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

Официальное название

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

Обзор

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.

Подробное описание

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

Вмешательства

• Препарат aerosolized aztreonam
  antibiotic with gram-negative bacteria coverage
• Препарат aerosolized vancomycin
  antibiotic with gram-positive bacteria coverage
• Препарат pembrolizumab
  standard of care therapy/monoclonal antibody for patients with advanced NSCLC

Первичные конечные точки

• Dose limiting toxicities (DLTs) - type and grade [Срок оценки: Start of therapy through 1 year after last study drug dose]

Вторичные конечные точки (2)

• Dose limiting toxicities (DLTs) - type and grade [Срок оценки: 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 [Срок оценки: Between start of therapy through 1 year after last study drug dose.]

Критерии участия

-INCLUSION CRITERIA:

• Histologically or cytologically non-small cell lung cancer confirmed by outside pathology report or via the Laboratory of Pathology, NCI.
• Have measurable disease, per RECIST 1.1, that is not amenable to surgery.
• 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.
• Patient s disease has progressed after FDA-approved frontline therapy for NSCLC.
• Age >=18 years.
• 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 >=60 mL/min/1.73 m\^2 (calculated based on CKD-EPI formula or directly measured) for participants with creatinine levels above institutional normal.
• Participants with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.
• 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.
• 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.
• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• 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.
• 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.
• Breastfeeding participants must be willing to discontinue breastfeeding for the duration of study treatment.
• Ability of participant to understand and the willingness to sign a written informed consent document.

Критерии исключения

• Participants who are receiving any other investigational agents.
• Participants with ongoing Epstein-Barr virus or cytomegalovirus infection
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab, aztreonam, vancomycin and albuterol.
• Pregnancy (confirmed with beta-HCG serum or urine pregnancy test performed in individuals of childbearing potential at screening).
• Pulmonary function FEV1 (Forced Expiratory Volume in the first second) <25% will be excluded based on the requirement of receiving aerosolized aztreonam.
• 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.
• Uncontrolled intercurrent illness that would limit compliance with study requirements.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• National Institutes of Health Clinical Center — Bethesda

Идентификаторы

NCT: NCT05777603 · 10001516 · 001516-C

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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