April 2016, Vol. 5, No. 3

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Stem Cell Inhibitor Active in Pancreatic Cancer, CRC

Gastrointestinal Cancers Symposium

A first-in-class cancer stem cell inhibitor demonstrated activity in advanced pancreatic cancer and colorectal cancer (CRC), according to 2 small studies reported at the Gastrointestinal Cancers Symposium in San Francisco.

About half of 31 patients with heavily pretreated pancreatic cancer achieved disease control when treated with BBI608 plus paclitaxel. All but 1 of 17 patients with metastatic CRC had at least stable disease in a trial of the stem cell inhibitor.

The data from the trial in pancreatic cancer are particularly encouraging, given the historically poor prognosis associated with regimens beyond first line, noted Matthew Hitron, MD, Medical Director for BBI608 developer, Boston Biomedical in Cambridge, MA.

“Paclitaxel has a response rate of 0%, even in patients who are taxane naive,” said Hitron. “With BBI608 added to paclitaxel, we had a response rate of 9% to 10%. That in itself is an important signal.”

A previous trial of the only approved second-line therapy-liposomal irinotecan-had a median progression-free survival (PFS) of 3.1 months, Hitron continued. In the trial of BBI608 and paclitaxel, the combination was given as third-line therapy or beyond and resulted in median PFS of almost 4 months.

Cancer stem cells and cells that have “stemness” properties are chemoresistant and can induce relapse and metastasis after treatment with conventional chemotherapeutic agents. BBI608 targets the STAT3 pathway to inhibit cancer stemness. Preclinical studies involving colorectal and pancreatic cancer xenograft models provided proof of principle, including synergy with paclitaxel, leading to clinical evaluation of BBI608.

Hitron reported findings from a phase 1b/2 trial of BBI608 administered in combination with paclitaxel to patients with previously treated pancreatic adenocarcinoma. The safety analysis included a total of 41 patients who had received a median of 2 prior regimens for pancreatic cancer, including 31 patients evaluable for response.

All but 4 patients had been treated previously with gemcitabine, and 70% to 90% had a history of exposure to FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil [5-FU], and leucovorin), 5-FU, gemcitabine plus 5-FU, platinum, and irinotecan. Additionally, 44% had received nab-paclitaxel.

The most common treatment-related adverse events were diarrhea (occurring in all patients), nausea (>50%), abdominal pain (46%), and fatigue (44%). Grade 3 toxicity consisted of 2 cases each of diarrhea and abdominal pain and 1 case each of nausea, oral mucositis, lymphopenia, and anemia.

By intent-to-treat analysis, the overall response rate was 5% and the disease control rate 37% (including disease control for at least 24 weeks in 12%). The 31 patients evaluated for response had an overall response rate of 6%, including 11% in 19 patients with no prior taxane exposure. The disease control rates were 48% in the 31 patients and 63% in the taxane-naive subgroup. Disease control for at least 24 weeks was observed in 16%.

The 41-patient cohort had a median PFS of 2.2 months and a median overall survival of 6.0 months. The subgroup of patients with no prior taxane exposure had a median PFS of 3.9 months and a median overall survival of 7.4 months.

The phase 1b trial of patients with CRC evaluated BBI608 in combination with FOLFIRI (leucovorin, 5-FU, irinotecan) chemotherapy with or without beva­cizumab. Investigators enrolled 18 patients, 17 of whom were evaluable for response. On average, the patients had received more than 3 prior regimens, including 10 patients whose disease had progressed during or after treatment with FOLFIRI, said Joleen Marie Hubbard, MD, Medical Oncologist at the Mayo Clinic in Rochester, MN.

The safety profile was similar to that observed in the cohort of patients with pancreatic cancer, as the most common adverse events were diarrhea, nausea, vomiting, abdominal pain, and anorexia, which were grade 1 or 2 in most cases. All adverse events resolved with dose reduction or administration of antidiarrheal medication, said Hubbard.

Overall, 16 of 17 evaluable patients attained disease control, including 2 patients who had partial responses associated with tumor regression of 44% and 33%. Of the 14 patients who had stable disease, 13 had some degree of tumor regression.

The evaluable patients had a median PFS of 5.56 months, and 10 of the 17 patients had disease control lasting 24 weeks or more.

“We are encouraged by the activity that was observed in this heavily pretreated group of patients,” said Hubbard. “Anti-tumor activity was seen even in patients who previously had progressive disease on FOLFIRI- based regimens.”

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