Clinical Trials /

A Study of Selinexor in Combination With Daunorubicin and Cytarabine for Untreated AML

NCT02403310

Description:

The main purpose of this study is to determine the safety of combining selinexor with daunorubicin and cytarabine. The maximal tolerated dose (MTD) of selinexor with daunorubicin and cytarabine will also be established.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of Selinexor in Combination With Daunorubicin and Cytarabine for Untreated AML
  • Official Title: A Phase 1 Investigator Sponsored Study of Selinexor in Combination With Daunorubicin and Cytarabine in Patients With Previously Untreated Poor-Risk Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: MCC-18157
  • NCT ID: NCT02403310

Conditions

  • Leukemia
  • Acute Myeloid Leukemia
  • AML

Interventions

DrugSynonymsArms
SelinexorKPT-330, SINE KPT-330Dose Escalation - Selinexor
DaunorubicinCerubidine®, daunomycin cerubidine, daunorubicin hydrochlorideDose Escalation - Selinexor
CytarabineCytosar-U, Tarabine PFS, ARA-CDose Escalation - Selinexor

Purpose

The main purpose of this study is to determine the safety of combining selinexor with daunorubicin and cytarabine. The maximal tolerated dose (MTD) of selinexor with daunorubicin and cytarabine will also be established.

Detailed Description

      Induction Therapy - Dose escalation of selinexor with Daunorubicin and cytarabine at fixed
      doses.

      Consolidation Phase - Patients who are in complete remission (CR) or complete remission with
      incomplete count recovery (CRi) by day ≤70 and have recovered from any previous non-
      hematologic toxicity to baseline or grade ≤1 by day ≤70 following induction chemotherapy may
      go on to receive consolidation therapy for up to 2 cycles. The consolidation treatment phase
      will include up to two courses of therapy (28 day cycles) as follows:

      Daunorubicin 45mg/m^2/day (days 1-2) Cytarabine 100mg/m^2/day (continuous infusion on days
      1-5) Selinexor same dose as induction (days 1,3,8,10) unless dose limiting toxicity (DLT)
      dictates a dose reduction. Selinexor will be given 2 hours prior to daunorubicin on day 1.

      A second cycle of consolidation therapy using the same doses as above will be administered,
      at the investigators discretion, between 28 and 42 days following initiation of the first
      consolidation treatment, after peripheral blood counts have recovered to CR, CRi levels, and
      after recovery from any non-hematologic toxicity to baseline or grade ≤1. Dose escalation of
      Selinexor will not occur during the consolidation phase.

      Maintenance Phase - Patients who remain in CR, CRi after up to 2 cycles of consolidation and
      are not eligible for allogeneic stem cell transplant will be eligible for the maintenance
      phase of treatment after recovery from any previous non-hematologic toxicity to baseline or
      grade ≤1. Maintenance therapy will consist of:

      Selinexor at the same dose as induction on days 1 and 8 of a 21 day cycle. They will continue
      for a maximum of 12 months.

      Expansion Phase - Once the MTD has been established, there will be an expansion phase to
      enroll an additional 13 subjects at the MTD to better characterize the safety profile and
      tolerability.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation - SelinexorExperimentalDose escalation of selinexor with fixed doses of daunorubicin and cytarabine. Induction Therapy may be followed by Consolidation Phase and Maintenance Phase as outlined in the Detailed Description and Intervention Descriptions.
  • Selinexor
  • Daunorubicin
  • Cytarabine

Eligibility Criteria

        Inclusion Criteria:

          -  Potential participants must have newly diagnosed, previously untreated acute myeloid
             leukemia (AML) (excluding M3); Must have adverse-risk AML defined as poor-risk
             karyotype (complex, monosomal or other known poor risk cytogenetic abnormality),
             poor-risk mutations/fusion genes or known history of antecedent hematologic disorder,
             or treatment related AML, or be ≥60 years of age; Cytogenetics, FISH or mutational
             analysis confirming adverse risk features must have been done within 90 days prior to
             enrollment.

          -  May not have undergone any prior therapy for their AML other than hydroxyurea.
             However, if patients had an antecedent myelodysplastic syndrome (MDS), prior treatment
             with a hypomethylating agent or any other therapy (with the exception of allogeneic
             stem cell transplant) used to treat their MDS is allowed.

