A phase I trial of talazoparib and irinotecan with and without temozolomide in children and young adults with recurrent or refractory solid malignancies. (September 2020)

• Record Type: Journal Article
• Authors: Federico, Sara M.; Pappo, Alberto S.; Sahr, Natasha; Sykes, April; Campagne, Olivia; Stewart, Clinton F.; Clay, Michael R.; Bahrami, Armita; McCarville, Mary B.; Kaste, Sue C.; Santana, Victor M.; Helmig, Sara; Gartrell, Jessica; Shelat, Anang; Brennan, Rachel C.; Hawkins, Dana; Godwin, Kimberly; Bishop, Michael W.; Furman, Wayne L.; Stewart, Elizabeth
• Is Part Of: European journal of cancer. Volume 137(2020)
• Page Start: 204
• Page End: 213
• Publication Date: 2020-09
• Subjects: Talazoparib -- Irinotecan -- Temozolomide -- Paediatric -- Phase I -- PARP inhibitor; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2020.06.014
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Background: Talazoparib combined with irinotecan and temozolomide demonstrated efficacy in a murine Ewing sarcoma model. Based on these data, we conducted a phase I trial of talazoparib and irinotecan with/without temozolomide in paediatric patients with recurrent/refractory solid malignancies. Patients and methods: Cohorts of 3–6 patients with recurrent/refractory solid malignancies received escalating doses of oral talazoparib and intravenous irinotecan (arm A) and oral talazoparib, oral temozolomide and intravenous irinotecan (arm B) in a 3 + 3 design. Talazoparib was administered on days 1–6, and intravenous irinotecan and oral temozolomide were administered on days 2–6, of a 21-day course. Serum for talazoparib and irinotecan pharmacokinetics was obtained during course 1. UGT1A1 polymorphism and Schlafen family member 11 (SLFN11) immunohistochemical staining were performed. Results: Forty-one patients (20 males; median age, 14.6 years; 24 with recurrent disease) were evaluable for dose escalation. Twenty-nine and 12 patients were treated on arm A and arm B, respectively, for a total of 208 courses. The most common diagnosis was Ewing sarcoma (53%). The most common ≥grade III haematologic toxicities in arms A and B included neutropenia (78% and 31%, respectively) and thrombocytopenia (42% and 31%, respectively). In arms A and B, febrile neutropenia (24% and 14%, respectively) and diarrhoea (21% and 7%, respectively) were the most common ≥grade III non-hematologic toxicities. Six patients (Ewing sarcoma [5 patients] and synovial sarcoma [1 patient]) had a response (1 with a complete response, 5 with a partial response). The objective response rates were 10.3% (arm A) and 25% (arm B). Pharmacokinetic testing demonstrated no evidence of drug-drug interaction between talazoparib and irinotecan. UGT1A1 was not related to response. SLFN11 positivity was associated with best response to therapy. Conclusions: The combination of talazoparib and irinotecan with/without temozolomide is feasible and active in Ewing sarcoma, and further investigation is warranted. Highlights: Talazoparib with irinotecan and temozolomide is tolerated in paediatric patients. There was no drug-drug interaction between talazoparib and irinotecan. UGT1A1 status was significantly associated with a course 1 dose-limiting toxicity. Schlafen family member 11 positivity was associated with best response to therapy. This regimen had clinical benefit in patients with Ewing sarcoma.