Supplementary Material and Methods: questionnaire for practical evaluation of OTL38 and the imaging system; description of immunohistochemistry and fluorescence microscopy. Fig. S1: Case report form (CRF) used to mark the location of a lesion found during surgery Fig. S2: Structure of OTL38 Fig. S3: CONSORT Flow diagram healthy volunteer study Fig. S4: Pharmacokinetics in blood plasma of healthy volunteers and patients. Fig. S5. CONSORT Flow diagram ovarian cancer patient study Fig. S6. Tumor-to-background ratio in ovarian cancer patients per dose group Fig. S7. FRα and β staining of ovarian carcinoma tissue and a metastatic lymph node Table S1. Listing of adverse events in the healthy volunteers study Table S2. Summary of pharmacokinetic parameters Table S3. Tumor-to-background ratio per dose group in ovarian cancer patients Table S4. Listing of adverse events in the patient study Table S5. Number and characteristics of lesions and lymph nodes identified with fluorescence
Funding
Centre for Human Drug Research (a not-for-profit foundation) and the Leiden University Medical Center received financial compensation, the study drug, and equipment for performing this study from On Target Laboratories LLC
ARTICLE ABSTRACT
Purpose: Completeness of cytoreductive surgery is a key prognostic factor for survival in patients with ovarian cancer. The ability to differentiate clearly between malignant and healthy tissue is essential for achieving complete cytoreduction. Using current approaches, this differentiation is often difficult and can lead to incomplete tumor removal. Near-infrared fluorescence imaging has the potential to improve the detection of malignant tissue during surgery, significantly improving outcome. Here, we report the use of OTL38, a near-infrared (796 nm) fluorescent agent, that binds folate receptor alpha, which is expressed in >90% of epithelial ovarian cancers.Experimental Design: We first performed a randomized, placebo-controlled study in 30 healthy volunteers. Four single increasing doses of OTL38 were delivered intravenously. At fixed times following drug delivery, tolerability and blood/skin pharmacokinetics were assessed. Next, using the results of the first study, three doses were selected and administered to 12 patients who had epithelial ovarian cancer and were scheduled for cytoreductive surgery. We measured tolerability and blood pharmacokinetics, as well as the ability to detect the tumor using intraoperative fluorescence imaging.Results: Intravenous infusion of OTL38 in 30 healthy volunteers yielded an optimal dosage range and time window for intraoperative imaging. In 12 patients with ovarian cancer, OTL38 accumulated in folate receptor alpha–positive tumors and metastases, enabling the surgeon to resect an additional 29% of malignant lesions that were not identified previously using inspection and/or palpation.Conclusions: This study demonstrates that performing real-time intraoperative near-infrared fluorescence imaging using a tumor-specific agent is feasible and potentially clinically beneficial. Clin Cancer Res; 22(12); 2929–38. ©2016 AACR.
