A Phase I/II Clinical Trial of Veliparib (ABT-888) and Radiation Followed by Maintenance Therapy with Veliparib and Temozolomide in Patients with Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG): A Pediatric Brain Tumor Consortium Interim Report of Phase I Study.

10053 Background: We report the results of the dose escalation component of a phase 1/2 trial in children with newly diagnosed DIPG designed to determine the maximum tolerated dose (MTD) and toxicities of veliparib in combination with radiation therapy (XRT) as well as the optimal dose for veliparib and TMZ post-XRT. We also evaluated the pharmacokinetics (PK) of veliparib and its impact on poly(ADP-ribose) (PAR) levels in PBMCs. Methods: Veliparib was given daily x 5, BID, during XRT (6-7 wks) followed by maintenance therapy with daily TMZ and twice daily veliparib for 5 days, every 28 days for up to 10 cycles. The veliparib starting dose during XRT was 50 mg/m2/dose BID. Maintenance therapy began at week 10 with veliparib 25 mg/m2/dose BID and 135 mg/m2/day TMZ. Blood for PK studies was obtained pre- and post veliparib days 1 and 4 of XRT. PAR levels, as measured using an ELISA assay, were assessed on days 1 and 3 to 5 of XRT. Results: 18 patients were enrolled in the phase 1 portion of the trial. Dose-limiting toxicities (DLT) during the XRT phase were a grade 2 intra-tumoral hemorrhage (n = 1), grade 3 maculo-papular rash (n = 2), and grade 3 nervous system disorder (generalized neurologic deterioration) (n = 1). The RP2D for veliparib was 65 mg/m2/dose BID during radiation therapy. After completion of veliparib and radiation, patients received veliparib at 25 mg/m2/dose BID and TMZ at 135 mg/m2/day for 5 days every 28 days, which was the RP2D from preceding PBTC027, a phase I trial in children with recurrent CNS tumors. Intra-patient escalation of TMZ during maintenance was attempted but was not feasible due to hematologic DLT. Conclusions: Veliparib, 65 mg/m2/dose BID, plus radiation therapy, followed by veliparib plus TMZ was reasonably well tolerated in children with newly diagnosed DIPG. A phase 2 trial is ongoing to study the efficacy of this treatment in children with newly diagnosed brainstem gliomas. Clinical trial information: NCT01514201.