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

Abstract

Background The combination of 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 tumor malignancies. Methods Patients were treated with veliparib (80mg-320mg daily) for a total of 3 cycles. LDFWAR consisted of 21.6Gy in 36 fractions, 0.6 Gytwice daily on days 1 and 5 for weeks 1-3 of each cycle. Circulating tumor cells (CTCs) were collected and evaluated for γ-H2AX. Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Results Twenty-two patients were treated. Treatment-related grade 3 and 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 γ-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.

Opportunities and challenges of radiotherapy for treating cancer

“…37 Because radiation therapy itself exploits differences in repair capacity between tissues, that the combination of radiation with PARP inhibitors is effective against cancers that have BRCA, MRE11, and other DNA-repair-protein mutations is no surprise. [39][40][41][42][43][44] However, PARP-1 is also activated by oxidative and nitrative stress, and is a known cofactor for nuclear factor κB (NF-κB)-driven inflammatory gene expression; 45 radiosensitization by PARP inhibitors might also be the result of inhibition of this crucial survival pathway ( Figure 2). 46 Not surprisingly, many clinical trials of PARP inhibitors in combination with radiation therapy are ongoing.…”

“…46 Not surprisingly, many clinical trials of PARP inhibitors in combination with radiation therapy are ongoing. 41,47 In evaluating their outcomes, it must be remembered that patients with germline mutations in DNA-repair genes will be also at increased risk of radiation-induced normal tissue toxicity in the presence of PARP inhibitors, and that different PARP inhibitors are available with differing specificities for what is a functionally very-complex family of molecules. A salutary lesson comes from the failure of the putative PARP inhibitor iniparib, in combination with gemcitabine/carboplatin, in a phase III clinical trial in women with triple-negative breast cancer: 48 iniparib was later shown to have little PARP-specific activity even in cells in vitro.…”

Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells

“…One such strategy exploits the difference in the capacity to repair radiation induced DNA damage between tumor and normal tissue cells. An example of such a strategy that is currently tested in clinical trials, is the combination of radiotherapy with PARP-1 inhibitors such as veliparib [5,6] and olaparib.…”

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

“…We previously reported the results of a phase I study combining low-dose whole fractionated abdominal radiation (LDFWAR) with veliparib (ABT-888) in patients with advanced solid tumors and peritoneal carcinomatosis[1]. The rationale for this approach was good preclinical evidence that, PARP inhibitors may act as sensitizing agents for DNA-damaging modalities such as chemotherapy and radiotherapy beyond their well-established anti-tumor effect in cancers with BRCA mutations [2–10].…”