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A Phase I/II Study of Entinostat in Combination With 5-Azacytidine in Patients With Recurrent Advanced Non-Small Cell Lung Cancer

Phase 1/Phase 2
18 Years
Open (Enrolling)
Recurrent Non-small Cell Lung Cancer, Stage IIIA Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer

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Trial Information

A Phase I/II Study of Entinostat in Combination With 5-Azacytidine in Patients With Recurrent Advanced Non-Small Cell Lung Cancer


I. Determine the maximum tolerated dose (MTD) of azacitidine when given together with MS-275
in patients with recurrent advanced non-small cell lung cancer. (Phase I) II. Determine the
safety and toxicity of this regimen in these patients. (Phase I) III. Determine the
objective response rate in patients treated with this regimen. (Phase II)


I. Determine the pharmacokinetic profile of azacitidine and MS-275 in these patients.

II. Assess the pharmacodynamic effects of azacitidine and MS-275 on DNA methylation, histone
acetylation, and gene re-expression by blood and sputum analysis (and tissue biopsies from
select patients).

III. Assess the effect of azacitidine and MS-275 on progression-free survival and overall
survival of these patients.

OUTLINE: This is a multicenter, phase I, dose-escalation study of azacitidine followed by an
open-label, phase II study.

PHASE I: Patients receive azacitidine subcutaneously (SC) on days 1-6 and 8-10 and MS-275
orally (PO) on days 3 and 10. Treatment repeats every 28 days in the absence of disease
progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of
azacitidine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the
dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

PHASE II: Patients receive azacitidine as in phase I at the MTD determined in phase I and
MS-275 as in phase I.

Patients undergo plasma sample collection for pharmacokinetic evaluation before beginning
treatment and then at days 1, 10, and 17. Patients also undergo blood and sputum collection
to evaluate the pharmacodynamic effects of azacitidine and MS-275 on deoxyribonucleic acid
(DNA) methylation before beginning treatment and then at days 10 and 29.

After completion of study treatment, patients are followed periodically for 4 weeks.

Inclusion Criteria:

- Histologically or cytologically confirmed non-small cell lung cancer (NSCLC):

- Metastatic or unresectable disease

- Patient must have failed at least one previous chemotherapy regimen

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >=
20 mm with conventional techniques or as >= 10 mm with spiral computed tomography
(CT) scan

- Life expectancy > 12 weeks

- Leukocytes >= 3,000/mcL

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2 (Karnofsky >=

- Absolute neutrophil count >= 1,500/mcL

- Platelet count >= 100,000/mcL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT] and
alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x
upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73m^2 for patients with creatinine levels above institutional normal

- The effects of entinostat and 5-AZA on the developing human fetus at the recommended
therapeutic dose are unknown; for this reason, 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

- Patients who have a major objective response to treatment on this protocol, and who
experience progression of disease at least 1 year after completion of protocol
consent and therapy, may be re- retreated at the previously effective dose and

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients may not be receiving any other investigational agents

- Patients with uncontrolled brain metastases; patients with brain metastases must have
stable neurologic status following local therapy (surgery or radiation) for at least
4 weeks, and must be without neurologic dysfunction that would confound the
evaluation of neurologic and other adverse events

- Patients with liver metastases that replace greater than 30% of the liver parenchyma

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to entinostat, 5-AZA, mannitol or other agents used in the study

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because entinostat and 5-AZA are agents
with the potential for teratogenic or abortifacient effects; because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with entinostat or 5-AZA, breastfeeding should be
discontinued if the mother is treated on this protocol; these potential risks may
also apply to other agents used in this study

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
entinostat or 5-AZA; in addition, these patients are at increased risk of lethal
infections when treated with marrow-suppressive therapy

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD) of azacitidine when given together with entinostat, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 (phase I)

Outcome Time Frame:

Up to 28 days

Safety Issue:


Principal Investigator

Charles Rudin

Investigator Role:

Principal Investigator

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital


United States: Food and Drug Administration

Study ID:




Start Date:

August 2006

Completion Date:

Related Keywords:

  • Recurrent Non-Small Cell Lung Cancer
  • Stage IIIA Non-Small Cell Lung Cancer
  • Stage IIIB Non-Small Cell Lung Cancer
  • Stage IV Non-Small Cell Lung Cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



Johns Hopkins University Baltimore, Maryland  21205
USC Norris Comprehensive Cancer Center Los Angeles, California  90089
M D Anderson Cancer Center Houston, Texas  77030
Johns Hopkins Bayview Medical Center Baltimore, Maryland  21224