Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 in Children and Adults

NCT02101736 | Completed Phase 2 Results DMC

• 1 other identifier: IRB-130423015
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 12

Brief Summary

This study, "A Phase II Study of Cabozantinib (XL l84) for Plexiform Neurofibromas in Subjects with Neurofibromatosis Type I in Children and Adults diagnosed with Neurofibromatosis Type 1 (NF1) and have a type of tumor called a plexiform neurofibroma (PN). Neurofibromas are tumors that develop from the cells and tissues that cover the nerves. Plexiform neurofibromas can be disfiguring, painful, and life-threatening. These types of tumors typically do not respond well to most treatment approaches such as chemotherapy, radiation, and surgery because of their slow growth and location near vital structures of the body such as nerves, blood vessels, and the airway. The primary objective is to determine the response rate of NF1 patients with plexiform neurofibromas treated with Cabozantinib therapy using MRI scans. The objective response rate to cabozantinib is defined as ≥ 20% reduction in tumor volume at the end of 12 cycles.

Conditions

NF1; Neurofibromatosis; Plexiform Neurofibromas

Keywords

Cohort A: 3-15 years, Cohort B: Ages >= 16 years; Cabozantinib; XL184; Plexiform Neurofibromas; Neurofibromatosis; Pathogenetic NF1 Mutations; Cometriq; NF1

Outcome Measures

Primary Outcomes (1)

• The Change in Tumor Size Based on Radiographic Assessment

  We will estimate the objective response rate (ORR) as defined by 20% volumetric MRI response of the target lesion to cabozantinib at 12 months in adolescents and adults with Neurofibromatosis type 1 (NF1) plexiform neurofibromas by volumetric MRI imaging.

  baseline to 12 Months

Secondary Outcomes (1)

• Number of Participants With Adverse Events

  baseline to 24 months

Study Arms (1)

Experimental Agent XL184 (Cabozantinib)

EXPERIMENTAL

Cohort A (≥ 16 years - closed to accrual): Starting cabozantinib of 40 mg daily by mouth per cycle. Duration of each cycle is 28 days. Subjects will dose escalate after 2 cycles to 60 mg based on dose tolerability. Subjects who do not tolerate 40 mg will dose reduce to 20 mg. Doses will be capped at 60 mg. Cohort B (3 - 15 years). The starting cabozantinib dose is 30 mg/m2/day by mouth per cycle. Duration of each cycle is 28 days. Subjects will dose escalate after 2 cycles to 40 mg/m2/day based on dose tolerability. Subjects who do not tolerate 30 mg/m2/day will dose reduce to 23 mg/m2/day. Doses will be capped at 60 mg/day max daily dose Each cohort will enroll up to 24 evaluable subjects with a target minimum of 17 evaluable subjects per cohort.

Drug: Cabozantinib

Interventions

Cabozantinib DRUG

This is an open label Phase II clinical trial. For both cohorts, subjects will receive cabozantinib orally in continuous cycles. Each cycle is 28 days. In absence of progressive disease or dose limiting toxicity (DLT), subjects may continue therapy for a total of 24 cycles. Subjects with radiographic response (20% or greater reduction in tumor volume) at the end of 12 cycles can continue on therapy for up to an additional year. However, for Cohort A, subjects who do not achieve 15% reduction in tumor volume after 8 cycles will be considered treatment failure and taken off study. For Cohort B, the criteria that subjects who do not achieve 15% reduction by 8 cycles are considered treatment failure and taken off study was eliminated. Subjects will be carefully monitored for toxicities associated with cabozantinib.

Also known as: XL184, Cometriq

Experimental Agent XL184 (Cabozantinib)

Eligibility Criteria

• Age: 3 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Clinical or molecular diagnosis of Neurofibromatosis Type 1
• Plexiform neurofibroma that is progressive OR causing significant morbidity.
• Measurable disease amenable to volumetric MRI imaging defined as lesion seen on at least 3 consecutive MRI slices and at least 3 mL in volume. Select tumors \<3 cm may be eligible on review.
• Central review or MRI required prior to enrollment.
• Age ≥ 3 years of age at the time of study entry. Subjects ≥ 16 years will be enrolled in Cohort A. Subjects 3 - 15 years will be enrolled in Cohort B.
• Performance Level Karnofsky ≥ 50%. Subjects unable to walk because of paralysis, but up in a wheel chair will be considered ambulatory for purpose of assessing performance score.
• Complete resection of plexiform neurofibroma is not feasible or if subject refuses surgery.
• Fully recovered from acute toxic effects of all prior chemotherapy or radiotherapy.
• No myelosuppressive chemotherapy within 4 weeks of study entry.
• At least 7 days since completion of hematopoietic growth factors.
• At least 14 days since completion of biologic agent.
• At least 4 weeks since receiving any investigational drug.
• Physiologic or stress doses of steroids allowed in patients with endocrine deficiencies.
• At least 6 months from radiation therapy to index tumor and at least 6 weeks from radiation to areas outside of index plexiform neurofibroma.
• At least 3 months from major surgery or at least 1 month from minor surgery. No major surgery anticipated within 3 months of enrollment.

