Abstract CT146: Plasma Pharmacokinetics of Liposomal Irinotecan (Nal-Iri) in Pediatric Oncology Patients with Recurrent or Refractory Solid Tumors: South Plains Oncology Consortium Study 2012-001

Abstract Background/Objectives: Children with relapsed or refractory solid tumors have a poor prognosis. Irinotecan is active in some pediatric solid tumors and synergizes with alkylating agents. nal-IRI encapsulates irinotecan into long-circulating, liposome-based nanoparticles. In adults, nal-IRI demonstrated extended plasma exposure compared with non-liposomal irinotecan. In pediatric solid tumor models, nal-IRI had robust preclinical activity and synergized with cyclophosphamide, and therefore merits testing in children with relapsed and refractory solid tumors. Herein we describe a phase 1 dose-escalation study of nal-IRI in combination with cyclophosphamide (NCT02013336) and preliminary pharmacokinetic and safety results. Methods: Cyclophosphamide was administered on days 1-5 of each cycle (250 mg/m2/d intravenously [IV]) with a single 90-min IV infusion of nal-IRI on day 3 of a Q3-week schedule, escalating from 60 mg/m2 to 210 mg/m2 (expressed as irinotecan HCL trihydrate salt), in a standard 3+3 dose-escalation design to determine the maximum tolerated dose. To date, the nal-IRI dose has been escalated from 60 mg/m2 to 150 mg/m2. Samples for pharmacokinetic analysis were collected during the first cycle of chemotherapy before infusion and at 4h, 24h, 48h, 120h, and 168h post-infusion. Plasma pharmacokinetics of total irinotecan and SN-38 were quantified using mixed effect modeling, and were compared with adult values from a population pharmacokinetic analysis of 6 clinical studies of nal-IRI.1 Results: To date, 10 males and 6 females with a median age of 12.8 years (range: 5-19) have been enrolled: 10 with Ewing sarcoma, 2 with neuroblastoma, 3 with osteosarcoma, and 1 with rhabdomyosarcoma. The estimated total irinotecan volume of distribution (Vd) was 1.9 L, clearance (CL) was 10.3 L/week, and half-life (t1/2) was 21.2 h, which were 42% (Vd and CL) of adult values and comparable to adult values (t1/2). The corresponding Cmax was 72% higher than that observed in adults. SN-38 clearance was 11.4 L/week (comparable to adults), t1/2 was 19.3 h (48% of adult values), and Cmax was 68% of adult values. Thrombocytopenia leading to treatment delay was a dose-limiting toxicity at 150 mg/m2 (n=1); other systemic toxicity attributed to chemotherapy within the 1st cycle was nausea/vomiting (n=1). Conclusions: Preliminary safety and pharmacokinetic data support continued investigation of nal-IRI in pediatric oncology. Clinical outcomes including safety of patients treated in this study will be reported once a maximum tolerated dose is achieved. 1. Adiwijaya B et al. Clin Pharmacol Ther. 2017. In press. Citation Format: Paul D. Harker-Murray, William H. Meyer, Patrick Leavey, Min H. Kang, Hwangeui Cho, Bambang S. Adiwijaya, Jonathan B. Fitzgerald, J Marc Pipas, Daryl C. Drummond, C. Patrick Reynolds. Plasma pharmacokinetics of liposomal irinotecan (nal-IRI) in pediatric oncology patients with recurrent or refractory solid tumors: South Plains Oncology Consortium Study 2012-001 [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 CT146. doi:10.1158/1538-7445.AM2017-CT146