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

NCT02212561 | Completed Phase 1 FDA Drug

• 2 other identifiers: SELHEMNCI-2014-01704
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 6

Brief Summary

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 subsequent Phase II portion of the study (insert NCT ID of SELHEM-2) 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), mixed phenotype acute leukemia (MPAL) 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

Conditions

Acute Myeloid Leukemia (AML); Acute Lymphoblastic Leukemia (ALL); Myelodysplastic Syndrome (MDS); Mixed Phenotype Acute Leukemia (MPAL)

Outcome Measures

Primary Outcomes (2)

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

  The MTD is empirically defined as the highest dose level at which six participants have been treated with at most one participant experiencing a DLT and the next higher dose has been determined to be too toxic. If the lowest dose level studied is too toxic or the highest dose level studied is considered safe, the MTD will not have been considered estimated.

  MTD will be determined at the end of cycle 1 (day 35 of therapy)

• Dose limiting toxicity of combination selinexor, fludarabine and cytarabine

  Any participant who experiences dose-limiting toxicities (DLT) at any time during the first 35 days after taking the initial dose of selinexor and before receiving non-protocol therapy (such as transplant) is considered evaluable for toxicity. Participants without DLT who receive at least 5 of the 6 prescribed cycle I doses of selinexor and can be followed for 35 days following their initial dose of selinexor are also considered evaluable for toxicity. Participants who are not evaluable for toxicity (such as those removed early from therapy to start alternate therapy) at a given dose level will be replaced.

  During cycle 1 of therapy (days 1-35)

Secondary Outcomes (4)

• Maximum plasma concentration (Cmax) of selinexor

  Days 1-3 (pre-dose, 30 minutes, and 1, 2, 4, 8, 24, and 48 hours after dose) and Day 22 (pre-dose and 1, 2, 4, and 8 hours after day 22 dose)

• complete response rate

  between days 28 and 35 of cycle 1

• Overall response rate

  Between days 28 and 35 of cycle 1

• Area under the curve (AUC) of selinexor

  Days 1-3 (pre-dose, 30 minutes, and 1, 2, 4, 8, 24, and 48 hours after dose) and Day 22 (pre-dose and 1, 2, 4, and 8 hours after day 22 dose)

Study Arms (1)

Treatment Arm

EXPERIMENTAL

Interventions: Selinexor, Fludarabine, and Cytarabine. Methotrexate/hydrocortisone/cytarabine (intrathecal triples) will be given prior to cycle 1.

Drug: Selinexor; Drug: Fludarabine; Drug: Cytarabine; Drug: methotrexate/hydrocortisone/cytarabine

Interventions

Selinexor DRUG

Given orally on days 1,3,8,10,22 and 24 of each cycle

Also known as: KPT-330

Treatment Arm

Fludarabine DRUG

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.

Also known as: Fludara®, Fludarabine phosphate, 2-fluoro-ara-AMP

Treatment Arm

Cytarabine DRUG

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.

Also known as: Cytosine arabinoside, Ara-C, Cytosar®

Treatment Arm

methotrexate/hydrocortisone/cytarabine DRUG

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).

Also known as: ITMHA, Intrathecal triples

Treatment Arm

Eligibility Criteria

• Age: Up to 24 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• Karyopharm Therapeutics Inc: collaborator

Study Sites (6)

Phoenix Children's Hospital

Phoenix, Arizona, 85016, United States

Location

Lucile Packard Children's Hospital Stanford University

Palo Alto, California, 94304, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Cook Children's Medical Center

Fort Worth, Texas, 76104, United States

Location

Related Publications (1)

• Alexander TB, Lacayo NJ, Choi JK, Ribeiro RC, Pui CH, Rubnitz JE. Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination With Fludarabine and Cytarabine, in Pediatric Relapsed or Refractory Acute Leukemia. J Clin Oncol. 2016 Dec;34(34):4094-4101. doi: 10.1200/JCO.2016.67.5066. Epub 2016 Oct 31.

  PMID: 27507877 RESULT

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes; Leukemia, Biphenotypic, Acute

Interventions

selinexor; fludarabine; fludarabine phosphate; Cytarabine; Methotrexate

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Jeffrey E. Rubnitz, MD,PhD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 30, 2014
• First Posted: August 8, 2014
• Study Start: August 1, 2014
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2015
• Last Updated: March 26, 2020

Record last verified: 2017-02

Locations

US (6)