NF105: A Phase II Study of Cabozantinib (XL184) for Plexiform Neurofibromas in Subjects With Neurofibromatosis Type 1 Age 16 Years or Greater

Why are we doing this research?


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).



  • 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 toxicity. Subjects who tolerate 40 mg for 2 cycles will escalate to 60 mg. The rationale for this is that the majority of subjects who develop toxicity do so after >2 weeks on drug as cabozantinib has a long half-life. Subjects who experience dose-limiting toxicity at 40 mg will dose reduce to 20 mg when their toxicities resolve. Subjects without toxicity at 40mg will increase to 60mg. Subjects who experience toxicity at 60 mg will dose reduce to 40 mg. This dosing schema is designed to maximize safety and tolerability in this new population of patients.
  • Subjects entered on the trial will be carefully monitored for the development of cabozantinib associated toxicities, and target modifications and interruptions will be performed.
  • In all consenting subjects entered on this trial a complete pharmacokinetic profile of cabozantinib after administration will be evaluated. In addition, cytokine and endothelial progenitor cell biomarkers will be drawn to assess treatment effect and to correlate with response.
  • In addition, since plexiform neurofibromas may significantly impact the lives of patients with NF1, this study will evaluate the effects of the disease and treatment with Cabozantinib on the quality of life (QOL) of these subjects by assessing NF1 disease-related QOL, pain intensity, and pain interference.

Study Type: Interventional
Intervention Model: Single Group Assignment

Masking: None

Primary Purpose: Treatment

Who can participate?

AGES ELIGIBLE FOR STUDY: 16 Years and older


Inclusion Criteria:

  • 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 ≥16 years of age at the time of study entry.
  • 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 2 weeks from surgery AND recovered from any effects of surgery.
  • Adequate bone marrow function.
  • Adequate renal function.
  • Adequate liver function.
  • Blood pressure within upper limit of normal.

Exclusion Criteria:

  • 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 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). NG tube is allowed.
  • Patients who have an uncontrolled infection.
  • Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
  • Hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment
  • Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
  • Radiographic evidence of cavitating pulmonary lesion(s).
  • Concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration)
  • Cardiovascular disorders including:
    • Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening
    • Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days before the first dose of study treatment
    • Any history of congenital long QT syndrome
    • Baseline QTc interval >470 msec in women and >450 msec in men
    • Concomitant treatment with medications that prolong the QT interval and have a known risk of Torsades de Pointes is not contraindicated, but should be avoided if possible and will require more frequent EKG monitoring.
    • Any of the following within 6 months before the first dose of study treatment:
      • unstable angina pectoris
      • clinically-significant cardiac arrhythmias
      • stroke (including TIA, or other ischemic event)
      • myocardial infarction
      • thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this study)


  • Brain Spinal Neurofibromatosis Plexiform Neurofibroma
  • Solid Tumor Neurofibromatosis Plexiform Neurofibroma
  • Adult - Brain Spinal Neurofibromatosis Plexiform Neurofibroma
  • Adult - Solid Tumor Neurofibromatosis Plexiform Neurofibroma


Cincinnati Children’s Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799