Nintedanib(BIBF1120) in Thyroid Cancer

Inclusion Criteria:

• Histologically confirmed differentiated or medullary thyroid cancer by local pathologist.
• Available tumor tissue at the time of initial diagnosis for histology review.
• Locally advanced or metastatic disease deemed incurable by surgery, radiotherapy and/or radioactive iodine
• No current symptomatic brain metastases; if previously present, must have been treated at least two months before randomization. CT or MRI scan of the brain is mandatory to assess the presence or not of brain metastases
• Patients must have measurable lesion with documented progression during the 12 months prior to randomization, according to RECIST V.1.1. Patients who were withdrawn from first line treatment due to toxicity without documented disease progression are not eligible
• Patients must have received one or 2 prior line of treatment (but no more than two) and must be off treatment for at least 4 weeks prior to randomization
• Age ≥18 years
• PS 0-1
• Life expectancy >12 weeks
• No history of other malignancy within the last 5 years, except for adequately treated carcinoma in situ of the cervix or basal cell or spinocellular carcinoma of the skin
• No ongoing treatment related toxicity due to prior treatment >grade I (except alopecia)
• Adequate organ function:
• Absolute neutrophil count > 1500 cells/mm3
• Platelet count > 100,000 cells/mm3
• Hemoglobin > 8.5 g/dL
• Total bilirubin within normal limits
• SGOT, SGPT, and ALP ≤ 1.5× ULN (or ≤ 2.5× ULN in the case of presence of liver metastases)
• GFR ≥ 45 ml/min according to MDRD formula or Cockcroft-Gault Formula
• Proteinuria CTC-AE < 2
• Coagulation parameters: INR ≤ 2, PT and PTT ≤ 1.5x institutional ULN
• No history of significant cardiac disease defined as:
• Symptomatic CHF (NYHA classes III-IV)
• High-risk uncontrolled arrhythmias, i.e. atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia or higher-grade AV-block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block)
• No prolongation of QT interval >480 msecs
• History of myocardial infarction within 12 months prior to randomization
• Clinically significant valvular heart disease
• No angina pectoris requiring anti-angina treatment
• No current uncontrolled hypertension (persistent systolic > 180 mmHg and/or diastolic > 100 mmHg). Initiation or adjustment of antihypertensive medication is permitted prior to study entry.
• No evidence of active bleeding or bleeding diathesis.
• No cerebrovascular accident at any time in the past, transient ischemic attack, deep venous thrombosis or pulmonary embolism in the past 6 months
• Therapeutic anticoagulation (except low-dose heparin and/or heparin flush for maintenance of an in-dwelling intravenous devise) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid <325mg/day) is not allowed
• No history of clinically significant gastrointestinal disorders
• No current severe, uncontrolled systemic disease
• No major surgical procedure or significant traumatic injury within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment and/or presence of any non-healing wound, fracture, or ulcer
• No history of receiving any investigational treatment within 28 days prior to randomization
• Women of child bearing potential must have a negative serum (or urine) pregnancy test within 72 hours prior to the first dose of study treatment.
• Patients of childbearing/reproductive potential should use adequate birth control measures, during the study treatment period and for at least 6 months after the last study treatment
• Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
• Written informed consent must be given according to ICH/GCP, and national/local regulations