Clinical Trials /

Study of MEK Inhibitor Selumetinib in Combination With Azacitidine in Patients With Higher Risk Chronic Myeloid Neoplasia

NCT03326310

Description:

This is a phase I, open-label, dose-escalation study to determine the MTD of selumetinib when combined with the standard dose of azacitidine. Treatment will begin within 28 days of screening procedures. Treatment will continue indefinitely, provided that the patient continues to derive benefit. A patient will be taken off study for reasons described in detail in section 3.12 including disease progression, unacceptable toxicity, inter-current illness, withdrawal of consent, or at the discretion of the investigator. Patients will be followed for 12 weeks after the last dose of study drug, until any study treatment related toxicities have stabilized, or until death. The total duration of the study is expected to be approximately 24 months.

Related Conditions:
  • Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasm
  • Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of MEK Inhibitor Selumetinib in Combination With Azacitidine in Patients With Higher Risk Chronic Myeloid Neoplasia
  • Official Title: Phase I Study of MEK Inhibitor Selumetinib in Combination With Azacitidine in Patients With Higher Risk Chronic Myeloid Neoplasia: MDS, MDS/MPNs, and Myelofibrosis

Clinical Trial IDs

  • ORG STUDY ID: IRB17-0774
  • NCT ID: NCT03326310

Conditions

  • Chronic Myeloid Leukemia
  • Myelofibroses

Interventions

DrugSynonymsArms
AzacitidineVidazaAzacitidine and selumetinib
SelumetinibAZD6244Azacitidine and selumetinib

Purpose

This is a phase I, open-label, dose-escalation study to determine the MTD of selumetinib when combined with the standard dose of azacitidine. Treatment will begin within 28 days of screening procedures. Treatment will continue indefinitely, provided that the patient continues to derive benefit. A patient will be taken off study for reasons described in detail in section 3.12 including disease progression, unacceptable toxicity, inter-current illness, withdrawal of consent, or at the discretion of the investigator. Patients will be followed for 12 weeks after the last dose of study drug, until any study treatment related toxicities have stabilized, or until death. The total duration of the study is expected to be approximately 24 months.

Detailed Description

      This is a phase I, open-label, dose-escalation study to determine the MTD of selumetinib when
      combined with the standard dose of azacitidine. For the purposes of DLT assessment, subjects
      will be stratified into 2 cohorts- cohort A will include subjects with MDS and MDS/MPN;
      cohort B will include subjects with myelofibrosis. Dose escalation will proceed independently
      in each of these cohorts. Determination of MTD will thus also proceed independently within
      each cohort. Three dose levels of selumetinib are planned for evaluation. Dose escalation
      will follow a 3+3 study design. Patients will be enrolled sequentially and stratified
      according to disease type as outlined above. An increased dose level will only open to
      accrual once at least 3 patients have been treated at the lower dose, followed for the
      defined DLT observation period (28 days, see section 2.8 below), and the lower dose level has
      been deemed safe.

      The 3+3 dose escalation algorithm will proceed as follows:

        1. If 0/3 patients develop a DLT at a dose level, escalate to the next dose level.

        2. If 1/3 patients develops a DLT at a dose level, enroll 3 additional patients at that
           dose level.

             1. At that dose level, if 1/6 patients develops a DLT, escalate to the next dose
                level.

             2. If ≥2/6 patients develop a DLT, that dose level will be determined to be too toxic.

        3. If 2-3/3 patients develop a DLT at a dose level, that dose level will be determined to
           be too toxic.

        4. Six patients will be treated at the MTD.

             1. If the study progresses to dose level 3 with 0/3 patients experiencing a DLT, an
                additional 3 patients will be enrolled at that dose level to gain additional
                information regarding toxicity.

             2. If a dose level is determined to be too toxic and the next lower dose level only
                included 3 patients, an additional 3 patients will be treated at the lower dose
                level to confirm tolerability.

        5. If no patients have a DLT reported at dose level 3, that will be defined as the MTD and
           the dose will not be escalated above that level.
    

Trial Arms

NameTypeDescriptionInterventions
Azacitidine and selumetinibExperimentalSubjects will receive azacitidine subcutaneously on days 1-7. Selumetinib will be administered on days 8-21. Subjects will continue on this schedule in cycles of 28 days duration in the absence of disease progression.
  • Azacitidine
  • Selumetinib

Eligibility Criteria

        Inclusion Criteria:

        All of the following criteria must be met:

          -  Age greater than or equal to 18 years of age

          -  Histologic confirmation of one of the following:

             a. MDS fulfilling all the criteria below: i. International Prognostic Scoring System
             (IPSS) intermediate-2 or high risk MDS; or Revised International Prognostic Scoring
             System (IPSS-R) intermediate, high, or very high risk MDS ii. - relapsed/refractory
             disease iii. Requiring therapy based on the presence of one or more cytopenias (Hb <10
             g/dL and/or red cell transfusion dependence, platelets- <50,000/μL, or ANC <1,000/ μL)
             or excess blasts (≥5% in the peripheral blood or bone marrow).

