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.

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.

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.

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.

A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors.

PURPOSE: Regorafenib is a novel oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-ß, FGFR), and oncogenic kinases (KIT, RET, and RAF). This first-in-man, phase I dose-escalation study assessed the safety, pharmacokinetic, pharmacodynamic, and efficacy profiles of regorafenib in patients with advanced solid tumors. PATIENTS AND METHODS: Patients aged 18 years or older with advanced solid tumors refractory to standard treatment were recruited. Regorafenib was administered orally for 21 days on/seven days off in repeating cycles, until discontinuation due to toxicity or tumor progression. Adverse events (AE) were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Pharmacokinetic profiles were measured after a single dose and on day 21. Pharmacodynamic and efficacy evaluations included tumor perfusion assessment using dynamic contrast-enhanced MRI, plasma cytokines, and tumor response using RECIST (v1.0). RESULTS: Fifty-three patients were enrolled into eight cohorts at dose levels from 10 to 220 mg daily. The recommended dose for future studies was determined to be 160 mg daily, with a treatment schedule of 21 days on/seven days off in repeating 28-day cycles. The most common drug-related grade 3 or 4 AEs were dermatologic AEs (hand-foot skin reaction, rash), hypertension, and diarrhea. Pharmacokinetic analysis revealed a similar exposure at steady state for the parent compound and two pharmacologically active metabolites. Tumor perfusion and plasma cytokine analysis showed biologic activity of regorafenib. Three of 47 evaluable patients achieved a partial response (renal cell carcinoma, colorectal carcinoma, and osteosarcoma). CONCLUSION: Regorafenib showed an acceptable safety profile and preliminary evidence of antitumor activity in patients with solid tumors.

Phase I study of telatinib (BAY 57-9352): analysis of safety, pharmacokinetics, tumor efficacy, and biomarkers in patients with colorectal cancer.

BACKGROUND: Telatinib (BAY 57-9352) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor ß tyrosine kinases. METHODS: In this multicenter phase I dose-escalation study including a phase II like expansion part, 39 patients with refractory colorectal cancer (CRC) were enrolled into 14 days on / 7 days off in repeating cycles of 28 days (n = 11) or continuous dosing groups (n = 28) to receive ≥ 600 mg telatinib twice-daily (bid). RESULTS: Hypertension (28%) and diarrhoea (15%) were the most frequent study drug-related adverse events of CTC grade 3. In this population, no clear relationship between telatinib dose and individual Cmax and AUC was apparent in the 600 mg bid to 1500 mg bid dose range. No partial remission according to RECIST was reached, but 41% of the patients reached some tumour shrinkage during treatment. Tumour blood flow measured by dynamic contrast-enhanced magnetic resonance imaging and sVEGFR-2 plasma levels decreased with increasing telatinib AUC(0-12). CONCLUSION: Telatinib treatment was well tolerated. The observed single agent antitumor activity in heavily pretreated CRC patients was limited. Pharmacodynamic results are suggestive for the biological activity of telatinib justifying a further evaluation of telatinib bid in combination with standard chemotherapy regimens in CRC patients.

Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors.

PURPOSE: BIBF 1120 is an oral, potent angiokinase inhibitor targeting receptors of the vascular endothelial growth factors, platelet-derived growth factors, and fibroblast growth factors. This phase I, accelerated titration study assessed the maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamic effects of BIBF 1120. PATIENTS AND METHODS: Sixty-one patients with advanced cancers received BIBF 1120 in successive cohorts. Twenty-five received 50 to 450 mg once daily and 36 received 150 to 300 mg twice daily in 4-week treatment courses interspersed by 1 week of washout. Dynamic contrast-enhanced magnetic resonance imaging assessed antiangiogenic effect in 42 patients. RESULTS: Most frequent BIBF 1120-related adverse events were mostly mild to moderate (Common Toxicity Criteria grade 1-2) nausea (68.9%), vomiting (45.9%), and diarrhea (44.3%). The majority of dose-limiting adverse events of Common Toxicity Criteria grade 3 or 4 were reversible liver enzyme elevations. The maximum tolerated dose was 250 mg of BIBF 1120 for once and twice daily dosing. BIBF 1120 was absorbed moderately fast (t(max) = 1-3 hours at steady state), with no deviation from dose linearity and no decrease of exposure over time. The gMean terminal half-life was from 13 to 19 hours. One complete and two partial responses occurred in patients with renal cell cancer (n = 2) and colorectal cancer (n = 1). Dynamic contrast-enhanced magnetic resonance imaging showed a significant reduction in tumor blood flow in 55% of evaluable patients. CONCLUSIONS: BIBF 1120 dosed continuously displayed a favorable safety and pharmacokinetics profile, and first efficacy signals were observed. Twice daily dosing permitted increased drug exposure without additional toxicity. Two hundred milligrams BIBF 1120 twice daily is the recommended dose for phase II monotherapy studies.

DCE-MRI assessment of the effect of vandetanib on tumor vasculature in patients with advanced colorectal cancer and liver metastases: a randomized phase I study.

