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

NCT01383447 | Terminated Phase 1 Results

• 3 other identifiers: NCI-2010-02202J1023U01CA070095
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

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

Conditions

Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• 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

  At 1 year

• Comparative Pharmacokinetics (PK) and Pharmacodynamics (PD) of Entinostat Alone vs. Entinostat Plus Imatinib Mesylate

  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

  Day 29

Study Arms (1)

Treatment (entinostat and imatinib mesylate)

EXPERIMENTAL

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; 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

Interventions

entinostat DRUG

Given PO

Also known as: HDAC inhibitor SNDX-275, SNDX-275

Treatment (entinostat and imatinib mesylate)

imatinib mesylate DRUG

Given PO

Also known as: CGP 57148, Gleevec, Glivec

Treatment (entinostat and imatinib mesylate)

laboratory biomarker analysis OTHER

Correlative studies

Treatment (entinostat and imatinib mesylate)

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Treatment (entinostat and imatinib mesylate)

western blotting GENETIC

Correlative studies

Also known as: Blotting, Western, Western Blot

Treatment (entinostat and imatinib mesylate)

immunohistochemistry staining method OTHER

Correlative studies

Also known as: immunohistochemistry

Treatment (entinostat and imatinib mesylate)

flow cytometry OTHER

Correlative studies

Treatment (entinostat and imatinib mesylate)

polymerase chain reaction GENETIC

Correlative studies

Also known as: PCR

Treatment (entinostat and imatinib mesylate)

high performance liquid chromatography OTHER

Correlative studies

Also known as: HPLC

Treatment (entinostat and imatinib mesylate)

mass spectrometry OTHER

Correlative studies

Treatment (entinostat and imatinib mesylate)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

Johns Hopkins University

Baltimore, Maryland, 21287-8936, United States

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

entinostat; Imatinib Mesylate; Blotting, Western; Immunohistochemistry; Flow Cytometry; Polymerase Chain Reaction; Chromatography, High Pressure Liquid; Mass Spectrometry

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Electrophoresis; Chemistry Techniques, Analytical; Investigative Techniques; Electrochemical Techniques; Immunoblotting; Immunoassay; Immunologic Techniques; Molecular Probe Techniques; Histocytochemistry; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Histological Techniques; Cell Separation; Cytophotometry; Fluorometry; Luminescent Measurements; Photometry; Nucleic Acid Amplification Techniques; Genetic Techniques; Chromatography, Liquid; Chromatography

Results Point of Contact

• Title: Dr. Patrick Brown
• Organization: Johns Hopkins Sidney Kimmel Cancer Center

pbrown2@jhmi.edu

410-614-4915

Study Officials

• Patrick Brown

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 5, 2011
• First Posted: June 28, 2011
• Study Start: October 1, 2010
• Primary Completion: April 1, 2012
• Study Completion: April 1, 2012
• Last Updated: August 8, 2017
• Results First Posted: August 8, 2017

Record last verified: 2017-07

Locations

US (1)