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
Trial status: Open for Enrollment
Why is this study being done?
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.
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) or recommended phase 2 dose (RP2D) of EPZ-5676. Once the MTD or RP2D is established, a second phase of the study will further evaluate the safety of EPZ-5676 given as a 28-day continuous IV infusion and assess the anti-leukemia activity of EPZ-5676 in MLL-rearranged leukemia.
Currently this study is in the MLL-r restricted/expansion phase and patients will receive EPZ-5676 as a continuous intravenous infusion.
Who is eligible to participate?
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
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.