Radiation Therapy and Temsirolimus or Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma

Sponsor

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

Overall Status

Completed

CT.gov ID

NCT01019434

Collaborator

Pfizer (Industry)

111

Enrollment

Locations

Arms

Duration (Months)

8.5

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. It is not yet known whether radiation therapy is more effective when given together with temsirolimus or temozolomide in treating patients with glioblastoma.

PURPOSE: This randomized phase II trial is studying giving radiation therapy together with temsirolimus to see how well it works compared with giving radiation therapy together with temozolomide in treating patients with newly diagnosed glioblastoma.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: temozolomide Drug: temsirolimus	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

111 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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.

Study Start Date :

Oct 1, 2009

Actual Primary Completion Date :

Dec 1, 2013

Actual Study Completion Date :

Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Other: Temozolomide TMZ will be given at 75 mg/m2 daily for the whole period of RT including weekends as registered.	Drug: temozolomide TMZ will be given at 75 mg/m2 daily for the whole period of RT including weekends as registered.
Experimental: Temsirolimus CCI-779 will be given i.v. once every week at 25 mg. Each treatment should be preceded by supportive medication with a histamine H2-receptor antagonist. A first dose of CCI-779, being 25 mg, will be given on day -7 from RT start.	Drug: temsirolimus CCI-779 will be given i.v. once every week at 25 mg. Each treatment should be preceded by supportive medication with a histamine H2-receptor antagonist. A first dose of CCI-779, being 25 mg, will be given on day -7 from RT start.

Arm

Intervention/Treatment

Other: Temozolomide

TMZ will be given at 75 mg/m2 daily for the whole period of RT including weekends as registered.

Drug: temozolomide

TMZ will be given at 75 mg/m2 daily for the whole period of RT including weekends as registered.

Experimental: Temsirolimus

CCI-779 will be given i.v. once every week at 25 mg. Each treatment should be preceded by supportive medication with a histamine H2-receptor antagonist. A first dose of CCI-779, being 25 mg, will be given on day -7 from RT start.

Drug: temsirolimus

Outcome Measures

Primary Outcome Measures

Overall survival at 1 year [1 year]

Secondary Outcome Measures

Percentages of worst Adverse Events or Laboratory Event grades as measured by CTCAEs Version 4.0 criteria [end of trial]
Progression-free survival (PFS) probability at 6 months and at 12 months, and overall survival (OS) probability at 2 years [end of trial]
Correlation between biomarkers relevant to temsirolimus and PFS and OS [end of trial]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UZ Leuven	Leuven		Belgium
2	Institut de Cancerologie de l'Ouest (ICO) - Centre Rene Gauducheau	Nantes-Saint Herblain		France	44805
3	CHU Pitie-Salpetriere AP-HP	Paris		France	FR 75651
4	Universitaetsklinikum Freiburg	Freiburg		Germany	DE 79106
5	Universitatsklinikum Heidelberg	Heidelberg		Germany	D-69120
6	Ospedale Bellaria	Bologna		Italy	I-40139
7	Medisch Centrum Haaglanden - Westeinde	Den Haag		Netherlands	NL 2501
8	Erasmus MC - Daniel den Hoed Cancer Center	Rotterdam		Netherlands	NL 3008
9	ICO Badalona - Hospital Germans Trias i Pujol	Badalona		Spain	ES 08916
10	Ospedale Regionale Bellinzona e Valli	Bellinzona		Switzerland
11	UniversitaetsSpital Zuerich	Zurich		Switzerland	CH-8091
12	Clatterbridge Cancer Centre NHS Foundation Trust	Bebington	Wirral	United Kingdom
13	Western General Hospital	Edinburgh		United Kingdom

Sponsors and Collaborators

European Organisation for Research and Treatment of Cancer - EORTC
Pfizer

Investigators

Study Chair: Wolfgang Wick, Universitatsklinikum Heidelberg
Study Chair: Gianfranco Pesce, MD, Istituto Oncologico della Svizzera Italiana - Ospedale San Giovanni