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

• Register: EUCTR
• Last refreshed on: 29 January 2018
• Main ID: EUCTR2009-012007-25-NL
• Date of registration: 15/10/2009
• Prospective Registration: Yes
• Primary sponsor: Bayer HealthCare AG, D-51368 Leverkusen, Germany
• Public 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
• Scientific 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
• Date of first enrolment: 01/02/2010
• Target sample size: 380
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-012007-25
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Bulgaria, Denmark, France, Germany, Italy, Netherlands, Slovakia, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
•Locally advanced or metastatic differentiated thyroid cancer (papillary, follicular and Hurthle cell)
•Progression within 14 months (RECIST should be used as a basis for the assessment of disease progression)
•RAI refractory: patients will be deemed to be refractory to radioactive iodine (RAI) if they have a known tumor lesion that qualifies as a target lesion per the protocol RECIST criteria, and that target lesion has no iodine uptake on a post-radioactive-iodine scan performed under conditions of a low iodine diet and adequate TSH elevation or rhTSH stimulation.
Certain patients whose tumors have iodine uptake may also be eligible for participation. They include the following categories of patients:
Patients who have some iodine uptake, who have had a radioactive iodine treatment (=100 mCi) within the last 16 months, and who have had progression (by RECIST) of their target lesion(s) despite that RAI treatment (which was performed under conditions of a low iodine diet and adequate TSH elevation or rhTSH stimulation);
OR
Patients who have some iodine uptake, who have had multiple RAI treatments, whose last RAI treatment was >16 months ago, and who had progression after each of two RAI treatments (=100 mCi each) that were done within 16 months of each other (and which were each performed under conditions of a low iodine diet and adequate TSH elevation or rhTSH stimulation);
OR
Any individual patient who has received RAI treatments with a cumulative RAI dose of =600 mCi.
•Not a candidate for surgery or radiotherapy with curative intent
•Subjects with at least one measurable lesion. Lesions must be measured by CT-scan or MRI (Magnetic Resonance Imaging) according to Response Evaluation Criteria in Solid Tumors [RECIST Criteria (v1.0), see Appendix 10.6].
For this study, bone lesions are considered to be measurable and eligible as target lesions if they are lytic lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be evaluated by CT or MRI and the soft tissue component meets the definition of measurability according to RECIST (vs. 1.0).
•Availability of histological material for central review of the diagnosis of differentiated thyroid cancer
•Adequate TSH-suppression (< 0.5 mU/l)
•Age > 18 years
•Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to randomization:
?Hemoglobin > 9.0 g/dl
?Absolute neutrophil count (ANC) >1,500/mm3
?Platelet count = 100,000/mm3
?Total bilirubin < 1.5 times the upper limit of normal
?Alanine aminotransaminase (ALT) and Aspartate aminotransferase (AST) < 2.5 x upper limit of normal
?Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.5 x upper limit of normal (ULN)
?Serum creatinine < 1.5 x ULN.
•Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
•Life expectancy of at least 12 weeks.
•Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment. Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test.
•Women and men of childbearing potential must agree to use adequate contraception (barrier method of birth control) since signing of the informed consent form until at least 30 days after the last study drug administration.
•Subjects must be able to understa
Exclusion criteria:
•Histologic subtypes of thyroid cancer other than differentiated (i.e. like anaplastic and medullary carcinoma, lymphoma or sarcoma).
•Prior anticancer treatment with tyrosine kinase inhibitors, monoclonal antibodies (licensed or investigational) that target VEGF 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.
•Major surgery, open biopsy, or significant traumatic injury within 30 days prior to randomization.
•Non-healing wound, ulcer, or bone fracture.
•Evidence or history of bleeding diathesis or coagulopathy disorder.
•Subjects with tracheal, bronchial or esophageal infiltration with significant risk of bleeding but without having received local treatment prior to enrollment in the study.
•Clinically significant cardiac disease including congestive heart failure > class II New York Heart Association (NYHA) (see Appendix 10.5), unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months) or myocardial infarction within the past 6 months prior to randomization.
•Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy or uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg) despite optimal medical management.
•Thrombotic or embolic venous or arterial events, such as a cerebrovascular accident, including transient ischemic attacks, arterial thrombosis, deep vein thrombosis and pulmonary embolism within the past 6 months.
•Hemorrhage/bleeding event ? National Cancer Institute NCI-Common Terminology Criteria for Adverse Events (CTCAE) greater than or equal to Grade 3 within 3 months of randomization.
•Infection > NCI-CTCAE (version 3) Grade 2.
•Known human immunodeficiency virus infection or infection with hepatitis B or C.
•Previous or concurrent cancer that is distinct in primary site or histology from thyroid cancer within 5 years prior to randomization EXCEPT cervical cancer in situ, treated basal cell carcinoma and superficial bladder tumors [Ta (Non invasive tumor), Tis (Carcinoma in situ) and T1 (Tumor invades lamina propria)].
•Known or suspected allergy to sorafenib or hypersensitivity to sorafenib or any agent given in the course of this trial.
•Subjects with seizure disorder requiring medication (such as steroids or anti-epileptics).
•Subjects undergoing renal dialysis.
•Substance abuse, medical, psychological or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results.
•Unresolved toxicity (i.e. neurotoxicity) attributed to any prior therapy higher than NCI-CTCAE (version 3) Grade 2 (excluding cases of alopecia).
•Any malabsorption condition.
•Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study.
History of brain metastases: allowed, provided definitive therapy (surgery and/or radiation) has been administered before randomization , no further treatment of brain metastases is planned, the subject is clinically stable for at least 2 weeks before study treatment (Prior and ongoing corticosteroid treatment is allowed, provided the dose is not high, stable and no dose adjustments are needed after randomization).
Pregnant or breast-feeding subjects: Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of tre

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Differentiated thyroid cancer
MedDRA version: 12.0 Level: LLT Classification code 10016935 Term: Follicular thyroid cancer
MedDRA version: 12.0 Level: LLT Classification code 10033701 Term: Papillary thyroid cancer
MedDRA version: 12.0 Level: LLT Classification code 10055107 Term: Thyroid cancer metastatic
MedDRA version: 12.0 Level: LLT Classification code 10066136 Term: Huerthle cell carcinoma

Intervention(s)

Trade Name: Nexavar
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Sorafenib
CAS Number: 284461-73-0
Current Sponsor code: BAY 43-9006
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: The primary objective of this phase III study in subjects with differentiated thyroid cancer (papillary, follicular, Hurthle cell carcinoma) who are refractory to radioactive iodine treatment is to compare the treatment groups in terms of progression free survival (PFS) evaluated by the Response Evaluation Criteria In Solid Tumors (RECIST) criteria.

Primary end point(s): The primary efficacy endpoint is Progression-Free Survival (PFS)

Secondary Objective: The secondary objectives are to compare the sorafenib and placebo treatment groups in terms of:
•Overall Survival (OS)
•Time to Progression (TTP)
•Disease Control Rate (DCR)
•Response Rate (RR)
•Duration of response
•Safety, which will include assessment of adverse events and abnormalities in laboratory parameters
•Exposure of sorafenib AUC(0-12) by population pharmacokinetic methods
Exploratory:
• Health Utility Values
• Health-Related Quality of Life (HRQoL)
• Biomarker analysis
• Progression-Free Survival after unblinding until further disease progression in subjects who had received sorafenib and continue sorafenib treatment
• Progression-Free Survival after unblinding until further disease progression in subjects who had received placebo and crossover to sorafenib treatment

Secondary ID(s)

2009-012007-25-DE

BAY 43-9006 / 14295