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
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Myelodysplastic Syndrome Myeloproliferative Disorders Chronic Myeloid Leukemia |
Drug: EPZ-5676 |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| 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 |
- The maximum tolerated dose (MTD) of EPZ-5676 as determined by incidence of protocol-specified dose-limiting adverse events [ Time Frame: up to 12 months ] [ Designated as safety issue: Yes ]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.
- Pharmacokinetic profile of EPZ-5676 [ Time Frame: up to 12 months ] [ Designated as safety issue: No ]analysis of Cmax, AUC and steady state concentration
- The incidence of adverse events in patients treated with EPZ-5676 [ Time Frame: up to 24 months ] [ Designated as safety issue: Yes ]Evaluation of adverse events, vital signs, physical examination, 12-lead ECG, and laboratory assessments
- Anti-leukemic activity of EPZ-5676 in patients with acute leukemia harboring a MLL-rearrangement [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]Evaluation of response by standard criteria for AML or ALL
- Effects of EPZ-5676 on histone H3K79 methylation in peripheral blood mononuclear cells (PBMC). [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]
- Effects of EPZ-5676 on histone H3K79 methylation in leukemia cells [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 40 |
| Study Start Date: | September 2012 |
| Estimated Study Completion Date: | November 2014 |
| Estimated Primary Completion Date: | September 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| Experimental: EPZ-5676 Dose-escalation and extension cohorts |
Drug: EPZ-5676
Dose-escalation, 21-day continuous IV infusion of each 28-day cycle. Number of cycles: until disease progression or unacceptable toxicity develops.
|
Detailed 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 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.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Male and female patients aged ≥ 18 years.
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.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
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
- Able and willing to give written informed consent.
- Life expectancy of at least 3 months
Exclusion Criteria:
- Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements.
- Active heart disease
- Receiving any other standard treatment for their hematologic malignancy,
- Receiving strong CYP3A4 inhibitors/ inducers.
- Known history of cerebrovascular accident in the past 6 months.
- Known bleeding diathesis.
- Known, active involvement of the central nervous system by leukemia.
- On immunosuppressive therapy.
- Known active infection.
- Pregnant or nursing females.
Contacts and Locations| Contact: Eric Hedrick, MD | 855-500-1011 | clinicaltrials@epizyme.com |
| United States, New York | |
| Memorial Sloan Kettering Cancer Center | Recruiting |
| New York, New York, United States, 10065 | |
| Contact: Martin S Tallman, MD 212-639-3842 TallmanM@mskcc.org | |
| Principal Investigator: Martin S Tallman, MD | |
| United States, Tennessee | |
| Sarah Cannon Research Institute | Recruiting |
| Nashville, Tennessee, United States, 37203 | |
| Contact: Michael Savona, MD 615-986-7604 msavona@tnonc.com | |
| Principal Investigator: Michael Savona, MD | |
| Principal Investigator: | Martin S. Tallman, MD | Memorial Sloan-Kettering Cancer Center |
| Principal Investigator: | Michael Savona, MD | Sarah Cannon Research Institute |
More Information
No publications provided
| Responsible Party: | Epizyme, Inc. |
| ClinicalTrials.gov Identifier: | NCT01684150 History of Changes |
| Other Study ID Numbers: | EPZ-5676-12-001 |
| Study First Received: | September 6, 2012 |
| Last Updated: | March 12, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by Epizyme, Inc.:
|
Leukemia Advanced hematologic malignancies Epizyme Phase 1 Mixed Lineage Leukemia (MLL) |
Additional relevant MeSH terms:
|
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 Neoplasms by Histologic Type Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Bone Marrow Diseases Hematologic Diseases Precancerous Conditions Neoplasms by Site |
ClinicalTrials.gov processed this record on May 23, 2013