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 ( 18 FLT) 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 SUV max of target lesions between baseline and early 18 FLT-PET (day 7-21; p trend =0.006). Continuous dosing of veliparib and every three week carboplatin demonstrated activity and acceptable toxicity. Decrease in SUV max on 18 FLT-PET scan during the first cycle of this therapy can identify patients likely to have a response. IMPLICATIONS FOR PRACTICE The BROCADE studies suggest that patients with BRCA mutation benefit from addition of PARP inhibitor veliparib to carboplatin plus paclitaxel. In this study, we demonstrate that a higher dose of veliparib is tolerable and active in combination with carboplatin alone. With growing interest in imaging-based early response assessment, we demonstrate that decrease in 18 FLT-PET SUV max in the first cycle of therapy is significantly associated with response. Collectively, this study provides clarity on dosing of veliparib with carboplatin in advanced breast cancer while providing additional data on the potential for novel PET imaging modalities in monitoring therapy response.