Exploratory Study on the Efficacy and Safety of Nebulized hUC-MSC-Derived Exosomes for Non-Acute CIP

Exploratory Study on the Efficacy and Safety of Nebulized Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes in the Treatment of Non-Acute Immune Checkpoint Inhibitor-Related Pneumonitis

Study Objectives The primary objective of Phase II is to evaluate the percentage of lesion resolution on high-resolution computed tomography (HRCT) as assessed by independent blinded reviewers. Secondary objectives include evaluating effects on pulmonary function, exercise capacity, dyspnea, quality of life, and oxygenation, as well as comprehensively assessing safety and tolerability. Phase I focuses on determining safety, dose-limiting toxicities (DLT), and recommended Phase II dose.

Study Population

The target population is patients with non-acute CIP aged 18-75 years with histologically confirmed malignancy. Key inclusion criteria include:

At least one cycle of immune checkpoint inhibitor (ICI) therapy and development of Grade 3-4 CIP per NCCN Guidelines V1.2025 Standard glucocorticoid treatment for ≥4 weeks, with current dose <20 mg/day prednisone equivalent or discontinued Persistent residual CIP lesions on HRCT without significant improvement in the past 4 weeks ECOG PS 0-1 and stable primary tumor for ≥6 months Effective contraception during the study and for 360 days after last dosing

Key exclusion criteria include:

Concomitant use of pirfenidone, nintedanib, or other antifibrotic agents Inability to perform pulmonary function tests or tolerate nebulization Unresolved interstitial lung disease from radiotherapy or targeted therapy Severe cardiac, hepatic, renal, or hematological dysfunction Organ transplantation, severe immunodeficiency, active epilepsy, or severe allergic status Other investigational drug use within 28 days Study Design and Sample Size Phase I: 9-18 subjects, open-label, dose-escalation design to evaluate DLT and safety Phase II: 40 subjects, randomized, double-blind, placebo-controlled design Study Endpoints Phase I Primary Endpoints Incidence of DLT Incidence of adverse events (AE) and serious adverse events (SAE) Phase II Primary Endpoint Percentage of HRCT lesion resolution at Weeks 4, 12, and 24, assessed by independent blinded reviewers Secondary Endpoints Pulmonary function: FVC%, TLC, RV, FRC, DLCO Functional and symptomatic measures: 6MWD, mMRC dyspnea score, SGRQ, LCQ Oxygenation: PaO₂, A-aDO₂, oxygenation index Exploratory Endpoints Dynamic changes in serum biomarkers: KL-6, cytokines (IL-1β, IL-6, IL-10), immune cell subsets (Tregs, Th1/Th17) Safety Assessments Monitoring of AEs/SAEs graded by CTCAE v5.0 and causality assessment Physical examination, vital signs, SpO₂, 12-lead ECG Laboratory tests: CBC, biochemistry, coagulation, urinalysis, CRP, ESR Study Termination Rules Overall Study Termination Successful completion after all 40 subjects finish 24-week follow-up and database lock Occurrence of unexpected serious or unacceptable safety risks Demonstration of overwhelming efficacy or futility Sponsor termination due to slow enrollment, funding, or major protocol deviations Regulatory or ethics committee requirements Individual Subject Discontinuation Development of DLT or severe hypersensitivity Rapid CIP progression (e.g., >50% radiological worsening) Tumor progression or clinical deterioration Withdrawal of informed consent Poor compliance unresponsive to intervention Loss to follow-up or death Investigator judgment of inappropriateness for continued participation Study Timeline Preparation and initiation: January 2026 - May 2026 Phase I/II enrollment: June 2026 - May 2027 Treatment and follow-up (overlapping with enrollment): through June 2028 Database lock and statistical analysis: July 2028 - August 2028 Study closeout: August 2028 - December 2028

Inclusion Criteria:

• Informed consent: Signed written informed consent.
• Age and diagnosis: Aged 18-75 years with histologically confirmed malignant tumor.
• Treatment history: Received at least one cycle of immune checkpoint inhibitor therapy and developed immune checkpoint inhibitor-related pneumonitis.
• Confirmed Grade 3-4 immune checkpoint inhibitor-related pneumonitis (CIP) by clinical evaluation (diagnosis and grading in accordance with the NCCN Guidelines for Management of Immunotherapy-Related Toxicities Version 1.2025), having received standard glucocorticoid therapy for ≥4 weeks, with glucocorticoids either discontinued or tapered to a prednisone-equivalent dose of <20 mg/day.
• Recent HRCT imaging: Persistent residual CIP-related lesions in both lungs, including ground-glass opacity, consolidation, reticular opacity, traction bronchiectasis, and/or honeycombing, involving a large extent of the lung fields; no significant resolution or improvement of these residual lesions on repeated HRCT within the past 4 weeks.
• General condition: ECOG PS score 0-1, with stable control of the primary tumor for ≥6 months.
• Contraception: Fertile subjects agree to use effective contraception during the study period and for 360 days after the last dose.

Exclusion Criteria:

• Concomitant medication: Current use of antifibrotic agents such as pirfenidone and nintedanib.
• Operational limitation: Inability to cooperate with pulmonary function testing or nebulized inhalation.
• History of other pulmonary diseases: Presence of unresolved interstitial lung disease or pulmonary fibrosis induced by targeted therapy, radiotherapy, or other causes.
• Severe comorbidities: Including severe cardiac, hepatic, or renal insufficiency, or severe hematological abnormalities.
• Specific medical history: Severe neuromuscular disease, history of organ transplantation, active epilepsy, primary or severe acquired/secondary immunodeficiency.
• Other factors: Severe allergic constitution, psychiatric disorders, use of other investigational products within 28 days, or any other condition deemed inappropriate by the investigator.