Glioblastoma, IDH-wildtypePhase 3NCT06419946
Lomustine in Addition to Standard of Care in Patients With MGMT Methylated Glioblastoma
A Phase 3 study testing Temozolomide and Lomustine in people with Glioblastoma, IDH-wildtype and MGMT-Methylated Glioblastoma, run by Vastra Gotaland Region at 20 sites in 4 countries.
Trial summary
Background: Glioblastoma (GBM) is notoriously difficult to treat, with current therapies often extending life by only a few months. The standard treatment involves surgery followed by radiation and chemotherapy with Temozolomide (TMZ). Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Glioblastoma, IDH-wildtype, MGMT-Methylated Glioblastoma
- What is being tested?
- Temozolomide and Lomustine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 200 participants
- Where
- 20 sitesin 4 countries
- Study dates
- 1 Feb 2025to 15 Dec 2033
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Newly diagnosed glioblastoma/gliosarcoma, IDH wild type
- Methylated MGMT promoter
- World Health Organization performance status 0-2
- Age 18-70
Who cannot join
- Previous malignancy within 3 y or malignancy treated non-curatively
- Previous chemotherapy or radiotherapy involving the head
- Off-protocol tumor-specific treatment
- Serious comorbidity
Trial locations and contacts
20 sites in 4 countries. Contact the study team or a site near you to ask about taking part.
Annika Malmström, MD. PhD contact
20 sites in 4 countries
Sweden10 sites, 10 recruiting
- Recruiting
Gävle Hospital
Gävle
PI Kyriaki Christodoulou, kyriaki.christodoulou@regiongavleborg.se
- Recruiting
Sahlgrenska University Hospital
Gothenburg
PI Erik Fernström, erik.fernstrom@vgregion.se
- Recruiting
Ryhov County Hospital
Jönköping
PI Michael Strandéus
michael.strandeus@rjl.se
- Recruiting
Kalmar Country Hospital
Kalmar
PI Nathalie Skarin, nathalie.skarin@regionkalmar.se
- Not yet recruiting
Skåne University Hospital
Lund
PI Sara Kinhult, Sara.Kinhult@skane.se
- Recruiting
Örebro University Hospital
Örebro
PI David Löfgren, david.lofgren@regionorebrolan.se
- Enrolling by invitation
Karolinska Institutet
Stockholm
- Enrolling by invitation
Sundsvall Hospital
Sundsvall
- Recruiting
Norrlands Universitetssjukhus, Umea, Sweden
Umeå
PI Maria Sandström, maria.sandstrom@umu.se
- Recruiting
Uppsala University Hospital
Uppsala
PI Pernilla Roswall, pernilla.roswall@regionuppsala.se
Norway5 sites, 5 recruiting
- Recruiting
Haukeland University Hospital
Bergen
PI Jorunn Brekke, jorunn.brekke@helse-bergen.no
- Recruiting
Sorlandet Sykehus
Kristiansand
PI Rene van Heilvort, Rene.helvoirt@sshf.no
- Recruiting
Oslo University Hospital
Oslo
PI Petter Brandal, pebra@ous-hf.no
- Not yet recruiting
Stavanger University Hospital
Stavanger
PI Line Sagerup Bjorland, line.bjorland@sus.no
- Not yet recruiting
St Olavs Hospital
Trondheim
PI Tora S. Solheim, Tora.Skeidsvoll.Solheim@stolav.no
Austria4 sites, 4 recruiting
- Not yet recruiting
University Hospital Graz
Graz
PI Tadeja Urbanic Purkart, tadeja.urbanic-purkart@medunigraz.at
- Not yet recruiting
Medizinische Universität Innsbruck
Innsbruck
PI Martha Nowosielski, martha.nowosielski@i-med.ac.at
- Recruiting
Kepler University Hospital
Linz
PI Isolde Hoellmueller, isolde.hoellmueller@kepleruniklinikum.at
- Enrolling by invitation
University Hospital St. Pölten
Sankt Pölten
Denmark1 site, 1 recruiting
- Recruiting
Aarhus University Hospital
Aarhus
PI Slavka Lukacova, Slavka.lukacova@auh.rm.dk
About this study
Official title: Phase III Trial of Temozolomide/Lomustine (TMZ/LOM) Combination Therapy vs. Standard TMZ Therapy for Newly Diagnosed MGMT Promoter Methylated Glioblastoma (IDHwt) Patients +/- Tumor Treating Fields (Optune)
Background: Glioblastoma (GBM) is notoriously difficult to treat, with current therapies often extending life by only a few months. The standard treatment involves surgery followed by radiation and chemotherapy with Temozolomide (TMZ). The efficacy of TMZ, however, is significantly enhanced when the tumor's o6-methylguanine-DNA-methyltransferase (MGMT) gene is methylated. Recent studies, such as the NOA-09 trial, have suggested that adding Lomustine (LOM) to TMZ could improve outcomes for patients with this specific tumor profile.
