A phase I extension study of BBI608, a first-in-class cancer stem cell (CSC) inhibitor, in patients with advanced solid tumors.

2546 Background: BBI608, an orally-administered first-in-class cancer stemness inhibitor, blocks CSC self-renewal and induces cell death in CSC as well as non-stem cancer cells by inhibiting Stat3, β-catenin, and Nanog pathways, and has shown potent anti-tumor and anti-metastatic activities pre-clinically. In a phase 1 study, BBI608 demonstrated tolerability as well as signs of anti-cancer activity in patients with solid tumors. This phase 1 extension study evaluated a formulation designed for pivotal trials to determine pharmacokinetics (PK) in patients with advanced cancer. Methods: Day 1, patients received a single 500mg dose of the original BBI608 formulation (DP1). Day 4 and 8, a higher strength capsule designed for pivotal trials (DP2A) was given with fasting then fed conditions. DP2A was then administered daily until disease progression or unacceptable toxicity. Endpoints were safety, PK and preliminary anticancer activity. Results: DP2A was evaluated in 24 patients. No significant difference in plasma exposure between DP1 and DP2A, and no significant food effect were observed. Nine patients received BBI608 DP2A 4 h apart (DP2A-4h) only, and 15 patients received BBI608 DP2A 500 mg bid 12 h apart (DP2A-12h). Despite PK equivalence to DP1, DP2A-4 h was associated with higher frequency of gastrointestinal (GI) adverse events (AE) than observed in the prior study, including diarrhea, abdominal cramps, nausea/vomiting, anorexia, and fatigue. In contrast, DP2A-12 h had fewer GI AE and was selected for the extension study. Among 15 patients receiving DP2A-12h, prolonged stable disease was observed in 2 of 7 non-CRC patients (ovarian cancer-16 wk and anal squamous cancer-32 wk) and among 8 CRC patients enrolled, disease control was observed in 67% evaluable for response (4/6), with progression free survival and overall survival at 17 weeks and 39 weeks, respectively. Conclusions: The recommended dosing regimen for BBI608 in pivotal trials was determined to be about 500 mg bid q12 h. Signs of anticancer activity were observed in patients with CRC, anal squamous carcinoma, and ovarian cancer. Clinical trial information: NCT01775423.