scholarly journals Vandetanib (ZD6474) in the Treatment of Medullary Thyroid Cancer

2011 ◽  
Vol 5 ◽  
pp. CMO.S6197 ◽  
Author(s):  
Hari Deshpande ◽  
Sanziana Roman ◽  
Jaykumar Thumar ◽  
Julie Ann Sosa
Keyword(s):  
Thyroid Cancer ◽  
Growth Factor ◽  
Phase Ii ◽  
Medullary Thyroid Cancer ◽  
Kinase Inhibitor ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Good Choice ◽  
Phase Ii Trials ◽  
Medullary Thyroid

Vandetanib (ZD6474) is an orally bioavailable small molecule tyrosine kinase inhibitor of multiple growth factor receptors, including RET (Rearrange during transfection), vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR). The activity against RET and VEGF made it a good choice in the treatment of medullary thyroid cancer (MTC). As there is considerable cross talk between growth factor pathways, dual inhibition with such agents has become an attractive strategy, in the treatment of many malignancies with encouraging Phase II clinical trial data to date. Vandetanib was tested in two Phase II trials in the treatment of patients with medullary thyroid cancer at doses of 100 mg and 300 mg daily respectively. The encouraging results of these 2 trials led to a randomized phase II trial comparing this medication to placebo using a crossover design. More than 300 patients were included in this study, which ultimately showed a significant improvement in progression-free survival in patients taking vandetanib. Based on these results, the Oncology Drug Advisory Committee (ODAC) of the Food and Drug Administration (FDA) recommended that vandetanib be approved for the treatment of patients with unresectable locally advanced or metastatic medullary thyroid cancer.

scholarly journals Vandetanib (100 mg) in Patients with Locally Advanced or Metastatic Hereditary Medullary Thyroid Cancer

2010 ◽  
Vol 95 (6) ◽  
pp. 2664-2671 ◽  
Author(s):  
Bruce G. Robinson ◽  
Luis Paz-Ares ◽  
Annetta Krebs ◽  
James Vasselli ◽  
Robert Haddad
Keyword(s):  
Thyroid Cancer ◽  
Growth Factor ◽  
Medullary Thyroid Cancer ◽  
Response Rate ◽  
Objective Response ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Once Daily ◽  
Medullary Thyroid ◽  
Hereditary Medullary Thyroid Cancer

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.

scholarly journals Cabozantinib in Progressive Medullary Thyroid Cancer

2013 ◽  
Vol 31 (29) ◽  
pp. 3639-3646 ◽  
Author(s):  
Rossella Elisei ◽  
Martin J. Schlumberger ◽  
Stefan P. Müller ◽  
Patrick Schöffski ◽  
Marcia S. Brose ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Growth Factor ◽  
Adverse Events ◽  
Medullary Thyroid Cancer ◽  
Response Rate ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
Mutation Status ◽  
Medullary Thyroid ◽  
Ret Mutation

PurposeCabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I.Patients and MethodsWe conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety.ResultsThe estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients.ConclusionCabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.

scholarly journals Multikinase Inhibitors for the Treatment of Progressive, Metastatic Medullary Thyroid Cancer – An Evolving Paradigm

2014 ◽  
Vol 10 (2) ◽  
pp. 145
Author(s):  
Barbara Jarzab ◽  
Jolanta Krajewska ◽  
◽  
Keyword(s):  
Thyroid Cancer ◽  
Growth Factor ◽  
Medullary Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
Medullary Thyroid ◽  
Modes Of Action ◽  
Phase Iii Trials ◽  
Endothelial Growth Factor

Medullary thyroid cancer (MTC) is an uncommon type of thyroid cancer, representing around 4 % of the all thyroid cancers, and is a challenging malignancy. So far, surgery has been the only curative treatment and until recently there have been no effective medications. Within the past 5 years, multi-targeted kinase inhibitors have emerged that have shown convincing efficacy against such tumours. These drugs have changed the landscape in MTC treatment by providing effective medication for the first time. The modes of action of these drugs differ, but most target RET, a tyrosine kinase shown to play an important role in the pathobiology of MTC, as well as other receptors including vascular endothelial growth factor receptors (VEGFRs), epidermal growth factor receptor (EGFR) and the hepatocyte growth factor receptor MET. Two agents in this class, vandetanib and cabozantinib, have demonstrated efficacy and safety in phase III trials and have consequently received regulatory approval. Other therapies for MTC treatment, including some with similar modes of action, are also in early development.

A phase II study of gefitinib in patients with advanced thyroid cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6020-6020 ◽  
Author(s):  
N. A. Pennell ◽  
G. H. Daniels ◽  
R. I. Haddad ◽  
D. S. Ross ◽  
L. J. Wirth ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Phase Ii ◽  
Tumor Volume ◽  
Kinase Inhibitor ◽  
Locally Advanced ◽  
Thyroid Tissue ◽  
Open Label ◽  
Serum Calcitonin ◽  
Medullary Thyroid ◽  
Advanced Thyroid Cancer

6020 Background: There are few effective treatments for locally advanced or metastatic thyroid cancers that are refractory to radioactive iodine (RaI). The epidermal growth factor receptor (EGFR) is highly expressed on normal and malignant thyroid tissue, and has been associated with a worse prognosis in well-differentiated thyroid cancer. The EGFR tyrosine kinase inhibitor gefitinib is effective in inhibiting the growth of thyroid cancer cells in vitro. This study sought to determine the efficacy and tolerability of gefitinib in patients with advanced thyroid cancer. Methods: In this open-label phase II trial, patients with RaI-refractory, locally advanced or metastatic thyroid cancer received 250mg of daily gefitinib. Anaplastic and medullary thyroid carcinoma were considered RaI refractory based on histology. The primary endpoint was overall response rate. Secondary endpoints were toxicity, progression-free survival (PFS), overall survival (OS), and tumor marker responses. Tumor markers consisted of serum thyroglobulin (Tg) in the differentiated cancers and serum calcitonin and carcinoembryonic antigen in medullary thyroid cancer. Results: A total of 27 patients were enrolled. 59% were male and the median age was 65. Histologic subtypes included papillary (41%), follicular (22%), anaplastic (19%), medullary (15%), and Hürthle cell carcinoma (4%). There were no objective tumor responses among the 25 patients evaluated, at which point the trial was halted. However, 32% of patients had objective reductions in tumor volume that did not meet criteria for PR. 48%, 24%, and 12% of patients had stable disease (SD) after 3, 6, and 12 months of treatment. Median PFS and OS were 3.7 [95% CI; 1.8, 5.7] and 17.5 months [9.2, not yet reached]. Five patients with SD had a decrease in Tg to <90% of baseline level that was maintained for at least 3 months. Gefitinib was well tolerated, with 11% of patients experiencing grade 3 toxicity. Conclusions: Gefitinib therapy did not result in any objective tumor responses. However, reductions in tumor volume, falling Tg levels, and prolonged SD in a subset of patients may indicate biologic activity. The OS of 17.5 months was superior to historical rates in this population. However, the significance of this is difficult to interpret in the absence of a randomized comparison group. No significant financial relationships to disclose.

A phase II multicenter trial of the multitargeted kinase inhibitor sulfatinib in advanced medullary thyroid cancer (MTC) and radioiodine (RAI)-refractory differentiated thyroid cancer (DTC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6037-6037 ◽  
Author(s):  
Jiaying Chen ◽  
Qinghai Ji ◽  
Junning Cao ◽  
Dongmei Ji ◽  
Chunmei Bai ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Growth Factor ◽  
Disease Progression ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Stage I ◽  
Grade 3

6037 Background: Sulfatinib is an oral tyrosine kinase inhibitor targeting Vascular Endothelial Growth Factor Receptor (VEGFR), Fibroblast Growth Factor Receptor 1 (FGFR 1), and Colony Stimulating Factor 1 Receptor (CSF1R). In a proof of concept (PoC) phase II study, sulfatinib showed promising efficacy in patients (pts) with neuroendocrine tumors (NETs). Methods: This is an open label, two cohorts phase II study using Simon's two-stage design. In stage I, 15 pts will be enrolled in each cohort (advanced MTC or iodine-refractory DTC), and 10 more pts will be enrolled in a cohort in stage II if at least 2 PR observed in that cohort in stage I. Pts are required to have progressive disease in the past 12 months, but could not have received > 1 prior anti-angiogenesis therapy. Pts are treated with oral sulfatinib 300 mg once daily until disease progression, death, or intolerable toxicity. Primary endpoint is Objective Response Rate (ORR) by investigator per RECIST 1.1. Results: As of Dec 31 2016,the studyenrolled 18 pts (MTC: 6, DTC: 12), amongst whom 17 pts were efficacy evaluable. There were a total of 4 confirmed PRs, 1 in the MTC cohort and 3 in the DTC cohort, respectively. The others best response was stable disease (SD). 11 pts (61.1%) had dose interruption due to adverse events (AEs) and 5 pts (27.8%) had dose reduction. Two pts discontinued therapy (1 patient due to disease progression, another due to subject's decision). The most commonly reported AEs were proteinuria 72.2% (Grade 3-4: 22.2%), hypertriglyceridemia 50.0% (Grade 3-4: 0%), hypertension 44.4% (Grade 3-4: 16.7%), blood bilirubin increased 44.4% (Grade 3-4: 5.6%), and diarrhea 33.3% (Grade 3-4: 0%). No Grade 5 AE was reported by the time of data cut-off. Conclusions: Sulfatinib appears to be well tolerated in the pts with advanced MTC and RAI refractory DTC. Safety profile seems to be consistent to previous report, with mostly manageable AEs. Efficacy is encouraging in both indications. Further investigation is warranted. Clinical trial information: NCT02614495.

scholarly journals A Phase II Trial of the Multi-Targeted Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer (MTC)

2012 ◽  
Vol 23 ◽  
pp. xi35-xi36 ◽  
Author(s):  
M. Schlumberger ◽  
B. Jarzab ◽  
M.E. Cabanillas ◽  
B. Robinson ◽  
P. Furio ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Phase Ii ◽  
Medullary Thyroid Cancer ◽  
Kinase Inhibitor ◽  
Phase Ii Trial ◽  
Medullary Thyroid

Vandetanib in metastatic hereditary medullary thyroid cancer: Follow-up results of an open-label phase II trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6018-6018 ◽  
Author(s):  
S. A. Wells ◽  
J. E. Gosnell ◽  
R. F. Gagel ◽  
J. F. Moley ◽  
D. G. Pfister ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Disease Control ◽  
Phase Ii ◽  
Tyrosine Kinases ◽  
Medullary Thyroid Cancer ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Disease Control Rate ◽  
Clinical Activity ◽  
Medullary Thyroid

6018 Background: Medullary thyroid cancer (MTC) is the most common cause of death in patients with hereditary syndromes caused by activating mutations in the RET protooncogene. RET activation is the initial oncogenic event, with the activity of other receptor tyrosine kinases, including VEGFR and EGFR, likely to contribute to tumor growth and metastasis. Vandetanib (ZD6474) is a once- daily oral agent that selectively targets RET, VEGFR and EGFR tyrosine kinases. Methods: Eligible patients had unresectable, measurable, locally advanced or metastatic hereditary MTC and a RET germline mutation. Patients received vandetanib 300 mg/day until disease progression or any other withdrawal criteria. The primary objective was to assess the objective tumor response (RECIST every 3 months). Secondary assessments included disease control rate, biochemical response (determined by decrements in plasma levels of calcitonin, a tumor marker for MTC) and safety and tolerability. Results: Thirty patients (21 female; median age 50 years) received initial treatment with vandetanib 300 mg. At data cut-off (20 Nov 2006), the median duration of treatment was 172 days. Based on site investigator assessments, 20% (6/30) of patients experienced a partial response (duration of response 59–260 days) and another 30% (9/30) of patients experienced stable disease =24 weeks, yielding a disease control rate of 50% (15/30). Centralized independent confirmation of response is planned. In 19 patients, plasma calcitonin levels showed a =50% decrease from baseline that was maintained for at least 6 weeks. Adverse events (AEs) occurring in >50% of patients were rash (73%), diarrhea (67%), fatigue (57%) and nausea (53%). Most AEs were grade 1 or 2; grade 3 AEs included asymptomatic QTc prolongation (n=5), rash and diarrhea (both n=3), all of which were manageable. Conclusions: Vandetanib has demonstrated clinical activity in this phase II study in metastatic hereditary MTC, and the safety profile is generally consistent with previous vandetanib monotherapy studies. Accrual is now complete (30 patients), and an updated analysis will be performed in April 2007. An international, randomized, placebo-controlled phase II trial of vandetanib in MTC is now recruiting patients. # No significant financial relationships to disclose.

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