Hypothesis: The investigators hypothesize that the addition of LOM to the TMZ regimen will lead to significantly improved survival rates among patients with newly diagnosed glioblastoma who have a methylated MGMT promoter compared to those receiving only TMZ.
Read more
Treatment Plans: The study will randomly assign participants to two groups:
- Control Group: Standard treatment with TMZ during and after radiation therapy.
- Experimental Group: TMZ combined with LOM, starting on the first day of radiation therapy.
Outcome Measures: The primary outcome measure will be survival. Other outcomes will include progression-free survival (time from randomization until tumor progression or death), safety profiles (adverse effects of the treatments), and quality of life measures as well as neurocognitive outcomes.
Read the detailed description
Current evidence:
In this section the investigators highlight the evidence behind the current standard fo care, and the emerging data supporting our approach. The RCT of Stupp showed that radiotherapy (RT) together with concomitant and adjuvant TMZ prolong survival. The NORDIC trial investigated the role of TMZ compared to RT for the subgroup of elderly patients, showing that survival was superior with TMZ, especially for those with mMGMT. LOM has been used for treatment of glioma for many decades, often used in combination with procarbazine and vincristine (PCV), but in recent years it is used in patients with glioblastoma as 2nd line therapy after failure of TMZ.
A phase 3 trial with Tumor Treating Fields (TTF, alternating low intensity electromagnetic fields) showed prolonged survival in patients with glioblastoma, but it is not universally applied/approved. Despite full multimodal treatment with surgery, RT, TMZ and TTFields, the median survival is <2 years. There is an unmet medical need to further improve treatments for these patients.
One RCT (NOA-09) provided preliminary data to exploit the specific vulnerability of mMGMT in glioblastoma (although no use of TTF in this trial). The overall tolerability of TMZ-LOM in combination was acceptable, as most adverse events (AE) were moderate and transient. Furthermore, health-related quality of life (HRQoL) and neurocognition did not differ between groups.
Estimated sample size and power:
Sample size calculation is based upon the results from the CeTeG/NOA-09 trial. Accounting for attrition, a total of 200 mMGMT GBM patients have to be randomised. Patients that drop-out before start of any therapy will be replaced, which will lead to more than 200 patients being randomized. For overall survival (OS) all patients that started day 1 of radiochemotherapy will be analysed (modified ITT). For per protocol all patients that have completed week 6 of treatment arm will be analysed for outcome. Patients lost to follow-up after the start of chemotherapy will be evaluated as observations censored at the time of dropout. Approximately 45% of newly diagnosed patients have a mMGMT, thus for 200 randomised patients a minimum of 445 patients will be screened.
Addition to the already described statistics:
Randomizations are stratified for center and for TTFields. The primary confirmatory analysis will be based on the modified intention-to-treat (mITT) population.
Survival parameters are measured in days starting from the day of randomization. Median time estimates as well as 95% confidence intervals will be reported. All additional analyses will be descriptive.
The statistical analysis plan (SAP) and blinding of statisticians will ensure analytic transparency and robustness.
Finally, similarly to avoid producing outdated results, the investigators plan to start TTF concomitant according to the Trident trial where results are expected soon. Nevertheless, if the Trident results are negative, the investigators will submit an amendment for using TTF according to the current standard of care. The reverse would not be possible in the middle of the trial as this has required extensive discussion, planning, and training with all sites. Balance with respect to TTF use is ensured with stratification in the randomization process.
