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

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.

• 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]