A Randomized, Double-Blind, Placebo-Controlled, MultiRegional Phase III Clinical Study of Toripalimab Alone or in Combination With Tifcemalimab (JS004/TAB004) as Consolidation Therapy in Patients With Limited-Stage Small Cell Lung Cancer Without Disease Progression Following Chemoradiotherapy

Prior treatment

• History of confirmed or suspected interstitial lung disease or pneumonitis (except for Grade 1 radiation pneumonitis not treated with corticosteroids).
• Patients with active tuberculosis by medical history or computed tomography (CT) examination, those with a history of treated active tuberculosis within 1 year prior to enrolment, or those with a history of untreated active tuberculosis more than 1 year prior to enrolment.
• Any other malignancy diagnosed prior to the first dose of investigational intervention, except those with a low risk for the development of metastases (5-year survival rate > 90%), such as adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix or breast, or adequately treated localized prostate cancer.
• More than or less than 4 cycles of chemotherapy during CRT or received a chemotherapy regimen other than intravenous etoposide and a platinum-based regimen.
• Received sequential chemoradiotherapy for LS-SCLC.
• Received any of the following treatments. a. Immune-mediated therapy, including but not limited to anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy. b. Any investigational interventions within 4 weeks or 5 half-lives prior to the first dose, whichever is shorter. c. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study, or the patient is in the follow-up period of an interventional clinical study. d. Systemic corticosteroids >10 mg/day prednisone or its equivalent or other immunosuppressive agents within 2 weeks before the first dose of the investigational intervention. Inhaled or topical use of corticosteroids are permitted. Short courses of corticosteroids (e.g., prior to intravenous contrast) within 2 weeks of the first dose of the investigational intervention are permitted. e. An antineoplastic vaccine or a live vaccine within 4 weeks prior to the first dose of the investigational intervention. f. Major surgery or serious trauma within 4 weeks prior to the first dose of the investigational intervention
• Failure to recover from the toxicity of prior anticancer therapy to Common Terminology Criteria for Adverse Events (CTCAE) Grade ≤ 1 (except alopecia) or levels specified in the inclusion/exclusion criteria, whichever is more severe.
• Severe or life-threatening infections (CTCAE Grade > 2) within 4 weeks prior to the first dose of investigational intervention, such as serious pneumonia, bacteraemia, or infectious complications requiring hospitalization; baseline chest imaging suggestive of active pulmonary inflammation; signs and symptoms of infection requiring oral or intravenous antibiotic therapy (except for prophylactic antibiotics) within 2 weeks prior to the first dose of investigational interventions.

Other illness

• Mixed SCLC and non-small cell lung cancer (NSCLC).
• The presence of active hepatitis B (HBV DNA ≥ 500 IU/mL), hepatitis C (hepatitis C antibodies positive and HCV-RNA higher than the lower limit of detection of the analytical method).
• Known allergy or hypersensitivity reaction to any investigational interventions or any investigational intervention excipients.
• Patients with active autoimmune disease, history of autoimmune disease (including but not limited to interstitial pneumonia, colitis, hepatitis, pituitary inflammation, vasculitis, nephritis, hyperthyroidism, or hypothyroidism). Patients with vitiligo or childhood asthma/allergies who do not require any intervention in adulthood, patients on a stable dose of thyroid replacement hormone for autoimmune-mediated hypothyroidism, and patients on a stable dose of insulin for Type I diabetes mellitus are eligible for enrolment.
• History of immunodeficiency, including human immunodeficiency virus (HIV) seropositivity, other acquired congenital immunodeficiency diseases, or a history of organ transplantation or allogeneic bone marrow transplantation.

Lab values

• Uncontrolled co-morbidities, including but not limited to symptomatic congestive heart failure, left ventricular ejection fraction (LVEF) < 50%, uncontrolled hypertension, unstable angina, uncontrolled arrhythmias, severe chronic gastrointestinal disease with diarrhoea, or psychiatric/social conditions that may compromise study compliance, result in a significantly increased risk of an AE, or affect the patient's ability to provide written consent.
• Patients, as determined by the Investigator, who may have other conditions likely to lead to early study withdrawal, such as other serious diseases (including psychiatric disease) requiring concomitant therapy, prisoners, participants who are involuntarily incarcerated or are expected to perform mandatory military service in the coming years, serious laboratory abnormalities, and/or family or social factors that may compromise patient safety or information collection.

Other

• Women who are pregnant or breastfeeding.
• Individuals who are dependent on the Sponsor, clinical site, or Investigator (e.g., an employee of the Sponsor or a clinical trial site, a dependent of the Investigator, or any site staff members otherwise supervised by the Investigator).
• Individuals who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities, in accordance with local regulations.

• Male or female with age ≥ 18 years old at the time of informed consent.
• Female patients of childbearing potential and male patients whose partners are women of childbearing age are required to use a medically approved form of highly effective methods of contraception (e.g., intrauterine device, birth control pill, or condom with spermicide) during study treatment and at least 4 months after the last dose of tifcemalimab/placebo or toripalimab/placebo
• Voluntarily agree to participate in the study, sign the informed consent form, and agree to comply with all study and follow-up procedures
• Histologically / cytologically confirmed limited-stage (Tumor Node Metastasis [TNM] Stage I-III [T any, N any, M0] by AJCC eighth edition) SCLC that can be safely treated with definitive radiation doses. Patients with Stage I or II disease must be medically inoperable (as determined by the Investigator) or the patient must refuse surgery.
• Received concurrent CRT defined as: (1) 4 cycles of chemotherapy consisting of carboplatin or cisplatin and intravenously administered etoposide; (2) a total radiation dose of 60-70 Gy for the standard once daily (QD) radiotherapy regimen or 45 Gy for the hyperfractionated twice daily (BID) radiotherapy regimen; (3) Patients must begin investigational interventions within 42 days of the last dose of chemotherapy or radiotherapy (whichever occurs last).
• Patients must achieve a complete response (CR), partial response (PR), or stable disease (SD) after receiving curative platinum-based CRT and must not have developed PD prior to study entry
• Prophylactic cranial irradiation (PCI) is permitted per Investigator’s discretion and local standard of care. PCI can be done prior to study entry or during the treatment period.
• Approximately 5 unstained formalin-fixed, paraffin-embedded serial slides from archival or recently obtained tumour tissue prior to radiotherapy (preferably recently obtained tissues) should be provided for biomarker analysis. Patients who cannot provide adequate tumour tissue samples as described above can only be enrolled after discussion and agreement between the Investigator and the Sponsor.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1
• Life expectancy ≥ 12 weeks.
• Adequate organ function as defined below (note: blood component transfusions or hematopoietic growth factors are not allowed within 14 days prior to obtaining screening tests); a. Absolute neutrophil count (ANC) ≥ 1.5×109/L; b. Platelets ≥ 100×109/L; c. Haemoglobin ≥ 9 g/dL; d. Bilirubin ≤ 1.5×upper limit of normal (ULN), alanine aminotransferase (ALT) ≤ 2.5×ULN, aspartate aminotransferase (AST) ≤ 2.5×ULN; e. Creatinine clearance ≥ 30 mL/min according to Cockcroft-Gault formula; f. Activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT) ≤ 1.5 × ULN and international normalized ratio (INR) ≤ 1.5 except for patients on stable doses of anticoagulant therapy, such as low molecular heparin or warfarin, where an INR within the expected therapeutic range of the anticoagulant is acceptable.