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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02702388




Registration number
NCT02702388
Ethics application status
Date submitted
3/03/2016
Date registered
8/03/2016
Date last updated
21/07/2020

Titles & IDs
Public title
A Phase 2 Trial of Lenvatinib (E7080) in Subjects With Iodine-131 Refractory Differentiated Thyroid Cancer to Evaluate Whether an Oral Starting Dose of 18 mg Daily Will Provide Comparable Efficacy to a 24 mg Starting Dose, But Have a Better Safety Profile
Scientific title
A Multicenter, Randomized, Double-Blind Phase 2 Trial of Lenvatinib (E7080) in Subjects With 131I-Refractory Differentiated Thyroid Cancer to Evaluate Whether an Oral Starting Dose of 18 mg Daily Will Provide Comparable Efficacy to a 24-mg Starting Dose, But Have a Better Safety Profile
Secondary ID [1] 0 0
2014-005199-27
Secondary ID [2] 0 0
E7080-G000-211
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Thyroid Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Thyroid
Metabolic and Endocrine 0 0 0 0
Other endocrine disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Lenvatinib
Treatment: Drugs - Lenvatinib matching placebo

Experimental: 24 mg Lenvatinib - Participants will receive 24 mg once daily (QD) as the starting dose. Dose reductions will occur in succession based on the previous dose level (24, 20, 14, 10, or 8 mg QD). To maintain blinded treatment assignment, participants will be administered study drug in the form of two 10-mg capsules and two 4-mg capsules containing either lenvatinib or placebo (total of 4 capsules) to be taken orally, at approximately the same time each morning and may be taken in a fasting state or following a meal.

Experimental: 18 mg Lenvatinib - Participants will receive 18mg QD as the starting dose. Dose reductions will occur in succession based on the previous dose level (18,14, 10, 8, or 4 mg QD). To maintain blinded treatment assignment, participants will be administered study drug in the form of two 10-mg capsules and two 4-mg capsules containing either lenvatinib or placebo (total of 4 capsules) to be taken orally, at approximately the same time each morning and may be taken in a fasting state or following a meal.


Treatment: Drugs: Lenvatinib
Lenvatinib capsule.

Treatment: Drugs: Lenvatinib matching placebo
Lenvatinib matching placebo capsule.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Objective response rate (ORR) - ORR at 24 weeks is defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR) at the Week 24 time point or earlier.
Timepoint [1] 0 0
At 24 Weeks
Primary outcome [2] 0 0
Percentage of treatment-emergent adverse event(s) (TEAEs) with Common Terminology Criteria for Adverse Events (CTCAE) grades of 3 or higher
Timepoint [2] 0 0
Up to 24 weeks after randomization
Secondary outcome [1] 0 0
Progression-free survival (PFS)
Timepoint [1] 0 0
The time from the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurs first up to approximately 30 months.
Secondary outcome [2] 0 0
PFS after next line of treatment (PFS2)
Timepoint [2] 0 0
PFS2 is defined as the time from randomization to second objective PD (occurring during treatment with next line of anticancer therapy) or death from any cause, whichever occurs first up to approximately 30 months.
Secondary outcome [3] 0 0
Number of participants with treatment emergent adverse events (AEs) and serious adverse events (SAEs)
Timepoint [3] 0 0
For each participant, from the date of first administration of study drug up to 28 days from last dose of study drug up to approximately 30 months.
Secondary outcome [4] 0 0
Time to treatment discontinuation due to an AE
Timepoint [4] 0 0
For each participant, from the date of first administration of study drug up to approximately 30 months.
Secondary outcome [5] 0 0
Number of dose reductions
Timepoint [5] 0 0
From the date of first administration of study drug up to approximately 30 months.
Secondary outcome [6] 0 0
Time to first dose reduction
Timepoint [6] 0 0
From the date of first administration of study drug up to approximately 30 months.
Secondary outcome [7] 0 0
Area under the concentration-time curve (AUC) of lenvatinib derived from the final pharmacokinetic model
Timepoint [7] 0 0
Cycle 1 Day 1 (C1D1) (0.5-4 hour [h] and 6-10 h postdose), C1D15 (predose, 0.5-4 h and 6-10 h postdose),predose on C1D8 ,predose on C1D22 (optional) and C2D1 (predose and 2-12 h postdose) (each cycle=28 days)
Secondary outcome [8] 0 0
Presence or absence of parameters/biomarkers associated with lenvatinib exposure as evaluated using a multi-parametric model - A multi-parametric model will be used to identify and report parameters and biomarkers that may be associated with lenvatinib exposure. These parameters will include tumor burden, PFS, safety parameters (hypertension, adverse events of weight loss, fatigue, nausea, vomiting, diarrhea, and proteinuria), and serum biomarkers (example, thyroglobulin, thyroid-stimulating hormone). Here, presence is defined as parameters/biomarkers associated with lenvatinib exposure as evaluated using multi-parametric model, and absence is defined as parameters/biomarkers not associated with lenvatinib exposure as evaluated using multi-parametric model.
Timepoint [8] 0 0
Baseline up to approximately 30 months
Secondary outcome [9] 0 0
Health-Related Quality of Life (HRQoL)
Timepoint [9] 0 0
Baseline Day -1 (prior to first dose of study drug), every 8 weeks until Week 24, then every 16 weeks, at the Off-Treatment Visitor up to approximately 30 months.

