Differential Toxicity in Patients with and without DNA Repair Mutations: Phase I Study of Carboplatin and Talazoparib in Advanced Solid Tumors

• Published in: Clinical cancer research 2017-11, Vol.23 (21), p.6400-6410
• Main Authors: Dhawan, Mallika S, Bartelink, Imke H, Aggarwal, Rahul Raj, Leng, Jim, Zhang, Jenna Z, Pawlowska, Nela, Terranova-Barberio, Manuela, Grabowsky, Jennifer A, Gewitz, Andrew, Chien, Amy J, Moasser, Mark, Kelley, Robin K, Maktabi, Tayeba, Thomas, Scott, Munster, Pamela N
• Format: Article
• Language: English
• Subjects: Anemia; BRCA1 protein; Breast cancer; Cancer; Carboplatin; Chemotherapy; Confidence intervals; Damage assessment; Damage tolerance; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Dosage; Experimental design; Fatigue; Females; Males; Modelling; Mutation; Neutropenia; Patients; Pharmacokinetics; Pharmacology; Platinum; Poly(ADP-ribose) polymerase; Quality; Repair; Solid tumors; Thrombocytopenia; Toxicity; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-0703

The PARP inhibitor (PARPi) talazoparib may potentiate activity of chemotherapy and toxicity in cells vulnerable to DNA damage. This phase I study evaluated the safety, tolerability, pharmacokinetics, and efficacy of talazoparib and carboplatin. Pharmacokinetic modeling explored associations between DNA vulnerability and hematologic toxicity. Twenty-four patients (eight males; 16 females) with solid tumors were enrolled in four cohorts at 0.75 and 1 mg daily talazoparib and weekly carboplatin (AUC 1 and 1.5, every 2 weeks or every 3 weeks), including 14 patients (58%) with prior platinum treatment. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia; the MTD was not reached. Grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). After cycle 2's dose, delays/reductions were required in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Four patients showed stable disease beyond 4 months, three of which had known mutations in DNA repair pathways. Pharmacokinetic toxicity modeling suggests that after three cycles of carboplatin AUC 1.5 every 3 weeks and talazoparib 1 mg daily, neutrophil counts decreased 78% [confidence interval (CI), 87-68] from baseline in gBRCA carriers and 63% (CI, 72-55) in noncarriers ( < 0.001). Pharmacokinetic toxicity modeling suggests an intermittent, pulse dosing schedule of PARP inhibition, differentiated by gBRCA mutation status, may improve the benefit/risk ratio of combination therapy. Carboplatin and talazoparib showed efficacy in DNA damage mutation carriers, but hematologic toxicity was more pronounced in gBRCA carriers. Carboplatin is best combined with intermittent talazoparib dosing differentiated by germline and somatic DNA damage mutation carriers. .