Clinical Trials Register

Summary
EudraCT Number:	2011-006250-90
Sponsor's Protocol Code Number:	EARL-2
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2012-03-16
Trial 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

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2011-006250-90

A.3

Full title of the trial

Randomized double-blind placebo controlled Phase II study to evaluate the efficacy and safety of Sorafenib treatment in patients with advanced (recurrent, persistent and/or metastasizing) medullary thyroid carcinoma (SUMMIT).

Randomisierte, doppelblinde, Placebo-kontrollierte Phase II-Studie zur Bewertung von Wirksamkeit und Sicherheit einer Behandlung mit Sorafenib bei Patienten mit medullärem Schilddrüsenkarzinom (SUMMIT)

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

SUMMIT

A.4.1

Sponsor's protocol code number

EARL-2

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	EANM Forschungs GmbH / EANM Research Ltd.
B.1.3.4	Country	Austria
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	EANM Forschungs GmbH / EANM Research Ltd.
B.4.2	Country	Austria
B.4.1	Name of organisation providing support	Bayer Vital GmbH
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	ABX-CRO advanced pharmaceutical services Forschungsgesellschaft m.b.H
B.5.2	Functional name of contact point	Dipl.-Med. Ingo Weigmann
B.5.3	Address:
B.5.3.1	Street Address	Blasewitzer Str. 78-80
B.5.3.2	Town/ city	Dresden
B.5.3.3	Post code	01307
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4935121444277
B.5.5	Fax number	+493512144415
B.5.6	E-mail	weigmann@abx-cro.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Nexavar
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 TOSILATE
D.3.9.1	CAS number	475207-59-1
D.3.9.4	EV Substance Code	SUB22347
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

Advanced (recurrent, persistent and/or metastasizing) medullary thyroid carcinoma

Fortgeschrittenes (rezidivierendes, anhaltendes und/oder metastasierendes) medulläres Schilddrüsenkarzinom

E.1.1.1

Medical condition in easily understood language

Advanced medullary thyroid carcinoma

Fortgeschrittenes medulläres Schilddrüsenkarzinom

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 study objective is to compare the Progression-free Survival (PFS) of the Sorafenib treatment group with the placebo treatment group in patients with advanced MTC

E.2.2

Secondary objectives of the trial

• Time To Progression (TTP)
• Disease Control Rate (DCR)
• Overall Response Rate (ORR) = Complete Response Rate (CR rate) + Partial Response Rate (PR rate)
• Response Duration
• Overall Survival (OS)
• PFS after cross-over (only descriptive analysis)
• TTP after cross-over
• DCR after cross-over
• Overall Response Rate (ORR = CR rate + PR rate) after cross-over
• Safety
• Quality of Life (QoL) as assessed by Patient-reported Outcome (PRO)

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Title: Biomarker Substudy

Date and Version: 02.03.2012; Vers. 1.1

Objectives:
• To assess the effect of Sorafenib on gene expressions, protein expressions, tumor immunogenicity and tumor cell signaling in MTC cells prior to and during (after 8 weeks) administration of study drug in a subset of patients with lesions amenable to biopsy (needle biopsy), who are willing to participate in this substudy, and to correlate the results with clinical outcome.
• To assess the (complementary) effects of Sorafenib on peripheral blood derived PBMC phenotype and function and
• To correlate results from assessment of (complementary) effects of Sorafenib on peripheral blood derived PBMC phenotype and function with data generated from analysis of tumor tissue (see previous objective) and with clinical outcome

E.3

Principal inclusion criteria

• Patient must be ≥ 18 years of age when signing the informed consent form
• Histologically confirmed medullary thyroid carcinoma (C-cell thyroid carcinoma)
• Recurrent or persistent local disease and/or distant metastases not suitable for local curative treatment (surgery or radiation therapy) assessed by Investigator
• No more than one prior line of systemic therapy (including no more than 1 prior line with a targeted drug, e.g. kinase inhibitor)
• Best available supportive care to control (endocrine) symptoms according to current standards established for at least 8 weeks before study entry
• At least one defined lesion in CT or MRI evaluable for RECIST (v1.1), no older than 42 days from planned treatment start, or at least one defined lesion in CT or MRI not evaluable by RECIST in combination with elevated tumour markers with minimum initial levels of 150 pg/ml for calcitonin or 5 x UILN for CEA (e.g., in case of bone metastases)
• Progression within previous 12 months (according to RECIST 1.1 criteria or tumour marker progression (calcitonin or CEA referred to normal Reference Ranges from Site Lab) can be used as a basis for the assessment of disease progression); tumour marker doubling time must be no longer than 12 months (30) and a minimum initial level of 150 pg/ml for calcitonin or 5 x UILN for CEA, respectively, need to be present. The tumour marker doubling time should be estimated using the calculator at the ATA-website: http://www.thyroid.org/professionals/calculators/CDTC.php
• Hb > 8g/dl, WBC >3.000 cells/mm³ (ANC > 1.500 cells/mm³), platelets > 100.000 cells/mm³, bilirubin < 2mg/dl, Alanine aminotransaminase (ALT) and Aspartate aminotransferase (AST) < 2.5 x upper limit of normal (referred to normal Reference Ranges from Site Lab)
• Performance status: WHO ≤ 2; Karnofsky index ≥ 50%
• Patients should have sufficient renal function, as determined by serum creatinine <1.5 mg/dl and CrCL > 30ml/min
• PT-INR and PTT < 1.5 x upper limit of normal (referred to normal Reference Ranges from Site Lab) [Patients who are being therapeutically anticoagulated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists]
• No acute infections at the time of therapy initiation
• Staging studies (MRT or CT and Calcitonin or CEA) completed within four weeks of protocol randomisation
• 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) from signing of the informed consent form until at least 30 days after the last study drug administration (men for at least 3 months after last administration of study medication)
• Patient is able to understand the study procedures, voluntarily agrees to participate in the study and has given a signed and dated written informed consent prior to study participation.

