Chemoimmunotherapy With or Without SBRT Before Surgery for Locally Advanced Oral and Oropharyngeal Cancer

Official title

Neoadjuvant Chemoimmunotherapy With or Without SBRT Followed by Surgery for Locoregionally Advanced Squamous Cell Carcinoma of the Oral Cavity and Oropharynx: A Phase II Randomized Trial

Overview

In this study, participants will be randomly assigned to either the experimental group or the control group. The experimental group will first receive SBRT (6Gy\*3 fractions) to treat the primary tumor and metastatic lymph nodes. This will be followed by a combination of Toripalimab, Docetaxel, and Cisplatin for three cycles, every three weeks. The control group will receive the same combination of Toripalimab, Docetaxel, and Cisplatin for three cycles, every three weeks, but without SBRT. After the final round of chemotherapy, all participants will have imaging scans and, three weeks later, undergo surgery. After surgery, they may also receive additional radiotherapy with or without chemotherapy. Patients can also choose whether to continue treatment with Toripalimab after surgery.

Detailed description

Participants will be randomly assigned to the experimental group and the control group. The experimental group will first receive SBRT (Stereotactic Body Radiotherapy) for the primary tumor and positive lymph nodes (prescribed dose: 6 Gy × 3 fractions, once every other day). One to two weeks after SBRT, they will receive 240 mg of Toripalimab + 75 mg/m² of Docetaxel + 75 mg/m² of Cisplatin, administered every 3 weeks for 3 cycles. The control group will receive 240 mg of Toripalimab + 75 mg/m² of Docetaxel + 75 mg/m² of Cisplatin, administered every 3 weeks for 3 cycles. Both groups will undergo imaging assessment 2 weeks after the final chemotherapy cycle. Three weeks after the last chemotherapy cycle, participants will receive curative surgery. Postoperative adjuvant radiotherapy ± chemotherapy will be administered according to preoperative staging and postoperative pathological characteristics. Patients may also choose to continue maintenance treatment with Toripalimab after surgery.

Interventions

• Radiation SBRT
  The experimental group will first receive SBRT (Stereotactic Body Radiotherapy) for the primary tumor and positive lymph nodes (prescribed dose: 6 Gy × 3 fractions, once every other day).
• Drug Docetaxel, Cisplatin, Toripalimab
  Toripalimab 240mg (free medicine) + Docetaxel 75mg/m2 + Cisplatin 75mg/m2, q3w for 3 courses
• Procedure Radical resection surgery
  Radical resection surgery
• Radiation IMRT ± chemotherapy/toripalimab
  According to the preoperative staging and postoperative pathological characteristics, all patients will receive postoperative radiotherapy with or without cisplatin-based chemotherapy. Additionally, patients can choose whether to continue maintenance therapy with toripalimab after surgery.

Primary outcome measures

• Pathological Complete Response (pCR) [Time frame: 2 weeks after the surgery]

Secondary outcome measures (6)

• Major Pathological Response (MPR) [Time frame: 2 weeks after the surgery]
• Objective response rate (ORR) [Time frame: two weeks after the chemoimmunotherapy]
• Disease-free survival (DFS): [Time frame: 2 years]
• Overall survival (OS) [Time frame: 2 years]
• Mandibular preservation rate: [Time frame: immediately after the surgery]
• Incidence of adverse events (AEs) and serious adverse events (SAEs) [Time frame: one month after the postoperative radiotherapy]

Eligibility criteria

Inclusion criteria

• Oral/oropharyngeal squamous cell carcinoma confirmed by histology and/or cytology.
• Clinical stage: resectable oral/oropharyngeal squamous cell carcinoma stage III-IVa (AJCC 8th edition)
• Age: 18-65 years old.
• According to the Eastern Cooperative Oncology Group (ECOG) criteria (performance status score of 0 or 1).
• Good organ function:

A. Hematology: WBC ≥ 4000/μL, neutrophil ≥ 2.000/μL, hemoglobin ≥ 9g/dL, platelet ≥ 100000/μL; B. Liver function: bilirubin ≤ 1.5 times the upper limit of normal (ULN) (patients with known Gilbert's disease and serum bilirubin level ≤ 3 times ULN can be included), AST and ALT ≤ 3 times, and alkaline phosphatase ≤ 3 times ULN; albumin ≥ 3g/dL; C. International normalized ratio (INR) or prothrombin time (PT) or activated partial thromboplastin time (aPTT) ≤ 1.5 times; D. Renal function: serum creatinine ≤ 1.5 times ULN or creatinine clearance ≥ 60mL/min according to the Cockcroft-Gault formula.

• Expected survival ≥ 3 months.
• The patient has signed an informed consent form and is willing and able to comply with the study visits, treatment plans, laboratory tests and other study procedures.
• Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days before enrollment and must agree to take effective contraceptive measures during the study and for at least 60 days after the last dose (including chemotherapy drugs and Teplizumab).
• If the female partner of the male subject is still of childbearing potential, the male subject must agree to take effective contraceptive measures during the study and for at least 60 days after the last dose.

Exclusion criteria

• Patients with other malignant tumors.
• Patients with known or suspected autoimmune diseases, including dementia and epilepsy.
• Patients with severe mental illness.
• Patients with necrotic lesions and who are assessed by the researchers to be at risk of major bleeding.
• Patients with severe heart disease, pulmonary dysfunction, heart function and pulmonary function below grade 3 (including grade 3).
• Patients whose laboratory test values do not meet the relevant standards within 7 days before enrollment.
• Patients who have received systemic or local glucocorticoid treatment within 4 weeks before enrollment.
• Patients with complications that require long-term use of immunosuppressive drugs or systemic or local use of corticosteroids with immunosuppressive effects.
• Patients with active pulmonary tuberculosis (TB) who are currently receiving anti-tuberculosis treatment or have received anti-tuberculosis treatment within 1 year before screening.
• Previous use of anti-toripalimab, anti-PD-L1 antibody, anti-PD-L2 antibody or anti-CTLA-4 antibody (or any other antibody acting on T cell co-stimulation or checkpoint pathway).
• Subjects with any active autoimmune disease or history of autoimmune disease (including but not limited to: interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, nephritis, hyperthyroidism, hypothyroidism; patients with vitiligo or complete remission of asthma in childhood and no need for any intervention as adults can be included; patients with asthma requiring medical intervention with bronchodilators cannot be included).
• HIV positive.
• HBsAg positive and HBVDNA copy number positive (quantitative detection ≥1000cps/ml); positive blood screening for chronic hepatitis C (HCV antibody positive).
• Any anti-infection vaccine (such as influenza vaccine, varicella vaccine, etc.) received within 4 weeks before enrollment.
• Women of childbearing age with positive pregnancy test and breastfeeding women.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Department of Radiation Oncology, Sun Yat-sen University Cancer Center — Guangzhou

Publications

• Caudell JJ, Gillison ML, Maghami E, Spencer S, Pfister DG, Adkins D, Birkeland AC, Brizel DM, Busse PM, Cmelak AJ, Colevas AD, Eisele DW, Galloway T, Geiger JL, Haddad RI, Hicks WL, Hitchcock YJ, Jimeno A, Leizman D, Mell LK, Mittal BB, Pinto HA, Rocco JW, Rodriguez CP, Savvides PS, Schwartz D, Shah JP, Sher D, St John M, Weber RS, Weinstein G, Worden F, Yang Bruce J, Yom SS, Zhen W, Burns JL, Dar PMID 35276673
• Harrington KJ, Burtness B, Greil R, Soulieres D, Tahara M, de Castro G Jr, Psyrri A, Brana I, Baste N, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Lin J, Gumuscu B, Swaby RF, Rischin D. Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. PMID 36219809
• Noronha V, Goswami C, Patil S, Joshi A, Patil VM, Murthy V, Arya S, Juvekar S, Goud S, Prabhash K. Response to docetaxel and cisplatin induction chemotherapy of locally advanced head and neck squamous cell carcinoma: a multicenter, non-comparative, open-label interventional pilot study. J Laryngol Otol. 2016 Sep;130(9):833-42. doi: 10.1017/S0022215116008513. Epub 2016 Jul 26. PMID 27456399
• Herman LC, Chen L, Garnett A, Feldman LE, Smith B, Weichselbaum RR, Spiotto MT. Comparison of carboplatin-paclitaxel to docetaxel-cisplatin-5-flurouracil induction chemotherapy followed by concurrent chemoradiation for locally advanced head and neck cancer. Oral Oncol. 2014 Jan;50(1):52-8. doi: 10.1016/j.oraloncology.2013.08.007. Epub 2013 Sep 19. PMID 24055193
• Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, Morrison W, Glisson B, Trotti A, Ridge JA, Thorstad W, Wagner H, Ensley JF, Cooper JS. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013 Mar 1;31(7):845-52. doi: 10.1200/JCO.2012.43.6097. Epub 2012 Nov 26. PMID 23182993
• Choi YJ, Chung J, Shin HJ, Cho GJ, Wang SG, Lee BJ, Cho BM, Kim DW, Kim HJ, Lee WS, Joo YD, Sohn CH. Induction chemotherapy of docetaxel and Cisplatin for the elderly patients with squamous cell carcinoma of the head and neck. Cancer Res Treat. 2007 Mar;39(1):1-5. doi: 10.4143/crt.2007.39.1.1. Epub 2007 Mar 31. PMID 19746234
• Lorch JH, Goloubeva O, Haddad RI, Cullen K, Sarlis N, Tishler R, Tan M, Fasciano J, Sammartino DE, Posner MR; TAX 324 Study Group. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol. 2011 Feb;12(2):153-9. doi: 10.1016/S147 PMID 21233014
• Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, Stewart JS, Jelic S, Betka J, Preiss JH, van den Weyngaert D, Awada A, Cupissol D, Kienzer HR, Rey A, Desaunois I, Bernier J, Lefebvre JL; EORTC 24971/TAX 323 Study Group. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007 Oct 25;357(17):1695-704. doi: 10.1056/NEJMoa071028. PMID 17960012

Identifiers

NCT: NCT06861712 · B2024-858-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