          -  Age ≥18 years

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

          -  Life expectancy of greater than 2 months

          -  Must have normal organ function

          -  Able and willing to adhere to the study visit schedule and other protocol requirements

          -  Baseline left ventricular ejection fraction (LVEF) ≥ 50%

          -  Women of child-bearing potential must have a negative serum or urine pregnancy test
             with a sensitivity of at least 50 milli-international units per milliliter (mIU)mL)
             within 10 days and again within 24 hours prior to beginning study treatment.
             Participants of childbearing potential must practice recommended contraception. Should
             a woman become pregnant or suspect she is pregnant while participating in this study,
             she should inform her treating physician immediately. Breastfeeding mothers must agree
             to discontinue nursing if the mother is treated with selinexor.

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Able to swallow capsules and have no evidence of GI tract abnormality that would alter
             the absorption of oral medications

          -  Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 x upper limit of
             normal (ULN)

        Exclusion Criteria:

          -  May not be receiving any other investigational agents

          -  Documented central nervous system (CNS) involvement of AML

          -  AML with favorable risk cytogenetic abnormalities including t(15;17), t(8;21) or
             inv(16)

          -  Potential participants who are in the blast phase of chronic myeloid leukemia

          -  Major surgery within 2 weeks of first dose of study drug; must have recovered from the
             effects of any surgery performed greater than 2 weeks prior

          -  White blood cell (WBC) count ≥50,000 on hydroxyurea

          -  Predicted inability to tolerate standard induction chemotherapy with daunorubicin and
             cytarabine

          -  Uncontrolled intercurrent illness including, but not limited to ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  HIV-positive, receiving combination anti-retroviral therapy

          -  No other malignancies in addition to AML that are currently requiring treatment with
             the exception of basal cell or squamous cell carcinoma of the skin, or carcinoma in
             situ of the cervix or breast

          -  History of allogeneic stem cell transplant for MDS or any other antecedent hematologic
             disorder.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximal Tolerated Dose (MTD) of Selinexor
Time Frame:Up to 18 months
Safety Issue:
Description:MTD / Recommended Phase II Dose (RP2D) of selinexor with daunorubicin and cytarabine. Dose Limiting Toxicity (DLT): Non-hematologic - Any grade 3-4 drug-related non-hematologic toxicity, with the following exceptions: Nausea/vomiting or diarrhea adequately controlled with antiemetics/antidiarrheals; Infection or febrile neutropenia adequately controlled with antibiotics; Liver function abnormalities (without clinical symptoms) that recover to baseline or grade 0-1 within 7 days; Grade 3-4 electrolyte or metabolic laboratory abnormalities that are not considered clinically significant by the treating investigator/physician and that recover to baseline or grade 0-1 within 7 days; Alopecia. Hematologic - Grade 3-4 neutropenia and/or thrombocytopenia (thought to be due to marrow hypoplasia and NOT leukemic burden) that does not recover to grade ≤2 by day 56.

Secondary Outcome Measures

Measure:Rate of Complete Response (CR) Plus Complete Response with Incomplete Count Recovery (CRi).
Time Frame:Up to 18 months
Safety Issue:
Description:A CR designation requires that the patient achieve the morphologic leukemia-free state and have an absolute neutrophil count of more than 1,000/μL and platelets of 100,000/μL. A CRi designation requires that the patient achieve the morphologic leukemia-free state with incomplete recovery of neutrophils (<1,000/μL) or platelets (<100,000/μL).
Measure:Disease Free Survival (DFS)
Time Frame:Up to 18 months
Safety Issue:
Description:Disease free survival is measured from the time measurement criteria are met for CR/CRi until the first date that relapse is objectively documented.
Measure:Time to Progression (TTP)
Time Frame:Up to 18 months
Safety Issue:
Description:Time to progression is a secondary endpoint that will be measured as the time from when the patient started treatment to the time the patient is first recorded as having relapsed, or the date of death if the patient dies due to causes other than disease progression.
Measure:Overall Survival (OS)
Time Frame:Up to 18 months
Safety Issue:
Description:Overall survival is a secondary endpoint that will be measured as time from the start of treatment until death from any cause, or the last date the patient was known to be alive.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:H. Lee Moffitt Cancer Center and Research Institute

Trial Keywords

  • adverse-risk AML
  • poor-risk karyotype
  • cytogenetic abnormality
  • poor-risk mutations
  • antecedent hematologic disorder
  • treatment related AML

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