Clinical Trials /

Decitabine and Selinexor in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

NCT02093403

Description:

This phase I trial studies the side effects and best dose of Selinexor when given together with decitabine in treating patients with acute myeloid leukemia that has returned after treatment (relapsed) or does not respond to treatment (refractory). Drugs used in chemotherapy, such as decitabine and Selinexor, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Decitabine and Selinexor in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
  • Official Title: Phase I Study of Decitabine (Dacogen) and Selinexor (KPT-330) in Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: OSU-13182
  • SECONDARY ID: NCI-2014-00559
  • NCT ID: NCT02093403

Conditions

  • Acute Myeloid Leukemia
  • Secondary Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
decitabine5-aza-dCyd, 5AZA, DACTreatment (decitabine and selinexor)
selinexorCRM1 nuclear export inhibitor KPT-330, KPT-330, selective inhibitor of nuclear export KPT-330, SINE KPT-330Treatment (decitabine and selinexor)

Purpose

This phase I trial studies the side effects and best dose of Selinexor when given together with decitabine in treating patients with acute myeloid leukemia that has returned after treatment (relapsed) or does not respond to treatment (refractory). Drugs used in chemotherapy, such as decitabine and Selinexor, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and tolerability of Selinexor (KPT‐330) in combination with
      decitabine in patients with acute myeloid leukemia (AML).

      II. To define the specific toxicities, maximum tolerated dose (MTD) and the dose limiting
      toxicity (DLT) of this combination.

      III. To determine the Recommended Phase 2 Dose (RP2D) of this combination.

      SECONDARY OBJECTIVES:

      I. To determine the overall response rate (ORR). II. To determine the rate and duration of
      complete remission (CR) +/- hematological recovery of KPT‐330 plus decitabine in AML.

      III. To conduct pharmacodynamic studies by measuring the effect of this chemotherapy
      combination on the kinome, micronome and epigenome.

      OUTLINE: This is a dose-escalation study of selinexor.

      INDUCTION: Patients receive decitabine intravenously (IV) over 1 hour on days 1-10 and
      Selinexor orally (PO) on days 11, 13, 18, 20, 25 and 27. Treatment repeats every 31 days for
      up to 4 courses in the absence of disease progression or unacceptable toxicity.

      MAINTENANCE: Patients receive decitabine IV over 1 hour on days 1-5 and Selinexor PO on days
      6, 8, 13, 15, 20 and 22. Courses repeat every 31 days in the absence of disease progression
      or unacceptable toxicity.

      After completion of study treatment, patients are followed up periodically.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (decitabine and selinexor)ExperimentalINDUCTION: Patients receive decitabine IV over 1 hour on days 1-10 and selinexor PO on days 11, 13, 18, 20, 25 and 27. Treatment repeats every 31 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive decitabine IV over 1 hour on days 1-5 and selinexor PO on days 6, 8, 13, 15, 20 and 22. Courses repeat every 31 days in the absence of disease progression or unacceptable toxicity.
  • decitabine
  • selinexor

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with relapsed or refractory AML

          -  Newly diagnosed elderly AML patients (> 60 years) unfit for intensive chemotherapy
             with cytarabine and anthracyclines are also eligible to this trial given that no
             clinically beneficial therapy exists for these patients

          -  Patients with secondary AML or therapy related disease (t‐AML) are eligible; patients
             who received decitabine or 5‐azacytidine as prior treatment for myelodysplastic
             syndrome (MDS) or AML remain eligible; however, none of these agents is permitted
             within 6 months of study entry

          -  If the patient has co‐morbid medical illness, life expectancy attributed to this must
             be greater than 6 months

          -  Eastern Cooperative Oncology Group (ECOG) performance status < 2

          -  Total bilirubin < 2.0 mg/dL

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             < 2.5 X institutional upper limit of normal

          -  Creatinine < 2.0 mg/d

          -  Glomerular filtration rate (GFR) > 50 mL/min

          -  New York Heart Association (NYHA) congestive heart failure (CHF) class II or better

          -  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 the written informed consent document

          -  Human immunodeficiency virus (HIV) infection without history of acquired immune
             deficiency syndrome (AIDS) and sufficiently high cluster of differentiation (CD)4
             cells (> 400/mm^3) and low HIV viral loads (< 30,000 copies/ml plasma) not requiring
             anti‐HIV therapy are eligible

          -  Patients must have recovered from the toxicity of prior therapy to less than grade 2

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study

          -  Patients receiving any other investigational agents or patients that have received
             other investigational agents within 14 days of enrollment

          -  Patients with active central nervous system (CNS) malignancy; asymptomatic small
             lesions are not considered active; treated lesions may be considered inactive if they
             are stable for at least 3 months; patients with malignant cells in their cerebrospinal
             fluid (CSF) without CNS symptoms may be included

          -  Patients with history of allergic reactions attributed to compounds of similar
             chemical or biologic composition to decitabine that are not easily managed

          -  Major surgery within 2 weeks before day 1

          -  Uncontrolled active infection requiring parenteral antibiotics, antivirals, or
             antifungals within one week prior to first dose

          -  Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C
             virus (HCV) ribonucleic acid (RNA) or HBsAg (hepatitis B virus [HBV] surface antigen)

          -  Patients with significantly diseased or obstructed gastrointestinal tract or
             uncontrolled vomiting or diarrhea

          -  History of seizures, movement disorders or cerebrovascular accident within the past 3
             years prior to cycle 1 day 1

          -  Patients with macular degeneration, uncontrolled glaucoma, or markedly decreased
             visual acuity

          -  Uncontrolled intercurrent illness including, but not limited to, symptomatic
             congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable
             angina pectoris, myocardial infarction within 6 months prior to enrollment, severe
             uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
             ischemia or active conduction system abnormalities; prior to study entry, any
             electrocardiogram (ECG) abnormality at screening has to be documented by the
             investigator as not medically relevant

          -  Patients with serious medical or psychiatric illness likely to interfere with
             participation in this clinical study

          -  Pregnant women or women who are breastfeeding are excluded from this study;
             confirmation that the subject is not pregnant must be established by a negative serum
             beta‐human chorionic gonadotropin (beta‐hCG) pregnancy test result obtained during
             screening; pregnancy testing is not required for post‐menopausal or surgically
             sterilized women

          -  Patients with advanced malignant solid tumors are excluded

          -  Patients with renal failure (GFR < 50 mL/min) are excluded

          -  Patients that in the opinion of the investigators are significantly below their ideal
             body weight
      
Maximum Eligible Age:N/A
Minimum Eligible Age:19 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:MTD defined as the dose where at most one patient experiences DLT with the next higher dose having at least 2 patients who experience DLT graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
Time Frame:31 days
Safety Issue:
Description:The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.

Secondary Outcome Measures

Measure:Overall response rate
Time Frame:Up to 3 years
Safety Issue:
Description:Responses will be summarized by simple descriptive summary statistics across all dose levels. Overall response rate will estimated at the MTD and defined as the number of patients who achieve any level of clinical response (e.g. CR, incomplete blood count recovery, morphologic CR) divided by the total number of evaluable patients (i.e. any patient who received at least one dose of study treatment).
Measure:Complete response rate
Time Frame:Up to 3 years
Safety Issue:
Description:Responses will be summarized by simple descriptive summary statistics across all dose levels. Complete response rate will be estimated in those patients treated at the MTD.
Measure:Change in expression of XPO1
Time Frame:Baseline to up to day 31 of course 1
Safety Issue:
Description:Changes in expression of these markers across time will be explored by dose level graphically. Relationships between baseline expression levels and changes in expression levels with response and certain toxicities will also be explored graphically (e.g. side‐by‐side boxplots) and with quantitative summaries. Confidence intervals will be presented as the primary method of analysis. Correlations among expression of the genes, micro-ribonucleic acids (miRs), and methylated signatures will be evaluated using scatterplots and the Spearman‐rank correlation coefficient.
Measure:Change in expression of genes associated with XPO1
Time Frame:Baseline to up to day 31 of course 1
Safety Issue:
Description:Changes in expression of these markers across time will be explored by dose level graphically. Relationships between baseline expression levels and changes in expression levels with response and certain toxicities will also be explored graphically (e.g. side‐by‐side boxplots) and with quantitative summaries. Confidence intervals will be presented as the primary method of analysis. Correlations among expression of the genes, miRs, and methylated signatures will be evaluated using scatterplots and the Spearman‐rank correlation coefficient.
Measure:Change in expression of miRs associated with XPO1
Time Frame:Baseline to up to day 31 of course 1
Safety Issue:
Description:Changes in expression of these markers across time will be explored by dose level graphically. Relationships between baseline expression levels and changes in expression levels with response and certain toxicities will also be explored graphically (e.g. side‐by‐side boxplots) and with quantitative summaries. Confidence intervals will be presented as the primary method of analysis. Correlations among expression of the genes, miRs, and methylated signatures will be evaluated using scatterplots and the Spearman‐rank correlation coefficient.
Measure:Change in expression of methylated signatures
Time Frame:Baseline to up to day 31 of course 1
Safety Issue:
Description:Changes in expression of these markers across time will be explored by dose level graphically. Relationships between baseline expression levels and changes in expression levels with response and certain toxicities will also be explored graphically (e.g. side‐by‐side boxplots) and with quantitative summaries. Confidence intervals will be presented as the primary method of analysis. Correlations among expression of the genes, miRs, and methylated signatures will be evaluated using scatterplots and the Spearman‐rank correlation coefficient.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Bhavana Bhatnagar

Trial Keywords

  • AML
  • Acute Myeloid Leukemia
  • Adult Acute Myeloid Leukemia with T(8;21)(Q22;Q22)
  • adult Acute Myeloid Leukemia with 11q23 (MLL) abnormalities
  • adult Acute Myeloid Leukemia with del(5q)
  • adult Acute Myeloid Leukemia with inv(16)(p13;q22)

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