Study of Selinexor and Venetoclax in Combination With Chemotherapy in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia

NCT04898894 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: SELCLAXNCI-2021-03435
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 8

Brief Summary

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.

Conditions

Acute Leukemia of Ambiguous Lineage in Relapse; Acute Myeloid Leukemia, in Relapse; Refractory Acute Leukemia of Ambiguous Lineage; Refractory Acute Myeloid Leukemia

Keywords

Acute Myeloid Leukemia, in Relapse; Refractory Acute Myeloid Leukemia; Acute Leukemia of Ambiguous Lineage in Relapse; Refractory Acute Leukemia of Ambiguous Lineage; Pediatric; Young Adult

Outcome Measures

Primary Outcomes (4)

• The recommended phase 2 dose (RP2D) of venetoclax plus selinexor plus chemotherapy.

  The primary endpoint is the recommended phase 2 dose (RP2D) of venetoclax plus selinexor plus chemotherapy.

  For each patient, the monitoring time period for dose-limiting toxicity will extend for 35 days from receipt of the first dose of protocol-directed selinexor or venetoclax.

• Number of patients treated

  A count of the number of patients treated at each dose level during the dose escalation phase will be provided

  35 days from the receipt of the first dose of protocol-directed selinexor or venetoclax

• Number of patients who experience a Non-Hematologic dose limiting toxicity (DLT) during the dose escalation phase

  A count of the number of patients at each dose level who experience a Non-Hematologic DLT defined as any grade 3 or higher event that occurs within 35 days of the first dose and is at least possibly attributable to study drug administration (venetoclax, selinexor, fludarabine and/or cytarabine).

  Within 35 days of the first dose of chemotherapy

• Number of patients who experience a Hematologic DLT during the dose escalation phase

  A count of the number of patients at each dose level who experience a Hematologic DLT defined as failure to recover counts (ANC \> 500/µl and platelet count \> 25,000/µl) by day 43 from the start of chemotherapy unless the delay in count recovery is due to another identifiable factor.

  From the start of chemotherapy up to day 43

Secondary Outcomes (6)

• The rates of complete remission (CR) for patients treated with selinexor and venetoclax in combination with chemotherapy at the RP2D.

  The final response of each patient will be determined no later than day 42 from the start of chemotherapy.

• The rates of complete remission with incomplete count recovery (CRi) for patients treated with selinexor and venetoclax in combination with chemotherapy at the RP2D.

  The final response of each patient will be determined no later than day 42 from the start of chemotherapy.

• The overall survival of patients treated at the RP2D.

  Survival of each patient will be determined one year from enrollment.

• The rates of exceptional response for those patients treated during the Dose-escalation phase.

  Day 15

• The rates of exceptional response for those patients treated during the Dose Expansion Phase (Cohort A).

  Day 15

Study Arms (1)

Treatment

EXPERIMENTAL

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.

Drug: Venetoclax; Drug: Selinexor; Drug: Cytarabine; Drug: Fludarabine; Biological: Filgrastim; Drug: Methotrexate; Drug: methotrexate/hydrocortisone/cytarabine

Interventions

Selinexor DRUG

Given Orally (PO)

Also known as: KPT-330

Treatment

Fludarabine DRUG

Given in to the vein (IV) - Because of the ongoing nationwide shortage of fludarabine, this agent may be omitted during the dose expansion phase of the trial.

Also known as: Fludara®, Fludarabine phosphate, 2-fluoro-ara-AMP

Treatment

Filgrastim BIOLOGICAL

Given subcutaneous (SubQ, SC)

Also known as: G-CSF

Treatment

Methotrexate DRUG

Given intrathecal (IT)

Also known as: MTX, amethopterin, Trexall®

Treatment

Venetoclax DRUG

Given orally (PO)

Also known as: Venclextra®, ABT-199

Treatment

Cytarabine DRUG

Given in to the vein (IV) or intrathecal (IT)

Also known as: Cytosine arabinoside, Ara-C, Cytosar®

Treatment

methotrexate/hydrocortisone/cytarabine DRUG

Given intrathecal (IT)

Also known as: ITMHA, Intrathecal triples

Treatment

Eligibility Criteria

• Age: 2 Years - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Participants must have a diagnosis of AML or ALAL and meet the criteria below:
• Refractory leukemia, defined as persistent leukemia after at least two courses of induction chemotherapy, OR
• Early relapsed leukemia, defined as the re-appearance of leukemia after the achievement of remission and within one year of diagnosis, OR
• Relapsed leukemia that is refractory to at least one course of salvage therapy (i.e., therapy given after the relapse has occurred), OR
• Relapsed leukemia following HCT, OR
• Second or greater relapse
• Patients with late first relapses, defined as the re-appearance of leukemia after the achievement of remission and greater than one year of diagnosis, may be enrolled in the dose expansion portion of the study after safety data from the dose escalation portion is available.
• Patients must have ≥ 5% blasts in the bone marrow as assessed by morphology or flow cytometry. However, if flow cytometry cannot be performed or if an adequate bone marrow sample cannot be obtained (e.g., in a patient with acute megakaryoblastic leukemia with marrow fibrosis), patients may be enrolled if there is unequivocal evidence of leukemia with ≥ 5% blasts in the blood.
• In addition, patients in all categories must not be eligible to undergo curative therapy, such as immediate HCT, because of disease burden, time to identify a stem cell donor, or other reasons.
• Adequate organ function defined as the following:
• Direct bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• Normal creatinine for age or a calculated creatinine clearance ≥ 30 mL/min/1.73m\^2
• Left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25%
• Patients must be ≥ 2 years of age and ≤ 30 years old. The upper age limit may be defined by each institution but may not exceed 30 years. Patients treated at St. Jude Children's Research Hospital must be ≤ 24 years old.
• Performance status: Lansky ≥ 50 for patients who are ≤ 16 years old and Karnofsky ≥ 50% for patients who are \> 16 years old.

You may not qualify if:

• Must not be pregnant or breastfeeding. Male or female of reproductive potential must agree to use effective contraception for the duration of study participation.
• Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocytic leukemia, or bone marrow failure syndromes are not eligible.
• Uncontrolled infection. Patients with infections that are controlled on concurrent anti-microbial agents are eligible.
• Impairment of GI function or GI disease that, in the opinion of the treating physician, may significantly alter the absorption of venetoclax or selinexor.
• History of cerebellar toxicity or cerebellar neurological findings on exam.
• Previous toxicity or hypersensitivity directly attributed to venetoclax.

Sponsors & Collaborators

• Gateway for Cancer Research: collaborator
• St. Jude Children's Research Hospital: lead
• Karyopharm Therapeutics Inc: collaborator
• AbbVie: collaborator

Study Sites (8)

Rady Children's Hospital-San Diego

San Diego, California, 92123, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Childrens Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

UT Southwestern/Simmons Cancer Center

Dallas, Texas, 75390, United States

Location

Cook Children's Medical Center

Fort Worth, Texas, 76104, United States

Location

Related Links

• St. Jude Children's Research Hospital
• ClinicalTrials Open at St. Jude

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia, Biphenotypic, Acute

Interventions

venetoclax; selinexor; Cytarabine; fludarabine; fludarabine phosphate; Filgrastim; Granulocyte Colony-Stimulating Factor; Methotrexate

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Seth Karol, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 14, 2021
• First Posted: May 24, 2021
• Study Start: November 15, 2021
• Primary Completion: July 12, 2023
• Study Completion (Estimated): September 1, 2027
• Last Updated: April 28, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be made available at the time of article publication.
• Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.

Locations

US (8)