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

Summary

This study combines the DNA methyltransferase inhibitor, 5-azacitidine (5-AZA), with an orally bioavailable histone deacetylase inhibitor, entinostat (SNDX-275), for the adjuvant treatment of patients with resected stage I non-small cell lung cancer. Patients will be randomized to the treated and control arms in a 2:1 ratio within 4-12 weeks after completing surgery. The schedule of 5-azacitidine and entinostat administration on this study is based on the ongoing study in metastatic lung cancer: 5-azacitidine is administered subcutaneously on days 1-5 and 8-10 with entinostat given orally on days 3 and 10 of a 28 day schedule. The phase I trial of entinostat in advanced solid tumors found that the area under the curve (AUC) of entinostat was independent of dose and body surface area between the doses of 4 and 12 mg/m2; based on these data, entinostat will be administered at a fixed oral dose of 7 mg (85). The 5-azacitidine dose will be 40 mg/m2 which was the final dose utilized in the trial of this combination of epigenetic therapy in metastatic lung cancer patients. Cycle length will be 28 days. Each patient will be treated for 6 cycles.
Patients will be followed for five years from enrollment on study, until completion of the study, or until death, whichever occurs first. Follow up after the off treatment visit will include obtaining weight, ECOG performance status, complete blood count with differential, comprehensive metabolic profile, assessment of toxicities, physical exam, and re-staging CT scan of the chest. Additionally we will collect sputum and blood for correlative analyses. These visits will occur every 3 months for 2 years. After 2 years of follow up patients will continue to be followed by their thoracic surgeon or oncologist every 6 months for the remainder of 5 years.
At the end of this study (3 years of accrual and 1.5 years of additional follow-up), assuming the event rate is the harmonic mean of the expected treated and untreated event rates, 0.078 per person year, the estimated number of events would be 53. 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%. Disease-free survival hazard rates will be estimated as the number of events divided by the sum of the exposure times and reported with 95% confidence intervals.

Participant Eligibility

-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
-Age >18 years.
-ECOG performance status <2
-Patients must have adequate organ and marrow function as defined below:
-- 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.