Using the PARP inhibitor veliparib as a radiosensitizer for chest wall radiation in women with inflammatory or locally recurrent breast cancer was associated with a high rate of late grade 3 adverse events, results of a phase 1 study show.
Although the trial’s upper limit of dose-limiting toxicities during 6 weeks of treatment and 4 weeks of follow-up was not met, 46.7% of 30 patients treated with veliparib and radiation after complete surgical resection had at least one grade 3 adverse event by 3 years of follow-up, reported Reshma Jagsi, MD, of the University of Michigan, Ann Arbor.
“In this multicenter phase 1 trial, severe acute toxicity did not exceed the prespecified target of 30%, even at the highest tested dose of veliparib (200 mg twice a day), and we observed no grade 4 or 5 events. However, given observations of grade 3 late toxicity in nearly one-half of all patients evaluated at 3 years, we recommend a phase 2 dose of 50 mg twice a day if veliparib is investigated further for radiosensitization in patients with breast cancer at high risk of locoregional recurrence and in need of treatment intensification,” they wrote in the Journal of Clinical Oncology.
In preclinical studies, PARP (poly [ADP-ribose] polymerase) inhibitors have been shown to enhance radiosensitivty of breast malignancies when given concurrently with radiation.
In a phase 1 dosing and safety study, 30 women with inflammatory or locally recurrent breast cancer of the chest wall underwent complete surgical resection and were then assigned to radiation consisting of 50 Gy to the chest wall and regional lymph nodes, plus a 10 Gy boost. The patients also received oral veliparib at a dose of either 50, 100, 150, or 200 mg taken twice daily during the 6-week course of radiotherapy.
During the 6 weeks of therapy and 4 weeks of follow-up, there were five dose-limiting toxicities, including two cases each of confluent moist desquamation greater than 100 cm2 in the 100- and 150-mg dose groups, and one case of neutropenia in a patient at the 200-mg dose level.
The respective rates of any grade 3 toxicity, treatment related or otherwise, at 1, 2, and 3 years of follow-up were 10%, 16.7%, and 46.7%.