NCT05184842

Metabolically Optimized, Non-cytotoxic Low Dose Weekly Decitabine/Venetoclax in MDS and AML

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 91 (estimated)
• Sponsor: Montefiore Medical Center · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Myeloid malignancies which include AML (acute myeloid leukemia) and MDS (myelodysplatic syndrome) are cancers of the bone marrow which lead to bone marrow failure. The bone marrow is the place or factory in the body where components of blood such as red cells, platelets and white cells are made. In bone marrow failure, the ability of the bone marrow to make these cells is decreased. The decreased bone marrow function is the result from abnormalities that develop in the malignant cells which prevent the normal maturation process by which bone marrow cells develop into red blood cells, white blood cells and platelets. The malignant cells in the bone marrow are not good at maturing to make the components of the blood that you need, they occupy space in the bone marrow and prevent the function of remaining normal bone marrow cells. DNA is a chemical substance within cells that stores information needed for cell growth and cell behavior. One approach to treating the malignant cells is to give chemotherapy which damages DNA within these cells and causes their death. Unfortunately, such therapy has side-effects, since even normal cells can be affected by the treatment. Decitabine is FDA approved for treatment of MDS and AML. Venetoclax is approved for AML in combination with Azacitidine for patients with AML or are over age 75 or unfit for chemotherapy. In this study, Decitabine and venetoclax will be administered using a low dose weekly schedule in an attempt to improve efficacy by decreasing the side effects often seen when these drugs are given at standard dosing.

Detailed description

The combination of Azacitidine and venetoclax (Aza/Ven) is FDA approved for patients AML \> 75 and/or unfit for induction chemotherapy. However, majority of patients receiving standard dosing of Aza/Ven require dose interruptions, treatment delays and dose reductions. In addition, Aza/ven has limited activity in various subgroups of myeloid malignancies such as P53 mutant MDS/AML. In the initial safety and tolerability phase of the study, 33 patients will be enrolled on this study, accounting for need for replacement subjects to evaluate endpoints. In the second expansion phase of the study up to 91 patients (including patients from the 1st stage), will be enrolled to obtain additional safety, tolerability and preliminary efficacy of the low dose regimen in selected subsets of patients with myeloid malignancies. As treatment with Hypomethylating agents (HMAs) requires extended drug exposure for efficacy, patients who do not complete 12 weeks of therapy for reasons other than disease progression or those who do not complete therapy due to toxicity or those who screen fail and do not start therapy, will be replaced. Any patient who starts therapy will be evaluable for safety. In the absence of overt disease progression or dose limiting toxicity, patients would be anticipated to remain on treatment for at least 12 weeks. After 12 weeks, patient may continue therapy if felt to be experiencing clinical benefit. The severe cytopenias encountered with Aza/ven is particularly challenging for patients with poor hematopoietic bone marrow reserve such as MDS and myelofibrosis (MF). Also some elderly patients with comorbidities cannot tolerate the prolonged cytopenias caused by Aza/ven. This pilot clinical trial will evaluate the tolerability of a non-cytotoxic regimen for patients with myeloid malignancies who either cannot tolerate or are not known to benefit from standard Aza/Ven dosing. This will be a single arm, open label pilot study of weekly dosing of subcutaneous decitabine and venetoclax. Patients will be treated for a minimum of 12 weeks in the absence of clear evidence of progressive disease. Patients who have any response will be permitted to continue treatment until relapse or progression of disease. Decitabine is given at a dose of 0.1-0.2 mg/kg/day for 1-2 days per week. All patients will receive at least one dose Decitabine every week. If decided by treating physician that the patient needs a more rapid debulking of high disease burden, a second dose can be added. If Decitabine is given twice a week, should preferably be given on two consecutive days. Venetoclax is dosed at 400 mg by mouth one day a week a day prior to the first decitabine dose. If patients are taking another CYP3A4 inhibitor dose adjustments should be made as recommended by pharmacist for a goal dose of venetoclax of 400 mg. If patient receives two days of decitabine a week, they still only take venetoclax on the day prior to the first dose of decitabine.

Conditions

• Myelodysplastic Syndromes
• Acute Myeloid Leukemia
• Chronic Myelomonocytic Leukemia

Interventions

Type	Name	Description
DRUG	Venetoclax	Venetoclax 400 mg po on days 1, 8, 15 and 22 of each cycle (28-day cycle)
DRUG	Decitabine	Decitabine 0.2 mg/kg subcutaneous (SQ) on days 2, 9, 16, 23 (for aggressive disease will add decitabine on days 3, 10, 17, 24)

Timeline

• Start date: 2022-03-23
• Primary completion: 2023-12-20
• Completion: 2027-03-01
• First posted: 2022-01-11
• Last updated: 2026-01-05
• Results posted: 2025-08-26

Locations

3 sites across 1 country: United States

Regulatory

• FDA-regulated drug study