Journal Article

A Multicenter Phase 1 Trial Evaluating Nanoliposomal Irinotecan for Heated Intraperitoneal Chemotherapy Combined with Cytoreductive Surgery for Patients with Peritoneal Surface Disease

Patel, Reema A., Park, Jinha M., Kim, Joseph, Vacchi-Suzzi, Caterina, Reynolds, Jeri, Georgakis, Georgios V., Harper, Megan M., Reusch, Ellen, Pandalai, Prakash K., Abdel-Misih, Sherif R. Z., Choi, Minsig, Ellis, Carleton S.

2023

Overview

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/m 2 ) 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/m 2 ( n = 3), 140 mg/m 2 ( n = 6), 210 mg/m 2 ( n = 3), and 280 mg/m 2 ( 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/m 2 , 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.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Chemotherapy / Colorectal cancer / Colorectal Neoplasms - pathology / Combined Modality Therapy / Cytoreduction Surgical Procedures - adverse effects / Hot Temperature / Humans / Hyperthermia, Induced - adverse effects / Irinotecan / Irinotecan - therapeutic use / Medicine / Medicine & Public Health / Morbidity / Mortality / Neutropenia / Oncology / Patients / Peritoneal Neoplasms / Peritoneal Surface Malignancy / Peritoneum / Pharmacokinetics / Surgery / Surgical Oncology / Survival Rate / Toxicity / Tumors