Clinical Trials Register

Summary
EudraCT Number:	2009-012007-25
Sponsor's Protocol Code Number:	BAY43-9006/14295
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-09-17
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2009-012007-25

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Phase III study comparing sorafenib to placebo in the treatment of Locally Advanced / Metastatic RAI-Refractory Differentiated Thyroid Cancer

A.4.1

Sponsor's protocol code number

BAY43-9006/14295

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Bayer AG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Bayer AG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Bayer AG
B.5.2	Functional name of contact point	Clinical Trials Contact
B.5.3	Address:
B.5.3.1	Street Address	CTP Team/ ref. "EU CTR"/ Bayer Pharma AG
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	13342
B.5.3.4	Country	Germany
B.5.6	E-mail	clinical-trials-contact@bayerhealthcare.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Nexavar
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3//13/1200 (PTC), EU/3/13/1199 (FTC)
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Sorafenib
D.3.9.1	CAS number	284461-73-0
D.3.9.2	Current sponsor code	BAY 43-9006
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Differentiated thyroid cancer

E.1.1.1

Medical condition in easily understood language

Differentiated Thyroid Cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10066136
E.1.2	Term	Huerthle cell carcinoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10016935
E.1.2	Term	Follicular thyroid cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10055107
E.1.2	Term	Thyroid cancer metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10033701
E.1.2	Term	Papillary thyroid cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

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

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Locally advanced or metastatic differentiated thyroid cancer (papillary, follicular and Hurthle cell)
•Poorly differentiated and other thyroid variants (eg. Insular, tall cell, etc.) are eligible provided that the histology has no medullary differentiation nor anaplastic features
•Progression within 14 months (RECIST should be used as a basis for the assessment of disease progression) prior to enrollment
•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 (diagnostic or therapeutic whole body 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.
•Both women and men of childbearing potential must agree to use adequate contraception that must include, at a minimum, a barrier method of birth control (from the time of signing of the informed consent form until at least 30 days after the last study drug administration).
•Subjects must be able to understand and willing to sign a written informed consent. A signed informed consent must be appropriately obtained prior to any study specific procedures.
•Subjects must be able to swallow and retain oral medication.

E.4

Principal 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)].
•Pregnant or breast-feeding women
•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, up to a maximum of 16mg dexamethasone daily or equivalent, provided the dose is 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 treatment. All subjects (both men and women) of child-bearing potential must agree to use adequate birth control measures during the course of the trial (which must include a barrier method of birth control). Women of childbearing potential may, in addition to use of the barrier birth control, use an oral contraceptive or other additional contraception to ensure adequate birth control. Women must not breastfeed during this study.
Screening: It is possible that a patient may have an abnormal lab value or violate an inclusion/exclusion criterion for reasons that do not violate the intended study population or design of this trial. If in the investigator's opinion, and with the agreement of the Sponsor, a subject fails screening for such reasons that are deemed temporary, correctable and not likely to persist, the study will allow subjects to be screened again a maximum of once more at a later date but they must fulfill all eligibility criteria at that time. If in the investigator's opinion a subject fails screening for such reasons that are deemed to be reflective of subject's baseline status (and thus likely to persist), re-screening is not permitted.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is Progression-Free Survival (PFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary endpoint will be evaluated once 267 PFS events are achieved.

E.5.2

Secondary end point(s)

Secondary end points are Overall Survival (OS) and Time to Progression (TTP)

E.5.2.1

Timepoint(s) of evaluation of this end point

Overall Survival (OS) will be measured from the date of randomization until the date of death due to any cause. If a subject is alive at the date of database cutoff then it will be censored at the database cutoff date. Overall survival will be collected until the end of the study. A follow-up analysis of OS will be performed approximately 9 months after the date of primary completion, as well as when 240 events of death have been observed.
Time to progression (TTP) will be measured from the date of randomization until the date of confirmed radiological progression. Subjects without tumor progression at the time of analysis will be censored at their last date of radiological tumor assessment. The date of disease progression will be the date of first observation of progression.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Biomarker

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Austria

Belgium

Bulgaria

China

Denmark

France

Germany

Italy

Japan

Korea, Republic of

Netherlands

Poland

Russian Federation

Saudi Arabia

Spain

Sweden

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The study will end when the last visit of the last patient occurs after the final Overall Survival analysis

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero