Venetoclax Added to Fludarabine + Busulfan Prior to Transplant and to Maintenance Therapy for AML, MDS, and MDS/MPN

NCT03613532 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 18-283
• Study Type: interventional
• Target: 102
• Locations: 1 country
• Sites: 1

Brief Summary

This clinical trial involves individuals who have been diagnosed with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML), or MDS/myeloproliferative neoplasm-unclassifiable (MDS/MPN-unclassifiable) and are planning to have an allogeneic hematopoietic stem cell transplant ("bone marrow transplant"). The goal of this research study is to (1) test the safety of adding the study drug, Venetoclax, to a standard of care conditioning regimen for bone marrow transplantation as a possible means of eliminating residual (left-over) disease prior to transplant, (2) to test the safety of combination Venetoclax and azacitidine as "maintenance therapy" after transplant to possibly prevent disease recurrence and (3) to test the safety of combination Venetoclax and oral decitabine/cedazuridine as "maintenance therapy" after transplant to possibly prevent disease recurrence.

• The name of the study drug involved in this study is Venetoclax.
• It is expected that about 102 people will take part in this research study.

Conditions

Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS); Chronic Myelomonocytic Leukemia (CMML); MDS/Myeloproliferative Neoplasm-unclassifiable (MDS/MPN-unclassifiable); Hematopoietic Stem Cell Transplant

Keywords

Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS); Chronic Myelomonocytic Leukemia (CMML); MDS/myeloproliferative neoplasm-unclassifiable (MDS/MPN-unclassifiable); Hematopoietic Stem Cell Transplant

Outcome Measures

Primary Outcomes (3)

• MTD of Venetoclax with Busulfan and Fludarabine

  Determine safe dose and schedule of venetoclax

  37 Days

• MTD of Venetoclax with Azacitidine as Maintenance Therapy

  Determine safe dose and schedule of venetoclax

  28 Days from Maintenance Therapy Start

• MTD of Venetoclax with Decitabine/cedazuridine as Maintenance Therapy

  Determine safe dose and schedule of venetoclax

  28 Days from Maintenance Therapy Start

Secondary Outcomes (12)

• Overall Survival

  12 Months

• Progression Free Survival

  12 Months

• Overall Response Rate

  At day 100, 6 months and 12 months

• Remission Duration Rate

  from start of the treatment until disease relapse (assessed at day 100, 6 months and 12 months)

• Rate of Disease Relapse

  12 Months

Study Arms (1)

Venetoclax

EXPERIMENTAL

Part 1 dose escalation * Venetoclax: 6-7 total doses based on level assigned * Busulfan: given 2x daily for 4 days * Fludarabine: given 1x daily for 4 days Part 2 includes post-transplant therapy with azacitidine and venetoclax for 8-12 cycles per dose level. Part 3 includes post-transplant therapy with oral decitabine/cedazuridine and venetoclax for 8 cycles. Part 4 assesses PTCy/Tac/MMF GVHD regimen instead of Tac/Methotrexate -post transplant period includes therapy with azacitidine and venetoclax for 8 cycles.

Drug: Venetoclax; Drug: Fludarabine; Drug: Busulfan; Drug: Azacitidine; Drug: Decitabine/cedazuridine

Interventions

Venetoclax DRUG

Part 1: 6-7 total doses depending on dose level assigned

Also known as: ABT199

Venetoclax

Fludarabine DRUG

Given once daily for 4 days

Also known as: Fludara

Venetoclax

Busulfan DRUG

Given twice daily for 4 days

Also known as: Busulfex, Myleran

Venetoclax

Azacitidine DRUG

Part 2 and Part 4: 5 doses for 8-12 cycles depending on dose level assigned

Venetoclax

Decitabine/cedazuridine DRUG

Part 3: 3 doses for 8 cycles

Venetoclax

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 years and older.
• Patients must have a prior diagnosis of one of the following:
• (Note: Mutational and cytogenetic studies performed at sites other than Dana-Farber Cancer Institute or Brigham and Women's Hospital will require review of the outside cytogenetic and/or molecular pathology reports by the overall PI.)
• High-risk MDS, which is defined as one of the following subsets:
• IPSS Intermediate-2 or higher
• Presence of a mutation in TP53
• Prescence of mutation in the RAS pathway including NRAS, KRAS, PTPN11, CBL, NF1, RIT1, FLT3, and KIT
• Therapy-related MDS
• High-risk AML, which is defined as one of the following subsets:
• AML with adverse risk disease according to ELN guidelines including one of the following features:
• a history of mutation in TP53, RUNX1, or ASXL1
• t(6;9)(p23;q34.1); DEK-NUP214
• t(v;11q23.3); KMT2A rearranged
• t(9;22)(q34.1;q11.2); BCR-ABL1
• inv(3)(q21.3q26.2) or t(3;3)(q21.3;26.2); GATA2,MECOM(EVI1)

You may not qualify if:

