Study of Aerosolized Antibiotics and Pembrolizumab in Advanced Non-small Cell Lung Cancer

Phase I Study of Aerosolized Antibiotics and Pembrolizumab in Advanced Non-Small Cell Lung Cancer

Background:

Non-small cell lung cancer (NSCLC) can be hard to treat and is often fatal. People with NSCLC commonly have changes in the bacteria that populate their lungs. These bacterial changes may aid tumor growth. Researchers want to find out if treating the bacteria, too, can help cancer treatment work better.

Objective:

To test 2 inhaled antibiotics (aztreonam and vancomycin), combined with a standard cancer treatment, in people with NSCLC.

Eligibility:

People aged 18 years and older with NSCLC that has returned or progressed after treatment and cannot be treated with surgery.

Design:

Participants will be screened. They will have a physical exam with blood tests. They may blow into a machine to test how well their lungs work. They will have imaging scans. They may need to have a small piece of tissue cut from their tumor (biopsy).

Participants will be treated in six 21-day cycles. They will visit the clinic to receive a drug for cancer treatment on the first day of each cycle. This drug will be administered through a tube attached to a needle inserted into a vein in the arm.

The 2 antibiotic drugs will be in the form of a fine mist that can be inhaled. Participants use a device to take these drugs at home. They will inhale aztreonam up to 3 times a day and vancomycin 1 or 2 times a day. They will take these drugs during only 3 of the treatment cycles.

Biopsies and other tests will be repeated halfway through and after the study treatment.

Follow-up visits will continue for 1 year after study treatment.

Study Overview

• Status: Recruiting
• Conditions: Advanced Non Small Cell Lung Cancer
• Intervention / Treatment: Drug: aerosolized aztreonam; Drug: aerosolized vancomycin; Drug: pembrolizumab

Detailed Description

Background:

• Dysbiosis of the lung microbiome is commonly seen in patients with advanced non-small cell lung cancer (NSCLC). It is associated with increased bacterial burden and decreased bacterial diversity in tumors
• Preclinical studies using genetically engineered mouse (GEM) models show that dysbiosis of the lung microbiome promotes tumor growth in NSCLC

Objective:

- To assess the safety of combined aerosolized antibiotics (aztreonam and vancomycin) with pembrolizumab IV, in participants with advanced NSCLC

Eligibility:

• Histological confirmation of NSCLC that is not amenable to surgery
• Disease has progressed after FDA-approved frontline therapy for NSCLC
• PD-L1Tumor Proportion Score (TPS) >=1% detected at any time since diagnosis.
• Measurable and progressive disease
• Age >=18 years
• ECOG performance status <=2
• Participants must have adequate organ and bone marrow function

Design:

• This is a phase I, open-label, single-arm study evaluating the safety and feasibility of combined aerosolized antibiotics (aztreonam and vancomycin) and pembrolizumab in advanced NSCLC
• Participants will be given six cycles of treatments; each cycle is three weeks (21 days)
• Participants receive pembrolizumab 200mg IV on Day 1 of each cycle
• During cycles 1, 3 and 5, participants will self-administer aerosolized aztreonam 3 times a day and vancomycin twice a day from Day 2 through Day 21
• There are two dose levels of aerosolized antibiotics: participants start with Dose Level 1 (aztreonam 75mg three times a day and vancomycin 250mg twice a day)
• If participants cannot tolerate Dose Level 1, treatment will be de-escalated to Dose Level
• 1 (aztreonam 75mg once a day and vancomycin 250mg once a day)
• Participants will be enrolled based on "3+3" scheme to test the primary endpoints of safety and feasibility
• Up to 18 evaluable participants will be enrolled

• Study Type: Interventional
• Enrollment (Estimated): 23
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Chen Zhao, M.D.; Phone Number: (301) 646-8331; Email: chen.zhao@nih.gov
• Study Contact Backup: Name: Shannon G Swift, R.N.; Phone Number: (240) 858-3157; Email: shannon.swift@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: National Cancer Institute Referral Office; Phone Number: 888-624-1937

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

-INCLUSION CRITERIA:

1. Histologically or cytologically non-small cell lung cancer confirmed by outside pathology report or via the Laboratory of Pathology, NCI.
2. Have measurable disease, per RECIST 1.1, that is not amenable to surgery.
3. PD-L1 Tumor Proportion Score (TPS) >=1% detected at any time since diagnosis, based on a pathology report from an outside hospital or Laboratory of Pathology, NCI. PD- L1 expression testing must be conducted using one of the FDA approved diagnostic devices listed here: https://www.fda.gov/medical-devices/in-vitro-diagnostics/list- cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools.
4. Patient s disease has progressed after FDA-approved frontline therapy for NSCLC.
5. Age >=18 years.
6. ECOG performance status <=2.

