Pilot Study of Cabozantinib for Recurrent or Progressive Central Nervous System Tumors in Children
Condition: Glioblastoma Multiforme; Anaplastic Astrocytoma; Malignant Brain Tumor; High Grade Glioma
MeSH terms: Glioblastoma; Brain Neoplasms; Astrocytoma; Nervous System Neoplasms; Central Nervous System Neoplasms
Intervention: Cabozantinib
Intervention description: Subjects will receive Cabozantinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 2 Years
Maximum age: 21 Years
Healthy volunteers: No
Keywords: High Grade Glioma; Cabozantinib; GBM; Children; AA

Summary:

      This pilot will study the feasibility and exploratory efficacy of using Cabozantinib for
      recurrent or refractory central nervous system tumors for which there are no curative
      options. Patients will also be followed for safety, time to progression, event free survival
      and overall survival
    

Eligibility criteria:

        Inclusion Criteria

          1. Age: Patients must be ≥2 years and ≤21 years of age

          2. Diagnosis: Patients with relapsed or refractory central nervous system tumors.
             Patients must have had histological verification of malignancy at original diagnosis
             or relapse. Metastatic disease to the spine or primary tumors in the spine are
             eligible. Patients may be in first, second, or third relapse. Subjects with intrinsic
             brain stem gliomas may be eligible with or without histological confirmation. Please
             contact study chair prior to enrollment.

          3. Disease Status: Patients must have measurable disease. Linear enhancement of
             leptomeningeal without measurable mass is excluded.

          4. Therapeutic Options: Patient's current disease state must be one for which there is no
             accepted standard therapy, no known curative therapy or therapy proven to prolong
             survival with an acceptable quality of life. For patients in whom surgery is feasible,
             maximal surgical resection must have occurred.

          5. Performance Level: Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50 for
             patients ≤ 16 years of age (See Appendix 1). Note: Neurologic deficits in patients
             must have been relatively stable for at least 7 days prior to study enrollment.
             Patients who are unable to walk because of paralysis, but who are in a wheelchair,
             will be considered ambulatory for the purpose of assessing the performance score.

          6. Subjects must have a reasonable life expectancy of at least 2 months.

          7. Prior Therapy

             a. Patients must have fully recovered from the acute toxic effects of all prior
             anti-cancer chemotherapy i. Cytotoxic chemotherapy (including investigational agents)
             or biologic agents (eg. Cytokines or antibodies): At least 3 weeks after the last
             dose.

             ii. Nitrosoureas/mitomycin C: At least 6 weeks from the last dose. iii. XRT: At least
             14 days after local palliative XRT (small port); At least 150 days must have elapsed
             if prior TBI, craniospinal XRT or if ≥ 50% radiation of pelvis; At least 42 days must
             have elapsed if other substantial BM radiation. e.g. Stem cell Infusion without TBI:
             No evidence of active graft vs. host disease and at least 56 days must have elapsed
             after transplant or stem cell infusion.

          8. Organ Function Requirements:

             a. Adequate bone marrow function defined as: absolute neutrophil count (ANC ≥1000/mm3)
             i. Platelet count ≥ 100,000/ mm3 (transfusion independent, defined as not receiving
             platelet transfusions for at least 7 days prior to enrollment) ii. Patients with bone
             marrow metastatic disease will not be eligible. b. Adequate renal function defined as:
             i. Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73 m² or a serum creatinine
             based on age/gender as follows:

             Age Maximum Serum Creatinine (mg/dL) Male Female 2 to < 6 years 0.8 0.8 6 to < 10
             years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4

             ≥ 16 years 1.7 1.4 The threshold creatinine values in this table were derived from the
             Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing
             child length and stature data published by the CDC.

             ii. Urine protein: ≤ 30 mg/dL in urinalysis or ≤ 1+ on dipstick, unless quantitative
             protein is < 1000 mg in a 24 hour urine sample.

             c. Adequate Liver Function Defined as:

             i. Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN)
             for age ii. SGPT (ALT) ≤ 110 U/L. For the purpose of this study, the ULN for SGPT is
             45 U/L.

             iii. Serum albumin ≥ 2.8 g/dL. d. Adequate coagulation status defined as: PT and INR ≤
             1.5x ULN e. Adequate pancreatic function defined as: Serum amylase and lipase ≤ 1.5 x
             ULN f. Adequate blood pressure control defined as: A blood pressure (BP) ≤ the 95th
             percentile for age, height and gender (Appendix II) despite optimal antihypertensive
             treatment within 7 days of the first dose of the study treatment. Please note that 3
             serial blood pressures should be obtained and averaged to determine baseline BP.

             g. Central nervous system function defined as: Patients with seizure disorder may be
             enrolled if receiving non-enzyme inducing anticonvulsants and well controlled. See
             Appendix III for a list of recommended non-enzyme inducing anticonvulsants.

             h. Adequate cardiac function defined as: i. No history of congenital QTc syndrome,
             NYHA Class III or IV congestive heart failure (CHF) ii. No clinical significant
             cardiac arrhythmias, stroke or myocardial infarction within 6 months prior to
             enrollment iii. QTc

             ≤ 480 msec. Note: One ECG must be performed for eligibility determination. If the QTc
             is > 480 msec, two additional ECGs must be performed and the average of the three ECGs
             will be used to determine eligibility. Patients with Grade 1 prolonged QTc (450-480
             msec) at the time of study enrollment should have correctable causes of prolonged QTc
             addressed if possible (i.e. electrolytes, medications). See Appendix IV for a list of
             drugs that prolong QTc.

