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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

Primary Purpose

Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

EPZ-5676

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring Leukemia, Advanced hematologic malignancies, Epizyme, Phase 1, Mixed Lineage Leukemia (MLL)

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male and female patients aged ≥ 18 years.
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.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
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
Able and willing to give written informed consent.
Life expectancy of at least 3 months

Exclusion Criteria:

Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements.
Active heart disease
Receiving any other standard treatment for their hematologic malignancy.
Receiving strong CYP3A4 inhibitors/ inducers.
Known history of cerebrovascular accident in the past 6 months.
Known bleeding diathesis.
Known, active (symptomatic) involvement of the central nervous system by leukemia.
On immunosuppressive therapy.
Known active infection.
Pregnant or nursing females.

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

EPZ-5676 Extension cohort

Arm Description

Outcomes

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.

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

analysis of Cmax, AUC and steady state concentration

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

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

Effects of EPZ-5676 on histone H3K79 methylation in peripheral blood mononuclear cells (PBMC).

Effects of EPZ-5676 on histone H3K79 methylation in leukemia cells

Full Information

NCT ID

NCT01684150

First Posted

September 6, 2012

Last Updated

June 15, 2023

Sponsor

Epizyme, Inc.

Collaborators

Celgene

1. Study Identification

Unique Protocol Identification Number

NCT01684150

Brief 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

Official Title

Study Type

Interventional

2. Study Status

Record Verification Date

June 2023

Overall Recruitment Status

Completed

Study Start Date

September 2012 (undefined)

Primary Completion Date

November 2015 (Actual)

Study Completion Date

February 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Epizyme, Inc.

Collaborators

Celgene

4. Oversight

Data Monitoring Committee

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

Leukemia, Advanced hematologic malignancies, Epizyme, Phase 1, Mixed Lineage Leukemia (MLL)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

51 (Actual)

8. Arms, Groups, and Interventions

Arm Title

EPZ-5676 Extension cohort

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

EPZ-5676

Intervention Description

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.

Primary Outcome Measure Information:

Title

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.

Description

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).

Time Frame

up to 12 months

Secondary Outcome Measure Information:

Title

Pharmacokinetic profile of EPZ-5676

Description

analysis of Cmax, AUC and steady state concentration

Time Frame

up to 24 months

Title

The incidence of adverse events in patients treated with EPZ-5676

Description

Evaluation of adverse events, vital signs, physical examination, 12-lead ECG, and laboratory assessments

Time Frame

up to 24 months

Title

Anti-leukemic activity of EPZ-5676 in patients with acute leukemia harboring a MLL-rearrangement

Description

Evaluation of response by standard criteria for AML or ALL

Time Frame

up to 24 months

Title

Effects of EPZ-5676 on histone H3K79 methylation in peripheral blood mononuclear cells (PBMC).

Time Frame

up to 24 months

Title

Effects of EPZ-5676 on histone H3K79 methylation in leukemia cells

Time Frame

up to 24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

90 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male and female patients aged ≥ 18 years. 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. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 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 Able and willing to give written informed consent. Life expectancy of at least 3 months Exclusion Criteria: Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements. Active heart disease Receiving any other standard treatment for their hematologic malignancy. Receiving strong CYP3A4 inhibitors/ inducers. Known history of cerebrovascular accident in the past 6 months. Known bleeding diathesis. Known, active (symptomatic) involvement of the central nervous system by leukemia. On immunosuppressive therapy. Known active infection. Pregnant or nursing females.

Overall Study Officials: