Low Dose Decitabine + Venetoclax for Blood Cancer

Recruiting at 3 trial locations

Overseen By Mendel Goldfinger, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Montefiore Medical Center

Must not be taking: Azacitidine, Decitabine, Venetoclax

Disqualifiers: APL, Chemotherapy candidates, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

85 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if lower doses of Decitabine and Venetoclax together can treat certain blood cancers, specifically AML (acute myeloid leukemia) and MDS (myelodysplastic syndrome), with fewer side effects. These conditions involve the bone marrow not producing enough healthy blood cells. The trial seeks individuals diagnosed with these blood cancers who have responded to similar treatments in the past. Participants should not have received previous treatments with Decitabine, Venetoclax, or Azacitidine and must meet specific organ function levels. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in cancer treatment.

Do I have to stop taking my current medications for the trial?

The trial requires that you stop any disease-directed therapy, except for hydroxyurea, for 14 days before starting the study. The protocol does not specify other medications, so it's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that combining Decitabine and Venetoclax can help treat certain blood cancers. The FDA has approved Decitabine for conditions like MDS and AML. Venetoclax is approved for AML when used with Azacitidine, particularly for older patients or those unable to tolerate regular chemotherapy.

Safety data indicates that combining these drugs commonly causes side effects such as nausea, diarrhea, and low blood cell levels, similar to those seen when Venetoclax is used with other drugs. Serious side effects can occur but are less common.

This treatment uses lower doses of both drugs to try to reduce these side effects. Prospective participants should discuss this information with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of low-dose Decitabine and Venetoclax for blood cancer because it offers a unique approach compared to standard treatments like chemotherapy. Unlike traditional therapies that often attack cancer cells broadly, Venetoclax specifically targets and inhibits a protein called BCL-2, which helps cancer cells survive. Adding Decitabine, which can reprogram cancer cell DNA, might enhance this effect, potentially leading to better outcomes. This combo is also administered differently; Decitabine is given as a subcutaneous injection, and Venetoclax is a convenient oral tablet, which could improve patient comfort and adherence.

What evidence suggests that this treatment might be an effective treatment for blood cancer?

Studies have shown that combining decitabine and venetoclax can effectively treat blood cancers like AML (acute myeloid leukemia) and MDS (myelodysplastic syndromes). This trial will evaluate this combination, which has achieved high success rates, with many patients experiencing complete remission, where cancer signs disappear. For instance, one study found that 60-73% of older AML patients who had not been treated before showed significant positive responses. Additionally, administering this treatment in low doses once a week can still be effective, reducing side effects. Overall, strong evidence supports the effectiveness of this treatment for these blood cancers. ^{6 7 8 9 10}

Who Is on the Research Team?

Mendel Goldfinger, MD

Principal Investigator

Montefiore Medical Center

Are You a Good Fit for This Trial?

Adults diagnosed with Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), or MDS/MPN who may benefit from hypomethylating agents. Participants must be over 18, have an ECOG status of ≥3, and adequate liver function. Pregnant or breastfeeding individuals, those with certain heart conditions, uncontrolled illnesses, active infections not well-managed by medication, or known allergies to the drugs are excluded.

Inclusion Criteria

My condition has previously responded well to HMA therapy.

I need help with my daily activities due to my health condition.

Patients must have adequate end organ function defined as: AST (aspartate aminotransferase) and ALT (alanine transaminase) < 4× the upper limit of normal (ULN), Bilirubin ≤ 2× the ULN (upper limit of normal). If elevated bilirubin is due to impaired conjugation (e.g Gilbert's disease or concomitant medication) or disease related hemolysis, then direct bilirubin ≤ 1.5× the ULN, Renal function with a creatinine clearance ≥30 mL/min or on dialysis is allowed, Subjects must have the ability to understand and the willingness to sign a written informed consent document and complete study related procedures

Exclusion Criteria

I have been treated with azacitidine, decitabine, or venetoclax before.

I have been diagnosed with acute promyelocytic leukemia.

I haven't taken any cancer treatment except hydroxyurea in the last 14 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive weekly doses of Decitabine and Venetoclax for a minimum of 12 weeks

12 weeks

Weekly visits for administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Open-label extension (optional)

Participants may continue treatment until relapse or progression of disease

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• Venetoclax

Trial Overview The trial is testing a combination of two drugs: Venetoclax and Decitabine at low doses on a weekly schedule for treating bone marrow cancers like AML and MDS. The goal is to see if this regimen can reduce side effects while effectively targeting malignant cells in the bone marrow.

