Combination therapy in difficult-to-treat patients with advanced and / or metastatic TROP-2-overexpressing cancer

Abstract

The present invention is in the field of improved combination therapy for select groups of difficult-to-treat cancer patients, including, for example, patients with Trop-2 overexpressing cancers such as advanced / metastatic triple-negative breast cancer (TNBC), recurrent or metastatic urothelial carcinoma (mUC), or non-small cell lung cancer (NSCLC), which includes the use of trilaciclib and sacituzumab govitecan, providing increased overall survival and / or reduced toxicity.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 217,716, filed July 1, 2021, the entirety of which is incorporated by reference herein for all purposes.

[0002] FIELD OF THEINVENTION The present invention is in the field of improved combination therapy for select populations of difficult-to-treat cancer patients, including, for example, patients with advanced / metastatic triple-negative breast cancer (TNBC), recurrent or metastatic urothelial carcinoma (mUC), or Trop-2 overexpressing cancers, including but not limited to non-small cell lung cancer (NSCLC), which improved combination therapy includes the use of trilaciclib and sacituzumab govitecan, providing increased overall survival and / or reduced toxicity. [Background technology]

[0003] Triple negative breast cancer Triple-negative breast cancer (TNBC) is characterized by several aggressive clinicopathological features, including early age of onset, large, aggressive tumors, and a propensity for visceral metastasis (Cheang et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res. 2008;14(5):1368-76; Foulkes et al., Triple-negative breast cancer. N Engl J Med. 2010 Nov 11;363(20):1938-48). The estimated median survival from the time of diagnosis is approximately 13-18 months, and the median age at diagnosis is approximately 50 years (Kassam et al. Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design. Clin Breast Cancer. 2009;9(1):29-33; Yardley et al. nab-Paclitaxel plus carboplatin or gemcitabine versus gemcitabine plus carboplatin as first-line treatment of patients with triple-negative metastatic breast cancer: results from the tnAcity trial. Ann Oncol. 2018;29(8):1763-70). Treatments that are effective for hormone receptor-positive breast cancer and human epidermal growth factor receptor 2 (HER2)-positive breast cancer, such as endocrine therapy or HER2-targeted therapy (e.g., trastuzumab), are ineffective for TNBC, which lacks expression of these markers, and therefore chemotherapy remains the mainstay of treatment for TNBC.In particular, chemotherapy that targets deoxyribonucleic acid (DNA) repair (e.g., platinum compounds) and cell proliferation (e.g., taxanes and anthracyclines such as doxorubicin) have proven most effective in TNBC, but these treatments are limited by toxicity and ultimately all patients develop drug resistance.

[0004] In addition to the above limitations, chemotherapy-induced immunosuppression may also affect antitumor efficacy due to the inability of the host immune system to mount an effective response against cancer. In 2019, atezolizumab, a programmed death-ligand 1 (PD-L1) blocking antibody (immune checkpoint inhibitor [ICI]), in combination with nab-paclitaxel, was approved in accelerated fashion by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for patients with PD-L1-positive locally advanced unresectable / metastatic TNBC (Tecentriq® Package Insert, 2020). This FDA accelerated approval was based on clinical trial results showing improved progression-free survival (PFS) in patients with PD-L1 positivity (PD-L1-stained tumor-infiltrating immune cells [IC] of any intensity occupying ≥1% of tumor area) (median 7.4 vs. 4.8 months; hazard ratio [HR]: 0.60 [0.48, 0.77]; p<0.0001). Furthermore, the PD-L1-positive subset survived a median of 25 months with atezolizumab plus nab-paclitaxel compared with 18 months with placebo plus nab-paclitaxel.The improved efficacy seen with the addition of atezolizumab to nab-paclitaxel was associated with a relatively low incidence of immune-related adverse events, which can cause significant morbidity and mortality.

[0005] Unfortunately, after confirmatory trials, approval of atezolizumab for use in the PD-L1-positive subset of TNBC patients was subsequently withdrawn. Results published in the Annal of Oncology in 2021 showed that the trial failed to meet its primary endpoint of PFS superiority in frontline treatment of PD-L1-positive patients (HR, 0.82; 95% CI, 0.60-1.12; P=0.20) (Miles et al. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced / metastatic triple-negative breast cancer. Ann Oncol. 2021;32(8):994-1004. doi:10.1016 / j.annonc.2021.05.801). Furthermore, there was no difference in survival advantage between the PD-L1-positive population (HR 1.11, 95% CI 0.76-1.64) and the intention-to-treat population.

[0006] Additionally, accelerated approval was granted for pembrolizumab in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC (CPS ≥ 10, CPS = combined positive score) whose tumors express PD-L1 as determined by an FDA-approved companion diagnostic test (KEYTRUDA® package insert, 2020). Approval was based on the primary efficacy outcome measure of PFS in the subgroup of patients with CPS ≥ 10 (median PFS: 9.7 months (95% confidence interval (CI): 7.6, 11.3) in the pembrolizumab + chemotherapy arm and 5.6 months (95% CI: 5.3, 7.5) in the placebo arm (HR 0.65, 95% CI: 0.49, 0.86, one-sided p-value = 0.0012).

[0007] Although the combination of certain ICIs with chemotherapy has shown to be a meaningful step forward in the treatment of patients with PD-L1-positive locally advanced unresectable / metastatic TNBC, it should be noted that due to potential treatment toxicities associated with ICIs, not all PD-L1-positive TNBC patients are suitable candidates for ICI treatment, and as expected, the PD-L1-negative TNBC patient population may not benefit.

[0008] Other available targeted therapies recently approved by the FDA are PARP inhibitors such as olaparib (approved January 2018) for the treatment of patients with germline BRCA-positive, HER2-negative metastatic breast cancer (MBC) who have previously received chemotherapy, and talazoparib (approved October 2018) for patients with locally advanced or metastatic breast cancer (MBC) who have harmful or suspected harmful germline BRCA mutations and are HER2-negative. These two targeted therapies provide benefit to TNBC patients, but only to those with germline BRCA mutations (approximately 9-18%; Hahnen et al., Germline Mutations in Triple-Negative Breast Cancer. Breast Care (Basel). 2017;12(1):15-19).

[0009] Overall, patients with TNBC have few approved treatment options beyond standard chemotherapy. Currently, there are targeted therapies available for TNBC, but these are limited to eligible patients who express PD-L1-positive disease (ICI) and / or have germline BRCA mutations (PARP inhibitors), which in the case of ICI, are associated with additional toxicities. There is clearly a need for novel combination treatments that can provide similar or improved antitumor efficacy for all TNBC patients, regardless of PD-L1 or BRCA status, without the associated potentially high-grade toxicities.

[0010] Metastatic urothelial carcinoma Patients with metastatic urothelial carcinoma (mUC) who progress after platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) also have limited treatment options (National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer Version 5.2020. https: / / www.nccn.org / professionals / physician_gls / ). After progression, the only widely available agents indicated in the NCCN and ESMO guidelines are taxanes and vinflunine (approved in the European Union). The response rate to these drugs is about 10%, with a median overall survival (OS) of 7-8 months (Petrylak et al: Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): A randomised, double-blind, phase 3 trial. Lancet 390:2266-2277, 2017; Raggi et al: Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: A systematic review and meta-analysis.Ann Oncol 27:49-61, 2016; Niegisch et al: A real-world data study to evaluate treatment patterns, clinical characteristics and survival outcomes for first- and second-line treatment in locally advanced and metastatic urothelial cancer patients in Germany. J Cancer 9:1337-1348, 2018; Fradet et al: Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: Results of 2 years of follow-up. Ann Oncol 30:970-976, 2019; Di Lorenzo et al: Third-line chemotherapy for metastatic urothelial cancer: A retrospective observational study. Medicine (Baltimore) 94: e2297, 2015; Vlachostergios et al: Antibody-drug conjugates in bladder cancer. Bladder Cancer 4:247-259, 2018)。.

[0011] In the United States, the treatment landscape for mUC has been expanded with the accelerated approval by the US Food and Drug Administration (FDA) of enfortumab vedotin (EV), a nectin-4-directed antibody-drug conjugate (ADC), following platinum-based chemotherapy and ICIs with erdafitinib, a pan-fibroblast growth factor receptor inhibitor, for patients with tumors harboring FGFR2 or FGFR3 activating mutations or fusions (following platinum-based chemotherapy) (Padosev [package insert]. Northbrook, IL, Astellas Pharma US, 2019; FDA Grants Accelerated Approval to Enfortumab Vedotin-ejfv for Metastatic Urothelial Cancer [Press Release]. Silver Spring, MD: US Food and Drug Administration, December 19, 2019; Loriot et al: Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med 381:338-348, 2019). Both EV and erdafitinib have objective response rates (ORR) of approximately 40%, but most patients progress on these therapies. Furthermore, erdafitinib is limited to patients with FGFR2 / 3 mutations or fusions (15%–20% of patients depending on cancer type) (de Almeida Carvalho et al: Estimation of percentage of patients with fibroblast growth factor receptor alterations eligible for off-label use of erdafitinib. JAMA Netw Open 2:e1916091, 2019).

[0012] Overall, patients with mUC currently have few treatment options beyond platinum-containing chemotherapy regimens. Although there are currently targeted therapies available for mUC, these are restricted to eligible patients who present with PD-L1-positive disease (ICI) with additional potential toxicities. There is clearly a need for new combination treatments that can provide similar or improved antitumor efficacy without the associated high-grade toxicities for all patients with mUC, regardless of PD-L1 status.

[0013] Non-small cell lung cancer More than 2 million lung cancer cases and 1.75 million lung cancer-related deaths were reported in 2018 (WHO, 2020). The American Cancer Society estimates that approximately 135,000 people will die from lung cancer in the United States alone in 2020 (American Cancer Society, 2020). Approximately 84% of these patients will be diagnosed with non-small cell lung cancer (NSCLC), and approximately 70% will present with locally advanced or metastatic disease (ASCO, 2020; Little, 2007). Historically, metastatic NSCLC has been treated almost exclusively through the use of systemic chemotherapy. However, in the last 10 to 20 years, an improved understanding of pathways that dictate tumor response and the emergence of multiple targeted therapies have significantly changed the landscape of treatment options. Lung tumors are routinely tested for the presence of specific driver mutations (e.g., epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), BRAF, rearrangements in proto-oncogene translocations (RET), AKT1, ERBB2, MEK1, MET, NRAS, PIK3CA, RET, TRK1, and c ROS oncogene 1 (ROS1), neurotrophic tyrosine receptor kinase (NTRK)) that predict favorable response to targeted tyrosine kinase inhibitors (Kalemkerian, 2018). As many as 50% to 64% of patients have been identified as harboring targetable genetic alterations, and treated patients have favorable outcomes (Kris, 2014; Barlesi, 2016).

[0014] For patients without targeted gene mutations, treatment options vary considerably. While systemic therapy remains an important treatment component in this regard, the advent of immunotherapy has significantly improved outcomes in this patient population. Multiple randomized trials in both squamous and non-squamous histologies have demonstrated that the addition of programmed death protein 1 (PD-1) / programmed death ligand 1 (PD-L1) inhibitors improves overall survival (OS) (Spigel, 2019; Reck, 2016; Gandhi, 2018; Paz-Ares, 2018). Patients with high PD-L1 expression levels generally receive first-line pembrolizumab or atezolizumab monotherapy followed by platinum-based chemotherapy to maximize treatment response and minimize toxicity. Patients with high disease burden or low PD-L1 expression levels who require more aggressive initial treatment generally receive dual immunotherapy and platinum-based chemotherapy.

[0015] Despite these improvements in therapy for metastatic NSCLC, the majority of patients ultimately progress during or after treatment with immunotherapy and platinum-based chemotherapy. Management of this pretreated patient population is challenging, and treatment options are limited to single-agent chemotherapies such as docetaxel, pemetrexed (for non-squamous histology), and gemcitabine (Shepherd, 2000; Fossella, 2010; Gridelli, 2004; Hanna, 2004; Anderson, 2000).

[0016] Because available treatments for patients with NSCLC who have progressed on immune checkpoint inhibitors are limited, novel therapies are needed after disease progression on currently available clinical treatments.

[0017] Sacituzumab govitecan Recently, sacituzumab govitecan-hziy was approved by the US FDA for the treatment of two very difficult-to-treat populations: 1) patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received at least two prior systemic therapies, at least one of which was for metastatic disease, and 2) patients with locally advanced or metastatic urothelial carcinoma (mUC) who have received platinum-containing chemotherapy and a programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor. Sacituzumab govitecan is a Trop-2-directed humanized monoclonal antibody, hRS7 IgG1κ (also called sacituzumab), which binds Trop-2 (trophoblast cell surface antigen-2) and is linked to the topoisomerase inhibitor drug SN-38 via a hydrolyzable linker (called CL2A). Trop-2 has been shown to be overexpressed in a majority of epithelial cancers, including breast, colon, prostate, pancreatic, urothelial, and lung cancers. Trop-2 plays an important role in anchorage-independent cell growth and tumorigenesis. Pharmacological data suggest that sacituzumab govitecan binds to cancer cells expressing Trop-2 and is internalized with subsequent release of SN-38 via hydrolysis of the linker. SN-38, the active metabolite of irinotecan, interacts with topoisomerase I and inhibits rejoining of topoisomerase I-induced single-strand breaks. The resulting DNA damage leads to apoptosis and cell death.

[0018] In early-stage clinical trials in patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who had relapsed after at least two prior lines of breast cancer chemotherapy (one of which could have been neoadjuvant or adjuvant and progression within 12 months), the median progression-free survival was 4.8 months (compared to 1.7 months with single-agent chemotherapy) and the median overall survival was 11.8 months (compared to 6.9 months with single-agent chemotherapy).In early-stage clinical trials in patients with locally advanced or mUC previously treated with platinum-containing chemotherapy, e.g., cisplatin, carboplatin, or oxaliplatin and a PD-1 inhibitor or PD-L1 inhibitor, the overall response rate was 27.7% and the median duration of response was 7.1 months.

[0019] Despite these encouraging results, administration of sacituzumab govitecan is associated with serious adverse side effects, and its U.S. FDA-approved label contains a "black box warning" regarding the occurrence of severe, life-threatening, or fatal neutropenia and severe diarrhea. As reported in the U.S. FDA-approved label for sacituzumab govitecan-Hyzy (Trodelvy®), neutropenia occurred in 61% of patients treated with sacituzumab govitecan-Hyzy. Grade 3-4 neutropenia occurred in 47% of patients. Febrile neutropenia occurred in 7% of patients. Diarrhea occurred in 65% of all patients treated with Trodelvy®. Grade 3-4 diarrhea occurred in 12% of all patients treated with Trodelvy®. One patient developed intestinal perforation following diarrhea. Neutropenic colitis occurred in 0.5% of patients. Other side effects associated with the use of sacituzumab govitecan-Hyzy include fatigue, alopecia, acute kidney injury, infections, anemia, and thrombocytopenia.

[0020] Importantly, these side effects can be life-threatening or fatal, as well as dose-limiting or treatment discontinuation. For example, sacituzumab govitecan was permanently discontinued due to adverse reactions in 5% of patients with mTNBC enrolled in the ASCENT trial. Forty-five percent of patients in the ASCENT trial experienced adverse reactions leading to treatment discontinuation, and 22% experienced adverse reactions leading to dose reduction. Discontinuation or dose reduction of sacituzumab govitecan may result in reduced efficacy and contribute to the development and progression of disease resistance. Granulocyte colony-stimulating factor (G-CSF) was used as salvage therapy in 44% of patients in the ASCENT trial.

[0021] With limited treatment options already available for patients with TNBC and mUC that have progressed despite standard and newly approved therapies, the toxicity of sacituzumab govitecan poses a major obstacle to its consistent, long-term use as a treatment. Summary of the Invention

[0022] Summary of the Invention The present invention provides an improved method for treating human patients with Trop-2 overexpressing cancers, such as advanced and / or metastatic triple-negative breast cancer (TNBC) or recurrent or metastatic urothelial carcinoma (mUC), or even NSCLC, in certain selected patient subgroups by administering the short-acting, selective and reversible cyclin-dependent kinase (CDK) 4 / 6 inhibitor trilaciclib, or a pharmacologic acceptable salt thereof, together with sacituzumab govitecan (sacituzumab govitecan-Hyzy; also known as Trodelvy®), or a biosimilar thereof, in a specific timed treatment protocol, wherein trilaciclib is administered within 24 hours, e.g., within about 4 hours, prior to administration of sacituzumab govitecan. The inclusion of the select CDK4 / 6 inhibitor trilaciclib (also known as Cosera®) in a sacituzumab-govitecan treatment regimen may provide improved survival outcomes, including overall survival (OS) and / or progression-free survival (PFS). Importantly, the inclusion of trilaciclib in a sacituzumab-govitecan treatment regimen significantly reduces toxicity for these hard-to-treat patients compared to sacituzumab-govitecan alone, including reduction or prevention of chemotherapy-induced myelosuppression (CIM), reduction or prevention of chemotherapy-induced neutropenia, reduction or prevention of chemotherapy-induced anemia, reduction or prevention of chemotherapy-induced mucositis, reduction or prevention of chemotherapy-induced diarrhea, reduction or prevention of chemotherapy-induced stomatitis, reduction or prevention of chemotherapy-induced gastrointestinal disorders, and / or reduction or prevention of alopecia.

[0023] Without wishing to be bound by any single theory, it is believed that trilaciclib administered prior to sacituzumab govitecan induces antitumor immune enhancement by differentially shutting down CD8+ T cell and Treg subsets while protecting the bone marrow from the cytotoxic effects of sacituzumab govitecan, and then allowing faster recovery of CD8+ T cells than Tregs in the tumor microenvironment. These mechanisms result in both improved safety with significantly reduced side effects and antitumor activity. In addition, trilaciclib administered prior to sacituzumab govitecan is believed to protect other CDK4 / 6 replication-dependent heathy cells, such as epithelial cells of the gastrointestinal tract. Protecting these cells from the significant side effects of sacituzumab govitecan could expand the use of sacituzumab govitecan by reducing dose delays, reducing dose reductions, and reducing treatment discontinuations in this difficult-to-treat population. Furthermore, trilaciclib can be combined with sacituzumab govitecan to reduce the use of salvage therapies, such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or erythropoiesis-stimulating agents. Thus, administration of trilaciclib prior to sacituzumab govitecan may improve antitumor efficacy while minimizing bone marrow toxicity in patients with Trop-2-expressing tumors.

[0024] Early results from an early human clinical trial (see, e.g., NCT05113966) have demonstrated the ability of trilaciclib to dramatically reduce side effects associated with sacituzumab govitecan administration, including a reduction in the incidence of severe (grade 3 / 4) neutropenia (see, e.g., Example 1, Figure 2A). In the initial study, eight female patients (median age 55.0 years) were enrolled and completed a median of three (range 1-6) 21-day cycles in which sacituzumab govitecan was administered on days 1 and 8 of each 21-day cycle and trilaciclib was administered intravenously 30 minutes within 4 hours prior to sacituzumab govitecan administration on days 1 and 8 of each 21-day cycle (see, e.g., Figure 1). All patients had received a taxane, and seven had received an immune checkpoint inhibitor (atezolizumab, n = 5; pembrolizumab, n = 2; adjuvant therapy, n = 4; metastatic therapy, n = 3). Only one patient experienced severe (grade 3 / 4) neutropenia (52% in the ASCENT study vs. 12.5% ​​with trilaciclib). No patients had grade 3 / 4 anemia or thrombocytopenia, and no patients had febrile neutropenia or severe infections. Granulocyte colony-stimulating factor was administered in two patients (25%), and one required intravenous antibiotics. No patients required red blood cell / platelet transfusions or erythropoietin stimulating agents. No patients withdrew due to adverse events, and no severe adverse events have been reported to date. The only treatment-related adverse event was diarrhea. Thus, from this initial study, the combination of trilaciclib dramatically reduces the side effects associated with sacituzumab-govitecan.

[0025] Metastatic / Locally Advanced Triple-Negative Breast Cancer In one aspect, provided herein is an improved method of treating metastatic and / or progressive triple-negative breast cancer, comprising administering trilaciclib, or a pharma- ceutically acceptable salt thereof, in combination with sacituzumab govitecan to a human patient with metastatic or locally progressive triple-negative breast cancer, where trilaciclib is administered prior to administration of sacituzumab govitecan, e.g., about 24 hours, 18 hours, 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, or 30 minutes prior to administration of sacituzumab govitecan. In some embodiments, the patient has had at least two prior chemotherapy treatments, at least one of which is in the metastatic setting.

[0026] In some embodiments, the method comprises administering to a TNBC patient an effective amount of trilaciclib on days 1 and 8 and administering an effective amount of sacituzumab govitecan on days 1 and 8 of a 21-day chemotherapy treatment cycle, where trilaciclib is administered prior to administration of sacituzumab govitecan. In some embodiments, trilaciclib is administered 18 hours, 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, or 30 minutes prior to administration of sacituzumab govitecan. In some embodiments, trilaciclib is administered within about 4 hours prior to administration of sacituzumab govitecan. In some embodiments, the 21-day therapeutic treatment cycle is repeated at least 2 times, at least 4 times, at least 6 times, at least 8 times, at least 10 times, at least 12 times, at least 14 times, at least 16 times, at least 18 times, at least 20 times, at least 22 times, at least 24 times, at least 26 times, at least 28 times, at least 30 times, at least 32 times, at least 34 times, or more than 34 times. In some embodiments, the 21-day treatment is repeated up to 34 times. In some embodiments, the 21-day therapeutic treatment cycle is repeated or continuous until disease progression.

