Treatment of advanced gastric and biliary tract cancer with BOLD-100, a ruthenium-based anticancer agent in Phase 1b /2a clinical ( identifier: NCT04421820) development in combination with FOLFOX (FOLFOX includes FOLinic acid (also known as leucovorin), Fluorouracil (also known as 5-FU), and OXaliplatin), demonstrates synergy in established preclinical models in combination with various anticancer therapies, particularly in resistant cell lines.

This is the conclusion of the first interim analysis of the phase 1b dose-escalation study with BOLD-100 plus FOLFOX. The results of the study, which were presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held June 2 – 6, 2023, in Chicago, Illinois, shows that the investigational agent was well-tolerated in patients with advanced GI solid cancers.

BOLD-100, being developed by Bold Therapeutics, alters the unfolded protein response (UPR) through selective GRP78 inhibition; and induces reactive oxygen species (ROS) which causes DNA damage and cell cycle arrest.

Collectively, these effects result in cell death in both sensitive and resistant cancers, giving BOLD-100 the potential to significantly improve outcomes in a wide range of both solid and liquid tumors in combination with other anticancer therapies ranging from traditional chemotherapies to targeted therapies and immuno-oncology agents.

The ongoing multinational Phase 1b/2 trial evaluates BOLD-100 in combination with FOLFOX in patients with advanced gastrointestinal cancers.

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The trial has enrolled 110 patients with advanced gastrointestinal (biliary tract, colorectal, gastric, and pancreatic) cancers at sites in Canada, the United States, Ireland and South Korea, and the primary endpoints for the trial are progression-free survival (PFS), with overall survival (OS) and overall response rate (ORR) as secondary endpoints. Disease control rate (DCR) was also captured. Data from the full Phase 2 trial, which will include an additional 20 patients with advanced colorectal cancer, should be available in late 2023.

Study outcomes
A total of 13 advanced gastric cancer patients (median 4th line) showed a median PFS of 5.5 months, OS of 15.0 months, ORR of 22%, and DCR of 89%, substantially higher than the most comparable benchmark values in a much earlier (median 2nd line) population of a median PFS of 4.6 months, OS of 7.1 months, ORR of 40%, and DCR of 69%. Mature data in an additional 8 advanced gastric cancer patients will be available in late 2023. 22 advanced biliary tract cancer patients (median 3rd line) showed a median PFS of 5.0 months, OS of 7.3 months, ORR of 6%, and DCR of 83%, substantially higher than the most comparable benchmark values in an earlier (true 2nd line) population from the ABC-06 FOLFOX study with a median PFS of 4.0 months, OS of 6.2 months, ORR of 5.0%, and DCR of 33%.

Consistent with prior data, BOLD-100 in combination with FOLFOX proved to be exceptionally well-tolerated, with no new safety signals, and with patients remaining on therapy for up to 25 treatment cycles. Treatment-emergent adverse events (TEAEs) were observed in 33 (94%) of patients, with the most common TEAEs being decreased neutrophil count (43%), nausea (29%), and fatigue (20%) – rates comparable to FOLFOX.

Previous presented data
Previously, interim data in metastatic colorectal cancer presented at the annual meeting of the American Association for Cancer Research (AACR), held April 14-19, 2023 in Orlando, Florida.[2]

indicated that patients treated with BOLD-100 and FOLFOX showed a median PFS of 4.7 months, OS of 9.8 months, ORR of 13%, and DCR of 87%, substantially higher than standard-of-care data for a similar patient population which showed a median PFS of up to 2.0 months, OS of up to 7.1 months, ORR of up to 1.6%, and DCR of up to 44%.

“Our presentation at ASCO marks a critical milestone for BOLD-100, with Bold Therapeutics successfully generating positive proof-of-concept data in three different difficult-to-treat gastrointestinal cancer indications where existing therapies are largely ineffective,” stated Jim Pankovich, EVP of Clinical Development.

“Importantly for patients, BOLD-100 achieves these improved outcomes safely, even in heavily pre-treated patients,” Pankovich added.

Bold Therapeutics is preparing to initiate a pivotal Phase 3 trial for BOLD-100 in the treatment of advanced colorectal cancer in 2024 and is currently evaluating potentially synergistic development and commercialization partnerships to support these efforts. Concurrently, Bold Therapeutics is exploring additional development indications for BOLD-100 while also advancing its pipeline of other novel metallotherapeutics.

Clinical trials
BOLD-100 in Combination With FOLFOX for the Treatment of Advanced Solid Tumours – NCT04421820

[1] O’Kane GM, Spratlin JL, Oh DY, Rha SY, Elimova E, Kavan P, Choi MK, Goodwin RA, et al. BOLD-100-001 (TRIO039): A phase 1b/2a study of BOLD-100 in combination with FOLFOX chemotherapy in patients with pre-treated advanced gastric and biliary tract cancer: Efficacy and safety analysis. J Clin Oncol 41, 2023 (suppl 16; abstr 4098) DOI 10.1200/JCO.2023.41.16_suppl.4098.
[2] Spratlin J, O’Kane G, Oh DY, Rha SY, McWhirter E, Elimova E, avan P, Choi MK, Kim DW, Goodwin R, Hecht JR, Kim ST, Koo DH, Halani K, McAllister ER, Jones M, Snow M, Yasmin Lemmerick, Gonzalo Spera, Jim Pankovich. BOLD-100-001 (TRIO039): a phase 1b/2a dose-escalation study of BOLD-100 in combination with FOLFOX chemotherapy in patients with pre-treated advanced colorectal cancer: interim efficacy, safety and tolerability analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT149.

Featured Image: General Views of the ASCO Annual Meeting, Chicago, IL – McCormick Place, Photo by © ASCO/Matt Herp 2023.  Used with permission.

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