Phase 3 Trial of N-803, Tislelizumab, and Docetaxel vs. Docetaxel in Advanced/Metastatic NSCLC with Acquired Resistance to Immune Checkpoint Inhibitors
- Trial ID
- 2025-521221-32-00
- Protocol
- ResQ201A-NSCLC
- Sponsor
- Immunitybio Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized, open-label, Phase 3 clinical trial is to compare **overall survival (OS)** between the experimental arm, which includes N-803 plus Tislelizumab and Docetaxel, and the control arm, which consists of Docetaxel monotherapy. This study targets participants with advanced or metastatic **non-small cell lung cancer** who have developed resistance to immune checkpoint inhibitor therapy. The primary objective is clinically significant as it aims to determine if the combination therapy can extend the lifespan of patients compared to standard treatment, thereby potentially offering a more effective therapeutic option for this patient population.
Secondary objectives include comparing the following between the experimental and control arms: immune disease control rate (iDCR), immune progression-free survival (iPFS), immune overall response rate (iORR), and immune duration of response (iDOR), as measured using immune Response Evaluation Criteria in Solid Tumors (iRECIST). These secondary endpoints are crucial for understanding the broader impact of the treatment on disease progression and response, providing insights into the potential benefits of the combination therapy beyond overall survival.
Participants
The clinical trial involves a total of **372 participants** diagnosed with **Advanced or Metastatic Non-Small Cell Lung Cancer**. The study population includes both male and female subjects, aged 18 years and older, with no vulnerable populations selected. Participants were selected based on specific inclusion criteria, including a pathologically confirmed stage IV NSCLC disease and acquired resistance to an immune checkpoint inhibitor. The trial population is required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and measurable tumor lesions according to RECIST v1.1. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to practice effective contraception if applicable. The selection process ensures that participants have the ability to attend required study visits and return for adequate follow-up as per the protocol.
Plans and Procedures
The clinical trial is a **randomized**, open-label, Phase 3 study designed to evaluate the efficacy and safety of a combination therapy involving **N-803 (NAI)** and **Tislelizumab** with **Docetaxel** compared to Docetaxel monotherapy in participants with advanced or metastatic **non-small cell lung cancer** (NSCLC) who have developed resistance to immune checkpoint inhibitors. The primary objective is to compare overall survival (OS) between the experimental and control arms. Secondary endpoints include comparing immune disease control rate (iDCR), immune progression-free survival (iPFS), immune overall response rate (iORR), and immune duration of response (iDOR) using immune Response Evaluation Criteria in Solid Tumors (iRECIST), as well as assessing safety profiles between the two groups.
The trial is expected to commence recruitment on June 17, 2025, and conclude by December 31, 2029. Participants will be involved in the study for a maximum treatment period of 30 days for the experimental drugs and 6 days for Docetaxel. The study will include an initial screening visit to confirm eligibility based on criteria such as age, disease stage, and previous treatment history. Participants must have pathologically confirmed stage IV NSCLC and have shown disease progression following an initial response to immune checkpoint inhibitors. Follow-up visits will be scheduled to monitor treatment response and safety, with the end-of-study visit marking the completion of the participant's involvement.
Participants will be randomly assigned to either the experimental arm receiving N-803 and Tislelizumab in combination with Docetaxel or the control arm receiving Docetaxel alone. The study will be conducted in an open-label manner, meaning both participants and investigators will be aware of the treatment assignments. The trial will adhere to rigorous ethical standards, requiring informed consent from all participants. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study protocols. The trial aims to provide valuable insights into the potential benefits of combination therapy in overcoming resistance to immune checkpoint inhibitors in NSCLC patients.
Treatment
The clinical trial involves the administration of **Tislelizumab**, a **solution for infusion** developed by BeiGene. Tislelizumab is an experimental medication administered intravenously. The dosage is calculated based on body surface area, with a maximum daily dose of 75 mg/m². The treatment period for Tislelizumab is set at 30 days. This medication is not formulated for pediatric use and is not classified as an orphan drug. Participant compliance with the dosing schedule will be monitored throughout the trial.
