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

Sponsor

Epizyme, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT02141828

Collaborator

Celgene Corporation (Industry)

Enrollment

Locations

Arm

Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia Acute Myeloid Leukemia Acute Lymphocytic Leukemia Acute Leukemias	Drug: EPZ-5676	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

18 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

May 1, 2014

Actual Primary Completion Date :

May 1, 2016

Actual Study Completion Date :

Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: EPZ-5676 EPZ-5676 Dose escalation and expansion cohorts	Drug: EPZ-5676 28-day continuous IV infusion of each 28-day cycle, given until disease progression or unacceptable toxicity develops. Other Names: EPZ5676 DOT1L

Arm

Intervention/Treatment

Experimental: EPZ-5676

EPZ-5676 Dose escalation and expansion cohorts

Drug: EPZ-5676

28-day continuous IV infusion of each 28-day cycle, given until disease progression or unacceptable toxicity develops.

Other Names:

EPZ5676

DOT1L

Outcome Measures

Primary Outcome Measures

Determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of EPZ-5676. [12 months]
To determine 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.
To assess the safety and tolerability of EPZ-5676 administered as a continuous intravenous (CIV) infusion [22 months]
Safety and tolerability will be assessed by the incidence of adverse events in patients treated with EPZ-5676 and the evaluation of adverse events, vital signs, physical examination, 12-lead ECG, and laboratory assessments.

Secondary Outcome Measures

Determine the pharmacokinetic (PK) and pharmacodynamic (PD) profile of EPZ-5676 [18 months]
The pharmacokinetic (PK) profile will include the analysis of Cmax, AUC and steady state concentration of EPZ-5676. The pharmacodynamic (PD) profile will assess the effects of EPZ-5676 in peripheral blood mononuclear (PBMC) and bone marrow cells.
Evaluate early evidence of anti-tumor activity [18 months]
Anti-tumor activity will be assessed by objective response (OR) in pediatric patients

Other Outcome Measures

To determine cerebrospinal fluid (CSF) concentrations EPZ-5676 in pediatric patients receiving EPZ-5676 by CIV infusion [18 months]
Analysis of tumor cells for somatic mutations as potential predictors of response [18 months]
Somatic mutations to include mRNA and proteins or markers of biological pathways as potential predictors of response to EPZ-5676 treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Months to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age: >3 months to <18 years of age.
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.

Therapeutic Options: Patients must be ineligible or inappropriate for other treatment regimens known to have curative potential.
Performance Level: Karnofsky > 50% for pts > 12 years; Lansky > 50% for pts < 12 years of age.
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)

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)

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:

Patients with CNS 3 disease or symptomatic CNS disease
Clinically active heart disease including prolonged QTc or prolonged PR interval, or history of arrhythmias
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
Patients with known bleeding diathesis or prothrombin time (PT) or aPTT >1.5 x ULN or fibrinogen <0.5 x LLN
Receiving prophylactic use of hematopoietic colony stimulating factors
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)
Being actively treated for another concurrent malignancy
Pregnant or nursing females;
Male patients not willing to use a condom
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
Patients who are concurrently receiving strong inducers/inhibitors of CYP3A
Patients with known history of Trisomy 21 (Down Syndrome), history of congenital immunodeficiency or inherited marrow failure disorder.
Patients with known bleeding diathesis, or PT (Prothrombin time) or aPTT (activated partial thromboplastin time) > 1.5x ULN or <0.5x LLN.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Childrens Hospital Los Angeles	Los Angeles	California	United States	90027
2	University of California San Francisco Medical Center-Parnassus	San Francisco	California	United States	94143
3	Children's Hospital Colorado	Aurora	Colorado	United States	80045
4	Emory Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
5	Johns Hopkins University	Baltimore	Maryland	United States	21287
6	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
7	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
8	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
9	The Hospital for Sick Kids	Toronto	Ontario	Canada

Sponsors and Collaborators

Epizyme, Inc.
Celgene Corporation

Investigators

Principal Investigator: Neal Shukla, MD, Memorial Sloan Kettering Cancer Center
Principal Investigator: Lia Gore, MD, Children's Hospital Colorado
Principal Investigator: Pat Brown, MD, Johns Hopkins University
Principal Investigator: Lewis Silverman, MD, Dana Farber
Principal Investigator: Maureen O'Brien, MD, Children's Hospital Medical Center, Cincinnati
Principal Investigator: Jim A Whitlock, MD, Hospital of Sick Kids
Principal Investigator: Cynthia Wetmore, MD PhD, Emory Children's Healthcare of Atlanta
Principal Investigator: Mignon Loh, MD, University of California, San Francisco
Principal Investigator: Paul Gaynon, MD, Children's Hospital Los Angeles
Principal Investigator: Todd Cooper, MD, Seattle Children's Hospital