This research study is being done to assess the safety and tolerability of toripalimab in combination with cisplatin and docetaxel (PDT) induction therapy for patients with CPS-positive locally advanced head and neck squamous cell carcinoma (HNSCC).

This is a single arm phase II study to assess treatment-related adverse events (TRAEs) and efficacy of PDT. The study employs a Simon two-stage design. After 12 evaluable participants start treatment with at least 2 participants experiencing no grade 3 or higher TRAEs during induction therapy, then enrollment will continue to the target number of participants of 26. Participants will receive treatment for three cycles or until disease progression, they experience unacceptable side effects, their condition changes rendering them unacceptable for further treatment, or they withdraw from the study. Participants will be followed for two years from registration. Coherus Biosciences, Inc. is supporting this research study by providing the study drug, toripalimab, and funding for research activities. The U.S. FDA has not approved toripalimab for CPS-positive locally advanced HNSCC but has approved it for other forms of head and neck cancer. Toripalimab is a lab-made antibody that works by allowed the immune system to attack cancer cells more effectively. Toripalimab is currently sold as LOQTORZI and is used with cisplatin and gemcitabine to treat nasopharyngeal carcinoma. The U.S. FDA has approved cisplatin and docetaxel as a treatment option for multiple types of cancers, including head and neck small cell carcinoma. Cisplatin is a chemotherapy agent that works by binding to cancer cells and initiating cell death. Docetaxel is a chemotherapy agent made from a compound found in the European yew tree. Docetaxel works by stabilizing tiny structures within cancer cells, prevent cell growth and, ultimately leading to cell death. The combination of toripalimab with cisplatin and docetaxel for induction therapy is investigational.

Inclusion Criteria:

• Participants must have a new diagnosis of histologically or cytologically confirmed squamous cell carcinoma (SCC) of the oral cavity, oropharynx, hypopharynx, larynx, nasopharynx, sinonasal cavities or unknown primary HNSCC.
• Participants with HPV-independent SCC or HNSCC or other head and neck subsites must have stage III or non-metastatic stage IV at the time of diagnosis. Participants with HPV-associated oropharynx SCC must have stage II or stage III disease.
• Participants must be determined by the investigator to be candidates for induction systemic therapy due to reasons such as the extent of primary tumor at the time of diagnosis, rate of progression, symptom burden or potential benefit of cytoreduction prior to definitive local therapy.
• CPS ≥ 1%
• Age ≥18 years. Because no dosing or adverse event data are currently available on the use of toripalimab in combination with cisplatin and docetaxel in participants <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• ECOG performance status ≤ 1
• Life expectancy of greater than 12 weeks.
• Participants must meet the following organ and marrow function as defined below:

Hemoglobin ≥8.0 g/dL absolute neutrophil count ≥1500/mcL platelets ≥100,000/mcL total bilirubin ≤ 2 institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤ 2 × institutional ULN creatinine ≤ 2 x institutional ULN OR glomerular filtration rate (GFR) ≥ 45 mL/min/1.73 m2

• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• Because immunotherapy agents as well as cisplatin and docetaxel are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of toripalimab administration.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Diagnosis of EBV-associated nasopharynx squamous cell carcinoma
• Strong clinical suspicion or histologic confirmation of cutaneous squamous cell carcinoma
• Histology other than squamous cell carcinoma.
• Proven distant metastases (below the clavicle) by clinical or radiographic measures.
• Prior radiotherapy to the head and/or neck with the exception of radiation for cutaneous malignancies involving radiation fields that do not overlap with areas of current disease involvement.
• Pre-existing peripheral neuropathy CTCAE grade 2 or higher
• Participants who are receiving any other investigational agents for this condition.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to toripalimab, cisplatin or docetaxel.
• An autoimmune condition requiring treatment with systemic corticosteroids within the past 30 days. Long-term steroid replacement for patients with adrenal insufficiency is allowed.
• Any second malignancy that required antineoplastic therapy in the previous 6 months.
• Participants receiving any medications or substances that are moderate or strong inhibitors or inducers of CYP3A4 are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
• Pregnant women are excluded from this study because toripalimab, cisplatin and docetaxel have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with toripalimab, cisplatin and docetaxel, breastfeeding should be discontinued if the mother is treated with toripalimab. These potential risks may also apply to other agents used in this study.

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: Thomas Roberts, MD, MBA at 617-726-5130. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Data can be shared no earlier than 1 year following the date of publication.

Contact the Partners Innovations team at http://www.partners.org/innovation