Clinical Trials /

MEK Inhibitor MEK162, Idarubicin, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

NCT02049801

Description:

This phase I trial studies the MEK inhibitor MEK162 to see if it is safe in patients when combined with idarubicin and cytarabine. MEK inhibitor MEK162 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving MEK inhibitor MEK162, cytarabine, and idarubicin may be an effective treatment for acute myeloid leukemia.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: MEK Inhibitor MEK162, Idarubicin, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
  • Official Title: A Phase I Study of MEK Inhibitor MEK162 Combined With Idarubicin and Cytarabine Induction in Patients With Relapsed/Refractory RAS-Mutated Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: IRB-29150
  • SECONDARY ID: NCI-2014-00169
  • SECONDARY ID: HEMAML0030
  • NCT ID: NCT02049801

Conditions

  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Recurrent Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
MEK inhibitor MEK162ARRY-162, ARRY-438162Treatment (MEK inhibitor, MEK162, idarubicin, cytarabine)
idarubicin4-demethoxydaunorubicin, 4-DMDR, DMDR, IDATreatment (MEK inhibitor, MEK162, idarubicin, cytarabine)
cytarabineARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinosideTreatment (MEK inhibitor, MEK162, idarubicin, cytarabine)

Purpose

This phase I trial studies the MEK inhibitor MEK162 to see if it is safe in patients when combined with idarubicin and cytarabine. MEK inhibitor MEK162 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving MEK inhibitor MEK162, cytarabine, and idarubicin may be an effective treatment for acute myeloid leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine maximum tolerated dose (MTD) of MEK162 (MEK inhibitor MEK162) in patients with
      RAS-mutated acute myeloid leukemia (AML) when combined with sequential induction chemotherapy
      (3+4) as measured by development of grade 3-4 dose-limiting toxicities (DLT).

      SECONDARY OBJECTIVES:

      I. Analyze downstream inhibition of RAS signaling following therapy with single-agent MEK162
      with exploratory pharmacodynamics (PD) studies.

      II. Perform preliminary efficacy analysis of combination of MEK162 and induction chemotherapy
      (3+4) in patients with RAS-mutated AML by measuring complete remission rate, 2-year overall
      survival, and duration of response.

      OUTLINE:

      INDUCTION THERAPY: Patients receive MEK inhibitor MEK162 orally (PO) twice daily (BID) on
      days -4 to -1 and days 5-18, cytarabine intravenously (IV) continuously over 24 hours on days
      1-4, and idarubicin IV over 1 hour on days 1-3. Patients may receive a second course of
      induction at the discretion of the principal investigator.

      POST-REMISSION THERAPY: Patients receive cytarabine IV continuously over 24 hours on days
      1-3, idarubicin IV over 1 hour on days 1 and 2, and MEK inhibitor MEK 162 PO BID on days
      4-17. Treatment repeats every 28 days for up to 4 courses in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (MEK inhibitor, MEK162, idarubicin, cytarabine)ExperimentalINDUCTION THERAPY: Patients receive MEK inhibitor MEK162 PO BID on days -4 to -1 and days 5-18, cytarabine IV continuously over 24 hours on days 1-4, and idarubicin IV over 1 hour on days 1-3. Patients may receive a second course of induction at the discretion of the principal investigator. POST-REMISSION THERAPY: Patients receive cytarabine IV continuously over 24 hours on days 1-3, idarubicin IV over 1 hour on days 1 and 2, and MEK inhibitor MEK 162 PO BID on days 4-17. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
  • MEK inhibitor MEK162
  • idarubicin
  • cytarabine

Eligibility Criteria

        Inclusion Criteria:

          -  Prior morphological diagnosis of AML other than acute promyelocytic leukemia according
             to the 2001 World Health Organization (WHO) diagnostic criteria; patients with
             biphenotypic, RAS-mutated acute leukemia are also eligible

          -  Requiring salvage chemotherapy for persistent/refractory or relapsed disease after at
             least one course of conventional chemotherapy, e.g. with "7+3", as defined by
             persistence of >= 20% myeloid blasts on bone marrow aspirate or peripheral blood
             smear; a bone marrow biopsy is not routinely required, but should be obtained if the
             aspirate is dilute, hypocellular, or inaspirable; outside bone marrow examinations
             performed within the stipulated time period are acceptable for screening as long as
             the slides are reviewed at the study institution; flow cytometric analysis of the bone
             marrow aspirate should be performed according to institutional practice guidelines

          -  Confirmed RAS mutation (NRAS or KRAS) or confirmed PTPN11 mutation, measured on
             peripheral blood or bone marrow aspirate as part of screening prior to study
             enrollment; mutation status must be confirmed within 45 days of initiation of therapy

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times upper
             limit of normal (ULN)

          -  Serum bilirubin =< 2 times ULN

          -  Serum creatinine =< 1.5 mg/dl and/or creatinine clearance >= 50 mL/min

          -  Ejection fraction >= 50% by echocardiogram

          -  Corrected QT (QTc) interval =< 480 ms

          -  Ability to take oral medications

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Ability to undergo standard induction chemotherapy

