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Cabozantinib S-malate in Treating Patients with Plexiform Neurofibromas or Neurofibromatosis Type 1

Trial Status: Active

This phase II trial studies how well cabozantinib S-malate works in treating patients with plexiform neurofibromas or neurofibromatosis type 1. Cabozantinib S-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Inclusion Criteria

  • All subjects must have an identified pathogenetic constitutional NF1 mutation OR the clinical diagnosis of NF1 using the National Institutes of Health (NIH) consensus conference criteria; in addition to a plexiform neurofibroma, one or more of the following diagnostic criteria for NF1 must be present: * Six or more Cafe Au Lait spots (>= 0.5 centimeter [cm] in prepubertal subjects or >= 1.5 cm in post pubertal subjects) * Freckling in the axilla or groin * Optic glioma * Two or more Lisch nodules * A distinctive bony lesion (dysplasia of the spheroid bone or dysplasia or thinning of long bone cortex) * A first-degree relative with NF1
  • Subjects must have plexiform neurofibroma(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 major deformity (e.g., orbital lesions) or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions; patients with paraspinal plexiform neurofibromas will be eligible for this trial; histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings, but should be considered if malignant degeneration of a plexiform neurofibroma is clinically suspected
  • For subjects enrolled for tumor progression, progression is defined as: * Presence of new plexiform neurofibroma on MRI or computed tomography (CT) (documented by comparison with prior MRI or CT), OR * A measurable increase in plexiform neurofibroma 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 approximately one year or less prior to evaluation for this study
  • For subjects enrolled for “major deformity” or a “significantly disfiguring” tumor, 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 plexiform neurofibroma for these indications, the Study Chair or Co-Chair must be contacted to review patient eligibility prior to enrollment
  • Subjects must have measurable plexiform neurofibroma(s) amenable to volumetric MRI analysis; 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 milliliter (mL) in volume (most plexiform neurofibromas [PN] 3 cm in longest diameter will meet this criteria); if the tumor is < 3 cm in longest diameter, the patient may still be eligible; central review of the MRI of the target plexiform is required prior to enrollment to ensure that the tumor is measurable and amenable to volumetric analysis
  • Adults who are unable to provide informed consent will NOT be enrolled on this study
  • Subjects must have Karnofsky >= 50%; Note: subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
  • Patients who underwent surgery for a progressive plexiform neurofibroma will be eligible to enter the study after the surgery, provided the plexiform neurofibroma was incompletely resected and is measurable
  • Patients are only eligible if complete resection of a plexiform neurofibroma with acceptable morbidity is not feasible, or if a patient with surgical option refuses surgery
  • Patients may have been previously treated for a plexiform neurofibroma but must have fully recovered from the acute toxic effects of all prior chemotherapy or radiotherapy prior to entering this study
  • Myelosuppressive chemotherapy: must not have received within 4 weeks of entry onto this study
  • Hematopoietic growth factors: at least 7 days since the completion of therapy with a growth factor that supports platelet, red or white cell number or function
  • Biologic (anti-neoplastic agent): at least 14 days since the completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 14 days after administration, this period must be extended beyond the time during which adverse events are known to occur; these patients must be discussed with the Study Chair on a case-by-case basis
  • Investigational drugs: subjects must not have received an investigational drug within 4 weeks
  • Steroids: patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary
  • Radiation therapy (XRT) >= 6 months from involved field radiation to index plexiform neurofibroma(s); >= 6 weeks must have elapsed if patient has received radiation to areas outside index plexiform neurofibroma(s)
  • Surgery: at least 2 weeks since undergoing any major surgery and must be recovered from effects of surgery
  • Peripheral absolute neutrophil count (ANC) >= 1500/uL
  • Platelet count >= 100,000/uL (transfusion independent)
  • Hemoglobin >= 10.0 gm/dL (may receive red blood cell count [RBC] transfusions)
  • Maximum serum creatinine 1.5 mg/dL OR a creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70ml/min/1.73 m^2
  • Serum calcium, magnesium, and phosphorous with institutional normal limits (supplementation is permissible)
  • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5 x ULN for age
  • Serum albumin >= 2 g/dL
  • Blood pressure (BP) =< 95th percentile for age, height, and gender and not receiving medication for treatment of hypertension
  • Major surgery: only patients who are not anticipated to need major surgery within the next 3 months of enrollment are eligible

