Vandetanib

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John V Heymach - One of the best experts on this subject based on the ideXlab platform.

  • systemic and cns activity of the ret inhibitor Vandetanib combined with the mtor inhibitor everolimus in kif5b ret re arranged non small cell lung cancer with brain metastases
    Lung Cancer, 2015
    Co-Authors: Vivek Subbiah, Jenny Berry, Michael Roxas, Nandita Guhathakurta, Ishwaria Mohan Subbiah, Caitlin Mcmahon, Vincent A Miller, Tina Cascone, Zhenya Tang, John V Heymach
    Abstract:

    Abstract In-frame fusion KIF5B (the-kinesin-family-5B-gene)-RET transcripts have been characterized in 1–2% of non-small cell lung cancers and are known oncogenic drivers. The RET tyrosine kinase inhibitor, Vandetanib, suppresses fusion-induced, anchorage-independent growth activity. In vitro studies have shown that Vandetanib is a high-affinity substrate of breast cancer resistance protein (Bcrp1/Abcg2) but is not transported by P-glycoprotein (P-gp), limiting its blood–brain barrier penetration. A co-administration strategy to enhance the brain accumulation of Vandetanib by modulating P-gp/Abcb1- and Bcrp1/Abcg2-mediated efflux with mTOR inhibitors, specifically everolimus, was shown to increase the blood–brain barrier penetration. We report the first bench-to-bedside evidence that RET inhibitor combined with an mTOR inhibitor is active against brain-metastatic RET-rearranged lung cancer and the first evidence of blood–brain barrier penetration. A 74-year-old female with progressive adenocarcinoma of the lung (wild-type EGFR and no ALK rearrangement) presented for therapy options. A deletion of 5′RET was revealed by FISH assay, indicating RET-gene rearrangement. Because of progressive disease in the brain, she was enrolled in a clinical trial with Vandetanib and everolimus (NCT01582191). Comprehensive genomic profiling revealed fusion of KIF5B (the-kinesin-family-5B-gene) and RET, in addition to AKT2 gene amplification. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. Interestingly, AKT2 amplification seen is a critical component of the PI3K/mTOR pathway, alterations of which has been associated with both de novo and acquired resistance to targeted therapy. The addition of everolimus may have both overcome the AKT2 amplification to produce a response in addition to its direct effects on the RET gene. Our case report forms the first evidence of blood–brain barrier penetration by Vandetanib in combination with everolimus. Further research is required in this setting.

  • baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from Vandetanib in non small cell lung cancer
    Clinical Cancer Research, 2009
    Co-Authors: Emer O Hanrahan, Peter Langmuir, Anderson J Ryan, Helen Mann, Sarah J Kennedy, Ronald B Natale, Roy S Herbst, Bruce E Johnson, John V Heymach
    Abstract:

    Purpose: Vandetanib [vascular endothelial growth factor (VEGF) receptor/epidermal growth factor receptor/RET inhibitor] has shown improvements in progression-free survival (PFS) in advanced non-small cell lung cancer in three randomized phase II studies: Vandetanib versus gefitinib (study 3), docetaxel ± Vandetanib (study 6), and carboplatin-paclitaxel and/or Vandetanib (study 7). In study 7, Vandetanib monotherapy was inferior to carboplatin-paclitaxel. We performed an exploratory retrospective analysis of the relationship between baseline circulating VEGF concentrations and PFS. Experimental Design: Mean baseline VEGF levels were determined by ELISA from two baseline samples of plasma (163 of 168 patients, study 3; 65 of 127, study 6) or serum (144 of 181, study 7). High baseline VEGF values were above the immunoassay reference range for healthy subjects; low baseline VEGF values were within the range. Results: Patients with low baseline VEGF had a lower risk of disease progression with Vandetanib versus gefitinib [hazard ratio (HR), 0.55; 95% confidence interval (95% CI), 0.35-0.86; P = 0.01] or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.25; 95% CI, 0.09-0.68; P = 0.01). High VEGF patients had a similar risk of disease progression with Vandetanib monotherapy versus gefitinib (HR, 1.03; 95% CI, 0.60-1.75; P = 0.92) or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.95; 95% CI, 0.25-3.61; P = 0.94). In study 7, low VEGF patients had a similar risk of disease progression with Vandetanib monotherapy 300 mg/d versus carboplatin-paclitaxel (HR, 0.80; 95% CI, 0.41-1.56; P = 0.51); high VEGF patients progressed more quickly (HR, 1.60; 95% CI, 0.81-3.15; P = 0.17). Conclusions: These analyses suggest that low baseline circulating VEGF may be predictive of PFS advantage in patients with advanced non-small cell lung cancer receiving Vandetanib versus gefitinib or Vandetanib + docetaxel versus docetaxel. Moreover, patients with low VEGF levels may have a similar outcome with either Vandetanib monotherapy or carboplatin-paclitaxel.

  • baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from Vandetanib in non small cell lung cancer
    Clinical Cancer Research, 2009
    Co-Authors: Emer O Hanrahan, Peter Langmuir, Anderson J Ryan, Helen Mann, Sarah J Kennedy, Ronald B Natale, Roy S Herbst, Bruce E Johnson, John V Heymach
    Abstract:

    Purpose: Vandetanib [vascular endothelial growth factor (VEGF) receptor/epidermal growth factor receptor/RET inhibitor] has shown improvements in progression-free survival (PFS) in advanced non-small cell lung cancer in three randomized phase II studies: Vandetanib versus gefitinib (study 3), docetaxel ± Vandetanib (study 6), and carboplatin-paclitaxel and/or Vandetanib (study 7). In study 7, Vandetanib monotherapy was inferior to carboplatin-paclitaxel. We performed an exploratory retrospective analysis of the relationship between baseline circulating VEGF concentrations and PFS. Experimental Design: Mean baseline VEGF levels were determined by ELISA from two baseline samples of plasma (163 of 168 patients, study 3; 65 of 127, study 6) or serum (144 of 181, study 7). High baseline VEGF values were above the immunoassay reference range for healthy subjects; low baseline VEGF values were within the range. Results: Patients with low baseline VEGF had a lower risk of disease progression with Vandetanib versus gefitinib [hazard ratio (HR), 0.55; 95% confidence interval (95% CI), 0.35-0.86; P = 0.01] or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.25; 95% CI, 0.09-0.68; P = 0.01). High VEGF patients had a similar risk of disease progression with Vandetanib monotherapy versus gefitinib (HR, 1.03; 95% CI, 0.60-1.75; P = 0.92) or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.95; 95% CI, 0.25-3.61; P = 0.94). In study 7, low VEGF patients had a similar risk of disease progression with Vandetanib monotherapy 300 mg/d versus carboplatin-paclitaxel (HR, 0.80; 95% CI, 0.41-1.56; P = 0.51); high VEGF patients progressed more quickly (HR, 1.60; 95% CI, 0.81-3.15; P = 0.17). Conclusions: These analyses suggest that low baseline circulating VEGF may be predictive of PFS advantage in patients with advanced non-small cell lung cancer receiving Vandetanib versus gefitinib or Vandetanib + docetaxel versus docetaxel. Moreover, patients with low VEGF levels may have a similar outcome with either Vandetanib monotherapy or carboplatin-paclitaxel.

  • randomized phase ii study of Vandetanib alone or with paclitaxel and carboplatin as first line treatment for advanced non small cell lung cancer
    Journal of Clinical Oncology, 2008
    Co-Authors: John V Heymach, Luis Pazares, Filippo De Braud, Martin Sebastian, David J Stewart, W Eberhardt, Anantbhushan Ranade, Graham Lawrence Cohen, Jose Manuel Trigo, Alan B Sandler
    Abstract:

    Purpose Vandetanib is a once-daily, oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. The antitumor activity of Vandetanib monotherapy or Vandetanib with paclitaxel and carboplatin (VPC) was compared with paclitaxel and carboplatin (PC) in previously untreated patients with non–small-cell lung cancer (NSCLC). Patients and Methods All NSCLC histologies and previously treated CNS metastases were permitted in this partially blinded, placebo-controlled, randomized phase II study. Patients were randomly assigned 2:1:1 to receive Vandetanib, VPC, or PC. Progression-free survival (PFS) was the primary end point, and the study was powered to detect a reduced risk of progression with VPC versus PC (hazard ratio = 0.70; one-sided P < .2) and to demonstrate noninferiority for Vandetanib versus PC. Overall survival was a secondary assessment. Results The risk of progression was reduced for patients receiving VPC (n = 56) versus PC (n = 52; hazard ratio = 0.7...

  • Vandetanib zd6474 an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis
    Expert Opinion on Investigational Drugs, 2007
    Co-Authors: Roy S Herbst, Amir Onn, John V Heymach, Michael A Oreilly, Anderson J Ryan
    Abstract:

    Vandetanib (ZD6474; ZACTIMA, AstraZeneca) is a once-daily, orally available agent with potential for use in a number of solid tumor types. Vandetanib targets key signaling pathways in cancer by inhibiting VEGFR-dependent tumor angiogenesis, and EGFR- and RET-dependent tumor cell proliferation and survival. Phase I studies showed Vandetanib to be generally well tolerated at doses of < or = 300 mg/day, with a pharmacokinetic profile that supports once-daily oral administration. Phase II evaluation of Vandetanib in patients with advanced refractory NSCLC has demonstrated improvements in progression-free survival both as monotherapy (versus gefitinib) and in combination with docetaxel (versus docetaxel alone). These positive outcomes have led to the initiation of Phase III trials of Vandetanib in advanced NSCLC. Clinical development is also ongoing in other tumor types and encouraging evidence of antitumor activity has been reported in patients with metastatic hereditary medullary thyroid cancer.

Robert I. Haddad - One of the best experts on this subject based on the ideXlab platform.

  • Efficacy and Safety of Vandetanib in Progressive and Symptomatic Medullary Thyroid Cancer: Post Hoc Analysis From the ZETA Trial
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2020
    Co-Authors: Michael C. Kreissl, Lars Bastholt, Rossella Elisei, Robert I. Haddad, Ole Hauch, Barbara Jarząb, Bruce G. Robinson, Raffaella Colzani, Meredith C. Foster, Richard Weiss
    Abstract:

    PURPOSEWe conducted a post hoc analysis of the Vandetanib phase III trial involving patients with advanced medullary thyroid cancer (MTC) to assess the efficacy and safety of Vandetanib in patients...

  • management of treatment related toxicities in advanced medullary thyroid cancer
    Cancer Treatment Reviews, 2018
    Co-Authors: Marcia S Brose, Keith C Bible, Laura Quan Man Chow, Jill Gilbert, Carolyn Grande, Francis P Worden, Robert I. Haddad
    Abstract:

    Abstract Progress in the treatment of advanced medullary thyroid cancer (MTC) has resulted from the approval of 2 drugs within the past 5 years, Vandetanib and cabozantinib. These multikinase inhibitors (MKIs) possess overlapping specificities for multiple kinase targets implicated in the progression of MTC. Both drugs are associated with toxicities, including hypertension, hemorrhage/perforation, diarrhea and other gastrointestinal events, several dermatologic events, and hypothyroidism. In addition, Vandetanib is uniquely associated with QTc prolongation through interaction with myocardial potassium channels, and cabozantinib is uniquely associated with hand-foot skin reaction. Treatment-related toxicities occur frequently and can be severe or life-threatening, and patients undergoing long-term treatment will likely experience adverse events (AEs). Here we offer specific practical recommendations for managing AEs commonly occurring with Vandetanib and cabozantinib. The recommended approach relies on early recognition and palliation of symptoms, dose interruption, and dose reduction as necessary in order for the patient to maintain the highest tolerable dose for as long as possible and optimal quality of life. Treatment guidelines do not specify a recommended sequence for treating with Vandetanib and cabozantinib; however, most patients will receive both drugs during their lifetime. The choice for first-line therapy is individualized after a risk-benefit assessment and depends on physician preference and patient-related factors, such as comorbid conditions. Because most generalist practices may not be familiar with the intricacies of agents such as Vandetanib and cabozantinib, we commend that patients with advanced MTC be managed and treated by a thyroid cancer specialist with coordination of care within a multidisciplinary team.

  • how to incorporate new tyrosine kinase inhibitors in the treatment of patients with medullary thyroid cancer
    Journal of Clinical Oncology, 2013
    Co-Authors: Robert I. Haddad
    Abstract:

    Medullary thyroid cancer (MTC), a neuroendocrine tumor arising from the parafollicular C cells of the thyroid gland, is rare and accounts for approximately 5% of all thyroid cancers. The majority of cases of MTC are sporadic, and in roughly 25% of cases, MTC is part of a hereditary cancer syndrome with a well-characterized germline RET mutation: multiple endocrine neoplasia 2A, multiple endocrine neoplasia (MEN) 2B, or familial MTC. Patients with newly diagnosed disease are treated with surgery. Calcitonin and carcinoembryonic antigen (CEA) are useful blood markers and are often used to monitor patients after surgery. Systemic chemotherapy and radiation therapy are not believed to represent important or useful options for most patients with MTC. Patients with metastatic disease are not curable and are often monitored with serial scans and biochemical markers. Metastatic MTC can be quite indolent, and timing to initiate therapy varies greatly among physicians and practices. Until recently, no satisfactory options existed for treating patients with metastatic disease in need of therapy. In 2011, the US Food and Drug Administration approved Vandetanib (which targets RET, epidermal growth factor receptor, and vascular endothelial growth factor receptor) for the treatment of patients with symptomatic or progressive, locally advanced, or metastatic MTC. This approval was based on the Zactima Efficacy in Thyroid Cancer Assessment (ZETA) phase III study. In 2012, the US Food and Drug Administration also approved cabozantinib for the same indication on the basis of the Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial reported in the article that accompanies this editorial. The ZETA study was a randomized double-blind phase III trial in which patients were randomly assigned in a 2:1 fashion to receive oral Vandetanib 300 mg per day (n 231) or a placebo (n 100) until disease progression. The primary end point was progression-free survival (PFS), and relevant secondary end points were objective response rate, overall survival, biochemical response, safety, and tolerability. Patients who were enrolled onto the ZETA trial were not required to have progressive disease before enrollment but were required to have measurable disease at baseline and a calcitonin level of at least 500 pg/mL. The study showed a significant prolongation of PFS with Vandetanib versus the placebo (hazard ratio, 0.46; 95% CI, 0.31 to 0.69; P .001). Statistically significant advantages for Vandetanib were also seen for objective response rate, disease control rate, and biochemical response. This study allowed patients receiving the placebo to cross over to Vandetanib, and an overall survival advantage was not seen at the time of the initial report. The median duration of treatment in the randomized phase was 90.1 weeks for Vandetanib and 39.9 weeks for the placebo. The ZETA trial clearly included many patients with indolent disease, as evidenced by a PFS of 19.3 months in the placebo group (with an estimated PFS of 30 months in the Vandetanib group). Adverse events such as diarrhea, rash, nausea, and hypertension occurred in more than 30% of patients receiving Vandetanib. More patients required dose reduction of Vandetanib compared with the placebo for adverse events or QTc prolongation (35% v 3%). Nineteen patients (8%) developed protocol-defined QTc prolongation, but there were no reports of torsades de pointes. The rate of treatment discontinuation because of toxicity was 12%. Because of this risk of QT prolongation, Vandetanib is currently only available through the US Food and Drug Administration Vandetanib Risk Evaluation Mitigation Strategy Program. This program is meant to educate practitioners about the risk, appropriate monitoring, and management of QT prolongation should it occur during Vandetanib therapy. The EXAM study that is reported in the article that accompanies this editorial sought to examine the effect of cabozantinib in progressive MTC. Cabozantinib is a tyrosine kinase inhibitor (TKI) that targets three potentially important pathways in MTC: MET, vascular endothelial growth factor receptor 2, and RET. EXAM is a double-blind phase III trial comparing oral cabozantinib at 140 mg per day with a placebo in 330 patients with documented radiographic progression of metastatic MTC. The primary end point is PFS. Other end points are response rate, overall survival, and safety. This study also used a 2:1 randomization schema, but unlike the ZETA trial, the EXAM study did not allow cross over to the active drug. The study met its primary end point of prolongation of PFS: 11.2 months for cabozantinib versus 4 months for the placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.4; P .001). There is no survival advantage noted so far, and analysis is ongoing for the overall survival end point. Objective tumor response rates and biochemical responses were also significantly improved with cabozantinib. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 29 OCTOBER 1

