Ignite Creation Date:
2024-05-19 @ 5:35 PM
Last Modification Date:
2024-10-26 @ 3:30 PM
Study NCT ID:
NCT06419946
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-05-17
First Post:
2024-04-29
Brief Title:
Lomustine in Addition to Standard of Care in Patients With MGMT Methylated Glioblastoma
Sponsor:
Vastra Gotaland Region
Organization:
Vastra Gotaland Region
Study Overview
Official Title:
Phase III Trial of TemozolomideLomustine TMZLOM Combination Therapy vs Standard TMZ Therapy for Newly Diagnosed MGMT Promoter Methylated Glioblastoma IDHwt Patients - Tumor Treating Fields Optune
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 tumors 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
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 appliedapproved 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 CeTeGNOA-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
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 appliedapproved 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 CeTeGNOA-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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None