A First-in-Human Phase 1 and Expanded Cohort Study of EPZ-5676 in Advanced Hematologic Malignancies, Including Acute Leukemia With Rearrangement of the MLL Gene

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).

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.