Utilizing novel fluorothymidine PET imaging in a phase I study of veliparib on an intermittent and continuous schedule given in combination with carboplatin in metastatic breast cancer

Abstract

Poly(ADP-ribose) polymerase inhibitors are FDA-approved for treatment of BRCA mutated metastatic breast cancer (MBC). Prior studies demonstrated benefit of adding oral PARPi veliparib to carboplatin and paclitaxel in BRCA mutation positive patients with MBC. We sought to find the recommended phase II dose (RP2D) and schedule of veliparib in combination with carboplatin in patients with advanced breast cancer, either triple negative (TNBC) or hormone receptor (HR) positive, HER2-negative with defective functional Fanconi Anemia (FA) DNA-repair pathway. Patients received escalating doses of veliparib on a 7, 14, or 21-day schedule with carboplatin every 3 weeks. Patients underwent [18]fluoro-3'-deoxythymidine (18FLT) positron emission tomography (PET) imaging, assessed in a blinded fashion. Forty-four patients (39 TNBC, 5 HR-positive/HER2-negative with a defective FA pathway) received a median of 5 cycles (range 1-36). Observed DLTs were grade (G) 4 thrombocytopenia (N=4), G4 neutropenia (N=1) and G3 akathisia (N=1). Common grade 3-4 toxicities included thrombocytopenia, lymphopenia, neutropenia, anemia, and fatigue. Of 43 patients evaluable for response, 18.6% achieved partial response and 48.8% had stable disease. Median progression free survival was 18.3 weeks. RP2D of veliparib was established at 250 mg twice daily on days 1-21 along with carboplatin at AUC 5. Patients with partial response had significant drop in SUVmax of target lesions between baseline and early 18FLT-PET (day 7-21; ptrend=0.006). Continuous dosing of veliparib and every three week carboplatin demonstrated activity and acceptable toxicity. Decrease in SUVmax on 18FLT-PET scan during the first cycle of this therapy can identify patients likely to have a response.