A First-in-Human Phase 1 and Expanded Cohort Study of EPZ-5676 in Advanced Hematologic Malignancies, Including Acute Leukemia With Rearrangement of the MLL Gene

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Epizyme, Inc.
Sponsor:
Collaborator:
Celgene Corporation
Information provided by (Responsible Party):
Epizyme, Inc.
ClinicalTrials.gov Identifier:
NCT01684150
First received: September 6, 2012
Last updated: May 4, 2014
Last verified: May 2014
  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).


Condition Intervention Phase
Acute Myeloid Leukemia
Acute Lymphoblastic Leukemia
Myelodysplastic Syndrome
Myeloproliferative Disorders
Chronic Myeloid Leukemia
Drug: EPZ-5676
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Epizyme, Inc.:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
    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:
  • Pharmacokinetic profile of EPZ-5676 [ Time Frame: up to 12 months ] [ Designated as safety issue: No ]
    analysis of Cmax, AUC and steady state concentration

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

  • Anti-leukemic activity of EPZ-5676 in patients with acute leukemia harboring a MLL-rearrangement [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]
    Evaluation of response by standard criteria for AML or ALL

  • Effects of EPZ-5676 on histone H3K79 methylation in peripheral blood mononuclear cells (PBMC). [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]
  • Effects of EPZ-5676 on histone H3K79 methylation in leukemia cells [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 40
Study Start Date: September 2012
Estimated Study Completion Date: November 2014
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: EPZ-5676 Dose-escalation and extension cohorts Drug: EPZ-5676
MLL-r restricted/expansion phase with option to dose escalate, 28-day continuous IV infusion of each 28-day cycle. Number of cycles: until disease progression or unacceptable toxicity develops.

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.

This is a first-in-human study of EPZ-5676. The primary purpose of this study is to determine what dose of EPZ-5676, when administered as a 21-day continuous intravenous infusion, can be given safely to patients with hematologic malignancies. The study will have two phases. The first phase will assess escalating doses of EPZ-5676 in order to determine the maximally tolerated dose (MTD) or recommended phase 2 dose (RP2D) of EPZ-5676. Once the MTD or RP2D is established, a second phase of the study will further evaluate the safety of EPZ-5676 given as a 28-day continuous IV infusion and assess the anti-leukemia activity of EPZ-5676 in MLL-rearranged leukemia.

Currently this study is in the MLL-r restricted/expansion phase and patients will receive EPZ-5676 as a continuous intravenous infusion.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01684150

Contacts
Contact: Eric Hedrick, MD 855-500-1011 clinicaltrials@epizyme.com

Locations
United States, Arizona
Mayo Clinic Scottsdale-Phoenix Recruiting
Scottsdale, Arizona, United States, 85259
Contact: Raoul Tibes, MD    480-301-8335    Tibes.Raoul@mayo.edu   
Principal Investigator: Raoul Tibes, MD         
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Jessica Altman, MD    312-695-0990    j-altman@northwestern.edu   
Principal Investigator: Jessica Altman, MD         
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Martin S Tallman, MD    212-639-3842    TallmanM@mskcc.org   
Principal Investigator: Martin S Tallman, MD         
United States, North Carolina
Duke University Health System Recruiting
Durham, North Carolina, United States, 27710
Contact: David A Rizzieri, MD    919-668-1014    rizzi003@mc.duke.edu   
Principal Investigator: David A Rizzieri, MD         
United States, Tennessee
Sarah Cannon Research Institute Recruiting
Nashville, Tennessee, United States, 37203
Contact: Jesus Berdeja, MD    615-329-7274    jberdeja@tnonc.com   
Principal Investigator: Jesus Berdeja, MD         
United States, Texas
UT MD Anderson Cancer Recruiting
Houston, Texas, United States, 77030
Contact: Guillermo Garcia-Manero, MD    713-745-3428      
Principal Investigator: Guillermo Garcia-Manero, MD         
Germany
Universitätsklinikum Ulm Recruiting
Ulm, Germany, 89081
Contact: Hartmut Döhner, MD       hartmut.doehner@uniklinik-ulm.de   
Principal Investigator: Hartmut Döhner, MD         
Netherlands
Erasmus University Medical Center Recruiting
Rotterdam, Netherlands
Contact: Mojca Jongen-Lavrencic, MD       m.lavrencic@erasmusmc.nl   
Principal Investigator: Mojca Jongen-Lavrencic, MD         
Sponsors and Collaborators
Epizyme, Inc.
Celgene Corporation
Investigators
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
  More Information

No publications provided

Responsible Party: Epizyme, Inc.
ClinicalTrials.gov Identifier: NCT01684150     History of Changes
Other Study ID Numbers: EPZ-5676-12-001
Study First Received: September 6, 2012
Last Updated: May 4, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Epizyme, Inc.:
Leukemia
Advanced hematologic malignancies
Epizyme
Phase 1
Mixed Lineage Leukemia (MLL)

Additional relevant MeSH terms:
Neoplasms
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Myelodysplastic Syndromes
Preleukemia
Myeloproliferative Disorders
Hematologic Neoplasms
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms by Site

ClinicalTrials.gov processed this record on July 20, 2014