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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

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ClinicalTrials.gov Identifier: NCT01684150
Recruitment Status : Completed
First Posted : September 12, 2012
Last Update Posted : August 4, 2016
Information provided by (Responsible Party):
Epizyme, Inc.

Brief Summary:

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).

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Myelodysplastic Syndrome Myeloproliferative Disorders Drug: EPZ-5676 Phase 1

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 51 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : September 2012
Actual Primary Completion Date : November 2015
Actual Study Completion Date : February 2016

Arm Intervention/treatment
Experimental: EPZ-5676 Extension cohort Drug: EPZ-5676
MLL-r and MLL-PTD 28-day continuous IV infusion of each 28-day cycle. Number of cycles: until disease progression or unacceptable toxicity develops.

Primary Outcome Measures :
  1. 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 ]
    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 :
  1. Pharmacokinetic profile of EPZ-5676 [ Time Frame: up to 24 months ]
    analysis of Cmax, AUC and steady state concentration

  2. The incidence of adverse events in patients treated with EPZ-5676 [ Time Frame: up to 24 months ]
    Evaluation of adverse events, vital signs, physical examination, 12-lead ECG, and laboratory assessments

  3. Anti-leukemic activity of EPZ-5676 in patients with acute leukemia harboring a MLL-rearrangement [ Time Frame: up to 24 months ]
    Evaluation of response by standard criteria for AML or ALL

  4. Effects of EPZ-5676 on histone H3K79 methylation in peripheral blood mononuclear cells (PBMC). [ Time Frame: up to 24 months ]
  5. Effects of EPZ-5676 on histone H3K79 methylation in leukemia cells [ Time Frame: up to 24 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01684150

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United States, Arizona
Mayo Clinic Scottsdale-Phoenix
Scottsdale, Arizona, United States, 85259
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, North Carolina
Duke University Health System
Durham, North Carolina, United States, 27710
United States, Tennessee
Sarah Cannon Research Institute
Nashville, Tennessee, United States, 37203
United States, Texas
UT MD Anderson Cancer
Houston, Texas, United States, 77030
Universitätsklinikum Ulm
Ulm, Germany, 89081
Erasmus University Medical Center
Rotterdam, Netherlands
Sponsors and Collaborators
Epizyme, Inc.
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Principal Investigator: Martin S. Tallman, MD Memorial Sloan Kettering Cancer Center
Principal Investigator: Jesus Berdeja, MD SCRI Development Innovations, LLC
Principal Investigator: David A Rizzieri, MD Duke University
Principal Investigator: Guillermo Garcia-Manero, MD M.D. Anderson Cancer Center
Principal Investigator: Jessica Altman, MD Northwestern University
Principal Investigator: Raoul Tibes, MD Mayo Clinic Scottsdale-Phoenix
Principal Investigator: Mojca Jongen-Lavrencic, MD Erasmus Medical Center
Principal Investigator: Hartmut Döhner, MD Universitätsklinikum Ulm
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Epizyme, Inc.
ClinicalTrials.gov Identifier: NCT01684150    
Other Study ID Numbers: EPZ-5676-12-001
First Posted: September 12, 2012    Key Record Dates
Last Update Posted: August 4, 2016
Last Verified: August 2016
Keywords provided by Epizyme, Inc.:
Advanced hematologic malignancies
Phase 1
Mixed Lineage Leukemia (MLL)
Additional relevant MeSH terms:
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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Myelodysplastic Syndromes
Myeloproliferative Disorders
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases