Pharmacogenomic and Circulating Biomarkers for CDK4/6 Inhibitors

NCT07100054 | Enrolling By Invitation

• 1 other identifier: P.CTP.1262
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this research study is to reduce adverse effects of anti-cancer medications known as kinase inhibitors, while preserving their therapeutic benefits. There have been major advances in the way cancers are treated. A class of drugs known as kinase inhibitors have proven to be highly effective for the treatment of cancers, including lung, kidney, gastrointestinal, and breast cancers. However, kinase inhibitor medications are well known for having unpredictable side effects. The body breaks down (metabolizes) medications such as kinase inhibitors using an enzyme known as cytochrome P450 3A4 (CYP3A4). CYP3A4 is the most important drug metabolizing enzyme in humans due to the fact that it is involved in the metabolism of nearly half of all prescribed medications and almost all of the currently prescribed kinase inhibitors. Among patients, there can be nearly 400 times difference in how efficiently CYP3A4 metabolizes drugs. Remarkably, very little is known about the role of genetic differences in CYP3A4 and a gene known as pregnane X receptor (PXR). PXR serves as a sensor for drugs in the body and helps to regulate how much CYP3A4 is made. Currently, there are no predictive biomarkers, whether in genes (genomic) or circulating in blood (endogenous) that could aid treating oncologists with regards predicting adverse effects or suboptimal response to this important class of anticancer drugs. The goal is to carry out DNA sequencing for genetic changes in CYP3A4 and PXR to assess differences in enzyme activity of not only common, but also rare genetic variants. CYP3A4 activity will be determined in participants blood samples based on break down products of the drug tamoxifen as well as cholesterol, the latter called 4β-hydroxycholesterol, both known to be influenced by the CYP3A4 enzyme. Since cholesterol is naturally made in the body, comparing blood cholesterol to 4β-hydroxycholesterol levels will be a biomarker of CYP3A4 metabolic activity that can be measured in anyone. Furthermore, circulating CYP3A4 messenger RNA from human blood will be measured as another independent marker of CYP3A4 gene expression. A model will be generated that includes these biomarkers of CYP3A4 expression and function, as well as genetic variation in CYP3A4 and PXR, that will aid in better identifying which patients may be at risk for loss of benefit or toxicity from kinase inhibitor therapy. This model will be evaluated in 100 breast cancer patients undergoing chemotherapy with kinase inhibitors, namely cyclin-dependent kinases CDK4 and CDK6 inhibitor (abemaciclib, ribociclib or palbociclib), as such kinase inhibitors are widely prescribed for breast cancer and are known to be broken down by CYP3A4.

Conditions

CDK4/6 Inhibitor; Breast Cancer; CYP3A4 Protein, Human; Drug Interaction; Pharmacogenetic Testing

Outcome Measures

Primary Outcomes (1)

• Predictive model for CDK4/6 inhibitor concentrations

  A linear mixed effect model will be applied using CDK4/6 inhibitor levels considering the following independent variables: sex, age, body surface area, height, weight, serum creatinine, drug dose, CYP3A4 and PXR genotype (any impaired-function SNV carrier vs. normal function SNV carrier status/wildtype as per in vitro analysis), CYP3A4 mRNA and 4β-hydroxycholesterol. The model that best describes the fit of CDK4/6 pharmacokinetics will be selected.

  From enrollment to 3 months

Secondary Outcomes (2)

• Patient reported outcomes

  From enrollment to 3 months

• Patient reported outcomes

  From enrollment to 3 months

Other Outcomes (1)

• Exploratory breast cancer outcomes

  From enrollment to 3 months

Interventions

Whole gene sequencing GENETIC

Whole gene sequencing of CYP3A4 and PXR

Drug-drug interaction analysis OTHER

Evaluating potential drug interactions with CYP3A4 inhibitors and inducers

Biomarker analysis OTHER

Determination of circulating CYP3A4 mRNA, and 4b-hydroxycholesterol

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

This observational cohort will consist of female adult cancer patients routinely seen at the London Regional Cancer Program for breast cancer chemotherapy. Patients must be starting or currently on the CDK4/6 inhibitors abemaciclib, ribociclib and palbociclib for the treatment of breast cancer.

You may qualify if:

• female
• breast cancer diagnosis
• over 18 years of age
• indication for a CDK4/6 inhibitor treatment
• proficient in English

You may not qualify if:

• None

Sponsors & Collaborators

• London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's: lead

Study Sites (1)

London Health Sciences Centre Research Institute

London, Ontario, Canada

Location

Biospecimen

Retention: SAMPLES WITH DNA

Blood will be collected at each in-person appointment for extraction of DNA (genotype) and plasma (drug level and biomarker analysis).

MeSH Terms

Conditions

Breast Neoplasms

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Pharmacologist

Study Record Dates

• First Submitted: July 8, 2025
• First Posted: August 1, 2025
• Study Start: October 10, 2025
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2028
• Last Updated: December 12, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)