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

Information source: St. Jude Children's Research Hospital
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Acute Myeloid Leukemia (AML); Acute Lymphoblastic Leukemia (ALL); Myelodysplastic Syndrome (MDS); Mixed Phenotype Acute Leukemia (MPAL)

Intervention: Selinexor (Drug); Fludarabine (Drug); Cytarabine (Drug); methotrexate/hydrocortisone/cytarabine (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: St. Jude Children's Research Hospital

Official(s) and/or principal investigator(s):
Jeffrey E. Rubnitz, MD,PhD, Principal Investigator, Affiliation: St. Jude Children's Research Hospital

Overall contact:
Jeffrey E. Rubnitz, MD,PhD, Phone: 866-278-5833, Email: referralinfo@stjude.org


The purpose of this study is to test the safety of selinexor (KPT-330) and to find the highest dose of selinexor (KPT-330) 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 I and Phase II. The goal of Phase I is to find the highest tolerable dose of selinexor (KPT-330) that we can give to patients with leukemia or MDS, when it is combined with fludarabine and cytarabine. The goal of the Phase II portion of the study 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 leukemia or MDS. The investigators will examine the effect of this combination treatment. PRIMARY OBJECTIVE:

- Determine a tolerable combination of selinexor, fludarabine, and cytarabine in

pediatric patients with relapsed or refractory hematologic malignancies included acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS). SECONDARY OBJECTIVES:

- To characterize the pharmacokinetics of selinexor, when administered in tablet form,

after the first dose and at steady-state, as well as in combination with fludarabine and cytarabine

- To estimate the overall response rate of selinexor given with fludarabine and

cytarabine in patients with relapsed or refractory hematologic malignancies

Clinical Details

Official title: 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

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Maximum tolerated dose (MTD) of combination selinexor, fludarabine and cytarabine

Dose limiting toxicity of combination selinexor, fludarabine and cytarabine

Secondary outcome:

Maximum plasma concentration (Cmax) of selinexor

complete response rate

Overall response rate

Area under the curve (AUC) of selinexor

Detailed description: Phase I will characterize the dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) or recommended phase II 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 six 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 six has enrolled or when the study endpoints have been met. Once the recommended Phase II dose is determined, additional patients will be enrolled, if necessary, so that at least 6 subjects are treated with the recommended Phase II 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.


Minimum age: N/A. Maximum age: 24 Years. Gender(s): Both.


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 two 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)


- 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 and

must meet the following criteria:

- At least 14 days must have elapsed since the completion of myelosuppressive


- 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 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.

Locations and Contacts

Jeffrey E. Rubnitz, MD,PhD, Phone: 866-278-5833, Email: referralinfo@stjude.org

St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States; Recruiting
Jeffrey E. Rubnitz, MD, PhD, Phone: 866-278-5833, Email: referralinfo@stjude.org
Jeffrey E. Rubnitz, MD, PhD, Principal Investigator

Cook Children's Medical Center, Fort Worth, Texas 76104, United States; Recruiting
Kenneth M. Heym, MD, Phone: 682-885-4007, Email: kenneth.heym@cookchildrens.org
Kenneth M. Heym, MD, Principal Investigator

Additional Information

St. Jude Children's Research Hospital

Clinical Trials Open at St. Jude

Starting date: August 2014
Last updated: August 5, 2015

Page last updated: August 20, 2015

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