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

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

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

Study Overview

• Status: Terminated
• Conditions: Recurrent Adult Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: flow cytometry; Genetic: polymerase chain reaction; Other: pharmacological study; Other: immunohistochemistry staining method; Other: mass spectrometry; Genetic: western blotting; Drug: entinostat; Other: high performance liquid chromatography; Drug: imatinib mesylate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287-8936
      • Johns Hopkins University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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: laboratory biomarker analysis; Correlative studies; Other: flow cytometry; Correlative studies; Genetic: polymerase chain reaction; Correlative studies; Other Names: PCR; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Other: immunohistochemistry staining method; Correlative studies; Other Names: immunohistochemistry; Other: mass spectrometry; Correlative studies; Genetic: western blotting; Correlative studies; Other Names: Blotting, Western; Western Blot; Drug: entinostat; Given PO; Other Names: HDAC inhibitor SNDX-275; SNDX-275; Other: high performance liquid chromatography; Correlative studies; Other Names: HPLC; Drug: imatinib mesylate; Given PO; Other Names: Gleevec; CGP 57148; Glivec

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Patrick Brown, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (ACTUAL): April 1, 2012
• Study Completion (ACTUAL): April 1, 2012

Study Registration Dates

• First Submitted: May 5, 2011
• First Submitted That Met QC Criteria: June 27, 2011
• First Posted (ESTIMATE): June 28, 2011

Study Record Updates

• Last Update Posted (ACTUAL): August 8, 2017
• Last Update Submitted That Met QC Criteria: July 7, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Chromosome Aberrations; Translocation, Genetic; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Philadelphia Chromosome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate; Histone Deacetylase Inhibitors; Entinostat
• Other Study ID Numbers: NCI-2010-02202; U01CA070095 (U.S. NIH Grant/Contract); J1023