Navitoclax + Venetoclax + Decitabine for Myelodysplastic Syndrome

Overseen By Gina Keiffer, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Thomas Jefferson University

Must be taking: Hypomethylating agents

Must not be taking: Coagulation medications

Disqualifiers: Active infection, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: 3

6 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—navitoclax, venetoclax, and decitabine—to evaluate their safety and effectiveness in treating myelodysplastic syndrome (MDS), a type of blood disorder. The goal is to determine the optimal dose and assess how well these drugs work together, particularly in MDS cases unresponsive to previous treatments. Navitoclax and venetoclax are oral medications that kill cancer cells by blocking proteins that help them survive, while decitabine, administered through an IV, interferes with cell growth. This trial may suit individuals with MDS that has returned or not responded to initial treatment and who have previously received drugs like azacitidine or decitabine. As a Phase 1, Phase 2 trial, it aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial requires that you stop taking medications that interfere with blood clotting or platelet function, except for low-dose aspirin and certain blood thinners, which must be stopped at least 3 days before starting the trial. If you are on these medications and cannot stop, you will not be able to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of venetoclax and decitabine is generally well-tolerated. In studies, patients with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) responded well to this treatment. However, some patients experienced side effects like low blood cell counts, leading to issues such as infections.

Navitoclax, similar to venetoclax, remains under study. It functions similarly to help kill cancer cells but can cause side effects like low platelet counts, which are crucial for blood clotting.

The current study is in its early stages, with a focus on closely monitoring safety. This phase aims to find the optimal dose with the fewest side effects. While navitoclax is not yet approved for MDS, it is being tested with venetoclax and decitabine to evaluate their combined effectiveness.

Overall, the treatment is still under investigation, and further research is needed to fully understand its safety for humans. Participants should be aware of possible side effects and discuss these with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of navitoclax, venetoclax, and decitabine for treating myelodysplastic syndrome (MDS) because it targets cancer cells in a unique way. While traditional treatments for MDS often rely on hypomethylating agents like azacitidine or decitabine alone, this combination introduces navitoclax and venetoclax, which work together to block proteins that prevent cancer cell death. This dual inhibition strategy aims to enhance the effectiveness of decitabine, potentially leading to better outcomes for patients who have not responded to standard therapies. By combining these drugs, researchers hope to offer a more effective solution for patients with high-risk MDS.

What evidence suggests that this trial's treatments could be effective for myelodysplastic syndrome?

Research has shown that combining venetoclax and decitabine can effectively treat high-risk myelodysplastic syndrome (MDS). Some patients have responded well, with a few even achieving complete remission. This combination blocks proteins that help cancer cells survive, effectively killing them. In this trial, participants will receive navitoclax, venetoclax, and decitabine. Navitoclax, like venetoclax, targets these proteins. By attacking cancer cells from different angles, this combination aims to enhance treatment effectiveness. Although more research is needed, early results appear promising for patients with high-risk MDS. ^{2 4 5 6 7}

Who Is on the Research Team?

Gina Keiffer, MD

Principal Investigator

Thomas Jefferson University

Are You a Good Fit for This Trial?

Adults with aggressive myelodysplastic syndrome (MDS) who have tried azacitidine or decitabine and venetoclax without success. They must be able to swallow pills, not pregnant or breastfeeding, willing to use contraception, and have an ECOG Performance Status of 0-2 indicating they are relatively active.

Inclusion Criteria

I am willing and able to follow all study rules and attend all appointments.

Creatinine clearance >= 40 mL/min, calculated with the use of the 24-hour creatinine clearance or modified Cockcroft-Gault equation

Provide signed and dated informed consent form

Exclusion Criteria

Known allergic reactions to components of the study product(s)

Pregnancy or lactation or intending to become pregnant during the study

I do not have uncontrolled HIV, HBV, or HCV with a detectable viral load.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Cycle 1

Participants receive navitoclax, venetoclax, and decitabine with bone marrow biopsy and blood sample collection

4 weeks

Multiple visits for drug administration and sample collection

Treatment Cycle 2 and Beyond

Participants continue receiving navitoclax, venetoclax, and decitabine with bone marrow biopsy and blood sample collection

28 days per cycle, up to 6 cycles

Multiple visits for drug administration and sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Every 3 months

Survival Follow-up

Participants are followed for overall survival

2 years from enrollment of the last patient

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• Navitoclax
• Venetoclax

Trial Overview The trial is testing the safety and optimal dose of navitoclax in combination with venetoclax and decitabine for MDS patients whose disease returned or didn't respond to initial treatment. It aims to assess how effective this drug combo is on patient health outcomes including quality of life.

