Adding decitabine and venetoclax to fludarabine/melphalan reduced‑intensity transplant for myeloid cancers

A Phase I Trial to Evaluate the Safety and Efficacy of Addition of Novel Anti-leukemia Agents to Flu/Mel RIC Transplant for High-risk Myeloid Malignancies

This study tests whether giving decitabine and venetoclax around a reduced‑intensity allogeneic transplant is safe for adults with high‑risk acute myeloid leukemia or myelodysplastic syndromes.

Quick facts

• Phase: PHASE1
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: University of Alabama at Birmingham (other)
• Drugs / interventions: Fludarabine
• Locations: 1 site (Birmingham, Alabama)
• Trial ID: NCT07044544 on ClinicalTrials.gov

What this trial studies

This is a Phase 1, 3+3 dose‑escalation study that adds decitabine (short course) with or without venetoclax to a fludarabine/melphalan reduced‑intensity conditioning regimen before allogeneic peripheral blood stem cell transplant. Patients are enrolled in cohorts with escalating doses of decitabine and venetoclax to identify dose‑limiting toxicities and a recommended safe dose. The dose‑limiting toxicity period runs from the first decitabine dose through day 28 post‑transplant, with adjustments made per standard 3+3 rules. Primary goals are safety and tolerability; preliminary activity will be recorded but efficacy conclusions are exploratory.

Who should consider this trial

Good fit: Adults aged 18–75 with high‑risk acute myeloid leukemia or myelodysplastic syndromes who are candidates for reduced‑intensity allogeneic peripheral blood stem cell transplant and have an eligible related or unrelated donor.

Not a fit: Patients who are not candidates for transplant, lack an appropriate donor, have poor organ function, or have low‑risk disease are unlikely to benefit from this trial.

Why it matters

Potential benefit: If safe, this approach could lower relapse risk and improve transplant outcomes for patients with high‑risk AML or MDS.

How similar studies have performed: Venetoclax combined with hypomethylating agents has shown activity in AML outside the transplant setting, but using decitabine and venetoclax around reduced‑intensity allogeneic transplant is relatively novel with limited prior data.

Eligibility criteria

Inclusion Criteria:

1. Adult male or female, age 18-75 years
2. Patients must have a related or unrelated peripheral blood stem cell donor. Sibling donor must be a 6/6 match for HLA-A and -B at intermediate (or higher) resolution, and -DRB1 at high resolution using DNA-based typing, and must be willing to donate peripheral blood stem cells and meet institutional criteria for donation. Unrelated donor must the following: have Optimum: HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1 and -DPB1; Minimum: HLA-A, -B, -C, -and DRB1 matching at high resolution using DNA-based typing and be willing to donate peripheral blood stem cells and be medically eligible to donate stem cells according to National Marrow Donor Program (NMDP) criteria.
3. A candidate for reduced intensity preparative regimen, based on age≥60, or HCT-CI of ≥4, or considered by the treating physician to have high risk for toxicity with myeloablative preparative regimen.
4. Cardiac function: Ejection fraction \>40%
5. Calculated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault formula and actual body weight).
6. Pulmonary function: DLCO ≥50% (adjusted for hemoglobin) and FEV1≥50%
7. Liver function: total bilirubin \< 1.5x the upper limit of normal and ALT/AST \< 2.5x the upper normal limit. Patients who have been diagnosed with Gilbert's Disease are allowed to exceed the defined bilirubin value up to \<3mg/dl.
8. Female subjects (unless postmenopausal for at least 1 year before the screening visit, or surgically sterilized), agree to practice two effective methods of contraception or agree to complete abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post-transplant.
9. Male subjects (even if surgically sterilized), of partners of women of childbearing potential must agree to practice effective barrier contraception or abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post-transplant.
10. Karnofsky performance status KPS ≥ 70 (Appendix B)
11. Patients must have a diagnosis of one of the following:

    -AML: A. Any AML with active disease (defined as ≥ 5% blasts in the marrow), with no available re-induction strategies, or further therapy is not felt to be effective by treating physician.

    B. Any AML with adverse risk disease, therapy-related or secondary-AML in CR1 or beyond C. AML with intermediate risk disease that is MRD+ in CR1 or beyond D. Any AML in CR2 or beyond (regardless of MRD) E. Marrow blast percentage needs to be 20-25% and total WBC counts needs to be ≤ 25000/µl before the start of the conditioning regimen. It is acceptable to use hydroxyurea or low dose cytarabine to maintain this WBC count.

    -MDS:

    MDS with IPSS-M ≥ high and/or with ≥5% blasts in the bone marrow with no available pre-transplant strategies, or further therapy is not felt to be effective by treating physician.- MDS/MPN:

    -MDS/MPN \>5% blasts and spleen \< 22 cm with no available pre-transplant strategies, or further therapy is not felt to be effective by treating physician.
12. Subject is willing and able to sign informed consent and abide by the protocol requirements.

Exclusion Criteria:

1. Autologous hematopoietic stem cell transplant \< 3 months prior to enrollment.
2. Previous allogeneic stem cell transplant.
3. Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or EKG suggestive of acute ischemia or active conduction system abnormalities.
4. Known hypersensitivity to Decitabine, Venetoclax and/or ATG.)
5. Pregnant and/or breastfeeding
6. Evidence of HIV infection or known HIV positive serology.
7. Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
8. Non-hematologic malignancy within prior three (3) years, with the exception of squamous cell or basal cell skin carcinoma. Patients with prior malignancies except resected localized non-melanoma skin cancer or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed as long as it is in remission. Cancer treated with curative intent \< 5 years previously must be reviewed and approved by the PI as long as it is in remission.
9. Participation in another clinical study with an investigational product during the last 28 days.
10. Patients with documented cirrhosis (will need imaging +/- biopsy confirmation, hepatology consult recommended)

Where this trial is running

Birmingham, Alabama

• University of Alabama at Birmingham — Birmingham, Alabama, United States (RECRUITING)

Study contacts

• Principal investigator: Omer A Jamy, MD — The University of Alabama at Birmingham
• Study coordinator: Omer Jamy, MD

Conditions: Myeloid Malignancy, Hematologic Malignancy, Acute Myeloid Leukemia, Myelodysplastic Syndromes, Leukemia, allogeneic transplant