Dataset Information

Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors.

ABSTRACT: To determine the maximum tolerated dose (MTD), toxicities, and pharmacodynamics effects of sirolimus combined with oral metronomic topotecan and cyclophosphamide in a pediatric population.Patients who were 1 to 30 years of age with relapsed/refractory solid tumors (including CNS) were eligible. Patients received daily oral sirolimus and cyclophosphamide (25-50 mg/m2/dose) on days 1-21 and oral topotecan (0.8 mg/m2/dose) on days 1-14 in 28-day cycles. Sirolimus steady-state plasma trough concentrations of 3-7.9 ng/mL and 8-12.0 ng/mL were evaluated, with dose escalation based on a 3+3 phase 1 design. Biomarkers of angiogenesis were also evaluated.Twenty-one patients were treated (median age 18 years; range 9-30). Dose-limiting toxicities included myelosuppression, ALT elevation, stomatitis, and hypertriglyceridemia. The MTD was sirolimus with trough goal of 8-12.0 ng/mL; cyclophosphamide 25 mg/m2/dose; and topotecan 0.8 mg/m2/dose. No objective responses were observed. Four patients had prolonged stable disease > 4 cycles (range 4-12). Correlative biomarker analyses demonstrated reductions in thrombospondin-1 (p=0.043) and soluble vascular endothelial growth factor receptor-2 plasma concentrations at 21 days compared to baseline.The combination of oral sirolimus, topotecan, and cyclophosphamide was well tolerated and biomarker studies demonstrated modulation of angiogenic pathways with this regimen.

SUBMITTER: Vo KT

PROVIDER: S-EPMC5410349 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors.

Vo Kieuhoa T KT Karski Erin E EE Nasholm Nicole M NM Allen Shelly S Hollinger Fabienne F Gustafson W Clay WC Long-Boyle Janel R JR Shiboski Stephen S Matthay Katherine K KK DuBois Steven G SG

Oncotarget 20170401 14

<h4>Purpose</h4>To determine the maximum tolerated dose (MTD), toxicities, and pharmacodynamics effects of sirolimus combined with oral metronomic topotecan and cyclophosphamide in a pediatric population.<h4>Materials and methods</h4>Patients who were 1 to 30 years of age with relapsed/refractory solid tumors (including CNS) were eligible. Patients received daily oral sirolimus and cyclophosphamide (25-50 mg/m2/dose) on days 1-21 and oral topotecan (0.8 mg/m2/dose) on days 1-14 in 28-day cycles. ...[more]

PMID: 27793021

Similar Datasets

Project description:BackgroundThe MAPK pathway is an emerging target across a number of adult and pediatric tumors. Targeting the downstream effector of MAPK, MEK1, is a proposed strategy to control the growth of MAPK-dependent tumors.ObjectiveiMATRIX-cobi assessed the safety, pharmacokinetics, and anti-tumor activity of cobimetinib, a highly selective MEK inhibitor, in children and young adults with relapsed/refractory solid tumors.Patients and methodsThis multicenter Phase I/II study enrolled patients aged 6 months to < 30 years with solid tumors with known/expected MAPK pathway involvement. Patients received cobimetinib tablet or suspension formulation on Days 1-21 of a 28-day cycle. Dose escalation followed a rolling 6 design. The primary endpoint was safety; secondary endpoints were pharmacokinetics and anti-tumor activity.ResultsOf 56 enrolled patients (median age 9 years [range 3-29]), 18 received cobimetinib tablets and 38 cobimetinib suspension. Most common diagnoses were low-grade glioma (LGG; n = 32, including n = 12 in the expansion cohort) and plexiform neurofibroma within neurofibromatosis type 1 (n = 12). Six patients (11 %) experienced dose-limiting toxicities (including five ocular toxicity events), which established a pediatric recommended Phase II dose (RP2D) of 0.8 mg/kg tablet and 1.0 mg/kg suspension. Most frequently reported treatment-related adverse events were gastrointestinal and skin disorders. Steady state mean exposure (Cmax, AUC0-24) of cobimetinib at the RP2D (1.0 mg/kg suspension) was ~ 50 % lower than in adults receiving the approved 60 mg/day dose. Overall response rate was 5.4 % (3/56; all partial responses in patients with LGG).ConclusionsThe safety profile of cobimetinib in pediatrics was similar to that reported in adults. Clinical activity was observed in LGG patients with known/suspected MAPK pathway activation. Cobimetinib combination regimens may be required to improve response rates in this pediatric population.Clinical trial registrationClinicalTrials.gov NCT02639546, registered December 24, 2015.

Dataset Information

Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors.

Publications

Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets