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Biomedical subjects

K Mross

Publications and source records attributed to K Mross.

At least 19 recordsLinked to original sources
PubMed2007

Variants in the SLCO1B3 gene: interethnic distribution and association with paclitaxel pharmacokinetics.

To explore retrospectively the relationships between paclitaxel pharmacokinetics and three known, non-synonymous single-nucleotide polymorphisms (SNPs) in SLCO1B3, the gene encoding organic anion transporting polypeptide (OATP)1B3. Accumulation of [(3)H]paclitaxel was studied in Xenopus laevis oocytes injected with cRNA of Oatp1b2, OATP1A2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and NTCP. The 334T>G (Ser112Ala), 699G>A (Met233Ile), and 1564G>T (Gly522Cys) loci of SLCO1B3 were screened in 475 individuals from five ethnic groups and 90 European Caucasian cancer patients treated with paclitaxel. Only OATP1B3 was capable of transporting paclitaxel to a significant extent (P=0.003). The 334T>G and 699G>A SNPs were less common in the African-American and Ghanaian populations (P<0.000001). Paclitaxel pharmacokinetics were not associated with the studied SNPs or haplotypes (P>0.3). The studied SNPs in SLCO1B3 appear to play a limited role in the disposition of paclitaxel, although their clinical significance in other ethnic populations remains to be investigated.

Animals↗
PubMed2006

Results from an in vitro and a clinical/pharmacological phase I study with the combination irinotecan and sorafenib.

PURPOSE: This single-centre, open-label, phase I dose-escalation study was performed to investigate the safety, pharmacokinetics (PK) and efficacy of sorafenib, a multi-kinase inhibitor, combined with irinotecan, a cytotoxic agent, in patients with advanced, refractory solid tumours. PATIENTS AND METHODS: In an initial dose-escalation phase, patients received irinotecan 125 mg/m(2) and sorafenib 100, 200 and 400 mg twice daily (bid) (cohorts 1-3). In an extended phase, colorectal cancer (CRC) patients received fixed-dose irinotecan 140 mg and sorafenib 400 mg bid (cohort 4). RESULTS: Thirty-four patients were treated: 20 in the dose-escalation phase (common tumour types: CRC [45%], ovarian [5%], pancreatic [5%]) and 14 patients in the CRC extension. Frequent drug-related adverse events were gastrointestinal symptoms, dermatological reactions and constitutional symptoms. The maximum tolerated dose was not reached. Generally, concomitant administration of irinotecan had no impact on the PK of sorafenib. Sorafenib 100 or 200 mg bid had no impact on the PK of irinotecan or its metabolite SN38. In contrast, sorafenib 400 mg bid significantly increased irinotecan and SN38 exposures; however, this was not associated with increased toxicities. Stable disease was achieved in 12/20 (60%) evaluable patients in cohorts 1-3, and 10/13 (77%) evaluable patients in cohort 4. A further patient from cohort 4 had a partial response of >200 days. The increase of SN38 exposure might be due to inhibition of formation of the SN38 glucuronide by sorafenib. In vitro, sorafenib strongly inhibited SN38 glucuronidation in human liver microsomes as indicated by a K(i) value of 2.7 micromol/l. CONCLUSION: Sorafenib 400 mg bid can be combined with irinotecan 125 mg/m(2) or 140 mg for the treatment of patients with advanced, refractory solid tumours, although monitoring for toxicity is recommended.

Adult↗
PubMed2005

Vinorelbine alternating oral and intravenous plus epirubicin in first-line therapy of metastatic breast cancer: results of a multicentre phase II study.

The combination of intravenous (i.v.) vinorelbine and epirubicin is highly active in the treatment of metastatic breast cancer (MBC). In an effort to improve patient convenience, we investigated a regimen alternating i.v. and oral vinorelbine in combination with epirubicin as first-line chemotherapy of patients with MBC. In all, 49 patients with MBC received, as first-line treatment, a combination regimen consisting of i.v. vinorelbine 25 mg m(-2) plus epirubicin 90 mg m(-2) given on day 1, and oral vinorelbine 60 mg m(-2) on day 8 (or day 15 if neutrophils <1500 mm(-3)) every 3 weeks, in an open-label, multicentre phase II study. Treatment was to be repeated for a maximum of six cycles. The study population had a median age of 55 years, half of the patients had received prior adjuvant chemotherapy and 86% presented a visceral involvement. In all, 25 responses were documented and validated by an independent panel review, yielding response rates of 51% (95% CI: 36-66) in the 49 enrolled patients and 54.5% (95% CI: 39-70) in the 44 evaluable patients. Median durations of progression-free survival and survival were 8 and 20 months, respectively. Neutropenia was the main dose-limiting toxicity, but complications were uncommon, four patients having experienced febrile neutropenia and six having developed neutropenic infection. Other frequently reported adverse events included stomatitis, nausea and vomiting, which were rarely severe. No toxic death was reported. Among patients who received six cycles, global score of quality of life remained stable. This regimen alternating oral and i.v. vinorelbine in combination with epirubicin is effective and safe. Oral vinorelbine on day 8 offers greater convenience to the patient, and decreases the need for i.v. injection and reduces time spent in hospital. Therefore, oral vinorelbine is a convenient alternative to the i.v. form in combination regimens commonly used to treat MBC.

Administration, Oral↗
PubMed2005

Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two phase I trials.

BACKGROUND: Plasma and serum biomarkers of angiogenesis and activated endothelial cells were evaluated to assess biological activity of PTK787/ZK 222584 (PTK/ZK), a novel oral angiogenesis inhibitor targeting all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases. PATIENTS AND METHODS: Patients with colorectal cancer (CRC) (n=63) were enrolled into two phase I/II dose escalation trials of PTK/ZK in 28-day cycles until discontinuation. Patients with stable disease for > or =2 months were categorized as 'non-progressors'. Plasma markers of angiogenesis, VEGF-A and basic fibroblast growth factor (bFGF), and the serum markers of activated endothelial cells, sTIE-2 and sE-Selectin, were assessed at baseline, and pre-dose on days 1, 8, 15, 22 and 28 of every cycle, with additional assessments 10 h post-dose on days 1 and 15. The percentage change from baseline was subsequently correlated with AUC and C(max) of PTK/ZK on day 1, cycle 1 and clinical outcome. RESULTS: A dose-dependent increase in plasma VEGF-A and bFGF was observed in the first cycle of PTK/ZK treatment. The correlation of change in plasma VEGF-A with AUC and C(max) was characterized by an E(max) model, suggesting that a change of > or =150% from baseline VEGF-A correlated with non-progressive disease. Change from baseline plasma VEGF-A within the first cycle of treatment was significantly correlated with clinical outcome by logistic regression analysis (P=0.027). CONCLUSIONS: In patients with CRC treated with PTK/ZK, changes in plasma VEGF-A and bFGF demonstrate biological activity of PTK/ZK, may help to establish optimal dose and correlate with outcome.

Aged↗
PubMed2004

[Adjuvant and palliative anticancer treatment of colon carcinoma in 2004].

This article reviews the available data regarding the acticity of postoperative adjuvant systemic therapy for colorectal cancer as first and second-line treatment in metastatic disease. The efficacy of adjuvant treatment of patients with stage III colorectal cancer is well established. 5-fluorouracil (5-FU) and folic acid over 6 months (still) represent todays standard and should serve as comparison in randomized studies. The risk of relapse is low in stage II colon carcinoma and consequently the efficacy is relatively small compared to stage III. New investigation indicate, Capecitabene has the potential to replace 5-FU/FS as standard treatment for patients with colon cancer. Efficacy results are expected to be available in 2004. In metastatic disease combination of 5-FU/folic acid plus CPT-11 or OXA are treatment of choice for the first-line therapy of metastatic colorectal carcinoma. FOLFOX is high-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second- line therapy for metastatic colorectal cancer. It resulted in prolongation of the median progress free survival from 6,8 to 8,8 months and increased the survival for 4,5 months. New perspectives are novel chemotherapeutic and targeted agents in metastatic colorectal cancer: For the first time, there has been a targeted therapy shown convincingly to prolong survival for patients with unresectable metastatic colorectal cancer in a well-performed Phase III trial. This agent is bevacizumab, a humanised monoclonal antibody targeting the circulating proangiogenic growth factor vascular endothelial growth factor. Results with bevacizumab should lead to rapid expansion of the number of strategies targeting tumour neovasculature. Additionally, an antibody against the epidermal growth factor, cetuximab, has been shown to have both single-agent activity and the potential ability to partially reverse resistance to a chemotherapy drug. These advancements, as well as data on other novel treatment agents that have been studied specifically in patients with colorectal neoplasms, are discussed in detail.

