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Chemoradiotherapy Versus Biomarker-Guided Therapy for Elderly and Frail GBM Patients

Primary Purpose

Glioblastoma Multiforme

Status
Recruiting
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Biomarker based treatment (Temozolomide monotherapy or Radiotherapy monotherapy)
Chemo-Radiotherapy consisting of 40 Gy in 15 daily fractions with concurrent temozolomide.
Sponsored by
AHS Cancer Control Alberta
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma Multiforme

Eligibility Criteria

65 Years - undefined (Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Newly-diagnosed, histologically proven, intracranial glioblastoma with maximal safe resection. Biopsy alone is expected if resection is not possible. MGMT promoter methylation status must be tested for all patients.
  2. History and physical examination, including neurological examination, within 14 days prior to randomization.
  3. Age ≥ 65 & KPS of 60 - 70
  4. Stable or decreasing dose of corticosteroids for at least 14 days prior to randomization.
  5. Laboratory evaluation within 7 days prior to randomization, with adequate function as defined below:

    1. ANC ≥ 1.5 x 109/L
    2. Platelets ≥ 100 x 109/L
    3. Estimated Glomerular Filtration Rate (eGFR) > 59
    4. Total serum bilirubin ≤ 30 umol/L (ie ≤ 1.5 times ULN)
    5. ALT < 150 U/L (ie < 3 times ULN)
    6. AST < 120 U/L (ie < 3 times ULN)
    7. Alkaline phosphatase < 390 U/L (ie < 3 times ULN)
  6. Patients must sign a study-specific informed consent prior to study registration.
  7. Patients of childbearing / reproductive potential should use highly effective birth control methods, as defined by the investigator, during the study treatment period and for a period of 6 months after the last dose of study drug. A highly effective method of birth control is defined as those that result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.

    Note: abstinence is acceptable if this is established and preferred contraception for the patient and is accepted as a local standard.

    1. This will apply for male patients only and their female partner if of child bearing potential.
    2. Effective contraception should also be used by male patients taking temozolomide. Men being treated with temozolomide are advised not to father a child during or up to 6 months after discontinuation of treatment (male patients).
  8. Male patients should agree to not donate sperm during the study treatment and for six months post treatment completion.

Exclusion Criteria:

  1. Recurrent malignant gliomas
  2. Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease free for ≥ 3 years.
  3. Prior head or neck RT (except for T1 glottic cancer), or systemic therapy precluding delivery of concurrent and adjuvant temozolomide
  4. Treatment with any other therapeutic clinical protocol within 30 days prior to study registration or during participation in the study.
  5. Severe, active co-morbidity, defined as follows:

    1. Unstable angina and/or congestive heart failure requiring hospitalization
    2. Transmural myocardial infarction within the last 6 months
    3. Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study registration
    4. Any severe, active co-morbidity precluding delivery of temozolomide.
    5. History of hypersensitivity reaction to temozolomide components or to dacarbazine.
    6. Active HBV infection

Sites / Locations

  • Tom Baker Cancer CentreRecruiting
  • Cross Cancer InstituteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Standard Arm: TMZ with concurrent RT (combined modality arm)

Biomarker based treatment

Arm Description

Patients will receive a total of 21 days of Temozolomide (TMZ), with 15 days of TMZ administered daily with concurrent RT. TMZ will be delivered at a dose of 75 mg/m2, given daily with RT for 15 days, one hour before each session of RT. After a 4-week break, patients will receive six cycles of adjuvant TMZ according to the standard 5-day schedule (days 1-5) every 28 days, up to 6 cycles as tolerated by the patient. The dose will be 150 mg/m2 for the first cycle and increased to 200 mg/m2 beginning with the second cycle, so long as there are no hematologic adverse events, intractable nausea or fatigue.

MGMT (+) Temozolomide monotherapy: Patients will receive Temozolomide (TMZ) at a dose of 75 mg/m2 daily for 21 consecutive days. This will be followed by six cycles of TMZ according to the standard 5-day schedule (days 1-5) every 28 days. The dose will be 150 mg/m2 for the first cycle and increased to 200 mg/m2 beginning with the second cycle, so long as there are no hematologic adverse events. Dose will be determined using body surface area (BSA) calculation. MGMT methylation (-) RT monotherapy: Participants will receive radiation treatment with 40Gy / 15 fractions over a period of 21 days (3 weeks).