Eligibility
Key inclusion criteria
1. Participants must have histologically or cytologically confirmed diagnosis of one of
the following differentiated thyroid cancer (DTC) subtypes:

1. Papillary thyroid cancer (PTC)

- Follicular variant

- Variants (including but not limited to tall cell, columnar cell,
cribriform-morular, solid, oxyphil, Warthin's-like, trabecular, tumor with
nodular fasciitis-like stroma, Hürthle cell variant of papillary carcinoma,
poorly differentiated)

2. Follicular thyroid cancer (FTC)

- Hurthle cell

- Clear cell

- Insular

2. Measurable disease meeting the following criteria and confirmed by central
radiographic review:

1. At least 1 lesion of =1.0 cm in the longest diameter for a non-lymph node or =1.5
cm in the short-axis diameter for a lymph node that is serially measurable
according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) using
computed tomography/magnetic resonance imaging (CT/MRI). If there is only 1
target lesion and it is a non-lymph node, it should have a longest diameter of
=1.5 cm.

2. Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies
such as radiofrequency (RF) ablation must show evidence of progressive disease
based on RECIST 1.1 to be deemed a target lesion.

3. Participants must show evidence of disease progression within 12 months (an additional
month will be allowed to accommodate actual dates of performance of screening scans,
ie, within =13 months) prior to signing informed consent, according to RECIST 1.1
assessed and confirmed by central radiographic review of CT and/or MRI scans.

4. Participants must be Iodine-131 refractory/resistant as defined by at least one of the
following:

1. One or more measurable lesions that do not demonstrate iodine uptake on any
radioiodine scan.

2. One or more measurable lesions that have progressed according to RECIST 1.1
within 12 months (an additional month will be allowed to accommodate actual dates
of performance of screening scans, ie, within =13 months) after Iodine-131
therapy, despite demonstration of radioiodine avidity at the time of that
treatment by pre- or posttreatment scanning. These participants must not be
eligible for possible curative surgery.

3. Cumulative activity of Iodine-131 of >600 mCi or 22 gigabecquerels (GBq), with
the last dose administered at least 6 months prior to study entry.

5. Participants with known brain metastases who have completed whole brain radiotherapy,
stereotactic radiosurgery or complete surgical resection, will be eligible if they
have remained clinically stable, asymptomatic, and off steroids for one month.

6. Participants must be receiving thyroxine suppression therapy and thyroid stimulating
hormone (TSH) should not be elevated (TSH should be =5.50 mcIU/ML). When tolerated by
the participant, thyroxine dose should be changed to achieve TSH suppression (TSH
<0.50 mcIU/ML) and this dose may be changed concurrently upon starting study drug
treatment.

7. All chemotherapy or radiation-related toxicities must have resolved to Grade <2
severity per Common Terminology Criteria for Adverse Events (CTCAE v4.03), except
alopecia and infertility.

8. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status
of 0, 1, or 2.

9. Adequately controlled blood pressure (BP) with or without antihypertensive
medications, defined as BP =150/90 mmHg at Screening and no change in antihypertensive
medications within 1 week prior to Cycle 1/Day 1.

10. Adequate renal function defined as calculated creatinine clearance =30 mL/min per the
Cockcroft and Gault formula.

11. Adequate bone marrow function:

1. Absolute neutrophil count (ANC) =1500/mm3 (=1.5 × 103/uL)

2. Platelets =100,000/mm3 (=100 × 109/L)

3. Hemoglobin =9.0 g/dL

12. Adequate blood coagulation function as evidenced by an International Normalized Ratio
(INR) =1.5.

13. Adequate liver function:

1. Bilirubin =1.5 × upper limit of normal (ULN) except for unconjugated
hyperbilirubinemia or Gilbert's syndrome.

2. Alkaline phosphatase, alanine aminotransferase (ALT), and aspartate
aminotransferase (AST) =3 × ULN (=5 × ULN if participant has liver metastases).
If alkaline phosphatase is >3 × ULN (in absence of liver metastases) or >5 × ULN
(in presence of liver metastases) AND the participant also is known to have bone
metastases, the liver-specific alkaline phosphatase must be separated from the
total and used to assess the liver function instead of total alkaline
phosphatase.

