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

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of eltanexor in combination with venetoclax for the treatment of patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Eltanexor works by trapping "tumor suppressing proteins" within the cell, thus causing the cancer cells to die or stop growing. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving eltanexor together with venetoclax may be safe, tolerable and/or effective in treating patients with relapsed or refractory MDS or AML.

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.

What data supports the effectiveness of the drug combination Eltanexor and Venetoclax for Myelodysplastic Syndrome and Acute Myeloid Leukemia?

Research shows that Venetoclax, when combined with other treatments, has been effective in treating acute myeloid leukemia and myelodysplastic syndrome, with some studies reporting promising response rates and survival outcomes. However, the specific combination of Eltanexor and Venetoclax has not been directly studied, so its effectiveness is inferred from Venetoclax's success in similar combinations. ^{1 2 3 4 5}

Is the combination of Eltanexor and Venetoclax safe for humans?

Venetoclax has been shown to have an acceptable safety profile in patients with chronic lymphocytic leukemia and is commonly used in combination with other drugs for acute myeloid leukemia and myelodysplastic syndrome, although dose adjustments may be needed due to therapy-related side effects. ^{3 4 6 7 8}

What makes the drug combination of Eltanexor and Venetoclax unique for treating myelodysplastic syndrome and acute myeloid leukemia?

The combination of Eltanexor and Venetoclax is unique because it pairs Eltanexor, a novel drug, with Venetoclax, which is already known for its effectiveness in treating acute myeloid leukemia and myelodysplastic syndrome when combined with other agents. This combination may offer a new approach by potentially enhancing the effectiveness of Venetoclax through the addition of Eltanexor, which could provide a different mechanism of action or improve patient outcomes. ^{2 3 4 5 9}

Research Team

Somedeb Ball, MD

Principal Investigator

Vanderbilt University/Ingram Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 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]

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]

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]

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]

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]

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]

References

1. China 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]. [2023]

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

Single-center experience with venetoclax combinations in patients with newly diagnosed and relapsed AML evolving from MPNs. [2021]

3. England 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. [2023]

4. England 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. [2021]

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

Why are hypomethylating agents or low-dose cytarabine and venetoclax so effective? [2020]

6. England pubmed.ncbi.nlm.nih.gov

Reduced duration and dosage of venetoclax is efficient in newly diagnosed patients with acute myeloid leukemia. [2023]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Single-institution experience of venetoclax combined with azacitidine in newly diagnosed acute myeloid leukemia patients. [2023]

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

9. England pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. [2022]