Neoadjuvant Anti-PD-1 and TP Versus TPF on Pathological Response in OSCC

Study Overview
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Brief Summary
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To compare the pathological efficacy of neoadjuvant Toripalimab and Albumin paclitaxel /Cisplatin (TTP) with Docetaxel/ Cisplatin/ 5-flurouracil (TPF) for patients with locally advanced resectable oral squamous cell carcinoma (OSCC), and to determine the safety of neoadjuvant TTP. In order to explore a better protocol of neoadjuvant therapy to improve the efficacy in patients with locally advanced OSCC.

Detailed Description
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In the previous Illuminate trial, neoadjuvant anti-programmed death-1 (PD-1) of Toripalimab and Albumin paclitaxel /Cisplatin (TTP) therapy was used in 20 patients with locally advanced and resectable oral squamous cell carcinoma (OSCC), and the neoadjuvant therapy was well-tolerated. The major pathologic response (MPR) rate was 60% (12/20), including 30% (6/20) pathological complete response (pCR). Furthermore, the MPR might transfer to survival benefit in the patients received neoadjuvant therapy. Therefore, in this randomized trial, we aimed to compare the pathological response of neoadjuvant TTP therapy versus TPF chemotherapy in the patients with locally advanced OSCC (Illuminate-2 trial). A total of 80 patients will be enrolled in this trial, and the primary endpoint is MPR rate. The neoadjuvant TTP arm will receive two cycles of intravenous Albumin paclitaxel (260mg/ m^2), Cisplatin (75mg/ m^2) and Toripalimab (anti-PD1 inhibitor, 240 mg) on d1 and d22, followed by the standard treatment of surgery and postoperative adjuvant therapy. The neoadjuvant TPF arm will received two cycles of intravenous Docetaxel (75mg/m^2), Cisplatin (75mg/m^2) on d1 (d22), and 5-Fu(750mg/m^2/day) for 5 days (d1-5 and d22-26), followed by the standard treatment of surgery and postoperative adjuvant therapy.

Official Title
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Neoadjuvant Toripalimab and Albumin Paclitaxel /Cisplatin Versus Docetaxel/ Cisplatin/ 5-fluorouracil (TPF) on Pathological Response in Patients With Locally Advanced and Resectable Oral Squamous Cell Carcinoma

Conditions
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Oral Squamous Cell Carcinoma, Neoadjvant Therapy, Anti-PD-1, Chemotherapy

Intervention / Treatment
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* Drug: Toripalimab (anti-programmed death-1 inhibitor)
* Drug: Albumin paclitaxel
* Drug: Cisplatin
* Drug: Docetaxel
* Drug: 5-Fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 18-75 years old Gender: male and female Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0-2 Histopathological diagnosis of oral squamous cell carcinoma (including tongue, gums, cheek, floor of mouth, hard palate, and posterior molar region) Primary tumor with a clinical stage of III/IVA (T1-2/N1-2/M0 or T3-4a/cN0-2/M0, AJCC2018) Patients must have at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) Blood routine: white blood cells (WBCs) >3,000/mm3, hemoglobin >8 g/L, platelets >80,000/mm3 Liver function: alanine amino transferase/aspartate amino transferase (ALAT/ASAT) <2.5 times the upper limit of normal and bilirubin <1.5 times the upper limit of normal Renal function: Serum creatinine <1.5 times the upper limit of normal Coagulation function: INR, PT, APTT<1.5 times the upper limit of normal Signed the informed consent form Exclusion Criteria: Unresolved grade 2 [(Common Terminology Criteria for Adverse Events (CTCAE 5.0)] or higher toxic reactions caused by previous anticancer treatments Known allergic reaction to any ingredients or excipients of the therapy Known history of malignancy, unless been cured and no recurrence for 5 years Known history of radiation to head and neck Active severe clinical infection (> National Cancer Institute (NCI)-CTCAE version 5.0 grade 2 infection) Obvious cardiovascular abnormalities [such as myocardial infarction, superior vena cava syndrome, grade 2 or higher heart disease diagnosed according to the New York Heart Association (NYHA) classification 3 months before enrollment] Patients receiving immunology-based treatment for any reason Patients with a history of active bleeding, coagulopathy, or receiving coumarin anticoagulation therapy Pregnant or lactating women Uncontrollable hypertension (systolic blood pressure >150 mmHg and/or diastolic blood pressure >90 mmHg) or cardiovascular diseases with clinical significance (such as activity), such as cerebrovascular accidents (≤ 6 months before screening), myocardial infarction (≤6 months before screening), unstable angina pectoris, NYHA grade II or above congestive heart failure, or severe arrhythmia that cannot be controlled by drugs or has a potential impact on trial treatment Complicated with severe, uncontrolled infection or known human immunodeficiency virus (HIV) infection, or diagnosed as acquired immunodeficiency syndrome (AIDS); or uncontrolled autoimmune disease; or history of allogeneic tissue/organ transplantation, stem cell or bone marrow transplantation, or solid organ transplantation Participation in other clinical trials within 30 days before enrollment Other situations that the investigator considers unsuitable with respect to participating in the trial

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant TTP<br>The participants will receive two cycles of intravenous Albumin paclitaxel (260mg/ m^2), Cisplatin (75mg/ m^2) and Toripalimab (anti-PD-1 inhibitor, 240 mg) on d1 and d22. | Drug: Toripalimab (anti-programmed death-1 inhibitor)<br>* The participants will receive two cycles of Toripalimab, with 21 days each. 240mg of Toripalimab will be used intravenously on the first day of each cycle.<br>Drug: Albumin paclitaxel<br>* The participants will receive two cycles of Albumin paclitaxel, with 21 days each. 260mg/m^2 of Albumin paclitaxel will be used intravenously on the first day of each cycle.<br>Drug: Cisplatin<br>* The participants will receive two cycles of Cisplatin, with 21 days each. 75mg/m^2 of Cisplatin will be used intravenously on the first day of each cycle.<br>|
| Active Comparator: Neoadjuvant TPF<br>The participants will receive two cycles of intravenous Docetaxel (75 mg/m^2) on d1 and d22, Cisplatin (75 mg/m^2) on d1 and d22, and 5-Fluorouracil (750 mg/m^2/day) for 5 days (d1-5 and d22-26), the interval is 16±1 days. | Drug: Cisplatin<br>* The participants will receive two cycles of Cisplatin, with 21 days each. 75mg/m^2 of Cisplatin will be used intravenously on the first day of each cycle.<br>Drug: Docetaxel<br>* The participants will receive two cycles of Docetaxel, with 21 days each. 75mg/m^2 of Docetaxel will be used intravenously on the first day of each cycle.<br>Drug: 5-Fluorouracil<br>* The participants will receive two cycles of 5-Fluorouracil, with 21 days each. 750mg/m^2/d of 5-Fluorouracil will be used as a 120-hour continuous intravenous infusion on days 1 through 5.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major pathologic response | The major pathologic response (MPR): the percentage of tumor cells before and after treatment was compared according to biopsy specimens before neoadjuvant therapy and pathological specimens after surgery; the percentage of residual viable tumor (RVT) cells was evaluated on resected tumor slides. MPR was defined as ≤ 10% RVT%. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year disease-free survival rate | Disease-free survival was calculated from the date of randomization to tumor recurrence or death from any cause. | 24 months | 
| 2-year overall survival rate | Overall survival was calculated from the date of randomization to death from any cause. | 24 months |