A phase 1 dose-escalation study of BBI503, a first-in-class cancer stemness kinase inhibitor in adult patients with advanced solid tumors
Abstract
2527 Background: Targeting cancer stem cells (CSC) may hold significant therapeutic promise. BBI503 is an orally-administered first-in-class multi-kinase inhibitor with potent activity against CSC. Preclinically, potent anti-CSC and broad-spectrum anti-tumor and anti-metastatic activity was seen in vitro and in vivo. Methods: A first-in-man phase 1 dose escalation studyin patients with advanced cancer was conducted to determine safety, tolerability, RP2D, pharmacokinetics and preliminary anti-tumor activity of BBI503. BBI503 was given orally, continuously, in 28-day cycles until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Results: Escalating doses from 10 mg to 450 mg once daily were administered to 26 patients. MTD was not reached. BBI503 was well tolerated, with mild GI adverse events, including grade 1, 2 diarrhea, abdominal cramping, nausea, anorexia. Grade 3 diarrhea was observed in 2 subjects at 450 mg once daily. BBI503 exhibited favorable pharmacokinetics with dose-dependent increases in plasma concentration up to 300 mg once daily. Inhibition of cancer stem cell markers was observed in biopsied tumor tissues. Of 20 evaluable patients, 11 (55%) had stable disease (SD) with a median time to progression of 16 wks. Of those patients with SD, tumor regression and/or prolonged stable disease (≥ 16 weeks) were observed in 10 (50% of all enrolled patients) (see Table). Clinical trial information: NCT01781455. Diagnosis Number of pa…
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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 Laurie et al., 2014
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 Laurie 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 Laurie 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 Laurie et al., 2014
Cited by
Sorted by citations
Targeting Cancer Stemness in the Clinic: From Hype to Hope
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
- Laurie, S. A., Jonker, D. J., Edenfield, W. J., Stephenson, J., Keller, D., Hitron, M., Li, W., Li, Y., Gada, K., Gao, Y., & Li, C.
- Affiliations
- Ottawa Hospital (CA)
- Ottawa Hospital Research Institute (CA)
- Institute for Translational Oncology Research, Greenville, SC
- Boston Biomedical (United States) (US)
- Boston Biomedical, Inc., Cambridge, MA
- Venue
- Journal of Clinical Oncology
- Published
- 2014-05-20
- Volume
- 32
- Issue
- 15_suppl
- Pages
- 2527-2527
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2474470599
- Cited by
- 14
- References
- 0
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 1 · 2014: 1
- 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 › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Keywords
- cancer stem cells, multikinase inhibitor, advanced solid tumors, dose escalation, safety and tolerability, pharmacokinetics, anticancer activity, colorectal cancer, head and neck cancer, hepatocellular carcinoma, renal cell carcinoma, gastric adenocarcinoma, pancreatic neuroendocrine tumors, non-small cell lung cancer, diarrhea
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