Antibodies, Monoclonal↗
PubMed2004

A phase I clinical and pharmacokinetic study of the camptothecin glycoconjugate, BAY 38-3441, as a daily infusion in patients with advanced solid tumors.

BACKGROUND: The aim of this study was to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of the camptothecin glycoconjugate BAY 38-3441, administered as an infusion for 30 min on two separate schedules every 3 weeks. PATIENTS AND METHODS: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules. RESULTS: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses > or = 470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses > or = 320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear. CONCLUSIONS: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.

Camptothecin↗
PubMed2003

Altered clearance of unbound paclitaxel in elderly patients with metastatic breast cancer.

The pharmacokinetic behaviour of anticancer drugs may be altered with aging due to (for example) differences in body composition and decreased hepatic and renal function. To address this issue for paclitaxel, we studied the pharmacokinetics of the drug in eight elderly women (>or=70 years) with metastatic breast cancer (median age (range), 77 years (70-84 years)) and a control group of 15 patients aged <70 years (median age (range), 54 years (22-69 years)). Paclitaxel was administered as a 1-h intravenous (i.v.) infusion at a dose of 80 (elderly) or 100 mg/m(2) (<70 years), and serial blood samples were obtained at baseline, and up to 24 h after the end of infusion. Paclitaxel concentration-time profiles were fitted to a linear three-compartment model without any demonstration of saturable behaviour. The clearance of unbound paclitaxel was 124+/-35.0 (elderly) versus 247+/-55.4 l/h/m(2) (<70 years) (P=0.002), and was inversely related to the patient's age (R(2)=0.857; P<0.00001). Total plasma clearance of the formulation vehicle Cremophor EL (CrEL) was 150+/-60.7 (elderly) versus 115+/-39.2 ml/h/m(2) (<70 years) (P=0.04). These data indicate an approximately 50% change in total body clearance of unbound paclitaxel and a concomitant significant increase in systemic exposure with age, most likely as a result of altered CrEL disposition. The clinical relevance of these observations with respect to toxicity profiles and antitumour efficacy requires further evaluation.

Adult↗
PubMed2002

Comparison of 1-hour and 3-hours paclitaxel infusion pharmacokinetics: results from a randomized trial.

PURPOSE: Aim of this study was to characterize the difference in pharmacokinetics (PK) of paclitaxel (PAC) after 1-h and 3-h infusion in humans and to define a pharmacodynamic relationship between PAC PK and myelotoxicity. PATIENTS AND METHODS: PAC PK were studied during the first PAC application in the first treatment cycle (1 treatment cycle = 6 PAC applications) in 25 patients. This patient group represents a subgroup of a large clinical study with neurotoxicity as primary endpoint. These 25 patients were those patients who were willing to give additional blood samples. The group size was sufficient for a full description of the PK of PAC. PAC was administered at 100 mg/m(2) weekly by 1-h (n = 12) or 3-h (n = 13) infusion to patients with advanced cancer (lung, breast, ovarian, cervix, and head and neck). Total PAC was quantified by high-performance liquid chromatography (HPLC). Pharmacokinetic parameters were calculated by noncompartmental and model-dependent methods. The leukocyte and neutrophil decrease during a 6-week treatment period was calculated by the percentage in decrease of white blood cell count (WBC) and absolute neutrophil count (ANC) as well as the area over the curve (AOC) of WBC and ANC. RESULTS: The area under the curve (AUC), the plasma clearance (Clp), the volume of distribution at steady state (V(ss)), the mean residence time (MRT) and the distribution half-life (t(1/2)) of PAC(tot) were not different in the two application modes. The elimination half-life (t1/2) and maximum plasma concentration C(max) were significantly different. No significant differences in the percentage of reduction of WBC and ANC were seen. Calculation of AOC of WBC showed a borderline significant difference (p = 0.0547) in case of WBC and no significant difference in case of ANC between the two PAC schedules. A considerable variance of AOC was observed. CONCLUSION: The pharmacokinetic study of total PAC of the two schedules investigated showed significant differences in the elimination half-life, which is longer in case of the 1-h infusion of PAC and in the maximum plasma concentration, which is higher in case of the 1-h infusion. The two schedules showed a similar myelotoxicity with a trend of less toxicity in the 1-h procedure.