[0027] In some embodiments, the method comprises administering to a TNBC patient an effective amount of trilaciclib on days 1, 8, and 15 of a 21-day chemotherapy treatment cycle, and administering an effective amount of sacituzumab govitecan on days 1 and 8, wherein trilaciclib is administered prior to administration of sacituzumab govitecan on days 1 and 8. In some embodiments, trilaciclib is administered 18 hours, 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, or 30 minutes prior to administration of sacituzumab govitecan on days 1 and 8. In some embodiments, trilaciclib is administered within about 4 hours prior to administration of sacituzumab govitecan. In some embodiments, the 21-day therapeutic treatment cycle is repeated at least 2 times, at least 4 times, at least 6 times, at least 8 times, at least 10 times, at least 12 times, at least 14 times, at least 16 times, at least 18 times, at least 20 times, at least 22 times, at least 24 times, at least 26 times, at least 28 times, at least 30 times, at least 32 times, at least 34 times, or more than 34 times. In some embodiments, the 21-day treatment is repeated up to 34 times. In some embodiments, the 21-day therapeutic treatment cycle is repeated or continuous until disease progression.

[0028] In some embodiments, the method comprises administering to a patient with advanced / metastatic TNBC an effective amount of trilaciclib on days 1 and 8 and an effective amount of sacituzumab govitecan on days 1 and 8 of a 21-day chemotherapy treatment cycle as a third line therapy, where trilaciclib is administered prior to administration of sacituzumab govitecan. In some embodiments, trilaciclib is administered 18 hours, 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, or 30 minutes prior to administration of sacituzumab govitecan. In some embodiments, trilaciclib is administered within about 4 hours prior to administration of sacituzumab govitecan. In some embodiments, the 21-day therapeutic treatment cycle is repeated at least 2 times, at least 4 times, at least 6 times, at least 8 times, at least 10 times, at least 12 times, at least 14 times, at least 16 times, at least 18 times, at least 20 times, at least 22 times, at least 24 times, at least 26 times, at least 28 times, at least 30 times, at least 32 times, at least 34 times, or more than 34 times. In some embodiments, the 21-day treatment is repeated up to 34 times. In some embodiments, the 21-day therapeutic treatment cycle is repeated or continuous until disease progression.

[0029] In some embodiments, the method comprises administering to a patient with advanced / metastatic TNBC an effective amount of trilaciclib on days 1, 8, and 15 of a 21-day chemotherapy treatment cycle, and administering an effective amount of sacituzumab govitecan on days 1 and 8, as a third line therapy, wherein trilaciclib is administered prior to administration of sacituzumab govitecan on days 1 and 8. In some embodiments, trilaciclib is administered 18 hours, 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, or 30 minutes prior to administration of sacituzumab govitecan on days 1 and 8. In some embodiments, trilaciclib is administered within about 4 hours prior to administration of sacituzumab govitecan. In some embodiments, the 21-day therapeutic treatment cycle is repeated at least 2 times, at least 4 times, at least 6 times, at least 8 times, at least 10 times, at least 12 times, at least 14 times, at least 16 times, at least 18 times, at least 20 times, at least 22 times, at least 24 times, at least 26 times, at least 28 times, at least 30 times, at least 32 times, at least 34 times, or more than 34 times. In some embodiments, the 21-day treatment is repeated up to 34 times. In some embodiments, the 21-day therapeutic treatment cycle is repeated or continuous until disease progression.

[0030] In some embodiments, prior to administration of sacituzumab govitecan, patients are premedicated to prevent infusion reactions and chemotherapy-induced nausea and vomiting (CINV). In some embodiments, prior to administration of sacituzumab govitecan, patients are premedicated with an antipyretic, a histamine receptor 1 (H1) and histamine receptor 2 (H2) blocker, and a corticosteroid to prevent infusion reactions. In some embodiments, prior to administration of sacituzumab govitecan, patients are premedicated with a combination of dexamethasone and a serotonin 5-HT3 receptor antagonist or a neurokinin 1 (NK1) receptor antagonist to prevent chemotherapy-induced nausea and vomiting (CINV).

[0031] In some embodiments, patients treated with the sacituzumab govitecan / trilaciclib dosing protocol have TNBC that is CDK4 / 6 positive. In some embodiments, the TNBC being treated is CDK4 / 6 negative. In some embodiments, the TNBC being treated has the following characteristics: a, CCNE1 amplification; b. CCNE2 amplification; or Retinoblastoma protein 1 (Rb1) deficiency, defined as ci) homozygous deletion, ii) frameshift mutation, or iii) stop-gain mutation (i.e., a mutation resulting in a premature stop codon (acquisition of a stop codon) In yet another embodiment, the TNBC is CDK4 / 6-deficient. In some embodiments, the patient is treated as a third line therapy.

[0032] In some embodiments, patients treated with the trilaciclib / sacituzumab govitecan protocol have documented PD-L1 status positive TNBC. In some embodiments, patients treated have documented PD-L1 status positive PD-L1 stained tumor infiltrating immune cells or tumor cells confirmed by an in vitro diagnostic (IVD) assay, e.g., the Ventana SP-142 assay or I IHC 22C3 pharmDx PDL1 assay or other approved assay.

[0033] In some embodiments, patients treated in the trilaciclib / sacituzumab-govitecan chemotherapy protocol described herein have documented disease progression during or after two lines of systemic therapy for NBC. In some embodiments, one line of prior therapy in either the neoadjuvant, adjuvant, or advanced / metastatic setting is with a taxane therapy. In some embodiments, the taxane therapy is paclitaxel. In some embodiments, the taxane therapy is docetaxel. In some embodiments, one line of prior therapy in either the neoadjuvant, adjuvant, or advanced / metastatic setting is with an anthracycline therapy. In some embodiments, the anthracycline therapy is doxorubicin. In some embodiments, the anthracycline therapy is daunorubicin. In some embodiments, the anthracycline therapy is idarubicin. In some embodiments, the anthracycline therapy is epirubicin. In some embodiments, the anthracycline therapy is mitoxantrone.

[0034] In some embodiments, the one line of prior therapy in either the neoadjuvant, adjuvant, or advanced / metastatic setting prior to administration of trilaciclib / sacituzumab govitecan is with a platinum-based chemotherapy, including but not limited to cisplatin, carboplatin, oxaliplatin, nedaplatin, satraplatin, platinum, and lobaplatin. In some embodiments, the platinum-based chemotherapy is carboplatin. In some embodiments, the platinum-based chemotherapy is cisplatin. In some embodiments, the one line of prior therapy in either the neoadjuvant, adjuvant, or advanced / metastatic setting is with antimetabolite chemotherapy. In some embodiments, the antimetabolite chemotherapy is gemcitabine. In some embodiments, the antimetabolite chemotherapy is capecitabine. In some embodiments, the one line of prior therapy in either the neoadjuvant, adjuvant, or advanced / metastatic setting is with a microtubule inhibitor. In some embodiments, the microtubule inhibitor is eribulin. In some embodiments, the microtubule inhibitor is vinorelbine. In some embodiments, the microtubule inhibitor is ixabepilone. In some embodiments, the first line of prior therapy in either neoadjuvant, adjuvant or advanced / metastatic therapy is with an alkylating agent. In some embodiments, the alkylating agent is cyclophosphamide. In some embodiments, the first line of prior therapy in either neoadjuvant, adjuvant or advanced / metastatic therapy for patients with documented germline BRCA1 / BRCA2 mutations is with a poly ADP-ribose polymerase (PARP) inhibitor. In some embodiments, the PARP inhibitor is olaparib. In some embodiments, the PARP inhibitor is talazoparib.

[0035] In some embodiments, the first line of prior therapy in either neoadjuvant, adjuvant or advanced / metastatic therapy for patients with positive PD1 or PDL1 status is a PD-1 or PDL1 inhibitor. In some embodiments, the PD-1 inhibitor is pembrolizumab. In some embodiments, the PD-1 inhibitor is nivolumab. In some embodiments, the PD-1 inhibitor is cemiplimab. In some embodiments, the PD-1 inhibitor is CS1003. In some embodiments, the PD-1 inhibitor is tislelizumab. In some embodiments, the PD-1 inhibitor is dostarlimab. In some embodiments, the PD-1 inhibitor is JTX-4014. In some embodiments, the PD-1 inhibitor is spartalizumab. In some embodiments, the PD-1 inhibitor is camrelizumab. In some embodiments, the PD-1 inhibitor is sintilimab. In some embodiments, the PD-1 inhibitor is toripalimab. In some embodiments, the PD-1 inhibitor is retifanlimab. In some embodiments, the PD-1 inhibitor is AMP-224. In some embodiments, the PD-1 inhibitor is AMP-514. In some embodiments, the PD-1 inhibitor is pidilizumab. In some embodiments, the PD-1 inhibitor is sasunlimab. In some embodiments, the PD-1 inhibitor is zimblerelimab. In some embodiments, the PD-L1 inhibitor is atezolizumab. In some embodiments, the PD-L1 inhibitor is avelumab. In some embodiments, the PD-L1 inhibitor is durvalumab. In some embodiments, the PD-L1 inhibitor is sugemalimab. In some embodiments, the PD-L1 inhibitor is embafolimab. In some embodiments, the PD-L1 inhibitor is cosibelimab. In some embodiments, the PD-L1 inhibitor is AUNP12. In some embodiments, the PD-L1 inhibitor is CA-170. In some embodiments, the PD-L1 inhibitor is BMS-986189. In some embodiments, the PD-L1 inhibitor is BMS-936559.In some embodiments, the PD-L1 inhibitor is lodapolimab. In some embodiments, the PD-L1 inhibitor is adebrerimab. In some embodiments, the PD-L1 inhibitor is CBT-502. In some embodiments, the PD-L1 inhibitor is BGB-A33.

[0036] Metastatic urothelial carcinoma (mUC) In another aspect, the improved method comprises administering mUC trilaciclib or a pharma- ceutically acceptable salt thereof in combination with sacituzumab govitecan to a patient, where trilaciclib is administered prior to administration of sacituzumab govitecan, e.g., about 24 hours, 18 hours, 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, or 30 minutes prior to administration of sacituzumab govitecan. In some embodiments, the trilaciclib / sacituzumab govitecan combination is administered to a patient as second- or third-line therapy for advanced / metastatic urothelial carcinoma that has been exposed to 1) platinum-containing chemotherapy as a recurrent or metastatic therapy, and 2) an immune checkpoint inhibitor, e.g., a PD-1 or PD-L1 inhibitor, as monotherapy or in combination with a first-line chemotherapy regimen, and has experienced disease progression.

[0037] In certain embodiments, the method comprises administering to the patient an effective amount of trilaciclib on days 1 and 8, and an effective amount of sacituzumab govitecan-hygiene on days 1 and 8 of a 21-day trilaciclib / sacituzumab govitecan treatment cycle, where trilaciclib is administered within about 4 hours prior to administration of sacituzumab govitecan. In some embodiments, trilaciclib is administered 18 hours, 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, or 30 minutes prior to administration of sacituzumab govitecan. In some embodiments, trilaciclib is administered within about 4 hours prior to administration of sacituzumab govitecan. In some embodiments, the 21-day therapeutic treatment cycle is repeated at least 2 times, at least 4 times, at least 6 times, at least 8 times, at least 10 times, at least 12 times, at least 14 times, at least 16 times, at least 18 times, at least 20 times, at least 22 times, at least 24 times, at least 26 times, at least 28 times, at least 30 times, at least 32 times, at least 34 times, or more than 34 times. In some embodiments, the 21-day trilaciclib / sacituzumab govitecan treatment cycle is repeated up to 34 times. In some embodiments, the 21-day trilaciclib / sacituzumab govitecan treatment cycle is repeated continuously. In some embodiments, the 21-day trilaciclib / sacituzumab govitecan treatment cycle is repeated until disease progression.

[0038] In another embodiment, the method comprises administering to the patient an effective amount of trilaciclib on days 1, 8, and 15, and an effective amount of sacituzumab govitecan-hygiene on days 1 and 8 of a 21-day trilaciclib / sacituzumab govitecan treatment cycle, wherein trilaciclib is administered within about 4 hours prior to administration of sacituzumab govitecan on days 1 and 8. In some embodiments, trilaciclib is administered 18 hours, 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, or 30 minutes prior to administration of sacituzumab govitecan. In some embodiments, trilaciclib is administered within about 4 hours prior to administration of sacituzumab govitecan. In some embodiments, the 21-day therapeutic treatment cycle is repeated at least 2 times, at least 4 times, at least 6 times, at least 8 times, at least 10 times, at least 12 times, at least 14 times, at least 16 times, at least 18 times, at least 20 times, at least 22 times, at least 24 times, at least 26 times, at least 28 times, at least 30 times, at least 32 times, at least 34 times, or more than 34 times. In some embodiments, the 21-day trilaciclib / sacituzumab govitecan treatment cycle is repeated up to 34 times. In some embodiments, the 21-day trilaciclib / sacituzumab govitecan treatment cycle is repeated continuously. In some embodiments, the 21-day trilaciclib / sacituzumab govitecan treatment cycle is repeated until disease progression.

[0039] In some embodiments, prior to administration of trilaciclib / sacituzumab govitecan, patients are premedicated for infusion reactions and chemotherapy-induced nausea and vomiting (CINV). In some embodiments, prior to administration of trilaciclib / sacituzumab govitecan, patients are premedicated with antipyretics, histamine receptor 1 (H1) and histamine receptor 2 (H2) blockers, and corticosteroids for infusion reactions. In some embodiments, prior to administration of trilaciclib / sacituzumab govitecan, patients are premedicated with dexamethasone in combination with either a serotonin 5-HT3 receptor antagonist or a neurokinin 1 (NK1) receptor antagonist for chemotherapy-induced nausea and vomiting (CINV).

[0040] In some embodiments, the patient has mUC that is CDK4 / 6 positive. In another embodiment, the mUC to be treated is CDK4 / 6 negative. In some embodiments, the mUC to be treated has the following characteristics: a, CCNE1 amplification; b. CCNE2 amplification; or Retinoblastoma protein 1 (Rb1) deficiency, defined as ci) homozygous deletion, ii) frameshift mutation, or iii) stop-gain mutation (i.e., a mutation resulting in a premature stop codon (acquisition of a stop codon) In another embodiment, the mUC being treated is CDK4 / 6 positive. In yet another embodiment, the mUC is CDK4 / 6 indeterminate.

[0041] In some embodiments, patients with mUC treated with a second-line or third-line trilaciclib / sacituzumab govitecan protocol have a documented PD-L1 status positive mUC. In some embodiments, patients treated with a second-line or third-line trilaciclib / sacituzumab govitecan protocol have a documented PD-L1 status positive mUC as confirmed by an in vitro diagnostic (IVD) assay, e.g., the Ventana SP-142 assay or the I IHC 22C3 pharmDx PDL1 assay or other approved assay, with greater than 10% of PD-L1 stained tumor-infiltrating immune cells or greater than 50% of tumor cells. In some embodiments, patients treated with second-line or third-line trilaciclib / sacituzumab govitecan dosing protocols have a documented PD-L1 status positive mUC with PD-L1 staining of greater than 20% of tumor cells as determined by an in vitro diagnostic (IVD) assay, e.g., the Ventana SP-142 assay or the I IHC 22C3 pharmDx PDL1 assay. In another embodiment, patients treated with second-line or third-line trilaciclib / sacituzumab govitecan chemotherapy protocols have a documented PD-L1 status positive with PD-L1 staining of greater than 1% of tumor cells as determined by an FDA approved test. In another embodiment, patients treated with second-line or third-line antibody drug conjugate chemotherapy protocols have a documented PD-L1 status negative mUC. In another embodiment, patients treated with second-line or third-line antibody drug conjugate chemotherapy protocols have a documented PD-L1 status negative mUC with PD-L1 staining of less than or equal to 1% of tumor cells as determined by an FDA approved test.

[0042] In some embodiments, mUC patients treated with second-line or third-line trilaciclib / sacituzumab-govitecan dosing protocols have been previously treated with a platinum-containing chemotherapy protocol and an ICI inhibitor. In some embodiments, the platinum-containing chemotherapy is cisplatin and gemcitabine. In some embodiments, the platinum-containing chemotherapy is cisplatin, methotrexate, vinblastine, and doxorubicin. In some embodiments, the platinum-containing chemotherapy is cisplatin, gemcitabine, and paclitaxel. In some embodiments, the platinum-containing chemotherapy is carboplatin and gemcitabine. In some embodiments, the platinum-containing chemotherapy is carboplatin, methotrexate, vinblastine, and doxorubicin. In some embodiments, the ICI is a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is nivolumab. In some embodiments, the PD-1 inhibitor is cemiplimab. In some embodiments, the PD-1 inhibitor is CS1003. In some embodiments, the PD-1 inhibitor is tislelizumab. In some embodiments, the PD-1 inhibitor is dostarlimab. In some embodiments, the PD-1 inhibitor is JTX-4014. In some embodiments, the PD-1 inhibitor is spartalizumab. In some embodiments, the PD-1 inhibitor is camrelizumab. In some embodiments, the PD-1 inhibitor is sintilimab. In some embodiments, the PD-1 inhibitor is toripalimab. In some embodiments, the PD-1 inhibitor is retifanlimab. In some embodiments, the PD-1 inhibitor is AMP-224. In some embodiments, the PD-1 inhibitor is AMP-514. In some embodiments, the PD-1 inhibitor is pidilizumab. In some embodiments, the PD-1 inhibitor is sasanlimab. In some embodiments, the PD-1 inhibitor is zimblerelimab.

[0043] In some embodiments, the PD-L1 inhibitor is atezolizumab. In some embodiments, the PD-L1 inhibitor is avelumab. In some embodiments, the PD-L1 inhibitor is durvalumab. In some embodiments, the PD-L1 inhibitor is sugemalimab. In some embodiments, the PD-L1 inhibitor is embafolimab. In some embodiments, the PD-L1 inhibitor is cosibelimab. In some embodiments, the PD-L1 inhibitor is AUNP12. In some embodiments, the PD-L1 inhibitor is CA-170. In some embodiments, the PD-L1 inhibitor is BMS-986189. In some embodiments, the PD-L1 inhibitor is BMS-936559. In some embodiments, the PD-L1 inhibitor is lodapolimab. In some embodiments, the PD-L1 inhibitor is adebulerimab. In some embodiments, the PD-L1 inhibitor is CBT-502. In some embodiments, the PD-L1 inhibitor is BGB-A33.

[0044] Targeting additional Trop-2-overexpressing cancers In another aspect, the present disclosure comprises administering trilaciclib, or a pharma- ceutically acceptable salt thereof, in combination with sacituzumab govitecan to a patient having advanced / metastatic cancer that overexpresses Trop-2, wherein trilaciclib is administered about 24 hours, 18 hours, 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, or 30 minutes prior to administration of sacituzumab govitecan, to a patient having advanced / metastatic cancer that overexpresses Trop-2, The present invention provides methods for treating cancer selected from the group consisting of breast cancer, cervical cancer, colon or colorectal cancer, endometrioid endometrial cancer, esophageal cancer, gastric cancer, glioma, hilar cholangiocarcinoma, oral squamous cell carcinoma, gastrointestinal cancer, chronic lymphocytic lymphoma, extranodal NK / T cell lymphoma, non-Hodgkin's lymphoma, Raji Burkitt's lymphoma, small lung adenocarcinoma, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, thyroid cancer, uterine cancer, and lung cancer, including small cell lung cancer and non-small cell lung cancer. In some embodiments, the patient has endometrial cancer. In some embodiments, the patient has bladder cancer. In some embodiments, the patient has prostate cancer. In some embodiments, the patient has HR+ / HER2- metastatic breast cancer.

[0045] In some embodiments, the Trop-2 overexpressing cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the NSCLC is metastatic or progressive NSCLC. In some embodiments, the NSCLC has progressed during or after receiving platinum-based chemotherapy and PD-1 or PD-L1 inhibitor therapy, either in combination or sequentially.

[0046] In some embodiments, the method comprises administering to a patient having a cancer that overexpresses Trop-2 an effective amount of trilaciclib on days 1 and 8, and an effective amount of sacituzumab govitecan on days 1 and 8 of a 21-day trilaciclib / sacituzumab govitecan treatment cycle, wherein trilaciclib is administered within about 4 hours prior to administration of sacituzumab govitecan. In some embodiments, trilaciclib is administered 18 hours, 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, or 30 minutes prior to administration of sacituzumab govitecan. In some embodiments, trilaciclib is administered within about 4 hours prior to administration of sacituzumab govitecan. In some embodiments, the 21-day therapeutic treatment cycle is repeated at least 2 times, at least 4 times, at least 6 times, at least 8 times, at least 10 times, at least 12 times, at least 14 times, at least 16 times, at least 18 times, at least 20 times, at least 22 times, at least 24 times, at least 26 times, at least 28 times, at least 30 times, at least 32 times, at least 34 times, or more than 34 times. In some embodiments, the 21-day treatment is repeated up to 34 times. In some embodiments, the 21-day trilaciclib / sacituzumab govitecan treatment cycle is repeated continuously. In some embodiments, the 21-day trilaciclib / sacituzumab govitecan treatment cycle is repeated until disease progression. In some embodiments, the Trop-2 overexpressing cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the NSCLC is metastatic or progressive NSCLC. In some embodiments, the NSCLC has progressed during or after receiving platinum-based chemotherapy and PD-1 or PD-L1 inhibitor therapy, either concomitantly or sequentially.

