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Vascular endothelial growth factor receptor 2 (VEGFR2), a key regulator of tumor angiogenesis, is highly expressed across numerous tumor types and has been an attractive target for anti-cancer therapy. However, clinical application of available VEGFR2 inhibitors has been challenged by limited efficacy and a wide range of side effects, potentially due to inadequate selectivity for VEGFR2. Thus, development of potent VEGFR2 inhibitors with improved selectivity is needed. Rivoceranib is an orally administered tyrosine kinase inhibitor that potently and selectively targets VEGFR2. A comparative understanding of the potency and selectivity of rivoceranib and approved inhibitors of VEGFR2 is valuable to inform rationale for therapy selection in the clinic. Here, we performed biochemical analyses of the kinase activity of VEGFR2 and of a panel of 270 kinases to compare rivoceranib to 10 FDA-approved kinase inhibitors ("reference inhibitors") with known activity against VEGFR2. Rivoceranib demonstrated potency within the range of the reference inhibitors, with a VEGFR2 kinase inhibition IC50 value of 16 nM. However, analysis of residual kinase activity of the panel of 270 kinases showed that rivoceranib displayed greater selectivity for VEGFR2 compared with the reference inhibitors. Differences in selectivity among compounds within the observed range of potency of VEGFR2 kinase inhibition are clinically relevant, as toxicities associated with available VEGFR2 inhibitors are thought to be partly due to their effects against kinases other than VEGFR2. Together, this comparative biochemical analysis highlights the potential for rivoceranib to address clinical limitations associated with off-target effects of currently available VEGFR2 inhibitors. [ABSTRACT FROM AUTHOR]

Purpose: The objective was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model linking everolimus and sorafenib exposure with biomarker dynamics and progression-free survival (PFS) based on data from EVESOR trial in patients with solid tumors treated with everolimus and sorafenib combination therapy and to simulate alternative dosing schedules for sorafenib. Patients and methods: Everolimus (5–10 mg once daily, qd) and sorafenib (200–400 mg twice daily, bid) were administered according to four different dosing schedules in 43 solid tumor patients. Rich PK and PD sampling for serum angiogenesis biomarkers was performed. Baseline activation of RAS/RAF/ERK (MAPK) pathway was assessed by quantification of mRNA specific gene panel in tumor biopsies. The PK-PD modeling was performed using NONMEM® software. Results: An indirect response PK-PD model linking sorafenib plasma exposure with soluble vascular endothelial growth factor receptor 2 (sVEGFR2) dynamics was developed. Progression-free survival (PFS) was described by a parametric time-to-event model. Higher decreases in sVEGFR2 at day 21 and higher baseline activation of MAPK pathway were associated with longer PFS (p = 0.002 and p = 0.007, respectively). The simulated schedule sorafenib 200 mg bid 5 days-on/2 days-off + continuous everolimus 5 mg qd was associated with median PFS of 4.3 months (95% CI 1.6–14.4), whereas the median PFS in the EVESOR trial was 3.6 months (95% CI 2.7–4.2, n = 43). Conclusion: Sorafenib 200 mg bid 5 days-on/2 days-off + everolimus 5 mg qd continuous was selected for an additional arm of EVESOR trial to evaluate whether this simulated schedule is associated with higher clinical benefit. Trial registration: ClinicalTrials.gov Identifier: NCT01932177. [ABSTRACT FROM AUTHOR]

Purpose: Sorafenib is an oral multikinase inhibitor with regulatory approval in advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC) and refractory differentiated thyroid carcinoma (DTC). Vascular endothelial growth factor receptor (VEGFR) inhibitors like sorafenib may cause proteinuria. This study aimed to analyze the effectiveness and safety of sorafenib in RCC, HCC and DTC patients with chronic kidney disease (CKD). Methods: This retrospective study analyzed integrated data from prospective post-marketing surveillance studies for advanced RCC, HCC and DTC. Background factors considered to affect patients' prognosis were balanced by propensity score matching using eGFR cut-off values of 60 mL/min/1.73 m2. Results: In the combined matched population (N = 2430), sorafenib was equally effective in patients with lower and higher eGFR values. Sorafenib had an overall response rate (ORR: complete + partial responses) of 18.9% and a disease control rate (DCR: complete + partial responses + stable disease) of 67.0%. There were no significant differences between lower and higher eGFR groups for response rates. Renal function was maintained throughout the 12-month study period in the combined population and in each indication. Adverse events (AEs) and serious AEs were reported in 91.6% and 58.2% of propensity score-matched patients, and with no significant differences between lower and higher eGFR groups. Conclusion: The effectiveness and safety of sorafenib were similar in patients with eGFR < 60 and ≥ 60 mL/min/1.73 m2 during the 12-month observation period, and without impairing renal function. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis, the formation of blood vessel, is required for invasive tumor growth and metastasis. In this study, the effects of lidocaine, an amide-link local anesthetic, on angiogenesis and tumor growth were investigated.Methods: In vitro angiogenesis assays were conducted using human umbilical vascular endothelial cell (HUVEC). Essential molecules involved in vascular endothelial growth factor (VEGF) signaling were analyzed. Tumor angiogenesis was analyzed using in vivo mouse tumor model.Results: Lidocaine at clinically relevant concentrations inhibited angiogenesis. Lidocaine inhibited endothelial cell in vitro capillary network formation on Matrigel through interfering early stage of angiogenesis. In addition, lidocaine inhibited vascular endothelial growth factor (VEGF)-stimulated endothelial cell migration and proliferation without affecting cell adhesion. Lidocaine also induced endothelial cell apoptosis in the presence of VEGF. Lidocaine suppressed VEGF-activated phosphorylation of VEGF receptor 2 (VEGFR2), PLCγ-PKC-MAPK and FAK-paxillin in endothelial cells, demonstrating that VEGF, PLC, MAPK and FAK-paxillin suppression is associated with the antiangiogenic effect of lidocaine. Importantly, the in vitro observations were translatable to in vivo B16 melanoma mouse model. Lidocaine significantly inhibited tumor angiogenesis, leading to delay of tumor growth.Conclusions: This study is the first to report that lidocaine acts as an angiogenesis inhibitor. The findings provide preclinical evidence into the potential mechanisms by which lidocaine may negatively affect cancer growth and metastasis. [ABSTRACT FROM AUTHOR]

Purpose: Optimal salvage chemotherapy for patients with treated advanced/metastatic gastric cancer (AGC) is unknown. Irinotecan is commonly used in Japan. Ramucirumab, a human IgG-1 monoclonal antibody targeting the extracellular domain of VEGF receptor 2, is the first molecularly targeted agent proven to be effective in second-line therapy for AGC in combination with chemotherapy. We sought to determine the maximum tolerated dose (MTD) and recommended dose (RD) of ramucirumab plus irinotecan for AGC previously treated with fluoropyrimidine with/without platinum and taxane.Methods: Patients received systemic chemotherapy with ramucirumab (8 mg/kg) and irinotecan on day 1, repeated every 2 weeks. A decrease in irinotecan dose was planned from start level 1 (irinotecan 150 mg/m2). This trial was registered with the University Hospital Medical Network (UMIN no. 000018606).Results: Six patients were enrolled from August 2015 to September 2017. No dose-limiting toxicity (DLT) was observed, and the maximum tolerated dose (MTD) was not reached at level 1. Irinotecan 150 mg/m2 in combination with ramucirumab 8 mg/kg was administered with acceptable toxicity, and all patients were treated at these doses. No treatment-related deaths were observed. Adverse events of Grade 3/4 were neutropenia (17%), anemia (17%) and hypertension (17%). Patients were evaluated using the RECIST criteria, and response rate and disease control rate were 17% and 83%, respectively.Conclusions: Salvage chemotherapy with irinotecan plus ramucirumab was well-tolerated by patients previously treated for AGC. RD was defined as irinotecan 150 mg/m2 in combination with ramucirumab 8 mg/kg. [ABSTRACT FROM AUTHOR]

