Investigating Mechanistic Predictors of Interpatient Variability and Temozolomide (TMZ) Induced Haematological Toxicity for Glioma Patients (Improve TMZ)

A medication called temozolomide has been used for many years in the treatment of high-grade gliomas, which are tumours that originate in the brain. While this drug is the normal treatment for high-grade glioma, a number of patients develop a side-effect which results in low levels of some important blood cells, such as platelets or white blood cells. If this side-effect occurs, treatment with temozolomide may have to be stopped or paused, which may affect how well this treatment works.

At present, it is unknown why some patients develop this side effect and others do not. It is known that patients with a higher concentration of temozolomide in their blood are at an increased risk of developing this toxicity. There may be some factors associated with the movement of the drug in the body or the removal of the drug from the body which may affect the concentration of temozolomide in blood. There are many factors which may be involved, including genes, other medicines that are taken, how well kidneys and liver are working or even the microbiome (which is the bacteria in the gut).

This study is being done to find out what these factors could be. In the future, this may lead to medical care teams being able to predict which patients are at higher risk of side-effects, allowing them to implement measures to reduce the risk of this occurring.

Study Overview

• Status: Recruiting
• Conditions: Glioma

Detailed Description

Concurrent (with radiotherapy) and adjuvant temozolomide (TMZ) is the standard of care treatment for high grade glioma, however, severe haematological toxicity is a major dose limiting factor, impacting 16-45% of patients in different studies. The investigators hypothesize that mechanistic factors such as genetic polymorphisms, renal function or other patient factors such as sex, concomitant medications or the microbiome result in this interpatient variability in toxicity. This study aims to develop a pharmacokinetic model of temozolomide to test the effect of these potential covariates on TMZ concentration (Part A) in patients with brain tumours being treated with TMZ. Using this model, the investigators aim to assess patients who develop haematological toxicity from TMZ for mechanistic predictors of this toxicity (Part B).

The investigators hypothesise that the development of severe TMZ-induced haematological toxicity is due to higher exposure to temozolomide in plasma, driven by mechanistic factors, such as pharmacogenomic variants, the microbiome or demographic factors.

• Study Type: Observational
• Enrollment (Estimated): 55

Contacts and Locations

• Study Contact: Name: Jack Gleeson; Phone Number: 0214922603; Email: jgleeson@ucc.ie

Study Locations

• Ireland
  • Cork, Ireland
    • Recruiting
    • Cork University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Patients under the care of a medical oncologist attending a hospital clinic for the treatment of their high grade glioma

Description

Part A

Inclusion Criteria:

1. 18 years of age or over
2. Will receive or are currently receiving concurrent phase treatment with TMZ for high grade glioma (WHO Grade 3 or Grade 4 Astrocytoma, Oligodendroglioma or Glioblastoma).
3. Provision of informed consent to participate.

Exclusion Criteria:

a. Patients who, in opinion of supervising clinician, are clinically too unwell to provide informed consent or for whom additional blood samples, or other research samples, would not be indicated or appropriate.

Part B

Inclusion Criteria:

1. 18 years of age or over
2. Receiving or received treatment with TMZ for high grade glioma (WHO Grade 3 or Grade 4 Astrocytoma, Oligodendroglioma or Glioblastoma).
3. Developed any CTCAE Grade ≥3 Haematological Toxicity associated with Temozolomide, and/or any 1 of:

i. Platelet count <100 x 109/L ii. Neutrophil Count <1.0 x 109/L iii. Haemoglobin value <8.0 g/L iv. Omission of daily TMZ dose for ≥3 consecutive days during concurrent phase due to FBC concerns v. Deferral of subsequently due TMZ cycle by ≥7 days during adjuvant phase; vi. Dose reduction or permanent discontinuation of TMZ for reasons of haematological toxicity (as per treating physician discretion); vii. Use of growth factors, platelets or packed-cell transfusions during the course of TMZ.

d. Provision of informed consent to participate.

Exclusion criteria:

a. Patients who, in opinion of supervising clinician, are clinically too unwell to provide informed consent or for whom additional blood samples, or other research samples, would not be indicated or appropriate.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Temozolamide treatment; Patients who are being started on Temozolamide treatment for high-grade glioma. Patients will provide blood, saliva and stool samples.
Temozolamide toxicity; Patients who have developed dose-limiting haematological toxicity during treatment with TMZ for a high grade glioma. Patients will provide blood, saliva and stool samples

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine potential predisposing factors for severe haematological toxicity from temozolamide	Analysis of pharmacogenes	On study registration
Determine potential predisposing factors for severe haematological toxicity from temozolamide	Microbiome analysis of stool bacterial composition	Baseline and study completion, an average of 9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess duration of haematological toxicity from temozolamide	Duration measured in time (days/weeks).	Up to 12 months
Assess severity of haematological toxicity from temozolamide	Severity measured by Common Terminology Criteria for Adverse Events (CTCAE) Grade (grades range from 1-5, with higher grades indicating higher severity).	Up to 12 months
Assess the impact of haematological toxicity on patients	Number of blood transfusions required as a result of the haematological toxicity	Up to 12 months
Assess the impact of haematological toxicity on patients	Number of platelet transfusions required as a result of the haematological toxicity	Up to 12 months
Assess the impact of toxicity on patients distress tool scores	The European Organisation for Research and Treatment of Cancer (EoRTC) Quality of Life questionnaires for cancer patients (C-30, scores range from 30-126). Higher scores indicate lower quality of life.	On date of study registration
Assess the impact of toxicity on patients quality of life scores	The European Organisation for Research and Treatment of Cancer (EoRTC) Quality of Life questionnaires for cancer patients brain-specific module BN-20 (scores range from 20-80). Higher scores indicate lower quality of life.	On date of study registration
Assess the impact of toxicity on patients distress tool scores	The National Comprehensive Cancer Network distress thermometer (scores range from 0-10). Higher scores indicate more extreme distress.	On date of study registration
Overall survival	Overall survival	From date of study registration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months

Collaborators and Investigators

• Sponsor: University College Cork
• Collaborators: University Hospital Waterford

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2024
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: July 29, 2024
• First Submitted That Met QC Criteria: August 7, 2024
• First Posted (Actual): August 9, 2024

Study Record Updates

• Last Update Posted (Actual): March 4, 2026
• Last Update Submitted That Met QC Criteria: March 2, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma
• Other Study ID Numbers: 24010

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No