Further details of study design of this phase 3, open-label, multicenter randomised controlled trial with parallel group design is presented under respective subheadings.
- Being tested
- Temozolomide, Lomustine
- Keywords
- precision medicine, temozolomide, lomustine, CCNU, survival
- Medical subject headings
- Glioblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TemozolomideDrug
Also called TMZ
In the experimental treatment arm: a combination of Temozolomide and Lomustine, taken together, two separate pills
LomustineDrug
Also called LOM
In the experimental treatment arm: a combination of Temozolomide and Lomustine, taken together, two separate pills
| Study group | Role | What they receive |
|---|---|---|
| treatment arm | Experimental | arm with temozolomide (TMZ) plus lomustine (LOM) treatment.
6 cycles of LOM/TMZ Start day 1 of RT. Cycle length of 42 days. Duration 9 months. Receives: Drug: Temozolomide; Drug: Lomustine |
| standard arm | Active comparator | arm with standard of care treatment with temozolomide only.
Oral TMZ 75 mg/m2 daily during RT and with start day 1 of RT. This is followed by 6 cycles of TMZ with start 4 weeks after the end of RT. Cycle length 28 days. Duration 8,5 months. Receives: Drug: Temozolomide |
What is being measured
The primary outcome is the main question the study is designed to answer.
overall survival
visualized with Kaplan-Meier plot, tested with log-rank test
Measured: Assessed from day of randomization to event or last day of follow-up (FU). Aanlyzed 36 months after last inclusion ensures that all patients have a potential of minimum 36 months FU
Secondary outcomes (11)
progression free survival (PFS)
radiological or clinical PFS according to the modified Response Assessment in Neuro-Oncology (mRANO) criteria (Kaplan-Meier plot, log-rank test)
Measured: Assessed from day of randomization to event or last day of follow-up (FU). Aanlyzed 36 months after last inclusion ensures that all patients have a potential of minimum 36 months FU
quality of life (QoL)
According to the EORTC Quality of Life Questionnaire (EORTC QLQ-30) with brain cancer module 20; Evaluate minimal clinically important difference (MCID) (i.e. clinically relevant difference) according to guidelines.
These questionnaires contain a total of 30 + 20 QoL-related questions which are scored on a nominal scale (0-5 points); the result of each question is recorded for computerized examination and the questions relating to the same dimension of QoL (e.g. emotional well-being) are taken together for an overall score of this dimension. The scores for the different dimensions will be compared between repeated assessments throughout the trial and between the two arms of the trial.
Analysed at 8 different time points:
- start of therapy = day 1
- since first assessment 6 weeks later: middle of the first months (1.5)
- from now on, every 6 months: month 7.5
- month 13.5
- month 19.5
- month 25.5
- month 31.5
- month 37.5 (end of the follow-up after 4 years)
Measured: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - verbal memory
Verbal Memory Test: Participants are tasked with learning and recalling 15 words. They are asked to recognize the words among 15 distractors (other words). The test is repeated at the end of the test session (after approximately 30 minutes). This test measures how well the participant can learn and recall words. Low scores indicate verbal memory difficulties.
Analysed at 8 different time points:
- start of therapy (RT/chemotherapy/TTFields) = day 1
- since first assessment 6 weeks later: middle of the first months (1.5)
- from now on, every 6 months: month 7.5
- month 13.5
- month 19.5
- month 25.5
- month 31.5
- month 37.5 (end of the follow-up after 4 years)
Patients will be monitored with the "CNS Vital Signs", a validated computerized test battery with proven sensitivity to detect cognitive impairments in patients with brain tumors. The battery consists of 8 subtests.
Measured: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - visual memory
Visual Memory Test: Participants are tasked with learning and recalling 15 geometric shapes. They are asked to recognize these among 15 distractors (other shapes). The test is repeated at the end of the test session (after approximately 30 minutes). This test measures how well the participant can learn and recall geometric shapes. Low scores indicate visual memory difficulties.
Analysed at 8 different time points:
- start of therapy (RT/chemotherapy/TTFields) = day 1
- since first assessment 6 weeks later: middle of the first months (1.5)
- from now on, every 6 months: month 7.5
- month 13.5
- month 19.5
- month 25.5
- month 31.5
- month 37.5 (end of the follow-up after 4 years)
Patients will be monitored with the "CNS Vital Signs" (CNS = central nervous system), a validated computerized test battery with proven sensitivity to detect cognitive impairments in patients with brain tumors. The battery consists of 8 subtests.
Measured: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - motor speed and fine motor control
Finger Tapping Test: The test measures motor speed and fine motor control. Participants are to perform three "tapping" sessions, lightly tapping the top of a key on the computer with each hand. This test measures how many "tappings" the participant performs with each hand. Motor speed varies according to hand dominance. Low scores indicate motor slowing.
Analysed at 8 different time points:
- start of therapy (RT/chemotherapy/TTFields) = day 1
- since first assessment 6 weeks later: middle of the first months (1.5)
- from now on, every 6 months: month 7.5
- month 13.5
- month 19.5
- month 25.5
- month 31.5
- month 37.5 (end of the follow-up after 4 years)
Patients will be monitored with the "CNS Vital Signs", a validated computerized test battery with proven sensitivity to detect cognitive impairments in patients with brain tumors. The battery consists of 8 subtests.
Measured: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - cognitive speed
Symbol Digit Coding: The test measures cognitive speed during simultaneous cognitive processes such as visual scanning, visual perception, visual memory, and motor skills. Low scores may indicate impulsivity, perception difficulties, or impaired processing speed.
Analysed at 8 different time points:
- start of therapy (RT/chemotherapy/TTFields) = day 1
- since first assessment 6 weeks later: middle of the first months (1.5)
- from now on, every 6 months: month 7.5
- month 13.5
- month 19.5
- month 25.5
- month 31.5
- month 37.5 (end of the follow-up after 4 years)
Patients will be monitored with the "CNS Vital Signs", a validated computerized test battery with proven sensitivity to detect cognitive impairments in patients with brain tumors. The battery consists of 8 subtests.
Measured: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - simple and complex reaction time, inhibition/disinhibition, mental flexibility, and focused attention.
Stroop Test: The test measures simple and complex reaction time, inhibition/disinhibition, mental flexibility, and focused attention. It also measures how well participants can adapt to changes and increasing complexity in the task. Long reaction times indicate mental slowing. A large number of errors indicate impulsivity, perception difficulties, or impaired processing speed.
Analysed at 8 different time points:
- start of therapy (RT/chemotherapy/TTFields) = day 1
- since first assessment 6 weeks later: middle of the first months (1.5)
- from now on, every 6 months: month 7.5
- month 13.5
- month 19.5
- month 25.5
- month 31.5
- month 37.5 (end of the follow-up after 4 years)
Patients will be monitored with the "CNS Vital Signs", a validated computerized test battery with proven sensitivity to detect cognitive impairments in patients with brain tumors. The battery consists of 8 subtests.
Measured: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - attention
Attention Shift Test: The test measures how well participants can shift attention and perform simultaneous tasks. Participants must adjust their responses to temporarily changed rules. Normal/good scores are achieved with a high proportion of correct answers and short reaction times.
Analysed at 8 different time points:
- start of therapy (RT/chemotherapy/TTFields) = day 1
- since first assessment 6 weeks later: middle of the first months (1.5)
- from now on, every 6 months: month 7.5
- month 13.5
- month 19.5
- month 25.5
- month 31.5
- month 37.5 (end of the follow-up after 4 years)
Patients will be monitored with the "CNS Vital Signs", a validated computerized test battery with proven sensitivity to detect cognitive impairments in patients with brain tumors. The battery consists of 8 subtests.
Measured: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - attention, vigilance, and reaction time
Continuous Performance Test: The test measures attention, vigilance, and reaction time. Most normal participants achieve nearly perfect results on this test. Long response times indicate mental slowing or impaired attention.
