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Study of Cabozantinib With Selumetinib for Plexiform Neurofibromas

ConditionsNeurofibromatosis 1Plexiform Neurofibroma
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age16+
SponsorGirish Dhall, MD

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Males: (140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)

Females: [(140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85 Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-h urine protein ≤ 1 g.

Disqualifiers

None

Trial design

Design model

Single group

Treatments tested in this trial

  • Cabozantinib Oral Tablet

    Drug

    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.

  • Selumetinib Oral Capsule

    Drug

    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.

Treatment groups

30 Participants
are divided into 1 treatment group
Group A: Phase 1 cabozantinib and selumetinib combinationExperimental treatment 2 interventions

Trial outcomes

Primary outcomes

1

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.

Time frame
12 months
2

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

Time frame
12 months

Secondary outcomes

1

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

Time frame
12 months

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Girish Dhall, MD

Lead sponsor

University of Alabama at Birmingham

Sponsor institution

Children's Hospital of Philadelphia

Collaborator

Indiana University

Collaborator

United States Department of Defense

Collaborator

Source ClinicalTrials.gov
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