Details

Autor(en) / Beteiligte

• 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.

Titel

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)

Ist Teil von

• Pediatric blood & cancer, 2020-02, Vol.67 (2), p.e28073-n/a

Ort / Verlag

United States

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Wiley Blackwell Single Titles

Beschreibungen/Notizen

• 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.