Adult↗
PubMed2001

[Chemotherapy of colonic carcinoma in the year 2001].

The systemic anticancer drug therapy is indicated in the adjuvant as well as in the palliative setting. There is an indication for an adjuvant therapy in case of Dukes B (stadium II) as well as in Dukes C (stadium III) colon cancer. An indication in the palliative setting remains for the Dukes D (stadium IV) colon cancer patients. Locoregional chemotherapeutical approaches represent no standard procedure and cannot be recommended outside clinical trials because the real value of this therapy is unknown due to a lack of large randomized trials. The mainstay of treatment of colon cancer is 5-Fluoruracil (5-FU), which should be combined with folinic acid in case of bolus (2-4 min. injection) therapy. In the adjuvant situation the Mayo scheme administered over a period of half a year remains the standard of choice because this procedure is validated by large randomized trials and replaces the combination 5-FU + levamisol given over a period of one year in former times. In the palliative situation 5-FU based therapy remains the goldstandard although more options than 5-FU plus folinic acid are now available. Oxaliplatin and irinotecan are approved for the treatment of metastatic colon cancer in first line in combination with 5-FU. Capecitabine and Ralitrexed are drugs, which are approved outside of Germany and can be used as well if indicated. The median survival of patients with metastatic colon cancer is between 12 and 18 month. It will be discussed in which way this range depends on the chemotherapeutical strategy.

Antineoplastic Agents↗
PubMed2001

Phase II study of combined 5-fluorouracil/ Ginkgo biloba extract (GBE 761 ONC) therapy in 5-fluorouracil pretreated patients with advanced colorectal cancer.

The aim of the study was to evaluate the efficacy, tolerability and quality of life in 5-fluorouracil (5-FU) pretreated colorectal cancer patients after combined 5-FU and Ginkgo biloba extract GBE 761 ONC (i.e. the Ginkgo biloba special extract EGb 761(R)) therapy. Following conventional 5-FU therapy, 44 patients (32 evaluable for response) with advanced progressive colorectal cancer were treated every 3 weeks with courses of 350 mg GBE 761 ONC as a 30 min i.v. infusion on days 1-6 followed by 500 mg/m(2)/d 5-FU as a 30 min i.v. infusion on days 2-6. The response to therapy was evaluated after the second and fourth course of treatment. The data of 32 patients could be evaluated for efficacy. We observed a progression of disease in 22 patients, no change in 8 patients and a partial response in 2 patients (overall response = 6.3%). Seventeen of 22 patients with observed progressive disease showed further progression after two cycles, two after three cycles and three after four cycles. The median survival time was 9.5 months (7.7-11.5 months). GBE 761 ONC was well tolerated. Adverse events that occurred during the study were mainly myelosuppression and gastrointestinal symptoms and were judged to be 5-FU related or consistent with liver toxicity and thus tumour related. Our results suggest a good benefit-risk ratio of the combined 5-FU and GBE 761 ONC therapy as second line treatment in metastatic colorectal cancer. The survival time was similar to that known from second line treatment according to the Ardalan scheme. Since an improvement was observed in some patients despite the failure of the conventional 5-FU pretreatment, it would be interesting to evaluate whether the application of 5-FU plus GBE 761 ONC as a first line treatment is of benefit.

Antineoplastic Combined Chemotherapy Protocols↗