  • Vandetanib for the treatment of medullary thyroid cancer
    Clinical Cancer Research, 2013
    Co-Authors: Nicole G Chau, Robert I. Haddad
    Abstract:

    Vandetanib (ZD6474, Caprelsa, AstraZeneca), an oral small-molecule tyrosine kinase inhibitor (TKI) that targets the rearranged during transfection receptor (RET), VEGF receptor (VEGFR2-3), and EGF receptor (EGFR), is the first systemic therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of symptomatic or progressive advanced medullary thyroid cancer (MTC). In a randomized phase III trial of patients with unresectable, locally advanced, or metastatic MTC, Vandetanib improved progression-free survival compared with placebo [HR, 0.46; 95% confidence interval (CI), 0.31-0.69; P < 0.001]. However, the benefits in delaying disease progression need to be balanced against the associated and potentially serious toxicities, including diarrhea, hypertension, and QTc prolongation. Here, we review the clinical development of Vandetanib leading to its integration into the current treatment paradigm and highlight the ongoing and future challenges in TKI use in MTC.

  • Vandetanib 100 mg in patients with locally advanced or metastatic hereditary medullary thyroid cancer
    The Journal of Clinical Endocrinology and Metabolism, 2010
    Co-Authors: Bruce G. Robinson, Luis Pazares, Annetta D Krebs, James Vasselli, Robert I. Haddad
    Abstract:

    Purpose: Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinases that also inhibits rearranged during transfection kinase activity. Vandetanib (300 mg/d) has previously demonstrated antitumor activity in patients with advanced hereditary medullary thyroid cancer (MTC). This study investigated the efficacy and safety of 100 mg/d Vandetanib in patients with advanced hereditary MTC. Patients and Methods: Eligible patients with unresectable, measurable, locally advanced, or metastatic hereditary MTC received 100 mg/d Vandetanib. Upon disease progression, eligible patients could enter postprogression treatment with 300 mg/d Vandetanib until a withdrawal criterion was met. The primary objective was to assess the objective response rate by response evaluation criteria in solid tumors. Results: The study comprised 19 patients (13 males, six females; mean age 45 yr). Confirmed objective partial responses were observed in three patients, yielding an objective response rate of 16% (95% confidence interval 3.4–39.6). Stable disease lasting 24 wk or longer was reported in a further 10 patients (53%); the disease control rate was therefore 68% (95% confidence interval 43.4–87.4). Serum levels of calcitonin and carcinoembryonic antigen showed a sustained 50% or greater decrease from baseline in 16% (three of 19) and 5% (one of 19) of patients, respectively. Adverse events were predominantly grade 1 or 2 and consistent with previous Vandetanib monotherapy studies. Conclusions: Vandetanib at a once-daily dose of 100 mg has clinically relevant antitumor activity in patients with locally advanced or metastatic hereditary MTC and an overall acceptable safety profile.

Anderson J Ryan - One of the best experts on this subject based on the ideXlab platform.

  • assessment of acute antivascular effects of Vandetanib with high resolution dynamic contrast enhanced computed tomographic imaging in a human colon tumor xenograft model in the nude rat
    Neoplasia, 2010
    Co-Authors: Anderson J Ryan, Joo Ho Tai, Jean Tessier, Lisa M Hoffman, Xiaogang Chen, Tingyim Lee
    Abstract:

    Tumor size is not a reliable marker for the assessment of early antivascular effects of antiangiogenics. In the present study, we used 200-µm in-plane high-resolution dynamic contrast-enhanced computed tomography (DCE-CT) to noninvasively assess the immediate antivascular effects of Vandetanib in a subcutaneous human colon cancer (LoVo) xenograft model in nude rats and to investigate correlation between changes in CT perfusion parameters and tumor volume or immunohistochemical end points. At 3 to 4 weeks after LoVo cell implantation, the animal was gavaged with either Vandetanib (50 mg/kg) or vehicle twice (22 hours apart) and scanned with a preclinical DCE-CT scanner before (0 hour) and after treatment (24 hours). Quantitative maps of blood flow (BF) and volume (BV) of the tumor were calculated from the acquired DCE-CT images. The rats were divided into nonhypovascular, hypovascular, and combined (regardless of vascularity) groups. In the nonhypovascular group, significant decreases in both tumor BF and BV were observed in the Vandetanib-treated rats compared with increases in the vehicle-treated rats. A significant decrease in BV was detected in the Vandetanib-treated rats in the combined group as well. No differences in tumor growth, vascular endothelial growth factor expression, microvessel density, or apoptosis were observed between Vandetanib- and vehicle-treated rats in all three groups. These results demonstrate that BF and BV imaging biomarkers from DCE-CT imaging can be used for rapid monitoring of immediate (24 hours after) antimicrovascular effects of Vandetanib on tumors, even in the absence of significant changes of tumor volume or clinically relevant immunohistochemical end points.

  • baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from Vandetanib in non small cell lung cancer
    Clinical Cancer Research, 2009
    Co-Authors: Emer O Hanrahan, Peter Langmuir, Anderson J Ryan, Helen Mann, Sarah J Kennedy, Ronald B Natale, Roy S Herbst, Bruce E Johnson, John V Heymach
    Abstract:

    Purpose: Vandetanib [vascular endothelial growth factor (VEGF) receptor/epidermal growth factor receptor/RET inhibitor] has shown improvements in progression-free survival (PFS) in advanced non-small cell lung cancer in three randomized phase II studies: Vandetanib versus gefitinib (study 3), docetaxel ± Vandetanib (study 6), and carboplatin-paclitaxel and/or Vandetanib (study 7). In study 7, Vandetanib monotherapy was inferior to carboplatin-paclitaxel. We performed an exploratory retrospective analysis of the relationship between baseline circulating VEGF concentrations and PFS. Experimental Design: Mean baseline VEGF levels were determined by ELISA from two baseline samples of plasma (163 of 168 patients, study 3; 65 of 127, study 6) or serum (144 of 181, study 7). High baseline VEGF values were above the immunoassay reference range for healthy subjects; low baseline VEGF values were within the range. Results: Patients with low baseline VEGF had a lower risk of disease progression with Vandetanib versus gefitinib [hazard ratio (HR), 0.55; 95% confidence interval (95% CI), 0.35-0.86; P = 0.01] or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.25; 95% CI, 0.09-0.68; P = 0.01). High VEGF patients had a similar risk of disease progression with Vandetanib monotherapy versus gefitinib (HR, 1.03; 95% CI, 0.60-1.75; P = 0.92) or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.95; 95% CI, 0.25-3.61; P = 0.94). In study 7, low VEGF patients had a similar risk of disease progression with Vandetanib monotherapy 300 mg/d versus carboplatin-paclitaxel (HR, 0.80; 95% CI, 0.41-1.56; P = 0.51); high VEGF patients progressed more quickly (HR, 1.60; 95% CI, 0.81-3.15; P = 0.17). Conclusions: These analyses suggest that low baseline circulating VEGF may be predictive of PFS advantage in patients with advanced non-small cell lung cancer receiving Vandetanib versus gefitinib or Vandetanib + docetaxel versus docetaxel. Moreover, patients with low VEGF levels may have a similar outcome with either Vandetanib monotherapy or carboplatin-paclitaxel.

  • baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from Vandetanib in non small cell lung cancer
    Clinical Cancer Research, 2009
    Co-Authors: Emer O Hanrahan, Peter Langmuir, Anderson J Ryan, Helen Mann, Sarah J Kennedy, Ronald B Natale, Roy S Herbst, Bruce E Johnson, John V Heymach
    Abstract:

    Purpose: Vandetanib [vascular endothelial growth factor (VEGF) receptor/epidermal growth factor receptor/RET inhibitor] has shown improvements in progression-free survival (PFS) in advanced non-small cell lung cancer in three randomized phase II studies: Vandetanib versus gefitinib (study 3), docetaxel ± Vandetanib (study 6), and carboplatin-paclitaxel and/or Vandetanib (study 7). In study 7, Vandetanib monotherapy was inferior to carboplatin-paclitaxel. We performed an exploratory retrospective analysis of the relationship between baseline circulating VEGF concentrations and PFS. Experimental Design: Mean baseline VEGF levels were determined by ELISA from two baseline samples of plasma (163 of 168 patients, study 3; 65 of 127, study 6) or serum (144 of 181, study 7). High baseline VEGF values were above the immunoassay reference range for healthy subjects; low baseline VEGF values were within the range. Results: Patients with low baseline VEGF had a lower risk of disease progression with Vandetanib versus gefitinib [hazard ratio (HR), 0.55; 95% confidence interval (95% CI), 0.35-0.86; P = 0.01] or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.25; 95% CI, 0.09-0.68; P = 0.01). High VEGF patients had a similar risk of disease progression with Vandetanib monotherapy versus gefitinib (HR, 1.03; 95% CI, 0.60-1.75; P = 0.92) or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.95; 95% CI, 0.25-3.61; P = 0.94). In study 7, low VEGF patients had a similar risk of disease progression with Vandetanib monotherapy 300 mg/d versus carboplatin-paclitaxel (HR, 0.80; 95% CI, 0.41-1.56; P = 0.51); high VEGF patients progressed more quickly (HR, 1.60; 95% CI, 0.81-3.15; P = 0.17). Conclusions: These analyses suggest that low baseline circulating VEGF may be predictive of PFS advantage in patients with advanced non-small cell lung cancer receiving Vandetanib versus gefitinib or Vandetanib + docetaxel versus docetaxel. Moreover, patients with low VEGF levels may have a similar outcome with either Vandetanib monotherapy or carboplatin-paclitaxel.