[0047] In another embodiment, the method comprises administering to a patient having a cancer that overexpresses Trop-2 an effective amount of trilaciclib on days 1, 8, and 15, and an effective amount of sacituzumab govitecan on days 1 and 8 of a 21-day trilaciclib / sacituzumab govitecan treatment cycle, where trilaciclib is administered within about 4 hours prior to administration of sacituzumab govitecan. In some embodiments, trilaciclib is administered 18 hours, 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, or 30 minutes prior to administration of sacituzumab govitecan. In some embodiments, trilaciclib is administered within about 4 hours prior to administration of sacituzumab govitecan on days 1 and 8. In some embodiments, the 21-day therapeutic treatment cycle is repeated at least 2 times, at least 4 times, at least 6 times, at least 8 times, at least 10 times, at least 12 times, at least 14 times, at least 16 times, at least 18 times, at least 20 times, at least 22 times, at least 24 times, at least 26 times, at least 28 times, at least 30 times, at least 32 times, at least 34 times, or more than 34 times. In some embodiments, the 21-day treatment is repeated up to 34 times. In some embodiments, the 21-day trilaciclib / sacituzumab govitecan treatment cycle is repeated continuously. In some embodiments, the 21-day trilaciclib / sacituzumab govitecan treatment cycle is repeated until disease progression. In some embodiments, the Trop-2 overexpressing cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the NSCLC is metastatic or progressive NSCLC. In some embodiments, the NSCLC has progressed during or after receiving platinum-based chemotherapy and PD-1 or PD-L1 inhibitor therapy, either concomitantly or sequentially.

[0048] In some embodiments, the patient has a Trop-2 overexpressing cancer that is CDK4 / 6 positive. In another embodiment, the Trop-2 overexpressing cancer to be treated is CDK4 / 6 negative. In some embodiments, the Trop-2 overexpressing cancer to be treated has the following characteristics: a, CCNE1 amplification; b. CCNE2 amplification; or Retinoblastoma protein 1 (Rb1) deficiency, defined as ci) homozygous deletion, ii) frameshift mutation, or iii) stop-gain mutation (i.e., a mutation resulting in a premature stop codon (acquisition of a stop codon) In another embodiment, the Trop-2 overexpressing cancer to be treated is CDK4 / 6 positive. In yet another embodiment, the Trop-2 overexpressing cancer is CDK4 / 6 indeterminate.

[0049] In some embodiments, patients with Trop-2 overexpressing cancer treated with the trilaciclib / sacituzumab govitecan protocol have a documented Trop-2 overexpressing cancer with a positive PD-L1 status. In some embodiments, the patients being treated have a documented PD-L1 stained tumor infiltrating immune cells or tumor cells with a positive PD-L1 status as confirmed by an in vitro diagnostic (IVD) assay, e.g., the Ventana SP-142 assay or the I IHC 22C3 pharmDx PDL1 assay or other approved assay.

[0050] In some embodiments, the above methods for the treatment of TNBC, mUC, and / or Trop-2 expressing cancer further comprise administration of an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is selected from a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a TIM3 inhibitor, a TIGIT inhibitor, a LAG3 inhibitor, a VISTA inhibitor, or a SIGLEC7 inhibitor. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is nivolumab. In some embodiments, the PD-1 inhibitor is cemiplimab. In some embodiments, the PD-1 inhibitor is CS1003. In some embodiments, the PD-1 inhibitor is tislelizumab. In some embodiments, the PD-1 inhibitor is dostarlimab. In some embodiments, the PD-1 inhibitor is JTX-4014. In some embodiments, the PD-1 inhibitor is spartalizumab. In some embodiments, the PD-1 inhibitor is camrelizumab. In some embodiments, the PD-1 inhibitor is sintilimab. In some embodiments, the PD-1 inhibitor is toripalimab. In some embodiments, the PD-1 inhibitor is retifanlimab. In some embodiments, the PD-1 inhibitor is AMP-224. In some embodiments, the PD-1 inhibitor is AMP-514. In some embodiments, the PD-1 inhibitor is pidilizumab. In some embodiments, the PD-1 inhibitor is sasanlimab. In some embodiments, the PD-1 inhibitor is zimblerelimab. In some embodiments, the PD-L1 inhibitor is atezolizumab. In some embodiments, the PD-L1 inhibitor is avelumab. In some embodiments, the PD-L1 inhibitor is durvalumab. In some embodiments, the PD-L1 inhibitor is sugemalimab. In some embodiments, the PD-L1 inhibitor is embafolimab. In some embodiments, the PD-L1 inhibitor is cosibelimab. In some embodiments, the PD-L1 inhibitor is AUNP12.In some embodiments, the PD-L1 inhibitor is CA-170. In some embodiments, the PD-L1 inhibitor is BMS-986189. In some embodiments, the PD-L1 inhibitor is BMS-936559. In some embodiments, the PD-L1 inhibitor is lodapolimab. In some embodiments, the PD-L1 inhibitor is adebrerimab. In some embodiments, the PD-L1 inhibitor is CBT-502. In some embodiments, the PD-L1 inhibitor is BGB-A33. In some embodiments, the immune checkpoint inhibitor is administered on day 1 of a 21 day cycle. In some embodiments, the immune checkpoint inhibitor is administered every 2 weeks. In some embodiments, the immune checkpoint inhibitor is administered every 4 weeks. In some embodiments, the immune checkpoint inhibitor is administered every 6 weeks.

[0051] In some embodiments, the methods described herein for the treatment of TNBC, mUC, or Trop-2-expressing tumors do not include the further administration of an immune checkpoint inhibitor.

[0052] Improved patient outcomes By administering trilaciclib in combination with sacituzumab govitecan as described herein, one or more mechanisms leading to resistance and disease progression are overcome and result in enhanced antigen presentation (major histocompatibility complex (MHC) class I), enhanced T cell clonality and tumor infiltration, inhibition of regulatory T cell proliferation, reduced expression of T cell exhaustion markers such as, but not limited to, PD-1, cytotoxic T lymphocyte-associated protein 4 (CTLA-4), or T cell immunoglobulin and mucin domain 3 (TIM3), stabilized expression of PD-L1 on tumor cells, enhanced dendritic cell migration, or enhanced T effector cell function via increased interferon-γ (IFN-γ) production, collectively resulting in a robust antitumor T cell response. Additionally, administering trilaciclib in combination with sacituzumab govitecan as described herein may result in reduced side effects attributable to sacituzumab govitecan, leading to fewer treatment discontinuations. By administering trilaciclib to these difficult-to-treat subgroups of patients, we may be able to largely overcome treatment discontinuation and the immunosuppressive tumor microenvironment within their tumors that renders previous chemotherapy and / or ICIs ineffective or ineffective and allows tumor progression, improving the ability of the patient's immune system to reduce or control tumor burden, improving quality of life, and improving overall survival for this difficult-to-treat subset of patients.

[0053] In some embodiments, administration of the trilaciclib / sacituzumab govitecan treatment regimen described herein to the patient subgroups described herein provides enhanced anti-tumor efficacy in patients with TNBC, mUC, or other Trop-2 overexpressing cancers. In some embodiments, administration of the trilaciclib / sacituzumab govitecan treatment regimen described herein in the specific patient subgroups described above provides patients with improved progression-free survival (PFS) and / or overall survival (OS) compared to patients receiving sacituzumab govitecan without trilaciclib. In some embodiments, the improved PFS is based on Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). In some embodiments, administration of trilaciclib in combination with sacituzumab govitecan improves the overall response rate (ORR, defined as the percentage of patients experiencing a best overall response (BOR) of complete response (CR) or partial response (PR) per RECIST v1.1) in a recipient patient population compared to a patient population receiving sacituzumab govitecan alone. In some embodiments, administration of trilaciclib in combination with sacituzumab govitecan improves the clinical benefit rate (CBR), defined as the percentage of patients experiencing a BOR of CR, PR, or stable disease (SD) sustained for at least 24 weeks since the first day of trilaciclib / sacituzumab govitecan administration per RECIST v1.1 in a recipient patient population compared to a patient population receiving sacituzumab govitecan alone. In some embodiments, administration of trilaciclib in combination with sacituzumab govitecan improves duration of response (DOR), defined as the time from first objective response of CR or confirmed PR (CR) to the date of first documented disease progression or death, whichever occurs first, in a recipient population compared to a patient population receiving sacituzumab govitecan alone, as appropriate for each treatment period as described for ORR.

[0054] In some embodiments, administration of the trilaciclib / sacituzumab-govitecan treatment regimen described herein to the above patient subgroups provides bone marrow preservation of hematopoietic stem and progenitor cells (HSPCs) and immune effector cells, e.g., lymphocytes, including T lymphocytes. In some embodiments, administration of the trilaciclib / sacituzumab-govitecan treatment regimen described herein to the above patient subgroups provides reduced chemotherapy-induced myelosuppression (CIM). In some embodiments, administration of the trilaciclib / sacituzumab-govitecan treatment regimen described herein provides bone marrow preservation of neutrophil lineages in patients compared to patients receiving sacituzumab-govitecan without trilaciclib. In some embodiments, administration of a trilaciclib / sacituzumab govitecan treatment regimen described herein provides a patient with a reduction in the duration of severe (Grade 4) neutropenia compared to patients receiving sacituzumab govitecan without trilaciclib. In some embodiments, administration of a trilaciclib / sacituzumab govitecan treatment regimen described herein provides a patient with a reduction in diarrhea compared to patients receiving sacituzumab govitecan without trilaciclib.

[0055] In some embodiments, administration of the trilaciclib / sacituzumab govitecan treatment regimen described herein to the above patient subgroups provides a reduction or improvement in one or more of the following in the recipient patient population compared to a patient population receiving sacituzumab govitecan without trilaciclib: diarrhea, incidence of severe neutropenia (SN); incidence of febrile neutropenia; incidence of G-CSF administration; incidence of grade 3 / 4 hemoglobin decline; red blood cell (RBC) transfusion after week 5; incidence of erythropoietin stimulating agent (ESA) administration; incidence of grade 3 / 4 platelet decline; platelet transfusions (incidence and number of transfusions); alopecia; incidence of severe infections; or IV antibiotic use.

[0056] In some embodiments, administration of the trilaciclib / sacituzumab govitecan treatment regimen described herein to the above patient subgroups provides the recipient patient population with a reduction or improvement in one or more of the following, compared to a patient population receiving sacituzumab govitecan without trilaciclib: occurrence and severity of adverse events (AEs) per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0; occurrence of grade 3 or 4 abnormalities in serum chemistry laboratory parameters; and discontinuation of sacituzumab govitecan infusions.

[0057] In some embodiments, administration of the trilaciclib / sacituzumab govitecan treatment regimens described herein provides all-cause dose reductions or cycle delays and reduced relative dose intensity for antibody drug conjugate chemotherapy. In some embodiments, administration of the trilaciclib / sacituzumab govitecan treatment regimens described herein provides i) reduced hospitalizations, including but not limited to those due to febrile neutropenia / neutropenia of any cause, anemia / RBC transfusions, thrombocytopenia / bleeding, and infection, or ii) reduced antibiotic use, including but not limited to intravenous (IV), oral, and oral and IV administered antibiotics.

[0058] In some embodiments, administration of a trilaciclib / sacituzumab govitecan treatment regimen described herein provides a patient with a reduction in chemotherapy-induced fatigue (CIF) compared to a patient receiving antibody drug conjugate chemotherapy without trilaciclib. In some embodiments, a reduction in CIF is a reduction in time to first confirmed worsening of fatigue (TTCD-Fatigue) as measured by the Functional Assessment of Cancer Therapy-Fatigue (FACIT-F).

[0059] In some embodiments, administration of the trilaciclib / sacituzumab govitecan treatment regimen described herein provides improvement in one or more of the following: Functional Assessment of Cancer Therapy-General (FACT-G) domain scores (physical, social / family, psychological, and functional); Functional Assessment of Cancer Therapy-Anemia (FACT-An); 5-level EQ-5D (EQ-5D-5L); Patient Global Impression of Change (PGIC) fatigue item; or Patient Global Impression of Severity (PGIS) fatigue item. [Brief description of the drawings]

[0060] [Figure 1] Figure 1 is a schematic diagram of a human clinical trial evaluating the safety and efficacy of trilaciclib administered in combination with sacituzumab-govitecan-hyzy (Trodelvy®) in patients with locally advanced or metastatic TNBC who have had at least two prior chemotherapy treatments, at least one of which belongs to the metastatic setting. The study includes three study phases: a screening phase, a treatment phase, and a survival follow-up phase. The treatment phase consists of 21-day cycles: trilaciclib is administered IV prior to sacituzumab-govitecan-hyzy infusion. Trilaciclib is administered IV at 240 mg / m2 prior to sacituzumab-govitecan-hyzy administration. Sacituzumab-govitecan-hyzy is administered IV at 10 mg / kg. The study includes three study phases: a screening phase, a treatment phase, and a survival follow-up phase. The treatment phase begins on the day of the first dose of study treatment and is completed at the safety follow-up visit. The first survival follow-up assessment should be performed approximately 3 months after the end of treatment visit. DC=Discontinued, PD=Progressive Disease, PI=Principal Investigator, WD=Withdrawn. [Figure 2A] Figures 2A-2H are summary tables showing safety data for trilaciclib administered in combination with sacituzumab-govitecan-hyzy (Trodelv) in female patients with locally advanced or metastatic TNBC who had received at least two prior lines of therapy, at least one of which was in metastatic setting. Percentages are based on the number of enrolled patients who received at least one dose of study drug (i.e., N), unless otherwise noted. Figure 2A is a table showing the characteristics of female participants. [Figure 2B] Figures 2A-2H are summary tables showing safety data for trilaciclib administered in combination with sacituzumab govitecan-hyzy (Trodelv) in female patients with locally advanced or metastatic TNBC who had received at least two prior lines of therapy, at least one of which was in metastatic therapy. Percentages are based on the number of enrolled patients (i.e., N) who received at least one dose of study drug, unless otherwise noted. Figure 2B is a table showing the exposure duration and number of treatment cycles received by study participants. [Figure 2C] Figures 2A-2H are summary tables showing safety data of trilaciclib administered in combination with sacituzumab govitecan-hyzy (Trodelv) in female patients with locally advanced or metastatic TNBC who had received at least two prior lines of therapy, at least one of which belonged to the metastatic setting. Percentages are based on the number of enrolled patients who received at least one dose of study drug (i.e., N), unless otherwise noted. Figure 2C is a table outlining the systemic anticancer therapy history administered to participants. Medications are coded using the WHO DD version Mar2021. Patients with multiple anticancer therapies enrolled in the same ATC (PT) are counted only once within a particular ATC (PT). Therapeutic drugs are sorted by ATC, then PT, in descending order of frequency. ATC=anatomical therapeutic classification; PT=preferred term; WHO DD=world health organization drug dictionary. [Figure 2D]Figures 2A-2H are summary tables showing safety data for trilaciclib administered in combination with sacituzumab govitecan-hyzy (Trodelvy) in female patients with locally advanced or metastatic TNBC who had received at least two prior lines of therapy, at least one of which was in metastatic therapy. Percentages are based on the number of enrolled patients who received at least one dose of study drug (i.e., N), unless otherwise noted. Figure 2D is a table showing an overview of adverse events (AEs) in the study population and the percentage of AEs related to trilaciclib or sacituzumab govitecan-hyzy administration. Related refers to events that are possibly related, probably related, or definitely related, as assessed by the investigator. AEs were coded using MedDRA version 24.0. AEs with missing information on relevance, severity, or possible effects are excluded from specific analyses related to those parameters, but are included in the overall summary, if applicable. Adverse event = AE; MedDRA = medical dictionary for regulatory activities. [Figure 2E] Figures 2A-2H are summary tables showing safety data of trilaciclib administered in combination with sacituzumab-govitecan-hyzy (Trodelv) in female patients with locally advanced or metastatic TNBC who had received at least two prior lines of therapy, at least one of which was in metastatic therapy. Percentages are based on the number of enrolled patients (i.e., N) who received at least one dose of study drug, unless otherwise noted. Figure 2E is a table summarizing the occurrence of myelosuppression endpoints related to the three blood lineages (white blood cells, red blood cells, and platelets) in the study population. G-CSF = granulocyte colony-stimulating factor; ESA = erythropoietin-stimulating factor. [Figure 2F]Figures 2A-2H are summary tables showing safety data for trilaciclib administered in combination with sacituzumab govitecan-hygiene (Trodelvy) in female patients with locally advanced or metastatic TNBC who had received at least two prior lines of therapy, at least one of which was in metastatic therapy. Percentages are based on the number of enrolled patients who received at least one dose of study drug (i.e., N), unless otherwise noted. Figure 2F is a summary table showing AEs by organ system class and preferred term in the study population and AEs related to the study drug trilaciclib or sacituzumab govitecan-hygiene. AEs are defined as AEs that began on or after the date of first study drug administration and up until the safety follow-up visit. AEs with unknown or unreported onset dates are included. AEs were coded using MedDRA version 24.0. Patients enrolled with multiple TEAEs in the same PT are counted only once within a particular preferred term with the highest CTCAE grade. Unless otherwise noted, percentages are based on the number of enrolled patients who received at least one dose of any study drug (i.e., N). Adverse event = AE; MedDRA = Medical Dictionary for Regenerative Medicine; CTCAE = common terminology criteria for adverse events. [Figure 2G] Figures 2A-2H are summary tables showing safety data for trilaciclib administered in combination with sacituzumab-govitecan-hyzy (Trodelvy) in female patients with locally advanced or metastatic TNBC who had received at least two prior lines of therapy, at least one of which was in metastatic therapy. Percentages are based on the number of enrolled patients (i.e., N) who received at least one dose of study drug, unless otherwise noted. Figure 2G is a table summarizing alopecia, neutropenia, and neutropenia in the study population. Adverse Event = AE. [Figure 2H]Figures 2A-2H are summary tables showing safety data for trilaciclib administered in combination with sacituzumab govitecan-hyzy (Trodelvy) in female patients with locally advanced or metastatic TNBC who had received at least two prior lines of therapy, at least one of which was in metastatic therapy. Percentages are based on the number of enrolled patients (i.e., N) who received at least one dose of study drug, unless otherwise noted. Figure 2H is a summary table showing best overall response rates based on derived assessment (confirmed) in the study population. [a] 95% CI for percentages was calculated using the exact Clopper-Pearson method. [b] SD lasting ≥24 weeks from the date of first dose of study drug according to RECIST v1.1. Overall responses were obtained according to RECIST (Response Evaluation Criteria in Solid Tumors) v1.1. CI = confidence interval. Description of the Invention

[0061] Detailed Description of the Invention definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this application belongs. In this specification, the singular form includes the plural form unless the context clearly indicates otherwise. In the practice and testing of this application, methods and materials similar or equivalent to those described herein can be used, but suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not admitted to be prior art to the claimed application. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0062] Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0063] In some embodiments of each of the compounds described herein, the compounds may be in the form of isomers, such as racemates, enantiomers, enantiomeric mixtures, diastereomers, diastereomeric mixtures, tautomers, N-oxides, or rotamers, as if each were specifically described, unless specifically excluded by context.

[0064] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" means "and / or." The recitation of ranges of values ​​is merely intended to serve as a shorthand method for individually referring to each separate value falling within the range, unless otherwise stated herein, and each separate value is incorporated herein as if it were individually recited herein. All range endpoints are included within the range and are independently combinable. All methods described herein may be performed in any suitable order unless otherwise stated herein or clearly contradicted by context. The use of examples or exemplary language (e.g., "such as") is intended merely to better illustrate the invention and does not limit the scope of the invention unless otherwise stated.

[0065] In some embodiments of each of the compounds described herein, the compounds may be in the form of isomers, such as tautomers, N-oxides, or rotamers, as if each were specifically set forth, unless specifically excluded by context.

[0066] "Effective amount" as used herein means an amount that provides a therapeutic or prophylactic benefit.

[0067] The term "about" as used herein means ±10%.

[0068] "Treating" a disease, as that term is used herein, means reducing the frequency or severity of at least one sign or symptom of the disease, disorder, or side effect experienced by a patient (i.e., palliative care), or reducing the cause or effect of the disease, disorder, or side effect experienced by a patient as a result of administration of a therapeutic agent (i.e., disease-modifying treatment).

[0069] Throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and should not be construed as limiting the scope of the invention. The description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values ​​within that range. For example, the description of a range such as 1-6 should be considered to have specifically disclosed subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, etc., as well as individual numerical values ​​within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0070] As used herein, a "pharmaceutical composition" is a composition comprising at least one active agent and at least one other substance, such as a carrier. A "pharmaceutical combination" is a combination of at least two active agents, which may be combined in a single dosage form or may be provided together in separate dosage forms with instructions that the active agents are used together to treat any of the disorders described herein.

