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

Acute Myeloid Leukemia Clinical Trial

Official 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 Translocation of the MLL Gene at 11q23 or Advanced Hematologic Malignancies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01684150
• Other study ID #: EPZ-5676-12-001
• Secondary ID: 2013-002355-15
• Status: Completed
• Phase: Phase 1
• Start date: September 2012
• Est. completion date: February 2016

Study information

• Verified date: March 2024
• Source: Ipsen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 51
• Est. completion date: February 2016
• Est. primary completion date: November 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Acute Myeloid Leukemia
• Leukemia
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Myeloproliferative Disorders
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

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.

Locations

Country	Name	City	State
Germany	Universitätsklinikum Ulm	Ulm
Netherlands	Erasmus University Medical Center	Rotterdam
United States	Northwestern University	Chicago	Illinois
United States	Duke University Health System	Durham	North Carolina
United States	UT MD Anderson Cancer	Houston	Texas
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mayo Clinic Scottsdale-Phoenix	Scottsdale	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
Epizyme, Inc.	Celgene

Countries where clinical trial is conducted

United States,  Germany,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Pharmacokinetic profile of EPZ-5676	analysis of Cmax, AUC and steady state concentration	up to 24 months
Secondary	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
Secondary	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
Secondary	Effects of EPZ-5676 on histone H3K79 methylation in peripheral blood mononuclear cells (PBMC).		up to 24 months
Secondary	Effects of EPZ-5676 on histone H3K79 methylation in leukemia cells		up to 24 months