A phase I trial of talazoparib and irinotecan with and without temozolomide in children and young adults with recurrent or refractory solid malignancies.
Eur J Cancer
; 137: 204-213, 2020 09.
Article
em En
| MEDLINE
| ID: mdl-32795876
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 ANDMETHODS:
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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Ftalazinas
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Protocolos de Quimioterapia Combinada Antineoplásica
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Inibidores de Poli(ADP-Ribose) Polimerases
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Irinotecano
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Temozolomida
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Neoplasias
Limite:
Adolescent
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Adult
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Child
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article