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Randomized Phase II Trial of Adjuvant Combined Epigenetic Therapy With 5-azacitidine and Entinostat in Resected Stage I Non-small Cell Lung Cancer Versus Standard Care


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Stage IA Non-small Cell Lung Cancer, Stage IB Non-small Cell Lung Cancer

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Trial Information

Randomized Phase II Trial of Adjuvant Combined Epigenetic Therapy With 5-azacitidine and Entinostat in Resected Stage I Non-small Cell Lung Cancer Versus Standard Care


PRIMARY OBJECTIVES:

I. To assess the effect of 5-azacitidine and entinostat on the hazard of 3 year
progression-free survival in patients with resected stage I non-small cell lung cancer.

SECONDARY OBJECTIVES:

I. To assess the safety, tolerability and toxicity of entinostat and 5-azacitidine in
patients with resected stage I non-small cell lung cancer.

II. To explore the effect of entinostat and 5-azacitidine on median disease-free and overall
survival in patients with resected stage I non-small cell lung cancer.

III. To assess the pharmacodynamic effects of 5-azacitidine and entinostat on DNA
methylation and gene re-expression in patients with resected stage I NSCLC through analysis
of sputum.

IV. To estimate the effect of entinostat and 5-azacitidine on progression free survival
comparing patients with N2 lymph nodes categorized as methylated pre-treatment with those
who are categorized as unmethylated.

V. To establish factors that predict clinical outcome in patients treated with combination
epigenetic therapy by performing genome-wide analyses on pre-treatment tumor DNA.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive azacitidine subcutaneously (SC) on days 1-5 and 8-10 and entinostat
orally (PO) once daily (QD) on days 3 and 10. Treatment repeats every 28 days for up to 6
courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive standard of care.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.


Inclusion Criteria:



- Patients must be status post complete (R0) surgical resection of
pathologically-proven NSCLC (stage IA-IB according to AJCC version 7)

- Patients must be at least 4 weeks out from completion of surgery

- ECOG performance status =< 2

- Absolute neutrophil count >= 1,000/mcL

- Platelets >= 100,000/mcL

- Total bilirubin =< 1.5 X institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit of normal

- Creatinine =< 1.5 X institutional upper limit of normal

- The effects of entinostat and 5-azacitidine 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

Exclusion Criteria:

- Patients must be within 8 weeks of completing surgery

- Patients who have received prior chemotherapy or radiation for treatment of their
current diagnosis of lung cancer

- Patients with sub-lobar resections (ie: wedge resection or segmentectomy)

- Patients without mediastinal lymph node specimens from mediastinoscopy or surgery (at
least level R4 or 7 for right sided tumors OR at least level 5, 6 or 7 for left sided
tumors)

- Patients may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to entinostat, 5-azacitidine 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-azacitidine 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-azacitidine, 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

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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Disease-free survival (DFS)

Outcome Description:

The DFS hazard rate and 95% confidence interval will be reported. At this time, event time distributions for disease-free survival in the two arms will be estimated with the method of Kaplan and Meier and compared using a stratified Cox-proportional hazards model (stratified for stage IA vs IB) with a two-sided alpha of 10%.

Outcome Time Frame:

3 years

Safety Issue:

No

Principal Investigator

Charles Rudin

Investigator Role:

Principal Investigator

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-02901

NCT ID:

NCT01207726

Start Date:

September 2010

Completion Date:

Related Keywords:

  • Stage IA Non-small Cell Lung Cancer
  • Stage IB Non-small Cell Lung Cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms

Name

Location

Johns Hopkins University Baltimore, Maryland  21205
H. Lee Moffitt Cancer Center and Research Institute Tampa, Florida  33612
University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania  15213
Anne Arundel Medical Center Annapolis, Maryland  21401
Vanderbilt University Nashville, Tennessee  37232-6305
University of Texas Southwestern Medical Center Dallas, Texas