Phase I study of ART-123 in combination with FOLFOX + bevacizumab for patients with metastatic colorectal cancer.

111 Background: Persistent peripheral neuropathy is a common adverse event (AE) of oxaliplatin. ART-123, a recombinant human soluble thrombomodulin, has shown a potential to prevent oxaliplatin-induced peripheral neuropathy (OIPN) in a previous randomized phase IIa study for stage II/III colon cancer patients receiving adjuvant FOLFOX. Given the unmet need for better tolerated first-line treatment options in metastatic colorectal cancer (mCRC), we conducted this phase I study to evaluate the safety of ART-123 in combination with FOLFOX + bevacizumab (Bev). We separately evaluated 2 groups of mCRC patients, those with and without primary tumor, and here present the results of the without (resected) primary tumor group. Methods: This was a randomized, double-blind, placebo-controlled, dose-escalating study. ART-123 was administered at 5 dose levels up to 0.12 mg/kg on day 1 of each chemotherapy for 3 cycles. Each dose-level cohort had more than 8 patients randomized to receive ART-123 or placebo in a ratio of 3:1. Dose-limiting toxicities (DLTs) with special interest to bleeding, thrombocytopenia, and anemia were evaluated. In addition, the pharmacokinetics (PK) of ART-123 and anti-cancer drugs were analyzed. Results: A total of 42 patients were evaluated. The patient backgrounds were well-balanced in ART-123 group (n=31) and placebo (n=11) groups. Only 1 (2.4%) patient in the placebo group experienced DLTs (abdominal infection and large intestine perforation). Serious AEs were reported in 2 (4.8%) patients; one in 0.09 mg/kg group (procedural pneumothorax) and the previous DLT case. Four patients (9.5%) reported grade 1 bleeding events which appeared to be ART-123 dose-independent. One grade 1 epistaxis in the placebo group (9.1%), two grade 1 epistaxis and gingival bleeding in ART-123 group at 0.03 mg/kg dose levels (33.3%), and one grade 1 epistaxis at 0.12 mg/kg dose level (16.7%). To assess the relationship of these AEs to ART-123, the investigators used a standardized causality assessment algorithm. This algorithm considered factors such as the temporal relationship, lack of alternative explanations, and previous experience with the drug. Based on this assessment, none of the bleeding events were considered to be related to ART-123 treatment. Additionally, there were no ART-123-related adverse events that led to delays or discontinuations of the study drug or anti-cancer drugs. The PK parameters of oxaliplatin, 5-FU, and Bev in the ART-123 group were similar to those in the placebo group, suggesting no interactions of ART-123. Conclusions: ART-123 up to the targeting dose of 0.12 mg/kg was safely combined with FOLFOX + Bev in mCRC patients without the primary tumors. Based on this favorable safety profile and lack of PK interactions with oxaliplatin, 5-FU or Bev, a phase III trial is currently underway to verify the efficacy of ART-123 in preventing OIPN in the first-line treatment of mCRC. Clinical trial information: NCT05251727 .