14. Males or females age =18 years at the time of informed consent.

15. Females must not be lactating or pregnant at Screening or Baseline (as documented by a
negative beta-human chorionic gonadotropin [B-hCG] test with a minimum sensitivity of
25 IU/L or equivalent units of B-hCG. A separate baseline assessment is required if a
negative screening pregnancy test was obtained more than 72 hours before the first
dose of study drug.

16. All females will be considered to be of childbearing potential unless they are
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age
group and without other known or suspected cause) or have been sterilized surgically
(ie, bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with
surgery at least 1 month before dosing).

17. Females of childbearing potential should avoid becoming pregnant and use highly
effective contraception while on treatment with lenvatinib and for at least 1 month
after finishing treatment. Females of childbearing potential must not have had
unprotected sexual intercourse within 30 days before study entry and must agree to use
a highly effective method of contraception (eg, total abstinence, an intrauterine
device, a contraceptive implant, an oral contraceptive, or have a vasectomized partner
with confirmed azoospermia) throughout the entire study period and for 30 days after
study drug discontinuation. Females who are using hormonal contraceptives must have
been on a stable dose of the same hormonal contraceptive product for at least 4 weeks
before dosing and must continue to use the same contraceptive during the study and for
30 days after study drug discontinuation. Women using oral hormonal contraceptives
should add a barrier method.

18. Participants must voluntarily agree to provide written informed consent.

19. Participants must be willing and able to comply with all aspects of the protocol.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Anaplastic or medullary carcinoma of the thyroid.

2. Diagnosed with meningeal carcinomatosis.

3. Two or more prior vascular endothelial growth factor (VEGF)/vascular endothelial
growth factor receptor (VEGFR)-targeted therapies or any ongoing treatment for RR-DTC
other than TSH-suppressive thyroid hormone therapy.

4. Prior treatment with lenvatinib.

5. Participants who have received any anticancer treatment within 21 days or any
investigational agent within 30 days (or 5 half-lives) prior to the first dose of
study drug and should have recovered from any toxicity related to previous anticancer
treatment. This does not apply to the use of TSH suppressive thyroid hormone therapy.

6. Major surgery (eg, laparotomy, thoracotomy or joint replacement) within 3 weeks prior
to randomization or elective surgery scheduled to be performed during the study.

7. Participants having >1+ proteinuria on urine dipstick testing will undergo 24-hour
urine collection for quantitative assessment of proteinuria. Participants with urine
protein =1 g/24 h will be ineligible.

8. Gastrointestinal malabsorption or any other condition that in the opinion of the
investigator might affect the absorption of study drug.

9. Significant cardiovascular impairment: history of congestive heart failure greater
than New York Heart Association (NYHA) Class II, unstable angina, myocardial
infarction or cerebral vascular accident within 6 months of the first dose of study
drug, or cardiac arrhythmia associated with hemodynamic instability.

10. Prolongation of corrected QT interval (QTc) to >480 ms as demonstrated by a repeated
electrocardiogram (ECG) or a clinically significant ECG abnormality, including a
marked prolonged QT/QTc interval (eg, a repeated demonstration of a QTc interval >500
ms).

11. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to
the first dose of study drug.

12. Active infection (any infection requiring treatment).

13. Active malignancy (except for DTC or definitively treated melanoma in-situ, basal or
squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the
past 24 months.

14. Bleeding or thrombotic disorders.

15. Known intolerance to study drug (or any of the excipients).

16. Any medical or other condition that in the opinion of the investigator(s) would
preclude the participant's participation in a clinical study.

