Abstract 1534P
Background
Berzosertib is a potent, first-in-class selective inhibitor of ataxia telangiectasia and Rad3-related (ATR) protein kinase. Berzosertib is well tolerated and synergises with topotecan (TOP) in patients with advanced solid tumours.
Methods
The Main Part of this single-arm phase 2 study (NCT04768296) evaluates the efficacy, safety, tolerability, and pharmacokinetics of intravenous berzosertib +TOP in patients with relapsed, pt-resistant SCLC. As there is no experience with berzosertib in Japanese patients, a Japanese Safety Run-in Part is being conducted concurrently, using a Bayesian Optimal Interval Design and enrolling cohorts of 3 patients, with 21-day treatment cycles and monitoring for dose-limiting toxicities (DLTs) during the first cycle. Patients with advanced solid tumours are eligible for dose level (DL)1 (berzosertib 105 mg/m2 Days 2 and 5 + TOP 1.25 mg/m2 Days 1 to 5). Patients with histologically confirmed pt-resistant SCLC and measurable disease are eligible for DL2 (berzosertib 210 mg/m2 Days 2 and 5+ TOP 1.25 mg/m2 Days 1 to 5).
Results
In DL1 3 patients completed the DLT period with no DLTs, treatment-emergent adverse events (TEAEs) of grade ≥3 or serious TEAEs. Most TEAEs were hematological. Three patients enrolled at DL2 completed the DLT period with no DLTs. One subject experienced grade 3 TEAEs (anemia, leukopenia, lymphopenia, and asymptomatic lipase increase); another experienced a creatinine increase Grade 1 which required TOP dose-adjustment. As of April 2022, 2 patients in DL1 (10 and 6 cycles completed) and 2 in DL2 (2 cycles completed each) remain on study treatment. One patient in DL1, with pt-sensitive SCLC, had a partial response. Berzosertib exposure increased approximately proportionally between 105 and 210 mg/m2 dose levels. At berzosertib 210 mg/m2 + TOP 1.25 mg/m2, berzosertib area under the curve, maximum concentration, clearance, and steady state volume of distribution were similar in Japanese compared to non-Japanese patients (who were investigated in another study, NCT02487095).
Conclusions
No DLTs or serious unexpected safety issues were observed in DL1 and DL2. DL2 was considered safe and tolerable for Japanese patients to participate in the study Main Part.
Clinical trial identification
NCT04768296.
Editorial acknowledgement
Medical writing assistance (funded by Merck) was provided by Grace Townshend on behalf of Bioscript Stirling Ltd, Macclesfield, UK.
Legal entity responsible for the study
Merck KGaA, Darmstadt, Germany.
Funding
Merck (CrossRef Funder ID: 10.13039/100009945).
Disclosure
T. Yoshida: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck Biopharma Co., Ltd., an affiliate of Merck KGaA. T. Kurata: Financial Interests, Personal, Speaker’s Bureau: MSD, AstraZeneca, Eli Lilly, Ono, Bristol, Meyers, Chugai, Nipponkayaku, Pfizer; Financial Interests, Institutional, Research Grant: MSD, AstraZeneca, Takeda, Bristol Meyers. N. Yamamoto: Financial Interests, Institutional, Advisory Board: Merck. A. Thomas: Financial Interests, Institutional, Funding: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, AstraZeneca, Ellipses Pharma, Prolynx, Tarveda Therapeutics and Immunomedics. B. Sarholz: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany. R. Hallwachs: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany; Financial Interests, Personal and Institutional, Stocks/Shares: Merck Healthcare KGaA, Darmstadt, Germany. J. Bolleddula: Financial Interests, Personal and Institutional, Full or part-time Employment: EMD Serono. T. Kuronita: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck Biopharma Co., Ltd., an affiliate of Merck KGaA. C. Moulin Correa: Financial Interests, Personal and Institutional, Full or part-time Employment: Ares Trading SA, Eysins, an affiliate of Merck KGaA. L. Paz-Ares: Financial Interests, Personal, Advisory Board: Lilly, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda. All other authors have declared no conflicts of interest.