Phase 1 trial of lipoplatin and gemcitabine as a second‐line chemotherapy in patients with nonsmall cell lung carcinoma

Abstract

BACKGROUND.Lipoplatin is a new liposomal cisplatin that already has been tested in solid tumors, with encouraging results. The purpose of the current study was to determine the maximum tolerated dose (MTD) and the dose‐limiting toxicity (DLT) of a 21‒day regimen of lipoplatin plus a fixed dose of gemcitabine in patients with refractory or resistant nonsmall cell lung carcinoma (NSCLC) with an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.METHODS.The lipoplatin dose was escalated at 100 mg/m2 by increments of 10 mg/m2 on Days 1 and 8, with gemcitabine at a dose of 1000 mg/m2 administered on Days 1 and 8, repeated every 21 days. Hematopoietic growth factors were not allowed. Thirteen patients with advanced stage NSCLC who had been pretreated with platinum combination chemotherapy were enrolled in this phase 1 trial. At least 3 patients were entered at each dose level.RESULTS.At the fourth dose level, the DLT was reached (grade 3 neutropenia [according to World Health Organization criteria] in 3 of 4 patients 75%]; the fourth patient demonstrated degradation of performance status). Therefore, the third dose level (lipoplatin at a dose of 120 mg/m2) was defined as the MTD. At the same dose level, 2 of 4 patients had grade 3 thrombocytopenia. At the fourth dose level, 1 patient achieved a partial response and 1 patient had stable disease. Another patient achieved stable disease at the second dose level. Therefore, the overall disease control rate was 23% (3 of 13 patients). The median overall survival was 29 weeks (range, 4 weeks‐59 weeks) and the median time to disease progression was 12 weeks (range, 3 weeks‐36 weeks).CONCLUSIONS.The pharmacokinetic profile of the 2 compounds used in the current study are not modified when they are administered according to the schedule evaluated in this trial. When one considers that the patients in the current study had refractory or resistant NSCLC, the authors concluded that the combination of lipoplatin administered at a dose of 120 mg/m2 and gemcitabine administered at a dose of 1000 mg/m2 on Days 1 and 8 every 3 weeks needs to be studied further in phase 2 trials. Cancer 2008. © 2008 American Cancer Society.

Intrapleural administration of lipoplatin in an animal model

“…Total platinum concentrations were determined in plasma using a GF-AAS (Graphite Furnace Atomic Absorption Spectrometry) assay using an Ati-Unicam model 939QZ, as previously described [14,18]. The quantification limit was 0.02 g/ml and the detection limit was 0.01 g/ml.…”

“…Preclinical studies on lipoplatin showed a low toxicity profile, an ability to concentrate in tumors and to escape immune cells and macrophages, a slow clearance rate from the kidneys, long circulation properties in body fluids, a half-life of 36 h in the blood, and promising therapeutic efficacy [11]. Phase I studies of lipoplatin alone [13] or in combination with antimetabolites [14] showed efficacy in patients with solid tumors and an excellent toxicity profile. This compound has also shown activity and low toxicity in association with gemcitabine in pleural and peritoneal mesothelioma [15].…”

Concurrent Liposomal Cisplatin (Lipoplatin), 5-Fluorouracil and Radiotherapy for the Treatment of Locally Advanced Gastric Cancer: A Phase I/II Study

“…In this study, the highest platinum levels among all tissues examined were found in gastric cancer specimens, most likely reflecting the high degree of vascularization of these tumors and the ability of the nanoparticle formulation for extravasation through the compromised endothelium of the tumor (17). In a Phase I trial performed at our institution in lung cancer patients, Froudarakis et al suggested that the maximum tolerated dose of Lipoplatin, when given together with gemcitabin, is 120 mg/m 2 for two weekly cycles, repeated every 21 days (12). Based on the above data, we postulated that Lipoplatin represents a candidate drug to test its activity together with radiation.…”

“…5-Fluorouracil (400 mg/m 2 ), leucovorin (200 mg flat dose), and Lipoplatin (120 mg/m 2 ) were administered on day 1 of each week. The choice of the Lipoplatin dose was based on the previous experience from our institute on a Phase II trial in lung cancer (12). Lipoplatin was diluted in 1L of D/W (dextrose 5% in water) and was administered as a 3 h infusion at an outpatient basis.…”

Phase II study of liposomal cisplatin (Lipoplatin™) plus gemcitabine versus cisplatin plus gemcitabine as first line treatment in inoperable (stage IIIB/IV) non-small cell lung cancer

“…Pharmacokinetics, safety and efficacy were studied in several phase I and II studies [37][38][39][40][41]; halflife was shown to be between 30 and 50 h depending on the dose, in comparison to 6 h for cisplatin. There was no need for pre-or posthydration during Lipoplatin administration contrary to cisplatin.…”