[0071] As used herein, "pharmaceutical acceptable salts" are derivatives of the disclosed compounds, which are modified from the parent compound by making inorganic and organic, non-toxic acid or base addition salts thereof. The salts of the compounds can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be made by reacting with a suitable base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.) or by reacting the free base forms of these compounds with a suitable acid. Such reactions are generally carried out in water or in an organic solvent, or in a mixture of both. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practical. The salts of the compounds further include solvates of the compounds and compound salts.

[0072] Examples of pharma- ceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2)n-COOH (where n is 0-4), or salts made with a different acid resulting in the same counterion. Further lists of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., p. 1418 (1985). Where the methods described herein specify administration of a particular compound, it is understood that administration of a pharma- ceutically acceptable salt of the compound is encompassed as an embodiment, where applicable.

[0073] As used herein, the term "prodrug" refers to a compound that is converted to a parent drug in vivo when administered to a host. As used herein, the term "parent drug" refers to any of the chemical compounds described herein that are useful for treating any of the disorders described herein or for controlling or ameliorating the underlying causes or symptoms associated with any of the physiological or pathological disorders described herein in a host, generally a human. Prodrugs can be used to achieve any desired effect, such as to enhance the properties of the parent drug or to improve the pharmaceutical or pharmacokinetic properties of the parent drug. Prodrug strategies provide the option to adjust the in vivo production conditions of the parent drug, all of which are considered to be included herein. Non-limiting examples of prodrug strategies include covalent attachment of a removable group or a removable portion of a group, such as, but not limited to, acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation, or anhydride, among others.

[0074] The term "carrier" applied to pharmaceutical compositions / combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided.

[0075] By "pharmaceutical acceptable excipient" is meant an excipient useful for preparing a pharmaceutical composition / combination that is not biologically or otherwise unsuitable for administration to a host, generally a human.

[0076] In non-limiting embodiments, trilaciclib can employ at least one desired isotopic substitution of an atom in an amount greater than the natural abundance of that isotope, i.e., enriched form. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but different numbers of neutrons.

[0077] Examples of isotopes that can be incorporated into trilaciclib for use in the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36CI and 125I, respectively. In one non-limiting embodiment, isotope-labeled compounds can be used for metabolic studies (using 14C), reaction kinetic studies (e.g., using 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), such as drug or substrate tissue distribution assays, or radiotherapy of patients. In particular, 18F-labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by following the procedures disclosed in the Schemes or Examples and the preparative methods described below, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0078] General examples include, but are not limited to, isotopes of hydrogen, such as deuterium ( 2 H) and tritium ( 3 H) can be used anywhere in the depicted structures that will produce the desired result. Alternatively or additionally, isotopes of carbon, such as 13 C and 14 C can also be used.

[0079] Isotopic substitution, for example deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced with deuterium. In certain embodiments, the isotope is enriched to 90, 95, or 99% or more at any location of interest. In one non-limiting embodiment, deuterium is enriched to 90, 95, or 99% at the desired location.

[0080] The "patient," "host," or "subject" to be treated is generally a human patient, although it should be understood that the methods described herein are also effective with respect to other animals, such as mammals. More particularly, the term patient can include animals used in assays, such as those used in preclinical trials, including, but not limited to, mice, rats, monkeys, dogs, pigs, and rabbits; as well as domestic pigs (pigs and hogs), ruminants, horses, poultry, cats, cows, rats, dogs, and the like. In certain embodiments, the patient, host, or subject is a human patient.

[0081] As generally contemplated herein, "hematopoietic stem and progenitor cells" (HSPCs) include, but are not limited to, long term hematopoietic stem cells (LT-HSCs), short term hematopoietic stem cells (ST-HSCs), hematopoietic progenitor cells (HPCs), multipotent progenitor cells (MPPs), oligodendrocyte progenitor cells (OPPs), monocytic progenitor cells, granulocyte progenitor cells, common myeloid progenitor cells (CMPs), common lymphoid progenitor cells (CLPs), granulocyte-monocyte progenitor cells (GMPs), granulocyte progenitor cells, monocytic progenitor cells, and monocytic progenitor cells. These include erythroid progenitors, and erythroid progenitors (MEPs), megakaryocyte progenitors, erythroid progenitors, HSC / MPPs (CD45dim / CD34+ / CD38-), OPPs (CD45dim / CD34+ / CD38+), monocyte progenitors (CD45+ / CD14+ / CD11b+), granulocyte progenitors (CD45+ / CD14- / CD11b+), erythroid progenitors (CD45- / CD71+), and megakaryocyte progenitors (CD45+ / CD61+).

[0082] The term "immune effector cells" generally refers to immune cells that perform one or more specific functions. Immune effector cells are known in the art and include, for example, but are not limited to, T cells, including naive T cells, memory T cells, activated T cells (T helper (CD4+) and cytotoxic T cells (CD8+)), TH1 activated T cells, TH2 activated T cells, TH17 activated T cells, naive B cells, memory B cells, plasma blasts, dendritic cells, monocytes, and natural killer (NK) cells.

[0083] As used herein, the term "immune checkpoint inhibitors (ICIs)" refers to therapies that target immune checkpoint proteins, which are key regulators of the immune system that, when expressed, can dampen the immune response to immune stimuli. Some cancers express ligands for checkpoint inhibitors, which can protect them from attack by binding to immune checkpoint targets. ICIs block inhibitory checkpoints, restoring immune system function. ICIs include those that target immune checkpoint proteins such as PD-1, PD-1 ligand-1 (PD-L1), PD-1 ligand-2 (PD-L2), CTLA-4, LAG-3, TIM-3, and V-domain Ig suppressor of T-cell activation (VISTA), B7-H3 / CD276, indoleamine 2,3-dioxygenase (IDO), killer immunoglobulin-like receptors (KIR), carcinoembryonic antigen cell adhesion molecule (CEACAM) (e.g., CEACAM-1, CEACAM-3, and CEACAM-5), sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15), T cell immunoreceptor with Ig and ITIM domains (V-domain Ig suppressor of T-cell activation) (TIGIT), and B and T lymphocyte attenuator (BTLA) proteins. Immune checkpoint inhibitors are known in the art.

[0084] Trop-2 expressing cancer Trophoblast cell surface antigen 2 (Trop-2) is a glycoprotein that coats the epithelial membrane surface and plays a role in cell self-renewal, proliferation, and transformation (Zaman et al., Targeting Trop-2 in solid tumors: future prospects. Onco Targets Ther. 2019;12:1781-1790). Under physiological conditions, Trop-2 plays an essential role in embryonic development, placental tissue formation, embryo implantation, stem cell proliferation, and organ development (Shvartsur et al., Trop2 and its overexpression in cancers: regulation and clinical / therapeutic implications. Genes Cancer. 2015;6(3-4):84-105). Low basal expression levels of Trop-2 are found on the surfaces of several normal epithelial tissues, including skin and oral mucosa (Strop P, Tran TT, Dorywalska M, et al. RN927C, a site-specific Trop-2 antibody-drug conjugate (ADC) with enhanced stability, is highly efficacious in preclinical solid tumor models. Mol Cancer Ther. 2016;15(11):2698-2708). Trop-2 can promote tumor growth, and its overexpression is common in many types of malignant epithelial tumors (Goldenberg DM, Stein R, Sharkey RM. The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget. 2018;9(48):28989-29006). Overexpression of Trop-2 accelerates the cancer cell cycle and promotes cancer proliferation. Overexpression of Trop2 is associated with decreased patient survival and increased tumor aggressiveness and metastasis in many cancers.In some embodiments, trilaciclib or a pharma- ceutically acceptable salt thereof is administered in combination with the antibody-drug conjugate sacituzumab govitecan in a specific timed administration protocol described herein to patients with advanced / metastatic cancers that overexpress Trop-2. In some embodiments, the advanced / metastatic cancers that overexpress Trop-2 are selected from the group consisting of breast cancer, cervical cancer, colon or colorectal cancer, endometrioid endometrial cancer, esophageal cancer, gastric cancer, glioma, hilar cholangiocarcinoma, oral squamous cell carcinoma, gastrointestinal cancer, chronic lymphocytic lymphoma, extranodal NK / T cell lymphoma, non-Hodgkin's lymphoma, Raji Burkitt's lymphoma, small lung adenocarcinoma, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, thyroid cancer, bladder cancer, uterine cancer, and lung cancer, including small cell lung cancer and non-small cell lung cancer.

[0085] In some embodiments, the Trop-2 expressing tumor to be treated is non-small cell lung cancer (NSCLC). NSCLC accounts for nearly 85% of all diagnosed lung cancers. Common types of NSCLC include adenocarcinoma, which generally shows glandular differentiation, squamous cell carcinoma, which generally shows squamous differentiation (keratinization), and large cell carcinoma, which generally shows large and poor differentiation.

[0086] Triple negative breast cancer Triple-negative breast cancer (TNBC) is an extremely aggressive subtype of breast cancer, accounting for 15-20% of breast cancer cases and 25% of all breast cancer deaths annually. TNBC is characterized by several aggressive clinicopathological features, including early age of onset, large, high-grade tumors, and a propensity for visceral metastasis (Cheang et al., Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res. 2008;14(5):1368-76.; Foulkes et al., Triple-negative breast cancer. N Engl J Med. 2010 Nov 11;363(20):1938-48).

[0087] Breast cancers are generally classified as TNBC based on focal ER-negative, progesterone receptor (PR)-negative, HER2-negative status, which can be determined by histological or cytological hormone receptor immunohistochemistry (IHC) assessment for estrogen and progesterone (defined as <1% nuclear staining) and HER2-negative, non-overexpressing by IHC [0 or 1+] or in situ hybridization [ratio <2.0] or mean gene copy number <4 signals / nucleus) (according to the 2018 American Society of Clinical Oncology and College of American Pathologists (ASCO CAP) criteria).

[0088] Metastatic urothelial carcinoma Metastatic urothelial (transitional cell) carcinoma (mUC) is the predominant histological type of bladder cancer in the Western world, accounting for 90% of all bladder cancers. Bladder cancer is the sixth most common cancer in men and the 17th most common in women worldwide. Bladder cancer is the most common malignancy involving the urinary system. Bladder cancer can be classified as non-muscle invasive, muscle invasive, or metastatic. Approximately 25% of patients will have muscle invasive disease with or subsequently develop metastases. Systemic chemotherapy is the standard approach for the initial treatment of patients with inoperable locally advanced or metastatic urothelial malignancies. Although initial response rates are high, median survival with multiagent chemotherapy is approximately 15 months.

[0089] PD-L1 status In some aspects, the Trop-2 overexpressing cancer being treated is PD-L1 positive, hi other aspects, the Trop-2 overexpressing cancer being treated is PD-L1 negative.

[0090] PD-L1 is a transmembrane protein that downregulates immune responses through binding to its two inhibitory receptors, programmed death-1 (PD-1) and B7.1. PD-1 is an inhibitory receptor expressed on T cells after T cell activation and persists in chronically stimulated conditions such as chronic infections or cancer (Blank, C and Mackensen, A, Contribution of the PD-L1 / PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother, 2007. 56(5): p. 739-745). Binding of PD-L1 to PD-1 inhibits T cell proliferation, cytokine production, and cytolytic activity, leading to functional inactivation or exhaustion of T cells. B7.1 is a molecule expressed on antigen-presenting cells and activated T cells. Binding of PD-L1 to B7.1 on T cells and antigen-presenting cells can mediate downregulation of immune responses, including inhibition of T cell activation and cytokine production (see Butte MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27(1):111-122). PD-L1 expression has been found on immune and tumor cells.See Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5(12):1365-1369; Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563-567. It has been reported that aberrant expression of PD-L1 in tumor cells inhibits antitumor immunity and leads to immune evasion.

[0091] PD-L1 expression can be determined by methods known in the art. For example, PD-L1 expression can be detected using PD-L1 IHC 22C3 pharmDx, an FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Bristol-Meyers Squibb as an adjunct test for pembrolizumab treatment. This is a qualitative assay that uses monoclonal mouse anti-PD-L1 clone 22C3 PD-L1 and the EnVision FLEX visualization system on an Autostainer Lin 48 to detect PD-L1 in formalin-fixed paraffin-embedded (FFPE) human cancer tissues. Expression levels can be measured using the tumor proportion score (TPS), which measures the percentage of viable tumor cells that show partial or complete membrane staining. Staining indicates PD-L1 expression between 1% and 100%.

[0092] PD-L1 expression can also be detected using PD-L1 IHC 28-8 pharmDx, an FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Merck as an adjunct test for nivolumab treatment. This qualitative assay uses monoclonal rabbit anti-PD-L1 clone 28-8 on an Autostainer Lin 48 and the EnVision FLEX visualization system to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) human metastatic urothelial carcinoma tissues.

[0093] Other commercially available tests for PD-L1 detection include the Ventana SP263 assay (Ventana in collaboration with AstraZeneca), which uses the monoclonal rabbit anti-PD-L1 clone SP263, and the Ventana SP142 assay (Ventana in collaboration with Genentech / Roche), which uses the rabbit monoclonal anti-PD-L1 clone SP142. PD-L1 status determination is indication-specific and is based on the percentage of tumor area occupied by tumor-infiltrating immune cells expressing PD-L1 at any intensity (%IC) or the percentage of tumor cells expressing PD-L1 at any intensity (%TC). For example, in TNBC, PD-L1 positive status is considered IC1% or higher, and in mUC, TC50% or IC10% or higher.

[0094] In some embodiments, the TNBC has a PD-L1 positive status of IC1% or greater.

[0095] In some embodiments, mUC patients treated with second or third line antibody drug conjugate chemotherapy protocols have a documented PD-L1 status positive mUC. In some embodiments, patients treated with second or third line antibody drug conjugate chemotherapy protocols have a documented PD-L1 status positive mUC of more than 10% PD-L1 stained tumor infiltrating immune cells or more than 50% of tumor cells as determined by an in vitro diagnostic (IVD) assay, e.g., Ventana SP-142 assay or other suitable assay. In some embodiments, patients treated with second or third line antibody drug conjugate chemotherapy protocols have a documented PD-L1 status mUC of more than 20% PD-L1 stained tumor cells as determined by an in vitro diagnostic (IVD) assay, e.g., Ventana SP-142 assay or other suitable assay. In another embodiment, patients treated with second or third line antibody drug conjugate chemotherapy protocols have a documented PD-L1 status mUC of more than 1% PD-L1 stained tumor cells as determined by an FDA approved test. In another embodiment, the patient treated with a second or third line antibody drug conjugate chemotherapy protocol has documented PD-L1 status negative mUC.

[0096] CDK4 / 6 Status As provided herein, in some embodiments, the Trop-2 overexpressing cancer being treated is CDK4 / 6 negative or CDK4 / 6 replication dependent. In other embodiments, the Trop-2 overexpressing cancer being treated is CDK4 / 6 positive or CDK4 / 6 replication dependent. In yet other embodiments, the Trop-2 overexpressing cancer being treated is CDK4 / 6 indefinite.

[0097] CDK4 / 6 replication-dependent cancers commonly harbor retinoblastoma gene (Rb1) abnormalities. The gene product of Rb1-Rb protein is a downstream target of CDK4 / 6. RB1 is commonly dysregulated in cancer cells through deletion, mutation or epigenetic modification leading to loss of RB expression, as well as by aberrant CDK kinase activity leading to hyperphosphorylation and inactivation of RB function (Chen et al. Novel RB1-Loss Transcriptomic Signature Is Associated with Poor Clinical Outcomes across Cancer Types. Clin Cancer Res. 2019;25(14); Sherr, CJ, and McCormick, F. The RB and p53 pathways in cancer. Cancer Cell, 2002;2:103 12). CCNE1 / 2 (cyclin E) are part of a parallel pathway that provides functional redundancy with CDK4 / 6 and helps transition cells from G1 to S phase. Overexpression reduces dependency on the CDK4 / 6 pathway, leading to CDK4 / 6 independence (Turner et al., Cyclin E1 Expression and Palbociclib Efficacy in Previously Treated Hormone Receptor-Positive Metastatic Breast Cancer. J Clin Oncol. 2019;37(14):1169-78). Thus, tumors with either CCNE1 / 2 amplification or RB loss are generally considered to be "CDK4 / 6 independent."

[0098] CDK4 / 6 replication-dependent cancers require CDK4 / 6 activity for replication or proliferation. CDK4 / 6 replication-dependent TNBCs generally have an intact and functional Rb pathway, CDK4 / 6 activator (cyclin D), and / or increased expression of d-type cyclin activation signatures (DCAFs), including CCND1 translocations, CCND1-3 3'UTR deletions, and CCND2 or CCND3 amplification (see Gong et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK5 inhibitor abemaciclib. Cancer Cell. 2017;32(6):761-76). Tumors that are wild-type for RB and CCNE1 / 2 and have one of the DCAFs listed above are generally classified as "CDK4 / 6-dependent."

[0099] Tumors that cannot be classified as either CDK4 / 6 replication-dependent or CDK4 / 6 replication-independent are generally classified as "CDK4 / 6 indeterminate" since they cannot be confirmed as either CDK4 / 6-dependent or -independent.

[0100] In some embodiments, the Trop-2 overexpressing cancer is classified as CDK4 / 6 replication dependent. In some embodiments, the Trop-2 overexpressing cancer is classified as CDK4 / 6 replication independent. In some embodiments, the Trop-2 overexpressing cancer is classified as CDK4 / 6 indefinite.

[0101] Methods for determining CDK4 / 6 gene signature analysis are known in the art and include utilizing tumor tissue taken from a patient biopsy (e.g., TNBC or mUC primary or metastatic site) and are described in Shapiro GI. Genomic biomarkers predicting response to selective CDK4 / 6 inhibition: Progress in an elusive search. Cancer Cell. 2017; 32(6):721-3 and Gong et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK5 inhibitor abemaciclib. Cancer Cell. 2017; 32(6):761-76.

[0102] In some embodiments, patients receiving trilaciclib in combination with sacituzumab govitecan include: a, CCNE1 amplification; b. CCNE2 amplification; or Retinoblastoma protein 1 (Rb1) deficiency, defined as ci) homozygous deletion, ii) frameshift mutation, or iii) stop-gain mutation (i.e., a mutation resulting in a premature stop codon (acquisition of a stop codon) Patients with CDK4 / 6-independent TNBC have at least one of the following:

[0103] In some embodiments, patients receiving trilaciclib in combination with sacituzumab govitecan: 1) The following: a, CCNE1 amplification; b. CCNE2 amplification; or Retinoblastoma protein 1 (Rb1) deficiency, defined as ci) homozygous deletion, ii) frameshift mutation, or iii) stop-gain mutation (i.e., a mutation resulting in a premature stop codon (acquisition of a stop codon) does not have at least one of 2) Wild type: i) CCNE1; ii) CCNE2; and iii) no RB1; and 3) Have at least one of the following D-cyclin activation features: i) CCND2 amplification; ii) CCND3 amplification; and iii) CCD1-3 3'UTR deletion (defined as homozygous or heterozygous deletion of any of these UTRs). Have CDK4 / 6-dependent TNBC.

[0104] In some embodiments, patients receiving trilaciclib in combination with sacituzumab govitecan include: d. CCNE1 amplification; e. CCNE2 amplification; or Retinoblastoma protein 1 (Rb1) deficiency, defined as fi) homozygous deletion, ii) frameshift mutation, or iii) stop-gain mutation (i.e., a mutation resulting in a premature stop codon (acquisition of a stop codon) The present invention relates to a method for treating CDK4 / 6-independent mUC comprising administering to a patient a therapeutically effective amount of CDK4 / 6-independent mUC having at least one of the following:

[0105] In some embodiments, patients receiving trilaciclib in combination with sacituzumab govitecan-Hyzy 1) The following: a, CCNE1 amplification; b. CCNE2 amplification; or Retinoblastoma protein 1 (Rb1) deficiency, defined as ci) homozygous deletion, ii) frameshift mutation, or iii) stop-gain mutation (i.e., a mutation resulting in a premature stop codon (acquisition of a stop codon) does not have at least one of 2) Wild type: i) CCNE1; ii) CCNE2; and iii) no RB1; and 3) Have at least one of the following D-cyclin activation features: i) CCND2 amplification; ii) CCND3 amplification; and iii) CCD1-3 3'UTR deletion (defined as homozygous or heterozygous deletion of any of these UTRs). Has CDK4 / 6-dependent mUC.

[0106] Improved antibody-drug conjugate chemotherapy protocols Trilaciclib Trilaciclib (2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro(cyclohexane-1,9'-pyrazino(1',2':1,5)pyrrolo(2,3-d)pyrimidin)-6'-one) has the structure: [ka] It is a highly selective CDK4 / 6 inhibitor with

[0107] As provided herein, trilaciclib or a pharma- ceutically acceptable salt, composition, isotopic analog, or prodrug thereof is administered in a suitable carrier. Trilaciclib is described in U.S. Patent Application Publication No. 2013 / 0237544, which is incorporated herein by reference in its entirety. Trilaciclib can be synthesized as described in U.S. Patent Application Publication No. 2019 / 0135820, which is incorporated herein by reference in its entirety. Trilaciclib may be administered in any manner that achieves the desired outcome, including systemically, parenterally, intravenously, intramuscularly, subcutaneously, or intradermally. For injection, trilaciclib may be provided in some embodiments, for example, 300 mg / vial as a sterile lyophilized yellow mass that provides 300 mg of trilaciclib (equivalent to 349 mg of trilaciclib dihydrochloride dihydrate). This product may be supplied, for example, in a single-use 20 mL clear glass vial without preservatives. For example, prior to administration, trilaciclib for injection 300 mg / vial may be reconstituted with 19.5 ml of 0.9% sodium chloride injection or 5% dextrose injection. This reconstituted solution has a trilaciclib concentration of 15 mg / mL and is generally then diluted prior to intravenous administration. Trilaciclib may be administered intravenously as described herein.

