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

NCT ID: NCT01684150

Last Updated: 2024-03-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 51 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-09-30
• Study Completion Date: 2016-02-29

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).

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).

Conditions

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

EPZ-5676 Extension cohort

Group Type: EXPERIMENTAL

EPZ-5676

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Celgene

INDUSTRY

Sponsor Role: collaborator

Epizyme, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Martin S. Tallman, MD

Role: PRINCIPAL_INVESTIGATOR

Memorial Sloan Kettering Cancer Center

Jesus Berdeja, MD

Role: PRINCIPAL_INVESTIGATOR

SCRI Development Innovations, LLC

David A Rizzieri, MD

Role: PRINCIPAL_INVESTIGATOR

Duke University

Guillermo Garcia-Manero, MD

Role: PRINCIPAL_INVESTIGATOR

M.D. Anderson Cancer Center

Jessica Altman, MD

Role: PRINCIPAL_INVESTIGATOR

Northwestern University

Raoul Tibes, MD

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic Scottsdale-Phoenix

Mojca Jongen-Lavrencic, MD

Role: PRINCIPAL_INVESTIGATOR

Erasmus Medical Center

Hartmut Döhner, MD

Role: PRINCIPAL_INVESTIGATOR

Universitätsklinikum Ulm

Ipsen Medical Director

Role: STUDY_DIRECTOR

Ipsen

Locations

Mayo Clinic Scottsdale-Phoenix

Scottsdale, Arizona, United States

Northwestern University

Chicago, Illinois, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Duke University Health System

Durham, North Carolina, United States

Sarah Cannon Research Institute

Nashville, Tennessee, United States

UT MD Anderson Cancer

Houston, Texas, United States

Universitätsklinikum Ulm

Ulm, , Germany

Erasmus University Medical Center

Rotterdam, , Netherlands

Countries

United States; Germany; Netherlands

References

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.

Reference Type: DERIVED

PMID: 29724899 (View on PubMed)

Other Identifiers

2013-002355-15

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EPZ-5676-12-001

Identifier Type: -

Identifier Source: org_study_id