Nexavar® Versus Placebo in Locally Advanced/Metastatic RAI-Refractory Differentiated Thyroid Cancer

A Double-Blind Randomized Phase III Study Evaluating the Efficacy and Safety of Sorafenib Compared to Placebo in Locally Advanced/Metastatic RAI-Refractory Differentiated Thyroid Cancer

Trial of sorafenib versus placebo in the treatment of locally advanced or metastatic differentiated thyroid cancer refractory to radioiodine

Study Overview

• Status: Completed
• Conditions: Thyroid Neoplasms
• Intervention / Treatment: Drug: Sorafenib (Nexavar, BAY43-9006); Drug: Placebo

Detailed Description

Eligible subjects were randomized 1:1 to sorafenib 800 mg daily or matching placebo. Progression was assessed every 8 weeks by modified RECIST criteria. Subjects had the option to unblind study treatment after progression and to receive open label sorafenib regardless of initial treatment assignment. Following discontinuation of study treatment, subjects were followed for survival every 3 months in long-term follow-up. Subjects who terminated study treatment (either double only or double blind and open label) for reasons other than death, lost to follow-up or consent withdrawn entered long-term follow up

• Study Type: Interventional
• Enrollment (Actual): 417
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Wien, Austria, 1090
• Belgium
  • Bruxelles - Brussel, Belgium, 1000
• Bulgaria
  • Sofia, Bulgaria, 1527
• China
  • Beijing, China, 100730
  • Beijing, China, 100021
  • Chengdu, China, 610041
  • Hangzhou, China, 310022
  • Shanghai, China, 200127
  • Shanghai, China, 200030
  • Tianjin, China, 300060
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
• Denmark
  • Odense C, Denmark, 5000
• France
  • Angers, France, 49933
  • Bordeaux, France, 33076
  • Caen, France, 14076
  • LILLE cedex, France, 59037
  • Lyon, France, 69373
  • MARSEILLE cedex, France, 13273
  • Paris, France, 75651
  • Villejuif, France, 94805
• Germany
  • Bayern
    • Erlangen, Bayern, Germany, 91054
    • München, Bayern, Germany, 81377
    • Würzburg, Bayern, Germany, 97080
  • Nordrhein-Westfalen
    • Essen, Nordrhein-Westfalen, Germany, 45122
    • Köln, Nordrhein-Westfalen, Germany, 50924
  • Sachsen
    • Leipzig, Sachsen, Germany, 04103
• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
  • Liguria
    • Genova, Liguria, Italy, 16132
  • Lombardia
    • Milano, Lombardia, Italy, 20133
    • Milano, Lombardia, Italy, 20122
    • Milano, Lombardia, Italy, 20162
  • Sicilia
    • Catania, Sicilia, Italy, 95029
  • Toscana
    • Pisa, Toscana, Italy, 56124
    • Siena, Toscana, Italy, 53100
  • Umbria
    • Perugia, Umbria, Italy, 06126
• Japan
  • Aichi
    • Nagoya, Aichi, Japan, 466-8560
    • Nagoya, Aichi, Japan, 464-8681
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
  • Tokyo
    • Koto-ku, Tokyo, Japan, 135-8550
• Korea, Republic of
  • Daejeon, Korea, Republic of, 301-721
  • Seoul, Korea, Republic of, 137-701
  • Seoul, Korea, Republic of, 110-744
  • Seoul, Korea, Republic of, 120-752
  • Seoul, Korea, Republic of, 135-710
  • Seoul Teugbyeolsi
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 138-736
      • Asan Medical Center
• Netherlands
  • Groningen, Netherlands, 9713 GZ
  • Leiden, Netherlands, 2333 ZA
• Poland
  • Gliwice, Poland, 44-101
  • Poznan, Poland, 60-355
  • Warszawa, Poland, 02-781
  • Warszawa, Poland, 04-141
• Russian Federation
  • Obninsk, Russian Federation, 249036
• Saudi Arabia
  • Riyadh, Saudi Arabia, 11211
• Spain
  • Barcelona, Spain, 08035
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
• Sweden
  • Göteborg, Sweden, 413 45
  • Linköping, Sweden, 581 85
  • Lund, Sweden, 221 85
  • Stockholm, Sweden, 171 76
• United Kingdom
  • Cardiff, United Kingdom, CF14 2TL
  • Glasgow, United Kingdom, G12 0YN
  • Leeds, United Kingdom, LS9 7TF
  • London, United Kingdom, SE1 9RT
  • London, United Kingdom, SM2 5PT
  • Manchester, United Kingdom, M20 4BX
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
  • Sutton, United Kingdom, SM2 5PT
  • Aberdeenshire
    • Aberdeen, Aberdeenshire, United Kingdom, AB25 2ZN
• United States
  • California
    • Los Angeles, California, United States, 90048
    • Stanford, California, United States, 94305-5820
  • Connecticut
    • New Haven, Connecticut, United States, 06520
  • Georgia
    • Atlanta, Georgia, United States, 30322
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
  • Missouri
    • Saint Louis, Missouri, United States, 63110
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
  • New York
    • New York, New York, United States, 10029
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
    • Pittsburgh, Pennsylvania, United States, 15213-1863
  • Texas
    • Houston, Texas, United States, 77030
  • Washington
    • Seattle, Washington, United States, 98109-1023

