IT or IA Infusion of PD1/PDL1/CTLA4 Inhibitors Versus IV for Immunotherapy of Head/Neck Cancers (HNC)

Study Overview
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Brief Summary
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This trial was designed to investigate the survival outcomes, response rates, and safety of patients with advanced Head/Neck Squamous cancer via intra-tumor or intra-artery versus vein infusion of PD1/PDL1/CTLA4 inhibitors.

Detailed Description
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Head/Neck cancer is a kind of hard-to-treat malignancy worldwide and its overall survival rate is still low. PD1/PDL1/CTLA4 inhibitors are widely used to treat various of cancers now. Delivery of antibody drugs through interventional approaches including intra-tumor or intra-artery, based on the theory of first pass effect of drug, can significantly increase the local drug concentration of the tumor, improve the efficacy, and reduce systemic adverse reactions. To the investigator's knowledge, no studies have been developed on the survival benefit of neck artery infusion or intra-tumor injection of immunotherapeutic agents in patients with advanced HNC. This phase II-III clinical trial was designed to compare the effects of PD1/PDL1/CTLA4 inhibitors via IA/IT and IV on the survival benefit of patients with advanced HNC, including ORR, DCR, median survival time, and safety.

Official Title
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A Phase II/III Randomized Trial of Comparison of Survival Benefit of Administration of PD1/PDL1/CTLA4 Inhibitors Via Neck Artery or Intratumor Versus Vein Infusion for Immunotherapy of HNC

Conditions
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Head/Neck Neoplasm

Intervention / Treatment
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* Drug: PD1/PDL1/CTLA4 inhibitors


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cytohistological confirmation is required for diagnosis of HNC. Signed informed consent before recruiting. Age between 18 to 80 years with estimated survival over 3 months. ECOG score < 2 Tolerable coagulation function or reversible coagulation disorders Laboratory examination test within 7 days prior to procedure: WBC≥3.0×10E9/L; Hb≥90g/L； PLT ≥50×10E9/L；INR < 2.3 or PT < 6 seconds above control；Cr ≤ 145.5 umul/L；Albumin > 28 g/L；Total bilirubin < 51 μmol/L At least one tumor lesion meeting measurable disease criteria as determined by RECIST v1.1. Patients with advanced HNC which would not be suitable for treatment with loco-regional therapies or have progressed following locoregional therapy such as surgical resection and other treatment. Birth control. Willing and able to comply with scheduled visits, treatment plan and laboratory tests. Exclusion Criteria: Patients participated in other clinical trials of equipment or drugs (signed informed consent) within 4 weeks; Any serious accompanying disease, which is expected to have an unknown, impact on the prognosis, include heart disease, inadequately controlled diabetes and psychiatric disorders; Patients accompanied with other tumors or past medical history of malignancy; Pregnant or lactating patients, all patients participating in this trial must adopt appropriate birth control measures during treatment; Patients have poor compliance. Any contraindications for neck artery infusion procedure: A. Impaired clotting test (platelet count < 60000/mm3, prothrombin activity < 50%). B. Renal failure / insufficiency requiring hemo-or peritoneal dialysis. C. Known severe atheromatosis. D. Known uncontrolled blood hypertension (> 160/100 mm/Hg). Allergic to adriamycin chemotherapy drugs，contrast agent or lipiodol; Any agents which could affect the absorption or pharmacokinetics of the study drugs Subjects unable to suffer the discomfort of the artery infusion procedure

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: PD1/PDL1/CTLA4 inhibitors infusion via neck artery<br>Interventional technique is used to localize neck artery to infuse the inhibitors directly into tumor. | Drug: PD1/PDL1/CTLA4 inhibitors<br>* Infusion of PD1/PDL1/CTLA4 inhibitors through peripheral vein or neck artery/intra-tumor.<br>|
| Experimental: PD1/PDL1/CTLA4 inhibitors infusion via peripheral vein<br>Routine peripheral vein infusion of PD1/PDL1/CTLA4 inhibitors is performed. | Drug: PD1/PDL1/CTLA4 inhibitors<br>* Infusion of PD1/PDL1/CTLA4 inhibitors through peripheral vein or neck artery/intra-tumor.<br>|
| Experimental: PD1/PDL1/CTLA4 inhibitors infusion via intra-tumor penetration<br>Interventional technique is used to intra-tumor injection of the inhibitors directly into tumor. | Drug: PD1/PDL1/CTLA4 inhibitors<br>* Infusion of PD1/PDL1/CTLA4 inhibitors through peripheral vein or neck artery/intra-tumor.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival (OS) will be defined as the elapsed time from the enrollment to death from any cause. For surviving patients, follow-up will be censored at the date of last contact (or last date known to be alive). Follow-up for OS will occur every 12 weeks (±1 month) until death or withdrawal of consent from the study. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Progression-free survival (PFS) will be defined as the elapsed time from the first date of study treatment until documented disease progression (as per mRECIST) or death from any cause, whichever is earlier. For patients who remain alive without progression, follow-up time will be censored at the date of last disease assessment. | 2 years | 
| Adverse event rate | Adverse event rate will be defined as the rate of patients who developed adverse event. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Head/Neck tumor, PD1 antibody, Artery infusion, PDL1 antibody, CTLA4 antibody, Intra-tumor, Interventional therapy