Selinexor in Combination With Fludarabine and Cytarabine in Patients With Refractory or Relapsed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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.

Detailed Description
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After the recommended Phase II dose was determined, additional patients began enrolling to receive selinexor at the recommended dose level for further evaluation of tolerability and response. PRIMARY OBJECTIVE: To estimate the overall response rate, as defined by complete response or complete response with incomplete count recovery, of selinexor in combination with fludarabine and cytarabine for patients with relapsed or refractory AML in the phase II portion of the study.

Official Title
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A 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

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: Selinexor
* Drug: Fludarabine
* Drug: Cytarabine
* Drug: methotrexate/hydrocortisone/cytarabine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Interventions: Selinexor, Fludarabine, and Cytarabine. Methotrexate/hydrocortisone/cytarabine (intrathecal triples) will be given prior to cycle 1. | Drug: Selinexor<br>* Given orally on days 1,3,8,10,22 and 24 of each cycle<br>* Other names: KPT-330;Drug: Fludarabine<br>* 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.<br>* Other names: 2-fluoro-ara-AMP;Drug: Cytarabine<br>* 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.<br>* Other names: Cytosar®;Drug: methotrexate/hydrocortisone/cytarabine<br>* 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).<br>* Other names: Intrathecal triples;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Overall Response (OR) Rate (Complete Response + Incomplete Count Recovery + Partial Response) | Complete response or complete response with incomplete count recovery or partial response, of selinexor in combination with fludarabine and cytarabine for patients with relapsed or refractory AML in the phase II portion of the study | Between days 28 and 35 of cycle 1 (cycle length is 42-56 days) | 
| Complete Response | Complete response, of selinexor in combination with fludarabine and cytarabine for patients with relapsed or refractory AML in the phase II portion of the study | Between days 28 and 35 of cycle 1 (cycle length is 42-56 days) | 
| Complete Response or Complete Response With Incomplete Count Recovery | Complete response or complete response with incomplete count recovery, of selinexor in combination with fludarabine and cytarabine for patients with relapsed or refractory AML in the phase II portion of the study | Between days 28 and 35 of cycle 1 (cycle length is 42-56 days) |