연구제목

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)

연구요약

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. ...

연구의뢰자

National Cancer Institute (NCI)

연구모집현황

NOT_YET_RECRUITING

임상시험의 목적

TREATMENT

ClinicalTrials.gov 등록번호

NCT06694454

추가 연구 번호

최신갱신일

2025-06-11

연구종료일

2034-12-31

연구 버전 기록

실시기관명

facility: National Institutes of Health Clinical Center
city: Bethesda
state: Maryland
zip: 20892
country: United States
contacts: [{name=NCI Referral Office, role=CONTACT, phone=1-888-NCI-1937, email=ncimo_referrals@mail.nih.gov}]
geoPoint: {lat=38.98067, lon=-77.10026}

연구대상 상태/질환

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

대상질환

id: M5534
name: Carcinoma
asFound: Carcinoma
relevance: HIGH

id: M11172
name: Lung Neoplasms
asFound: Lung Cancer
relevance: HIGH

id: M5546
name: Carcinoma, Non-Small-Cell Lung
asFound: Non-small Cell Lung Cancer
relevance: HIGH

id: M27137
name: Respiratory Aspiration
relevance: LOW

id: M3152
name: Pathologic Complete Response
relevance: LOW

id: M12320
name: Neoplasms, Glandular and Epithelial
relevance: LOW

id: M12315
name: Neoplasms by Histologic Type
relevance: LOW

id: M14979
name: Respiratory Tract Neoplasms
relevance: LOW

id: M16658
name: Thoracic Neoplasms
relevance: LOW

id: M11168
name: Lung Diseases
relevance: LOW

id: M14977
name: Respiratory Tract Diseases
relevance: LOW

id: M5540
name: Carcinoma, Bronchogenic
relevance: LOW

id: M5260
name: Bronchial Neoplasms
relevance: LOW

제품명(코드명)

활성대조약 여부

대조약 여부

위약 여부

대조약

-

중재/치료

type: DRUG
name: azacytidine
description: 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.
armGroupLabels: [1/ Phase I Dose Escalation, 2/ Phase II Dose Expansion]

type: DRUG
name: carboplatin
description: 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.
armGroupLabels: [1/ Phase I Dose Escalation, 2/ Phase II Dose Expansion]

type: DRUG
name: paclitaxel
description: 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.
armGroupLabels: [1/ Phase I Dose Escalation, 2/ Phase II Dose Expansion]

type: DRUG
name: durvalumab
description: 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.
armGroupLabels: [1/ Phase I Dose Escalation, 2/ Phase II Dose Expansion]

type: DRUG
name: cisplatin
description: Cisplatin (IV), 75 mg/m\^2, administered on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.
armGroupLabels: [1/ Phase I Dose Escalation, 2/ Phase II Dose Expansion]

type: DRUG
name: gemcitabine
description: 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.
armGroupLabels: [1/ Phase I Dose Escalation, 2/ Phase II Dose Expansion]

type: DRUG
name: pemetrexed
description: Pemetrexed (IV), 500 mg/m\^2, administered on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.
armGroupLabels: [1/ Phase I Dose Escalation, 2/ Phase II Dose Expansion]

중재 방법

id: D017239
term: Paclitaxel

id: D016190
term: Carboplatin

id: D000093542
term: Gemcitabine

id: D000068437
term: Pemetrexed

id: D001374
term: Azacitidine

id: C000613593
term: Durvalumab

연구종류

INTERVENTIONAL

임상시험단계

PHASE1

PHASE2

배정

NON_RANDOMIZED

중재모형

SEQUENTIAL

눈가림대상자

중재군명

중재군 유형

label: 1/ Phase I Dose Escalation
type: EXPERIMENTAL
description: Histology specific SOC platinum-based chemotherapy with durvalumab plus escalating/de-escalating doses of aerosolized azacytidine
interventionNames: [Drug: azacytidine, Drug: carboplatin, Drug: paclitaxel, Drug: durvalumab, Drug: cisplatin, Drug: gemcitabine, Drug: pemetrexed]

label: 2/ Phase II Dose Expansion
type: EXPERIMENTAL
description: Histology specific SOC platinum-based chemotherapy with durvalumab plus RP2D of aerosolized azacytidine
interventionNames: [Drug: azacytidine, Drug: carboplatin, Drug: paclitaxel, Drug: durvalumab, Drug: cisplatin, Drug: gemcitabine, Drug: pemetrexed]

중재군 수

0

중재군 별 설명 및 등록 환자수

중재군 목표대상자 수

0

기관소재지

실시기관 전화번호

연구참여기관

국가

환자모집국가

최초 연구대상자 등록일

2025-06-16

상세내용

대상자 선정 및 제외기준

* 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.

참여 가능한 연령 하한

18 Years

참여 가능한 연령 상한

120 Years

참여 가능한 표준 연령

ADULT

OLDER_ADULT

대상자 포함기준 성별

ALL

건강인 참여 여부

NO

실제 대상자수

60

기존 목표대상자 수(실제)

0

최종 연구대상자 수

0

최종 시험대상자 선정일

시험대상자 > 분석대상군

시험대상자 > 인구학적 정보

주요결과변수

measure: 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...
description: DLTs noted at each dose level will be reported.
timeFrame: starts at initiation of study drug, though end of DLT period

measure: 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
description: 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.
timeFrame: baseline (pre-treatment biopsy), and at the time of SOC surgery post-cycle 3

보조결과변수

measure: To evaluate pharmacokinetics
description: Pharmacokinetic endpoints will be reported using descriptive statistics.
timeFrame: 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.

measure: To evaluate safety of the combination of AZA and chemo-durvalumab in participants with operable early-stage NSCLC
description: Safety of the agents will be assessed by determining the grade of adverse events noted in each participant and reporting the fraction with Grade 3 and Grade 4 adverse events. Safety data will be presented in a summary. The safety data will consist of the reporting of all adverse events, and may also include reporting vital signs, physical examination data, and laboratory safety data.
timeFrame: starts at initiation of study drug, through 64 days after the last study drug administration

measure: To evaluate event-free survival (EFS)
description: Event-free survival (EFS) at three years post treatment will be determined as the duration of time from start of treatment to time of disease recurrence or appearance of new primary cancer, whichever occurs first as appropriate using the Kaplan-Meier method and reported along with a 95% confidence interval, separately for phase I and II. The median EFS will also be reported along with a 95% confidence interval.
timeFrame: 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

measure: To evaluate objective response (complete response [CR] + partial response [PR]) and stable disease [SD] per RECIST 1.1
description: The objective response rate will be based on CR+PR and the disease stabilization rate (SD) and reported separately in phase I and II along with a 95% confidence interval for each.
timeFrame: baseline, and at Day 64 (treatment evaluation)

measure: To evaluate major pathologic response (MPR) rate
description: MPR rate is defined as \<10% viable cancer cells in samples collected per histopathologic assessment. The objective response rate based on the MPR rate will be reported separately in phase I and II along with a 95% confidence interval for each.
timeFrame: baseline (pre-treatment biopsy), and at the time of SOC surgery post-cycle 3

주요 평가 > 1차 평가변수 결과

최종 주평가변수 수집 완료일

2031-12-31

임상시험결과요약

연구책임자 전화번호

연구책임자 주소

연구실무담당자 성명

연구실무담당자 직위

연구실무담당자 전화번호

name: Deneise C Francis, R.N.
role: CONTACT
phone: (240) 858-3974
email: deneise.francis@nih.gov

name: David S Schrump, M.D.
role: CONTACT
phone: (240) 760-6239
email: david_schrump@nih.gov

연구실무담당자 기관명