Please select the eligibility criteria that correspond to the clinical trial below.
Title: BRF113929: An Open-Label, Two-Cohort, Multicentre Study of GSK2118436 as a Single Agent in Treatment Naïve and Previously Treated Subjects With BRAF Mutation-Positive Metastatic Melanoma to the Brain
Brief Summary: This study is designed to assess the efficacy, pharmacokinetics, safety, and tolerability of an oral, twice daily dose of 150 mg GSK2118436 administered to subjects with BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. Subjects in Cohort A will not have received any local brain therapy, and subjects in Cohort B will have received prior local therapy for brain metastases. Subjects will continue on treatment until disease progression, death, or unacceptable adverse event.


Options:
A: Inclusion Criteria:

* Histologically or cytologically confirmed diagnosis of unresectable Stage III or metastatic MEL not amenable to local therapy
* Participants must be refractory to ipilimumab
* Participants with BRAF gene mutant melanoma must have had a prior treatment regimen that included vemurafenib, dabrafenib, or an approved BRAF gene and/or mitogen-activated protein kinase (MEK) protein inhibitor
* Must consent to allow correlative studies; must provide a newly obtained tissue/biopsy specimen (or specimen obtained within 60 days of consenting)
* Radiographically measurable disease
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion Criteria:

* Chemotherapy, radiation therapy, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or not recovered from the AEs due to cancer therapies administered more than 4 weeks earlier
* Disease progression within 24 weeks of last dose of ipilimumab
* Participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study drug
* Expected to require any other form of systemic or localized antineoplastic therapy while on study
* Chronic systemic steroid therapy within 2 weeks before the planned date for first dose randomized treatment or on any other form of immunosuppressive medication
* Known history of any other than the current malignancy excepting adequately treated basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, breast cancer, or other in situ cancers
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Active autoimmune disease or a history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents
* Prior treatment with any other anti-programmed cell death (PD) agent
* Active infection requiring systemic therapy
* Known history of Human Immunodeficiency Virus (HIV)
* Active Hepatitis B or Hepatitis C
* Regular user (including recreational use of) illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol)
* Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study through 120 days after last dose of study drug
B: Inclusion Criteria:

* STEP 1 REGISTRATION (RANDOMIZATION): Patients must have clinically detectable stage III (clinically detectable N1b, N1c, N2b, N2c, N3b and N3c) or stage IV resectable melanoma. Patients with melanoma of mucosal or acral origin are eligible. Patients with melanoma of uveal origin are not eligible. Patients with a history of brain metastases are not eligible. Clinically detectable is defined as disease that is apparent and measurable via physical examination or radiographic imaging.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients are eligible for this trial either at initial presentation of their melanoma or at the time of the first detected nodal, satellite/in-transit, distant metastases, or recurrent disease in prior lymphadenectomy basin or distant site. Nodal, satellite/in-transit metastasis, distant metastases or disease in a prior complete lymphadenectomy basin must have been confirmed histologically by hematoxylin (H) \& eosin (E) stained slides.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients with multiple regional nodal basin involvement are eligible. Gross or microscopic extracapsular nodal extension is permitted.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must have histologically proven stage IIIB or higher. This would entail pathologic confirmation beyond the primary or initial diagnosis of melanoma involving fine needle aspiration cytology or biopsy confirmation of any N-category or M-category resectable site.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have received previous neoadjuvant treatment for their melanoma. Patients may have received prior non-immunotherapy adjuvant therapy. Patients must not have had prior immunotherapy including, but not limited to ipilimumab, interferon alfa-2b, high dose interleukin (IL)-2, pegylated-interferon (PEG-IFN), anti-PD-1, anti-PD-L1 intra-tumoral, or vaccine therapies. Patients must not be planning to receive any of the prohibited therapies during treatment phases on the study.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must not be planning to receive concomitant other biologic therapy, hormonal therapy, other chemotherapy, surgery, while on protocol therapy.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients may have received prior radiation therapy, including after prior surgical resection. All adverse events associated with prior surgery and radiation therapy must have resolved to =\< grade 1 prior to randomization.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must be \>= 18 years of age
* STEP 1 REGISTRATION (RANDOMIZATION): All patients must have disease status documented by a complete physical examination and imaging studies within 42 days prior to randomization. Imaging studies must include a CT of the chest, abdomen and pelvis with intravenous contrast (unless contraindicated). For patients with melanoma arising from the head and neck, dedicated neck imaging (CT with intravenous contrast is required. If the patient has unknown primary with disease in the axilla, neck imaging is required CT imaging must be done with intravenous contrast if there are no contraindications for it. Extremity melanomas must be imaged using CT with intravenous contrast or MRI with and without gadolinium

  * Note: PET-CT scans are NOT acceptable to establish eligibility. Non-iodinated CT scans that are part of common PET-CT imaging protocols do not provide contrast for difficult to ascertain areas such as the neck and liver, and do not provide enough CT detail to perform appropriate RECIST 1.1 measurements. As such, a PET-CT with non-contrast CT or non-diagnostic quality CT images is considered insufficient for the detection of melanoma.
* STEP 1 REGISTRATION (RANDOMIZATION): All patients must have a CT or magnetic resonance imaging (MRI) of the brain within 42 days prior to randomization. The brain CT or MRI should be performed with intravenous contrast (unless contraindicated).
* STEP 1 REGISTRATION (RANDOMIZATION): Absolute neutrophil count (ANC) \>= 1,500/microliter (mcL) (within 42 days prior to randomization).
* STEP 1 REGISTRATION (RANDOMIZATION): Platelets \>= 100,000/mcL (within 42 days prior to randomization).
* STEP 1 REGISTRATION (RANDOMIZATION): Hemoglobin \>= 10 g/dL (within 42 days prior to randomization).
* STEP 1 REGISTRATION (RANDOMIZATION): Total bilirubin =\< 1.5 x institutional upper limit of normal (IULN) (except patients with Gilbert's syndrome, who must have a total bilirubin \< 3.0 mg/dL) (within 42 days prior to randomization).
* STEP 1 REGISTRATION (RANDOMIZATION): Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 2 x IULN (within 42 days prior to randomization).
* STEP 1 REGISTRATION (RANDOMIZATION): Alkaline phosphatase =\< 2 x IULN (within 42 days prior to randomization).
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must have lactate dehydrogenase (LDH) performed within 42 days prior to randomization.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must have adequate renal function as evidenced by calculated creatinine clearance \> 30 mL/min. The creatinine level (mg/dL) used in the calculation must be obtained within 42 days prior to randomization.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must have Zubrod performance status =\< 2.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have an active infection requiring systemic therapy.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have received live vaccines within 42 days prior to randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed.