Purpose: This phase II study evaluated the safety and clinical activity of pazopanib, a potent and mutlitargeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs)-1, -2 and -3, platelet-derived growth factor receptor (PDGFR)-α and β, and cKit, in combination with metronomic paclitaxel in patients with metastatic melanoma.Experimental Design: Sixty chemotherapy-naive patients received pazopanib at a starting dose of 800 mg daily in combination with metronomic dosing of paclitaxel 80 mg/m2 weekly thrice every 4 weeks. The primary endpoint was 6-month progression-free survival (PFS) rate, while secondary endpoints included 1-year overall survival rate, RECIST response rates, progression-free survival rates and median overall survival. Prior BRAF-targeted therapy or checkpoint inhibitors were permitted.Results: The 6-month PFS rate was 68%, with a 1-year OS rate of 48%. Objective response rate was 37% comprising one complete and 20 partial responses. Stable disease at 8 weeks was noted in 32 patients (55%) with an overall clinical benefit rate of 93%. Six-month median progression-free survival was 8 months and median OS was 12.7 months. The most frequently (> 15%) reported non-hematologic, treatment-related adverse events were fatigue, diarrhea, hypertension, transaminitis and peripheral neuropathy. Treatment-related non-fatal bowel perforation, a known class effect, occurred in one patient. No significant association was noted between plasma levels of pazopanib and response.Conclusions: The combination of pazopanib and metronomic paclitaxel was well-tolerated, demonstrating significant activity in metastatic melanoma. Further evaluation of this combination is warranted. [ABSTRACT FROM AUTHOR]

Antiangiogenic therapy has a proven survival benefit in metastatic colorectal cancer. Inhibition of the VEGF pathway using a variety of extracellular antibody approaches has clear benefit in combination with chemotherapy, while intracellular blockade using tyrosine kinase inhibitors (TKIs) such as sorafenib and regorafenib has had more limited success. Pharmacodynamic modeling using modalities such as DCE-MRI indicates potent antiangiogenic effects of these TKIs, yet numerous combination therapies, primarily with chemotherapy, have failed to demonstrate an additive benefit. The sole comparative study of a single agent TKI against placebo showed a survival benefit of regorafenib in patients with advanced, refractory disease. Preclinical data demonstrate synergy between antiantiogenic TKIs and targeted interventions including autophagy inhibition, and together with a renewed effort to define markers of susceptibility, such combinations may be a way to improve the limited efficacy of this once-promising drug class. [ABSTRACT FROM AUTHOR]

Purpose: Fruquintinib (HMPL-013) is a novel, potent, and highly selective tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptors (1, 2 and 3). This study was conducted to investigate the metabolism, excretion, and pharmacokinetics of HMPL-013 after a single oral dose to healthy Chinese men.Methods: Six subjects were administrated an oral suspension containing 5 mg of 14C-labeled HMPL-013 (100 μCi) in a fasted state. Blood and excreta samples were collected at the designated time points or intervals for pharmacokinetics and radiometric analyses. Safety assessments were conducted throughout the study.Results: Over a 336-h post-dose collection period, mean recovery was 90.11% of the radiolabeled dose, with 60.31% in urine and 29.80% in feces. Mean C max, AUC0-∞, and T max for HMPL-013 in plasma were 113 ng/mL, 4797 h ng/mL, and 2 h, respectively. Radioactivity and HMPL-013 were cleared from circulation with terminal half-lives of 41.1 and 33.4 h. HMPL-013 was the predominant circulating radioactive component, representing 72.48% of the total radioactivity. M11 was the major circulating metabolite, accounting for 17.31% of the total radioactivity. An additional seven circulating metabolites were identified, each accounting for less than 5% of the total radioactivity. In urine, HMPL-013 accounted for only 0.50% of the administered dose. Three major metabolites M285, M381, and M409-4 were identified in urine accounting for 10.48, 21.16, and 8.92% of the dose, respectively. In feces, HMPL-013 accounted for 5.34% of the dose. M205, M365-2, and M380 were the major metabolites, accounting for 2.29, 3.30, and 2.59% of the dose, respectively.Conclusion: HMPL-013 was well tolerated and absorbed rapidly, with parent compound being the predominant circulating component. HMPL-013 was extensively metabolized prior to excretion, and urine was the major route of excretion. [ABSTRACT FROM AUTHOR]

Purpose: RO5323441 is a humanized anti-placental growth factor (PlGF) monoclonal antibody that has shown preclinical activity in several cancer models. The objective of this analysis is to examine the pharmacokinetic (PK) results from four Phase I studies that have been conducted with RO5323441 (n = 61) and to report an apparent drug-drug interaction observed when RO5323441 was administered in combination with bevacizumab.Methods: The four Phase I studies were a multiple-ascending dose study in 23 patients with solid tumors (Study 1), an open-label study in seven patients with colorectal/ovarian cancer (Study 2), a sorafenib combination study in nine patients with hepatocellular carcinoma (Study 3), and a bevacizumab combination study in 22 patients with recurrent glioblastoma (Study 4). A two-compartment linear population PK model was developed from these four studies to characterize the PK of RO5323441 in patients with cancer.Results: The PK properties of RO5323441 were similar in the first three studies. However, substantially higher RO5323441 exposures were observed in Study 4 when RO5323441 was administered in combination with bevacizumab. A linear two-compartmental population PK model indicated that the co-administration of bevacizumab would decrease the clearance of RO5323441 by 53%. Clinical data suggested that the decrease in RO5323441 clearance was inversely associated with bevacizumab exposure.Conclusions: The exact reason for the increase in RO5323441 exposure following bevacizumab co-administration is not currently known. One possibility is a drug-drug interaction via a target-trapping mechanism that is mediated by the vascular endothelial growth factor receptor-1 (VEGFR-1). [ABSTRACT FROM AUTHOR]

Purpose: Axitinib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors 1-3, is approved for second-line treatment of advanced renal cell carcinoma. Axitinib is partially metabolized by cytochrome P450 1A2, which is induced by chronic heavy smoking. The effect of smoking on axitinib pharmacokinetics was evaluated in a non-small-cell lung cancer (NSCLC) patient population with a large number of active and ex-smokers.Methods: Data were pooled from six clinical studies-serial pharmacokinetics from two healthy volunteer studies (n = 58) and sparse pharmacokinetics from four NSCLC studies (n = 152)-for a nonlinear mixed effects modeling (NONMEM v7.2) analysis. Demographics, smoking status, liver and renal function status, and Eastern Cooperative Oncology Group performance status were tested as covariates.Results: There were 83 (40%) active smokers and 56 (27%) ex-smokers in the pooled dataset. Axitinib pharmacokinetics was adequately described with a linear, two-compartment model with a lagged first-order absorption. Final parameter estimates (inter-individual variability) were 16.1 L/h (59.1%) and 45.3 L (54.4%) for systemic clearance (CL) and central volume of distribution (Vc), respectively. Smoking status was found not to alter CL or Vc. Asian ethnicity and body weight were significant covariates for Vc, but were not considered clinically relevant since individual values of Vc for Asians were within the range of non-Asians.Conclusions: Based on this analysis, smoking status does not affect area under plasma concentration-time curve, and thus no dose adjustment is required for smokers. [ABSTRACT FROM AUTHOR]

