Nintedanib(BIBF1120) in Thyroid Cancer

NCT ID: NCT01788982

Last Updated: 2020-07-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-05-31
• Study Completion Date: 2019-08-28

Brief Summary

For the treatment of thyroid cancer with the so called targeted therapy the angiogenesis pathway has several potential targets. The Receptors for Vascular endothelial growth factor (VEGF) and especially VEGFR-2 is considered to be crucial for the initiation of the formation as well as the maintenance of tumor vasculature.

In thyroid cancer these VEGF receptors (VEGFR-1, VEGFR-2), VEGF itself and receptors of the fibroblast growth factor (FGF) and for the platelet-derived growth factor (PDGF) are often overexpressed. Other cells as pericytes and smooth muscle cells that are also involved in tumor angiogenesis express these receptors as well.

Inhibitors of the VEGFR or PDGFR pathway have been tested in thyroid cancer with positive results. However there is no treatment that is generally considered as standard of care for patients with differentiated thyroid cancer (DTC) or medullar thyroid cancer (MTC) who have progressed on one line of therapy. The classical cytotoxic chemotherapy has not shown a clinically meaningful benefit yet.

Nintedanib is a triple angiogenesis inhibitor which inhibits receptors of VEGF, FGF and PDGF. Therefore it might act not only on endothelial cells but also on pericytes and smooth muscle cells. Nintedanib also interacts with other kinases such as RET. Because of this multi-kinase activity rationale exists to investigate the effect in MTC and DTC.

Because it targets these three major angiogenesis signaling pathways it might prevent further tumor growth and related tumor escape mechanisms. Therefore nintedanib may be active in patients who have progressed on agents that target only one pathway.

Conditions

Medullary Thyroid Cancer (MTC); Differentiated Thyroid Cancer (DTC)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Nintedanib

Nintedanib should be administered orally at a dose of 200 mg twice daily.

Group Type: EXPERIMENTAL

Nintedanib

Intervention Type: DRUG

Nintedanib should be administered orally at a dose of 200 mg twice daily.

Placebo

Placebo should be administered orally at a dose of 200 mg twice daily. Cross-over to nintedanib is allowed after progression.

Group Type: PLACEBO_COMPARATOR

Nintedanib

Intervention Type: DRUG

Nintedanib should be administered orally at a dose of 200 mg twice daily.

Placebo

Intervention Type: DRUG

Interventions

Nintedanib

Nintedanib should be administered orally at a dose of 200 mg twice daily.

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Other Intervention Names

BIBF1120

Eligibility Criteria

Inclusion Criteria

• Histologically confirmed differentiated or medullary thyroid cancer by local pathologist.
• Available tumor tissue at the time of initial diagnosis for histology review. The provision of tumor tissue for histology review is mandatory for every patient/site.
• Locally advanced or metastatic disease deemed incurable by surgery, radiotherapy and/or radioactive iodine (RAI).
• No current symptomatic brain metastases or if previously present, must have been treated at least two months before randomization. CT or MRI scan of the brain is mandatory (within 4 weeks prior to randomization) 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 or who received placebo (in the context of a clinical trial) as prior treatment 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.
• Performance status (PS) 0-1 (WHO, Appendix C).
• Life expectancy of more than 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, evidenced by the following laboratory results within 3 weeks prior to randomization: (patients with a buffer range from the normal values of +/- 5% for hematology and +/- 10% for biochemistry [with the EXCEPTION of Glomerular Filtration Rate] are acceptable)

• Absolute neutrophil count > 1500 cells/mm3
• Platelet count > 100,000 cells/mm3
• Hemoglobin > 8.5 g/dL
• Total bilirubin within normal limits
• SGOT (AST), SGPT (ALT), and alkaline phosphatase ≤ 1.5× ULN (or ≤ 2.5× ULN) in the case of presence of liver metastases)
• Glomerular Filtration Rate (GFR) ≥ 45 ml/min according to Cockcroft and Gault Formula (see Appendix E.).
• Proteinuria CTC-AE < 2
• Coagulation parameters: International normalized ratio (INR) ≤ 2, prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5x institutional ULN
• No history of significant cardiac disease defined as:

• Symptomatic CHF (NYHA classes III-IV, see Appendix D)
• High-risk uncontrolled arrhythmias, i.e. atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade AV-block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block)
• No prolongation of corrected QT interval (QTc) > 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) (with or without medication). Initiation or adjustment of antihypertensive medication(s) 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 (DVT) or pulmonary embolism in the past 6 months.
• Therapeutic anticoagulation (except low-dose heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous devise) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid < 325mg per day) is not allowed.
• No history of clinically significant gastrointestinal disorders including: malabsorption syndrome, major resection of the stomach or small bowel that could affect the absorption of study drug, active peptic ulcer disease, known intraluminal metastatic lesions with risk of bleeding, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation. No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment.
• No current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures, known infection with HIV, active hepatitis B and/or hepatitis C virus) or any other systemic disease/symptoms that may hamper compliance to study protocol, according to physician's judgment.
• 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 (WOCBP) 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, as defined by the investigator, during the study treatment period and for at least 6 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
• 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; those conditions should be discussed with the patient before registration in the trial.
• Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

• Tissue availability for central confirmation of the histological diagnosis is mandatory. All other TR projects are optional for the patient and a separate consent form for these will be provided to the patient.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

European Organisation for Research and Treatment of Cancer - EORTC

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Martin Schlumberger, MD

Role: PRINCIPAL_INVESTIGATOR

Gustave Roussy, Cancer Campus, Grand Paris

Locations

A.Z. St. Jan

Bruges, , Belgium

Hopitaux Universitaires Bordet-Erasme - Institut Jules Bordet

Brussels, , Belgium

Cliniques Universitaires Saint-Luc

Brussels, , Belgium

Universitair Ziekenhuis Antwerpen

Edegem, Antwerpen, , Belgium

Universitair Ziekenhuis Gent

Ghent, , Belgium

U.Z. Leuven - Campus Gasthuisberg

Leuven, , Belgium

Odense University Hospital

Odense, , Denmark

CHU d'Angers

Angers, , France

Institut Bergonie

Bordeaux, , France

Centre Regional Francois Baclesse

Caen, , France

Centre Georges-Francois-Leclerc

Dijon, , France

Centre Leon Berard

Lyon, , France

Assitance Publique - Hopitaux de Paris - Hopital Saint-Louis

Paris, , France

Assistance Publique - Hopitaux de Paris - La Pitié Salpétrière

Paris, , France

Centre Jean Godinot

Reims, , France

Institut Gustave Roussy

Villejuif, , France

Ludwig-Maximilians-Universitaet Muenchen - Klinikum der Universitaet Muenchen - Campus Grosshadern

Munich, , Germany

Universitaetsklinikum Wuerzburg

Würzburg, , Germany

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, , Italy

Azienda Ospedaliera Universitaria "Federico II"

Napoli, , Italy

University Medical Center Groningen

Groningen, , Netherlands

Leiden University Medical Centre

Leiden, , Netherlands

Radboud University Medical Center Nijmegen

Nijmegen, , Netherlands

Maria Sklodowska-Curie Memorial Cancer Centre

Warsaw, , Poland

Hospital General Vall D'Hebron

Barcelona, , Spain

Royal Marsden Hospital - Sutton, Surrey

Sutton, Surrey, United Kingdom

NHS Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre - Gartnavel General Hospital

Glasgow, , United Kingdom

Countries

Belgium; Denmark; France; Germany; Italy; Netherlands; Poland; Spain; United Kingdom

Other Identifiers

2012-004295-19

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EORTC-1209

Identifier Type: -

Identifier Source: org_study_id