Study of Cabozantinib With Selumetinib for Plexiform Neurofibromas

NCT06502171 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: IRB-300012653W81XWH-17-2-0037NF160012
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

Plexiform Neurofibroma; Neurofibromatosis 1

Keywords

adolescents; adults

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (1)

• Evaluating objective response rate

  12 months

Study Arms (1)

Phase 1 cabozantinib and selumetinib combination

EXPERIMENTAL

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.

Drug: Cabozantinib Oral Tablet; Drug: Selumetinib Oral Capsule

Interventions

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.

Also known as: Koselugo

Phase 1 cabozantinib and selumetinib combination

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.

Phase 1 cabozantinib and selumetinib combination

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• All participants must have a diagnosis of NF1 based on the 2021 revised consensus criteria.
• 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 PN will be eligible for this trial. Histologic confirmation of tumor is not necessary but should be considered if there are clinical or radiographic findings concerning for malignant transformation of a PN.
• For participants enrolled for tumor progression, progression is defined as: Presence of new PN on MRI or CT (documented by comparison with prior MRI or CT), OR A measurable increase in PN size (≥ 20% increase in the volume, or a ≥ 13% increase in the product of the two longest perpendicular diameters, or a ≥ 6% increase in the longest diameter) documented by comparison of two scans (MRI or CT) in the time period of 18 months or less prior to evaluation for this study.
• For participants enrolled for tumors causing "significant disfigurement" without meeting another criterion (i.e., not progressive or causing other significant morbidity), eligible tumors will be limited to tumors of the head \& neck or those on other areas of the body that are unable to be concealed by standard garments. In order to enroll a participant with PN for these indications, photographs must be reviewed by a Study Chair and/or Co-Chair for decision regarding participant eligibility prior to enrollment.
• Disease status: Measurable disease: Participants must have measurable PN(s) amenable to volumetric MRI analysis. For the purpose of this study, the target lesion must be seen on at least 3 consecutive MRI slices and the field of view must contain the entire tumor of interest. Tumors must be at least 3 mL in volume (most PN 3 cm in longest diameter will meet this criteria). If the tumor is \<3 cm in longest diameter, the participant may still be eligible. Central review of the MRI of the target PN is required prior to enrollment to ensure that the tumor is measurable and amenable to volumetric analysis.
• Age: Participants must be ≥16 years of age at the time of study entry.
• Performance Level: Participants must have Karnofsky ³ 50%. Note: Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for assessing the performance score.
• Body Surface Area (BSA): Participants must have a BSA of 1.0 m2 or greater.
• Organ Function Requirements:
• Adequate Bone Marrow Function Defined as: Absolute neutrophil count (ANC) ≥ 1500/µL without granulocyte colony-stimulating factor support.
• White blood cell count ≥ 2500/µL Platelet count ³ 100,000/mL without transfusion Hemoglobin ³10.0 gm/dL (\>5 days between enrollment and last RBC transfusion)
• Adequate Renal Function Defined as: Maximum serum creatinine based on age/gender as per institutional standards OR a creatinine clearance, radioisotope GFR, or calculated creatinine clearance using the Cockcroft-Gault equation ³70ml/min/1.73 m2.
• Cockcroft-Gault equation:
• 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.

You may not qualify if:

