Princess Margaret Cancer Centre Toronto, ON, Canada
B. H. Lok1, A. G. Sacher2, A. Bezjak1,3, S. Raman1,4, A. J. Hope1,4, A. Sun1,4, N. Leighl2, L. Eng5, F. Shepherd2, G. Liu6, and P. Bradbury2; 1Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, 2Division of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada, 3University of Toronto, Toronto, ON, Canada, 4Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada, 5Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada, 6Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Purpose/Objective(s): For patients with extensive-stage (ES) small cell lung cancer (SCLC), systemic therapy followed by low dose consolidative thoracic radiotherapy (CTRT) is a standard treatment option. Talazoparib, a potent PARP inhibitor, has been shown to be a radiosensitizer in SCLC preclinical models. We aimed to test the hypothesis that combining talazoparib with CTRT is safe in a single institution, open label, single-arm Phase I clinical trial. Materials/
Methods: Patients with ES-SCLC without disease progression following 4-6 cycles of platinum/etoposide +/- durvalumab were treated with talazoparib for 1 week prior to and then 2 weeks concurrently with CTRT (30Gy over 10 fractions) for a total of 3 weeks. Talazoparib dose escalation was conducted by a 3+3 design starting at 0.25mg once daily escalating at 0.25mg per dose level to a maximum of 1mg once daily, which is the single agent dose of talazoparib. Total planned accrual of 24 patients. The primary objectives were to assess the safety and recommended phase II dose (RP2D) of combining talazoparib with CTRT. Results: From Oct 2020 to Dec 2023, 20 patients have been accrued and were treated with no dose limiting toxicities across all dose escalation levels (0.25mg [n=3], 0.50mg [n=3], 0.75mg [n=3], 1mg [n=6]). An expansion cohort at 1mg [n=5] was enrolled. The RP2D was 1mg once daily. For each adverse event (AE) attributed as possibly, probably, or definitely related to the study treatment, across all 20 patients there was 1 Grade (Gr) 4 talazoparib related hematologic AE: thrombocytopenia, and 1 Gr3 TRT or talazoparib+TRT related non-hematologic AE: esophagitis. Additional talazoparib related hematologic AEs included thrombocytopenia: Gr3 [n=1], Gr2 [1]; neutropenia: Gr3 [1], Gr2 [1]; lymphopenia: Gr3 [1], Gr2 [1]; anemia Gr3 [1], Gr2 [1]. Talazoparib-related non-hematologic AEs were fatigue: Gr3 [2], Gr2 [1]; anorexia: Gr2 [1]; vomiting: Gr2 [1]; nausea Gr2 [1]. TRT or talazoparib+TRT related AE Gr3 was fatigue [1]. The most common TRT or talazoparib+TRT Gr2 AEs were esophagitis [n=6], fatigue [2], pain [2], then dermatitis, nausea, dysphagia and vomiting [n=1 each]. Conclusion: Talazoparib can be administered safely with CTRT and was found to be tolerable. We identified the RP2D of concurrent RT and talazoparib as 1mg once daily for patients with ES-SCLC. Secondary efficacy endpoints and exploratory correlative assessments are ongoing.
