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)

Schafer ES, Rau RE, Berg SL, Liu X, Minard CG, Bishop AJR, Romero JC, Hicks MJ, Nelson MD Jr, Voss S, Reid JM, Fox E, Weigel BJ, Blaney SM. 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). Pediatr Blood Cancer. 2020 Feb;67(2):e28073. doi: 10.1002/pbc.28073. Epub 2019 Nov 14. PMID: 31724813; PMCID: PMC9134216.

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). Talazoparib (400–600 mcg/m2/dose, maximum daily dose 800–1000 mcg) was administered QD or BID orally on day 1 followed by QD dosing concomitant with QD dosing of oral TMZ (20–55 mg/m2/day) on days 2–6, every 28 days. Forty patients, aged 4–25 years were enrolled. Talazoparib was increased to 600 mcg/m2/dose BID on day 1, and QD thereafter, with 20 mg/m2/day of TMZ, without DLTs. TMZ was subsequently increased during which dose-limiting neutropenia and thrombocytopenia occurred in 2/3 subjects at 55 mg/m2/day, 2/6 subjects at 40 mg/m2/day and 1/6 subjects at 30 mg/m2/day. During dose-finding 2/5 EWS and 4/25 non-EWS subjects experienced prolonged stable disease (SD) and one subject with malignant glioma experienced a partial response. In phase 2, 0/10 EWS subjects experienced an objective response; two experienced prolonged SD. 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 mcg/m2 BID on day 1 followed by 600 mcg/m2 QD on days 2–6 (daily maximum 1000 mcg) in combination with temozolomide 30 mg/m2/day on days 2–6. Antitumor activity was not observed in EWS and limited antitumor activity was observed in central nervous system tumors.