Single Dose Investigator Initiated Pilot Study to Investigate CYTALUX (Pafolacianine) for Intraoperative Detection of Malignant Tissue in Subjects Undergoing Surgical Resection for Cancer.

Background and Rationale:

Gastroesophageal and pancreatic cancers are aggressive malignancies with limited curative options. Complete surgical resection (R0) remains the cornerstone of curative intent. However, current intraoperative tools-visual inspection, palpation, and endoscopy-are limited in accurately delineating tumor margins and detecting occult lesions. High recurrence rates after surgery suggest a need for improved intraoperative detection techniques.

Folate receptor-alpha (FRα) is overexpressed in a variety of epithelial tumors, including gastric and pancreatic cancers. Recent studies have demonstrated that over one-third of gastric cancers and a subset of peritoneal metastases from gastrointestinal tumors overexpress FRα, making them amenable to targeted imaging. Pafolacianine is a folate analog conjugated to a near-infrared fluorescent dye designed to bind to FRα, enabling real-time intraoperative visualization of cancerous tissue using NIR imaging systems.

Investigational Product:

CYTALUX™ (pafolacianine) is an intravenously administered imaging agent developed by On Target Laboratories, Inc. It consists of OTL0038, a folate analog conjugated to an indole-cyanine green-like dye. The agent selectively binds FRα and emits fluorescence in the NIR spectrum (excitation: 760-785 nm; emission: 790-815 nm), providing high-contrast imaging during surgery.

Mechanism of Action:

Following IV administration, pafolacianine distributes systemically and is cleared rapidly from normal tissues. In FRα-expressing tumor cells, the agent is retained due to receptor-mediated endocytosis. Upon NIR illumination, malignant tissues fluoresce, allowing surgeons to visualize tumors, metastatic nodules, and lymph nodes intraoperatively. This mechanism supports improved tumor localization, identification of positive margins, and enhanced detection of otherwise occult lesions.

Preclinical and Clinical Data:

Preclinical studies in KB human carcinoma cell lines and murine xenograft models have shown high binding affinity to FRα (KD = 10.4 nM) and specific tumor fluorescence. Safety evaluations in rats and dogs demonstrated no phototoxicity or systemic toxicity. Pafolacianine has been evaluated in completed Phase 1, 2, and 3 trials in ovarian and lung cancers (e.g., NCT03180307), where it identified additional malignant lesions or positive margins in 25-40% of patients, reinforcing its clinical utility.

Clinical Need and Future Application:

There is a substantial unmet need for real-time intraoperative tools that enhance surgical decision-making in gastrointestinal oncology. Pafolacianine offers potential benefits in:

Identifying primary and metastatic lesions in gastroesophageal and pancreatic cancer

Assessing peritoneal carcinomatosis in advanced gastric and appendiceal malignancies

Improving accuracy in cytoreductive surgeries and guiding HIPEC decisions

Given the expression profile of FRα in gastrointestinal and other epithelial malignancies, CYTALUX is anticipated to be beneficial for a broader spectrum of tumors beyond ovarian and lung cancers.

Imaging Protocol:

Participants will receive a single IV dose of pafolacianine prior to surgery. NIR imaging will be conducted intraoperatively using a compatible device. Fluorescent lesions will be documented and evaluated for correlation with histopathology. Standard-of-care surgical procedures (e.g., resection, lymphadenectomy) will proceed per usual protocol, supplemented by fluorescent signal guidance.

Endpoints:

Primary: Proportion of additional malignant lesions detected with NIR imaging not identified through standard visualization techniques.

Secondary: Rate of complete (R0) resections, correlation of fluorescence with histologically confirmed malignancy, adverse events related to pafolacianine administration.

Safety Considerations:

CYTALUX has demonstrated a favorable safety profile with no significant toxicity observed in preclinical or clinical settings. The agent is not associated with phototoxicity, and systemic clearance is rapid in non-target tissues.

Inclusion criteria

• Male and Female patients 18 years of age and older
• Have a primary diagnosis, or a high clinical suspicion, of gastrointestinal, fore gut, pancreatic, hepatobiliary, esophageal malignancies and gyn malignancies planned for HIPEC/debulking, warranting surgery.
• Are scheduled to undergo surgical intervention for tumor resection or diagnostic laparoscopy for assessment of disease burden.
• Willingness to stop the use of folate, folic acid, or folate-containing supplements within 48 hours before administration of Cytalux
• Willingness of research participant or legal guardian/representative to give written informed consent.

Exclusion criteria

• Any medical condition that in the opinion of the investigators could potentially jeopardize the safety of the subject
• History of anaphylactic reactions to products containing indocyanine green for near infrared imaging. Subjects with a medical history of 'idiopathic anaphylaxis' will require evaluation.
• History of allergy to any of the components of CYTALUX™ (pafolacianine) injection
• Presence of any psychological, familial, sociological condition or geographical challenges potentially hampering compliance with the study protocol or follow-up schedule