NCT06129734

Decitabine and Venetoclax Treatment as Maintenance Therapy in Patients Post Allograft Stem Cell Transplant

Phase 1B/2A Study of Weekly Decitabine and Venetoclax Treatment as Maintenance Therapy in High-Risk Myeloid Malignancy Patients Post Allograft Stem Cell Transplant

• Status: Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 20 (estimated)
• Sponsor: Benjamin Tomlinson · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

The goal of this interventional clinical trial is to determine if low doses of gentle chemotherapy after bone marrow transplant may prevent relapse and promote an increase in survival and decrease in side effects in participants with acute myeloid leukemia and myelodysplastic syndromes. The main question it aims to answer is whether or not providing a new, gentler way of administering chemotherapy will help control leftover cancer with minimal side effects. This treatment involves decitabine and venetoclax. Participants will receive standard post-transplant care. Participants will be administered decitabine once per week with normal transplant follow up visits, and then will take a venetoclax pill about 6 to 8 hours later. Participants will meet their study team at the beginning, midway, and at the end of the trial to receive bone marrow testing. Participants will receive treatment until either one year of therapy, relapse, or recurrent dose limiting toxicity (DLT) despite dose reduction.

Detailed description

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While 60-80% patients can achieve remission, a high rate of relapse mandates consolidative treatment. Unfortunately, 40% of AML patients and 30% of myelodysplastic syndrome patients will relapse after alloSCT, and those who relapse after transplant exhibit poor outcomes. As such, prevention of post-transplant relapse remains a key interest. Maintenance therapy with low-intensity chemotherapy and/or targeted therapy is one strategy that holds promise to reduce post-transplant relapse, controlling residual subclinical disease before frank relapse. As post-transplant maintenance strategies yield mixed results, standard of care maintenance therapy remains an unmet clinical need. The combination of hypomethylating agents (HMAs), such as decitabine or 5-azacytidine, and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax combination has transformed the management of transplant-ineligible AML patient improving median overall survival (OS) to 14.7 months compared to 9.6 months with azacytidine and placebo at the cost of more pronounced cytopenias (Grade 3 and 4 thrombocytopenia and neutropenia occurring in 45%/38% and 42%/28% respectively). Recent work has demonstrated a mechanism by which HMAs cooperate with venetoclax, via priming AML cells for death via the integrated stress response (ISR). The ISR transcription factor activating transcription factor-4 (ATF4) is upregulated in a matter of hours after HMA treatment, and in turn activates Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1) (NOXA) that degrades the BCL2-family member myeloid cell leukemia sequence 1 (MCL1), thus creating greater dependence in HMA-exposed malignant cells on BCL2 to avoid BAX/BAK mediated mitochondrial outer membrane permeabilization (MOMP), caspase release, and subsequent apoptosis. An irreversible step toward apoptosis is mitochondrial outer membrane permeabilization (MOMP) by BAX/BAK oligomers, which releases caspase proteases into the cells, a commitment into apoptosis that is fundamentally counteracted by BCL2-family antiapoptotic proteins, e.g., BCL2, the target of venetoclax inhibition. This mechanism primes AML blasts for venetoclax-mediated toxicity. Through rigorous pharmacological optimization, it has been shown that the decitabine 5 mg/m2 weekly with a single dose of venetoclax 6 hours after the decitabine can control disease with limited effects normal hematopoietic cells.9 This novel dosing regimen may maximize decitabine/venetoclax anti-leukemic activity while minimizing hematologic toxicity and represents an attractive regimen for post-alloSCT maintenance therapy.

Conditions

• Myeloid Malignancy
• Acute Myeloid Leukemia

Interventions

Type	Name	Description
DRUG	Venetoclax	Venetoclax is a BCL2 inhibitor. It is administered at low doses and used in combination with other hypomethylating agents such as decitabine to manage participants with acute myeloid lymphoma who have undergone stem cell transplant. Participants will initiate therapy with decitabine that will be followed by venetoclax 400 mg oral 6-8 hours later. Participants will continue this dose each week. The venetoclax dose will be reduced to 100 mg once per week if the participant is being treated with posaconazole or voriconazole (strong CYP3A4 inhibitors) (considered dose equivalent to venetoclax 400 mg 1X/week). The venetoclax dose will be reduced 200 mg once per week if the participant is being treated with fluconazole or isavuconazole (moderate CYP3A4 inhibitors) (considered dose equivalent to venetoclax 400 mg 1X/week). This clinical trial is administering venetoclax well below the current FDA approved dosing.
DRUG	Decitabine	Decitabine is a hypomethylating agent. It is administered at low doses and used in combination with venetoclax to manage participants with acute myeloid lymphoma who have undergone stem cell transplant. Participants initiate therapy with 5 mg/m2 decitabine subcutaneous every week followed by venetoclax.

Timeline

• Start date: 2025-07-28
• Primary completion: 2026-12-01
• Completion: 2027-07-01
• First posted: 2023-11-13
• Last updated: 2025-08-26

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study