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A phase I trial of talazoparib and irinotecan with and without temozolomide in children and young adults with recurrent or refractory solid malignancies.
- Source :
-
European Journal of Cancer . Sep2020, Vol. 137, p204-213. 10p. - Publication Year :
- 2020
-
Abstract
- 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. 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. 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. The combination of talazoparib and irinotecan with/without temozolomide is feasible and active in Ewing sarcoma, and further investigation is warranted. • 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *ANTINEOPLASTIC agents
*BLOOD testing
*BLOOD diseases
*CANCER patients
*CANCER relapse
*COMBINATION drug therapy
*CLINICAL trials
*DIARRHEA
*DRUG interactions
*DRUG toxicity
*ENZYME inhibitors
*EWING'S sarcoma
*GENETIC polymorphisms
*HETEROCYCLIC compounds
*IMMUNOHISTOCHEMISTRY
*INTRAVENOUS therapy
*LONGITUDINAL method
*NEUTROPENIA
*ORAL drug administration
*PEDIATRICS
*STAINS & staining (Microscopy)
*THROMBOCYTOPENIA
*TREATMENT effectiveness
*DESCRIPTIVE statistics
*IRINOTECAN
*TEMOZOLOMIDE
*EVALUATION
*ADOLESCENCE
*CHILDREN
Subjects
Details
- Language :
- English
- ISSN :
- 09598049
- Volume :
- 137
- Database :
- Academic Search Index
- Journal :
- European Journal of Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 145406597
- Full Text :
- https://doi.org/10.1016/j.ejca.2020.06.014