SELHEM: Selinexor With Fludarabine and Cytarabine for Treatment of Refractory or Relapsed Leukemia or Myelodysplastic Syndrome

Phase I/II Study of the Selective Inhibitor of Nuclear Export Selinexor (KPT-330) in Combination with Fludarabine and Cytarabine in Patients with Refractory or Relapsed Leukemia or Myelodysplastic Syndrome

Categories:

Leukemia / Lymphoma

Phase I/II

Diseases Treated:

Relapsed or refractory leukemia or hematologic malignancies

Eligibility Overview:

  • Up to 21 years of age
  • Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS) or mixed phenotype acute leukemia (MPAL) that has come back or did not respond to previous treatment
  • No history of HIV infection

Protocol Update January 2016

We have completed the Phase I portion of the trial and are now enrolling patients on the Phase II portion. Patients will receive selinexor at a dose of 40 mg/m2 in combination with fludarabine and cytarabine to confirm that this dose is safe and to explore the activity of this combination.

  1. Brief Summary

    The purpose of this study is to test the safety of selinexor (KPT-330) and to find the highest dose of selinexor that can be given safely when it is combined with two chemotherapy drugs (fludarabine and cytarabine). This study will be done in two parts: Phase 1 and Phase 2.

    • Phase 1 – to find the highest tolerable dose of selinexor that we can give to patients with leukemia or MDS, when it is combined with fludarabine and cytarabine.
    • Phase 2 – to give the highest dose of selinexor in combination with fludarabine / cytarabine that was found in phase 1 to be safe for children with leukemia or MDS.

    Primary Objective

    To determine a tolerable combination of selinexor, fludarabine, and cytarabine in pediatric patients with relapsed or refractory hematologic malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS).

    Trial Outline

    • Phase 1 will characterize the dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) or recommended phase 2 dose of selinexor when given in combination with fludarabine and cytarabine.
    • Selinexor will be given twice weekly (on Days 1 and 3) and escalated or de-escalated based on tolerability. The rolling-6 design will be used for this study. Only cycle 1 of therapy will be used to evaluate the DLT. Two to 6 participants can be concurrently enrolled onto a dose level, dependent on 1) the number of participants enrolled at the current dose level, 2) the number of participants who have experienced DLT at the current dose level, and 3) the number of participants entered but with tolerability data pending at the current dose level. Accrual is suspended when a cohort of 6 has enrolled or when the study endpoints have been met.
    • Once the recommended phase 2 dose is determined, additional patients will be enrolled, if necessary, so that at least 6 subjects are treated with the recommended phase 2 dose to determine MTD. After the MTD is determined, 12 additional patients will be treated at this dose level for further evaluation of tolerability and response.

    Study Arm

    Experimental treatment

    Intervention

    Drugs: Selinexor, fludarabin, cytarabine, methotrexate/hydrocortisone/cytarabine

    Eligibility Criteria

    Inclusion Criteria:

    • Participants must have a diagnosis of AML, MDS, ALL or MPAL and must have disease that has relapsed or is refractory to chemotherapy, or that has relapsed after hematopoietic stem cell transplantation (HSCT)
      • Refractory disease is defined as persistent disease after at least 2 courses of induction chemotherapy
      • Patients with AML, MPAL or MDS are eligible at first or subsequent relapse, whereas patients with ALL are eligible at second or subsequent relapse or any relapse that is refractory to salvage chemotherapy.
      • Patients with AML or ALL must have ≥ 5% leukemic blasts in the bone marrow. If an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia in the peripheral blood.
    • Adequate organ function defined as the following:
      • Direct bilirubin ≤ 1.5 x institutional upper limit of normal (IULN)
      • AST (SGOT) / ALT (SGPT) < 3 x IULN
      • Creatinine within normal institutional limits for age
      • Prothrombin time (PT) and partial thromboplastin (PTT) ≤ 1.5 x IULN
    • Age criteria: patients treated at collaborating sites and current St. Jude patients who are on therapy or within 3 years of completion of therapy must be ≤ 24 years old. All other St. Jude patients must be < 21 years old.
    • Patients must be able to swallow tablets.
    • Performance status:
      • Lansky ≥ 50 for patients who are ≤ 16 years old
      • Karnofsky ≥ 50% for patients who are > 16 years old
    • Patients must have fully recovered from the acute effects of all prior therapy and must meet the following criteria:
      • At least 14 days must have elapsed since the completion of myelosuppressive therapy
      • At least 24 hours must have elapsed since the completion of hydroxyurea, low-dose cytarabine (up to 100 mg/m2/day), and intrathecal chemotherapy
      • For patients who have received prior HSCT, there can be no evidence of GVHD and greater than 60 days must have elapsed since the HSCT. Patients cannot be receiving therapy, including steroids, for GVHD.

