Building on the positive phase II results reported in June 2018 for pamrevlumab to treat pancreatic cancer, the first dose has been administered in Fibrogen Inc.'s phase III study in patients with unresectable locally advanced pancreatic cancer.

An investigator in the phase II didn't spare the praise for the data produced in one of the toughest cancers to successfully treat.

"These are some of the most exciting clinical trial results in locally advanced pancreatic cancer I have seen since I began treating pancreatic cancer patients," said principal investigator Vincent J. Picozzi Jr., director of the Pancreas Center of Excellence at the Seattle-based Virginia Mason Cancer and Digestive Diseases Institutes. "The data suggest that pamrevlumab in combination with chemotherapy has the potential to become a neoadjuvant treatment regimen for locally advanced unresectable pancreatic cancer patients that has not existed before."

Picozzi returned as a principal investigator for the phase III. He's in Seattle recruiting, as are other investigators in Pennsylvania, Ohio, Michigan, California and Connecticut. The estimated primary completion date was about two years away as the first dose was administered. While the phase II evaluated pamrevlumab's efficacy in treating patients with locally advanced unresectable pancreatic cancer, the phase III is similar but with a slightly different approach: this time, pamrevlumab, an antifibrotic used as a neoadjuvant therapy, is being evaluated to see if it changes tumor status from unresectable to resectable, potentially increasing five-year survival rates.

The prognosis is dire for local advanced pancreatic cancer (LAPC) patients, but the median and five-year survival rates are much improved for the unresectable group than for those who did not have a resection. Median survival for unresectable LAPC patients is six to 10 months, only slightly better than metastatic pancreatic cancer patients. Only 20% of newly diagnosed patients are classified as having resectable disease. Patients whose tumors are removed have a median survival of about 23 months. Some of those are cured.

The primary outcome measures for the phase III study are overall survival and the proportion of all randomized adults who achieve R0 or R1 resection. The randomized, double-blind, two-armed trial will test neoadjuvant treatment with pamrevlumab combined with chemotherapy (gemcitabine and nab-paclitaxel) in LAPC. About 260 patients will be randomized 1-to-1 to receive 35-mg/kg doses of pamrevlumab or placebo in up to six 28-day treatment cycles. Those completing six treatment cycles will be evaluated for surgical exploration.

The resection rate is a surrogate endpoint. If resection rates favor the pamrevlumab combination, Fibrogen said it will ask for an FDA meeting to discuss accelerated approval.

For the phase II, Fibrogen reported that a higher proportion of patients whose tumors were previously considered unresectable became eligible for resection after receiving pamrevlumab and chemotherapy than after receiving chemotherapy alone at the end of six months treatment, 70.8% vs. 15.4%. A higher proportion of pamrevlumab-treated patients achieved surgical resection than those who received chemotherapy alone, 33.3% vs. 7.7%. Patients who had successful resections in that study had a statistically significant longer median survival benefit as compared to patients who did not undergo resection, 40 months vs. 18.6 months (p=0.0141).

The failure of phase III trials in advanced pancreatic cancer is 87%. A recent trial that went by the wayside was Abbvie Inc.'s Resolve phase III study for metastatic pancreatic adenocarcinoma. In January, the trial evaluating BTK inhibitor ibrutinib in combination with chemotherapy agents nab-paclitaxel and gemcitabine vs. placebo in combination with chemotherapy did not show statistically significant progression-free or overall survival benefit. Abbvie took a financial hit from the failure.

Another failure was Merrimack Pharmaceuticals Inc.'s phase II Carrie study, which faltered in June 2018. The randomized study evaluated the addition of MM-141 (istiratumab) to standard-of-care treatment in patients with previously untreated metastatic pancreatic cancer and high serum levels of free insulin-like growth factor-1. The study did not meet its primary or secondary efficacy endpoints in patients who received MM-141 in combination with nab-paclitaxel and gemcitabine, compared to nab-paclitaxel and gemcitabine alone. Those results were consistent in all subgroups analyzed. Based on those results, Merrimack opted not to devote additional resources to the development of MM-141.

Fibrogen stock (NASDAQ:FGEN) closed at $38.83, down 1.9%, Wednesday.

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