Another experimental treatment in the study is **N-803 (NAI)**, an **intravesical solution** produced by ImmunityBio. The active substance in N-803 is **Nogapendekin Alfa Inbakicept**, which is administered subcutaneously. The maximum daily dose for N-803 is 1.2 mg, with a treatment duration of 30 days. Similar to Tislelizumab, N-803 is not intended for pediatric use and does not have orphan drug status. Compliance with the administration schedule will be closely observed.
The comparator treatment in this trial is **Docetaxel Seacross 20 mg/ml**, a **solution for infusion** provided by Seacross Pharma (Europe) Ltd. The active substance, **Docetaxel**, is a chemical compound administered intravenously. The maximum daily dose is 75 mg/m², and the treatment period is limited to 6 weeks. Docetaxel serves as the standard-of-care therapy in this study, and participant adherence to the dosing regimen will be monitored to ensure accurate comparison with the experimental treatments.
Efficacy
The efficacy of the clinical trial will be assessed primarily by comparing **Overall Survival (OS)** between the experimental and control arms. This primary endpoint will provide a direct measure of the treatment's impact on the lifespan of participants with advanced or metastatic non-small cell lung cancer who have acquired resistance to immune checkpoint inhibitor therapy.
Secondary efficacy endpoints include the comparison of immune Disease Control Rate (iDCR), immune Progression-Free Survival (iPFS), immune Overall Response Rate (iORR), and immune Duration of Response (iDOR) between the experimental and control arms. These will be measured using the immune Response Evaluation Criteria in Solid Tumors (iRECIST). The iRECIST criteria are specifically designed to evaluate the efficacy of immunotherapies by accounting for unique response patterns observed with these treatments.
The collection and analysis of these efficacy parameters will be conducted at predetermined intervals throughout the trial, ensuring a comprehensive assessment of the treatment's impact over time. The trial is designed to provide robust data on both the efficacy and safety of the treatment regimen, contributing to the understanding of its potential benefits for patients with this challenging condition.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants must meet ALL of the following criteria for inclusion in the study: 1. Age ≥ 18 years old. 2. Able to understand and provide a signed informed consent that fulfills the relevant Institutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines. 3. Pathologically confirmed stage IV NSCLC disease. 4. Have acquired resistance to an immune checkpoint inhibitor, defined as disease progression immediately following an initial response or stable disease (≥ 6 months duration) to exactly 1 line of anti-PD-L1 or anti-CTLA-4 therapy (for Stage III, IV, or recurrent disease) that was given alone or in combination with chemotherapy. 5. Participants with actionable genomic alteration (AGA) must have 1 or more documented AGA(s): EGFR, ROS1, NTRK, BRAF, MET exon 14 skipping, RET, KRAS. 6. Participants with AGA must meet the following criteria for advanced or metastatic NSCLC. Participants who have been treated with 1 or 2 prior lines of applicable targeted therapy that is locally approved (and is standard of care) for the participant's genomic alteration at the time of screening: 7. Participants who have tumors with EGFR L858R or exon 19 deletion mutations must have received prior osimertinib. 8. Participants who received a targeted agent as adjuvant therapy for early-stage disease must have relapsed or progressed while on the treatment or within 6 months of the last dose or received at least one additional course of targeted therapy for the same genomic alteration (which may or may not be same agent used in the adjuvant setting) for relapsed/progressive disease. 9. Participants who have been treated with a prior tyrosine kinase inhibitor (TKI) must receive additional approved targeted therapy, if locally available and clinically appropriate, for the applicable genomic alteration, or the participant will not be allowed in the study. 10. Participants must meet the inclusion criteria #4 listed above. 11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 12. Measurable tumor lesions according to RECIST v1.1. 13. Ability to attend required study visits and return for adequate follow-up, as required by this protocol. 14. Agreement to practice effective contraception for female participants of child-bearing potential and non-sterile males. Female participants of child-bearing potential must agree to use effective contraception for up to 7 months after completion of therapy, and non-sterile male participants must agree to use a condom for up to 7 months after treatment. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), orals, injectables, 2 forms of barrier methods (eg, condom, diaphragm) used with spermicide, intrauterine devices (IUDs), and hormonal therapy. 15. Participants with known human immunodeficiency virus (HIV) infection must be receiving anti-retroviral therapy and have an undetectable viral load at their most recent viral load test within 6 months prior to enrollment.
Exclusion Criteria
- Participants with ANY of the following criteria are excluded from participation in the study: 1. Systemic autoimmune disease currently requiring treatment (eg, lupus erythematosus, rheumatoid arthritis, Addison’s disease, or autoimmune disease associated with lymphoma). The participant must have been off treatment for 180 days. 2. History of allogeneic hematopoietic stem cell transplant or organ transplant requiring immunosuppression; or history of pneumonitis or interstitial lung disease requiring treatment with systemic steroids; or a history of receiving systemic steroid therapy or any other immunosuppressive medication ≤ 3 days prior to study initiation. Daily steroid replacement therapy (eg, prednisone or hydrocortisone) and corticosteroids used to manage AEs are permitted. 3. Participants with AGA of ALK. 4. History of known active hepatitis B or C infection. 5. Active infection requiring antibiotic therapy. 6. Active treatment with CYP3A4 inhibitors. 7. Received a live vaccine ≤ 4 weeks prior to the first dose of study drug(s). 8. History of or active inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis). 9. Participants with known history of severe hypersensitive reactions to docetaxel or to other drugs formulated with polysorbate 80. 10. Had major surgery within 28 days prior to study randomization. Participants must have fully recovered from the effects of prior surgery in the opinion of the treating Investigator. 11. Inadequate organ function, evidenced by the following laboratory results: a. Absolute lymphocyte count < institutional lower limit of normal (LLN). b. Absolute neutrophil count < 1,500 cells/mm3 . c. Platelet count < 100,000 cells/mm3 . d. Total bilirubin 1.5 times greater than the ULN; unless the participant has documented Gilbert’s syndrome). e. Aspartate aminotransferase (AST [serum glutamic-oxaloacetic transaminase; SGOT]) or alanine aminotransferase (ALT [serum glutamic pyruvic transaminase; SGPT]) > 1.5 × ULN. f. Alkaline phosphatase (ALP) levels > 2.5 × ULN. g. Hemoglobin < 9.0 g/dL. h. Serum creatinine > 2.0 mg/dL or 177 μmol/L or creatinine clearance < 40 mL/min (using the Cockcroft-Gault formula below): Female = [(140 - age in years) × weight in kg × 0.85] / [72 × serum creatinine in mg/dL] Male = [(140 - age in years) × weight in kg × 1.00] / [72 × serum creatinine in mg/dL] 12. Have any of following: a. Cirrhosis at a level of Child-Pugh B (or worse); b. Cirrhosis (any degree) and a history of hepatic encephalopathy; or c. Clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis. 13. Participation in an investigational drug study or history of receiving any investigational treatment within 21 days prior to the start of treatment on this study, except for hormone-lowering therapy in participants with hormone-sensitive cancer. 14. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol. 15. Pregnant and nursing women. 16. History of allergic reactions to tislelizumab. 17. History of prior adverse reaction to immunotherapy that led to its permanent discontinuation.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Yet Recruiting | 17 Jun 2025 | 5 |
 France | Not Yet Recruiting | 17 Jun 2025 | 17 |
 Germany | Not Yet Recruiting | 17 Jun 2025 | 90 |
 Greece | Not Yet Recruiting | 17 Jun 2025 | 6 |
 Hungary | Not Yet Recruiting | 17 Jun 2025 | 20 |
 Italy | Not Yet Recruiting | 17 Jun 2025 | 24 |
 Poland | Not Yet Recruiting | 17 Jun 2025 | 20 |
 Romania | Not Yet Recruiting | 17 Jun 2025 | 4 |
 Spain | Not Yet Recruiting | 17 Jun 2025 | 20 |
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 |
|---|---|---|---|---|---|---|
Tislelizumab | Test | SOLUTION FOR INFUSION | INTRAVENOUS | 75 | 30 | PRD5423108 |
Docetaxel Seacross 20 mg/ml concentrado para solução para perfusão | Comparator | CONCENTRADO PARA SOLUÇÃO PARA PERFUSÃO | INTRAVENOUS | 75 | 6 | PRD9487372 |
N-803NAI | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | 1.2 | 30 | PRD12111488 |