Analysed at 8 different time points:
- start of therapy (RT/chemotherapy/TTFields) = day 1
- since first assessment 6 weeks later: middle of the first months (1.5)
- from now on, every 6 months: month 7.5
- month 13.5
- month 19.5
- month 25.5
- month 31.5
- month 37.5 (end of the follow-up after 4 years)
Patients will be monitored with the "CNS Vital Signs", a validated computerized test battery with proven sensitivity to detect cognitive impairments in patients with brain tumors. The battery consists of 8 subtests.
Measured: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - Perception
Emotional Perception Test: The test measures how well participants can perceive and identify specific emotions and their ability to perceive and understand social information. Low scores indicate difficulties with emotional perception.
Analysed at 8 different time points:
- start of therapy (RT/chemotherapy/TTFields) = day 1
- since first assessment 6 weeks later: middle of the first months (1.5)
- from now on, every 6 months: month 7.5
- month 13.5
- month 19.5
- month 25.5
- month 31.5
- month 37.5 (end of the follow-up after 4 years)
Patients will be monitored with the "CNS Vital Signs", a validated computerized test battery with proven sensitivity to detect cognitive impairments in patients with brain tumors. The battery consists of 8 subtests.
Measured: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
Adverse events (AE)
according to the Common Terminology Criteria for Adverse Events (CTCAE). (descriptive statistics between groups). A complementary analysis of AE by severity of event and by relationship to treatment will be performed (Chi2 test). Dose reductions, delay of therapy in subsequent courses and premature withdrawals will also be described.
The Pharmacovigilance Sahlgrenska University Hospital will provide an unbiased evaluation of all serious adverse events. This ensures a qualified evaluation to support the sponsor to ensure patient safety. A Data Safety Monitoring Board (DSMB) is appointed to perform pre-planned interim analyses. Prompt ad-hoc meeting of the DSMB will be held in case of suspected unexpected serious adverse events. The committee can recommend a break or the stopping of the trial.
Measured: assessed from day of randomization to death or 36 months FU
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 May 2024
- Study start1 Feb 2025
- Primary completion15 Dec 2031 (estimated)
- Study completion15 Dec 2033 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Glioblastoma, IDH-wildtypeStudies of the same condition, open and under way.
- More trials run by Vastra Gotaland RegionThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Everyone: Radiotherapy (RT) consists of 60 Gy standard RT (RT 30x2Gy) Experimental treatment arm (TMZ/LOM): 6 cycles of LOM/TMZ Start day 1 of RT. Cycle length of 42 days. Duration 9 months. Standard treatment arm (TMZ): Oral TMZ 75 mg/m2 daily during RT and with start day 1 of RT. This is followed by 6 cycles of TMZ with start 4 weeks after the end of RT. Cycle length 28 days. Duration 8,5 months. Everyone: TTFields start with radiotherapy/chemotherapy - but only in Sweden where TTF is part of standard of care (SOC). Ongoing until 2nd progression or max 2 years.
- Masking
- None (open label)
- Enrolment
- 200 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Vastra Gotaland Region
- Sponsor type
- Other government
- Collaborators
- Skane University Hospital, Gävle Hospital, Karolinska Institutet, Sahlgrenska University Hospital, Ryhov County Hospital, Kalmar County Hospital, Oslo University Hospital, St. Olavs Hospital, Haukeland University Hospital, Sorlandet Hospital HF, Helse Stavanger HF, Aarhus University Hospital, Region Örebro County, University Hospital, Umeå, Uppsala University Hospital, Universitäts-Frauenklinik Graz, University Hospital of Sankt Pölten, Sundsvalls Hospital, Kepler University Hospital, medizinische universität innsbruck, Austria
- Responsible party
- Sponsor
- Investigators
- Annika Malmström, MD, PhD, Principal investigator, University Hospital, Linkoeping
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06419946
- Sponsor's protocol ID
- 2023-506998-35-00
- Other IDs
- 2023
- Status last verified
- Mar 2026
- First submitted
- 29 Apr 2024
- Last updated
- 13 Apr 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Since the proposed randomized controlled trial (RCT) will be running for many year and since the investigators want to avoid outdated results, there will be - independent of the results of this proposed RCT - a collaboration to pool this study's data with the very similar phase 3 trial, the NOA-09 study. Here, the investigators will set a meta-analysis in place to balance clinical benefit with time and costs in a good manner. Hence, data is used for new sub-projects to endorse findings.
