Study on Low Dose Temozolomide Plus Metformin or Placebo in Patient With Recurrent or Refractory Glioblastoma

Study Overview
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Brief Summary
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A phase 2 clinical trial for the efficacy and safety of low dose Temozolomide plus metformin as combination chemotherapy compared with low dose Temozolomide plus placebo in patient with recurrent or refractory Glioblastoma

Detailed Description
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Studies will investigate the efficacy and safety of low dose Temozolomide with Metformin or placebo for the patients with recurrent or refractory Glioblastoma. The dosage of the Metformin will follow the domestically permitted dose to minimize side effects. The patients will be allocated randomly to arm 1(experimental) and arm 2(placebo controlled) and administered the investigational products for up to 6 cycle. Each cycle consists of 4 weeks. After 6 cycle(24 weeks), the patients will be checked progression and survival every 24 weeks up to 96 weeks.

Official Title
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Efficacy and Safety of Low Dose Temozolomide Plus Metformin as Combination Chemotherapy Compared With Low Dose Temozolomide Plus Placebo in Patient With Recurrent or Refractory Glioblastoma

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: Temozolomide+Metformin
* Drug: Temozolomide+Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Progressive or recurrent Glioblastoma conformed by histopathological or radiological diagnosis. Progressive or recurrent Glioblastoma during or after standard therapy (Temozolomide after Temozolomide and radiation therapy; Stupp regimen) after histopathological diagnosis of Glioblastoma Recurrence or progression is diagnosed according to histopathological diagnosis or revised RANO(Response Assessment in Neuro-Oncology) criteria c Karnofsky performance status(KPS) ≥ 60% Age ≥ 19 years old At least 4 weeks after operation or chemotherapy Normal in hematological finding, liver and kidney function Hematology ANC > 1.500/mm³, Platelet > 100,000/mm³, WBC > 3×10^9/L, Hemoglobin > 9g/dL Liver function Total Bilirubin level ≤ 1.5×ULN(in case of isolated hyperbilirubinemia ≤2.5 x ULN) AST / ALT < 2.5×ULN Renal function Serum creatinine ≤ 1.5mg/dL Be informed of the nature of the study and obtained a written informed consent A legal representative agrees to the trial when a subject is unable to communicate smoothly due to neurologic defect If a fertile woman who has been confirmed negative to a urine or blood pregnancy test within 28 days prior to the trial Exclusion Criteria: Pregnant or breast feeding Cancer history within 5 years excluding cancer in the skin cells and cervix Active infections within two weeks Leptomeningeal metastasis Patients diagnosed with diabetes Hypersensitive or intolerance to Metformin Patients who are currently taking Metformin, sulfonylureas, thiazolidinediones, and insulin, regardless of reason Other serious diseases or medical conditions that include : Patients who suffer from unstable heart disease despite treatment. Patients having a heart attack within 6 months prior to the start of trial Patients who suffer from severe nerve or psychosis that includes dementia or strokes. Patients with an uncontrolled infection Patient with uncontrolled hypertension, congestive heart failure, unstable angina, or incomplete arrhythmia Those who have participated in other clinical trials may not recover from the toxicity of the treatment.

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Arm 1 : Low dose temozolomide+metformin Arm 2 : Low dose temozolomide+placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Temozolomide+metformin<br>Temozolomide : 1 cycle of 4 weeks with daily dose 50mg/m2(BSA: Body Surface Area) up to 6 cycles for 24 weeks Metformin : 1st cycle (4 weeks) 1 week(1st 7th day) = 1,000mg/day 1 week(8th 14th day) = 1,500mg/day 2 weeks(15th  28th day) = 2,000mg/day 2nd to 6th cycle (20 weeks) = 2,000mg/day | Drug: Temozolomide+Metformin<br>* Low dose temozolomide+metformin for 24 weeks<br>|
| Placebo Comparator: Temozolomide+placebo<br>Temozolomide : 1 cycle of 4 weeks with daily dose 50mg/m2(BSA: Body Surface Area) up to 6 cycles for 24 weeks Placebo: 1st cycle (4 weeks) 1 week(1st 7th day) = 1,000mg/day 1 week(8th 14th day) = 1,500mg/day 2 weeks(15th 28th day) = 2,000mg/day 2nd to 6th cycle (20 weeks) = 2,000mg/day | Drug: Temozolomide+Placebo<br>* Low dose temozolomide+placebo for 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of progression-free survival obtained from progression-free survival curve | Comparison of progression-free survival obtained from progression-free survival curve | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Tumor Response Rate | 4 weeks, 8 weeks, 16 weeks, 24 weeks thereafter every 24 weeks up to 96 weeks | 
| Tumor control probability | Tumor control probability | 4 weeks, 8 weeks, 16 weeks, 24 weeks thereafter every 24 weeks up to 96 weeks | 
| 6 month progression free survival | 6 month progression free survival | 24 weeks | 
| 6 month overall survival | 6 month overall survival | 24 weeks | 
| Assessment of the quality of life of cancer patients | EORTC QLQ-C30 and EORTC QLQ-BN20 | 4 weeks, 8 weeks, 16 weeks, 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma