Clinical Trials /

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

NCT02416908

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of CLAG + Selinexor in Relapsed or Refractory Acute Myeloid Leukemia
  • Official Title: An Investigator Sponsored Phase I/II Study of CLAG + Selinexor in Relapsed or Refractory Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 201505084
  • NCT ID: NCT02416908

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
SelinexorKPT-330Phase I Schedule A (selinexor)
CladribineLeustatin®, 2-CdA, 2-Chloro-2'-deoxyadenosine, CdA, ChlorodeoxyadenosinePhase I Schedule A (selinexor)
G-CSFPlerixafor, Mozobil®Phase I Schedule A (selinexor)
CytarabineCytosar-U ®, 1-β-Arabinofuranosylcytosine, Cytosine arabinoside, Ara-CPhase I Schedule A (selinexor)

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Phase I Schedule A (selinexor)ExperimentalSelinexor 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.
  • Selinexor
  • Cladribine
  • G-CSF
  • Cytarabine
Phase I Schedule B (selinexor)ExperimentalSelinexor 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.
  • Selinexor
  • Cladribine
  • G-CSF
  • Cytarabine
Phase II (selinexor)ExperimentalSelinexor 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.
  • Selinexor
  • Cladribine
  • G-CSF
  • Cytarabine

Eligibility 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.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I only: Safety and tolerability of treatment as measured by adverse event grade and frequency
Time Frame:Estimated to be 12-18 months
Safety Issue:
Description: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

Secondary Outcome Measures

Measure:Time to hematologic recovery (neutrophils and platelets)
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Event-free survival
Time Frame:Up to 2 years
Safety Issue:
Description: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).
Measure:Duration of remission
Time Frame:Up to 2 years
Safety Issue:
Description:Duration of remission (DOR): Defined as the interval from the date complete remission is documented to the date of recurrence.
Measure:Relapse-free survival
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Overall survival
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Number of participants who were able to undergo hematopoietic stem cell transplantation
Time Frame:Up to 2 months following end of study
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated

February 2, 2017