Publications
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330.
PubMed 15758009Malmstrom A, Gronberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R; Nordic Clinical Brain Tumour Study Group (NCBTSG). Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012 Sep;13(9):916-26. doi: 10.1016/S1470-2045(12)70265-6. Epub 2012 Aug 8.
PubMed 22877848Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. doi: 10.1056/NEJMoa043331.
PubMed 15758010Weller M, Le Rhun E. How did lomustine become standard of care in recurrent glioblastoma? Cancer Treat Rev. 2020 Jul;87:102029. doi: 10.1016/j.ctrv.2020.102029. Epub 2020 May 4.
PubMed 32408220Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, Di Meco F, Lieberman F, Zhu JJ, Stragliotto G, Tran D, Brem S, Hottinger A, Kirson ED, Lavy-Shahaf G, Weinberg U, Kim CY, Paek SH, Nicholas G, Bruna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA. 2017 Dec 19;318(23):2306-2316. doi: 10.1001/jama.2017.18718.
PubMed 29260225Herrlinger 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.
PubMed 30782343Weller 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.
PubMed 31488360
Study at a glance
From the registry record, last updated by the sponsor on 13 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase III Trial of Temozolomide/Lomustine (TMZ/LOM) Combination Therapy vs. Standard TMZ Therapy for Newly Diagnosed MGMT Promoter Methylated Glioblastoma (IDHwt) Patients +/- Tumor Treating Fields (Optune)
- ClinicalTrials.gov ID
- NCT06419946
- Acronym / sponsor ID
- 2023-506998-35-00
- Keywords
- precision medicine, temozolomide, lomustine, CCNU, survival
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 200 participants (estimated)
- Lead sponsor
- Vastra Gotaland RegionOther government
- Collaborators
- Skane University Hospital, Gävle Hospital, Karolinska Institutet, Sahlgrenska University Hospital, Ryhov County Hospital, Kalmar County Hospital, Oslo University Hospital, St. Olavs Hospital, Haukeland University Hospital, Sorlandet Hospital HF, Helse Stavanger HF, Aarhus University Hospital, Region Örebro County, University Hospital, Umeå, Uppsala University Hospital, Universitäts-Frauenklinik Graz, University Hospital of Sankt Pölten, Sundsvalls Hospital, Kepler University Hospital, medizinische universität innsbruck, Austria
- Study start
- 1 Feb 2025 (actual)
- Primary completion
- 15 Dec 2031 (estimated)
- Study completion
- 15 Dec 2033 (estimated)
- First posted
- 17 May 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background: Glioblastoma (GBM) is notoriously difficult to treat, with current therapies often extending life by only a few months. The standard treatment involves surgery followed by radiation and chemotherapy with Temozolomide (TMZ). The efficacy of TMZ, however, is significantly enhanced when the tumor's o6-methylguanine-DNA-methyltransferase (MGMT) gene is methylated. Recent studies, such as the NOA-09 trial, have suggested that adding Lomustine (LOM) to TMZ could improve outcomes for patients with this specific tumor profile.
Hypothesis: The investigators hypothesize that the addition of LOM to the TMZ regimen will lead to significantly improved survival rates among patients with newly diagnosed glioblastoma who have a methylated MGMT promoter compared to those receiving only TMZ.
Treatment Plans: The study will randomly assign participants to two groups:
- Control Group: Standard treatment with TMZ during and after radiation therapy.
- Experimental Group: TMZ combined with LOM, starting on the first day of radiation therapy.
Outcome Measures: The primary outcome measure will be survival. Other outcomes will include progression-free survival (time from randomization until tumor progression or death), safety profiles (adverse effects of the treatments), and quality of life measures as well as neurocognitive outcomes.
