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Acute Myeloid Leukemia (AML)Phase 1NCT02212561

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

A Phase 1 study testing Selinexor, Fludarabine and Cytarabine in people with Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL), run by St. Jude Children's Research Hospital at 6 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages Up to 24 years
What is being tested?
Selinexor, Fludarabine and Cytarabine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
19 participants
Where
6 sitesUnited States
Study dates
Aug 2014to Dec 2015
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 24 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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)
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  • 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.

Who cannot join

  • 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:
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  • 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.

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

United States6 sites

  • University of Chicago

    Chicago, Illinois, 60637

  • Duke University Medical Center

    Durham, North Carolina, 27710

  • Cook Children's Medical Center

    Fort Worth, Texas, 76104

  • St. Jude Children's Research Hospital

    Memphis, Tennessee, 38105

  • Lucile Packard Children's Hospital Stanford University

    Palo Alto, California, 94304

  • Phoenix Children's Hospital

    Phoenix, Arizona, 85016

Other trials in United States

About this study

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

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.

Read more

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
Read the 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.

Being tested
Selinexor, Fludarabine, Cytarabine, methotrexate/hydrocortisone/cytarabine
Medical subject headings
Leukemia, Myeloid, Acute, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Myelodysplastic Syndromes, Leukemia, Biphenotypic, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • SelinexorDrug

    Also called KPT-330

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

  • FludarabineDrug

    Also called Fludara®, Fludarabine phosphate, 2-fluoro-ara-AMP

    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.

  • CytarabineDrug

    Also called Cytosine arabinoside, Ara-C, Cytosar®

    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.

  • methotrexate/hydrocortisone/cytarabineDrug

    Also called ITMHA, Intrathecal triples

    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).

Study groups in NCT02212561
Study groupRoleWhat they receive
Treatment ArmExperimentalInterventions: Selinexor, Fludarabine, and Cytarabine. Methotrexate/hydrocortisone/cytarabine (intrathecal triples) will be given prior to cycle 1.
Receives: Drug: Selinexor; Drug: Fludarabine; Drug: Cytarabine; Drug: methotrexate/hydrocortisone/cytarabine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

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

  2. 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.

    Measured: During cycle 1 of therapy (days 1-35)

Secondary outcomes (4)

  1. Maximum plasma concentration (Cmax) of selinexor

    The pharmacokinetics of selinexor as well as selinexor in combination with fludarabine and cytarabine will be determined.

    Plasma samples will be analyzed for selinexor concentration. Selinexor concentration data will be analyzed in a non-linear mixed effects population PK model with potential covariates including age, body weight, gender, disease state, hepatic or renal function, concomitant medications, and treatment. Details of the population PK analysis, including software, post-processing and statistical analysis, will be outlined in a separate Data Analysis Plan. Interim analysis may be conducted on plasma selinexor concentration data throughout the study. Summary statistics, including mean, median, standard deviation, coefficient of variation and group size may be compiled and reported during the study. Interim analysis of PK parameters and biomarker analyses may be performed in order to provide a pharmacokinetic-pharmacodynamic assessment throughout the study.

    Measured: 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)

  2. complete response rate

    The efficacy of the combination of selinexor, fludarabine, and cytarabine, as measured by the complete response (CR) rate and the overall response (OR) rate (CR + CRi + PR) will be assessed for the patients enrolled at the MTD. The rates of CR and OR will be presented as a point estimate with a 95% exact binomial confidence interval.

    Measured: between days 28 and 35 of cycle 1

  3. Overall response rate

    The efficacy of the combination of selinexor, fludarabine, and cytarabine, as measured by the complete response (CR) rate and the overall response (OR) rate (CR + CRi + PR) will be assessed for the patients enrolled at the MTD. The rates of CR and OR will be presented as a point estimate with a 95% exact binomial confidence interval.

    Measured: Between days 28 and 35 of cycle 1

  4. Area under the curve (AUC) of selinexor

    The pharmacokinetics of selinexor as well as selinexor in combination with fludarabine and cytarabine will be determined.

    Plasma samples will be analyzed for selinexor concentration. Selinexor concentration data will be analyzed in a non-linear mixed effects population PK model with potential covariates including age, body weight, gender, disease state, hepatic or renal function, concomitant medications, and treatment. Details of the population PK analysis, including software, post-processing and statistical analysis, will be outlined in a separate Data Analysis Plan. Interim analysis may be conducted on plasma selinexor concentration data throughout the study. Summary statistics, including mean, median, standard deviation, coefficient of variation and group size may be compiled and reported during the study. Interim analysis of PK parameters and biomarker analyses may be performed in order to provide a pharmacokinetic-pharmacodynamic assessment throughout the study.

    Measured: 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)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Aug 2014 (estimated)
  2. Study startAug 2014
  3. Primary completionDec 2015
  4. Study completionDec 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
19 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02212561
Sponsor's protocol ID
SELHEM
Other IDs
NCI-2014-01704
Status last verified
Feb 2017
First submitted
30 Jul 2014
Last updated
26 Mar 2020
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 27507877

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Selinexor, Fludarabine and Cytarabine in people with Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL), run by St. Jude Children's Research Hospital at 6 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Mar 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated dose (MTD) of combination selinexor, fludarabine and cytarabine (time frame: MTD will be determined at the end of cycle 1 (day 35 of therapy)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02212561, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Mar 2020.

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