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Locally advanced or metastatic differentiated thyroid cancer (papillary, follicular and Hurthle cell)
• Poorly differentiated and other thyroid variants (e.g. insular, tall cell, etc.) are eligible provided that the histology has no medullary differentiation nor anaplastic features
• Progression within 14 months (RECIST [Response Evaluation Criteria in Solid Tumors] should be used as a basis for the assessment of disease progression)
• RAI (radioactive iodine) refractory

Exclusion Criteria:

• Histologic subtypes of thyroid cancer other than differentiated (i.e. like anaplastic and medullary carcinoma, lymphoma or sarcoma)
• Prior anti-cancer treatment with tyrosine kinase inhibitors, monoclonal antibodies (licensed or investigational) that target VEGF (vascular endothelial growth factor) or VEGF Receptors or other targeted agents
• Prior anti-cancer treatment for thyroid cancer with use of chemotherapy (low dose chemotherapy for radiosensitization is allowed) or Thalidomide or any of its derivatives

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sorafenib (Nexavar, BAY43-9006); Participants received 2 tablets of Sorafenib (2×200 mg) orally twice daily (12 hours apart without food), 28 days comprise a cycle	Drug: Sorafenib (Nexavar, BAY43-9006); Sorafenib 400 mg will be administered orally, twice daily (approximately every 12 hours).
Placebo Comparator: Placebo; Participants received 2 tablets of Sorafenib-matching placebo orally twice daily (12 hours apart without food), 28 days comprise a cycle	Drug: Placebo; Placebo (2 tablets) will be administered orally, twice daily (approximately every 12 hours).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) Based on Central Assessment Incl. Clinical Progression Due to Bone Irradiation	PFS=time from randomization to first observed disease progression (radiological according to central assessment or clinical due to bone irradiation, whichever is earlier), or death due to any cause, if death occurred before progression. Progression was assessed by RECIST criteria, version 1.0, modified for bone lesions. PFS for participants without disease progression or death at the time of analysis or unblinding were censored at the last date of tumor assessment before unblinding. Participants with no tumor evaluation after baseline were censored at Day 1. PD (Progression Disease)=At least a 20% increase in sum of longest diameters (LD) of measured lesions taking as reference the smallest sum LD on study since the treatment started or the appearance of 1 or more new lesions. New lesions also constituted PD. In exceptional circumstances, unequivocal progression of a nonmeasured lesion may have been accepted as evidence of disease progression in participants with measurable disease.	Final analysis to be performed when approximately 267 progression-free survival events (centrally assessed) had occurred, study duration approximately three years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Overall survival was defined as the time (days) from date of randomization to date of death due to any cause. Subjects still alive at the time of analysis were censored at their date of last contact. Since the median value could not be estimated due to censored data, the percentage of participants who died is presented.	From randomization of the first subject until the database cut-off (30 AUG 2017), study duration approximately eight years
Time to Progression (TTP) Based on Central Assessment Incl. Clinical Progression Due to Bone Irradiation	Time to progression was defined at the time (days) from randomization to progression (based on central assessment [radiological and clinical progression due to bone irradiation])	From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years
Disease Control Rate (DCR) Based on Central Assessment	Disease control rate was defined as the proportion of subjects whose best response was complete response (CR), partial response (PR), or stable disease (SD). Per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, CR and PR were to be confirmed by another scan at least 4 weeks later; SD had to be documented at least 4 weeks after date of randomization. CR = Disappearance of all clinical and radiological evidence of tumor (both target and no-target). PR = At least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum. SD = steady state of disease which is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.	From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years
Response Rate Based on Central Assessment	Response rate was defined as the proportion of subjects whose best response was CR or PR. Per RECIST, CR and PR was to be confirmed by another scan at least 4 weeks later. CR = Disappearance of all clinical and radiological evidence of tumor (both target and no-target). PR = At least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum.	From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years
Duration of Response (DOR) Based on Central Assessment	Duration of response was defined as the time from the first documented objective response of PR or CR, whichever was noted earlier, to disease progression or death (if death occurred before progression was documented). CR = Disappearance of all clinical and radiological evidence of tumor (both target and no-target). PR = At least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum.	From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years
Maximum Percent Reduction in Target Lesion Size Based on Central Assessment	The magnitude of change from baseline in target lesion size in evaluable participants with scans was determined.	From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years
AUC(0-12h),ss (Area Under the Concentration Time Curve From Time 0 to 12 Hours at Steady State)	Sorafenib AUC(0-12h),ss (area under the concentration time curve from time 0 to 12 hours at steady state) was estimated from the steady state plasma concentration.	A single pharmacokinetic plasma sample was collected at steady state (after 14 days of uninterrupted, unmodified sorafenib dosing)

