Temozolomide and Radiation Therapy With or Without Vatalanib in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Completed

CT.gov ID

NCT00128700

Collaborator

(none)

Enrollment

Locations

Patients Per Site

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: temozolomide Drug: vatalanib Procedure: adjuvant therapy Radiation: radiation therapy	Phase 1/Phase 2

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

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

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

Randomized

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I/II Study on Concomitant and Adjuvant Temozolomide and Radiotherapy With or Without PTK787/ZK222584 in Newly Diagnosed GBM

Study Start Date :

Jun 1, 2005

Actual Primary Completion Date :

Nov 1, 2007

Outcome Measures

Primary Outcome Measures

Dose-limiting toxicity and maximum tolerated dose of vatalanib as determined by CTCAE v3.0 during phase I []
Progression-free survival at 6 months during phase II []

Secondary Outcome Measures

Severe toxic events as assessed by CTCAE v3.0 at weeks 3 and 6 (concomitant treatment), weeks 2 and 4 after radiotherapy, before each course of adjuvant treatment, monthly during maintenance treatment, and every 3 months during follow-up in phase II []
Overall survival at 1 year during phase II []
Correlation of angiogenesis and hypoxia markers expression and O-6-methylguanine DNA methyltransferase (MGMT) methylation status with clinical outcome during phase II []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 69 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed glioblastoma multiforme
Newly diagnosed disease
Deemed to be amenable to concurrent and adjuvant temozolomide treatment by the principal investigator

PATIENT CHARACTERISTICS:

Age

18 to 69

Performance status

ECOG 0-1

Life expectancy

Not specified

Hematopoietic

Absolute neutrophil count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3

Hepatic

Bilirubin < 1.5 times upper limit of normal (ULN)
Alkaline phosphatase < 2.5 times ULN
ALT and AST < 2.5 times ULN

Renal

Creatinine ≤ 1.7 mg/dL

Cardiovascular

Cardiac function clinically normal
12-lead ECG normal
No ischemic heart disease within the past 6 months
No uncontrolled cardiac arrhythmia
No uncontrolled hypertension
No history of stroke
No history of congenital long QT syndrome
QTc interval ≤ 450 msec for males or ≤ 470 msec for females by 12-lead ECG

Other

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No other malignancy except adequately treated basal cell or squamous cell skin cancer or cone biopsied carcinoma in situ of the cervix
No active uncontrolled infection
No other unstable systemic disease
No psychological, familial, sociological, or geographical condition that would preclude study compliance or follow-up schedule

PRIOR CONCURRENT THERAPY:

Biologic therapy

No prior anti-vascular endothelial growth factor therapy

Chemotherapy

No prior chemotherapy

Endocrine therapy

Concurrent corticosteroids allowed provided the patient is on stable or decreasing doses for ≥ 2 weeks before study entry

Radiotherapy

No prior radiotherapy

Surgery

More than 8 days, but < 6 weeks, since prior surgery or biopsy

Other

No prior randomization on this study
No concurrent warfarin, warfarin-derived drugs, or similar anticoagulants
No other concurrent anticancer therapy
No other concurrent investigational agents
No concurrent enzyme inducing antiepileptic drugs, including any of the following:
Carbamazepine
Fosphenytoin
Oxcarbazepine
Phenobarbital
Phenytoin
Primidone
No concurrent grapefruit or grapefruit juice

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	U.Z. Gasthuisberg	Leuven	Belgium	B-3000
2	Klinikum der Universitaet Regensburg	Regensburg	Germany	D-93053
3	Azienda Ospedaliera di Padova	Padova	Italy	35128
4	Daniel Den Hoed Cancer Center at Erasmus Medical Center	Rotterdam	Netherlands	3075 EA
5	Centre Hospitalier Universitaire Vaudois	Lausanne	Switzerland	CH-1011