Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II clinical trials.

Purpose: Dermatofibrosarcoma protuberans (DFSP) is a dermal sarcoma typically carrying a translocation between chromosomes 17 and 22 that generates functional platelet-derived growth factor B (PDGFB).

Patients And Methods: Two distinct phase II trials of imatinib (400 to 800 mg daily) in patients with locally advanced or metastatic DFSP were conducted and closed prematurely, one in Europe (European Organisation for Research and Treatment of Cancer [EORTC]) with 14-week progression-free rate as the primary end point and the other in North America (Southwest Oncology Group [SWOG]) with confirmed objective response rate as the primary end point. In the EORTC trial, confirmation of PDGFB rearrangement was required, and surgery was undertaken after 14 weeks if feasible.

Phase II study of plitidepsin 3-hour infusion every 2 weeks in patients with unresectable advanced medullary thyroid carcinoma.

Objectives: To evaluate the antitumor response, time-to-event efficacy endpoints and toxicity of plitidepsin (Aplidin) 5 mg/m as a 3-hour intravenous (i.v.) infusion every 2 weeks in patients with unresectable advanced medullary thyroid carcinoma (MTC).

A sarcoma at the site of previous extravasation of adriamycin.

We report the case of a 66-year-old man presenting with a high-grade pleomorphic sarcoma at the left elbow 16 years after the extravasation of adriamycin given for a malignant ifbrous histiocytoma of the tibia.We suggest that this sarcoma originated in a multistep way over many years, out of the chronic inflammatory tissue that developed due to a non-specific cellular damage at the nuclear level, interfering with normal cell replication necessary for normal healing tissue healing. As a result, the non-healed chronic inflammatory tissue transformed over several years into a preneoplastic mesenchymal tumour and later into a high-grade pleomorphic sarcoma.

Clinical impact of trabectedin (ecteinascidin-743) in advanced/metastatic soft tissue sarcoma.

Background: Patients with advanced or metastatic non-gastrointestinal stromal tumour soft tissue sarcoma (STS) whose disease progresses during or after chemotherapy with doxorubicin or ifosfamide have few options and very limited life expectancy. In this setting, the DNA and transcription interacting agent trabectedin (ecteinascidin-743), isolated originally from the tunicate Ecteinascidia turbinata, has encouraging activity and is now approved in the European Union.

Objective: To review evidence for the efficacy of trabectedin in STSs.

Intra-hepatic Mitomycin C bolus infusion in the treatment of extensive liver metastases of breast cancer.

Background: In the treatment of extensive liver metastasis of breast cancer (LMBC), locally administered Mitomycin C (MMC) to the liver might be an effective approach with limited toxicity.

Patients And Methods: We retrospectively reviewed the records of 30 patients with LMBC treated with intra-hepatic MMC at our institution. MMC (12 mg) was administered by transcatheter bolus infusion into the hepatic arteries every 4 weeks.

Proteomics in cancer research: methods and application of array-based protein profiling technologies.

With the human genome sequence now determined, the field of molecular medicine is moving beyond genomics to proteomics, the large-scale analysis of proteins. It is now possible to examine the expression of more than 1000 proteins using mass spectrometry technology coupled with various separation methods. Microarray technology is a new and efficient approach, for extracting relevant biomedical data and has a wide range of applications.

A phase II trial of docetaxel (Taxotere) as second-line chemotherapy in patients with metastatic breast cancer.

The efficacy and tolerability of docetaxel 100 mg/m(2) every 3 weeks as second-line chemotherapy in patients with metastatic breast cancer was investigated. In addition, the efficacy of a 3-day prophylaxis against cumulative dose-related fluid retention was examined with methylprednisolone 32 mg twice daily for 3 days starting 12 and 3 h before the docetaxel infusion together with oral cetirizine 10 mg 12 and 3 h before start of docetaxel for prevention of acute hypersensitivity reactions. According to the intent to treat-analysis 35% (95%CI: 25; 46) of the 94 patients entered responded to therapy.

Imatinib for the treatment of patients with unresectable or metastatic malignant KIT-positive gastrointestinal stromal tumours: an open-label Belgian trial.

Background: Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract. They are defined immunohistologically as KIT positive tumours. The only effective treatment for malignant GIST was surgery until 2000.

Imatinib does not induce cardiac left ventricular failure in gastrointestinal stromal tumours patients: analysis of EORTC-ISG-AGITG study 62005.

Recent publications have suggested that imatinib (Glivec) may be cardiotoxic. We have therefore assessed the largest study on the agent performed in patients with gastrointestinal stromal tumours, randomising a daily dose of 400mg versus 800 mg. 946 Patients were entered, 942 patients received at least one dose of imatinib.

A phase I and pharmacokinetic study of LAF389 administered to patients with advanced cancer.

LAF389 is a synthetic analogue of bengamide B, a natural product isolated from Jaspidae sponges. LAF389 has both antiproliferative and antiangiogenetic properties, and preclinical investigations showed a broad antitumour activity. This clinical trial aimed to determine the safety and pharmacokinetic profile of LAF389 administered as a slow intravenous injection for 3 consecutive days every 3 weeks in patients with advanced solid tumours.

Docetaxel and gemcitabine combination therapy in advanced transitional cell carcinoma of the urothelium: results of a phase II and pharmacologic study.

Our objective was to determine the response to gemcitabine plus docetaxel in advanced urothelial transitional cell carcinoma in a phase II trial, and gemcitabine distribution between plasma and erythrocytes, following docetaxel administration. Patients with locally advanced or metastatic transitional cell carcinoma, following a maximum of one prior chemotherapy regimen, were given gemcitabine 800 mg/m on days 1 and 8 plus docetaxel 85 mg/m on day 8, every 21 days. Gemcitabine was measured in the plasma and erythrocytes of nine patients before and after docetaxel administration.

Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial.

Background: No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib.

Methods: Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment.

Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib.

Objective: Our objective was to explore the relationships between imatinib pharmacokinetics and 9 allelic variants in 7 genes coding for adenosine triphosphate-binding cassette transporters (ABCB1 and ABCG2) and enzymes (cytochrome P450 [CYP] 2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) of putative relevance for imatinib.

Methods: Imatinib transport in vitro was studied by use of human embryonic kidney 293 cells transfected with wild-type ABCG2 and an ABCG2 Q141K clone. Steady-state pharmacokinetics of imatinib was obtained in 82 patients with gastrointestinal stromal tumors treated with oral imatinib at doses ranging from 100 to 1000 mg/d.

Predicting toxicities for patients with advanced gastrointestinal stromal tumours treated with imatinib: a study of the European Organisation for Research and Treatment of Cancer, the Italian Sarcoma Group, and the Australasian Gastro-Intestinal Trials Group (EORTC-ISG-AGITG).

The aim of this study was to identify prognostic factors for toxicity to treatment with imatinib. The study was based on 942 patients with gastrointestinal stromal tumours (GIST) randomised to receive imatinib at different doses. The correlation between toxicities occurring with a Common Toxicity Criteria (CTC) grade 2 or more (non-haematological) or grade 3 or 4 (haematological) and imatinib dose, age, sex, performance status, original disease site, site and size of lesions at trial entry, baseline haematological and biological parameters was investigated.

Everolimus alters imatinib blood partition in favour of the erythrocyte.

The signal transduction inhibitor imatinib is one of the latest breakthroughs in cancer pharmacotherapy. It is administered orally over prolonged periods of time for the treatment of gastro-intestinal stromal tumours. Routine therapeutic drug monitoring of blood plasma versus red blood cells over several years by liquid chromatography coupled tandem mass spectrometry has high-lighted a very intriguing phenomenon.

KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours.

A recent randomized EORTC phase III trial, comparing two doses of imatinib in patients with advanced gastrointestinal stromal tumours (GISTs), reported dose dependency for progression-free survival. The current analysis of that study aimed to assess if tumour mutational status correlates with clinical response to imatinib. Pre-treatment samples of GISTs from 377 patients enrolled in phase III study were analyzed for mutations of KIT or PDGFRA by combination of D-HPLC and direct sequencing of tumour genomic DNA.

Imatinib (Gleevec, Glivec) tumour tissue analysis by measurement of sediment and by liquid chromatography tandem mass spectrometry.

