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

Phase 2 Portion

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

Secondary Objectives

To determine:

• Safety of this regimen as per NCI toxicity criteria
• Time to neutrophil and platelet engraftment
• Incidence of acute and chronic GVHD
• Relapse incidence
• Non-relapse mortality
• Overall survival
• Graft versus host disease-relapse free survival (GRFS)

Phase 3 Portion

Primary Objective

• To compare progression free survival between two arms Arm 1 Standard of Care: fludarabine + IV busulfan (FluBu) versus Arm 2 Experimental: Venetoclax + Fractionated busulfan, cladribine, and fludarabine

Secondary Objectives To compare following between two arms

• Safety of this regimen as per NCI toxicity criteria
• Time to neutrophil and platelet engraftment
• Incidence of acute and chronic GVHD
• Relapse incidence
• Non-relapse mortality
• Overall survival
• Graft versus host disease-relapse free survival (GRFS)

Inclusion criteria

Phase II

• Age ≥ 18 and ≤ 70 years. English and non-English speaking patients are eligible.
• Patients with acute myeloid leukemia who have previously received induction therapy and one of the following high-risk features:

• ELN17 adverse risk prognostic group irrespective of remission status (see Appendix 2)
• Measurable residual disease positive (MRD +)
• 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.
• AML secondary to MDS or MPD
• Therapy-related AML.
• Not in complete remission after one course of induction therapy

Or

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

• Poor or Very poor cytogenetic risk group as per IPSS-R
• Mutated P53 or Ras pathway genes (CBL, NRAS, KRAS, NF1, PTPN1) or DNMT 3a or ASXL1 or RUNX1
• Maximum IPSS-R >3.5 between diagnosis and the start of the preparative regimen.
• ≥ 5% BM blasts at transplant
• Therapy-related MDS
• HLA-identical sibling or a minimum of 7/8 matched unrelated donor, or a haploidentical related donor available
• Subject must voluntarily sign an informed consent
• Female subjects of childbearing potential must have negative results for pregnancy test
• 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)
• Subject 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

• Age ≥ 18 and ≤ 65 years. English and non-English speaking patients are eligible.
• Patients with acute myeloid leukemia who have previously received induction therapy and one of the following high-risk features:

• ELN22 adverse risk prognostic group irrespective of remission status (see Appendix
• Measurable residual disease positive (MRD +) including MRD + any time after induction therapy.
• 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.
• AML secondary to MDS or MPD
• Therapy-related AML.
• Not in complete remission after one course of induction therapy
• Second or higher complete remission

Or

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

• Poor or Very poor cytogenetic risk group as per IPSS-R
• 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
• Maximum IPSS-R >3.5 between diagnosis and the start of the preparative regimen.
• ≥ 5% BM blasts at transplant
• Therapy-related MDS

Or

Patients with CMML

• HLA-identical sibling or a minimum of 7/8 matched unrelated donor
• Subject must voluntarily sign an informed consent
• Female subjects of childbearing potential must have negative results for pregnancy test
• 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)
• Subject 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

• Subject is known to be positive for HIV.
• Subject has cognitive impairments and/or is a prisoner.
• Subject has acute promyelocytic leukemia
• Subject has known active CNS involvement with AML.
• Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

• Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
• Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects 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.
• Cardiac history of CHF requiring treatment or Ejection Fraction < 50% or unstable angina;
• Corrected DLCO < 50% or FEV1 <65%.
• 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
• Patients 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.
• Prior allogeneic stem cell transplantation.