A Study Investigating the Change in Metabolism Phenotype in Paediatric, Adolescent & Young Adults With Hodgkin or Non-Hodgkin Lymphoma.

Официальное название

A Prospective Feasibility Study Investigating PhEnoconversion of CYP3A4, CYP2C19 and CYP2D6 Genotype in Paediatric and Adolescent and Young Adult patientS With an acUte diagnosiS of Hodgkin or Non-Hodgkin Lymphoma.

Обзор

PEGASUS aims to test acceptability and feasibility of studying phenoconversion (the change in metabolism phenotype) using probe medications in a paediatric oncology patient population. The study will be conducted in patients (6-25 years of age) with Hodgkin lymphoma or non-Hodgkin lymphoma as exemplar cohort, but with the understanding that cancer-directed and supportive care medicines of the CYP3A4, CYP2C19, and CYP2D6 metabolic pathways are commonly utilised for the treatment of many paediatric, adolescent, young adult, and adult cancers. The study involves administration of the probe medication at timepoints which align with pre-determined hospital visits for the treatment of lymphoma and subsequent blood draws to measure the metabolism of the probe medications. The acceptability and feasibility of this study will inform future studies in phenoconversion within the paediatric cancer population to direct more personalised precision medicine.

Вмешательства

• Препарат Omeprazole
  Sub-therapeutic probe drug administration to measure phenoconversion.
• Препарат Dextromethorphan
  Sub-therapeutic probe drug administration to measure phenoconversion.

Первичные конечные точки

• Proportion of patients who consent to study and complete baseline and at least two longitudinal timepoints with successful measurement of probe drug MR (Metabolic ratio) [Срок оценки: 12 months, 24 Months]

Вторичные конечные точки (12)

• Percentage of participants completing all required longitudinal blood sampling [Срок оценки: Baseline through to 24 Months]
• Proportion of participants with successful detection of probe drug overall and at each sampling timepoint [Срок оценки: Baseline through to 24 Months]
• Proportion of participants where phenotype can be classified according to MR overall at each sampling timepoint [Срок оценки: Baseline through to 24 Months]
• The level of acceptability of participation in pharmacogenomic & phenoconversion testing using the PEGASUS specific survey tool (based on the Theoretical Framework of Acceptability [TFA]) [Срок оценки: Baseline through to 24 Months]
• Percentage of participants experiencing an adverse event (AE) during probe drug administration [Срок оценки: Baseline through to 24 Months]
• Incidence of genotype and phenotype mismatch, overall and across longitudinal timepoints [Срок оценки: Baseline through to 24 Months]
• Proportion of participants with disease staging and biomarkers of extent of disease [Срок оценки: Baseline through to 24 Months]
• Proportion of participants with a systemic inflammatory state [Срок оценки: Baseline through to 24 Months]
• Proportion of participants taking medications involving the CYP P450 pathway [Срок оценки: Baseline through to 24 Months]
• Participant demographic information [Срок оценки: Baseline]
• Proportion of participants with other environmental factors [Срок оценки: Baseline through to 24 Months]
• Longitudinal inflammatory profile of participants with Hodgkin or non-Hodgkin Lymphoma as measured by a panel including serum levels of procalcitonin, c-reactive protein and cytokine analysis. [Срок оценки: Baseline through to 24 Months]

Критерии участия

Критерии включения

• Age 6-25 years of age.
• New diagnosis of Hodgkin Lymphoma or Non-Hodgkin Lymphoma.
• Able to swallow and absorb oral or nasogastric tube (NGT) administration of probe drugs.
• Able to provide written informed consent.

Критерии исключения

• Failure to comply with inclusion criteria.
• Has a known previous allergy to any of the probe medications (i.e., omeprazole or dextromethorphan).
• Common Terminology Criteria for Adverse Events (CTCAE) Grade IV end organ dysfunction (i.e., hepatic, renal, gastrointestinal).
• Had previous oncological treatment (not first cancer diagnosis).
• Is a clinically unstable patient requiring intensive care admission in high-risk circumstances will not be considered eligible for consent.
• Any patient requiring urgent initiation of anti-cancer treatment outside hours where a member of the study staff is unable to approach the parent/guardian or participant for consent prior to commencing anti-cancer therapy will be ineligible for consent.
• Unable to provide written informed consent.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Одна группа

Маскирование

Открытое

Основная цель

Фундаментальное исследование

Центры проведения

Австралия · 1 центр

• Peter MacCallum Cancer Centre — Melbourne

Публикации

• Helsby N, Yong M, Burns K, Findlay M, Porter D. Cyclophosphamide bioactivation pharmacogenetics in breast cancer patients. Cancer Chemother Pharmacol. 2021 Sep;88(3):533-542. doi: 10.1007/s00280-021-04307-0. Epub 2021 Jun 10. PMID 34114066
• Burns KE, Goldthorpe MA, Porteus F, Browett P, Helsby NA. CYP2C19 genotype-phenotype discordance in patients with multiple myeloma leads to an acquired loss of drug-metabolising activity. Cancer Chemother Pharmacol. 2014 Mar;73(3):651-5. doi: 10.1007/s00280-014-2409-9. Epub 2014 Feb 12. PMID 24519754
• Kim S, Ostor AJ, Nisar MK. Interleukin-6 and cytochrome-P450, reason for concern? Rheumatol Int. 2012 Sep;32(9):2601-4. doi: 10.1007/s00296-012-2423-3. Epub 2012 Mar 27. PMID 22451032
• Rodieux F, Daali Y, Rollason V, Samer CF, Ing Lorenzini K. Practice of CYP450 genotyping and phenotyping in children in a real-life setting. Front Pharmacol. 2023 Feb 27;14:1130100. doi: 10.3389/fphar.2023.1130100. eCollection 2023. PMID 36937881
• Bosilkovska M, Samer CF, Deglon J, Rebsamen M, Staub C, Dayer P, Walder B, Desmeules JA, Daali Y. Geneva cocktail for cytochrome p450 and P-glycoprotein activity assessment using dried blood spots. Clin Pharmacol Ther. 2014 Sep;96(3):349-59. doi: 10.1038/clpt.2014.83. Epub 2014 Apr 10. PMID 24722393
• Lloret-Linares C, Rollason V, Lorenzini KI, Samer C, Daali Y, Gex-Fabry M, Aubry JM, Desmeules J, Besson M. Screening for genotypic and phenotypic variations in CYP450 activity in patients with therapeutic problems in a psychiatric setting, a retrospective study. Pharmacol Res. 2017 Apr;118:104-110. doi: 10.1016/j.phrs.2016.07.002. Epub 2016 Jul 1. PMID 27378571
• Rollason V, Lloret-Linares C, Lorenzini KI, Daali Y, Gex-Fabry M, Piguet V, Besson M, Samer C, Desmeules J. Evaluation of Phenotypic and Genotypic Variations of Drug Metabolising Enzymes and Transporters in Chronic Pain Patients Facing Adverse Drug Reactions or Non-Response to Analgesics: A Retrospective Study. J Pers Med. 2020 Oct 27;10(4):198. doi: 10.3390/jpm10040198. PMID 33121061
• Ing Lorenzini K, Desmeules J, Rollason V, Bertin S, Besson M, Daali Y, Samer CF. CYP450 Genotype-Phenotype Concordance Using the Geneva Micrococktail in a Clinical Setting. Front Pharmacol. 2021 Aug 26;12:730637. doi: 10.3389/fphar.2021.730637. eCollection 2021. PMID 34512355

Идентификаторы

NCT: NCT06383338 · PEGASUS 2023/ETH01954

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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