Danvatirsen + Venetoclax for MDS & AML

Recruiting at 2 trial locations

Overseen By Aditi Shastri

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Montefiore Medical Center

Disqualifiers: Acute promyelocytic leukemia, uncontrolled infection, CNS leukemia, others

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

Compensation: Varies

Number of Visits: Unknown

38 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety and effectiveness of a new treatment for individuals with difficult-to-treat blood cancers, specifically myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Researchers will first test Danvatirsen alone and then in combination with Venetoclax to evaluate their combined efficacy. Candidates may be suitable for this trial if they have MDS or AML that hasn't responded to other treatments and are experiencing frequent symptoms or rapid disease progression. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop your current medications. However, you cannot be on any concurrent anticancer treatment or non-permitted medications as noted in the protocol appendix.

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

Research shows that Danvatirsen is being tested alone to determine its safety for patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). As this is an early research stage, limited safety information is available. However, this phase is crucial for identifying any potential side effects.

When combined with Venetoclax, studies suggest this combination might be safe and tolerable for treating MDS and AML. Venetoclax has FDA approval for other uses, with manageable side effects. The goal of combining these drugs is to enhance treatment while monitoring safety.

In summary, both treatments are in early testing stages. This phase focuses on understanding patient tolerance and identifying side effects. Trial participants will contribute to gathering this vital safety information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Danvatirsen and Venetoclax for treating Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) because they offer a new approach compared to traditional chemotherapy and hypomethylating agents. Danvatirsen is an antisense oligonucleotide, which means it targets specific RNA molecules to reduce the production of proteins that help cancer cells survive. Venetoclax is a BCL-2 inhibitor that promotes the death of cancer cells by helping them self-destruct. This combination targets cancer at the genetic and cellular levels, offering a potentially more precise treatment with the hope of improved effectiveness and fewer side effects.

What evidence suggests that this trial's treatments could be effective for MDS and AML?

Research shows that Danvatirsen targets a protein called STAT3, which aids cancer cell growth. By targeting this protein, Danvatirsen can kill cancer cells, particularly in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In this trial, some participants will receive Danvatirsen as a monotherapy, which has proven effective in killing cancer cells in these diseases. Others will receive a combination of Danvatirsen and Venetoclax, another cancer-fighting drug. Venetoclax demonstrated a 32% complete response rate when combined with other drugs in similar conditions. These early findings suggest that this combination treatment could be effective for MDS and AML. ^{1 2 3 4 6}

Who Is on the Research Team?

Aditi Shastri

Principal Investigator

Montefiore Medical Center

Are You a Good Fit for This Trial?

Adults diagnosed with relapsed/refractory myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML), who have tried conventional therapies without success, can join this trial. They must be in relatively good health otherwise, with a decent performance status and proper liver and kidney function. Pregnant women, those with certain other cancers or severe heart issues, active infections, CNS leukemia, or drug abuse cannot participate.

Inclusion Criteria

My AML or MDS has not responded to standard treatments, including at least 6 cycles of specific therapy.

I must have a bone marrow biopsy after joining the trial.

My white blood cell count is below 25,000, possibly after treatment.

Exclusion Criteria

I have been diagnosed with Acute Promyelocytic Leukemia.

I had CNS leukemia but my latest tests show no active disease.

I am not taking any medications that are not allowed in the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Danvatirsen Monotherapy

Participants receive Danvatirsen as monotherapy in a dose-escalation study to determine the Maximum Tolerated Dose (MTD).

4 weeks per cycle

Weekly infusions

Danvatirsen + Venetoclax Combination

Participants receive a combination of Danvatirsen and Venetoclax to evaluate safety and efficacy.

4 weeks per cycle

Daily oral Venetoclax, weekly Danvatirsen infusions

Follow-up

Participants are monitored for safety and effectiveness after treatment, with response evaluations every 3 months.