[0108] Trilaciclib for use in the present invention may be in the form of a salt, for example, a dihydrochloride salt. In certain aspects of the present invention, trilaciclib is a crystalline dihydrochloride salt and can be reconstituted for intravenous delivery. In certain embodiments, trilaciclib is a crystalline dihydrochloride dihydrate and can be reconstituted for intravenous delivery.

[0109] In certain embodiments, trilaciclib is in the form of a solvate with a solvent (such as water). The term "solvate" refers to a molecular complex of trilaciclib (including its salts) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethylsulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex of the compound of the present invention with water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent is isotopically substituted, for example, D2O, d6-acetone, d6-DMSO. The solvate may be in liquid or solid form.

[0110] In certain embodiments, trilaciclib is in the form of a dihydrochloride salt, optionally as a hydrate. For example, trilaciclib can be used in the present invention as a dihydrochloride dihydrate or as a pharmaceutical composition formed from trilaciclib dihydrochloride dihydrate.

[0111] In some embodiments, trilaciclib is administered at about 180 mg / m 2 ~300mg / m 2 In some embodiments, trilaciclib is administered at about 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, or about 280 mg / m 2 In some embodiments, trilaciclib is administered at a dose of at least 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, or 240 mg / m 2In some embodiments, trilaciclib is administered at about 240 mg / m, e.g., within about 4 hours, e.g., within about 4 hours, within 3 hours, within 2 hours, within about 1 hour, or about 30 minutes, prior to administration of sacituzumab govitecan. 2 In some embodiments, trilaciclib is administered intravenously over about 30 minutes. In some embodiments, trilaciclib is administered completely prior to administration of sacituzumab govitecan.

[0112] As provided herein, for the treatment of advanced / metastatic TNBC, trilaciclib is administered on days 1 and 8 of each 21-day cycle, or as otherwise provided herein. Trilaciclib is administered prior to the start of sacituzumab govitecan administration, generally over about 30 minutes intravenous injection / infusion, within about 4 hours, e.g., within about 3 hours, within 2 hours, within 1 hour, or about 30 minutes, prior to the start of sacituzumab govitecan administration in the protocol. In some embodiments, trilaciclib is administered completely within 4 hours prior to the start of sacituzumab govitecan administration on days 1 and 8.

[0113] In another embodiment, for the treatment of advanced / metastatic TNBC, trilaciclib is administered on days 1, 8, and 15 of each 21-day cycle, or as otherwise provided herein. Trilaciclib is administered by intravenous injection / infusion over about 30 minutes prior to the start of sacituzumab govitecan administration on days 1 and 8, generally within about 4 hours, e.g., within about 3 hours, within 2 hours, within 1 hour, or about 30 minutes prior to the start of sacituzumab govitecan administration in the protocol. In some embodiments, trilaciclib is administered completely within 4 hours of the start of sacituzumab govitecan administration on days 1 and 8.

[0114] In another embodiment, for the treatment of advanced / metastatic urothelial carcinoma as provided herein, trilaciclib is administered on days 1 and 8 of each 21-day cycle, or as otherwise provided herein. Trilaciclib is administered prior to the initiation of sacituzumab govitecan administration, generally by intravenous injection / infusion over about 30 minutes within about 4 hours, e.g., within about 3 hours, within 2 hours, within 1 hour, or about 30 minutes, prior to the initiation of sacituzumab govitecan administration in the protocol. In some embodiments, trilaciclib is administered completely within 4 hours prior to the initiation of sacituzumab govitecan administration on days 1 and 8.

[0115] In another embodiment, for the treatment of advanced / metastatic urothelial carcinoma as provided herein, trilaciclib is administered on days 1, 8, and 15 of each 21-day cycle, or as otherwise provided herein. Trilaciclib is administered on days 1 and 8 prior to the initiation of sacituzumab govitecan administration, generally by intravenous injection / infusion over about 30 minutes within about 4 hours, e.g., within about 3 hours, within 2 hours, within 1 hour, or about 30 minutes, prior to the initiation of sacituzumab govitecan administration in the protocol. In some embodiments, trilaciclib is administered completely within 4 hours prior to the initiation of sacituzumab govitecan administration on days 1 and 8.

[0116] In another embodiment, as provided herein, for Trop-2 overexpressing cancers, trilaciclib is administered on days 1 and 8 of each 21-day cycle, or as otherwise provided herein. Trilaciclib is administered by intravenous injection / infusion over about 30 minutes prior to the initiation of sacituzumab govitecan administration, generally within about 4 hours, e.g., within about 3 hours, within 2 hours, within 1 hour, or about 30 minutes prior to the initiation of sacituzumab govitecan administration of the protocol. In some embodiments, trilaciclib is administered completely within 4 hours prior to the initiation of sacituzumab govitecan administration on days 1 and 8. In some embodiments, the Trop-2 overexpressing cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the NSCLC is metastatic or progressive NSCLC. In some embodiments, the NSCLC has progressed during or after receiving platinum-based chemotherapy and PD-1 or PD-L1 inhibitor therapy, either concomitantly or sequentially.

[0117] In another embodiment, as provided herein, for the treatment of Trop-2 overexpressing cancer, trilaciclib is administered on days 1 and 8 of each 21-day cycle, or as otherwise provided herein. Trilaciclib is administered prior to the initiation of sacituzumab govitecan administration on days 1 and 8, generally by intravenous injection / infusion over about 30 minutes, within about 4 hours, e.g., within about 3 hours, within 2 hours, within 1 hour, or about 30 minutes, prior to the initiation of sacituzumab govitecan administration of the protocol. In some embodiments, trilaciclib is administered completely within 4 hours prior to the initiation of sacituzumab govitecan administration on days 1 and 8. In some embodiments, the Trop-2 overexpressing cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the NSCLC is metastatic or progressive NSCLC. In some embodiments, the NSCLC has progressed during or after receiving platinum-based chemotherapy and PD-1 or PD-L1 inhibitor therapy, either concomitantly or sequentially.

[0118] In another embodiment, a different CDK4 / 6 inhibitor is administered. For example, in another embodiment, the CDK4 / 6 inhibitor used in place of trilaciclib in the protocols described herein is ribociclib (Novartis), palbociclib (Pfizer), or abemaciclib (Eli Lily), or a pharma- ceutically acceptable salt thereof. In yet another embodiment, the CDK4 / 6 inhibitor has the structure: [ka] or a pharma- ceutically acceptable composition, salt, isotopic analog, or prodrug thereof, which is described in U.S. Patent Application Publication No. 2013 / 0237544, which is incorporated herein by reference in its entirety, and which can be synthesized as described in U.S. Patent Application Publication No. 2019 / 0135820, which is incorporated herein by reference in its entirety. In some embodiments, relociclib is administered as a pharma- ceutically acceptable salt, for example, the dihydrochloride salt.

[0119] In yet another embodiment, the CDK4 / 6 inhibitor has the structure: [ka] or a pharma- ceutically acceptable composition, salt, isotopic analog, or prodrug thereof, and can be synthesized as described in US2013-0237544, which is incorporated by reference in its entirety, and as described in US2019-0135820, which is incorporated by reference in its entirety.

[0120] Sacituzumab govitecan Sacituzumab govitecan (Trodelv®) is an antibody-drug conjugate (ADC) composed of the humanized RS7 (hRS7) anti-Trop-2 monoclonal antibody linked to the cytotoxic payload SN-38, an active metabolite of the topoisomerase I inhibitor irinotecan, and a cleavable CL2A linker. The FDA has designated Trodelvy sacituzumab govitecan-hydine to distinguish it from biosimilar molecules. It should be understood that the methods described herein include sacituzumab govitecan-hydine and all biosimilars thereof, and that the use of the term sacituzumab govitecan-hydine is intended to be non-limiting with respect to the biosimilars. Sacituzumab govitecan-hydine has a molecular weight of approximately 160 kilodaltons. Sacituzumab govitecan-hydine has the following chemical structure: [ka] has.

[0121] Trop-2 is a calcium signaling factor that is overexpressed in many epithelial cancers, including breast and urothelial cancers, and is involved in enhancing cell proliferation, survival, and invasion. High levels of Trop-2 expression are associated with worse survival in these indications. Sacituzumab-govitecan-Hyzy site-specifically conjugates 7.6 molecules of SN-38 per monoclonal antibody without altering the pharmacokinetics or reducing the therapeutic index of the conjugated antibody. This allows for the local delivery of high concentrations of SN-38 to tumor tissue. After binding to Trop-2, the ADC is internalized and trafficked to lysosomes. SN-38 is released during degradation of the antibody and subsequent hydrolysis of the linker at low pH, where it can be found in the lysosomes as well as extracellularly in the tumor microenvironment.

[0122] In 2020, sacituzumab govitecan-Hyzy (Trodelvy®) received accelerated approval from the FDA for the treatment of adult patients with metastatic TNBC who have received at least two prior lines of therapy for metastatic disease. This accelerated approval was based on results from the phase 2 IMMU-132-01 study, in which patients (N=108) treated with sacituzumab govitecan-Hyzy had an ORR of 33.3%, a median duration of response (DOR) of 7.7 months (95% CI=4.9-10.8 months), and 55.5% and 16.7% of patients had a DOR of 6 months or more and 12 months or more, respectively (Bardia, 2019). In 2021, it received full approval from the FDA based on results from the phase 3 ASCENT study (Bardia, 2021). The median PFS for patients receiving sacituzumab govitecan-Hyzy was 4.8 months (95% CI = 4.1-5.8 months) compared to 1.7 months (95% CI = 1.5-2.5 months) for patients receiving physician's choice of single-agent chemotherapy (HR = 0.43, 95% CI = 0.35-0.54, P < 0.0001), and the median overall survival (OS) was 11.8 months (95% CI = 10.5-13.8 months) versus 6.9 months (95% CI = 5.9-7.6 months), respectively (HR = 0.51, 95% CI = 0.41-0.62, P < 0.0001) (Trodelvipsis Prescribing Information, 2021).

[0123] In April 2021, sacituzumab govitecan-hyzy (TRODELVY®) received accelerated approval from the FDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have previously received either platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor. Efficacy and safety were evaluated in TROPHY (IMMU-132-06; NCT03547973), a single-arm, multicenter study that enrolled 112 patients with locally advanced or mUC who had previously received platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor. Patients received sacituzumab govitecan 10 mg / kg intravenously on days 1 and 8 of a 21-day treatment cycle. The primary efficacy outcome measures were objective response rate (ORR) and duration of response (DOR), assessed by independent review using RECIST 1.1 criteria. The ORR was 27.7% (95%CI:19.6, 36.9), with 5.4% complete responses and 22.3% partial responses. The median DOR was 7.2 months (n=31, 95%CI:4.7, 8.6; range 1.4+, 13.7).

[0124] According to the "Warnings and Precautions" section of the prescribing information for sacituzumab govitecan-Hyzy (Trodelvy® Package Insert, 2021), important risks associated with the use of sacituzumab govitecan-Hyzy are: ·Severe or life-threatening neutropenia (BOXED WARNING); ·Severe diarrhea (Boxed Warning); Hypersensitivity and infusion-related reactions, including severe anaphylactic reactions; Nausea and vomiting; Patients with reduced UGT1A1 activity: Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) * Patients homozygous for the 28 allele are at increased risk of neutropenia, febrile neutropenia, and anemia. Embryo-fetal toxicity.

[0125] The occurrence of chemotherapy-induced myelosuppression (CIM) can be problematic with all chemotherapy regimens, but is particularly problematic during sacituzumab govitecan treatment because this treatment is generally administered after significant damage to blood cell populations has occurred from a previous course of treatment. Patients who develop CIM are likely to experience infection, sepsis, bleeding, and fatigue, often resulting in hospitalization, the need for hematopoietic growth factor support, transfusions (red blood cells [RBCs] and / or platelets), and even death (see, e.g., Gustinetti et al., Bloodstream infections in neutropenic cancer patients: A practical update. Virulence. 2016; 7(3): 280-97; Li et al., Relationship between severity and duration of chemotherapy-induced neutropenia and risk of infection among patients with non-myeloid malignancies. Support Care Cancer 2016; 24(10): 4377-83; Caggiano et al., Incidence, cost, and mortality of neutropenia hospitalization associated with chemotherapy. Cancer. 2005; 103(9): 1916-24). In addition, CIM commonly leads to dose reduction and delay, which may limit the intensity of the treatment dose and reduce the benefits of the antitumor effect of chemotherapy. In some cases, treatment is discontinued. For example, if grade 4 neutropenia ≥ 7 days or grade 3 febrile neutropenia (ANC < 1000 / mm3), the patient may be unable to receive chemotherapy. 3For the first instance of either grade 3 or 4 neutropenia (and fever ≥ 38.5°C) or grade 3 or 4 neutropenia where dosing is delayed by 2 or 3 weeks to recover to grade 1 or less at any time during scheduled treatment, a 25% dose reduction is recommended, for a second instance a 50% dose reduction is recommended, and for a third instance treatment discontinuation is recommended. For the first instance of grade 3 or 4 neutropenia where dosing is delayed for more than 3 weeks to recover to grade 1 or less, treatment discontinuation is recommended.

[0126] Attempts to develop and implement clinical algorithms to guide chemotherapy dose reductions and treatment delays in patients with neutropenia and / or thrombocytopenia during treatment are being investigated (see, for example, Clinical Trial of a Novel Dose Adjustment Algorithm for Preventing Cytopenia-Related Delays During FOLFOX Chemotherapy, ClinicalTrials.gov Identifier: NCT04526886). Nonetheless, chemotherapy-induced immune system cytotoxicity may also limit antitumor efficacy due to the inability of the host immune system to effectively mount a response against the cancer. Prolonged exposure to myelosuppressants may lead to cumulative myelotoxicity and myelosuppression, limiting the ability to deliver subsequent lines of therapy at standard-of-care doses and schedules. Currently, there is no single treatment to prevent or mitigate the myelosuppressive effects of sacituzumab-govitecan chemotherapy protocols before they occur.Existing therapies are generally used reactively to treat acute cytoreduction and are lineage specific, and each of these has its own set of associated risks (e.g., Blumberg et al., (2010) Platelet transfusions: trigger, dose, benefits, and risks. F1000 Med Rep 2:5. https: / / doi.org / 10.3410 / m2-5; Bohlius et al., (2019) Management of cancer-associated anemia with erythropoiesis-stimulating agents: ASCO / ASH Clinical Practice Guideline Update. J Clin Oncol 37 (15):1336-1351. https: / / doi.org / 10.1200 / jco.18.02142; Xu et al., (2016) Risk factors for bone pain among patients with cancer receiving myelosuppressive chemotherapy and pegfilgrastim. Support Care Cancer 24 (2):723-730. https: / / doi.org / 10.1007 / s00520-015-2834-2; Corey-Lisle et al., (2014) Transfusions and patient burden in chemotherapy-induced anaemia in France. Ther Adv Med Oncol 6 (4):146-153. See https: / / doi.org / 10.1177 / 1758834014534515).

[0127] The occurrence of chemotherapy-induced diarrhea (CID) is debilitating and in some cases life-threatening. Findings in such patients include volume depletion, renal failure, and electrolyte disturbances such as metabolic acidosis and hyponatremia (increased fluid intake that cannot be excreted due to hypovolemic stimulation of antidiuretic hormone release) or hypernatremia (insufficient fluid intake to replace losses) that are dependent on fluid intake (Maroun et al., (2007) Prevention and management of chemotherapy-induced diarrhea in patients with colorectal cancer: a consensus statement by the Canadian working group on chemotherapy-induced diarrhea. Curr Oncol 14: 13-20). CID can interfere with and be detrimental to cancer treatment by causing dose delays or reductions that may affect survival. For example, a 25% dose reduction is recommended for the first case of grade 3-4 diarrhea that cannot be managed with antiemetics and antidiarrheals, a 50% dose reduction is recommended for the second case, and discontinuation is recommended for the third case.

[0128] Stomatitis / mucositis is the result of the toxic effects of chemotherapy drugs on the rapidly dividing epithelial cells that line the gastrointestinal tract (from the mouth to the anus), exposing the mucosal tissues to ulceration and infection. Stomatitis / mucositis generally begins 5-10 days after chemotherapy initiation and lasts for 1-6 weeks or more. Many patients with stomatitis / mucositis have significant nutritional problems as they are unable to eat due to the associated pain, leading to hypovolemia, electrolyte abnormalities, malnutrition, and even death. Severe stomatitis / mucositis often results in dose reduction or interruption of the treatment protocol. For example, a 25% dose reduction is recommended for the first case of grade 4 mucositis or stomatitis, or grade 3-4 mucositis or stomatitis that persists for more than 48 hours despite optimal medical management, or grade 3-4 mucositis or stomatitis where dosing is delayed for 2 or 3 weeks to recover to grade 1 or below at some point in the planned treatment, a 50% dose reduction is recommended for the second case, and discontinuation is recommended for the third case. Discontinuation of treatment is recommended for the first instance of grade 3-4 mucositis or stomatitis that does not resolve to grade 1 or less within 3 weeks.

[0129] Sacituzumab govitecan is generally administered by intravenous infusion on days 1 and 8 of each 21-day cycle following administration of trilaciclib. As provided herein, administration of sacituzumab govitecan should not be longer than 3 hours. In some embodiments, the infusion is administered over 3 hours. In some embodiments, the infusion is administered over 2 hours. In some embodiments, the infusion is administered over 1 hour. In the methods provided herein, sacituzumab govitecan can be administered according to institutional guidelines. In some embodiments, sacituzumab govitecan can be administered at its standard therapeutic dose of 10 mg / kg. In some embodiments, sacituzumab govitecan can be administered at a dose of about 5 mg / kg to 15 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 5 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 6 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 7 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 8 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 9 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 10 mg / kg.

[0130] In some embodiments, prior to administration of sacituzumab govitecan, patients are premedicated for the prevention of infusion reactions and chemotherapy-induced nausea and vomiting (CINV). In some embodiments, prior to administration of sacituzumab govitecan-hygiene, patients are premedicated with an antipyretic, a histamine receptor 1 (H1) and histamine receptor 2 (H2) blocker, and a corticosteroid for the prevention of infusion reactions. In some embodiments, prior to administration of sacituzumab govitecan-hygiene, patients are premedicated with dexamethasone in combination with either a serotonin 5-HT3 receptor antagonist or a neurokinin 1 (NK1) receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting (CINV).

[0131] Treatment of Advanced / Metastatic TNBC with Trilaciclib and Sacituzumab Govitecan As provided herein, trilaciclib, or a pharma- ceutically acceptable salt thereof, is administered in combination with the antibody-drug conjugate sacituzumab govitecan in a specific timed administration protocol to a defined subpopulation of patients with advanced / metastatic TNBC as described herein. Accordingly, provided herein is a method of treating a human patient with advanced / metastatic TNBC, comprising: i) administering to the patient an effective amount of a compound having the structure: [ka] or a pharma- ceutically acceptable salt, composition, isotope, or prodrug thereof; and ii) administering to said patient an effective amount of sacituzumab govitecan comprising A method is provided in which trilaciclib is administered prior to initiation of administration of sacituzumab govitecan, and the patient has previously received at least two prior therapies, at least one of which is in a metastatic setting.

[0132] In some embodiments, trilaciclib is administered within 4 hours prior to administration of sacituzumab govitecan. In some embodiments, trilaciclib is administered within about 2 hours prior to administration of sacituzumab govitecan, e.g., about 2 hours, about 1 hour and 30 minutes, about 1 hour, about 45 minutes, about 40 minutes, about 35 minutes, or about 30 minutes.

[0133] In some embodiments, trilaciclib is administered to a patient at about 190-280 mg / m 2 In some embodiments, trilaciclib is administered intravenously at about 240 mg / m 2 It is administered at .

[0134] In some embodiments, sacituzumab govitecan is administered at a dose of about 5 mg / kg to 15 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 5 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 6 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 7 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 8 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 9 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 10 mg / kg. In some embodiments, sacituzumab govitecan is administered as a continuous infusion (CI) over a period of about 1 hour to 3 hours. In some embodiments, the first infusion of sacituzumab govitecan is administered over 3 hours. In some embodiments, subsequent infusions of sacituzumab govitecan are administered over 2 hours. In some embodiments, subsequent infusions of sacituzumab govitecan are administered over 1 hour.

[0135] In some embodiments, the trilaciclib / sacituzumab govitecan regimen is administered for 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, 30 or more, 31 or more, 32 or more, 33 or more, or 34 or more cycles. In some embodiments, the trilaciclib / sacituzumab govitecan regimen is administered for up to 35 cycles.

[0136] In some embodiments, the protocol comprises one or more 21-day treatment cycles, where trilaciclib and sacituzumab govitecan are administered on days 1 and 8 of each 21-day cycle, where trilaciclib is administered within 4 hours prior to administration of sacituzumab govitecan, and where trilaciclib is administered completely prior to the start of administration of sacituzumab govitecan.

