Pirfenidone Capsules in the Treatment of Radiation-induced Lung Injury With or Without Immune Pneumonia

A Randomized, Double-blind, Placebo-controlled, Multicenter Phase II/III Clinical Trial on the Efficacy and Safety of Pirfenidone Capsules in the Treatment of Radiation-induced Lung Injury With or Without Immune-related Pneumonia

Radiation-induced lung injury (RILI) is one of the most common thoracic-radiotherapy complications, with an incidence as high as 31.4 %. Multiple studies have shown that RILI can adversely affect patient prognosis by disrupting treatment schedules. Moreover, the widespread clinical use of immune-checkpoint inhibitors (ICIs) has further increased pulmonary toxicity when radiotherapy (RT) is combined with ICIs. Checkpoint-inhibitor-related pneumonitis (CIP)-i.e., immune-mediated lung injury-may necessitate permanent discontinuation of ICIs, diminish survival benefit, and, in severe cases, directly threaten life. The diagnosis of both RILI and CIP is based on an integrated assessment of subjective symptoms and imaging findings.RILI typically occurs 1-3 months after completion of radiotherapy, whereas CIP may emerge at any point during treatment. The two entities share similar clinical presentations: fever, dry cough, chest tightness, dyspnoea, and pleuritic chest pain. Computed tomography (CT) is the most sensitive imaging modality. Pulmonary-function testing is another routinely used clinical metric; vital capacity, total lung capacity, forced expiratory volume in 1 s (FEV₁), and diffusing capacity of the lung for carbon monoxide (DLCO) may all decline, with DLCO being the most sensitive parameter. In advanced cases, arterial oxygen and carbon-dioxide tensions may also deteriorate.Currently, RILI is managed empirically with systemic corticosteroids and supportive care; however, this approach yields limited improvement in diffusing capacity or ventilatory function, and its ability to prevent radiation-induced pulmonary fibrosis (RPF) remains undefined. Corticosteroids also remain the mainstay of CIP therapy. Pirfenidone, a potent cytokine inhibitor, attenuates fibroblast activity by reducing production of transforming growth factor-β1 (TGF-β1), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF), thereby suppressing fibroblast proliferation and extracellular-matrix collagen synthesis. Pre-clinical efficacy studies have demonstrated robust anti-inflammatory, anti-oxidant, and anti-fibrotic effects in the lung.Because RILI and pneumonitis arising from combined radio-immunotherapy are often indistinguishable in clinical practice, and because both share pathogenetic features with idiopathic pulmonary fibrosis (IPF), the investigators initiated this phase II/III trial to address the unmet medical need for effective therapy. Building on prior pre-clinical and clinical data, the study aims to establish the optimal dose of pirfenidone capsules for RILI with or without concomitant CIP and to confirm efficacy and safety.Phase II (dose-finding): The study consists of a screening period (Day -28 to Day -1), a 168-day treatment-observation period (Day 1-Day 168), a safety follow-up (28 ± 7 days after the last dose), and subsequent disease-progression and survival follow-up. Ninety subjects with RILI, with or without CIP, who meet all eligibility criteria will be randomly assigned 1:1:1 to low-dose pirfenidone (400 mg TID), high-dose pirfenidone (600 mg TID), or matching placebo.Phase III (confirmatory): The dose of pirfenidone capsules for phase III will be determined jointly by the sponsor and investigators based on accumulated efficacy and safety data. The trial structure mirrors phase II: screening (Day -28 to Day -1), 168-day treatment-observation (Day 1-Day 168), safety follow-up (28 ± 7 days after the last dose), and disease-progression and survival follow-up. Eligible subjects with RILI ± CIP will be randomized 1:1 to receive either pirfenidone capsules (400 mg or 600 mg TID, taken with meals) or identical placebo. After completion of the 28-day post-treatment follow-up, all phase III participants will enter an extension phase for long-term survival assessment every 3 months (± 7 days).This trial will investigate the progression-free survival (PFS) and overall survival (OS) associated with pirfenidone capsules in patients with Grade 2 and 3 radiation-induced lung injury (RILI), with or without chemotherapy-induced pneumonitis (CIP).

Inclusion Criteria:

• The subjects must meet all the following inclusion criteria to be enrolled in this study:

• Voluntary signing of the informed consent form, and being capable of understanding and signing the informed consent form before the study.

• Age 18 to 75 years (inclusive of 18 and 75), with no gender restrictions.

• Malignant tumors diagnosed by pathological histology/cytology, and having received radiotherapy to the chest.

