Peramprizumab Combined With GP ± Anlotinib as Neoadjuvant Therapy in Locoregionally Advanced Nasopharyngeal Carcinoma

Study Overview
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Brief Summary
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The purpose of this study is to explore the efficacy and safety of a combination of GP chemotherapy and Peramprizumab ± Anlotinib in neoadjuvant therapy combined with Peramprizumab in adjuvant therapy of locoregionally advanced nasopharyngeal carcinoma patients.

Detailed Description
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Radiotherapy combined with chemotherapy is the standard treatment method for locally advanced NPC. In the 2020 National Comprehensive Cancer Network (NCCN) guidelines, GP regimen induction chemotherapy combined with concurrent chemoradiotherapy has been established as evidence-based grade 2A. Based on the results of phase 3 clinical trials, the addition of PD-1 monoclonal antibody to GP chemotherapy as a first-line treatment for patients with recurrent or metastatic nonkeratinizing NPC provided superior PFS, ORR and DoR than GP alone while maintaining a manageable safety profile. Therefore, the combination of PD-1 monoclonal antibody in GP induction chemotherapy may further improve the prognosis of patients with locally advanced NPC. There is a complex interaction between tumor immune microenvironment and tumor vascular remodeling. Anti-PD-1 monoclonal antibody combined with anti-VEGF have synergistic effect and inhibit tumor growth. Peramprizumab is a new type of PD-1 monoclonal antibody. It has the characteristics of strong antigen binding and slow dissociation rate, which can maintain the antitumor activity of T cells. Anlotinib is a multi-target tyrosine kinase inhibitor (TKI). It can effectively inhibit a variety of receptors, including vascular endothelial growth factor receptor (VEGFR), and block tumor angiogenesis more comprehensively. Based on the above research background, this study adopts a two-stage design: Stage I (Pick the Winner Study): For patients with locally advanced NPC, the complete response rate (CR) of tumor after induction chemotherapy was compared between the two groups of patients receiving GP + peramprizumab and GP + peramprizumab + arotinib before radiotherapy. The regimen with higher CR rate was the winner at this stage. Stage II ( Cohort Expansion Study): The 3-year failure free survival (FFS) of patients in the winning regimen of expansion cohort was calculated through long-term follow-up and compared with the data in previous trials.

Official Title
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Peramprizumab Combined With GP ± Arotinib Induction Therapy + Concurrent Chemoradiotherapy + Adjuvant Peramprizumab in Locoregionally Advanced Nasopharyngeal Carcinoma: A Phase II Clinical Trial

Conditions
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Nasopharyngeal Carcinoma

