The Effects of Treatment With Vemurafenib on the Immune System in Advanced Melanoma

• Status: Terminated
• Trial end date: 2015-11-01
• Target enrollment: 0
• Participant gender: All

Summary

Approximately 40-60 % of cutaneous melanomas select for a mutation in a protein called BRAF which is part of a signaling pathway called the Mitogen Activated Protein Kinase (MAPK) pathway. When BRAF is mutated the MAPK pathway remains active allowing for melanoma to grow. Vemurafenib is an oral treatment which blocks the activity of BRAF which leads to decreasing the activity of the MAPK pathway. When patients with melanoma expressing specific mutation in BRAF are treated with vemurafenib approximately 50% will develop a response to treatment with shrinkage of tumor. When compared to a standard chemotherapy called dacarbazine used to treat melanoma, treatment with vemurafenib leads to a statistically significant overall survival or living longer benefit. Because of this survival benefit vemurafenib was Food and Drug Administration (FDA) approved for the treatment of metastatic melanoma expressing a BRAF mutation called V600E BRAF. There is increasing evidence that the immune system can also be important in affecting melanoma growth and survival and there are immune treatments FDA approved for the treatment of metastatic melanoma. There is some limited evidence that blocking BRAF with vemurafenib may affect the activity of components of the immune system. It is important to better characterize and understand the effects of vemurafenib treatment on various components of the immune system. The purpose of this study is to systematically evaluate the effects of vemurafenib treatment (at FDA approved dosing regimen) on parts of the immune systems called the innate and adaptive immune systems. The hypothesis is that vemurafenib treatment will affect the immune system.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Philip Friedlander
• Collaborator: Genentech, Inc.
• Treatments: Vemurafenib

Criteria

Inclusion Criteria:

• Histologically confirmed stage IV or unresectable stage III melanoma with documented BRAF V600 mutation

• Age > 18 years

• ECOG Performance Status 0,1, or 2

• Measurable disease by RECIST v1.1

• Adequate organ function: Hemoglobin > 9 g/dl, ANC> 1.5 x 109/L, platelets > 100 x 109/L, AST and ALT < 2.5 x upper limit of normal, bilirubin < 1.5 x upper limit normal, Cr < 1.5 x upper limit normal

• Adequate recovery from prior systemic or local melanoma therapy. No systemic anticancer therapy in the 4 weeks and no ipilimumab in the 6 weeks from planned vemurafenib administration. No radiation therapy in 2 weeks prior to date plan to initiate vemurafenib treatment and no surgery in 3 weeks prior to date of planned vemurafenib administration.

• Agreement for females of childbearing potential use 2 acceptable methods contraception. Men with female partners of childbearing potential must agree to use of latex condom and advise female partner to use additional method contraception during the study and 6 months after discontinuation of vemurafenib

• Negative serum or urine pregnancy test within 7 days prior to and including the morning of day -7 (first potential day of research blood draw and tumor biopsy)

• Agreement not to donate blood or blood products or to donate sperm during the study and for at least 6 months after discontinuation of vemurafenib.

Exclusion Criteria:

• Prior vemurafenib treatment

• Use of oral or intravenous corticosteroids or other immunosuppressive medications such as cyclosporine or azathioprine. Subjects must not have received any systemic immunosuppressive drug such as corticosteroids for at least 2 weeks prior to study entry. Maintenance inhaled corticosteroids for controlled asthma or COPD or maintenance systemic steroids to correct autoimmune endocrinopathy due to prior ipilimumab treatment is allowed as is the use of topical steroids and anti-inflammatory eye drops.

• Symptomatic CNS metastases requiring steroid use.

• No active second malignancy

• Pregnant or breast feeding

• Mean QTc interval > 450 (triplicate ECGs) or history congenital prolonged QT interval

• Any of the following within 3 months prior to study drug administration: myocardial infarction, unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism

• Inability to swallow pills

• Ongoing cardiac dysrhythmia >2 (per NCI CTCAE, v4.0)

• Unwillingness to practice birth control

• Inability to comply with requirements of the protocol

• Uncontrolled medical illness such as infection requiring intravenous antibiotics.

• Known allergy to treatment medication (vemurafenib)

• Known active or chronic infection with HIV.