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Danvatirsen
• Venetoclax

Trial Overview The study is testing Danvatirsen alone first and then in combination with Venetoclax to see how safe and effective they are for treating MDS/AML that hasn't responded to standard treatments. It's an early-phase trial which means it's one of the first times these drugs are being tested together in humans.

How Is the Trial Designed?

Group I: Danvatirsen Monotherapy Experimental Treatment 1 Intervention

Patients will be enrolled in cohorts of 3 for the Danvatirsen dose escalation substudy. Based on the DLT of the first cohort of participants, subsequent cohorts will either be administered doses at the next higher dose level, de-escalated to the next lower dose level, or remain the same. Dose escalation discontinuations and MTD will be determined as described in the 'Detailed Study Description.' The total duration of 1 cycle is approximately 4 weeks (28 days). Proposed dose levels and treatment schedule are as follows: Dose Level 1 (DL1): Danvatirsen Day 1 - Day 28 (1mg/kg loading dose on Cycle 1/Day 1 (C1D1), Cycle 1/Day 3 (C1D3); and Cycle 1/Day 5 (C1D5) followed by weekly 1mg/kg infusion for 3 weeks) Dose Level 2 (DL2): Danvatirsen Day 1 - Day 28 (2mg/kg loading dose on C1D1, C1D3, and C1D5 followed by weekly 2mg/kg infusion for 3 weeks) Dose Level 3 (DL3): Danvatirsen Day 1 - Day 28 (3mg/kg loading dose on C1D1, C1D3, and C1D5 followed by weekly 3mg/kg infusion for 3 weeks)

Group II: Danvatirsen + Venetoclax Combination Therapy Experimental Treatment 1 Intervention

Patients will be enrolled in cohorts of 3 for the Danvatirsen + Venetoclax dose escalation substudy. Dose escalation administration will be as described in the Danvatirsen monotherapy substudy arm and dose escalation discontinuations and MTD will be determined as described in the 'Detailed Study Description.' Up to 2 dose levels of Danvatirsen will be evaluated based on data from the Danvatirsen monotherapy arm. Dose 1 will be one level lower than the dose with expected target activity. Venetoclax: 400 mg (or equivalent) administered as fixed dose daily (except for specific dose modifications described in the protocol) orally for 28 days per cycle. To mitigate risk of tumor lysis syndrome, during Cycle 1 Venetoclax will be dose escalated daily to the goal dose of 400mg daily (100mg on Day 1, 200mg on Day 2 and 400mg on Day 3, and onwards, or adjusted dose ramp-up per Venetoclax label if on concomitant azoles). The three cycles are approximately 28 days each in duration.

Who Is Running the Clinical Trial?

Montefiore Medical Center

Lead Sponsor

Trials

468

Recruited

599,000+

Flamingo Therapeutics NV

Industry Sponsor

Trials

2

Recruited

110+

M.D. Anderson Cancer Center

Collaborator

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In a study of 60 patients with high-risk MDS and AML, venetoclax demonstrated a 35% overall response rate, indicating its efficacy as a treatment option for these conditions.

However, the treatment was associated with significant hematologic toxicity, with 86.7% of patients experiencing grade 2 or higher side effects, and infections, particularly pneumonia, being the most common nonhematologic complication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Real-life Turkish Experience of Venetoclax Treatment in High-risk Myelodysplastic Syndrome and Acute Myeloid Leukemia. Gemici, A., Ozkalemkas, F., Dogu, MH., et al.[2022]

The combination of venetoclax (Ven) and azacitidine (AZA) shows a high efficacy in treating acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), with an overall complete response rate of 57.9% across 19 studies involving 1615 patients.

This treatment is particularly effective for newly diagnosed AML patients, achieving a complete response rate of 67.5%, although it is less effective for those with relapsed or refractory AML, which had a response rate of only 30%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of venetoclax and azacytidine combination treatment in patients with acute myeloid leukemia and myelodysplastic syndrome: systematic review and meta-analysis. Du, Y., Li, C., Yan, J.[2023]

In a meta-analysis of 10 studies involving 243 patients, Venetoclax combined with hypomethylating agents (HMAs) showed a 32% complete response rate and an overall response rate of 48% for relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after transplantation.

