Phase III Evaluation of Lomustine and Temozolomide Versus Temozolomide in MGMT Promoter Methylated Glioblastoma with or without Tumor Treating Fields

Trial ID: 2023-506998-35-00
Protocol: TMZ-LOM
Sponsor: Vaestra Goetalandsregionen

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Diseases & Conditions

Glioblastoma

Objectives

The primary objective of this phase III trial is to evaluate whether the combination of **temozolomide** (TMZ) and **lomustine** (LOM) chemotherapy, alongside standard radiotherapy with or without concomitant tumor treating fields (TTFields), offers superior overall survival compared to TMZ monotherapy with the same radiotherapy and TTFields options in patients with newly diagnosed MGMT promoter methylated **glioblastoma**. This investigation is clinically significant as it seeks to determine if the addition of LOM to the standard treatment regimen can provide a meaningful survival advantage for this patient population.

Secondary objectives include:

Assessing progression-free survival and acute and late toxicity of the TMZ/LOM therapy with or without TTFields, compared to TMZ monotherapy.
Evaluating the best response rate via MRI, time to treatment failure, frequency of pseudoprogression, and location of tumor recurrences.
Conducting quality of life and neurocognitive evaluations, particularly in relation to radiotherapy dose in the hippocampus and normal brain, and assessing treatment-related neurotoxicity on MRI.
Investigating the role of baseline comorbidities in relation to overall survival.
Exploring potential differences in survival, quality of life, and neurocognition between patients receiving TTFields or not.
Conducting basic diagnostic and translational research on tumor tissue from primary surgery, and analyzing blood for liquid biopsies, including "Tumor Educated Platelets," circulating free tumor DNA, and exosomes.

Participants

The clinical trial involves participants diagnosed with **glioblastoma**, specifically those with newly diagnosed histologically proven GBM, giant-cell GBM, or gliosarcoma WHO Grade 4, confirmed as IDHwt by a local neuropathologist. The study population includes both male and female subjects aged between 18 and 75 years, with an estimated life expectancy of at least 12 weeks. Participants are required to have a WHO Performance Score of 0-2, indicating a relatively stable health status. The trial does not include a vulnerable population. Participants must demonstrate adequate organ function and compliance, with geographic proximity allowing for adequate follow-up. Lifestyle considerations include the use of approved contraceptive methods for participants with reproductive potential during and for six months after chemotherapy. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is a **Phase III** study designed to evaluate the efficacy of a combination therapy involving **temozolomide** and **lomustine** compared to standard temozolomide therapy in patients with newly diagnosed MGMT promoter methylated **glioblastoma**. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The primary objective is to assess whether the addition of lomustine to the standard treatment regimen, which may include tumor treating fields (TTFields), improves overall survival. The trial is expected to run until March 2031, with recruitment starting in March 2024.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed through criteria such as written informed consent, adequate organ function, and a histologically proven diagnosis of glioblastoma. Follow-up visits will be scheduled to monitor treatment response, side effects, and overall health. These visits will include assessments such as MRI scans to evaluate progression-free survival and best response rate, as well as quality of life and neurocognitive evaluations. The end-of-study visit will conclude the participant's involvement, with a final assessment of overall survival and any long-term effects of the treatment.

The expected length of participant involvement is approximately 66 weeks, corresponding to the maximum treatment period. Participants may be withdrawn from the study early if they experience significant adverse effects, disease progression, or if they fail to comply with the study protocol. The trial will also monitor secondary endpoints, including the frequency of treatment delays, acute toxicity, and the impact of TTFields on survival and neurocognition. The study aims to provide comprehensive data on the potential benefits and risks of the combination therapy, contributing valuable insights into the treatment of glioblastoma.

Treatment

The clinical trial involves the administration of **temozolomide**, an alkylating chemotherapy agent, as part of the experimental treatment regimen. **Temozolomide** is provided in an oral pharmaceutical form, identified by the code PHF00005MIG. The maximum daily dose is set at 200 mg/m², with a total maximum dose of 9425 mg/m² over a treatment period of 66 days. The administration route is oral, and the dosing schedule is designed to ensure optimal therapeutic efficacy while monitoring participant compliance. The trial aims to evaluate the efficacy of **temozolomide** in combination with other treatments for patients with newly diagnosed MGMT promoter methylated glioblastoma.