How Is the Trial Designed?

Group I: Treatment (navitoclax, decitabine, venetoclax) Experimental Treatment 7 Interventions

This is a single-center phase Ib/II trial of navitoclax, venetoclax and decitabine in adult patients with R/R HR-MDS who have previously failed HMA therapy. In the phase I dose escalation portion, patients will receive navitoclax in combination with standard dosing of venetoclax and decitabine. The maximally tolerated dose (MTD) will be the recommended phase II dose (RP2D). Previously, navitoclax in combination with venetoclax and chemotherapy in ALL found the MTD to 50mg of nativoclax po. In the phase II dose expansion portion, patients will receive navitoclax at the RP2D in combination with standard dose venetoclax and decitabine. Patients will continue on treatment with navitoclax, venetoclax and decitabine until relapse, dose-limiting toxicity, availability of alternate therapy or withdrawal of consent.

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?

Thomas Jefferson University

Lead Sponsor

Trials

475

Recruited

189,000+

AbbVie

Industry Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Published Research Related to This Trial

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 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 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]

The combination of azacitidine and venetoclax is safe and well-tolerated in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia, with a recommended phase 2 dose established as azacitidine 75 mg/m2 for 5 days plus venetoclax 400 mg for 14 days.

The treatment showed a high overall response rate of 87% among the 23 enrolled patients, indicating promising preliminary activity for this combination therapy in treatment-naive and relapsed or refractory cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1-2 study. Bazinet, A., Darbaniyan, F., Jabbour, E., et al.[2022]

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]

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]

The combination of venetoclax with hypomethylating agents (HMA) has significantly improved survival rates in patients with acute myeloid leukemia (AML), as demonstrated in a phase 3 study.

Venetoclax is also safe when added to standard intensive regimens, leading to high remission rates and measurable residual disease negativity in both newly diagnosed and relapsed/refractory AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with nucleoside analogs in acute myelogenous leukemia. Ball, BJ., Koller, PB., Pullarkat, V.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05455294

NCT05455294 | Combination Navitoclax, Venetoclax and ... The purpose of this research study is to test the safety of a new three drug combination of navitoclax, decitabine, and venetoclax to treat advanced myeloid ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12241227/

The efficacy and safety of venetoclax combined with ... In summary, our findings demonstrated that the VEN + DEC regimen was effective and safe for treatment of elderly patients with AML. Results of ...

3. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/6732/528927/Efficacy-and-Safety-of-Venetoclax-in-Combination

Efficacy and Safety of Venetoclax in Combination with ... Conclusion Venetoclax in combination with HMA is an effective and safe treatment option in patients with HR MDS. Continuous attention to the ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.6549

A phase II study of venetoclax (VEN) in combination with ... DEC10-VEN demonstrated expected safety and efficacy in a particularly high-risk cohort of ND and R/R pts, with no evidence that 10-days of DEC provides ...

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

Venetoclax Plus 10-Day Decitabine Produces Responses ... In the newly diagnosed AML group, 66% achieved a complete response (CR) and 15% achieved a CR with incomplete hematologic recovery (CRi), ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05455294

Combination Navitoclax, Venetoclax and Decitabine for ... The purpose of this research study is to test the safety of a new three drug combination of navitoclax, decitabine, and venetoclax to treat advanced myeloid ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.e19035

Outcomes with venetoclax in myelodysplastic syndromes Prospective clinical trial data is needed to ascertain safety and efficacy of venetoclax in MDS and impact on overall survival, in ...