Selinexor + Venetoclax + Chemotherapy for Acute Myeloid Leukemia

Recruiting in Palo Alto (17 mi)

+10 other locations

Overseen by Seth E. Karol, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Waitlist Available

Sponsor: St. Jude Children's Research Hospital

Must not be taking: CYP3A inducers

Disqualifiers: Pregnancy, Down syndrome, Uncontrolled infection, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the safety and determine the best dose of venetoclax and selinexor when given with chemotherapy drugs in treating pediatric and young adult patients with acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage (ALAL) that has come back (relapsed) or did not respond to treatment (refractory). Primary Objective * To determine the safety and tolerability of selinexor and venetoclax in combination with chemotherapy in pediatric patients with relapsed or refractory AML or ALAL. Secondary Objectives * Describe the rates of complete remission (CR) and complete remission with incomplete count recovery (CRi) for patients treated with selinexor and venetoclax in combination with chemotherapy at the recommended phase 2 dose (RP2D). * Describe the overall survival of patients treated at the RP2D. Exploratory Objectives * Explore associations between leukemia cell genomics, BCL2 family member protein quantification, BH3 profiling, and response to therapy as assessed by minimal residual disease (MRD) and variant clearance using cell-free deoxyribonucleic acid (DNA) (cfDNA). * Describe the quality of life of pediatric patients undergoing treatment with selinexor and venetoclax in combination with chemotherapy and explore associations of clinical factors with patient-reported quality of life outcomes. * Describe the clinical and genetic features associated with exceptional response to the combination of venetoclax and selinexor without the addition of chemotherapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but you cannot take certain drugs like strong CYP3A inducers (e.g., rifampin) within 3 days of starting venetoclax. Some medications may require dose adjustments, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Selinexor and Venetoclax for treating Acute Myeloid Leukemia?

Research shows that Selinexor, when used alone, has shown some effectiveness in treating Acute Myeloid Leukemia (AML), with 14% of patients achieving a response and improved survival rates. Additionally, studies indicate that Selinexor can enhance the effectiveness of Venetoclax, another drug used for AML, by promoting cancer cell death, suggesting that the combination could be more effective than either drug alone. ^{1 2 3 4 5}

Is the combination of Selinexor, Venetoclax, and Chemotherapy safe for treating Acute Myeloid Leukemia?

Selinexor, when combined with chemotherapy drugs like fludarabine and cytarabine, has been studied in both children and adults with relapsed or refractory acute leukemia. Common side effects include low sodium levels, infections, diarrhea, and fatigue, but these are generally manageable. The combination is considered tolerable at certain doses, and further studies are ongoing to explore its safety and effectiveness. ^{1 2 3 6 7}

What makes the Selinexor + Venetoclax + Chemotherapy treatment unique for acute myeloid leukemia?

This treatment is unique because it combines selinexor, which blocks a protein that helps cancer cells survive, with venetoclax, a drug that targets a protein called BCL-2 to promote cancer cell death. The combination is designed to enhance the effectiveness of chemotherapy by overcoming resistance that often develops with venetoclax alone. ^{1 2 3 4 8}

Research Team

Seth E. Karol, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for young patients aged 2-30 with Acute Myeloid Leukemia or ALAL that's resistant to treatment or has returned after therapy. They must have had at least two prior treatments, no severe heart, liver, kidney issues, and not be eligible for curative therapies like stem cell transplant due to disease severity.

Inclusion Criteria

I am not a candidate for treatments that could cure my condition.

I had a stem cell transplant and do not have GVHD.

I have waited the required time after finishing my calcineurin inhibitor treatment.

Exclusion Criteria

My digestive system works well and doesn't affect how my body absorbs medication.

I have no history of brain-related side effects or neurological issues.

Previous toxicity or hypersensitivity directly attributed to venetoclax is an exclusion

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Characterize the dose-limiting toxicity (DLT) and determine the recommended phase 2 dose (RP2D) of venetoclax plus selinexor with and without chemotherapy

5 weeks

Weekly visits for monitoring

Dose Expansion

Two expansion cohorts will be treated at the recommended phase 2 dose (RP2D) to further assess safety and explore efficacy

4 cycles of therapy

Regular visits as per cycle schedule

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Cytarabine (Antimetabolite)
• Fludarabine (Antimetabolite)
• Methotrexate (Antimetabolite)
• Selinexor (Selective Inhibitor of Nuclear Export (SINE))
• Venetoclax (BCL-2 Inhibitor)

Trial Overview The study tests the safety and best dose of venetoclax and selinexor combined with chemotherapy in children and young adults with relapsed/refractory AML/ALAL. It aims to find out how well this combination works for remission rates, survival time, leukemia cell response, quality of life impacts, and genetic factors influencing treatment success.

