Phase I Dose-Escalation Study Combining Irinotecan-Loaded Drug-Eluting Bead Chemoembolization with Yttrium-90 Glass Microspheres Radioembolization in Colorectal Liver Metastases (DEBIR90Y)

Purpose: To find the maximum tolerated dose (MTD) of yttrium-90 (90Y) glass microspheres, with drug-eluting beads preloaded with irinotecan (DEBIRI) in patients with colorectal liver metastases (CRLMs). Materials and Methods: In this prospective study, participants with bilobar, unresectable, liver-dominant CRLM progressing after first-line systemic therapy received sequential bilobar 90Y glass microsphere radioembolization at increasing dose levels (60-Gy, 80-Gy, and 100-Gy perfused normal liver absorbed doses), followed by DEBIRI, using a 3 + 3 dose-escalation design. The primary endpoint was MTD determination. Secondary endpoints included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST), (serious) adverse events ([S]AEs), carcinoembryonic antigen (CEA) response, conversion to resection, and overall survival. Descriptive statistics and independent t-tests were applied. Results: Twelve participants were enrolled. One dose-limiting toxicity (DLT; possible treatment-related fatal liver failure) occurred in the 80-Gy cohort, with no additional DLTs after cohort expansion (n = 6). At 100 Gy, 2 additional DLTs (probable and possible treatment-related fatal liver failure) occurred, establishing 80 Gy as the MTD when combined with full-dose DEBIRI. Eighty treatment-related (S)AEs occurred, most commonly increased gamma-glutamyl transferase (12/12, Grades 1–3) and abdominal pain (10/12, Grades 1–2). ORRs were 9% (RECIST) and 18% (PERCIST). Index lesion response rates were 20% (RECIST) and 35% (PERCIST). CEA response occurred in 42%. Conclusions: In this Phase I study in patients with liver-dominant colorectal metastases, receiving a combination of 90Y radioembolization with DEBIRI combined with DEBIRI, the MTD was 80 Gy. Considerable treatment-related toxicity was observed, and ORRs were limited.