BACKGROUND: Vandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling pathways. In patients with advanced colorectal cancer and liver metastases, the effect of vandetanib on tumor vasculature was assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). METHODS: Eligible patients received vandetanib 100 or 300 mg/day. DCE-MRI (iAUC(60 )and K(trans)) was used to quantify the primary endpoints of tumor perfusion and vascular permeability. An exploratory assessment of tumor oxygenation was performed using MRI/T2*. All MRI parameters were measured at baseline (twice) and on days 2, 8, 29 and 57. RESULTS: Twenty-two patients received vandetanib (n = 10, 100 mg; n = 12, 300 mg). Baseline measurements of iAUC(60 )and K(trans )were reproducible, with low intrapatient coefficients of variation (11% and 24%, respectively). Estimates of mean % changes from baseline were -3.4% (100 mg) and -4.6% (300 mg) for iAUC(60), and -4.6% (100 mg) and -2.7% (300 mg) for K(trans); these changes were not significantly different between doses. The exploratory T2* measurement showed a significant increase at 300 mg versus 100 mg (P = 0.006). Both doses of vandetanib were generally well tolerated; common toxicities were fatigue, rash and diarrhea (majority CTC grade 1 or 2). The pharmacokinetic profile of vandetanib was similar to that observed previously. There were no RECIST-defined objective responses; five patients experienced stable disease >/=8 weeks. CONCLUSION: In this study in patients with advanced colorectal cancer, vandetanib did not modulate gadolinium uptake in tumor vasculature and tissue measured by the DCE-MRI parameters iAUC(60 )and K(trans). TRIAL REGISTRATION: NCT00496509 (ClinicalTrials.gov); D4200C00050 (AstraZeneca).

Phase I dose escalation and pharmacokinetic study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors.

PURPOSE: BI 2536 is a novel, potent, and highly specific inhibitor of polo-like kinase 1 (Plk1), which has an essential role in the regulation of mitotic progression. The aim of this trial was to identify the maximum tolerated dose (MTD) of BI 2536 and to determine the safety, pharmacokinetics, and antitumor activity in patients who had advanced solid tumors. PATIENTS AND METHODS: This phase I trial followed an open label, toxicity-guided, dose-titration design. Single doses of BI 2536 (25 to 250 mg) were administered as a 1-hour intravenous infusion; patients who experienced clinical benefit were eligible for additional treatment courses. Safety and pharmacokinetics were investigated. Tumor response was evaluated according to Response Evaluation Criteria in Solid Tumors Group guidelines. RESULTS: The MTD was defined at 200 mg in a total of 40 patients entered; reversible neutropenia constituted the dose-limiting toxicity (DLT) and the most frequent adverse event at the MTD (grade 3 to 4; 56%). Nausea (52%), fatigue (52%), and anorexia (44%) also were common and were mostly of mild to moderate intensity (Common Terminology Criteria of Adverse Events

Treatment of anthracycline extravasation with dexrazoxane -- clinical experience.

BACKGROUND: Accidental extravasation is a severe complication when administering anthracyclines. We describe 3 cases of extravasation with 3 different anthracyclines. PATIENTS AND METHODS: One patient came from another hospital for a second opinion after an epirubicin extravasation. Only surgical debridement of the necrotic tissue was possible. The other two extravasations occurred during treatment with doxorubicin and doxorubicin- EMCH, respectively, in our department. Both patients were treated with dexrazoxane within 6 h of the event. RESULTS: The 2 patients treated with dexrazoxane recovered completely without any sequelae. CONCLUSIONS: Treatment of antracycline extravasation with dexrazoxane is potentially useful and safe.

PAC fixed dose: pharmacokinetics of a 1-hour paclitaxel infusion and comparison to BSA-normalized drug dosing.

BACKGROUND: The aim of this study was to determine the pharmacokinetics (PKs) of a 175-mg fixed dose of paclitaxel (PAC) after a 1-h infusion in cancer patients and to compare them with the PK parameters from a study with a dose normalized to the body surface area (BSA) (100 mg/m2). PATIENTS AND METHODS: PAC PKs were studied during the first course of therapy in 13 patients. A fixed dose of 175 mg PAC was administered weekly by a 1-h infusion to patients with advanced cancer. Total PAC in serum was quantified by high-performance liquid chromatography (HPLC). PK parameters were calculated by non-compartmental and model-dependent methods. RESULTS: The mean BSA of 12 patients (1 patient excluded from all analyses because of prolonged infusion duration) was 1.79 m2 (coefficient of variation (CV) 7.8%), the mean dose referred to the individual BSAs was 98.3 mg/m2 (CV 8.3%). The mean area under the curve (AUC) was 6,193 ng/ml x h (CV 46%), the mean plasma clearance (Clp) was 19.7 l/h/m2 (CV 45%), and the volume of distribution at steady state (Vss) was 121.6 l/m2 (CV 52%). The mean residence time (MRT) was 7.6 h (CV 46%), the mean distribution half-life (t1/2 alpha) of PAC(tot) was 0.4 h (CV 62%), and the elimination half-life (t1/2 beta) 10.0 h (CV 42%). Maximum plasma concentration Cmax was 3,161 ng/ml (CV 36%). The mean time above 0.05 microM (42.7 ng/ml) was 19.7 h, and the mean time above 0.1 microM (85.4 ng/ml) was 10.6 h. CONCLUSIONS: In this study, a fixed dose of PAC of 175 mg corresponds to a mean BSA-normalized dose of 98.3 mg/m2 (range 88.8-117.4 mg/m2). A higher variability of PK parameters was observed compared to previously published results of a PK study with BSA-normalized dosing of 100 mg/m2. However, the AUC and the time above threshold concentrations did not depend on the dose. Therefore, a fixed dose of 175 mg weekly could be an option for palliative treatment with PAC and may offer a simple but effective schedule for PAC treatment.