Intraperitoneal aerosolization of albumin-stabilized paclitaxel nanoparticles (Abraxane™) for peritoneal carcinomatosis - a phase I first-in-human study

Leen Van De Sande, Martin Graversen, Martin Hubner, Marc Pocard, Marc Reymond, Marco Vaira, Sarah Cosyns, Wouter Willaert, Wim Ceelen, Leen Van De Sande, Martin Graversen, Martin Hubner, Marc Pocard, Marc Reymond, Marco Vaira, Sarah Cosyns, Wouter Willaert, Wim Ceelen

Abstract

Background: Nanoparticles hold considerable promise for aerosol-based intraperitoneal delivery in patients with carcinomatosis. Recently, results from preclinical and early clinical trials suggested that albumin-bound paclitaxel (ABP, Abraxane™) may result in superior efficacy in the treatment of peritoneal metastases (PM) compared to the standard solvent-based paclitaxel formulation (Taxol™). Here, we propose a phase I study of pressurized intraperitoneal aerosol chemotherapy (PIPAC) using ABP in patients with upper Gastrointestinal, breast, or ovarian cancer.

Methods: Eligible patients with advanced, biopsy-proven PM from ovarian, breast, gastric, hepatobiliary, or pancreatic origin will undergo three PIPAC treatments using ABP with a 4-week interval. The dose of ABP will be escalated from 35 to 140 mg/m² using a Bayesian approach until the maximally tolerated dose is determined. The primary end point is dose-limiting toxicity. Secondary analyses include surgical morbidity, non-access rate, pharmacokinetic and pharmacodynamic analyses, quality of life, and exploratory circulating biomarker analyses.

Discussion: ABP holds considerable promise for intraperitoneal aerosol delivery. The aim of this study is to determine the dose level for future randomized phase II trials using ABP in PIPAC therapy.

Trial registration: This trial is registered as EudraCT: 2017-001688-20 and Clinicaltrials.gov: NCT03304210.

Keywords: Abraxane; aerosol; albumin; carcinomatosis; intraperitoneal; pressurized intraperitoneal aerosol chemotherapy (PIPAC)..

Conflict of interest statement

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

    1. Huang CQ, Min Y, Wang SY, Yang XJ, Liu Y, Xiong B, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival for peritoneal carcinomatosis from colorectal cancer: a systematic review and meta-analysis of current evidence. Oncotarget 2017;8:55657–83.
    1. Van Driel WJ, Koole SN, Sikorska K, Schagen van Leeuwen JH, Schreuder HW, Hermans RH, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med 2018;378:230–40.
    1. Solass W, Kerb R, Murdter T, Giger-Pabst U, Strumberg D, Tempfer C, et al. Intraperitoneal chemotherapy of peritoneal carcinomatosis using pressurized aerosol as an alternative to liquid solution: first evidence for efficacy. Ann Surg Oncol 2014;21:553–9.
    1. Grass F, Vuagniaux A, Teixeira-Farinha H, Lehmann K, Demartines N, Hubner M. Systematic review of pressurized intraperitoneal aerosol chemotherapy for the treatment of advanced peritoneal carcinomatosis. Br J Surg 2017;104:669–78.
    1. Tempfer CB, Rezniczek GA, Ende P, Solass W, Reymond MA. Pressurized intraperitoneal aerosol chemotherapy with cisplatin and doxorubicin in women with peritoneal carcinomatosis: a cohort study. Anticancer Res 2015;35:6723–9.
    1. Scheithauer W, Kornek G, Prager G, Stranzl N, Laengle F, Schindl M, et al. Phase II trial of capecitabine plus nab-paclitaxel in patients with metastatic pancreatic adenocarcinoma. J Gastrointest Oncol 2016;7:234–8.
    1. Tsai M, Lu Z, Wang J, Yeh TK, Wientjes MG, Au JLS. Effects of carrier on disposition and antitumor activity of intraperitoneal paclitaxel. Pharm Res 2007;24:1691–701.
    1. Coccolini F, Acocella F, Morosi L, Brizzola S, Ghiringhelli M, Ceresoli M, et al. High penetration of paclitaxel in abdominal wall of rabbits after hyperthermic intraperitoneal administration of nab-paclitaxel compared to standard paclitaxel formulation. Pharm Res 2017;34:1180–6.
    1. Cristea MC, Synold TW, Frankel PH, Rivkin SE, Lim D, Chung VM, et al. Pharmacologic advantage (PA) of intraperitoneal (IP) nab-paclitaxel in patients with advanced malignancies primarily confined to the peritoneal cavity. J Clin Oncol 2015;33:15 suppl, abstract 2553.
    1. Garrett-Mayer E. The continual reassessment method for dose-finding studies: a tutorial. Clin Trials 2006;3(1):57–71.
    1. Dakwar GR, Shariati M, Willaert W, Ceelen W, De Smedt SC, Remaut K. Nanomedicine-based intraperitoneal therapy for the treatment of peritoneal carcinomatosis – mission possible? Adv Drug Deliv Rev Jan 1 2017;108:13–24.
    1. Infante JR, Matsubayashi H, Sato N, Tonascia J, Klein AP, Riall TA, et al. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. JClin Oncol 2007;25:319–25.
    1. Cullis J, Siolas D, Avanzi A, Barui S, Maitra A, Bar-Sagi D. Macropinocytosis of nab-paclitaxel drives macrophage activation in pancreatic cancer. Cancer Immunol Res 2017;5:182–90.
    1. Merlot AM, Kalinowski DS, Richardson DR Unraveling the mysteries of serum albumin-more than just a serum protein. Fron Physiol 2014;5:299.

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