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A Phase I/II Study of Sacituzumab Govitecan Plus Berzosertib in Small Cell Lung Cancer and Homologous Recombination-Deficient Cancers Resistant to PARP Inhibitors

Background: Several small molecule poly-(ADP)-ribose polymerase inhibitors (PARPi) have been approved by the FDA for multiple cancers with homologous recombination (HR) deficiencies. Despite their measurable initial benefit, PARPi resistance is a major problem in the clinic. There are no established standards for care of patients who have disease progression after PARPi. Small cell lung cancer (SCLC) is an aggressive cancer with poor prognosis. Despite being chemo-sensitive initially, the tumors are invariably chemo-resistant at recurrence. Currently available therapies for patients who have disease progression after chemotherapy yield limited benefit, and most patients die within months of relapse. In preclinical studies, ataxia telangiectasia and Rad3-related protein (ATR) inhibition can overcome PARPi/chemotherapy-resistance in tumors with restored HR or restored fork protection. However, combinations of DNA damage response inhibitors and chemotherapy may be challenging in clinic due to overlapping toxicities, specifically myelosuppression. To mitigate some of the overlapping toxicities relating to myelosuppression, we have proposed a strategy that incorporates tumor targeted DNA-damaging chemotherapy delivery (using approaches such as antibody drug conjugates) and dose scheduling of ATR inhibitors. Sacituzumab govitecan is an antibody-drug conjugate, comprising a topoisomerase-I inhibiting camptothecin, SN-38, linked to a humanized antibody targeting trophoblastic cell-surface antigen 2 (Trop-2), and is FDA approved as Trodelvy for triple-negative breast cancer patients who have received at least two prior therapies for metastatic disease. Berzosertib is a potent and selective kinase inhibitor of ATR in phase I and II clinical trials as a single agent and in combination with chemotherapy, radiation and other anticancer agents. We hypothesize that a combination of berzosertib with sacituzumab govitecan will provide an effective therapeutic option for patients with PARPi resistant tumors and chemotherapy-resistant SCLCs. Primary objectives: Phase I: To identify the maximum tolerated dose (MTD) of sacituzumab govitecan in combination with berzosertib. Phase II HRD cohort: To assess the efficacy with respect to objective response rate (ORR) of the combination of sacituzumab govitecan and berzosertib in previously treated participants with HRD. Phase II SCLC cohort: To assess the efficacy with respect to ORR of the combination of sacituzumab govitecan and berzosertib in previously treated participants with SCLC. Eligibility: All phases: Subjects must be greater than or equal to 18 years of age and have a performance status (ECOG) less than or equal to 2. Phase I: Adult participants with advanced solid tumors with progression on at least one prior chemotherapy. Phase II HRD cohort: Known HRD cancer and documented evidence of germline or somatic BRCA mutation or other HRD germline mutation, or tumor is HRD positive; progressive disease while taking a PARPi as a previous therapy or within 6 months of completing PARPi therapy. Phase II SCLC cohort: Recurrent SCLC after at least one prior platinum-based therapy. Design: This is a Phase I/II, open label clinical trial identifying the maximum tolerated dose (MTD) of sacituzumab govitecan in combination with berzosertib in a phase I trial, and assessing the efficacy with respect to clinical response rate of a combination of sacituzumab govitecan and berzosertib as treatment of subjects with recurrent SCLC and HRD positive tumors in a phase II trial. The accrual ceiling will be set to 70 for this study. Participants will receive sacituzumab govitecan on days 1 and 8 and berzosertib on days 2 and 9, administered every 21 days (1 cycle), until disease progression or development of intolerable side effects. Blood, hair follicles, and tumor will be collected at various time points to support the exploratory objectives. The Phase I will follow a 3+3 design: dose will be escalated in cohorts of 3-6 participants each with the individual dose of berzosertib and sacituzumab govitecan increased in successive dose levels. The phase II HRD cohort and phase II SCLC cohort will be conducted using a Simon two-stage Minimax design in order to rule out an unacceptably low 5% response rate (p0=0.05) for HRD and 10% (p=0.10) response rate for SCLC in favor of a targeted response rate of 20% (p1=0.20) and 30% (p1=0.30), respectively.

Start: June 2021