Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 in Children and Adults
Condition: NF1; Neurofibromatosis; Plexiform Neurofibromas
MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurofibroma, Plexiform
Intervention: Cabozantinib
Intervention description: 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 24 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, for Cohort A, subjects who do not achieve 15% reduction in tumor volume after 8 cycles will be considered treatment failure and taken off study. For Cohort B, the criteria that subjects who do not achieve 15% reduction by 8 cycles are considered treatment failure and taken off study was eliminated. Subjects will be carefully monitored for toxicities associated with cabozantinib.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: Cohort A: Single-arm open label two-stage Simon optimal study design Cohort B: Single-arm open-label study design
Masking: None (Open Label)
Enrollment: 45.0
Sex: All
Minimum age: 3 Years
Healthy volunteers: No
Keywords: Cohort A: 3-15 years, Cohort B: Ages >= 16 years; Cabozantinib; XL184; Plexiform Neurofibromas; Neurofibromatosis; Pathogenetic NF1 Mutations; Cometriq; NF1

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 NF1 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.
    

Eligibility 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 adverse events
             (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). Nasogastric tube (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
                  percutaneous endoscopic gastrostomy (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 heart-rate corrected QT (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 transient ischemic attack (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.