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).

INTERVENTION: Trade Name: Nexavar Product Name: Nexavar Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: SORAFENIB TOSILATE CAS Number: 475207‐59‐1 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 CONDITION: Advanced (recurrent, persistent and/or metastasizing) medullary thyroid carcinoma Therapeutic area: Diseases [C] ‐ Cancer [C04] PRIMARY OUTCOME: Main Objective: 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 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. Secondary Objective: • 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) 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. SECONDARY OUTCOME: 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; Timepoint(s) of evaluation of this end point: At end of trial. 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) • Progre