Clinical Trial - NCT02702388

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

Recruiting

Sponsor: Eisai Inc.

Collaborators:

Information provided by (Responsible party): Sponsor

ClinicalTrials.gov Identifier: NCT02702388

Protocol Info

Short Description: Phase 2 Lenvatinib in Thyroid Cancer
Long Description: 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
MGH Status: Open
Sponsor: Eisai Biopharmaceuticals
Disease Program: Head & Neck

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.




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 Title Intervention Phase
Thyroid Cancer Lenvatinib Lenvatinib matching placebo Phase 2
Study Type Interventional
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

Primary Outcome Measures

Objective response rate (ORR) [Time Frame: At 24 Weeks] [Designated as safety issue: ]

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] [Designated as safety issue: ]


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 up to approximately 30 months.] [Designated as safety issue: ]

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 up to approximately 30 months.] [Designated as safety issue: ]

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 up to approximately 30 months.] [Designated as safety issue: ]

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 30 months.] [Designated as safety issue: ]

Number of dose reductions [Time Frame: From the date of first administration of study drug up to approximately 30 months.] [Designated as safety issue: ]

Time to first dose reduction [Time Frame: From the date of first administration of study drug up to approximately 30 months.] [Designated as safety issue: ]

Area under the concentration-time curve (AUC) of lenvatinib derived from the final pharmacokinetic model [Time Frame: 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)] [Designated as safety issue: ]

Presence or absence of parameters/biomarkers associated with lenvatinib exposure as evaluated using a multi-parametric model [Time Frame: Baseline up to approximately 30 months] [Designated as safety issue: ]

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 30 months.] [Designated as safety issue: ]

Estimated Enrollment: 152
Study Start Date: June 2017
Estimated Study Completion Date: February 2020
Estimated Primary Completion Date: February 2020
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 matching placebo
Lenvatinib matching placebo capsule.

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.

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

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 (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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT02702388

