BBI608-224: A phase Ib/II study of cancer stemness inhibitor napabucasin (BBI-608) administered with panitumumab in KRAS wild-type patients with metastatic colorectal cancer.

Abstract

677 Background: Napabucasin a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting Stat3-driven gene transcription. Preclinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with other agents. In a phase 1 study, napabucasin monotherapy was well tolerated with encouraging signs of anti-tumor activity at the RP2D of 500 mg BID. Methods: The current open-label, multi-center study includes phase II expansion in pts with refractory, K- Raswt mCRC to confirm safety and anti-tumor activity of napabucasin administered orally at 480mg BID in combination with panitumumab (6mg/kg bi-weekly). Results: 72 pts were enrolled, 48 pts were evaluable by RECIST of which 7 (15%) and 41 (85%) had 2 or >3 prior treatment lines, respectively. Of the 48 evaluable pts, 64.6% (31/48) were previously treated with an anti-EGFR agent. No new adverse events (AEs) were observed and most common AEs included grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. Among 48 pts enrolled who received RECIST evaluation, Disease Control Rate (DCR) was observed in 25 pts (52.1%) of which 3 pts achieved PR (6%) and 22 pts achieved SD (45%). Among 31 pts previously treated with anti-EGFR therapy, DCR was observed in 15 pts (48%) compared with DCR of 59% observed in 10 out of 17 anti-EGFR naïve pts receiving a scan. Conclusions: This phase II study confirmed that napabucasin can be safely combined with panitumumab at full dose and shows encouraging anti-tumor activity in pts with K- Ras wt mCRC, regardless of prior anti-EGFR exposure, suggesting that napabucasin may sensitize pts to repeat anti-EGFR therapy. Clinical trial information: NCT01776307. [Table: see text]

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

“…Drug-related AEs were predominantly gastrointestinal in nature with onset most frequently occurring in the first 2 weeks after first dose. These findings are generally in line with previously reported safety profiles of napabucasin [19,22] and the findings from an earlier Phase I study in non-Japanese patients, which recommended at the time that the dosing regimen for napabucasin should be 500 mg BID [13]. Furthermore, another dose-escalation study reported similar AEs but did not observe any DLT at 2000 mg/day, therefore no MTD was determined [12].…”

“…As CSCs are resistant to conventional therapies [4], we hypothesize that concomitant treatment with napabucasin (targeting both tumor and CSCs) may have higher antitumor activity than napabucasin or conventional therapies alone. One study of napabucasin in combination with paclitaxel showed tolerability and signs of anti-cancer activity in breast cancer [23], and several Phase 1b/2 studies have reported complete or partial tumor responses when administering napabucasin in combination with monoclonal antibodies or chemotherapy [19,22,24]. Additionally, one study of napabucasin plus FOLFIRI (folinic acid [leucovorin], fluorouracil, and irinotecan) showed the potential of napabucasin to sensitize cancer cells to FOLFIRI in colorectal cancer [20].…”

A Phase I Study of Napabucasin Plus Paclitaxel for Japanese Patients With Advanced/Recurrent Gastric Cancer

“…AEs related to napabucasin were gastrointestinal, generally mild in nature and controlled with concomitant administration of loperamide. The safety profile is also in line with that in vivo 33: 933-937 (2019) reported in other phase I clinical trials of napabucasin monotherapy (14,15) and there were no specific AEs reported due to the combination of napabucasin with weekly paclitaxel. Furthermore, the PK results suggested that paclitaxel did not affect the PK profile of napabucasin and that the napabucasin PK profiles were similar between patients with previous gastrectomy and those without.…”

STAT3: An Emerging Therapeutic Target for Hepatocellular Carcinoma

“…The targeted drug panitumumab, a human anti-EGFR monoclonal antibody, could also be safely combined with full-dose napabucasin in KRAS wild-type metastatic (m) CRC as reported in a phase Ib/II trial (NCT10776307) [95,96]. This combination has shown positive antitumor activity in both anti-EGFR-naïve patients ( n = 24) and those who failed anti-EGFR therapy ( n = 48), with DCR being 48% versus 59% and PFS being 16.9 weeks versus 9 weeks respectively, suggesting that prior anti-EGFR exposure is not limiting the efficacy of this combination therapy and that napabucasin may sensitize patients to repeat anti-EGFR therapy.…”