A Phase 1/1b/2 Study of Cabozantinib in Combination With Selumetinib for Plexiform Neurofibroma in Adults and Adolescents With Neurofibromatosis Type 1
Girish Dhall, MD
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.
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 transf…
Eligibility
- Age range
- 16+ years
- Sex
- All
- Healthy volunteers
- No
1.0 INCLUSION CRITERIA 1.1. All participants must have a diagnosis of NF1 based on the 2021 revised consensus criteria. 1.2. Participants must have PN(s) that are progressive OR are causing significant morbidity, such as (but not limited to) head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus lesions that are causing nerve compression and loss of function, lesions causing significant disfigurement (e.g., orbital lesions), lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. Participants with paraspinal P…
Interventions
- DrugCabozantinib 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.
- DrugSelumetinib 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.
Location
- University of Alabama at BirminghamBirmingham, Alabama