• Evidence of an optic pathway or other low-grade glioma, high-grade glioma, malignant peripheral nerve sheath tumor, or other cancer/tumor requiring treatment with chemotherapy, biologic therapy or radiation therapy.
• Patients with high-grade glioma, atypical or malignant peripheral nerve sheath tumor, or other malignancy who received treatment in the last 12 months. Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that have undergone potentially curative therapy.
• Dental braces or prosthesis that interfere with volumetric analysis of the neurofibroma(s).
• Prior Therapy: Participants may have received treatment for a PN or other tumor/malignancy but must have fully recovered to baseline or CTCAE ≤ Grade 1 from acute toxicities from prior therapies except alopecia.
• Myelosuppressive chemotherapy: Must not have received within 28 days of entry onto this study.
• Hematopoietic growth factors: Must not have received a growth factor that supports platelet, red or white cell number or function within 14 days of initiation of therapy.
• Biologic (anti-neoplastic agent): At least 28 days (or 5 half-lives whichever is longer) since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 28 days after administration (or 5 half-lives whichever is longer), this period must be extended beyond the time during which adverse events are known to occur. These participants must be discussed with the Study Chair on a case-by-case basis.
• Investigational Drugs: At least 28 days (or 5 half-lives whichever is longer) since the completion of therapy with an investigational drug or systemic anticancer treatment. For agents that have known adverse events occurring beyond 28 days after administration (or 5 half-lives whichever is longer), this period must be extended beyond the time during which adverse events are known to occur. These participants must be discussed with the Study Chair on a case-by-case basis.
• \- Prior treatment with cabozantinib or selumetinib is permitted for participants on Phase 1 of this study only (not Phase 1b/2). Participants may have previously received cabozantinib and/or a MEK inhibitor but not simultaneously. If participants have received either cabozantinib or selumetinib previously, they must have tolerated either medication at the recommended entry doses for this study or greater and must not have discontinued therapy due to toxicity. Participants who have received the combination of cabozantinib with any MEK inhibitor previously will not be eligible. Prior treatment with cabozantinib and/or selumetinib will not be permitted for participants on Phase 1b or Phase 2.
• Radiation therapy: 6 months from involved field radiation to index PN(s) must have elapsed prior to study entry; ³ 6 weeks must have elapsed if participant has received radiation to areas outside index PN(s) Participants who received radiation to the orbit at any time previously are not eligible.
• \>12 weeks must have elapsed between systemic treatment with radionuclides and first dose of study treatment.
• Participants with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• Surgery:
• Participants are not eligible if complete resection of a PN with acceptable morbidity is feasible, or if a participant with a feasible surgical option with minimal risk for surgical morbidity refuses surgery. Participants who underwent surgery for a progressive PN will be eligible to enter the study after the surgery, provided the PN was incompletely resected and is measurable.
• Any major surgery within 3 months before first dose of study treatment.

Sponsors & Collaborators

• Indiana University: collaborator
• United States Department of Defense: collaborator
• Girish Dhall, MD: lead
• Children's Hospital of Philadelphia: collaborator

Study Sites (1)

University of Alabama at Birmingham

Birmingham, Alabama, 34294, United States

Location

MeSH Terms

Conditions

Neurofibromatosis 1; Neurofibroma, Plexiform

Interventions

cabozantinib; AZD 6244

Condition Hierarchy (Ancestors)

Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Peripheral Nervous System Neoplasms; Nervous System Neoplasms

Study Officials

• Girish Dhall, MD

  University of Alabama at Birmingham

  STUDY DIRECTOR

Central Study Contacts

Juliette Southworth, BS

CONTACT

2055298967; jsouthworth@uab.edu

Karen Cole-Plourde, BA

CONTACT

2055141317; kplourde@uab.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: This will be an open label, single arm, prospective, multicenter study to assess the tolerability and efficacy of selumetinib and cabozantinib in combination in patients with NF1 ≥16 years old with progressive or symptomatic PN. The primary goal of the phase 1 is to determine the feasibility of combination therapy with cabozantinib and selumetinib to treat plexiform neurofibromas in people with NF1 based on toxicity and tolerability. If the results of Phase 1 show it is feasible to combine the study drugs, the plan is to submit amendments for phases 1b and 2 to evaluate the efficacy of these agents at a reduced dose compared with the prior monotherapy clinical trials and determine if these biologically active agents are effective at lower doses in combination; specifically, if that they have improved rates of response, improved depth of response and tolerability profiles that could translate into long term use to support durability of response.

Study Record Dates

• First Submitted: July 9, 2024
• First Posted: July 16, 2024
• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): August 1, 2033
• Study Completion (Estimated): August 1, 2034
• Last Updated: March 12, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)