Purpose: Metastasis of solid tumors to regional lymph nodes is facilitated by tumor lymphangiogenesis, which is primarily mediated by the vascular endothelial growth factor receptor 3 (VEGFR-3). We conducted a phase 1 dose-escalation (part A) study of the VEGFR-3 human immunoglobulin G subclass 1 monoclonal antibody LY3022856 in advanced solid tumors, followed by a colorectal cancer (CRC) expansion (part B).Methods: Part A evaluated the safety profile and maximum tolerated dose (MTD) of LY3022856 in patients treated intravenously at doses of 5-30 mg/kg weekly (qwk). Part B further evaluated tolerability in CRC patients treated with 30 mg/kg. Secondary objectives were pharmacokinetics, anti-tumor activity, and pharmacodynamics (exploratory).Results: A total of 44 patients (23 in part A; 21 in part B) were treated; only one dose-limiting toxicity was observed at the lowest dose level. The MTD was not reached. Treatment-emergent adverse events (TEAEs) of any grade included in ≥15 % of all patients were: nausea (41 %), fatigue (32 %), vomiting (30 %), decreased appetite (27 %), pyrexia (25 %), peripheral edema (23 %), and urinary tract infection (UTI, 20 %). The most common grade 3/4 TEAEs included UTI and small intestinal obstruction (7 % each). No radiographic responses were noted. Median progression-free survival in part B was 6.3 weeks (95 % confidence interval: 5.1, 14.4), and a best overall response of stable disease was observed in 4 CRC patients (19.0 %).Conclusions: LY3022856 was well tolerated up to a dose of 30 mg/kg qwk, but with minimal anti-tumor activity in CRC. CLINICALTRIALS.Gov Identifier: NCT01288989. [ABSTRACT FROM AUTHOR]

Background: Since 2013, informative trials exploring the optimal use of available biologic agents in the first-line setting of metastatic colorectal cancer (mCRC) have been presented. These trials have opened a stimulating debate on the biological effect that first-line therapies may have on subsequent lines of treatment even long after the first-line progression.Materials and Methods: We reviewed available preclinical and clinical data on the effect of different sequences of the biological drugs approved for use in mCRC patients. The importance of molecular selection of patients based on RAS mutational status and toxicity and quality-of-life issues were also analyzed.Results: Convincing evidence exists on the optimal therapeutic effect obtained by using anti-EGFR agents in first-line treatment before anti-VEGF agents. On the contrary, up-front anti-VEGF agents' use seems to determine biological changes that increase the risk of acquired resistance to subsequent EGFR inhibitors. This hypothesis is confirmed by the scarce evidence of EGFR inhibitor activity in second-line treatment. Such a therapeutic optimum is subject to a fine molecular selection based on RAS mutational status.Conclusion: There is accumulating evidence suggesting that, after precise and well-established molecular selection, anti-EGFR agents deliver their maximum efficacy in mCRC patients when given early in the treatment strategy. Their toxicity profile seems manageable under the supervision of experienced physicians. Large randomized trials prospectively confirming the impact of different sequencing strategies are eagerly awaited. [ABSTRACT FROM AUTHOR]

Purpose: Sirolimus, an oral mTOR inhibitor, may complement the anti-angiogenic and anti-tumor activity of sunitinib, an oral small molecule inhibitor of multiple receptor tyrosine kinases, by vertical disruption of vascular epithelial growth factor receptor (VEGFR) signaling, by reducing the compensatory production of VEGF in sunitinib-treated patients and also by directly inhibiting tumor cell proliferation. We conducted this phase 1 study to investigate the maximum tolerated dose (MTD) for this combination of sunitinib and sirolimus in humans. Patients and Methods: Sunitinib was given at 50 mg daily × 28 every 6 weeks. The first cohort received sunitinib alone for cycle 1 (50 mg daily for 2 weeks followed by 2 weeks off) and received sunitinib at standard dose 50 mg daily for 4 weeks followed by 2 weeks off in combination with sirolimus 4 mg weekly; this dose and schedule were further investigated in second cohort. The third cohort received decreased dose of sunitinib at 37.5 mg daily for 4 weeks followed by 2 weeks off in combination with sirolimus at 4 mg weekly. Sirolimus dose was escalated to 8 mg weekly in fourth cohort. Results: Eighteen patients with ECOG PS of 0 or 1 were enrolled, median age 57 years (range 24-76), M:F ratio: 11:7. Median number of prior treatments is 2 (range 0-5); six patients had no prior systemic therapy. Half of patients from the first two cohorts required dose reduction or early discontinuation of treatment; therefore, sunitinib dose was decreased to 37.5 mg daily in third and fourth cohort. In third and fourth cohort, one-third of patients required dose modification during cycle 1 or cycle 2. Multiple patients had significant toxicities including fatigue and hand-foot syndrome. One patient developed interstitial pneumonitis, and one patient died suddenly on day 8 due to progressive disease. There were six patients who tolerated four or more cycles. Among these six patients, two patients with renal cell carcinoma (RCC) achieved partial response; one subsequently underwent surgical resection of residual renal mass and lymph node dissection and achieved complete response afterward. One with metastatic melanoma also achieved complete response after metastatectomy. There was no apparent pharmacokinetic interaction between sunitinib and sirolimus. 4 mg weekly sirolimus did not reduce the sunitinib-induced circulating VEGF production but stimulated more VEGF production through some unknown compensatory mechanism. Conclusion: Toxicity precluded dose escalation of weekly sirolimus in combination with a standard sunitinib dose/schedule. These results suggest caution when combining targeted agents lacking specificity for tumor signaling or vasculature. [ABSTRACT FROM AUTHOR]

Purpose: PF-00337210 is an oral, highly selective vascular endothelial growth factor receptor (VEGFR) inhibitor. We evaluated a composite of biomarkers in real time to identify the recommended phase 2 dose (RP2D) and preliminary anticancer activity of PF-00337210.Patients and Methods: Patients (Pts) with advanced cancers were treated once (QD) or twice daily (BID) with escalating doses. Acute effects on tumor perfusion and vascularity were assessed using DCE-MRI, weekly BP readings, soluble VEGFR-2, and hemoglobin levels.Results: Forty-six pts were treated with 0.67-9 mg QD and 4-6 mg BID of PF-00337210. Nineteen pts (41%) previously received VEGF/VEGFR inhibitors. Two pts had dose-limiting toxicity (DLT) at 9 mg QD (troponin I increase and hypertension). The MTD at QD dose was 8 mg. Common drug-related adverse events were hypertension, fatigue, proteinuria, and nausea. Hypertension incidence and intensity corresponded with dose, but was well controlled with medication. Two confirmed partial responses and minor regressions (>10 to <30% reduction in target lesions) were noted. Complete DCE-MRI was acquired in 21 pts (20 evaluable for vascular response). Ten pts were vascular responders, including 5/6 pts at BID doses. Greatest modulation of soluble VEGFR-2 was at 6 mg BID. The maximum change from baseline in diastolic BP was higher at BID doses. There were no significant differences for systolic BP and hemoglobin levels.Conclusions: PF-00337210 has profound VEGFR inhibition effects at well-tolerated doses. Antitumor activity and VEGF inhibition effects were observed across BID doses. The RP2D was 6 mg BID. [ABSTRACT FROM AUTHOR]

