Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00011465

Trial Description

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Title

A Multicenter, Randomized, Double-blind Phase 2 Trial of Lenvatinib (E7080) in Subjects With Iodine-131 Refractory Differentiated Thyroid Cancer (RR-DTC) to Evaluate Whether an Oral Starting Dose of 20 mg or 14 mg Daily Will Provide Comparable Efficacy to a 24 mg Starting Dose, But Have a Better Safety Profile

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

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 other than the approved 24 mg once daily (QD) that
provides comparable efficacy but has a better safety profile in participants with RR-DTC
with radiographic evidence of disease progression within the prior 12 months.

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Brief Summary in Scientific Language

This study consists of 2 phases, the Prerandomization Phase and the Randomization Phase. The
Prerandomization Phase will last no longer than 28 days and will include a Screening Period
to establish protocol eligibility and a Baseline Period to confirm eligibility and establish
disease characteristics prior to randomization and treatment.

The Randomization Phase will consist of a Treatment Period and a Follow-up Period. It will
begin at the time of randomization of the first participant and will consist of 28-day
blinded study treatment cycles. The End of Study will occur at the end of the Randomization
Phase, which is defined as when the last participant enrolled completes the Week 24 tumor
assessments or discontinues study treatment if before Week 24. Participants will be randomly
assigned to treatment with 1 of 3 blinded dosages of lenvatinib in a 1:1:1 ratio to receive
lenvatinib 24 mg, 20 mg, or 14 mg orally QD. Dose reductions will occur in succession based
on the previous dose level (24, 20, 14, 10, 8, or 4 mg QD). Once the dose has been reduced,
it may not be increased at a later date.

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Organizational Data

  •   DRKS00011465
  •   2017/05/08
  •   2016/03/03
  •   no
  •   [---]*
  •   [---]*
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Secondary IDs

  •   NCT02702388  (ClinicalTrials.gov)
  •   E7080-G000-211  (Eisai Inc.)
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Health Condition or Problem studied

  •   Thyroid Cancer
  •   C73 -  Malignant neoplasm of thyroid gland
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Interventions/Observational Groups

  •   Drug: Lenvatinib
  •   Drug: Lenvatinib matching placebo
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Characteristics

  •   Interventional
  •   [---]*
  •   Randomized controlled trial
  •   Blinded
  •   patient/subject, investigator/therapist
  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   II
  •   [---]*
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Primary Outcome

- Objective response rate (ORR) at 6 months; time frame: At Month 6; ORR at 6 months is defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR).
- Percentage of treatment-emergent adverse event(s) (TEAEs) with Common Terminology Criteria for Adverse Events (CTCAE) grades of 3 or higher; time frame: Up to 6 months after randomization

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Secondary Outcome

- Progression-free survival (PFS); time frame: From the date of randomization to the date of first documentation of disease progression or date of death, whichever occurs first, or up to approximately 18 months
- PFS after next line of treatment (PFS2); time frame: From the time of randomization to second objective disease progression, or death, or up to approximately 18 months
- Number of participants with treatment emergent adverse events (AEs) and serious adverse events (SAEs); time frame: For each participant, from the date of first administration of study drug up to 28 days from last dose of study drug or up to approximately 18 months.
- Health-Related Quality of Life (HRQoL); time frame: Baseline Day -1 (prior to first dose of study drug), every 8 weeks until Week 24, then every 16 weeks, at the Off-Treatment Visit, or up to approximately 18 months.
- Area under the concentration-time curve (AUC) of lenvatinib; time frame: Cycle 1 Day 1 (0.5-4 hour and 6-10 hour postdose), Cycle 1 Day 15 (predose, 0.5-4 hour and 6-10 hour postdose), and Cycle 2 Day 1 (predose and 2-12 hour postdose)
- Time to treatment discontinuation due to an AE; time frame: For each participant, from the date of first administration of study drug up to approximately 18 months.
- Number of dose reductions; time frame: From the date of first administration of study drug up to approximately 18 months.
- Time to first dose reduction; time frame: From the date of first administration of study drug up to approximately 18 months.

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Countries of Recruitment

  •   Australia
  •   Austria
  •   Belgium
  •   Denmark
  •   France
  •   Germany
  •   Italy
  •   Korea, Republic of
  •   Poland
  •   Portugal
  •   Romania
  •   Russian Federation
  •   Spain
  •   Sweden
  •   United Kingdom
  •   United States
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Locations of Recruitment

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Recruitment

  •   [---]*
  •   2016/03/31
  •   41
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional 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.

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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 within 3 weeks prior to randomization or elective surgery scheduled to
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 stroke within 6 months of the first dose of study drug, or cardiac
arrhythmia requiring medical treatment.

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

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

16. Females who are pregnant or breastfeeding.

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Addresses

  • start of 1:1-Block address primary-sponsor
    • Eisai Inc.
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    •   [---]*
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Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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    •   [---]*
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Status

  •   Recruiting complete, follow-up continuing
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Trial Publications, Results and other Documents

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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   1
  •   2016/12/12
* This entry means the parameter is not applicable or has not been set.