Exclusion Criteria

  • Evidence of an active optic glioma or other low-grade glioma, requiring treatment with chemotherapy or radiation therapy; patients not requiring treatment are eligible for this protocol
  • Patients with 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)
  • The subject is unable to swallow tablets
  • Women who are pregnant or breast-feeding
  • Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during the period they are receiving the study drug and for 3 months thereafter; abstinence is an acceptable method of birth control; women of childbearing potential will be given a pregnancy test within 7 days prior to administration of cabozantinib and must have a negative urine or serum pregnancy test
  • The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 14 days or 5 half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment -OR- the subject has ever taken Cabozantinib; Note: subjects with prostate cancer currently receiving luteinizing hormone releasing hormone (LHRH) or gonadotropin releasing hormone (GnRH) agonist may be maintained on these agents
  • The subject has not recovered to baseline or Common Terminology Criteria For Adverse Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs)
  • The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=< 81 mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted
  • The subject requires chronic concomitant treatment of strong cytochrome P450, family 3, subfamily A polypeptide 4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s Wort); the subject requires chronic concomitant treatment of strong CYP3A4 inhibitors (e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, telithromycin, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil, diltiazem, cimetidine, amiodarone, chloramphenicol, boceprevir, ciprofloxacin, delavirdine, diethyl-dithiocarbamate, fluvoxamine, gestodene, imatinib, mibefradil, mifepristone, norfloxacin, norfluoxetine, starfruit, telaprevir, voriconazole); as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
  • History of noncompliance to medical regimens
  • Patients unwilling to or unable to comply with the protocol, or who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study
  • A known history of human immunodeficiency virus (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 significantly alter the absorption of cabozantinib (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection); a nasogastric tube (NG tube) is allowed
  • Patients who have an uncontrolled infection
  • The subject has experienced any of the following: * 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 * The subject has radiographic evidence of cavitating pulmonary lesion(s); chest x-ray will not be required as part of this trial, unless cavitating pulmonary lesion is clinically suspected
  • Other 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 gastrointestinal [GI] tract ulceration)
  • Cardiovascular disorders
  • Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening
  • Hypertension defined as sustained BP > 140 millimeter of mercury (mm Hg) systolic, or > 90 mm Hg diastolic within 7 days before the first dose of study treatment and/or receiving medication to treat hypertension
  • Any history of congenital long QT syndrome
  • Baseline corrected QT Interval (QTc) > 470 milliseconds (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 electrocardiogram (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 transient ischemic attack [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)
  • Any of the following within 28 days before the first dose of study treatment * Intra-abdominal tumor/metastases invading gastrointestinal (GI) mucosa * Active peptic ulcer disease * Inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis * Malabsorption syndrome
  • Any of the following within 6 months before the first dose of study treatment: * Abdominal fistula * Gastrointestinal perforation * Bowel obstruction or gastric outlet obstruction * Intra-abdominal abscess; Note: complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 6 months before the first dose of study treatment
  • Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy
  • Other clinically significant disorders such as: * Active infection requiring systemic treatment within 28 days before the first dose of study treatment * Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment * History of organ transplant * Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment
  • History of major surgery as follows: * Major surgery within 3 months of the first dose of cabozantinib if there were no wound healing complications or within 6 months of the first dose of cabozantinib if there were wound complications * Minor surgery within 1 months of the first dose of cabozantinib if there were no wound healing complications or within 3 months of the first dose of cabozantinib if there were wound complications
  • In addition, complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of cabozantinib irrespective of the time from surgery


University of Alabama at Birmingham Cancer Center
Status: ACTIVE
Contact: Bruce Richard Korf
Phone: 205-934-9411


Los Angeles
Children's Hospital Los Angeles
Status: ACTIVE
Contact: Tena L. Rosser
Phone: 323-361-2471

District of Columbia

Children's National Medical Center
Status: ACTIVE
Contact: Roger Joseph Packer
Phone: 202-884-2120


University of Chicago Comprehensive Cancer Center
Status: ACTIVE
Contact: James H. Tonsgard
Phone: 773-702-6488


Indiana University / Melvin and Bren Simon Cancer Center
Status: ACTIVE
Contact: Michael James Ferguson
Riley Hospital for Children
Status: ACTIVE
Contact: Chie-Schin Shih
Phone: 317-948-8568


Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Jaishri O'Neill Blakeley
Phone: 410-955-8837
National Institutes of Health Clinical Center
Contact: Brigitte C. Widemann
Phone: 301-496-7387


Boston Children's Hospital
Status: ACTIVE
Contact: Nicole J. Ullrich
Phone: 617-355-2066


Saint Louis
Washington University School of Medicine
Contact: Karen M. Gauvain

New York

New York
Laura and Isaac Perlmutter Cancer Center at NYU Langone
Status: ACTIVE
Contact: Jeffrey C. Allen
Phone: 212-263-9907


Cincinnati Children's Hospital Medical Center
Status: ACTIVE
Contact: Elizabeth Schorry
Phone: 513-636-4760


Children's Hospital of Philadelphia
Status: ACTIVE
Contact: Michael J. Fisher
Phone: 215-590-2800


UT Southwestern / Simmons Cancer Center-Dallas
Status: ACTIVE
Contact: Laura J. Klesse
Phone: 214-456-3727


Salt Lake City
Huntsman Cancer Institute / University of Utah
Contact: David Viskochil
Phone: 801-581-8943


I. To estimate the objective response rate (ORR) as defined by 20% volumetric magnetic resonance imaging (MRI) response of the target lesion to cabozantinib (cabozantinib S-malate) at 12 months in adolescents and adults with neurofibromatosis type 1 (NF1) plexiform neurofibromas by volumetric MRI imaging.


I. To assess the tolerability and toxicity of cabozantinib in subjects with NF1.

II. To estimate the objective response rate of up to 2 non-target plexiform neurofibromas to cabozantinib by MRI.

III. To assess quality of life and pain in subjects with NF1 and plexiform neurofibromas on cabozantinib.

IV. To assess the pediatric quality of life inventory (PedsQL) NF1 quality of life (QOL) module, a disease specific QOL scale, for use in this patient population.

V. To assess activity of cabozantinib on mast cell activity by mast cell culture and fluorescence activated cell sorting (FACS).

VI. To describe changes by flow cytometry in peripheral blood monocyte counts, circulating endothelial cells, and plasma angiogenic factors during treatment with cabozantinib.

VII. To describe the baseline and change in 17 circulating cytokine factors related to proliferating cells.

VIII. To characterize the pharmacokinetic profile of cabozantinib in this population.

IX. To 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.


Patients receive cabozantinib S-malate orally (PO) daily on days 1-28. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients achieving radiographic response (>= 20% reduction in tumor volume) may continue treatment for up to 24 courses total.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
University of Alabama at Birmingham Cancer Center

Principal Investigator
Bruce Richard Korf

  • Primary ID NF Protocol 105 (CABO)
  • Secondary IDs NCI-2015-01578, 105, Exelixis: XL184-IST14, F130502005, s14-00969
  • ID NCT02101736