Lomustine in Addition to Standard of Care in Patients With MGMT Methylated Glioblastoma

Get Involved

Lomustine in Addition to Standard of Care in Patients With MGMT Methylated Glioblastoma

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years - 70 Years
Gender	All

More Inclusion & Exclusion 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

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT06419946
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 3
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Vastra Gotaland Region
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Annika Malmström, MD, PhD
Principal Investigator Affiliation	University Hospital, Linkoeping
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Not yet recruiting
Countries
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Glioblastoma, IDH-wildtype, MGMT-Methylated Glioblastoma
Study Website:	View Trial Website

Additional Details

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.

Arms & Interventions

Arms

Experimental: treatment arm

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.

Active Comparator: standard arm

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.

Interventions

Drug: - Temozolomide

In the experimental treatment arm: a combination of Temozolomide and Lomustine, taken together, two separate pills

Drug: - Lomustine

In the experimental treatment arm: a combination of Temozolomide and Lomustine, taken together, two separate pills

Contact Information

This trial has no sites locations listed at this time. If you are interested in learning more, you can contact the trial's primary contact:

Asgeir S Jakola, MD, PhD

[email protected]

+46313429741

For additional contact information, you can also visit the trial on clinicaltrials.gov.

Clinical Trial Finder