Inhaled azacytidine with platinum chemotherapy and durvalumab before surgery for early-stage non-small cell lung cancer

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)

This tests whether adding inhaled azacytidine to platinum chemotherapy and durvalumab before surgery helps people with early-stage, operable non-small cell lung cancer.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 60 (estimated)
• Ages: 18 Years to 120 Years
• Sex: All
• Sponsor: National Institutes of Health Clinical Center (CC) (NIH)
• Drugs / interventions: durvalumab, chemotherapy, prednisone, immunotherapy
• Locations: 1 site (Bethesda, Maryland)
• Trial ID: NCT06694454 on ClinicalTrials.gov

What this trial studies

This Phase 1/2 neoadjuvant protocol gives inhaled azacytidine directly to the lungs together with standard platinum-based chemotherapy and the PD-L1 inhibitor durvalumab prior to planned tumor resection. The Phase 1 portion identifies the safest and most effective inhaled azacytidine dose, and Phase 2 expands to measure anti-tumor activity including pathologic complete response and safety. The inhaled route aims to increase drug exposure in lung tumors while limiting systemic toxicity, and participants undergo baseline and on-treatment tumor biopsies, imaging per RECIST 1.1, and standard perioperative care. Surgery is performed after induction therapy and outcomes include safety, pharmacokinetics, tumor response, and surgical/pathologic endpoints.

Who should consider this trial

Good fit: Adults (≥18 years) with resectable stage IB–IIIA non-small cell lung cancer, no prior therapy, adequate pulmonary reserve, ECOG ≤1, measurable disease, and willingness to undergo biopsies and planned surgery are the intended candidates.

Not a fit: People with unresectable or metastatic disease, poor lung function, prior treatment for the current NSCLC, or contraindications to platinum chemotherapy or durvalumab are unlikely to benefit from this regimen.

Why it matters

Potential benefit: If successful, the approach could increase the chance of eliminating tumor before surgery and reduce systemic side effects by delivering azacytidine directly to the lungs.

How similar studies have performed: Platinum chemotherapy combined with immune checkpoint inhibitors has improved pathologic response rates in early-stage NSCLC, but inhaled azacytidine as a delivery strategy is novel and has limited clinical data to date.

Eligibility criteria

* 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.

Where this trial is running

Bethesda, Maryland

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

Study contacts

• Principal investigator: David S Schrump, M.D. — National Cancer Institute (NCI)
• Study coordinator: Rebecca B Alexander

Conditions Non-small Cell Lung Cancer; Carcinoma, Non-Small Cell Lung; Non-Small Cell Lung Carcinoma; Non Small Cell Lung Cancer; Non Small Cell Lung Carcinoma; immune checkpoint inhibitor; pathologic complete response; aerosolized drug delivery