Etoposide, Prednisone, Vincristine Sulfate, Cyclophosphamide, and Doxorubicin in Treating Patients With Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

Overview

This phase II trial studies how well etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin (DA-EPOCH) works in treating patients with acute lymphoblastic leukemia or lymphoblastic lymphoma. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Full Title of Study: “A Phase II Study of Dose-Adjusted Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin (DA-EPOCH) as Front-Line Therapy for Adults With Acute Lymphoblastic Leukemia/Lymphoma”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: May 20, 2021

Detailed Description

PRIMARY OBJECTIVES: I. To examine the potential efficacy of DA-EPOCH as front-line therapy for adults with acute lymphoblastic leukemia/lymphoma (ALL). SECONDARY OBJECTIVES: I. To evaluate the safety and feasibility of this regimen. II. To evaluate the progression-free (PFS) and overall survival (OS) of patients after receiving DA-EPOCH for newly-diagnosed ALL. III. To explore for novel genetic/genomic biomarkers of prognosis and response to treatment in adults with ALL. IV. To compare outcomes predicted by the presence or absence of minimal residual disease (MRD) as determined by either multiparameter flow cytometry (MFC) or high-throughput sequencing (HTS). OUTLINE: Patients receive etoposide intravenously (IV) over 96 hours, doxorubicin IV over 96 hours, and vincristine sulfate IV over 96 hours on days 1-4. Patients also receive cyclophosphamide IV over 1 hour on day 5 and prednisone orally (PO) twice a day (BID) on days 1-5. Patients with disease features that predict sensitivity to ABL kinase inhibitors (e.g., Philadelphia Chromosome positive (Ph+) [i.e., t(9;22)]; rearrangements involving PDGFRA, PDGFRB, ABL2, or other genetic lesions that activate kinase receptor signaling): imatinib mesylate or dasatinib PO once per day (QD) on days 1-14. The decision to add imatinib or dasatinib will be left to the treating physician and will be based on the available scientific literature to support the sensitivity of genomic alterations to these TKIs. Patients who are CD20+ also receive rituximab IV on day 1 or day 5. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years and every 6 months for 3 years.

Interventions

  • Drug: Cyclophosphamide
    • Given IV
  • Drug: Dasatinib
    • Given PO
  • Drug: Doxorubicin
    • Given IV
  • Drug: Etoposide
    • Given IV
  • Drug: Imatinib Mesylate
    • Given PO
  • Other: Laboratory Biomarker Analysis
    • Correlative studies
  • Drug: Prednisone
    • Given PO
  • Biological: Rituximab
    • Given IV
  • Drug: Vincristine Sulfate
    • Given IV

Arms, Groups and Cohorts

  • Experimental: Treatment (chemotherapy)
    • Patients receive etoposide IV over 96 hours, doxorubicin IV over 96 hours, and vincristine sulfate IV over 96 hours on days 1-4. Patients also receive cyclophosphamide IV over 1 hour on day 5 and prednisone PO BID on days 1-5. Patients who are Ph+ also receive imatinib mesylate or dasatinib PO QD on days 1-14. Patients who are CD20+ also receive rituximab IV on day 1 or day 5. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

Clinical Trial Outcome Measures

Primary Measures

  • Complete minimal residual disease response rate
    • Time Frame: Up to 12 weeks
    • Will be assessed by a Simon two-stage minimax design.

Secondary Measures

  • Incidence of adverse events
    • Time Frame: Within 28 days of the last dose of the study drugs
    • Will be assessed by Common Terminology Criteria for Adverse Events version 5.0. Incidence of adverse events will be evaluated.
  • Next-Generation gene sequencing
    • Time Frame: Up to 2 years
    • Correlations between specific genetic abnormalities and outcome with this treatment will be explored. Reporting will be primarily descriptive, using established statistical methods.
  • Overall survival
    • Time Frame: Up to 2 years
    • Reporting will be primarily descriptive, with comparisons using established statistical methods. Binary outcomes will be estimated with proportions and associated confidence intervals. Will be estimated using Kaplan-Meier or cumulative incidence estimates.
  • Presence or absence of minimal residual disease
    • Time Frame: Up to 2 years
    • Will be assessed by multiparameter flow cytometry or high-throughput sequencing. Reporting will be primarily descriptive, with comparisons using established statistical methods. Binary outcomes will be estimated with proportions and associated confidence intervals, time-to-event outcomes will be estimated using Kaplan-Meier or cumulative incidence estimates, as appropriate. Outcomes will be compared between those with and those without minimal residual disease. The chi-square test (or Fisher’s exact test) will be used for binary outcomes; the log-rank test will be used for time-to-event outcomes.
  • Progression-free survival
    • Time Frame: Up to 2 years
    • Reporting will be primarily descriptive, with comparisons using established statistical methods. Binary outcomes will be estimated with proportions and associated confidence intervals. Will be estimated using Kaplan-Meier or cumulative incidence estimates.

Participating in This Clinical Trial

Inclusion Criteria

  • Patients must have a confirmed diagnosis of either: – Acute lymphoblastic leukemia – Lymphoblastic lymphoma with detectable abnormal blasts in the bone marrow – In the opinion of the treating investigator, patients must be an unsuitable candidate for a pediatric-inspired regimen, reasons for which may include (but not be limited to) older age (i.e., >= 40 years), practical/logistical barriers to or toxicity concerns from administration of a pediatric-inspired regimen, or Ph+ disease – Total bilirubin =< 2.0 x institutional upper limit of normal ([ULN]; unless attributable to Gilbert's disease or other causes of inherited indirect hyperbilirubinemia, at which point total bilirubin must be =< 4.0 x ULN) – Aspartate aminotransferases (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5.0 x institutional ULN; (Note: patients with liver test abnormalities attributable to hepatic involvement by ALL will be permitted if the total bilirubin is =< 5.0 x ULN and ALT/AST are =< 8.0 x ULN) – Creatinine =< 2.0 mg/dL; however, patients with a creatinine > 2.0 mg/dL but with a calculated creatinine clearance of > 30 ml/min, as measured by the Modification of Diet in Renal Disease (MDRD) equation, will be eligible – As patients with ALL frequently have cytopenias, no hematologic parameters will be required for enrollment or to receive the first cycle of treatment; however, adequate recovery of blood counts will be required to receive subsequent cycles) – Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2; (performance status of 3 will be allowed if poor performance status is thought to be directly secondary to ALL) – Must agree to the use of effective contraception while on study treatment, unless they are highly unlikely to conceive (defined as [1] surgically sterilized, or [2] postmenopausal [i.e., a woman who is > 50 years old or who has not had menses for >= 1 year], or [3] not heterosexually active for the duration of the study) – Ability to give informed consent and comply with the protocol – Anticipated survival of at least 3 months, independent of ALL Exclusion Criteria:

  • Patients with Burkitt lymphoma/leukemia – Patients must not have received any prior systemic therapy for ALL, except for the acute management of hyperleukocytosis or acute symptoms (e.g., corticosteroids, cytarabine, etc.) – Patients with isolated extramedullary disease or with known parenchymal central nervous system (CNS) disease – Known hypersensitivity or intolerance to any of the agents under investigation – Other medical or psychiatric conditions that in the opinion of the investigator would preclude safe participation in the protocol – May not be pregnant or nursing

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Washington
  • Collaborator
    • National Cancer Institute (NCI)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Ryan D. Cassaday, Principal Investigator, Fred Hutch/University of Washington Cancer Consortium

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