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

The purpose of this study is to assess the objective response rate of lenvatinib in previously treated participants with American Joint Committee on Cancer (AJCC) unresectable Stage III or Stage IV melanoma and disease progression.

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.

Eligibility Criteria:
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.