Azacitidine, Entinostat, and Nivolumab or Nivolumab Alone in Treating Patients with Recurrent Metastatic Non-small Cell Lung Cancer

This phase II trial studies how well azacitidine, entinostat, and nivolumab or nivolumab alone work in treating patients with non-small cell lung cancer that has come back (recurrent) and has spread to other places in the body (metastatic). Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.. It is not yet known if azacitidine and entinostat followed by nivolumab or nivolumab alone is more effective in treating non-small cell lung cancer.

Inclusion 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 tumor 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 computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam; a CT scan of the abdomen and pelvis is not required for patients with no disease in these areas
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
• Life expectancy of greater than 12 weeks
• Leukocytes >= 2,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 X institutional upper limit of normal
• Creatinine within normal institutional limits OR creatinine clearance >= 40 mL/min for patients with creatinine levels above institutional normal
• Resting and walking oxygen (O2) saturation must remain above 90% at the time of screening
• 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 the last dose of nivolumab
• Ability to understand and the willingness to sign a written informed consent document
• All adenocarcinoma patients must be tested for ALK rearrangements and EGFR (exon 19 deletion and exon 21 L8585R substitution) mutations and must have been treated with EGFR or ALK tyrosine kinase inhibitor (TKI) therapy if found to have an actionable alteration; if patients are KRAS positive, testing for ALK rearrangements and EGFR mutations is not applicable
• All patients should have been offered a platinum-based chemotherapy; for EGFR/ALK wild type patients, no more than two prior chemotherapy-based lines of therapy for advanced or metastatic non-small cell lung cancer (NSCLC) is permitted; for EGFR mutated or ALK translocated patients, no more than three prior lines of therapy for advanced or metastatic NSCLC is permitted; patients who refuse platinum based chemotherapy, may be allowed to enroll if they meet all other criteria * 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 * Patients who have been treated with prior standard of care PD-1/L1 agents, alone or in combination with chemotherapy, are eligible; patients previously treated on clinical trials with non PD-1/PD-L1 immunotherapy agents are eligible; patients who have been treated with a PD-1/L1 agent in more than 1 line of therapy (as standard of care or in clinical trial) are not eligible
• Arm-specific eligibility criteria * Arm D: Anti-PD-1/PD-L1 treatment naive patients only * Arm E & F: Anti-PD-1/PD-L1 treatment experienced patients: Patients must have had refractory (Arm E = less than 24 weeks from first dose of anti-PD-1/PD-L1) or recurrent (Arm F = more than 24 weeks from first dose of anti-PD-1/PD-L1) disease during or after anti-PD-1 or anti-PD-L1 therapy and, in the opinion of the investigator, must be unlikely to benefit from nivolumab monotherapy
• Patients must have disease amenable to biopsy at the time of enrollment as biopsies are required for study participation

Exclusion Criteria

• 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 or lung disease that has required intubation in the past (i.e. such as asthma or chronic obstructive pulmonary disease [COPD])
• Patients who have had chemotherapy 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 have had radiation therapy within 1 week prior to entering the study
• 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 =< 10 mg 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
• 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, uncontrolled cardiac arrhythmia, myocardial infarction or new onset angina within six months of enrollment, 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
• Human immunodeficiency virus (HIV)-positive patients are excluded; (patients cannot have known history of HIV; testing for it at baseline is not required unless it is suspected they may have it)
• Patients with active hepatitis B or hepatitis C are excluded; (patients cannot have known history of hepatitis B or hepatitis C; testing for it at baseline is not required unless it is suspected they may have it)
• 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 deoxyribonucleic acid (DNA) methyltransferase therapy or HDAC inhibitor therapy

PRIMARY OBJECTIVE:

I. Objective response rate.

SECONDARY OBJECTIVES:

I. Progression-free survival.

II. Time to progression.

III. Overall survival.

IV. Safety and tolerability.

EXPLORATORY OBJECTIVE:

I. Assessment of tumor baseline PD-L1 expression will be performed.

OUTLINE: Patients are assigned to 1 of 2 treatment arms.

ARM C (CLOSED TO ENROLLMENT): Patients receive nivolumab intravenously (IV) over 30 minutes on days 1 and 15. Beginning in cycle 7, patients may receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. As of 12/20/2018, patients MAY crossover to Arms E or F if they progress and are otherwise eligible.

ARMS D-F: Patients receive azacitidine subcutaneously (SC) on days 1-5 and 8-10 and entinostat orally (PO) on days 3 and 10. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 30 minutes on days 1 and 15. Beginning in cycle 7, patients may receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 5 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Julie R. Brahmer

• Primary ID J1353
• Secondary IDs NCI-2013-02334, NA_00084192, NA_00084192/CIR00003289
• Clinicaltrials.gov ID NCT01928576