Glioblastoma
Conditions
Brief summary
The purpose of this study is to show if prolonging treatment with temozolomide to 12 cycles improve progression-free survival in patients with glioblastoma included in this study, randomized according to o6-methylguanine-DNA-methyltransferase (MGMT) methylation status and residual disease or not, to receive an additional 6 cycles of temozolomide.
Interventions
DRUGTemozolomide
Sponsors
Grupo Español de Investigación en Neurooncología
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Ability to understand and sign the informed consent document . 2. Age greater than or equal 18. 3. Patients with glioblastoma according to WHO classification (glioblastoma ) who received chemo- radiotherapy and temozolomide -based chemotherapy ( Stupp scheme ) and have completed 6 cycles of adjuvant temozolomide (with or without bevacizumab) in the context of standard treatment without presenting progression of disease. 4. Availability of tumor tissue from the first surgery for centralized histological review , for determining the MGMT study if you have not done in the center of origin. (If they were made in the center of origin the result of the center will be accepted ). 5. Stable dose of dexamethasone in the inclusion never above corticoids dose received in cycle 6 of the adjuvant . 6. Index greater than or equal 60 % Karnofsky. 7. All patients must show no progression of disease in a brain nuclear magnetic resonance (NMR) as defined in RANO established criteria before randomization . 8. Basal NMR study on a maximum of 6 weeks prior to inclusion, in which no progress is observed and is permitted to manage the care 6th cycle ( NMR performed after the 6th cycle of adjuvant is also acceptable as long as no progression was observed). 9. Adequate bone marrow reserve : hematocrit greater or equal 29% , white blood cell\> 3,000 , RAN greater or equal 1,500 cells / ul , platelets greater or equal 100,000 cells / ul. 10. Creatinine \<1.5 times the upper limit of normal (ULN) of the laboratory performing the analysis. 11. Serum bilirubin \<1.5 / ULN; SGOT , SGPT \< 2.5 times the upper limit of normal of the laboratory performing the analysis. Serum \< 3/ULN alkaline phosphatases . 12. Effective contraceptive method in patients and their partners.
Exclusion criteria
1. Less than 5 years of any previous invasive neoplasia. In situ cervical carcinoma or basal cell skin carcinoma accepted. 2. Concomitant treatment with other investigational agents (other concomitant bevacizumab) . 3. Presence of any clinically significant gastrointestinal abnormalities that may affect the decision , transit or absorption of study drug , such as the inability to take medication in tablets by mouth. 4. Presence of any psychiatric or cognitive disorder that limits understanding or written informed consent and / or impair compliance with the requirements of this protocol. 5. Concurrent disease that prevents the continuation of temozolomide treatment. 6. Presence of leptomeningeal dissemination. 7. Pregnant or breastfeeding. 8. Positive patients receiving combination antiretroviral therapy in HIV
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival at 6 Month | 6 month | Percentage of patients without progression of disease and time between start of treatment and progression of disease. The progression disease is defined as the time from the date of randomization to the date of progression defined according to the RANO criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progresion Free Survival Median Values | Through the whole study. 4 years. The median follow up for each patient was 33.4 months | It will be measured following Response assessment in neuro-oncology (RANO) guidelines: progression-free survival |
| Overall Survival | Through the whole study. 4 years. The median follow up for each patient was 33.4 months | Time between start of treatment and death |
| Number of Participants With Adverse Effects | Through the whole study. 4 years | Total number of patients presenting adverse events, stratified by type of event and grade. Adverse Events of special interest: Only relevant differences in toxicity by arm. |
| Median Overall Survival (OS) by Arm and MGMT Methylation Status | Through the whole study. 4 years. The median follow up for each patient was 33.4 months | Median OS depending on treatment arm in patients with methylated MGMT |
| Translational Sub-study - Biomarkers: mutS Homolog 6 (MSH6) Immunoreactivity | baseline | partial immunoreactivity of MSH6 in patients by treatment arm. Tumor samples were stained by immuno-histochemical techniques. |
| Median Progression-free Survival (PFS) by Arm and MGMT Methylation Status | Through the whole study. 4 years. The median follow up for each patient was 33.4 months | Median Progression Free Survival depending on treatment arm in patients with MGMT methylation |
Countries
Spain
Participant flow
Pre-assignment details
7 patients do not meet inclusion criteria. Only 159 patients were randomized
Participants by arm
| Arm | Count |
|---|---|
| Temozolomide Temozolomide dose 150/200 mg/m2/d for 5 days every 28 days for 6 cycles (total 12 cycles of adjuvant temozolomide). | 80 |
| Without Treatment No treatment (total 6 cycles of adjuvant Temozolomide). | 79 |
| Total | 159 |
