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
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|ClinicalTrials.gov Identifier: NCT02141828|
Recruitment Status : Completed
First Posted : May 20, 2014
Last Update Posted : May 8, 2020
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|Condition or disease||Intervention/treatment||Phase|
|Leukemia Acute Myeloid Leukemia Acute Lymphocytic Leukemia Acute Leukemias||Drug: EPZ-5676||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||18 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
EPZ-5676 Dose escalation and expansion cohorts
28-day continuous IV infusion of each 28-day cycle, given until disease progression or unacceptable toxicity develops.
- 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.
- 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.
- 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.
- Evaluate early evidence of anti-tumor activity [ Time Frame: 18 months ]Anti-tumor activity will be assessed by objective response (OR) in pediatric patients
- To determine cerebrospinal fluid (CSF) concentrations EPZ-5676 in pediatric patients receiving EPZ-5676 by CIV infusion [ Time Frame: 18 months ]
- 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
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|Ages Eligible for Study:||3 Months to 18 Years (Child, Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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.
- 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.
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02141828
|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|
|The Hospital for Sick Kids|
|Toronto, Ontario, Canada|
|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|
|Responsible Party:||Epizyme, Inc.|
|Other Study ID Numbers:||
|First Posted:||May 20, 2014 Key Record Dates|
|Last Update Posted:||May 8, 2020|
|Last Verified:||May 2020|
Advanced hematologic malignancies
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Immune System Diseases