PD-1 Blockade and Bevacizumab Replace Cisplatin in Locoregionally Advanced Nasopharyngeal Carcinoma

Study Overview
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Brief Summary
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At present, the treatment regimen of locally advanced nasopharyngeal carcinoma still needs to be further improved, and the focus of improvement lies in replacing cisplatin with high-efficiency and low-toxicity treatment regimen. Considering the synergistic effect among radiotherapy, immunotherapy and anti-angiogenesis therapy, we chose PD-1 inhibitor combined with bevacizumab to replace cisplatin chemotherapy.

Detailed Description
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We plan to use PD-1 inhibitor combined with bevacizumab to replace cisplatin (induction + concurrent ± adjuvant) in patients with locally advanced nasopharyngeal carcinoma. Considering the safety of the original study, we will set up two groups for the adjuvant treatment stage: one group will only use PD-1 inhibitor at the adjuvant treatment stage (low risk group), and the other group will use bevacizumab +PD-1 inhibitor combined treatment (high risk group). Once the efficacy and safety of this protocol are confirmed, it may provide a new treatment option for locally advanced nasopharyngeal carcinoma.

Official Title
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PD-1 Inhibitor and Bevacizumab Replace Cisplatin in Induction, Concurrent, and/or Adjuvant Therapy for High-risk Locoregionally Advanced Nasopharyngeal Carcinoma.

Conditions
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Nasopharyngeal Carcinoma

Intervention / Treatment
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* Drug: Bevacizumab+Toripalimab+gemcitabine, adjuvant with Bevacizumab and Toripalimab
* Drug: Bevacizumab+Toripalimab+gemcitabine, adjuvant with Toripalimab


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. Histologically confirmed with Nonkeratinizing carcinoma of the nasopharynx (differentiated or undifferentiated type). Original clinical staged as III-IVa (according to the 8th AJCC edition). Stage III patients should meet the criteria of EBV DNA≥4000 cps/ml. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Patients must have adequate organ function: 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. INR, APTT≤1.5 x ULN. Exclusion Criteria: Subjects with recurrent or metastatic nasopharyngeal carcinoma. Histologically or cytologically confirmed with keratinizing squamous cell carcinoma of the nasopharynx. Prior therapy with systemic therapy for nasopharyngeal carcinoma. Prior exposure to immune checkpoint inhibitors,including anti-PD-1, anti-PD-L1, anti-CTLA-4 antibodies. Prior exposure to antiangiogenic agents. Tumor invasion to the intracranial with clinical symptoms accompanied by cerebral edema, requiring hormone therapy. Any grade ≥2 bleeding event (according to CTCAE 5.0) occurred within 4 weeks prior to enrollment. Subjects with an active, known or suspected autoimmune disease. Subjects with clinically significant cardiovascular and cerebrovascular diseases. Subjects with high blood pressure who cannot be controlled well with antihypertensive drugs. Subjects with previous digestive tract bleeding history within 3 months or evident gastrointestinal bleeding tendency. Subjects with arterial / venous thrombosis events occurred within 6 months of the first dose. 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).

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: low risk<br>Patients will receive induction therapy with toripalimab plus bevacizumab and gemcitabine every 3 weeks for 3 cycles before radiotherapy, then followed by IMRT and concurrent therapy with toripalimab plus bevacizumab for 2 cycles, then followed by adjuvant therapy with toripalimab every 3 weeks for a maximum of 1 year after radiotherapy. | Drug: Bevacizumab+Toripalimab+gemcitabine, adjuvant with Toripalimab<br>* Induction therapy: Toripalimab (240mg iv drip)+Bevacizumab (7.5mg/kg iv drip)+gemcitabine (1,000 mg/m2), every 3 weeks for 3 cycles before radiotherapy. Concurrent therapy: Toripalimab (240mg iv drip)+Bevacizumab (7.5mg/kg iv drip), every 3 weeks for 2 cycles during radiotherapy. Adjuvant therapy: Toripalimab (240mg iv drip), every 3 weeks for 1 year after radiotherapy. Radiation: Intensity-modulated radiotherapy.<br>|
| Experimental: high risk<br>Patients will receive induction therapy with toripalimab plus bevacizumab and gemcitabine every 3 weeks for 3 cycles before radiotherapy, then followed by IMRT and concurrent therapy with toripalimab plus bevacizumab for 2 cycles, then followed by adjuvant therapy with toripalimab and bevacizumab every 3 weeks for a maximum of 1 year after radiotherapy. | Drug: Bevacizumab+Toripalimab+gemcitabine, adjuvant with Bevacizumab and Toripalimab<br>* Induction therapy: Toripalimab (240mg iv drip)+Bevacizumab (7.5mg/kg iv drip)+gemcitabine (1,000 mg/m2), every 3 weeks for 3 cycles before radiotherapy. Concurrent therapy: Toripalimab (240mg iv drip)+Bevacizumab (7.5mg/kg iv drip), every 3 weeks for 2 cycles during radiotherapy. Adjuvant therapy: Toripalimab (240mg iv drip)+Bevacizumab (7.5mg/kg iv drip), every 3 weeks for 1 year after radiotherapy. Radiation: Intensity-modulated radiotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| grade ≥3 nasopharyngeal necrosis or hemorrhage | Incidence of nasopharyngeal necrosis or massive hemorrhage (grade ≥3). Grade ≥3 hemorrhage: Grade 3, Transfusion indicated; invasive intervention indicated; hospitalization. Grade 4, Life-threatening consequences; urgent intervention indicated (e.g., tracheotomy or intubation). Grade 5, death. Grade ≥3 nasopharyngeal necrosis: Grade 3, Severe pain; unable to adequately aliment or hydrate orally; limiting self care ADL. Grade 4, Life-threatening consequences; urgent intervention indicated. Grade 5, death. | At the end of each cycle (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | The proportion of patients whose tumors shrink to a certain size and maintain such size for a certain period of time, including patients with complete response (CR) and partial response (PR). | 3 weeks after indution therapy; 3 months after concurrent therapy | 
| Progression-free survival | Progress-free survival is calculated from the date of enrollment to the date of the first progression at any site or death from any cause or censored at the date of the last follow-up. | 3 year | 
| Overall survival | Overall survival is calculated from the date of enrollment to the date of the death from any cause or censored at the date of the last follow-up. | 3 year | 
| Locoregional failure-free survival (LRRFS) | Defined as the time from registration to local or regional relapse, or death from any cause. | 3 year | 
| Distant metastasis-free survival (DMFS) | Defined as the time from registration to distant metastasis, or death from any cause. | 3 year | 
| 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 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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antiangiogenesis, immunotherapy, Locoregionally Advanced Nasopharyngeal Carcinoma