Eltanexor + Venetoclax for Myelodysplastic Syndrome and Acute Myeloid Leukemia

Overseen By Vanderbilt-Ingram Services for Timely Access

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Vanderbilt-Ingram Cancer Center

Must not be taking: SINE compounds

Disqualifiers: Active infection, CNS leukemia, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of two drugs, eltanexor and venetoclax, to treat certain blood cancers called myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The researchers aim to determine the safety of these drugs, identify potential side effects, and establish the optimal dose when combined. This trial may suit individuals whose MDS or AML has returned after treatment or has not responded to previous therapies. Participants will receive these medications in cycles and undergo regular check-ups, including blood tests and bone marrow evaluations, to monitor their progress. 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 therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but you cannot have had anticancer therapy within 2 weeks before starting the trial, except for hydroxyurea, which is allowed.

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

Research shows that venetoclax, one of the treatments being tested, is generally safe for patients with chronic lymphocytic leukemia, meaning most people tolerate it well when combined with other treatments. Eltanexor, the other treatment in this trial, demonstrated good results in earlier studies for other conditions, such as multiple myeloma, where it was also well-tolerated.

As this is an early-phase trial, the main goal is to assess the safety of combining eltanexor and venetoclax for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). While earlier research suggests that using these two drugs together might be safe and tolerable, this trial aims to provide more detailed information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Eltanexor and Venetoclax for treating Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) because these drugs work together to target cancer cells in a unique way. While current treatments often rely on chemotherapy or targeted therapies like azacitidine or decitabine, Eltanexor and Venetoclax focus on inhibiting proteins that help cancer cells survive. Venetoclax targets the BCL-2 protein, which is crucial for cancer cell survival, while Eltanexor inhibits exportin-1, disrupting the cell's ability to manage proteins that control growth and death. This dual mechanism offers a promising new approach for patients who might not respond well to existing therapies.

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

Research has shown that combining eltanexor and venetoclax might help treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) when they return or resist other treatments. In this trial, participants will receive both eltanexor and venetoclax. Eltanexor works by retaining proteins inside cancer cells that can inhibit tumors, causing the cancer cells to die or stop growing. Venetoclax blocks a protein called Bcl-2, which cancer cells need to survive. Studies have found that targeting both XPO1 and Bcl-2 in AML cells can lead to cancer cell death and reduce leukemia in lab tests and patient samples. Although researchers are still studying this combination, these findings suggest it could be effective for people whose MDS or AML has returned or not responded to past treatments. ^{1 2 3 6 7}

Who Is on the Research Team?

Somedeb Ball, MD

Principal Investigator

Vanderbilt University/Ingram Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) that has returned after treatment or hasn't responded to past treatments. Participants must meet specific health criteria not detailed here.

Inclusion Criteria

My liver and kidney functions are within normal ranges.

I am 18 or older and can sign the consent form and meet all study needs.

WBC must be less than 25,000/ul prior to study start (hydroxyurea allowed)

Exclusion Criteria

I have leukemia that has spread to my brain.

I have not had radiation or major surgery in the last 3 weeks.

I have recovered from previous cancer treatment side effects, except for hair loss or tiredness.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive eltanexor orally once per day for 5 days per week for 14, 21, or 28 days every cycle, and venetoclax orally once per day on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Regular visits for bone marrow aspiration, biopsy, and blood sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Every 3 months for up to 24 months

What Are the Treatments Tested in This Trial?

Interventions

• Eltanexor
• Venetoclax

Trial Overview The trial is testing the safety and optimal doses of eltanexor combined with venetoclax in treating relapsed or refractory MDS/AML. Eltanexor aims to kill cancer cells by trapping certain proteins, while Venetoclax targets a protein essential for cancer cell survival.

How Is the Trial Designed?

Group I: Eltanexor + Venetoclax Experimental Treatment 4 Interventions

Participants receive eltanexor PO QD for 5 days per week for 14, 21, or 28 days every cycle, and venetoclax PO QD on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Participants undergo bone marrow aspiration and biopsy and blood sample collection throughout the study.

Who Is Running the Clinical Trial?

Vanderbilt-Ingram Cancer Center

Lead Sponsor

Trials

221

Recruited

64,400+

Karyopharm Therapeutics Inc

Industry Sponsor

Trials

89

Recruited

7,200+

Richard Paulson

Karyopharm Therapeutics Inc

Chief Executive Officer since 2021

MBA from the University of Toronto's Rotman School of Management

Reshma Rangwala

Karyopharm Therapeutics Inc

Chief Medical Officer since 2023

MD, PhD

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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 study of 57 elderly patients (average age 69.9 years) with acute myeloid leukemia, the combination of venetoclax and azacitidine (VEN + AZA) showed a high overall response rate of 87.5% and a complete remission (CR) rate of 68.8%, indicating strong efficacy in this population.

