Clinical trial NCT04926168: 6 Months Adjuvant Temozolomide (TMZ) vs No Adjuvant TMZ in Newly Diagnosed MGMT Methylated Glioblastoma (GBM)
Official title: Randomized Pilot Study of Six Months Adjuvant Temozolomide (TMZ) vs No Adjuvant TMZ in Patients With Newly Diagnosed MGMT Methylated Glioblastoma (GBM) Following Standard Concurrent Radiation and TMZ
Study type: OBSERVATIONAL
Overall status: WITHDRAWN
Conditions: MGMT-Methylated Glioblastoma
Keywords: TMZ
MGMT
adjuvant TMZ
GBM, Newly Diagnosed
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
First posted: 2021-06-15
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: patients who have completed 6weeks of TMZ + RT and have had good performance in that setting are eligible to be enrolled in this study to observe outcomes from being randomized to receive Standard of Care Adjuvant TMZ (6months TMZ 5 Days 1-5 or each cycle) or delay of adjuvant TMZ until recurrence post TMZ and RT. At recurrence patient may choose to start TMZ or some other treatment.

Brief summary: The primary objective of this trial is to evaluate overall survival of patients with O\[6\]-methylguanine-DNA methyltransferase (MGMT) methylated glioblastoma treated with or without six months of adjuvant TMZ after standard radiation (6000 centigray (cGy)) plus concurrent Temozolomide (TMZ).

Secondary Objectives include to prospectively assess the overall adverse event profile in the two treatment arms. To compare lymphocyte counts overtime between the two treatment arms and to prospectively compare quality of life in the two treatment arms as assessed by MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) and Neurological quality of Life/minimal infecting dose (NeuroQoL) (MID). The study will also compare progression-free survival between the two treatment arms.

Detailed description: Recent phase III trials in patients with newly diagnosed patients with glioblastoma have demonstrated that adding new agents (such as cilengitide, bevacizumab, or nivolumab) to standard radiation and TMZ do not improve survival in this disease. The modest effects on survival observed with the Optune® device are offset by the high costs, inconvenience, and impact on the social interactions of patients wearing this device. Unfortunately, there are currently no novel therapies poised to displace the European Organization Research \& Treatment Cancer (EORTC) regimen as the standard of care for patients with newly diagnosed Glioblastoma Multiforme (GBM).As a result, a formal evaluation of the efficacy of the 6 months of adjuvant TMZ in this regimen is important to patients and research studies.

This is of particular importance in the 40% of patients who have MGMT methylated glioblastoma. The very small benefit observed in MGMT unmethylated patients has led investigators in Europe and the United States of America (including Cancer Therapy Evaluation Program (CTEP) sponsored studies) to approve clinical trials in MGMT unmethylated patients with newly diagnosed glioblastoma that entirely omit TMZ in both the concurrent and the adjuvant settings Given the marginal value of TMZ in the MGMT unmethylated patient population, the investigator's propose to study the value of adjuvant TMZ in the subset of the MGMT methylated population. If omitting adjuvant TMZ is not detrimental to outcomes in the methylated population then it is extremely unlikely to benefit the unmethylated population where TMZ has even less effect.

Therefore, exploring the value of the six months of adjuvant TMZ in patients with newly diagnosed MGMT methylated glioblastoma is important. If this was shown to be of minimal value in prolonging survival there would be an immediate impact on both the standard care of patients and research efforts to improve therapeutic outcomes.

Eligibility criteria: Inclusion Criteria:

1. Patients must be 18 years of age or older.
2. Patients must have a Karnofsky Performance Status ≥ 60% (i.e. the patient must be able to care for himself/herself with occasional help from others).
3. Patients must have had a pathologically confirmed recently diagnosed primary glioblastoma before they began concurrent radiation and temozolomide.
4. Patients must have tumor MGMT methylation status of methylated using a Clinical Laboratory Improvement Amendments (CLIA)-approved diagnostic test. Results of routinely-used methods for MGMT methylation testing (e.g. Mutagenically separated- polymerase chain reaction (MS-PCR) or quantitative PCR) are acceptable.
5. Documented mutated isocitrate dehydrogenase 1 gene (IDH1) isocitrate dehydrogenase 1 gene (IDH2)status: patients with either wild-type or(IDH) status are eligible. Patients with no documented status are also eligible and the status should be listed as unknown.
6. Patients must be completing or have completed 6 weeks of standard concurrent RT/TMZ.
7. Patients' post-operative treatment must have included at least 80% of standard radiation and concomitant temozolomide. Patients may not have received any other prior chemotherapy, immunotherapy or therapy with biologic agent (including immunotoxins, immunoconjugates, antisense, peptide receptor antagonists, interferons, interleukins, tumor-infiltrating lymphocytes (TIL), lymphokine activated killer cells (LAK) or gene therapy), or hormonal therapy for their brain tumor. Prior Gliadel Wafers are allowed. Glucocorticoid therapy is allowed.
8. Patients must be clinically eligible for the six months of adjuvant temozolomide.
9. Patients must be able to provide written informed consent.
10. Patients must have baseline MRI performed within the 21 days prior to starting entering the "adjuvant" treatment or observation period.
11. Patients must have the following organ and marrow functions:

Absolute neutrophil count ≥1,500/µL Platelets ≥100,000/µL Hemoglobin ≥ 9 g/dL Total bilirubin ≤1.5 × institutional upper limit of normal (ULN), (except for patients with known Gilbert's syndrome who must have normal direct bilirubin) aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/ alanine transaminase (ALT) serum glutamic-pyruvic transaminase (SGPT) ≤ 2.5 × ULN Creatinine ≤1.5 × ULN OR Creatinine clearance ≥ 60 mL/min/1.73m2

Exclusion Criteria:

1. Patients receiving any other standard or investigational agents or who plan to use the OPTUNE device or other therapies for the glioblastoma are ineligible.
2. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible.
3. Patients must not have received prior RT, chemotherapy (except for their concurrent radiation and temozolomide for their recently diagnosed glioblastoma), immunotherapy or therapy with a biologic agent (including immunotoxins, immunoconjugates, antisense, peptide receptor antagonists, interferons, interleukins, tumor-infiltrating lymphocytes, lymphokine-activated killer cells, or gene therapy), or hormonal therapy for their brain tumor. Corticosteroid therapy is allowed.
4. Patients must not have had a prior diagnosis of a lower grade glioma.
5. No active treatment for other cancers in the past 3 years.

Primary outcomes:
measure: Overall Survival
timeFrame: Up to 2 years
Secondary outcomes:
measure: Grade 3 or above adverse events
timeFrame: 6 months
measure: Change in Lymphocyte count
timeFrame: Up to 1 year
measure: Change in Quality of life as assessed by MDASI-BT
timeFrame: Up to 6 months
measure: Change in Quality of life as assessed by NeuroQoL/MID.
timeFrame: Up to 6 months
measure: Progression-free survival
timeFrame: Up to 2 years
Other outcomes:
Locations:
Study officials:
affiliation: Johns Hopkins University
name: Stuart Grossman, MD
role: STUDY_CHAIR
References: