Herboxidiene br Intraoperative molecular imaging requires
Intraoperative molecular imaging requires a fluorescent contrast agent that can be injected systemically and selectively accumulates in tumor tissue. In order to target ovarian adenocarcinomas with a fluorophore, we selected the folate receptor alpha (FRa). FRa is overexpressed 10- to 100-fold in non-mucinous epithelial ovarian carci-nomas compared to normal cells [5–8]. Furthermore, the FRa expression is not altered after chemotherapy so it is a strong, reliable target for mo-lecular imaging , even in the interval and secondary cytoreductive setting. OTL38 is comprised of the vitamin folic Herboxidiene conjugated to an in-docyanine green-like near infrared dye termed S0456. OTL38 was de-veloped in order to detect folate receptor positive lesions in ovarian cancer patients using an investigational camera imaging system.
We hypothesized that the intravenous injection of OTL38 was safe and had adequate sensitivity and positive predictive value (PPV) to war-rant further investigation as an adjunct to surgery for epithelial ovarian cancer.
2. Materials and methods
This was a single-arm, open label, prospective phase II study that was conducted at 4 tertiary ovarian cancer centers with gynecologic on-cologists experienced in radical surgical cytoreductive procedures. The two primary objectives were to determine the efficacy of OTL38 accord-ing to sensitivity and positive predictive value (PPV) for FRa positive ovarian cancer by immunohistochemistry (IHC) and to report the safety and tolerability of single-dose OTL38. Sensitivity and PPV of OTL38 were determined by comparing OTL38 results with the “gold standard” of FRa status (positive or negative). Safety was investigator-assessed from the time of study drug administration and at follow-up visits on days 7 (±
4) and 28 (± 4) after surgery. Incident adverse events (AEs) were re-corded based on Medical Dictionary for Regulatory Activities (MedDRA)
definitions. AEs were classified as mild, moderate, or severe in nature and the attribution to study drug was classified as definitely related, probably related, possibly related, or not related by the investigator. The secondary objective of the study was to assess the safety of three NIR imaging systems: Quest Artemis, Novadaq PINPOINT LI, and
Visionsense VS3 fluorescence imaging systems. An exploratory objec-tive was to determine the number of additional lesions identified by OTL38 that were undetected by usual visual and tactile techniques.
2.2. Patient population
Women over age 18 with known or suspected ovarian cancer planned for cytoreductive surgery by laparotomy were eligible to par-ticipate. Surgical cytoreduction was permitted in the settings of primary (no prior surgery or chemotherapy), interval (prior neoadjuvant che-motherapy), or secondary (regional, oligometastatic recurrence)
surgery. All surgery was performed as standard of care. Exclusion criteria were pregnancy, impaired renal function (eGFR b50 mL/min/ 1.73 m2), impaired liver function (ALT, AST, or total bilirubin N 3× the upper limit of normal), abnormal ECG at baseline, known brain metas-tases, receipt of another investigational agent up to 30 days prior to sur-gery, and previous anaphylactic reaction to any drug. The study was IRB approved at each of the participating site and was conducted in accor-dance with ICH-GCP guidelines and US laws and regulations. All subjects provided informed consent prior to study enrollment. The trial was reg-istered with ClinicalTrials.gov with identifier: NCT02317705.
An open-label single dose of OTL38 was administered intravenously. The chemical structure, preparation, and dose selection of OTL38 were elucidated in the phase I trial informing this study . In the phase I trial, the initial dose of 0.025 mg/kg yielded acceptable side effects and optimal tumor to background ratio of the OTL38 signal, but a higher dose could shorten the image acquisition time. Therefore, the dose was escalated to 0.05 mg/kg. Nausea, abdominal pain and pruritus in-creased at this higher dose, but not to a dose-limiting level. Therefore, the initial plan for this study was to perform a safety lead-in of 5 subjects at the 0.025 mg/kg dose and subsequently escalate the dose to 0.05 mg/kg for the remainder of the study if the safety profile was ac-ceptable. However, after an interim safety review of the lead-in cohort, the 0.025 mg/kg dose was chosen as the phase II dose and was the only dose used in this study. The injection was administered in the pre-operative area approximately 2 to 3 h prior to surgery. Vitals signs (blood pressure, pulse, peripheral oxygen saturation, respiratory rate, temperature, skin examination, and ECG) and adverse events were assessed every 15 min for 1 h and then every 30 min until in the OR where they were monitored continuously.