A Phase I/II Study of Veliparib (ABT-888) with Radiation and Temozolomide in Newly Diagnosed Diffuse Pontine Glioma: A Pediatric Brain Tumor Consortium Study

BACKGROUND: A Pediatric Brain Tumor Consortium (PBTC) phase 1/2 trial of veliparib and radiation, followed by veliparib and temozolomide (TMZ) was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). The objectives were to: 1) estimate the recommended phase 2 dose (RP2D) of veliparib with concurrent radiation; 2) evaluate the pharmacokinetic (PK) parameters of veliparib during radiation; 3) evaluate feasibility of intra-patient TMZ dose escalation; 4) describe toxicities of protocol therapy; and 5) estimate the overall survival distribution compared to historical series. METHODS: Veliparib was given Monday through Friday BID during radiation followed by a 4-week rest. Patients then received veliparib at 25 mg/m2 BID and TMZ 135 mg/m2 daily for 5 days every 28 days. Intra-patient dose escalation of TMZ was investigated for patients experiencing minimal toxicity. RESULTS: 66 patients (65 eligible) were enrolled. The RP2D of veliparib was 65 mg/m2 BID with radiation. Dose-limiting toxicities (DLT) during radiation with veliparib therapy included: grade-2 intra-tumoral hemorrhage (n=1), grade-3 maculopapular rash (n=2), and grade-3 nervous system disorder (generalized neurologic deterioration) (n=1). Intra-patient TMZ dose escalation during maintenance was not tolerated. Following a planned interim analysis, it was concluded that this treatment did not show a survival benefit compared to PBTC historical controls and accrual was stopped for futility. The 1- and 2-year OS rates were 37.2% (SE 7%) and 5.3% (SE 3%), respectively. CONCLUSION: Addition of veliparib to radiation followed by TMZ and veliparib was tolerated but did not improve survival for patients with newly diagnosed DIPG.