NCT06502171

Study of Cabozantinib With Selumetinib for Plexiform Neurofibromas

A Phase 1/1b/2 Study of Cabozantinib in Combination With Selumetinib for Plexiform Neurofibroma in Adults and Adolescents With Neurofibromatosis Type 1

• Status: Not Yet Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 30 (estimated)
• Sponsor: Girish Dhall, MD · Academic / Other
• Sex: All
• Age: 16 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Neurofibromatosis 1
• Plexiform Neurofibroma

Interventions

Type	Name	Description
DRUG	Cabozantinib Oral Tablet	Cabozantinib will be taken once a day. It must be swallowed whole and not crushed and taken on an empty stomach. The dose will depend on when a participant enrolls on the study. First group will take 20 mg. If participants are enrolled early in this study, they may receive doses that are lower than those who are enrolled later. Participants will be told what dose they will take when they start the study. Once a dose is started, the dose will not be increased. However, a dose can be reduced up to 2 times if a participant experience adverse events. Cabozantinib may be taken simultaneously with selumetinib.
DRUG	Selumetinib Oral Capsule	Selumetinib will be taken twice a day, at least 6 hours apart. It must be swallowed whole and not crushed and taken on an empty stomach. The dose will depend on when a participant enrolls on the study. First group will take 15 mg twice a day. If participants are enrolled early in this study, they may receive doses that are lower than those who are enrolled later. Participants will be told what dose they will take when they start the study. Once a dose is started, the dose will not be increased. However, a dose can be reduced up to 2 times if a participant experience adverse events.

Timeline

• Start date: 2026-08-01
• Primary completion: 2033-08-01
• Completion: 2034-08-01
• First posted: 2024-07-16
• Last updated: 2026-03-12

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study