Clinical trial NCT02141828: A Phase 1 Dose Escalation and Expanded Cohort Study of EPZ-5676 in the Treatment of Pediatric Patients With Relapsed/Refractory Leukemias Bearing a Rearrangement of the MLL Gene
Official title: A Phase 1 Dose Escalation and Expanded Cohort Study of EPZ-5676 in the Treatment of Pediatric Patients With Relapsed/Refractory Leukemias Bearing a Rearrangement of the MLL Gene
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Leukemia
Acute Myeloid Leukemia
Acute Lymphocytic Leukemia
Acute Leukemias
Keywords: Leukemia
Advanced hematologic malignancies
Epizyme
Phase 1b
MLL gene
11q23
Ambiguous lineage
ALL
AML
Acute leukemias
MLL-r
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
Collaborators: name: Celgene Corporation
First posted: 2014-05-20
Enrollment: 18
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: This is a Phase 1b study of EPZ-5676 in pediatric patients. 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 as a 28-day continuous IV infusion. Once the MTD and/or RP2D is established, a second phase of the study will further evaluate the safety of EPZ-5676 and assess the anti-leukemia activity.

Eligibility criteria: Inclusion Criteria:

1. Age: \>3 months to \<18 years of age.
2. Diagnosis: Patients must have documented relapsed/refractory ALL, AML, or acute leukemia of ambiguous lineage and meet the following criteria:

   * Patients must have at least received an appropriate induction therapy regimen. Patients with persistent leukemia after induction therapy, or with recurrence of leukemia at any time during the course of treatment (including allogeneic HSCT) are eligible;
   * Patients must have \> 10% leukemic blasts in the bone marrow;
   * Patients must have rearrangement involving the MLL gene, including reciprocal chromosomal translocations involving 11q23 by FISH, cytogenetic analysis, polymerase chain reaction (PCR) or next-generation sequencing (NGS) OR partial tandem duplication (PTD) of MLL by PCR or NGS.
3. Therapeutic Options: Patients must be ineligible or inappropriate for other treatment regimens known to have curative potential.
4. Performance Level: Karnofsky \> 50% for pts \> 12 years; Lansky \> 50% for pts \< 12 years of age.
5. Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

   Myelosuppressive Chemotherapy:
   * 14 days must have elapsed since the completion of cytotoxic therapy
   * Patients may receive hydroxyurea, low-dose cytarabine and/or glucocorticoids to control peripheral blood leukemic cell counts at study entry
   * At least 7 days since the completion of therapy with hematopoietic growth factors
   * At least 7 days since the completion of therapy with a biologic agent
   * At least 21 days since receipt of chimeric antigen receptor therapy or other modified T cell therapy
   * At least 60 days from prior total body irradiation (TBI)
   * At least 60 days must have elapsed from hematopoietic stem cell transplantation (HSCT)
6. Renal and Hepatic Function: Patient must have adequate renal and hepatic functions as indicated by the following laboratory values:

   * Patient must have a calculated creatinine clearance or radioisotope GFR \> 60mL/min/1.73m2 or a normal serum creatinine based on age/gender
   * Total bilirubin \< 1.5 x ULN for age or normal conjugated bilirubin
   * ALT and AST \< 3 x ULN (unless attributed to leukemic involvement)
7. Cardiac Function: Patient must have a shortening fraction (SF) of \> 27% or an ejection fraction (EF) of \> 50% by echocardiogram or MUGA scan.

Exclusion Criteria:

1. Patients with CNS 3 disease or symptomatic CNS disease
2. Clinically active heart disease including prolonged QTc or prolonged PR interval, or history of arrhythmias
3. On immunosuppressive or other anti-leukemic therapy, excluding patients receiving glucocorticoids for management of circulating blast count or patients on a stable dose (\<20mg/m2/day prednisone or equivalent) of systemic or topical glucocorticoid therapy with ≤ Grade 1 GvHD or tapering dose of calcineurin inhibitor
4. Patients with known bleeding diathesis or prothrombin time (PT) or aPTT \>1.5 x ULN or fibrinogen \<0.5 x LLN
5. Receiving prophylactic use of hematopoietic colony stimulating factors
6. Known history of infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HBsAg positive) or hepatitis C virus (anti-HCV positive)
7. Being actively treated for another concurrent malignancy
8. Pregnant or nursing females;
9. Male patients not willing to use a condom
10. Uncontrolled intercurrent illness including, but not limited to uncontrolled infection, significant graft-versus-host-disease (GvHD) (Grade 2-4), or psychiatric illness/social situations that would limit compliance with study requirements
11. Patients who are concurrently receiving strong inducers/inhibitors of CYP3A
12. Patients with known history of Trisomy 21 (Down Syndrome), history of congenital immunodeficiency or inherited marrow failure disorder.
13. Patients with known bleeding diathesis, or PT (Prothrombin time) or aPTT (activated partial thromboplastin time) \> 1.5x ULN or \<0.5x LLN.

Primary outcomes:
measure: Determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of EPZ-5676.
timeFrame: 12 months
measure: To assess the safety and tolerability of EPZ-5676 administered as a continuous intravenous (CIV) infusion
timeFrame: 22 months
Secondary outcomes:
measure: Determine the pharmacokinetic (PK) and pharmacodynamic (PD) profile of EPZ-5676
timeFrame: 18 months
measure: Evaluate early evidence of anti-tumor activity
timeFrame: 18 months
Other outcomes:
measure: To determine cerebrospinal fluid (CSF) concentrations EPZ-5676 in pediatric patients receiving EPZ-5676 by CIV infusion
timeFrame: 18 months
measure: Analysis of tumor cells for somatic mutations as potential predictors of response
timeFrame: 18 months
Locations:
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center-Parnassus
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Atlanta
country: United States
facility: Emory Children's Healthcare of Atlanta
state: Georgia
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Toronto
country: Canada
facility: The Hospital for Sick Kids
state: Ontario
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Neal Shukla, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Colorado
name: Lia Gore, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins University
name: Pat Brown, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dana Farber
name: Lewis Silverman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Medical Center, Cincinnati
name: Maureen O'Brien, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital of Sick Kids
name: Jim A Whitlock, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory Children's Healthcare of Atlanta
name: Cynthia Wetmore, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Mignon Loh, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Los Angeles
name: Paul Gaynon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Seattle Children's Hospital
name: Todd Cooper, MD
role: PRINCIPAL_INVESTIGATOR
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