Evaluation of Sentinel Lymph Node Detection in Early Oral Cancer Using Gallium-68-Tilmanocept PET/CT and Technetium-99m Lymphoscintigraphy

The primary objective of this study is to evaluate the **diagnostic accuracy** of preoperative 68Ga-Tilmanocept PET/CT in combination with conventional lymphoscintigraphy for sentinel lymph node (SLN) detection in patients with early oral cancer. This assessment focuses on sensitivity and negative predictive value, which are critical for ensuring accurate staging and treatment planning. Additionally, the study aims to compare the diagnostic accuracy of preoperative 68Ga-Tilmanocept PET/CT alone with conventional preoperative lymphoscintigraphy alone, providing insights into the potential benefits of each imaging modality.

Secondary objectives include: - Comparing the number of SLNs detected by 68Ga-Tilmanocept PET-CT with those detected by 99mTc-Tilmanocept lymphoscintigraphy on a per-subject basis. - Comparing the histopathologic assessment of excised lymph nodes detected by conventional preoperative 99mTc-Tilmanocept lymphoscintigraphy and intraoperative gammaprobe localization with SLNs identified by preoperative 68Ga-Tilmanocept PET-CT. - Observing contralateral drainage patterns in lateralized tumors and comparing these patterns between 68Ga-Tilmanocept PET-CT and 99mTc-Tilmanocept lymphoscintigraphy, particularly in cases of histopathologically positive sentinel nodes. - Assessing pairwise inter-observer agreements between 68Ga-Tilmanocept PET-CT and 99mTc-Tilmanocept lymphoscintigraphy regarding preoperative SLN detection.

The clinical trial focuses on individuals diagnosed with **oral cancer**, specifically primary oral squamous cell carcinoma located in various anatomical sites such as the mucosal lip, buccal mucosa, and oral tongue. The study population includes both male and female participants aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of Grade 0 to 2. Participants are required to have a clinical TNM-stage of T1-T2 and T3, with specific criteria for T3 based on tumor dimensions and depth of invasion. The trial does not include a vulnerable population. The selection criteria ensure that participants have no evidence of head and neck malignancy recurrence in the past five years and are candidates for transoral excision. The sponsor has not provided the total number of participants involved in the study. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **diagnostic accuracy** of preoperative 68Ga-Tilmanocept PET/CT combined with conventional lymphoscintigraphy for sentinel lymph node (SLN) detection in patients with early-stage oral squamous cell carcinoma. This study is a randomized, double-blind, controlled trial, with an estimated duration from April 2025 to December 2028. The trial aims to compare the sensitivity and negative predictive value of the combined imaging techniques against each method used independently. Participants will be randomly assigned to receive either the 68Ga-Tilmanocept PET/CT or the conventional 99mTc-Tilmanocept lymphoscintigraphy, with the primary endpoint being the diagnostic accuracy of these imaging modalities.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as a confirmed diagnosis of primary oral squamous cell carcinoma and a clinical TNM-stage of T1-T2 or T3 under certain conditions. Participants must also have a negative result from ultrasound-guided fine needle aspiration cytology within 30 days of the SLN procedure. Following the screening, participants will undergo the assigned imaging procedure, with follow-up visits scheduled to monitor outcomes and any adverse events. The end-of-study visit will conclude the trial, assessing the final outcomes and collecting data for analysis.

The expected length of participant involvement is approximately one day, corresponding to the imaging and SLN biopsy procedures. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial will ensure rigorous adherence to ethical standards and regulatory requirements, with all participants providing written informed consent prior to enrollment. The study's findings are anticipated to contribute valuable insights into the optimal imaging strategy for SLN detection in oral cancer, potentially influencing future clinical practice.

The clinical trial involves the use of **TILMANOCEPT**, a polymer-based active substance, formulated as a kit for radiopharmaceutical preparation. This experimental medication is utilized in the study for sentinel lymph node biopsy in patients with oral squamous cell carcinoma. **TILMANOCEPT** is administered peritumorally, with a maximum daily and total dose of 0.05 mg. The treatment period is limited to a single day. In this trial, **TILMANOCEPT** is used in two different roles: as a test product when bound to **GALLIUM (68GA) CHLORIDE** and as a comparator when bound to **TECHNETIUM (99MTC)**.

**GALLIUM (68GA) CHLORIDE** is employed as a radionuclide generator in the trial, serving as a radiotracer when bound to **TILMANOCEPT** for sentinel lymph node detection. The administration route is peritumoral, with a maximum daily and total dose of 10 MBq. The treatment period is restricted to one day. This combination is evaluated for its diagnostic accuracy in preoperative PET/CT imaging.

**TECHNETIUM (99MTC)**, another radionuclide generator, is used as a comparator in the study. It is also bound to **TILMANOCEPT** and administered peritumorally. The maximum daily and total dose for **TECHNETIUM (99MTC)** is 74 MBq, with the treatment period limited to one day. This combination is compared against the **GALLIUM (68GA) CHLORIDE**-**TILMANOCEPT** combination to assess diagnostic accuracy in sentinel lymph node detection.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the specified administration protocols. The study aims to evaluate the diagnostic performance of these radiotracer combinations in detecting sentinel lymph nodes in early oral cancer, comparing the efficacy of preoperative PET/CT imaging with conventional lymphoscintigraphy.

The efficacy of the clinical trial will be assessed by evaluating the diagnostic accuracy of **68Ga-Tilmanocept PET/CT** in detecting sentinel lymph nodes (SLNs) in patients with early-stage oral squamous cell carcinoma. The primary endpoints include the sensitivity and negative predictive value of the **68Ga-Tilmanocept PET/CT** when used in combination with conventional lymphoscintigraphy for SLN detection. Additionally, the study aims to compare the diagnostic accuracy of preoperative **68Ga-Tilmanocept PET/CT** alone with conventional preoperative lymphoscintigraphy alone.

Secondary endpoints involve comparing the number of SLNs detected by **68Ga-Tilmanocept PET-CT** with those identified through **99mTc-Tilmanocept** lymphoscintigraphy on a per-subject basis. The trial will also assess the histopathologic presence or absence of metastasis in excised lymph nodes detected by conventional preoperative **99mTc-Tilmanocept** lymphoscintigraphy and intraoperative gammaprobe localization, compared to SLNs identified by **68Ga-Tilmanocept PET-CT**. Observations will include contralateral drainage patterns in lateralized tumors and inter-observer agreements between the two imaging modalities regarding preoperative SLN detection.