Purpose: To assess the efficacy of vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) rechallenge for metastatic renal cell carcinoma (mRCC) patients and to identify predictive factors for increased progression-free survival (PFS) or overall survival (OS). Methods: The clinicopathological features, outcomes, and prognostic factors of mRCC patients who were treated with VEGFR-TKI after treatment failure using both VEGFR-TKIs and mTOR inhibitors (mTORi) were reviewed. Results: A total of 29 eligible patients were included. Five (17 %) patients achieved partial response (PR) with a median response duration of 9.5 months (95 % CI 5.7-13.4 months), and additional 16 patients (55 %) achieved stable disease. With a median follow-up period of 19.2 months (95 % CI 18.9-19.6 months), the median PFS and OS were 3.0 months (95 % CI 1.1-4.9 months) and 4.9 months (95 % CI 2.9-6.8 months), respectively. In univariate analysis, the best response to first-line VEGFR-TKI (PR vs. non-PR, p < 0.001) and time to rechallenge (TTR, ≤12 months vs. between 12 and 24 months vs. >24 months, p = 0.005) were identified as predictive factors for longer PFS on VEGFR-TKI rechallenge. In addition, an MSKCC risk group (intermediate- vs. poor-risk group, p = 0.027), better response at first-line VEGFR-TKI (PR vs. non-PR, p = 0.003), and TTR (≤12 months vs. between 12 and 24 months vs. >24 months, p = 0.026) were identified as prognostic factors for longer OS. Conclusions: VEGFR-TKI rechallenge may be a viable option for select metastatic RCC patients who fail both VEGFR-TKI and mTORi therapies. [ABSTRACT FROM AUTHOR]

Purpose: Bevacizumab or temsirolimus regimens have clinical activity in the first-line treatment of advanced renal cell carcinoma (RCC). This phase I/II trial was conducted to determine the safety of combining both agents and its efficacy in RCC patients who progressed on at least one prior anti-VEGF receptor tyrosine kinase inhibitor (RTKI) agent. Methods: In the phase I portion, eligible patients were treated with temsirolimus (25 mg IV weekly) and escalating doses of IV bevacizumab (level 1 = 5 mg/kg; level 2 = 10 mg/kg) every other week. The primary endpoint for the phase II portion (RTKI resistant patients) was the 6-month progression-free rate. Secondary endpoints were response rate, toxicity evaluation, and PFS and OS. Results: Maximum tolerated dose was not reached at the maximum dose administered in 12 phase I patients. Forty evaluable patients were treated with the phase II recommended dose (temsirolimus 25 mg IV weekly and bevacizumab 10 mg/kg IV every 2 weeks). The 6-month progression-free rate was 40 % (16/40 pts). Median PFS was 5.9 (4-7.8) months, and median OS was 20.6 (11.5-23.7) months. Partial response, stable disease, and progressive disease were seen in 23, 63, and 14 % of patients, respectively. Most common grade 3-4 AEs included fatigue (17.8 %), hypertriglyceridemia (11.1 %), stomatitis (8.9 %), proteinuria (8.9 %), abdominal pain (6.7 %), and anemia (6.7 %). Baseline levels of serum sFLT-1 and VEGF-A were inversely correlated with PFS and OS, respectively. Conclusions: Temsirolimus and bevacizumab is a feasible combination in patients with advanced RCC previously exposed to oral anti-VEGF agents. The safety and efficacy results warrant further confirmatory studies in this patient population. [ABSTRACT FROM AUTHOR]

Purpose: Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3, approved for second-line treatment of advanced renal cell carcinoma (RCC). Preclinical studies did not indicate potential for axitinib-induced delayed cardiac repolarization. Methods: The effect of axitinib on corrected QT (QTc) prolongation was evaluated with one-stage concentration-QTc response modeling using data from a definitive randomized crossover QT phase I study in healthy volunteers administered one single 5-mg axitinib dose alone or in the presence of steady-state ketoconazole (400 mg once daily). Results: Axitinib and ketoconazole had opposite effects on heart rate: Axitinib lowered it, ketoconazole raised it. The final analysis showed a flat relationship between QTc and axitinib concentration (slope −0.0314 ms·mL/ng) for axitinib alone. Mean highest placebo-matched change from baseline in QTc was −3.0 [90 % confidence interval (CI) −5.4, −0.6] ms. At supratherapeutic axitinib exposures achieved with potent cytochrome P450 3A4/5 inhibition by ketoconazole, the model predicted mean QTc change of 6.5 (90 % CI 4.4-8.5) ms. The slope population mean estimate was −0.331 (95 % CI −0.860, 0.198) ms·mL/µg for ketoconazole alone and 0.0725 (0.0445-0.1005) ms·mL/ng for axitinib in the presence of ketoconazole. The results were then compared with those obtained based on more widely used Fridericia's, Bazett's, and study-specific correction methods. Conclusions: Since axitinib plasma concentrations observed in this study exceeded the range of concentrations observed in patients with RCC at the highest approved clinical dose (10 mg twice daily), axitinib was not associated with clinically significant QTc prolongation in target populations. [ABSTRACT FROM AUTHOR]

Purpose: MK-0888 is an investigational VEGFR-2 inhibitor with demonstrated potent in vitro enzyme activity. Clinical investigation in healthy volunteers and cancer patients was undertaken to evaluate its pharmacokinetic properties and early safety profile. Early data were used to guide whether further clinical development was warranted. Methods: Five phase I studies were conducted. Studies 1-4 were conducted in healthy male volunteers and examined safety and pharmacokinetics across a dose range of 0.5-100 mg. Single-dose and limited multiple-dose escalations were performed. Three formulations and food effect were assessed. Study 5 was a dose escalation study in cancer patients, evaluating pharmacokinetics and safety at doses of 6-100 mg administered up to twice daily. Results: Safety: MK-0888 was generally well tolerated in healthy volunteers at single doses up to 100 mg and in cancer patients at doses up to 100 mg twice daily. Pharmacokinetics: After single-dose administration, MK-0888 was readily absorbed with a T of 4-5 h and a half-life of 11.3-22.7 h. AUC, C and C increased in a slightly less than dose proportional manner. With longer duration multiple-dose administration (2 weeks), trough concentrations decreased from Day 2 at doses of 50 mg twice daily and higher, suggestive of autoinduction of metabolism. The efficacious trough pharmacokinetic target was not attained at steady state. Conclusions: The pharmacokinetic behavior of MK-0888 does not support continued development. The early pharmacokinetic profile of the compound provides important information as to the probability of success of MK-0888 achieving efficacious exposures. [ABSTRACT FROM AUTHOR]

Purpose: There are several reasons why combining an inhibitor of the vascular endothelial and the platelet-derived growth factor receptor with a taxane might induce synergistic antitumor activity. This phase I study aimed to determine the maximal tolerated dose (MTD) of the combination of pazopanib with two different schedules of docetaxel. Methods: In a 3 + 3 + 3 design, patients with advanced solid tumors received escalating doses of oral pazopanib combined with docetaxel given either every 3 weeks (D3w) or weekly at days 1, 8, and 15 every 28 days (D1w). Pharmacokinetic data of docetaxel and pazopanib were obtained through extensive sampling and WinNonlin modeling. Results: Forty-six patients were enrolled to six dose levels. Both schedules of docetaxel could be combined with 400 mg/day pazopanib. The MTD of D3w docetaxel was 50 mg/m, while for D1w MTD, it was 20 mg/m. In the D3w schedule, the administration of pazopanib led to a 33 % lower docetaxel clearance (mean 31.5 vs 21.1 L/h/m; P = 0.019) and >50 % increase in AUC (mean 1,602 vs 2,414 ng*h/mL; P = 0.029) compared with docetaxel single-agent data. Data for the D1w schedule were comparable. Conclusions: Both treatment schedules of docetaxel combined with pazopanib are feasible but at doses for both drugs that are considerably lower than the recommended single-agent doses. This is largely due to a clinically relevant pharmacokinetic interaction with pazopanib, substantially increasing docetaxel exposure. This interaction is most likely due to CYP3A4 and OATP1B1 inhibition. [ABSTRACT FROM AUTHOR]