Participant Groups

Group I: Treatment Experimental Treatment 7 Interventions

Dose Escalation Phase: Venetoclax plus selinexor will initially be given at dose level 1 in combination with intravenous (IV) cytarabine and fludarabine. Dosing of venetoclax and selinexor will be based on tolerability. Intrathecal (IT) chemotherapy (IT cytarabine, IT methotrexate, and IT methotrexate/hydrocortisone/cytarabine (MHA) are all acceptable) will be given. G-CSF SC may be given. Part 1 has been completed and RP2D has been determined to be Dose Level 2. All participants will be treated at Dose Level 2. Dose Expansion Phase: Two expansion cohorts will be treated at the recommended phase 2 dose (RP2D). Cohort A will include venetoclax-naïve patients, whereas Cohort B will include patients with prior exposure to venetoclax.

Cytarabine is already approved in Canada for the following indications:

Approved in Canada as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Vanderbilt University Medical Center Nashville, TN

Memorial Sloan-Kettering Cancer Center New York, NY

University of North Carolina at Chapel Hill Chapel Hill, NC

Children's Hospital Colorado Aurora, CO

More Trial Locations

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Patients Recruited

5,326,000+

Gateway for Cancer Research

Collaborator

Trials

47

Patients Recruited

2,500+

Karyopharm Therapeutics Inc

Industry Sponsor

Trials

89

Patients Recruited

7,200+

AbbVie

Industry Sponsor

Trials

1079

Patients Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

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

Findings from Research

Selinexor, a selective inhibitor of nuclear export, was found to be safe and well-tolerated in a phase 1 study involving 95 patients with relapsed or refractory acute myeloid leukemia (AML), with manageable side effects primarily being mild gastrointestinal and constitutional toxicities.

The study showed that 14% of evaluable patients achieved an objective response, leading to significantly improved progression-free survival (5.1 months vs. 1.3 months) and overall survival (9.7 months vs. 2.7 months) compared to nonresponders, indicating its potential efficacy as a treatment for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia. Garzon, R., Savona, M., Baz, R., et al.[2021]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 2:1 randomized, open-label, phase II study of selinexor vs. physician's choice in older patients with relapsed or refractory acute myeloid leukemia. Sweet, K., Bhatnagar, B., Döhner, H., et al.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of selinexor in combination with salvage chemotherapy in Adults with relapsed or refractory Acute myeloid leukemia. Bhatnagar, B., Zhao, Q., Mims, AS., et al.[2023]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor Synergistically Promotes the Antileukemia Activity of Venetoclax in Acute Myeloid Leukemia by Inhibiting Glycolytic Function and Downregulating the Expression of DNA Replication Genes. Jiang, J., Wang, Y., Liu, D., et al.[2023]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax response is enhanced by selective inhibitor of nuclear export compounds in hematologic malignancies. Fischer, MA., Friedlander, SY., Arrate, MP., et al.[2021]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination With Fludarabine and Cytarabine, in Pediatric Relapsed or Refractory Acute Leukemia. Alexander, TB., Lacayo, NJ., Choi, JK., et al.[2022]

In a phase I trial involving 14 younger patients with relapsed or refractory acute myeloid leukemia (AML), the combination of selinexor (100 mg weekly) and FLAG-Ida showed promising efficacy, with a complete remission rate of 66.7% and a median overall survival of 13.6 months.

The treatment was well-tolerated, with no dose-limiting toxicities reported, although 78.6% of patients experienced grade ≥3 non-hematologic adverse events, indicating that while the regimen is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of selinexor plus FLAG-Ida for the treatment of refractory/relapsed adult acute myeloid leukemia patients. Martínez Sánchez, MP., Megías-Vericat, JE., Rodríguez-Veiga, R., et al.[2021]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus low-dose cytarabine in Japanese patients with untreated acute myeloid leukaemia ineligible for intensive chemotherapy. Yamauchi, T., Yoshida, C., Usuki, K., et al.[2022]

References

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

A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia. [2021]

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

A 2:1 randomized, open-label, phase II study of selinexor vs. physician's choice in older patients with relapsed or refractory acute myeloid leukemia. [2022]

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

Phase 1 study of selinexor in combination with salvage chemotherapy in Adults with relapsed or refractory Acute myeloid leukemia. [2023]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Selinexor Synergistically Promotes the Antileukemia Activity of Venetoclax in Acute Myeloid Leukemia by Inhibiting Glycolytic Function and Downregulating the Expression of DNA Replication Genes. [2023]

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

Venetoclax response is enhanced by selective inhibitor of nuclear export compounds in hematologic malignancies. [2021]

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

Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination With Fludarabine and Cytarabine, in Pediatric Relapsed or Refractory Acute Leukemia. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

A phase I trial of selinexor plus FLAG-Ida for the treatment of refractory/relapsed adult acute myeloid leukemia patients. [2021]

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

Venetoclax plus low-dose cytarabine in Japanese patients with untreated acute myeloid leukaemia ineligible for intensive chemotherapy. [2022]