Phase I/II Evaluation of Meclofenamate Sodium and Temozolomide in Progressive MGMT-Methylated Glioblastoma

The primary objective of this Phase I/II trial is to evaluate the **toxicity** of meclofenamate sodium therapy in combination with standard temozolomide in patients with progressive MGMT-methylated **glioblastoma**. This assessment will inform the recommended daily dose of meclofenamate sodium for Phase II. In Phase II, the primary focus shifts to determining the efficacy of this combination therapy. The clinical relevance of these objectives lies in optimizing treatment regimens for glioblastoma, a highly aggressive brain tumor, by potentially enhancing the therapeutic effects of temozolomide with the addition of meclofenamate sodium.

Secondary objectives include: - Determining the efficacy of meclofenamate sodium therapy in addition to standard temozolomide throughout the trial. - Assessing the safety and tolerability of this combination therapy. - Evaluating the clinical effect of meclofenamate sodium therapy in conjunction with temozolomide and its impact on the quality of life of patients during the trial.

The clinical trial focuses on patients diagnosed with **glioblastoma**, specifically targeting those experiencing their first relapse after initial treatment with radiotherapy and alkylating chemotherapy. The study population includes both male and female participants, aged 18 years and older, with a **Karnofsky performance score** of 60% or higher, indicating a requirement for a certain level of functional independence. Participants must have a life expectancy greater than six months and demonstrate adequate bone marrow and liver function. The trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria emphasize the necessity for participants to have a cognitive state sufficient to comprehend the study's rationale and procedures, and they must provide written informed consent. Additionally, participants are required to use approved contraceptive methods if they have reproductive potential. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not disclosed further details regarding the selection process or additional demographic information.

The clinical trial is designed to evaluate the **efficacy** and safety of **meclofenamate sodium** in combination with standard **temozolomide** therapy in patients with progressive MGMT-methylated **glioblastoma**. This is a Phase I/II trial, structured as a randomized, double-blind, controlled study. The trial is expected to last until September 2025, with recruitment having commenced in April 2022. The primary objective of Phase I is to determine the toxicity of meclofenamate sodium when added to standard therapy and to establish the recommended daily dose for Phase II. In Phase II, the focus shifts to assessing the efficacy of the treatment combination.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as tumor progression according to RANO criteria, adequate liver function, and a Karnofsky performance score of at least 60%. The inclusion visit will also involve obtaining written informed consent and ensuring the participant's cognitive ability to understand the study's rationale and procedures. Follow-up visits will be scheduled to monitor the incidence of dose-limiting toxicities during the first 8 weeks of treatment in Phase I and to assess progression-free survival (PFS) in Phase II. The end-of-study visit will evaluate overall survival and safety, including continuous monitoring of adverse events (AEs), serious adverse events (SAEs), and suspected unexpected serious adverse reactions (SUSARs).

The expected length of participant involvement varies between the two phases, with Phase I focusing on an 8-week period to assess initial safety and dose-limiting toxicities, while Phase II extends to evaluate long-term efficacy and safety. Participants may be subject to early termination from the study if they experience unacceptable toxicity levels, fail to comply with study procedures, or withdraw consent. The trial's endpoints include the incidence of dose-limiting toxicities in Phase I and progression-free survival in Phase II, with secondary endpoints encompassing overall survival and quality of life assessments throughout the trial duration.

The clinical trial involves the administration of **Meclofenamate Sodium** in two different dosages, 100 mg and 50 mg, both formulated as oral capsules. The **Meclofenamate 100** and **Meclofenamate 50** capsules are chemically derived and are not pediatric formulations. The maximum daily dose for both formulations is 400 mg, with a total maximum dose of 100,000 mg over a treatment period of up to 250 days. The primary objective of the trial is to assess the toxicity and efficacy of meclofenamate sodium when used in conjunction with standard therapy. Participants will receive the medication orally, and compliance will be monitored throughout the study.

In addition to meclofenamate sodium, the trial includes the administration of **Temozolomide**, a chemical compound used as a standard-of-care therapy. Temozolomide is administered orally, with a maximum daily dose of 200 mg/m² and a total maximum dose of 8,000 mg/m² over a treatment period of up to 8 weeks. The pharmaceutical form of temozolomide is designated as PHF00005MIG. This medication is not a pediatric formulation and is used as a comparator treatment in the study. The trial aims to evaluate the combined effect of temozolomide and meclofenamate sodium on patients with progressive MGMT-methylated glioblastoma.

The efficacy of meclofenamate sodium in combination with standard temozolomide therapy for progressive MGMT-methylated glioblastoma will be assessed in a Phase I/II clinical trial. The primary endpoint for Phase II is **progression-free survival (PFS)**, measured from the day of randomization until the diagnosis of progressive disease, as determined by MRI using RANO criteria at the local center. A sensitivity analysis will include patients from Phase I who received meclofenamate sodium at the same dose as in Phase II, with PFS measured from the day of trial inclusion.

Secondary endpoints for Phase II include overall survival (OS), measured from the day of randomization, with a sensitivity analysis incorporating Phase I patients who received the same dose, starting from their day of inclusion. Additional assessments include the Karnofsky performance score (KPS), quality of life (QoL) throughout the trial, and the Mini Mental State Examination (MMSE). Safety will be continuously monitored through adverse events (AE), serious adverse events (SAE), and suspected unexpected serious adverse reactions (SUSARs) until three days after the end of therapy.

In Phase I, the primary endpoint is the incidence of dose-limiting toxicities (DLTs) during the first 8 weeks of meclofenamate sodium treatment. Secondary endpoints include PFS from trial inclusion until progressive disease diagnosis, overall survival from trial inclusion, and safety beyond 8 weeks of treatment, with continuous monitoring of AE/SAE/SUSARs. PFS will also be analyzed according to post hoc central reference neuroradiological assessment.