Purpose: Dovitinib is a small molecule kinase inhibitor with activity against the fibroblast growth factor and vascular endothelial growth factor receptor families. The purpose of this phase Ib study was to define the recommended phase 2 dose of the combinations of gemcitabine and cisplatin or gemcitabine and carboplatin plus dovitinib. Methods: Patients with advanced solid tumors were enrolled in two parallel dose escalation arms (cisplatin- or carboplatin-based regimens). Treatment was administered with gemcitabine (1,000 mg/m on days 1 and 8), cisplatin (70 mg/m), or carboplatin (AUC 5) on day 1, and dovitinib (orally on days 1-5, 8-12, and 15-19), every 21 days. The starting dose of dovitinib was 300 mg and was dose escalated in successive cohorts using 3 + 3 dose escalation rules. Results: Fourteen patients with advanced solid tumors were enrolled, five to the cisplatin arm and nine to the carboplatin arm. Patients enrolled in the cisplatin arm received a median of two cycles of treatment (range 1-5), and patients enrolled in the carboplatin arm received a median of one cycle of treatment (range 1-4). There were no protocol-defined dose-limiting toxicities in the cisplatin arm. However, the cohort was closed due to the need for frequent dose delays and/or reductions and two patients experiencing severe thromboembolic events. There were two dose-limiting toxicities in the carboplatin arm at the starting dose level of dovitinib (both prolonged neutropenia), and the dose of dovitinib was de-escalated to 200 mg. Two additional dose-limiting toxicities (prolonged neutropenia and febrile neutropenia) occurred in the lower dose cohort, and the study was closed. No patients achieved an objective response to treatment. Conclusions: Dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin was poorly tolerated due to myelosuppression. [ABSTRACT FROM AUTHOR]

Purpose: Vatalanib (PTK 787/ZK22584) is an oral poly-tyrosine kinase inhibitor with strong affinity for platelet-derived growth factor and vascular endothelial growth factor (VEGF) receptors. We conducted an open-label, phase II multicenter therapeutic trial investigating the efficacy and tolerability of vatalanib in patients with metastatic or advanced pancreatic cancer who failed first-line gemcitabine-based therapy. Methods: Vatalanib treatment consisted of a twice daily oral dosing using a 'ramp-up schedule,' beginning with 250 mg bid during week 1,500 mg bid during week 2, and 750 mg bid on week three and thereafter. The primary objective of this study was to evaluate the 6-month survival rate. Results: Sixty-seven patients were enrolled. The median age was 64, and 66 % ( N = 43) had only one prior regimen. Common grade 3/4 adverse events included hypertension (20 %; N = 13), fatigue (17 %; N = 11), abdominal pain (17 %; N = 11), and elevated alkaline phosphatase (15 %; N = 10). Among the 65 evaluable patients, the 6-month survival rate was 29 % (95 % CI 18-41 %) and the median progression-free survival was 2 months. Fifteen patients survived 6 months or more. Two patients had objective partial responses, and 28 % of patients had stable disease. Changes in biomarkers including soluble VEGF and vascular endothelial growth factor receptor did not correlate with response to drug. Conclusion: Vatalanib was well tolerated as a second-line therapy and resulted in favorable 6-month survival rate in patients with metastatic pancreatic cancer, compared with historic controls. [ABSTRACT FROM AUTHOR]

Purpose: Hypothyroidism is a common adverse event in patients treated with anti-VEGFR-2 targeting agents and may be a valuable predictive factor of efficacy. Famitinib is an inhibitor of multiple tyrosine kinases mainly targeting VEGFR-2. The objectives of this study were to assess the efficacy and safety of famitinib in patients with pretreated HER2-negative metastatic breast cancer (MBC) and to explore potential of famitinib-induced hypothyroidism and serum vascular endothelial growth factor (VEGF) level for efficacy prediction. Materials and methods: The primary end point was objective response rate (ORR). Famitinib was administered 25 mg/d. Thyroid function assessments were done at baseline and then every 4 weeks. Plasma levels of VEGF were determined at baseline and 2 cycles after treatment. Results: A total of 28 patients were enrolled. ORR was 14.3 %. The most common grade 3/4 AEs were hand-foot syndrome (25.0 %), proteinuria (21.4 %) and hypertension (17.9 %). 64.0 % patients were observed with elevated thyroid-stimulating hormone (TSH) (>4.94 mIU/L) at any time during the entire treatment period. Sixteen patients with an elevated TSH had a significantly longer PFS than nine patients with no TSH elevation (107 vs. 53 days, respectively, P = 0.002). TSH elevation was also an independent predictor of PFS in a Cox regression model. Plasma VEGF levels did not correlate significantly with clinical outcomes. Conclusions: Famitinib did show substantial anti-tumor activities with a good safety profile in heavily pretreated patients with HER2-negative MBC. Famitinib-related TSH increase may be an early indicator of its efficacy. Serial monitoring of serum TSH may help define VEGFR-2-dependent or VEGFR-2-independent drug resistance. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the preclinical pharmacokinetics (PK) and disposition of Fruquintinib (HMPL-013), a small molecule vascular endothelial growth factor receptors inhibitor. Methods: In vitro and in vivo PK/ADME assays were conducted. Allometry and PK modeling/simulation were conducted to predict human PK parameters and the time course profiles. Results: HMPL-013 has high permeability without efflux. It shows moderate oral bioavailability of 42-53 % and T < 4 h in mouse, rat, dog and monkey, with exposure-dose linearity proved in rats and dogs. No significant food effect is on dog PK. HMPL-013 has moderately high tissue distribution. It majorly distributes in gastrointestinal tract, liver, kidney, adrenal and adipose. The plasma protein binding fraction is 88-95 % in mouse, rat, dog and human, invariable up to 10 µM. The in vivo clearance of HMPL-013 is low, consistent with the in vitro scaling. Three major oxidative metabolites were identified in liver microsomes of mouse, rat, dog, monkey and human. Dog is mostly similar to human regarding in vitro metabolism. Demethylation, hydroxylation and sequential glucuronidation are the major in vivo metabolic reactions. Direct urinary and biliary excretion of HMPL-013 is negligible. Metabolizing to M1 (demethylation), sequentially glucuronidating, followed by biliary excretion, and to a less extent, by urinary excretion, are important elimination pathways for HMPL-013 in rats. HMPL-013 has low risk of drug-drug interaction. It is predicted to have favorable human PK properties and low efficacious dose. Conclusion: HMPL-013 demonstrates good preclinical PK and enables successful human PK and dose projection. It is valuable for further clinical development. [ABSTRACT FROM AUTHOR]

The landscape of castration-resistant prostate carcinoma has changed completely in the last few years, with the approval of four new agents with proven benefit in overall survival. Abiraterone, cabazitaxel, enzalutamide and radium-223 dichloride have been added to the armamentarium of available agents for the treatment of these patients. We still lack information about which agent works best in an individual patient and how to optimally use them in a sequential strategy. Cabozantinib, a targeted agent against MET and vascular endothelial growth factor receptor-2, has shown promising results and could become the first targeted therapy to be approved for castration-resistant prostate carcinoma. This paper reviews the clinical development of cabozantinib in prostate cancer and future research possibilities for this drug. [ABSTRACT FROM AUTHOR]

