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

• ClinicalTrials.gov Identifier: NCT05777603
• Recruitment Status: Recruiting
• First Posted: March 21, 2023
• Last Update Posted: September 29, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Advanced Non Small Cell Lung Cancer	Drug: aerosolized aztreonam; Drug: aerosolized vancomycin; Drug: pembrolizumab	Phase 1

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
• Received at least one previous line of standard frontline therapy that must include a PD-1/PD-L1-targeting ICI
• 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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Study of Aerosolized Antibiotics and Pembrolizumab in Advanced Non-Small Cell Lung Cancer
• Estimated Study Start Date: October 4, 2023
• Estimated Primary Completion Date: June 1, 2024
• Estimated Study Completion Date: June 1, 2025

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 120 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• 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. Received at least one previous line of standard frontline therapy that must include a PD-1/PD-L1-targeting ICI.
  5. Age >=18 years.

  6. ECOG performance status <=2.

     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<TAB>>=60 mL/min/1.73 m^2 (calculated based on CKD-EPI formula or directly measured) for participants with creatinine levels above institutional normal.

  7. Participants with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.
  8. Participants with new or progressive brain metastases (active brain metastases) are eligible if immediate CNS specifictreatment is not required per standard of care and is unlikely to be required during the first cycle of therapy.
  9. 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.
  10. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
  11. 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.
  12. Women of child-bearing potential (WOCBP) 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.
  13. Breastfeeding participants must be willing to discontinue breastfeeding for the duration of study treatment.
  14. 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 females 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. Participants with targetable EGFR, ALK, ROS1, BRAF V600E, NTRK1/2/3, METex14 skipping, RET, and HER2 genomic tumor aberrations. Genomic testing must be based on a pathology report from an outside hospital or Laboratory of Pathology, NCI and 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.
7. Participants with KrasG12C mutation not previously treated with sotorasib or other approved KrasG12C small molecule inhibitor.
8. 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.
9. Uncontrolled intercurrent illness that would limit compliance with study requirements.

Contacts and Locations

Contacts

Contact: Shannon G Swift, R.N.; (240) 858-3157; shannon.swift@nih.gov

Contact: Chen Zhao, M.D.; (301) 646-8331; chen.zhao@nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: National Cancer Institute Referral Office 888-624-1937

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

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

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT05777603
• Other Study ID Numbers: 10001516; 001516-C
• First Posted: March 21, 2023
• Last Update Posted: September 29, 2023
• Last Verified: September 12, 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• 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.
• 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.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

Immune Checkpoint Inhibitor; lung microbiota; anti-PD1 antibody; inhaled antibiotic

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Vancomycin; Aztreonam; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Bacterial Agents; Anti-Infective Agents