You may not qualify if:

• Active optic glioma or other low-grade glioma requiring treatment with chemotherapy or radiation therapy.
• Malignant glioma, malignant peripheral nerve sheath tumor, or other malignancy requiring treatment in the last 12 months.
• Dental braces or prosthesis that interferes with volumetric analysis of the neurofibroma(s).
• Unable to swallow tablets.
• Women who are pregnant or breast-feeding.
• Subjects of reproductive potential who have not agreed to use effective contraception.
• Subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs).
• Subject requires anticoagulants. Low dose aspirin, low-dose warfarin, and prophylactic low molecular weight heparin are permitted.
• Concomitant treatment of strong CYP3A4 inducers or inhibitors.
• History of noncompliance to medical regimens
• A known history of HIV seropositivity or known immunodeficiency. HIV testing will not be required as part of this trial, unless HIV is clinically suspected.
• Impairment of gastrointestinal function or gastrointestinal disease that may affect the absorption of cabozantinib. (e.g. ulcerative disease, malabsorption syndrome, or small bowel resection). Nasogastric tube (NG) tube is allowed.
• Any of the following within 28 days before the first dose of study treatment:
• intra-abdominal tumor/metastases invading GI mucosa
• active peptic ulcer disease

Sponsors & Collaborators

• University of Alabama at Birmingham: lead

Study Sites (12)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Indiana Unversity

Indianapolis, Indiana, 46202, United States

Location

National Cancer Institute (NCI)

Bethesda, Maryland, 20892, United States

Location

Children' Hospital Boston and Massachusetts General Hospital

Boston, Massachusetts, 02115, United States

Location

Washington University - St. Louis

St Louis, Missouri, 63110, United States

Location

New York University Medical Center

New York, New York, 10016, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19096, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Related Publications (2)

• Fisher MJ, Shih CS, Rhodes SD, Armstrong AE, Wolters PL, Dombi E, Zhang C, Angus SP, Johnson GL, Packer RJ, Allen JC, Ullrich NJ, Goldman S, Gutmann DH, Plotkin SR, Rosser T, Robertson KA, Widemann BC, Smith AE, Bessler WK, He Y, Park SJ, Mund JA, Jiang L, Bijangi-Vishehsaraei K, Robinson CT, Cutter GR, Korf BR; Neurofibromatosis Clinical Trials Consortium; Blakeley JO, Clapp DW. Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial. Nat Med. 2021 Jan;27(1):165-173. doi: 10.1038/s41591-020-01193-6. Epub 2021 Jan 13.

  PMID: 33442015 DERIVED

• Armstrong AE, Brossier NM, Hirbe AC. Neurofibromatosis type 1-related tumours in paediatrics: an evolving treatment landscape. Lancet Child Adolesc Health. 2020 Jul;4(7):488-490. doi: 10.1016/S2352-4642(20)30169-3. No abstract available.

  PMID: 32562630 DERIVED

MeSH Terms

Conditions

Neurofibromatoses; Neurofibroma, Plexiform

Interventions

cabozantinib

Condition Hierarchy (Ancestors)

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; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Peripheral Nervous System Diseases; Neuromuscular Diseases

Results Point of Contact

• Title: Karen Cole-Plourde, Program Director -NFCTC
• Organization: The University of Alabama at Birmingham

kplourde@uab.edu

(205) 514-1317

Study Officials

• Chie-Schin Shih, MD

  Indiana University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Cohort A: Single-arm open label two-stage Simon optimal study design Cohort B: Single-arm open-label study design

Study Record Dates

• First Submitted: March 14, 2014
• First Posted: April 2, 2014
• Study Start: June 1, 2014
• Primary Completion: February 16, 2022
• Study Completion: February 16, 2022
• Last Updated: May 24, 2023
• Results First Posted: May 24, 2023

Record last verified: 2023-05

Locations

US (12)