Outcomes

Primary Outcome Measures

Overall survival
Time between randomization and death due to any cause. Patients without an event will be censored the last time they were known to be alive.

Secondary Outcome Measures

Progression-free survival
Time between randomization and radiographic progression based on RANO criteria or death due to any cause. Patients without an event will be censored at the date of last follow-up for progression.
Frequency of Adverse Events related to the treatment administered
Adverse events related to the treatment(s) administered will be recorded from screening until one month post adjuvant treatment. Adverse events will be assessed according to NCI CTCAE version 4.0 criteria.
Health Related Quality of Life (EORTC QLQ-C30)
All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.
Health Related Quality of Life (EORTC QLQ-BN20)
All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.
Cost effectiveness
Assessed by the incremental cost-effectiveness ratio (ICER), calculated as: Cost per life-year gained = (Difference in direct costs between biomarker-guided therapy and chemoradiotherapy) ÷ (Difference in life-years gained between biomarker-guided therapy and chemoradiotherapy). The direct unit costs of TMZ and associated laboratory testing, RT, and costs associated with any grade 3-4 adverse events (eg hospitalization) will be included.
Cognitive and mental function
Assessed by Montreal Cognitive Assessment (MoCA). This assessment was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. The total possible score is 30 points; a score of 26 or above is considered normal.

Full Information

First Posted
January 12, 2021
Last Updated
October 31, 2022
Sponsor
AHS Cancer Control Alberta
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1. Study Identification

Unique Protocol Identification Number
NCT04765514
Brief Title
Chemoradiotherapy Versus Biomarker-Guided Therapy for Elderly and Frail GBM Patients
Official Title
A Randomized Controlled Trial of Chemo-Radiotherapy Versus Biomarker-Guided Therapy for Elderly and Frail Patients With Newly Diagnosed Glioblastoma
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
July 27, 2022 (Actual)
Primary Completion Date
June 2032 (Anticipated)
Study Completion Date
June 2032 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AHS Cancer Control Alberta

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Currently, the optimal treatment regimen for elderly Glioblastoma (GBM) patients with poor performance status (PS) is unknown. Based on data for elderly GBM patients and the limited data for patients with poor PS, hypofractionated RT or a short course of Temozolomide (TMZ) may provide survival benefit without the added toxicity and inconvenience of a more protracted treatment regimen. In particular, treatment with RT or TMZ monotherapy on the basis of methylated O6 - methyl guanine - DNA methyltransferase (MGMT) promoter methylation status, followed by the alternative therapy at progression, may provide a safe and effective treatment regimen for patients with poor PS. The hypothesis of this trial is that in elderly GBM patients with poor performance status (age ≥ 65 years and KPS 50-70), a biomarker-guided approach to therapy results in non-inferior overall survival compared to combined TMZ/RT. Specifically, biomarker-guided therapy will consist of TMZ monotherapy for patients with a methylated MGMT promoter, and hypofractionated RT (40 Gy in 15 fractions) for patients with a non-methylated MGMT promoter. It is hypothesized that biomarker-guided therapy will result in non-inferior progression-free survival, reduced toxicity and increased cost-effectiveness compared to combined chemoradiotherapy. Primary objective: • To compare overall survival of standard vs biomarker-guided therapy in elderly and frail patients with newly diagnosed GBM. Secondary objective: To evaluate progression-free survival following treatment in both arms. To evaluate adverse events according to CTCAE criteria in both arms. To evaluate health-related quality-of-life as assessed by MoCA and EORTC QLQ-C30/QLQ-BN20 questionnaires in both arms. To evaluate cost-effectiveness of standard vs biomarker-guided therapy Methods: Patients will be randomized to two treatment groups in a 1:1 ratio. Standard Arm: TMZ with concurrent RT (combined modality arm) Patients will receive 15 days of TMZ daily with concurrent RT. TMZ will be delivered at a dose of 75 mg/m2, given daily with RT. TMZ will be administered 1 hour before each session of RT. After a 4-week break, patients will receive six cycles of adjuvant TMZ according to the standard 5-day schedule (days 1-5) every 28 days, up to 6 cycles as tolerated by the patient. The dose will be 150 mg/m2 for the first cycle and increased to 200 mg/m2 beginning with the second cycle, so long as there are no hematologic adverse events, intractable nausea or fatigue. Investigational Arm: Biomarker based treatment MGMT (+): TMZ monotherapy Patients will receive TMZ at a dose of 75 mg/m2 daily for 15 days on weekdays (Monday through Friday). This will be followed by six cycles of TMZ according to the standard 5-day schedule (days 1-5) every 28 days. The dose will be 150 mg/m2 for the first cycle and increased to 200 mg/m2 beginning with the second cycle, so long as there are no hematologic adverse events. Dose will be determined using the body surface area (BSA) calculation. MGMT methylation (-): No TMZ will be given. Participants will receive radiation treatment with 40Gy / 15 fractions over a period of 21 days (3 weeks). Upon treatment completion, participants will be followed by every 3 months for 2 years and every 6 months for years 3-5. Response and progression will be evaluated using the new international criteria proposed by the Response Assessment in Neuro-Oncology working group (RANO).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma Multiforme

