A Phase 2 Trial of Lenvatinib for the Treatment of Anaplastic Thyroid Cancer (ATC)
Condition: Thyroid Carcinoma, Anaplastic
MeSH terms: Thyroid Neoplasms; Thyroid Carcinoma, Anaplastic; Carcinoma; Thyroid Diseases
Intervention: Lenvatinib 24 mg
Intervention MeSH terms: Lenvatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 34.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Lenvatinib; Thyroid Cancer, Anaplastic; Lenvima; E7080

Summary:

      The primary purpose of the study is to evaluate objective response rate ([ORR]: complete
      response [CR] and partial response [PR]) by investigator review in participants with
      anaplastic thyroid cancer (ATC) treated with lenvatinib.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Participants must have histological diagnosis consistent of Anaplastic Thyroid Cancer
             (ATC). Cytologic diagnosis by fine needle aspiration alone is not sufficient.
             Histologic diagnosis may be made by core needle biopsy, incisional biopsy,
             thyroidectomy, or other surgical biopsy. Fresh tumor biopsies (re-biopsy) should be
             obtained whenever feasible. The central pathology review may take place prior to or
             after the participant starts treatment with lenvatinib.

               1. Central review of pathology is required for study participation, but not required
                  prior to enrollment or start of treatment in order to avoid delay. If the results
                  of central pathology review are not available prior to the start of study
                  treatment, the confirmation of diagnosis of ATC at the local laboratory is
                  mandatory prior to scheduled start of treatment with lenvatinib.

               2. If central pathology review indicates a diagnosis other than ATC, the participant
                  may continue treatment with lenvatinib per standard of care, at the discretion of
                  the treating investigator. Participants deemed to have another diagnosis (not
                  ATC) will be taken off this study and replaced for the purpose of efficacy
                  analyses.

               3. Differentiated thyroid carcinoma (DTC) with focus loci of ATC is allowed. If a
                  participant has pathology showing a small focus of ATC arising out of DTC and the
                  measurable disease is not fully consistent with ATC, confirmation of ATC by
                  biopsy is required.

               4. An incidental focus of medullary thyroid cancer (MTC), DTC, and/or poorly
                  differentiated thyroid cancer in a participant with ATC is allowed.

               5. Histological diagnosis of ATC made through surgical resection is also acceptable.

          2. Prior neoadjuvant, adjuvant, or palliative chemotherapy for ATC is allowed.

          3. Measurable disease based on investigator's assessments meeting the following criteria:

               1. At least 1 lesion of ≥ 10 millimeters (mm) in the longest diameter for a
                  non-lymph node or ≥ 15 mm in the short-axis diameter for a lymph node which is
                  serially measurable according to Response Evaluation Criteria In Solid Tumors
                  (RECIST) 1.1 using computerized tomography (CT) or magnetic resonance imaging
                  (MRI).

               2. Lesions that have had external beam radiotherapy or locoregional therapies such
                  as radiofrequency ablation must show evidence of subsequent progressive disease
                  (substantial size increase of ≥ 20%) to be deemed a target lesion.

          4. 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 1 month prior to
             enrollment.

          5. All previous chemotherapy or radiation therapy-related toxicities, except dry mouth,
             dysphagia, esophagitis, mucositis, alopecia, and irreversible late sequelae of
             radiation therapy, must have resolved to Grade 0 or 1 per Common Terminology Criteria
             for Adverse Events (CTCAE v 4.03), and all wounds from prior surgery must have
             adequately recovered.

          6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

          7. Blood pressure (BP) ≤ 140/90 millimeter of mercury (mmHg) at screening with or without
             antihypertensive medications and no change in antihypertensive medications within 1
             week prior to Cycle 1/Day 1.

          8. Adequate renal function as evidenced by calculated creatinine clearance ≥ 30
             milliliter/ minute (mL/min) according to the Cockcroft and Gault formula.

          9. Adequate bone marrow function:

               1. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/liter (L) and

               2. Hemoglobin ≥ 9.0 grams/deciliter (g/dL) (can be corrected by growth factor or
                  transfusion) and

               3. Platelet count ≥ 100 x 10^9/L.

         10. Adequate blood coagulation function as evidenced by an International Normalized Ratio
             (INR) ≤ 1.5.

         11. Adequate liver function:

               1. Bilirubin ≤ 1.5 x upper limit of normal (ULN) except for unconjugated
                  hyperbilirubinemia or Gilbert's syndrome;

               2. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate
                  aminotransferase (AST) ≤ 3 x ULN (≤ 5 x ULN if participant has liver metastases).
                  If ALP is > 3 x ULN (in the absence of liver metastases) or > 5 x ULN (in the
                  presence of liver metastases) AND participants are also known to have bone
                  metastases, the liver-specific ALP must be separated from the total and used to
                  assess the liver function instead of the total ALP.

         12. Voluntary agreement to provide written informed consent and the willingness and
             ability to comply with all aspects of the protocol.

        Exclusion Criteria:

          1. Differentiated thyroid cancer (DTC) or MTC. However, ATC arising out of DTC is
             allowed, as long as the measurable disease is clinically consistent with ATC i.e.,
             rapidly progressive and/or 18F fluorodeoxyglucose (FDG)-avid.

          2. Newly diagnosed participants who are considered appropriate candidates for
             comprehensive multimodality treatment (involving surgery and/or external beam
             radiotherapy or chemo radiotherapy).

          3. Prior treatment with lenvatinib or any tyrosine kinase inhibitor (TKI) - (except for
             combination therapy of radiation and reduced dose of TKI given for the purpose of
             radiosensitization).

          4. Major surgery within 2 weeks prior to the first dose of lenvatinib.

          5. Any anti-cancer treatment within 14 days or any investigational agent within 30 days
             before the first dose of study drug.

          6. Radiotherapy within 3 weeks prior to the first dose of lenvatinib.

          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 gram/24 hours will be ineligible.

          8. Significant cardiovascular impairment: History of (a) congestive heart failure greater
             than New York Heart Association (NYHA) Class II, (b) unstable angina, (c) myocardial
             infarction, (d) stroke, or (e) cardiac arrhythmia associated with impairment within 6
             months of the first dose of study drug.

          9. A clinically significant electrocardiogram (ECG) abnormality, including a marked
             Baseline prolonged QT/QTc interval (e.g., a repeated demonstration of a QTc interval
             >500 milliseconds (msec)).

         10. Active infection requiring systemic therapy.

         11. Clinically significant hemoptysis or tumor bleeding within two weeks prior to first
             dose of lenvatinib.

         12. Radiographic evidence of major blood vessel invasion/infiltration.

         13. Other active malignancy (except definitively treated melanoma in-situ, basal or
             squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder)
             within past 24 months.

         14. Scheduled for major surgery during the study.

         15. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a
             positive beta-human chorionic gonadotropin [ß-hCG] or human chorionic gonadotropin
             [hCG] test with a minimum sensitivity of 25 international units/liter (IU/L) or
             equivalent units of ß-hCG [or 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. Females of childbearing potential who:

               1. Do not agree to use a highly effective method of contraception (ie, total
                  abstinence, [if it is their preferred and usual lifestyle], an intrauterine
                  device or intrauterine system, a contraceptive implant, an oral contraceptive, or
                  have a vasectomized partner with confirmed azoospermia) within 30 days before
                  study entry and throughout the entire study period and for 30 days after study
                  drug discontinuation.

               2. Are currently totally abstinent (as their preferred and usual lifestyle), and who
                  do not agree to be totally abstinent during the study period and for 30 days
                  after study drug discontinuation.

               3. Are using hormonal contraceptives but are not on a stable dose of the same
                  hormonal contraceptive product for at least 4 weeks before dosing and who do not
                  agree to use the same contraceptive during the study and for 30 days after study
                  drug discontinuation.

               4. Are using oral hormonal contraceptives and who do not agree to add a barrier
                  method.

             (NOTE: 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
             [i.e. bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all
             with surgery at least 1 month before dosing]).

             For sites outside of the European Union (EU), it is permissible that if a highly
             effective method of contraception is not appropriate or acceptable to the subject,
             then the subject must agree to use a medically acceptable method of contraception,
             i.e. double barrier methods of contraception such as condom plus diaphragm or
             cervical/vault cap with spermicide.

         17. Evidence of clinically significant disease (e.g., cardiovascular, respiratory,
             gastrointestinal, renal disease) that in the opinion of the investigator(s) could
             affect the participant's safety or interfere with the study assessments.

         18. Known intolerance to the study drug or any of the excipients.

         19. Any medical or other condition that in the opinion of the investigator(s) would
             preclude the participant's participation in a clinical study.