Boston Biomedical Inc. shuttered phase III study Canstem111P of napabucasin for patients with metastatic pancreatic ductal adenocarcinoma, adding to the list of studies that have fallen in pancreatic cancer.

An independent data and safety monitoring board found a prespecified interim analysis of futility of 50% of total planned events in the study. While the board found no new safety concerns, it did recommend stopping the trial. Boston Biomedical said it will complete a full evaluation of the study and will make the details public at a later date.

Napabucasin, a cancer stem cell pathway inhibitor, is an orally administered investigational agent that is bioactivated by NQO1, which generates reactive oxygen species to affect multiple oncogenic cellular pathways, including the STAT3 pathway, which is expected to result in cancer cell death. Napabucasin is being investigated in CanStem303C, a phase III trial for metastatic colorectal cancer. It is also being investigated in earlier phase trials in multiple solid malignancies.

Canstem111P is a randomized, open-label, multicenter study testing napabucasin plus weekly nab-paclitaxel with gemcitabine vs. weekly nab-paclitaxel with gemcitabine for adult patients with metastatic pancreatic ductal adenocarcinoma. The phase III trial began in December 2016 and was projected to wrap up in December 2020. Arm 1 randomized patients to receive napabucasin administered orally, twice daily in combination with weekly nab-paclitaxel and gemcitabine administered intravenously, once weekly, on three of every four weeks. Arm 2 was nab-paclitaxel with gemcitabine in which patients received weekly nab-paclitaxel and gemcitabine administered intravenously, once weekly, on three of every four weeks.

Two years ago, Boston Biomedical unblinded a global phase III study of napabucasin in advanced gastric and gastroesophageal junction cancer after the trial's data and safety monitoring board determined that combining napabucasin with paclitaxel is unlikely to yield better overall survival at 36 months than paclitaxel alone. The trial, Brighter, was designed as a randomized, parallel assignment, double-blind study to evaluate the efficacy and safety of napabucasin plus weekly paclitaxel vs. placebo plus weekly paclitaxel. It has included a little more than 700 patients with advanced, previously treated gastric or gastroesophageal junction cancer and began in August 2014. (See BioWorld, June 27, 2017.)

Cambridge, Mass.-based Boston Biomedical is owned by Sumitomo Dainippon Pharma Co. Ltd., of Osaka, Japan.

String of failures in pancreatic cancer

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 those chemotherapy agents 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.

Tyme Technologies Inc.'s lead program, SM-88, received mix reviews of its midstage pancreatic data earlier this year in an open-label phase II study. In the Tyme-88-Panc study, the company is testing the regimen in 38 heavily pretreated patients with actively progressing metastatic pancreatic cancer, of which 28 were evaluable. On the primary endpoint, response rate by blinded independent central review, investigators had 17 patients to work with – those from whom they were able to secure two-month imaging data. Among them, about half achieved some clinical benefit, either in the form of stable disease for seven patients or a partial response for one patient. Two of the 17 patients, or 12%, saw target lesion reductions of greater than 30%. (See BioWorld, Jan. 22, 2019.)

Astrazeneca plc's PARP inhibitor, Lynparza (olaparib), meanwhile, has produced some recent success in pancreatic research. One of the highlights of the 2019 annual meeting of the American Society of Clinical Oncology earlier this month were results from the phase III POLO trial, demonstrating that treatment with Lynparza (olaparib, Astrazeneca plc/Merck & Co. Inc.) after platinum chemotherapy nearly doubled the progression-free interval (progression-free survival, PFS) in a group of 154 metastatic pancreatic cancer patients with germline BRCA mutations, from 3.8 months to 7.4 months. Also roughly doubled was the proportion of patients who had not progressed after two years, from 9.6% to 22.1%. Overall survival is not yet mature. Study lead and University of Chicago professor of medicine Hedy Kindler called the results "truly remarkable for metastatic pancreatic cancer" and said the study "should lead to a new standard of care" for metastatic pancreatic cancer patients with BRCA mutations. (See BioWorld, June 24, 2019.)

Pancreatic cancer patients have a five-year survival rate of less than 9%. Part of the problem for those patients is that the disease often is identified late, meaning the tumors are inoperable. For some, it may be possible to shrink the tumor with existing chemotherapy drugs; however, with that disease, 75% of patients die within a year of diagnosis, meaning time is of the essence.

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