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


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome, Myeloproliferative Disorders, Chronic Myeloid Leukemia

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Trial Information

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


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
flourescent 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.

This is a first-in-human study of EPZ-5676. The primary purpose of this study is to
determine what dose of EPZ-5676, when administered as a 21-day continuous intravenous
infusion, can be given safely to patients with hematologic malignancies. The study will have
two phases. The first phase will assess escalating doses of EPZ-5676 in order to determine
the maximally tolerated dose (MTD) of EPZ-5676. Once the MTD is established, a second phase
of the study will further evaluate the safety of EPZ-5676 and assess the anti-leukemia
activity of EPZ-5676 in MLL-rearranged leukemia.


Inclusion Criteria:



1. Male and female patients aged ≥ 18 years.

2. AML, ALL, acute mixed lineage leukemia, myelodysplastic syndrome (International
Prognostic Scoring System Int-2 or high-risk), myeloproliferative disorder, or
chronic myelogenous leukemia meeting the following criteria (NOTE: only patients
with acute leukemia with rearrangement of the MLL gene will be 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.

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 ≤1.5 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 involvement of the central nervous system by leukemia.

8. On immunosuppressive therapy.

9. Known active infection.

10. Pregnant or nursing females.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The maximum tolerated dose (MTD) of EPZ-5676 as determined by incidence of protocol-specified dose-limiting adverse events

Outcome Description:

The MTD is defined as one dose level below the level in which >1 dose-limiting adverse events (as defined by the protocol) are observed.

Outcome Time Frame:

up to 12 months

Safety Issue:

Yes

Principal Investigator

Martin S. Tallman, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

EPZ-5676-12-001

NCT ID:

NCT01684150

Start Date:

September 2012

Completion Date:

November 2014

Related Keywords:

  • Acute Myeloid Leukemia
  • Acute Lymphoblastic Leukemia
  • Myelodysplastic Syndrome
  • Myeloproliferative Disorders
  • Chronic Myeloid Leukemia
  • Leukemia
  • Advanced hematologic malignancies
  • Epizyme
  • Phase 1
  • Mixed Lineage Leukemia (MLL)
  • Neoplasms
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders
  • Hematologic Neoplasms

Name

Location

Memorial Sloan Kettering Cancer Center New York, New York  10021
Sarah Cannon Research Institute Nashville, Tennessee  37203
Duke University Health System Durham, North Carolina  27705
UT MD Anderson Cancer Houston, Texas  77030