  • Vandetanib zd6474 an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis
    Expert Opinion on Investigational Drugs, 2007
    Co-Authors: Roy S Herbst, Amir Onn, John V Heymach, Michael A Oreilly, Anderson J Ryan
    Abstract:

    Vandetanib (ZD6474; ZACTIMA, AstraZeneca) is a once-daily, orally available agent with potential for use in a number of solid tumor types. Vandetanib targets key signaling pathways in cancer by inhibiting VEGFR-dependent tumor angiogenesis, and EGFR- and RET-dependent tumor cell proliferation and survival. Phase I studies showed Vandetanib to be generally well tolerated at doses of < or = 300 mg/day, with a pharmacokinetic profile that supports once-daily oral administration. Phase II evaluation of Vandetanib in patients with advanced refractory NSCLC has demonstrated improvements in progression-free survival both as monotherapy (versus gefitinib) and in combination with docetaxel (versus docetaxel alone). These positive outcomes have led to the initiation of Phase III trials of Vandetanib in advanced NSCLC. Clinical development is also ongoing in other tumor types and encouraging evidence of antitumor activity has been reported in patients with metastatic hereditary medullary thyroid cancer.

Roy S Herbst - One of the best experts on this subject based on the ideXlab platform.

  • Vandetanib plus docetaxel versus docetaxel as second line treatment for patients with advanced non small cell lung cancer zodiac a double blind randomised phase 3 trial
    Lancet Oncology, 2010
    Co-Authors: Roy S Herbst, W Eberhardt, Paul Germonpre, Nagahiro Saijo, Caicun Zhou, Jie Wang, Longyun Li, Fairooz F Kabbinavar, Yukito Ichinose, Li Zhang
    Abstract:

    Summary Background Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET) tyrosine kinases. In a randomised phase 2 study in patients with previously treated non-small-cell lung cancer (NSCLC), adding Vandetanib 100 mg to docetaxel significantly improved progression-free survival (PFS) compared with docetaxel alone, including a longer PFS in women. These results supported investigation of the combination in this larger, definitive phase 3 trial (ZODIAC). Methods Between May, 2006, and April, 2008, patients with locally advanced or metastatic (stage IIIB–IV) NSCLC after progression following first-line chemotherapy were randomly assigned 1:1 through a third-party interactive voice system to receive Vandetanib (100 mg/day) plus docetaxel (75 mg/m 2 intravenously every 21 days; maximum six cycles) or placebo plus docetaxel. The primary objective was comparison of PFS between the two groups in the intention-to-treat population. Women were a coprimary analysis population. This study has been completed and is registered with ClinicalTrials.gov, number NCT00312377. Findings 1391 patients received Vandetanib plus docetaxel (n=694 [197 women]) or placebo plus docetaxel (n=697 [224 women]). Vandetanib plus docetaxel led to a significant improvement in PFS versus placebo plus docetaxel (hazard ratio [HR] 0·79, 97·58% CI 0·70–0·90; p vs 7/690 [1%]), neutropenia (199/689 [29%] vs 164/690 [24%]), leukopenia (99/689 [14%] vs 77/690 [11%]), and febrile neutropenia (61/689 [9%] vs 48/690 [7%]) were more common with Vandetanib plus docetaxel than with placebo plus docetaxel. The most common serious adverse event was febrile neutropenia (46/689 [7%] in the Vandetanib group vs 38/690 [6%] in the placebo group). Interpretation The addition of Vandetanib to docetaxel provides a significant improvement in PFS in patients with advanced NSCLC after progression following first-line therapy. Funding AstraZeneca.

  • baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from Vandetanib in non small cell lung cancer
    Clinical Cancer Research, 2009
    Co-Authors: Emer O Hanrahan, Peter Langmuir, Anderson J Ryan, Helen Mann, Sarah J Kennedy, Ronald B Natale, Roy S Herbst, Bruce E Johnson, John V Heymach
    Abstract:

    Purpose: Vandetanib [vascular endothelial growth factor (VEGF) receptor/epidermal growth factor receptor/RET inhibitor] has shown improvements in progression-free survival (PFS) in advanced non-small cell lung cancer in three randomized phase II studies: Vandetanib versus gefitinib (study 3), docetaxel ± Vandetanib (study 6), and carboplatin-paclitaxel and/or Vandetanib (study 7). In study 7, Vandetanib monotherapy was inferior to carboplatin-paclitaxel. We performed an exploratory retrospective analysis of the relationship between baseline circulating VEGF concentrations and PFS. Experimental Design: Mean baseline VEGF levels were determined by ELISA from two baseline samples of plasma (163 of 168 patients, study 3; 65 of 127, study 6) or serum (144 of 181, study 7). High baseline VEGF values were above the immunoassay reference range for healthy subjects; low baseline VEGF values were within the range. Results: Patients with low baseline VEGF had a lower risk of disease progression with Vandetanib versus gefitinib [hazard ratio (HR), 0.55; 95% confidence interval (95% CI), 0.35-0.86; P = 0.01] or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.25; 95% CI, 0.09-0.68; P = 0.01). High VEGF patients had a similar risk of disease progression with Vandetanib monotherapy versus gefitinib (HR, 1.03; 95% CI, 0.60-1.75; P = 0.92) or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.95; 95% CI, 0.25-3.61; P = 0.94). In study 7, low VEGF patients had a similar risk of disease progression with Vandetanib monotherapy 300 mg/d versus carboplatin-paclitaxel (HR, 0.80; 95% CI, 0.41-1.56; P = 0.51); high VEGF patients progressed more quickly (HR, 1.60; 95% CI, 0.81-3.15; P = 0.17). Conclusions: These analyses suggest that low baseline circulating VEGF may be predictive of PFS advantage in patients with advanced non-small cell lung cancer receiving Vandetanib versus gefitinib or Vandetanib + docetaxel versus docetaxel. Moreover, patients with low VEGF levels may have a similar outcome with either Vandetanib monotherapy or carboplatin-paclitaxel.

  • baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from Vandetanib in non small cell lung cancer
    Clinical Cancer Research, 2009
    Co-Authors: Emer O Hanrahan, Peter Langmuir, Anderson J Ryan, Helen Mann, Sarah J Kennedy, Ronald B Natale, Roy S Herbst, Bruce E Johnson, John V Heymach
    Abstract:

    Purpose: Vandetanib [vascular endothelial growth factor (VEGF) receptor/epidermal growth factor receptor/RET inhibitor] has shown improvements in progression-free survival (PFS) in advanced non-small cell lung cancer in three randomized phase II studies: Vandetanib versus gefitinib (study 3), docetaxel ± Vandetanib (study 6), and carboplatin-paclitaxel and/or Vandetanib (study 7). In study 7, Vandetanib monotherapy was inferior to carboplatin-paclitaxel. We performed an exploratory retrospective analysis of the relationship between baseline circulating VEGF concentrations and PFS. Experimental Design: Mean baseline VEGF levels were determined by ELISA from two baseline samples of plasma (163 of 168 patients, study 3; 65 of 127, study 6) or serum (144 of 181, study 7). High baseline VEGF values were above the immunoassay reference range for healthy subjects; low baseline VEGF values were within the range. Results: Patients with low baseline VEGF had a lower risk of disease progression with Vandetanib versus gefitinib [hazard ratio (HR), 0.55; 95% confidence interval (95% CI), 0.35-0.86; P = 0.01] or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.25; 95% CI, 0.09-0.68; P = 0.01). High VEGF patients had a similar risk of disease progression with Vandetanib monotherapy versus gefitinib (HR, 1.03; 95% CI, 0.60-1.75; P = 0.92) or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.95; 95% CI, 0.25-3.61; P = 0.94). In study 7, low VEGF patients had a similar risk of disease progression with Vandetanib monotherapy 300 mg/d versus carboplatin-paclitaxel (HR, 0.80; 95% CI, 0.41-1.56; P = 0.51); high VEGF patients progressed more quickly (HR, 1.60; 95% CI, 0.81-3.15; P = 0.17). Conclusions: These analyses suggest that low baseline circulating VEGF may be predictive of PFS advantage in patients with advanced non-small cell lung cancer receiving Vandetanib versus gefitinib or Vandetanib + docetaxel versus docetaxel. Moreover, patients with low VEGF levels may have a similar outcome with either Vandetanib monotherapy or carboplatin-paclitaxel.

  • Vandetanib zd6474 an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis
    Expert Opinion on Investigational Drugs, 2007
    Co-Authors: Roy S Herbst, Amir Onn, John V Heymach, Michael A Oreilly, Anderson J Ryan
    Abstract:

    Vandetanib (ZD6474; ZACTIMA, AstraZeneca) is a once-daily, orally available agent with potential for use in a number of solid tumor types. Vandetanib targets key signaling pathways in cancer by inhibiting VEGFR-dependent tumor angiogenesis, and EGFR- and RET-dependent tumor cell proliferation and survival. Phase I studies showed Vandetanib to be generally well tolerated at doses of < or = 300 mg/day, with a pharmacokinetic profile that supports once-daily oral administration. Phase II evaluation of Vandetanib in patients with advanced refractory NSCLC has demonstrated improvements in progression-free survival both as monotherapy (versus gefitinib) and in combination with docetaxel (versus docetaxel alone). These positive outcomes have led to the initiation of Phase III trials of Vandetanib in advanced NSCLC. Clinical development is also ongoing in other tumor types and encouraging evidence of antitumor activity has been reported in patients with metastatic hereditary medullary thyroid cancer.

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  • Vandetanib versus placebo in patients with advanced non small cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor a randomized double blind phase iii trial zephyr
    Journal of Clinical Oncology, 2012
    Co-Authors: Vera Hirsh, Cesar R Blajman, Laura Emerson, Peter Langmuir, Keunchil Park, Reury-perng Perng, Yuh-min Chen, C Manegold
    Abstract:

    Purpose Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor (EGFR), and RET signaling. This placebo-controlled trial assessed whether Vandetanib conferred an overall survival benefit in patients with advanced non–small-cell lung cancer (NSCLC) after prior treatment with an EGFR tyrosine kinase inhibitor and one or two chemotherapy regimens. Patients and Methods Eligible patients were randomly assigned 2:1 to receive Vandetanib 300 mg/d or placebo until disease progression or unacceptable toxicity. The primary objective was to compare the outcomes between the two arms with respect to overall survival. Results Overall, 924 patients received Vandetanib (n = 617) or placebo (n = 307). No significant increase in overall survival was detected in the Vandetanib cohort compared with placebo (hazard ratio = 0.95; 95.2% CI, 0.81 to 1.11; P = .527); median overall survival was 8.5 months versus 7.8 months for Vandetanib and placebo patients, resp...

  • Vandetanib versus erlotinib in patients with advanced non small cell lung cancer nsclc after failure of at least one prior cytotoxic chemotherapy a randomized double blind phase iii trial zest
    Journal of Clinical Oncology, 2009
    Co-Authors: Ronald B Natale, Peter Langmuir, Sumitra Thongprasert, F A Greco, Michael Thomas, Chunming Tsai, Patrapim Sunpaweravong, David Ferry, Jacqui Rowbottom, Glenwood D Goss
    Abstract:

    8009 Background: Vandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling. This phase III study compared the efficacy of Vandetanib vs erlotinib in patients (pts) with advanced, p...

  • baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from Vandetanib in non small cell lung cancer
    Clinical Cancer Research, 2009
    Co-Authors: Emer O Hanrahan, Peter Langmuir, Anderson J Ryan, Helen Mann, Sarah J Kennedy, Ronald B Natale, Roy S Herbst, Bruce E Johnson, John V Heymach
    Abstract:

    Purpose: Vandetanib [vascular endothelial growth factor (VEGF) receptor/epidermal growth factor receptor/RET inhibitor] has shown improvements in progression-free survival (PFS) in advanced non-small cell lung cancer in three randomized phase II studies: Vandetanib versus gefitinib (study 3), docetaxel ± Vandetanib (study 6), and carboplatin-paclitaxel and/or Vandetanib (study 7). In study 7, Vandetanib monotherapy was inferior to carboplatin-paclitaxel. We performed an exploratory retrospective analysis of the relationship between baseline circulating VEGF concentrations and PFS. Experimental Design: Mean baseline VEGF levels were determined by ELISA from two baseline samples of plasma (163 of 168 patients, study 3; 65 of 127, study 6) or serum (144 of 181, study 7). High baseline VEGF values were above the immunoassay reference range for healthy subjects; low baseline VEGF values were within the range. Results: Patients with low baseline VEGF had a lower risk of disease progression with Vandetanib versus gefitinib [hazard ratio (HR), 0.55; 95% confidence interval (95% CI), 0.35-0.86; P = 0.01] or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.25; 95% CI, 0.09-0.68; P = 0.01). High VEGF patients had a similar risk of disease progression with Vandetanib monotherapy versus gefitinib (HR, 1.03; 95% CI, 0.60-1.75; P = 0.92) or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.95; 95% CI, 0.25-3.61; P = 0.94). In study 7, low VEGF patients had a similar risk of disease progression with Vandetanib monotherapy 300 mg/d versus carboplatin-paclitaxel (HR, 0.80; 95% CI, 0.41-1.56; P = 0.51); high VEGF patients progressed more quickly (HR, 1.60; 95% CI, 0.81-3.15; P = 0.17). Conclusions: These analyses suggest that low baseline circulating VEGF may be predictive of PFS advantage in patients with advanced non-small cell lung cancer receiving Vandetanib versus gefitinib or Vandetanib + docetaxel versus docetaxel. Moreover, patients with low VEGF levels may have a similar outcome with either Vandetanib monotherapy or carboplatin-paclitaxel.

  • baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from Vandetanib in non small cell lung cancer
    Clinical Cancer Research, 2009
    Co-Authors: Emer O Hanrahan, Peter Langmuir, Anderson J Ryan, Helen Mann, Sarah J Kennedy, Ronald B Natale, Roy S Herbst, Bruce E Johnson, John V Heymach
    Abstract:

    Purpose: Vandetanib [vascular endothelial growth factor (VEGF) receptor/epidermal growth factor receptor/RET inhibitor] has shown improvements in progression-free survival (PFS) in advanced non-small cell lung cancer in three randomized phase II studies: Vandetanib versus gefitinib (study 3), docetaxel ± Vandetanib (study 6), and carboplatin-paclitaxel and/or Vandetanib (study 7). In study 7, Vandetanib monotherapy was inferior to carboplatin-paclitaxel. We performed an exploratory retrospective analysis of the relationship between baseline circulating VEGF concentrations and PFS. Experimental Design: Mean baseline VEGF levels were determined by ELISA from two baseline samples of plasma (163 of 168 patients, study 3; 65 of 127, study 6) or serum (144 of 181, study 7). High baseline VEGF values were above the immunoassay reference range for healthy subjects; low baseline VEGF values were within the range. Results: Patients with low baseline VEGF had a lower risk of disease progression with Vandetanib versus gefitinib [hazard ratio (HR), 0.55; 95% confidence interval (95% CI), 0.35-0.86; P = 0.01] or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.25; 95% CI, 0.09-0.68; P = 0.01). High VEGF patients had a similar risk of disease progression with Vandetanib monotherapy versus gefitinib (HR, 1.03; 95% CI, 0.60-1.75; P = 0.92) or Vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.95; 95% CI, 0.25-3.61; P = 0.94). In study 7, low VEGF patients had a similar risk of disease progression with Vandetanib monotherapy 300 mg/d versus carboplatin-paclitaxel (HR, 0.80; 95% CI, 0.41-1.56; P = 0.51); high VEGF patients progressed more quickly (HR, 1.60; 95% CI, 0.81-3.15; P = 0.17). Conclusions: These analyses suggest that low baseline circulating VEGF may be predictive of PFS advantage in patients with advanced non-small cell lung cancer receiving Vandetanib versus gefitinib or Vandetanib + docetaxel versus docetaxel. Moreover, patients with low VEGF levels may have a similar outcome with either Vandetanib monotherapy or carboplatin-paclitaxel.