The primary objective is to explore the efficacy of nintedanib (as measured by progression free survival) as second line therapy for patients with either differentiated or medullary thyroid cancer progressing after first line therapy.
ID
Source
Brief title
Condition
- Thyroid gland disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Progression free survival (RECIST 1.1)
Secondary outcome
* Secondary end-points
* Response Rate (RECIST 1.1)
* Duration of response
* Exploration of the molecular mechanisms of action of drug
* PFS at second progression (PFS-2) for patients crossing over from placebo to
nintedanib.
Safety
* Toxicity profile (CTCAE version 4.0 will be used for adverse event reporting)
Background summary
Angiogenesis pathway represents a set of potential targets for targeted
therapies in thyroid cancer. VEGF receptors (VEGFR) and especially VEGFR-2 is
considered to be the crucial receptor involved in initiation of the formation
as well as the maintenance of tumor vasculature. VEGF and VEGF receptors
(VEGFR-1, VEGFR-2) as well as receptors of the fibroblast growth factor (FGF)
and for the platelet-derived growth factor (PDGF) are often overexpressed in
thyroid cancer (Ref. 11). These receptors are also expressed on perivascular
cells, such as pericytes and smooth muscle cells, that are also involved in
tumor angiogenesis. Tyrosine kinase inhibitors of the VEGFR or PDGFR pathway
have been tested in thyroid cancer with
EORTC-1209-EnTF Nintedanib (BIBF1120) in thyroid cancer
Version 2.0 18 / 84 April 02, 2013
positive results. Vandetanib is approved for MTC and it is expected soon that
sorafenib will be approved for differentiated thyroid cancer.
The treatment options for patients with DTC and MTC who have progressed on one
line of therapy are limited and there is no treatment that is generally
considered as standard of care. No clinically meaningful benefit has yet been
demonstrated with cytotoxic chemotherapy. On the other hand patients are still
in good general condition and may still benefit from treatment and experience
survival prolongation.
Nintedanib is a triple angiogenesis inhibitor which inhibits receptors of VEGF,
FGF and PDGF, therefore acting potentially not only on endothelial cells but
also on pericytes and smooth muscle cells. Nintedanib also interacts with other
kinases such as RET. Because of its multi-kinase activity rationale exists to
develop it in both MTC and DTC.
By targeting these three major angiogenesis signaling pathways it is believed
that nintedanib can prevent further tumor growth and related tumor escape
mechanisms. This also means that nintedanib may be active in patients who have
progressed on agents that target only one pathway.
Study objective
The primary objective is to explore the efficacy of nintedanib (as measured by
progression free survival) as second line therapy for patients with either
differentiated or medullary thyroid cancer progressing after first line
therapy.
Study design
This is a randomized blinded, placebo controlled phase II trial.
Intervention
Treatment cycles are defined as a four week period to facilitate scheduling of
visits and assessments. Treatment should start within 2 days from randomization.
Patients will receive drug in a blinded fashion. Nintedanib should be
administered orally at a dose of 200 mg twice daily. It should be swallowed
unchewed, preferably together with a glass of water of about 250 mL. The doses
should be taken with a dose interval of approximately 12 hours.
Treatment should be administered until documented disease progression,
unacceptable toxicity, or patient refusal.
Comparator treatment in this study will be placebo capsules, matching those of
nintedanib, but with no active drug. Treatment in the placebo arm should also
be administered until documented disease progression, unacceptable toxicity, or
patient refusal. After documented disease progression (according to RECIST 1.1)
patients will be unblinded and will be offered the option of receiving
nintedanib.
Study burden and risks
Risks:
Before the start of each treatment cycle, the subject will be evaluated for
possible toxicities that may have occurred after the previous cycle(s).
Toxicities are to be assessed according to the CTCAE, Version 4.0.
The predominant adverse events of nintedanib were diarrhea, nausea and vomiting
followed by fatigue, decreased appetite and abdominal pain. These adverse
events were reversible, mostly of low to moderate severity of CTCAE grade I or
II and manageable in most cases with symptomatic therapy.
Benefit:
The treatment options for patients with DTC and MTC who have progressed on one
line of therapy are limited and there is no treatment that is generally
considered as standard of care. No clinically meaningful benefit has yet been
demonstrated with cytotoxic chemotherapy. On the other hand patients are still
in good general condition and may still benefit from treatment and experience
survival prolongation.
Nintedanib is a triple angiogenesis inhibitor which inhibits receptors of VEGF,
FGF and PDGF, therefore acting potentially not only on endothelial cells but
also on pericytes and smooth muscle cells. Nintedanib also interacts with other
kinases such as RET. Because of its multi-kinase activity rationale exists to
develop it in both MTC and DTC.
By targeting these three major angiogenesis signaling pathways it is believed
that nintedanib can prevent further tumor growth and related tumor escape
mechanisms. This also means that nintedanib may be active in patients who have
progressed on agents that target only one pathway.
Avenue E. Mounierlaan 83
Brussel 1200
BE
Avenue E. Mounierlaan 83
Brussel 1200
BE
Listed location countries
Age
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 (RAI).
* Patients must have measurable lesion with documented progression
during the 12 months prior to randomization.
* 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. Patients with an MTC 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. If it is available and reimbursed in the respective country one of the prior lines of treatment needs to be with Vandetanib as long as there is no contraindication or the patient refuses the treatment with Vandetanib.
* Age *18 years.
* Performance status (PS) 0-1 (WHO, Appendix C).
* Life expectancy of more than 12 weeks.
* Adequate organ function, evidenced by the following laboratory
results within 3 weeks prior to randomization
Exclusion criteria
* Current symptomatic brain metastases or if previously present, must
have been treated at least two months before randomization.
* 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.
* Ongoing treatment related toxicity due to prior treatment > grade I
(except alopecia).
* History of significant cardiac disease
* Current uncontrolled hypertension
* Evidence of active bleeding or bleeding diathesis.
* Cerebrovascular accident at any time in the past, transient ischemic
attack, deep venous thrombosis (DVT) or pulmonary embolism in the
past 6 months
* History of clinically significant gastrointestinal disorders .
* Current severe, uncontrolled systemic disease or any other systemic
disease/symptom that can hamper compliance with the protocol.
* Major surgical procedure or significant traumatic injury within 28 days
prior to randomization or anticipation of the need for major surgery.
* History of receiving any investigational treatment within 28 days prior
to randomization
* Women or patients of child bearing potential who do not use any
contraceptive methods
* Any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up
schedule.
* No hypersensitivity to nintedanib, peanut or soya, or to any of the excipients of nintedanib.
* 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 3 months after the last dose of 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 at least 3 months after the last dose of study treatment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-004295-19-NL |
| ClinicalTrials.gov | NCT01788982 |
| CCMO | NL46582.091.13 |