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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

This study is currently recruiting participants.
Verified May 2017 by Eisai Inc.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02702388
First Posted: March 8, 2016
Last Update Posted: May 18, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Eisai Inc.
  Purpose
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.

Condition Intervention Phase
Thyroid Cancer Drug: Lenvatinib Drug: Lenvatinib matching placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official 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

Resource links provided by NLM:


Further study details as provided by Eisai Inc.:

Primary Outcome Measures:
  • Objective response rate (ORR) [ Time Frame: At 24 Weeks ]
    ORR at 24 weeks 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 24 weeks after randomization ]

Secondary Outcome Measures:
  • Progression-free survival (PFS) [ Time Frame: The time 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: 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 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 Visitor 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 on C1D1),predose on C1D8 ,predose on C1D22 (optional)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 or up to approximately 18 months. ]
  • Number of dose reductions [ Time Frame: From the date of first administration of study drug or up to approximately 18 months. ]
  • Time to first dose reduction [ Time Frame: From the date of first administration of study drug or up to approximately 18 months. ]

Estimated Enrollment: 161
Actual Study Start Date: March 28, 2016
Estimated Study Completion Date: October 30, 2020
Estimated Primary Completion Date: October 30, 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Lenvatinib
Other Names:
  • Lenvima
  • E7080
Drug: Lenvatinib matching placebo
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 18, 14, 10, 8 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.
Drug: Lenvatinib
Other Names:
  • Lenvima
  • E7080
Drug: Lenvatinib matching placebo

Detailed Description:

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 2 blinded dosages of lenvatinib in a 1:1 ratio to receive lenvatinib 18 mg, or 24mg orally once daily (QD). Dose reductions will occur in succession based on the previous dose level (24, 20, 14, 10, and 8 mg QD, or 18, 14, 10, 8, and 4 mg QD, respectively). Once the dose has been reduced, it may not be increased at a later date.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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. 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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02702388


Contacts
Contact: Eisai Medical Information 1-888-274-2378 esi_medinfo@eisai.com

  Show 86 Study Locations
Sponsors and Collaborators
Eisai Inc.
  More Information

Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT02702388     History of Changes
Other Study ID Numbers: E7080-G000-211
First Submitted: March 3, 2016
First Posted: March 8, 2016
Last Update Posted: May 18, 2017
Last Verified: May 2017

Keywords provided by Eisai Inc.:
Lenvatinib
E7080
Iodine-131 Refractory Differentiated Thyroid Cancer
Lenvima
Phase 2
RR-DTC

Additional relevant MeSH terms:
Thyroid Diseases
Thyroid Neoplasms
Endocrine System Diseases
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Head and Neck Neoplasms
Lenvatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action