Locations

  • United States, California
    • Facility #1 San Diego, California, United States, 92307
    • Facility #1 Torrance, California, United States, 90502
  • United States, District of Columbia
    • Facility #1 Washington, District of Columbia, United States, 20010
  • United States, Massachusetts
    • Facility #1 Boston, Massachusetts, United States, 02215
  • United States, Michigan
    • Facility #1 Ann Arbor, Michigan, United States, 48109
  • United States, New York
    • Facility #1 Bronx, New York, United States, 10461
  • United States, Ohio
    • Facility #1 Columbus, Ohio, United States, 43210
  • United States, Oregon
    • Facility #1 Portland, Oregon, United States, 97239
  • United States, Pennsylvania
    • Facility #2 Philadelphia, Pennsylvania, United States, 19104
    • Facility #1 Philadelphia, Pennsylvania, United States, 19111
  • United States, Washington
    • Facility #1 Seattle, Washington, United States, 98109
  • Australia, New South Wales
    • Facility #1 Darlinghurst, New South Wales, Australia,
    • Facility #1 Saint Leonards, New South Wales, Australia,
  • Australia, Queensland
    • Facility #1 Herston, Queensland, Australia,
  • Australia, Victoria
    • Facility #1 Melbourne, Victoria, Australia,
  • Australia, Western Australia
    • Facility #1 Nedlands, Western Australia, Australia,
  • Australia,
    • Facility #1 Melbourne, , Australia,
    • Facility #1 Saint Leonards, , Australia,
  • Austria, Karnten
    • Facility #1 Klagenfurt, Karnten, Austria, 9020
  • Austria, Oberosterreich
    • Facility #1 Linz, Oberosterreich, Austria, 4020
  • Austria,
    • Facility #1 Salzburg, , Austria, 5020
    • Facility #1 Wien, , Austria, 1090
  • Belgium, Antwerpen
    • Facility #1 Edegem, Antwerpen, Belgium, 2650
  • Belgium, Brussels
    • Facility #1 Bruxelles, Brussels, Belgium, 1200
  • Belgium,
    • Facility #2 Namur, , Belgium, 5000
    • Facility #1 Namur, , Belgium,
  • Canada, Alberta
    • Facility #2 Calgary, Alberta, Canada, T2N 4N2
    • Facility #1 Calgary, Alberta, Canada,
  • Canada, Ontario
    • Facility #1 Toronto, Ontario, Canada,
  • Canada,
    • Facility #1 Quebec, , Canada,
  • Denmark, Syddanmark
    • Facility #1 Odense, Syddanmark, Denmark, DK-5000
  • France, Bas-Rhin
    • Facility #1 Strasbourg, Bas-Rhin, France,
  • France, Calvados
    • Facility #1 Caen, Calvados, France, 14076
  • France, Cote-d'Or
    • Facility #1 Dijon, Cote-d'Or, France, 21079
  • France, Gironde
    • Facility #1 Bordeaux, Gironde, France,
  • France, Maine-et-Loire
    • Facility #1 Angers, Maine-et-Loire, France,
  • France, Val-de-Marne
    • Facility #2 Villejuif, Val-de-Marne, France, 94805
    • Facility #1 Villejuif, Val-de-Marne, France,
  • France,
    • Facility #2 Angers, , France, 49933
    • Facility #1 Bordeaux, , France, 33076
    • Facility #1 Caen, , France,
    • Facility #1 Clermont-Ferrand, , France, 63003
    • Facility #2 Clermont-Ferrand, , France, 63003
    • Facility #1 Dijon, , France, 21079
    • Facility #2 Lyon, , France, 69373
    • Facility #1 Paris, , France, 75013
    • Facility #1 Strasbourg, , France, 67000
  • Germany, Baden-Wurttemberg
    • Facility #1 Tubingen, Baden-Wurttemberg, Germany, 72076
  • Germany, Bayern
    • Facility #1 Wurzburg, Bayern, Germany, 97080
  • Germany, Niedersachsen
    • Facility #1 Hannover, Niedersachsen, Germany, 30625
  • Germany, Nordrhein-Westfalen
    • Facility #1 Essen, Nordrhein-Westfalen, Germany,
    • Facility #2 Essen, Nordrhein-Westfalen, Germany,
  • Germany, Rheinland-Pfalz
    • Facility #1 Mainz, Rheinland-Pfalz, Germany, 55131
  • Germany,
    • Facility #1 Essen, , Germany, 45147
    • Facility #2 Leipzig, , Germany, 4103
    • Facility #1 Leipzig, , Germany,
  • Israel,
    • Facility #1 Petach Tikva, , Israel,
  • Italy, Lazio
    • Facility #6 Roma, Lazio, Italy, 144
    • Facility #1 Roma, Lazio, Italy,
    • Facility #2 Roma, Lazio, Italy,
    • Facility #3 Roma, Lazio, Italy,
  • Italy, Lombardia
    • Facility #1 Milano, Lombardia, Italy, 20141
    • Facility #2 Milano, Lombardia, Italy,
    • Facility #3 Milano, Lombardia, Italy,
    • Facility #4 Milano, Lombardia, Italy,
    • Facility #5 Milano, Lombardia, Italy,
