IMCISION: Towards organ preservation and cure via ultra-short immunotherapy in advanced oral cancer. The IMCISION II trial, an investigator-initiated multicentre randomised phase 3 trial (M24IMS)

The primary objective is to determine the rate of patients achieving a complete clinical response (CCR) with organ preservation of the face and oral cavity at two years of follow-up without compromising clinical outcome for all patients. This endpoint is clinically relevant as it assesses the feasibility of preserving anatomical structures and function in patients with advanced oral cancer while maintaining oncological efficacy.

The secondary objectives include:

• To determine the CCR rate (as defined in the primary endpoint) in Arm A at intermediate time-points.

• To evaluate health-related quality of life (QoL).

• To compare other time to event endpoints between Arm A and Arm B.

• Assessment of adverse events (AEs) and immune-related adverse events (ir-AEs).

• To investigate cost-effectiveness.

• To measure oncological treatment duration and treatment stops.

• Health care consumption/burden.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consists of adult patients, aged **18 years or older**, of both **male and female** gender, diagnosed with primary advanced **oral cavity squamous cell carcinoma** classified as **Stage III-IVA** according to TNM version 8.0. Eligible participants must have **head and neck squamous cell carcinoma** affecting specific anatomical sites including parts of the tongue, gum, floor of mouth, hard palate, and other parts of the mouth. The trial population was selected based on patients requiring standard of care treatment who have not received prior systemic oncological therapy or radiotherapy to the head and neck region. Participants must demonstrate a **World Health Organization performance status** of 0-2 and meet specific laboratory criteria including adequate white blood cell count, neutrophil count, platelet count, hemoglobin levels, and liver and kidney function parameters. Patients with immunosuppression are excluded from participation. Women of child-bearing potential must use appropriate contraceptive methods and demonstrate negative pregnancy testing prior to treatment initiation.

This is a multicentre **randomized** **phase 3** clinical trial investigating immunotherapy in patients with advanced **oral cavity squamous cell carcinoma** classified as stage III-IVA according to TNM version 8.0. The study evaluates the efficacy of ultra-short immunotherapy treatment aimed at organ preservation of the face and oral cavity compared to standard of care treatment. The trial employs a two-arm design where participants will be randomly assigned to receive either the experimental immunotherapy regimen (Arm A) or standard of care treatment (Arm B). The investigational medicinal products include **ipilimumab** administered as YERVOY 5 mg/ml concentrate for **solution for infusion** via **intravenous administration** at a maximum daily dose of 1 mg/kg and maximum total dose of 1 mg/kg over a treatment period of 1 day, and **nivolumab** administered as OPDIVO 10 mg/mL concentrate for solution for infusion via intravenous administration at a maximum daily dose of 3 mg/kg and maximum total dose of 6 mg/kg over a treatment period of 2 weeks.

The primary objectives of the trial are to determine the rate of patients achieving complete clinical response with organ preservation at two years of follow-up in the experimental arm, and to demonstrate non-inferiority of the experimental arm compared to the standard of care arm in terms of **recurrence free survival** after a minimum follow-up of 24 months. Secondary endpoints include assessment of complete clinical response rates at 12 and 18 months, comparison of **quality of life** measures using EORTC QLQ H&N43, EORTC QLQ-C30, EQ-5D-5L, and HADS questionnaires between treatment arms and between responders and non-responders, evaluation of other survival endpoints including locoregional control, distant metastasis free survival, disease specific survival, event free survival, and **overall survival** at 12, 18, and 24 months, comparison of **adverse events** and immune-related adverse events using CTCAE v5.0 and Clavien-Dindo classification up to 100 days after last treatment, cost-effectiveness analysis, treatment duration, and extent of surgical and adjuvant interventions.

Eligible participants must be 18 years of age or older with primary advanced oral cavity squamous cell carcinoma affecting specific anatomical sites including tongue, gum, floor of mouth, hard palate, and other parts of the mouth. Patients must have an indication for standard of care treatment, **WHO performance status** of 0-2, and adequate baseline laboratory values including white blood cell count ≥2.0x10⁹/L, **neutrophils** ≥1.5x10⁹/L, **platelets** ≥100x10⁹/L, **hemoglobin** ≥5.5 mmol/L, **creatinine** ≤1.5 times upper limit of normal, AST and ALT ≤1.5 times upper limit of normal, and **bilirubin** ≤1.5 times upper limit of normal except for patients with Gilbert Syndrome. Participants must not have received prior systemic oncological therapy, prior radiotherapy to the head and neck region, or be immunosuppressed. Women of child-bearing potential must use appropriate contraception methods for 23 weeks after the last dose of investigational medicinal product and must have a negative pregnancy test prior to treatment initiation.

