Vascular effects, efficacy and safety of nintedanib in patients with advanced, refractory colorectal cancer: a prospective phase I subanalysis.

BACKGROUND: Nintedanib is a potent, oral angiokinase inhibitor that targets VEGF, PDGF and FGF signalling, as well as RET and Flt3. The maximum tolerated dose of nintedanib was evaluated in a phase I study of treatment-refractory patients with advanced solid tumours. In this preplanned subanalysis, the effect of nintedanib on the tumour vasculature, along with efficacy and safety, was assessed in 30 patients with colorectal cancer (CRC). METHODS: Patients with advanced CRC who had failed conventional treatment, or for whom no therapy of proven efficacy existed, were treated with nintedanib ranging from 50-450 mg once-daily (n = 14) or 150-250 mg twice-daily (n = 16) for 28 days. After a 1-week rest, further courses were permitted in the absence of progression or undue toxicity. The primary objective was the effect on the tumour vasculature using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and expressed as the initial area under the DCE-MRI contrast agent concentration-time curve after 60 seconds (iAUC60) or the volume transfer constant between blood plasma and extravascular extracellular space (Ktrans). RESULTS: Patients received a median of 4.0 courses (range: 1-13). Among 21 evaluable patients, 14 (67%) had a ≥40% reduction from baseline in Ktrans and 13 (62%) had a ≥40% decrease from baseline in iAUC60, representing clinically relevant effects on tumour blood flow and permeability, respectively. A ≥40% reduction from baseline in Ktrans was positively associated with non-progressive tumour status (Fisher's exact: p = 0.0032). One patient achieved a partial response at 250 mg twice-daily and 24 (80%) achieved stable disease lasting ≥8 weeks. Time to tumour progression (TTP) at 4 months was 26% and median TTP was 72.5 days (95% confidence interval: 65-114). Common drug-related adverse events (AEs) included nausea (67%), vomiting (53%) and diarrhoea (40%); three patients experienced drug-related AEs ≥ grade 3. Four patients treated with nintedanib once-daily had an alanine aminotransferase and/or aspartate aminotransferase increase ≥ grade 3. No increases > grade 2 were seen in the twice-daily group. CONCLUSIONS: Nintedanib modulates tumour blood flow and permeability in patients with advanced, refractory CRC, while achieving antitumour activity and maintaining an acceptable safety profile.

FOLFIRI and sunitinib as first-line treatment in metastatic colorectal cancer patients with liver metastases--a CESAR phase II study including pharmacokinetic, biomarker, and imaging data.

BACKGROUND: The aim of this study was the evaluation of pharmacokinetic parameters, biomarkers, clinical outcome, and imaging parameters in metastatic colorectal cancer (mCRC) patients treated with FOLFIRI plus sunitinib. METHODS: mCRC patients with liver metastases were treated with FOLFIRI and sunitinib as 1st line therapy. At protocol-defined time points, multicontrast magnetic resonance imaging (MRI)measurements, computed tomography (CT) scans, pharmacokinetics (PK), and biomarker analyses were performed during the first and second treatment cycle. Thereafter, patients were treated until tumor progression, investigator’s decision due to toxicity, or patient withdrawal. RESULTS: 28 patients were screened, 26 were included, and 23 received at least one study medication. Full safety analysis was performed in 23 patients. Full PK and biomarker analyses were performed in 21 patients. Strong responses in tumor size reduction forced a change from the original imaging timing scheme. This unforeseen change in the timing scheme resulted in subgroups too small for meaningful statistical analysis of most imaging parameters. Thus, only a descriptive analysis of the MRI data was possible. In 21/22 patients, MRI showeda decrease of the liver metastases. Best response was partial remission (PR) in 8/17 patients. Plasma concentrations of sVEGFR-2 and sVEGFR-3 decreased in all patients. The majority of the patients developed some kind of toxicity not always deducible to FOLFIRI or sunitinib. CONCLUSIONS: Due to the observed side effect profile, FOLFIRI plus sunitinib 37.5 mg per day cannot be recommended for previously untreated mCRC.

Correction to: Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer.

The article Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer.

Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer.

BACKGROUND: Dual inhibition of PI3K and MAPK signaling is conceptually a promising anticancer therapy. OBJECTIVE: This phase 1b trial investigated the safety, maximum tolerated dose (MTD), recommended phase II dose, pharmacokinetics, tumor response, fluorodeoxyglucose positron emission tomography (FDG-PET) pharmacodynamics, and biomarker explorations for the combination of pan-PI3K inhibitor copanlisib and allosteric MEK inhibitor refametinib in patients with advanced solid tumors. PATIENTS AND METHODS: This was an adaptive trial with eight dose cohorts combining dose escalation and varying schedules in repeated 28-day cycles. Patients received copanlisib (0.2-0.8 mg/kg intravenously) intermittently (days 1, 8, 15) or weekly (days 1, 8, 15, 22) each cycle, and refametinib (30-50 mg twice daily orally) continuously or 4 days on/3 days off. Patients with KRAS, NRAS, BRAF, or PI3KCA mutations were eligible for the expansion cohort. RESULTS: In the dose-escalation (n = 49) and expansion (n = 15) cohorts, the most common treatment-emergent adverse events included diarrhea (59.4%), nausea, acneiform rash, and fatigue (51.6% each). Dose-limiting toxicities included oral mucositis (n = 4), increased alanine aminotransferase/aspartate aminotransferase (n = 3), rash acneiform, hypertension (n = 2 each), and diarrhea (n = 1). MTD was copanlisib 0.4 mg/kg weekly and refametinib 30 mg twice daily. No pharmacokinetic interactions were identified. Decreased tumor FDG uptake and MEK-ERK signaling inhibition were demonstrated during treatment. Best response was stable disease (n = 21); median treatment duration was 6 weeks. CONCLUSIONS: Despite sound rationale and demonstrable pharmacodynamic tumor activity in relevant tumor populations, a dose and schedule could not be identified for this drug combination that was both tolerable and offered clear efficacy in the population assessed. CLINICALTRIALS. GOV IDENTIFIER: NCT01392521.

Phase II STUdy with 3rd- or 4th-line bendamustine (flat dose) therapy in patients with metastatic breast cancer.

BACKGROUND: Bendamustine is a drug with a favorable side effect spectrum and it offers a chance to overcome tumor resistance in pretreated patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Bendamustine was given as flat dose with 200 mg at days 1 + 2 in MBC patients pretreated with 2-3 different chemotherapies. Therapy was repeated at day 28 or fully recovered neutrophils. After 2 treatment cycles, a tumor response evaluation was performed. Toxicity was graded according to the National Cancer Institute common toxicity criteria (NCI-CTC) catalogue. RESULTS: 22 patients were evaluated for toxicity. 4 patients dropped out before the first tumor response evaluation; thus, 18 patients were evaluable for anticancer efficacy evaluation. 3/18 patients reached a partial remission (PR), 4 stable disease and 11 showed progression after 2 treatment cycles. The time to progression (TTP) was 5 months in patients with PR and 4 months in patients with no change (NC). In patients with progressive disease (PD), TTP was < 2 months. The main toxicities were nausea, weight loss and fatigue. CONCLUSIONS: Bendamustine can be given with a fixed flat dose, which simplifies the drug preparation. 2/5th of all treated patients responded to this therapy whereas bendamustine showed no anticancer effect in 3/5th of all patients. Bendamustine is definitely a drug with anticancer potential.

Phase I and pharmacokinetic study of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin.

PURPOSE: The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that shows superior antitumor efficacy in murine tumor models and a favorable toxicity profile in mice, rats, and dogs compared with doxorubicin. The purpose of the phase I study was to characterize the toxicity profile of DOXO-EMCH, establish a recommended dose for phase II studies, and assess potential anticancer activity. EXPERIMENTAL DESIGN: A starting dose of 20 mg/m2 doxorubicin equivalents was chosen. Forty-one patients with advanced cancer disease were treated with an i.v. infusion of DOXO-EMCH once every 3 weeks at a dose level of 20 to 340 mg/m2 doxorubicin equivalents. RESULTS: Treatment with DOXO-EMCH was well tolerated up to 200 mg/m2 without manifestation of drug-related side effects. Myelosuppression (grade 1-2) and mucositis (grade 1-2) were the predominant adverse effects at dose levels of 260 mg/m2 and myelosuppression (grade 1-3) as well as mucositis (grade 1-3) were dose limiting at 340 mg/m2. No cardiac toxicity was observed. Of 30 of 41 evaluable patients, 12 patients (40%) had progressive disease, 15 patients (57%) had stable disease, and 3 patients (10%) had a partial remission. CONCLUSIONS: DOXO-EMCH showed a good safety profile and was able to induce tumor regressions in tumor types known to be anthracycline-sensitive tumors, such as breast cancer, small cell lung cancer, and sarcoma. The recommended doxorubicin equivalent dose for phase II studies is 260 mg/m2.

Risk assessment of Bundeswehr (German Federal Armed Forces) permethrin-impregnated battle dress uniforms (BDU).

In an age when vector-borne diseases are emerging worldwide, personal protective measures are essential for shielding soldiers and other exposed persons from arthropod attack. The development of permethrin-impregnated clothing has been one recent advance in protecting persons at-risk. However, to date risk assessment has not been performed related to wearing permethrin-impregnated clothing over longer time periods. Therefore, this paper describes relevant toxicological aspects of permethrin and estimates the extent of dermal permethrin uptake by soldiers wearing impregnated uniforms by determining urine metabolites of permethrin. The exposure monitoring conducted in wearers of untreated uniforms did not show any signs of increased permethrin uptake and was similar to that of the general population in Germany. By contrast, studies involving the soldiers wearing permethrin-impregnated uniforms identified far higher internal exposure, the amounts of urine metabolites clearly above the reference value for the background exposure of the German population at large. Comparing the median excretion values, an approximately 200 times higher exposure can be assumed. The excretion levels of the subject with the maximum amount of metabolites correspond to an internal exposure of around 5-6microg/kg body weight and day thereby considering that biomonitoring could not take all urine metabolites and other elimination routes into account. Based on an oral absorption rate of 50%, the internal dose of 5-6microg/kg body weight and day would correspond to an oral uptake of permethrin which is around 20% of the ADI value of 50microg/kg body weight and day. In addition, based on these data and using a dermal absorption rate of 2% the permethrin dose reaching the skin was estimated to be 250microg/kg body weight and day. Considering a standard body weight and the area covered by the uniform, an exposure level of about 1.25microg permethrin/cm(2) skin and day can be calculated. Clinical subjective symptoms were recorded by means of a self-reporting questionnaire which has been developed and used for this specific purpose in environmental outpatient departments in both groups (wearers of impregnated versus non-impregnated uniforms). Only minor sensory impairments were identified in one of the studies (Kabul/Afghanistan) which may represent skin paraesthesiae. Based on these results, it can be assumed that the normal use of permethrin-treated uniforms does not affect human health to a clinical relevant extent. We recommend that the release rate of permethrin from the textile material should be strictly monitored by means of a quality assurance method. It should comply with standards to which the results of this study may contribute.

Metronomic antiangiogenic therapy with capecitabine and celecoxib in advanced tumor patients--results of a phase II study.