[0137] In some embodiments, the protocol comprises one or more 21-day treatment cycles, where trilaciclib and sacituzumab govitecan are administered on days 1 and 8 of each 21-day cycle, trilaciclib without sacituzumab govitecan is administered on day 15 of each 21-day cycle, trilaciclib is administered within 4 hours prior to administration of sacituzumab govitecan, and trilaciclib is administered completely prior to the start of administration of sacituzumab govitecan on days 1 and 8.

[0138] In some embodiments, prior to administration of sacituzumab govitecan, patients are premedicated for infusion reactions and chemotherapy-induced nausea and vomiting (CINV). In some embodiments, prior to administration of sacituzumab govitecan, patients are premedicated with an antipyretic, a histamine receptor 1 (H1) and histamine receptor 2 (H2) blocker, and a corticosteroid for infusion reaction prevention. In some embodiments, prior to administration of sacituzumab govitecan, patients are premedicated with dexamethasone in combination with either a serotonin 5-HT3 receptor antagonist or a neurokinin 1 (NK1) receptor antagonist for chemotherapy-induced nausea and vomiting (CINV) prevention.

[0139] Treatment of Advanced / Metastatic Urothelial Carcinoma with Trilaciclib + Sacituzumab Govitecan As provided herein, trilaciclib or a pharma- ceutically acceptable salt thereof is administered in combination with the antibody-drug conjugate sacituzumab govitecan in a specific timed administration protocol to a defined subpopulation of patients with advanced / metastatic urothelial cancer as described herein. Accordingly, provided herein is a method of treating a human patient with advanced / metastatic urothelial cancer, comprising: i) administering to the patient an effective amount of a compound having the structure: [ka] or a pharma- ceutically acceptable salt, composition, isotope, or prodrug thereof; and ii) administering to said patient an effective amount of sacituzumab govitecan comprising Methods are provided in which trilaciclib is administered prior to initiation of administration of sacituzumab govitecan, and the patient has received platinum-containing chemotherapy and either a programmed death receptor-1 (PD-1) or a programmed death ligand-1 (PD-L1) inhibitor.

[0140] In some embodiments, trilaciclib is administered within 4 hours prior to administration of sacituzumab govitecan. In some embodiments, trilaciclib is administered within about 2 hours prior to administration of sacituzumab govitecan, e.g., about 2 hours, about 1 hour and 30 minutes, about 1 hour, about 45 minutes, about 40 minutes, about 35 minutes, or about 30 minutes. In some embodiments, trilaciclib is administered to a patient at about 190-280 mg / m 2 In some embodiments, trilaciclib is administered intravenously at about 240 mg / m 2 It is administered at .

[0141] In some embodiments, sacituzumab govitecan is administered at a dose of about 5 mg / kg to 15 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 5 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 6 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 7 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 8 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 9 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 10 mg / kg. In some embodiments, sacituzumab govitecan is administered as a continuous infusion (CI) over a period of about 1 hour to 3 hours. In some embodiments, the first infusion of sacituzumab govitecan is administered over 3 hours. In some embodiments, subsequent infusions of sacituzumab govitecan are administered over 2 hours. In some embodiments, subsequent infusions of sacituzumab govitecan are administered over 1 hour.

[0142] In some embodiments, the trilaciclib / sacituzumab govitecan regimen is administered for 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, 30 or more, 31 or more, 32 or more, 33 or more, or 34 or more cycles. In some embodiments, the trilaciclib / sacituzumab govitecan regimen is administered for up to 35 cycles.

[0143] In some embodiments, prior to administration of sacituzumab govitecan, patients are premedicated for infusion reactions and chemotherapy-induced nausea and vomiting (CINV). In some embodiments, prior to administration of sacituzumab govitecan, patients are premedicated with an antipyretic, a histamine receptor 1 (H1) and histamine receptor 2 (H2) blocker, and a corticosteroid for infusion reaction prevention. In some embodiments, prior to administration of sacituzumab govitecan, patients are premedicated with dexamethasone in combination with either a serotonin 5-HT3 receptor antagonist or a neurokinin 1 (NK1) receptor antagonist for chemotherapy-induced nausea and vomiting (CINV).

[0144] In some embodiments, the protocol comprises one or more 21-day treatment cycles, where trilaciclib and sacituzumab govitecan are administered on days 1 and 8 of each 21-day cycle, where trilaciclib is administered within 4 hours prior to administration of sacituzumab govitecan, and where trilaciclib is administered completely prior to the start of administration of sacituzumab govitecan.

[0145] In some embodiments, the protocol comprises one or more 21-day treatment cycles, where trilaciclib and sacituzumab govitecan are administered on days 1 and 8 of each 21-day cycle, trilaciclib is administered on day 15 of each 21-day cycle without sacituzumab govitecan, trilaciclib is administered within 4 hours prior to administration of sacituzumab govitecan on days 1 and 8, and trilaciclib is administered completely prior to the start of administration of sacituzumab govitecan.

[0146] Trilaciclib plus sacituzumab govitecan for the treatment of Trop-2-overexpressing cancers To a defined subpopulation of patients with Trop-2 overexpressing cancer as described herein, trilaciclib or a pharma- ceutical acceptable salt thereof is administered in combination with the antibody-drug conjugate sacituzumab govitecan in a specific timed administration protocol. Thus, provided herein is a method of treating a human patient with Trop-2 overexpressing cancer, comprising: i) administering to the patient an effective amount of a compound having the structure: [ka] or a pharma- ceutically acceptable salt, composition, isotope, or prodrug thereof; and ii) administering to said patient an effective amount of sacituzumab govitecan comprising Methods are provided wherein trilaciclib is administered prior to initiation of administration of sacituzumab govitecan.

[0147] In some embodiments, the Trop-2 overexpressing cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the NSCLC is metastatic or progressive NSCLC. In some embodiments, the NSCLC has progressed during or after receiving platinum-based chemotherapy and PD-1 or PD-L1 inhibitor therapy, either in combination or sequentially.

[0148] In some embodiments, trilaciclib is administered within 4 hours prior to administration of sacituzumab govitecan. In some embodiments, trilaciclib is administered within about 2 hours prior to administration of sacituzumab govitecan, e.g., about 2 hours, about 1 hour and 30 minutes, about 1 hour, about 45 minutes, about 40 minutes, about 35 minutes, or about 30 minutes. In some embodiments, trilaciclib is administered to a patient at about 190-280 mg / m 2 In some embodiments, trilaciclib is administered intravenously at about 240 mg / m 2 It is administered at .

[0149] In some embodiments, sacituzumab govitecan is administered at a dose of about 5 mg / kg to 15 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 5 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 6 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 7 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 8 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 9 mg / kg. In some embodiments, sacituzumab govitecan is administered at a dose of about 10 mg / kg. In some embodiments, sacituzumab govitecan is administered as a continuous infusion (CI) over a period of about 1 hour to 3 hours. In some embodiments, the first infusion of sacituzumab govitecan is administered over 3 hours. In some embodiments, subsequent infusions of sacituzumab govitecan are administered over 2 hours. In some embodiments, subsequent infusions of sacituzumab govitecan are administered over 1 hour.

[0150] In some embodiments, the trilaciclib / sacituzumab govitecan regimen is administered for 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, 30 or more, 31 or more, 32 or more, 33 or more, or 34 or more cycles. In some embodiments, the trilaciclib / sacituzumab govitecan regimen is administered for up to 35 cycles.

[0151] In some embodiments, prior to administration of sacituzumab govitecan, patients are premedicated for infusion reactions and chemotherapy-induced nausea and vomiting (CINV). In some embodiments, prior to administration of sacituzumab govitecan, patients are premedicated with an antipyretic, a histamine receptor 1 (H1) and histamine receptor 2 (H2) blocker, and a corticosteroid for infusion reactions. In some embodiments, prior to administration of sacituzumab govitecan, patients are premedicated with dexamethasone and a serotonin 5-HT3 receptor antagonist or neurokinin for chemotherapy-induced nausea and vomiting (CINV). These patients are pretreated with either a NK1 receptor antagonist or a vasodilator.

[0152] In some embodiments, the protocol comprises one or more 21-day treatment cycles, where trilaciclib and sacituzumab govitecan are administered on days 1 and 8 of each 21-day cycle, where trilaciclib is administered within 4 hours prior to administration of sacituzumab govitecan, and where trilaciclib is administered completely prior to the start of administration of sacituzumab govitecan.

[0153] Trop-2 overexpressing cancers for treatment with the methods described herein include advanced / metastatic cancers selected from the group consisting of breast cancer, including TNBC, cervical cancer, colon or colorectal cancer, endometrioid endometrial cancer, esophageal cancer, gastric cancer, glioma, hilar cholangiocarcinoma, oral squamous cell carcinoma, gastrointestinal cancer, chronic lymphocytic lymphoma, extranodal NK / T cell lymphoma, non-Hodgkin's lymphoma, Raji Burkitt's lymphoma, small lung adenocarcinoma, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, thyroid cancer, urothelial cancer, uterine cancer, and lung cancer, including small cell lung cancer and non-small cell lung cancer. In some embodiments, the Trop-2 overexpressing cancer is breast cancer. In some embodiments, the Trop-2 overexpressing cancer is triple negative breast cancer. In some embodiments, the Trop-2 overexpressing cancer is urothelial cancer. In some embodiments, the Trop-2 overexpressing cancer is colon or colorectal cancer. In some embodiments, the Trop-2 overexpressing cancer is prostate cancer. In some embodiments, the Trop-2 overexpressing cancer is pancreatic cancer. In some embodiments, the Trop-2 overexpressing cancer is lung cancer. In some embodiments, the Trop-2 overexpressing lung cancer is non-small cell lung cancer. In some embodiments, the Trop-2 overexpressing lung cancer is small cell lung cancer. In some embodiments, the Trop-2 overexpressing cancer is cervical cancer. In some embodiments, the Trop-2 overexpressing cancer is endometrioid endometrial cancer. In some embodiments, the Trop-2 overexpressing cancer is esophageal cancer. In some embodiments, the Trop-2 overexpressing cancer is gastric cancer. In some embodiments, the Trop-2 overexpressing cancer is glioma. In some embodiments, the Trop-2 overexpressing cancer is perihilar cholangiocarcinoma. In some embodiments, the Trop-2 overexpressing cancer is oral squamous cell carcinoma. In some embodiments, the Trop-2 overexpressing cancer is gastrointestinal cancer. In some embodiments, the Trop-2 overexpressing cancer is a chronic lymphocytic lymphoma. In some embodiments, the Trop-2 overexpressing cancer is an extranodal NK / T cell lymphoma. In some embodiments, the Trop-2 overexpressing cancer is a non-Hodgkin's lymphoma.In some embodiments, the Trop-2 overexpressing cancer is Raji Burkitt's lymphoma. In some embodiments, the Trop-2 overexpressing cancer is small lung adenocarcinoma. In some embodiments, the Trop-2 overexpressing cancer is ovarian cancer. In some embodiments, the Trop-2 overexpressing cancer is pancreatic cancer. In some embodiments, the Trop-2 overexpressing cancer is prostate cancer. In some embodiments, the Trop-2 overexpressing cancer is gastric cancer. In some embodiments, the Trop-2 overexpressing cancer is thyroid cancer. In some embodiments, the Trop-2 overexpressing cancer is uterine cancer.

[0154] Trophoblast cell surface antigen 2 (Trop-2) is a glycoprotein that coats the epithelial membrane surface and plays a role in cell self-renewal, proliferation, and transformation (Zaman et al., Targeting Trop-2 in solid tumors: future prospects. Onco Targets Ther. 2019;12:1781-1790). Under physiological conditions, Trop-2 plays an essential role in embryonic development, placental tissue formation, embryo implantation, stem cell proliferation, and organ development (Shvartsur et al., Trop2 and its overexpression in cancers: regulation and clinical / therapeutic implications. Genes Cancer. 2015;6(3-4):84-105). Low basal expression levels of Trop-2 are found on the surfaces of several normal epithelial tissues, including skin and oral mucosa (Strop P, Tran TT, Dorywalska M, et al. RN927C, a site-specific Trop-2 antibody-drug conjugate (ADC) with enhanced stability, is highly efficacious in preclinical solid tumor models. Mol Cancer Ther. 2016;15(11):2698-2708). Trop-2 can promote tumor growth, and its overexpression is common in many types of malignant epithelial tumors (Goldenberg DM, Stein R, Sharkey RM. The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget. 2018;9(48):28989-29006). Overexpression of Trop-2 accelerates the cancer cell cycle and promotes cancer proliferation. Overexpression of Trop2 is associated with decreased patient survival and increased tumor aggressiveness and metastasis in many cancers.In some embodiments, trilaciclib or a pharma- ceutically acceptable salt thereof is administered in combination with the antibody-drug conjugate sacituzumab govitecan in a specific timed administration protocol described herein to patients with advanced / metastatic cancers that overexpress Trop-2. In some embodiments, the advanced / metastatic cancers that overexpress Trop-2 are selected from the group consisting of breast cancer, cervical cancer, colon and colorectal cancer, endometrioid endometrial cancer, esophageal cancer, gastric cancer, glioma, perihilar cholangiocarcinoma, oral squamous cell carcinoma, gastrointestinal cancer, chronic lymphocytic lymphoma, extranodal NK / T cell lymphoma, non-Hodgkin's lymphoma, Raji Burkitt's lymphoma, small lung adenocarcinoma, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, thyroid cancer, bladder cancer, and uterine cancer.

[0155] Methods for measuring Trop-2 expression are known in the art. One method is to measure the presence of TROP2 gene from tumor sample mRNA using expressed sequence tag (EST) analysis, SAGE (Serial Analysis of Gene Expression), DNA microarray analysis and / or quantitative RT-PCR, and directly from tumor sample using immunohistochemistry. These methods are described in Trerotola, M., Cantanelli, P., Guerra, E. et al. Upregulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene 32, 222-233 (2013). Trop-2 expression has also been described in Zeybek B, Manzano A, Bianchi A, et al. Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan. Sci Rep. 2020; 10(1): 973. Published 2020 Jan 22. Immunofluorescence techniques can also be used to measure Trop-2 expression as described in Strop et al., N927C, a Site-Specific Trop-2 Antibody-Drug Conjugate (ADC) with Enhanced Stability, Is Highly Efficacious in Preclinical Solid Tumor Models; Mol Cancer Ther November 1 2016 (15) (11) 2698-2708.

[0156] Antitumor efficacy evaluation In some embodiments, the inclusion of trilaciclib in the sacituzumab-govitecan chemotherapy protocol described herein for the treatment of Trop-2 overexpressing cancers, such as advanced or metastatic TNBC or metastatic urothelial carcinoma, or NSCLC, provides enhanced antitumor efficacy compared to patients undergoing the sacituzumab-govitecan chemotherapy protocol without trilaciclib. Methods for assessing tumor response are well known in the art, including, for example, RECIST v1.1 (Eisenhauer et al., New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228-247).

[0157] In some embodiments, the inclusion of trilaciclib in a sacituzumab govitecan chemotherapy protocol described herein for the treatment of progressive or metastatic TNBC, alternatively progressive or metastatic urothelial carcinoma, or alternatively progressive or metastatic Trop-2 overexpressing cancer, such as, but not limited to, non-small cell lung cancer, provides an enhancement or prolongation of progression-free survival (PFS) compared to patients not receiving trilaciclib. PFS is generally defined as the time (in months) from the date of first administration of trilaciclib + sacituzumab govitecan as provided herein to the date of documented radiological disease progression (PD) according to RECIST v1.1 or death from any cause, whichever occurs first. Methods for assessing increased PFS are well known in the art and include, for example, RECIST v1.1 (Eisenhauer et al., New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228-247).

[0158] In some embodiments, the inclusion of trilaciclib in a sacituzumab-govitecan chemotherapy protocol described herein for the treatment of advanced or metastatic TNBC, or alternatively advanced or metastatic urothelial carcinoma, or other Trop-2 overexpressing cancers, including but not limited to NSCLC, provides an enhancement or prolongation of overall survival (OS) compared to patients not receiving trilaciclib. OS is generally calculated as the time (in months) from the date of first administration of trilaciclib + sacituzumab-govitecan as provided herein to the date of death for patients who died from any cause, compared to patients not receiving trilaciclib.

[0159] In some embodiments, the inclusion of trilaciclib in the sacituzumab-govitecan chemotherapy protocol described herein for the treatment of advanced or metastatic TNBC, alternatively advanced or metastatic urothelial carcinoma, or alternatively Trop-2 overexpressing cancer, including but not limited to NSCLC, provides an improved objective response rate (ORR) compared to patients not receiving trilaciclib. ORR is generally defined as the proportion of patients with a best overall response (BOR), either a complete response (CR) or a partial response (PR) according to RECIST v1.1. Examples of objective responses (OR) include a complete response (CR), which is the disappearance of all signs of a tumor in response to treatment, and a partial response (PR), which is a reduction in the size of a tumor in response to treatment. In some embodiments, the objective response (OR) is a complete response (CR). In some embodiments, the objective response (OR) is a partial response (PR). ORR is an important parameter indicating the efficacy of a treatment and serves as a primary or secondary endpoint in clinical trials. Methods for assessing ORR are well known in the art and include, for example, RECIST v1.1 (Eisenhauer et al., New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228-247) and the World Health Organization (WHO) (World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. World Health Organization Offset Publication No. 48; Geneva (Switzerland), 1979).Statistical methods for measuring objective response rates are well known in the art, and include, for example, the Clopper-Pearson method (Clopper, C.; Pearson, ES (1934). "The use of confidence or fiducial limits illustrated in the case of the binomial". Biometrika. 26 (4): 404-413. doi:10.1093 / biomet / 26.4.404).

[0160] In some embodiments, the inclusion of trilaciclib in the sacituzumab-govitecan chemotherapy protocol described herein for the treatment of advanced or metastatic TNBC, alternatively advanced or metastatic urothelial carcinoma, or alternatively Trop-2 overexpressing cancer, including but not limited to NSCLC, provides an improved clinical benefit rate (CBR) compared to patients not receiving trilaciclib. CBR is generally defined as the proportion of patients who have a best overall response of complete response (CR), partial response (PR), or stable disease (SD) lasting for at least 24 weeks from the first day of study administration. Methods for assessing improved CBR are well known in the art, including, for example, RECIST v1.1 (Eisenhauer et al., New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228-247).

[0161] In some embodiments, the inclusion of trilaciclib in the sacituzumab-govitecan chemotherapy protocol described herein for the treatment of advanced or metastatic TNBC, alternatively advanced or metastatic urothelial carcinoma, or alternatively Trop-2 overexpressing cancer, including but not limited to NSCLC, provides an improvement in duration of objective response (DOR) compared to patients not receiving trilaciclib. DOR is generally defined as the time (in months) from the date of achieving the first confirmed objective response (CR or PR) at the next tumor scan to the date of documented disease progression according to RECIST v1.1 or death, whichever occurs first. Methods for assessing improvement in DOR are well known in the art, and include, for example, RECIST v1.1 (Eisenhauer et al., New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228-247).

[0162] In some embodiments, the inclusion of trilaciclib in a sacituzumab-govitecan chemotherapy protocol described herein for the treatment of advanced or metastatic TNBC, or alternatively advanced or metastatic urothelial carcinoma, or further alternatively a Trop-2 overexpressing cancer, including but not limited to NSCLC, provides T cell immune activation against the tumor. In some embodiments, the T cell immune activation results in T cell receptor (TCR) modulation. In some embodiments, the T cell activation results in increased interferon gamma (IFNγ) expression. In some embodiments, the T cell activation results in increased activation-induced expression of CD137. In some embodiments, the T cell activation results in increased TCR diversity.

[0163] In one aspect, the improved therapeutic method is administered to select a subgroup of patients with progressive / metastatic TNBC, or alternatively progressive / metastatic urothelial carcinoma, or alternatively Trop-2 overexpressing cancer, including but not limited to NSCLC, that exhibit a threshold Simpson clonality score. Simpson clonality is a single numerical index of T cell clonal diversity that describes the characteristic shape of a sample's repertoire. Simpson clonality measures the evenness of the repertoire, i.e., the extent to which one or a few clones dominate the sample's repertoire. Simpson clonality is calculated as follows:

[0164]

number

[0165] In some embodiments, administration of the trilaciclib / sacituzumab govitecan regimen results in a decrease from baseline Simpson clonality, where baseline is measured at the time of initiation of trilaciclib / sacituzumab govitecan.

[0166] Reduced toxicity In some embodiments, the inclusion of trilaciclib in the sacituzumab-govitecan chemotherapy protocols described herein for the treatment of advanced or metastatic TNBC, or alternatively advanced or metastatic urothelial carcinoma, or further alternatively Trop-2 overexpressing cancers, including but not limited to NSCLC, results in improved bone marrow preservation of immune effector cells, such as hematopoietic stem and progenitor cells (HSPCs) and / or lymphocytes, including T lymphocytes, and enhanced anti-tumor efficacy in patients compared to patients receiving the sacituzumab-govitecan chemotherapy protocol without trilaciclib. Improved bone marrow preservation of immune effector cells such as hematopoietic stem and progenitor cells (HSPCs) and lymphocytes, including immune T lymphocytes, will be assessed by increases in hematological assessments (complete blood count (CBC), red blood cell count (RBC), platelet count, white blood cell count (WBC) and absolute neutrophil count (ANC)), reduction in severe adverse events (AEs), reduction in supportive care interventions (including transfusions and G-CSF administration), reduction in dose modifications, and improvement in patient recorded outcomes (PROs).

