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Cancer Chemotherapy and Pharmacology Jul 2013Hepatic impairment may impede tyrosine kinase inhibitor metabolism. This phase I study compared the pharmacokinetics of brivanib in patients with hepatocellular...
The effects of liver impairment on the pharmacokinetics of brivanib, a dual inhibitor of fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases.
PURPOSE
Hepatic impairment may impede tyrosine kinase inhibitor metabolism. This phase I study compared the pharmacokinetics of brivanib in patients with hepatocellular carcinoma (HCC) and varying levels of hepatic impairment with those with non-HCC malignancies and normal liver function.
METHODS
Patients were assigned to the following groups: Groups A, B, and C (HCC plus mild, moderate, or severe hepatic impairment, respectively) and Group D (non-HCC malignancy and normal hepatic function). Brivanib alaninate (brivanib prodrug) doses were 400 mg in Groups A, B, and D and 200 mg in Group C. Brivanib exposure was determined on day 1 (single dose) and day 28 (multiple doses).
RESULTS
Twenty-four patients participated in the study. After a single brivanib alaninate dose, brivanib exposure was comparable between Groups A, B, and D. Area under the concentration-time curve was 50 % higher in Group C versus Group D. There were not enough data to draw conclusions on multiple doses. Safety profile in Groups A, B, and D was consistent with previous brivanib monotherapy experience. Tolerability could not be assessed in Group C because of dose interruptions and discontinuations, generally due to the disease natural history.
CONCLUSIONS
Brivanib exposure was similar in patients with HCC and mild or moderate hepatic impairment (Child-Pugh [CP] A or B status) and those with non-HCC malignancies and normal hepatic function, suggesting dose adjustment is unnecessary with CP A or B status. Experience with HCC and severe hepatic impairment (CP C status) is insufficient to recommend brivanib use in this population.
Topics: Aged; Aged, 80 and over; Alanine; Antineoplastic Agents; Carcinoma, Hepatocellular; Cohort Studies; Dose-Response Relationship, Drug; Female; Half-Life; Hepatic Insufficiency; Humans; Liver; Liver Neoplasms; Male; Metabolic Clearance Rate; Middle Aged; Patient Dropouts; Prodrugs; Protein Kinase Inhibitors; Receptors, Fibroblast Growth Factor; Receptors, Vascular Endothelial Growth Factor; Severity of Illness Index; Triazines
PubMed: 23719718
DOI: 10.1007/s00280-013-2168-z -
Clinical Cancer Research : An Official... Apr 2012Brivanib, a selective dual inhibitor of fibroblast growth factor and VEGF signaling, has recently been shown to have activity as first-line treatment for patients with...
PURPOSE
Brivanib, a selective dual inhibitor of fibroblast growth factor and VEGF signaling, has recently been shown to have activity as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). This phase II open-label study assessed brivanib as second-line therapy in patients with advanced HCC who had failed prior antiangiogenic treatment.
EXPERIMENTAL DESIGN
Brivanib was administered orally at a dose of 800 mg once daily. The primary objectives were tumor response rate, time to response, duration of response, progression-free survival, overall survival (OS), disease control rate, time to progression (TTP), and safety and tolerability.
RESULTS
Forty-six patients were treated. Best responses to treatment with brivanib (N = 46 patients) using modified World Health Organization criteria were partial responses for two patients (4.3%), stable disease for 19 patients (41.3%), and progressive disease for 19 patients (41.3%). The tumor response rate was 4.3%; the disease control rate was 45.7%. Median OS was 9.79 months. Median TTP as assessed by study investigators following second-line treatment with brivanib was 2.7 months. The most common adverse events were fatigue, decreased appetite, nausea, diarrhea, and hypertension.
CONCLUSION
Brivanib had a manageable safety profile and is one of the first agents to show promising antitumor activity in advanced HCC patients treated with prior sorafenib.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Alanine; Appetite; Carcinoma, Hepatocellular; Collagen Type IV; Disease-Free Survival; Drug Administration Schedule; Fatigue; Female; Humans; Hypertension; Liver Neoplasms; Male; Middle Aged; Nausea; Treatment Outcome; Triazines; Young Adult; alpha-Fetoproteins
PubMed: 22238246
DOI: 10.1158/1078-0432.CCR-11-1991 -
Cancer Chemotherapy and Pharmacology Dec 2009Brivanib alaninate is a prodrug of brivanib (BMS-540215), a potent oral VEGFR-2 inhibitor and is currently in development for the treatment of hepatocellular and colon...
