Study of Cabozantinib With Selumetinib for Plexiform Neurofibromas
NCT Number: NCT06502171
Acronym: NF113
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE1
Conditions: Neurofibromatosis 1|Plexiform Neurofibroma
Interventions: DRUG: Cabozantinib Oral Tablet|DRUG: Selumetinib Oral Capsule
Sponsor: Girish Dhall, MD
Collaborators: Children's Hospital of Philadelphia|Indiana University|United States Department of Defense
Sex: ALL
Age: CHILD, ADULT, OLDER_ADULT
Enrollment: 30
Study Design: Allocation: NA|Intervention Model: SINGLE_GROUP|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-10-01
Completion Date: 2032-10-01
Locations: University of Alabama at Birmingham, Birmingham, Alabama, 34294, United States

Summary:
Based on the clinical activity of both selumetinib and cabozantinib as monotherapies in clinical trials, the demonstrated activity of these agents in reduced doses in preclinical studies, and the non-overlapping toxicity profiles, the study will assess the tolerability and efficacy of selumetinib and cabozantinib in combination in participants with NF1 ≥16 years old with progressive and/or symptomatic PN in a phase 1/1b/2 clinical trial.

Trial Design Phase 1 This will be an open label, dose escalation phase. Dose level escalation will be determined by a rolling six design. In this design, up to 6 participants can be enrolled at a given dose level and then evaluated for dose limiting toxicity (DLT) within the DLT window. The DLT window is defined as 16 weeks in this study based on the long half-life of cabozantinib and the desire to have maximum confidence about long-term tolerability of the combination prior to proceeding to the next dose level.

Phase 1b Once the recommended phase 2 dose has been determined in phase 1, an expanded cohort of 12 participants will be enrolled in phase 1b portion of the study.

Phase 2 This will be an open label, single-arm phase using the recommended phase 2 dose.

Primary Outcome Measures: The number of participants that experienced a dose limiting toxicity when taking cabozantinib and selumetinib together., The phase 1 uses a modified Rolling 6 design to test up to 5 dose level combinations of selumetinib and cabozantinib. In this design, six participants can be enrolled at a given dose level and then evaluated for dose limiting toxicity (DLT) within the DLT window. The DLT window is defined as 16 weeks in this study based on the long half-life of cabozantinib and the desire to have maximum confidence about long-term tolerability of the combination prior to proceeding to the next dose level. Enrollment will start at dose level one and enrollment to the next dose level will occur when 3/3, 4/4, 5/5, 5/6 or 6/6 participants have completed 16 weeks of therapy without DLT. From 6 to 30 participants, depending on the number enrolled at each dose level, will be enrolled for the Rolling 6 design evaluation of DLT., 12 months|To define and describe the toxicities of the combination therapy with cabozantinib and selumetinib, Adverse events based on the NCI Common Terminology Criteria (CTC) version 5.0, 12 months
Secondary Outcome Measures: Evaluating objective response rate, Objective response rate is defined by a ≥20% volumetric MRI reduction of the target lesion by 12 month of combination therapy, 12 months