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

Phase 1

Completed

• Conditions: Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Myeloproliferative Disorders; Myelodysplastic Syndrome
• Interventions: Drug: EPZ-5676

• Registration Number: NCT01684150
• Lead Sponsor: 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).

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 Timeline

• Study Start: 2012-09
• Study First Submitted: 2012-09-06
• Study First Submitted QC: 2012-09-10
• Study First Posted: 2012-09-12
• Primary Completion: 2015-11
• Study Completion: 2016-02
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-24
• Last Update Posted: 2024-03-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 51

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
EPZ-5676 Extension cohort	EPZ-5676	-

Primary Outcome Measures

Name	Time	Method
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.	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

Name	Time	Method
Pharmacokinetic profile of EPZ-5676	up to 24 months	analysis of Cmax, AUC and steady state concentration
The incidence of adverse events in patients treated with EPZ-5676	up to 24 months	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	up to 24 months	Evaluation of response by standard criteria for AML or ALL
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

Trial Locations

Locations (8)

Sarah Cannon Research Institute; 🇺🇸 Nashville, Tennessee, United States

Erasmus University Medical Center; 🇳🇱 Rotterdam, Netherlands

Mayo Clinic Scottsdale-Phoenix; 🇺🇸 Scottsdale, Arizona, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

Duke University Health System; 🇺🇸 Durham, North Carolina, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

UT MD Anderson Cancer; 🇺🇸 Houston, Texas, United States

Universitätsklinikum Ulm; 🇩🇪 Ulm, Germany