             b. MDS/MPN as defined by the WHO criteria, including CMML, atypical CML, and
             MDS/MPN-Unclassifiable fulfilling the criteria listed below i. relapsed/refractory
             disease ii. Requiring therapy based on the presence of one or more cytopenias (Hb <10
             g/dL and/or red cell transfusion dependence, platelets <50,000/μL, or ANC <1,000/ μL),
             excess blasts (≥5% in the peripheral blood or bone marrow), or palpable splenomegaly
             iii. or previously untreated subsets (e.g atypical CML, MDS/MPN unclassifiable)
             requiring therapy as defined above and in whom no approved therapies exist.

             c. Myelofibrosis, including primary myelofibrosis, post-polycythemia vera
             myelofibrosis, or post-essential thrombocythemia myelofibrosis fulfilling the criteria
             listed below: i. Intermediate-2 or high risk disease according to the Dynamic
             International Prognostic Scoring System (DIPSS) classification ii. refractory or
             intolerant to JAK inhibitor therapy, or deemed - ineligible for ruxolitinib therapy
             due to pre- existing cytopenias (thrombocytopenia <50,000/uL, anemia hemoglobin <9g/dL
             or red cell transfusion dependence).Requiring further therapy based on the presence of
             one or more cytopenias (Hb <10 g/dL and/or red cell transfusion dependence, platelets
             <50,000/μL, or ANC <1,000/μL), excess blasts (≥5% in the peripheral blood or bone
             marrow), or palpable splenomegaly

          -  No history of prior exposure to a MEK inhibitor

          -  ECOG performance status of ≤ 2

          -  Adequate renal function, defined as serum creatinine ≤ 1.5 x ULN or creatinine
             clearance >30 mL/min based on the Cockroft-Gault equation: (140 − Age) x (weight in
             kg) x (0.85 if female) / 72 x serum creatinine

          -  Adequate liver function, defined as conjugated bilirubin ≤ 2 x ULN as well as
             aspartate transaminase (AST) and alanine aminotransaminase (ALT) ≤ 3 x ULN

          -  Patients must be at least 2 weeks from major surgery, radiation therapy, participation
             in other investigational trials and must have recovered from clinically significant
             toxicities of these prior treatments

          -  Female patients of childbearing potential must have a negative serum pregnancy test
             within 2 weeks prior to enrollment

          -  Female and male patients must use an effective contraceptive method during the study
             and for at least 6 months thereafter

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

        Exclusion Criteria:

        Patients are excluded if any one of the following is present:

          -  Receipt of any anti-cancer therapy within 14 days prior to study entry, with the
             exception of hydroxyurea. If clinically indicated in order to keep WBC <30,000/uL,
             hydroxyurea may be continued through the first cycle.

          -  Concurrent active malignancy, with the exception of early stage basal cell or squamous
             cell skin cancer

          -  Active cardiac conditions, including any of the following:

               1. Uncontrolled hypertension (BP >150/95 mmHg despite medical therapy)

               2. Acute coronary syndrome within 6 months prior to starting treatment

               3. Uncontrolled angina despite medical therapy

               4. Symptomatic heart failure (NYHA class II-IV despite medical therapy)

               5. Baseline LV EF <50% measured by either echocardiography or MUGA scan

               6. Severe valvular heart disease

               7. Atrial fibrillation with ventricular rate >100 bpm on EKG at rest.

          -  Ophthalmologic conditions, including any of the following:

               1. Current or past history of central serous retinopathy

               2. Current or past history of retinal vein occlusion

               3. Intraocular pressure (IOP) >21 mmHg or uncontrolled glaucoma

          -  Any uncontrolled concurrent illness that, in the judgment of the investigators or
             treating physician, may put the patient at undo risk including but not limited to
             active infection, symptomatic cardiac or pulmonary disease, ventricular arrhythmia, or
             psychiatric illness.

          -  Pregnant or lactating patients
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of patients with adverse events
Time Frame:Up to 24 months.
Safety Issue:
Description:To determine the maximum tolerated dose (MTD) of selumetinib when combined with azacitidine and measure any toxicities that may arise.

Secondary Outcome Measures

Measure:Time to completion of next generation sequencing panel.
Time Frame:From the start of treatment to the record of patient death from any cause, or 100 months, whichever comes first.
Safety Issue:
Description:To assess the feasibility of prospectively screening patients for RAS pathway activating mutations by next generation sequencing at our center in the context of a clinical trial.
Measure:Rate of overall response.
Time Frame:From the start of treatment to the first record of response, up to 100 months, whichever comes first.
Safety Issue:
Description:Calculated by complete response + partial response + hematologic improvement.
Measure:Rate of symptom response.
Time Frame:From the start of treatment to the first record of symptom response, up to 100 months, whichever comes first.
Safety Issue:
Description:
Measure:Rate of overall survival.
Time Frame:From the start of treatment to the date of death, not to exceed 100 months, whichever comes first.
Safety Issue:
Description:
Measure:Rate of progression free survival.
Time Frame:From the start of treatment to the first record of disease progression or the date of death, not to exceed 100 months, whichever comes first.
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Chicago

Trial Keywords

  • Chronic Myeloid Leukemia
  • Myelofibrosis
  • selumetinib
  • azacitidine

Last Updated

October 12, 2018