An Open-Label, 2-Cohort, Multicenter, Study of Lenvatinib in Previously Treated Subjects With Unresectable Stage III or Stage IV Melanoma

This was a Phase 2, multicenter, open-label, 2-cohort, 2-stage study that assessed the ORR
of lenvatinib in previously treated participants with AJCC unresectable Stage III or Stage
IV melanoma and disease progression. Cohort 1 enrolled participants not harboring the V600E
BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens
(excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma, and is referred to as
Cohort 1 or V600E BRAF negative. Other less common BRAF activating mutations were allowed as
long as the participant did not receive a BRAF-targeted therapy. Cohort 2 enrolled
participants harboring the activating BRAF mutations (mainly the V600E mutation) with
disease progression following BRAF V600E-targeted therapy, and is referred to as Cohort 2 or
V600E BRAF positive. Eligible participants had measurable disease according to RECIST 1.1.

Inclusion Criteria:

1. Histologically confirmed diagnosis of melanoma.

2. Unresectable Stage III or Stage IV melanoma.

3. Evidence of disease progression according to RECIST 1.1 on prior regimen.

4. Participants with brain metastases will be eligible if they have undergone complete
surgical excision and are more then 1 month post surgery with no radiographic
evidence of disease recurrence in the brain or have undergone stereotactic radio
surgery (gamma knife procedure) and are more then 1 month post procedure and with no
radiographic evidence of disease progression in the brain; and are asymptomatic, and
discontinued corticosteroid treatment at least 30 days prior starting treatment.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. Adequately controlled blood pressure.

7. Adequate renal function, bone marrow function, blood coagulation function, and liver
function, as defined in the study protocol.

Exclusion Criteria:

1. Melanoma of intraocular origin.

2. Leptomeningeal metastases or brain metastases except as for participants with brain
metastases will be eligible if they have undergone complete surgical excision and are
more then 1 month post surgery with no radiographic evidence of disease recurrence in
the brain or have undergone stereotactic radio surgery (gamma knife procedure) and
are more then 1 month post procedure and with no radiographic evidence of disease
progression in the brain; and are asymptomatic, and discontinued corticosteroid
treatment at least 30 days prior starting treatment.

3. More than 2 prior systemic anticancer regimen treatments including immunotherapies
for unresectable Stage III or Stage IV disease (if BRAF V600E mutation negative) or
not previously treated with BRAF V600E-targeted therapy or received in the past more
than 2 prior systemic anticancer regimen treatments, including immunotherapies, in
addition to a BRAF-V600E-targeted therapy (if BRAF V600E mutation positive).

4. Significant cardiovascular impairment.

5. Bleeding disorder or a thrombotic disorder requiring anticoagulant therapy.

6. Females who are pregnant or breastfeeding.

7. Prolongation of QTc interval to greater than 480 msec.

8. 24 hour urine protein greater than or equal to 1 gm.

9. Active hemoptysis within 3 wks prior to the first dose of study drug.