• According to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 standard, diagnosed by the investigator as clinical RILI grade 2-3 with or without CIP. For those with CIP, the investigator determines that only hormone treatment is required.

• At the time of enrollment, 40% ≤ DLCO as a percentage of the predicted value < 80% (mild to moderate lung diffusion function impairment).

• The course of radiation-induced lung injury is less than 2 months.

• If receiving radiation-induced lung injury-related treatment (including glucocorticoids, antibiotics, etc.) at the time of enrollment, the types and doses of medication must remain stable within 2 weeks before enrollment, and the hormone medication does not exceed 4 weeks.

• At the time of enrollment, the investigator assesses that the subjects can take oral administration of the investigational drug.

• Eastern Cooperative Oncology Group score (ECOG) 0-2.

• Expected survival period ≥ 6 months.

• The functional level of major organs meets the following standards:

  1. Blood routine examination: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count (PLT) ≥ 75 × 109/L or hemoglobin (Hb) ≥ 90 g/L;

  2. Biochemical examination: Total bilirubin (TBIL), blood urea nitrogen (BUN), and creatinine (Cr) ≤ 1.5 upper limit of normal value (ULN), or creatinine clearance rate ≥ 50 mL/min; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.0 ULN.

     • Creatinine clearance rate = [(140 - age) × weight (kg)] / [0.818 × Scr (umol/L)] (for females × 0.85)

• For all fertile women, the serum pregnancy test within 7 days before the first administration must be negative, and fertile male and female subjects must agree to use reliable contraceptive methods (hormonal or barrier method or abstinence) with their partners during the entire study period and at least 6 months after the last use of the investigational drug.

Exclusion Criteria:

• Subjects with Child-Pugh grade C at the time of enrollment or with severe liver diseases such as liver failure, hepatic encephalopathy, etc.
• Subjects who have had Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug eruption with eosinophilia and systemic symptoms (DRESS), or severe skin diseases in the past or currently;
• Subjects who have other diseases that the investigator deems unsuitable for participation in this study during the screening process.
• Subjects with active untreated brain metastases or meningeal metastases; for subjects with treated central nervous system (CNS) metastases, if the symptoms are controlled for at least 4 weeks, they are eligible for enrollment;
• Subjects who have a second malignancy that requires concurrent systemic cytotoxic chemotherapy, investigational treatment or biological therapy (such as anti-cytotoxic T lymphocyte-associated protein 4 [CTLA4] or human epidermal growth factor receptor 2 [HER2] monoclonal antibodies), but are allowed to enroll if they have a second malignancy that only requires hormone therapy (such as gonadotropin-releasing hormone [LHRH] agonists, tamoxifen, etc.);
• Subjects with a history of human immunodeficiency virus (HIV) infection, or positive HIV antibodies or suspected HIV infection.
• Subjects who cannot discontinue tetracycline antibiotics (such as doxycycline, minocycline, etc.) within 14 days before screening or during the study.
• Subjects who the investigator deems unable to follow the testing procedures (such as being unable to tolerate the interruption of assisted oxygen supply during pulmonary function tests).
• Subjects who have used or are to use drugs that may have preventive and/or therapeutic effects on radiation pneumonitis within 1 month before screening or during the study, such as pentoxifylline, angiotensin-converting enzyme inhibitors, berberine, ursolic acid, statins, nicorandil, stem cells, interferon-γ, penicillamine, etc.;
• Subjects who have used nintedanib or high-dose acetylcysteine within 1 month before randomization;
• Subjects who have used known or judged by the investigator to be beneficial to lung injury Chinese herbal medicines or other substances during the 1 month before randomization;
• Subjects who have received or been exposed to live vaccines or attenuated live vaccines or plan to receive live vaccines or attenuated live vaccines (except anti-tumor treatment live vaccines) during the study;
• Subjects who have used drugs that are strong inhibitors or inducers of cytochrome CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 within 1 month before screening or during the study;
• Female subjects who are breastfeeding at the time of screening or male subjects whose partner is planning to get pregnant during the study.
• Subjects with known mental disorders that may affect the study assessment or with poor compliance.
• Subjects who are allergic to any active ingredients of this drug or its excipients (such as lactose) or lactose intolerant.
• Subjects who had severe trauma or received surgery within 1 month before screening or during the study, or who plan to undergo surgery during the study.
• Subjects who, according to the investigator's judgment, have other serious systemic diseases or laboratory test abnormalities or other reasons that make them unsuitable for participating in this clinical trial.
• Subjects who plan to participate in other drug clinical trials during the study.