          9. Informed consent: All patients and/or their parents or legally authorized
             representatives must sign a written informed consent. Assent, when appropriate will be
             obtained according to institutional guidelines.

         10. Archival tumor tissue slides must be sent or available, except for patients with
             intrinsic pontine glioma meeting the remainder of the inclusion criteria.

        Exclusion Criteria

          1. Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on
             this study due to risks of fetal and teratogentic adverse events as seen in
             animal/human studies. Pregnancy tests must be obtained in girls who are
             post-menarchal. Males or females of reproductive potential may not participate unless
             they have agreed to use two methods of birth control- a medically accepted barrier
             method of contraceptive method (e.g., male or female condom) and a second effective
             method of birth control- during protocol therapy and for at least 4 months after the
             last dose of cabozantinib. Abstinence is an acceptable method of birth control.

          2. Concomitant Medications:

               1. Corticosteroids: Patients receiving corticosteroids who have not been on a stable
                  or decreasing dose of corticosteroid for at least 7 days prior to enrollment are
                  not eligible.

               2. Investigational drugs: Patients who are currently receiving another
                  investigational drug are not eligible.

               3. Anti-cancer agents: patients who are currently receiving other anti-cancer agents
                  are not eligible.

               4. CYP3A4 active agents: Patients must not be receiving any of the following potent
                  CYP3A4 inducers or inhibitors: erythromycin, clarithromycin, ketoconazole,
                  azithromycin, itraconazole, grapefruit juice or St. John's wort. A list of other
                  known CYP3A4 inducers and inhibitors that should be discontinued prior to
                  initiation of protocol therapy and should be avoided during study therapy if
                  reasonable alternatives exist is included in Appendix V.

               5. Patients who are receiving systemic therapeutic treatment anticoagulation are not
                  eligible. Patients receiving prophylactic systemic anticoagulation will be
                  allowed with heparin or LMWH as long as eligibility PT/INR requirements are met.
                  Concomitant anticoagulation with oral anticoagulations (e.g. warfarin, direct
                  thrombin and Factor Xa inhibitors) or platelet inhibitors (eg. Clopidogrel) are
                  not allowed.

               6. Enzyme-inducing anticonvulsants: Patients must not have received enzyme-inducing
                  anticonvulsants within 14 days prior to enrollment (See Appendix III for a list
                  of unacceptable enzyme inducing anticonvulsants).

               7. QTc Agents: Patients who are receiving drugs that prolong QTc are not eligible
                  (See Appendix IV for a list of agents).

          3. Patients must be able to swallow intact tablets. Patients who cannot swallow intact
             tablets are not eligible.

          4. Patients with active bleeding are not eligible. Specifically, no clinically
             significant GI bleeding, GI perforation, intra-abdominal abscess or fistula for 6
             months prior to enrollment, no hemoptysis or other signs of pulmonary hemorrhage for 3
             months prior to enrollment.

          5. Patients with evidence of an acute intracranial or intratumoral hemorrhage on CT or
             MRI are not eligible (patients with evidence of resolving hemorrhage will be
             eligible).

          6. Major surgery within 28 days of enrollment. Complete wound healing from major or minor
             surgery must have occurred prior to enrollment. Minor surgery (including uncomplicated
             tooth extractions) within 7 days of enrollment. Subjects with clinically relevant
             ongoing complications from prior surgery are not eligible;

          7. Concurrent uncontrolled hypertension defined as sustained blood pressure>95% for age,
             height and gender (systolic or diastolic) despite optimal antihypertensive treatment
             within 7 days of the first dose of study treatment.

          8. Patients with any medical or surgical conditions that would interfere with
             gastrointestinal absorption of this oral agent are not eligible.

          9. Infection: Patients who have an uncontrolled infection are not eligible.

         10. Patients who have received a prior solid organ transplantation are not eligible.

         11. Patients who in the opinion of the investigator may not be able to comply with the
             safety monitoring requirements of the study are not eligible.

         12. Subjects who have received cabozantinib or have an allergy to cabozantinib are
             excluded. Subjects who have previously received tyrosine kinase inhibitors are
             allowed.

         13. Subjects who have not received radiation therapy as part of their prior treatment are
             excluded.