In addition to **temozolomide**, the trial also includes the administration of **lomustine**, another alkylating chemotherapy agent. **Lomustine** is also administered orally, with a pharmaceutical form identified by the code PHF00006MIG. The maximum daily dose for **lomustine** is 100 mg/m², with a total maximum dose of 600 mg/m² over the same 66-day treatment period. The inclusion of **lomustine** in the treatment regimen is intended to assess its potential to enhance overall survival when combined with **temozolomide** and standard radiotherapy, with or without concomitant tumor treating fields (TTFields).

The trial compares the combination therapy of **temozolomide** and **lomustine** against standard **temozolomide** monotherapy, both in conjunction with standard radiotherapy and optional TTFields. The primary objective is to determine if the addition of **lomustine** to the treatment regimen provides a significant survival benefit for patients with newly diagnosed MGMT promoter methylated glioblastoma. Participant compliance with the dosing schedule is closely monitored to ensure adherence to the treatment protocol and to accurately assess the therapeutic outcomes of the experimental regimen.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the measurement of **overall survival (OS)**. This primary endpoint will be evaluated from the day of randomization until death or a follow-up period of at least 36 months. Secondary endpoints include **progression-free survival (PFS)**, which will be measured from the day of randomization until the diagnosis of progressive disease as determined by MRI using RANO 2.0 criteria. Additional secondary endpoints involve the best response rate, frequency of treatment delays, acute toxicity, quality of life, neurocognition, frequency of pseudoprogression, tumor recurrence location, and treatment-related neurotoxicity.

Quality of life will be assessed using EORTC questionnaires QLQ-30 and BN-20, while neurocognition will be evaluated using CNS Vital Signs. The trial will also analyze the dose to the hippocampus and healthy brain in relation to quality of life and neurocognitive testing. The analysis will include subgroups of patients receiving tumor treating fields (TTFields) compared to those not receiving TTFields, examining both OS and PFS, as well as neurocognitive outcomes. Time to treatment failure, defined as the premature cessation of study treatment for any reason, will also be evaluated. The trial will further explore OS in relation to baseline comorbidities and treatment-related neurotoxicity as observed on MRI.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written informed consent
Patient capable of understanding the rationale and necessity of study therapy and procedures.
Newly diagnosed histologically proven GBM, giant-cell GBM or gliosarcoma WHO Grad 4, histology confirmed by the local neuropathologist as IDHwt. Histology obtained by complete resection, partial resection, open biopsy or stereotactic biopsy.
Methylated MGMT promoter in the tumor as determined according to local routine. For centers using the same method/kit the same cut-off for mMGMT will be used.
Males or females 18-75 years of age, estimated life expectancy of at least 12 weeks
WHO Performance Score 0-2
Patient compliance and geographic proximity that allow adequate follow up
Male and female patients with reproductive potential must use an approved contraceptive method (intrauterine device, birth control pills, or barrier device) during and for 6 months after end of chemotherapy (Pearl index <1%)
Pre-menopausal female patients with childbearing potential: a negative serum pregnancy test must be obtained within 14 days prior to treatment start
Adequate organ function as described in the protocol
Patients on anticoagulation can be included at the discretion of the investigator, but oral anticoagulants, including NOAC/DOAC are recommended to be switched to Low-molecular-weight heparin (LMWH) during the treatment phase and until platelets are >50 or according to local guidelines.

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Exclusion Criteria

Prior malignancy (except adequately treated carcinoma in situ of the cervix or non-melanoma skin cancer), unless the prior malignancy was diagnosed and curatively treated ≥3 years previously with no subsquent evidence of recurrence
Prior systemic chemotherapy with DNA-damaging agents for any cancer
Prior RT to the brain
Concurrent administration of any other antitumor therapy not described in the protocol
Concurrent administration of complementary or alternative drugs
Allergy or intolerability of temozolomide, dacarbazine, lomustine or other nitrosourea derivatives including celiac disease and wheat allergy
Unable to perform MRI
Past medical history of diseases with poor prognosis, e.g. severe coronary heart disease, heart failure (NYHA III/IV), severe and poorly controlled diabetes, immune deficiency, residual deficits after stroke or other serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator)
Severly reduced lung function (at the discretion of the investigator)
Any active infection (at the discretion of the investigator)
Female patients that are breastfeeding and not willing to refrain
Patients with reproductive potential who do not accept to use contraception during chemotherapy and 6 months thereafter
Treatment in another clinical trial with oncological therapeutic intervention or use of any other investigational agent within 30 days before enrolment
Any psychological, cognitive, familial, social or geographical condition potentially hampering compliance with the study protocol and follow-up scheduled visits (at the discretion of investigator)