Glioma
Conditions
Brief summary
The main purpose of this study is to assess the effect of a two-week pre-surgery treatment with low-dose temozolomide (TMZ) on brain tumor methylguanine-DNA (deoxyribonucleic acid) methyltransferase (MGMT) activity in patients with gliomas.
Interventions
DRUGtemozolomide
Temozolomide 75 mg/m\^2 daily for 14 days prior to surgery. As standard of care, it could also be given at the same dose for up to 28 days after surgery, per investigator discretion.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Presence of a brain tumor with high probability of being a glioma as detected by Magnetic Resonance Imaging (MRI). These would include newly diagnosed tumors or potentially recurrent gliomas. * No prior treatment for the tumor including chemotherapy or radiotherapy. * Amenable to surgery for biopsy or resection of the brain tumor. Surgically confirmed diagnosis of glioma (glioblastoma multiforme \[GBM\], anaplastic astrocytoma \[AA\], anaplastic oligodendroglioma \[AO\], anaplastic oligoastrocytoma \[AOA\], astrocytoma \[A\] or oligodendroglioma \[O\]) will be required for patients to be maintained in the study. Those not fulfilling this requirement will be discontinued and will be replaced. * Use of medically approved contraception in fertile males and females. * Women with childbearing potential must have a negative urine or serum pregnancy test (urinary excretion or serum level of beta-Human Chorionic Gonadotropin \[bHCG\]) within 72 hours of randomization. * Karnofsky Performance Status score \>= 70%. * Signed informed consent form
Exclusion criteria
* Prior chemotherapy. * Prior radiotherapy at the tumor site. * History of non-compliance to other therapies. * Inadequate haematological, renal and hepatic function according to all of the following laboratory values (to be performed within 14 days, inclusive, prior to study inclusion): * Absolute neutrophil count ≤1.5 x 10\^9/L; * Platelets ≤100 x 10\^9/L; * Haemoglobin \<90 g/L; * Serum creatinine ≥1.5 times upper limit of laboratory normal; * Total serum bilirubin ≥1.5 times upper limit of laboratory normal (ULN); * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2.0 ULN; * Alkaline phosphatase of \> 2.5 ULN. * Known Human Immunodeficiency Virus \[HIV\] infection. * Known chronic hepatitis B or hepatitis C infection. * Any other serious medical condition according to the medical judgment of the physician prior to inclusion in the study. * Any medical condition, which could interfere with oral medication intake (e.g., frequent vomiting, partial bowel obstruction).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MethylGuanine-DNA MethylTransferase [MGMT] Activity Measured From the Tumor Tissue During Surgery | 14 days | An experimental assay was developed to measure MGMT levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety: Number of Participants Who Experienced Grade 3 or 4 Toxicities | 12 months | Grade 3 was defined as severe per Common Terminology Criteria for Adverse Events (CTCAE). Grade 4 was defined as life-threatening per CTCAE. |
| Tolerability: Number of Participants Discontinuing Treatment Due to Adverse Events (AE) | 12 months | An AE was defined as any event which was adverse, including what were commonly described as adverse or undesirable experiences, adverse events, adverse reactions, side effects, or death due to any cause associated with, or observed in conjunction with the use of a drug, biological product, or device in humans, whether or not considered related to the use of that product. Additionally, any event which was associated with, or observed in conjunction with product overdose whether accidental or intentional, or product abuse and/or withdrawal was also considered an AE. |
| Concentrations of Temozolomide in the Serum, Cerebrospinal Fluid, and Brain Tumor | 14 days | No data available: at the time of tumor collection, the temozolomide levels were below the detection limits of the assay. |
| MGMT Activity in the Brain Tumor Tissues by Temozolomide Levels | 14 days | No data available: at the time of tumor collection, the temozolomide levels were below the detection limits of the assay. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Temozolomide (TMZ) Temozolomide 75 mg/m\^2 daily for 14 days prior to surgery.
As standard of care, it could also have been given at the same dose for up to 28 days after surgery, per investigator discretion. | 34 |
| No Intervention No pre-surgery treatment with temozolomide | 6 |
| Total | 40 |
Baseline characteristics
| Characteristic | Temozolomide (TMZ) | No Intervention | Total |
|---|---|---|---|
| Age, Customized | 34 Participants | 6 Participants | 40 Participants |
| Region of Enrollment Canada | 34 participants | 6 participants | 40 participants |
| Sex: Female, Male Female | 17 Participants | 4 Participants | 21 Participants |
| Sex: Female, Male Male | 17 Participants | 2 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 34 | 5 / 6 |
| serious Total, serious adverse events | 0 / 34 | 0 / 6 |
Outcome results
Primary
MethylGuanine-DNA MethylTransferase [MGMT] Activity Measured From the Tumor Tissue During Surgery
An experimental assay was developed to measure MGMT levels.
Time frame: 14 days
Population: All participants for which a MGMT activity assay could be~performed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Temozolomide (TMZ) | MethylGuanine-DNA MethylTransferase [MGMT] Activity Measured From the Tumor Tissue During Surgery | 333.7 fmol/mg of proteins | Standard Deviation 288.5 |
| No Intervention | MethylGuanine-DNA MethylTransferase [MGMT] Activity Measured From the Tumor Tissue During Surgery | 105.1 fmol/mg of proteins | Standard Deviation 155 |
p-value: 0.09t-test, 2 sided
Secondary
Concentrations of Temozolomide in the Serum, Cerebrospinal Fluid, and Brain Tumor
No data available: at the time of tumor collection, the temozolomide levels were below the detection limits of the assay.
Time frame: 14 days
Secondary
MGMT Activity in the Brain Tumor Tissues by Temozolomide Levels
No data available: at the time of tumor collection, the temozolomide levels were below the detection limits of the assay.
Time frame: 14 days
Secondary
Safety: Number of Participants Who Experienced Grade 3 or 4 Toxicities
Grade 3 was defined as severe per Common Terminology Criteria for Adverse Events (CTCAE). Grade 4 was defined as life-threatening per CTCAE.
Time frame: 12 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Temozolomide (TMZ) | Safety: Number of Participants Who Experienced Grade 3 or 4 Toxicities | Grade 3 | 4 participants |
| Temozolomide (TMZ) | Safety: Number of Participants Who Experienced Grade 3 or 4 Toxicities | Grade 4 | 0 participants |
| No Intervention | Safety: Number of Participants Who Experienced Grade 3 or 4 Toxicities | Grade 3 | 0 participants |
| No Intervention | Safety: Number of Participants Who Experienced Grade 3 or 4 Toxicities | Grade 4 | 0 participants |
Secondary
Tolerability: Number of Participants Discontinuing Treatment Due to Adverse Events (AE)
An AE was defined as any event which was adverse, including what were commonly described as adverse or undesirable experiences, adverse events, adverse reactions, side effects, or death due to any cause associated with, or observed in conjunction with the use of a drug, biological product, or device in humans, whether or not considered related to the use of that product. Additionally, any event which was associated with, or observed in conjunction with product overdose whether accidental or intentional, or product abuse and/or withdrawal was also considered an AE.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temozolomide (TMZ) | Tolerability: Number of Participants Discontinuing Treatment Due to Adverse Events (AE) | 0 participants |
| No Intervention | Tolerability: Number of Participants Discontinuing Treatment Due to Adverse Events (AE) | 0 participants |