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

• ClinicalTrials.gov Identifier: NCT02141828
• Recruitment Status: Completed
• First Posted: May 20, 2014
• Last Update Posted: May 8, 2020
• Sponsor: Epizyme, Inc.
• Collaborator: Celgene Corporation
• Information provided by (Responsible Party): Epizyme, Inc.

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 (Clinical Trial)
• 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 2014
• Actual Primary Completion Date: May 2016
• Actual Study Completion Date: June 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

Outcome Measures

Primary Outcome Measures :

1. Determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of EPZ-5676. [ Time Frame: 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.
2. To assess the safety and tolerability of EPZ-5676 administered as a continuous intravenous (CIV) infusion [ Time Frame: 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 :

1. Determine the pharmacokinetic (PK) and pharmacodynamic (PD) profile of EPZ-5676 [ Time Frame: 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.

2. Evaluate early evidence of anti-tumor activity [ Time Frame: 18 months ]
   Anti-tumor activity will be assessed by objective response (OR) in pediatric patients

Other Outcome Measures:

1. To determine cerebrospinal fluid (CSF) concentrations EPZ-5676 in pediatric patients receiving EPZ-5676 by CIV infusion [ Time Frame: 18 months ]
2. Analysis of tumor cells for somatic mutations as potential predictors of response [ Time Frame: 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

• Ages Eligible for Study: 3 Months to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, California

Childrens Hospital Los Angeles

Los Angeles, California, United States, 90027

University of California San Francisco Medical Center-Parnassus

San Francisco, California, United States, 94143

United States, Colorado

Children's Hospital Colorado

Aurora, Colorado, United States, 80045

United States, Georgia

Emory Children's Healthcare of Atlanta

Atlanta, Georgia, United States, 30322

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, New York

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

Canada, Ontario

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

More Information

• Responsible Party: Epizyme, Inc.
• ClinicalTrials.gov Identifier: NCT02141828
• Other Study ID Numbers: EPZ-5676-12-002
• First Posted: May 20, 2014
• Last Update Posted: May 8, 2020
• Last Verified: May 2020

Keywords provided by Epizyme, Inc.:

Leukemia; Advanced hematologic malignancies; Epizyme; Phase 1b; MLL gene; 11q23; Ambiguous lineage; ALL; AML; Acute leukemias; MLL-r

Additional relevant MeSH terms:

Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Neoplasms by Histologic Type; Neoplasms; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases