FG-3019, A Human Monoclonal Antibody to Connective Tissue Growth Factor, Combined with Chemotherapy in Patients with Locally Advanced or Metastatic Pancreatic Ductal Adenocarcinoma

Purpose: Connective tissue growth factor (CTGF) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and facilitates local desmoplasia, tumor progression and metastasis in animal models. This study evaluated safety and initial efficacy of the anti-CTGF antibody FG-3019 in combination with gemcitabine and erlotinib in patients with previously untreated Stage III or Stage IV PDAC. Methods: Eight escalating FG-3019 doses/regimens ranging from 3 to 45 mg/kg Q2W and 17.5 and 22.5 mg/kg QW were evaluated. Toxicity, tumor response by CA19.9 and CT scan RECIST criteria, progression-free and overall survival were assessed. FG-3019 day 15 trough plasma levels (D15Cmin), as a measure of exposure, and baseline CTGF levels were correlated with clinical outcomes. Results: Seventy-five patients were enrolled over 39.6 months. Median and longest treatment duration were 3.3 and 20.9 months, respectively. FG-3019 was well tolerated with no dose-related trends observed in type or incidence of SAEs. No FG-3019dose-liming toxicity was observed. Median PFS and OS were 3.7 and 7.4 months, respectively. High FG-3019 exposure (D15 Cmin ≥ 150 μg/mL), compared to low exposure, was associated with improved median OS (9.0 vs. 4.4 months, respectively, p=0.024), 1-year OS rate (34.2% vs. 10.8%, respectively, p=0.026), and median PFS (6.0 vs. 2.4 months, respectively, p=0.032). Plasma CTGF showed potential as a prognostic biomarker, as low baseline CTGF levels (<10 ng/mL) were associated with improved OS (10.1 vs. 4.4 months, p=0.028); and PFS (5.5 vs. 2.3 months, p=0.019). Conclusions: FG-3019 can be safely combined with gemcitabine and erlotinib without incremental toxicity in advanced pancreatic cancer patients. Low baseline CTGF and high FG-3019 exposure were associated with improved survival. Targeting of PDAC by FG-3019 in combination with cytotoxic chemotherapy represents a novel approach to this difficult disease and further trials are warranted.