Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS

Registration Number
NCT04708054
Lead Sponsor
M.D. Anderson Cancer Center
Brief Summary

This phase II trial studies the effect of venetoclax together with busulfan, cladribine, and fludarabine in treating patients with high-risk acute myeloid leukemia or myelodysplastic syndrome who are undergoing stem cell transplant. Chemotherapy drugs, such as venetoclax, busulfan, cladribine, and fludarabine, work in different ways to stop the growth of can...

Detailed Description

Phase 2 Portion

Primary Objective 1) To obtain preliminary evidence of efficacy as defined by 1-year progression free survival.

Secondary Objectives

To determine:

1. Safety of this regimen as per NCI toxicity criteria

2. Time to neutrophil and platelet engraftment

3. Incidence of acute and chronic GVHD

4. Relapse incidence

5. Non-relapse mortality
...

Recruitment & Eligibility

Status
RECRUITING
Sex
All
Target Recruitment
324
Inclusion Criteria

Phase II

  1. Age ≥ 18 and ≤ 70 years. English and non-English speaking participants are eligible.

  2. Participants with acute myeloid leukemia who have previously received induction therapy and one of the following high-risk features:

    1. ELN17 adverse risk prognostic group irrespective of remission status (see Appendix 2).
    2. Measurable residual disease positive (MRD +)
    3. Not in complete remission including complete remission without count recovery (Cri) and/or morphologic leukemia free state (MLFS), primary refractory, or relapsed disease. See Appendix 3 for details.
    4. AML secondary to MDS or MPD
    5. Therapy-related AML.
    6. Not in complete remission after one course of induction therapy Or

    Participants with myelodysplastic syndrome or CMML and one of the following high-risk features:

    1. Poor or Very poor cytogenetic risk group as per IPSS-R
    2. Mutated P53 or Ras pathway genes (CBL, NRAS, KRAS, NF1, PTPN1) or DNMT 3a or ASXL1 or RUNX1
    3. Maximum IPSS-R >3.5 between diagnosis and the start of the preparative regimen.
    4. ≥ 5% BM blasts at transplant
    5. Therapy-related MDS

  3. HLA-identical sibling or a minimum of 7/8 matched unrelated donor, or a haploidentical related donor available

  4. Participants must voluntarily sign an informed consent

  5. Female participants of childbearing potential must have negative results for pregnancy test

  6. Adequate hepatic and renal function per local laboratory reference range as follows:

    • Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0X ULN
    • Bilirubin <1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
    • Participants must have adequate renal function as demonstrated by a creatinine clearance ≥ 50 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection.

Phase III

  1. Age ≥ 18 and ≤ 65 years. English and non-English speaking participants are eligible.

  2. Participants with acute myeloid leukemia who have previously received induction therapy and one of the following high-risk features:

    1. ELN22 adverse risk prognostic group irrespective of remission status (see Appendix 3).
    2. Measurable residual disease positive (MRD +)
    3. Not in complete remission including complete remission without count recovery (Cri) and/or morphologic leukemia free state (MLFS), primary refractory, or relapsed disease. See Appendix 4 for details.
    4. AML secondary to MDS or MPD
    5. Therapy-related AML.
    6. Not in complete remission after one course of induction therapy
    7. Second or higher complete remission Or

    Patients with myelodysplastic syndrome and one of the following high-risk features:

    1. Poor or Very poor cytogenetic risk group as per IPSS-R
    2. Mutated P53 or Ras pathway genes (CBL, NRAS, KRAS, NF1, PTPN11) or ASXL1 or RUNX1 or moderate high, or high, or very high-risk group as per IPSS-M
    3. Maximum IPSS-R >3.5 between diagnosis and the start of the preparative regimen.
    4. ≥ 5% BM blasts at transplant
    5. Therapy-related MDS Or Patients with CMML

  3. HLA-identical sibling or a minimum of 7/8 matched unrelated donor

  4. Participants must voluntarily sign an informed consent

  5. Female participants of childbearing potential must have negative results for pregnancy test

  6. Adequate hepatic and renal function per local laboratory reference range as follows:

    • Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0X ULN
    • Bilirubin <1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
    • Participants must have adequate renal function as demonstrated by a creatinine clearance ≥ 50 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection.

