NCT06694454

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)

Phase I/II Study of 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)

• Status: Not Yet Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 60 (estimated)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years – 120 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

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.

Conditions

• 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

Interventions

Type	Name	Description
DRUG	azacytidine	Aerosolized azacytidine (AZA) via nebulizer on 3 consecutive days during the first week of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles. Azacytidine will be given at escalating doses in phase 1, and at the established RP2D in phase 2.
DRUG	carboplatin	Carboplatin (intravenous/IV), area under the serum drug concentration-time curve (AUC)=5-6 mg/mL/min based on cancer histology administered on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.
DRUG	paclitaxel	Paclitaxel (IV), 200 mg/m\^2, is administered on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.
DRUG	durvalumab	Durvalumab (IV) administered as a flat dose of 1500 mg on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.
DRUG	cisplatin	Cisplatin (IV), 75 mg/m\^2, administered on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.
DRUG	gemcitabine	Gemcitabine (IV), 1,250 mg/m\^2, administered on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.
DRUG	pemetrexed	Pemetrexed (IV), 500 mg/m\^2, administered on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.

Timeline

• Start date: 2026-04-22
• Primary completion: 2031-12-31
• Completion: 2034-12-31
• First posted: 2024-11-19
• Last updated: 2026-04-17

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study