Phase I study of intraperitoneal aerosolized nanoparticle albumin based paclitaxel (NAB-PTX) for unresectable peritoneal metastases

Wim Ceelen, Louis Sandra, Leen Van de Sande, Martin Graversen, Michael Bau Mortensen, An Vermeulen, Elke Gasthuys, Dries Reynders, Sarah Cosyns, Anne Hoorens, Wouter Willaert, Wim Ceelen, Louis Sandra, Leen Van de Sande, Martin Graversen, Michael Bau Mortensen, An Vermeulen, Elke Gasthuys, Dries Reynders, Sarah Cosyns, Anne Hoorens, Wouter Willaert

Abstract

Background: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a novel method to treat patients with peritoneal metastases (PM). We aimed to study the tolerability, safety, pharmacokinetics, and tumour response of nanoparticle albumin bound paclitaxel (NAB-PTX) during PIPAC in a Phase I study.

Methods: Eligible patients with biopsy-proven PM from ovarian, breast, gastric, hepatobiliary, or pancreatic origin underwent three PIPAC treatments using NAB-PTX with a four-week interval. The dose of NAB-PTX was escalated from 35 to 140 mg/m2 using a Bayesian design to estimate the maximum tolerated dose (MTD).

Findings: Twenty-three patients were included; thirteen (65%) patients combined PIPAC therapy with continued systemic chemotherapy. The most frequent toxicities were liver toxicity and anaemia. Treatment resulted in seven (35%) responders, six (30%) non-responders and seven (35%) patients with stable PM. Systemic absorption of NAB-PTX was slow, with median peak plasma concentrations reached after 3 to 4 h. Median NAB-PTX tumour tissue concentrations suggested accumulation: 14.6 ng/mg, 19.2 ng/mg and 40.8 ng/mg after the first, second and third PIPAC procedure respectively. EORTC QoL and VAS scores remained stable. Overall survival after one year was 57%.

Interpretation: PIPAC with NAB-PTX results in a favourable PK profile and promising anticancer activity in patients with unresectable PM. The MTD and recommended Phase II clinical trial dose are 140 mg/m2. In patients with impaired hepatobiliary function, a dose of 112.5 mg/m2 is recommended.

Funding: Kom op tegen Kanker (Flemish League against Cancer).

Keywords: Nanoparticle; PIPAC; Paclitaxel; Peritoneal carcinomatosis; Peritoneal metastases.

Conflict of interest statement

Declaration of interests None of the authors have a conflict of interest to declare.

Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.

Figures

Figure 1
Figure 1
Illustration of pressurized intraperitoneal aerosol chemotherapy (PIPAC). After creation of a CO2 pneumoperitoneum, the peritoneal cavity is explored, the extent of peritoneal disease is scored, biopsies are taken, and anticancer drug is nebulized using a high-pressure injector and nebulizer. The drug containing aerosol is left in situ for 30 minutes.
Figure 2
Figure 2
a: Box plots represent the fraction of free PTX of 1 mg/mL (circular dots) and 5 mg/mL (square dots) NAB-PTX concentrations. b: Relative cell viability of human ovarian cancer cells (SKOV-3) following 2 h incubation of non-nebulized (black bars) and nebulized (grey bars) NAB-PTX concentrations. Experiments were performed in triplicate; error bars represent one standard deviation. All differences were non-significant (p > 0.05, Student t test). PTX, paclitaxel; NAB-PTX, nanoparticle albumin bound paclitaxel.
Figure 3
Figure 3
Patient flow diagram. Red boxes represent patients that were excluded and replaced. Green boxes represent patients who completed the trial, or dropped out after two PIPACs but were considered to be eligible for study analysis. The need for replacement of patients was calculated based on the time-to-event continual reassessment method. The results of 20 patients (green boxes) were used for the analysis of this clinical trial.
Figure 4
Figure 4
Thrombocytes (panel a) and absolute neutrophil count (ANC, panel b) after PIPAC with escalating doses of NAB-PTX. Bars represent one standard deviation.
Figure 5
Figure 5
Evolution of C-reactive protein (CRP) (a) and comprehensive complication index (CCI) (b) according to dose level.
Figure 6
Figure 6
Waterfall plot of the change in mean peritoneal regression grading score (PRGS) of all sampled biopsies according to pathology, concomitant systemic treatment, and dose level. Every bar represents a single PIPAC treatment; if no bar is shown the change was zero. ID, patient identifier; Tx, treatment.
Figure 7
Figure 7
Mean (±SD) plasma concentration vs. time profiles of paclitaxel and its respective metabolites across doses of nab-paclitaxel following PIPAC administration. PIPAC = pressurized intraperitoneal aerosol chemotherapy, PTX = paclitaxel.
Figure 8
Figure 8
Median dose-normalized tumour paclitaxel concentrations in each of the abdominal quadrants, sampled 0.5 h after initiation of the PIPAC procedure. All concentrations were dose-normalized to 140 mg/m2. Colored boxes: median dose-normalized tumour concentrations stratified per sampling location; Black dots: median dose-normalized tumour PTX concentrations across sampling location; PTX = paclitaxel, PIPAC = pressurized intraperitoneal aerosol chemotherapy, LUA = left upper abdomen, RUA = right upper abdomen, LF = left iliac fossa, RF = right iliac fossa.
Figure 9
Figure 9
Individual tumour-to-plasma concentration ratios at different doses of nab-paclitaxel following PIPAC administration. PIPAC = pressurized intraperitoneal aerosol chemotherapy.
Figure 10
Figure 10
EORTC QLQ-30 global health (a), functional scale (b), symptom scale (c), and visual analog pain score (d) over time in patients undergoing PIPAC with NAB-PTX.

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