Study of CLAG + Selinexor in Relapsed or Refractory Acute Myeloid Leukemia

March 6, 2020 updated by: Washington University School of Medicine

An Investigator Sponsored Phase I/II Study of CLAG + Selinexor in Relapsed or Refractory Acute Myeloid Leukemia

Selinexor has shown single-agent activity in a current phase I study enrolling patients with relapsed/refractory AML with durable complete remissions (CR), complete remissions with incomplete hematologic recovery (CRi), partial remissions (PR), and stable disease (SD) observed. Furthermore, common toxicities included nausea, fatigue, and anorexia and were manageable with supportive care agents. Additionally, CLAG chemotherapy has proven activity in relapsed and refractory AML, and has been shown to be a relatively well tolerated regimen without significant non-hematologic toxicity. Given the established role of CLAG chemotherapy, the single agent activity of selinexor, and their non-overlapping toxicities, the investigators propose a phase I/II open label study of selinexor in combination with CLAG for the treatment of patients with relapsed/refractory AML.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
40

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Washington University School of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Histologically confirmed AML (defined using WHO criteria) with one of the following:

    • Primary refractory disease following ≤ 2 cycles of induction chemotherapy, or
    • First relapse with no prior unsuccessful salvage chemotherapy, or
    • Relapsed or refractory to hypomethylating agent, defined as a lack of response, disease progression, loss of response, or intolerance as deemed by the study investigator
  • Age between 18 and 70 years old.
  • ECOG performance status ≤ 3

  • Adequate organ function as defined below:

    • AST(SGOT), ALT(SGPT), total bilirubin ≤ 2 x IULN except when in the opinion of treating physician is due to direct involvement of leukemia (eg. hepatic infiltration or biliary obstruction due to leukemia) or Gilbert's disease
    • Creatinine clearance >50 ml/min, calculated using the formula of Cockroft and Gault: (140-Age) x Mass (kg) / (72 x Creatinine mg/dL); multiply by 0.85 if female.
    • Left ventricular ejection fraction of ≥ 40% by MUGA scan or echocardiogram
  • To ensure that no patient will receive a dose of selinexor >70mg/m^2, body surface area (BSA) calculated by Dubois method must be >1.43 m^2
  • Patients should not become pregnant or father a baby while on this study because the drugs in this study can affect an unborn baby. Women should not breastfeed a baby while on this study. It is important patients understand the need to use birth control while on this study. It is not anticipated that female patients enrolling in this study will be able to conceive. However, in the rare event that this is possible, 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.
  • Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

  • Acute promyelocytic leukemia (AML with t(15;17)(q22;q11) and variants).
  • Previous treatment with CLAG or other chemotherapy regimen containing both cladribine and cytarabine.
  • Colony stimulating factors within 2 weeks of study.
  • Active graft versus host disease (GVHD) after allogeneic stem cell transplantation. At least 2 months must have elapsed since completion of an allogeneic stem cell transplantation.
  • Less than 2 weeks from the completion of any previous cytotoxic chemotherapy (with the exception of hydroxyurea).
  • Concurrent active malignancy under treatment except prostate or breast cancer undergoing treatment with hormonal therapy.
  • Treatment with any investigational agent within three weeks prior to first dose in this study.
  • Active CNS involvement with leukemia.

  • Unstable cardiovascular function:

