Posted February 24, 2021

Children and adults diagnosed with Neurofibromatosis Type 1 (NF1) can develop a type of tumor called a plexiform neurofibroma (PN) that develops from cells and tissues that cover the nerves. PNs can be disfiguring and painful, impact function, and are life-threatening when they compress vital structures. Standard treatment approaches such as chemotherapy and radiation are not effective, and surgery is often not feasible given the tumor's involvement of the nerve and location near vital body structures such as blood vessels, the spinal cord, and the airway. Cabozantinib, an oral Food and Drug Administration-approved multi-receptor tyrosine kinase inhibitor, was tested in an animal model of PN in the laboratory of consortium member Dr. Wade Clapp (Riley Hospital for Children). After finding significant reduction of tumor number and size in Cabozantinib-treated animals, investigators sought to translate these findings to a phase 2 human study.

Based on preclinical observations, the Neurofibromatosis Clinical Trials Consortium (NFCTC) launched a clinical trial (NFCTC FY11) to determine the response rate (by MRI) of NF1 patients with plexiform neurofibromas treated with Cabozantinib. They performed a multicenter, nonrandomized phase 2 trial (NCT02101736) of Cabozantinib in participants 16 years and older with NF1 and either progressive or clinically significant inoperable PN. Participants took the drug daily for up to 2 years. No participant experienced disease progression while taking Cabozantinib, and 42% of the participants had a partial response (defined as 20% or greater reduction in tumor volume), demonstrating that this drug has considerable clinical activity against PN. Additional analyses revealed that inhibition of DDR1, DDR2, AXL, MERTK, and MET might underpin the therapeutic responses seen in these patients. The drug was reasonably well tolerated, with rare severe side effects. However, the low-grade side effects experienced led to several participants deciding to stop the treatment. Lower doses of Cabozantinib may be optimal for the NF1 population and still lead to therapeutic response. This trial is now enrolling a pediatric cohort of children aged 3 to 15 years.

The NFCTC was established through fiscal year 2005 (FY05) Neurofibromatosis Research Program (NFRP) funding to develop and perform Phase I and II clinical trials for the management and treatment of NF complications in children and adults. Over the years, the NFCTC has expanded from 9 to 15 primary sites with an additional 10 affiliate sites. The Operations Center is housed at the University of Alabama at Birmingham under the direction of Dr. Bruce Korf, and the NFCTC Steering Committee is led by Dr. Michael Fisher at the Children's Hospital of Philadelphia/ University of Pennsylvania. Since the first development award offered in FY05, the NFCTC has been supported by additional awards from the NFRP in FY06, FY11, and FY16.

This work was also supported by National Institutes of Health/National Cancer Institute funding (U54-CA196519-04) and Exelixis.

Links: 

Fisher, M.J., Shih, CS., Rhodes, S.D. et al. Cabozantinib for neurofibromatosis type 1�related plexiform neurofibromas: a phase 2 trial. Nat Med 27, 165�173 (2021). https://doi.org/10.1038/s41591-020-01193-6

Public and Technical Abstract: Neurofibromatosis Clinical Consortium Award

https://cdmrp.health.mil/nfrp/consortium/nfrpctc

https://www.uab.edu/nfconsortium/

Top of Page