Neoadjuvant Toripalimab Plus Nimotuzumab in Oral Squamous Cell Carcinoma Prior to Radical Therapy

Neoadjuvant Toripalimab Plus Nimotuzumab in Primary Limited-Stage Oral Squamous Cell Carcinoma Prior to Radical Therapy：A Single-arm, Phase Ⅱ Study

This study aims to investigate the efficacy and safety of neoadjuvant Toripalimab combined with Nimotuzumab in primary limited stage oral squamous cell carcinoma prior to radical therapy.

The purpose of this study is to investigate the efficacy and safety of neoadjuvant PD-1 inhibitor toripalimab plus nimotuzumab in subjects with primary limited stage, oral squamous cell carcinoma prior to radical therapy. Patients would be treated with neoadjuvant toripalimab plus nimotuzumab for 2 cycles and then received radical surgery or radiotherapy based on the efficacy assessed by investigators per RECIST v1.1.

Inclusion Criteria:

1. Aged ≥18 years old；male or female.

2. Oral squamous cell carcinoma confirmed by cytology or histology. Evaluation by the investigators to confirmed primary limited-stage (clinical stage T1N+M0, T2-4 anyNM0, AJCC 8th) without prior treatment.

3. Patients who are suitable and agree radical therapy.

4. At least 1 evaluable lesion according to RECIST v1.1.

5. ECOG PS ≤ 1

6. Adequate organ function, defined as achieving the following laboratory test results ≤ 14 days before treatment

   1. Patients must meet the following laboratory test results: i. ANC ≥ 1.5 x 10^9 / L ii. Platelets ≥100 x 10^9 / L iii. Hb ≥90 g / L Note: Patients must not receive blood transfusion or growth factor within 14 days before blood sample collection due to neutrophil count, platelet, or hemoglobin below study requirements.
   2. Renal function requirements within 4 weeks before treatment: Endogenous creatinine clearance ≥ 60 mL / min or more (based on 24-hour urine creatinine calculation or Cockcroft-Gault formula method).
   3. Serum total bilirubin ≤ 1.5×ULN (Gilbert syndrome patients can be enrolled if the total bilirubin is <3 × ULN).
   4. AST and ALT ≤ 3 × ULN. If the patient has liver metastases, AST and ALT ≤ 5×ULN

7. Patients with hepatitis B virus (HBV) infection and inactive / asymptomatic HBV carriers; or patients with chronic or active HBV, if HBV DNA <500 IU / mL (or 2500 copies/ mL) will be allowed to enroll. Hepatitis C antibody-positive patients will be allowed to enroll if HCV-RNA is negative during screening.

   NOTE: Patients with detect hepatitis B surface antigen (HBsAg) or HBV DNA, and patients receiving antiviral therapy during screening should be treated for> 2 weeks before enrollment, and Continue treatment for 6 months after study drug therapy

8. Women of childbearing age (WOCBP) must be willing to take effective contraception during the study period and ≥60 days after the last study treatment (including chemotherapy) administration, and the urine or serum pregnancy test result is negative within ≤7 days before treatment.

   a. Women of childbearing age are defined as any woman who has had menarche and has not undergone sterilization (hysterectomy or bilateral ovariectomy) and has not yet reached menopause. Menopause is defined as amenorrhea for 12 months in women> 45 without other biological or physiological causes. In addition, to confirm menopause, women under 55 must have serum follicle stimulating hormone (FSH) levels> 40 mIU / mL.

9. Unsterilized male must be willing to take effective contraception during the study and ≥ 60 days after the last study treatment (including chemotherapy) was administered.

Exclusion Criteria:

1. Not suitable for toripalimab or nimotuzumab treatment.

2. Have previously received any treatment for oral squamous cell carcinoma.

3. Patients with evidence of fistula (esophagus / bronchus or esophagus / aorta)

4. Presence of uncontrollable pleural effusion, pericardial effusion, or ascites that require repeated drainage or medical intervention (with clinically significant recurrence requiring additional intervention within 2 weeks after the intervention).