PURPOSE
Brivanib alaninate is a prodrug of brivanib (BMS-540215), a potent oral VEGFR-2 inhibitor and is currently in development for the treatment of hepatocellular and colon carcinomas. In vitro and in vivo studies were conducted to characterize the preclinical pharmacokinetics and disposition of brivanib and brivanib alaninate, and antitumor efficacy in mice bearing human xenografts.
METHODS
In vitro studies were conducted in liver and intestinal fractions, plasma and Caco-2 cells to assess the metabolic stability. Pharmacokinetics of brivanib were determined in preclinical species after administration of single intravenous or oral doses of both brivanib and brivanib alaninate. The antitumor efficacy was assessed at equimolar doses in nude mice bearing human tumor xenografts. Human efficacious dose was predicted based on projected human pharmacokinetic parameters and exposure at efficacious doses in the mouse efficacy models.
RESULTS
In vitro and in vivo studies indicated that brivanib alaninate was efficiently converted to brivanib. Brivanib showed good brain penetration in rats consistent with its high intrinsic permeability and lack of active efflux in Caco-2 cells. The oral bioavailability of brivanib varied among species (22-88%) and showed dissolution rate-limited absorption even when combined with organic co-solvents. Administration of brivanib as brivanib alaninate allowed completely aqueous vehicles, and an improvement in the oral bioavailability (55-97%) was observed. The clearance of brivanib in humans is anticipated to be low to intermediate (hepatic extraction ratio < 0.7), while its volume of distribution is expected to be high. The minimum efficacious dose of brivanib alaninate was determined to be 60 mg/kg per day.
CONCLUSIONS
Brivanib alaninate is rapidly and efficiently converted to the parent, brivanib, as demonstrated both in vitro and in vivo and offers an excellent mode to deliver brivanib orally.
Topics: Administration, Oral; Alanine; Animals; Antineoplastic Agents; Biological Availability; Brain; Caco-2 Cells; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Humans; Injections, Intravenous; Macaca fascicularis; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Prodrugs; Pyrroles; Rats; Solubility; Tissue Distribution; Triazines; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays
PubMed: 19396600
DOI: 10.1007/s00280-009-1002-0 -
AJR. American Journal of Roentgenology Jun 2014The purpose of this article is to evaluate the antiangiogenic effects of brivanib using dynamic contrast-enhanced MRI (DCE-MRI) in an orthotopic mouse model of human...
OBJECTIVE
The purpose of this article is to evaluate the antiangiogenic effects of brivanib using dynamic contrast-enhanced MRI (DCE-MRI) in an orthotopic mouse model of human hepatocellular carcinoma (HCC).
MATERIALS AND METHODS
With human HCC (HepG2 cell line) orthotopic nude mouse xenografts, brivanib was administered orally to the treatment group, and the vehicle was administered to the control group for 14 days. DCE-MRI was performed before the start of the therapy and 7 and 14 days after the start of therapy. Treatment-induced changes in tumor volume and microvessel density (MVD) assessed by CD31 immunohistochemistry were analyzed. Perfusion parameters, including volume transfer constant between blood plasma and extravascular extracellular space (K(trans)), fractional extravascular extracellular space per unit volume of tissue (ve), and rate constant between extravascular extracellular space and blood plasma (Kep), were calculated using the two-compartment model.
RESULTS
Brivanib shows potent antitumor activity in tumor volume. The mean (± SD) MVD of the tumors was statistically significantly lower in the brivanib-treated group (40.8 ± 17.3 vessels/field) than in the control group (55.2 ± 9.05 vessels/field) (p < 0.05). In the control group, the K(trans) value increased statistically significantly between the baseline and 14 days after treatment (p = 0.048). In the brivanib-treated group, the K(trans) and ve values decreased statistically significantly between baseline and 7 days after treatment (p = 0.024 and p = 0.031, respectively) and between baseline and 14 days after treatment (p = 0.043 and p = 0.018, respectively). The difference between the K(trans) and ve values between baseline and 14 days after treatment showed a statistically significant difference between the two groups (p = 0.004 and p = 0.034, respectively).
CONCLUSION
DCE-MRI is feasible in the orthotopic mouse model of human HCC, and it can noninvasively monitor brivanib-induced changes in tumor microvasculature.
