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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

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ClinicalTrials.gov Identifier: NCT02250937
Recruitment Status : Recruiting
First Posted : September 26, 2014
Last Update Posted : May 31, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

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 stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Acute Myeloid Leukemia in Remission Myelodysplastic Syndrome Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Busulfan Drug: Cladribine Drug: Fludarabine Phosphate Other: Laboratory Biomarker Analysis Procedure: Peripheral Blood Stem Cell Transplantation Other: Pharmacological Study Drug: Venetoclax Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 116 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Allogeneic Transplantation Using Venetoclax, Timed Sequential Busulfan,Cladribine, and Fludarabine Conditioning in Patients With AML and MDS
Actual Study Start Date : October 27, 2014
Estimated Primary Completion Date : October 1, 2019
Estimated Study Completion Date : October 1, 2020


Arm Intervention/treatment
Experimental: Arm I (busulfan days -13 and -12 before PBSCT)

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.

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic PBSCT
Other Names:
  • Allogeneic Hematopoietic Cell Transplantation
  • Allogeneic Stem Cell Transplantation
  • HSC
  • HSCT

Drug: Busulfan
Given IV
Other Names:
  • 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

Drug: Cladribine
Given IV
Other Names:
  • 2-CdA
  • 2CDA
  • CdA
  • Cladribina
  • Leustat
  • Leustatin
  • Leustatine
  • RWJ-26251

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586

Other: Laboratory Biomarker Analysis
Correlative studies

Procedure: Peripheral Blood Stem Cell Transplantation
Undergo allogeneic PBSCT
Other Names:
  • PBPC transplantation
  • PBSCT
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplant
  • Peripheral Stem Cell Transplantation

Other: Pharmacological Study
Correlative studies

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta

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

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.

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic PBSCT
Other Names:
  • Allogeneic Hematopoietic Cell Transplantation
  • Allogeneic Stem Cell Transplantation
  • HSC
  • HSCT

Drug: Busulfan
Given IV
Other Names:
  • 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

Drug: Cladribine
Given IV
Other Names:
  • 2-CdA
  • 2CDA
  • CdA
  • Cladribina
  • Leustat
  • Leustatin
  • Leustatine
  • RWJ-26251

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586

Other: Laboratory Biomarker Analysis
Correlative studies

Procedure: Peripheral Blood Stem Cell Transplantation
Undergo allogeneic PBSCT
Other Names:
  • PBPC transplantation
  • PBSCT
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplant
  • Peripheral Stem Cell Transplantation

Other: Pharmacological Study
Correlative studies

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta




Primary Outcome Measures :
  1. Progression free survival [ Time Frame: At 6 months ]
    The method of Kaplan and Meier will be used to estimate distribution of progression free survival.

  2. Disease free survival (DFS) [ Time Frame: Up to 2.5 years ]
    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 :
  1. Incidence of toxicity of these regimens [ Time Frame: Up to 2.5 years ]
  2. Cumulative incidence of acute graft versus host disease (GVHD) [ Time Frame: Up to 2.5 years ]
    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.

  3. Cumulative incidence of chronic GVHD [ Time Frame: Up to 2.5 years ]
    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.

  4. Overall survival [ Time Frame: Up to 2.5 years ]
    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.

  5. Time to neutrophil engraftment [ Time Frame: Up to 2.5 years ]
    The method of Kaplan and Meier will be used to estimate time to neutrophil engraftment.

  6. Time to platelet engraftment [ Time Frame: Up to 2.5 years ]
    The method of Kaplan and Meier will be used to estimate time to platelet engraftment.

  7. Cumulative incidence of relapse [ Time Frame: Up to 2.5 years ]
    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.

  8. Non-relapse mortality [ Time Frame: Up to 2.5 years ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   2 Years to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02250937


Contacts
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Contact: Uday Popat, MD 713-792-8750 upopat@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Uday R. Popat    713-792-8750      
Principal Investigator: Uday R. Popat         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Uday R Popat M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02250937     History of Changes
Other Study ID Numbers: 2014-0431
NCI-2014-02324 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2014-0431 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: September 26, 2014    Key Record Dates
Last Update Posted: May 31, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Bone Marrow Diseases
Venetoclax
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Hematologic Diseases
Precancerous Conditions
Vidarabine
Fludarabine
Fludarabine phosphate
Busulfan
Cladribine
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents
Alkylating Agents
Antineoplastic Agents, Alkylating