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

NCT ID: NCT02141828

Last Updated: 2023-06-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-05-31
• Study Completion Date: 2016-06-30

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.

Conditions

Leukemia; Acute Myeloid Leukemia; Acute Lymphocytic Leukemia; Acute Leukemias

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

EPZ-5676

EPZ-5676 Dose escalation and expansion cohorts

Group Type: EXPERIMENTAL

EPZ-5676

Intervention Type: DRUG

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

Interventions

EPZ-5676

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

Intervention Type: DRUG

Other Intervention Names

EPZ5676; DOT1L

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.

• Minimum Eligible Age: 3 Months
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Celgene Corporation

INDUSTRY

Sponsor Role: collaborator

Epizyme, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Neal Shukla, MD

Role: PRINCIPAL_INVESTIGATOR

Memorial Sloan Kettering Cancer Center

Lia Gore, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital Colorado

Pat Brown, MD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Lewis Silverman, MD

Role: PRINCIPAL_INVESTIGATOR

Dana Farber

Maureen O'Brien, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital Medical Center, Cincinnati

Jim A Whitlock, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital of Sick Kids

Cynthia Wetmore, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Emory Children's Healthcare of Atlanta

Mignon Loh, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Paul Gaynon, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital Los Angeles

Todd Cooper, MD

Role: PRINCIPAL_INVESTIGATOR

Seattle Children's Hospital

Locations

Childrens Hospital Los Angeles

Los Angeles, California, United States

University of California San Francisco Medical Center-Parnassus

San Francisco, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Emory Children's Healthcare of Atlanta

Atlanta, Georgia, United States

Johns Hopkins University

Baltimore, Maryland, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

The Hospital for Sick Kids

Toronto, Ontario, Canada

Countries

United States; Canada

Other Identifiers

EPZ-5676-12-002

Identifier Type: -

Identifier Source: org_study_id