    Exclusion Criteria:

    • Must not be pregnant or breastfeeding. Female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose.
    • Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocytic leukemia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or other bone marrow failure syndromes are not eligible
    • Use of investigational agents within 30 days
    • Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, study participation, follow up, or interpretation of study research
    • Unstable cardiovascular function:
      • symptomatic ischemia
      • congestive heart failure NYHA Class > 3
      • myocardial infarction (MI) within 3 months
    • Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to first dose. Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines are acceptable.
    • Known human immunodeficiency virus (HIV) infection (pre-study testing not required).
    • Patients with malabsorption syndrome, or any other disease significantly affecting gastrointestinal function.

    Study Design

    • Endpoint Classification: Safety / Efficacy Study
    • Intervention Model: Single Group Assignment
    • Masking: Open Label
    • Primary Purpose: Treatment
  2. About this clinical trial

    SELHEM is a Phase I/Phase II clinical trial for children with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS) or mixed phenotype acute leukemia (MPAL). Known as hematologic cancers, or blood cancers, AML, ALL, MDS and MPAL affect the body’s ability to make healthy bone marrow and can be difficult to treat when they come back or do not respond to previous treatment. At St. Jude, researchers are determined to find new treatments for patients with AML, ALL, MDS and MPAL, which is why this clinical trial is being offered.

    Purpose of this clinical trial

    The main goal of this clinical trial is to find out if an investigational drug called selinexor is safe and if it can benefit children, adolescents and young adults with AML, ALL, MDS or MPAL. Selinexor is an experimental drug, which means it has not been approved by the U.S. Food and Drug Administration (FDA). The other two drugs used in this clinical trial, fludarabine and cytarabine, are approved chemotherapy drugs.

    Treatment

    This study will be done in two parts:

    • Phase I: the goal is to find the highest dose of selinexor that can be safely given to young patients with AML, ALL, MDS or MPAL when it is given with two chemotherapy drugs called fludarabine and cytarabine. Once a safe dose is found, Phase II of the study will begin.
    • Phase II: the goal is to find out how well the safe dose of selinexor works when given together with fludarabine and cytarabine to reach a remission (no signs or symptoms) of the leukemia.

    Treatment (Phases I and II)

    • Treatment (up to three months) – All  participants will be receive selinexor/fludarabine/cytarabine combination therapy,
    • Post-treatment (at least four weeks) – After the treatment phase is completed, participants will be watched for side effects. 

    Eligibility overview

    • Up to 21 years of age
    • Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS) or mixed phenotype acute leukemia (MPAL) that has come back or did not respond to previous treatment
    • No history of HIV infection
  3. SELHEM  Quick View
    Sponsor St. Jude Children's Research Hospital
    Collaborator Karyopharm Therapeutics, Inc
    ClinicalTrials.gov identifier NCT02212561
    Trial start date  August 2014
    Estimated enrollment 45
    Estimated trial completion date September 2018
    Study type Interventional
    Study phases Phase 1/Phase 2
    Conditions
    • Acute Myeloid Leukemia (AML)
    • Acute Lymphoblastic Leukemia (ALL)
    • Myelodysplastic Syndrome (MDS)
    • Mixed Phenotype Acute Leukemia (MPAL)
    Ages Up to 24 years
    Principal investigator Jeffrey E. Rubnitz, MD, PhD
    Study site St. Jude Children's Research Hospital
    For a consultation or to discuss SELHEM St. Jude Physician/Patient Referral Office
    1-888-226-4343
    referralinfo@stjude.org

Principal Investigator

Jeffrey E. Rubnitz, MD, PhD

St. Jude Children’s Research Hospital
262 Danny Thomas Place
Memphis, TN 38105  USA
Voice: 1-888-226-4343 or 901-595-4055
24-Hour Emergency Access Pager: 1-800-349-4334

Referring or consulting clinicians only: protocolinfo@stjude.org
For all other inquiries about St. Jude Children's Research Hospital studies: referralinfo@stjude.org

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