The analysis of the signal transduction inhibitor imatinib in patient tumour tissue using LC and MS/MS is described. The anticancer agent is eluted over RP-C18 within 2 mm together with its internal standard STI571-d8. Calibration curves were prepared in red blood cells (RBC).

Cellular uptake of the tyrosine kinase inhibitors imatinib and AMN107 in gastrointestinal stromal tumor cell lines.

Imatinib and AMN107 are protein tyrosine kinase inhibitors which reduce KIT autophosphorylation with similar potency. This report describes the cellular uptake of these compounds in two human gastrointestinal stromal tumor (GIST)-derived cell lines (GIST882 and GIST GDG1), which both express constitutively activated KIT. In GIST882 and GIST GDG1 cell lines, HPLC analysis revealed AMN107 intracellular concentrations to be 7- and 10-fold greater than those of imatinib.

Phase I and pharmacologic study of PKI166, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies.

Purpose: This phase I study was conducted to assess the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor tyrosine kinase inhibitor PKI166 in patients with advanced solid malignancies.

Experimental Design: PKI166 was first given once daily continuously and in the second part of the study once daily for 2 weeks every 4 weeks to establish the maximum tolerated dose (MTD). Ten additional patients were studied at MTD to acquire additional safety information and characterize the effect of food intake on PKI166 pharmacokinetics.

Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group study.

Purpose: The aim of this study was to identify factors predicting initial and late resistance of GI stromal tumor (GIST) patients to imatinib and to document the dose-response relationship in the prognostic subgroups. This study is based on the European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group randomized trial comparing two doses of imatinib in advanced disease.

Patients And Methods: Initial resistance was defined as progression within 3 months of randomization, and late resistance was defined as progression beyond 3 months.

In vitro partition of irinotecan (CPT-11) in human volunteer blood: the influence of concentration, gender and smoking.

We have performed in vitro incubations of blood from male and female volunteers, smokers and non-smokers, with irinotecan at a gradient of different concentrations in order to investigate changes of partition between red blood cells (RBCs), total plasma and the free fraction. Since irinotecan (CPT-11) is not metabolized in vitro, there is no data available on its active metabolite SN-38. After extraction and sample pre-treatment, a validated high-performance liquid chromatography method followed by fluorescence detection was used to determine the concentration of the drug in the different blood constituents.

In vitro partition of docetaxel and gemcitabine in human volunteer blood: the influence of concentration and gender.

We have performed in vitro incubations of blood from male and female volunteers with gemcitabine and docetaxel alone, and in combination, at different concentration gradients in order to investigate changes in partition between red blood cells (RBCs), total plasma and the free fraction. After extraction and sample pre-treatment, a validated high-performance liquid chromatography method followed by UV detection was used to determine the concentrations of both drugs in the different blood constituents. The partition ratio [the concentration in the erythrocytes divided by the concentration in plasma (E/P)] was calculated.

Randomized phase II/III trial of interferon Alfa-2a with and without 13-cis-retinoic acid in patients with progressive metastatic renal cell Carcinoma: the European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group (EORTC 30951).

Purpose: A randomized phase II/III trial was conducted to determine whether combination treatment with 13-cis-retinoic acid (13-CRA) plus interferon alfa-2a (IFN-alpha-2a) was superior to IFN-alpha-2a alone in patients with progressive metastatic renal cell carcinoma.

Patients And Methods: Three hundred twenty patients were randomly assigned to treatment with IFN-alpha-2a plus 13-CRA or to IFN-alpha-2a alone. IFN-alpha-2a was given daily subcutaneously, starting at a dose of 3 million units (MU).

Phase I pharmacokinetic, food effect, and pharmacogenetic study of oral irinotecan given as semisolid matrix capsules in patients with solid tumors.

Purpose: To characterize the maximum-tolerated dose, recommended dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and food effect of orally administered irinotecan formulated as new semisolid matrix capsules.

Experimental Design: Irinotecan was given orally in fasted patients once daily for 5 consecutive days and repeated every 3 weeks. Patients were randomly assigned to take the drug along with a high-fat, high-calorie breakfast for the administration at day 1 of the first or second cycle.