How Is the Trial Designed?

Group I: Decitabine/Venetoclax (Single Arm) Experimental Treatment 2 Interventions

Administration: Decitabine is reconstituted with 5 ml sterile water to facilitate subcutaneous administration. Decitaboine is given by subcutaneous injection. Venetoclax is taken as a tablet prepared by patients pharmacy. Venetoclax is given at a dose of 400 mg po once per week concurrently with the Decitabine dose (+/- 1 day allowed ).

Decitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Dacogen for:

• Acute myeloid leukemia
• Myelodysplastic syndromes

Approved in United States as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Canada as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Montefiore Medical Center

Lead Sponsor

Trials

468

Recruited

599,000+

The V Foundation for Cancer Research

Collaborator

Trials

21

Recruited

1,300+

Published Research Related to This Trial

A case of early-relapsed high-risk T-cell acute lymphoblastic leukemia (T-ALL) with high BCL-2 expression was successfully treated with a combination of decitabine and venetoclax, leading to complete remission (CR).

The results suggest that decitabine and venetoclax may work synergistically in treating BCL-2 positive acute lymphoblastic leukemia, indicating a potential new therapeutic strategy for this high-risk group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T-cell lymphoblastic leukemia. Zappone, E., Cencini, E., Defina, M., et al.[2020]

The combination of irinotecan and raltitrexed is feasible for treating advanced colorectal cancer, showing mild toxicity and an overall response rate of 17% in patients who had previously not responded to 5-fluorouracil.

Diarrhea was identified as the main dose-limiting toxicity, but its severity was comparable to that seen with irinotecan alone, indicating that the combination does not increase the risk of severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase I study of irinotecan plus raltitrexed in patients with 5-fluorouracil-refractory advanced colorectal cancer. Aparicio, J., de las Peñas, R., Vicent, JM., et al.[2018]

In a study involving 27 patients receiving 81 courses of Exatecan mesylate (DX-8951f), the recommended safe dose was established as 0.8 mg/m² for minimally pretreated patients and 0.53 mg/m² for heavily pretreated patients, indicating its potential for use in different patient populations.

The study found that while dose-limiting toxicities included neutropenia and thrombocytopenia, non-hematological side effects were generally mild, suggesting that DX-8951f has a manageable safety profile when administered as a weekly 24-hour infusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of topoisomerase I inhibitor exatecan mesylate (DX-8951f) given as weekly 24-hour infusions three of every four weeks. Sharma, S., Kemeny, N., Schwartz, GK., et al.[2017]

In a phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

A once-weekly low-dose decitabine (LDDec) combined with venetoclax (VEN) showed high efficacy in treating elderly patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), achieving an overall response rate of 88% for AML and 64% for MDS in a retrospective study of 39 patients.

Patients receiving the LDDec/VEN regimen experienced longer treatment durations and a trend towards higher transfusion independence compared to those on standard dosing, suggesting that this approach may reduce severe myelosuppression while maintaining effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Metabolically Optimized, Noncytotoxic Low-Dose Weekly Decitabine/Venetoclax in MDS and AML. Levitz, D., Saunthararajah, Y., Fedorov, K., et al.[2023]

Venetoclax, a BCL-2 inhibitor, shows promise in combination therapies for newly diagnosed or relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), achieving high remission rates and deep molecular responses.

Despite these encouraging results, there are concerns about side effects such as incomplete blood count recovery and increased infection rates, particularly when used with chemotherapy, and more research is needed to understand the long-term effectiveness and durability of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. Shimony, S., Stone, RM., Stahl, M.[2023]

In a study of 22 heavily pre-treated patients with relapsed or refractory acute myeloid leukaemia (RR-AML), the combination of venetoclax and decitabine resulted in a 45.5% overall response rate, with 40.9% achieving complete remission, demonstrating its efficacy in a real-world setting.

While the treatment was effective, it was associated with significant side effects, including grade IV neutropenia and thrombocytopenia in all patients, but no deaths were attributed to the treatment side effects, indicating that the adverse effects were manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting. Tong, J., Zhao, N., Hu, X., et al.[2022]

In a phase II trial involving 48 patients with untreated advanced colorectal cancer, the combination of irinotecan and raltitrexed showed an overall response rate of 27%, with a median duration of response of 10 months.

Despite its activity, the treatment was associated with significant side effects, including grade III-IV diarrhea and neutropenia, leading to a dose reduction and highlighting the need for careful patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer. Chiara, S., Nobile, MT., Tomasello, L., et al.[2018]

In a study involving 145 older patients (median age 74) with acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy, the combination of venetoclax with decitabine or azacitidine resulted in a high complete remission (CR) rate of 67%, demonstrating its efficacy in this challenging population.