• Patients who have had chemotherapy (with the exception of hydroxyurea and/or dexamethasone) or radiotherapy or investigational therapy within 14 days prior to starting treatment on study. Exceptions: Patients already on venetoclax therapy prior to transplant need a three day wash out prior to first treatment dose on study. Patients on BCR-ABL, IDH and FLT3 small molecule inhibitors can stay on this treatment up until 5 days prior to first treatment dose on study.
• Patients with \> 10% morphologic blasts on bone marrow biopsy if they have a diagnosis of MDS or MDS/MPN. Patients \> 5% morphologic blasts on bone marrow biopsy if they have a diagnosis of AML.
• Patients recommended to receive a myeloablative conditioning regimen prior to transplantation (since there is a known survival advantage for AML using higher intensity).
• Patients who have a history of prior allogeneic stem cell transplantation.
• Symptomatic or untreated known CNS involvement of disease
• Patients with active heart disease (New York Heart Association class 3-4 as assessed by history and physical exam, or a critical event including unstable angina/stroke/myocardial infarction within the last 6 months prior to first dose on study).
• Patients who have consumed grapefruit, grapefruit products, Seville oranges or starfruit within 3 days prior to study treatment. Patients who a strong or moderate inducer within 7 days prior to the first dose of study drug.
• Malabsorption syndrome or other clinically significant condition that would preclude enteral administration.
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study.
• Patients with known active hepatitis B virus (HBV) infection should be excluded because of potential effects on immune function and/or drug interactions. However, if a patient has HBV history with an undetectable HBV load by polymerase chain reaction (PCR), no liver-related complications, and is on definitive HBV therapy that is not contraindicated on this study, then he/she would be eligible for study.
• Patients with known active hepatitis C virus (HCV) infection. However, if a patient with a history of HCV infection has received definitive therapy (and is now HCV viral load negative), or if a patient has a reactive HCV antibody test but has an undetectable viral load by PCR, then he/she would be eligible.
• Patients with known active HIV infection out of concern for the drug-drug interaction with venetoclax and HAART therapy.
• Pregnant or breastfeeding women or those intending to become pregnant during the study or within 3 months after the final dose of study treatment are excluded from this study. Women of childbearing potential must have a negative serum pregnancy test resulted during screening and repeated within 7 days prior to study drug (local labs are allowed).
• Vaccination with live, attenuated vaccines within 4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study.
• Patients with uncontrolled infection at time of first dose of treatment on study. Patients receiving anti-microbial agents including antibiotics, antiviral and antifungal therapies are allowed if hemodynamically stable.

Sponsors & Collaborators

• Jacqueline Garcia, MD: lead
• National Institutes of Health (NIH): collaborator

Study Sites (1)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Related Publications (3)

• Garcia JS, Kim HT, Murdock HM, Cutler CS, Brock J, Gooptu M, Ho VT, Koreth J, Nikiforow S, Romee R, Shapiro R, Loschi F, Ryan J, Fell G, Karp HQ, Lucas F, Kim AS, Potter D, Mashaka T, Stone RM, DeAngelo DJ, Letai A, Lindsley RC, Soiffer RJ, Antin JH. Adding venetoclax to fludarabine/busulfan RIC transplant for high-risk MDS and AML is feasible, safe, and active. Blood Adv. 2021 Dec 28;5(24):5536-5545. doi: 10.1182/bloodadvances.2021005566.

  PMID: 34614506 BACKGROUND

• Garcia JS, Kim HT, Murdock HM, Ansuinelli M, Brock J, Cutler CS, Gooptu M, Ho VT, Koreth J, Nikiforow S, Romee R, Shapiro R, DeAngelo DJ, Stone RM, Bat-Erdene D, Ryan J, Contreras ME, Fell G, Letai A, Ritz J, Lindsley RC, Soiffer RJ, Antin JH. Prophylactic maintenance with venetoclax/azacitidine after reduced-intensity conditioning allogeneic transplant for high-risk MDS and AML. Blood Adv. 2024 Feb 27;8(4):978-990. doi: 10.1182/bloodadvances.2023012120.

  PMID: 38197938 BACKGROUND

• Garcia JS, Kim HT, Murdock HM, Bosch-Vilaseca A, Panaro KM, Lim F, Fiorilla J, Auriemma E, Brock J, Gooptu M, Ho VT, Cutler CS, Shapiro R, Kelkar AH, Abel GA, DeAngelo DJ, Stone RM, Bat-Erdene D, Ryan J, Fell G, Letai A, Ritz J, Lindsley RC, Antin JH, Soiffer RJ. Venetoclax/FluBu2 RIC transplant followed by all-oral venetoclax/decitabine maintenance for poor-risk MDS/AML. Blood Adv. 2026 Mar 10;10(5):1548-1558. doi: 10.1182/bloodadvances.2025018631.

  PMID: 41348911 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic

Interventions

venetoclax; fludarabine; fludarabine phosphate; Busulfan; Azacitidine; decitabine and cedazuridine drug combination

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Aza Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Jacqueline S. Garcia, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 26, 2018
• First Posted: August 3, 2018
• Study Start: October 24, 2018
• Primary Completion: May 1, 2026
• Study Completion (Estimated): March 1, 2027
• Last Updated: December 24, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)