Collaborators and Investigators

• Sponsor: Bayer
• Collaborators: Amgen

Publications and helpful links

General Publications

• Worden F, Fassnacht M, Shi Y, Hadjieva T, Bonichon F, Gao M, Fugazzola L, Ando Y, Hasegawa Y, Park DJ, Shong YK, Smit JW, Chung J, Kappeler C, Meinhardt G, Schlumberger M, Brose MS. Safety and tolerability of sorafenib in patients with radioiodine-refractory thyroid cancer. Endocr Relat Cancer. 2015 Dec;22(6):877-87. doi: 10.1530/ERC-15-0252.
• Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, de la Fouchardiere C, Pacini F, Paschke R, Shong YK, Sherman SI, Smit JW, Chung J, Kappeler C, Pena C, Molnar I, Schlumberger MJ; DECISION investigators. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014 Jul 26;384(9940):319-28. doi: 10.1016/S0140-6736(14)60421-9. Epub 2014 Apr 24.
• Brose MS, Nutting CM, Sherman SI, Shong YK, Smit JW, Reike G, Chung J, Kalmus J, Kappeler C, Schlumberger M. Rationale and design of decision: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer. BMC Cancer. 2011 Aug 11;11:349. doi: 10.1186/1471-2407-11-349.
• Brose MS, Schlumbeger M, Jeffers M, Kappeler C, Meinhardt G, Pena CEA. Analysis of Biomarkers and Association With Clinical Outcomes in Patients With Differentiated Thyroid Cancer: Subanalysis of the Sorafenib Phase III DECISION Trial. Clin Cancer Res. 2019 Dec 15;25(24):7370-7380. doi: 10.1158/1078-0432.CCR-18-3439. Epub 2019 Sep 26.
• Capdevila J, Matos I, Mancuso FM, Iglesias C, Nuciforo P, Zafon C, Palmer HG, Ogbah Z, Muinos L, Hernando J, Villacampa G, Pena CE, Tabernero J, Brose MS, Schlumberger M, Vivancos A. Identification of Expression Profiles Defining Distinct Prognostic Subsets of Radioactive-Iodine Refractory Differentiated Thyroid Cancer from the DECISION Trial. Mol Cancer Ther. 2020 Jan;19(1):312-317. doi: 10.1158/1535-7163.MCT-19-0211. Epub 2019 Sep 20.

Helpful Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2009
• Primary Completion (Actual): August 31, 2012
• Study Completion (Actual): August 30, 2017

Study Registration Dates

• First Submitted: September 24, 2009
• First Submitted That Met QC Criteria: September 24, 2009
• First Posted (Estimate): September 25, 2009

Study Record Updates

• Last Update Posted (Actual): September 13, 2018
• Last Update Submitted That Met QC Criteria: August 15, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Papillary; Follicular; Differentiated; RAI-Refractory; Hurthle
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Endocrine System Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Thyroid Diseases; Thyroid Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Sorafenib
• Other Study ID Numbers: 14295 (City of Hope Medical Center); 2009-012007-25 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No