Phase II Study of Safety and Efficacy of Motesanib in Patients With Progressive or Symptomatic, Advanced or Metastatic Medullary Thyroid Cancer

2009 ◽  
Vol 27 (23) ◽  
pp. 3794-3801 ◽  
Author(s):  
Martin J. Schlumberger ◽  
Rossella Elisei ◽  
Lars Bastholt ◽  
Lori J. Wirth ◽  
Renato G. Martins ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Growth Factor ◽  
Stable Disease ◽  
Medullary Thyroid Cancer ◽  
Phase Ii Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Free Survival ◽  
Medullary Thyroid ◽  
Duration Of Response

PurposeThis phase II study investigated the efficacy and tolerability of motesanib, an investigational, highly selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit in advanced medullary thyroid cancer (MTC).Patients and MethodsPatients with locally advanced or metastatic, progressive or symptomatic MTC received motesanib 125 mg/d orally for up to 48 weeks or until unacceptable toxicity or disease progression. The primary end point was objective response by independent review. Other end points included duration of response, progression-free survival, safety, pharmacokinetics, and changes in tumor markers.ResultsOf 91 enrolled patients who received motesanib, two (2%) achieved objective response (95% CI, 0.3% to 7.7%); their duration of response was 32 weeks (censored) and 21 weeks (disease progressed). Eighty-one percent of patients had stable disease (48% had durable stable disease ≥ 24 weeks), 8% had disease progression as best response, and 9% were not evaluated; 76% experienced a decrease from baseline in target lesion measurement. Median progression-free survival was 48 weeks (95% CI, 43 to 56 weeks). Among patients with tumor marker analysis, 69 (83%) of 83 and 63 (75%) of 84 had decreased serum calcitonin and carcinoembryonic antigen during treatment, respectively, compared with baseline. The most common treatment-related adverse events were diarrhea (41%), fatigue (41%), hypothyroidism (29%), hypertension (27%), and anorexia (27%). In pharmacokinetic analyses, motesanib trough concentrations were lower compared with differentiated thyroid cancer patients from the same study.ConclusionAlthough the objective response rate was low, a significant proportion of MTC patients (81%) achieved stable disease while receiving motesanib.

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 Prolonged duration of response in lenvatinib responders with thyroid cancer (Russian translation)

2018 ◽  
Vol 8 (3) ◽  
pp. 53-60
Author(s):  
A. G. Gianoukakis ◽  
C. E. Dutcus ◽  
N. Batty ◽  
M. Guo ◽  
M. Baig
Keyword(s):  
Thyroid Cancer ◽  
Disease Burden ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Analysis ◽  
Phase 3 ◽  
Double Blind ◽  
Free Survival ◽  
Prolonged Duration ◽  
Duration Of Response

We present an updated analysis of lenvatinib in radioiodine-refractory differentiated thyroid cancer (RR-DTC) with new duration of response (DOR) data unavailable for the primary analysis. In this randomized, double-blind, multicenter, placebo-controlled phase 3 study, patients ≥18 years old with measurable, pathologically confirmed RR-DTC with independent radiologic confirmation of disease progression within the previous 13 months were randomized 2:1 to oral lenvatinib 24 mg/day or placebo. The main outcome measures for this analysis are DOR and progression-free survival (PFS). The median DOR for all lenvatinib responders (patients with complete or partial responses; objective response rate: 60.2 %; 95 % confidence interval (CI) 54.2–66.1) was 30.0 months (95 % CI 18.4–36.7) and was generally similar across subgroups. DOR was shorter in patients with greater disease burden and with brain and liver metastases. Updated median PFS was longer in the overall lenvatinib group vs placebo (19.4 vs 3.7 months; hazard ratio (HR) 0.24; 99 % CI 0.17–0.35; nominal P <0.0001). In lenvatinib responders, median PFS was 33.1 months (95 % CI 27.8–44.6) vs 7.9 months (95 % CI 5.8–10.7) in nonresponders. The median DOR of 30.0 months seen with patients who achieved complete or partial responses with lenvatinib (60.2 %) demonstrates that lenvatinib responders can have prolonged, durable and clinically meaningful responses. Prolonged PFS (33.1 months) was also observed in these lenvatinib responders.