Baseline characteristics
| Characteristic | Temozolomide | Total | Without Treatment |
|---|---|---|---|
| Age, Continuous | 60.7 Years | 60.4 Years | 60.4 Years |
| Anticonvulsant therapy No | 43 Participants | 84 Participants | 41 Participants |
| Anticonvulsant therapy Yes | 37 Participants | 75 Participants | 38 Participants |
| Barthel index 0 | 12 Participants | 21 Participants | 9 Participants |
| Barthel index 1 | 68 Participants | 138 Participants | 70 Participants |
| Dexamethasone (DXM) dose at inclusion 0.5-2 mg | 9 Participants | 15 Participants | 6 Participants |
| Dexamethasone (DXM) dose at inclusion 0 mg | 67 Participants | 137 Participants | 70 Participants |
| Dexamethasone (DXM) dose at inclusion >2 mg | 4 Participants | 7 Participants | 3 Participants |
| Initial surgery- Treatment at diagnosis. Biopsy | 7 Participants | 17 Participants | 10 Participants |
| Initial surgery- Treatment at diagnosis. Complete resection by post-op MRI) | 28 Participants | 63 Participants | 35 Participants |
| Initial surgery- Treatment at diagnosis. Complete resection without post-op MRI | 20 Participants | 34 Participants | 14 Participants |
| Initial surgery- Treatment at diagnosis. Subtotal resection | 25 Participants | 45 Participants | 20 Participants |
| Isocitrate dehydrogenase 1 (IDH1) Mutation status IDH1-R132 mutated by ICH | 1 Participants | 8 Participants | 7 Participants |
| Isocitrate dehydrogenase 1 (IDH1) Mutation status IDH1-R132 non mutated by ICH | 71 Participants | 137 Participants | 66 Participants |
| Isocitrate dehydrogenase 1 (IDH1) Mutation status not determined | 8 Participants | 14 Participants | 6 Participants |
| Karnofski Performance Status (KPS) index <70% | 2 Participants | 4 Participants | 2 Participants |
| Karnofski Performance Status (KPS) index >=70% | 78 Participants | 155 Participants | 77 Participants |
| Mini-mental status examinaion (MMSE) <27 | 16 Participants | 26 Participants | 10 Participants |
| Mini-mental status examinaion (MMSE) ≥27 | 51 Participants | 111 Participants | 60 Participants |
| Mini-mental status examinaion (MMSE) NP/ND | 13 Participants | 22 Participants | 9 Participants |
| O6-methylguanine DNA methyltransferase (MGMT) Methylation status Methylated | 49 Participants | 97 Participants | 48 Participants |
| O6-methylguanine DNA methyltransferase (MGMT) Methylation status Unmethylated | 31 Participants | 62 Participants | 31 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Spain | 80 participants | 159 participants | 79 participants |
| Residual disease (>10mm) No | 39 Participants | 76 Participants | 37 Participants |
| Residual disease (>10mm) Yes | 41 Participants | 83 Participants | 42 Participants |
| Residual Neurological symptom NA | 1 Participants | 1 Participants | 0 Participants |
| Residual Neurological symptom No | 60 Participants | 131 Participants | 71 Participants |
| Residual Neurological symptom Yes | 19 Participants | 27 Participants | 8 Participants |
| Sex: Female, Male Female | 38 Participants | 76 Participants | 38 Participants |
| Sex: Female, Male Male | 42 Participants | 83 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 63 / 80 | 52 / 79 |
| other Total, other adverse events | 80 / 80 | 79 / 79 |
| serious Total, serious adverse events | 9 / 80 | 5 / 79 |
Outcome results
Primary
Progression Free Survival at 6 Month
Percentage of patients without progression of disease and time between start of treatment and progression of disease. The progression disease is defined as the time from the date of randomization to the date of progression defined according to the RANO criteria.
Time frame: 6 month
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temozolomide | Progression Free Survival at 6 Month | 61.3 percentage of patients |
| Without Treatment | Progression Free Survival at 6 Month | 55.7 percentage of patients |
Secondary
Median Overall Survival (OS) by Arm and MGMT Methylation Status
Median OS depending on treatment arm in patients with methylated MGMT
Time frame: Through the whole study. 4 years. The median follow up for each patient was 33.4 months
Population: Patients with MGMT methylation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temozolomide | Median Overall Survival (OS) by Arm and MGMT Methylation Status | 20.7 months |
| Without Treatment | Median Overall Survival (OS) by Arm and MGMT Methylation Status | 27.1 months |
p-value: 0.1395% CI: [0.89, 2.33]Regression, Cox
Secondary
Median Progression-free Survival (PFS) by Arm and MGMT Methylation Status
Median Progression Free Survival depending on treatment arm in patients with MGMT methylation
Time frame: Through the whole study. 4 years. The median follow up for each patient was 33.4 months
Population: Patients with MGMT methylation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temozolomide | Median Progression-free Survival (PFS) by Arm and MGMT Methylation Status | 11.4 months |
| Without Treatment | Median Progression-free Survival (PFS) by Arm and MGMT Methylation Status | 8.5 months |
p-value: 0.9995% CI: [0.65, 1.5]Regression, Cox
Secondary
Number of Participants With Adverse Effects
Total number of patients presenting adverse events, stratified by type of event and grade. Adverse Events of special interest: Only relevant differences in toxicity by arm.
