Pharmacokinetics of Venetoclax in Patients With Chronic Lymphocytic Leukemia

Venetoclax is a treatment for chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, the pharmacokinetic data in Chinese population, as well as the change of venetoclax plasma concentration while taking CYP enzyme inducers or inhibitors, remained unknown so far. Therefore, the aim of this study is to investigate the pharmacokinetic characteristics of venetoclax.

Study Overview

• Status: Recruiting
• Conditions: Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: Venetoclax

Detailed Description

Venetoclax has been approved for treatment of adult patients with chronic lymphocytic leukemia (CLL). Currently, there is not enough data of CLL populations from Chinese or other Asian regarding its efficacy or adverse reactions. In the phase 3 MURANO trial (NCT02005471), only 8 Asians (2.06%) were included, while other phase 1 or phase 2 studies did not show the percentage of Asian population. According to a venetoclax population pharmacokinetic study published in 2016, which integrated 505 subjects from 8 clinical trials, concluded that race was not a covariate that affect venetoclax PK. However, only 6 Asians (1.19%) were included, and some of the subjects were small lymphocytic lymphoma (SLL), non-Hodgkin's lymphoma (NHL) or healthy volunteers.

The pharmacokinetics of venetoclax is affected by many factors, and the most influential factors may be fat content from dietary and concomitant use of CYP3A inhibitors or inducers. In particular, patients with hematological malignancies often require antifungal agents (such as voriconazole, posaconazole) as prophylaxis or treatment of fungal infections during chemotherapy. Therefore, these two factors will be considered in this study.

The most common side effect after using venetoclax is neutropenia. About 60.8% of patients developed any grades neutropenia, 43.3% required dose interruption, 8.2% required dosage reduction, and 2.6% required permanent treatment discontinuation because of neutropenia in phase 3 MURANO trial. Recent studies have found that the probability of ≥ grade 3 neutropenia and infection seems to be inversely related to the blood concentration of venetoclax, that is, the higher the blood concentration of venetoclax, the lower the probability of neutropenia and infection.

This observational study is designed to examine the plasma concentration of venetoclax in patients with CLL or AML, to create a pharmacokinetic model of venetoclax in Chinese population, and to analyze the extent to which CYP enzyme inhibitors and inducers may have effect on venetoclax plasma concentration. Moreover, the association between therapeutic effectiveness, adverse events, and venetoclax plasma concentration will also be analyzed in this study, and the final purpose is to establish the principle of clinical dose adjustment in the future.

• Study Type: Observational
• Enrollment (Anticipated): 500

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan
    • Recruiting
    • National Taiwan University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Adult chronic lymphocytic leukemia patients (≥ 20 year-old) who have already initiated or are going to receive venetoclax treatment at National Taiwan University Hospital/National Taiwan University Cancer Center from August 2020 to December 2025.

Description

Inclusion Criteria:

• Adult patients (≥ 20 year-old) with diagnosis of chronic lymphocytic leukemia
• Patients who meet the above criteria and have already initiated or are going to receive venetoclax treatment at National Taiwan University Hospital/National Taiwan University Cancer Center from July 2020 to December 2025

Exclusion Criteria:

• Patients who are unable to cooperate with blood drawing
• Patients who have not submit the informed consent

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Venetoclax; Adult CLL patients (≥ 20 year-old) who have already initiated or are going to receive venetoclax treatment at National Taiwan University Hospital/National Taiwan University Cancer Center from July 2020 to December 2025.	Drug: Venetoclax; This prospective study will draw blood from every patient to measure the venetoclax blood concentration. After blood concentration analysis by ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS), the investigator will report the concentration to clinicians.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under curve (AUC) of venetoclax in Chinese population	Area under curve (AUC) will be calculated through multiple plasma concentrations drawn from the patients after taking venetoclax.	July 1, 2020 to December 31, 2025
Half-life (T1/2) of venetoclax in Chinese population	Half-life (T1/2) will be calculated through multiple plasma concentrations drawn from the patients after taking venetoclax.	July 1, 2020 to December 31, 2025
Clearance (CL) of venetoclax in Chinese population	Clearance (CL) will be calculated through multiple plasma concentrations drawn from the patients after taking venetoclax.	July 1, 2020 to December 31, 2025

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of venetoclax plasma concentration with concomitant CYP enzyme inhibitors or inducers	Concomitant CYP enzyme inhibitors or inducers of each patients will be recorded and analyzed its actual impact on venetoclax pharmacokinetic parameters.	July 1, 2020 to December 31, 2025
Association between venetoclax plasma concentration and therapeutic effectiveness, adverse events	The relationship between venetoclax plasma concentration and its therapeutic effectiveness, adverse events will be investigated during continuous follow-ups this study.	July 1, 2020 to December 31, 2025
Establishment of venetoclax clinical dose adjustment	Identify the concentration cut-off points of effectiveness and toxicity respectively, and validate these cut-off points externally in future clinical practice.	July 1, 2020 to December 31, 2025

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2020
• Primary Completion (Anticipated): December 31, 2025
• Study Completion (Anticipated): December 31, 2025

Study Registration Dates

• First Submitted: November 2, 2020
• First Submitted That Met QC Criteria: November 2, 2020
• First Posted (Actual): November 4, 2020

Study Record Updates

• Last Update Posted (Actual): October 28, 2021
• Last Update Submitted That Met QC Criteria: October 27, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Antineoplastic Agents; Venetoclax
• Other Study ID Numbers: 202006213RINC

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: Yes
• Studies a U.S. FDA-regulated device product: No