Phase IB/II Study of Bortezomib and Temozolomide in Recurrent Grade IV Glioma with Unmethylated MGMT Promoter

The primary objective of this study is to evaluate the **safety** and tolerability of **Bortezomib** when administered in combination with **Temozolomide** in patients with recurrent grade IV glioma, including both glioblastoma and grade IV IDH-mutated astrocytoma. This is crucial for determining the optimal dosing regimen for this combination therapy. Additionally, the study aims to assess the efficacy of this combination by estimating the median progression-free survival (PFS) and overall survival (OS) of patients, as well as the progression-free rate at 6 months. These outcomes are clinically relevant as they provide insights into the potential benefits of the treatment in extending survival and delaying disease progression in this patient population.

Secondary objectives include: identifying novel biomarkers by determining physiological, molecular, and biochemical changes in blood and tumor tissue that correlate with treatment responses; evaluating changes in natural killer cell phenotype and function; and assessing changes in autophagy flux. These objectives are intended to enhance the understanding of the biological mechanisms underlying treatment responses and potentially guide future therapeutic strategies.

The clinical trial involves participants diagnosed with **Grade IV recurrent glioma**, specifically including both glioblastoma classified as IDH wildtype and grade IV IDH mutated astrocytoma. The study population comprises both male and female subjects, with an age range of 18 years and older. Participants are required to have a Karnofsky performance status of 70% or higher, indicating a relatively stable general health status. The trial does not include a vulnerable population. The total number of participants is not specified as the sponsor has not provided this information. Selection criteria include histologically confirmed recurrent or progressed WHO grade IV intracranial gliomas, with MRI evidence of recurrence within 14 days prior to enrollment. Participants must have adequate hematologic and hepatic function, and stable or reduced doses of corticosteroids for at least one week prior to enrollment. Lifestyle considerations such as diet and physical activity are not specified. The trial includes both male and female participants, and there are no specific exclusions based on gender. The study does not involve a vulnerable population, and participants must be capable of providing informed consent. The sponsor has not provided information on the total number of participants.

The clinical trial is designed to evaluate the **safety**, tolerability, and efficacy of **Bortezomib** in combination with **Temozolomide** for patients with recurrent grade IV glioma, including glioblastoma and IDH-mutated astrocytoma. This trial is structured as a randomized, double-blind, controlled study, divided into two phases: Phase IB and Phase II. Phase IB focuses on assessing the safety and determining the optimal dose of the combination therapy in a sample size of 10 patients. Phase II aims to evaluate the efficacy of the treatment, with a sample size of 53 patients, by estimating the median progression-free survival (PFS) and overall survival (OS) of the participants. The trial is expected to conclude by December 30, 2025, with recruitment having commenced on September 4, 2018.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed recurrent or progressed WHO grade IV glioma, adequate organ function, and a Karnofsky performance status of ≥ 70%. Following the screening, participants will attend regular follow-up visits, including neurological assessments every four weeks and MRI evaluations every 12 weeks to monitor tumor response using RANO criteria. The end-of-study visit will occur upon completion of the treatment regimen or in the event of disease progression or unacceptable toxicity.

The expected length of participant involvement in the trial is contingent upon individual response to treatment and disease progression, with a minimum life expectancy of eight weeks required for inclusion. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study protocols. The primary endpoints of the trial include the assessment of safety and tolerability in Phase IB and the evaluation of efficacy in Phase II, focusing on overall survival and progression-free survival metrics. Secondary endpoints involve tumor response assessments and the identification of novel tumor biomarkers correlating with treatment responses.

The clinical trial involves the administration of **Temozolomide**, an antineoplastic agent, in various dosages and formulations. The experimental medications include Temozolomide SUN 250 mg, 140 mg, 100 mg, and 180 mg hard capsules, as well as Temozolomide Accord 20 mg, 100 mg, 140 mg, and 180 mg hard capsules. All formulations are administered orally. The active substance in these medications is **temozolomide**, a chemical compound classified under the ATC code L01AX03. The pharmaceutical form for all Temozolomide products is hard capsules, and they are not pediatric formulations. The administration schedule and dosage frequency are determined based on the trial phase and patient response, with compliance monitored through regular assessments.

In addition to Temozolomide, the trial also includes the administration of **Bortezomib**, another antineoplastic agent. The formulations used are Bortezomib Accord 2.5 mg/mL solution for injection and Bortezomib Viatris 3.5 mg powder for solution for injection. Bortezomib is administered via intravenous bolus injection or IV infusion. The active substance, **bortezomib**, is a chemical compound with the ATC code L01XG01. The dosing schedule for Bortezomib is designed to optimize its sensitization effect on recurrent grade-4 glioma with unmethylated MGMT promoter when used in combination with Temozolomide. Participant compliance is monitored through scheduled clinical evaluations and laboratory assessments.

Throughout the trial, the safety and tolerability of the combination therapy are assessed, with the aim of determining the optimal dosing regimen. The trial does not include any non-experimental treatments such as placebo or standard-of-care therapy, focusing solely on the investigational combination of Temozolomide and Bortezomib. The trial's primary objective is to evaluate the efficacy of this combination in improving progression-free survival and overall survival in patients with recurrent or progressed grade-4 glioma.

The efficacy of the clinical trial will be assessed during Phase II, focusing on the combination of **Temozolomide** and Bortezomib in patients with recurrent glioblastoma. The primary endpoints include overall survival (OS) at one year, median OS from the first relapse, progression-free survival (PFS) at six months, median PFS from the first relapse, and time to progression. These parameters will provide a comprehensive evaluation of the treatment's impact on patient survival and disease progression.

Secondary endpoints will involve assessing tumor response using contrast-enhanced MRI according to RANO criteria and conducting neurological exams. MRI assessments will occur at the start of treatment and every 12 weeks, while neurological exams will be conducted every four weeks. If disease progression is suspected based on NANO criteria, further confirmation with MRI (RANO) is required. Additionally, the trial will identify novel tumor biomarkers by analyzing physiological, molecular, and biochemical changes in blood and tumor tissue that correlate with treatment responses.