The treatment demonstrated a 6-month survival rate of 42% and a 1-year survival rate of 23%, indicating a moderate benefit for patients post-transplantation, suggesting that this combination therapy could be a viable option for managing relapse in AML/MDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of venetoclax combined with hypomethylating agents for relapse of acute myeloid leukemia and myelodysplastic syndrome post allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis. Du, Y., Li, C., Zhao, Z., et al.[2023]

In a study of 82 adult patients with acute myeloid leukemia (AML), 57% were able to start venetoclax treatment safely in an outpatient setting, demonstrating its feasibility outside of the hospital.

The risk of tumor lysis syndrome (TLS) was very low, with only 2.1% of patients experiencing TLS after starting venetoclax, and 98% of patients did not require hospitalization for TLS within the first week of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. Palmer, S., Patel, A., Wang, C., et al.[2023]

In a study comparing treatment regimens for relapsed/refractory acute myeloid leukemia (R/R AML), the venetoclax (VEN) combination therapy showed a comparable overall response rate (59.3%) to intensive chemotherapy (IC) (44.0%), suggesting it is an effective alternative for patients who have failed previous treatments.

Patients receiving the VEN combination had a significantly higher percentage of successful stem cell transplants at blast clearance (86.5% vs. 62.3% for IC), indicating better disease control and potentially lower treatment-related mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective comparison of salvage intensive chemotherapy versus venetoclax-combined regimen in patients with relapsed/refractory acute myeloid leukemia (AML). Park, S., Kwag, D., Kim, TY., 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]

In a review of 13 studies involving 1059 patients, the combination of venetoclax (VEN) with hypomethylating agents (HMAs) showed a high overall complete remission (CR) rate of 62% for newly diagnosed acute myeloid leukemia (ND-AML) and 61% for myelodysplastic syndrome (MDS), indicating its efficacy in these conditions.

However, the treatment was associated with significant adverse effects, particularly grade 3-4 events like cytopenia and infections, highlighting the need for careful monitoring of patients for potential complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and adverse events of venetoclax in combination with hypomethylating agents treatment for patients with acute myeloid leukemia and myelodysplastic syndrome: a systematic review and meta-analysis. Liu, B., Guo, Y., Deng, L., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05986240

Study Details | NCT05986240 | Danvatirsen Monotherapy ... This is a Phase 1 study investigating the safety and efficacy of Danvatirsen as a monotherapy followed by combination with Venetoclax in patients with relapsed/ ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-03174

Danvatirsen With or Without Venetoclax for the Treatment ... Giving danvatirsen with or without venetoclax may be safe and tolerable in treating patients with relapsed or refractory MDS or AML. Eligibility Criteria ...

3. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper208998.html

Paper: A Phase 1 Study Investigating the Safety and ... A Phase 1 Study Investigating the Safety and Efficacy of Danvatirsen As Monotherapy Followed By Combination with Venetoclax in Patients with Relapsed/ ...

4. mdsf.sparkcures.com mdsf.sparkcures.com/trial/1749/NCT05986240

Danvatirsen Plus Venetoclax This is a Phase 1 study investigating the safety and efficacy of Danvatirsen as a monotherapy followed by combination with Venetoclax in patients with ...

5. rarediseaseadvisor.com rarediseaseadvisor.com/news/danvatirsen-venetoclax-aml-mds/

New Trial to Investigate Danvatirsen and Venetoclax in MDS Researchers plan to investigate the use of danvatirsen and venetoclax in treating myelodsyplastic syndromes and acute myeloid leukemia.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12350645/

Comprehensive view on chemotherapy-free management ... Venetoclax and targeted therapy combinations for acute myeloid leukemia. Drug class combined with VEN, Drug combination, NCT ID, Phase, N ...