CYP3A4 Activity in Patients With Prostate Cancer Versus Male Patients With Other Solid Tumours

NCT05518799 | Completed

• 1 other identifier: N20CYM
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

The hepatic enzyme, cytochrome P450 3A4 (CYP3A4) is important for the metabolism of many drugs including taxanes. Previous reported studies reported a decreases in docetaxel exposure in prostate cancer patients compared to patients with other solid tumours. The difference was 1.8-fold for intravenous administration and 2.8-fold for oral administration. The underlying mechanism for these observations remains to be elucidated. The lower docetaxel exposure with IV and oral docetaxel treatment might be related to a higher CYP3A4 activity in prostate cancer patients. Therefore, it is important to directly compare the CYP3A4 activity with a phenotyping test in prostate cancer patients and patients with other types of solid tumours. This is an in vivo phenotyping studying using midazolam as a probe for CYP3A4 activity in patients with prostate cancer and patients with other solid tumours. The primary objective is the comparison of CYP3A4 activity in prostate cancer patients versus male patients with other types of solid tumours by use of an oral midazolam phenotyping test. Secondary objectives are: (1) measurement of plasma concentrations of midazolam and it's two primary metabolites (1'-hydroxy midazolam and 4'-hydroxy midazolam), (2) determination of the metabolite pharmacokinetics of midazolam. (3) retrospective assessment of single nucleotide polymorphisms of CYP3A4. The exploratory objective is to differentiate between gastro-intestinal and hepatic CYP3A4 activity with oral and intravenous administration of midazolam.

Conditions

Prostate Cancer; Solid Tumor, Adult

Keywords

midazolam; CYP3A4; pharmacokinetics; phenotyping

Outcome Measures

Primary Outcomes (1)

• CYP3A4

  Midazolam clearance is a generally accepted biomarker for CYP3A4 actiivty

  One study day

Secondary Outcomes (3)

• Measurement of plasma concentrations of midazolam, 1'-hydroxy midazolam and 4'-hydroxy midazolam

  through study completion, an average of 1 year

• Pharmacokinetics of midazolam, 1'-hydroxy midazolam, and 4'-hydroxymidazolam

  through study completion, an average of 1 year

• Single nucleotide polymorphisms in the genes encoding for CYP3A4

  through study completion, an average of 1 year

Other Outcomes (1)

• Differentiation between gastro-intestinal and hepatic CYP3A4 activity with oral and intravenous administration of midazolam.

  through study completion, an average of 1 year

Study Arms (2)

Patients with prostate cancer

OTHER

Drug: Midazolam

Male patients with other types of solid tumours

OTHER

Drug: Midazolam

Interventions

Midazolam DRUG

Patients will receive 2 mg midazolam orally on day 1 of the study and 1 mg midazolam intravenously on day 2 of the study.

Male patients with other types of solid tumours; Patients with prostate cancer

Eligibility Criteria

• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male patients receiving anticancer treatment or supportive care within our institute
• Group 1: histological or cytological proof of prostate cancer, for which the treatment leads to castrate levels of testosterone. Both metastatic as non-metastatic patients can be included. Both hormone-sensitive as castration-resistant patients can be included. Castrate levels of testosterone are defined as ≤ 50 ng/dL (or ≤ 0.50 ng/mL or 1.73 nmol/L)
• Group 2: men with histological or cytological proof of cancer. Both metastatic as non-metastatic patients can be included.
• Considered fit for midazolam treatment as assessed by the treating physician.
• Age ≥ 18 years.
• Able and willing to give written informed consent.
• Able and willing to undergo blood sampling for PK and pharmacogenetic analysis.
• Able and willing to comply with study restrictions and to remain at the study center for the required duration. The obligated duration is up to 8 hours after oral administration of midazolam on day 1. Day 2 has a duration of 8 hours after the intravenous administration of midazolam.
• Adequate organ system function as defined as:
• Absolute neutrophil count equal or greater than 1.5x 10\^9 /L
• Hemoglobin equal or greater to 6.0 mmol/L
• Platelets greater or equal to 100 x 10\^9 /L
• Total bilrubin equal or smaller than 1.5 x ULN
• AST and ALT equal or smaller than 2.5 x ULN
• Serum creatinine clearance equal or smaller of 1.5 x ULN or eGRF greater or equal to 40 mL/min determined by de MDRD-4.

You may not qualify if:

• Concomitant use of medication, herbs or food which could influence the pharmacokinetics of midazolam within 14 days or five half-lives of the drug (whichever is shorter) before start of the study, consisting of (but not limited to) CYP3A4-inhibitors/inducers. In particularly, bicalutamide and dexamethasone are not allowed within 14 days before start of the study. The use of enzalutamide is prohibited within 30 days before start of the study. The use of prednisolone is allowed before and during the study at a maximum daily dose of 10 mg.
• Current smokers or patients who stopped smoking within 7 days before study allocation

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead

Study Sites (1)

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital

Amsterdam, 1066CX, Netherlands

Location

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

Midazolam

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• F Opdam, MD, PhD

  Antoni van Leeuwenhoek/The Netherland Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 15, 2022
• First Posted: August 29, 2022
• Study Start: April 22, 2021
• Primary Completion: December 2, 2022
• Study Completion: December 2, 2022
• Last Updated: May 22, 2023

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)