A Study of Penpulimab (AK105) in the First-line Treatment of Recurrent or Metastatic Nasopharyngeal Carcinoma

Study Overview
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Brief Summary
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This study is a randomized, double-blind, multi-center phase III clinical study to compare the efficacy and safety of penpulimab combined with chemotherapy and placebo combined with chemotherapy in the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma.

Official Title
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A Randomized, Double-blind, Multi-center Phase III Study of Penpulimab (AK105) Combined With Chemotherapy Versus Placebo Combined With Chemotherapy in the First-line Treatment of Recurrent or Metastatic Nasopharyngeal Carcinoma

Conditions
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Nasopharyngeal Carcinoma

Intervention / Treatment
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* Drug: Penpulimab
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntarily signed written Informed Consent Form(ICF). Main study: Age of ≥ 18 years and ≤ 75 years at the time of enrollment. Substudy: Age of ≥ 12 years and < 18 years. Weight≥ 35KG. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Expected survival of ≥ 3 months. Histologically or cytologically confirmed nasopharyngeal carcinoma. Subjects with primary metastatic (nasopharyngeal carcinoma, stage IVB defined by the Union for International Cancer Control and the American Joint Committee on Cancer Staging System edition 8) nasopharyngeal carcinoma who are not suitable for local treatment or radical treatment; or nasopharyngeal carcinoma subjects who have a local-regional recurrence and/or distant metastasis more than 6 months after the end of previous radical treatment (radiotherapy with induction, concurrent, adjuvant chemotherapy)；No systemic treatment has been received for recurrent or metastatic nasopharyngeal carcinoma, and local regional recurrence is not suitable for local treatment or has received local treatment. At least one measurable lesion according to RECIST v1.1; Has adequate organ function. All female and male subjects of reproductive potential must agree to use an effective method of contraception, as determined by the Investigator, during and for 150 days after the last dose of study treatment. Exclusion Criteria: Subjects with pathologically diagnosed nasopharyngeal adenocarcinoma or sarcoma. Subjects have had another malignancy within 3 years before the first dose, except nasopharyngeal carcinoma. Subjects with other malignancies that have been cured by local therapy such as basal or cutaneous squamous cell carcinoma, superficial bladder cancer, cervix or breast carcinoma in situ are not excluded. Participation in treatment with an investigational drug or use of an investigational device within 4 weeks before first study dosing. Have previously received immunotherapy, including immune checkpoint inhibitors, immune checkpoint agonists , immune cell therapy, and other treatments against tumor immune mechanism. Active autoimmune disease requiring systemic treatment within 2 years prior to initial administration, or as an autoimmune disease that can recur or for which treatment is planned determined by the investigator. Active or past history of definite inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis). History of immunodeficiency; those who test positive for HIV antibody; current chronic use of systemic corticosteroids or immunosuppressive agents. Known active tuberculosis (TB) (suspected of having active TB need to undergo clinical examination for exclusion of such possibility); known active syphilis infection. Known history of allotransplantation and allogeneic hematopoietic stem cell transplantation. Has known active Hepatitis B or Hepatitis C. Active or untreated CNS metastases. Subjects with peripheral neuropathy. Unresolved toxicity from prior anti-tumor therapy, defined as toxicity that has not recovered . Received a live vaccine within 30 days before the first dose or planned to receive a live vaccine during the study. Known allergy to any study drug component; known history of serious hypersensitivity to other monoclonal antibodies. Pregnant or nursing (lactating) women.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 75 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: Group A<br>Group A (study group): Penpulimab plus cisplatin and gemcitabine | Drug: Penpulimab<br>* Arm A: Penpulimab (200 mg, administered on Day 1 of each cycle, Q3W) + cisplatin 80 mg/m2, administered on Day 1 of each cycle, Q3W, up to 6 cycles) + gemcitabine 1000 mg/ m2, administered on Days 1 and 8 of each cycle, Q3W, up to 6 cycles), 3 weeks (21 days) per treatment cycle (Q3W), and then followed by penpulimab monotherapy as maintenance treatment, Q3W.<br>* Other names: gemcitabine;|
| Placebo Comparator: Group B<br>Group B (control group): Placebo plus cisplatin and gemcitabine | Drug: placebo<br>* Arm B: Placebo (200 mg, administered on Day 1 of each cycle, Q3W) + cisplatin (80 mg/m2, administered on Day 1 of each cycle, Q3W, up to 6 cycles) + gemcitabine (1000 mg/m2, on Days 1 and 8 of each cycle, Q3W, up to 6 cycles), every 3 weeks (21 days) per treatment cycle and then followed by placebo monotherapy as maintenance treatment, Q3W. Subjects in Arm B will have the opportunity to crossover to open-label treatment with penpulimab monotherapy after radiographic disease progression.<br>* Other names: gemcitabine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | PFS assessed by BIRC based on RECIST v1.1 . | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival(OS) | OS is defined as the time from the date of randomization to death from any cause. | Up to 4 years | 
| Objective response rate (ORR) | ORR is the proportion of subjects with CR or PR based on RECIST v1.1. | Up to 2 years | 
| Duration of response (DoR) | DoR is defined as the duration from the first documentation of objective response to the first documented disease progression or death due to any cause, whichever occurs first. | Up to 2 years | 
| Disease control rate (DCR) | DCR is defined as the proportion of subjects with CR, PR, or SD, based on RECIST v1.1; | Up to 2 years | 
| Adverse event (AE) | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment | From the time of informed consent signed through 90 days after the last dose of penpulimab | 
| Maximum observed concentration (Cmax) | Serum concentrations of penpulimab in individual subjects at different time points after penpulimab administration. | From first dose of penpulimab through 30 days after last dose of penpulimab | 
| Anti-drug antibodies (ADA) | Number and percentage of subjects with detectable anti-drug antibody (ADA). | From first dose of penpulimab through 30 days after last dose of penpulimab | 
| PD-L1 expression | Detect PD-L1 expression in tumor samples and evaluate the correlation between PD-L1 and efficacy. | Baseline (Tumor tissue samples must be provided to the research center or central laboratory prior to initial administration). | 
| Blood EBV level | Detect the blood EBV level at baseline and changes after administration and evaluate the correlation between EBV and efficacy | Up to 2 years |