A final report of a phase I study of veliparib (ABT-888) in combination with low-dose fractionated whole abdominal radiation therapy (LDFWAR) in patients with advanced solid malignancies and peritoneal carcinomatosis with a dose escalation in ovarian and fallopian tube cancers

Abstract

Background The combination of low-dose radiation therapy with PARP inhibition enhances anti-tumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with ABT-888 in patients with peritoneal carcinomatosis with a dose escalation in ovarian and fallopian cancer patients (OV). Methods Patients were treated with veliparib, 40–400mg orally BID on days 1–21 of 3 28-day cycles on 6 dose levels. Dose levels 5 and 6 included only OV patients. LDFWAR consisted of 21.6Gy in 36 fractions, 0.6 Gy twice daily on days 1 and 5 for weeks 1–3 of each cycle. Circulating tumor material and quality of life were serially assessed. Results 32 pts were treated. Median follow-up was 45 months (10–50). The most common treatment-related grade 3 and 4 toxicities were lymphopenia (59%), anemia (9%), thrombocytopenia (12%), neutropenia (6%), leukopenia (6%), nausea (6%), diarrhea (6%), anorexia (6%), vomiting (6%) and fatigue (6%). The maximum tolerated dose was determined to be 250mg PO BID. Median PFS was 3.6 months and median OS was 9.1 months. In OV patients, OS was longer for platinum-sensitive patients (10.9mo) compared to platinum-resistant patients (5.8mo). QoL decreased for all groups during treatment. Germline BRCA status was known for 14/18 patients with OV cancers, 5 of whom were BRCA mutation carriers. One objective response (3%) was observed. Conclusion ABT-888 plus LDFWAR is tolerable with gastrointestinal symptoms, fatigue and myelosuppression as the most common toxicities. The single observed objective response was in a germline BRCA mutated, platinum-sensitive patient.

PARP inhibitors: Clinical utility and possibilities of overcoming resistance

“…In a phase I trial to determine veliparib maximum tolerated dose (MTD) in platinum refractory ovarian or basal-like breast cancer, both mutant and wildtype BRCA2 tumors responded with clinical benefit rates of 68 and 38%, respectively (NCT00892736). In contrast, a phase I clinical trial examining veliparib in combination with low-dose fractionated whole abdominal radiation found an objective response rate of 3% (1 of 32 patients), but noted a potential benefit to patients with platinum-sensitive BRCA-mutated ovarian cancer [24]. Veliparib was noted to have lower efficacy than previously reported PARPi in a similar patient population.…”

<p>Current status and future prospects of PARP inhibitor clinical trials in ovarian cancer</p>

“…The MTD of veliparib combined with radiation was identified as 250 mg twice daily. The most common grade 3/4 toxicities were fatigue, myelosuppression and gastrointestinal symptoms 66…”

Study protocols of three parallel phase 1 trials combining radical radiotherapy with the PARP inhibitor olaparib

“…To date several trials have been published that assessed the tolerability of the PARP inhibitor veliparib in combination with radiotherapy. Radiotherapy in these combination trials was delivered to the whole abdomen [21, 22], the brain [23–27], the pelvic area for locally advanced rectal cancer [28] and the chest wall and regional lymph node areas for inflammatory or locoregionally recurrent breast cancer [29]. Haematological toxicity impeded the determination of a tolerable dose of veliparib in a triple treatment combination with radiation and temozolomide for glioblastoma multiforme [25].…”