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)

Plain English Summary

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) is a Phase 2 clinical trial sponsored by National Cancer Institute (NCI) studying 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. This trial tests a new inhaled form of azacytidine combined with standard chemotherapy and immunotherapy (durvalumab) before surgery for early-stage lung cancer. It is for adults with early-stage non-small cell lung cancer (NSCLC) that can be surgically removed. Participants will receive the study drugs for 3 cycles and undergo biopsies before and after treatment. Alternatives include standard chemotherapy and immunotherapy without the inhaled azacytidine, or surgery alone if the cancer is very early. The trial aims to enroll 60 participants.

Official 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 ca

Who Can Participate

Here is what you need to know about eligibility for this trial. You can join if you are 18 or older and have early-stage NSCLC that can be removed by surgery. You cannot join if you have had certain immune reactions to prior cancer drugs, have active autoimmune disease, or have specific types of lung tumors. Your lung and heart function must be adequate, and you need to have a good overall health status (ECOG performance status of 0 or 1). You must be willing to have tumor biopsies taken before treatment and during surgery, and to enroll in a related study for additional research. This trial is studying 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, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary goal is to find the safest and most effective dose of the inhaled drug, and for patients, this means assessing how well the new treatment combination works to eliminate cancer cells before The specific primary outcome measures are: 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... (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 (baseline (pre-treatment biopsy), and at the time of SOC surgery post-cycle 3). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial aims to improve treatment for early-stage lung cancer by delivering a new epigenetic drug directly to the lungs, potentially reducing side effects and improving outcomes for patients whose Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets 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, where improved treatment options are needed.

Investor Insight

This trial explores a novel drug delivery method for an existing drug class in a large market (NSCLC), with potential to improve neoadjuvant therapy, signaling a competitive area with ongoing innovati Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor if this inhaled treatment is suitable for you, considering your specific lung cancer stage and overall health. Be prepared for regular visits to the NIH Clinical Center for drug administration and monitoring, including biopsies. Understand that you will need to use effective birth control during and after the study, as required by the trial. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NON_RANDOMIZED
• Model: SEQUENTIAL
• Masking: NONE
• Enrollment: 60 participants

Interventions

• 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.

Primary Outcomes

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

Secondary Outcomes

• 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)

Full 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 sc

Trial Locations

• National Institutes of Health Clinical Center, Bethesda, Maryland, United States

Frequently Asked Questions

Related Conditions

• Lung Cancer
• Non-Small Cell Lung Cancer (NSCLC)
• Early-Stage Lung Cancer
• Resectable Lung Cancer
• Neoadjuvant Therapy
• Immunotherapy
• Chemotherapy
• Epigenetic Therapy
• Thoracic Malignancies
• Cancer Treatment

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