Intraperitoneal aerosolized nanoparticle albumin based paclitaxel (NAB-PTX) for irresectable peritoneal metastases: A first in human phase I study

4065 Background: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) was recently introduced in the palliative treatment of peritoneal metastases (PM). Results from preclinical experiments suggest that intraperitoneal (IP) Nab-PTX may result in superior efficacy compared to solvent based paclitaxel (PTX). We performed a phase I first-in-human trial of PIPAC using Nab-PTX in patients with PM from upper gastrointestinal, breast, or ovarian cancer. Methods: Eligible patients with biopsy-proven PM underwent up to three PIPAC treatments using Nab-PTX with a four-week interval at two university hospitals. Patients underwent laparoscopy with IP nebulization of Nab-PTX over 5 min; the procedure was completed after 30 min. The dose of Nab-PTX was escalated from 35 to 140 mg/m2 using a Bayesian approach until the maximally tolerated dose (MTD) was reached. Secondary endpoints included surgical morbidity, pharmacokinetics (PK), histological treatment response, and overall survival. Blood and tissue samples were taken after each PIPAC procedure. Population PK analysis was performed using Monolix version 2020R1. Quality of life was measured using the EORTC QLQ-C30 questionnaire and visual analogue pain scales (VAS). Results: Twenty-three patients were included. The primary tumor was gastric cancer (55%), ovarian cancer (20%), hepatobiliary or pancreatic cancer (15%), breast cancer (5%), and miscellaneous (5%). No dose limiting toxicity was observed. Grade 3 thrombopenia was observed in one patient allocated to a dose of 90 mg/m2. One patient allocated to the highest dose experienced grade 3 neutropenia one week after each PIPAC. The most frequent treatment-related toxicities were liver toxicity (grade 1 to 3, 75%) and anemia (grade 1 to 3, 70%). Eight patients (40%) showed surgical site infections including wound infection and wound dehiscence (grade 1 to 3), four of whom required treatment with antibiotics. Treatment was associated with histological response in 35% of patients, while stable disease and progressive disease were found in 35% and 30%, respectively. The absorption of PTX continued long after the end of the procedure (30 min), with the Tmax reached between 2 and 6 h after initiation of the procedure. Median tumor PTX concentrations suggested accumulation: 9.37 ng/mg, 14.78 ng/mg and 25.75 ng/mg after the first, second and third PIPAC, respectively. EORTC global health, functional, and symptom scores as well as VAS scores remained stable throughout the treatment period. Overall survival after one year was 57%. Conclusions: PIPAC with Nab-PTX may be applied safely up to a dose of 140 mg/m2 and results in a favorable PK profile and promising anticancer activity. At the MTD of 140 mg/m2, considerable surgical site infections and liver toxicity were observed. Therefore, the recommended dose for future phase II trials is 112.5 mg/m2. Clinical trial information: NCT03304210.