Neoadjuvant Inhaled Azacytidine With Platinum-Based Chemotherapy and Durvalumab (MEDI4736) - a Combined Epigenetic-Immunotherapy (AZA-AEGEAN) Regimen for Operable Early-Stage Non-Small Cell Lung Cancer (NSCLC)

Recruiting now · Phase 1/Phase 2

Conditions studied: Non-small Cell Lung Cancer (NSCLC), Carcinoma, Non-Small Cell Lung, Non-Small Cell Lung Carcinoma, Non Small Cell Lung Cancer, Non Small Cell Lung Carcinoma

In brief

Background: Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Surgery to remove the tumors is the standard treatment for people diagnosed with early stages of NSCLC. Despite complete removal of these tumors, many recur (happen again). An FDA-approved drug combination to treat early-stage NSCLC prior to the surgery is durvalumab plus standard chemotherapy. The FDA approved infusion drug azacytidine \[AZA\] is used to treat several diseases because it can rapidly kill dividing cells (including cancer cells) but it is not approved for NSCLC. An inhaled (aerosolized) form of AZA is also not approved for NSCLC. However, researchers want to know if an inhaled version of AZA can help improve treatment of people with NSCLC because inhaled AZA goes directly into the lungs with limited absorption into the bloodstream. Objective: To find the safest and most effective dose of inhaled AZA in participants with early-stage non-small cell lung cancer (NSCLC) that can still be removed by surgery. Eligibility: Adults aged 18 and older with operable early-stage NSCLC. Participants will be required to also enroll in NIH protocol 06C0014 which allows for pre- and post-treatment biopsies and bloodwork to be obtained for additional research studies. Design: Participants will be screened. They will have a physical exam with blood tests. Their medical records will be reviewed. They will have imaging scans and tests of their heart and lung functions. Participants will be required to have a tissue sample (biopsy) taken of their tumor prior to receiving study drug and again during surgery after Cycle 3; airway tissue biopsies and collection of collect bronchial (lung) fluid may also be done. Participants will receive the study treatment for 3 cycles. Each cycle is 21 days. They will need to come to the NIH Clinical Center (CC) on days 1-4 of Cycles 1-3. AZA will be given as a drug mist that can be inhaled (like the type of mist in an asthma inhaler) using a nebulizer at the NIH Clinical Center (CC) for 3 days in a row (consecutive days) during the first week of each cycle. The participant will inhale the AZA drug mist for 20 to 30 minutes each time. Participants will also receive durvalumab and a specific 2-drug assigned chemotherapy by intravenous (IV) infusion on day 4 of each cycle. Participants will have a follow-up visit 2 weeks after their last dose of study drugs. Then they will have planned surgery to remove the tumors. Participants will have additional follow-up visits at the NIH CC about 1 and 3 months after the surgery, and then for every 3 months for up to 3 years.

Key facts

Study ID: NCT06694454
Run by: National Cancer Institute (NCI)
People needed: 60
Starts: 2026-08-13
Expected to finish: 2034-12-31
Last updated by the study team: 2026-08-10

Who can join

Age: 18 and older, up to 120. Sex: any. Healthy volunteers: not accepted.

You may not qualify if…

Medically inoperable because of clinical co-morbidities.
Participants with T4 tumors invading the diaphragm, mediastinum, carina, trachea, esophagus, heart, great vessels, recurrent laryngeal nerve, or vertebral body.
Participants who experienced serious immune adverse events that required discontinuation of immune checkpoint inhibitor therapy for a prior non-NSCLC malignancy.
History of known EGFR or ALK alterations in the tumor.
History of active autoimmune disease including colitis, nephritis, hypophysitis, or neuropathy, with the exceptions of:
-Diabetes type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment.
History of pneumonitis or interstitial lung disease.
Clinically significant cardiovascular/cerebrovascular disease as follows:
cerebral vascular accident/stroke (within 6 months prior to study treatment initiation)
myocardial infarction (within 6 months prior to study treatment initiation)
unstable angina, congestive heart failure (New York Heart Association Classification Class >= II, https://manual.jointcommission.org/releases/TJC2016A/DataElem0439.html#:\~:text=Class%20II%20%2D%20Mild%20symptoms%20(mild,Class%20IV%20%2D%20Severe%20limitations), serious cardiac arrhythmia, clinically significant bleeding or clinically significant pulmonary embolism at screening.
Active Hepatitis A (HAV), Hepatitis B (HBV) (HbsAg reactive), or Hepatitis C (HCV) (HCV RNA [qualitative] is detected) at screening.
Other active infections requiring systemic therapy at screening.
Positive beta human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test performed in females of childbearing potential at screening.
Systemic corticosteroids at doses above physiologic levels (> 10 mg of prednisone or equivalent per day), or inhaled corticosteroids within 14 days before study treatment initiation. Administration of steroids through a route known to result in a minimal systemic exposure (i.e., topical, intro-ocular, or intra-articular) is allowed.
Major surgical procedure within 28 days prior to the study treatment initiation. Note: Local surgery of isolated lesions for palliative intent is acceptable provided other site(s) of disease is available for response assessment.
History of allogenic organ transplantation.
History of another primary malignancy except for malignancy treated with curative intent and with no known active disease >= 5 years before the study treatment initiation.
Administration of live attenuated vaccines within 30 days prior to study treatment initiation. Note: Administration of inactivated vaccines (e.g., inactivated influenza vaccines) is permitted before or during the study.
Administration of investigational drug on other clinical trial within 14 days prior to study treatment initiation.
History of hypersensitivity to Mannitol.
Herbal and natural remedies that may have immune-modulating effects within 7 days prior to study treatment initiation.
Uncontrolled intercurrent illness evaluated by history and physical exam or situation that would limit compliance with study requirements.

Where it is running

National Institutes of Health Clinical Center — Bethesda, Maryland, United States (enrolling)

Full record on ClinicalTrials.gov

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