Entinostat And Imatinib Mesylate In Treating Patients With Relapsed or Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
|Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia Recurrent Adult Acute Lymphoblastic Leukemia||Drug: entinostat Drug: imatinib mesylate Other: laboratory biomarker analysis Other: pharmacological study Genetic: western blotting Other: immunohistochemistry staining method Other: flow cytometry Genetic: polymerase chain reaction Other: high performance liquid chromatography Other: mass spectrometry||Phase 1 Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||A Phase 1/2 Study of SNDX-275 in Combination With Imatinib for Relapsed/Refractory Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia|
- 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.
- 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.
|Study Start Date:||October 2010|
|Study Completion Date:||April 2012|
|Primary Completion Date:||April 2012 (Final data collection date for primary outcome measure)|
Experimental: Treatment (entinostat and imatinib mesylate)
Patients receive entinostat 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.
Other Names:Drug: imatinib mesylate
Other Names:Other: laboratory biomarker analysis
Correlative studiesOther: pharmacological study
Other Name: pharmacological studiesGenetic: western blotting
Other Names:Other: immunohistochemistry staining method
Other Name: immunohistochemistryOther: flow cytometry
Correlative studiesGenetic: polymerase chain reaction
Other Name: PCROther: high performance liquid chromatography
Other Name: HPLCOther: mass spectrometry
I. To determine the maximum tolerated dose (MTD) of entinostat when given in combination with imatinib (matinib mesylate).
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01383447
|United States, Maryland|
|Johns Hopkins University|
|Baltimore, Maryland, United States, 21287-8936|
|Principal Investigator:||Patrick Brown||Johns Hopkins University|