Clinical Trial: Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 (16 Years +)

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: A Phase II Study of Cabozantinib (XL184) for Plexiform Neurofibromas in Subjects With Neurofibromatosis Type 1 Age 16 Years or Greater

Brief Summary:

This study, "A Phase II Study of Cabozantinib (XL l84) for Plexiform Neurofibromas in Subjects with Neurofibromatosis Type I Age 16 years or greater" is for participants that have been diagnosed with Neurofibromatosis Type 1 (NF1) and have a type of tumor called a plexiform neurofibroma. 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 purpose of this Phase II Study is to determine the response rate of NFI patients with plexiform neurofibromas treated with Cabozantinib therapy using MRI scans. Cabozantinib is thought to work on tumors by blocking pathways that are involved in the growth of tumors and blood vessels that supply tumors. Cabozantinib is considered experimental because it has not been approved by the Food and Drug Administration (FDA).

Detailed Summary:

This phase II open label study will evaluate adolescents and adults with neurofibromatosis type-1 (NF1) and plexiform neurofibromas treated with cabozantinib (XL184). This study will enroll subjects who either meet clinical diagnostic criteria or have an identified pathogenetic NF1 mutation. Subjects on study must have clinically significant plexiform neurofibroma defined as potentially life-threatening, impinging on vital structures or significantly impairing the quality of life from pain or other symptoms. Patients must not have lesions suspicious for malignant tumors such as MPNSTs (malignant peripheral nerve sheath tumors) and suspicious tumors must be proven negative by histopathology prior to enrollment on study. This study will be open to patients ≥16 years of age that meet eligibility criteria.

The study will be a Simon two-stage study design. It will be a single-arm open-label study of cabozantinib and the primary endpoint is the ORR to cabozantinib at 1 year. In the first stage, 9 evaluable subjects will be accrued. If there is at least 1 response, accrual will continue to the second stage and an additional 8 evaluable subjects will be enrolled. To allow for 10% unevaluable subjects, a maximum of 19 subjects will be enrolled. Radiographic response will be evaluated as the primary endpoint with 20% volumetric MRI response of the target lesion being the threshold criteria for tumor response. A target lesion will be selected at time of enrollment and tumor evaluations will occur serially while on study.

All subjects will start cabozantinib at 40 mg. The published MTD for Cabozantinib is 140 mg and the current recommended dose in Phase 3 clinical trials for subjects with medullary thyroid cancer is 100 mg. Doses of 40 mg and 60 mg continue to show efficacy in on-going phase 2 and phase 3 trials with reduced tox
Sponsor: University of Alabama at Birmingham

Current Primary Outcome: The change in tumor size based on radiographic assessment [ Time Frame: baseline to 12 Months ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• The number of subjects experiencing an SAE after receiving cabozantinib [ Time Frame: baseline to 24 months ]
  We will evaluate the toxicity of protracted cabozantinib administration in this patient population by assessing the number of adverse events experienced by subjects.
• The change in non-target tumor size based on radiographic assessment [ Time Frame: baseline to 12 months ]
  We will estimate the objective response rate of up to 2 non-target plexiform neurofibromas to cabozantinib by MRI.
• Quality of Life of subjects receiving Cabozantinib using age-based measurement tools [ Time Frame: baseline to up to 24 months post baseline ]
  We will assess quality of life and pain in subjects on cabozantinib
• Confirm that the PedsQL NF1 QOL Module is valid in this patient population [ Time Frame: baseline to up to 24 months after baseline ]
  We will validate the PedsQL NF1 QOL Module, a disease specific QOL scale, for use in this patient population
• The change in Mast Cell Activity [ Time Frame: baseline to 4 months ]
  We will assess activity of cabozantinib on mast cell activity by mast cell culture and FACS
• The change in peripheral blood monocyte counts, endothelial cells and plasma angiogenic factors [ Time Frame: baseline to 4 months ]
  We will describe changes by flow cytometry in peripheral blood monocyte counts, circulating endothelial cells, and plasma angiogenic factors during treatment with Cabozantinib.
• The change in 17 circulating cytokine factors [ Time Frame: baseline to 4 months ]
  We will characterized the activity of cabozantinib on plasma cytokines and growth factors.
• The calculated exposure of drug in subjects receiving cabozantinib [ Time Frame: at 1 month ]
  We will characterize the pharmacokinetic profile of cabozantinib when administered to this patient population.
• The change in tumor size based on radiographic assessment 12 months after going off cabozantinib for those subjects who respond [ Time Frame: baseline to 36 months ]
  We will determine whether patients who respond (≥20% objective radiographic response of target lesion by 12 cycles) to cabozantinib will maintain that response for 1 year off therapy

Original Secondary Outcome: Same as current

Information By: University of Alabama at Birmingham

Dates:
Date Received: March 14, 2014
Date Started: June 2014
Date Completion: October 2019
Last Updated: September 26, 2016
Last Verified: March 2016