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

• ClinicalTrials.gov Identifier: NCT00984282
• Recruitment Status: Completed
• First Posted: September 25, 2009
• Results First Posted: December 10, 2013
• Last Update Posted: September 13, 2018
• Sponsor: Bayer
• Collaborator: Amgen
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: September 24, 2009
• First Posted Date: September 25, 2009
• Results First Submitted Date: August 19, 2013
• Results First Posted Date: December 10, 2013
• Last Update Posted Date: September 13, 2018
• Actual Study Start Date: October 15, 2009
• Actual Primary Completion Date: August 31, 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 7, 2013)

Progression-free Survival (PFS) Based on Central Assessment Incl. Clinical Progression Due to Bone Irradiation [ Time Frame: Final analysis to be performed when approximately 267 progression-free survival events (centrally assessed) had occurred, study duration approximately three years ]

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.

• Original Primary Outcome Measures (submitted: September 24, 2009): Progression-Free Survival (PFS) [ Time Frame: Radiologic tumor asssessments will be done every 56 days (two cycles) during treatment and at EOT visit. ]

Current Secondary Outcome Measures (submitted: August 15, 2018)

• Overall Survival (OS) [ Time Frame: From randomization of the first subject until the database cut-off (30 AUG 2017), study duration approximately eight years ]
  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.
• Time to Progression (TTP) Based on Central Assessment Incl. Clinical Progression Due to Bone Irradiation [ Time Frame: From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years ]
  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])
• Disease Control Rate (DCR) Based on Central Assessment [ Time Frame: From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years ]
  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.
• Response Rate Based on Central Assessment [ Time Frame: From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years ]
  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.
• Duration of Response (DOR) Based on Central Assessment [ Time Frame: From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years ]
  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.
• Maximum Percent Reduction in Target Lesion Size Based on Central Assessment [ Time Frame: From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years ]
  The magnitude of change from baseline in target lesion size in evaluable participants with scans was determined.
• AUC(0-12h),ss (Area Under the Concentration Time Curve From Time 0 to 12 Hours at Steady State) [ Time Frame: A single pharmacokinetic plasma sample was collected at steady state (after 14 days of uninterrupted, unmodified sorafenib dosing) ]
  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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Nexavar® Versus Placebo in Locally Advanced/Metastatic RAI-Refractory Differentiated Thyroid Cancer
• Official Title: 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
• Brief Summary: Trial of sorafenib versus placebo in the treatment of locally advanced or metastatic differentiated thyroid cancer refractory to radioiodine
• 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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Thyroid Neoplasms

Intervention

• Drug: Sorafenib (Nexavar, BAY43-9006)
  Sorafenib 400 mg will be administered orally, twice daily (approximately every 12 hours).
• Drug: Placebo
  Placebo (2 tablets) will be administered orally, twice daily (approximately every 12 hours).

Study Arms

• 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
  Intervention: Drug: Sorafenib (Nexavar, BAY43-9006)
• Placebo Comparator: Placebo
  Participants received 2 tablets of Sorafenib-matching placebo orally twice daily (12 hours apart without food), 28 days comprise a cycle
  Intervention: Drug: Placebo

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 7, 2013): 417
• Original Estimated Enrollment (submitted: September 24, 2009): 380
• Actual Study Completion Date: August 30, 2017
• Actual Primary Completion Date: August 31, 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Belgium, Bulgaria, China, Denmark, France, Germany, Italy, Japan, Korea, Republic of, Netherlands, Poland, Russian Federation, Saudi Arabia, Spain, Sweden, United Kingdom, United States
• Removed Location Countries: Slovakia

Administrative Information

• NCT Number: NCT00984282
• Other Study ID Numbers: 14295; 2009-012007-25 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bayer
• Original Responsible Party: Therapeutic Area Head, Bayer HealthCare Paharmaceutical Inc.
• Current Study Sponsor: Bayer
• Original Study Sponsor: Same as current
• Collaborators: Amgen

Investigators

• Study Director: Bayer Study Director; Bayer

• PRS Account: Bayer
• Verification Date: August 2018