BACKGROUND: Combined therapy of continuous low dose capecitabine and high dose celecoxib targeting angiogenesis was used in a phase II trial to treat advanced cancer patients. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to monitor antiangiogenic effects. MATERIAL AND METHODS: 37 Patients (21 men, 16 women), mean age 60 years, with advanced and progressive cancer of various tumor types were included. Therapy consisted of 2 x 500 mg oral capecitabine/ day and 2 x 400 mg oral celecoxib/day continuously until progression of disease. To monitor antiangiogenic effects, DCE-MRI measurements were performed at baseline, after 1 month, and after 3 months of therapy. Tumor assessment was performed according to RECIST criteria, toxicity was evaluated according to the CTC version 2.0 catalogue. RESULTS: Therapy was well tolerated without grade 3 and 4 toxicities. The mean number of treatment cycles was 4 (range: 1-15+). Disease stabilization after 3 cycles was seen in 11 patients. 6 patients were stable over long periods. The mean number of treatment cycles in this group was 10 (range: 7-15+). DCE-MRI demonstrated a reduction of tumor vessel permeability and blood flow in patients who reached stable disease or some minor regression. CONCLUSION: Continuous dosing of the combination of capecitabine and celecoxib was well tolerated, produced antiangiogenic effects, and has antitumor activity. Patients with rapid progression did not benefit.

Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer.

PURPOSE: In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated. PATIENTS AND METHODS: Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus. RESULTS: Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%). CONCLUSION: In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.

Peripheral neuropathy: a persisting challenge in paclitaxel-based regimes.

Cumulative peripheral neuropathy (PNP) still remains a limitation to optimal treatment with paclitaxel (PAC), especially in more dose-dense schedules. This primary sensory PNP may affect the majority of patients after administration of certain cumulative dosages of PAC, while the exact mechanisms of PAC-induced PNP are not known. While a number of preclinical models revealed its vehicle Cremophor EL (CrEL) to be mainly responsible for ganglionopathy, axonopathy and demyelination, clinical data also supports a strong and independent effect of PAC itself, which is most likely based on disturbances in the microtubules in perikaryons, axons and glia cells. Indeed, clinical trials of CrEL-free formulations of PAC still report grade III neurotoxicity as dose-limiting. As treatment options of PAC-induced PNP are rare the use of specific scoring systems for screening purposes is strongly encouraged. In this report we review and discuss the pathogenesis, incidence, risk factors, diagnosis, pharmacodynamics and treatment options for PAC-induced PNP.

Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia.

Here, we evaluated the relationships between ABCB1 (P-glycoprotein, MDR1) polymorphisms and paclitaxel (Taxol)-induced toxicity and pharmacokinetics. Twenty-six patients were assessable for pharmacogenetics and pharmacokinetics, 22 for neurotoxicity and 18 for myelotoxicity. Patients carrying two reference alleles for the ABCB1 3435C>T polymorphism trended toward a reduced risk to develop neuropathy as compared to patients carrying at least one variant allele (P=0.09). Additionally, patients who were homozygous variant at the 2677 and 3435 loci had a significantly greater percent decrease in absolute neutrophil count at nadir (P=0.02). Neither polymorphism correlated with paclitaxel pharmacokinetics. This pilot study suggests that paclitaxel-induced neuropathy and neutropenia might be linked to inherited variants of ABCB1 through a mechanism that is unrelated to altered plasma pharmacokinetics.

Association of Paclitaxel pharmacokinetics with the development of peripheral neuropathy in patients with advanced cancer.