E.4

Principal exclusion criteria

• Unresolved toxicity (i.e. neurotoxicity) attributed to any prior therapy higher than NCI-CTCAE (version 4) Grade 2 (excluding cases of alopecia)
• Patients with history of allergic or hypersensitivity reaction to study drug or placebo or their excipients or with a history of allergic reactions attributed to compounds with similar composition to any of the study drug or placebo.
• Current participation in another investigational trial
• Patients with significant cardiovascular disease, such as myocardial infarction < 6 months, unstable coronary artery disease (anginal symptoms at rest), new-onset angina within 3 months before randomization, or chronic heart failure (New York Heart Association grade III or IV)
• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy other than beta-blockers or digoxin
• Congenital long QTc syndrome, history of drug induced QTc prolongation, or QTc interval unmeasurable or more than 450 ms
• Abnormal serum electrolytes such as potassium, magnesium and calcium
• Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg or diastolic pressure > 90 mm Hg, despite optimal management
• 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
• Hemorrhage/bleeding event ≥ Grade 3 within 3 months prior to first dose of study drug
• Thrombotic or embolic events including transient ischemic attacks within the past 6 months
• Subjects with symptomatic brain metastases or Subjects with brain metastases under corticosteroid treatment. 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 tumours [Ta (Non invasive tumour), Tis (Carcinoma in situ) and T1 (Tumour invades lamina propria)]
• Pregnant or breast-feeding patients
• Patients with uncontrolled infections
• Known human immunodeficiency virus (HIV) infection or infection with hepatitis B or C
• Immunosuppression
• 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
• Any malabsorption condition
• Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study

E.5 End points

E.5.1

Primary end point(s)

Progression-free survival (PFS) measured as time from randomization to disease progression or death based on RECIST v1.1 evaluation or based on Tumour marker progress (CEA or calcitonin) in the first section of the study before cross-over (for the former placebo group) will be used as primary efficacy variable. The Sorafenib group and the placebo group will be compared by log rank test and Kaplan-Meier plot.
The potential influence of important prognostic factors on PFS (e.g. hereditary or spontaneous MTC, pretreatment with tyrosine kinase inhibitors or other targeted drugs) will be evaluated in an exploratory fashion using a Cox regression analysis.

E.5.1.1

Timepoint(s) of evaluation of this end point

Progression free survival will be evaluated when the data are mature, i.e. when 69 PFS events have been reached.

E.5.2

Secondary end point(s)

Secondary efficacy variables are:
• Time To Progression (TTP)
• DCR (CR + PR + SD rate) in first period of the study before cross-over
• Overall Response Rate (ORR = CR rate + PR rate) in first period
• Response duration in first period
• Overall Survival (OS)
• PFS after cross-over (only descriptive analysis)
• TTP after cross-over
• DCR after cross-over
• Overall Response Rate (ORR = CR rate + PR rate) after cross-over
• Patient reported outcomes (PROs), defined as health-related quality of life using the self administered FACT-G or EQ-5D by treatment group and period

Secondary safety variables are:
Type, severity (graded by the National Cancer Institute, Common Terminology Criteria for Adverse Events [CTCAE] Version 4.03), seriousness and relatedness of adverse events by treatment group and period, primarily based on
• Clinical assessment
• Laboratory values
• Vital signs

E.5.2.1

Timepoint(s) of evaluation of this end point

At end of trial.

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

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

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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 continue until the data for the primary endpoint are reached. If at the time of study endpoint there are still subjects on the study who are continuing to benefit from treatment, they may continue treatment, if deemed beneficial by their physician, either through commercial supply or through an extension program.

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

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

110

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

110

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

110

F.4.2.2

In the whole clinical trial

110

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

If at the time of study endpoint there are still subjects on the study who are continuing to benefit from treatment, they may continue treatment, if deemed beneficial by their physician, either through commercial supply or through an extension program.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-07-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-06-14

P. End of Trial
P.	End of Trial Status	Ongoing

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