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

Lymphocytopenia, or lymphopenia, is the condition of having an abnormally low level of lymphocytes in the blood. 
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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 - Gynecologic Oncology
 

Publication History

Published online: January 18, 2017

• Abstract

Highlights

• •Combining PARP inhibition with radiation potentiates DNA damage in tumor cells.
• •This effect may be enhanced in those with an underlying DNA damage deficiency.
• •Combining PARP inhibition with radiation can be tolerable.
• •A single response was observed in a platinum-sensitive, BRCA-mutation + patient.

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, 40–400 mg 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 250 mg 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 (10.9 mo) compared to platinum-resistant patients (5.8 mo). 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.

Keywords:

Peritoneal carcinomatosis, PARP inhibition, Veliparib, Radiation, Ovarian cancer, BRCA