Venetoclax, Busulfan, Cladribine, and Fludarabine for the Treatment of High-Risk Acute Myeloid Leukemia or Myelodysplastic Syndrome

Overview

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.

Full Title of Study: “Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 31, 2021

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.

Interventions

  • Drug: Busulfan
    • Given IV
  • Drug: Cladribine
    • Given IV
  • Drug: Fludarabine Phosphate
    • Given IV
  • Procedure: Hematopoietic Cell Transplantation
    • Undergo stem cell transplantation
  • Drug: Thiotepa
    • Given IV
  • Drug: Venetoclax
    • Given PO

Arms, Groups and Cohorts

  • Experimental: Treatment (venetoclax, busulfan, fludarabine, cladribine)
    • 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.

Clinical Trial Outcome Measures

Primary Measures

  • 1-year progression free survival (PFS)
    • Time Frame: 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 Measures

  • Overall survival (OS)
    • Time Frame: 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)
    • Time Frame: Up to 3 years post-transplant
    • GRFS will be calculated from the time of transplant by the method of Kaplan and Meier.
  • Time to platelet engraftment
    • Time Frame: From 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.
  • Time to neutrophil engraftment
    • Time Frame: From 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.
  • Incidence of acute and chronic graft-vs.-host disease (GvHD)
    • Time Frame: 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 mortality
    • Time Frame: Up 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.
  • Incidence of adverse events
    • Time Frame: Up 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.

Participating in This Clinical Trial

Inclusion Criteria

  • Age >= 18 and =< 70 years – 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 – Measurable residual disease positive (MRD +) – Not in complete remission including complete remission without count recovery (Cri), primary refractory, or relapsed disease or Patients with myelodysplastic syndrome or chronic myelomonocytic leukemia (CMML) and one of the following high-risk features: – Poor or very poor cytogenetic risk group as per Revised International Prognostic Scoring System (IPSS-R) – Mutated P53 or Ras pathway genes (CBL, NRAS, KRAS, NF1, PTPN1) or DNMT 3a or ASXL1 or RUNX1 – IPSS-R > 3.5 at diagnosis – >= 5% bone marrow (BM) blasts at transplant – HLA-identical sibling or a 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 – Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0 x upper limit of normal (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 human immunodeficiency virus (HIV) – Subject has acute promyelocytic leukemia – Subject has known active central nervous system (CNS) involvement with acute myeloblastic leukemia (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 (hepatitis C virus [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 congestive heart failure (CHF) requiring treatment or ejection fraction < 50% or unstable angina – Corrected diffusion capacity of the lung for carbon monoxide (DLCO) < 65% or forced expiratory volume in 1 second (FEV1) < 65% – Treatment with any of the following within 7 days prior to the first dose of study drug: – Steroid therapy for anti-neoplastic intent – Moderate or strong cytochrome P450 3A (CYP3A) inhibitors, moderate or strong CYP3A inducers. These agents may be used once venetoclax is discontinued – 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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 70 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • M.D. Anderson Cancer Center
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Uday R Popat, Principal Investigator, M.D. Anderson Cancer Center
  • Overall Contact(s)
    • Uday R. Popat, 713-745-3055, upopat@mdanderson.org

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