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

Hodgkin Lymphoma Clinical Trial

— PEGASUS  

Official title:

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.

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06383338
• Other study ID #: PEGASUS
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: May 2024
• Est. completion date: May 2026

Study information

• Verified date: April 2024
• Source: Murdoch Childrens Research Institute
• Contact: Ben Felmingham, BPharma
• Phone: +61393455522
• Email: ben.felmingham[@]mcri.edu.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 10
• Est. completion date: May 2026
• Est. primary completion date: May 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 25 Years

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Hodgkin Lymphoma
• Lymphoma
• Lymphoma, Non-Hodgkin
• Non Hodgkin Lymphoma

Intervention

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

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria

Sponsors (1)

Lead Sponsor	Collaborator
Murdoch Childrens Research Institute

Country where clinical trial is conducted

Australia, 

References & Publications (11)

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. — View Citation

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. — View Citation

Doerflinger M, Haeusler GM, Li-Wai-Suen CSN, Clark JE, Slavin M, Babl FE, Allaway Z, Mechinaud F, Smyth GK, De Abreu Lourenco R, Phillips B, Pellegrini M, Thursky KA. Procalcitonin and Interleukin-10 May Assist in Early Prediction of Bacteraemia in Children With Cancer and Febrile Neutropenia. Front Immunol. 2021 May 20;12:641879. doi: 10.3389/fimmu.2021.641879. eCollection 2021. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Lenoir C, Niederer A, Rollason V, Desmeules JA, Daali Y, Samer CF. Prediction of cytochromes P450 3A and 2C19 modulation by both inflammation and drug interactions using physiologically based pharmacokinetics. CPT Pharmacometrics Syst Pharmacol. 2022 Jan;11(1):30-43. doi: 10.1002/psp4.12730. Epub 2021 Nov 17. — View Citation

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. — View Citation

Mandrioli R, Mercolini L, Protti M. Blood and Plasma Volumetric Absorptive Microsampling (VAMS) Coupled to LC-MS/MS for the Forensic Assessment of Cocaine Consumption. Molecules. 2020 Feb 26;25(5):1046. doi: 10.3390/molecules25051046. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	This measure is to help inform whether future studies of this nature are feasible and identify if any procedures need to be adjusted to ensure study participant completion.	12 months, 24 Months
Secondary	Percentage of participants completing all required longitudinal blood sampling	This measure is to help inform whether future studies of this nature are feasible and identify if any procedures need to be adjusted to ensure study participant completion.	Baseline through to 24 Months
Secondary	Proportion of participants with successful detection of probe drug overall and at each sampling timepoint	This measure is to help inform whether future studies of this nature are feasible and identify if the method for probe drug detection requires improvement.	Baseline through to 24 Months
Secondary	Proportion of participants where phenotype can be classified according to MR overall at each sampling timepoint	This measure is to help inform whether future studies of this nature are feasible and identify if the phenotype can be clearly classified at each timepoint; (i) Prior to commencing first lymphoma chemotherapy cycle (ii) 2 months (week 8) (iii) 4 months (week 16) (iv) Completion of therapy (> week 16) (v) Up to a maximum of 2 febrile neutropenic episodes and for how many patients.	Baseline through to 24 Months
Secondary	The level of acceptability of participation in pharmacogenomic & phenoconversion testing using the PEGASUS specific survey tool (based on the Theoretical Framework of Acceptability [TFA])	This measure is to help inform whether future studies of this nature are feasible and acceptable. Participants will complete the survey which asks 26 questions, with a numerical scale of 1-7 or a wording scale of 7 choices depending on the question.	Baseline through to 24 Months
Secondary	Percentage of participants experiencing an adverse event (AE) during probe drug administration	This measure is to help inform whether future studies of this nature are feasible and identify if/how many adverse events are experienced during probe drug administration.	Baseline through to 24 Months
Secondary	Incidence of genotype and phenotype mismatch, overall and across longitudinal timepoints	This measure is to help inform whether future studies of this nature are feasible and identify if genotype and phenotype mismatch occurs throughout each timepoint and the overall study.	Baseline through to 24 Months
Secondary	Proportion of participants with disease staging and biomarkers of extent of disease	This measure is to help inform whether future studies of this nature are feasible, to identify any variables that stand out and inform future research questions.	Baseline through to 24 Months
Secondary	Proportion of participants with a systemic inflammatory state	This measure is to help inform whether future studies of this nature are feasible, to identify any variables that stand out and inform future research questions.	Baseline through to 24 Months
Secondary	Proportion of participants taking medications involving the CYP P450 pathway	This measure is to help inform whether future studies of this nature are feasible, to identify any variables that stand out and inform future research questions.	Baseline through to 24 Months
Secondary	Participant demographic information	This measure is to help inform whether future studies of this nature are feasible, to identify any variables that stand out and inform future research questions.	Baseline
Secondary	Proportion of participants with other environmental factors	This measure is to help inform whether future studies of this nature are feasible, to identify any variables that stand out and inform future research questions.	Baseline through to 24 Months
Secondary	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.	This measure is to identify if there are fluctuations within the inflammatory profile of the patients which helps to inform whether future studies of this nature are feasible. The panel detects a comprehensive set of studied and biologically relevant inflammatory markers including those shown to be predictive of severe infection in children with cancer and febrile neutropenia when out of normal ranges.	Baseline through to 24 Months