Abstract 1666TiP
Background
Small cell lung cancer (SCLC) displays high genomic instability. Therefore, targeting key proteins involved in maintaining genomic stability, such as ataxia telangiectasia and Rad3-related (ATR) protein kinase and topoisomerase I (TOP1), is a rational treatment strategy for SCLC. Berzosertib (M6620), an intravenous, highly potent and selective, first-in-class ATR inhibitor, is well tolerated and synergizes with topotecan (TOP1 inhibitor) in patients with advanced solid tumors, particularly those with platinum (plt)-resistant SCLC. This study (NCT04768296) includes a global primary cohort and a Japan safety run-in with two dose levels (DL1 and DL2). The study will evaluate efficacy, safety, tolerability and pharmacokinetics of berzosertib + topotecan in patients with relapsed, plt-resistant SCLC. The primary endpoints are objective response (primary cohort) and establishing the recommended phase II dose in Japanese patients (safety run-in).
Trial design
Patients with advanced solid tumors with no effective standard therapy are eligible for DL1. Patients with histologically confirmed SCLC, disease progression on/after first-line of chemoradiation plt-based treatment with a plt-free interval <90 days, and measurable disease per Response Evaluation Criteria in Solid Tumors 1.1, are eligible for the primary cohort and DL2. Patients previously treated with an ATR or TOP1 inhibitor, or those with unstable brain metastases, are excluded. Berzosertib (Days 2, 5) + topotecan (Days 1–5) will be administered intravenously in 21day cycles until disease progression. The safety run-in will follow a Bayesian Optimal Interval Design. Japanese patients in the DL1 arm (n=3–9) will receive berzosertib 105 mg/m2 + topotecan 1.25 mg/m2; if tolerated, patients will be enrolled to the DL2 arm (same dose as primary cohort; n=3–9). If DL2 is tolerated, Japanese patients will be enrolled to the primary cohort. In the primary cohort, ∼80 patients will receive berzosertib 210 mg/m2 + topotecan 1.25 mg/m2. Interim analysis is planned after 40 patients. The treatment effect assumption is an objective response rate of 30%.
Clinical trial identification
NCT04768296.
Editorial acknowledgement
Medical writing assistance (funded by Merck) was provided by David Lester of Bioscript Stirling Ltd., Macclesfield, UK.
Legal entity responsible for the study
Merck.
Funding
Merck (CrossRef Funder ID: 10.13039/100009945).
Disclosure
A. Thomas: Financial Interests, Institutional, Research Grant: EMD Serono, AstraZeneca, Ellipses Pharma, Prolynx, Tarveda. F. Cappuzzo: Financial Interests, Personal, Other, Honoraria: Roche, AstraZeneca, BMS, MSD, Lilly, Bayer, Pfizer, Merck, Takeda; Financial Interests, Personal, Advisory Role: Roche, AstraZeneca, BMS, MSD, Lilly, Bayer, Pfizer, Merck, Takeda; Financial Interests, Personal, Speaker’s Bureau: Roche, AstraZeneca, BMS, MSD, Lilly, Bayer, Pfizer, Merck, Takeda. N. Yamamoto: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Daiichi Sankyo, Eli Lilly, Ono, Pfizer, Sysmex; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Chugai, Cimic, Eisai, Otsuka, Takeda; Financial Interests, Personal and Institutional, Principal Investigator: AbbVie, Astellas, Bayer, BMS, Boehringer Ingelheim, Chiome Bioscience, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, GSK, Janssen Pharma, Kyow-Hakko Kirin, Merck, MSD, Novartis, Ono, Otsuka, Pfizer, Sumitomo Dainippon, Taiho, Takeda. Y. Chen: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, BMS, Pfizer, Takeda, Merck, Jazz, Guardant Health; Financial Interests, Institutional, Research Grant: AstraZeneca. A.B. Cortot: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Novartis, Pfizer, Roche, Takeda, MSD; Financial Interests, Personal, Advisory Role: AstraZeneca, Novartis, Roche, Takeda; Financial Interests, Personal, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Merck, Novartis; Financial Interests, Personal, Other, Travel/accommodation expenses: AstraZeneca, Novartis, Pfizer, Roche, Takeda, MSD. T. Berghmans: Financial Interests, Personal, Advisory Role: Inhatarget, Roche; Non-Financial Interests, Personal, Other, Not specified: Bayer; Financial Interests, Institutional, Research Grant: BMS. N. Reguart Aransay: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Boehringer Ingelheim, Guardant, MSD, Pfizer; Financial Interests, Personal, Advisory Board: Bayer, MSD, Novartis, Roche, Sanofi, Takeda; Financial Interests, Personal, Research Grant: Novartis, Pfizer. Y. Shibata: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Ono. T. Yoshida: Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, Chugai, Lilly, Novartis; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Boehringer Ingelheim, Chigai, Ono, MSD, Roche, ArcherDx; Financial Interests, Institutional, Research Grant: AstraZeneca, Chugai, Ono, AbbVie, Takeda, MSD, ArcherDx. C. Moulin: Financial Interests, Personal, Full or part-time Employment: Merck KGaA. B. Sarholz: Financial Interests, Personal, Full or part-time Employment: Merck KGaA; Financial Interests, Personal, Stocks/Shares: Merck KGaA. A. Kalapur: Financial Interests, Personal, Full or part-time Employment: Merck KGaA. L. Paz-Ares: Financial Interests, Personal, Other, Honoraria: Roche, MSD, Merck Serono, BMS, AstraZeneca, Lilly, Pfizer, PharmaMar, Bayer, AbbVie, Amgen, GSK, Novartis, Ipsen, Boehringer Ingelheim, Takeda, Sanofi, Tesaro, Blueprint, Mirati; Financial Interests, Personal, Advisory Role: Roche, MSD, Merck Serono, BMS, AstraZeneca, Lilly, Pfizer, PharmaMar, Bayer, AbbVie, Amgen, GSK, Novartis, Ipsen, Boehringer Ingelheim, Takeda, Sanofi, Tesaro, Blueprint, Mirati; Financial Interests, Personal, Research Grant: BMS, AstraZeneca, PharmaMar. All other authors have declared no conflicts of interest.