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

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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	Unknown
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Observational
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

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:

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT06546631
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	University College Cork
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	N/A
Principal Investigator Affiliation	N/A
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	Ireland
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Glioma

Additional Details

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.

Arms & Interventions

Arms

: 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

Interventions

Contact a Trial Team

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