Pharmacokinetics of Venetoclax in Patients With Acute Myeloid 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: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Venetoclax

Detailed Description

Venetoclax has been approved in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. There are several clinical trials of Venetoclax for the treatment of AML. In trial M14-358 (NCT02203773), 91% of the combination of venetoclax and azacitidine were Caucasian, while about 87% of the the combination of Venetoclax and decitabine were Caucasian. In another trial M14-387 (NCT02287233), up to 94.9% of the combination of venetoclax and low-dose cytarabine group were Caucasian. However, the actual proportion of Asian or other races is unknown in both trials. Therefore, there is not enough data from Chinese other Asian races regarding its efficacy or adverse reactions in clinical trials.

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 most of the subjects were chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) or non-Hodgkin's lymphoma (NHL), and the results may not be directly generalized to AML patients. 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 cytopenia. About 40% of patients developed severe neutropenia, 4.7% required interruption of treatment, and 3.7% required dosage reduction in phase 2 clinical trials. Although no patient requires permanent venetoclax treatment discontinuation because of neutropenia, 9% of patients need to discontinue venetoclax treatment due to infection. The incidence of severe thrombocytopenia and anemia is 18% and 15%. Recent studies have found that the incidence of 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 incidence 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 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)
• 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 August 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?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Venetoclax; Adult 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.	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.	August 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.	August 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.	August 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.	August 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.	August 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.	August 1, 2020 to December 31, 2025

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 1, 2020
• Primary Completion (ANTICIPATED): December 31, 2025
• Study Completion (ANTICIPATED): December 31, 2025

Study Registration Dates

• First Submitted: October 23, 2020
• First Submitted That Met QC Criteria: October 30, 2020
• First Posted (ACTUAL): November 3, 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: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Antineoplastic Agents; Venetoclax
• Other Study ID Numbers: 202007124RIND

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