  * NOTE: The COVID-19 vaccines (currently available and those in the pipeline for FDA emergency use authorization or FDA approval) do not contain live virus, and therefore, COVID-19 vaccination does not affect or preclude eligibility for the S1801 trial. For patients who have undergone lymphadenectomy, vaccines should be delivered to a limb with an intact lymph node basin (Sentinel lymph node biopsy in a limb is acceptable). The vaccine should not be administered in a limb that has undergone lymphadenectomy.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients known to be human immunodeficiency virus (HIV) positive are eligible if they meet the following criteria within 30 days prior to randomization: stable and adequate CD4 counts (\>= 350 mm\^3), and serum HIV viral load of \< 25,000 IU/ml. Patients may be on or off anti-viral therapy so long as they meet the CD4 count criteria.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection prior to randomization. Note: No testing for hepatitis B and hepatitis C is required unless mandated by local health authority.
* STEP 1 REGISTRATION (RANDOMIZATION): Prior malignancy is allowed providing it does not require concurrent therapy.
* STEP 1 REGISTRATION (RANDOMIZATION): Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days prior to randomization. Women/men of reproductive potential must have agreed to use an effective contraceptive method for the course of the study through 120 days after the last dose of study medication. 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. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures. Patients must not be pregnant or nursing due to unknown teratogenic side effects.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must be deemed medically fit to undergo surgery by the treating medical/surgical team.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must be willing to submit the following surgical specimens: either all tissue blocks from the surgical specimen or two slides per block (\[1\] hematoxylin and eosin \[H\&E\] slide and \[1\] unstained slide OR \[2\] unstained slides if H\&E stained slides cannot be provided).
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must be offered the opportunity to participate in specimen banking.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must be informed of the investigational nature of this study and must sign and give written informed consent for this protocol in accordance with institutional and federal guidelines.
* STEP 1 REGISTRATION (RANDOMIZATION): As a part of the Oncology Patient Enrollment Network (OPEN) randomization process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.
* STEP 2 REGISTRATION (SURGERY): Patients randomized to arm 2 (neoadjuvant arm) must be willing to submit tissue to determine pathologic response regardless of number of pre-operative doses of pembrolizumab (MK-3475) received. Determination of pathologic response cannot be done on less than the full surgical specimen.
* STEP 2 REGISTRATION (SURGERY): Patients must have disease assessments by CT chest/abdomen/pelvis with IV contrast, and neck CT with IV contrast if primary head and neck melanoma, performed within 42 days (and no more than 49 days) before the planned date of surgery. MRI combined with non-contrast CT is an acceptable alternative for patients with CT contrast allergy, but imaging must encompass total body.
* STEP 2 REGISTRATION (SURGERY): Patients must register to step 2 within 17 days prior to planned date of surgery.
* STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients must have undergone surgery prior to Step 3 registration. The Step 2 surgery must have completely resected their melanoma.

  * Patients with gross positive residual disease following surgery do not qualify as having disease-free status, and, therefore, such patients are not eligible to register for adjuvant therapy.
  * Patients with microscopic residual disease (i.e., positive margins) can be treated with re-excision or radiation, per site discretion, to render the patient disease-free prior to registration of adjuvant therapy.
  * Disease-free status must be documented by a complete physical examination and radiographic imaging studies within 42 days prior to Step 3 registration. Imaging studies must include a CT of the chest, abdomen, and pelvis (unless contraindicated). Extremity melanomas must be imaged using CT with intravenous contrast or MRI with and without gadolinium. CT imaging must be done with intravenous contrast if there are no contraindications for it.
  * For patients with melanoma arising from the head and neck, dedicated neck imaging (CT with IV contrast, unless contraindicated) is required.
  * If the patient has had unknown primary with disease in the axilla, neck imaging is required to assure the region is clear of cancer.
  * Any other clinically indicated imaging studies if performed (e.g., bone scan) must show no evidence of disease.
* STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients must be registered to step 3 no more than 84 days after date of surgery.
* STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients with R0 or R1 resections must have disease-free status documented by a complete physical examination and imaging studies within 42 days prior to step 3 registration. These patients must have disease assessments by CT chest/abdomen/pelvis with IV contrast, and neck CT with IV contrast if primary head and neck melanoma. MRI combined with non-contrast CT is an acceptable alternative for patients with CT contrast allergy, but imaging must encompass total body.
* STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients with R2 resections are not eligible for step 3 and must be removed from study treatment
C: Inclusion Criteria:

* Cohort A:
* No prior local therapy for brain metastases.
* Subjects who are receiving concomitant corticosteroids must be on a stable or decreasing dose for at least 3 weeks prior to first dose of study treatment.
* No prophylactic or preventive anti-epileptic therapy. Exception: anti-epileptic therapy indicated in order to prevent neurologic symptoms caused by a pre-existing condition and not related to brain metastasis is allowed.
* Cohort B:
* Subjects must have received at least one local therapy for brain metastases including but not restricted to brain surgery, Whole Brain Radiotherapy or Stereotactic Radiosurgery (e.g. gamma knife, linear-accelerated-based radiosurgery, charged particles, and CyberKnife). Multiple local therapies or combinations of local therapies are allowed. For subjects receiving local therapy to all brain lesions (including WBRT), progression of pre-existing lesions based on RECIST 1.1 (\> 20% increase in longest diameter on baseline scan) or new measurable lesions are required. For subjects receiving local therapy for some but not all lesions, disease progression based on RECIST 1.1 is not required as long as there are remaining brain lesions that are measurable and not previously treated.
* Subjects who are receiving concomitant corticosteroids must be on a stable or decreasing dose for at least 2 weeks prior to first dose of study treatment.
* Prophylactic or preventive anti-epileptic therapy is allowed.
* General:
* Must sign written informed consent.
* Must be at least 18 years of age.
* Histologically confirmed metastatic melanoma (Stage IV), carrying BRAF V600E- or V600K-mutation.
* Up to two previous treatment regimens for extracranial metastatic melanoma including chemo-, cytokine-, immuno-, biological- and vaccine-therapy.
* At least one measurable intracranial target lesion for which all of the following criteria have to be met:
* previously untreated or progressive according to RECIST 1.1 (greater than or equal to 20% increase in longest diameter on baseline scan) after previous local therapy
* immediate local therapy clinically not indicated or patient is not a suitable candidate to receive immediate local therapy
* largest diameter of greater than or equal to 0.5cm but less than or equal to 4 cm as determined by contrast-enhanced MRI
* for target lesions (for definition see Section 6.1.1) with diameter of greater than 0.5 cm but less than or equal to 1 cm documented measurement by a neuroradiologist is required.
* for all lesions with diameter of greater than or equal to 3 cm but less than or equal to 4 cm documented measurement by a neuroradiologist is required.
* Time interval between last day of previous anti-tumour systemic treatment and first dose of GSK2118436:
* 14 days elapsed from last treatment with surgery, SRS or gamma knife
* 28 days elapsed from last treatment with WBRT
* Greater than or equal to 28 days or five half-lives (whichever is longer) have elapsed from last dose of approved or investigational chemo-, cytokine-, immune-, biological-, or vaccine-therapy.
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
* Adequate organ function.
* Women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study.
* Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to the first dose of study treatment.

Exclusion Criteria:

* Neurological symptoms related to brain metastasis.
* Previous treatment with a BRAF or MEK inhibitor.
* Current or expected use of a prohibited medication during treatment with GSK2118436.
* Presence of leptomeningeal disease or primary dural metastases.
* Known allergies against contrast agents required for magnetic resonance imaging (MRI) of intracranial lesions.
* Current use of therapeutic warfarin. NOTE: Low molecular weight heparin and prophylactic low-dose warfarin are permitted.
* Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI v4.0) Grade 2 or higher from previous anti-cancer therapy, except alopecia.
* Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs.
* A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection.
* Acute infection requiring intravenous antibiotics
* History of another malignancy. Exception: (a) Subjects who have been disease-free for 5 years, (b) a history of completely resected non-melanoma skin cancer, (c) successfully treated in situ carcinoma, (d) CLL in stable remission, or (e) indolent prostate cancer requiring no or only anti-hormonal therapy with histologically confirmed tumour lesions that can be clearly differentiated from melanoma target and non-target lesions are eligible.
* Certain cardiac abnormalities.
D: For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

* Men \& women ≥ 18 years of age
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
* Histologically confirmed Stage III (unresectable)/Stage IV melanoma
* Measurable disease by computed tomography (CT)/magnetic resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
* Objective evidence of disease progression (clinical or radiological) during or after at least 1 (V600 Wildtype) or at least 2 (V600 mutation positive) prior treatment regimens
* Pre-treatment fresh core, excision or punch tumor biopsy
* Archival Formalin-fixed paraffin-embedded (FFPE) tumor material if available

Exclusion Criteria:

* Any treatment in a BMS-936558 (Nivolumab) trial
* Subjects with condition requiring systemic treatment with either corticosteroids (\> 10mg daily prednisone/equivalent) or other immunosuppressive medications within 14 days of study drug administration
* Active, known or suspected autoimmune disease
* Unknown BRAF status
* Active brain metastasis or leptomeningeal metastasis
* Ocular melanoma
* Prior therapy with anti programmed death-1 (anti-PD-1), anti programmed death-ligand 1 (anti-PD-L1) or anti-programmed death-ligand 2 (anti-PD-L2)

Answer: C