Procalcitonin levels predict clinical course and progression-free survival in patients with medullary thyroid cancer

Cancer ◽  
2009 ◽  
pp. NA-NA ◽  
Author(s):  
Martin A. Walter ◽  
Christian Meier ◽  
Tanja Radimerski ◽  
Fabienne Iten ◽  
Marius Kränzlin ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Medullary Thyroid Cancer ◽  
Clinical Course ◽  
Progression Free Survival ◽  
Free Survival ◽  
Medullary Thyroid

scholarly journals Prolonged duration of response in lenvatinib responders with thyroid cancer

2018 ◽  
Vol 25 (6) ◽  
pp. 699-704 ◽  
Author(s):  
Andrew G Gianoukakis ◽  
Corina E Dutcus ◽  
Nicolas Batty ◽  
Matthew Guo ◽  
Mahadi Baig
Keyword(s):  
Thyroid Cancer ◽  
Disease Burden ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Analysis ◽  
Phase 3 ◽  
Double Blind ◽  
Free Survival ◽  
Prolonged Duration ◽  
Duration Of Response

We present an updated analysis of lenvatinib in radioiodine-refractory differentiated thyroid cancer (RR-DTC) with new duration of response (DOR) data unavailable for the primary analysis. In this randomized, double-blind, multicenter, placebo-controlled phase 3 study, patients ≥18 years old with measurable, pathologically confirmed RR-DTC with independent radiologic confirmation of disease progression within the previous 13 months were randomized 2:1 to oral lenvatinib 24 mg/day or placebo. The main outcome measures for this analysis are DOR and progression-free survival (PFS). The median DOR for all lenvatinib responders (patients with complete or partial responses; objective response rate: 60.2%; 95% confidence interval (CI) 54.2–66.1) was 30.0 months (95% CI 18.4–36.7) and was generally similar across subgroups. DOR was shorter in patients with greater disease burden and with brain and liver metastases. Updated median PFS was longer in the overall lenvatinib group vs placebo (19.4 vs 3.7 months; hazard ratio (HR) 0.24; 99% CI 0.17–0.35; nominal P < 0.0001). In lenvatinib responders, median PFS was 33.1 months (95% CI 27.8–44.6) vs 7.9 months (95% CI 5.8–10.7) in non-responders. The median DOR of 30.0 months seen with patients who achieved complete or partial responses with lenvatinib (60.2%) demonstrates that lenvatinib responders can have prolonged, durable and clinically meaningful responses. Prolonged PFS (33.1 months) was also observed in these lenvatinib responders.

scholarly journals A Phase II Study of Glembatumumab Vedotin for Metastatic Uveal Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2270
Author(s):  
Merve Hasanov ◽  
Matthew J. Rioth ◽  
Kari Kendra ◽  
Leonel Hernandez-Aya ◽  
Richard W. Joseph ◽  
...  
Keyword(s):  
Overall Survival ◽  
Uveal Melanoma ◽  
Phase Ii ◽  
Stable Disease ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Free Survival

Glembatumumab vedotin (CDX-011, GV) is a fully human Immunoglobulin G2 monoclonal antibody directed against glycoprotein NMB coupled via a peptide linker to monomethyl auristatin E (MMAE), a potent cytotoxic microtubule inhibitor. This phase II study evaluated the overall response rate and safety of GV, glycoprotein NMB (GPNMB) expression, and survival in patients with metastatic uveal melanoma. Eligible patients with metastatic uveal melanoma who had not previously been treated with chemotherapy received GV 1.9 mg/kg every three weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints included GPNMB expression, progression-free survival (PFS), overall survival (OS), and toxicity analysis. GPNMB expression was assessed pre- and post-treatment via immunohistochemistry for patients with available tumor tissue. Out of 35 patients who received treatment, two patients had confirmed partial responses (PRs; 6%), and 18 patients had a stable disease (SD; 51%) as the best objective response. 38% of the patients had stable disease >100 days. The grade 3 or 4 toxicities that occurred in two or more patients were neutropenia, rash, hyponatremia, and vomiting. The median progression-free survival was 3.1 months (95% CI: 1.5–5.6), and the median overall survival was 11.9 months (95% CI 9.0–16.9) in the evaluable study population. GV is well-tolerated in metastatic uveal melanoma. The disease control rate was 57% despite a low objective response rate. Exploratory immune correlation studies are underway to provide insight into target saturation, combination strategies, and antigen release.

scholarly journals Efficacy and Safety of Vandetanib in Progressive and Symptomatic Medullary Thyroid Cancer: Post Hoc Analysis From the ZETA Trial

2020 ◽  
Vol 38 (24) ◽  
pp. 2773-2781 ◽  
Author(s):  
Michael C. Kreissl ◽  
Lars Bastholt ◽  
Rossella Elisei ◽  
Robert Haddad ◽  
Ole Hauch ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Medullary Thyroid Cancer ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Medullary Thyroid ◽  
Post Hoc Analysis ◽  
Post Hoc

PURPOSE We 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 with progressive and symptomatic MTC. The primary objective of the analysis was to determine progression-free survival (PFS) of these patients. PATIENTS AND METHODS Eligible patients from the ZETA trial were divided into 4 disease severity subgroups: progression and symptoms, symptoms only, progression only, and no progression and no symptoms assessed at baseline. PFS, determined from objective tumor measurements performed by the local investigator, overall survival (OS), time to worsening of pain (TWP), and objective response rate (ORR) were evaluated. RESULTS Of the 331 patients in this trial, 184 had symptomatic and progressive disease at baseline. In this subgroup, results were similar in magnitude to those observed in the overall trial for PFS (hazard ratio [HR], 0.43; 95% CI, 0.28 to 0.64; P < .0001), OS (HR, 1.08; 95% CI, 0.72 to 1.61; P = .71), and TWP (HR, 0.67; 95% CI, 0.43 to 1.04; P = .07), and the observed adverse events were consistent with the known safety profile of vandetanib. In this subgroup, the ORR was 37% in the treatment arm versus 2% in the placebo arm. CONCLUSION Vandetanib demonstrated clinical benefit—specifically, increased PFS—in patients with symptomatic and progressive MTC.

