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Dose Escalation Study of EPZ-5676 in Pediatric Patients With Leukemias Bearing a Rearrangement of the MLL Gene

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by Epizyme, Inc.
Sponsor:
Collaborator:
Celgene Corporation
Information provided by (Responsible Party):
Epizyme, Inc.
ClinicalTrials.gov Identifier:
NCT02141828
First received: May 11, 2014
Last updated: November 12, 2014
Last verified: October 2014
  Purpose

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.


Condition Intervention Phase
Leukemia
Acute Myeloid Leukemia
Acute Lymphocytic Leukemia
Acute Leukemias
Drug: EPZ-5676
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Dose Escalation and Expanded Cohort Study of EPZ-5676 in the Treatment of Pediatric Patients With Relapsed/Refractory Leukemias Bearing a Rearrangement of the MLL Gene

Resource links provided by NLM:


Further study details as provided by Epizyme, Inc.:

Primary Outcome Measures:
  • Determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of EPZ-5676. [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]
    To determine 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.

  • To assess the safety and tolerability of EPZ-5676 administered as a continuous intravenous (CIV) infusion [ Time Frame: 18 months. ] [ Designated as safety issue: Yes ]
    Safety and tolerability will be assessed by the incidence of adverse events in patients treated with EPZ-5676 and the evaluation of adverse events, vital signs, physical examination, 12-lead ECG, and laboratory assessments.


Secondary Outcome Measures:
  • Determine the pharmacokinetic (PK) and pharmacodynamic (PD) profile of EPZ-5676 [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]

    The pharmacokinetic (PK) profile will include the analysis of Cmax, AUC and steady state concentration of EPZ-5676.

    The pharmacodynamic (PD) profile will assess the effects on histone H3K79 methylation in peripheral blood mononuclear (PBMC) and bone marrow cells.



Other Outcome Measures:
  • To determine cerebrospinal fluid (CSF) concentrations EPZ-5676 in pediatric patients receiving EPZ-5676 by CIV infusion [ Time Frame: 18 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 40
Study Start Date: May 2014
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: EPZ-5676
EPZ-5676 Dose escalation and expansion cohorts
Drug: EPZ-5676
28-day continuous IV infusion of each 28-day cycle, given until disease progression or unacceptable toxicity develops.
Other Names:
  • EPZ5676
  • DOT1L

Detailed Description:

This is a Phase 1b study of EPZ-5676 in pediatric patients. 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 as a 28-day continuous IV infusion. Once the MTD and/or RP2D is established, a second phase of the study will further evaluate the safety of EPZ-5676 and assess the anti-leukemia activity.

  Eligibility

Ages Eligible for Study:   3 Months to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age: 3 months to <18 years of age.
  2. Diagnosis: Patients must have documented relapsed/refractory ALL, AML, or acute leukemia of ambiguous lineage and meet the following criteria:

    • Patients must have at least received an appropriate induction therapy regimen. Patients with persistent leukemia after induction therapy, or with recurrence of leukemia at any time during the course of treatment (including allogeneic HSCT) are eligible;
    • Patients must have > 10% leukemic blasts in the bone marrow;
    • Patients must have rearrangement involving the MLL gene, including reciprocal chromosomal translocations involving 11q23 by FISH, cytogenetic analysis, polymerase chain reaction (PCR) or next-generation sequencing (NGS) OR partial tandem duplication (PTD) of MLL by PCR or NGS.
  3. Therapeutic Options: Patients must be ineligible or inappropriate for other treatment regimens known to have curative potential.
  4. Performance Level: Karnofsky > 50% for pts > 12 years; Lansky > 50% for pts < 12 years of age.
  5. Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

    Myelosuppressive Chemotherapy:

    • 14 days must have elapsed since the completion of cytotoxic therapy
    • Patients may receive hydroxyurea, low-dose cytarabine and/or glucocorticoids to control peripheral blood leukemic cell counts at study entry
    • At least 7 days since the completion of therapy with hematopoietic growth factors
    • At least 7 days since the completion of therapy with a biologic agent
    • At least 21 days since receipt of chimeric antigen receptor therapy or other modified T cell therapy
    • At least 60 days from prior total body irradiation (TBI)
    • At least 60 days must have elapsed from hematopoietic stem cell transplantation (HSCT)
  6. Renal and Hepatic Function: Patient must have adequate renal and hepatic functions as indicated by the following laboratory values:

    • Patient must have a calculated creatinine clearance or radioisotope GFR > 60mL/min/1.73m2 or a normal serum creatinine based on age/gender
    • Total bilirubin < 1.5 x UNL for age or normal conjugated bilirubin
    • ALT and AST < 3 x ULN (unless attributed to leukemic involvement)
  7. Cardiac Function: Patient must have a shortening fraction (SF) of > 27% or an ejection fraction (EF) of > 50% by echocardiogram or MUGA scan.

