A phase I study of intraperitoneal nanoparticulate paclitaxel (Nanotax®) in patients with peritoneal malignancies

Abstract

Purpose This multicenter, open-label, dose-escalating, phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary tumor response of a nanoparticulate formulation of paclitaxel (Nanotax®) administered intraperitoneally for multiple treatment cycles in patients with solid tumors predominantly confined to the peritoneal cavity for whom no other curative systemic therapy treatment options were available. Methods Twenty-one patients with peritoneal malignancies received Nanotax® in a modified dose-escalation approach utilizing an accelerated titration method. All patients enrolled had previously received chemotherapeutics and undergone surgical procedures, including 33 % with optimal debulking. Six doses (50–275 mg/m2) of Cremophor-free Nanotax® were administered intraperitoneally for one to six cycles (every 28 days). Results Intraperitoneal (IP) administration of Nanotax® did not lead to increases in toxicity over that typically associated with intravenous (IV) paclitaxel. No patient reported ≥Grade 2 neutropenia and/or ≥Grade 3 neurologic toxicities. Grade 3 thrombocytopenia unlikely related to study medication occurred in one patient. The peritoneal concentration–time profile of paclitaxel rose during the 2 days after dosing to peritoneal fluid concentrations 450–2900 times greater than peak plasma drug concentrations and remained elevated through the entire dose cycle. Best response assessments were made in 16/21 patients: Four patients were assessed as stable or had no response and twelve patients had increasing disease. Five of 21 patients with advanced cancers survived longer than 400 days after initiation of Nanotax® IP treatment. Conclusions Compared to IV paclitaxel administration, Cremophor-free IP administration of Nanotax® provides higher and prolonged peritoneal paclitaxel levels with minimal systemic exposure and reduced toxicity.

Targeting of p32 in peritoneal carcinomatosis with intraperitoneal linTT1 peptide-guided pro-apoptotic nanoparticles

“…Compared to free drugs, IP-administered nanoformulated cancer drugs may have favorable pharmacokinetic and biodistribution profiles [45], and at least 2 nano-therapeutics, Abraxane™ and Nanotax™ are being clinically evaluated in PC clinical trials [46,47]. Our study was designed to evaluate the effect of functionalizing NPs with the p32-binding linTT1 peptide on the tumor targeting and antitumor efficacies of drug-loaded NPs upon IP administration.…”

Improving paclitaxel pharmacokinetics by using tumor-specific mesoporous silica nanoparticles with intraperitoneal delivery

“…Their recent Phase I clinical trial demonstrated that IP administration of Nanotax ® particles provides higher and prolonged peritoneal paclitaxel levels with minimal systemic exposure and reduced toxicity compared to IV paclitaxel administration. 9 IP therapy has not been widely accepted despite the positive clinical results, due to catheter-related complications, the high rate of grade 3/4 toxicities and the poor tolerance of the regimen. An implantable, nonresorbable IP micro-device was developed to release a chemotherapeutic agent to the peritoneal cavity at a constant rate.…”

Pharmacokinetic studies and anticancer activity of curcumin-loaded nanostructured lipid carriers

“…administration of chemotherapeutics has obvious advantages in pharmacokinetics, which could elevate the local drug concentration about 450-2900 times compared to systemic chemotherapy (17). A previous report indicated that nanoparticles could target the lymphatic system and act as slow-release formulations after i.p.…”