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)

• Published in: Pediatric blood & cancer Vol. 67; no. 2; pp. e28073 - n/a
• Main Authors: Schafer, Eric S., Rau, Rachel E., Berg, Stacey L., Liu, Xiaowei, Minard, Charles G., Bishop, Alexander J.R., Romero, J. Carolina, Hicks, M. John, Nelson, Marvin D., Voss, Stephan, Reid, Joel M., Fox, Elizabeth, Weigel, Brenda J., Blaney, Susan M.
• Format: Journal Article
• Language: English
• Published: United States 01.02.2020
• Subjects: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bone Neoplasms - drug therapy; Bone Neoplasms - pathology; Child; Child, Preschool; Drug Resistance, Neoplasm - drug effects; Female; Follow-Up Studies; Humans; Infant; Male; Maximum Tolerated Dose; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - pathology; PARP inhibitor; pharmacokinetics; phase 1; Phthalazines - administration & dosage; Prognosis; Salvage Therapy; Sarcoma, Ewing - drug therapy; Sarcoma, Ewing - pathology; Survival Rate; talazoparib; temozolomide; Temozolomide - administration & dosage; Tissue Distribution; Young Adult; temozolomide; pharmacokinetics; phase 1; talazoparib; PARP inhibitor
• ISSN: 1545-5009; 1545-5017; 1545-5017
• DOI: 10.1002/pbc.28073

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.