Differential toxicity in patients with and without DNA repair mutations: Phase I Study of Carboplatin and Talazoparib in advanced solid tumors

<p>Purpose: The PARP inhibitor, talazoparib, may potentiate activity of chemotherapy in cells vulnerable to DNA damage. Experimental Design: This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of talazoparib and carboplatin. Pharmacokinetic-modeling explored associations between dosing and hematological toxicity. Results: 24 patients with solid tumors were enrolled in 4 cohorts at 0.75mg and 1mg daily talazoparib and weekly carboplatin (AUC 1 and 1.5, Q2W or Q3W). Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia; the maximum tolerated dose was not reached. Grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). Post-cycle 2 dose modifications 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 four months, three of which had mutations in DNA repair pathways. Pharmacokinetic-toxicity modeling showed that after 3 cycles of carboplatin AUC 1.5 Q3W and talazoparib 1mg daily, neutrophil counts decreased 78% (CI: 87 to 68%) from baseline in gBRCA carriers and 63% (CI: 72 to 55%) in non-carriers (p<0.001). This modeling suggests an intermittent, pulse dosing schedule of PARP inhibition, differentiated by gBRCA mutation status may improve tolerance of combination therapy. Conclusions: In order to optimize efficacy and minimize toxicity, we feel that the combination of carboplatin and talazoparib is likely best pursued using differentiated dosing schedules for patients with somatic DNA repair mutations vs. gBRCA mutations.

http://ift.tt/2wGu8p3