Selinexor in Combination With Fludarabine and Cytarabine in Patients With Refractory or Relapsed Acute Myeloid Leukemia
Condition: Acute Myeloid Leukemia (AML)
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Selinexor; Fludarabine; Cytarabine; methotrexate/hydrocortisone/cytarabine
Intervention description: Given orally on days 1,3,8,10,22 and 24 of each cycle; Will be given intravenously (IV) over 30 minutes daily on days 16 through 20. Fludarabine may be given prior to day 16 if it is determined to be in the participant's best interest based on disease progression. Chemotherapy may be delayed by 1-3 days if clinically indicated.; Will be given IV over 4 hours daily on days 16 through 20. Cytarabine may be given prior to day 16 if it is determined to be in the participant's best interest based on disease progression. Chemotherapy may be delayed by 1-3 days if clinically indicated.; Intrathecal (IT) triples will be given prior to cycle 1: IT cytarabine, IT methotrexate, and IT methotrexate/hydrocortisone/cytarabine (MHA) are acceptable. Patients without evidence of central nervous system (CNS) leukemia will receive no further IT therapy during cycle 1. Patients with CNS disease will receive weekly ITMHA until the cerebrospinal fluid becomes free of leukemia (minimum of 4 doses).
Intervention MeSH terms: Cytarabine; Hydrocortisone; Methotrexate; Fludarabine phosphate; Fludarabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 37.0
Sex: All
Maximum age: 24 Years
Healthy volunteers: No

Summary:

      This study will be done in two parts: Phase I (NCT02212561) has been completed and published.
      The goal of the Phase I portion of this study was to find the highest tolerable dose of
      selinexor (KPT-330) that can be given to patients with leukemia or myelodysplastic syndrome
      (MDS), when it is combined with fludarabine and cytarabine.

      The Phase II portion of the protocol is reflected in this registration.

      The goal of the Phase II portion of this protocol is to give the highest dose of selinexor
      (KPT-330) in combination with fludarabine/cytarabine that was found in Phase I to be safe for
      children with acute myeloid leukemia (AML). The investigators will examine the effect of this
      combination treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants must have a diagnosis of AML 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 two courses of
                  induction chemotherapy.

               -  Patients are eligible at first or subsequent relapse or any relapse that is
                  refractory to salvage chemotherapy.

               -  Patients must have ≥ 5% leukemic blasts in the bone marrow and/or increasing
                  levels of MRD in the bone marrow as assessed by flow cytometry. 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 and Karnofsky ≥
             50% for patients who are > 16 years old.

          -  Patients must have fully recovered from the acute effects of all prior therapy.

          -  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.

        Exclusion Criteria:

          -  History of cerebellar toxicity or cerebellar neurological findings on exam.

          -  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, with the exception of gemtuzumab ozogamicin, 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 one 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.

          -  Prior treatment with selinexor.