Abstract A090: Pharmacokinetic modeling of differential toxicity to predict alternate dosing schedules
Authors: Dhawan Mallika Sachdev , Bartelink Imke Heleen , Aggarwal Rahul , Pawlowska Nela , Terranova-Barberio Manuela , Thomas Scott , Munster Pamela 
Published: August 2018

Abstract
Purpose: Synthetic toxicity of PARP inhibitors (PARPi) and platinum salts may prohibit combination therapy in cells vulnerable to DNA damage and require alternate dosing schedule in germline BRCA (gBRCA) carriers. Experimental Design: In a phase 1 study we evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of talazoparib (PARPi) and carboplatin. Pharmacokinetic-modeling explored associations between DNA vulnerability and hematologic toxicity. Differential toxicity profiles between gBRCA carriers compared to non-BRCA carriers were assessed using a PK-toxicity model accounting for dose delivery and variability in talazoparib PK. A previously developed semi-mechanistic hematologic toxicity model was used to estimate the effect of talazoparib and carboplatin on platelets and white blood cells, accounting for dose delivery of carboplatin and talazoparib and variability in talazoparib PK. To assess synergy, we compared carboplatin adduct formation alone and when used with a PARPi measured by ICP-MS in patient blood samples and fresh frozen mouse xenograft tumor sections. Results: 24 patients (8M: 16F) 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 delays/reductions were required in all patients. One complete and two partial responses occurred in gBRCA patients. Four patients showed stable disease beyond four months. PK-toxicity modeling suggests that after 3 cycles of carboplatin AUC 1.5 Q3W and talazoparib 1mg daily, neutrophil counts decreased by 78% (CI: 87 to 68%) from baseline in gBRCA carriers and 63% (CI: 72 to 55%) in noncarriers (p&lt;0.001). Synergy, assessed as a correlation between PARPi concentrations and platinum adduct formation, was observed in a small number of xenograft mice (R2=0.657), but was not observed in patient-PBMCs at the doses/schedules in this phase 1 study. Simulations factoring in in vitro efficacy data suggest that the combination of PARPi and platinum therapy may be optimized best by introducing talazoparib-free periods (pulse dosing). PK-toxicity modeling supports using talazoparib at 0.75mg daily (days 1-14/month) with carboplatin AUC 6 monthly in gBRCA carriers. Conclusions: Carboplatin and talazoparib showed efficacy in DNA damage mutation carriers, but hematologic toxicity was more pronounced in gBRCA carriers. The synthetic lethality with combination therapy in patients with gBRCA mutations appears to potentiate toxicities in other tissues with heterozygous BRCA mutations such as the bone marrow. ICP-MS can be used to measure platinum adducts in PBMCs and tumor biopsies and may be used to assess synergistic toxicity and efficacy in future studies. In order to optimize efficacy and minimize toxicity, treatment modification for carboplatin and talazoparib should include alternate dosing schedules for patients with gBRCA carriers compared to non-gBRCA carriers. PK/toxicity modeling suggests an intermittent pulse dosing schedule may have a more favorable risk/benefit ratio than continuous daily dosing of PARPi in combination with platinum chemotherapy.
Citation Format: Mallika Sachdev Dhawan, Imke Heleen Bartelink, Rahul Aggarwal, Nela Pawlowska, Manuela Terranova-Barberio, Scott Thomas, Pamela Munster. Pharmacokinetic modeling of differential toxicity to predict alternate dosing schedules [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A090.