A Multicenter, Open-Label Phase 2 Study of the Safety and Activity of Lenvatinib (E7080) in Subjects With KIF5B-RET-Positive Adenocarcinoma of the Lung
1. Subjects must have a cytological or histological confirmed diagnosis of
adenocarcinoma of the lung.
2. Subjects must have tumors expressing the KIF5B-RET translocation as detected by gene
sequencing, or other confirmed RET translocations (e.g., CCDC6-RET).
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) ≥ 1.5 × 109/L (≥ 1500/mm3)
2. Hemoglobin (Hb) ≥ 8.5 g/dL
3. Platelet count ≥ 75 × 109/L (≥ 75,000/mm3)
8. Adequate liver function, defined as:
1. Bilirubin ≤ 1.5 × upper limit of normal (ULN) except for unconjugated
hyperbilirubinemia or Gilbert's syndrome
2. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline
phosphatase (ALP) ≤ 3 × ULN (≤ 5 × ULN if subject has liver metastases). If
alkaline phosphatase is > 3 × ULN (in absence of liver metastases) or > 5 × 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
9. Adequate renal function, defined as calculated creatinine clearance ? 40 mL/min per
the Cockcroft and Gault formula.
10. 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 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 [?-hCG] test with a
minimum sensitivity of 25 IU/L or equivalent units of ?-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
20. In Japan, only subjects who have archived tumor sample will be eligible for the
study. A fresh biopsy to obtain tumor sample for genetic screening is not permitted
for Japanese subjects.
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 < 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 > 1+ proteinuria on urine dipstick testing will undergo 24-hour urine
collection for quantitative assessment of proteinuria. Subjects with urine protein ≥
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.