          -  Ability to adhere to the study visit schedule and other protocol requirements

          -  Life expectancy of greater than 2 months

          -  Negative serum beta-human chorionic gonadotropin (HCG) test (female patient of
             childbearing potential only) performed locally within 72 hrs prior to first dose

        Exclusion Criteria:

          -  Concomitant treatment with other anti-neoplastic agents, with the exception of
             hydroxyurea

          -  Anti-neoplastic treatment less than 14 days prior to enrollment, with the exceptions
             of hydroxyurea or, in the case of a patient with primary refractory AML, prior
             induction chemotherapy

          -  Prior therapy with a MEK inhibitor

          -  Uncontrolled opportunistic infection or treatment for opportunistic infection within 4
             weeks of first day of study drug dosing

          -  Other medical or psychiatric illness or organ dysfunction or laboratory abnormality
             which in the opinion of the investigator would compromise the patient's safety or
             interfere with data interpretation, e.g., infection/inflammation, intestinal
             obstruction, unable to swallow medication, social/ psychological issues, etc.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to MEK162, anthracycline, or cytarabine

          -  Known impairment of gastrointestinal (GI) function or GI disease that may
             significantly alter the absorption of MEK162 (e.g., ulcerative disease, uncontrolled
             nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)

          -  Previous or concurrent malignancy with the following exceptions:

               -  Carcinoma in situ

               -  Adequately treated skin basal cell or squamous cell carcinoma (adequate wound
                  healing is required prior to study entry)

               -  In situ carcinoma of the cervix, treated curatively and without evidence of
                  recurrence for at least 3 years prior to the study

               -  A primary malignancy which has been completely resected and in complete remission
                  for >= 5 years

          -  Impaired cardiovascular function or clinically significant cardiovascular diseases,
             including any of the following:

               -  History of acute coronary syndromes (including myocardial infarction, unstable
                  angina, coronary artery bypass grafting [CABG], coronary angioplasty, or
                  stenting) < 6 months prior to screening

               -  Symptomatic chronic heart failure

               -  Evidence of clinically significant cardiac arrhythmias and/or conduction
                  abnormalities < 6 months prior to screening except atrial fibrillation and
                  paroxysmal supraventricular tachycardia

          -  Uncontrolled arterial hypertension despite appropriate medical therapy

          -  Patients who have neuromuscular disorders that are associated with elevated creatine
             kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral
             sclerosis, spinal muscular atrophy)

          -  Known confirmed diagnosis of human immunodeficiency virus (HIV) infection or active
             viral hepatitis (hepatitis B or hepatitis C)

          -  Any surgical procedure, excluding central venous catheter placement, bone marrow
             biopsy, lumbar puncture, or other minor procedures (e.g., skin biopsy) within 14 days
             of day 1; patients who have undergone major surgery =< 21 days prior to starting study
             drug or who have not recovered from side effects of such procedure are ineligible for
             the study

          -  Pregnant or nursing (lactating) women confirmed by a positive hCG laboratory test

               -  Women of child-bearing potential unless they are using highly effective methods
                  of contraception throughout the study and for 30 days after study drug
                  discontinuation

          -  Sexually active males unless they use a condom during intercourse while taking the
             drug and for 30 days after stopping treatment and should not father a child in this
             period; a condom is required to be used also by vasectomized men in order to prevent
             delivery of the drug via seminal fluid

          -  Unwillingness or inability to comply with the protocol

          -  Known active leukemia of the central nervous system

          -  Known history of Gilbert's syndrome

          -  History or current evidence of retinal pigment epithelial detachment (RPED), retinal
             vein occlusion (RVO), or predisposing factors to RPED or RVO (e.g. uncontrolled
             glaucoma or ocular hypertension, uncontrolled diabetes mellitus, hyperviscosity or
             hypercoagulability syndromes)

          -  History of retinal degenerative disease
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:MTD of MEK inhibitor MEK162 in combination with chemotherapy, defined as the dose associated with a dose-limiting toxicity rate of 35% assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03
Time Frame:28 days
Safety Issue:
Description:Dose limiting toxicities will be tabulated by dose, severity and major organ system.

Secondary Outcome Measures

Measure:Pharmacodynamic analysis of downstream inhibition of RAS signaling following therapy with single-agent MEK inhibitor MEK162
Time Frame:Day -4, -1, and 18
Safety Issue:
Description:Pharmacodynamic correlative data will be summarized with medians and ranges for each dose group. If there are a sufficient number of patients assigned to both doses, the medians will be compared with a Wilcoxon Rank Sum test.
Measure:Complete remission rate, defined as bone marrow biopsy demonstrating < 5% blasts and recovery of peripheral blood counts after induction chemotherapy
Time Frame:Up to day 19
Safety Issue:
Description:The proportion of patients who achieve complete remission will be estimated overall with an exact 95% confidence interval; for descriptive purpose the same proportion at each dose will similarly described.
Measure:Overall survival
Time Frame:Time of study entry to the time of death from any cause, assessed at 2 years
Safety Issue:
Description:The proportion of patients who achieve 2-year overall survival will be estimated overall with an exact 95% confidence interval; for descriptive purpose the same proportion at each dose will similarly described.
Measure:Duration of response
Time Frame:Time of complete response to biopsy-documented recurrence of disease, assessed up to 4 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Bruno C. Medeiros

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