Evaluation of Temozolomide and Lomustine Chemotherapy Versus Radiotherapy and PCV in Newly Diagnosed WHO Grade 2 or 3 Glioma with 1p/19q Co-deletion

The primary objective of the study is to demonstrate the superiority of an initial chemotherapy regimen consisting of **temozolomide** plus **lomustine** (CETEG) followed by partial brain radiotherapy (RT) and PCV (procarbazine, lomustine, and vincristine) at progression, compared to partial brain radiotherapy followed by PCV chemotherapy and the best investigator's choice at progression. This is evaluated in terms of qualified overall survival (qOS) for patients with newly diagnosed WHO grade 2 or 3 glioma with co-deletion of 1p/19q. The clinical relevance of this objective lies in potentially improving survival outcomes for this patient population, which could lead to a new standard of care.

Secondary objectives include the evaluation and comparison of the two groups regarding secondary endpoints such as short-term qOS, progression-free survival (PFS), overall survival (OS), and complete and partial response rates. These secondary endpoints provide additional insights into the efficacy and potential benefits of the treatment regimens under investigation.

The clinical trial involves participants diagnosed with **newly diagnosed WHO grade 2 or 3 glioma**. The study population includes both male and female subjects, aged 18 years and older, with a Karnofsky Performance Status of at least 60%, indicating a relatively stable general health status. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on specific criteria, including a histologically confirmed diagnosis, adequate healing post-craniotomy or biopsy, and a life expectancy greater than six months. The trial population includes individuals who are willing to comply with regular neurocognitive and health-related quality of life assessments. Lifestyle considerations such as the use of contraception are relevant, as female participants of reproductive potential must have a negative pregnancy test and agree to use adequate contraception during and after the study period. Male participants are also required to use contraception and are advised on sperm conservation. The trial includes a vulnerable population, and participants must have tumors with specific genetic characteristics, such as an isocitrate dehydrogenase mutation and co-deletion of 1p/19q. The study requires the availability of tissue and blood samples for biomarker research, and standard MRI must be conducted within 72 hours post-surgery according to guidelines.

The clinical trial is designed to evaluate the efficacy of an initial treatment regimen of **temozolomide** plus **lomustine** followed by partial brain radiotherapy and **procarbazine**, **lomustine**, and **vincristine** chemotherapy in patients with newly diagnosed WHO grade 2 or 3 glioma with co-deletion of 1p/19q. This is a randomized, double-blind, controlled trial with an estimated duration extending until March 31, 2031. The trial aims to demonstrate the superiority of the initial chemotherapy regimen over standard treatment options in terms of qualified overall survival (qOS), which is defined as overall survival without functional, cognitive, or quality of life deterioration over a period of 90 days.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed glioma, adequate healing post-surgery, and specific genetic markers. Follow-up visits will be scheduled to monitor treatment response, side effects, and overall health status. These visits will include regular neurocognitive and health-related quality of life assessments. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination from the study.

The expected length of participant involvement is contingent upon the treatment regimen, with a maximum treatment period of 84 weeks for **procarbazine**. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or disease progression that necessitates alternative treatment. Participants are required to comply with study protocols, including the use of contraception for both male and female participants, to mitigate risks associated with treatment. The trial's primary endpoint is the assessment of qOS, while secondary endpoints include overall survival and progression-free survival.

The clinical trial involves the administration of several **cytostatic** agents, each with specific pharmaceutical forms, dosages, and routes of administration. **Vincristine** is provided as a **solution for injection** and is administered **intravenously**. The dosage is calculated based on body surface area, with a maximum daily dose of 2 mg/m² and a total maximum dose of 24 mg/m² over a treatment period of up to 12 weeks. Participant compliance is monitored through regular assessments of drug administration records and adherence to the dosing schedule.

**Lomustine** is administered in the form of a **hard capsule** for **oral use**. The dosage is also based on body surface area, with a maximum daily dose of 200 mg/m² and a total maximum dose of 1200 mg/m² over a treatment period of up to 6 weeks. Compliance is ensured by tracking capsule intake and maintaining a dosing log.

**Procarbazine** is provided as a **capsule** for **oral** administration. The maximum daily dose is 100 mg, with a total maximum dose of 8400 mg over a treatment period of up to 84 weeks. Participants are instructed to adhere to the dosing schedule, and compliance is monitored through pill counts and patient diaries.

**Temozolomide** is administered as a **capsule** for **oral** use. The dosage is determined by body surface area, with a maximum daily dose of 200 mg/m² and a total maximum dose of 6000 mg/m² over a treatment period of up to 30 weeks. Compliance is monitored through patient self-reports and periodic verification of capsule consumption.

In this trial, the experimental treatments are compared against standard-of-care therapies, including partial brain radiotherapy followed by chemotherapy regimens. The trial aims to evaluate the efficacy of these treatments in improving the functional outcome for patients with newly diagnosed grade 2 or 3 glioma with co-deletion of 1p/19q. The study design includes rigorous monitoring of participant adherence to treatment protocols and regular assessments to ensure accurate data collection and analysis.

Efficacy in the clinical trial titled "Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 glioma with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial (IMPROVE CODEL)" will be assessed using several primary and secondary endpoints. The primary efficacy endpoint is **qualified overall survival (qOS)**, which is defined as overall survival without functional, cognitive, or quality of life deterioration over a period of 90 days. This includes a detriment of ≥ 1.5 standard deviations below the normative mean in two or more NeuroCog FX® subtests, a decrease in the Karnofsky Performance Index (KPI), a worsening of at least 10 points in selected domains of health-related quality of life (HrQoL), a decline in the NANO scale, or death due to any cause.

Secondary endpoints include short-term qOS, overall survival (OS), and progression-free survival (PFS). Short-term qOS is similar to the primary endpoint but neglects the subsequent time interval of 3 months. OS is defined as the time from randomization until death due to any cause, with patients still alive being censored at the last date they were known to be alive. PFS is defined as the time from randomization to the first documentation of clinical or radiographic tumor progression or death from any cause, with patients without a PFS event being censored at the last disease assessment showing no progression.