ONCAlert | 2018 ASCO Annual Meeting

Oral Stemness Inhibitor Shows Responses in Heavily Pretreated Metastatic Pancreatic Cancer

Wayne Kuznar
Published Online: 7:00 PM, Tue January 26, 2016
Oral Stemness Inhibitor in Heavily Pretreated Metastatic Pancreatic Cancer

Tanios S. Bekaii-Saab, MD

An orally administered first-in-class cancer stemness inhibitor, BBI608, administered twice daily with weekly paclitaxel has promising activity in patients with refractory, heavily pretreated metastatic pancreatic cancer; particularly in patients who are taxane naïve.
 
In a group of patients who are taxane naïve enrolled in a phase Ib/II extension study of BBI608, median progression-free survival (PFS) was approximately 4 months and median overall survival (OS) was about 7 months, said Tanios S. Bekaii-Saab, MD, at the 2016 Gastrointestinal Cancers Symposium.
 
"Historically, if you look at weekly paclitaxel on its own in the second line, there has been a 0% response rate and reported survival is close to 4.1 months, so we believe that our results are at least promising enough to consider this interesting and to continue to proceed with the development of this agent in pancreatic cancer," said Bekaii-Saab, professor of medicine and pharmacy, The Ohio State University, Columbus.
 
Cancer stem cells are difficult to eradicate. "They tend to be resistant to chemotherapy and radiotherapy," he said. "Even after surgery, some of the cells that eventually linger and lead to cancer recurrence are those stem cells." Cancer stem cells often metastasize while retaining their stemness, causing relapse after treatment.
 
Cancer cells that don't respond to chemotherapy can induce stemness and these stem-like cells eventually become the predominant pool of cancer cells, which are less responsive to multiple lines of therapy.
 
BBI608 blocks cancer stem cell self-renewal and induces cell death in cancer stem cells and non-stem cancer cells by inhibiting the Stat3 and Wnt pathways, said Bekaii-Saab.
 
Preclinically, BBI608 has shown potent antitumor and antimetastatic activities, and in a phase I study, it was well tolerated and demonstrated signs of anticancer activity in patients with solid tumors. BBI608 has also shown potent synergistic antitumor activity with paclitaxel in vivo. In a phase Ib dose-escalation study, BBI608 plus weekly paclitaxel was well tolerated and a recommended phase II dose of 480 mg twice daily was determined.
 
In the extension phase, 41 patients received oral BBI608 continuously at a starting dose of 480 mg or 500 mg twice daily along with paclitaxel, 80 mg/m2 IV, on days 3, 10, and 17 of each 28-day cycle. Cycles were repeated until progression of disease, unacceptable toxicity, or another discontinuation criterion is met. Dosage adjustment was permitted in the event of toxicity.
 
"The initial dose escalation study had seen a number of patients that responded to treatment even at lower doses, frankly," he said. "The maximally tolerated dose with chemotherapy went into various extension-phase studies, including metastatic pancreatic cancer."
 
A total of 41 patients were enrolled in the phase Ib/II extension study. "The average exposure was between two and three lines of therapy, so this was a heavily pretreated patient population," said Dr. Bekaii-Saab.
 
Prior treatment included FOLFIRINOX (71%), gemcitabine/nab-paclitaxel (44%), or both (37%). Overall, prior therapy included gemcitabine in 90%, a thymidylate synthetase inhibitor (eg, 5-fluorouracil, capecitabine) in 80%, platinum in 76%, irinotecan in 73%, and a taxane in 44%.
 
Median PFS in the overall population of 41 patients was 2.2 months and median OS was 6.0 months. In the 23 patients who were taxane-naïve, the objective response rate was 11%, median PFS was 3.9 months and median OS was 7.4 months.
 
Treatment-related grade 3 adverse effects included diarrhea (4.9%), abdominal pain (4.9%), and nausea (2.4%), and were rapidly reversible.
 
The durable disease control and the prolonged OS in this pretreated population are notable, said Bekaii-Saab. His group has also studied BBI608 with gemcitabine and nab-paclitaxel in a first-line setting in patients with metastatic pancreatic cancer, and among the first eight patients treated, all had a response, "with about half having a partial response and the others having some level of tumor shrinkage, except for one patient, and their CA19-9 also dropped, so eight of eight had clinical benefit," he said. "First line is probably where we would like to start."
 

References

 

  1. Bekaii-Saab T, Mikhail S, Langleben A, et al. A phase Ib/II study of BBI608 combined with weekly paclitaxel in advanced pancreatic cancer. J Clin Oncol. 2016;34(suppl 4S; abstr 196).


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