scholarly journals Analysis of treatment outcomes in patients with progressive locally advanced non-resectable and disseminated medullary thyroid cancer receiving vandetanib outside of clinical trials (Russian experience)

2020 ◽  
Vol 10 (2) ◽  
pp. 46-53
Author(s):  
I. S. Romanov ◽  
А. М. Mudunov ◽  
S. О. Podvyaznikov ◽  
А. V. Ignatova ◽  
Yu. V. Alymov
Keyword(s):  
Overall Survival ◽  
Thyroid Cancer ◽  
Adverse Events ◽  
Treatment Outcomes ◽  
Medullary Thyroid Cancer ◽  
Locally Advanced ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Free Survival ◽  
Medullary Thyroid

The study objective is to perform retrospective analysis of the efficacy and safety of vandetanib for metastatic and non-resectable medullary thyroid cancer in routine clinical practice. Materials and methods. We analyzed treatment outcomes in 46 patients treated with vandetanib. We also evaluated progression-free survival, overall survival, time to progression, and frequency of adverse events. Results. At a median follow-up time of 27.4 months (range: 2.5–106.5 months) and median duration of vandetanib therapy of 21 months, disease progression was registered in 32.6 % of cases, whereas stable disease was observed in 28.3 % of cases and 8.7 % of study participants demonstrated partial response. One patient had complete response to treatment. Almost one-third of patients (28.2 %) died, including 2 individuals whose death was not associated with cancer. The one-year and three-year progression-free survival rates were 67.3 % and 33.3 %, respectively; the two-year and five-year overall survival rates were 82.4 % and 29.4 %, respectively. The efficacy of therapy was confirmed by a 79.4 % decrease in the serum level of calcitonin after treatment initiation. Side effects were observed in 33.9 % of patients (primarily skin and gastrointestinal toxic reactions) and were easily managed in most of the cases. Eight individuals (17.4 %) required cessation of vandetanib due to adverse events. Conclusion. Our findings suggest high efficacy and acceptable safety profile of vandetanib in the treatment of progressive locally advanced non-resectable and disseminated medullary thyroid cancer

scholarly journals Phase II Clinical Trial of Sorafenib in Metastatic Medullary Thyroid Cancer

2010 ◽  
Vol 28 (14) ◽  
pp. 2323-2330 ◽  
Author(s):  
Elaine T. Lam ◽  
Matthew D. Ringel ◽  
Richard T. Kloos ◽  
Thomas W. Prior ◽  
Michael V. Knopp ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Tumor Markers ◽  
Phase Ii ◽  
Medullary Thyroid Cancer ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Toxicity Assessment ◽  
Multikinase Inhibitor ◽  
Medullary Thyroid

PurposeMutations in the RET proto-oncogene and vascular endothelial growth factor receptor (VEGFR) activity are critical in the pathogenesis of medullary thyroid cancer (MTC). Sorafenib, a multikinase inhibitor targeting Ret and VEGFR, showed antitumor activity in preclinical studies of MTC.Patients and MethodsIn this phase II trial of sorafenib in patients with advanced MTC, the primary end point was objective response. Secondary end points included toxicity assessment and response correlation with tumor markers, functional imaging, and RET mutations. Using a two-stage design, 16 or 25 patients were to be enrolled onto arms A (hereditary) and B (sporadic). Patients received sorafenib 400 mg orally twice daily.ResultsOf 16 patients treated in arm B, one achieved partial response (PR; 6.3%; 95% CI, 0.2% to 30.2%), 14 had stable disease (SD; 87.5%; 95% CI, 61.7% to 99.5%), and one was nonevaluable. In a post hoc analysis of 10 arm B patients with progressive disease (PD) before study, one patient had PR of 21+ months, four patients had SD ≥ 15 months, four patients had SD ≤ 6 months, and one patient had clinical PD. Median progression-free survival was 17.9 months. Arm A was prematurely terminated because of slow accrual. Common adverse events (AEs) included diarrhea, hand-foot-skin reaction, rash, and hypertension. Although serious AEs were rare, one death was seen. Tumor markers decreased in the majority of patients, and RET mutations were detected in 10 of 12 sporadic MTCs analyzed.ConclusionSorafenib is reasonably well tolerated, with suggestion of clinical benefit for patients with sporadic MTC. Caution should be taken because of the rare but fatal toxicity potentially associated with sorafenib.

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