Background: Nanoliposomal irinotecan (nal-IRI) is a promising novel hyperthermic intraperitoneal chemotherapy (HIPEC) agent given its enhanced efficacy against gastrointestinal tumors, safety profile, thermo-synergy, and heat stability. This report describes the first in-human phase 1 clinical trial of nal-IRI during cytoreductive surgery (CRS) and HIPEC. Methods: Patients with peritoneal surface disease (PSD) from appendiceal and colorectal neoplasms were enrolled in a 3 + 3 dose-escalation trial using nal-IRI (70–280 mg/m2) during HIPEC for 30 min at 41 ± 1 °C. The primary outcome was safety. The secondary outcomes were pharmacokinetics (PK) and disease-free survival. Adverse events (AEs) categorized as grade 2 or higher were recorded. The serious AEs (SAEs) were mortality, grade ≥ 3 AEs, and dose-limiting toxicity (DLT). Irinotecan and active metabolite SN38 were measured in plasma and peritoneal washings. Results: The study enrolled 18 patients, who received nal-IRI during HIPEC at 70 mg/m2 (n = 3), 140 mg/m2 (n = 6), 210 mg/m2 (n = 3), and 280 mg/m2 (n = 6). No DLT or mortality occurred. The overall morbidity for CRS/HIPEC was 39% (n = 7). Although one patient experienced neutropenia, no AE (n = 131) or SAE (n = 3) was definitively attributable to nal-IRI. At 280 mg/m2, plasma irinotecan and SN38 measurements showed maximum concentrations of 0.4 ± 0.6 µg/mL and 3.0 ± 2.4 ng/mL, a median time to maximum concentration of 24.5 and 26 h, and areas under the curve of 22.6 h*µg/mL and 168 h*ng/mL, respectively. At the 6-month follow-up visit, 83% (n = 15) of the patients remained disease-free. Conclusions: In this phase 1 HIPEC trial (NCT04088786), nal-IRI was observed to be safe, and PK profiling showed low systemic absorption overall. These data support future studies testing the efficacy of nal-IRI in CRS/HIPEC.
|Number of pages||10|
|Journal||Annals of Surgical Oncology|
|State||Published - Feb 2023|
Bibliographical noteFunding Information:
Ipsen provided financial support for this clinical trial. Ipsen had no input into the study design, analysis, or interpretation of results. Many thanks are extended to Donna Gilbreath for assistance with the associated visual abstract for this publication and the additional clinical research staff at UK (Shelley Cooper, BA; Heather Pavlik, RN) and SBUH (Margaret Andrew, RN; Giuseppina Caravella, MS, MPH; Sumbul Yousafi, MPH). Ipsen reviewed this manuscript for scientific accuracy but did not have any input into its content or its final approval.
Jinha M. Park is President, co-founder, and board member, and holds stock in The Radiology Experts, Inc. This research was supported by NIH training grant T32CA160003 (Megan M. Harper). The remaining authors have no conflicts of interest.
© 2022, Society of Surgical Oncology.
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