The treatment was well tolerated, with no cases of tumor lysis syndrome reported, and the median overall survival was 17.5 months, indicating that venetoclax combined with hypomethylating agents is a promising option for elderly patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. DiNardo, CD., Pratz, K., Pullarkat, V., et al.[2021]

In a phase 2 trial involving 168 patients with acute myeloid leukaemia (AML), the combination of venetoclax and a 10-day regimen of decitabine resulted in a high overall response rate of 74%, with particularly impressive results in newly diagnosed AML patients (89%).

The treatment demonstrated a manageable safety profile, with common adverse events including neutropenia and infections, and a 30-day mortality rate of only 3.6%, indicating that this combination therapy is both effective and relatively safe for older patients or those unfit for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. DiNardo, CD., Maiti, A., Rausch, CR., et al.[2021]

Raltitrexed (RTX) shows a more favorable toxicity profile when administered at 2 mg/m2 every 2 weeks compared to the standard 3 mg/m2 every 3 weeks, making it a potential alternative for patients intolerant to 5-fluorouracil.

The study found that using individual factors like creatinine clearance and sex to determine RTX dosing can reduce variability in drug exposure and predict liver toxicity more accurately than traditional body surface area-based dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-response analysis of Raltitrexed assessing liver toxicity. Royer, B., Schmitt, A., Nguyen, T., et al.[2022]

In vitro studies using the human colon cancer cell line HCT-8 showed that the combination of raltitrexed (ZD1694) and irinotecan's active metabolite (SN-38) resulted in synergistic cytotoxicity, particularly when administered sequentially with a 24-hour interval.

The optimal administration schedule for achieving the best synergistic effect involved short-term exposures to SN-38 followed by ZD1694, suggesting a promising strategy for clinical trials in treating colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Schedule-dependent synergism between raltitrexed and irinotecan in human colon cancer cells in vitro. Aschele, C., Baldo, C., Sobrero, AF., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39316768/

A weekly low-dose regimen of decitabine and venetoclax is ... A metronomic, low-dose schedule of decitabine and Venetoclax was safe and effective in myeloid malignancies with few dose reductions or interruptions in an ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03941964

NCT03941964 | A Study of the Effectiveness of Venetoclax ... A study evaluating the effectiveness and safety of venetoclax, in combination with azacitidine or decitabine, in an outpatient setting for treatment-naïve ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7549397/

Ten-day Decitabine with Venetoclax in Acute Myeloid Leukemia A phase I/II study with 145 reported patients confirmed effectiveness of venetoclax with 5-day decitabine with CR/CRi in 60–73% of treatment-naïve elderly AML ...

4. onclive.com onclive.com/view/venetoclax-plus-10-day-decitabine-produces-responses-in-high-risk-mds-aml

Venetoclax Plus 10-Day Decitabine Produces Responses ... Venetoclax and decitabine combination shows high overall response rates in AML and high-risk MDS, with CR/CRi rates varying by patient group.

5. venclexta.com venclexta.com/aml/why-venclexta/venclexta-decitabine

How Effective is VENCLEXTA® + decitabine Against AML? The median length of time spent in complete remission (CR) was 13 months and in complete remission (CR) + complete remission with partial hematologic recovery ( ...

6. venclextahcp.com venclextahcp.com/aml/side-effects/ven-dec-safety-profile.html

VEN+DEC: Summary of safety data from Study M14-358 The risk of TLS is a continuum based on multiple factors, particularly reduced renal function, tumor burden, and type of malignancy. Assess all patients for ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6551

Phase II trial of 10-day ASTX727 (decitabine/cedazuridine ... Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant ... venetoclax for relapsed or refractory acute myeloid leukemia.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04657081

Study Details | NCT04657081 | Pharmacokinetics, Safety, ... Pharmacokinetics, Safety, and Efficacy of ASTX727 in Combination With Venetoclax in Acute Myeloid Leukemia (AML) ... History of other malignancies prior to study ...

9. venclexta.com venclexta.com/important-safety-information

Important Safety Information The most common side effects of VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine in people with AML include nausea; diarrhea; low ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12317167/

Safety of venetoclax in real-world experience: data from the ... Venetoclax was approved for treating two types of blood cancers: chronic lymphocytic leukemia (CLL) in 2016 and acute myeloid leukemia (AML) ...