Study of the Safety and Activity of Lenvatinib (E7080) in Subjects With KIF5B-RET-Positive Adenocarcinoma of the Lung
Condition: KIF5B-RET-Positive Adenocarcinoma of the Lung
MeSH terms: Adenocarcinoma; Adenocarcinoma of Lung
Intervention: Lenvatinib
Intervention description: Starting dose of 24 mg orally, once per day
Intervention MeSH terms: Lenvatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: KIF5B-RET-Positive Adenocarcinoma; Lung Cancer; NSCLC; Non-Small Cell Lung Cancer

Summary:

      This is a Phase 2, open-label, safety and activity study of lenvatinib in subjects with
      KIF5B-RET-positive adenocarcinoma of the lung and other confirmed RET translocations. At
      least 20 subjects with KIF5B-RET and other RET translocations will be treated and will
      receive lenvatinib at a starting dose of 24 mg orally, once per day. The study will consist
      of 3 phases: The Pretreatment Phase, The Treatment Phase and the Extension Phase. The
      Pretreatment Phase will include screening procedures and eligibility assessments. The
      Pretreatment Phase consists of a Screen 1, Screen 2 and Baseline Period. The Treatment Phase
      will begin when the subject has met all eligibility criteria on Day 1 of the first Treatment
      Cycle. The Treatment Phase contains the Treatment and Follow-up Periods. The Extension Phase
      will begin for subjects who received treatment in the study (either in the Treatment Period
      or Follow-up Period) at the time of database cutoff.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subjects must have a cytological or histological confirmed diagnosis of adenocarcinoma
             of the lung.

          2. Subject must be known to be RET positive (known KIF5B-RET translocation, or other
             confirmed RET translocations (e.g., CCDC6-RET)) or have an available tumor sample for
             local or central testing obtained prior to consent (Screen 1). Subjects whose samples
             need to be submitted for central laboratory testing must be current non-smokers and
             not known to have mutation in EGFR, KRAS, or ALK.

          3. Subjects may have received up to three prior systemic anticancer treatment regimens
             for adenocarcinoma of the lung (including adjuvant therapies and tyrosine-kinase
             inhibitors [TKI]), unless discussed with the sponsor.

          4. Subjects must have a clinically indicated need for systemic chemotherapy for
             adenocarcinoma of the lung based on the investigator's assessment

          5. Presence of measurable disease meeting the following criteria:

               1. At least one lesion of at least 1.0 cm in the long-axis diameter for a non-lymph
                  node or at least 1.5 cm in the short-axis diameter for a lymph node which is
                  serially measurable according to Response Evaluation Criteria in Solid Tumors 1.1
                  (RECIST 1.1) using either computerized tomography (CT) or magnetic resonance
                  imaging (MRI). If there is only one target lesion and it is a non-lymph node, it
                  should have a longest diameter of at least 1.5 cm.

               2. Lesions previously treated with radiotherapy or locoregional therapy must show
                  radiographic evidence of disease progression to be deemed a target lesion.

          6. Subjects 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 of steroids for 28 days.

          7. Adequate bone marrow function, defined as:

               1. Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10^9/L (greater
                  than or equal to 1500/mm^3)

               2. Hemoglobin (Hb) greater than or equal 8.5 g/dL

               3. Platelet count greater than or equal 75 x 10^9/L (greater than or equal
                  75,000/mm^3)

          8. Adequate liver function, defined as:

               1. Bilirubin less than or equal 1.5 x upper limit of normal (ULN) except for
                  unconjugated hyperbilirubinemia or Gilbert's syndrome

               2. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline
                  phosphatase (ALP) less than or equal 3 x ULN (less than or equal 5 x ULN if
                  subject has liver metastases). If alkaline phosphatase is greater than 3 x ULN
                  (in absence of liver metastases) or greater than 5 x ULN (in presence of liver
                  metastases) AND the subject 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.

          9. Adequate renal function, defined as calculated creatinine clearance greater than 40
             mL/min per the Cockcroft and Gault formula.

         10. Adequately controlled blood pressure (BP) with or without antihypertensive
             medications, defined as BP less than 150/90 mmHg at screening and no change in
             antihypertensive medications within 1 week before Cycle 1/Day 1 (C1D1).

         11. Eastern Cooperative Oncology Group (ECOG)-Performance Status (PS) of 0 or 1.

         12. Survival expectation of 12 weeks or longer after starting study drug.

         13. Males or females aged at least 18 years (or any age greater than 18 years as
             determined by country legislation) at the time of informed consent (Screen 1).

         14. Females must not be breast-feeding 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.

         15. 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 one month before dosing).

         16. 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 (e.g., total abstinence, an intrauterine device, a double-barrier method
             [such as condom plus diaphragm with spermicide], 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. If currently
             abstinent, the subject must agree to use a double barrier method as described above if
             she becomes sexually active during the study period or 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.

         17. Male subjects must have had a successful vasectomy (confirmed azoospermia) or they and
             their female partners must meet the criteria above (i.e., not of childbearing
             potential or practicing highly effective contraception throughout the study period and
             for 30 days after study drug discontinuation). No sperm donation is allowed during the
             study period and for 30 days after study drug discontinuation.

         18. Provide written informed consent (Screen 1 and Screen 2)

         19. Willing and able to comply with all aspects of the protocol

        Exclusion Criteria:

          1. Subjects who have received any anticancer therapy (including surgery, locoregional,
             biological, immunotherapy, hormonal, or radiotherapy) within 21 days before the first
             dose of study drug (28 days for investigational therapies).

          2. Leptomeningeal metastases or brain metastases except as for Inclusion Criterion #6.

          3. Subjects who have not recovered from toxicities as a result of prior anticancer
             therapy to less than Grade 2 severity per the National Cancer Institute Common
             Terminology Criteria for Adverse Events (CTCAE) v4.0, except alopecia and infertility.

          4. 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 at Screening.

          5. Gastrointestinal malabsorption or any other condition in the opinion of the
             investigator that might affect the absorption of lenvatinib.

          6. Active malignancy (except for adenocarcinoma of the lung or definitively treated
             melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ
             of the cervix) within the past 24months.

          7. Major surgery within 3 weeks before the first dose of study drug.

          8. Bleeding or thrombotic disorders or use of anticoagulants such as warfarin or similar
             agents requiring therapeutic international normalized ratio (INR) monitoring.
             (Treatment with low molecular weight heparin is allowed.)

          9. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks before
             the first dose of study drug.

         10. Active infection (any infection requiring treatment).

         11. Symptomatic central nervous system (CNS) disease.

         12. Subjects having greater than 1+ proteinuria on urine dipstick testing will undergo
             24-hour urine collection for quantitative assessment of proteinuria. Subjects with
             urine protein greater than or equal to 1 g/24-hour will be ineligible.

         13. Any medical or other condition that in the opinion of the investigator(s) would
             preclude the subject's participation in a clinical study or would preclude them from
             completing the study.

         14. Scheduled for surgery during the study.