1198P - Analytical validation of an NGS panel-based ecDNA detection device for use as a clinical trial assay for the POTENTIATE clinical study of the novel CHK1 inhibitor, BBI-355

Background

Extrachromosomal DNA (ecDNA) has emerged as a unique, enabling biology of cancer cells and a root cause of oncogene amplification observed in more than 14% of cancer patients. Recent research has shown ecDNA portents a worse prognosis for cancer patients, including poorer time to progression, overall survival, and response to targeted therapies. The Phase 1/2 POTENTIATE clinical trial (NCT05827614) investigates the use of an oral, selective CHK1 inhibitor (BBI-355) as a single agent and together with targeted agents in patients with oncogene amplified cancer. Though fluorescence in situ hybridization (FISH) and whole genome sequencing (WGS) are commonly used to detect ecDNA in a research setting, neither method is practical nor validated for routine clinical use. Thus, there is a need for a validated clinical trial assay (CTA) that complements standard of care panel-based genomic testing, to enable detection of ecDNA and facilitate patient selection for ecDNA-directed therapies (ecDTx) such as BBI-355.

Methods

A proprietary algorithm was developed to detect ecDNA from outputs of several commercial next-generation sequencing (NGS) panels routinely used to detect genetic alterations in patient tumors. The ecDNA detection algorithm was trained using cell lines and FFPE patient tumor samples with known oncogene amplifications. The accuracy and precision of the algorithm were then validated in compliance with US Investigational Device Exemption (IDE) regulations using FFPE patient tumor samples blinded to the device.

Results

Herein, we show the ecDNA detection algorithm analytical validation results for use as a CTA. The CTA is compatible with multiple NGS panels currently used for genomic profiling of patient tumors and demonstrates high accuracy, precision, and robustness when compared to established orthogonal methods for ecDNA detection, such as FISH and WGS with AmpliconArchitect analysis.

Conclusions

We developed and validated a novel CTA to detect ecDNA using routine clinical NGS panel data. This CTA will be used to facilitate patient enrollment in Part 3 of the precision medicine POTENTIATE study of BBI-355.

Clinical trial identification

NCT05827614.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Boundless Bio.

Disclosure

P. Julien: Financial Interests, Personal and Institutional, Project Lead: SOPHiA Genetics; Financial Interests, Personal and Institutional, Stocks/Shares: SOPHiA Genetics. D. Lu, J. Wahl: Financial Interests, Personal and Institutional, Full or part-time Employment: Boundless Bio; Financial Interests, Personal and Institutional, Stocks/Shares: Boundless Bio. J. Bieler, T. Zimmermann, E. Magrinelli, A.C. Tuck: Financial Interests, Personal and Institutional, Full or part-time Employment: SOPHiA Genetics. P. Krein: Financial Interests, Personal and Institutional, Principal Investigator: Boundless Bio; Financial Interests, Personal and Institutional, Stocks/Shares: Boundless Bio.