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
121 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Standard Arm: TMZ with concurrent RT (combined modality arm)
Arm Type
Active Comparator
Arm Description
Patients will receive a total of 21 days of Temozolomide (TMZ), with 15 days of TMZ administered daily with concurrent RT. TMZ will be delivered at a dose of 75 mg/m2, given daily with RT for 15 days, one hour before each session of RT. After a 4-week break, patients will receive six cycles of adjuvant TMZ according to the standard 5-day schedule (days 1-5) every 28 days, up to 6 cycles as tolerated by the patient. The dose will be 150 mg/m2 for the first cycle and increased to 200 mg/m2 beginning with the second cycle, so long as there are no hematologic adverse events, intractable nausea or fatigue.
Arm Title
Biomarker based treatment
Arm Type
Experimental
Arm Description
MGMT (+) Temozolomide monotherapy: Patients will receive Temozolomide (TMZ) at a dose of 75 mg/m2 daily for 21 consecutive days. This will be followed by six cycles of TMZ according to the standard 5-day schedule (days 1-5) every 28 days. The dose will be 150 mg/m2 for the first cycle and increased to 200 mg/m2 beginning with the second cycle, so long as there are no hematologic adverse events. Dose will be determined using body surface area (BSA) calculation. MGMT methylation (-) RT monotherapy: Participants will receive radiation treatment with 40Gy / 15 fractions over a period of 21 days (3 weeks).
Intervention Type
Other
Intervention Name(s)
Biomarker based treatment (Temozolomide monotherapy or Radiotherapy monotherapy)
Intervention Description
Temozolomide or Radiotherapy
Intervention Type
Combination Product
Intervention Name(s)
Chemo-Radiotherapy consisting of 40 Gy in 15 daily fractions with concurrent temozolomide.
Intervention Description
Temozolomide will be administered at a dose of 75 mg/m2 daily for a total of 21 days. This will be followed by adjuvant temozolomide (150-200 mg/m2 daily for 5 day
Primary Outcome Measure Information:
Title
Overall survival
Description
Time between randomization and death due to any cause. Patients without an event will be censored the last time they were known to be alive.
Time Frame
Through study completion, an average of 2 years.
Secondary Outcome Measure Information:
Title
Progression-free survival
Description
Time between randomization and radiographic progression based on RANO criteria or death due to any cause. Patients without an event will be censored at the date of last follow-up for progression.
Time Frame
Median, 6-month, 1-year, and 2-year rates will be measured.
Title
Frequency of Adverse Events related to the treatment administered
Description
Adverse events related to the treatment(s) administered will be recorded from screening until one month post adjuvant treatment. Adverse events will be assessed according to NCI CTCAE version 4.0 criteria.
Time Frame
From screening until one month post adjuvant treatment.
Title
Health Related Quality of Life (EORTC QLQ-C30)
Description
All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.
Time Frame
Throughout study completion, up to 5 years.
Title
Health Related Quality of Life (EORTC QLQ-BN20)
Description
All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.
Time Frame
Throughout study completion, up to 5 years.
Title
Cost effectiveness
Description
Assessed by the incremental cost-effectiveness ratio (ICER), calculated as: Cost per life-year gained = (Difference in direct costs between biomarker-guided therapy and chemoradiotherapy) ÷ (Difference in life-years gained between biomarker-guided therapy and chemoradiotherapy). The direct unit costs of TMZ and associated laboratory testing, RT, and costs associated with any grade 3-4 adverse events (eg hospitalization) will be included.
Time Frame
Upon study completion, an average of 5 years
Title
Cognitive and mental function
Description
Assessed by Montreal Cognitive Assessment (MoCA). This assessment was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. The total possible score is 30 points; a score of 26 or above is considered normal.
Time Frame
Throughout study completion, up to 5 years.