Time frame: Through the whole study. 4 years
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Temozolomide | Number of Participants With Adverse Effects | Thrombocytopenia | Grade 3-4 | 2 Participants |
| Temozolomide | Number of Participants With Adverse Effects | Nausea and vomiting | not affected | 50 Participants |
| Temozolomide | Number of Participants With Adverse Effects | Lymphopenia | Grade 3-4 | 3 Participants |
| Temozolomide | Number of Participants With Adverse Effects | Fatigue | Grade 1-2 | 35 Participants |
| Temozolomide | Number of Participants With Adverse Effects | Thrombocytopenia | not affected | 42 Participants |
| Temozolomide | Number of Participants With Adverse Effects | Fatigue | Grade 3-4 | 0 Participants |
| Temozolomide | Number of Participants With Adverse Effects | Thrombocytopenia | Grade 1-2 | 36 Participants |
| Temozolomide | Number of Participants With Adverse Effects | Fatigue | not affected | 45 Participants |
| Temozolomide | Number of Participants With Adverse Effects | Nausea and vomiting | Grade 1-2 | 30 Participants |
| Temozolomide | Number of Participants With Adverse Effects | Leucopenia | Grade 1-2 | 29 Participants |
| Temozolomide | Number of Participants With Adverse Effects | Lymphopenia | Grade 1-2 | 52 Participants |
| Temozolomide | Number of Participants With Adverse Effects | Leucopenia | Grade 3-4 | 1 Participants |
| Temozolomide | Number of Participants With Adverse Effects | Nausea and vomiting | Grade 3-4 | 0 Participants |
| Temozolomide | Number of Participants With Adverse Effects | Leucopenia | not affected | 50 Participants |
| Temozolomide | Number of Participants With Adverse Effects | Lymphopenia | not affected | 25 Participants |
| Without Treatment | Number of Participants With Adverse Effects | Leucopenia | not affected | 59 Participants |
| Without Treatment | Number of Participants With Adverse Effects | Lymphopenia | Grade 1-2 | 33 Participants |
| Without Treatment | Number of Participants With Adverse Effects | Lymphopenia | Grade 3-4 | 0 Participants |
| Without Treatment | Number of Participants With Adverse Effects | Lymphopenia | not affected | 46 Participants |
| Without Treatment | Number of Participants With Adverse Effects | Thrombocytopenia | Grade 1-2 | 17 Participants |
| Without Treatment | Number of Participants With Adverse Effects | Thrombocytopenia | Grade 3-4 | 0 Participants |
| Without Treatment | Number of Participants With Adverse Effects | Thrombocytopenia | not affected | 62 Participants |
| Without Treatment | Number of Participants With Adverse Effects | Nausea and vomiting | Grade 1-2 | 10 Participants |
| Without Treatment | Number of Participants With Adverse Effects | Nausea and vomiting | Grade 3-4 | 0 Participants |
| Without Treatment | Number of Participants With Adverse Effects | Nausea and vomiting | not affected | 69 Participants |
| Without Treatment | Number of Participants With Adverse Effects | Fatigue | Grade 1-2 | 21 Participants |
| Without Treatment | Number of Participants With Adverse Effects | Fatigue | Grade 3-4 | 0 Participants |
| Without Treatment | Number of Participants With Adverse Effects | Fatigue | not affected | 58 Participants |
| Without Treatment | Number of Participants With Adverse Effects | Leucopenia | Grade 1-2 | 20 Participants |
| Without Treatment | Number of Participants With Adverse Effects | Leucopenia | Grade 3-4 | 0 Participants |
Secondary
Overall Survival
Time between start of treatment and death
Time frame: Through the whole study. 4 years. The median follow up for each patient was 33.4 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temozolomide | Overall Survival | 18.2 months |
| Without Treatment | Overall Survival | 23.3 months |
p-value: 0.1695% CI: [0.9, 1.88]Regression, Cox
Secondary
Progresion Free Survival Median Values
It will be measured following Response assessment in neuro-oncology (RANO) guidelines: progression-free survival
Time frame: Through the whole study. 4 years. The median follow up for each patient was 33.4 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temozolomide | Progresion Free Survival Median Values | 9.5 months |
| Without Treatment | Progresion Free Survival Median Values | 7.77 months |
p-value: 0.943Log Rank
Secondary
Translational Sub-study - Biomarkers: mutS Homolog 6 (MSH6) Immunoreactivity
partial immunoreactivity of MSH6 in patients by treatment arm. Tumor samples were stained by immuno-histochemical techniques.
Time frame: baseline
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Temozolomide | Translational Sub-study - Biomarkers: mutS Homolog 6 (MSH6) Immunoreactivity | MSH6 partial immunoreactivity | 5 Participants |
| Temozolomide | Translational Sub-study - Biomarkers: mutS Homolog 6 (MSH6) Immunoreactivity | no MSH6 partial immunoreactivity | 75 Participants |
| Without Treatment | Translational Sub-study - Biomarkers: mutS Homolog 6 (MSH6) Immunoreactivity | MSH6 partial immunoreactivity | 6 Participants |
| Without Treatment | Translational Sub-study - Biomarkers: mutS Homolog 6 (MSH6) Immunoreactivity | no MSH6 partial immunoreactivity | 73 Participants |