Liposomal cisplatin combined with gemcitabine in pretreated advanced pancreatic cancer patients: A phase I-II study

Abstract

The present trial is a phase I-II study based on a new liposomal cisplatin (lipoplatin). Previous preclinical and clinical data (phase I pharmacokinetics) led to the investigation of a combined treatment modality involving lipoplatin and gemcitabine. The gemcitabine dose was kept standard at 1000 mg/m 2 and the lipoplatin dose was escalated from 25 mg/m 2 to 125 mg/m 2. The treatment was administered to advanced pretreated pancreatic cancer patients who were refractory to previous chemotherapy which included gemcitabine. Lipoplatin at 125 mg/m 2 was defined as dose limiting toxicity (DLT) and 100 mg/m 2 as the maximum tolerated dose (MTD) in combination with 1000 mg/m 2 of gemcitabine. Preliminary objective response rate data showed a partial response in 2/24 patients (8.3%), disease stability in 14 patients (58.3%) for a median duration of 3 months (range 2-7 months) and clinical benefit in 8 patients (33.3%). Liposomal cisplatin is a non-toxic alternative agent to bare cisplatin. In combination with gemcitabine, it has an MTD of 100 mg/m 2 and shows promising efficacy in refractory pancreatic cancer.

In vitro and in vivo reversal of resistance to 5-fluorouracil in colorectal cancer cells with a novel stealth double-liposomal formulation

“…Despite these promising features, with regard to improving of the therapeutic index of anticancer chemotherapies, only doxorubicine (Caelyx s ) has been marketed to date as a liposomal formulation. In addition to anthracyclines, several experimental or clinical studies involving encapsulated gemcitabine, methotrexate and platinum derivatives, have been reported over the past 20 years, but thus far, none of them has made its way to the bedside, in a routine, clinical setting (Doddoli et al, 2005;Stathopoulos et al, 2006;Brusa et al, 2007).…”

The status of platinum anticancer drugs in the clinic and in clinical trials

“…Phase I trials in pancreatic cancer 225 and NSCLC 226 patients in combination with 1000 mg m -2 gemcitabine found MTDs of 100 and 120 mg m -2 , respectively. 215, 216 These regimes produced almost negligible nephrotoxicity, ototoxicity and neurotoxicity following IV infusion.…”

Liposomal polychemotherapy improves adrenocortical carcinoma treatment in a preclinical rodent model

“…Sterically stabilized lipospomal variants of doxorubicin and cisplatin are commercially available and have been shown to exhibit higher therapeutic efficacy or at least better tolerability than the free drugs. Both agents have so far been successfully tested against various solid tumors including breast cancer (Rivera 2003, O'Brien 2008), Kaposi's sarcoma (Coukell & Spencer 1997, Sharpe et al 2002, non-squamous non-small-cell lung cancer (Mylonakis et al 2009, Stathopoulos et al 2011, and pancreatic cancer (Stathopoulos et al 2006), among others. Recently, we have demonstrated an extraordinary uptake phenomenon of liposomes, specifically in adrenocortical tumor cells (Hantel et al 2010(Hantel et al , 2012.…”

“…Although successful liposomal encapsulation has also been described for etoposide with reduced volume of distribution and decreased plasma clearance (Sengupta et al 2000, Sistla et al 2009), this formulation is not yet available as a commercial preparation. As doxorubicin and cisplatin have been shown to result in good therapeutic responses together with paclitaxel (Stathopoulos et al 2006, Leonardi et al 2010, we included two further study arms where etoposide was replaced either with conventional paclitaxel (paclitaxel, doxorubicin, cisplatin plus mitotane (PDP-M)) or with a novel nanotechnologically optimized variant of this drug (nab-paclitaxel, LPDP-M (nab-paclitaxel, liposomal doxorubicin, liposomal cisplatin plus mitotane)).…”