This research study is studying a combination of targeted therapies as a possible treatment for advanced melanoma that was found to have a BRAF V600E or BRAF V600K genetic mutation

The interventions involved in this study are:

• LY3022855
• Vemurafenib
• Cobimetinib

This is a Phase I/II clinical trial. A Phase I clinical trial tests the safety of an investigational intervention and also tries to define the appropriate dose of the investigational intervention to use for further studies. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved LY3022855 as a treatment for any disease.

The FDA has approved vemurafenib and cobimetinib as treatment options for this disease.

LY3022855 is a colony-stimulating factor-1 receptor (CSF-1R) inhibitor. It is a human monoclonal antibody. A monoclonal antibody is a type of protein made in the laboratory that can locate and bind to substances in the body, including tumor cells. By binding to the tumor cells, the antibody might prevent the tumor cell from growing and spreading. LY3022855 is being developed as a treatment for patients with advanced cancer.

Vemurafenib and cobimetinib attack different proteins that promote the growth of cancerous cells. Vemurafenib is a BRAF inhibitor that works by blocking altered BRAF proteins from stimulating the growth of melanoma cancer cells. Cobimetinib works by blocking a protein called MEK that has been known to promote melanoma growth. In order to participate in the study, participant's disease needs to be tested positive for a mutation (a permanent change in the DNA sequence of a gene) of the BRAF gene that belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. Once the BRAF gene is mutated, the normal functioning of the BRAF protein may be changed.

In this research study, the investigators are combining LY3022855 with vemurafenib and cobimetinib in the hopes that the LY3022855 will enhance how your cancer responds to vemurafenib and cobimetinib.

Inclusion Criteria:

• For enrollment to the phase I portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective.
• For enrollment to the phase II portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) and cannot have received prior BRAF or MEK inhibitor therapy.
• Participants enrolling to the phase I portion of the trial must have evaluable or measurable disease (see Section 11 for definitions).
• Participants enrolling to the phase II portion of the trial must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease.
• Age ≥ 18 years. As no dosing or adverse event data are currently available in participants < 18 years of age, children are excluded from this study but will be eligible for future pediatric trials.
• ECOG performance status 0 - 1 (see APPENDIX A).
• Participants must have normal organ and marrow function as defined below:
• Absolute neutrophil count ≥ 1.5 K/uL
• Platelets ≥ 100 K/uL
• Hemoglobin ≥ 9 g/dL
• Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)
• AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN
• Serum creatinine ≤ 1.5 × institutional ULN
• PT-INR ≤ 1.5 × institutional ULN (for participants on anticoagulation therapy, ≤ 1.5 × their baseline value)
• aPTT ≤ 1.5 × institutional ULN (for participants on anticoagulation therapy, ≤ 1.5 × their baseline value)
• Participants must have a left ventricular ejection fraction (LVEF) ≥ 50%.
• Participants must have a QTc of ≤ 470 msec on the screening EKG.
• The effects of LY3022855 on the developing human fetus are unknown. For this reason and because anti-cancer agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of LY3022855 administration.
• Ability to understand and the willingness to sign a written informed consent document.
• Participants must have archival tumor tissue available. Participants without archival tissue may be enrolled at the discretion of the principal investigator.

Exclusion Criteria:

• Participants who have had chemotherapy, radiotherapy, biologic therapy, major surgery, or another investigational agent within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
• Participants who have not recovered to ≤ CTCAE grade 1 or baseline from toxicity as a result of previous cancer treatment prior to entering the study (with the exception of alopecia and peripheral neuropathy which can be ≤ grade 2).
• For enrollment to the phase II portion: participants who have received prior BRAF or MEK inhibitor therapy.
• Participants with known untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with a history of brain metastases that have been treated, are no longer taking corticosteroids, and have been stable on imaging for ≥ 4 weeks following the last date of treatment are permitted.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to LY3022855, vemurafenib, or cobimetinib.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because LY3022855 is an anti-cancer agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with LY3022855, breastfeeding should be discontinued if the mother is treated with LY3022855. These potential risks may also apply to the other agents used in this study.
• Participants with a known history of HIV are ineligible because of the potential for pharmacokinetic interactions with LY3022855, vemurafenib, and cobimetinib with antiretroviral agents. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
• Participants with a personal or family history of long QT syndrome.
• Participants with a history of a second primary malignancy. Exceptions include: patients with a history of malignancies that were treated curatively and have not recurred within 3 years prior to study entry; resected basal and squamous cell carcinomas of the skin, and completely resected carcinoma in situ of any type.
• Participants with impairment of GI function or GI disease that may significantly alter the absorption of vemurafenib and cobimetinib in the opinion of the treating investigator (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
• Participants who are unable to swallow or retain oral medication.
• Participants that require co-administration of strong or moderate CYP3A inhibitors, as these medications may alter vemurafenib and cobimetinib concentrations.
• Participants who require treatment with medications that are strong or moderate CYP3A inducers, as these medications may alter the concentration of cobimetinib.
• Participants with evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration.

Measured while on-treatment of 1 cycle = 28 days. Mortality observation period is median of 202 days and maximum of 480 days.

A serious adverse event (SAE) is any adverse event during this study that results in one of the following outcomes: death; hospitalization for greater than 24 hours; prolonging an existing inpatient hospitalization; a life-threatening experience (that is, immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect; considered significant by the investigator for any other reason. All others are classified as other adverse event (OAE).