NCT04826341

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

• Status: Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 120 (estimated)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years – 120 Years
• Healthy volunteers: Not accepted

Summary

Background: Small cell lung cancer and PARP inhibitor resistant tumors are aggressive cancers. Current treatments for people with these tumors yield little benefit. Researchers want to see if a combination of drugs can help. Objective: To find a safe combination of sacituzumab govitecan and berzosertib and to see if this will cause small cell lung cancer and PARP inhibitor resistant tumors to shrink. Eligibility: People ages 18 and older with a solid tumor, small cell lung cancer, or a homologous recombination-deficient cancer that is resistant to PARP inhibitors Design: Participants will be screened with: Standard clinical exams and tests EKG to test the heart Medical documentation to confirm cancer diagnosis Participants will get sacituzumab govitecan by vein on days 1 and 8 of each 21-day cycle. They will get berzosertib by vein on days 2 and 9. Treatment will continue as long as they can tolerate the drugs and their tumors are either stable or getting better. Before treatment and at least once per cycle, participants will have a physical exam and blood tests. Before treatment and every 2 or 3 cycles, they will have a CT scan. They will have a contrast agent injected into a vein for the scan. Participants will give blood and hair samples and tumor biopsies for research. Biopsies will be taken with a small needle under imaging guidance. After they stop treatment, participants will have a visit 1 month later. They will then be contacted by phone or email every 3 months for the rest of their lives.

Detailed description

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. Extra pulmonary small cell neuroendocrine (EP-SCNC) cancers are exceedingly rare cancers with small cell morphology arising from non-lung primary sites. The striking responses that we see to combinations of TOP1 and ATR inhibitors suggest high replication stress in these tumors, and provide compelling rationale to rigorously investigate the effect of this combination using a less toxic combination of IMMU132 and berzosertib. 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 (Trademark) for triple-negative breast cancer patients and hormone receptor-positive, HER2-negative breast cancer. 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. This combination will also be evaluated for efficacy in EP-SCNC and HRD positive tumors. 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 \>= 18 years of age and have a performance status (ECOG) \<= 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 or EP-SCNC cohort: Recurrent SCLC or EP-SCNC 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, EPSCNC and HRD positive tumors. The accrual ceiling will be set to 120 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. A small cohort of extra-pulmonary small cell neuroendocrine cancers (EP-SCNC) will also be included to provide limited assessment of efficacy in this rare population.

Conditions

• HRD Cancer
• SCLC
• Advanced Solid Tumors

Interventions

Type	Name	Description
DRUG	Berzosertib	Berzosertib will be supplied as 20 mg/mL M6620 to be diluted with 5% dextrose in water solution before intravenous infusion.
DRUG	Sacituzumab Govitecan	Sacituzumab Govitecan will be administered as an intravenous infusion once weekly on Days 1 and 8 of 21-day treatment cycles.

Timeline

• Start date: 2021-09-20
• Primary completion: 2028-03-01
• Completion: 2029-03-01
• First posted: 2021-04-01
• Last updated: 2026-03-27

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study