Sara M Federico1, Alberto S Pappo2, Natasha Sahr3, April Sykes3, Olivia Campagne4, Clinton F Stewart4, Michael R Clay5, Armita Bahrami5, Mary B McCarville6, Sue C Kaste6, Victor M Santana2, Sara Helmig2, Jessica Gartrell7, Anang Shelat8, Rachel C Brennan2, Dana Hawkins7, Kimberly Godwin7, Michael W Bishop2, Wayne L Furman2, Elizabeth Stewart9. 1. Departments of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; The Departments of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA. Electronic address: sara.federico@stjude.org. 2. Departments of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; The Departments of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA. 3. Departments of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. 4. Departments of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. 5. Departments of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. 6. Departments of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. 7. Departments of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. 8. Departments of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. 9. Departments of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Departments of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; The Departments of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
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.
BACKGROUND:Talazoparib combined with irinotecan and temozolomide demonstrated efficacy in a murineEwing 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.
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