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 Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Leukemia, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, Acute Leukemias

Intervention / Treatment
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* Drug: EPZ-5676


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EPZ-5676<br>EPZ-5676 Dose escalation and expansion cohorts | Drug: EPZ-5676<br>* 28-day continuous IV infusion of each 28-day cycle, given until disease progression or unacceptable toxicity develops.<br>* Other names: DOT1L;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of EPZ-5676. | 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. | 12 months | 
| To assess the safety and tolerability of EPZ-5676 administered as a continuous intravenous (CIV) infusion | 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. | 22 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the pharmacokinetic (PK) and pharmacodynamic (PD) profile of EPZ-5676 | 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. | 18 months | 
| Evaluate early evidence of anti-tumor activity | Anti-tumor activity will be assessed by objective response (OR) in pediatric patients | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ambiguous lineage, Leukemia, Advanced hematologic malignancies, Epizyme, Phase 1b, MLL gene, 11q23, ALL, AML, Acute leukemias, MLL-r