Topics: Administration, Oral; Alanine; Angiogenesis Inhibitors; Animals; Carcinoma, Hepatocellular; Contrast Media; Hep G2 Cells; Humans; Liver Neoplasms; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Microvessels; Receptors, Vascular Endothelial Growth Factor; Reproducibility of Results; Sensitivity and Specificity; Treatment Outcome; Triazines; Tumor Burden
PubMed: 24848850
DOI: 10.2214/AJR.13.11042 -
European Journal of Cancer (Oxford,... Jun 2010Tamoxifen, a selective oestrogen receptor modulator (SERM), and brivanib alaninate, a vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, are two target...
Experimental treatment of oestrogen receptor (ER) positive breast cancer with tamoxifen and brivanib alaninate, a VEGFR-2/FGFR-1 kinase inhibitor: a potential clinical application of angiogenesis inhibitors.
PURPOSE
Tamoxifen, a selective oestrogen receptor modulator (SERM), and brivanib alaninate, a vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, are two target specific agents that result in a substantial decrease in tumour growth when given alone. Tamoxifen activates SERM stimulated breast and endometrial tumour growth. Tamoxifen and brivanib alaninate have side-effects that can affect therapeutic outcomes. The primary goal of the current study was to evaluate the therapeutic effects of lower doses of both agents when given in combination to mice with SERM sensitive, oestrogen stimulated tumour xenografts (MCF-7 E2 tumours). Experiments were conducted to evaluate the response of SERM stimulated breast (MCF-7 Tam, MCF-7 Ral) and endometrial tumours (EnCa 101) to demonstrate the activity of brivanib alaninate in SERM resistant models.
EXPERIMENTAL DESIGN
In the current study, tumour xenografts were minced and bi-transplanted into the mammary fat pads of athymic, ovariectomised mice. Preliminary experiments were conducted to determine an effective oral dose of tamoxifen and brivanib alaninate that had minimal effect on tumour growth. Doses of 125 microg of tamoxifen and 0.05 mg/g of brivanib alaninate were evaluated. An experiment was designed to evaluate the effect of the two agents together when started at the time of tumour implantation. An additional experiment was done in which tumours were already established and then treated, to obtain enough tumour tissue for molecular analysis.
RESULTS
Brivanib alaninate was effective at inhibiting tumour growth in SERM sensitive (MCF-7 E2) and SERM stimulated (EnCa 101, MCF-7 Ral, MCF-7 Tam) models. The effect of the low dose drug combination as an anti-tumour strategy for SERM sensitive (MCF-7 E2) in early treatment was as effective as higher doses of either drug used alone. In established tumours, the combination is successful at decreasing tumour growth, while neither agent alone is effective. Molecular analysis revealed a decreased phosphorylation of VEGFR-2 in tumours that were treated with brivanib alaninate and an increase in VEGFA transcription to compensate for the blockade of VEGFR-2 by increasing the transcription of VEGFA. Tamoxifen increases the phosphorylation of VEGFR-2 and this effect is abrogated by brivanib alaninate. There was also increased necrosis in tumours treated with brivanib alaninate.
CONCLUSION
Historically, tamoxifen has a role in blocking angiogenesis as well as the blockade of the ER. Tamoxifen and a low dose of an angiogenesis inhibitor, brivanib alaninate, can potentially be combined not only to maximise therapeutic efficacy but also to retard SERM resistant tumour growth.
Topics: Alanine; Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Immunohistochemistry; Mice; Mice, Nude; Neoplasm Transplantation; Pyrroles; Random Allocation; Receptor, Fibroblast Growth Factor, Type 1; Reverse Transcriptase Polymerase Chain Reaction; Tamoxifen; Transplantation, Heterologous; Triazines; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 20303261
DOI: 10.1016/j.ejca.2010.02.018 -
Molecular Medicine Reports Nov 2013Angiogenesis inhibition is an attractive therapeutic strategy in the management of solid tumors. Vascular endothelial growth factor (VEGF) and fibroblast growth factor...