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Newly-diagnosed, histologically proven, intracranial glioblastoma with maximal safe resection. Biopsy alone is expected if resection is not possible. MGMT promoter methylation status must be tested for all patients. History and physical examination, including neurological examination, within 14 days prior to randomization. Age ≥ 65 & KPS of 60 - 70 Stable or decreasing dose of corticosteroids for at least 14 days prior to randomization. Laboratory evaluation within 7 days prior to randomization, with adequate function as defined below: ANC ≥ 1.5 x 109/L Platelets ≥ 100 x 109/L Estimated Glomerular Filtration Rate (eGFR) > 59 Total serum bilirubin ≤ 30 umol/L (ie ≤ 1.5 times ULN) ALT < 150 U/L (ie < 3 times ULN) AST < 120 U/L (ie < 3 times ULN) Alkaline phosphatase < 390 U/L (ie < 3 times ULN) Patients must sign a study-specific informed consent prior to study registration. Patients of childbearing / reproductive potential should use highly effective birth control methods, as defined by the investigator, during the study treatment period and for a period of 6 months after the last dose of study drug. A highly effective method of birth control is defined as those that result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Note: abstinence is acceptable if this is established and preferred contraception for the patient and is accepted as a local standard. This will apply for male patients only and their female partner if of child bearing potential. Effective contraception should also be used by male patients taking temozolomide. Men being treated with temozolomide are advised not to father a child during or up to 6 months after discontinuation of treatment (male patients). Male patients should agree to not donate sperm during the study treatment and for six months post treatment completion. Exclusion Criteria: Recurrent malignant gliomas Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease free for ≥ 3 years. Prior head or neck RT (except for T1 glottic cancer), or systemic therapy precluding delivery of concurrent and adjuvant temozolomide Treatment with any other therapeutic clinical protocol within 30 days prior to study registration or during participation in the study. Severe, active co-morbidity, defined as follows: Unstable angina and/or congestive heart failure requiring hospitalization Transmural myocardial infarction within the last 6 months Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study registration Any severe, active co-morbidity precluding delivery of temozolomide. History of hypersensitivity reaction to temozolomide components or to dacarbazine. Active HBV infection
Facility Information:
Facility Name
Tom Baker Cancer Centre
City
Calgary
State/Province
Alberta
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gerald Lim, MD
Phone
1-403-521-3095
Email
Gerald.Lim@albertahealthservices.ca
First Name & Middle Initial & Last Name & Degree
Gerald Lim, MD
Facility Name
Cross Cancer Institute
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 1Z2
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Wilson Roa, MD, FRCPC
Phone
780-432-8783
Email
Wilson.Roa@ahs.ca
First Name & Middle Initial & Last Name & Degree
Wilson Roa, MSc, MD, FRCPC

12. IPD Sharing Statement

Plan to Share IPD
No

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Chemoradiotherapy Versus Biomarker-Guided Therapy for Elderly and Frail GBM Patients

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