Clinical trial NCT01788982: Nintedanib(BIBF1120) in Thyroid Cancer
Official title: A Phase II Study Exploring the Safety and Efficacy of Nintedanib (BIBF1120) as Second Line Therapy for Patients With Either Differentiated or Medullary Thyroid Cancer Progressing After First Line Therapy.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Medullary Thyroid Cancer (MTC)
Differentiated Thyroid Cancer (DTC)
Keywords: Thyroid Cancer
Medullary thyroid cancer (MTC)
Differentiated thyroid cancer (DTC)
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
First posted: 2013-02-11
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Progression free survival (PFS)
timeFrame: 2,5 years from FPI
Secondary outcomes:
measure: Occurence of Adverse Events
timeFrame: 2,5 years from FPI
measure: Response Rate
timeFrame: 2,5 years from FPI
measure: Duration of response
timeFrame: 2,5 years form FPI
measure: Exploration of the molecular mechanisms of action of drug
timeFrame: 3 years from FPI
Other outcomes:
Locations:
city: Brugge
country: Belgium
facility: A.Z. St. Jan
city: Brussels
country: Belgium
facility: Hopitaux Universitaires Bordet-Erasme - Institut Jules Bordet
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Edegem, Antwerpen
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Leuven
country: Belgium
facility: U.Z. Leuven - Campus Gasthuisberg
city: Odense
country: Denmark
facility: Odense University Hospital
city: Angers
country: France
facility: CHU d'Angers
city: Bordeaux
country: France
facility: Institut Bergonie
city: Caen
country: France
facility: Centre Regional Francois Baclesse
city: Dijon
country: France
facility: Centre Georges-Francois-Leclerc
city: Lyon
country: France
facility: Centre Leon Berard
city: Paris
country: France
facility: Assitance Publique - Hopitaux de Paris - Hopital Saint-Louis
city: Paris
country: France
facility: Assistance Publique - Hopitaux de Paris - La Pitié Salpétrière
city: Reims
country: France
facility: Centre Jean Godinot
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Munich
country: Germany
facility: Ludwig-Maximilians-Universitaet Muenchen - Klinikum der Universitaet Muenchen - Campus Grosshadern
city: Wuerzburg
country: Germany
facility: Universitaetsklinikum Wuerzburg
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria "Federico II"
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Leiden
country: Netherlands
facility: Leiden University Medical Centre
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center Nijmegen
city: Warsaw
country: Poland
facility: Maria Sklodowska-Curie Memorial Cancer Centre
city: Barcelona
country: Spain
facility: Hospital General Vall D'Hebron
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital - Sutton, Surrey
state: Surrey
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre - Gartnavel General Hospital
Study officials:
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
name: Martin Schlumberger, MD
role: PRINCIPAL_INVESTIGATOR
References: