Phase 1 study of napabucasin, a cancer stemness inhibitor, in patients with advanced solid tumors

Abstract

Purpose Napabucasin is a cancer stemness inhibitor that targets a number of oncogenic pathways, including signal transducer and activator of transcription 3 (STAT3). Phase 1/2 studies suggest tolerability and anti-tumor activity in various types of cancer; a Phase 3 study of napabucasin plus standard therapy in colorectal cancer is ongoing. This is a Phase 1 dose-escalation study in patients with advanced solid tumors, and the first study of napabucasin in Japanese patients. Methods Patients received napabucasin 480, 960, or 1440 mg daily in 28-day cycles until disease progression or intolerable toxicity. Primary objectives were to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and the pharmacokinetic (PK) profile of napabucasin. Blood samples were taken for PK analysis on Days 1, 2, 8, and 15 of Cycle 1, and Days 29 and 30 of Cycle 2. Secondary objectives were to assess napabucasin antitumor activity, and the relationship between biomarkers and antitumor activity. JapicCTI-No: JapicCTI-132152. Results Enrolled were 14 patients (480 mg [n = 3], 960 mg [n = 4], 1440 mg [n = 7]). One patient experienced a DLT (Grade 3, anorexia). MTD was 1440 mg/day. Most common drug-related adverse events were diarrhea (n = 9), nausea (n = 4), vomiting (n = 3), and anorexia (n = 3). Napabucasin showed a similar PK profile to previous studies and no abnormal accumulation was observed. Following treatment, two patients had stable disease; the remaining 12 had progressive disease. Conclusion Napabucasin was well-tolerated at doses up to 1440 mg/day in Japanese patients with advanced solid tumors; the PK profile was comparable to that reported previously.

Potent antitumor effects of cell-penetrating peptides targeting STAT3 axis

“…We further compared the specificity of PS-acet.-STAT3 peptide with the most advanced clinical small-molecule STAT3 inhibitor, napabucasin (BBI608), currently under several phase III clinical trials (39)(40)(41). Napabucasin has been shown to target cancer stem cells through blocking many different pathways, including STAT3 (42,43). We treated HCT116 tumor cells with either napabucasin or PS-acet.-STAT3 peptide, followed by Western blotting to assess phosphorylated STAT3 (p-STAT3) and p-STAT5 levels.…”

“…For example, only mild toxicities in tissues were observed upon systemic MYC inhibition by Omomyc in mice ( 64 ). In addition, a STAT3 inhibitor, napabucasin, already passed phase I and II clinical trials and currently is in a phase III clinical trial ( 42 , 70 , 71 ). Those animal experiments and clinical trials argue for an existing therapeutic window for MYC and STAT3 ( 42 , 64 ).…”

“…In addition, a STAT3 inhibitor, napabucasin, already passed phase I and II clinical trials and currently is in a phase III clinical trial ( 42 , 70 , 71 ). Those animal experiments and clinical trials argue for an existing therapeutic window for MYC and STAT3 ( 42 , 64 ). In our systemic toxicity test in vivo, PS-peptide treatments did not cause mouse body weight loss, behavior changes, or abnormal blood counts ( Supplemental Figures 10 and 12 ).…”

Nanog is a promising chemoresistant stemness marker and therapeutic target by iron chelators for esophageal cancer

“…BBI608 (napabucasin) was developed to target CSCs via inhibition of STAT3 signaling. 32,33 However, this agent failed to suppress the expressions of Nanog, c-Myc or Klf4, even though STAT3 signaling correlated with expressions of these stemness markers. 34 SSZ was developed to target CD44-positive CSCs via suppression of xCT.…”

“…No CSC‐targeting drugs have been established, although many candidate drugs have been developed. BBI608 (napabucasin) was developed to target CSCs via inhibition of STAT3 signaling 32,33 . However, this agent failed to suppress the expressions of Nanog, c‐Myc or Klf4, even though STAT3 signaling correlated with expressions of these stemness markers 34 .…”