5. Evidence of complete esophageal obstruction that is not suitable for treatment

6. Have been treated with antitumor agents targeted to PD-1, PD-L1 or PD-L2.

7. Have active meningeal disease or uncontrolled brain metastases.

8. Patients with active autoimmune disease or history of autoimmune diseases may relapse.

   Note: Patients with the following diseases can be entered for further screening:

   1. Controllable type 1 diabetes
   2. Hypothyroidism (only if it could be controlled by hormone replacement therapy)
   3. Controlled celiac disease
   4. Skin diseases that do not require systemic treatment (eg vitiligo, psoriasis, hair loss)
   5. Any other disease that is not expected to recur without external triggers

9. Any active malignancy within ≤ 2 years before treatment, expect specific cancers which being studied in this study and locally recurrent cancers that have been cured (such as resected basal cell or squamous cell skin cancer, superficial bladder cancer, cervical cancer and breast cancer in situ).

10. Any condition requiring systemic treatment with corticosteroids (dose above 10 mg / day of prednisone or equivalent dose of similar agents) or other immunosuppressive agents within ≤ 14 days prior to treatment.

    Note: Patients who are currently or previously using any of the following steroid regimens can be enrolled:

    1. Adrenaline replacement (prednisone ≤10mg / day or equivalent dose of similar agents)
    2. Local, ophthalmic, intra-articular, intranasal, and inhaled corticosteroids with minimal systemic absorption.
    3. Prophylactic short-term (≤7 days) use of corticosteroids (for example, to prevent hypersensitivity caused by contrast agent) or to treat non-autoimmune conditions (for example, delayed-type hypersensitivity reactions caused by exposure to allergens).

11. Have a history of interstitial lung disease, non-infectious pneumonia or uncontrolled disease including pulmonary fibrosis, acute lung disease, etc.

12. Severe chronic or active infections (including tuberculosis infections, etc.) that require systemic antibacterial, antifungal, or antiviral treatment within 14 days of treatment.

13. History of HIV infection.

14. Underwent any major surgery requiring general anesthesia ≤ 28 days before treatment.

15. Previously allogeneic stem cell transplantation or organ transplantation.

16. Have any of the following cardiovascular risk factors:

    1. Cardiogenic chest pain occurs within ≤ 28 days prior to treatment and is defined as moderate pain that limits applianceal activities of daily life.
    2. Symptomatic pulmonary embolism occurred within ≤ 28 days before treatment
    3. Acute myocardial infarction occurred within 6 months before treatment
    4. History of heart failure that has reached New York Heart Association Class III or IV ≤ 6 months before treatment.
    5. Ventricular arrhythmia of grade ≥ 2 occurred within ≤ 6 months before treatment
    6. Cerebrovascular accident occurred within ≤ 6 months before treatment
    7. Uncontrolled hypertension: SBP ≥160 mmHg or DBP ≥100 mmHg, although antihypertensive drugs were used ≤ 28 days before treatment or before the first study drug
    8. Any syncope or convulsions ≤ 28 days before treatment

17. History of severe hypersensitivity to other monoclonal antibodies.

18. Have received Chinese herbal medicine or proprietary Chinese medicine for cancer control within 14 days before the first study drug administration.

19. Live vaccinations within ≤ 4 weeks before treatment. Note: Seasonal flu vaccines are usually inactivated vaccines and are allowed. The vaccine used in the nasal cavity is a live vaccine and is not allowed.

20. Presence of basic medical conditions (including abnormal laboratory test values) or alcohol / drug abuse or dependence that are detrimental to study drug administration or affect drug toxicity or AE interpretation, or that may reduce compliance during the study .

21. Participate in another clinical trial at the same time

22. Unintentional weight loss ≥ 5% within 1 month before treatment or severe malnutrition.

23. Nutritional risk index (Shirasu et al 2018) can be used to determine severe malnutrition

24. Pregnant or lactating women

25. Peripheral neuropathy ≥ grade 2 at baseline

26. Uncontrolled diabetes, abnormalities of laboratory tests in potassium, sodium or corrected calcium>grade 1 despite standard medication，or hypoalbuminemia ≥ grade 3 within 14 days before treatment.

27. Have received any chemotherapy, immunotherapy (eg interleukin, interferon, thymosin) or any research treatment within 14 days or 5 half-lives (whichever is longer) before the first study drug administration.

28. Other exclusion criteria

    1. Prisoner or jailer.
    2. People who have been compulsorily detained for the treatment of a mental or physical illness, such as an infectious disease.