Exclusion criteria:

  1. Participants is known to be positive for HIV.

  2. Participants has cognitive impairments and/or is a prisoner.

  3. Participants has acute promyelocytic leukemia

  4. Participants has known active CNS involvement with AML.

  5. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

    1. Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
    2. Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: participants with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate.

  6. Cardiac history of CHF requiring treatment or Ejection Fraction < 50% or unstable angina;

  7. Corrected DLCO < 50% or FEV1 < 65%;

  8. Administration or consumption of any of the following within 3 days prior to the first dose of study drug:

    • grapefruit or grapefruit products
    • Seville oranges (including marmalade containing Seville oranges)
    • star fruit

  9. Participants with cognitive impairments and/or any serious unstable pre-existing medical condition or psychiatric disorder that can interfere with safety or with obtaining informed consent or compliance with study procedures.

  10. Prior allogeneic stem cell transplantation.

Read More
Exclusion Criteria

Not provided

Read More

Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
Treatment (venetoclax, busulfan, fludarabine, cladribine)Hematopoietic Cell TransplantationPatients receive venetoclax PO QD on days -22 to -3, busulfan IV over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0.
Treatment (venetoclax, busulfan, fludarabine, cladribine)Fludarabine PhosphatePatients receive venetoclax PO QD on days -22 to -3, busulfan IV over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0.
Treatment (venetoclax, busulfan, fludarabine, cladribine)BusulfanPatients receive venetoclax PO QD on days -22 to -3, busulfan IV over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0.
Treatment (venetoclax, busulfan, fludarabine, cladribine)CladribinePatients receive venetoclax PO QD on days -22 to -3, busulfan IV over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0.
Treatment (venetoclax, busulfan, fludarabine, cladribine)ThiotepaPatients receive venetoclax PO QD on days -22 to -3, busulfan IV over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0.
Treatment (venetoclax, busulfan, fludarabine, cladribine)VenetoclaxPatients receive venetoclax PO QD on days -22 to -3, busulfan IV over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0.
Primary Outcome Measures
NameTimeMethod
1-year progression free survival (PFS)At 1 year post-transplant

The proportion of patients who are alive without disease relapse (PFS) at one year will be reported along with the corresponding 95% credible interval. Cox proportional hazards regression will be used to assess the association between PFS and clinical and treatment covariates of interest.

Secondary Outcome Measures
NameTimeMethod
Overall survival (OS)Up to 3 years post-transplant

OS will be calculated from the time of transplant by the method of Kaplan and Meier.

Graft-versus (vs.)-host disease-free, relapse-free survival (GRFS)Up to 3 years post-transplant

GRFS will be calculated from the time of transplant by the method of Kaplan and Meier.

Incidence of acute and chronic graft-vs.-host disease (GvHD)Up to 3 years post-transplant

The cumulative incidence of acute and chronic GvHD with the competing risks of relapse and death will be estimated using the method of Gooley, and the method of Fine and Gray will be used to model the association between both parameters and clinical and treatment characteristics of interest.

Incidence of relapse and non-relapse mortalityUp to 3 years post-transplant

The cumulative incidence of non-relapse mortality and relapse will also be assessed in a competing risks framework, with similar analyses performed.

Time to platelet engraftmentFrom the time of transplant up to 3 years

The time to platelet engraftment will be calculated from the time of transplant and estimated by the Kaplan-Meier method.

Incidence of adverse eventsUp to 3 years post-transplant

Descriptive statistics will be used to summarize adverse events. The number and proportion of subjects with treatment emergent adverse events will be reported. All other safety parameters will be summarized using descriptive statistics or frequency counts. Graphical summaries will be used where appropriate.

Time to neutrophil engraftmentFrom the time of transplant up to 3 years

The time to neutrophil engraftment will be calculated from the time of transplant and estimated by the Kaplan-Meier method.

Trial Locations

Locations (1)

M D Anderson Cancer Center

🇺🇸

Houston, Texas, United States

© Copyright 2024. All Rights Reserved by MedPath
HomeTerms & ConditionsPrivacy Policy