Phase 1/2 trial of talazoparib in combination with temozolomide in children and adolescents with refractory/recurrent solid tumors including Ewing sarcoma: A Children's Oncology Group Phase 1 Consortium study (ADVL1411)

Purpose: We conducted a phase 1/2 trial of the poly(ADP-ribose) polymerase 1/2 inhibitor talazoparib in combination with low-dose temozolomide (TMZ) to determine the dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and pharmacokinetics of this combination in children with recurrent/refractory solid tumors; and to explore clinical activity in Ewing sarcoma (EWS) (NCT02116777). Methods: Talazoparib (400-600 µg/m²/dose, maximum daily dose 800-1000 µg) was administered q.d. or b.i.d. orally on day 1 followed by q.d. dosing concomitant with q.d. dosing of oral TMZ (20-55 mg/m²/day) on days 2 to 6, every 28 days. Results: Forty patients, aged 4 to 25 years, were enrolled. Talazoparib was increased to 600 µg/m²/dose b.i.d. on day 1, and q.d. thereafter, with 20 mg/m²/day of TMZ, without DLTs. TMZ was subsequently increased, during which dose-limiting neutropenia and thrombocytopenia occurred in two of three subjects at 55 mg/m²/day, two of six subjects at 40 mg/m²/day, and one of six subjects at 30 mg/m²/day. During dose-finding, two of five EWS and four of 25 non-EWS subjects experienced prolonged stable disease (SD), and one subject with malignant glioma experienced a partial response. In phase 2, 0 of 10 EWS subjects experienced an objective response; two experienced prolonged SD. Conclusions: Talazoparib and low-dose TMZ are tolerated in children with recurrent/refractory solid tumors. Reversible neutropenia and thrombocytopenia were dose limiting. The RP2D is talazoparib 600 µg/m² b.i.d. on day 1 followed by 600 µg/m² q.d. on days 2 to 6 (daily maximum 1000 µg) in combination with temozolomide 30 mg/m²/day on days 2 to 6. Antitumor activity was not observed in EWS, and limited antitumor activity was observed in central nervous system tumors.