Pharmacokinetics of Venetoclax in Patients With Acute Myeloid Leukemia

Sponsor
National Taiwan University Hospital (Other)
Overall Status
Recruiting
CT.gov ID
NCT04613622
Collaborator
(none)
500
Enrollment
1
Location
65
Anticipated Duration (Months)
7.7
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or DiseaseIntervention/TreatmentPhase

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 Design

Study Type:
Observational
Anticipated Enrollment :
500 participants
Observational Model:
Cohort
Time Perspective:
Prospective
Official Title:
Pharmacokinetics of Venetoclax in Patients With Acute Myeloid Leukemia
Actual Study Start Date :
Aug 1, 2020
Anticipated Primary Completion Date :
Dec 31, 2025
Anticipated Study Completion Date :
Dec 31, 2025

Arms and Interventions

ArmIntervention/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.

Outcome Measures

Primary Outcome Measures

  1. Area under curve (AUC) of venetoclax in Chinese population [August 1, 2020 to December 31, 2025]

    Area under curve (AUC) will be calculated through multiple plasma concentrations drawn from the patients after taking venetoclax.

  2. Half-life (T1/2) of venetoclax in Chinese population [August 1, 2020 to December 31, 2025]

    Half-life (T1/2) will be calculated through multiple plasma concentrations drawn from the patients after taking venetoclax.

  3. Clearance (CL) of venetoclax in Chinese population [August 1, 2020 to December 31, 2025]

    Clearance (CL) will be calculated through multiple plasma concentrations drawn from the patients after taking venetoclax.

Secondary Outcome Measures

  1. Analysis of venetoclax plasma concentration with concomitant CYP enzyme inhibitors or inducers [August 1, 2020 to December 31, 2025]

    Concomitant CYP enzyme inhibitors or inducers of each patients will be recorded and analyzed its actual impact on venetoclax pharmacokinetic parameters.

  2. Association between venetoclax plasma concentration and therapeutic effectiveness, adverse events [August 1, 2020 to December 31, 2025]

    The relationship between venetoclax plasma concentration and its therapeutic effectiveness, adverse events will be investigated during continuous follow-ups this study.

  3. Establishment of venetoclax clinical dose adjustment [August 1, 2020 to December 31, 2025]

    Identify the concentration cut-off points of effectiveness and toxicity respectively, and validate these cut-off points externally in future clinical practice.

Eligibility Criteria

Criteria

Ages Eligible for Study:
20 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1National Taiwan University HospitalTaipeiTaiwan

Sponsors and Collaborators

  • National Taiwan University Hospital

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
National Taiwan University Hospital
ClinicalTrials.gov Identifier:
NCT04613622
Other Study ID Numbers:
  • 202007124RIND
First Posted:
Nov 3, 2020
Last Update Posted:
Oct 28, 2021
Last Verified:
Oct 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

No Results Posted as of Oct 28, 2021