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

Study Overview
=================
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 cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding venetoclax to the current standard of care stem cell transplant regimen of busulfan, fludarabine, and cladribine may help to control high-risk acute myeloid leukemia or myelodysplastic syndrome.

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: 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 1) 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)

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

Conditions
-----------------
Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
-----------------
* Drug: Busulfan
* Drug: Cladribine
* Drug: Fludarabine Phosphate
* Procedure: Hematopoietic Cell Transplantation
* Drug: Thiotepa
* Drug: Venetoclax


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Phase II Age ≥ 18 and ≤ 70 years. English and non-English speaking participants are eligible. Participants 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 Participants 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 Participants must voluntarily sign an informed consent Female participants 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) 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 Age ≥ 18 and ≤ 65 years. English and non-English speaking participants are eligible. Participants 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 Participants 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 8/8 matched unrelated donor Participants must voluntarily sign an informed consent Female participants 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) 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: Participants is known to be positive for HIV. Participants has cognitive impairments and/or is a prisoner. Participants has acute promyelocytic leukemia Participants 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: 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. Cardiac history of CHF requiring treatment or Ejection Fraction < 50% or unstable angina; Corrected DLCO < 65% 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 Prior gemtuzumab ozogamicin and/or inotuzumab ozogamicin use 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (venetoclax, busulfan, fludarabine, cladribine)<br>Patients 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. | Drug: Busulfan<br>* Given IV<br>* Other names: WR-19508;Drug: Cladribine<br>* Given IV<br>* Other names: RWJ-26251;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Procedure: Hematopoietic Cell Transplantation<br>* Undergo stem cell transplantation<br>* Other names: stem cell transplantation;Drug: Thiotepa<br>* Given IV<br>* Other names: WR 45312;Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1-year progression free survival (PFS) | 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. | At 1 year post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | OS will be calculated from the time of transplant by the method of Kaplan and Meier. | Up to 3 years post-transplant | 
| Graft-versus (vs.)-host disease-free, relapse-free survival (GRFS) | GRFS will be calculated from the time of transplant by the method of Kaplan and Meier. | Up to 3 years post-transplant | 
| Time to platelet engraftment | The time to platelet engraftment will be calculated from the time of transplant and estimated by the Kaplan-Meier method. | From the time of transplant up to 3 years | 
| Time to neutrophil engraftment | The time to neutrophil engraftment will be calculated from the time of transplant and estimated by the Kaplan-Meier method. | From the time of transplant up to 3 years | 
| Incidence of acute and chronic graft-vs.-host disease (GvHD) | 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. | Up to 3 years post-transplant | 
| Incidence of relapse and non-relapse mortality | The cumulative incidence of non-relapse mortality and relapse will also be assessed in a competing risks framework, with similar analyses performed. | Up to 3 years post-transplant | 
| Incidence of adverse events | 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. | Up to 3 years post-transplant |