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Importance: Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan., Objective: To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC., Design, Setting, and Participants: Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible., Interventions: Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI., Results: Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%])., Conclusions and Relevance: In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS., Trial Registration: ClinicalTrials.gov Identifier: NCT03896503.

Grip myotonia and weakness are attractive treatment response biomarkers in clinical trials of myotonic dystrophy type 1 (DM1). There is a need to develop simple, patient-friendly and reproducible methods of quantifying grip myotonia in multisite trial settings. We designed a HandClench Relaxometer (HCR) that measures grip myotonia and strength. In contrast with the existing quantitative myometry (QMA) setup, the HCR is portable, economical, can be used with any laptop and generates automated command prompts. We demonstrate the feasibility and reliability of HCR device in twenty DM1 individuals and ten age-matched controls; patients returned for follow up within two months. The device showed excellent day to day reproducibility (ICC >0.80) in patients. The HCR device detected myotonia in milder muscle disease and measured longer myotonia duration than QMA indicating enhanced sensitivity for quantifying myotonia in DM1. The reaction time to the relax but not squeeze command was delayed and showed warm up similar to myotonia in DM1. HCR outcomes were correlated with key pinch strength, hand dexterity test, and fat replacement in the MRI of the long finger flexor muscles. Use of the HCR is warranted for grip myotonia and strength measurements in longitudinal observational and interventional studies of DM1., Competing Interests: Conflict of Interest TCB, AGr, and AM are named inventors on a provisional patent application covering the HandClench Relaxometer used in this study, which is held by the NIH. Authors declare no other conflicts of interest., (Published by Elsevier B.V.)