[0167] In some embodiments, the inclusion of trilaciclib in the sacituzumab-govitecan chemotherapy protocols described herein for the treatment of advanced or metastatic TNBC, or alternatively, advanced or metastatic urothelial carcinoma, or further alternatively, Trop-2 overexpressing cancers, including but not limited to NSCLC, results in a reduced incidence of chemotherapy-induced myelosuppression (CIM). Patients who develop myelosuppression while receiving chemotherapy drugs such as sacituzumab govitecan are likely to experience infections, sepsis, bleeding, and fatigue, and are often required for hospitalization, hematopoietic growth factor requirements, transfusions (red blood cells [RBCs] and / or platelets), and even death (see, e.g., Gustinetti et al., Bloodstream infections in neutropenic cancer patients: A practical update. Virulence. 2016; 7(3): 280-97; Li et al., Relationship between severity and duration of chemotherapy-induced neutropenia and risk of infection among patients with nonmyeloid malignancies. Support Care Cancer 2016; 24(10): 4377-83; Caggiano et al., Incidence, cost, and mortality of neutropenia hospitalization associated with chemotherapy. Cancer. 2005; 103(9): 1916-24). Furthermore, CIM commonly leads to dose reductions and delays, which may limit therapeutic dose intensity and compromise the benefits of the antitumor effects of chemotherapy.Attempts to develop and implement clinical algorithms to guide chemotherapy dose reductions and treatment delays in patients who exhibit neutropenia and / or thrombocytopenia during treatment are being investigated (see, for example, Clinical Trial of a Novel Dose Adjustment Algorithm for Preventing Cytopenia-Related Delays During FOLFOX Chemotherapy, ClinicalTrials.gov Identifier: NCT04526886). Nevertheless, chemotherapy-induced cytotoxicity to the immune system may also limit antitumor efficacy due to the inability of the host immune system to mount an effective response against the cancer. Prolonged exposure to myelosuppressants may result in cumulative myelotoxicity and myelosuppression, limiting the ability to deliver subsequent lines of therapy at standard-of-care doses and schedules.

[0168] In some embodiments, the inclusion of trilaciclib in the sacituzumab-govitecan chemotherapy protocol described herein for the treatment of advanced or metastatic TNBC, or alternatively advanced or metastatic urothelial carcinoma, or alternatively Trop-2 overexpressing cancer, including but not limited to NSCLC, results in bone marrow preservation of neutrophil lineage in patients compared to patients undergoing the sacituzumab-govitecan chemotherapy protocol without trilaciclib. Endpoints for measuring bone marrow preservation of neutrophil lineage include, for example, reduced duration of severe neutropenia after cycle 1, and reduced occurrence of severe neutropenia. Neutropenia is generally defined as a condition found when the body does not have enough neutrophils, which are important white blood cells that fight infection. Neutropenia is generally quantified as an absolute neutrophil count (ANC) of less than 1500 per microliter (1500 / μL). Severe neutropenia is generally quantified as an absolute neutrophil count (ANC) less than 500 per microliter (500 / μL). Methods for calculating the absolute neutrophil count (ANC) are well known in the art and include multiplying the WBC count by the percentage of neutrophils in the differential WBC count. The percentage of neutrophils consists of segmented neutrophils (fully mature neutrophils) + band neutrophils (nearly mature neutrophils).

[0169] In some embodiments, the inclusion of trilaciclib in a sacituzumab-govitecan chemotherapy protocol described herein for the treatment of advanced or metastatic TNBC, or alternatively advanced or metastatic urothelial carcinoma, or further alternatively a Trop-2 overexpressing cancer, including but not limited to NSCLC, results in a reduced occurrence of severe (grade 4) neutropenia (DSN) in patients compared to patients receiving a sacituzumab-govitecan chemotherapy protocol without trilaciclib. Severe neutropenia is defined as a toxicity of grade 4 or higher according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 criteria (i.e., ANC<0.5×10 in SI units). 9Severe neutropenia is defined as an absolute neutrophil count (ANC) test value that meets the 500 / μL threshold. Severe neutropenia is commonly quantified as an absolute neutrophil count (ANC) of less than 500 per microliter (500 / μL). Methods for calculating the absolute neutrophil count (ANC) are well known in the art and include multiplying the WBC count by the percentage of neutrophils in the differential WBC count. The percentage of neutrophils consists of segmented (fully mature) neutrophils) + band-nucleated neutrophils (nearly mature neutrophils).

[0170] In some embodiments, the inclusion of trilaciclib in a sacituzumab-govitecan chemotherapy protocol described herein for the treatment of advanced or metastatic TNBC, or alternatively advanced or metastatic urothelial carcinoma, or further alternatively a Trop-2 overexpressing cancer, including but not limited to NSCLC, results in a reduction in the duration of severe (grade 4) neutropenia (DSN) in patients compared to patients receiving a sacituzumab-govitecan chemotherapy protocol without trilaciclib. The duration of DSN generally occurs when an ANC value initially exceeds 0.5×10 9 / L for the first time since the ANC value was 0.5 × 10 9 / L or higher (but not more than 0.5 × 10 9 Severe neutropenia is defined as an absolute neutrophil count (ANC) of less than 500 per microliter (500 / μL). Methods for calculating the absolute neutrophil count (ANC) are well known in the art and include multiplying the WBC count by the percentage of neutrophils in the differential WBC count. The percentage of neutrophils consists of segmented (fully mature) neutrophils) + band-nucleated neutrophils (nearly mature neutrophils).

[0171] In some embodiments, the inclusion of trilaciclib in a sacituzumab-govitecan chemotherapy protocol described herein for the treatment of advanced or metastatic TNBC, or alternatively advanced or metastatic urothelial carcinoma, or alternatively a Trop-2 overexpressing cancer, including but not limited to NSCLC, results in a reduction in chemotherapy-induced fatigue (CIF) in a patient compared to a patient receiving a sacituzumab-govitecan chemotherapy protocol without trilaciclib. In some embodiments, the reduction in CIF is a reduction in time to first documented worsening of fatigue (TTCD-for fatigue) as measured by the Functional Assessment of Cancer Therapy-for Fatigue (FACIT-F). The FACIT-F is a 13-item subscale that measures the severity of fatigue and the impact of fatigue on function, and is described in Yellen et al., Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage. 1997; 13: 63-74.

[0172] In some embodiments, the inclusion of trilaciclib in a sacituzumab-govitecan chemotherapy protocol described herein for the treatment of advanced or metastatic TNBC, or alternatively advanced or metastatic urothelial carcinoma, or further alternatively a Trop-2 overexpressing cancer, including but not limited to NSCLC, results in fewer severe neutropenic events, fewer granulocyte-colony stimulating factor (G-CSF) treatments, or fewer febrile neutropenic (FN) adverse events (AEs) in patients compared to patients receiving a sacituzumab-govitecan-Hydzy chemotherapy protocol without trilaciclib. G-CSF therapy is utilized according to the treatment guidelines outlined in Aapro et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011; 47:8-32.

[0173] In some embodiments, the inclusion of trilaciclib in a sacituzumab-govitecan chemotherapy protocol described herein for the treatment of advanced or metastatic TNBC, or alternatively, advanced or metastatic urothelial carcinoma, or further alternatively, a Trop-2 overexpressing cancer, including, but not limited to, NSCLC, results in a reduction in Grade 3 or 4 low hemoglobin test results, red blood cell (RBC) transfusions, or erythropoietin stimulating agent (ESA) administration.

[0174] In some embodiments, the inclusion of trilaciclib in the sacituzumab-govitecan chemotherapy protocols described herein for the treatment of advanced or metastatic TNBC, or alternatively advanced or metastatic urothelial carcinoma, or further alternatively Trop-2 overexpressing cancers, including but not limited to NSCLC, results in a reduction in grade 3 or 4 low platelet count labs and / or platelet transfusions. As described in (Kaufman, 2015; Schiffer, 2017), platelets are generally transfused at a threshold of 10,000 / μL or greater. Platelets are also generally transfused to bleeding patients with platelet counts below 50,000 / μL (100,000 / μL for central nervous system or ocular bleeding).

[0175] In some embodiments, the inclusion of trilaciclib in a sacituzumab-govitecan chemotherapy protocol described herein for the treatment of progressive or metastatic TNBC, or alternatively progressive or metastatic urothelial carcinoma, or further alternatively Trop-2 overexpressing cancers, including but not limited to NSCLC, results in a reduction in grade 3 or 4 blood test values. In some embodiments, the use of trilaciclib as described herein in a sacituzumab-govitecan chemotherapy protocol for the treatment of progressive or metastatic TNBC, or alternatively progressive or metastatic urothelial carcinoma, or further alternatively Trop-2 overexpressing cancers, results in an all-cause dose reduction or cycle delay and a reduction in the relative dose intensity of the sacituzumab-govitecan chemotherapy protocol described herein.

[0176] In some embodiments, the inclusion of trilaciclib in a sacituzumab-govitecan chemotherapy protocol described herein for the treatment of advanced or metastatic TNBC, or alternatively, advanced or metastatic urothelial carcinoma, or further alternatively, a Trop-2 overexpressing cancer, including but not limited to NSCLC, results in i) a reduction in hospitalizations, including but not limited to those due to any cause of febrile neutropenia / neutropenia, anemia / RBC transfusion, thrombocytopenia / bleeding, and infection, or ii) a reduction in the use of antibiotics, including but not limited to intravenous (IV), oral, and oral-IV administered antibiotics.

[0177] In some embodiments, the inclusion of trilaciclib in a sacituzumab-govitecan chemotherapy protocol described herein for the treatment of advanced or metastatic TNBC, or alternatively advanced or metastatic urothelial carcinoma, or further alternatively a Trop-2 overexpressing cancer, including but not limited to NSCLC, results in improvement in one or more of the following: Functional Assessment of Cancer Therapy-General (FACT-G) domain scores (physical, social / family, psychological, and functional); Functional Assessment of Cancer Therapy-Anemia (FACT-An): 5-level EQ-5D (EQ-5D-5L); Patient Global Impression of Change (PGIC) fatigue item; or Patient Global Impression of Severity (PGIS) fatigue item.

[0178] In some embodiments, the inclusion of trilaciclib in the sacituzumab-govitecan chemotherapy protocols described herein for the treatment of advanced or metastatic TNBC, or alternatively advanced or metastatic urothelial carcinoma, or further alternatively a Trop-2-overexpressing cancer, including but not limited to NSCLC, results in a reduction in the number of severe diarrhea episodes (grade 3 or greater) experienced by a patient compared to a patient receiving the sacituzumab-govitecan chemotherapy protocol described herein without trilaciclib.

[0179] In some embodiments, the inclusion of trilaciclib in a sacituzumab-govitecan chemotherapy protocol described herein for the treatment of advanced or metastatic TNBC, or alternatively, advanced or metastatic urothelial carcinoma, or further alternatively, a Trop-2-overexpressing cancer, including but not limited to NSCLC, results in a reduction in the occurrence, severity, or episodes of mucositis experienced by a patient compared to a patient receiving a sacituzumab-govitecan chemotherapy protocol described herein without trilaciclib.

[0180] In some embodiments, the inclusion of trilaciclib in a sacituzumab-govitecan chemotherapy protocol described herein for the treatment of advanced or metastatic TNBC, or alternatively advanced or metastatic urothelial carcinoma, or further alternatively a Trop-2 overexpressing cancer, including but not limited to NSCLC, results in a reduction in the occurrence, severity, or episodes of stomatitis experienced by a patient compared to a patient undergoing a sacituzumab-govitecan chemotherapy protocol described herein without trilaciclib.

[0181] In some embodiments, the inclusion of trilaciclib in the sacituzumab-govitecan chemotherapy protocols described herein for the treatment of advanced or metastatic TNBC, or alternatively, advanced or metastatic urothelial carcinoma, or further alternatively, Trop-2 overexpressing cancers, including but not limited to NSCLC, results in a reduction in the incidence, severity, and / or severity of alopecia experienced by patients compared to patients receiving the sacituzumab-govitecan chemotherapy protocols described herein without trilaciclib.

[0182] In some embodiments, the inclusion of trilaciclib in the sacituzumab-govitecan chemotherapy protocols described herein for the treatment of advanced or metastatic TNBC, or alternatively, advanced or metastatic urothelial carcinoma, or further alternatively, a Trop-2 overexpressing cancer, including but not limited to NSCLC, results in a reduction in the incidence and severity of gastrointestinal adverse events experienced by patients compared to patients receiving the sacituzumab-govitecan chemotherapy protocols described herein without trilaciclib.

[0183] In some embodiments, the inclusion of trilaciclib in the sacituzumab-govitecan chemotherapy protocols described herein for the treatment of advanced or metastatic TNBC, or alternatively advanced or metastatic urothelial carcinoma, or further alternatively Trop-2 overexpressing cancers, including but not limited to NSCLC, results in a reduction in the number of severe anemia episodes (grade 3 or greater) experienced by a patient compared to a patient receiving the sacituzumab-govitecan chemotherapy protocol described herein without trilaciclib.

[0184] In some embodiments, the inclusion of trilaciclib in a sacituzumab-govitecan chemotherapy protocol for the treatment of advanced or metastatic TNBC, or alternatively advanced or metastatic urothelial carcinoma, or further alternatively a Trop-2 overexpressing cancer, including but not limited to NSCLC not described herein, results in a reduction in the number of severe neutropenic episodes (grade 3 or greater) experienced by a patient compared to a patient receiving a sacituzumab-govitecan chemotherapy protocol described herein without trilaciclib.

[0185] In some embodiments, the inclusion of trilaciclib in the sacituzumab-govitecan chemotherapy protocols described herein for the treatment of advanced or metastatic TNBC, or alternatively advanced or metastatic urothelial carcinoma, or further alternatively a Trop-2-overexpressing cancer, including but not limited to NSCLC, results in a reduction in the number of febrile neutropenic episodes (grade 3 or greater) experienced by a patient compared to a patient receiving the sacituzumab-govitecan chemotherapy protocol described herein without trilaciclib.

[0186] Pharmaceutical Compositions The selected compounds of the protocols described herein, or their pharma- ceutically acceptable salts, may be administered as neat chemicals, but are more commonly administered as pharmaceutical compositions containing an effective amount in a pharma- ceutically acceptable carrier to a patient, typically a human, in need of such treatment. The pharmaceutical composition may contain the compound or its salt as the only active agent, or, in another embodiment, may contain the compound or its salt and at least one additional active agent to the bamboo strip being treated.

[0187] The pharmaceutical composition can be administered in a therapeutically effective amount by any desired mode of administration, but is generally administered as an intravenous injection or infusion.In another embodiment, the compound or pharmacologic acceptable salt is delivered in an effective amount with a pharmacologic acceptable carrier for oral delivery.As a more general, non-limiting example, the pharmaceutical composition is suitable for oral (including buccal and sublingual), rectal, nasal, topical, transdermal, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous), injection, inhalation or spray, intra-aortic, intracranial, subdermal, intraperitoneal, subcutaneous, or other administration means, containing a conventional pharmacologic acceptable carrier.

[0188] The appropriate dosage range depends on a number of factors, such as the severity of the disease being treated, the age and relative health of the patient, the potency of the compound used, the route and form of administration, and the preferences and experience of the practitioner involved. Those of ordinary skill in the art of treating such diseases can ascertain, without undue experimentation, relying on their personal knowledge and the disclosure of this application, a therapeutically effective amount of the compositions of the present disclosure for a given disease.

[0189] In certain embodiments, the pharmaceutical composition is in a dosage form containing about 0.01 mg to about 1000 mg, about 0.1 mg to about 750 mg, about 1 mg to about 500 mg, or about 5, 10, 15, or 20 mg to about 250 mg of the active compound or a pharma- ceutically acceptable salt thereof. Examples include dosage forms that deliver at least 0.01, 0.05, 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of the active compound or a salt thereof. When weight is used herein, it can refer to either the compound alone or the combination of the compound and a pharma- ceutically acceptable salt.

[0190] An effective amount of the disclosed compound or its salt can be administered based on the weight, size or age of the patient. For example, a therapeutic amount can be, for example, about 0.01 mg / kg to about 250 mg / kg body weight, or about 0.1 mg / kg to about 10 mg / kg, at least in one dose. The patient can be administered multiple doses as needed to alleviate and / or relieve and / or cure the targeted disorder. If desired, the formulation can be enteric coated to accommodate sustained or controlled release administration of the active ingredient.

[0191] In certain embodiments, the dose is about 0.01 to 100 mg / kg of patient weight, e.g., about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 10 ... In some embodiments, the range is about 5 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg.

[0192] The pharmaceutical preparation is preferably in unit dosage form.In such form, the preparation is subdivided into unit doses containing an appropriate amount of active ingredient.The unit dosage form can be a packaged preparation, the package containing discrete amounts of preparation, such as packaged tablets, capsules, and powders in vials or ampoules.The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0193] In certain embodiments, the compound is administered as a pharma- ceutically acceptable salt. Non-limiting examples of pharma-ceutically acceptable salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfate, and the like. Representative salts of alkali or alkaline earth metals include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0194] Depending on the intended mode of administration, the pharmaceutical composition may be in solid, semi-solid or liquid dosage form, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrups, suspensions, creams, ointments, lotions, pastes, gels, sprays, aerosols, foams, or oils, injections or infusions, transdermal patches, subcutaneous patches, inhalation formulations, within medical devices, suppositories, buccal or sublingual formulations, parenteral formulations, or ophthalmic solutions, preferably in a unit dosage form suitable for single administration of a precise dose.

[0195] Some dosage forms, such as tablets and capsules, are subdivided into unit doses of suitable size containing an appropriate amount of the active ingredient, e.g., an effective amount to achieve a desired purpose. The composition contains an effective amount of the selected drug in combination with a pharma- ceutically acceptable carrier, and may further include other pharmaceutical agents, adjuvants, diluents, buffers, etc.

[0196] Carriers include excipients and diluents and must be of sufficient purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. Carriers may be inert or may have pharmaceutical benefits of their own. The amount of carrier used in combination with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound.

[0197] Types of carriers include, but are not limited to, adjuvants, binders, buffers, colorants, diluents, disintegrants, excipients, emulsifiers, flavorings, gels, glidants, lubricants, preservatives, stabilizers, surfactants, solubilizers, tableting, wetting agents or solidifying agents.

[0198] Some carriers may be listed in more than one category; for example, vegetable oils are used as lubricants and as diluents in some formulations.

[0199] Exemplary pharma- ceutically acceptable carriers include sugars, starches, cellulose, powdered tragacanth gum, malt, gelatin, talc, petrolatum, lanolin, polyethylene glycol, alcohol, transdermal enhancers and vegetable oils.Optional active agents that do not substantially interfere with the activity of the compound of the present invention may be included in the pharmaceutical composition.

[0200] Some excipients include, but are not limited to, liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, etc. Compounds can be provided in the form of, for example, solid, liquid, spray-dried material, microparticles, nanoparticles, controlled release systems, etc., as desired according to the purpose of therapy. Suitable excipients for non-liquid formulations are also known to those skilled in the art. A detailed discussion of pharma-ceutically acceptable excipients and salts is available in Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).

[0201] Additionally, auxiliary substances such as wetting or emulsifying agents, biological buffer substances, surfactants, etc. may be present in such vehicles. The biological buffer may be any solution that is pharmacologically acceptable and provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range. Examples of buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank's buffered saline, etc.

[0202] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. Liquid pharma-ceutically administrable compositions can be prepared, for example, by dissolving the active compound as described herein and optional pharmaceutical adjuvants in an excipient, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, etc., for example, sodium acetate, sorbitan monolaurate, sodium triethanolamine acetate, triethanolamine oleate, etc. Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, cited above.

[0203] In yet another embodiment, there is provided the use of permeation enhancing excipients including polymers such as polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethylchitosan, polyacrylic acid); and thiolated polymers (carboxymethylcellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione complexes).

[0204] In certain embodiments, the excipient is selected from butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0205] The pharmaceutical composition containing the active agent can be prepared for oral administration. For oral administration, the composition may take the form of a tablet, capsule, soft gel capsule, or may be an aqueous or non-aqueous solution, suspension, or syrup. Tablets and capsules are typical oral dosage forms. Tablets and capsules for oral use may contain one or more conventional carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are also generally added. In general, the composition of the present disclosure can be combined with an oral, non-toxic, pharma- ceutically acceptable inert carrier, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and the like. Furthermore, suitable binders, lubricants, disintegrants, and coloring agents can be incorporated into the mixture, if desired or necessary. Suitable binders include starch, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic (such as gum arabic, gum tragacanth, or sodium alginate), carboxymethylcellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0206] When liquid suspension is used, the active agent can be combined with any oral, non-toxic, pharma- ceutically acceptable inert carrier, such as ethanol, glycerol, water, etc., and with emulsifiers and suspending agents. Flavoring agents, coloring agents, and / or sweetening agents can also be added as desired. Other optional ingredients for incorporation into oral preparations include, but are not limited to, preservatives, suspending agents, thickening agents, etc.

[0207] Parenteral preparations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in liquid before injection, or as emulsions. Generally, sterile injectable suspensions are prepared using suitable carriers, dispersing or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in acceptable non-toxic parenterally acceptable diluents or solvents. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile hardened oils, fatty esters, or polyols are conventionally used as solvents or suspending media. In addition, parenteral administration can include the use of slow release or sustained release systems to maintain a constant dosage level.

[0208] Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. Specific parenteral route administration may include introducing the disclosed formulation into the patient's body through a sterile needle or catheter propelled by a sterile syringe or some other mechanical device, such as a continuous infusion system. The formulations provided by the present disclosure may be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.

[0209] The claimed invention is further illustrated by the following non-limiting examples. Further aspects and embodiments of the present invention will become apparent to those skilled in the art from consideration of the above disclosure and the following experimental illustrations, which are included by way of illustration and not by way of limitation, and taken in conjunction with the accompanying drawings. EXAMPLES

[0210] Example 1. A Phase 2, Single-Arm, Open-Label Study of Trilaciclib Administered Prior to Sacituzumab-Govitecan-Hydro in Patients with Unresectable Locally Advanced or Metastatic Triple-Negative Breast Cancer Who Have Had At Least Two Prior Therapies, At Least One of Which Was a Metastatic Therapy Overview Provided herein is an exploratory Phase 2, multicenter, open-label study evaluating the safety and efficacy of trilaciclib administered in combination with sacituzumab govitecan-hyzy in patients with unresectable advanced or metastatic TNBC who have received at least two prior therapies, at least one of which is a metastatic therapy.

[0211] A general scheme describing the clinical trial is shown in Figure 1. Approximately 45 patients will be enrolled in this study.

[0212] Trilaciclib and sacituzumab govitecan-hydipine will be administered intravenously (IV) on a 21-day cycle as follows: Trilaciclib 240 mg / m administered as a 30-minute IV infusion completed within 4 hours prior to the start of sacituzumab-govitecan-Hygiene on days 1 and 8 of each 21-day treatment cycle 2 Sacituzumab-govitecan-hydidine 10 mg / kg administered IV on days 1 and 8 of each 21-day treatment cycle

[0213] The first infusion of sacituzumab govitecan-hygiene will be given over 3 hours, and patients should be observed during the infusion and for at least 30 minutes after the first dose for signs or symptoms of infusion-related reactions. If the pre-infusion is tolerated, subsequent infusions of sacituzumab govitecan-hygiene should be given over 1 to 2 hours, and patients should be observed during the infusion and for at least 30 minutes after the infusion. Pre-medication is recommended before each infusion of sacituzumab govitecan-hygiene for prevention of infusion reactions and chemotherapy-induced nausea and vomiting (CINV). Pre-infusion antipyretics, histamine receptor 1 (H1) and histamine receptor 2 (H2) blockers, and corticosteroid premedication may be used in patients with a history of infusion reactions. Prior administration of a two- or three-drug combination regimen (e.g., either a 5-HT3 receptor antagonist or a neurokinin 1 (NK1) receptor antagonist with dexamethasone, as well as other agents as indicated).

[0214] The study includes three study phases: a screening phase, a treatment phase, and a survival follow-up phase (see Figure 1). The treatment phase begins on the date of the first dose of study treatment and is completed at the safety follow-up visit. Survival follow-up assessments should be performed approximately every 3 months after the end-of-treatment visit.

[0215] Patients enrolled in this study may receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, investigator's discretion, or termination of the study, whichever occurs first. Treatment cycles will be consecutive and uninterrupted, except as necessary for toxicity management or administrative reasons. A 3-week delay from the scheduled administration of sacituzumab govitecan-Hyzy is permitted. For example, if an administration delay is required at the scheduled visit on Day 1 of Cycle X (e.g., Day 1 of Cycle 2), a delay of up to 3 weeks from Day 1 of Cycle X of sacituzumab govitecan-Hyzy is permitted, and if an administration delay is required at the scheduled visit on Day 8 of Cycle X (Day 8 of Cycle 1), a delay of up to 3 weeks from Day 1 of Cycle X of sacituzumab govitecan-Hyzy is permitted on a case-by-case basis with the approval of the investigator and medical monitor.

[0216] The End of Treatment visit will occur approximately 14 days after the patient's last dose of study treatment. A safety follow-up visit (which may be by telephone) will occur 30 days after the last dose of study treatment. Patient survival will be tracked approximately every 3 months following the End of Treatment visit. Survival follow-up visits may be conducted by telephone, email, or office visit. Unless otherwise determined by the Sponsor, the study will continue until at least 70% of patients enrolled in the study have died.

[0217] Diagnosis and Key Eligibility Criteria Patients aged 18 years or older at the time of signing informed consent with measurable locally advanced, unresectable, or metastatic TNBC (defined as <1% estrogen receptor [ER] and progesterone receptor by immunohistochemistry [IHC] and human epidermal growth factor receptor 2 [HER2] negative by IHC or in situ hybridization [ISH]) and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients must have measurable disease as defined by RECIST v1.1 and be considered eligible to receive sacituzumab govitecan-Hyzy. Patients with confirmed brain metastases at the time of enrollment are not eligible. Patients must have refractory or recurrent disease after at least two standard-of-care chemotherapy regimens for unresectable, locally advanced, or metastatic breast cancer (these regimens are eligible regardless of TNBC status at the time of administration). There is no upper limit on the number of prior therapies for locally advanced or metastatic disease. Adjuvant or neoadjuvant treatment for more limited disease is accepted as one of the required prior regimens if the development of unresectable locally advanced or metastatic disease occurs within 12 months of completion of chemotherapy. Patients with documented germline BRCA1 / BRCA2 mutations and who have received an approved PARP inhibitor can meet the criteria of one of two prior standard of care chemotherapy regimens with a PARP inhibitor. All patients must have prior taxane treatment in either the neoadjuvant, adjuvant, or advanced / metastatic setting. Prior radiation therapy for recurrent disease is acceptable as long as there is at least one unirradiated measurable disease. Patients must also have adequate organ function as demonstrated by laboratory tests.

[0218] Trilaciclib dose, administration schedule, and route Trilaciclib for Injection 300 mg / vial (also referred to as "Trilaciclib concentrated sterile powder for intravenous solution 300 mg / vial") is supplied as a sterile, preservative-free, yellow lyophilized cake in a single-dose vial (300 mg / 20 mL).

[0219] Trilaciclib must be reconstituted and further diluted prior to IV infusion. Upon reconstitution, the solution is then diluted to a dose calculated based on the patient's body surface area (BSA) (240 mg / m 2 ) Actual body weight (not ideal body weight) must be used in dose calculations.

[0220] The diluted trilaciclib solution is administered as a 30-minute IV infusion within 4 hours prior to the administration of sacituzumab-govitecan-Hyzy. Trilaciclib should not be administered as a bolus. Trilaciclib is always administered first. Blood test results should be reverified before administration of trilaciclib. If administration of sacituzumab-govitecan-Hyzy therapy is omitted or interrupted, trilaciclib should also be omitted or interrupted.

[0221] Sacituzumab govitecan-Hyzy (Trodelvy®) A description of the commercially available formulations of sacituzumab govitecan-hygiene can be found in the respective current prescribing information. Protocol-specified doses of sacituzumab govitecan-hygiene will be administered IV according to institutional guidelines and standard practice at the study site.

[0222] Actual body weight (not ideal body weight) must be used for dose calculations. At a minimum, doses should be recalculated if there is a change in body weight of more than 10% from the weight at the time of the last dose calculation. More frequent dose recalculation is acceptable according to local institutional guidelines. Dose recalculation to adjust for a change in body weight is not considered a dose reduction.

[0223] Premedication for infusion reaction and CINV prevention is recommended before each infusion of sacituzumab govitecan-Hygiene. Pre-infusion antipyretics, H1 and H2 blockers, and corticosteroid premedication may be used in patients with a history of infusion reactions. Prior administration of a two- or three-drug combination regimen (e.g., either a 5-HT3 receptor antagonist or an NK1 receptor antagonist with dexamethasone, as well as other agents as indicated).

[0224] The initial infusion should be given over 3 hours and the patient should be observed during the infusion and for at least 30 minutes after the first dose for signs or symptoms of infusion-related reactions. If the pre-infusion is tolerated, subsequent infusions may be given over 1-2 hours and the patient should be observed during the infusion and for at least 30 minutes after the infusion. Protect the infusion bag from light. Do not administer IV or as a bolus dose.

[0225] Trilaciclib is always administered first, followed by sacituzumab govitecan-Hyzy. Diluted trilaciclib is administered as a 30-minute IV infusion to be completed within 4 hours before the start of sacituzumab govitecan-Hyzy. If trilaciclib administration is delayed or interrupted, sacituzumab govitecan-Hyzy therapy will also be delayed or interrupted. Similarly, if sacituzumab govitecan-Hyzy is delayed or interrupted, trilaciclib will also be delayed or interrupted.

[0226] Entrance Criteria for Cycle 1 and Each Subsequent Cycle To initiate treatment, patients must meet all of the following criteria for receiving study treatment on Day 1 of Cycle 1: ANC≧1.5×10 9 / L; Platelet count ≥ 100 × 10 9 / L; Total bilirubin ≤ 1.5 × ULN; and If liver metastases are present, AST / ALT ≤ 3xULN or ≤ 5xULN Other non-hematologic drug-related toxicities must be ≤ Grade 1 (except for alopecia or peripheral neuropathy, which may be ≤ Grade 2)

[0227] Patients must also have an ANC ≥ 1.5 × 10 to receive day 1 of any subsequent cycle of study treatment.9 / L, and ANC ≥ 1.0 × 10 to receive day 8 of any cycle of study treatment 9 Must be / L.

[0228] In the case of dose delays due to toxicity, patients should be followed (at least) weekly, including CBC if the AE is hematologic, to monitor for toxicity until treatment criteria are met or the patient discontinues treatment (e.g., if >3 weeks have passed since the last treatment dose).

[0229] A 3-week delay from the scheduled infusion of sacituzumab govitecan-Hyzy is permitted for toxicity and / or administrative reasons. For example, if a toxicity delay is required at the scheduled Cycle X Day 1 visit (e.g., Cycle 2 Day 1), a maximum 3-week delay from Cycle X Day 1 is permitted; if a toxicity delay is required at the scheduled Cycle X Day 8 visit (e.g., Cycle 1 Day 8), a maximum 3-week delay from Cycle X Day 1 is permitted. Delays of more than 3 weeks from the scheduled infusion of sacituzumab govitecan-Hyzy are permitted on an individual basis with written approval from the investigator and medical monitor.

[0230] Study drug administration will continue until disease progression by RECIST v1.1 or clinical progression as determined by the investigator, unacceptable toxicity, withdrawal of consent, investigator's discretion, the patient has received up to 34 cycles of treatment, or the end of the study, whichever occurs first.

[0231] Evaluation criteria Efficacy: Antitumor efficacy evaluations included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR) and overall survival (OS). Tumor response criteria were based on RECIST v1.1.

[0232] Myelosuppression endpoints were based on reported hematological assessments, details of myelosuppression-related adverse events (AEs), dose reductions / delays, and supportive care interventions (including transfusions).

[0233] Safety: Safety will be assessed by monitoring AEs, clinical laboratory results (hematology, clinical chemistry), vital sign measurements (blood pressure, heart rate, and oral temperature), 12-lead safety electrocardiogram (ECG) results, dose modifications, and physical examination findings.

[0234] result: As of June 3, 2022, eight female patients (median age 55.0 years) (Figure 2A) have been enrolled and completed a median of three (range 1–6) 21-day cycles (Figure 2B). All patients had a taxane history, and seven had a history of immune checkpoint inhibitors (five atezolizumab, two pembrolizumab; four adjuvant therapy and three metastatic therapy) (Figure 2C). Overall, five patients had one or more treatment-related adverse events (TRAEs), including two trilaciclib-related AEs and five sacituzumab-govitecan-related AEs (Figure 2D). No patients withdrew due to AEs, and no severe AEs have been reported to date. Severe (grade 3 / 4) neutropenia occurred in one patient (Figure 2E). No patients had grade 3 / 4 anemia or thrombocytopenia, and no patients had febrile neutropenia or severe infections. Granulocyte colony-stimulating factor was administered in two patients, and one patient required intravenous antibiotics. No patients required red blood cell / platelet transfusions or erythropoietin stimulating agents. The most common TRAEs were nausea (n = 3), fatigue (n = 3), and headache (n = 2) (Figure 2F). There was one TRAE of diarrhea (trilaciclib- and sacituzumab govitecan-related). Two patients had grade 3 or higher TRAEs, including grade 3 alopecia and grade 3 neutropenia (both sacituzumab govitecan-related), and grade 4 neutropenia (trilaciclib- and sacituzumab govitecan-related) (Figure 2G). Currently, one patient has a partial response and three patients have stable disease (Figure 2H).

[0235] Preliminary data are promising, indicating that administration of trilaciclib prior to sacituzumab govitecan is well tolerated and may provide clinical benefit in patients with mTNBC who have received two or more prior systemic therapies.

Claims

1. A pharmaceutical composition for use in a method of treating a human patient having a progressive or metastatic Trop-2 overexpressing cancer, the composition comprising a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor having the following structure: 【Chemical Formula 1】 or a pharmaceutically acceptable salt, composition, isotope, or prodrug thereof, wherein the method comprises i. administering to the patient an effective amount of the CDK4 / 6 inhibitor or a pharmaceutically acceptable salt, composition, isotope, or prodrug thereof; and ii. administering to the patient an effective amount of sacituzumab govitecan wherein trilaciclib is administered within about 4 hours prior to the initiation of administration of sacituzumab govitecan, a pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein trilaciclib is administered within about 1 hour prior to the administration of sacituzumab govitecan.

3. The pharmaceutical composition according to claim 1, wherein trilaciclib is administered within about 30 minutes prior to the administration of sacituzumab govitecan.

4. The pharmaceutical composition according to claim 1, wherein trilaciclib is administered at a dose of about 190 to 280 mg / m ２ of the body surface area.

5. Trilaciclib is administered at about 240 mg / m ２ The pharmaceutical composition according to claim 4, wherein the administration is carried out at said dose.

6. The pharmaceutical composition according to claim 1, wherein sacituzumab govitecan is administered at a dose of about 5 mg / kg to 15 mg / kg.

7. The pharmaceutical composition according to claim 6, wherein sacituzumab govitecan is administered at a dose of about 10 mg / kg.

8. The pharmaceutical composition according to claim 1, wherein the method comprises one or more 21-day treatment cycles, and trilaciclib and sacituzumab govitecan are administered on day 1 and day 8 of each 21-day cycle.

9. The pharmaceutical composition according to claim 8, wherein the 21-day cycle is performed 2 to 35 times.

10. The pharmaceutical composition according to claim 1, wherein the patient's Trop-2 overexpressing cancer is CDK4 / 6 status positive.

11. The pharmaceutical composition according to claim 1, wherein the patient's Trop-2 overexpressing cancer is CDK4 / 6 status negative.

12. The pharmaceutical composition according to claim 1, wherein the patient's Trop-2 overexpressing cancer is CDK4 / 6 status indeterminate.

13. The pharmaceutical composition according to claim 1, wherein the patient's Trop-2 overexpressing cancer is PD-L1 positive.

14. The pharmaceutical composition according to claim 1, wherein the patient's Trop-2 overexpressing cancer is PD-L1 negative.

15. The pharmaceutical composition according to claim 1, wherein the patient has previously received at least two lines of chemotherapy treatment before receiving trilaciclib and sacituzumab govitecan.

16. The pharmaceutical composition according to claim 1, wherein at least one of the previously received chemotherapy line treatments belongs to palliative therapy.

17. The pharmaceutical composition according to claim 1, wherein the Trop-2 overexpressing cancer is unresectable locally advanced.

18. The pharmaceutical composition according to claim 1, wherein the Trop-2 overexpressing cancer is metastatic.

19. The pharmaceutical composition according to claim 1, wherein the Trop-2 overexpressing cancer is selected from the group consisting of breast cancer, cervical cancer, colon or colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma, hilar cholangiocarcinoma, oral squamous cell carcinoma, gastrointestinal cancer, chronic lymphocytic lymphoma, extranodal NK / T cell lymphoma, non-Hodgkin lymphoma, Raji Burkitt lymphoma, small lung adenocarcinoma, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, thyroid cancer, uterine cancer, and lung cancer.

20. The pharmaceutical composition according to claim 19, wherein the Trop-2 overexpressing cancer is non-small cell lung cancer.

21. The pharmaceutical composition according to claim 19, wherein the Trop-2 overexpressing cancer is breast cancer.

22. The pharmaceutical composition according to claim 19, wherein the Trop-2 overexpressing cancer is HR+ / HER2-metastatic breast cancer.

23. The pharmaceutical composition according to claim 19, wherein the Trop-2 overexpressing cancer is triple-negative breast cancer (TNBC).

24. The pharmaceutical composition according to claim 19, wherein the Trop-2 overexpressing cancer is locally advanced unresectable TNBC.

25. The pharmaceutical composition according to claim 19, wherein the Trop-2 overexpressing cancer is metastatic TNBC.

26. The pharmaceutical composition according to claim 8, further comprising administering trilaciclib on the 15th day of each 21-day chemotherapy cycle.

27. The pharmaceutical composition according to claim 1, wherein the treatment does not include administration of an immune checkpoint inhibitor.

28. The pharmaceutical composition according to claim 1, further comprising administering an immune checkpoint inhibitor.

29. The pharmaceutical composition according to claim 28, wherein the immune checkpoint inhibitor is selected from a PD-1 inhibitor or a PD-L1 inhibitor.

30. The pharmaceutical composition according to claim 1, wherein the administered sacituzumab govitecan is sacituzumab govitecan-hziy.

31. For use in a method of treating a patient having progressive or metastatic triple-negative breast cancer (TNBC), the following structure: [Chemical 2] A pharmaceutical composition comprising a CDK4 / 6 inhibitor having the formula: or a pharmaceutically acceptable salt, composition, isotope, or prodrug thereof, wherein the method comprises: i. administering to the patient an effective amount of the CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt, composition, isotope, or prodrug thereof; and ii. administering to the patient an effective amount of sacituzumab govitecan comprising: Trilaciclib is administered within about 4 hours prior to the start of administration of sacituzumab govitecan, pharmaceutical composition.

32. The pharmaceutical composition according to claim 31, wherein trilaciclib is administered within about 1 hour prior to the administration of sacituzumab govitecan.

33. The pharmaceutical composition according to claim 31, wherein trilaciclib is administered within about 30 minutes prior to the administration of sacituzumab govitecan.

34. The pharmaceutical composition according to claim 31, wherein trilaciclib is administered at a dose of about 190-280 mg / m2.

35. The pharmaceutical composition according to claim 34, wherein trilaciclib is administered at about 240 mg / m2.

36. The pharmaceutical composition according to claim 31, wherein sacituzumab govitecan is administered at a dose of about 5 mg / kg to 15 mg / kg.

37. The pharmaceutical composition according to claim 36, wherein sacituzumab govitecan is administered at a dose of about 10 mg / kg.

38. The pharmaceutical composition according to claim 31, wherein the method comprises one or more 21-day treatment cycles, and trilaciclib and sacituzumab govitecan are administered on days 1 and 8 of each 21-day cycle.

39. The pharmaceutical composition according to claim 38, wherein the 21-day cycle is performed 2 to 35 times.

40. The pharmaceutical composition according to claim 31, wherein the TNBC is locally advanced unresectable TNBC.

41. The pharmaceutical composition according to claim 31, wherein the TNBC is metastatic TNBC.

42. For use in a method of treating a patient having progressive or metastatic urothelial cancer, the following structure: 【Chemical Formula 3】 A pharmaceutical composition comprising a CDK4 / 6 inhibitor having the following, or a pharmaceutically acceptable salt, composition, isotope, or prodrug thereof, wherein the method comprises: i. Administering to the patient an effective amount of the CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt, composition, isotope, or prodrug thereof; and ii. Administering to the patient an effective amount of sacituzumab govitecan comprising: Trilaciclib is administered within about 4 hours before the start of administration of sacituzumab govitecan. Pharmaceutical composition. **Claim 43** The pharmaceutical composition according to claim 42, wherein trilaciclib is administered within about 1 hour before the administration of sacituzumab govitecan. **Claim 44** The pharmaceutical composition according to claim 42, wherein trilaciclib is administered within about 30 minutes before the administration of sacituzumab govitecan. **Claim 45** The pharmaceutical composition according to claim 42, wherein trilaciclib is administered at a dose of about 190 - 280 mg / m2. **Claim 46** The pharmaceutical composition according to claim 45, wherein trilaciclib is administered at about 240 mg / m2. **Claim 47** The pharmaceutical composition according to claim 42, wherein sacituzumab govitecan is administered at a dose of about 5 mg / kg - 15 mg / kg. **Claim 48** The pharmaceutical composition according to claim 47, wherein sacituzumab govitecan is administered at a dose of about 10 mg / kg. **Claim 49** The pharmaceutical composition according to claim 42, wherein the method comprises one or more 21-day treatment cycles, and trilaciclib and sacituzumab govitecan are administered on the 1st and 8th days of each 21-day cycle.

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