A Study to Assess Toripalimab Alone or in Combination With Tifcemalimab as Consolidation Therapy in Patients With Limited-stage Small Cell Lung Cancer (LS-SCLC)

Study Overview
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Brief Summary
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The Study is a Phase 3, randomized, double-blind, placebo-controlled, multi-regional clinical research study to evaluate the use of toripalimab alone or in combination with tifcemalimab as consolidation therapy in patients with limited-stage small cell lung cancer without disease progression following chemoradiotherapy. Tifcemalimab is a monoclonal antibody against B and T lymphocyte attenuator (BTLA). Toripalimab is a monoclonal antibody against programmed death protein-1 (PD-1). This combination regimen is investigational in small cell lung cancer.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multi-Regional 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

Conditions
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Limited-stage Small Cell Lung Cancer (LS-SCLC)

Intervention / Treatment
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* Drug: Tifcemalimab injection
* Drug: toripalimab injection
* Drug: Placebo for Tifcemalimab
* Drug: Placebo for toripalimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet all of the following inclusion criteria to be enrolled: Male or female with age ≥ 18 years old at the time of informed consent. Histologically or cytologically confirmed LS-SCLC using the Veteran's Administration Lung Study Arm (VALSG) staging criteria (Appendix 3). Patients with TNM Stage I or II disease per AJCC 8th edition must be medically inoperable (as determined by the Investigator) or the patient must refuse surgery. Received CRT defined as: (1) 4 cycles of chemotherapy consisting of carboplatin or cisplatin and intravenously administered etoposide; (2) a total radiation dose of 60-66 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. 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. Eastern Cooperative Collaboration Oncology Group (ECOG) performance status (PS) score of 0-1 . Adequate organ function Female patients of childbearing potential and male patients whose partners are women of childbearing age. 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: Patients will be excluded from the study if they meet any of the following criteria. Mixed SCLC and non-small cell lung cancer (NSCLC). Received sequential chemoradiotherapy for LS-SCLC. Failure to recover from 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. History of immunodeficiency, including HIV seropositivity, other acquired congenital immunodeficiency diseases, or a history of organ transplantation or allogeneic bone marrow transplantation. History of confirmed or suspected interstitial lung disease or pneumonitis (except for Grade 1 radiation pneumonitis not treated with corticosteroids). 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group A<br>Tifcemalimab (200 mg intravenous infusion [IV]) combined with toripalimab (240 mg IV) | Drug: Tifcemalimab injection<br>* 200mg once per 3weeks<br>Drug: toripalimab injection<br>* 240mg once per 3 weeks<br>|
| Experimental: Experimental group B<br>Placebo for tifcemalimab (IV) combined with toripalimab (240 mg IV) | Drug: toripalimab injection<br>* 240mg once per 3 weeks<br>Drug: Placebo for Tifcemalimab<br>* per 3weeks<br>|
| Placebo Comparator: Placebo group C<br>Placebos for both tifcemalimab and toripalimab (IV) | Drug: Placebo for Tifcemalimab<br>* per 3weeks<br>Drug: Placebo for toripalimab<br>* per 3weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS | 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 LS-SCLC as measured by overall survival (OS) | up to 3years | 
| OS | Estimand for the primary objective to compare and evaluate the efficacy of toripalimab (Arm B) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLC as measured by OS | up to 3years | 
| PFS | 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 LS-SCLC as measured by Blinded Independent Review Committee (BIRC)-assessed progression-free survival (PFS). | up to 2years | 
| PFS | To compare and evaluate the efficacy of toripalimab (Arm B) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLC as measured by OS and BIRC-assessed PFS. | up to 2years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | To compare and evaluate the efficacy of tifcemalimab combined with toripalimab (Arm A) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLC as measured by Investigator-assessed PFS | up to 2years | 
| 1-year OS rate | To compare and evaluate the efficacy of tifcemalimab combined with toripalimab (Arm A) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLC 1year OS | up to 1year | 
| 2-year OS rate | To compare and evaluate the efficacy of tifcemalimab combined with toripalimab (Arm A) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLC 2year OS | up to 2 years | 
| objective response rate (ORR) | To compare and evaluate the efficacy of tifcemalimab combined with toripalimab (Arm A) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLC ORR | up to 2 years | 
| disease control rate (DCR) | To compare and evaluate the efficacy of tifcemalimab combined with toripalimab (Arm A) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLC DCR | up to 2 years | 
| duration of response (DoR) | To compare and evaluate the efficacy of tifcemalimab combined with toripalimab (Arm A) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLC DoR | up to 2years | 
| PFS | To compare and evaluate the efficacy of toripalimab (Arm B) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLS as measured by Investigator-assessed PFS | up to 2 years | 
| 1 year OS rate | To compare and evaluate the efficacy of toripalimab (Arm B) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLS 1 year OS rate | up to 1 years | 
| 2 year OS rate | To compare and evaluate the efficacy of toripalimab (Arm B) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLS 2 year OS rate | up to 2 years | 
| ORR | To compare and evaluate the efficacy of toripalimab (Arm B) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLS ORR | up to 2 years | 
| DCR | To compare and evaluate the efficacy of toripalimab (Arm B) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLS 2 year DCR | up to 2 years | 
| DoR | To compare and evaluate the efficacy of toripalimab (Arm B) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLS 2 year DoR | up to 2 years | 
| safety | To compare and evaluate the safety of tifcemalimab combined with toripalimab (Arm A) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLC as measured by the incidence of adverse events(Number ofparticipants with treatment-related adverse events as assessed by CTCAEv5.0.) and abnormal laboratory parameters（Laboratory values are compared numerically in the same unit of the same parameter）. | up to 2 years | 
| safety | To compare and evaluate the safety of toripalimab (Arm B) versus placebo (Arm C) as consolidation therapy after CRT for patients with LS-SCLC as measured by the incidence of adverse events(Number ofparticipants with treatment-related adverse events as assessed by CTCAEv5.0.) and abnormal laboratory parameters（Laboratory values are compared numerically in the same unit of the same parameter）. | up to 2 years | 
| pharmacokinetic (PK) | To characterize the pharmacokinetic (PK)/trough concentrations of tifcemalimab and toripalimab. | up to 2 years | 
| immunogenicity profiles | To evaluate the immunogenicity profiles of tifcemalimab and of toripalimab and to assess the impact of immunogenicity on PK//trough concentrations, safety(Number ofparticipants with treatment-related adverse events as assessed by CTCAEv5.0.), and efficacy(PFS/OS), if data allow. | up to 2 years |