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Clinical translation of OTL38 in ovarian cancer 165
RESULTS
Clinical trial in healthy volunteers
This study included a total of 30 subjects (18 females and 12 males), 18-64 years of age with a BMI of 18-30 kg/m2 (see Fig. S3 for the CONSORT ow diagram, online available).
Tolerability
OTL38 at 0.025mg/kg diluted in 20 ml 0.9% NaCl infused for 10 or 60 minutes caused moderate hypersensitivity in two out of the four subjects receiving this dose. These reactions were not classic allergic reactions, as they were not accompanied by an increase in tryptase or IgE, nor did they involve the complement system (see Data File S1, online available). Subsequent studies using dynamic light scattering and scanning electron microscopy revealed that these reactions may have been due to aggregation of the OTL38 compound in the 0.9% NaCl solution. This aggregation was reduced considerably when OTL38 was diluted in 5% dextrose and when the infusion volume was increased. Because OTL38 did not aggregate measurably when diluted to 7.5 μM in 5% dextrose, the study was restarted at the lowest dose with OTL38 dissolved in 220 ml 5% dextrose; this volume was infused for a period of 60 minutes.
Infusion of 0.025, 0.05, and 0.1 mg/kg OTL38 diluted in 5% dextrose was associated with mild adverse events that disappeared gradually during and/or after the infusion. These adverse events were dose-dependent and suggestive of hypersensitivity (e.g., abdominal discomfort, nausea, and pruritus), but did not require intervention. All adverse events are listed in Table S1 (online available). At the 0.2 mg/kg dose, some subjects developed adverse events of moderate severity, which required the temporary interruption of the infusion or the administration of an antihistamine (e.g., 1-2 mg clemastine intravenously). Overall, more than 80% of these adverse events were mild in severity, and all other adverse events were moderate in severity. Despite the development of adverse events, the infusion of OTL38 at 0.025-0.2 mg/kg did not cause clinically meaningful changes relative to baseline with respect to laboratory values, ECG, or vital signs.