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)

NCT06694454 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 10001609001609-C
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief 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. ...

Conditions

Non-small Cell Lung Cancer (NSCLC); Non-Small Cell Lung Carcinoma; Non Small Cell Lung Cancer; Non Small Cell Lung Carcinoma; Carcinoma, Non-Small Cell Lung

Keywords

immune checkpoint inhibitor (CPI); pathologic complete response (pCR); aerosolized drug delivery; immunosuppressive tumor microenvironment (TME); reversible epigenetic mechanisms; DNA demethylating agents; nebulizer treatment; AZA

Outcome Measures

Primary Outcomes (2)

• 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 du...

  DLTs noted at each dose level will be reported.

  starts at initiation of study drug, though end of DLT period

• 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

  Pathologic complete responses (pCR) is defined as no viable cancer cells in samples collected on histopathologic assessment. Fraction of evaluable participants who experience a pCR will be determined and reported along with 80% and 95% two-sided confidence intervals.

  baseline (pre-treatment biopsy), and at the time of SOC surgery post-cycle 3

Secondary Outcomes (5)

• To evaluate pharmacokinetics

  All participants: Cycle 1, Day 1 or 2, and Cycle 3, Day 1 or 2. Participants with MTD treatment: Cycle 1, Day 1 or 2, and Cycle 2, Day 1 or 2, and Cycle 3, Day 1 or 2.

• To evaluate safety of the combination of AZA and chemo-durvalumab in participants with operable early-stage NSCLC

  starts at initiation of study drug, through 64 days after the last study drug administration

• To evaluate event-free survival (EFS)

  baseline, Day 64 (treatment evaluation), then post-surgical 1 month, 3 months, and every 3 months thereafter until disease progression, until up to 3 years from the treatment initiation

• To evaluate objective response (complete response [CR] + partial response [PR]) and stable disease [SD] per RECIST 1.1

  baseline, and at Day 64 (treatment evaluation)

• To evaluate major pathologic response (MPR) rate

  baseline (pre-treatment biopsy), and at the time of SOC surgery post-cycle 3

Study Arms (2)

1/ Phase I Dose Escalation

EXPERIMENTAL

Histology specific SOC platinum-based chemotherapy with durvalumab plus escalating/de-escalating doses of aerosolized azacytidine

Drug: azacytidine; Drug: carboplatin; Drug: paclitaxel; Drug: durvalumab; Drug: cisplatin; Drug: gemcitabine; Drug: pemetrexed

2/ Phase II Dose Expansion

EXPERIMENTAL

Histology specific SOC platinum-based chemotherapy with durvalumab plus RP2D of aerosolized azacytidine

Drug: azacytidine; Drug: carboplatin; Drug: paclitaxel; Drug: durvalumab; Drug: cisplatin; Drug: gemcitabine; Drug: pemetrexed

Interventions

carboplatin DRUG

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.

1/ Phase I Dose Escalation; 2/ Phase II Dose Expansion

paclitaxel DRUG

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.

1/ Phase I Dose Escalation; 2/ Phase II Dose Expansion

durvalumab DRUG

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.

1/ Phase I Dose Escalation; 2/ Phase II Dose Expansion

gemcitabine DRUG

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.

1/ Phase I Dose Escalation; 2/ Phase II Dose Expansion

azacytidine DRUG

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.

1/ Phase I Dose Escalation; 2/ Phase II Dose Expansion

pemetrexed DRUG

Pemetrexed (IV), 500 mg/m\^2, administered on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.

1/ Phase I Dose Escalation; 2/ Phase II Dose Expansion

cisplatin DRUG

Cisplatin (IV), 75 mg/m\^2, administered on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.

1/ Phase I Dose Escalation; 2/ Phase II Dose Expansion

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Pathologic Complete Response

Interventions

Azacitidine; Carboplatin; Paclitaxel; durvalumab; Cisplatin; Gemcitabine; Pemetrexed

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Disease Progression; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Coordination Complexes; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Deoxycytidine; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic

Study Officials

• David S Schrump, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rebecca B Alexander

CONTACT

(240) 781-4037; rebecca.alexander@nih.gov

David S Schrump, M.D.

CONTACT

(240) 760-6239; david_schrump@nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 16, 2024
• First Posted: November 19, 2024
• Study Start (Estimated): June 17, 2026
• Primary Completion (Estimated): December 31, 2031
• Study Completion (Estimated): December 31, 2034
• Last Updated: June 12, 2026

Record last verified: 2026-06-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data from this study will be shared after the completion of the primary endpoint per the data management sharing plan.
• Access Criteria: Data from this study may be requested by contacting the PI.

Locations

US (1)