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

  • Peritoneal Surface Malignancy
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

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.

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Acknowledgment

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.

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Author notes

  1. Minsig Choi and Megan M. Harper: co-first authors.

Authors and Affiliations

  1. Department of Hematology and Oncology, Stony Brook University, Stony Brook, NY, USA

    Minsig Choi MD

  2. Division of Surgical Oncology, University of Kentucky, Lexington, KY, USA

    Megan M. Harper MS, MD, Prakash K. Pandalai MD & Joseph Kim MD

  3. Division of Surgical Oncology, Stony Brook University, Stony Brook, NY, USA

    Sherif R. Z. Abdel-Misih MD & Georgios V. Georgakis MD, PhD

  4. Division of Hematology and Oncology, University of Kentucky, Lexington, KY, USA

    Reema A. Patel MD

  5. College of Pharmacy, University of Kentucky, Lexington, KY, USA

    Carleton S. Ellis PharmD

  6. Markey Cancer Center, University of Kentucky, Lexington, KY, USA

    Ellen Reusch BS & Jeri Reynolds RN

  7. Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA

    Caterina Vacchi-Suzzi PhD

  8. Department of Radiology, University of Iowa, Iowa City, IA, USA

    Jinha M. Park MD, PhD

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Correspondence to Joseph Kim MD.

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Disclosure

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.

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Choi, M., Harper, M.M., Pandalai, P.K. et al. A Multicenter Phase 1 Trial Evaluating Nanoliposomal Irinotecan for Heated Intraperitoneal Chemotherapy Combined with Cytoreductive Surgery for Patients with Peritoneal Surface Disease. Ann Surg Oncol 30, 804–813 (2023). https://doi.org/10.1245/s10434-022-12723-6

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