Radiation Therapy and Concurrent Plus Adjuvant Temsirolimus (CCI-779) Versus Chemo-Irradiation With Temozolomide in Newly Diagnosed Glioblastoma Without Methylation of the MGMT Gene Promoter - A Randomized Multicenter, Open-Label, Phase II Study.
18 Years
N/A
Both
Brain and Central Nervous System Tumors
Trial Information
Radiation Therapy and Concurrent Plus Adjuvant Temsirolimus (CCI-779) Versus Chemo-Irradiation With Temozolomide in Newly Diagnosed Glioblastoma Without Methylation of the MGMT Gene Promoter - A Randomized Multicenter, Open-Label, Phase II Study.
OBJECTIVES:
Primary
- Document the activity profile of temsirolimus by the evaluation of overall survival at
1 year in patients with newly diagnosed glioblastoma multiforme, without methylation of
the MGMT gene promoter, treated with temsirolimus before and concomitantly with
radiotherapy, followed by temsirolimus maintenance therapy.
Secondary
- Investigate safety and tolerability of this therapy regimen in these patients.
- Assess progression-free survival and overall survival of these patients.
- Assess biomarkers in the tumor tissue relevant to temsirolimus and disease state, and
their correlation to clinical outcome in these patients.
OUTLINE: This is a multicenter study. Patients are stratified according to institution, age
in years (< 50 vs ≥ 50), Karnofsky performance status (PS) (< 80% vs ≥ 80%) OR ECOG PS (0 or
1 vs 2), and corticosteroid use (yes vs no). Patients are randomized to 1 of 2 treatment
arms.
- Arm I: Within 7 weeks after surgery or open biopsy, patients undergo radiotherapy 5
days a week for 6 weeks and receive oral temozolomide concurrently once daily for 6
weeks. Beginning 4 weeks after completion of concurrent chemoradiotherapy, patients
receive adjuvant oral temozolomide once daily on days 1-5. Treatment with adjuvant
temozolomide repeats every 28 days for up to 12 courses in the absence of disease
progression and unacceptable toxicity.
- Arm II: Within 7 weeks after surgery or open biopsy, patients undergo radiotherapy 5
days a week for 6 weeks. Patients also receive temsirolimus IV over 30-60 minutes once
weekly beginning 7 days before initiation of radiotherapy. After completion of
chemoradiotherapy, patients receive maintenance temsirolimus IV once weekly in the
absence of disease progression and unacceptable toxicity.
Frozen tumor biopsies or paraffin-embedded tumor material obtained from surgery or open
biopsy and blood samples are collected for analysis of molecular markers, determination of
the methylation status of the MGMT gene promoter (before randomization and at a later time),
and other studies.
After completion of study therapy, patients are followed every 3 months.
Inclusion Criteria
DISEASE CHARACTERISTICS:
- Histologically confirmed (by open brain biopsy or from a neurosurgical resection of
the tumor) supratentorial glioblastoma multiforme (GBM)
- WHO grade IV disease
- Newly diagnosed disease
- Must provide demonstration of an unmethylated MGMT-promoter
- At least 2 weeks and no more than 6 weeks since surgery or open biopsy
- Tumor tissue specimens (paraffin-embedded and/or frozen) from the GBM surgery or open
biopsy must be available for central pathology review, MGMT status determination, and
exploratory analysis of PI3-K/Akt/mTOR targets (P70S6K)
PATIENT CHARACTERISTICS:
- ECOG performance status 0-2
- Life expectancy ≥ 12 weeks
- WBC ≥ 3.0 x 10^9/L
- Absolute neutrophil count ≥ 1.5 x10^9/L
- Platelet count ≥ 75.0 x 10^9/L
- Hemoglobin ≥ 10.0 g/dL
- Bilirubin ≤ 1.5 times the upper limit of normal (ULN)
- Alkaline phosphatase ≤ 2.5 x ULN
- AST and/or ALT ≤ 2.5 x ULN
- Serum creatinine < 1.5 x ULN
- PT and PTT normal
- Negative pregnancy test
- Not pregnant or nursing
- Fertile patients must use highly effective contraception
- No ischemic heart disease in the past 6 months
- 12-lead ECG normal
- No history of stroke
- No psychological, familial, sociological, or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule
- No other malignancy within the past 5 years except adequately treated carcinoma in
situ of the cervix or nonmelanoma skin cancer (with no subsequent evidence of
recurrence)
- No serious concurrent systemic disorder including any of the following that, in the
opinion of the investigator, would compromise the patient's ability to adhere to the
protocol:
- Active infection
- HIV infection
- Cardiac disease
- QTc prolongation > 450/470 msec (males/females)
- No patients with a congenital long-QT-syndrome in their own or family medical
history, unless eligible at the investigator's discretion
- No known hypersensitivity to the study treatment
- No known hypersensitivity to antihistamines or other medical reason that prohibits
the intake of antihistamines
- No current alcohol dependence or drug abuse
- No legal incapacity or limited legal capacity
- Able to undergo a gadolinium-enhanced MRI of the brain
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- At least 4 weeks since prior and no concurrent investigational agent
- No prior stereotactic biopsy
- At least 30 days since prior drug therapy that has not received regulatory approval
for any indication
- No chemotherapy within the past 5 years
- No prior chemotherapy for a brain tumor
- No prior radiotherapy to the head
- No other concurrent anticancer therapy
- No concurrent anticoagulation therapy except low-dose prophylactic low molecular
weight heparin
- Concurrent steroid therapy allowed provided patient is on a stable or decreasing dose
for ≥ 1 week
- At least 14 days since prior and no concurrent enzyme-inducing anticonvulsants (e.g.,
carbamazepine, phenobarbital, and phenytoin)
- No concurrent strong inducers or inhibitors of CYP3A4
- No concurrent planned surgery for other diseases (e.g., dental extraction)
- No placement of Gliadel® wafer during prior surgery
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Overall survival at 1 year
Outcome Time Frame:
1 year
Safety Issue:
No
Principal Investigator
Wolfgang Wick
Investigator Role:
Study Chair
Investigator Affiliation:
Universitatsklinikum Heidelberg
Authority:
Belgium: Federal Agency for Medicinal Products and Health Products
Study ID:
EORTC-26082-22081
NCT ID:
NCT01019434
Start Date:
October 2009
Completion Date:
Related Keywords:
- Brain and Central Nervous System Tumors
- adult glioblastoma
- Glioblastoma
- Nervous System Neoplasms
- Central Nervous System Neoplasms
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