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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

NCT02141828

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: EPZ-5676-12-002
  • NCT ID: NCT02141828

Conditions

  • Leukemia
  • Acute Myeloid Leukemia
  • Acute Lymphocytic Leukemia
  • Acute Leukemias

Interventions

DrugSynonymsArms
EPZ-5676EPZ5676, DOT1LEPZ-5676

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
EPZ-5676ExperimentalEPZ-5676 Dose escalation and expansion cohorts
  • EPZ-5676

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.
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:3 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of EPZ-5676.
Time Frame:12 months
Safety Issue:
Description: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.

Secondary Outcome Measures

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

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Epizyme, Inc.

Trial Keywords

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

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