    • symptomatic ischemia, or
    • uncontrolled clinically significant conduction abnormalities (i.e. ventricular tachycardia on antiarrhythmics are excluded and 1st degree AV block or asymptomatic LAFB/RBBB will not be excluded), or
    • congestive heart failure (CHF) of NYHA class ≥3, or
    • myocardial infarction (MI) within 3 months
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to KPT-330 or other agents used in the study.
  • 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 is acceptable.
  • Any medical condition which, in the investigator's opinion, could compromise the patient's safety.
  • Pregnant and/or breastfeeding. Patient must have a negative urine pregnancy test within 5 days of study entry.
  • Unable to swallow tablets, or diagnosed malabsorption syndrome, or any other disease significantly affecting gastrointestinal function.
  • Known active hepatitis B virus (HBV) or C virus (HCV) infection; or known to be positive for HCV ribonucleic acid (RNA) or HBsAg (HBV surface antigen).
  • Known human immunodeficiency virus (HIV) infection.
  • Serious psychiatric or medical conditions that could interfere with treatment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Phase I Schedule A (selinexor)
  • Selinexor will be dosed on Days 1, 5, 10, and 12 of the 28-day cycle. All doses will be 60 mg each PO.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.
Drug: Cytarabine
Other Names:
  • Ara-C
  • Cytosar-U ®
  • 1-β-Arabinofuranosylcytosine
  • Cytosine arabinoside
Drug: G-CSF
Other Names:
  • Mozobil®
  • Plerixafor
Drug: Selinexor
Other Names:
  • KPT-330
Drug: Cladribine
Other Names:
  • Leustatin®
  • 2-CdA
  • 2-Chloro-2'-deoxyadenosine
  • CdA
  • Chlorodeoxyadenosine
Procedure: Bone marrow biopsy
Other Names:
  • Bone marrow aspirate
Experimental: Phase I Schedule B (selinexor)
  • Selinexor will be dosed on Days 1, 5, 10, 12, 17, and 19 of the 28-day cycle. All doses will be 60 mg each PO.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.
Drug: Cytarabine
Other Names:
  • Ara-C
  • Cytosar-U ®
  • 1-β-Arabinofuranosylcytosine
  • Cytosine arabinoside
Drug: G-CSF
Other Names:
  • Mozobil®
  • Plerixafor
Drug: Selinexor
Other Names:
  • KPT-330
Drug: Cladribine
Other Names:
  • Leustatin®
  • 2-CdA
  • 2-Chloro-2'-deoxyadenosine
  • CdA
  • Chlorodeoxyadenosine
Procedure: Bone marrow biopsy
Other Names:
  • Bone marrow aspirate
Experimental: Phase II (selinexor)
  • Selinexor will be given at the schedule as determined in Phase 1.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.
Drug: Cytarabine
Other Names:
  • Ara-C
  • Cytosar-U ®
  • 1-β-Arabinofuranosylcytosine
  • Cytosine arabinoside
Drug: G-CSF
Other Names:
  • Mozobil®
  • Plerixafor
Drug: Selinexor
Other Names:
  • KPT-330
Drug: Cladribine
Other Names:
  • Leustatin®
  • 2-CdA
  • 2-Chloro-2'-deoxyadenosine
  • CdA
  • Chlorodeoxyadenosine
Procedure: Bone marrow biopsy
Other Names:
  • Bone marrow aspirate

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants
Time Frame: From start of treatment until 30 days following last day of study treatment or until the start of a subsequent treatment for AML, whichever came first (41 days)
-All adverse events will be classified using the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0
From start of treatment until 30 days following last day of study treatment or until the start of a subsequent treatment for AML, whichever came first (41 days)
Complete Remission Rate (CR + CRi)
Time Frame: Median follow-up of 34 days
  • Morphologic complete remission (CR): neutrophil count > 1.0 x 109 /L, platelet count ≥ 100 x 109/L, < 5% bone marrow blasts by morphologic review, no Auer rods, no evidence of extramedullary disease. (No requirements for marrow cellularity, hemoglobin concentration).
  • Morphologic complete remission with incomplete blood count recovery (CRi): same as CR but ANC may be <1000/mcl or platelet count <100,000/mcl
  • Participants in the phase I portion of the study, treated at the MTD will count towards the phase II accrual goal for evaluation of the primary endpoint.
Median follow-up of 34 days

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Time to Platelet Engraftment
Time Frame: 56 days
-Time to platelet engraftment: Defined as the date of the first dose of study drug to the date that the platelet count is >100,000/mm^3 in the absence of platelet transfusions.
56 days
Time to Neutrophil Engraftment
Time Frame: Up to 2 years
-Time to neutrophil engraftment: Defined as the date of the first dose of study drug to the date that the absolute neutrophil count is >1,000/mm3
Up to 2 years
Event-free Survival
Time Frame: Up to 2 years (median follow-up of 307 days)
Event-free survival (EFS): Defined as the interval from the date of first dose of study drug to date of treatment failure including progressive disease, recurrence, or discontinuation for any reason (including toxicity, patient preference, initiation of new treatment without documented progression, or death due to any cause).
Up to 2 years (median follow-up of 307 days)
Duration of Remission
Time Frame: Up to 2 years
-Duration of remission (DOR): Defined as the interval from the date complete remission is documented to the date of recurrence.
Up to 2 years
Relapse-free Survival
Time Frame: Median follow-up of 307 days
Relapse-free survival (RFS): For patients achieving a complete remission, defined as the interval from the date of first documentation of a leukemia free state to date of recurrence or death due to any cause.
Median follow-up of 307 days
Overall Survival
Time Frame: Up to 2 years (median follow-up of 307 days)
Overall survival (OS): Defined as the date of first dose of study drug to the date of death from any cause. OS will be evaluated at 3 month intervals for at least 12 months and up to a maximum of 2 years.
Up to 2 years (median follow-up of 307 days)
Number of Participants Who Were Able to Undergo Hematopoietic Stem Cell Transplantation
Time Frame: Up to 2 years (median follow-up of 307 days)
Allogeneic stem cell transplant utilization: the number of patients proceeding to allogeneic transplant within 2 months following end of study without any additional salvage therapy following study treatment.
Up to 2 years (median follow-up of 307 days)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Washington University School of Medicine

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Karyopharm Therapeutics Inc

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 16, 2015

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 21, 2019

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 21, 2019

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 30, 2015

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 9, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 15, 2015

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 13, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 6, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 201505084

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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