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A Phase 1, Open-Label, Dose-Escalation & Expanded Cohort, Continuous IV Infusion, Multi-center Study of the Safety, Tolerability,PK & PD of EPZ-5676 in Treatment Relapsed/Refractory Patients With Leukemias Involving

NCT01684150

Description:

The purpose of this study is to determine the safe dose of EPZ-5676, to evaluate the safety of EPZ-5676 in patients with advanced hematologic malignancies, and to conduct a preliminary assessment of the anti-leukemia activity of EPZ-5676 in patients with acute leukemias bearing rearrangements of the MLL gene. Currently this study is in the MLL-r restricted/expansion phase and is only enrolling patients with rearrangements involving the MLL gene, including 11q23 or partial tandem duplications (PTD).

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Myeloproliferative Neoplasm
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1, Open-Label, Dose-Escalation & Expanded Cohort, Continuous IV Infusion, Multi-center Study of the Safety, Tolerability,PK & PD of EPZ-5676 in Treatment Relapsed/Refractory Patients With Leukemias Involving
  • Official Title: A Phase 1, Open-Label, Dose-Escalation & Expanded Cohort, Continuous IV Infusion, Multi-center Study of the Safety, Tolerability,PK & PD of EPZ-5676 in Treatment Relapsed/Refractory Patients With Leukemias Involving Translocation of the MLL Gene at 11q23 or Advanced Hematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: EPZ-5676-12-001
  • NCT ID: NCT01684150

Conditions

  • Acute Myeloid Leukemia
  • Acute Lymphoblastic Leukemia
  • Myelodysplastic Syndrome
  • Myeloproliferative Disorders

Interventions

DrugSynonymsArms
EPZ-5676EPZ-5676 Extension cohort

Purpose

The purpose of this study is to determine the safe dose of EPZ-5676, to evaluate the safety of EPZ-5676 in patients with advanced hematologic malignancies, and to conduct a preliminary assessment of the anti-leukemia activity of EPZ-5676 in patients with acute leukemias bearing rearrangements of the MLL gene. Currently this study is in the MLL-r restricted/expansion phase and is only enrolling patients with rearrangements involving the MLL gene, including 11q23 or partial tandem duplications (PTD).

Detailed Description

      A subset of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)
      harbor rearrangements of the MLL gene, which are detected either by cytogenetic or
      fluorescent in situ hybridization evaluation at the time of diagnosis. A protein called DOT1L
      plays an important role in the malignant process in these leukemias. EPZ-5676 is a molecule
      that blocks the activity of DOT1L, and is therefore being evaluated in the treatment of
      patients with MLL-rearranged leukemias.

      The dose escalation portion has been completed. Currently this study is in the expansion
      phase and patients with MLL-r and MLL-PTD will receive EPZ-5676 as a 28-day continuous
      intravenous infusion (CIV).
    

Trial Arms

NameTypeDescriptionInterventions
EPZ-5676 Extension cohortExperimental
  • EPZ-5676

Eligibility Criteria

        Inclusion Criteria:

          1. Male and female patients aged ≥ 18 years.

          2. Patients with relapsed /refractory AML, ALL, or MLL with rearrangement of the MLL
             gene, including 11q23 or PTD, are eligible for the expanded cohort:

               -  At least one prior therapy;

               -  Refractory disease on most recent therapy, or disease recurrence following
                  remission on most recent therapy;

               -  Received and failed all known effective therapies for their disease;

               -  Not a candidate for allogeneic stem cell transplantation

               -  > 10% blasts or biopsy-documented leukemia cutis or myeloid sarcoma.

          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

          4. Patients must have the following clinical laboratory values:

               -  Serum creatinine ≤2 mg/dL or creatinine clearance > 60 mL/minute;

               -  Total bilirubin ≤2.0 times the ULN for the institution, unless considered due to
                  Gilbert's syndrome;

               -  ALT or AST ≤ twice the upper limit of normal (ULN), unless considered due to
                  organ leukemic involvement;

               -  Absolute neutrophil count ≥1,000/µL (unless due to documented leukemic
                  involvement of the bone marrow at the time of study entry)

               -  Platelets ≥100,000/µL (unless due to documented leukemic involvement of the bone
                  marrow at the time of study entry).

               -  PT or aPTT < 1.5 times the ULN

          5. Able and willing to give written informed consent.

          6. Life expectancy of at least 3 months

        Exclusion Criteria:

          1. Uncontrolled intercurrent illness or psychiatric illness/social situations that would
             limit compliance with study requirements.

          2. Active heart disease

          3. Receiving any other standard treatment for their hematologic malignancy.

          4. Receiving strong CYP3A4 inhibitors/ inducers.

          5. Known history of cerebrovascular accident in the past 6 months.

          6. Known bleeding diathesis.

          7. Known, active (symptomatic) involvement of the central nervous system by leukemia.

          8. On immunosuppressive therapy.

          9. Known active infection.

         10. Pregnant or nursing females.
      
Maximum Eligible Age:90 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of EPZ-5676 as determined by incidence of protocol-specified dose-limiting adverse events.
Time Frame:up to 12 months
Safety Issue:
Description:The MTD is defined as the dose level below in which >1 patient out of 3 or >2 patients out of 6 experience dose-limiting adverse events (as defined by the protocol).

Secondary Outcome Measures

Measure:Pharmacokinetic profile of EPZ-5676
Time Frame:up to 24 months
Safety Issue:
Description:analysis of Cmax, AUC and steady state concentration
Measure:The incidence of adverse events in patients treated with EPZ-5676
Time Frame:up to 24 months
Safety Issue:
Description:Evaluation of adverse events, vital signs, physical examination, 12-lead ECG, and laboratory assessments
Measure:Anti-leukemic activity of EPZ-5676 in patients with acute leukemia harboring a MLL-rearrangement
Time Frame:up to 24 months
Safety Issue:
Description:Evaluation of response by standard criteria for AML or ALL
Measure:Effects of EPZ-5676 on histone H3K79 methylation in peripheral blood mononuclear cells (PBMC).
Time Frame:up to 24 months
Safety Issue:
Description:
Measure:Effects of EPZ-5676 on histone H3K79 methylation in leukemia cells
Time Frame:up to 24 months
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Epizyme, Inc.

Trial Keywords

  • Leukemia
  • Advanced hematologic malignancies
  • Epizyme
  • Phase 1
  • Mixed Lineage Leukemia (MLL)

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