, NFKBIA, NLRC5, NMI, NOD1, NOTCH1, NOTCH2, NUP93, OAS2, OAS3, OASL, OGFR, P2RY14, PARP12, PARP14, PDE4B, PD1, PELI1, PFKP, PIM1, PLA2G4A, PLSCR1, PML, PNP, PNPT1, POU2F3, PSMA2, PSMA3, PSMB10, PSMB2, PSMB8, PSMB9, PSME1, PSME2, PTGS2, PTPN1, PTPN2, PTPN6, RAPGEF6, RBCK1, RCOR2, REST, RIPK1, RIPK2, RNF31, RSAD2, RTP4, SAMD9L, SAMHD1, SECTM1, SELP, SERPINGLSGK1, SLAMF7, SLC25A28, SOCS1, SOCS3, SOD2, SOX2, SP110, SPPL2A, SRI, SSPN, ST3GAL5, ST8SIA4, STAT1, STAT2, STAT3, STAT4, TAP1, TAPBP, TDRD7, THBS1, TNFAIP2, TNFAIP3, TNFAIP6, TNFAIP10, TOR1B, TRAFD1, TRIM14, TRIM 21, TRIM25, TRIM 26, TXNIP, UBE2L6, UPP1, USP18, VAMP5, VAMP8, VEGF, VCAM1, WARS, WNT11, XAF1, XCL1, ZBP1, ZEB1, ZEB2, or ZNFX1.

[0025] Both the foregoing summary and the following description of the drawings and detailed description are exemplary and explanatory. They are intended to provide further details of the invention, but are not to be construed as limiting. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.