Study of Cabozantinib With Selumetinib for Plexiform Neurofibromas
- Conditions
- Neurofibromatosis 1Plexiform Neurofibroma
- Interventions
- Registration Number
- NCT06502171
- Lead Sponsor
- Girish Dhall, MD
- Brief 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.
- Detailed Description
Neurofibromatosis type 1 (NF1) is one of the most common inherited tumor predisposition syndromes, affecting approximately 1 in 3000 people worldwide. NF1 is an autosomal dominant condition caused by pathogenic variants in the NF1 tumor suppressor gene resulting in a deficiency in the protein neurofibromin resulting in constitutive activation of the Ras oncoprotein and subsequent tumors. Plexiform neurofibromas (PN) are a complex of Schwann cells, fibroblasts, endothelial cells, and mast cells, which can cause disfigurement, pain, life threatening complications and can undergo malignant transformation. These tumors are refractory to most therapeutic approaches including chemotherapy, radiation, and surgery; thus, novel treatment interventions are urgently needed. Two agents have shown substantial activity in shrinking PN in adults with symptomatic or progressive PN in clinical trials through the NCI and the Congressionally Directed Medical Research Programs (CDMRP) Neurofibromatosis Clinical Trials Consortium (NFCTC): the MEK inhibitor selumetinib and the multi-tyrosine kinase inhibitor cabozantinib. Unfortunately, confirmed objective responses are not uniformly achieved and the degree of volumetric tumor reduction might be improved in patients with partial response as only a small percentage of patients have deep responses. In an open-label, phase 2 study evaluating selumetinib for children with inoperable PN, 68% of participants treated with selumetinib achieved a partial response (defined as a reduction in tumor volume by ≥20%). In a phase 2 trial (NCT02101736) of cabozantinib in participants \>16 years old with symptomatic or progressive PN, 42% of patients had a partial response. Of note, dose reductions and/or discontinuation of treatment was common in both studies, with 28% of patients in the selumetinib study requiring dose reductions and 10% eventually requiring permanent discontinuation of treatment. In the cabozantinib study 42% of the participants required dose reductions or discontinuation of therapy due to either dose-limiting toxicity or low-grade adverse events (AEs) perceived to be intolerable.
Based on the demonstrated significant clinical activity of both selumetinib and cabozantinib as monotherapies in clinical trials and the demonstrated activity of these agents in reduced doses in the preclinical studies, as well as the non-overlapping toxicity profiles, the study will assess the tolerability and efficacy of selumetinib and cabozantinib in combination in patients with NF1 ≥16 years old with progressive or symptomatic PN in a phase 1/1b/2 clinical trial.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 30
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Phase 1 cabozantinib and selumetinib combination Cabozantinib Oral Tablet The first enrolled participants will start at dose level one with a starting dose of cabozantinib of 20 mg once daily and a starting dose of selumetinib of 15 mg/m2 twice daily. The doses of drug a participant receives will depend on when the participant enrolls on the study. The first group of participants (3 - 6) will receive selumetinib and cabozantinib at half of the typical dose when given separately. If the side effects are tolerable, the second group of 3 to 6 participants will receive a higher dose of selumetinib and cabozantinib. If the drug combination is well-tolerated, there could be up to 5 groups (maximum 6 participants in each group) with each group taking an increased dose from the previous group's dose. If this is tolerated, then this will be the recommended dose of this combination for the Phase 1b of this study. If the side effects are too severe, the participants will receive a lower dose of both drugs. Phase 1 cabozantinib and selumetinib combination Selumetinib Oral Capsule The first enrolled participants will start at dose level one with a starting dose of cabozantinib of 20 mg once daily and a starting dose of selumetinib of 15 mg/m2 twice daily. The doses of drug a participant receives will depend on when the participant enrolls on the study. The first group of participants (3 - 6) will receive selumetinib and cabozantinib at half of the typical dose when given separately. If the side effects are tolerable, the second group of 3 to 6 participants will receive a higher dose of selumetinib and cabozantinib. If the drug combination is well-tolerated, there could be up to 5 groups (maximum 6 participants in each group) with each group taking an increased dose from the previous group's dose. If this is tolerated, then this will be the recommended dose of this combination for the Phase 1b of this study. If the side effects are too severe, the participants will receive a lower dose of both drugs.
- Primary Outcome Measures
Name Time Method The number of participants that experienced a dose limiting toxicity when taking cabozantinib and selumetinib together. 12 months 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.
To define and describe the toxicities of the combination therapy with cabozantinib and selumetinib 12 months Adverse events based on the NCI Common Terminology Criteria (CTC) version 5.0
- Secondary Outcome Measures
Name Time Method Evaluating objective response rate 12 months Objective response rate is defined by a ≥20% volumetric MRI reduction of the target lesion by 12 month of combination therapy
Trial Locations
- Locations (1)
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
University of Alabama at Birmingham🇺🇸Birmingham, Alabama, United StatesKaren Cole-Plourde, BAContact2055141317kplourde@uab.eduJuliette Southworth, BSContact2055298967jsouthworth@uab.eduGirish Dhall, MDContact