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

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ClinicalTrials.gov Identifier: NCT02416908
Recruitment Status : Active, not recruiting
First Posted : April 15, 2015
Last Update Posted : July 18, 2019
Sponsor:
Collaborator:
Karyopharm Therapeutics Inc
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Selinexor Drug: Cladribine Drug: G-CSF Drug: Cytarabine Procedure: Bone marrow biopsy Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Investigator Sponsored Phase I/II Study of CLAG + Selinexor in Relapsed or Refractory Acute Myeloid Leukemia
Actual Study Start Date : June 16, 2015
Estimated Primary Completion Date : December 20, 2019
Estimated Study Completion Date : December 20, 2019


Arm Intervention/treatment
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: Selinexor
Other Name: KPT-330

Drug: Cladribine
Other Names:
  • Leustatin®
  • 2-CdA
  • 2-Chloro-2'-deoxyadenosine
  • CdA
  • Chlorodeoxyadenosine

Drug: G-CSF
Other Names:
  • Plerixafor
  • Mozobil®

Drug: Cytarabine
Other Names:
  • Cytosar-U ®
  • 1-β-Arabinofuranosylcytosine
  • Cytosine arabinoside
  • Ara-C

Procedure: Bone marrow biopsy
Other Name: 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: Selinexor
Other Name: KPT-330

Drug: Cladribine
Other Names:
  • Leustatin®
  • 2-CdA
  • 2-Chloro-2'-deoxyadenosine
  • CdA
  • Chlorodeoxyadenosine

Drug: G-CSF
Other Names:
  • Plerixafor
  • Mozobil®

Drug: Cytarabine
Other Names:
  • Cytosar-U ®
  • 1-β-Arabinofuranosylcytosine
  • Cytosine arabinoside
  • Ara-C

Procedure: Bone marrow biopsy
Other Name: 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: Selinexor
Other Name: KPT-330

Drug: Cladribine
Other Names:
  • Leustatin®
  • 2-CdA
  • 2-Chloro-2'-deoxyadenosine
  • CdA
  • Chlorodeoxyadenosine

Drug: G-CSF
Other Names:
  • Plerixafor
  • Mozobil®

Drug: Cytarabine
Other Names:
  • Cytosar-U ®
  • 1-β-Arabinofuranosylcytosine
  • Cytosine arabinoside
  • Ara-C

Procedure: Bone marrow biopsy
Other Name: Bone marrow aspirate




Primary Outcome Measures :
  1. Phase I only: Safety and tolerability of treatment as measured by adverse event grade and frequency [ Time Frame: Estimated to be 12-18 months ]
    • The phase I portion will use a Bayesian optimal interval design to identify a schedule with grade 3-4 non-hematologic toxicity that does not exceed 20%.
    • There is no de-escalation below the starting schedule. If 1 DLT is observed in the initial cohort with schedule A dosing and the schedule A dosing is repeated in the second cohort, the study will be stopped if 3 DLTs are observed in the second cohort, a total of 4 DLTs in cohorts 1 and 2 together.
    • If the schedule is intensified after schedule A dosing and de-intensification is indicated after schedule B dosing, 6 additional patients will be treated using the schedule A.
    • Schedule A dosing will be accepted if no more than 2 DLTs are observed in a maximum of 18 patients treated using that schedule.
    • All AEs will be classified using the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0

  2. Phase II only: Complete remission rate (CR + CRi) [ Time Frame: Up to 2 years ]
    • 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.


Secondary Outcome Measures :
  1. Time to hematologic recovery (neutrophils and platelets) [ Time Frame: Up to 2 years ]
    • Time to neutrophil recovery: Defined as the date of the first dose of study drug to the date that the absolute neutrophil count is >1,000/mm3
    • Time to platelet recovery: Defined as the date of the first dose of study drug to the date that the platelet count is >100,000/mm3 in the absence of platelet transfusions.

  2. Event-free survival [ Time Frame: Up to 2 years ]
    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).

  3. 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.

  4. Relapse-free survival [ Time Frame: Up to 2 years ]
    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.

  5. Overall survival [ Time Frame: Up to 2 years ]
    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.

  6. Number of participants who were able to undergo hematopoietic stem cell transplantation [ Time Frame: Up to 2 months following end of study ]
    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.



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02416908


Locations
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United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Karyopharm Therapeutics Inc
Investigators
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Principal Investigator: Geoffrey Uy, M.D. Washington University School of Medicine

Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT02416908     History of Changes
Other Study ID Numbers: 201505084
First Posted: April 15, 2015    Key Record Dates
Last Update Posted: July 18, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Cladribine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs