Selinexor + Venetoclax + Chemotherapy for Acute Myeloid Leukemia

Not currently recruiting at 10 trial locations

Overseen By Jeffrey E. Rubnitz, MD, PhD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: St. Jude Children's Research Hospital

Must not be taking: CYP3A inducers

Disqualifiers: Pregnancy, Down syndrome, Uncontrolled infection, others

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

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to assess the safety of two drugs, venetoclax and selinexor, when combined with chemotherapy for treating young people with acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage (ALAL) that has not responded to treatment or has recurred. Researchers seek to determine the optimal dose combination and its effects on remission and survival rates. The trial is open to individuals with persistent leukemia despite multiple treatments who are not eligible for immediate curative therapy. 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 potentially groundbreaking therapy.

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.

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

Research has shown that combining selinexor and venetoclax may enhance their cancer-fighting abilities, particularly for acute myeloid leukemia (AML). Earlier studies tested this combination in labs and found it effective against cancer cells.

Managing side effects, such as low blood cell counts, is important, but overall, the treatments are generally well-tolerated. Patients have experienced some side effects, though many were manageable with medical assistance.

As this trial is in an early stage, it primarily aims to determine the safest dose and assess how well patients tolerate the combination. While promising evidence exists, further research is necessary to fully confirm its safety in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of selinexor and venetoclax with chemotherapy for acute myeloid leukemia (AML) because it introduces a novel approach to treatment. While traditional treatments, like cytarabine and daunorubicin, primarily target rapidly dividing cells, selinexor works differently by inhibiting XPO1, a protein that helps cancer cells grow and survive. Venetoclax adds another layer by targeting BCL-2, a protein that prevents cancer cell death. This dual action, combined with chemotherapy, could potentially enhance the effectiveness against AML compared to existing treatments.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

In this trial, participants will receive a combination of selinexor and venetoclax. Research has shown that this combination can enhance the ability to fight acute myeloid leukemia (AML) cells. It works by blocking the cancer cells' energy supply, making survival more difficult. Venetoclax is particularly effective in killing cancer cells when used with selinexor. Lab studies have demonstrated that this combination can damage leukemia cells, leading to their death. Although data on humans is limited, these early findings suggest potential effectiveness in treating AML and similar conditions. ^{1 6 7 8 9}

Who Is on the Research Team?

Seth E. Karol, MD

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• Cytarabine
• Fludarabine
• Methotrexate
• Selinexor
• Venetoclax

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.

How Is the Trial Designed?

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 United States, European Union, Canada for the following indications:

Approved in United States as Cytosar-U for:

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

Approved in European Union as Depocyt for:

• Lymphomatous meningitis

Approved in Canada as Cytosar-U for:

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

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Gateway for Cancer Research

Collaborator

Trials

47

Recruited

2,500+

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

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

The combination of the BCL-2 inhibitor venetoclax and the exportin-1 inhibitor selinexor significantly enhances the apoptosis of acute myeloid leukemia (AML) cells in vitro, suggesting a potent synergistic effect against leukemia.

This combination therapy works by inhibiting glycolytic function and downregulating genes related to DNA replication, indicating a novel mechanism of action that could improve treatment outcomes for AML patients.

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]

The combination of SINE compounds (selinexor and eltanexor) with venetoclax significantly enhances cell death in models of acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL), primarily through increased apoptosis and activation of tumor suppressor protein p53.

This synergistic effect not only reduces tumor growth in xenograft models but also shows promise in primary patient cells, suggesting a strong rationale for further clinical trials of this combination therapy in aggressive hematologic cancers.

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]

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]

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]

In a subgroup of 27 Japanese patients with newly diagnosed acute myeloid leukaemia, venetoclax combined with low-dose cytarabine showed a higher complete remission rate (44.4%) compared to placebo (11.1%), indicating potential efficacy in this population.

Despite the higher remission rate, the median overall survival was similar between the venetoclax (4.7 months) and placebo (8.1 months) groups, suggesting limited survival benefit, which may be influenced by small sample size and baseline health differences among patients.

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]

In a phase 1 study involving 23 patients with relapsed/refractory acute myeloid leukemia (AML), the combination of selinexor with mitoxantrone, etoposide, and cytarabine showed an overall response rate of 43%, with 26% of patients achieving complete remission.

The maximum tolerated dose of selinexor was determined to be 30 mg/m2 due to dose-limiting side effects, including hyponatremia, indicating that while the treatment is promising, careful monitoring for toxicity is necessary.

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]

In a phase II study involving 175 patients aged 60 and older with relapsed/refractory acute myeloid leukemia, selinexor did not significantly improve overall survival compared to physician's choice treatment, with median survival times of 3.2 months versus 5.6 months.

Patients treated with selinexor experienced a higher incidence of serious adverse events, including thrombocytopenia and febrile neutropenia, indicating a need for careful patient selection and monitoring in future studies.

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]

In a clinical trial involving 18 children with relapsed or refractory leukemia, selinexor combined with fludarabine and cytarabine showed promising efficacy, with 47% of evaluable patients achieving a complete response or complete response with incomplete count recovery.

Selinexor was found to be tolerable at doses up to 55 mg/m2, with the most common side effect being asymptomatic hyponatremia, while dose-limiting toxicity was observed at 70 mg/m2 due to reversible cerebellar toxicity.

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]

Citations

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Venetoclax (ABT-199), a BH3-mimetic and selective BCL-2 inhibitor, was recently approved by the US Food and Drug Administration (FDA) for the treatment of acute ...

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Preclinical data indicate that selinexor and venetoclax are synergistic and that selinexor may abrogate resistance to venetoclax. We thus aimed ...