7. Must have adequate organ and marrow function as defined below:

   • Leukocytes >=3,000/mcL
   • absolute neutrophil count >=1,500/mcL
   • platelets >=100,000/mcL
   • total bilirubin<TAB>within normal institutional limits
   • AST/ALT <=2.5 X institutional upper limit of normal
   • creatinine clearance >=60 mL/min/1.73 m^2 (calculated based on CKD-EPI formula or directly measured) for participants with creatinine levels above institutional normal.
8. Participants with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.
9. Participants with new or progressive brain metastases (active brain metastases) are eligible if immediate CNS specific treatment is not required per standard of care and is unlikely to be required during the first cycle of therapy.
10. Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within the 6 months before study treatment initiation are eligible for this trial.
11. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
12. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
13. Individuals of child-bearing potential (IOCBP) must agree to use effective contraception (e.g., hormonal intrauterine device [IUD], tubal ligation, partner has had prior vasectomy) beginning at study entry until 4 months after the completion of therapy. Note: abstinence, defined as no heterosexual sexual intercourse when this is in line with the preferred and usual lifestyle of the participant, is also acceptable.
14. Breastfeeding participants must be willing to discontinue breastfeeding for the duration of study treatment.
15. Ability of participant to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

1. Participants who are receiving any other investigational agents.
2. Participants with ongoing Epstein-Barr virus or cytomegalovirus infection
3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab, aztreonam, vancomycin and albuterol.
4. Pregnancy (confirmed with beta-HCG serum or urine pregnancy test performed in individuals of childbearing potential at screening).
5. Pulmonary function FEV1 (Forced Expiratory Volume in the first second) <25% will be excluded based on the requirement of receiving aerosolized aztreonam.
6. History of severe immune-related adverse events (irAEs), defined as any grade neurological or cardiac irAEs, any grade 3 or 4 irAE (except fully controlled endocrine irAEs with appropriate hormone supplementation), and any grade pneumonitis.
7. Uncontrolled intercurrent illness that would limit compliance with study requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; Pembrolizumab + de-escalating doses of aztreonam and vancomycin	Drug: aerosolized aztreonam; antibiotic with gram-negative bacteria coverage; Drug: aerosolized vancomycin; antibiotic with gram-positive bacteria coverage; Drug: pembrolizumab; standard of care therapy/monoclonal antibody for patients with advanced NSCLC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limiting toxicities (DLTs) - type and grade	Safety will be evaluated by reported grades of toxicities, including DLTs at each dose levels.	Start of therapy through 1 year after last study drug dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limiting toxicities (DLTs) - type and grade	Recommended phase 2 dose will be determined by reported grades of toxicities, including DLTs at each dose levels.	Start of therapy through 1 year after last study drug dose.
Fraction of participants who received adequate doses of all agents at each dose level	Feasibility will be reported as the fraction of participants who receive adequate doses of all drug agents without DLT at each dose level.	Between start of therapy through 1 year after last study drug dose.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Chen Zhao, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): April 18, 2024
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: March 18, 2023
• First Submitted That Met QC Criteria: March 18, 2023
• First Posted (Actual): March 21, 2023

Study Record Updates

• Last Update Posted (Actual): August 28, 2026
• Last Update Submitted That Met QC Criteria: August 27, 2026
• Last Verified: August 26, 2026

More Information

Terms related to this study

• Keywords: Immune Checkpoint Inhibitor; anti-PD1 antibody; lung microbiota; inhaled antibiotic
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Anti-Bacterial Agents; Anti-Infective Agents; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; pembrolizumab
• Other Study ID Numbers: 10001516; 001516-C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: -- All IPD recorded in the medical record will be shared with intramural investigators upon request. -- All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.
• IPD Sharing Time Frame: -- Clinical data available during the study and indefinitely. -- Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• IPD Sharing Access Criteria: -- Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. -- Genomic data are made available via dbGaP through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No