A phase I extension study of BBI608, a first-in-class cancer stem cell (CSC) inhibitor, in patients with advanced solid tumors
Abstract
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…
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Grade 3 TEAE were GI-related (7.3%) and fatigue (2.4%).
“Grade 3 TEAE were GI-related (7.3%) and fatigue (2.4%).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Jonker et al., 2014
In Phase I and II trials, TEAE related to the administration of napabucasin were generally mild and included predominantly grades 1 and 2 GI TEAE.
“Phase I and II trials showed that TEAE related to the administration of the napabucasin were generally mild and included predominantly grades 1 and 2 GI TEAE.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Jonker et al., 2014
Dose escalation of napabucasin was stopped because of pill burden, and no maximum tolerated dose was established.
“Dose escalation was stopped because of pill burden, and no maximum tolerated dose was established.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Jonker et al., 2014
At a daily dose of 400 mg, plasma levels of napabucasin were over its half-maximal inhibitory concentration (1.5 μM) for 8 hours.
“At daily dose of 400 mg, plasma levels of napabucasin were over its half-maximal inhibitory concentration (1.5 µM) for 8 hours (Jonker et al., 2014; Laurie et al., 2014).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Jonker et al., 2014
Cited by
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Saygin, C., Matei, D., Majeti, R., Reizes, O., & Lathia, J. D. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2018.11.017 · Cited by 517 · see citing works
Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
- Authors
- Jonker, D. J., Stephenson, J., Edenfield, W. J., Supko, J. G., Li, Y., Li, W., Hitron, M., Leggett, D., Kerstein, D., & Li, C.
- Affiliations
- Ottawa Hospital Research Institute (CA)
- Institute for Translational Oncology Research, Greenville, SC
- Massachusetts General Hospital (US)
- Boston Biomedical (United States) (US)
- Venue
- Journal of Clinical Oncology
- Published
- 2014-05-20
- Volume
- 32
- Issue
- 15_suppl
- Pages
- 2546-2546
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2481032118
- Cited by
- 19
- References
- 0
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 3 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 3
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- advanced solid tumors, pharmacokinetics, dosing regimen, gastrointestinal adverse effects, colorectal cancer, ovarian cancer, STAT3 inhibition, β-catenin signaling, Nanog, food effect, anticancer activity, safety and tolerability, progression-free survival, overall survival, stable disease
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