Clinical Trial: Entinostat And Imatinib Mesylate In Treating Patients With Relapsed or Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: A Phase 1/2 Study of SNDX-275 in Combination With Imatinib for Relapsed/Refractory Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Brief Summary: This phase I/II trial is studying the side effects and best dose of entinostat when given together with imatinib mesylate and to see how well it works in treating patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. Entinostat and imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth

Detailed Summary:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of entinostat when given in combination with imatinib (matinib mesylate).

SECONDARY OBJECTIVES:

I. To estimate the rate of complete response (CR) for patients greater ≥ 18 years of age with relapsed/refractory Ph+ ALL treated with a combination of entinostat and imatinib.

II. To estimate the 1 year progression free survival (PFS) for patients greater ≥ 18 years of age with relapsed/refractory Ph+ ALL treated with a combination of entinostat and imatinib III. To describe the comparative pharmacokinetics (PK) and pharmacodynamics (PD) of entinostat when administered alone vs. in combination with imatinib.

IV. To assess the predictive value of levels of flow cytometric minimal residual disease (MRD) on duration of progression free survival for the study population.

OUTLINE: This is a phase I, dose-escalation study of entinostat followed by a phase II study.

Patients receive entinostat orally (PO) daily on days 1, 8, 15, and 22 and imatinib mesylate PO twice daily on days 1-28 (days 4-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.


Sponsor: National Cancer Institute (NCI)

Current Primary Outcome: Maximum tolerated dose (MTD) of entinostat when given in combination with imatinib mesylate [ Time Frame: Up to 30 days post-treatment ]

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.


Original Primary Outcome:

  • Maximum tolerated dose (MTD) of entinostat when given in combination with imatinib [ Time Frame: After completion of study treatment, treatment may last up to 1 year ]
  • Rate of complete response (CR) for adults with relapsed/refractory Ph+ ALL treated with a combination of entinostat (at the dose determined in phase 1) and imatinib [ Time Frame: After completion of study treatment, treatment may last up to 1 year ]


Current Secondary Outcome:

  • Rate of complete response (CR) for adults with relapsed/refractory Ph+ ALL treated with a combination of entinostat (at the dose determined in phase 1) and imatinib mesylate [ Time Frame: Up to 30 days post-treatment ]
  • Progression free survival (PFS) for adults with relapsed/refractory Ph+ ALL treated with combination of entinostat and imatinib mesylate [ Time Frame: At 1 year ]
    The Kaplan-Meier estimator will be used to estimate PFS with a 95% confidence interval from study entry.
  • Comparative pharmacokinetics (PK) and pharmacodynamics (PD) of entinostat alone vs. entinostat plus imatinib mesylate [ Time Frame: Day 4 and 11 ]
    Entinostat concentrations will be compared when administered alone or in combination with imatinib by paired Student's t test (day 4 vs 11 concentrations) or Wilcoxon signed rank tests as appropriate. Association between exposure parameters and PD endpoints (e.g., apoptosis, histone acetylation, BCR-ABL expression) will be assessed using Fisher's exact tests or Wilcoxon rank sum tests as appropriate.
  • Predictive values of levels of flow cytometric minimal residual disease (MRD) on duration of progression free survival for the study population [ Time Frame: Day 29 ]
    Kaplan-Meier PFS curves and cumulative incidence of progression curves will be generated for patients above vs. below each threshold, and log rank will be used to compare the curves.


Original Secondary Outcome:

  • Progression free survival (PFS) for adults with relapsed/refractory Ph+ ALL treated with combination of entinostat and imatinib [ Time Frame: At 1 year ]
  • Comparative pharmacokinetics (PK) and pharmacodynamics (PD) of entinostat alone vs. entinostat plus imatinib [ Time Frame: After completion of study treatment, treatment may last up to 1 year ]
  • Predictive values of levels of flow cytometric minimal residual disease (MRD) on duration of progression free survival for the study population [ Time Frame: After completion of study treatment, treatment may last up to 1 year ]


Information By: National Cancer Institute (NCI)

Dates:
Date Received: May 5, 2011
Date Started: October 2010
Date Completion:
Last Updated: March 11, 2013
Last Verified: March 2013