The estimated recruitment start date is January 1, 2026, with an estimated study completion date of September 30, 2031, providing an overall trial duration of approximately 5 years and 9 months. Participants will undergo an initial screening visit to assess eligibility criteria and baseline characteristics. Following randomization, participants will receive their assigned treatment according to the study protocol with regular follow-up visits scheduled at predetermined intervals to monitor treatment response, assess adverse events, and evaluate quality of life measures. Follow-up assessments will continue for a minimum of 24 months after randomization for each participant to evaluate the primary and secondary endpoints. Participants may be withdrawn from the study early in cases of disease progression to unresectable disease before surgery or before adjuvant chemoradiotherapy, development of unacceptable toxicity, participant withdrawal of consent, or at the discretion of the investigator if continuation in the study is not in the best interest of the participant. The end-of-study visit will occur after completion of the required follow-up period or upon early termination from the study.

The experimental treatment regimen consists of two investigational medicinal products administered in combination. **YERVOY** (ipilimumab) is supplied as a 5 mg/ml concentrate for solution for infusion, with the pharmaceutical form being solution for infusion. The active substance is **ipilimumab**, a protein therapeutic. YERVOY is administered via **intravenous administration** at a dosage of 1 mg/kg body weight. The maximum daily dose is 1 mg/kg, with a maximum total dose of 1 mg/kg administered over a treatment period of 1 day. The medicinal product holds marketing authorization EU/1/11/698/001 and is manufactured by Bristol-Myers Squibb Pharma EEIG.

**OPDIVO** (nivolumab) is supplied as a 10 mg/ml concentrate for solution for infusion, with the pharmaceutical form being solution for infusion. The active substance is **nivolumab**, also a protein therapeutic with known synonyms including BMS936558 and ABP 206. OPDIVO is administered via intravenous administration at a dosage of 3 mg/kg body weight. The maximum daily dose is 3 mg/kg, with a maximum total dose of 6 mg/kg administered over a treatment period of 2 weeks. The medicinal product holds marketing authorization EU/1/15/1014/001 and is manufactured by Bristol-Myers Squibb Pharma EEIG.

Both investigational medicinal products are classified as test products in this clinical trial. The treatment regimen involves the combination of these two immune checkpoint inhibitors administered according to the specified dosing schedules. Neither product is formulated as a **paediatric formulation**. The dosing is weight-based, expressed in milligrams per kilogram of body weight, requiring accurate patient weight measurement for proper dose calculation and administration.

Efficacy will be assessed through two primary endpoints. The first primary endpoint is the percentage of patients in the experimental arm achieving complete clinical response with organ preservation of the face and oral cavity at 24 months of follow-up, with success defined as a lower bound of the 95% confidence interval greater than 10%. The second primary endpoint evaluates non-inferiority of the experimental arm compared to the control arm in Recurrence Free Survival after a minimum follow-up of 24 months since randomization for each patient. An event is defined as disease progression to unresectable disease before surgery or before adjuvant chemoradiotherapy, or recurrent disease after treatment, or death due to any cause.

Secondary efficacy endpoints include the complete clinical response rate in the experimental arm at 12 and 18 months. Additional survival endpoints will be compared between arms, including locoregional control, distant metastasis free survival, disease specific survival, recurrence free survival, event free survival, and overall survival at 12, 18, and 24 months of follow-up. Quality of life differences between arms will be assessed on all domains of the EORTC QLQ H&N43, EORTC QLQ-C30, EQ-5D-5L, and HADS questionnaires, with comparisons performed between responders and non-responders in the experimental arm, as well as between responders in the experimental arm versus the control arm, and between non-responders in the experimental arm versus the control arm. Adverse events and immune-related adverse events will be compared in both arms using CTCAE version 5.0 and Clavien-Dindo classification up to 100 days after last treatment. Cost-effectiveness of the experimental arm will be compared to the control arm in terms of incremental costs and quality adjusted life years. Treatment duration and treatment stops will be compared between arms. The extent of surgery, radiotherapy parameters, chemotherapy regimens, days of admission, visits, and other interventions will be compared between arms, between responders and non-responders in the experimental arm, and between responders in the experimental arm versus the control arm.