Low Dose Decitabine + Venetoclax for Blood Cancer

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

Trial Summary

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.

What data supports the idea that Low Dose Decitabine + Venetoclax for Blood Cancer is an effective drug?

The available research shows that Low Dose Decitabine combined with Venetoclax is effective for treating blood cancer, specifically acute myeloid leukemia (AML), in older patients who cannot undergo intensive chemotherapy. In one study, 67% of patients achieved complete remission, meaning their cancer symptoms disappeared. Another study found that this combination is now a standard treatment for elderly patients with AML, showing promising results even in high-risk groups. This suggests that the drug combination is effective and well-tolerated, offering a viable option for patients who have limited treatment choices. ^{1 2 3 4 5}

What safety data exists for Low Dose Decitabine + Venetoclax treatment for blood cancer?

The provided research does not contain safety data for Low Dose Decitabine + Venetoclax treatment for blood cancer. The studies focus on different drugs, primarily irinotecan and raltitrexed, and their effects on colorectal cancer, not on Decitabine or Venetoclax. ^{6 7 8 9 10}

Is the drug combination of Decitabine and Venetoclax promising for treating blood cancer?

Yes, the combination of Decitabine and Venetoclax is promising for treating blood cancer. It has shown effectiveness in treating certain types of leukemia, especially in patients who are older or cannot handle intense chemotherapy. This drug combination has been successful in achieving remission in some cases and is considered a new standard of care for specific blood cancers. ^{2 3 5 11 12}

What is the purpose of this trial?

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.

Research Team

Mendel Goldfinger, MD

Principal Investigator

Montefiore Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

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 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 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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021]

2. England 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. [2021]

3. New Zealand 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. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

A Metabolically Optimized, Noncytotoxic Low-Dose Weekly Decitabine/Venetoclax in MDS and AML. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Multicenter phase I study of irinotecan plus raltitrexed in patients with 5-fluorouracil-refractory advanced colorectal cancer. [2018]

7. United States 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. [2017]

8. England pubmed.ncbi.nlm.nih.gov

Exposure-response analysis of Raltitrexed assessing liver toxicity. [2022]

9. Greece pubmed.ncbi.nlm.nih.gov

Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer. [2018]

10. United States pubmed.ncbi.nlm.nih.gov

Schedule-dependent synergism between raltitrexed and irinotecan in human colon cancer cells in vitro. [2022]

11. England 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. [2020]

12. United States pubmed.ncbi.nlm.nih.gov

Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. [2023]