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2N-13-6 A Randomized Phase II Study of Epigenetic Priming with Azacitidine and Entinostat Prior to Nivolumab versus Nivolumab Alone in Subjects with Recurrent Metastatic Non-Small Cell Lung Cancer


Lung cancer is the most common cause of death from cancer in both men and women. Over 160,000 people in the United States died from lung cancer in 2011. Most non-small cell lung cancer(NSCLC) patients present with advanced disease. Metastatic disease is typically treated with chemotherapy alone and is considered incurable with current therapy. New, effective therapies and strategies for lung cancer are a critical need. Azacitidine is an agent that that has been shown to inhibit cancer cell growth by interfering with DNA processes for gene expression. Entinostat is an agent that inhibits cancer cell growth and promotes cell death by repressing the transfer of genetic information. Nivolumab is a monoclonal antibody (a protein that attaches to specific proteins called antigens) that has been shown to have activity against solid tumors including NSCLC. A previous study has shown that advanced lung cancer patients who have received multiple prior therapies showed responses to treatment after initial treatment with azacitidine and entinostat. The most notable responses were in those patients who received Nivolumab or a similar agent after receiving azacitidine and entinostat. In this trial, participants will receive azacitidine for injection and entinostat and then receive Nivolumab or receive Nivolumab alone. The primary objective is to evaluate the number of patients whose disease does not worsen at 32 weeks from the time of randomization. Participants will be randomized to receive either azacitidine for injection and entinostat followed by Nivolumab or Nivolumab alone. During the study, participants in both groups will have the following procedures done during each cycle: physical exam, vital signs, blood tests, performance status, assessment of side effects, review of medications, and tumor assessments with radiographic scans. All participants will stop taking study drug(s) if they do not study drugs for more than 6 weeks, their disease worsens, they have another illness which prevents them from taking the study drug(s), they cannot tolerate the side effects, pregnancy, imprisonment, they withdraw from the study, or their study doctor thinks that being on the study is no longer in their best interest. All participants will be followed every 3 months until death or for 5 years, whichever occurs first.The primary endpoint of being progression-free at 32 weeks after randomization will be assessed from baseline scans at randomization (i.e., within 4 weeks prior to starting epigenetic therapy). All participants included in the study must be assessed for response to treatment (nivolumab), even if there are major protocol treatment deviations or if they are ineligible. All participants will be evaluable for side effects from the time of their first treatment with any study therapy. Progression-free survival and overall survival will be estimated using the Kaplan-Meier method. Toxicities will be categorized for azacitidine/entinostat, and for Nivolumab, by frequency and type, and reported in tabular form.


Phase 2 - takes the treatment one step further, assessing the activity of a particular therapy in a disease, often building upon leads from the Phase I trial. While patients are generally required to be previously untreated, participation in a Phase II trial doesn't usually preclude the patient from getting the standard treatment after they've received the investigational agent. At best they are allowed to get a new drug they wouldn't be able to get otherwise that may turn out to be better for their disease.

Inclusion and Exclusion Criteria

  • Patients must have histologically proven stage IIIB, IV or recurrent non-small cell lung cancer. Patients must be willing to undergo a pre-treatment biopsy, either core needle biopsy or equivalent amount or via excisional specimen. (cytology specimen not acceptable for this purpose).
  • 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 for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease.
  • Patients must have received at least one platinum based chemotherapy, and not more than three, prior therapies for stage IIIB/IV disease.
  • Patients who received adjuvant or neoadjuvant platinum-doublet chemotherapy (after surgery and/or radiation therapy) and developed recurrent or metastatic disease within 6 months of completing therapy are eligible and the adjuvant or neoadjuvant chemotherapy will count as a line of therapy as above.
  • Subjects with recurrent disease > 6 months after adjuvant or neoadjuvant platinum-based chemotherapy, who also subsequently progressed during or after a platinum-doublet regimen given to treat the recurrences, are eligible and do not count as another line of therapy for advanced disease.
  • Subjects who received pemetrexed, bevacizumab, or erlotinib as maintenance therapy (nonprogressors with platinum-based doublet chemotherapy) and subsequently progressed after maintenance therapy) are eligible and do not count as a line of therapy. However, subject who received a tyrosine kinase inhibitor after failure of a prior platinum-based therapy, that tyrosine kinase inhibitor therapy would count as an additional line of therapy.
  • Age >18 years. Because no dosing or adverse event data are currently available on the use of azacitidine with entinostat, or of Nivolumab, in patients <18 years of age, children are excluded from this study.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
  • Life expectancy of greater than 12 weeks.
  • Patients must have adequate organ and marrow function.
  • The effects of entinostat, azacitidine, and Nivolumab, on the developing human fetus 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 and for up to 23 weeks after the last dose of nivolumab. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men who are sexually active with women of childbearing potential must also use an adequate contraceptive method for up to 31 weeks after fhe last dose of nivolumab.
  • Ability to understand and the willingness to sign a written informed consent document.
  • Patients with documented EGFR or ALK mutations must have been treated with prior EGFR or ALK therapy as well as a platinum containing doublet.
  • All adenocarcinoma patients will be tested for ALK rearrangements and EGFR (Exon 19 Deletion and Exon 21 L8585R Substitution) mutations and must have been treated with prior EGFR or ALK therapy as well as a platinum containing doublet.
  • Patients must have disease amenable to biopsy at the time of enrollment as biopsies are required for study participation.

  • Any active history of a known autoimmune disease. Subjects with vitiligo, type 1 diabetes mellitus, residual hypothyroidism requiring hormone replacement, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  • Subjects with a history of interstitial lung disease. Patients requiring continuous supplemental oxygen are excluded to avoid possible complications from pneumonitis.
  • Patients who have had chemotherapy or radiotherapy within 2 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 2 weeks earlier.
  • Patients who are receiving any other anticancer therapy.
  • Patients with uncontrolled brain metastases. Patients with brain metastases must have stable neurologic status following local therapy (surgery or radiation) for at least 2 weeks without the use of steroids or on stable or decreasing dose of < 10mg daily prednisone (or equivalent), and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with a history of carcinomatous meningitis are not eligible.
  • Patients with advanced malignant hepatic tumors.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to entinostat, azacitidine, or Nivolumab.
  • Known or suspected hypersensitivity to azacitidine or mannitol
  • Uncontrolled inter-current 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, azacitidine, and Nivolumab 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, azacitidine, or Nivolumab breastfeeding should be discontinued if the mother is treated on this protocol.
  • HIV-positive patients are excluded.
  • Patients with active hepatitis B or hepatitis C are excluded.
  • Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
  • Patients with malabsorption in the small intestine or other conditions that would preclude administration of oral medication.
  • Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody therapies, any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways, DNA methyltransferase therapy or HDAC inhibitor therapy.


Please contact Loriel Liwanag to learn more about where you can participate in this trial. Please use the contact form on the right side.

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