Detailed description
Current evidence:
In this section the investigators highlight the evidence behind the current standard fo care, and the emerging data supporting our approach. The RCT of Stupp showed that radiotherapy (RT) together with concomitant and adjuvant TMZ prolong survival. The NORDIC trial investigated the role of TMZ compared to RT for the subgroup of elderly patients, showing that survival was superior with TMZ, especially for those with mMGMT. LOM has been used for treatment of glioma for many decades, often used in combination with procarbazine and vincristine (PCV), but in recent years it is used in patients with glioblastoma as 2nd line therapy after failure of TMZ.
A phase 3 trial with Tumor Treating Fields (TTF, alternating low intensity electromagnetic fields) showed prolonged survival in patients with glioblastoma, but it is not universally applied/approved. Despite full multimodal treatment with surgery, RT, TMZ and TTFields, the median survival is <2 years. There is an unmet medical need to further improve treatments for these patients.
One RCT (NOA-09) provided preliminary data to exploit the specific vulnerability of mMGMT in glioblastoma (although no use of TTF in this trial). The overall tolerability of TMZ-LOM in combination was acceptable, as most adverse events (AE) were moderate and transient. Furthermore, health-related quality of life (HRQoL) and neurocognition did not differ between groups.
Estimated sample size and power:
Sample size calculation is based upon the results from the CeTeG/NOA-09 trial. Accounting for attrition, a total of 200 mMGMT GBM patients have to be randomised. Patients that drop-out before start of any therapy will be replaced, which will lead to more than 200 patients being randomized. For overall survival (OS) all patients that started day 1 of radiochemotherapy will be analysed (modified ITT). For per protocol all patients that have completed week 6 of treatment arm will be analysed for outcome. Patients lost to follow-up after the start of chemotherapy will be evaluated as observations censored at the time of dropout. Approximately 45% of newly diagnosed patients have a mMGMT, thus for 200 randomised patients a minimum of 445 patients will be screened.
Addition to the already described statistics:
Randomizations are stratified for center and for TTFields. The primary confirmatory analysis will be based on the modified intention-to-treat (mITT) population.
Survival parameters are measured in days starting from the day of randomization. Median time estimates as well as 95% confidence intervals will be reported. All additional analyses will be descriptive.
The statistical analysis plan (SAP) and blinding of statisticians will ensure analytic transparency and robustness.
Finally, similarly to avoid producing outdated results, the investigators plan to start TTF concomitant according to the Trident trial where results are expected soon. Nevertheless, if the Trident results are negative, the investigators will submit an amendment for using TTF according to the current standard of care. The reverse would not be possible in the middle of the trial as this has required extensive discussion, planning, and training with all sites. Balance with respect to TTF use is ensured with stratification in the randomization process.
Further details of study design of this phase 3, open-label, multicenter randomised controlled trial with parallel group design is presented under respective subheadings.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Everyone: Radiotherapy (RT) consists of 60 Gy standard RT (RT 30x2Gy) Experimental treatment arm (TMZ/LOM): 6 cycles of LOM/TMZ Start day 1 of RT. Cycle length of 42 days. Duration 9 months. Standard treatment arm (TMZ): Oral TMZ 75 mg/m2 daily during RT and with start day 1 of RT. This is followed by 6 cycles of TMZ with start 4 weeks after the end of RT. Cycle length 28 days. Duration 8,5 months. Everyone: TTFields start with radiotherapy/chemotherapy - but only in Sweden where TTF is part of standard of care (SOC). Ongoing until 2nd progression or max 2 years.
