Clinical Trial - NCT02101736

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

Recruiting

Sponsor: University of Alabama at Birmingham

Collaborators:

Information provided by (Responsible party): Principal Investigator University of Alabama at Birmingham Bruce Korf, MD Principal Investigator

ClinicalTrials.gov Identifier: NCT02101736

Protocol Info

Short Description: Phase II of Cabozantinib for Plexiform Neurofibromas with Neurofibromatosis Type 1
Long Description: A Phase II Study of Cabozantinib (XL184) for Plexiform Neurofibromas in Subjects with Neurofibromatosis Type 1 age 16 years or greater
MGH Status: Open
Sponsor: Department of Defense (USAMRMC)
Disease Program: Brain/CNS

Next Steps


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Purpose

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 Title Intervention Phase
NF1 Neurofibromatosis Plexiform Neurofibromas Cabozantinib Phase 2
Study Type Interventional
Official Title A Phase II Study of Cabozantinib (XL184) for Plexiform Neurofibromas in Subjects With Neurofibromatosis Type 1 in Children and Adults

Primary Outcome Measures

The change in tumor size based on radiographic assessment [Time Frame: baseline to 12 Months] [Designated as safety issue: ]


Secondary Outcome Measures

The number of subjects experiencing an SAE after receiving cabozantinib [Time Frame: baseline to 24 months] [Designated as safety issue: ]

Estimated Enrollment: 48
Study Start Date: June 2014
Estimated Study Completion Date: May 2022
Estimated Primary Completion Date: May 2021
Arms Assigned Interventions

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.

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT02101736

Locations

  • United States, California
    • Children's Hospital Los Angeles Los Angeles, California, United States, 90027
  • United States, District of Columbia
    • Children's National Medical Center Washington, District of Columbia, United States, 20010
  • United States, Illinois
    • Lurie Children's Hospital of Chicago Chicago, Illinois, United States, 60611
    • University of Chicago Chicago, Illinois, United States, 60637
  • United States, Indiana
    • Indiana Unversity Indianapolis, Indiana, United States, 46202
  • United States, Maryland
    • National Cancer Institute (NCI) Bethesda, Maryland, United States, 20892
  • United States, Massachusetts
    • Children' Hospital Boston and Massachusetts General Hospital Boston, Massachusetts, United States, 02115
  • United States, Missouri
    • Washington University - St. Louis Saint Louis, Missouri, United States, 63110
  • United States, New York
    • New York University Medical Center New York, New York, United States, 10016
  • United States, Ohio
    • Cincinnati Children's Hospital Medical Center Cincinnati, Ohio, United States, 45229
  • United States, Pennsylvania
    • Children's Hospital of Philadelphia Philadelphia, Pennsylvania, United States, 19096
  • United States, Utah
    • University of Utah Salt Lake City, Utah, United States, 84132

Sponsors and Collaborators

University of Alabama at Birmingham

More Information

No publications provided

Responsible Party: Principal Investigator University of Alabama at Birmingham Bruce Korf, MD Principal Investigator
ClinicalTrials.gov Identifier: NCT02101736
Other Study ID Numbers:
Study First Received:
Last Updated:
Health Authority:

Keywords provided by 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

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on May 16, 2019