Purpose: We investigated potential biomarkers of efficacy in a phase III trial of sunitinib versus interferon-alpha (IFN-α), first-line in metastatic renal cell carcinoma (mRCC), by analyzing plasma levels of vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGF receptor-3 (sVEGFR-3) and interleukin (IL)-8. Methods: Seven hundred and fifty mRCC patients were randomized to oral sunitinib 50 mg/day in repeated cycles of a 4-week on/2-week off schedule or IFN-α 9 million units subcutaneously thrice weekly. Plasma samples collected from a subset of 63 patients on days 1 and 28 of cycles 1-4 and at end of treatment were analyzed by ELISA. Results: Baseline characteristics of biomarker-evaluated patients in sunitinib ( N = 33) and IFN-α ( N = 30) arms were comparable to their respective intent-to-treat populations. By univariate Cox regression analysis, low baseline soluble protein levels were associated with lower risk of progression/death (all P < 0.05): in both treatment arms, baseline VEGF-A and IL-8 were associated with overall survival (OS) and baseline VEGF-C with progression-free survival (PFS); in the sunitinib arm, baseline VEGF-A was associated with PFS and baseline sVEGFR-3 with PFS and OS; in the IFN-α arm, baseline IL-8 was associated with PFS. In multivariate analysis, baseline sVEGFR-3 and IL-8 remained independent predictors of OS in the sunitinib arm, while no independent predictors of outcome remained in the IFN-α arm. Pharmacodynamic changes were not associated with PFS or OS for any plasma protein investigated. Conclusions: Our findings suggest that, in mRCC, baseline VEGF-A and IL-8 may have prognostic value, while baseline sVEGFR-3 may predict sunitinib efficacy. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the safety, tolerability, pharmacokinetics and antitumor activities of famitinib (famitinib l-malate), a novel oral multitargeting tyrosine kinase inhibitor that acts against vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor, stem cell factor receptor (c-kit), FMS-like tyrosine kinase-3 receptor and protooncogene tyrosine kinase receptor in patients with advanced solid cancer. Methods: Patients received once daily oral famitinib. Doses were increased from 4 to 8, 13, 20, 27, 24, 25 and eventually 30 mg. Each cycle was defined as 28 days. The pharmacokinetic profile and various biomarkers were evaluated during the first cycle. Antitumor efficacy was evaluated every 8 weeks. Results: Fifty-four patients were evaluable for safety and efficacy. Dose-limiting toxicities were observed in 2 of 3 patients at 30 mg. The dose-limiting toxicities observed in the first cycle of famitinib treatment included hypertension, hand-foot skin reaction and diarrhea. Grade 3 hypertriglyceridemia/hypercholesterolemia and proteinuria were notable side effects in the subsequent treatment cycles. Other common side effects included bone marrow suppression, oral mucositis, fatigue, pain, elevated transaminase or bilirubin, peripheral sensory disturbance and hypothyroidism, most of which were mild to moderate in severity. Pharmacokinetic studies revealed no significant accumulation of famitinib or its major metabolite, M3. The half-lives of famitinib and M3 were approximately 28.7-33.8 and 41.3-47.7 h, respectively. Food demonstrated a minimal effect on the pharmacokinetics of famitinib. Eight partial responses were determined, including 6 cases of renal cell carcinoma, 1 case of gastrointestinal stromal tumor (GIST) and 1 case of alveolar soft part sarcoma. Fourteen patients demonstrated stable disease with various degrees of tumor shrinkage. Conclusions: Famitinib is generally well tolerated. Famitinib demonstrates a wide spectrum of antitumor activities, which warrants further study in renal cell carcinoma, GIST, hepatocellular carcinoma and soft tissue sarcoma. The recommended dose for future phase II clinical trials is 25 mg. [ABSTRACT FROM AUTHOR]

Background: Combining anti-angiogenesis agents with cytotoxic agents for the treatment of malignant gliomas may affect the cytotoxic drug distribution by normalizing the blood-brain barrier (BBB). This study examines the intratumoral concentration of temozolomide (TMZ) in the presence and absence of the pan-VEGF receptor tyrosine kinase inhibitor, cediranib. Methods: Seven nude rats bearing U87 intracerebral gliomas had a microdialysis probe centered within the tumor. Ten-days after tumor implantation, TMZ (50 mg/kg) was given orally. The extracellular fluid (ECF) concentrations of TMZ within the tumor were assessed via microdialysis for 6 h following TMZ administration. Cediranib (6 mg/kg) was then given orally, and 12 h later, TMZ was re-administered with subsequent microdialysis collection. A subset of animals also underwent functional MRI to assess angiogenesis in vivo at post-inoculation days 12 and 21, before and after the cediranib treatment. Results: After dosing of oral TMZ only, ECF-TMZ mean- C and area under the concentration curve(AUC) within the tumor were 0.59 μg/mL and 1.82 μg h/mL, respectively. Post-cediranib, ECF-TMZ mean- C and AUC were 0.83 μg/mL and 3.72 ± 0.61 μg h/mL within the tumor, respectively. This represented a 1.4-fold ( p = 0.3) and 2.0-fold ( p = 0.06) increase in the ECF-TMZ C and AUC, respectively, after cediranib administration. In vivo MRI measurements of the various vascular parameters were consistent with a BBB 'normalization' profile following cediranib treatment. Conclusions: In the U87 intracerebral glioma model, within the first day of administration of cediranib, the intratumoral concentrations of TMZ in tumor ECF were slightly, but not statistically significantly, increased when compared to the treatment of TMZ alone with radiographic evidence of a normalized BBB. [ABSTRACT FROM AUTHOR]

Purpose: Skeletal-related events (SREs) negatively affect the quality of life of patients with cancer. Vascular endothelial growth factor receptor (VEGFR)-targeted therapy is effective against bone metastasis in animal models, but the clinical efficacy of anti-VEGFR inhibitors against bone metastases remains unclear. Therefore, we aimed to investigate the efficacy of chemotherapy with bevacizumab, an anti-VEGF antibody, against bone metastases. Methods: We retrospectively reviewed consecutive patients with non-squamous non-small cell lung cancer who received first-line platinum-based chemotherapy with zoledronic acid at Shizuoka Cancer Center between 2007 and 2011. Results: Of 25 patients, 13 received bevacizumab-based chemotherapy (BEV group) and 12 received chemotherapy without bevacizumab (non-BEV group). The overall response (54 vs. 8 %, p = 0.01) and disease control (100 vs. 50 %, p = 0.01) rates were higher in the BEV group than in the non-BEV group. The bone-specific response (23 vs. 0 %, p = 0.038) and disease control (100 vs. 67 %, p = 0.01) rates were also higher in the BEV group. The median time to progression (TTP) for bone metastases was higher in the BEV group (13.7 vs. 4.3 months, p = 0.06), whereas that for overall disease was similar between the groups (5.7 vs. 2.6 months, p = 0.17). The proportions of patients with SREs were 23 and 50 % in the BEV and non-BEV groups, respectively ( p = 0.16). Conclusion: Bevacizumab might potentiate the antitumor activity of chemotherapy against systemic disease and bone metastases, prolonging bone-specific TTP and reducing the incidence of SRE. [ABSTRACT FROM AUTHOR]

Purpose: Sorafenib and everolimus are both active against neuroendocrine tumors (NET). Because of potential synergy between VEGF pathway and mTOR inhibitors, we performed a phase I study to evaluate the safety and feasibility of combining sorafenib and everolimus in patients with advanced NET. Methods: Patients were treated with everolimus 10 mg daily in combination with sorafenib (dose level 1: 200 mg twice daily; dose level 2: 200 mg per morning, 400 mg per evening) using standard phase I dose escalation design. Dose-limiting toxicity (DLT) was defined within the first cycle (28 days) of therapy. Treatment was continued until tumor progression, unacceptable toxicity, or withdrawal of consent. Twelve additional patients were treated at the maximum tolerated dose (MTD) level to further characterize safety and a preliminary assessment of activity. Results: One patient in Cohort 1 experienced DLT (grade 3 skin rash); the cohort was expanded to 6 patients with no further DLTs. All 3 patients in Cohort 2 experienced DLT, consisting of thrombocytopenia, hand-foot skin reaction, and rash/allergic reaction. Sorafenib 200 mg twice daily in combination with everolimus 10 mg daily was established as the MTD. Independently reviewed best objective responses revealed that 62 % of patients had some degree of tumor shrinkage. By RECIST, we observed partial response in 1 patient, stable disease in 13 patients, and progressive disease in 3 patients. Conclusion: Sorafenib 200 mg twice daily with everolimus 10 mg daily represents the MTD of this combination in patients with advanced NET. While the combination is active, toxicity concerns may preclude more widespread use. [ABSTRACT FROM AUTHOR]