PURPOSE: The shortening of infusion time from 3 to 1 hour decreases the systemic exposure (area under the curve, AUC) of total and unbound paclitaxel but increases the AUC of its vehicle Cremophor EL, whereas the time above total paclitaxel concentrations of 0.05 micromol/L (T >0.05) remains almost constant. As both Cremophor EL and paclitaxel are neurotoxic, we evaluated their pharmacodynamic effects on the development of peripheral neuropathy as the most important nonhematologic toxicity. EXPERIMENTAL DESIGN: Patients with advanced cancer of different origin were randomized to receive a maximum of 12 weekly-given 1- or 3-hour infusions of 100 mg/m2 paclitaxel (Taxol). Twenty-four patients were assessable for both pharmacokinetics and peripheral neuropathy development evaluated by a clinical scoring system including sensory symptoms, strength, tendon reflexes, and vibratory sense. RESULTS: Patients with peripheral neuropathy development (n=14) received more weeks of therapy (P=0.056) and showed significantly higher T(>0.05) (P=0.022) and overall systemic drug exposures (weeks of therapy x AUC) for total paclitaxel (P=0.002) and unbound paclitaxel (P=0.003) than those without peripheral neuropathy. In Kaplan-Meier analyses, T(>0.05) > or = 10.6 hours (P=0.023), AUC of total paclitaxel > or = 4.7 microg/mL x hour (P = 0.047), and AUC of unbound paclitaxel > or = 0.375 microg/mL x hour (P = 0.095) were identified as being potential factors for peripheral neuropathy development. In a Cox regression analysis, only T(>0.05) > or = 10.6 hours remained as an independent risk factor (relative risk, 18.43; P = 0.036) after adjusting for prior vincamycin (relative risk, 11.28; P = 0.038). CONCLUSIONS: From the results obtained in this study, it is concluded that exposure to paclitaxel but not Cremophor EL is associated with peripheral neuropathy development.

Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel.

PURPOSE: To retrospectively evaluate the effects of six known allelic variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes on the pharmacokinetics of the anticancer agent paclitaxel (Taxol). EXPERIMENTAL DESIGN: A cohort of 97 Caucasian patients with cancer (median age, 57 years) received paclitaxel as an i.v. infusion (dose range, 80-225 mg/m(2)). Genomic DNA was analyzed using PCR RFLP or using Pyrosequencing. Pharmacokinetic variables for unbound paclitaxel were estimated using nonlinear mixed effect modeling. The effects of genotypes on typical value of clearance were evaluated with the likelihood ratio test within NONMEM. In addition, relations between genotype and individual pharmacokinetic variable estimates were evaluated with one-way ANOVA. RESULTS: The allele frequencies for the CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP3A4*3, CYP3A5*3C, and ABCB1 3435C>T variants were 0.7%, 9.2%, 2.1%, 0.5%, 93.2%, and 47.1%, respectively, and all were in Hardy-Weinberg equilibrium. The population typical value of clearance of unbound paclitaxel was 301 L/h (individual clearance range, 83.7-1055 L/h). The CYP2C8 or CYP3A4/5 genotypes were not statistically significantly associated with unbound clearance of paclitaxel. Likewise, no statistically significant association was observed between the ABCB1 3435C>T variant and any of the studied pharmacokinetic variables. CONCLUSIONS: This study indicates that the presently evaluated variant alleles in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not explain the substantial interindividual variability in paclitaxel pharmacokinetics.

A phase I study of BI 811283, an Aurora B kinase inhibitor, in patients with advanced solid tumors.

PURPOSE: This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and antitumor activity of the Aurora B kinase inhibitor BI 811283 in patients with advanced solid tumors. METHODS: BI 811283 was administered via 24-h infusion on Days 1 and 15 of a 4-week cycle (schedule A) or Day 1 of a 3-week cycle (schedule B) in a modified 3 + 3 dose-escalation design. Pharmacodynamic assessments included immunohistochemistry for phosphorylated histone H3 (pHH3) on skin biopsies to determine Aurora B kinase inhibition and plasma concentrations of caspase-cleaved CK-18 (apoptosis marker). RESULTS: A total of 121 patients were treated. The MTDs of BI 811283 were 125 mg (schedule A) and 230 mg (schedule B). Dose-limiting toxicities were primarily hematological (febrile neutropenia and grade 4 neutropenia); the most common drug-related adverse effects included neutropenia, fatigue, leukopenia, nausea, alopecia, diarrhea, and decreased appetite. A trend toward a decrease in pHH3 was observed, with increasing BI 811283 doses, indicating target engagement; there was no consistent trend regarding caspase-cleaved CK-18 levels. No objective response was observed although 19 patients in each schedule achieved clinical benefit (stable disease). CONCLUSIONS: BI 811283 demonstrated a generally manageable safety profile and disease stabilization in some patients. TRIAL REGISTRATION: EudraCT No: 2007-000191-17, ClinicalTrials.gov Identifier: NCT00701324.

