Pinkney, Kerice

Abstract Purpose: Selinexor is a first-in-class, central nervous system (CNS)–penetrant, oral inhibitor of exportin 1 (XPO1), the main nuclear exporter of many key tumor suppressors. We report a phase I trial of selinexor in children and adolescents with recurrent CNS and solid tumors (NCT02323880). Patients and Methods: A rolling six design was used to evaluate the maximum tolerated dose (MTD) and first dose pharmacokinetics of selinexor administered once (35–45 mg/m2) or twice (20–35 mg/m2) weekly during a 28-day cycle (part A). Ten additional patients with high-grade glioma (HGG) were treated at the MTD administered once weekly (part B). Results: In part A, 49 patients were enrolled. Continuous twice weekly dosing was limited by extended hematologic toxicity. The MTD on a twice weekly schedule for 3 weeks on/1 week off (twice weekly 3/1) was 20 mg/m2/dose. Dose-limiting toxicities (DLTs) on this schedule included fatigue, acute reversible neurologic changes, neutropenia, thrombocytopenia, and aspartate aminotransferase/alanine aminotransferase increase. On a continuous once weekly schedule, the MTD was 35 mg/m2/dose; DLTs included seizure and thrombocytopenia. In part B (HGG expansion), there were no additional DLTs observed. Non-DLTs included lymphopenia, leukopenia, neutropenia, thrombocytopenia, anorexia, fatigue, hypophosphatemia, nausea, and vomiting. There were no objective responses. The median number of cycles received was 1 (range, 1–9); eight of 59 patients (13.5%) received 5 to 9 cycles, five of whom had HGG. Conclusions: Selinexor-related toxicities were primarily hematologic and neurologic, requiring dose or dose-frequency reduction. The MTD and recommended initial phase II dose of selinexor in children and adolescents with recurrent solid and CNS tumors is 35 mg/m2/dose once weekly.

Abstract Background The National Cancer Institute-Children’s Oncology Group Pediatric Molecular Analysis for Therapy Choice (MATCH) precision oncology platform trial enrolled children aged 1-21 years with treatment-refractory solid tumors and predefined actionable genetic alterations. Patients with tumors harboring alterations in DNA damage repair (DDR) genes were assigned to receive olaparib. Methods Tumor and blood samples were submitted for centralized molecular testing. Tumor and germline sequencing were conducted in parallel. Olaparib was given twice daily for 28-day cycles starting at a dose 30% lower than the adult recommended phase 2 dose (RP2D). The primary endpoint was the objective response. Results Eighteen patients matched (1.5% of those screened) based on the presence of a deleterious gene alteration in BRCA1/2, RAD51C/D, or ATM detected by tumor sequencing without germline subtraction or analysis of loss of heterozygosity (LOH). Eleven (61%) harbored a germline mutation, with only one exhibiting LOH. Six patients enrolled and received the olaparib starting dose of 135 mg/m2/dose. Two participants were fully evaluable; 4 were inevaluable because <85% of the prescribed dose was administered during cycle 1. There were no dose-limiting toxicities or responses. Minimal hematologic toxicity was observed. Conclusion Most DDR gene alterations detected in Pediatric MATCH were germline, monoallelic, and unlikely to confer homologous recombination deficiency predicting sensitivity to olaparib monotherapy. The study closed due to poor accrual. ClinicalTrials.gov Identifier NCT03233204. IRB approved: initial July 24, 2017.

Abstract Introduction: Selinexor is a first-in-class, central nervous system (CNS) penetrant, oral inhibitor of exportin 1 (XPO1), the sole nuclear exporter of many key tumor suppressors. Selinexor is FDA-approved for refractory multiple myeloma and DLBCL and has been evaluated in a phase 1 trial in children with leukemia. We report a phase 1 trial of selinexor in children and adolescents with recurrent CNS and solid tumors, including lymphoma (NCT02323880). Methods: A rolling-six design was used to evaluate selinexor (10 or 25 mg tablets) administered twice or once weekly during a 28-day cycle. Dose determination was based on protocol-defined dose limiting toxicity (DLT) using CTCAEv4 during cycle 1. First dose pharmacokinetics (PK) were performed. Results: 43 subjects were enrolled (17 males); median (range) age was 15 (6-20) years. 27 (63%) had CNS tumors, most commonly high-grade glioma (n=12); 16 (37%) had extracranial solid tumors. 42 were evaluable for DLT. At the starting dose (35 mg/m2/dose, twice weekly), no DLTs were observed in 6 subjects, however, 2 subjects had unexpected late myelosuppression delaying initiation of cycle 2. The dosing schedule was amended to twice weekly for 3 weeks followed by a 1 week break. 12 subjects received 35 mg/m2/dose; 4 experienced DLTs [grade 3 fatigue (n=2), grade 3 thrombocytopenia (n=1), or grade 3 ALT increase (n=1)]. The dose was de-escalated to 20 mg/m2/dose, 3 weeks on, 1 week off. 12 subjects enrolled; 3 experienced a DLT [grade 3 increased AST/ALT, acute reversible neurologic changes, or neutropenia (each n=1)]. At the 20 mg/m2 (n=12) and 35 mg/m2 (n=19) dose levels, respectively, the mean ± SD Cmax (ng/ml) was 324±116 and 535±174, and AUC (hr•ng/ml) was 3092 ± 842 and 5156 ± 1227. This was comparable to PK in adults receiving 35 and 50 mg/m2. Based on a desire to achieve a higher Cmax and avoid breaks in schedule, and emerging evidence for similar effectiveness with decreased toxicity in adults receiving continuous once weekly dosing, we evaluated a dosing schedule with once weekly dosing for all 4 weeks of each cycle. At the initial dose level (45 mg/m2 weekly), 2 of 6 subjects had DLTs [prolonged grade 2 thrombocytopenia or grade 3 seizure in a primary CNS tumor patient]. Six subjects received 35 mg/m2/dose once weekly; 1 DLT [grade 3 thrombocytopenia] was observed. Non-dose-limiting toxicity (Grade ≥2 occurring in >10% of subjects during cycle 1) included lymphopenia, leukopenia, neutropenia, thrombocytopenia, anorexia, fatigue, hypophosphatemia, nausea, and vomiting. Subjects received a median (range) of 1 (1-9) cycle; 13 received 2-3 cycles, and 6 received 5-9 cycles. Conclusions: Selinexor-related toxicities were primarily hematological and gastrointestinal. The maximum tolerated dose (MTD) of selinexor in children and adolescents with recurrent solid and CNS tumors is 20 mg/m2/dose twice weekly for 3 weeks followed by one week off. On a continuous once weekly schedule, the MTD and recommended phase 2 starting dose of selinexor is 35 mg/m2/dose. Citation Format: Adam L. Green, Charles G. Minard, Xiaowei Liu, Joel M. Reid, Kerice Pinkney, Stephan Voss, Marvin D. Nelson, Elizabeth Fox, Brenda J. Weigel, Julia Glade Bender. Phase 1 trial of selinexor in children and adolescents with recurrent/refractory solid and CNS tumors (ADVL1414): A Children’s Oncology Group Phase 1 Consortium trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P162.