The treatment was associated with a median overall survival (OS) of 11.5 months, and achieving minimal residual disease (MRD) negativity (<0.1%) was more common with VEN + AZA compared to traditional chemotherapy, although older patients (≥75 years) and those with higher ECOG scores faced more challenges in achieving MRD negativity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-institution experience of venetoclax combined with azacitidine in newly diagnosed acute myeloid leukemia patients. Yu, H., Wang, C., Lei, Y., et al.[2023]

In a study of 31 patients with acute myeloid leukemia evolving from myeloproliferative neoplasms, venetoclax showed some efficacy in newly diagnosed patients, achieving complete remission in 6 patients with a median overall survival of 7 months, but no formal responses in relapsed/refractory patients with a median survival of only 3 months.

The treatment was associated with significant hematologic toxicities, with 83% of patients experiencing severe infections and 14 patients suffering from severe hemorrhagic complications, highlighting the need for safer and more effective treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-center experience with venetoclax combinations in patients with newly diagnosed and relapsed AML evolving from MPNs. Masarova, L., DiNardo, CD., Bose, P., et al.[2021]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

A lower dosage of Venetoclax (100 mg) combined with Azacitidine showed favorable outcomes in newly diagnosed acute myeloid leukemia (AML) patients, with a median overall survival of 17 months and an overall response rate of 69.4% based on a study of 36 patients.

The study suggests that even with dose reductions of Venetoclax, the combination therapy remains effective, indicating a potential strategy to manage therapy-related toxicity while still achieving significant treatment responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced duration and dosage of venetoclax is efficient in newly diagnosed patients with acute myeloid leukemia. Cui, J., Chen, X., Li, C., et al.[2023]

Venetoclax combined with hypomethylators and low-dose cytarabine has shown high response rates and improved overall survival in older, untreated patients with acute myeloid leukemia, based on preliminary data from small, uncontrolled studies.

The efficacy of venetoclax appears to stem from its ability to target leukemia stem cells by altering the metabolic environment, which is particularly effective in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Why are hypomethylating agents or low-dose cytarabine and venetoclax so effective? Pollyea, DA., Jordan, CT.[2020]

In a study of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia (R/R ETP-ALL), Venetoclax combined with multidrug chemotherapy resulted in a 67.7% overall response rate and a 60% complete response rate, indicating significant efficacy.

The treatment was found to be safe, with manageable hematological toxicities and no severe adverse reactions, suggesting that Venetoclax combined with chemotherapy could be a promising option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical efficacy and safety of venetoclax combined with multidrug chemotherapy in the treatment of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia]. Kong, JY., Zong, LH., Pu, Y., et al.[2023]

In a study of 50 adults with acute myeloid leukemia (AML) in Mexico and Peru, venetoclax-based therapy showed a high complete response rate of 78.6% in newly diagnosed patients and 45.5% in those with relapsed/refractory disease, indicating its efficacy in treating AML.

The median overall survival was 9.6 months for newly diagnosed patients and 8 months for relapsed/refractory patients, suggesting that venetoclax is a viable treatment option even in real-world settings, despite common hematologic toxicities and dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. Gómez-De León, A., Demichelis-Gómez, R., Pinedo-Rodríguez, A., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06399640

NCT06399640 | Eltanexor and Venetoclax in Relapsed or ... Giving eltanexor together with venetoclax may be safe, tolerable and/or effective in treating patients with relapsed or refractory MDS or AML. Detailed ...

2. withpower.com withpower.com/trial/phase-1-leukemia-6-2024-cb7cf

Eltanexor + Venetoclax for Myelodysplastic Syndrome and ... Venetoclax has been shown to have an acceptable safety profile in patients with chronic lymphocytic leukemia and is commonly used in combination with other ...

3. ctsearchsupport.org ctsearchsupport.org/clinical-trials/eltanexor-and-venetoclax-in-relapsed-or-refractory-myelodysplastic-syndrome-and-acute-myeloid-leukemia

Trial Summary | NMDP℠ CTSS If the combination of eltanexor and venetoclax is safe and works well to treat AML and MDS that has relapsed or is refractory. You may be able ...

4. mdsf.sparkcures.com mdsf.sparkcures.com/trial/1913/NCT06399640

Eltanexor and Venetoclax Giving eltanexor together with venetoclax may be safe, tolerable and/or effective in treating patients with relapsed or refractory MDS or AML. Trial status.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7013257/

Venetoclax response is enhanced by selective inhibitor of ... Co-inhibition of XPO1 and BCL2 induces apoptosis in AML cells and decreases leukemia burden in cell line and patient-derived xenografts.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12411709/

Novel small-molecule therapies for myelodysplastic ... Additionally, a new phase I trial (NCT06399640) is assessing the safety and optimal dosage of eltanexor in conjunction with venetoclax for R/R ...

7. investors.karyopharm.com investors.karyopharm.com/2017-12-10-Karyopharm-Presents-Positive-Phase-1-2-Eltanexor-Data-at-the-American-Society-of-Hematology-2017-Annual-Meeting

Karyopharm Presents Positive Phase 1/2 Eltanexor Data at ... ... − Preliminary Data Show that Eltanexor is Well Tolerated and Demonstrates Promising Activity in Multiple Myeloma —.