Cole, Kristina A.

AbstractBackgroundInhibition of the WEE1 kinase by adavosertib (AZD1775) potentiates replicative stress from genomic instability or chemotherapy. This study reports the pediatric solid tumor phase 2 results of the ADVL1312 trial combining irinotecan and adavosertib.MethodsPediatric patients with recurrent neuroblastoma (part B), medulloblastoma/central nervous system embryonal tumors (part C), or rhabdomyosarcoma (part D) were treated with irinotecan and adavosertib orally for 5 days every 21 days. The combination was considered effective if there were at least three of 20 responses in parts B and D or six of 19 responses in part C. Tumor tissue was analyzed for alternative lengthening of telomeres and ATRX. Patient's prior tumor genomic analyses were provided.ResultsThe 20 patients with neuroblastoma (part B) had a median of three prior regimens and 95% had a history of prior irinotecan. There were three objective responses (9, 11, and 18 cycles) meeting the protocol defined efficacy end point. Two of the three patients with objective responses had tumors with alternative lengthening of telomeres. One patient with pineoblastoma had a partial response (11 cycles), but parts C and D did not meet the protocol defined efficacy end point. The combination was well tolerated and there were no dose limiting toxicities at cycle 1 or beyond in any parts of ADVL1312 at the recommended phase 2 dose.ConclusionThis is first phase 2 clinical trial of adavosertib in pediatrics and the first with irinotecan. The combination may be of sufficient activity to consider further study of adavosertib in neuroblastoma.

Abstract Purpose: Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Antitumor activity of adavosertib has been demonstrated in preclinical models of pediatric cancer. This phase I trial was performed to define dose-limiting toxicities (DLT), recommended phase II dose (RP2D), and pharmacokinetics of adavosertib in combination with irinotecan in children and adolescents with relapsed or refractory solid tumors or primary central nervous system tumors. Patients and Methods: Using a 3+3 escalation design, five dose cohorts of the combination of adavosertib and irinotecan (50/70; 65/70; 65/90; 85/90; 110/90 mg/m2/day) delivered on days 1–5 of a 21-day cycle were studied. Pharmacokinetics and analysis of peripheral blood γH2AX was performed. Results: Thirty-seven patients were enrolled; 27 were evaluable. The median (range) age was 14 (2–20) years. Twenty-five (93%) received prior chemotherapy (median, three regimens) and 21 (78%) received prior radiotherapy. Eleven patients had a primary central nervous system (CNS) malignancy. Common toxicities were hematologic and gastrointestinal. Two patients receiving adavosertib (110 mg/m2) in combination with irinotecan (90 mg/m2) experienced dose-limiting grade 3 dehydration. A patient with Ewing sarcoma had a confirmed partial response and 2 patients (ependymoma and neuroblastoma) had prolonged stable disease (≥ 6 cycles). Pharmacokinetics of adavosertib were variable but generally dose proportional and clearance was lower in younger patients. Conclusions: Adavosertib (85 mg/m2) in combination with irinotecan (90 mg/m2) administered orally for 5 days was the MTD in children and adolescents with solid and CNS tumors.

Abstract Background: Inhibition of the WEE1 kinase by AZD1775 potentiates replicative stress induced by oncogenes or chemotherapy, and demonstrated anti-tumor activity in preclinical models of pediatric cancer. A pediatric phase I dose escalation study of AZD1775 in combination with irinotecan was completed within the COG DVL consortium. Methods: Patients age 1-21 years with relapsed/refractory solid or CNS tumors were eligible. Both agents were administered orally once daily on days 1-5 of a 21-day cycle with a step-wise inter-patient dose escalation of both agents. AZD1775 dose levels (DL) were 50 mg/m2 (DL1), 65 mg/m2 (DL 2 and 3), 85 mg/m2 (DL4) and 110 mg/m2 (DL5). Irinotecan, 70 mg/m2 day (DL 1-2), or 90 mg/m2/day (DL3-5), was administered with cefixime for diarrheal prophylaxis. Toxicity was graded according to CTCAE v4.0. Results: Thirty-one eligible patients, median age 14 years (range 5-20) were enrolled; 29 (93%) received prior chemotherapy (median 3 regimens) and 25 (81%) received prior radiation therapy. Sixteen patients had a primary CNS malignancy: malignant glioma (9), ependymoma (4), medulloblastoma (2) and CNS Ewings sarcoma (1). Fifteen patients had extracranial solid tumors: soft tissue sarcoma (6), neuroblastoma (2), carcinoma (4), osteosarcoma (2) and Wilms’ Tumor (1). The most common toxicities were hematologic and gastrointestinal (nausea, vomiting, diarrhea). Two patients experienced dose limiting toxicity, grade 3 diarrhea and dehydration at DL5 (AZD1775 110 mg/m2 and irinotecan 90 mg/m2). Conclusion: This is the first pediatric clinical trial of AZD1775 in combination with chemotherapy. The maximum tolerated dose in children and adolescents with solid tumors was AZD1775 85 mg/m2/day in combination with irinotecan 90 mg/m2/day for five days every 21 days. Accrual is ongoing for a pediatric PK expansion, PD analysis and Phase 2 expansion in patients with neuroblastoma or medulloblastoma / CNS PNET. Clinical trial information: NCT02095132 Citation Format: Kristina A. Cole, Joel M. Reid, Xiaowei Liu, Charles G. Minard, John M. Maris, Elizabeth Fox, Brenda J. Weigel. Pediatric phase I trial of the WEE1 inhibitor AZD1775 and irinotecan in patients with refractory solid and CNS malignancies; A Children’s Oncology Group Study (ADVL1312) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT144. doi:10.1158/1538-7445.AM2017-CT144