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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT01383447
• Collaborator: (none)
• Enrollment: 2
• Location: 1
• Arm: 1
• Duration (Months): 18
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
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

Detailed Description

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

1. 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.

2. 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

3. To describe the comparative pharmacokinetics (PK) and pharmacodynamics (PD) of entinostat when administered alone vs. in combination with imatinib.

4. 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 Design

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: N/A
• 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
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

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.

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

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of Entinostat When Given in Combination With Imatinib Mesylate [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.

Secondary Outcome Measures

1. 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]

2. Progression Free Survival (PFS) for Adults With Relapsed/Refractory Ph+ ALL Treated With Combination of Entinostat and Imatinib Mesylate [At 1 year]

   The Kaplan-Meier estimator will be used to estimate PFS with a 95% confidence interval from study entry.

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

4. Predictive Values of Levels of Flow Cytometric Minimal Residual Disease (MRD) on Duration of Progression Free Survival for the Study Population [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University	Baltimore	Maryland	United States	21287-8936

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Patrick Brown, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01383447
• Other Study ID Numbers: NCI-2010-02202; J1023; U01CA070095
• First Posted: Jun 28, 2011
• Last Update Posted: Aug 8, 2017
• Last Verified: Jul 1, 2017

• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Philadelphia Chromosome; Imatinib Mesylate; Entinostat; Histone Deacetylase Inhibitors

Study Results

Participant Flow

Arm/Group Title	Treatment (Entinostat and Imatinib Mesylate)
Arm/Group Description	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. entinostat: Given PO imatinib mesylate: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies western blotting: Correlative studies immunohistochemistry staining method: Correlative studies flow cytometry: Correlative studies polymerase chain reaction: Correlative studies high performance liquid chromatography: Correlative studies mass spectrometry: Correlative studies
Period Title: Overall Study
STARTED	2
COMPLETED	0
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Treatment (Entinostat and Imatinib Mesylate)
Arm/Group Description	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. entinostat: Given PO imatinib mesylate: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies western blotting: Correlative studies immunohistochemistry staining method: Correlative studies flow cytometry: Correlative studies polymerase chain reaction: Correlative studies high performance liquid chromatography: Correlative studies mass spectrometry: Correlative studies
Overall Participants	2
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 50%
>=65 years	1 50%
Sex: Female, Male (Count of Participants)
Female	1 50%
Male	1 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	2 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	2 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

This study was halted prematurely by the NCI for low accrual. No results were analyzed.

Arm/Group Title	Treatment (Entinostat and Imatinib Mesylate)
Arm/Group Description	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. entinostat: Given PO imatinib mesylate: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies western blotting: Correlative studies immunohistochemistry staining method: Correlative studies flow cytometry: Correlative studies polymerase chain reaction: Correlative studies high performance liquid chromatography: Correlative studies mass spectrometry: Correlative studies
Measure Participants	0

2. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

This study was halted prematurely by the NCI for low accrual. No results were analyzed.

Arm/Group Title	Treatment (Entinostat and Imatinib Mesylate)
Arm/Group Description	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. entinostat: Given PO imatinib mesylate: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies western blotting: Correlative studies immunohistochemistry staining method: Correlative studies flow cytometry: Correlative studies polymerase chain reaction: Correlative studies high performance liquid chromatography: Correlative studies mass spectrometry: Correlative studies
Measure Participants	0

3. Secondary Outcome

Title	Progression Free Survival (PFS) for Adults With Relapsed/Refractory Ph+ ALL Treated With Combination of Entinostat and Imatinib Mesylate
Description	The Kaplan-Meier estimator will be used to estimate PFS with a 95% confidence interval from study entry.
Time Frame	At 1 year

Outcome Measure Data

Analysis Population Description

This study was halted prematurely by the NCI for low accrual. No results were analyzed.

Arm/Group Title	Treatment (Entinostat and Imatinib Mesylate)
Arm/Group Description	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. entinostat: Given PO imatinib mesylate: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies western blotting: Correlative studies immunohistochemistry staining method: Correlative studies flow cytometry: Correlative studies polymerase chain reaction: Correlative studies high performance liquid chromatography: Correlative studies mass spectrometry: Correlative studies
Measure Participants	0

4. Secondary Outcome

Title	Comparative Pharmacokinetics (PK) and Pharmacodynamics (PD) of Entinostat Alone vs. Entinostat Plus Imatinib Mesylate
Description	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.
Time Frame	Day 4 and 11

Outcome Measure Data

Analysis Population Description

This study was halted prematurely by the NCI for low accrual. No results were analyzed.

Arm/Group Title	Treatment (Entinostat and Imatinib Mesylate)
Arm/Group Description	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. entinostat: Given PO imatinib mesylate: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies western blotting: Correlative studies immunohistochemistry staining method: Correlative studies flow cytometry: Correlative studies polymerase chain reaction: Correlative studies high performance liquid chromatography: Correlative studies mass spectrometry: Correlative studies
Measure Participants	0

5. Secondary Outcome

Title	Predictive Values of Levels of Flow Cytometric Minimal Residual Disease (MRD) on Duration of Progression Free Survival for the Study Population
Description	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.
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

This study was halted prematurely by the NCI for low accrual. No results were analyzed.

Arm/Group Title	Treatment (Entinostat and Imatinib Mesylate)
Arm/Group Description	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. entinostat: Given PO imatinib mesylate: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies western blotting: Correlative studies immunohistochemistry staining method: Correlative studies flow cytometry: Correlative studies polymerase chain reaction: Correlative studies high performance liquid chromatography: Correlative studies mass spectrometry: Correlative studies
Measure Participants	0

Adverse Events

Arm/Group Title	Treatment (Entinostat and Imatinib Mesylate)
Arm/Group Description	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. entinostat: Given PO imatinib mesylate: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies western blotting: Correlative studies immunohistochemistry staining method: Correlative studies flow cytometry: Correlative studies polymerase chain reaction: Correlative studies high performance liquid chromatography: Correlative studies mass spectrometry: Correlative studies
All Cause Mortality
	Treatment (Entinostat and Imatinib Mesylate)
	Affected / at Risk (%)	# Events
Total	0/2 (0%)
Serious Adverse Events
	Treatment (Entinostat and Imatinib Mesylate)
	Affected / at Risk (%)	# Events
Total	0/2 (0%)
Other (Not Including Serious) Adverse Events
	Treatment (Entinostat and Imatinib Mesylate)
	Affected / at Risk (%)	# Events
Total	1/2 (50%)
Gastrointestinal disorders
nausea	1/2 (50%)
General disorders
Edema: lower limb	1/2 (50%)
Fatigue	1/2 (50%)
Metabolism and nutrition disorders
Hypophosphatemia	1/2 (50%)
Musculoskeletal and connective tissue disorders
Pain: bone marrow site	1/2 (50%)
Psychiatric disorders
Insomnia	1/2 (50%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.