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

• ClinicalTrials.gov Identifier: NCT04765514
• Recruitment Status: Not yet recruiting
• First Posted: February 21, 2021
• Last Update Posted: August 20, 2021
• Sponsor: AHS Cancer Control Alberta
• Information provided by (Responsible Party): AHS Cancer Control Alberta

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 MMSE 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).

Condition or disease	Intervention/treatment	Phase
Glioblastoma Multiforme	Other: Biomarker based treatment (Temozolomide monotherapy or Radiotherapy monotherapy); Combination Product: Chemo-Radiotherapy consisting of 40 Gy in 15 daily fractions with concurrent temozolomide.	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 121 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Controlled Trial of Chemo-Radiotherapy Versus Biomarker-Guided Therapy for Elderly and Frail Patients With Newly Diagnosed Glioblastoma
• Estimated Study Start Date: December 2021
• Estimated Primary Completion Date: January 2031
• Estimated Study Completion Date: January 2031

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Standard Arm: TMZ with concurrent RT (combined modality arm); 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.	Combination Product: Chemo-Radiotherapy consisting of 40 Gy in 15 daily fractions with concurrent temozolomide.; 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
Experimental: Biomarker based treatment; 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).	Other: Biomarker based treatment (Temozolomide monotherapy or Radiotherapy monotherapy); Temozolomide or Radiotherapy

Outcome Measures

Primary Outcome Measures :

1. Overall survival [ Time Frame: Through study completion, an average of 2 years. ]
   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 :

1. Progression-free survival [ Time Frame: Median, 6-month, 1-year, and 2-year rates will be measured. ]
   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.
2. Frequency of Adverse Events related to the treatment administered [ Time Frame: From screening until one month post adjuvant treatment. ]
   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.
3. Health Related Quality of Life (EORTC QLQ-C30) [ Time Frame: Throughout study completion, up to 5 years. ]
   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.
4. Health Related Quality of Life (EORTC QLQ-BN20) [ Time Frame: Throughout study completion, up to 5 years. ]
   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.
5. Cost effectiveness [ Time Frame: Upon study completion, an average of 5 years ]
   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.
6. Cognitive and mental function [ Time Frame: Throughout study completion, up to 5 years. ]
   Assessed by Mini-mental status examination (MMSE). The test is divided in two sections: the first requires the patient to provide vocal responses only and tests orientation, memory and attention; the second part tests the patient's ability to name, follow verbal and written commands, write a sentence spontaneously and copy a complex polygon. The highest score that can be obtained is 30. A score of 24 or more indicates a normal cognition. Below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment.

Eligibility Criteria

• Ages Eligible for Study: 65 Years and older (Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

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. Serum creatinine ≤ 158 umol/L ( ie ≤ 1.5 times upper limit of normal (ULN ))
   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 one month 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

Contacts and Locations

Locations

Canada, Alberta

Cross Cancer Institute

Edmonton, Alberta, Canada, T6G 1Z2

Sponsors and Collaborators

AHS Cancer Control Alberta

More Information

• Responsible Party: AHS Cancer Control Alberta
• ClinicalTrials.gov Identifier: NCT04765514
• Other Study ID Numbers: IIT-0012
• First Posted: February 21, 2021
• Last Update Posted: August 20, 2021
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Temozolomide; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents