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

Primary Purpose

Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Busulfan
Cladribine
Fludarabine Phosphate
Hematopoietic Cell Transplantation
Thiotepa
Venetoclax
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age ≥ 18 and ≤ 70 years
  2. Patients 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.

    Or

    Patients 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
  3. HLA-identical sibling or a minimum of 7/8 matched unrelated donor, or a haploidentical related donor available
  4. Subject must voluntarily sign an informed consent
  5. Female subjects 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)
    • 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:

  1. Subject is known to be positive for HIV.
  2. Subject has cognitive impairments and/or is a prisoner.
  3. Subject has acute promyelocytic leukemia
  4. Subject has known active CNS involvement with AML.
  5. 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
  6. Cardiac history of CHF requiring treatment or Ejection Fraction < 50% or unstable angina;
  7. Corrected DLCO < 65% 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. Prior gemtuzumab ozogamicin and/or inotuzumab ozogamicin use

Sites / Locations

  • M D Anderson Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (venetoclax, busulfan, fludarabine, cladribine)

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Overall survival (OS)
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)
GRFS will be calculated from the time of transplant by the method of Kaplan and Meier.
Time to platelet engraftment
The time to platelet engraftment will be calculated from the time of transplant and estimated by the Kaplan-Meier method.
Time to neutrophil engraftment
The time to neutrophil engraftment will be calculated from the time of transplant and estimated by the Kaplan-Meier method.
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.
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.
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.

Full Information

First Posted
January 12, 2021
Last Updated
May 9, 2023
Sponsor
M.D. Anderson Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT04708054
Brief Title
Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS
Official Title
Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 21, 2021 (Actual)
Primary Completion Date
December 31, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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
PRIMARY OBJECTIVE: I. To obtain preliminary evidence of efficacy as defined by 1-year progression free survival. SECONDARY OBJECTIVES: I.To determine safety of this regimen as per National Cancer Institute (NCI) toxicity criteria. II.To determine time to neutrophil and platelet engraftment. III.To determine incidence of acute and chronic graft versus host disease (GVHD). IV.To determine relapse incidence. V.To determine non-relapse mortality. VI.To determine overall survival. VII.To determine graft versus host disease-relapse free survival (GRFS). OUTLINE: Patients receive venetoclax orally (PO) once daily (QD) on days -22 to -3, busulfan intravenously (IV) over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate (fludarabine) 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. After completion of study treatment, patients are followed up at 7 days, at engraftment, at 1, 3, 6, and 12 months, then annually for up to 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (venetoclax, busulfan, fludarabine, cladribine)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Cladribine
Other Intervention Name(s)
2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
Hematopoietic Cell Transplantation
Other Intervention Name(s)
HCT, Hematopoietic Stem Cell Transplantation, HSCT, Stem Cell Transplant, stem cell transplantation
Intervention Description
Undergo stem cell transplantation
Intervention Type
Drug
Intervention Name(s)
Thiotepa
Other Intervention Name(s)
1,1'',1''''-Phosphinothioylidynetrisaziridine, Girostan, N,N'', N''''-Triethylenethiophosphoramide, Oncotiotepa, STEPA, Tepadina, TESPA, Tespamin, Tespamine, Thio-Tepa, Thiofosfamide, Thiofozil, Thiophosphamide, Thiophosphoramide, Thiotef, Tifosyl, TIO TEF, Tio-tef, Triethylene Thiophosphoramide, Triethylenethiophosphoramide, Tris(1-aziridinyl)phosphine sulfide, TSPA, WR 45312
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Other Intervention Name(s)
ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
1-year progression free survival (PFS)
Description
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.
Time Frame
At 1 year post-transplant
Secondary Outcome Measure Information:
Title
Overall survival (OS)
Description
OS will be calculated from the time of transplant by the method of Kaplan and Meier.
Time Frame
Up to 3 years post-transplant
Title
Graft-versus (vs.)-host disease-free, relapse-free survival (GRFS)
Description
GRFS will be calculated from the time of transplant by the method of Kaplan and Meier.
Time Frame
Up to 3 years post-transplant
Title
Time to platelet engraftment
Description
The time to platelet engraftment will be calculated from the time of transplant and estimated by the Kaplan-Meier method.
Time Frame
From the time of transplant up to 3 years
Title
Time to neutrophil engraftment
Description
The time to neutrophil engraftment will be calculated from the time of transplant and estimated by the Kaplan-Meier method.
Time Frame
From the time of transplant up to 3 years
Title
Incidence of acute and chronic graft-vs.-host disease (GvHD)
Description
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.
Time Frame
Up to 3 years post-transplant
Title
Incidence of relapse and non-relapse mortality
Description
The cumulative incidence of non-relapse mortality and relapse will also be assessed in a competing risks framework, with similar analyses performed.
Time Frame
Up to 3 years post-transplant
Title
Incidence of adverse events
Description
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 Frame
Up to 3 years post-transplant

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Non-English speaking patients are eligible. 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. 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 < 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 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Uday R. Popat
Phone
713-745-3055
Email
upopat@mdanderson.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Uday R Popat
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Uday R. Popat
Phone
713-745-3055
Email
upopat@mdanderson.org
First Name & Middle Initial & Last Name & Degree
Uday R. Popat

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
MD Anderson Cancer Center

Learn more about this trial

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

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