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

NCT01942993 | Terminated Phase 2 Results DMC

• 1 other identifier: GCO 13-0427
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Melanoma

Keywords

melanoma; unresectable; mutation; BRAF protein

Outcome Measures

Primary Outcomes (1)

• Changes in the Immune Cellular Signature in the Blood Circulation

  Immuno-fluorescence and flow cytometry will be performed on blood specimens obtained to determine changes in the immune cell signature in the blood on day 8 and day 57 after initiation of vemurafenib treatment as compared to baseline

  baseline, day 8, and day 57

Secondary Outcomes (13)

• Changes in the Immune Cellular Signature in the Tumor

  baseline, day 8-10, and day 57

• Changes in Transcriptional Profile in the Blood

  baseline, day 8, and day 57

• Change in Transcriptional Profile in Tumor

  baseline and day 8-10

• Changes in Dendritic Cell Function in Blood

  baseline day 8, and day 57

• Changes in Dendritic Cell Function in Tumor

  baseline and day 8-10

Study Arms (1)

Vemurafenib

EXPERIMENTAL

960 mg (four tablets of 240 mg each) of vemurafenib PO BID

Drug: Vemurafenib

Interventions

Vemurafenib DRUG

Vemurafenib will be administered at the FDA approved dose of 960 mg approximately 12 hours apart with or without a meal. Vemurafenib is provided at 240-mg film-coated tablets packed in bottles for oral administration. Vemurafenib should be swallowed whole with a glass of water and the medication should not be chewed or crushed. Management of symptomatic adverse events may require dose reductions, treatment interruptions, or treatment discontinuation. Dose reductions below 480 mg twice daily are not recommended.

Vemurafenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Philip Friedlander: lead
• Genentech, Inc.: collaborator

Study Sites (1)

Icahn School of Medicine at Mount Sinai

New York, New York, 11103, United States

Location

MeSH Terms

Conditions

Melanoma; Hereditary Sensory and Autonomic Neuropathies

Interventions

Vemurafenib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

Too few subjects to assess for correlation. Also no subject underwent tissue tumor biopsy which were not mandatory.

Results Point of Contact

• Title: Dr. Philip A Friedlander
• Organization: Icahn School of Medicine at Mount Sinai

philip.friedlander@mssm.edu

212-824-8584

Study Officials

• Philip Friedlander, MD, PhD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: September 11, 2013
• First Posted: September 16, 2013
• Study Start: September 1, 2013
• Primary Completion: November 1, 2015
• Study Completion: November 1, 2015
• Last Updated: September 30, 2020
• Results First Posted: September 30, 2020

Record last verified: 2020-09

Locations

US (1)