Venetoclax and Sequential Busulfan, Cladribine, and Fludarabine Phosphate Before Donor Stem Cell Transplant in Treating Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Acute Myeloid Leukemia Clinical Trial

Official title:

Allogeneic Transplantation Using Venetoclax, Timed Sequential Busulfan,Cladribine, and Fludarabine Conditioning in Patients With AML and MDS

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02250937
• Other study ID #: 2014-0431
• Secondary ID: NCI-2014-0232420
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: October 27, 2014
• Est. completion date: October 31, 2025

Study information

• Verified date: April 2024
• Source: M.D. Anderson Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase II trial studies how well venetoclax and sequential busulfan, cladribine, and fludarabine phosphate before donor stem cell transplant work in treating patients with acute myelogenous leukemia or myelodysplastic syndrome. Giving chemotherapy before a donor peripheral blood stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. When the healthy stem cells from a donor are infused into a patient, they may help the patient's bone marrow make more healthy cells and platelets and may help destroy any remaining cancer cells.

Description:

PRIMARY OBJECTIVE:

I. To compare progression free survival of two schedules of venetoclax, timed sequential busulfan, cladribine and fludarabine conditioning regimen in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS).

SECONDARY OBJECTIVES:

I. Compare overall survival between the two schedules. II. Compare non relapse mortality between the two schedules. III. Compare neutrophil and platelet engraftment between the two schedules. IV. Compare acute and chronic graft-versus-host disease (GVHD) between the two schedules.

V. Compare cumulative incidence of relapse between the two schedules. VI. Compare grade III/IV toxicity between the two schedules.

TERTIARY OBJECTIVES:

I. To study chemotherapy resistance. II. To study deoxyribonucleic acid (DNA) damage. III. To study immune recovery and cytokines (both in plasma and cells). IV. To study BCL-2 family expression, stem cell surface markers and intracellular signaling markers in AML cells at the time of relapse.

OUTLINE:

PREPARATIVE REGIMEN: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive venetoclax orally (PO) once daily (QD) on days -22 to -3 and busulfan intravenously (IV) over 3 hours on days -13 and -12. Patients then receive fludarabine phosphate IV over 1 hour, cladribine IV over 2 hours, and busulfan IV over 3 hours on days -6 to -3.

ARM II: Patients receive venetoclax PO QD on days -22 to -3 and busulfan IV over 3 hours on days -20 and -13. Patients then receive fludarabine phosphate IV over 1 hour, cladribine IV over 2 hours, and busulfan IV over 3 hours on days -6 to -3.

TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant (PBSCT) on day 0.

After completion of study treatment, patients are followed up for 2.5 years.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 116
• Est. completion date: October 31, 2025
• Est. primary completion date: October 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 70 Years

Eligibility

Inclusion Criteria:

• Patients with biopsy-proven acute myeloid leukemia or myelodysplastic syndrome with persistent disease or in remission

• Human leukocyte antigen (HLA)-identical sibling or 8/8 matched unrelated donor transplant

• Patients age 18 to 70 years old; eligibility for pediatric patients will be determined in conjunction with an MD Anderson Cancer Center (MDACC) pediatrician; patients age 2-17 years may be enrolled after at least 10 adults (ages 18-70 years old) have been assessed for safety at day 30

• Direct bilirubin < 1 mg/dl

• Alanine aminotransferase (ALT) < 3 times upper limit of normal

• Creatinine clearance > 50 ml/min (calculated creatinine clearance is permitted)

• Forced expiratory volume in 1 second (FEV1) >= 50% of expected corrected for hemoglobin and/or volume

• Forced vital capacity (FVC) >= 50% of expected corrected for hemoglobin and/or volume

• Diffusing capacity of the lungs for carbon monoxide (DLCO) >= 50% of expected corrected for hemoglobin and/or volume

• Children unable to perform pulmonary function tests (e.g., less than 7 years old) pulse oximetry of >= 92% on room air

• Left ventricular ejection fraction (LVEF) >= 40%

• Patient, legally authorized representative (LAR), or parent able to sign informed consent; able to give assent for patients age 7-17

• Negative beta human chorionic gonadotropin (HCG) test in a woman with child bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization; women of child bearing potential must be willing to use an effective contraceptive measure while on study

• Performance score of >= 70 by Karnofsky/Lansky or performance status (PS) 0 or 1 (Eastern Cooperative Oncology Group [ECOG] =< 1)

Exclusion Criteria:

• Prior allogeneic or autologous transplantation

• Uncontrolled infections

• Human immunodeficiency virus (HIV) seropositivity

• Hematopoietic cell transplantation (HCT) co-morbidity index score > 3; the principal investigator is the final arbiter of eligibility for comorbidity score > 3

• Patients with prior coronary artery disease

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Procedure:
• Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic PBSCT

Drug:
• Busulfan
Given IV
• Cladribine
Given IV
• Fludarabine Phosphate
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Procedure:
• Peripheral Blood Stem Cell Transplantation
Undergo allogeneic PBSCT

Other:
• Pharmacological Study
Correlative studies

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
Primary	Progression free survival	The method of Kaplan and Meier will be used to estimate distribution of progression free survival.	At 6 months
Primary	Disease free survival (DFS)	Will test whether there is strong evidence that DFS differs between the two arms using a stratified log-rank test. Will use the Lan-DeMets alpha spending approach with an O'Brien-Fleming stopping boundary to compare the two arms.	Up to 2.5 years
Secondary	Incidence of toxicity of these regimens		Up to 2.5 years
Secondary	Cumulative incidence of acute graft versus host disease (GVHD)	Will use the method of Gooley et al to estimate the cumulative incidence of acute GVHD. Will use the method of Fine and Gary to fit regression models to the cumulative incidence outcomes.	Up to 2.5 years
Secondary	Cumulative incidence of chronic GVHD	Will use the method of Gooley et al to estimate the cumulative incidence of chronic GVHD. Will use the method of Fine and Gary to fit regression models to the cumulative incidence outcomes.	Up to 2.5 years
Secondary	Overall survival	The method of Kaplan and Meier will be used to estimate the distribution of overall survival. Cox proportional hazards regression analysis will be used to model the association between overall survival and covariates of interest.	Up to 2.5 years
Secondary	Time to neutrophil engraftment	The method of Kaplan and Meier will be used to estimate time to neutrophil engraftment.	Up to 2.5 years
Secondary	Time to platelet engraftment	The method of Kaplan and Meier will be used to estimate time to platelet engraftment.	Up to 2.5 years
Secondary	Cumulative incidence of relapse	Will use the method of Gooley et al to estimate the cumulative incidence of relapse. Will use the method of Fine and Gary to fit regression models to the cumulative incidence outcomes.	Up to 2.5 years
Secondary	Non-relapse mortality	Will use the method of Gooley et al to estimate the cumulative incidence of non-relapse mortality. Will use the method of Fine and Gary to fit regression models to the cumulative incidence outcomes. Logistic regression will be used to model the association between 100-day NRM and clinical and demographic covariates of interest.	Up to 2.5 years

External Links

•   MD Anderson Cancer Center