Efficacy and Safety Study of Lomustine/Temozolomide Combination Therapy vs. Standard Therapy for Glioblastoma Patients

Phase III Trial of CCNU/Temozolomide (TMZ) Combination Therapy vs. Standard TMZ Therapy for Newly Diagnosed MGMT-methylated Glioblastoma Patients

The prognosis of patients with newly diagnosed glioblastoma is dismal despite recent therapeutic improvements Using standard therapy with temozolomide (TMZ) and radiotherapy (60 Gy), the median overall survival time (mOS) is 14.6 months (Stupp et al., 2005). Since in a previous non-randomized bicentric phase II trial, primary combination chemotherapy with lomustine (CCNU) and TMZ was highly effective (mOS 23 months; UKT-03 trial; Herrlinger et al., 2006; Glas et al., 2009) the proposed trial further investigates the efficacy of CCNU/TMZ in a randomized multicenter phase III setting against standard therapy. In case the projected phase III trial confirms the phase II data, CCNU/TMZ combination would be significantly better than TMZ monotherapy and would thus be the new standard treatment for newly diagnosed GBM patients with a methylated MGMT promotor. Thus, this trial has the potential to profoundly change the standard therapy of this most aggressive brain tumor. Since in the previous trial only patients with a methylated MGMT (mMGMT) promoter had a benefit from CCNU/TMZ (mOS in the mMGMT group 34 months, in the non-mMGMT group 12.5 months; Glas et al., 2009) while patients with a non-methylated MGMT did not have any benefit, the trial is restricted to mMGMT patients.The CeTeG trial randomizes in a 1:1 fashion newly diagnosed GBM patients (18-70 years) for either standard TMZ therapy (concomitant and 6 courses à 4 weeks of adjuvant TMZ therapy) or experimental CCNU/TMZ therapy (6 courses à 6 weeks). Both arms include standard radiotherapy (RT) of the tumor site (30 x 2 Gy). Assuming that CCNU/TMZ therapy increases the median overall survival (mOS) from 48.9% (standard TMZ) to 70% (CCNU/TMZ; 75% in the previous phase II trial, Glas et al., 2009), 2 x 68 patients have to be accrued. Patients will be accrued over 24 months and each patient will be followed for at least 24 months adding up to a total minimal duration of the time from first patient in until the end of the follow-up time of 48 months. The primary endpoint is overall survival; secondary endpoints include progression-free survival, response rate, acute and late toxicity, and quality of life.

Inclusion Criteria:

• written informed consent
• patients have to be in a cognitive state that allows them to understand the rationale and necessity of study therapy and procedures.
• newly diagnosed histologically proven GBM or gliosarcoma WHO Grad IV
• methylated MGMT promoter in the tumor
• estimated life expectancy of at least 12 weeks
• Karnofsky Performance Score (KPS) ≥ 70%
• patient compliance and geographic proximity that allow adequate follow up
• male and female patients with reproductive potential must use an approved contraceptive method
• pre-menopausal female patients with childbearing potential: a negative serum pregnancy test must be obtained prior to treatment start
• Adequate organ function as described below:

Adequate bone marrow reserve:

white blood cell (WBC) count > 3000/µl, granulocyte count >1500/µl, platelets > 100000/µl, haemoglobin ≥ 10 g/dl Adequate liver function bilirubin < 1.5 times above upper limit of normal range (ULN), ALT and AST < 3 times ULN creatinine < 1.5 times ULN

Adequate blood clotting:

PT and PTT within normal limits Negative HIV test

Exclusion Criteria:

• prior malignancy
• prior chemotherapy
• prior radiotherapy to the brain
• concurrent administration of any other anti-tumor therapy
• allergy or other intolerability of temozolomide, CCNU, dacarbazine or other nitrosourea derivatives
• unable to undergo MRI
• past medical history of diseases with poor prognosis
• known HIV infection, active Hepatitis B or C infection
• any active infection
• female patients that are pregnant or breastfeeding
• patients with reproductive potential who do not accept to use contraception
• treatment in another clinical trial
• any psychological, cognitive, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up scheduled visits (at the discretion of investigator)