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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT03214562
Other study ID # 2016-0979
Secondary ID NCI-2018-0111920
Status Recruiting
Phase Phase 1/Phase 2
First received
Last updated
Start date September 26, 2017
Est. completion date September 30, 2025

Study information

Verified date May 2024
Source M.D. Anderson Cancer Center
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This phase Ib/II trial studies the best dose and side effects of venetoclax and how well it works when given with combination chemotherapy in treating patients with newly diagnosed acute myeloid leukemia or acute myeloid leukemia that has come back or does not respond to treatment. Venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine, cytarabine, filgrastim and idarubicin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax together with combination chemotherapy may work better in treating patients with acute myeloid leukemia.


Description:

PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability and to determine the dose-limiting toxicity and the maximum tolerated dose MTD of the combination of fludarabine, cytarabine, filgrastim (GCSF), idarubicin (FLAG-IDA) + venetoclax for patients with acute myeloid leukemia (AML) (Phase 1b). II. To determine the overall activity of this combination in patients newly diagnosed or relapsed/refractory (AML) (Phase 2). SECONDARY OBJECTIVES: I. Determine the preliminary assessment of efficacy by response to revised International Working Group (IWG) criteria and time to response variables including overall survival (OS), event-free survival (EFS) and duration of response (DOR). II. Determine biomarkers that may be predictive of venetoclax activity. OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study. INDUCTION THERAPY: Patients receive venetoclax orally (PO) on days 1-14, fludarabine intravenously (IV) over 30 minutes on days 2-6, cytarabine IV over 4 hours on days 2-6, idarubicin IV over 15-30 minutes on days 4 and 5, filgrastim subcutaneously (SC) on days 1-7, or pegfilgrastim SC after day 5. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY: Patients receive venetoclax PO on days 1-7, fludarabine IV over 30 minutes on days 2-4, cytarabine IV over 4 hours on days 2-4, filgrastim SC on days 1-7, or pegfilgrastim SC after days 3. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may also receive idarubicin as in Induction Therapy during 1 cycle of Consolidation Therapy per the treating physician. MAINTENANCE THERAPY: Patients receive venetoclax PO on days 1-28. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up within 30 days.


Recruitment information / eligibility

Status Recruiting
Enrollment 116
Est. completion date September 30, 2025
Est. primary completion date September 30, 2025
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: - Diagnosis of AML by World Health Organization (WHO) criteria. Patients with high risk myelodysplastic syndrome (MDS) as defined by the presence of >= 10% blasts are also eligible at the discretion of the principal investigator - Patients older than 65 who are deemed fit to receive intensive chemotherapy by the treating physician will be eligible after discussion with the principal investigator (PI). - Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 - Creatinine clearance >= 30 mL/min based on the Cockcroft-Gault equation - Total bilirubin < 1.5 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement - Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN unless considered due to leukemic involvement - Ability to understand and provide signed informed consent - Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug - Only patients who are relapsed, refractory, or intolerant of standard AML therapy will be eligible for Part 1 (minimum of 1 prior line of AML-directed therapy) Exclusion Criteria: - Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML) - Patients having received any prior BCL2 inhibitor therapy - Subject has known active central nervous system (CNS) involvement with AML - Patients with New York Heart Association (NYHA) class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 40% by echocardiogram or multi-gated acquisition (MUGA) scan - Patients with a history of myocardial infarction within the last 6 months or unstable / uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias - Patients with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C - Patients with known dysphagia, short-gut syndrome, or other conditions that would affect the ingestion or gastrointestinal absorption of drugs administered orally - Subject has any other significant medical or psychiatric history that in the opinion of the investigator would adversely affect participation in this study - Subject has a white blood cell count > 25 x 10{9}/L. (Note: hydroxyurea is permitted to meet this criterion) - Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception (a) appropriate method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide)

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Cytarabine
Given IV
Biological:
Filgrastim
Given SC
Drug:
Fludarabine
Given IV
Idarubicin
Given IV
Biological:
Pegfilgrastim
Given SC
Drug:
Venetoclax
Given PO

Locations

Country Name City State
United States M D Anderson Cancer Center Houston Texas

Sponsors (2)

Lead Sponsor Collaborator
M.D. Anderson Cancer Center National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Other Exploratory biomarkers Will be summarized graphically and with descriptive statistics. Peripheral blood and bone marrow aspirate samples will be obtained at study specified time points. Biomarker assays may include, but are not limited to, BH3 profiling and characterization of BCL-2 and related proteins, and assessment of the depth of response and monitoring of disease recurrence by assessment of minimal residual disease (MRD) in the bone marrow. Up to 6 years
Primary Overall response rate (ORR) Defined as complete response (CR) + CR with incomplete blood count recovery (CRi) + partial response (PR). Will be estimated along with the 95% credible interval. Up to 6 years
Primary CR/CRi rate Will be estimated along with the 95% credible interval. Up to 6 years
Primary Hematologic response Will be estimated along with the 95% credible interval. Up to 6 years
Primary Duration of response Defined as the number of days from the date of initial response (PR or better) to the date of first documented disease progression/relapse or death, whichever occurs first. Will be calculated for all patients. From the date of initial response, assessed up to 6 years
Primary Event-free survival Defined as the number of days from the date of treatment initiation (i.e., course 1 day 1) to the date of documented treatment failure, relapses from CR, or death from any cause, whichever occurs first. Will be calculated for all patients. Estimated using Kaplan-Meier method. Log-rank tests will be used to compare among subgroups of patients. From the date of treatment initiation, assessed up to 6 years
Primary Overall survival Estimated using Kaplan-Meier method. Log-rank tests will be used to compare among subgroups of patients. Up to 6 years
Primary Anti-tumor activity Will be summarized graphically and with descriptive statistics. Up to 6 years
Primary Pharmacodynamic markers Two samples t-test /Wilcoxon rank sum tests will be used to compare pharmacodynamics/pharmacokinetics (PD/PK) parameters between responder and non-responders, and logistic regression analysis will also be used to evaluate the association of PD/PK parameters with response. Up to 6 years
Primary Drug exposure levels Will be summarized graphically and with descriptive statistics. Up to 6 years
Primary Overall incidence and severity of all adverse events Graded using Common Toxicity Criteria version 4.0. Safety data will be summarized using frequency and percentage, by category and severity. Up to 6 years
Secondary Morphologic leukemia-free state Will be estimated along with the 95% credible interval. Up to 6 years
See also
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Completed NCT04146038 - Salsalate, Venetoclax, and Decitabine or Azacitidine for the Treatment of Acute Myeloid Leukemia or Advanced Myelodysplasia/Myeloproliferative Disease Phase 2
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Active, not recruiting NCT04207190 - Talazoparib and Gemtuzumab Ozogamicin for the Treatment of CD33 Positive Relapsed or Refractory Acute Myeloid Leukemia Phase 1
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Withdrawn NCT04493099 - Alvocidib in Combination With Decitabine and Venetoclax in Patients With Relapsed or Refractory AML or as Frontline Therapy in Unfit Patients With AML Phase 1/Phase 2
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