Temozolomide and Radiation Therapy With or Without Vatalanib in Treating Patients With Newly Diagnosed Glioblastoma Multiforme
Condition: Brain and Central Nervous System Tumors
MeSH terms: Glioblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop
      the growth of tumor cells, either by killing the cells or by stopping them from dividing.
      Radiation therapy uses high-energy x-rays to kill tumor cells. Vatalanib may stop the growth
      of tumor cells by blocking blood flow to the tumor. Giving temozolomide and radiation therapy
      together with vatalanib may kill more tumor cells.

      PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of
      vatalanib when given together with temozolomide and radiation therapy and to see how well
      they work in treating patients with newly diagnosed glioblastoma multiforme.
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  Determine the maximum tolerated dose and recommended phase II dose of vatalanib when
           given in combination with temozolomide and radiotherapy in patients with newly diagnosed
           glioblastoma multiforme. (Phase I)

        -  Determine the safety and tolerability of this regimen in these patients. (Phase I)

        -  Determine the 6-month progression-free survival of patients treated with
           chemoradiotherapy comprising temozolomide and radiotherapy with or without vatalanib
           followed by adjuvant therapy comprising temozolomide and vatalanib or temozolomide alone
           with or without maintenance therapy comprising vatalanib alone. (Phase II)

      Secondary

        -  Determine 12-month overall survival of patients treated with these regimens. (Phase II)

        -  Determine the toxicity profile of these regimens in these patients. (Phase II)

        -  Correlate expression of angiogenesis and hypoxia markers and MGMT methylation status
           with clinical outcome in patients treated with these regimens.

      OUTLINE: This is a phase I, multicenter, open-label, non-randomized, dose-escalation study of
      vatalanib followed by a phase II, randomized, controlled study. Patients enrolled in the
      phase II portion of the study are stratified according to participating center, age (< 50
      years vs ≥ 50 years), corticosteroid intake (yes vs no), and mini-mental status evaluation
      score (< 27 vs 27-29 vs 30).

        -  Phase I:

             -  Chemoradiotherapy: Patients receive oral temozolomide once daily for 6-7 weeks and
                oral vatalanib once daily for 6 weeks. Patients also undergo radiotherapy once
                daily, 5 days a week, for 6 weeks. Four weeks after the completion of
                chemoradiotherapy, patients proceed to adjuvant therapy. During the 4-week period
                between chemoradiotherapy and adjuvant therapy, patients continue to receive oral
                vatalanib twice daily.

      Cohorts of 3-6 patients receive escalating doses of vatalanib during chemoradiotherapy until
      the maximum tolerated dose is determined (MTD). The MTD is defined as the dose preceding that
      at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are
      treated at the MTD.

        -  Adjuvant therapy: Patients receive oral temozolomide once daily on days 1-5 and oral
           vatalanib twice daily on days 1-28. Treatment repeats every 28 days for 6 courses in the
           absence of disease progression or unacceptable toxicity. Patients then proceed to
           maintenance therapy.

        -  Maintenance therapy: Patients continue to receive oral vatalanib twice daily in the
           absence of disease progression or unacceptable toxicity.

             -  Phase II: Patients are randomized to 1 of 3 treatment arms.

        -  Arm I:

             -  Chemoradiotherapy: Patients receive oral temozolomide once daily for 6-7 weeks and
                undergo radiotherapy once daily, 5 days a week, for 6 weeks. Four weeks after the
                completion of chemoradiotherapy, patients proceed to adjuvant therapy.

             -  Adjuvant therapy: Patients receive oral temozolomide once daily on days 1-5.
                Treatment repeats every 28 days for up to 6 courses in the absence of disease
                progression or unacceptable toxicity.

        -  Arm II:

             -  Chemoradiotherapy: Patients receive temozolomide and undergo radiotherapy as in arm
                I. Patients also receive vatalanib twice daily for 6 weeks at the MTD determined in
                phase I. Four weeks after the completion of chemoradiotherapy, patients proceed to
                adjuvant therapy. During the 4-week period between chemoradiotherapy and adjuvant
                therapy, patients continue to receive oral vatalanib twice daily.

             -  Adjuvant therapy: Patients receive temozolomide and vatalanib as in phase I
                adjuvant therapy. Patients then proceed to maintenance therapy.

             -  Maintenance therapy: Patients continue to receive vatalanib as in phase I
                maintenance therapy.

        -  Arm III:

             -  Chemoradiotherapy: Patients receive temozolomide and undergo radiotherapy as in arm
                I. Four weeks after the completion of chemoradiotherapy, patients proceed to
                adjuvant therapy. During the 4-week period between chemoradiotherapy and adjuvant
                therapy, patients receive oral vatalanib twice daily.

             -  Adjuvant therapy: Patients receive temozolomide and vatalanib as in phase I
                adjuvant therapy. Patients then proceed to maintenance therapy.

             -  Maintenance therapy: Patients continue to receive vatalanib as in phase I
                maintenance therapy.

      After completion of study treatment, patients are followed every 3 months for survival.

      PROJECTED ACCRUAL: Approximately 3-18 patients will be accrued for the phase I portion of
      this study. A total of 201 patients (67 per treatment arm) will be accrued for the phase II
      portion of this study.
    

Intervention name(s): temozolomide; vatalanib; adjuvant therapy; radiation therapy
Intervention type(s): Drug; Drug; Procedure; Radiation
Intervention MeSH terms: Temozolomide; Vatalanib
Allocation: Randomized
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma