Study of Irinotecan and Bevacizumab With Temozolomide in Refractory/Relapsed Central Nervous System (CNS) Tumors
Condition: Central Nervous System Tumors
MeSH terms: Nervous System Neoplasms; Central Nervous System Neoplasms
Intervention: Bevacizumab; Irinotecan; Temozolomide
Intervention description: Bevacizumab 10 mg/kg IV on day 1 and day 15 of a 28 day cycle; Irinotecan 125 mg/m2 on day 1 and day 15 of a 28 day course given IV for the first 3 dose levels. If the Maximum Tolerated Dose of temozolomide is not reached at dose level 3, then dose level 4 will be an escalation of irinotecan to 150mg/m2.; For the first cohort (dose level 0) of patients, dosing is 75 mg/m2/day day 1-5 of a 28 day course given PO for the first course. Doses will be escalated according to standard phase I dose escalation criteria. Dose levels are as follows (Dose level 1 = 125mg/m2, Dose level 2 = 175mg/m2, Dose levels 3 and 4 = 200 mg/m2)
Intervention MeSH terms: Bevacizumab; Irinotecan; Temozolomide
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 26.0
Sex: All
Minimum age: 18 Months
Maximum age: 23 Years
Healthy volunteers: No

Summary:

      Bevacizumab, irinotecan, and temozolomide are three agents shown to have promising activity
      in a variety of central nervous system tumors. No prospective studies have been published or
      are currently in progress within the major consortiums with this combination of drugs. Brain
      tumors are the second most common cause of cancer in pediatrics and the leading cause of
      cancer death in children. For children with High Grade Gliomas or with relapsed/refractory
      brain tumors, new agents in new combinations are needed. Historical data shows that newly
      diagnosed high grade gliomas 5 year progression free survival is 28-42%. Recurrent malignant
      gliomas median survival is 3-9 months. Recurrent medulloblastoma's 2 years survival is 9%.
      This study is a phase I study designed to provide an objective observation of toxicity and
      establish a maximum tolerated dose of this combination. In addition, this study will observe
      the response of children with relapsed or refractory central nervous system tumors.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Medulloblastomas, high-grade glioma, low-grade glioma, and ependymoma are eligible.
             Other central nervous system tumors may be considered for treatment at discretion of
             investigator. Pathology is required unless diffuse intrinsic pontine glioma or optic
             pathway tumor.

          -  The patient should have failed first line therapy and be considered refractory,
             relapsed, or recurrent. Exceptions are high grade gliomas including brain stem
             gliomas.

          -  Age 18 months though age 23 years are eligible for this protocol.

          -  The patient may have received any of the agents, but not in this combination. Patients
             will not be eligible if they have received the combination of bevacizumab and IV
             irinotecan as prior therapy. They will not be eligible if they had progressive disease
             on any of these agents. Investigator discretion may also be used.

          -  Bone marrow should be recovered from prior therapy with ANC >1500 and platelets
             >100,000.

          -  Serum creatinine should be less than institutional upper limit of norm.

          -  ALT/AST <3 times normal and bilirubin <1.5 times normal.

          -  Neurologic symptoms should be stable for 1 week with stable or decreasing doses of
             steroids.

          -  Patients should not be pregnant or breast feeding.

        Exclusion Criteria:

          -  Patients with bleeding disorders or on anticoagulants.

          -  Uncontrolled hypertension.

          -  Other risks of bleeding determined on individual basis.

          -  Patients receiving enzyme inducing anticonvulsants.

          -  Patients with significant cardiac or pulmonary dysfunction that would compromise the
             patient's ability to tolerate protocol therapy or would likely interfere with the
             study procedures or results.

          -  For patients receiving bevacizumab, those who have had surgical procedures should not
             receive bevacizumab within 28 days of a major procedure, 14 days of an intermediate
             procedure and 7 days of a minor procedure. Lumbar punctures or placement of PICC lines
             are not considered minor procedures and may occur at any time prior to or during
             therapy.