Angiogenesis inhibition is an attractive therapeutic strategy in the management of solid tumors. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are key factors in growth and neovascularization of hepatocellular carcinoma (HCC). Brivanib is a novel, orally available dual tyrosine kinase inhibitor that selectively targets the key angiogenesis receptors VEGF‑R2, FGF‑R1 and FGF‑R2. Recently, high‑resolution magic angle spinning magnetic resonance spectroscopy (HR‑MAS MRS) has provided the opportunity to investigate more detailed metabolic profiles from intact tissue specimens that are correlated with histopathology and is thus, a promising tool for monitoring changes induced by treatment. In the present study, 1H HR‑MAS MRS and immunohistochemistry were used to investigate the antitumor efficacy of brivanib in HCC xenograft models. Tumor growth was significantly suppressed in brivanib‑treated mice compared with the controls and treatment was associated with the inhibition of angiogenesis, increased apoptosis and inhibition of cell proliferation. Furthermore, HR‑MAS techniques showed altered metabolic profiles between the two groups. HR‑MAS spectra demonstrated a significant decrease in choline metabolite levels in the treated groups, concurrent with decreased cell proliferation and increased apoptosis. The results showed that 1H HR‑MAS MRS provides quantitative metabolite information that may be used to analyze the efficacy of brivanib treatment in Hep3B tumor xenografts. Thus, the HR‑MAS MRS technique may be a complementary method to support histopathological results and increase its potential for use in the clinic.
Topics: Alanine; Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Humans; Immunoenzyme Techniques; Liver Neoplasms; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred BALB C; Triazines; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 24064967
DOI: 10.3892/mmr.2013.1690 -
Gynecologic Oncology Sep 2017Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy...
BACKGROUND
Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients.
METHODS
Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) >6months and objective tumor response.
RESULTS
Of 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had >2cycles of brivanib with 4 (14%) receiving >10cycles (range: 1-20). Seven (25%) patients had PFS >6months (90% CI: 7.3%-33.9%). Two (7%) (90% CI: 1.3%-20.8%) patients had partial tumor response with duration of 8 and 22months and 12 (43%) had stable disease. The median PFS was 3.2months (90% CI: 2.1-4.4). The median overall survival was 7.9months (90% CI: 6.1-11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension.
CONCLUSIONS
Based on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability.
Topics: Adult; Aged; Aged, 80 and over; Alanine; Antineoplastic Agents; Carcinoma; Disease Progression; Disease-Free Survival; Early Termination of Clinical Trials; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Response Evaluation Criteria in Solid Tumors; Retreatment; Survival Rate; Triazines; Uterine Cervical Neoplasms
PubMed: 28728751
DOI: 10.1016/j.ygyno.2017.05.033 -
Annals of Oncology : Official Journal... Jun 2011This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors.
A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors.
BACKGROUND
This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors.
PATIENTS AND METHODS
Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD.
RESULTS
Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180-800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts.
CONCLUSION
In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.
Topics: Adult; Aged; Aged, 80 and over; Alanine; Angiogenesis Inhibitors; Antineoplastic Agents; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Receptors, Fibroblast Growth Factor; Receptors, Vascular Endothelial Growth Factor; Triazines
PubMed: 21131369
DOI: 10.1093/annonc/mdq599 -
International Journal of Pharmaceutics Jul 2014A quality by design approach was applied to the development of brivanib alaninate tablets. Brivanib alaninate, an ester pro-drug, undergoes hydrolysis to its parent...
A quality by design approach was applied to the development of brivanib alaninate tablets. Brivanib alaninate, an ester pro-drug, undergoes hydrolysis to its parent compound, BMS-540215. The shelf-life of the tablets is determined by the rate of the hydrolysis reaction. Hydrolysis kinetics in the tablets was studied to understand its dependence on temperature and humidity. The BMS-540215 amount versus time profile was simulated using a kinetic model for the formation of BMS-540215 as function of relative humidity in the environment and a sorption-desorptiom moisture transfer model for the relative humidity inside the package. The combined model was used to study the effect of initial tablet water content on the rate of degradation and to identify a limit for initial tablet water content that results in acceptable level of the degradant at the end of shelf-life. A strategy was established for the moisture and degradant control in the tablet based on the understanding of its stability behavior and mathematical models. The control strategy includes a specification limit on the tablet water content and manufacturing process controls that achieve this limit at the time of tablet release testing.
Topics: Alanine; Angiogenesis Inhibitors; Chemistry, Pharmaceutical; Computer Simulation; Drug Stability; Humidity; Hydrolysis; Kinetics; Models, Chemical; Prodrugs; Quality Control; Solubility; Tablets; Technology, Pharmaceutical; Temperature; Triazines; Water
PubMed: 24780101
DOI: 10.1016/j.ijpharm.2014.04.059 -
PloS One 2015
PubMed: 26528545
DOI: 10.1371/journal.pone.0142355