Phase III Randomized, Double-Blind Study of Toripalimab and Tifcemalimab as Consolidation Therapy in Limited-Stage Small Cell Lung Cancer Post-Chemoradiotherapy
- Trial ID
- 2023-507097-41-01
- Protocol
- JS004-008-III-SCLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare and evaluate the **efficacy** of tifcemalimab combined with toripalimab (Arm A) versus placebo (Arm C) as consolidation therapy after chemoradiotherapy (CRT) for patients with limited-stage small cell lung cancer (LS-SCLC). This is measured by overall survival (OS) and Blinded Independent Review Committee (BIRC)-assessed progression-free survival (PFS). The clinical relevance of this objective lies in determining the potential of this combination therapy to improve survival outcomes in LS-SCLC patients, a group with limited treatment options and poor prognosis.
Secondary objectives include: - Comparing and evaluating the efficacy of tifcemalimab combined with toripalimab (Arm A) versus placebo (Arm C) as measured by investigator-assessed PFS, 1-year and 2-year OS rates, objective response rate (ORR), disease control rate (DCR), and duration of response (DoR). - Comparing and evaluating the efficacy of toripalimab (Arm B) versus placebo (Arm C) using the same efficacy measures. - Assessing the safety of tifcemalimab combined with toripalimab (Arm A) versus placebo (Arm C) and toripalimab (Arm B) versus placebo (Arm C) by incidence of adverse events and laboratory parameters. - Characterizing the pharmacokinetics (PK) of tifcemalimab and toripalimab. - Evaluating the immunogenicity profiles of tifcemalimab and toripalimab and assessing the impact of immunogenicity on PK, safety, and efficacy, if data allow.
Participants
The clinical trial involves a total of **607 participants** diagnosed with **limited-stage small cell lung cancer (LS-SCLC)** who have not experienced disease progression following chemoradiotherapy (CRT). The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their ability to provide informed consent and their compliance with study procedures. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have achieved a complete response, partial response, or stable disease after receiving curative platinum-based CRT. The trial population is characterized by adequate organ function and a life expectancy of at least 12 weeks. Lifestyle considerations such as diet and physical activity are not specified, but participants are required to use medically approved contraception methods if applicable. The selection criteria ensure that the study includes a diverse group of individuals who meet the necessary health and treatment response requirements.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled, multi-regional Phase III study**. The primary objective is to evaluate the efficacy of **tifcemalimab** combined with **toripalimab** versus placebo as consolidation therapy in patients with limited-stage small cell lung cancer (LS-SCLC) who have not shown disease progression following chemoradiotherapy (CRT). The trial will assess overall survival (OS) and progression-free survival (PFS) as determined by a Blinded Independent Review Committee (BIRC). The study is expected to commence recruitment on January 29, 2025, and conclude by October 10, 2029.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and organ function. Following successful screening, participants will be randomized to receive either the investigational drugs or placebo. The trial includes regular follow-up visits to monitor safety, efficacy, and any adverse events. These visits will also involve assessments of pharmacokinetics and immunogenicity. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected duration of participant involvement is up to 24 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. Participants must adhere to study protocols, including the use of effective contraception for those of childbearing potential. The trial will ensure rigorous monitoring to maintain the integrity of the double-blind design, with data collected to support both primary and secondary endpoints, including safety and pharmacokinetic profiles.
Treatment
The clinical trial involves the administration of **Toripalimab**, a liquid pharmaceutical form, as an experimental medication. Toripalimab is a protein-based therapeutic agent developed by Shanghai Junshi Biosciences Co. Ltd. It is administered intravenously with a maximum daily dose of 200 mg and a total dose not exceeding 8400 mg over a treatment period of 24 weeks. The administration schedule is designed to ensure optimal therapeutic efficacy while monitoring participant compliance through regular assessments.
Another experimental medication used in the trial is **Tifcemalimab**, also known as TAB004, which is provided in a solution form. This monoclonal antibody, developed by Topalliance Biosciences Inc., targets the B and T lymphocyte attenuator (BTLA). Tifcemalimab is administered intravenously with a maximum daily dose of 200 mg and a total dose not exceeding 7000 mg over a 24-week treatment period. The dosing schedule is structured to maximize therapeutic outcomes while ensuring participant adherence through systematic monitoring.
The trial also includes the use of placebo controls to evaluate the efficacy of the experimental treatments. The **Toripalimab Placebo** is provided in a 6 mL vial, and the **Tifcemalimab Placebo** is provided in a 5 mL vial. Both placebos are administered intravenously, mimicking the administration route of the active treatments to maintain the study's double-blind design. The placebo administration schedule aligns with that of the active treatments to ensure consistency in the trial protocol.
Efficacy
The efficacy of the clinical trial will be assessed by comparing the outcomes of patients receiving **tifcemalimab** combined with **toripalimab** (Arm A) versus those receiving a placebo (Arm C) as consolidation therapy in patients with limited-stage small cell lung cancer (LS-SCLC) following chemoradiotherapy (CRT). The primary efficacy endpoints include overall survival (OS) and progression-free survival (PFS) as assessed by a Blinded Independent Review Committee (BIRC) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Secondary efficacy endpoints will include investigator-assessed PFS, 1-year and 2-year OS rates, overall response rate (ORR), disease control rate (DCR), and duration of response (DoR). Safety will be evaluated by the incidence of adverse events (AEs) and abnormal laboratory parameters. Pharmacokinetics (PK) of **tifcemalimab** and **toripalimab** will be assessed through trough concentrations, and immunogenicity will be evaluated by the incidence and titers of anti-drug antibodies (ADAs) and, if ADA positive, neutralizing antibodies (NAbs).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female with age ≥ 18 years old at the time of informed consent.
- 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.
- 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
Exclusion Criteria
- Mixed SCLC and non-small cell lung cancer (NSCLC).
- 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.
- Known allergy or hypersensitivity reaction to any investigational interventions or any investigational intervention excipients.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- Women who are pregnant or breastfeeding.
- 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.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 29 Jan 2025 | 15 |
 France | Not Yet Recruiting | 29 Jan 2025 | 32 |
 Germany | Not Yet Recruiting | 29 Jan 2025 | 6 |
 Italy | Not Recruiting | 29 Jan 2025 | 33 |
 The Netherlands | Recruiting | 29 Jan 2025 | — |
 Poland | Not Recruiting | 29 Jan 2025 | 14 |
 Romania | Not Recruiting | 29 Jan 2025 | 20 |
 Spain | Recruiting | 29 Jan 2025 | 17 |
| Netherlands | — | — | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Toripalimab | Test | LIQUID | INTRAVENOUS USE | 200 | 24 | PRD8831688 |
TAB004 | Test | SOLUTION | INTRAVENOUS USE | 200 | 24 | PRD9858054 |
Tifcemalimab Placebo 5 mL/vial | Placebo | N/A | — | — | — | N/A |
Toripalimab Placebo 6 mL/vial | Placebo | N/A | — | — | — | N/A |