A phase I trial of the monoclonal antibody FG-3019 to connective tissue growth factor (CTGF) in locally advanced or metastatic pancreatic cancer.

Abstract

269 Background: CTGF is highly expressed in pancreatic tumors and is thought to mediate local desmoplasia. FG-3019 is a fully human monoclonal antibody against CTGF. Studies using FG-3019 in murine xenograft models have shown reduced tumor growth and metastasis. Methods: This open-label, dose escalation study assessed the safety and pharmacokinetics of FG-3019 (3, 10, 15, and 25 mg/kg q14D). FG-3019 was initiated on D1 to assess single-agent toxicity. Standard gemcitabine and erlotinib were added on D15. Chemotherapy-naive patients with locally advanced or metastatic adenocarcinoma were eligible. Seventeen subjects (median age 66 yrs) were enrolled: n=4, 3, and 10 at 3, 10, and 15 mg/kg respectively. Enrollment is ongoing in the 25 mg/kg cohort. Seven subjects were female; four were stage 3, and 13 were stage 4. Results: No safety signals were detected with single-agent FG-3019. After beginning chemotherapy, four subjects experienced seven SAEs, which were deemed unrelated to FG-3019 including three deaths: sepsis, suicide, and disease progression. Nine subjects experienced grade 3 AEs, all of which were expected in patients with pancreatic cancer. There were no grade 4 hematologic abnormalities. AEs related to gemcitabine (hematologic, abnormal LFTs) and erlotinib (rash) occurred at a rate and severity consistent with the prescribing information (preliminary data). Steady-state Cmax (median 428, range 236-455 μg/mL), and T1/2 (median 6.6, range 6.3-6.7 days) at the 10 mg/kg dose level were comparable to PK data from subjects in non-oncological trials who received FG-3019 at the same dose level. One subject had a partial response by RECIST criteria for 9.7+ months. Another subject had a minor response for 7.7 months. Three of five subjects with PET scans at baseline and D15 experienced stable to reduced PET activity before starting chemotherapy. The median TTP across all cohorts was 3.7 months (95% CI 1.9-6.2), and the median OS was 9.4 months (95% CI 1.9-10.6). Conclusions: FG-3019 is well tolerated and dose escalation continues. Reduced PET activity after treatment with single-agent FG-3019 may indicate a biological effect of the agent. [Table: see text]

Deregulated expression of connective tissue growth factor (CTGF/CCN2)is linked to poor outcome in human cancer

“…CTGF deregulation acts to increase tumour angiogenesis in tumours over‐ and underexpressing CTGF compared to normal cell counterparts. CTGF increased tumour angiogenesis in vivo in breast cancer, glioblastoma multiforme and pancreatic cancer . In all these cancer types, CTGF is over expressed compared to normal cells.…”

“…In a pancreatic mouse flank‐tumour model, a CTGF monoclonal antibody (FG‐3019, Fibrogen, San Francisco, CA) reduced tumour growth . In humans, a Phase 1 clinical trial of FG‐3019 was used in locally advanced or metastatic pancreatic cancer patients and was well tolerated . Recently in pancreatic cancer, Neesse et al found in vivo that gemcitabine delivered alongside FG‐3019 increased tumour cell death without altering gemcitabine delivery, reported to be due to FG‐3019 disrupting the survival signal x‐linked inhibitor of apoptosis protein ( XIAP ).…”

“…CTGF increased tumour angiogenesis in vivo in breast cancer, glioblastoma multiforme and pancreatic cancer. 11,84,91 In all these cancer types, CTGF is over expressed compared to normal cells. In a bone metastasis model of breast cancer, treatment with an anti-CTGF antibody reduced angiogenesis, revealing a role for CTGF at a secondary site.…”

Targeting connective tissue growth factor (CTGF) in acute lymphoblastic leukemia preclinical models: anti-CTGF monoclonal antibody attenuates leukemia growth

“…FG-3019 has been evaluated in several phase 1 clinical studies in patients with diabetic kidney diseases [35], idiopathic lung fibrosis and pancreatic cancer and is currently in phase 2 testing in idiopathic lung fibrosis (NCT01262001) and chronic hepatitis B infection-related liver fibrosis (NCT01217632). The phase 1 study of FG-3019 in combination with Gemcitabine and Erlotinib in patients with advanced pancreatic cancer (NCT01181245) has completed patient enrollment, and results of interim analysis demonstrated impressive PET responses at the highest dose in some patients [36]. It is noteworthy, that at least in pancreatic cancer, CTGF is expressed not only in the cancer cells, but also in the tumor stroma and is most abundant in pancreatic stellate cells within the stroma [37].…”

CCN: core regulatory proteins in the microenvironment that affect the metastasis of hepatocellular carcinoma?

“…The experimental drug was administered combination with Erlotinib and Gemcitabine; no toxicity was found relating to FG-3019. Patients progressed after a median time of 3.7 months and had a median survival of 9.4 months [ 110 ]. FG-3019 has been tested previously in a phase I study in patients with microalbuminuric diabetic kidney disease.…”