Purpose: A phase I dose escalation study was performed to determine the maximum tolerated dose (MTD) of intercalated dosing of BMS-690514, a reversible oral panHER/VEGF receptor inhibitor, combined with paclitaxel/carboplatin (PC) in advanced solid tumors. Secondary endpoints included safety, pharmacokinetics (PK), exploratory pharmacodynamics (PD), and preliminary efficacy. Experimental design: Patients received fixed doses of P (200 mg/m) and C (AUC 6 mg/mL min) q21 days with intercalated BMS-690514 (Days 4-19) starting at 100 mg/day and increasing by 50 mg/day using a 3 + 3 dose escalation design until the MTD was reached. Twenty additional patients were enrolled in the expansion cohort at the recommended phase II dose (RP2D). Results: The MTD was reached at 150 mg/day. DLTs included grade 3 thrombosis at 100 mg (1 patient) and grade 3 diarrhea at 150 mg (1 patient) and 200 mg (2 patients). Serious adverse events (AEs) occurring in 20/37 patients included neutropenia ( n = 5), diarrhea ( n = 4), pulmonary embolism ( n = 3), and simultaneous dehydration, acute renal failure, and febrile neutropenia ( n = 2). BMS-690514-related AEs included diarrhea (97 %), acneiform rash (60 %), fatigue (43 %), nausea (30 %), and anorexia (30 %). There were no treatment-related deaths. Sequential intermittent administration of PC did not affect the PK of BMS-690514. Of the 32 patients evaluable for efficacy, there were 12 partial responses including five patients with non-small-cell lung cancer and 12 patients with stable disease. Conclusions: The MTD of intercalated BMS-609514 combined with PC was 150 mg/day. This approach was tolerable with manageable toxicities and antitumor activity in a variety of solid tumor types. [ABSTRACT FROM AUTHOR]

Purpose: Cediranib (AZD2171) is a highly potent inhibitor of all three vascular endothelial growth factor receptors. The aim of this preclinical study was to examine the effect of combining cediranib with mechanistically distinct anti-tumour therapies. Methods: Cediranib (1.5 or 3 mg/kg/day) was evaluated alone and in combination with either gefitinib, imatinib, ZD6126, saracatinib, selumetinib, bevacizumab, 5-fluorouracil (5-FU), docetaxel, oxaliplatin, gemcitabine, pemetrexed, irinotecan or cisplatin in human tumour xenograft models. Anti-tumour activity was measured by assessing the change in tumour volume following treatment compared with vehicle-treated time-matched controls. Results: In all cases, the combination regimens, at tolerated doses and schedules, inhibited tumour growth to a greater extent than the corresponding monotherapy treatments. Compared with cediranib alone, statistically significant enhancements in anti-tumour activity were observed with all combination regimens. Notably, after 14 days of treatment, the combination of cediranib with ZD6126 induced substantial tumour regression (60 % compared with pre-treatment volume), whilst treatment with each agent alone led only to partial growth inhibition. A combination of cediranib with gefitinib also induced tumour regressions, and cediranib combined with either gemcitabine or irinotecan was found to inhibit tumour growth profoundly (by 99 and 98 %, respectively). Conclusions: Combining cediranib with selected cytotoxic or targeted agents proved efficacious in a range of human tumour xenograft models. [ABSTRACT FROM AUTHOR]

Purpose: As tyrosine kinase inhibitors have been associated with cardiotoxicity, we evaluated the effect of pazopanib, an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, on electrocardiographic parameters in patients with cancer. Methods: This double-blind, placebo-controlled, parallel-group study randomized patients ( N = 96) to moxifloxacin (positive control) or placebo on Day 1 followed by pazopanib or placebo 800 mg/day (fasted) on Days 2-8 and 1,600 mg (with food) on Day 9. Treatment effects were evaluated by baseline-adjusted, time-matched, serial Holter electrocardiograms. Results: Sixty-five patients were evaluable for preplanned analyses. On Day 1, the maximum mean difference in baseline-adjusted, time-matched Fridericia-corrected QT (QTcF) interval in moxifloxacin-treated patients versus placebo was 10.6 ms (90 % confidence interval [CI]: 4.2, 17.0). The administration scheme increased plasma pazopanib concentrations approximately 1.3- to 1.4-fold versus the recommended 800 mg once-daily dose. Pazopanib caused clinically significant increases from baseline in blood pressure, an anticipated class effect, and an unexpected reduction in heart rate from baseline that correlated with pazopanib exposure. On Day 9, the maximum mean difference in baseline-adjusted, time-matched QTcF interval in pazopanib-treated patients versus placebo was 4.4 ms (90 % CI: −2.4, 11.2). Mixed-effects modeling indicated no significant concentration-dependent effect of pazopanib or its metabolites on QTcF interval. Conclusions: Pazopanib as administered in this study achieved supratherapeutic concentrations, produced a concentration-dependent decrease in heart rate, and caused a small, concentration-independent prolongation of the QTcF interval. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the metabolism and excretion of dovitinib (TKI258), a tyrosine kinase inhibitor that inhibits fibroblast, vascular endothelial, and platelet-derived growth factor receptors, in patients with advanced solid tumors. Methods: Four patients (cohort 1) received a single 500 mg oral dose of C-dovitinib, followed by the collection of blood, urine, and feces for ≤10 days. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of dovitinib by liquid chromatography-tandem mass spectrometry. Both techniques were applied for metabolite profiling and identification. A continuous-dosing extension phase (nonlabeled dovitinib 400 mg daily) was conducted with the 3 patients from cohort 1 and 9 additional patients from cohort 2. Results: The majority of radioactivity was recovered in feces (mean 61 %; range 52-69 %), as compared with urine (mean 16 %; range 13-21 %). Only 6-19 % of the radioactivity was recovered in feces as unchanged dovitinib, suggesting high oral absorption. C-dovitinib was eliminated predominantly via oxidative metabolism, with prominent primary biotransformations including hydroxylation on the fluorobenzyl ring and N-oxidation and carbon oxidation on the methylpiperazine moiety. Dovitinib was the most prominent radioactive component in plasma. The high apparent volume of distribution (2,160 L) may indicate that dovitinib distributes extensively to tissues. Adverse events were predominantly mild to moderate, and most common events included nausea, vomiting, constipation, diarrhea, and fatigue. Conclusions: Dovitinib was well absorbed, extensively distributed, and eliminated mainly by oxidative metabolism, followed by excretion, predominantly in feces. The adverse events were as expected for this class of drug. [ABSTRACT FROM AUTHOR]

Purpose: Combining cytotoxic agents with bevacizumab has yielded significant benefits in a number of solid tumors. Combining small-molecule kinase inhibitors of VEGFR with chemotherapy has yet to demonstrate clinical benefit. The dose, schedule and agents used may be critical to the development of this combinatorial therapy. Methods: We performed a phase I trial of sunitinib and gemcitabine in patients with advanced solid tumor malignancies based on strong preclinical rationale. Results: Two different MTDs were determined. The schedule of gemcitabine 800 mg/m2 on days 1, 8, 15 and sunitinib 25 mg daily was considered to be a MTD. However, omission of day 15 gemcitabine was common, and thus, a second MTD of gemcitabine of 675 mg/m2 on days 1 and 8 with sunitinib 25 mg daily was determined to be the recommended phase II dose. Grade 4 neutropenia and thrombocytopenia occurred in 33 and 6 %, respectively. Grade 3/4 non-hematological toxicities were uncommon. Four of 33 patients had a partial response. Another 11 patients had stable disease ranging from 3 to 36 months. Thus, the recommended phase II dose of this combination is gemcitabine 675 mg/m2 on days 1 and 8 on an every 21-day schedule along with sunitinib 25 mg continuous daily. Conclusions: This combination is well-tolerated and has significant clinical activity. [ABSTRACT FROM AUTHOR]

