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Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 in Children and Adults (NF105-CABO)

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ClinicalTrials.gov Identifier: NCT02101736
Recruitment Status : Recruiting
First Posted : April 2, 2014
Last Update Posted : November 1, 2018
Sponsor:
Information provided by (Responsible Party):
Bruce Korf, MD, University of Alabama at Birmingham

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 NFI 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.


Condition or disease Intervention/treatment Phase
NF1 Neurofibromatosis Plexiform Neurofibromas Drug: Cabozantinib Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Cabozantinib (XL184) for Plexiform Neurofibromas in Subjects With Neurofibromatosis Type 1 in Children and Adults
Actual Study Start Date : June 2014
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : May 2022


Arm Intervention/treatment
Experimental: Experimental Agent XL184 (Cabozantinib)

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
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 12 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, subjects who do not achieve 15% reduction in tumor volume after 8 cycles will be considered treatment failure and taken off study. Subjects will be carefully monitored for toxicities associated with cabozantinib.
Other Names:
  • XL184
  • Cometriq




Primary Outcome Measures :
  1. The change in tumor size based on radiographic assessment [ Time Frame: baseline to 12 Months ]
    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 NF1 plexiform neurofibromas by volumetric MRI imaging.


Secondary Outcome Measures :
  1. 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.



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Ages Eligible for Study:   3 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Clinical or molecular diagnosis of Neurofibromatosis Type 1
  2. Plexiform neurofibroma that is progressive OR causing significant morbidity.
  3. 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.
  4. Central review or MRI required prior to enrollment.
  5. 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.
  6. 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.
  7. Complete resection of plexiform neurofibroma is not feasible or if subject refuses surgery.
  8. Fully recovered from acute toxic effects of all prior chemotherapy or radiotherapy.
  9. No myelosuppressive chemotherapy within 4 weeks of study entry.
  10. At least 7 days since completion of hematopoietic growth factors.
  11. At least 14 days since completion of biologic agent.
  12. At least 4 weeks since receiving any investigational drug.
  13. Physiologic or stress doses of steroids allowed in patients with endocrine deficiencies.
  14. At least 6 months from radiation therapy to index tumor and at least 6 weeks from radiation to areas outside of index plexiform neurofibroma.
  15. At least 3 months from major surgery or at least 1 month from minor surgery. No major surgery anticipated within 3 months of enrollment.
  16. Adequate bone marrow function.
  17. Adequate renal function.
  18. Adequate liver function.
  19. Blood pressure within upper limit of normal.

Exclusion Criteria:

  1. Active optic glioma or other low-grade glioma requiring treatment with chemotherapy or radiation therapy.
  2. Malignant glioma, malignant peripheral nerve sheath tumor, or other malignancy requiring treatment in the last 12 months.
  3. Dental braces or prosthesis that interferes with volumetric analysis of the neurofibroma(s).
  4. Unable to swallow tablets.
  5. Women who are pregnant or breast-feeding.
  6. Subjects of reproductive potential who have not agreed to use effective contraception.
  7. 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.
  8. Subject requires anticoagulants. Low dose aspirin, low-dose warfarin, and prophylactic low molecular weight heparin are permitted.
  9. Concomitant treatment of strong CYP3A4 inducers or inhibitors.
  10. History of noncompliance to medical regimens
  11. 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.
  12. 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.

    • Any of the following within 28 days before the first dose of study treatment:

      1. intra-abdominal tumor/metastases invading GI mucosa
      2. active peptic ulcer disease
      3. inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
      4. malabsorption syndrome
    • Any of the following within 6 months before the first dose of study treatment:

      1. abdominal fistula
      2. gastrointestinal perforation
      3. bowel obstruction or gastric outlet obstruction
      4. intra-abdominal abscess. Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating study treatment even if abscess occurred more than 6 months before the first dose of study treatment.
    • Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy
  13. Patients who have an uncontrolled infection.
  14. Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
  15. Hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment
  16. Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
  17. Radiographic evidence of cavitating pulmonary lesion(s).
  18. 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)
  19. 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:

      1. unstable angina pectoris
      2. clinically-significant cardiac arrhythmias
      3. stroke (including TIA, or other ischemic event)
      4. myocardial infarction
      5. thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this study)
  20. Other clinically significant disorders such as:

    • Active infection requiring systematic 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
  21. Complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of study treatment irrespective of time from surgery.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02101736


Contacts
Contact: Bruce Korf, MD, PhD 205.934.9411 bkorf@uab.edu
Contact: Karen C Plourde, BS 205.934.5140 kcole@uab.edu

Locations
United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Tena Rosser, MD    323-361-5825    trosser@chla.usc.edu   
Contact: Kelly Haley    323-361-5825    khaley@chla.usc.edu   
Principal Investigator: Tena Rosser, MD         
United States, District of Columbia
Children's National Medical Center Active, not recruiting
Washington, District of Columbia, United States, 20010
United States, Illinois
Lurie Children's Hospital of Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Robert Listernick, MD    773-880-3832    rlisternick@luriechildrens.org   
Contact: Stewart Goldman, MD    773-755-7425    sgoldman@luriechildrens.org   
University of Chicago Active, not recruiting
Chicago, Illinois, United States, 60637
United States, Indiana
Indiana Unversity Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Cindy Dwight    317-274-4928    cdwight@iu.edu   
Contact: Chie Shih, MD    317-944-8784    shih2@iu.edu   
Sub-Investigator: Kent Robertson, MD         
Principal Investigator: Wade Clapp, MD         
United States, Maryland
National Cancer Institute (NCI) Active, not recruiting
Bethesda, Maryland, United States, 20892
United States, Massachusetts
Children' Hospital Boston and Massachusetts General Hospital Active, not recruiting
Boston, Massachusetts, United States, 02115
United States, Missouri
Washington University - St. Louis Active, not recruiting
Saint Louis, Missouri, United States, 63110
United States, New York
New York University Medical Center Active, not recruiting
New York, New York, United States, 10016
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Elizabeth Schorry, MD    513-636-4760    Elizabeth.Schorry@cchmc.org   
Contact: Lori Backus    513.636.5336    lori.backus@cchmc.org   
Principal Investigator: Elizabeth Schorry, MD         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19096
Contact: Michael Fisher, MD    215-590-5188    fisherm@email.chop.edu   
Contact: Ratnakar Patti    215.590.5188    ratnakarp@email.chop.edu   
Principal Investigator: Michael Fisher, MD         
United States, Utah
University of Utah Active, not recruiting
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
University of Alabama at Birmingham
Investigators
Principal Investigator: Chie-Schin Shih, MD Indiana University

Responsible Party: Bruce Korf, MD, Principal Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT02101736     History of Changes
Other Study ID Numbers: IRB-130423015
First Posted: April 2, 2014    Key Record Dates
Last Update Posted: November 1, 2018
Last Verified: October 2018

Keywords provided by Bruce Korf, MD, University of Alabama at Birmingham:
Ages 3 - 15 years
Cabozantinib
XL184
Plexiform Neurofibromas
Neurofibromatosis
Pathogenetic NF1 Mutations
Cometriq
NF1

Additional relevant MeSH terms:
Neurofibromatoses
Neurofibromatosis 1
Neurofibroma
Neurofibroma, Plexiform
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
Peripheral Nervous System Diseases
Neuromuscular Diseases
Peripheral Nervous System Neoplasms
Nervous System Neoplasms