Comparative pharmacokinetics of unbound paclitaxel during 1- and 3-hour infusions.

PURPOSE: The paclitaxel vehicle Cremophor EL (CrEL) profoundly influences the cellular distribution of paclitaxel in human blood in vitro by a concentration-dependent decrease of the unbound drug fraction. Because CrEL clearance increases by extending the infusion duration from 3 to 24 hours, we hypothesized that exposure to unbound paclitaxel might also be schedule-dependent. PATIENTS AND METHODS: CrEL and unbound paclitaxel pharmacokinetics were prospectively analyzed in 29 patients with advanced solid tumors treated with paclitaxel 100 mg/m(2) given as a 1-hour (n = 15) or 3-hour (n = 14) intravenous infusion. RESULTS: The systemic exposure (area under the curve [AUC]) to CrEL was significantly higher with the 1-hour as compared with the 3-hour schedule (80.2 +/- 24.2 v. 48.5 +/- 24.1 microL x h/mL; P =.002). In contrast, the AUC of unbound paclitaxel was substantially reduced after the 1-hour infusion (0.50 +/- 0.10 v. 0.62 +/- 0.12 micromol/L x h; P =.009). Similarly, clearance and volume of distribution were significantly dependent on infusion duration (P <.005). A trend was observed toward more severe hematologic toxicity with the 3-hour schedule (P =.053), consistent with increased exposure to unbound drug. CONCLUSION: Overall, these findings explain, at least in part, previous observations that short-infusion schedules of paclitaxel lack significant myelotoxicity, whereas potentially CrEL-related side effects, including peripheral neuropathy, are augmented.

Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies.

PURPOSE: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. PATIENTS AND METHODS: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. RESULTS: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P =.01 for oral dose; P =.0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P =.004%; and 51%, P =.006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. CONCLUSION: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitors, such as PTK/ZK, for further clinical development.

Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours.

The family of VEGF receptors are important mediators of angiogenesis, which is essential for tumour growth and metastasis. PTK/ZK is a multiple VEGF receptor inhibitor that blocks the activity of all known VEGF receptor tyrosine kinases. This phase I/II trial evaluated the safety, pharmacokinetics and efficacy of PTK/ZK in patients with liver metastases from solid tumours. Patients were administered oral PTK/ZK monotherapy once daily at doses of 300-1200 mg/day in 28-day cycles until unacceptable toxicity or tumour progression occurred. Twenty-seven patients were enrolled and treatment with PTK/ZK was generally well tolerated. The most frequently reported adverse events were fatigue, nausea, dizziness, and vomiting (mostly National Cancer Institute Common Toxicity Criteria grade 1 or 2). The area under the concentration-time curve (AUC) of PTK/ZK increased between 300 and 1000 mg/day with no further increase from 1000 to 1200 mg/day; the AUC decreased by 50% between day 1 and day 15. The DCE-MRI showed a statistically significant early reduction of tumour blood supply (measured as Ki) at day 2 at doses > or = 750 mg/day. Disease progression was significantly correlated with percent change from baseline Ki. Thirteen patients had stable disease for at least two cycles (56 days). Median overall survival was 11.8 months (95% CI = 6.6, 17.1 months). Long-term therapy with PTK/ZK demonstrated predictable pharmacokinetics, was safe and feasible in patients with metastatic disease, and showed promising clinical activity. The minimum biologically active dose was established at 750 mg/day whereas the recommended dose for phase III studies is 1200 mg/day.

Paclitaxel pharmacokinetics and response to chemotherapy in patients with advanced cancer treated with a weekly regimen.