Purpose: BMS-690514 is a novel oral tyrosine kinase inhibitor of ErbB and vascular endothelial growth factor receptor. This open-label phase I dose-escalation study (ClinicalTrials.gov Identifier: NCT00516451) aimed to assess the safety, preliminary efficacy, pharmacokinetics, and pharmacodynamics of BMS-690514 in Japanese patients with advanced or metastatic solid tumors. Methods: Patients with advanced or metastatic solid tumors received oral BMS-690514 once daily continuously until disease progression or intolerable toxicity occurred. Dose-limiting toxicity (DLT) was evaluated from the first dose to Day 29. Dose levels at 100 and 200 mg were investigated. Assessments included adverse events, tumor response, pharmacokinetics, pharmacodynamics, 2 [18F] fluoro-2-deoxyglucose positron-emitting tomography, and epidermal growth factor receptor and K-ras mutations. Results: BMS-690514 at the dose of 100 mg ( n = 3) or 200 mg ( n = 3) was administered once daily to totally nine patients and was well tolerated up to 200 mg. No treatment-related serious adverse events or DLTs were reported. Frequently observed treatment-related AEs were acne, diarrhea, dry skin, hypertension, stomatitis, blood fibrinogen increased, hemoglobin decreased, pruritus, and hypoalbuminemia. These were generally reported as Grade 1 and 2. Five of 9 patients (56 %) had stable disease. Plasma concentrations of BMS-690514 reached Cmax within 3 h and declined with an effective half-life of approximately 10 and 12 h at 100 and 200 mg, respectively. Conclusions: Oral BMS-690514 was well tolerated in Japanese patients with advanced or metastatic solid tumors up to 200 mg. [ABSTRACT FROM AUTHOR]

Central to the process of brain tumor development is angiogenesis, which involves a host of molecules and receptors. In recent years, antiangiogenic therapies have been developed and tested for their effectiveness against these tumors. Among them are inhibitors against vascular endothelial growth factor and its receptors, as well as inhibitors targeting the platelet-derived growth factor family, integrins, and histone deacetylase. While many have been shown to be effective with limited toxicity, some tumors are able to adopt escape mechanisms. Further research is needed in the development of effective multi-targeted agents to reduce these effects. [ABSTRACT FROM AUTHOR]

Purpose: We previously reported that barbigerone (BA), an isoflavone isolated from Suberect Spatholobus, exhibited inhibitory effects on proliferation of many cancer cell lines in vitro. The objective of this study was to explore whether BA could effectively suppress tumor angiogenesis and tumor growth. Methods: Zebrafish model and Matrigel assay were performed to access the anti-angiogenesis effects of BA. A549 and SPC-A1 tumor xenografts in mice models were used to examine the antitumor activity of BA. The anti-angiogenic effects and underlying mechanisms were also investigated using human umbilical vein endothelial cells (HUVECs) and A549 cells. Results: In zebrafish model, 2.5 μmol/L of BA significantly inhibited angiogenesis. Intravenous administration of BA effectively inhibited the tumor growth of A549 and SPC-A1 xenograft models in mice. The anti-angiogenic effect was indicated by CD31 immunohistochemical staining, Matrigel plug assay, and mouse aortic ring assay. BA could inhibit vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, and capillary-like tuber formation of HUVECs in a dose-dependent manner, suggesting that BA inhibited tumorigenesis by targeting angiogenesis. Western blots revealed that BA directly inhibited the phosphorylation of VEGFR2, followed by inhibiting the activations of its downstream protein kinases, including ERK, p38, FAK, AKT, and expression of iNOS, but had no effect on COX2. Additionally, BA could also down-regulate VEGF secretion in A549 cancer cells, which may correlate with the suppression of ERK, AKT activation, indicating that BA inhibits tumor angiogenesis and tumor growth through VEGFR2 signaling pathways. Conclusions: These findings suggest that BA may be a novel candidate in inhibiting tumor angiogenesis and NSCLC tumor growth. [ABSTRACT FROM AUTHOR]

Purpose: This phase 1 study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of linifanib in Japanese patients with advanced solid tumors. Methods: Patients were assigned to one of four sequential cohorts (0.05, 0.10, 0.20, or 0.25 mg/kg) of oral, once-daily linifanib on a 21-day cycle. Adverse events (AEs) were assessed per common terminology criteria for adverse events v3.0; tumor responses were assessed by response evaluation criteria in solid tumors. Results: Eighteen patients were enrolled. Eleven (61%) received ≥3 prior therapies. Dose-limiting toxicities were Grade 3 ALT increase (0.10 mg/kg linifanib) and Grade 1 T-wave inversion (0.25 mg/kg linifanib) requiring dose interruption for >7 days and discontinuation on day 29. The most common linifanib-related AE was hypertension. Other significant treatment-related AEs included proteinuria, fatigue, and palmar-plantar erythrodysaesthesia. Linifanib pharmacokinetics were dose-proportional across 0.10-0.25 mg/kg. Two patients (11.1%) had confirmed partial responses, 12 had a best response of stable disease (11 had stable disease for ≥12 weeks), and four patients were not evaluable due to incomplete data. Four patients (lung cancer, breast cancer, thymic cancer, sarcoma) have continued linifanib for ≥48 weeks (range, 48-96+ weeks). Conclusion: Linifanib was well tolerated with promising preliminary clinical activity in Japanese patients. Later-phase global studies examining linifanib efficacy will include Japanese patients. [ABSTRACT FROM AUTHOR]

Purpose: Vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) play a significant role in glioblastoma angiogenesis and proliferation, making tyrosine kinase (TK) receptors logical targets for treatment. We evaluated AEE788, a reversible TK inhibitor that inhibits EGFR and VEGFR, in recurrent glioblastoma patients. Methods: In this dose-escalation, phase I study, patients with recurrent glioblastoma received AEE788 once daily in 28-day cycles in stratified subgroups: those receiving (1) non-enzyme-inducing anticonvulsants drugs or no anticonvulsants (Group A) and (2) enzyme-inducing anticonvulsant drugs (Group B). A dose-expansion phase stratified patients by surgical eligibility. Primary objectives were to determine dose-limiting toxicity (DLT) and maximum tolerated dose; secondary objectives included evaluating (1) safety/tolerability, (2) pharmacokinetics, and (3) preliminary antitumor activity. Results: Sixty-four glioblastoma patients were enrolled. Two Group A patients experienced DLTs (proteinuria and stomatitis) at 550 mg; 550 mg was, therefore, the highest dose evaluated and dose limiting. One Group B patient receiving 800 mg experienced a DLT (diarrhea). The initially recommended dose for dose-expansion phase for Group A was 400 mg; additional patients received 250 mg to assess the hepatotoxicity. Most frequently reported adverse events (AEs) included diarrhea and rash. Serious AEs, most commonly grade 3/4 liver function test elevations, were responsible for treatment discontinuation in 17% of patients. AEE788 concentrations were reduced by EIACD. The best overall response was stable disease (17%). Conclusions: Continuous, once-daily AEE788 was associated with unacceptable toxicity and minimal activity for the treatment of recurrent glioblastoma. The study was, therefore, discontinued prematurely. [ABSTRACT FROM AUTHOR]