Exclusion Criteria:

  1. Patients with CNS 3 disease or symptomatic CNS disease
  2. Clinically active heart disease including prolonged QTc or prolonged PR interval, or history of arrhythmias
  3. On immunosuppressive or other anti-leukemic therapy, excluding patients receiving glucocorticoids for management of circulating blast count or patients on a stable dose (<20mg/m2/day prednisone or equivalent) of systemic or topical glucocorticoid therapy with ≤ Grade 1 GvHD or tapering dose of calcineurin inhibitor
  4. Patients with known bleeding diathesis or prothrombin time (PT) or aPTT >1.5 x ULN or fibrinogen <0.5 x LLN
  5. Receiving prophylactic use of hematopoietic colony stimulating factors
  6. Known history of infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HBsAg positive) or hepatitis C virus (anti-HCV positive)
  7. Being actively treated for another concurrent malignancy
  8. Pregnant or nursing females;
  9. Male patients not willing to use a condom
  10. Uncontrolled intercurrent illness including, but not limited to uncontrolled infection, significant graft-versus-host-disease (GvHD) (Grade 2-4), or psychiatric illness/social situations that would limit compliance with study requirements
  11. Patients who are concurrently receiving strong inducers/inhibitors of CYP3A
  12. Patients with known history of Trisomy 21 (Down Syndrome), history of congenital immunodeficiency or inherited marrow failure disorder.
  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: NCT02141828

Contacts
Contact: Blythe Thomson, MD 855-500-1011 clinicaltrials@epizyme.com
Contact: Peter Ho, MD, PhD 855-500-1011 clinicaltrials@epizyme.com

Locations
United States, California
Childrens Hospital Los Angeles Not yet recruiting
Los Angeles, California, United States, 90027
Contact: Paul Gaynon, MD       PGaynon@chla.usc.edu   
Principal Investigator: Paul Gaynon, MD         
University of California San Francisco Medical Center-Parnassus Not yet recruiting
San Francisco, California, United States, 94143
Contact: Mignon Loh, MD    877-827-3222    LohM@peds.ucsf.edu   
Principal Investigator: Mignon Loh, MD         
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Lia Gore, MD       Lia.Gore@ucdenver.edu   
Principal Investigator: Lia Gore, MD         
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21287
Contact: Pat Brown, MD       pbrown2@jhmi.edu   
Principal Investigator: Pat Brown, MD         
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Lewis Silverman, MD       Lewis_Silverman@dfci.harvard.edu   
Principal Investigator: Lewis Silverman, MD         
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Neal Shukla, MD       shuklan@MSKCC.ORG   
Principal Investigator: Neal Shukla, MD         
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Maureen O'Brien, MD       maureen.obrien@cchmc.org   
Principal Investigator: Maureen O'Brien, MD         
Canada, Ontario
The Hospital for Sick Kids Recruiting
Toronto, Ontario, Canada
Contact: Jim A Whitlock, MD    416-813-8885    jim.whitlock@sickkids.ca   
Principal Investigator: Jim A Whitlock, MD         
Sponsors and Collaborators
Epizyme, Inc.
Celgene Corporation
Investigators
Principal Investigator: Neal Shukla, MD Memorial Sloan-Kettering Cancer Center
Principal Investigator: Lia Gore, MD Children's Hospital Colorado
Principal Investigator: Pat Brown, MD Johns Hopkins University
Principal Investigator: Lewis Silverman, MD Dana Farber
Principal Investigator: Paul Gaynon, MD Children's Hospital Los Angeles
Principal Investigator: Maureen O'Brien, MD Children's Hospital Medical Center, Cincinnati
Principal Investigator: Jim A Whitlock, MD Hospital of Sick Kids
  More Information

No publications provided

Responsible Party: Epizyme, Inc.
ClinicalTrials.gov Identifier: NCT02141828     History of Changes
Other Study ID Numbers: EPZ-5676-12-002
Study First Received: May 11, 2014
Last Updated: November 12, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Epizyme, Inc.:
Leukemia
Advanced hematologic malignancies
Epizyme
Phase 1b
MLL gene
11q23
Ambiguous lineage
ALL
AML
Acute leukemias
MLL-r

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on November 25, 2014