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

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

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).

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Myeloproliferative Disorders; Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome
• Intervention / Treatment: Drug: EPZ-5676

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).

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm
• Netherlands
  • Rotterdam, Netherlands
    • Erasmus University Medical Center
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic Scottsdale-Phoenix
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Health System
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Houston, Texas, United States, 77030
      • UT MD Anderson Cancer

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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).	up to 12 months

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Epizyme, Inc.
• Collaborators: Celgene
• Investigators: Principal Investigator: Martin S. Tallman, MD, Memorial Sloan Kettering Cancer Center; Principal Investigator: Jesus Berdeja, MD, SCRI Development Innovations, LLC; 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; Study Director: Ipsen Medical Director, Ipsen; 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

Publications and helpful links

General Publications

• Stein EM, Garcia-Manero G, Rizzieri DA, Tibes R, Berdeja JG, Savona MR, Jongen-Lavrenic M, Altman JK, Thomson B, Blakemore SJ, Daigle SR, Waters NJ, Suttle AB, Clawson A, Pollock R, Krivtsov A, Armstrong SA, DiMartino J, Hedrick E, Lowenberg B, Tallman MS. The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. Blood. 2018 Jun 14;131(24):2661-2669. doi: 10.1182/blood-2017-12-818948. Epub 2018 May 3.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: September 6, 2012
• First Submitted That Met QC Criteria: September 10, 2012
• First Posted (Estimated): September 12, 2012

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 24, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Epizyme; Phase 1; Leukemia; Advanced hematologic malignancies; Mixed Lineage Leukemia (MLL)
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Leukemia, Lymphoid; Myelodysplastic Syndromes; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myeloproliferative Disorders
• Other Study ID Numbers: EPZ-5676-12-001; 2013-002355-15 (EudraCT Number)