Characteristics and Predictors of Liver Injury in Cyclin-dependent Kinase Inhibitors 4/6 (CDK4/6)-Treated Patients With Advanced Breast Cancer (ETIC)

April 11, 2024 updated by: Antonio Ciaccio, University of Milano Bicocca

Characteristics and Predictors of Chemotherapy-induced Liver Injury in Advanced Breast Cancer Patients Treated With Cyclin-dependent Kinase Inhibitors CDK4/6

The main objective of the study is to evaluate the presence of predictors (single characteristics at the baseline and / or a combination of two or more parameters) useful for predicting the development of Drug-Induced liver Injury (DILI) during treatment with cyclin-dependent kinase inhibitors (CKI) with the possibility of obtaining a pre-treatment prognostic score that can assist the clinician in pre-therapy decision making.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Drug Induced Liver Injury (DILI) is a rare liver disease that occurs as a reaction to exposure to drugs, herbal products and dietary supplements. Its onset is due to the interaction of several risk factors, associated with causative agent, host and environment. DILI is usually detected by an increase in liver enzymes with or without symptoms of liver disease1. It can occur with a variety of manifestations such as cholestasis, chronic hepatitis, steatosis, veno-occlusive disease and also neoplasm. According to last European Association for the Study of the Liver (EASL) guidelines, DILI should be suspected when one of the following thresholds is met, even in the absence of symptoms: alanine transferase (ALT) ≥ 5 times upper limit of normal (ULN), alkaline phosphatase (ALP) ≥ 2 ULN (particularly with accompanying elevations in concentrations of gamma-glutamyl transferase (GGT) in the absence of known bone pathology driving the rise in ALP level), total bilirubin concentration > 2 ULN associated with ALT ≥3 ULN. However, a stepwise clinical and laboratory approach is recommended to make the diagnosis of DILI.

The Roussel Uclaf Causality Assessment Method (RUCAM) scale has been demonstrated to be a valuable tool for assessing the possible causality of liver damage with the suspected drug. Liver biopsy should be performed only if discontinuation of the suspected culprit drug is not followed by improvement of liver damage after a reasonable observation period, or when autoimmune hepatitis (AIH) is suspected.

There are two types of DILI: the intrinsic direct form, which is dose-related and occurs early after agent exposure (hours or days), and the idiosyncratic indirect form, which is due to interactions between environment and host factors, and is not related to a threshold dose, with a longer latency period (a few days to several months). The incidence of this latter form is difficult to assess2 and is the one most observed during treatment with chemotherapy drugs.

There is mounting evidence of idiosyncratic DILI in patients with metastatic breast cancer (MBC) undergoing therapy with cyclin dependent kinases 4/6 (CDK4/6) inhibitors. Currently three CDK4/6 inhibitors have been approved for the treatment of MBC (palbociclib, ribociclib, and abemaciclib) and ribociclib has been reported to determine liver injury more frequently than the others.

Several randomized clinical trials have shown that these drugs improve both progression-free survival (PFS) and overall survival (OS) in Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) MBC with an acceptable toxicity profile. Recent reports have highlighted the distinct roles and occasional divergences between randomized controlled trials (RCTs) and population-based observational research, in general. The RCT rests on excellent internal validity, which is based on the randomization to ensure that the only difference between two treatment arms is their exposure to the treatment of interest. Given the differences between patients recruited to trials and those seen in routine practice, increased toxicity might be expected when the results of RCTs are applied to routine practice. Population-based studies can provide information about toxicity associated with treatment. With respect to the topic of our interest, although the incidence of adverse events seems comparable with that reported in RCTs, a higher incidence of treatment discontinuation with possible implications on treatment efficacy has been reported.

According to the experience of our Centre since the introduction of CDK4/6 inhibitors into clinical practice (unpublished data), toxicity of these drugs is apparently more frequent and severe than reported in previous publications, mainly registration trials, and, most importantly, produces a significant impact on the management of the treated patients, with a number of them needing temporary suspension, reintroduction at lower dose and even definitive withdrawal, without mention the burden of extra examinations prescribed and the concerns for the patient and her/his family. The weight of such treatment derailment on hard clinical outcomes has not been assessed yet, but it is certainly a potential cause of switching to less effective options.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
128

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Monza, Italy, 20900
        • University of Milano-Bicocca,

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Patients affected by advanced breast cancer who are treated with regimens that include a cyclin-dependent kinase inhibitor (CKI).

Description

Inclusion Criteria:

  • All patients with advanced breast cancer (Stage IV) consecutively evaluated at the Oncology Unit of our institution and who have received at least one dose of cyclin-dependent kinase inhibitors CDK4/6 (palbociclib, ribociclib, abemaciclib) since the European Union (EU) approval date (2016, 2017, 2018) and who have been followed-up for at least three months after the administration of the last dose of drug;
  • Subjects willing to participate at the study data collection and aged at least 18.

Exclusion Criteria:

  • Subjects with hepatocellular carcinoma (HCC).
  • Subjects with chronic active hepatitis of any cause AND/OR cirrhosis.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Incidence of DILI
Time Frame: 12 months
Incidence of liver toxicity emerging on treatment, and defined according to EASL definition of drug-induced liver injury (DILI)
12 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
withdrawal of therapy
Time Frame: 12 months
Proportion of patients who had to stop antineoplastic therapy due to liver injury of any grade.
12 months
delayed reprise of antineoplastic therapy
Time Frame: 12 months
Time interval of therapy missed for liver toxicity issues, in days
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Milano Bicocca

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 1, 2022

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 1, 2022

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 20, 2022

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 11, 2024

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 16, 2024

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 16, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 11, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • ETIC

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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