17. Females who are pregnant or breastfeeding.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC,WA
Recruitment hospital [1] 0 0
Facility #1 - Darlinghurst
Recruitment hospital [2] 0 0
Facility #1 - Saint Leonards
Recruitment hospital [3] 0 0
Royal Brisbane and Women's Hospital - Brisbane
Recruitment hospital [4] 0 0
Facility#2 - Chermside
Recruitment hospital [5] 0 0
Facility #1 - Herston
Recruitment hospital [6] 0 0
Facility #1 - Melbourne
Recruitment hospital [7] 0 0
Facility #1 - Nedlands
Recruitment postcode(s) [1] 0 0
- Darlinghurst
Recruitment postcode(s) [2] 0 0
- Saint Leonards
Recruitment postcode(s) [3] 0 0
4006 - Brisbane
Recruitment postcode(s) [4] 0 0
- Chermside
Recruitment postcode(s) [5] 0 0
- Herston
Recruitment postcode(s) [6] 0 0
- Melbourne
Recruitment postcode(s) [7] 0 0
- Nedlands
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
District of Columbia
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United States of America
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Massachusetts
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United States of America
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Michigan
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United States of America
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New Jersey
Country [6] 0 0
United States of America
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New York
Country [7] 0 0
United States of America
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Ohio
Country [8] 0 0
United States of America
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Oregon
Country [9] 0 0
United States of America
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Pennsylvania
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United States of America
State/province [10] 0 0
Washington
Country [11] 0 0
Belgium
State/province [11] 0 0
Antwerpen
Country [12] 0 0
Belgium
State/province [12] 0 0
Brussels
Country [13] 0 0
Belgium
State/province [13] 0 0
Namur
Country [14] 0 0
Canada
State/province [14] 0 0
Alberta
Country [15] 0 0
Canada
State/province [15] 0 0
Ontario
Country [16] 0 0
Canada
State/province [16] 0 0
Quebec
Country [17] 0 0
Denmark
State/province [17] 0 0
Syddanmark
Country [18] 0 0
France
State/province [18] 0 0
Bas-Rhin
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France
State/province [19] 0 0
Calvados
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France
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Cote-d'Or
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France
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Gironde
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France
State/province [22] 0 0
Maine-et-Loire
Country [23] 0 0
France
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Val-de-Marne
Country [24] 0 0
France
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Angers
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France
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Bordeaux
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France
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Caen
Country [27] 0 0
France
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Dijon
Country [28] 0 0
France
State/province [28] 0 0
Lyon
Country [29] 0 0
France
State/province [29] 0 0
Paris
Country [30] 0 0
Germany
State/province [30] 0 0
Baden-Wurttemberg
Country [31] 0 0
Germany
State/province [31] 0 0
Bayern
Country [32] 0 0
Germany
State/province [32] 0 0
Niedersachsen
Country [33] 0 0
Germany
State/province [33] 0 0
Nordrhein-Westfalen
Country [34] 0 0
Germany
State/province [34] 0 0
Essen
Country [35] 0 0
Germany
State/province [35] 0 0
Leipzig
Country [36] 0 0
Israel
State/province [36] 0 0
Petach Tikva
Country [37] 0 0
Italy
State/province [37] 0 0
Lazio
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Italy
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Lombardia
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Italy
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Toscana
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Italy
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Milano
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Italy
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Pisa
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Italy
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Roma
Country [43] 0 0
Italy
State/province [43] 0 0
Rozzano
Country [44] 0 0
Italy
State/province [44] 0 0
Torino
Country [45] 0 0
Italy
State/province [45] 0 0
Viagrande
Country [46] 0 0
Korea, Republic of
State/province [46] 0 0
Busan
Country [47] 0 0
Korea, Republic of
State/province [47] 0 0
Goyang-si
Country [48] 0 0
Korea, Republic of
State/province [48] 0 0
Seoul
Country [49] 0 0
Poland
State/province [49] 0 0
Kielce
Country [50] 0 0
Romania
State/province [50] 0 0
Cluj
Country [51] 0 0
Romania
State/province [51] 0 0
Bucharest
Country [52] 0 0
Russian Federation
State/province [52] 0 0
Leningradskaya O
Country [53] 0 0
Russian Federation
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Moscow
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Russian Federation
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Obninsk
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Russian Federation
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Saint Petersburg
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Spain
State/province [56] 0 0
Cataluna
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Spain
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Madrid, Communidad Delaware
Country [58] 0 0
Spain
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Badalona
Country [59] 0 0
Spain
State/province [59] 0 0
Barcelona
Country [60] 0 0
Spain
State/province [60] 0 0
Madrid
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Spain
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Malaga
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Sweden
State/province [62] 0 0
Goteborg
Country [63] 0 0
Sweden
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Lund
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United Kingdom
State/province [64] 0 0
City Of London
Country [65] 0 0
United Kingdom
State/province [65] 0 0
Glasgow City

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Eisai Inc.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This is a multicenter, randomized, double-blind study being conducted as a postmarketing
requirement to the US Food and Drug Administration (FDA) to evaluate whether there is a lower
starting dosage of lenvatinib 24 mg once daily (QD) that provides comparable efficacy but has
a better safety profile in participants with radioiodine-refractory differentiated thyroid
cancer RR-DTC with radiographic evidence of disease progression within the prior 12 months.
Trial website
https://clinicaltrials.gov/show/NCT02702388
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
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Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications