Trial record 16 of 103 for:    Neurofibromatosis

Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 (16 Years +) (XL184)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by University of Alabama at Birmingham
Sponsor:
Information provided by (Responsible Party):
University of Alabama at Birmingham
ClinicalTrials.gov Identifier:
NCT02101736
First received: March 14, 2014
Last updated: August 19, 2014
Last verified: July 2014
  Purpose

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).


Condition Intervention Phase
NF1
Neurofibromatosis
Plexiform Neurofibromas
Drug: Cabozantinib
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Cabozantinib (XL184) for Plexiform Neurofibromas in Subjects With Neurofibromatosis Type 1 Age 16 Years or Greater

Resource links provided by NLM:


Further study details as provided by University of Alabama at Birmingham:

Primary Outcome Measures:
  • The change in tumor size based on radiographic assessment [ Time Frame: baseline to 12 Months ] [ Designated as safety issue: Yes ]
    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:
  • The number of subjects experiencing an SAE after receiving cabozantinib [ Time Frame: baseline to 24 months ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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


Estimated Enrollment: 19
Study Start Date: June 2014
Estimated Study Completion Date: October 2017
Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Experimental Agent XL184 (Cabozantinib)
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.
Drug: Cabozantinib
Open label Phase II clinical trials. All subjects will start cabozantinib at 40 mg. Subjects who tolerate 40 mg for 2 cycles will escalate to 60 mg.
Other Names:
  • XL184
  • Cometriq

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
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 ≥16 years of age at the time of study entry.
  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 2 weeks from surgery AND recovered from any effects of surgery.
  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.
  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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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 Recruiting
Washington, District of Columbia, United States, 20010
Contact: Roger Packer, MD    202-884-2120    rpacker@childrensnational.org   
Contact: Caroline Stephens    202.476.6485    CaStephe@childrensnational.org   
Principal Investigator: Jaishri Blakeley, MD         
United States, Illinois
University of Chicago Recruiting
Chicago, Illinois, United States, 60637
Contact: James Tonsgard, MD    773-702-6488    tonsgard@midway.uchicago.edu   
Contact: Cynthia MacKenzie, RN, BSN    773.702.6487    cmackenzie@peds.bsd.uchicago.edu   
Principal Investigator: Stewart Goldman, MD         
Sub-Investigator: Robert Listernick, MD         
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) Not yet recruiting
Bethesda, Maryland, United States, 20892
Contact: Brigitte Widemann, MD    301-496-7387    widemannb@mail.nih.gov   
Contact: Janet Therrien    301.402.1848    TherrienJ@mayo.nih.gov   
Principal Investigator: Brigitte Widemann, MD         
United States, Massachusetts
Children' Hospital Boston and Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Nicole Ullrich, MD    617-355-3193    nicole.ullrich@childrens.harvard.edu   
Contact: Mark Kieran, MD, PhD    (617) 632-4386    Mark_Kieran@dfci.harvard.edu   
Sub-Investigator: Scott Plotkin, MD         
Sub-Investigator: Mark Kieran, MD         
United States, Missouri
Washington University - St. Louis Recruiting
St. Louis, Missouri, United States, 63110
Contact: David Gutmann, MD    314-362-7379    gutmann@neuro.wustl.edu   
Contact: Brunilda Lluka    314.286-1728    Lluka_B@kids.wustl.edu   
Principal Investigator: David Gutmann, MD         
United States, New York
New York University Medical Center Not yet recruiting
New York, New York, United States, 10016
Contact: Jeffrey C Allen, MD    212-263-9907    jeffrey.allen@nyumc.org   
Contact: Anna Yaffe       Anna.Yaffe@nyumc.edu   
Sub-Investigator: Matthias Karajannis, MD         
United States, Ohio
Cincinnati Children's Hospital Medical Center Not yet 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 Not yet recruiting
Salt Lake City, Utah, United States, 84132
Contact: David Viskochil, MD, PhD    801-581-8943    dave.viskochil@hsc.utah.edu   
Contact: Healther Hanson    801.587.7689    Heather.Hanson@hsc.utah.edu   
Principal Investigator: David Viskochil, MD, PHD         
Sponsors and Collaborators
University of Alabama at Birmingham
  More Information

No publications provided

Responsible Party: University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT02101736     History of Changes
Other Study ID Numbers: XL184-IST14
Study First Received: March 14, 2014
Last Updated: August 19, 2014
Health Authority: United States: Food and Drug Administration
United States: CDMRP US Army Department of Defense
United States: Exelixis, Inc.
United States: Data Safety Monitoring Board (DSMB)
United States: Medical Monitor
United States: UAB IRB of Record

Keywords provided by University of Alabama at Birmingham:
Ages 16 or greater
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
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn

ClinicalTrials.gov processed this record on August 21, 2014