Intervention / Treatment
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* Drug: GP+Peramprizumab+Anlotinib
* Drug: GP+Peramprizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary participation with Written informed consent. Age ≥ 18 years and ≤ 65 years, male or non-pregnant female. Histologically confirmed with Nonkeratinizing carcinoma of the nasopharynx (differentiated or undifferentiated type, WHO II or III). Original clinical staged as III-IVa (according to the 8th AJCC edition),exclude T3-4N0, T3N1(Only retropharyngeal lymph nodes metastasized), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. White blood cell count (WBC)≥4.0×109 /L, Hemoglobin ≥ 90g/L, Platelet count ≥100×109/L. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×upper limit of normal (ULN),serum total bilirubin (TBIL) ≤2.0 times the upper limit of normal (ULN) . Adequate renal function: creatinine clearance rate≥60 ml/min or Creatinine ≤1.5× upper limit of normal value. Exclusion Criteria: Patients with recurrent or metastatic nasopharyngeal carcinoma. Histologically or cytologically confirmed with keratinizing squamous cell carcinoma of the nasopharynx. Prior therapy with Systemic chemotherapy. Women in the period of pregnancy, lactation, or reproductive without effective contraceptive measures. Seropositivity for human immunodeficiency virus (HIV). Known history of other malignancies (except cured basal cell carcinoma or carcinoma in situ of the cervix). Prior exposure to immune checkpoint inhibitors,including anti-PD-1, anti-PD-L1, anti-CTLA-4 antibodies. Patients with immunodeficiency disease or a history of organ transplantation. Received large doses of glucocorticoids, anticancer monoclonal antibodies, or other immunosuppressants within 4 weeks. Patients with severe dysfunction of heart, liver, lung, kidney or marrow. Patients with severe, uncontrolled disease or infections. Received other research drugs or in other clinical trials at the same time. Refuse or fail to sign the informed consent . Patients with other treatment contraindications. Patients with personality or mental disorders, incapacity or limited capacity for civil conduct. Hepatitis B surface antigen (HBsAg) positive and peripheral blood HBV deoxyribonucleic acid (HBV DNA) ≥1000cps/ml. Patients with positive HCV antibody test will only be enrolled in this study if the PCR test for HCV RNA is negative.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GP combine with peramprizumab and anlotinib neoadjuvant therapy+CCRT+peramprizumab adjuvant therapy<br>Patients receive neoadjuvant therapy with gemcitabine(1000mg per square meter on days 1,8) , cisplatin (80mg per square meter on day 1), peramprizumab (200mg, day1), and anlotinib (10mg days 1-14) every three weeks for three cycles before radiotherapy, then followed by concurrent IMRT and cisplatin (100mg per square meter) concurrent every three weeks during radiotherapy (D1, D22, D43 of RT) ,then followed by adjuvant therapy with peramprizumab (200mg) every three weeks for a maximum of nine cycles after radiotherapy. | Drug: GP+Peramprizumab+Anlotinib<br>* GP combine with peramprizumab and anlotinib neoadjuvant therapy+CCRT+peramprizumab adjuvant therapy<br>* Other names: GP+AK105+AL3818;|
| Active Comparator: GP combine with Peramprizumab neoadjuvant therapy+CCRT+Peramprizumab adjuvant therapy<br>Patients receive neoadjuvant therapy with gemcitabine(1000mg per square meter on days 1,8) , cisplatin (80mg per square meter on day 1), peramprizumab (200mg, day1) every three weeks for three cycles before radiotherapy, then followed by concurrent IMRT and cisplatin (100mg per square meter) concurrent every three weeks during radiotherapy (D1, D22, D43 of RT) ,then followed by adjuvant therapy with peramprizumab (200mg) every three weeks for a maximum of nine cycles after radiotherapy. | Drug: GP+Peramprizumab<br>* GP combine with peramprizumab neoadjuvant therapy+CCRT+peramprizumab adjuvant therapy<br>* Other names: GP+AK105;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1(Pick the Winner Study): Complete Response | The proportion of patients who had a complete response was defined as those with all pathological cervical lymph nodes being less than 10 mm in the short axis and no unequivocal soft tissue mass in the local region. Disease response was evaluatedby by the Investigator using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) 95% confidence intervals (CIs) were calculated using the Clopper Pearson method | 9 weeks | 
| Stage 2 (Cohort Expansion Study): Failure-free survival (FFS) | Defined as the time from registration to documented local or regional relapse, distant metastasis, or death from any cause, whichever occurred first. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Defined as the time from registration to death from any cause or censored at the date of last follow-up. | 3 years | 
| Locoregional failure-free survival (LRRFS) | Defined as the time from registration to local or regional relapse, or death from any cause. | 3 years | 
| Distant metastasis-free survival (DMFS) | Defined as the time from registration to distant metastasis, or death from any cause. | 3 years | 
| Incidence rate of adverse events (AEs) | Analysis of acute and late adverse events (AEs) are evaluated. Numbers of patients of treatment-related adverse events (acute toxicity) and late radiation toxicities were assessed by CTCAE v5.0. | 3 years | 
| Objective Response Rate (ORR) | Objective response rate (ORR) was assessed by the site Investigator using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) and was defined as the percentage of patients with a confirmed overall response of complete response (CR) or partial response (PR) and was based on all treated patients who had measurable disease at baseline (Day 1). 95% confidence intervals (CIs) were calculated using the Clopper Pearson method. | 9 weeks |