The Lynx Group

First-in-Class Stem-Cell Inhibitor Active in Pancreatic and Colorectal Cancers

May 2016, Vol 7, No 4

The first-in-class cancer stem-cell inhibitor BBI608 demonstrated activity in advanced pancreatic cancer and colorectal cancer (CRC), according to results of 2 small studies reported at the 2016 Gastrointestinal Cancers Symposium.

Approximately 50% of 31 patients with heavily pretreated pancreatic cancer achieved disease control with BBI608 plus paclitaxel, and all but 1 of 17 patients with metastatic CRC had at least stable disease with the stem-cell inhibitor.

Impressive Results for BBI608 in Pancreatic Cancer

The data are particularly encouraging for pancreatic cancer, given the historically poor prognosis associated with treatment regimens beyond first line, said Matthew Hitron, MD, Director of Clinical Trials and Pharmacovigilance for Boston Biomedical, the manufacturer of BBI608.

Dr Hitron reported findings from a phase 1b/2 trial of BBI608 plus paclitaxel (Taxol) in patients with previously treated pancreatic adenocarcinoma. The safety analysis included 41 patients who had received a median of 2 previous treatments, including 31 patients who were evaluable for response.

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

In a previous trial of the only approved second-line therapy, liposomal irinotecan (Onivyde), patients with metastatic pancreatic cancer had a median progression-free survival (PFS) of 3.1 months. In the trial of BBI608 and paclitaxel, this combination was used as a third-line therapy or beyond and resulted in a 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 the clinical evaluation of BBI608.

All but 4 patients had previously received gemcitabine (Gemzar), and 70% to 90% of the patients had a history of exposure to FOLFIRINOX (leucovorin, fluorouracil, irinotecan hydrochloride, and oxaliplatin), 5-fluorouracil (5-FU), gemcitabine plus 5-FU, platinum, or irinotecan hydrochloride. In addition, 44% of the patients had received nab-­paclitaxel (Abraxane).

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.

The 41-patient cohort had a median PFS of 2.2 months and a median overall survival (OS) of 6 months. The subgroup of patients with no previous taxane exposure had a median PFS of 3.9 months and a median OS of 7.4 months.

BBI608 plus FOLFIRI for Colorectal Cancer

A phase 1b trial of 18 patients with CRC evaluated BBI608 plus FOLFIRI (leucovorin, fluorouracil, and irinotecan hydrochloride) chemotherapy with or without bevacizumab (Avastin). Of the 18 patients, 17 were evaluable for response.

On average, patients had received >3 previous regimens, including 10 patients whose disease had progressed during or after treatment with FOLFIRI, said Joleen M. Hubbard, MD, Assistant Professor of Medical Oncology, Mayo Clinic, Rochester, MN.

The safety profile was similar to that observed in the patients with pancreatic cancer: the most frequent 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 with the administration of antidiarrheal medication, said Dr Hubbard.

Overall, 16 of the 17 evaluable patients with CRC 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.

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

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