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 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.
Who is eligible to participate?
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 ≤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.