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

Study Overview
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Brief Summary
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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 Description
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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.

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

Conditions
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Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia, Recurrent Adult Acute Lymphoblastic Leukemia

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed BCR-ABL1 associated (Ph+) acute lymphoblastic leukemia (ALL) with primary refractory or relapsed disease; demonstration of BCR-ABL1 in leukemia cells by one or more of the following is required: t(9;22)(q34;q11.2) cytogenetics; FISH for BCR-ABL1 fusion; RT-PCR for BCR-ABL1 fusion Prior treatment with tyrosine kinase inhibitors (including imatinib, nilotinib and/or dasatinib) is allowed, although patients must be off any tyrosine kinase inhibitor for a minimum of 72 hours prior to beginning protocol therapy ECOG performance status of 0, 1 or 2 Total WBC =< 150,000 with no evidence for ongoing or impending leukostasis Total bilirubin =< 2.0 mg/dL unless elevated due to Gilbert's, hemolysis or leukemic infiltration Aspartate transaminase (AST)/alanine transaminase (ALT) =< 2.5 × upper limit of normal (ULN) unless due to leukemic infiltration Serum creatinine =< 2.0 mg/dL or creatinine clearance > 50 ml/min Left ventricular ejection fraction (LVEF) >= 45% as measured by echocardiogram (ECHO) or MUGA Patients who have undergone stem cell transplantation (SCT), autologous or allogeneic, are eligible provided that they are > 4 weeks from stem cell infusion, have no active GVHD, and meet other eligibility criteria Patients who fail primary induction therapy or relapse after achieving complete remission (CR) are eligible if they are > 3 weeks off cytotoxic chemotherapy and > 2 weeks off radiation therapy; patients must be off biologic therapies including hematopoietic growth factors > 1 week; if using hydroxyurea (HU), steroids, or other non-cytotoxics for blast count control, patient must be off for > 24 hrs before starting protocol therapy; patients must have recovered from all acute toxicities from any previous therapy Female patients of childbearing age must have negative pregnancy test; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients may not be receiving any other investigational agents Active CNS leukemia; patients with known previous CNS leukemia may continue to receive intrathecal therapy with ara-C, methotrexate, and/or thiotepa plus steroids as prophylaxis against reactivation of previous CNS disease Patients may not have received previous treatment with entinostat or other HDAC inhibitors History of allergic reactions attributed to compounds of similar chemical or biologic composition to entinostat or other agents used in study Uncontrolled intercurrent illness including, but not limited to, ongoing or active untreated infection, symptomatic congestive heart failure, unstable angina pectoris, unstable cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with entinostat HIV-positive patients on combination antiretroviral therapy are ineligible

Ages Eligible for Study
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Minimum 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: Treatment (entinostat and imatinib mesylate)<br>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. | Drug: entinostat<br>* Given PO<br>* Other names: SNDX-275;Drug: imatinib mesylate<br>* Given PO<br>* Other names: Glivec;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Genetic: western blotting<br>* Correlative studies<br>* Other names: Western Blot;Other: immunohistochemistry staining method<br>* Correlative studies<br>* Other names: immunohistochemistry;Other: flow cytometry<br>* Correlative studies<br>Genetic: polymerase chain reaction<br>* Correlative studies<br>* Other names: PCR;Other: high performance liquid chromatography<br>* Correlative studies<br>* Other names: HPLC;Other: mass spectrometry<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Entinostat When Given in Combination With Imatinib Mesylate | 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. | Up to 30 days post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | 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 | The Kaplan-Meier estimator will be used to estimate PFS with a 95% confidence interval from study entry. | At 1 year | 
| Comparative Pharmacokinetics (PK) and Pharmacodynamics (PD) of Entinostat Alone vs. Entinostat Plus Imatinib Mesylate | 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. | Day 4 and 11 | 
| Predictive Values of Levels of Flow Cytometric Minimal Residual Disease (MRD) on Duration of Progression Free Survival for the Study Population | 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. | Day 29 |