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

Jonker, Derek J.; Stephenson, Joe; Edenfield, William J.; Supko, Jeffrey G.; Li, Youzhi; Li, Wei; Hitron, Matthew; Leggett, David; Kerstein, David; Li, Chiang

doi:10.1200/jco.2014.32.15_suppl.2546

Cited by 14 publications

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“…Dose escalation was stopped because of pill burden, and no maximum tolerated dose was established. At daily dose of 400 mg, plasma levels of napabucasin were over its half-maximal inhibitory concentration (1.5 mM) for 8 hours (Jonker et al, 2014;Laurie et al, 2014). Preclinical studies in mouse models of several cancers show that napabucasin was effective both as monotherapy and in combination with other agents, particularly paclitaxel where synergy was observed.…”

Section: Janus Kinases Inmentioning

confidence: 99%

Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution

et al. 2020

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Section: Janus Kinases Inmentioning

confidence: 99%

Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution

et al. 2020

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“…Finally, two novel CSC-specific small-molecule multi-kinase inhibitors, amcasertib and napabucasin, demonstrated significant anti-NANOG activity and were reported to be safe in early phase 1 studies of advanced or R/R solid tumors (Jonker et al, 2014;Laurie et al, 2014). These drugs have rapidly entered phase 2 development, and efficacy results are eagerly awaited.…”

Section: Csc-directed Immunotherapymentioning

confidence: 99%

Targeting Cancer Stemness in the Clinic: From Hype to Hope

et al. 2019

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Tumors are composed of non-homogeneous cell populations exhibiting varying degrees of genetic and functional heterogeneity. Cancer stem cells (CSCs) are capable of sustaining tumors by manipulating genetic and non-genetic factors to metastasize, resist treatment, and maintain the tumor microenvironment. Understanding the key traits and mechanisms of CSC survival provides opportunities to improve patient outcomes via improved prognostic models and therapeutics. Here, we review the clinical significance of CSCs and results of potential CSC-targeting therapies in various cancers. We discuss barriers to translating cues from pre-clinical models into clinical applications and propose new strategies for rational design of future anti-CSC trials.

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“…A dose-escalation study in adult patients (14 cohorts; N = 41) with advanced cancer showed that napabucasin was well tolerated at doses up to 2000 mg/day; the maximum tolerated dose (MTD) was not reached (no dose-limiting toxicities [DLTs]) and adverse events (AEs) were generally mild, the most frequent being grade 1-2 gastrointestinal toxicities [12]. The recommended dosing regimen for napabucasin was determined as 500 mg BID at the time of a Phase I extension study in patients with advanced solid tumors [13]. A further clinical study of napabucasin in combination with paclitaxel demonstrated tolerability and signs of antitumor activity in patients with gastric or gastroesophageal junction adenocarcinoma [14].…”

Section: Signal Transducer and Activator Of Transcription 3 (Stat3)mentioning

confidence: 99%

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

Kawazoe

Kuboki

Bando

et al. 2020

Cancer Chemother Pharmacol

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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.

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

Cited by 14 publications

References 0 publications

Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution

Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution

Targeting Cancer Stemness in the Clinic: From Hype to Hope

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

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