    • Facility #1 Rozzano, Lombardia, Italy, 20089
  • Italy, Piemonte
    • Facility #2 Torino, Piemonte, Italy, 10126
  • Italy, Sicilia
    • Facility #1 Catania, Sicilia, Italy, 95122
    • Facility #2 Viagrande, Sicilia, Italy, 95029
  • Italy, Toscana
    • Facility #1 Livorno, Toscana, Italy, 57100
    • Facility #1 Pisa, Toscana, Italy,
  • Italy,
    • Facility #2 Catania, , Italy,
    • Facility #6 Milano, , Italy, 20122
    • Facility #8 Milano, , Italy, 20133
    • Facility #7 Milano, , Italy, 20149
    • Facility #2 Pisa, , Italy, 56124
    • Facility #5 Roma, , Italy, 161
    • Facility #4 Roma, , Italy,
    • Facility #1 Rome, , Italy, 168
    • Facility #2 Rozzano, , Italy,
    • Facility #1 Torino, , Italy,
    • Facility #1 Viagrande, , Italy,
  • Korea, Republic of,
    • Facility #1 Goyang-si, , Korea, Republic of,
    • Facility #1 Seoul, , Korea, Republic of,
    • Facility #2 Seoul, , Korea, Republic of,
    • Facility #3 Seoul, , Korea, Republic of,
    • Facility #4 Seoul, , Korea, Republic of,
  • Poland, Slaskie
    • Facility #1 Gliwice, Slaskie, Poland, 44-101
  • Poland, Swietokrzyskie
    • Facility #1 Kielce, Swietokrzyskie, Poland, 25-734
  • Poland, Wielkopolskie
    • Facility #1 Poznan, Wielkopolskie, Poland, 60-355
  • Poland,
    • Facility #2 Kielce, , Poland,
  • Portugal, Lisboa
    • Facility #1 Lisbon, Lisboa, Portugal, 1500-650
  • Portugal,
    • Facility #1 Porto, , Portugal, 4200-072
    • Facility #2 Porto, , Portugal, 4200-319
  • Romania, Cluj
    • Facility #2 Cluj-Napoca, Cluj, Romania, 400015
    • Facility #1 Cluj-Napoca, Cluj, Romania, 400058
  • Romania,
    • Facility #1 Bucharest, , Romania, 11863
  • Russian Federation, Leningradskaya O
    • Facility #4 Saint Petersburg, Leningradskaya O, Russian Federation, 197758
  • Russian Federation,
    • Facility #3 Moscow, , Russian Federation, 115478
    • Facility #4 Moscow, , Russian Federation, 117036
    • Facility #1 Moscow, , Russian Federation,
    • Facility #2 Moscow, , Russian Federation,
    • Facility #1 Obninsk, , Russian Federation, 249036
    • Facility #3 Saint Petersburg, , Russian Federation, 197758
    • Facility #1 Saint Petersburg, , Russian Federation,
    • Facility #2 Saint Petersburg, , Russian Federation,
  • Spain, Cataluna
    • Facility #1 Barcelona, Cataluna, Spain,
  • Spain, Madrid, Communidad Delaware
    • Facility #2 Madrid, Madrid, Communidad Delaware, Spain,
  • Spain,
    • Facility #1 Badalona, , Spain, 8035
    • Facility #2 Barcelona, , Spain, 8036
    • Facility #1 Madrid, , Spain, 28034
    • Facility #4 Madrid, , Spain, 28046
    • Facility #2 Madrid, , Spain,
    • Facility #3 Madrid, , Spain,
    • Facility #1 Malaga, , Spain, 29010
  • Sweden,
    • Facility #1 Goteborg, , Sweden, SE-41345
    • Facility #1 Lund, , Sweden, SE-22185
  • United Kingdom, Aberdeen City
    • Facility #1 Aberdeen, Aberdeen City, United Kingdom, AB25 2ZN
  • United Kingdom, Cambridgeshire
    • Facility #1 Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
  • United Kingdom, City Of Bristol
    • Facility #1 Bristol, City Of Bristol, United Kingdom, BS2 8ED
  • United Kingdom, City Of London
    • Facility #1 London, City Of London, United Kingdom,
  • United Kingdom, Glasgow City
    • Facility #1 Glasgow, Glasgow City, United Kingdom,
  • United Kingdom, Surrey
    • Facility #1 Sutton, Surrey, United Kingdom, SM25PT
  • United Kingdom, York
    • Facility #1 Sheffield, York, United Kingdom, S10 2SJ
  • United Kingdom,
    • Facility #2 Glasgow, , United Kingdom, G12 0YN
    • Facility #1 Leeds, , United Kingdom, LS9 7TF
    • Facility #1 Liverpool, , United Kingdom, L14 3LB
    • Facility #2 London, , United Kingdom, SE1 9ER
    • Facility #4 London, , United Kingdom, SW36JJ
    • Facility #3 London, , United Kingdom, W2 1NY
    • Facility #1 Manchester, , United Kingdom, M20 4BX

Sponsors and Collaborators

Eisai Inc.

More Information

No publications provided

Responsible Party: Sponsor
ClinicalTrials.gov Identifier: NCT02702388
Other Study ID Numbers: 2014-005199-27
Study First Received:
Last Updated:
Health Authority:

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

Lenvatinib

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on May 30, 2019