Clinical trial NCT01684150: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Acute Lymphoblastic Leukemia
Myelodysplastic Syndrome
Myeloproliferative Disorders
Keywords: Leukemia
Advanced hematologic malignancies
Epizyme
Phase 1
Mixed Lineage Leukemia (MLL)
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
Collaborators: name: Celgene
First posted: 2012-09-12
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Currently this study is in the MLL-r restricted/expansion phase and is only enrolling patients with rearrangements involving the MLL gene, including 11q23 or partial tandem duplications (PTD).

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 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).

Eligibility criteria: 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.

Primary outcomes:
measure: The maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of EPZ-5676 as determined by incidence of protocol-specified dose-limiting adverse events.
timeFrame: up to 12 months
Secondary outcomes:
measure: Pharmacokinetic profile of EPZ-5676
timeFrame: up to 24 months
measure: The incidence of adverse events in patients treated with EPZ-5676
timeFrame: up to 24 months
measure: Anti-leukemic activity of EPZ-5676 in patients with acute leukemia harboring a MLL-rearrangement
timeFrame: up to 24 months
measure: Effects of EPZ-5676 on histone H3K79 methylation in peripheral blood mononuclear cells (PBMC).
timeFrame: up to 24 months
measure: Effects of EPZ-5676 on histone H3K79 methylation in leukemia cells
timeFrame: up to 24 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Scottsdale-Phoenix
state: Arizona
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Health System
state: North Carolina
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: UT MD Anderson Cancer
state: Texas
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Martin S. Tallman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: SCRI Development Innovations, LLC
name: Jesus Berdeja, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: David A Rizzieri, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: M.D. Anderson Cancer Center
name: Guillermo Garcia-Manero, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Northwestern University
name: Jessica Altman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic Scottsdale-Phoenix
name: Raoul Tibes, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Erasmus Medical Center
name: Mojca Jongen-Lavrencic, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitätsklinikum Ulm
name: Hartmut Döhner, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ipsen
name: Ipsen Medical Director
role: STUDY_DIRECTOR
References:
citation: Stein EM, Garcia-Manero G, Rizzieri DA, Tibes R, Berdeja JG, Savona MR, Jongen-Lavrenic M, Altman JK, Thomson B, Blakemore SJ, Daigle SR, Waters NJ, Suttle AB, Clawson A, Pollock R, Krivtsov A, Armstrong SA, DiMartino J, Hedrick E, Lowenberg B, Tallman MS. The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. Blood. 2018 Jun 14;131(24):2661-2669. doi: 10.1182/blood-2017-12-818948. Epub 2018 May 3.