The Feasibility and Efficacy of Dose Timing (Morning vs Evening) of Temozolomide in the Treatment of Glioblastoma

TMZ-CHRONO is a randomized, multi-centre pilot trial evaluating the feasibility of chronotherapy (dose-timing) for temozolomide (TMZ) in IDH-wildtype glioblastoma (GBM).

The body's biological functions follow a circadian rhythm. Chronotherapy is the deliberate timing of medications to enhance therapeutic benefit and/or minimize toxicity, and can be achieved by dose-timing treatments. There is evidence suggesting that cancer cells may react differently to chemotherapy based on the time of day they are exposed. In fact, researchers have already found that giving anti-cancer treatments at a particular time of the day works better in rectal and ovarian cancer. TMZ is a standard of care treatment for GBM, however there is currently no consensus or guideline with respect to the optimal timing of adjuvant TMZ administration. The study team recently conducted systematic review on TMZ chronotherapy in the treatment of glioma. With emerging evidence that TMZ timing may be important, it is paramount to conduct a large pragmatic randomized study to assess this claim in GBM. The current study is a minimal risk pilot trial to inform the development of a larger, pragmatic randomized clinical trial in the future.

Prospective participants will be approached by their physician (or a member within the circle of care) during their routine clinic visit to begin the integrated verbal consent model process. The physician will explain that the patient is receiving standard of care treatment, with the only change being the timing of adjuvant TMZ (morning vs evening). The physician will then ask the patient for verbal consent to participate in this research study and document this consent in the patient's electronic medical record. Eligible and consenting patients will be randomized to one of two study arms (morning administration of TMZ, and evening administration of TMZ) in a 1:1 fashion using a permuted block design through the Ottawa Methods Centre. Randomization will be stratified by cancer centre \[The Ottawa Hospital Cancer Centre (TOHCC) and the London Health Sciences Centre (LHSC); Canada\]. The participants and investigators will not be blinded to treatment arm allocations. The participants will wear a wrist actigraphy device during the first cycle of TMZ.

The primary aim of the study is to understand if taking TMZ at a prescribed time of day (morning/evening) is feasible in adults with GBM. The secondary aims of the study are to evaluate participant recruitment, safety, health-related quality of life, biological timing of TMZ deliver, and changes in condition over time. Data is collected throughout the study at baseline, randomization, pre/post-TMZ cycles, and at 4-, 8-, 12-, 24-, and 48-weeks after baseline. The study team will continue to follow the participant conditions after TMZ completion for up to 5 years.

This pilot trial is the first and necessary step to assess the feasibility of randomized treatment allocation, rate of pill diary completion, and metrics surrounding participant accrual. This will help determine the number of recruitment sites and expected duration of accrual for a future pragmatic, randomized clinical trial on chronotherapy of TMZ in IDH-wildtype GBM.

• Participant recruitment: proportion of patients providing consent to participate [Срок оценки: The number of patients providing consent to participate will be collected during the recruitment period and the total number/proportion will be calculated upon completion of recruitment. The anticipated recruitment period length is one year.]
• Participant recruitment: participant withdrawal rate and reasons [Срок оценки: Withdrawal rate and reasons will be collected from enrollment to start of adjuvant TMZ]
• Participant recruitment: rate of patient enrollment [Срок оценки: The number of patients enrolled in the study will be collected during the recruitment period. The anticipated recruitment period is one year.]
• Safety: rate of hospital admissions [Срок оценки: The number of hospitalizations will be collected from the start of adjuvant TMZ until 6 weeks after the last TMZ cycle (28-day cycles for up to 6 cycles). The number of hospitalizations per participant will be calculated at Week 48.]
• Safety: number of TMZ cycles [Срок оценки: The number of TMZ cycles will be calculated at Week 48, once all questionnaires and adjuvant treatment cycles are complete.]
• Safety: reasons for early discontinuation of adjuvant TMZ [Срок оценки: The reasons for early discontinuation of adjuvant TMZ will be collected during the treatment period: post-cycle 1, post-cycle 2, post-cycle 3, post-cycle 4, post-cycle 5. Each TMZ cycle is 28 days.]
• Safety: rate of TMZ delay [Срок оценки: TMZ delay is collected during the treatment period: post-cycle 1, post-cycle 2, post-cycle 3, post-cycle 4, post-cycle 5. Each TMZ cycle is 28 days. The rate of TMZ delay is calculated at Week 48.]
• Health-related quality of life (HR-QoL): FACT-Br Version 4 [Срок оценки: Baseline and 4-, 8-, 12-, 24-, and 48-weeks after baseline.]
• HR-QoL: Time to HR-QoL deterioration [Срок оценки: FACT-Br is collected at baseline and 4-, 8-, 12-, 24-, and 48-weeks after baseline..]
• Treatment-related side effects [Срок оценки: Modified FACT-Br GP1, GP2, and GP5 are collected within 1 month of each TMZ cycle (28-day cycle). Post-cycle 1, post-cycle 2, post-cycle 3, post-cycle 4, post-cycle 5, post-cycle 6.]
• Change in Trial Outcome Index [Срок оценки: Baseline to 12-weeks]
• Change in FACT-Br scores [Срок оценки: FACT-Br is collected at baseline and 4-, 8-, 12-, 24-, and 48-weeks after baseline.]