BOLD-100-001 (TRIO039): A phase 1b dose-escalation study of BOLD-100 in combination with FOLFOX chemotherapy in patients with advanced gastrointestinal solid cancers: Interim safety, tolerability, and efficacy.

3031 Background: BOLD-100 is a first-in-class ruthenium-based anticancer agent in Phase 1b / 2 clinical development for the treatment of advanced gastrointestinal (GI) cancers in combination with FOLFOX. Being developed primarily as a combinational agent, BOLD-100 induces cellular stress through modulation of the unfolded protein response, production of reactive oxygen species and induction of DNA damage. BOLD-100 demonstrates synergy in established preclinical models in combination with various anticancer therapies, particularly in resistant cell lines. Methods: This is a prospective, Phase 1b dose-escalation (Part A) and Phase 2 dose-expansion (Part B) study of BOLD-100 in combination with FOLFOX for colorectal (CRC), pancreatic (PDAC), gastric (GC) and biliary tract (BTC) cancers. Patients (pts) receive BOLD-100 with FOLFOX on day 1 of each 14-day cycle. In Part A, pts are enrolled in a 3+3 design to determine the combination recommended Phase 2 dose (RP2D), with BOLD-100 dose-escalation (420, 500 and 625 mg/m2) up to dose level 3. Part B comprises 5 cohorts treated at the RP2D until progressive disease or unacceptable toxicity. In Part A, reported here, the primary endpoints are safety, tolerability and maximum tolerated dose; the Part B endpoints are efficacy (primary), pharmacokinetic (PK) and pharmacodynamic parameters (secondary), and duration of response (exploratory) (NCT04421820). Results: As of 07 Feb 2022 (contains Part A preliminary data), 19 pts (mean age 65 years) were treated: 9 (47%) CRC, 5 (26%) BTC, 4 (21%) PDAC, 1 (5%) GC. Patients had a median of 3 prior systemic therapies, and 18 (95%) were enrolled with stage IV disease. Median number of cycles completed was 5 (range 1-15). 18 pts reported ≥1 treatment-emergent adverse events (AEs), most commonly fatigue (n = 12, 63%), nausea (n = 9, 47%) and stomatitis (n = 8, 42%). The majority of AEs were grade (G) 1-2. 7 G4 AEs (all neutropenia), and 1 unrelated G5 AE of pulmonary embolism occurred. There were 8 serious AEs in 6 different pts, with 1 SAE of dyspnea reported as related to BOLD-100. 2 pts experienced infusion-related reactions, related to chemotherapy. 2 dose-limiting toxicities have been observed: G3-4 neutropenia complicated by fever > 38.5°C or infection (n = 1, cohort #2) and inability to receive planned doses due to AEs (n = 1, cohort #3). To date for evaluable pts (n = 16), disease control rate of 75%, 1 partial response (48% target lesion reduction) and 11 stable disease have been observed. Conclusions: BOLD-100 plus FOLFOX is well-tolerated with no clinically significant safety findings. Dose-escalation data supports a BOLD-100 RP2D of 625 mg/m2 for the expansion phase. Progression-free survival, overall survival, and PK data are forthcoming. Clinical trial information: NCT04421820.