Clinical trial NCT01149109: Efficacy and Safety Study of Lomustine/Temozolomide Combination Therapy vs. Standard Therapy for Glioblastoma Patients
Official title: Phase III Trial of CCNU/Temozolomide (TMZ) Combination Therapy vs. Standard TMZ Therapy for Newly Diagnosed MGMT-methylated Glioblastoma Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Glioblastoma
Keywords: MGMT promotor status
overall survival
Lead sponsor: University Hospital, Bonn
Sponsor class: OTHER
First posted: 2010-06-23
Enrollment: 141
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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)

Primary outcomes:
measure: overall survival
timeFrame: after follow up (4 years)
Secondary outcomes:
measure: progression free survival
timeFrame: after follow up (4 years)
measure: best response rate determined by MRI
timeFrame: after follow up (4 years)
measure: frequency of delay of the next Lomustine/Temozolomide or Temozolomide course
timeFrame: during treatment period (2 years)
measure: acute toxicity during radiotherapy and chemotherapy according to CTC AE V3.0
timeFrame: during treatment period (2 years)
measure: quality of life
timeFrame: including follow up (4 years)
measure: Evaluation of late neurotoxicity
timeFrame: after follow up (4 years)
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Depatment of Neurosurgery, Charité, University Hospital Berlin
city: Bochum
country: Germany
facility: Department of Neurology, University Hospital Bochum
city: Bonn
country: Germany
facility: Department of Neurology, University Hospital Bonn
city: Cologne
country: Germany
facility: Department of Neurosurgery, University Hospital Cologne
city: Dresden
country: Germany
facility: Department of Neurosurgery, University Hospital Dresden
city: Duesseldorf
country: Germany
facility: Department of Neurosurgery, University Hospital Duesseldorf
city: Frankfurt
country: Germany
facility: Department of Neurosurgery, University Hospital Frankfurt
city: Leipzig
country: Germany
facility: Department of Radiooncology, University Hospital Leipzig
city: Mannheim
country: Germany
facility: Department of Neurosurgery, University of Heidelberg, Medical Faculty of Mannheim
city: Muenster
country: Germany
facility: Department of Neurosurgery, University Hospital Muenster
city: Munich
country: Germany
facility: Department of Neurosurgery, University Hospital Munich (LMU)
city: Regensburg
country: Germany
facility: Department of Neurology, University Hospital Regensburg
Study officials:
affiliation: Division of Neurooncology, Departement of Neurology, University Hospital Bonn
name: Ulrich Herrlinger, Prof. Dr.
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.