Abstract LB-171: A phase 1 dose escalation study of BBI608, a first-in-class cancer stem cell pathway inhibitor in patients with advanced malignancies
Bibliographic record
Abstract
Abstract Background: Cancer stem cells (CSC) have self-renewal capability and can differentiate into heterogeneous cancer cells. CSC have been isolated from a variety of human cancers and are considered to be fundamentally responsible for malignant growth, relapse, metastasis, and resistance to conventional therapies [J Clin Oncol. 2008 Jun 10;26(17)]. Therefore, targeting CSC may hold significant clinical promise for treating cancer. BBI608 is the first-in-class cancer cell stemness inhibitor discovered from Boston Biomedical’s cancer stem cell pathway inhibitor program (BBI6000). This novel orally-administered cancer cell stemness inhibitor blocks CSC self-renewal and induces cell death in CSC as well as non-stem cancer cells. In preclinical models, BBI608 showed potent and broad-spectrum anti-tumor and anti-metastatic activities in vitro and in vivo. Methods: A phase 1 dose escalation study in adult patients with advanced cancer who had failed standard therapies was initiated to determine the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics and preliminary anti-tumor activity of BBI608. A cycle consists of twice-daily oral administration of BBI608 for 4 weeks. Cycles were repeated every 4 weeks (28 days) until progression of disease, unacceptable toxicity, or another discontinuation criterion was met. A modified Simon accelerated titration scheme was used for dose escalation. Results: As of March 26th, 2010, eighteen patients have been enrolled with safety data available for 15 patients. Thus far, seven cohorts have been dosed from 20 mg to 600 mg/day and the dose escalation has been well tolerated. Adverse events have generally been mild with the most common being grade 1-2 diarrhea and nausea. Two grade 3 events included fatigue and diarrhea. To date, neither MTD nor RP2D has been reached. Thus far, BBI608 has exhibited favorable pharmacokinetics. At the 400 mg/day dose level the plasma concentration of BBI608 was sustained for over 8 hours at a concentration above 1.5 μM (several folds above the IC50). Of the patients enrolled to date, 9 were evaluable for tumor response; 6 (6/9 evaluable patients) have achieved stable disease for at least 8 weeks. Prolonged stable disease was observed in two patients with colon cancer (54+ and 20+ weeks) and one with head and neck cancer (17 weeks). Complete regression of a metastatic lesion to the kidney was also observed in one colon cancer patient. No new metastatic lesions have been observed in any patients except one patient with gastric adenocarcinoma on 40mg/day of BBI608. Conclusions: Initial dose escalation of BBI608, a first-in-class cancer stem cell pathway inhibitor, has been achieved without dose limiting toxicity. Thus far, BBI608 has shown an excellent safety profile, favorable pharmacokinetics, and preliminary signs of clinical activity. Enrollment and dose escalation are continuing and updated results will be presented. Citation Format: Adrian Langleben, Jeffrey G. Supko, Sebastien Hotte, Patricia Lorusso, Wilson H. Miller, Annie Hurtubise, David S. Leggett, Wei Li, Laura Borodyanski, Chiang J. Li. A phase 1 dose escalation study of BBI608, a first-in-class cancer stem cell pathway inhibitor in patients with advanced malignancies [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-171.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.004 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".