| Arm | Type | Receives |
|---|---|---|
| treatment arm | Experimental | Drug: Temozolomide, Drug: Lomustinearm with temozolomide (TMZ) plus lomustine (LOM) treatment. 6 cycles of LOM/TMZ Start day 1 of RT. Cycle length of 42 days. Duration 9 months. |
| standard arm | Active comparator | Drug: Temozolomidearm with standard of care treatment with temozolomide only. Oral TMZ 75 mg/m2 daily during RT and with start day 1 of RT. This is followed by 6 cycles of TMZ with start 4 weeks after the end of RT. Cycle length 28 days. Duration 8,5 months. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Newly diagnosed glioblastoma/gliosarcoma, IDH wild type
- Methylated MGMT promoter
- World Health Organization performance status 0-2
- Age 18-70
Key exclusion criteria (4 listed)
- Previous malignancy within 3 y or malignancy treated non-curatively
- Previous chemotherapy or radiotherapy involving the head
- Off-protocol tumor-specific treatment
- Serious comorbidity
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TemozolomideAlso: TMZIn the experimental treatment arm: a combination of Temozolomide and Lomustine, taken together, two separate pills | Drug | standard arm, treatment arm |
| LomustineAlso: LOMIn the experimental treatment arm: a combination of Temozolomide and Lomustine, taken together, two separate pills | Drug | treatment arm |
Primary outcome
overall survival
Time frame: Assessed from day of randomization to event or last day of follow-up (FU). Aanlyzed 36 months after last inclusion ensures that all patients have a potential of minimum 36 months FU
visualized with Kaplan-Meier plot, tested with log-rank test
11 secondary outcomes
progression free survival (PFS)
Time frame: Assessed from day of randomization to event or last day of follow-up (FU). Aanlyzed 36 months after last inclusion ensures that all patients have a potential of minimum 36 months FU
quality of life (QoL)
Time frame: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - verbal memory
Time frame: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - visual memory
Time frame: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - motor speed and fine motor control
Time frame: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - cognitive speed
Time frame: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - simple and complex reaction time, inhibition/disinhibition, mental flexibility, and focused attention.
Time frame: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - attention
Time frame: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - attention, vigilance, and reaction time
Time frame: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
neurocognition - Perception
Time frame: done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.
Adverse events (AE)
Time frame: assessed from day of randomization to death or 36 months FU
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Apr 2026.
- Background: PubMed 15758009Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330.
- Background: PubMed 22877848Malmstrom A, Gronberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R; Nordic Clinical Brain Tumour Study Group (NCBTSG). Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012 Sep;13(9):916-26. doi: 10.1016/S1470-2045(12)70265-6. Epub 2012 Aug 8.
- Background: PubMed 15758010Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. doi: 10.1056/NEJMoa043331.
- Background: PubMed 32408220Weller M, Le Rhun E. How did lomustine become standard of care in recurrent glioblastoma? Cancer Treat Rev. 2020 Jul;87:102029. doi: 10.1016/j.ctrv.2020.102029. Epub 2020 May 4.
- Background: PubMed 29260225Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, Di Meco F, Lieberman F, Zhu JJ, Stragliotto G, Tran D, Brem S, Hottinger A, Kirson ED, Lavy-Shahaf G, Weinberg U, Kim CY, Paek SH, Nicholas G, Bruna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA. 2017 Dec 19;318(23):2306-2316. doi: 10.1001/jama.2017.18718.
- Background: PubMed 30782343Herrlinger 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.
- Background: PubMed 31488360Weller 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.
- PubMed ID: 15758009Link provided by the sponsor.
- PubMed ID: 22877848Link provided by the sponsor.
- PubMed ID: 15758010Link provided by the sponsor.
- PubMed ID: 32408220Link provided by the sponsor.
- PubMed ID: 29260225Link provided by the sponsor.
- PubMed ID: 30782343Link provided by the sponsor.
- Individual participant dataSharing planned: Yes. Since the proposed randomized controlled trial (RCT) will be running for many year and since the investigators want to avoid outdated results, there will be - independent of the results of this proposed RCT - a collaboration to pool this study's data with the very similar phase 3 trial, the NOA-09 study. Here, the investigators will set a meta-analysis in place to balance clinical benefit with time and costs in a good manner. Hence, data is used for new sub-projects to endorse findings.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Annika Malmström, MD. PhD contact
Annika Malmström, MD, PhD principal investigator
University Hospital, Linkoeping
20 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Temozolomide and Lomustine in people with Glioblastoma, IDH-wildtype and MGMT-Methylated Glioblastoma, run by Vastra Gotaland Region at 20 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 13 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 20 sites in Sweden, Norway, Austria, Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Asgeir S Jakola, MD, PhD (+46313429741, asgeir.jakola@vgregion.se), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
overall survival (time frame: Assessed from day of randomization to event or last day of follow-up (FU). Aanlyzed 36 months after last inclusion ensures that all patients have a potential of minimum 36 months FU). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06419946, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Apr 2026.