Purpose: Folate receptor alpha (FRα) expression is highly restricted in normal adult tissues, but upregulated in a wide range of human cancer types including epithelial ovarian cancer (EOC). Farletuzumab, a humanized monoclonal antibody against FRα, has demonstrated anti-tumor activity and favorable toxicity in preclinical evaluation. This phase I dose-escalation study was conducted to determine the safety of weekly intravenous farletuzumab and establish the maximum tolerated dose (MTD).
Experimental Design: Patients with platinum-refractory or platinum-resistant EOC received farletuzumab (12.5-400 mg/m2) on days 1, 8, 15, and 22 of a 5-week cycle. Intra-patient dose escalation was not permitted. Dose-limiting toxicity (DLT) was defined by treatment-related Adverse Event (AE) ≥Grade 3 and the MTD was the highest dose at which ≤1 of 6 patients experienced a DLT. Disease progression was recorded using RECIST criteria and serum CA-125.
Results: Twenty-five heavily-pretreated patients were included in the safety, efficacy, and PK analyses. No DLTs or MTDs were encountered and dose escalation was continued to farletuzumab 400 mg/m2. Cmax and AUC0-24 increased in an approximately dose-proportional manner and a nuclear imaging substudy confirmed tumor targeting. There were no objective responses. SD by RECIST was observed in nine (36%) patients and CA-125 reduction in four. Three patients received continued therapy and completed a total of up to three cycles. Conclusions: In this phase I study, farletuzumab administered as an IV infusion at doses of 12.5 to 400 mg/m2 was generally safe and well-tolerated in the management of heavily pretreated patients with EOC.
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