Trial Title:
Lomustine in Addition to Standard of Care in Patients With MGMT Methylated Glioblastoma
NCT ID:
NCT06419946
Condition:
Glioblastoma, IDH-wildtype
MGMT-Methylated Glioblastoma
Conditions: Official terms:
Glioblastoma
Temozolomide
Lomustine
Conditions: Keywords:
precision medicine
temozolomide
lomustine
CCNU
survival
Study type:
Interventional
Study phase:
Phase 3
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention 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.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Temozolomide
Description:
In the experimental treatment arm: a combination of Temozolomide and Lomustine, taken
together, two separate pills
Arm group label:
standard arm
Arm group label:
treatment arm
Other name:
TMZ
Intervention type:
Drug
Intervention name:
Lomustine
Description:
In the experimental treatment arm: a combination of Temozolomide and Lomustine, taken
together, two separate pills
Arm group label:
treatment arm
Other name:
LOM
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). 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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Newly diagnosed glioblastoma/gliosarcoma, IDH wild type
- Methylated MGMT promoter
- World Health Organization performance status 0-2
- Age 18-70
Exclusion Criteria:
- Previous malignancy within 3 y or malignancy treated non-curatively
- Previous chemotherapy or radiotherapy involving the head
- Off-protocol tumor-specific treatment
- Serious comorbidity
Gender:
All
Minimum age:
18 Years
Maximum age:
70 Years
Healthy volunteers:
No
Start date:
May 15, 2024
Completion date:
December 15, 2031
Lead sponsor:
Agency:
Vastra Gotaland Region
Agency class:
Other
Collaborator:
Agency:
Skane University Hospital
Agency class:
Other
Collaborator:
Agency:
Gävle Hospital
Agency class:
Other
Collaborator:
Agency:
Karolinska Institutet
Agency class:
Other
Collaborator:
Agency:
Sahlgrenska University Hospital, Sweden
Agency class:
Other
Collaborator:
Agency:
Karlstad Central Hospital
Agency class:
Other
Collaborator:
Agency:
Ryhov County Hospital
Agency class:
Other
Collaborator:
Agency:
Kalmar County Hospital
Agency class:
Other
Collaborator:
Agency:
Oslo University Hospital
Agency class:
Other
Collaborator:
Agency:
St. Olavs Hospital
Agency class:
Other
Collaborator:
Agency:
Haukeland University Hospital
Agency class:
Other
Collaborator:
Agency:
Sorlandet Hospital HF
Agency class:
Other
Collaborator:
Agency:
Helse Stavanger HF
Agency class:
Other
Collaborator:
Agency:
Aarhus University Hospital
Agency class:
Other
Collaborator:
Agency:
University Hospital, Umeå
Agency class:
Other
Collaborator:
Agency:
Eskilstuna Lasarettet
Agency class:
Other
Collaborator:
Agency:
Region Örebro County
Agency class:
Other
Source:
Vastra Gotaland Region
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06419946
https://pubmed.ncbi.nlm.nih.gov/15758009/
https://pubmed.ncbi.nlm.nih.gov/22877848/
https://pubmed.ncbi.nlm.nih.gov/15758010/
https://pubmed.ncbi.nlm.nih.gov/32408220/
https://pubmed.ncbi.nlm.nih.gov/29260225/
https://pubmed.ncbi.nlm.nih.gov/30782343/
https://pubmed.ncbi.nlm.nih.gov/31488360/
