A Phase I study of veliparib (ABT-888) in combination with low-dose fractionated whole abdominal radiation therapy in patients with advanced solid malignancies and peritoneal carcinomatosis
Mené sur 22 patients présentant une carcinomatose péritonéale ayant pour origine une tumeur solide de stade avancé, cet essai de phase I évalue la toxicité du véliparib, une petite molécule inhibitrice de PARP, en combinaison avec une radiothérapie fractionnée à faibles doses de rayonnements ciblant l'ensemble de l'abdomen
Background : Combined low-dose radiation therapy with poly (ADP-ribose) polymerase (PARP) inhibition has been shown to enhance anti-tumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with escalating doses of veliparib (ABT-888),a small molecule PARP inhibitor, in patients with peritoneal carcinomatosis from advanced solid tumors. Methods : Patients were treated with veliparib (80mg-320mg daily) for a total of 3 cycles. LDFWAR consisted of 21.6 Gy in 36 fractions, 0.6 Gy twice daily on days 1 and 5 for weeks 1-3 of each cycle. Circulating tumor cells (CTCs) were collected and evaluated for ɣ-H2AX. Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Results : Twenty-two patients were treated. Treatment-related grade 3/4 toxicites included lymphopenia (68%), anemia (9%), thrombocytopenia (14%), neutropenia (4%), leukopenia (9%), ascites (4%), vomiting (4%) and dyspnea (4%). No objective responses were observed. Disease stabilization (≥24 wks) was observed in 7 patients (33%). Median PFS was 4.47 months and mOS was 13.04 months. In the subset of 8 ovarian and fallopian cancers (OV), mPFS was 6.77 months and mOS was 17.54 months compared to mPFS 2.71 months and mOS 13.01 months in others. Patients with OV had better QoL over time than those with other cancers. An increased percentage of ɣ-H2AX-positive CTCs was observed in a subset of patients (3/6 with >2 CTCs at baseline). Conclusions : Combined veliparib and LDFWAR is a well-tolerated regimen that resulted in prolonged disease stability for some patients with advanced solid tumors and carcinomatosis, particularly in the OV subpopulation.