FibroGen, Inc. (FibroGen) today announced results from a Phase 2 open-label study of FG-3019, an investigational anti-fibrotic antibody, in combination with gemcitabine and erlotinib for the treatment of patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). In the study, FG-3019 demonstrated a dose-dependent improvement in one-year and overall survival rates, and appeared to be safe and well tolerated. The full data will be presented today at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting in a poster session from 8:00 AM to 11:45 AM CDT, Location S Hall A2, Abstract Number 4138.
The Phase 2 study is an open-label, single-arm, dose-escalation study to evaluate safety, tolerability, pharmacokinetics and ability of FG-3019 to improve outcomes in patients with pancreatic cancer treated with chemotherapy. Seventy-five patients were enrolled in the trial, 66 (88%) with stage 4 metastatic disease. The study evaluated FG-3019 doses of 3 mg/kg, 10 mg/kg, 15 mg/kg, 25 mg/kg, 35 mg/kg and 45 mg/kg administered every two weeks, and FG-3019 doses of 17.5 mg/kg and 22.5 mg/kg administered weekly after a double loading dose. On Day 15, treatment began with gemcitabine 1000 mg/m2 twice weekly for three of every four weeks and erlotinib 100 mg daily. Treatment continued until progression of the cancer or the patient withdrew for other reasons. Patients were then followed until death. Tumor status was evaluated by CT imaging every eight weeks to assess changes in tumor mass.
The study demonstrated a dose-related increase in survival. At the lowest doses, no patients survived for one year, while at the highest doses approximately 30% of patients survived one year. The results showed a significant relationship between patient survival and trough plasma levels of FG-3019 (Cmin) measured immediately before the second dose of drug at Day 15. Cmin greater than or equal to 150 µg/mL was associated with significantly improved progression free survival>
Most adverse events in the study were mild to moderate, and were consistent with those observed for erlotinib plus gemcitabine treatment without FG-3019. No evolving dose-dependent pattern was identified, and higher doses of FG-3019 were not associated with higher numbers or greater severity of SAEs. FG-3019 treatment was associated with improved survival with no apparent increase to the toxicity of the chemotherapy regimen, suggesting that FG-3019 could provide an effective adjunct to other chemotherapeutic regimens.
FibroGen plans to open a randomized Phase 2 trial of FG-3019 combined with gemcitabine plus nab-paclitaxel chemotherapy versus the chemotherapy regimen alone in patients with marginally inoperable pancreatic cancer that has not been previously treated. The overall goal of the trial is to determine whether FG-3019 in combination with other treatments can convert inoperable pancreatic cancer to operable cancer. Tumor removal is generally the only chance for cure of pancreatic cancer, but only 20% of patients are eligible for surgery.
Preclinical Studies of FG-3019 for Pancreatic Cancer
FG-3019 has demonstrated a reduction of tumor mass and metastasis in several mouse models of pancreatic cancer including the genetically engineered KPC mouse model. KPC mice spontaneously develop pancreatic cancer that closely approximates many features of the human disease, including similar genetic mutations, expression of CTGF, extensive stroma, metastases and ascites, or abdominal fluid, formation. KPC mouse tumors, like human pancreatic cancer tumors, are highly resistant to anti-cancer therapies. FG-3019 plus gemcitabine more than doubled the survival time of mice treated with chemotherapy alone. FG-3019 inhibited expression of XIAP, one of a family of proteins whose function is to inhibit apoptosis. Elevated expression of XIAP promotes cell survival and is one mechanism by which tumor cells can become resistant to chemotherapeutic agents. FG-3019 decreased XIAP levels significantly whereas gemcitabine did not, and the combination of FG-3019 and gemcitabine was even more effective. In both the KPC mouse study and in this clinical trial, FG-3019 treatment had a substantial effect on survival with no apparent increase to the toxicity of the chemotherapeutic regimen.