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)

Background:

• Lung cancer is the leading cause of cancer-related mortality worldwide and accounted for nearly 160,000 deaths in 2023 in the US.
• Paradigm shifting results of immune checkpoint inhibitor (CPI) therapy in locally advanced, inoperable, and metastatic non-small cell lung cancer (NSCLC) have prompted clinical evaluation of these agents administered in the perioperative setting for patients with earlystage, operable disease.
• Pathologic complete responses (pCR) are observed in approximately 10% of early-stage NSCLC following CPI monotherapy and between 20-30% following platinum based chemotherapy and CPI treatment; as such most NSCLC are intrinsically resistant to immune checkpoint blockade.
• Many of the pathways that drive pulmonary carcinogenesis and render NSCLC resistant to immunotherapy are mediated by potentially reversible epigenetic mechanisms of which DNA methylation appears to be predominant.
• DNA demethylating agents such as azacytidine and decitabine can directly enhance the immunogenicity of lung cancer cells and ameliorate immunosuppression within the tumor microenvironment (TME).
• Poor bioavailability, as well as pharmacokinetic/pharmacodynamic limitations and systemic toxicities prevent optimal dosing of DNA demethylating agents for the treatment of solid tumors.
• One potential strategy to enhance the delivery of DNA demethylating agents to early-stage NSCLC while minimizing systemic toxicities is to administer these drugs by inhalation techniques.
• Preclinical studies have demonstrated that aerosolized AZA mediates epigenetic activation of tumor suppressor gene expression in orthotopic human NSCLC, and significantly prolongs the survival of mice bearing these xenografts without systemic toxicities.
• Conceivably, by simultaneously targeting lung cancer cells and their immunosuppressive TME, inhaled AZA may enhance the efficacy of chemo-immunotherapy for early-stage NSCLC.

Objectives:

• Phase I: --To determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of neoadjuvant aerosolized AZA in participants with operable early-stage NSCLC treated with standard of care (SOC) platinum-based chemotherapy and Durvalumab.
• Phase II:
• To determine the frequency of pathologic complete responses (pCR) in participants receiving aerosolized AZA, durvalumab, and SOC platinum-based chemotherapy as induction therapy for early-stage NSCLC.

Eligibility Criteria:

• Stage IB-IIIA NSCLC irrespective of programmed death-ligand 1 (PD-L1) expression status.
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• No prior therapy for NSCLC.
• Disease that can be safely accessed via bronchoscopic, thoracoscopic, or percutaneous biopsy, and participant willingness to undergo tumor biopsy before treatment (all participants) and bronchoscopic evaluation for PK analysis during treatment (Phase I only).
• Willing to undergo tumor resection per standard of care (SOC) guidelines following induction therapy.
• Age >=18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of <=1.
• Adequate organ and marrow function.

Design:

• Eligible participants will receive aerosolized AZA via AeroEclipse(R) II Breath Actuated nebulizer on three consecutive days (i.e., days 1, 2, 3) of a 21-day cycle for 3 cycles. Platinumdoublet chemotherapy using SOC guidelines and durvalumab will be administered on day 4 of each cycle.
• Anatomic resection [lobectomy/segmentectomy/pneumonectomy with mediastinal lymph node dissection (MLND)] will be performed within 3 weeks following completion of neoadjuvant therapy regimen.
• The dose of AZA will be escalated using a 3+3 design with no intra-patient dose escalation (45 - 75 mg/m^2/inhalation) to maximize intra-tumoral DNA methyltransferase (DNMT) 1 depletion while avoiding dose-limiting pulmonary or systemic toxicities attributable to this agent during the three cycles of therapy.
• Once the RP2D of aerosolized AZA has been defined either by toxicity or feasibility, that cohort will be expanded to a total of 17 participants to determine pathologic complete response rates at the RP2D using a Simon optimal design for phase II trials.
• If 4 or more of 17 participants treated at the RP2D experience pCR, an additional 20 evaluable participants will be accrued (2nd stage).
• Pharmacokinetic (PK) / pharmacodynamic (PD) effects as well as DNMT, CTA, and immune-related gene expression levels in tumor tissues may be evaluated.
• Additional studies will be performed to examine if the treatment regimen alters DNA methylation and cytokine levels and modulates the phenotypes of immune cells in pulmonary lavage fluids.
• Up to 52 participants may receive study intervention on this protocol.