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

Primary Purpose

Acute Myeloid Leukemia, Myelodysplastic Syndrome

Status

Active

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Allogeneic Hematopoietic Stem Cell Transplantation

Busulfan

Cladribine

Fludarabine Phosphate

Laboratory Biomarker Analysis

Peripheral Blood Stem Cell Transplantation

Pharmacological Study

Venetoclax

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia

Eligibility Criteria

2 Years - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

M D Anderson Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Arm I (busulfan days -13 and -12 before PBSCT)

Arm II (busulfan days -20 and -13 before PBSCT)

Arm Description

PREPARATIVE REGIMEN: Patients receive venetoclax PO QD on days -22 to -3 and busulfan 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. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0.

PREPARATIVE REGIMEN: 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 PBSCT on day 0.

Outcomes

Primary Outcome Measures

Progression free survival

The method of Kaplan and Meier will be used to estimate distribution of progression free survival.

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.

Secondary Outcome Measures

Incidence of toxicity of these regimens

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.

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.

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.

Time to neutrophil engraftment

The method of Kaplan and Meier will be used to estimate time to neutrophil engraftment.

Time to platelet engraftment

The method of Kaplan and Meier will be used to estimate time to platelet engraftment.

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.

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.

Full Information

NCT ID

NCT02250937

First Posted

September 24, 2014

Last Updated

September 11, 2023

Sponsor

M.D. Anderson Cancer Center

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT02250937

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

October 27, 2014 (Actual)

Primary Completion Date

October 31, 2025 (Anticipated)

Study Completion Date

October 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

M.D. Anderson Cancer Center

Collaborators

National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief 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.

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Myeloid Leukemia, Myelodysplastic Syndrome

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

116 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm I (busulfan days -13 and -12 before PBSCT)

Arm Type

Experimental

Arm Description

Arm Title

Arm II (busulfan days -20 and -13 before PBSCT)

Arm Type

Experimental

Arm Description

Intervention Type

Procedure

Intervention Name(s)

Allogeneic Hematopoietic Stem Cell Transplantation

Other Intervention Name(s)

Allogeneic, Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC, HSCT, Stem Cell Transplantation, Allogeneic

Intervention Description

Undergo allogeneic PBSCT

Intervention Type

Drug

Intervention Name(s)

Busulfan

Other Intervention Name(s)

1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Cladribine

Other Intervention Name(s)

2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Fludarabine Phosphate

Other Intervention Name(s)

2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586

Intervention Description

Given IV

Intervention Type

Other

Intervention Name(s)

Laboratory Biomarker Analysis

Intervention Description

Correlative studies

Intervention Type

Procedure

Intervention Name(s)

Peripheral Blood Stem Cell Transplantation

Other Intervention Name(s)

PBPC transplantation, PBSCT, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplant, Peripheral Stem Cell Transplantation

Intervention Description

Undergo allogeneic PBSCT

Intervention Type

Other

Intervention Name(s)

Pharmacological Study

Intervention Description

Correlative studies

Intervention Type

Drug

Intervention Name(s)

Venetoclax

Other Intervention Name(s)

ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Intervention Description

Given PO

Primary Outcome Measure Information:

Title

Progression free survival

Description

The method of Kaplan and Meier will be used to estimate distribution of progression free survival.

Time Frame

At 6 months

Title

Disease free survival (DFS)

Description

Time Frame

Up to 2.5 years

Secondary Outcome Measure Information:

Title

Incidence of toxicity of these regimens

Time Frame

Up to 2.5 years

Title

Cumulative incidence of acute graft versus host disease (GVHD)

Description

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.

Time Frame

Up to 2.5 years

Title

Cumulative incidence of chronic GVHD

Description

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.

Time Frame

Up to 2.5 years

Title

Overall survival

Description

Time Frame

Up to 2.5 years

Title

Time to neutrophil engraftment

Description

The method of Kaplan and Meier will be used to estimate time to neutrophil engraftment.

Time Frame

Up to 2.5 years

Title

Time to platelet engraftment

Description

The method of Kaplan and Meier will be used to estimate time to platelet engraftment.

Time Frame

Up to 2.5 years

Title

Cumulative incidence of relapse

Description

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.

Time Frame

Up to 2.5 years

Title

Non-relapse mortality

Description

Time Frame

Up to 2.5 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Uday R Popat

Organizational Affiliation

M.D. Anderson Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

M D Anderson Cancer Center

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

12. IPD Sharing Statement

Links:

URL

http://www.mdanderson.org

Description

MD Anderson Cancer Center

Learn more about this trial

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

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