A phase I study of simvastatin in combination with topotecan and cyclophosphamide in pediatric patients with relapsed and/or refractory solid and CNS tumors.

Abstract

10541 Background: HMG-CoA reductase inhibitors (statins) can inhibit IL-6-mediated STAT3 activation, a critical pathway in pediatric CNS and solid tumors. Statins also inhibit tumor proliferation, angiogenesis, and restore apoptosis in preclinical pediatric solid tumor models. We therefore conducted a phase 1 trial of simvastatin in combination with topotecan and cyclophosphamide in children with relapsed/refractory (r/r) solid and CNS tumors. Methods: Eligible patients were 1-29 years of age with a r/r solid or CNS tumor. Simvastatin was administered orally twice daily on days 1-21, with topotecan 0.75 mg/m2/dose IV and cyclophosphamide 250 mg/m2/dose IV on days 1-5. Four dose levels (DLs) were planned: 140, 180, 225, 290 mg/m2/dose. A 3+3 design was used to determine the maximum tolerated dose (MTD). Pharmacokinetic and pharmacodynamic analyses were performed. Results: The median (range) age of 14 eligible patients was 11.5 years (1 - 23). Diagnoses included neuroblastoma (N = 4), sarcoma (N = 7), and one each of malignant rhabdoid tumor of kidney, medulloblastoma, and Wilms tumor. Eleven DLT-evaluable patients received a median of 4 cycles (range: 1-6). There were 3 cycle 1 DLTs, grade 3 diarrhea and grade 4 creatine phosphokinase (CPK) increased at DL 1, and grade 4 CPK increased at DL 0 (100 mg/m2/dose). Grade 3/4 treatment-related cycle 1 adverse events occurring in ≥ 10% patients were neutropenia (100%), leukopenia (100%), thrombocytopenia (91%), lymphopenia (91%), anemia (55%), febrile neutropenia (55%) and CPK increased (18%). Best overall response was partial response in 1 patient and stable disease in four. Simvastatin and simvastatin acid Cmax (geomean 82.5 and 12.6 ng/mL) and AUC0-6 (geomean 82.5 and 12.6 ng•h/mL) were comparable with reported pediatric literature values (Cmax 3.5 and 0.4-2.1 ng/mL; AUC0-8 10.7 and 3.8 ng•h/mL) after correction for the higher doses (3.77 vs 0.16 mg/kg) used in our study. Patient peripheral blood mononuclear cells showed maximum phospho-(p)STAT3 inhibition on Day 5, with recurrence by Day 21 despite continued simvastatin dosing. Plasma IL6 levels showed sustained IL6 inhibition with decrease to normal values by Day 21 in all patients, indicating potential on target effects. Conclusions: For this first-in-pediatrics trial of statins as anti-cancer therapy, the MTD of simvastatin with chemotherapy was 100 mg/m2/dose. This combination was well-tolerated with predominantly hematologic toxicity and predictable DLTs related to simvastatin. Clinical trial information: NCT02390843.