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

NCT ID: NCT01149109

Last Updated: 2017-06-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 141 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-10-31
• Study Completion Date: 2017-04-06

Brief Summary

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.

Conditions

Glioblastoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

lomustine (CCNU) + temozolomide (TMZ) and radiotherapy

60 Gy standard radiotherapy (RT, 30 x 2 Gy) Six 42-day courses of oral CCNU 100 mg/m2 (day 1) and oral TMZ 100 mg/m2 (day 2-6), first CCNU application during the first week of RT CCNU/TMZ and radiotherapy start 2-5 weeks after diagnosis (day of surgery for glioblastoma (GBM)). In courses 2-6, TMZ dose are adjusted according to the hematotoxicity observed in the previous course and can be increased stepwise up to 200 mg/m2/day

Group Type: EXPERIMENTAL

Temozolomide and lomustine

Intervention Type: DRUG

temozolomide and radiotherapy

60 Gy standard radiotherapy (RT, 30 x 2 Gy) and concomitant TMZ therapy (daily TMZ 75 mg/m2) starting with the first day of radiotherapy Six 28-day courses of TMZ (day 1-5) starting 4 weeks after completion of radiotherapy. In the first course TMZ is given at a dose of 150 mg/m2/day, in case no toxicity is observed, the 2nd course is applied at a daily dose of 200 mg/m2

Group Type: ACTIVE_COMPARATOR

Temozolomide

Intervention Type: DRUG

Interventions

Temozolomide and lomustine

Intervention Type: DRUG

Temozolomide

Intervention Type: DRUG

Other Intervention Names

Temodal, Temomedac, CeCeNu; Temodal, Temomedac

Eligibility Criteria

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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Bonn

OTHER

Sponsor Role: lead

Responsible Party

Ulrich Herrlinger

Head, Division of Clinical Neurooncology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ulrich Herrlinger, Prof. Dr.

Role: STUDY_DIRECTOR

Division of Neurooncology, Departement of Neurology, University Hospital Bonn

Locations

Depatment of Neurosurgery, Charité, University Hospital Berlin

Berlin, , Germany

Department of Neurology, University Hospital Bochum

Bochum, , Germany

Department of Neurology, University Hospital Bonn

Bonn, , Germany

Department of Neurosurgery, University Hospital Cologne

Cologne, , Germany

Department of Neurosurgery, University Hospital Dresden

Dresden, , Germany

Department of Neurosurgery, University Hospital Duesseldorf

Düsseldorf, , Germany

Department of Neurosurgery, University Hospital Frankfurt

Frankfurt, , Germany

Department of Radiooncology, University Hospital Leipzig

Leipzig, , Germany

Department of Neurosurgery, University of Heidelberg, Medical Faculty of Mannheim

Mannheim, , Germany

Department of Neurosurgery, University Hospital Munich (LMU)

Munich, , Germany

Department of Neurosurgery, University Hospital Muenster

Münster, , Germany

Department of Neurology, University Hospital Regensburg

Regensburg, , Germany

Countries

Germany

References

Weller J, Schafer N, Schaub C, Tzaridis T, Zeyen T, Schneider M, Potthoff AL, Giordano FA, Steinbach JP, Zeiner PS, Kowalski T, Sabel M, Hau P, Krex D, Grauer O, Goldbrunner R, Schnell O, Tabatabai G, Ringel F, Schmidt-Graf F, Brehmer S, Tonn JC, Bullinger L, Vajkoczy P, Glas M, Vatter H, Herrlinger U, Seidel C. Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial. J Neurooncol. 2023 Jan;161(1):147-153. doi: 10.1007/s11060-022-04203-4. Epub 2023 Jan 7.

Reference Type: DERIVED

PMID: 36609807 (View on PubMed)

Tzaridis T, Schafer N, Weller J, Steinbach JP, Schlegel U, Seidel S, Sabel M, Hau P, Seidel C, Krex D, Goldbrunner R, Tonn JC, Grauer O, Kebir S, Schneider M, Schaub C, Vatter H, Coch C, Glas M, Fimmers R, Pietsch T, Reifenberger G, Herrlinger U, Felsberg J. MGMT promoter methylation analysis for allocating combined CCNU/TMZ chemotherapy: Lessons learned from the CeTeG/NOA-09 trial. Int J Cancer. 2021 Apr 1;148(7):1695-1707. doi: 10.1002/ijc.33363. Epub 2020 Nov 10.

Reference Type: DERIVED

PMID: 33113214 (View on PubMed)

Weller J, Tzaridis T, Mack F, Steinbach JP, Schlegel U, Hau P, Krex D, Grauer O, Goldbrunner R, Bahr O, Uhl M, Seidel C, Tabatabai G, Brehmer S, Bullinger L, Galldiks N, Schaub C, Kebir S, Stummer W, Simon M, Fimmers R, Coch C, Glas M, Herrlinger U, Schafer N. Health-related quality of life and neurocognitive functioning with lomustine-temozolomide versus temozolomide in patients with newly diagnosed, MGMT-methylated glioblastoma (CeTeG/NOA-09): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1444-1453. doi: 10.1016/S1470-2045(19)30502-9. Epub 2019 Sep 2.

Reference Type: DERIVED

PMID: 31488360 (View on PubMed)

Herrlinger U, Tzaridis T, Mack F, Steinbach JP, Schlegel U, Sabel M, Hau P, Kortmann RD, Krex D, Grauer O, Goldbrunner R, Schnell O, Bahr O, Uhl M, Seidel C, Tabatabai G, Kowalski T, Ringel F, Schmidt-Graf F, Suchorska B, Brehmer S, Weyerbrock A, Renovanz M, Bullinger L, Galldiks N, Vajkoczy P, Misch M, Vatter H, Stuplich M, Schafer N, Kebir S, Weller J, Schaub C, Stummer W, Tonn JC, Simon M, Keil VC, Nelles M, Urbach H, Coenen M, Wick W, Weller M, Fimmers R, Schmid M, Hattingen E, Pietsch T, Coch C, Glas M; Neurooncology Working Group of the German Cancer Society. Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial. Lancet. 2019 Feb 16;393(10172):678-688. doi: 10.1016/S0140-6736(18)31791-4. Epub 2019 Feb 14.

Reference Type: DERIVED

PMID: 30782343 (View on PubMed)

Related Links

http://neurologie.uni-bonn.de/forschungsbereiche/clinical-neurooncology.htm

Clinical Neuro-Oncology, University of Bonn

Other Identifiers

2009-011252-22

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CeTeG

Identifier Type: -

Identifier Source: org_study_id