Clinical Trials /

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

NCT02250937

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: 2014-0431
  • SECONDARY ID: NCI-2014-02324
  • SECONDARY ID: 2014-0431
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02250937

Conditions

  • Acute Myeloid Leukemia
  • Acute Myeloid Leukemia in Remission
  • Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Busulfan1, 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-19508Arm I (busulfan days -13 and -12 before PBSCT)
Cladribine2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251Arm I (busulfan days -13 and -12 before PBSCT)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Arm I (busulfan days -13 and -12 before PBSCT)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, VenclextaArm I (busulfan days -13 and -12 before PBSCT)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (busulfan days -13 and -12 before PBSCT)ExperimentalPREPARATIVE 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.
  • Busulfan
  • Cladribine
  • Fludarabine Phosphate
  • Venetoclax
Arm II (busulfan days -20 and -13 before PBSCT)ExperimentalPREPARATIVE 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.
  • Busulfan
  • Cladribine
  • Fludarabine Phosphate
  • Venetoclax

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
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival
Time Frame:At 6 months
Safety Issue:
Description:The method of Kaplan and Meier will be used to estimate distribution of progression free survival.

Secondary Outcome Measures

Measure:Incidence of toxicity of these regimens
Time Frame:Up to 2.5 years
Safety Issue:
Description:
Measure:Cumulative incidence of acute graft versus host disease (GVHD)
Time Frame:Up to 2.5 years
Safety Issue:
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.
Measure:Cumulative incidence of chronic GVHD
Time Frame:Up to 2.5 years
Safety Issue:
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.
Measure:Overall survival
Time Frame:Up to 2.5 years
Safety Issue:
Description: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.
Measure:Time to neutrophil engraftment
Time Frame:Up to 2.5 years
Safety Issue:
Description:The method of Kaplan and Meier will be used to estimate time to neutrophil engraftment.
Measure:Time to platelet engraftment
Time Frame:Up to 2.5 years
Safety Issue:
Description:The method of Kaplan and Meier will be used to estimate time to platelet engraftment.
Measure:Cumulative incidence of relapse
Time Frame:Up to 2.5 years
Safety Issue:
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.
Measure:Non-relapse mortality
Time Frame:Up to 2.5 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

December 27, 2019