BACKGROUND: Paclitaxel pharmacokinetics were shown to be related to toxicity and survival. PATIENTS AND METHODS: We evaluated the effects of time above paclitaxel concentrations of 0.05 micromol/l (T(>0.05) and systemic exposures (AUC) to total and unbound paclitaxel (tPAC, uPAC) on response in patients with advanced cancer treated with weekly 1-h or 3-h infusions. RESULTS: After 6 weeks of therapy (WOT), 13 out of 21 assessable patients showed either partial response (PR) or stable disease (SD), while 8 had progressive disease (PD). As compared to patients with PD, those with PR or SD showed similar AUCs to uPAC and tPAC but higher (p < 0.05) T (>0.05). Patients with T(>0.05) > or = 20.7 hours had lower probability (p < 0.05) to progress within 12 WOT. CONCLUSION: Taking the heterogeneity of the studied tumor types into account, we found T(>0.05) to be associated with response to treatment. This emphasizes the value of threshold models for the investigation of paclitaxel pharmacodynamics.

Anti-angiogenesis therapy:concepts and importance of dosing schedules in clinical trials.

The biological control of angiogenesis is critical to the clinical control of cancer. Understanding the mechanism of formation and regulation of new blood vessel development would open a new avenue for cancer treatment. Intense research effort has revealed a variety of factors which initiate, control and terminate the multi-stage process of angiogenesis, as well as target structures which interfere with this process. Protease inhibitors, inhibitors of the endothelial cell proliferation, suppressors of angiogenic growth factors, copper chelators, and other compounds interfering with the process of angiogenesis were screened for inhibition of tumor angiogenesis and some of them are in clinical trials. Very recently, a new term, 'metronomic dosing regimen' has been introduced, which implicates the use of the old cytostatic anticancer agents as anti-angiogenic agents. Results from recent studies will be discussed briefly and the prospects of inhibition of tumor angiogenesis as a new treatment modality will be outlined. Copyright 2000 Harcourt Publishers Ltd.

Pharmacokinetics of liposomal doxorubicin (TLC-D99; Myocet) in patients with solid tumors: an open-label, single-dose study.

PURPOSE: Liposomal encapsulation of doxorubicin is designed to increase safety and tolerability by decreasing cardiac and gastrointestinal toxicity through decreased exposure of these tissues to doxorubicin, while effectively delivering drug to the tumor. We conducted an open-label phase I study to determine the pharmacokinetic profile of a single dose of liposome-encapsulated doxorubicin (Myocet) in patients with various solid tumors. Safety and tolerability were monitored. EXPERIMENTAL DESIGN: Patients received a single intravenous infusion of Myocet 75 mg/m2. Plasma samples were analyzed for concentration of liposome-encapsulated doxorubicin, total doxorubicin, and doxorubicinol. RESULTS: A total of 18 patients aged 20-73 years (median 60 years) participated; 17 were evaluable for pharmacokinetic analysis. The most common primary tumor was soft tissue sarcoma (22%). Total body clearance for total doxorubicin was 5.6 l/h/m2 while the volume (Vss) was 82 l/m2. The terminal half-life was 52.6 h. Based on the AUC and Cmax values for total doxorubicin and encapsulated doxorubicin, an estimated 85% of circulating doxorubicin was encapsulated. Doxorubicinol was detected in all patients; the mean AUC was 2.03+/-1.10 micromol/l/h. The mean 48-h urinary excretion of doxorubicin was 6.44% of the dose. The most common adverse events were nausea (94%), fatigue (78%) and vomiting (67%). Cardiotoxicity (measured as ten-point fall in LVEF to <50%) was observed in one patient. Pharmacokinetic values did not correlate with hematological, laboratory or demographic variables. CONCLUSIONS: The pharmacokinetic profile of Myocet suggests that the liposomal formulation results in a longer half-life with less free drug available for tissue distribution than conventional doxorubicin, consistent with the enhanced therapeutic index observed in clinical studies.