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.

• INCLUSION CRITERIA:
• Histologically or cytologically confirmed, resectable per standard of care stage IB-IIIA non-small cell lung cancer (NSCLC) irrespective of programmed death-ligand 1 (PD-L1) expression. Note: Confirmation is required by NCI Laboratory of Pathology (LP).
• Willingness to undergo tumor resection surgery per standard of care (SOC) guidelines following induction therapy (platinum chemotherapy and durvalumab).
• Participants must have disease that can be safely accessed via bronchoscopic, thoracoscopic, or percutaneous biopsy techniques, and be willing to undergo tumor biopsy before treatment.
• No prior therapy for the NSCLC.
• Measurable disease per RECIST 1.1
• Age >= 18 years.
• Body weight > 30kg.
• ECOG Performance Status <= 1
• Participants must have adequate pulmonary reserve evidenced by predicted post-op FEV1 and adjusted DLCO >= 40% at screening.
• Participants must have pCO2 <= 45 and pO2 >=60 on room air by arterial blood gas (ABG) if O2 sat by pulse oximetry is<= 92% on room air at screening.
• Adequate organ and marrow function as defined below:

• Leukocytes >3,000/microL
• Absolute neutrophil count >1,500/microL (without transfusion or cytokine support)
• Absolute lymphocyte count > 800/microL
• Platelets >100,000/microL
• Hemoglobin >= 9.0 g/dL
• Prothrombin time (PT) no more than 2 seconds above the upper limit of normal (ULN)
• Total bilirubin OR Direct bilirubin < 1.5 X institutional upper limit of normal OR <= ULN for participants with total bilirubin >= 1.5 ULN
• Aspartate aminotransferase (AST) / Alanine aminotransferase (ALT) < 2.5 X institutional ULN
• Serum albumin >= 2.0 mg/dL
• Creatinine OR Creatinine clearance (eGFR) <= 1.6 mg/ml OR >60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal
• Individuals of child-bearing potential (IOCBP) must agree to use a highly effective method of contraception (hormonal, intrauterine device (IUD), surgical sterilization, abstinence) for the duration of the study treatment and up to 6 months after the last dose of the study drug(s). Note: participants who have cisplatin as part of SOC chemo must agree to use a highly effective method of contraception for 14 months.

Individuals able to father a child must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) for the duration of the study treatment and up to 3 months after the last dose of the study drug(s). Note: participants who have cisplatin as part of SOC chemo must agree to use an effective method of contraception for 11 months. We also will recommend these individuals with partners of childbearing potential to ask partners to be on highly effective birth control (hormonal, intrauterine device (IUD), surgical sterilization).

• Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 3 months after the last dose of the study drug(s).
• Participants with history of human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness are included if on appropriate antiretroviral therapy with HIV viral load <400 copies/mL.
• Participants must agree to not donate blood from the study entry and up to 3 months after the last dose of the study drug(s).
• Participants must be co-enrolled in protocol 06C0014: Prospective Evaluation of Genetic and Epigenetic Alterations in Patients with Thoracic Malignancies .
• The ability of a participant to understand and the willingness to sign a written informed consent document.

Exclusion criteria

• 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.