A National Phase I Study of Cabozantinib in Combination With 13-cis-Retinoic Acid in Children With Relapsed or Refractory Solid Tumors

Description

Participants will be treated in an open-label, non-randomized phase I trial to determine the safety, dose-limiting toxicities, tolerability, and maximum tolerated dose of cabozantinib combined with 13-cis-retinoic acid in children with relapsed or refractory solid tumors.

Eligible Participants must have a histologically confirmed solid tumor at time of initial diagnosis, and have either progressive, recurrent, or refractory disease. Cabozantinib will be given orally once every day with cycles repeated every 4 weeks (28 days, +/- 3 days), with no rest periods between cycles, combined with 13-cis-retinoic acid at 80mg/m2/dose twice daily for two consecutive weeks (14 days) out of every four weeks (28 days, +/- 3 days). Participants with disease response or stable disease at the end of each cycle will be allowed to continue treatment, and patients may continue to receive therapy until there is evidence of clinical or radiographic disease progression.

The investigator will perform a phase I trial to define the maximum tolerated dose (MTD) of cabozantinib in combination with 13-cis-retinoic acid using the standard 3+3 study design. Cohorts of patients will be enrolled at doses determined as detailed below. The first cycle will be used to determine the dose-limiting toxicities. Toxicity will be summarized by dose levels. Response rates will be estimated. Kaplan-Meier curves will be plotted to graphically present time to progression (PFS) and other time-to-event endpoints. Median PFS and the corresponding 95% confidence intervals will be reported.

Cabozantinib dosing will be started and modified, if necessary, during the course of the trial as detailed below. The tablet formulation of the drug will be used with doses in 20mg increments.

Baseline evaluation to determine eligibility will include medical history (including a review of current medications), physical examination, blood count with differential, chemistry panel blood or urine pregnancy test for women of child-bearing potential (not post-menopausal for at least 12 months and not surgically sterile), echocardiogram, electrocardiogram, and disease evaluation (appropriate for disease). Samples for correlative studies will be collected accordingly.

Participants will be evaluated weekly (+/- three days) during the first cycle. The interim evaluations will consist of interval history (with a review of current medications), physical examination, blood count with differential, and chemistry panel. Pregnancy tests will be performed prior to each cycle in women of childbearing potential. After the first cycle, patients will be evaluated monthly (+/- seven days).

Participants who have had therapy discontinued will undergo end-of-therapy evaluations and will continue to be monitored with interval histories, physical examinations, and laboratory evaluations every three months (+/- seven days), with disease evaluations every three months (+/- 28 days) until they fulfill criteria for removal from study or the study is completed

Details