Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Pilot Study of the Neo-adjuvant Use of Vemurafenib Plus Cobimetinib (GDC-0973) in Patients With BRAF Mutant Melanoma With Palpable Lymph Node Metastases.
Brief Summary: This study will evaluate the clinical and pathological response to vemurafenib and cobimetinib in the neoadjuvant treatment of patients with histologically confirmed, BRAF V600 mutation-positive Stage IIIB and C melanoma. 20 patients will be treated with vemurafenib and cobimetinib for 2 months. Then they will be assessed for surgery. Patients will undergo surgery and subsequently resume taking vemurafenib and cobimetinib after recovery from surgery. Patients will undergo radiation therapy if appropriate then continue vemurafenib and cobimetinib. The maximum treatment period is 12 months. After 12 months of treatment, patients will be followed for disease recurrence and survival during for a total of 5 years.


Options:
A: Key Inclusion Criteria:

* Capable of given written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
* Male or female age 18 years or greater; able to swallow and retain oral medication.
* BRAF mutation positive melanoma or colorectal cancer; other BRAF mutation positive tumor types may be considered.
* Measurable disease according to RECIST version 1.1.
* Eastern Cooperative Oncology Group Performance Status of 0 or 1 for Parts A and B. Subjects with Eastern Cooperative Oncology Group Performance Status of 2 or less may be entered into Part C with approval of medical monitor.
* Agree to contraception requirements.
* Calcium phosphorus product less than 4.0mmol2/L2.
* Adequate organ system function.

Key Exclusion Criteria:

* Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy).
* Part A and Part B: Prior exposure to BRAF or MEK inhibitors unless approved by the GSK Medical Monitor.
* Part C: Prior exposure to BRAF or MEK inhibitors. Prior anti-cancer therapy in the metastatic setting, with the exception of up to one regimen of chemotherapy and/or interleukin-2 (IL-2).
* Part D: Prior exposure to BRAF inhibitors. A washout period of 6 weeks is required for ipilimumab.
* Received an investigational anti-cancer drug within 4 weeks or 5 half-lives (whichever is shorter) of study drug administration--- at least 14 days must have passed between the last dose of prior investigational anti-cancer drug and the first dose of study drug.
* Current use of a prohibited medication or requires any of these medications during treatment with study drug.
* Current use of therapeutic warfarin.
* Any major surgery, radiotherapy, or immunotherapy within the last 4 weeks. Limited radiotherapy within the last 2 weeks.
* Chemotherapy regimens with delayed toxicity within the last 4 weeks. Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last 2 weeks.
* Unresolved toxicity greater than National Cancer Institute-Common Terminology Criteria for Adverse Events version 4 Grade 1 from previous anti-cancer therapy except alopecia.
* History of retinal vein occlusion, central serous retinopathy or glaucoma.
* Predisposing factors to retinal vein occlusion including uncontrolled hypertension, uncontrolled diabetes, uncontrolled hyperlipidemia, and coagulopathy.
* Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for retinal vein occlusion or central serous retinopathy.
* Intraocular pressure greater than 21mm Hg as measured by tonography.
* Glaucoma diagnosed within one month prior to study Day 1.
* Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism or excretion of drugs.
* Known human immunodeficiency virus, Hepatitis B or Hepatitis C infection.
* Primary malignancy of the central nervous system.
* Untreated or symptomatic brain metastasis, leptomeningeal disease or spinal cord compression. Subjects who are on a stable dose of corticosteroids for more than 1 month or off corticosteroids for 2 weeks can be enrolled with approval of medical monitor. Subjects are not permitted to receive enzyme-inducing anti-epileptic drugs.
* Subjects with brain metastases are excluded, unless

  a. All known lesions must be previously treated with surgery or stereotactic radiosurgery, and- b. Brain lesion(s), if still present, must be confirmed stable (i.e. no increase in lesion size) for ≥90 days prior to first dose on study (must be documented with two consecutive MRI or CT scans using contrast), and c. Asymptomatic with no corticosteroids requirement for ≥ 30 days prior to first dose on study, and d. No enzyme-inducing anticonvulsants for ≥ 30 days prior to first dose on study.
* History of alcohol or drug abuse within 6 months prior to screening.
* Psychological, familial, sociological or geographical conditions that do not permit compliance with the protocol.
* QTc interval greater than or equal to 480msecs.
* History of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks.
* Class II, III, or IV heart failure as defined by the New York Heart Association functional classification system.
* Abnormal cardiac valve morphology (subjects with minimal abnormalities can be entered on study with approval from the medical monitor.
* Treatment refractory hypertension defined as a blood pressure of systolic\> 140 mmHg and/or diastolic \> 90 mm Hg which cannot be controlled by anti-hypertensive therapy
* Patients with intra-cardiac defibrillators or permanent pacemakers.
* Cardiac metastases
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs or excipients.
* Pregnant or lactating female.
* Unwillingness or inability to follow the procedures required in the protocol.
* Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity.
* Subjects with known glucose 6 phosphate dehydrogenase deficiency.
B: Inclusion Criteria

* In Part A: Histological or cytological diagnosis of MEL or any type of carcinoma, progressive metastatic disease, or progressive locally advanced disease not amenable to local therapy. In Parts B and D of the study, histological or cytological diagnoses of metastatic MEL with progressive locally advanced or metastatic disease. In Parts C and F, histological or cytological diagnosis of NSCLC. In Part F1, participants with Stage IV NSCLC without prior systemic therapy may be eligible.
* Failure of established standard medical anti-cancer therapies for a given tumor type or intolerance to such therapy.
* In Parts B, C, D, or F of the study, MEL or NSCLC must be measurable by imaging.
* In Part F of the study, NSCLC with PD-L1 gene expression.
* Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
* Adequate organ function.
* Female participants of childbearing potential should have a negative urine or serum pregnancy test prior to receiving study medication
* Female participants of childbearing potential must be willing to use adequate contraception from study start, through the course of the study, and for 120 days after the last dose of study medication
* Male participants of childbearing potential must agree to use adequate contraception from the first dose of study medication through 120 days after the last dose of study medication

Exclusion Criteria

* Chemotherapy, radioactive, or biological cancer therapy within 4 weeks prior to the first dose of study therapy, or not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from the adverse events caused by therapy administered more than 4 weeks prior to first dose.
* Participation in a study of an investigational agent or using an investigational device within 30 days of administration of pembrolizumab, with the exception of participants in the follow-up phase.
* Other form(s) of antineoplastic therapy anticipated during the period of the study.
* History of non-infectious pneumonitis requiring treatment with steroids, or has a history of interstitial lung disease.
* Medical condition that requires chronic systemic steroid therapy, or on any other form of immunosuppressive medication, excepting use of inhaled steroids.
* Risk factors for bowel obstruction or bowel perforation (including a history of acute diverticulitis, intra-abdominal abscess, abdominal carcinomatosis).
* History of a hematologic malignancy, malignant primary brain tumor, malignant sarcoma, or another malignant primary solid tumor, unless no evidence of that disease for 5 years.
* Active central nervous system (CNS) metastases and/or carcinomatous meningitis.
* Previous severe hypersensitivity reaction to another monoclonal antibody (mAb).
* Active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents, except vitiligo or resolved childhood asthma/atopy.
* Prior therapy with another anti-programmed cell death (PD)-1 agent or previously enrolled in any pembrolizumab trial.
* Active infection requiring therapy.
* Positive for Human Immunodeficiency Virus (HIV), Hepatitis B (Hepatitis B Surface Antigen \[HBsAg\] reactive), or Hepatitis C virus (Hepatitis C Virus Ribonucleic Acid \[HCV RNA\] (qualitative) is detected).
* Regular use of illicit drugs or a recent history (within the last year) of substance abuse (including alcohol).
* Symptomatic ascites or pleural effusion.
* Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
C: Inclusion Criteria:

1. Naïve to treatment for locally advanced unresectable disease (Stage IIIB and C). Prior adjuvant therapy (including immunotherapy, e.g., ipilimumab) is allowed if prior to nodal recurrence and ≥ 3 months have elapsed from the last day of adjuvant therapy to start of study treatment.
2. Biopsy proven unresected melanoma patients with palpable regional lymph node metastases, presenting with AJCC stage IIIB-C or with recurrent regional lymphadenopathy that are not suitable or not preferred for surgical intervention.
3. BRAF V600 mutation positive.
4. Eastern Cooperative Oncology Group performance status of 0 or 1.
5. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
6. Adequate hematologic, renal and liver function within 7 days prior to the first dose of vemurafenib and cobimetinib.
7. Agree to always use an effective form(s) of contraception beginning from the informed consent signature date until at least 6 months after completion of study therapy.
8. Negative serum pregnancy test within 14 days prior to start of treatment in women of childbearing potential only.
9. Absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Exclusion Criteria:

1. Cannot have received any prior therapy for the current recurrence or nodal disease. Previous adjuvant immunotherapy is allowed if prior to nodal recurrence and ≥ 3 months have elapsed from the last day of adjuvant therapy to start of study treatment.
2. History of prior RAF or MEK pathway inhibitor treatment.
3. Active malignancy (other than BRAF-mutated melanoma) or a previous malignancy within the past 3 years are excluded; except for patients with resected melanoma, resected basal cell carcinoma (BCC), resected cutaneous squamous cell carcinoma (SCC), resected melanoma in situ, resected carcinoma in-situ of the cervix, and resected carcinoma in-situ of the breast.
4. Evidence of distant metastatic disease.
5. History of clinically significant liver disease (including cirrhosis), current alcohol abuse, or known infection with Human Immunodeficiency Virus (HIV), hepatitis B virus, or hepatitis C virus.
6. Active infection or chronic infection requiring chronic suppressive antibiotics.
7. Pregnant or breastfeeding at the time of enrollment.
8. Active autoimmune disease (e.g., systemic lupus erythematosus, autoimmune vasculitis, inflammatory bowel disease \[Crohn's disease and ulcerative colitis\]).
9. Acromegaly
10. History of malabsorption or other clinically significant metabolic dysfunction.
11. Any other serious concomitant medical condition that would compromise safety or compromise the ability to participate in the study.
12. Requires a concomitant medication or dietary supplement that is prohibited during the study.
13. Unwillingness or inability to comply with study and follow-up procedures.
14. Current, recent (within 28 days of enrolment) or planned use of any investigational product outside of this study.
15. The following foods or supplements are prohibited at least 7 days prior to initiation of and during study treatment:

    1. St. John's wort or hyperforin
    2. Grapefruit juice
16. History of or 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.
17. Currently are known to have the following conditions:

    1. Uncontrolled glaucoma with intra-ocular pressures with \> 21 mmHg
    2. Retinal venous occlusion (RVO)
    3. Hypertensive retinopathy
18. Clinically significant cardiac dysfunction, including the following:

    1. Current unstable angina
    2. Current symptomatic congestive heart failure of New York Heart Association class 2 or higher
    3. History of congenital long QT syndrome or QTcF \> 450 msec at baseline or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, phosphorus).
    4. Current uncontrolled hypertension ≥Grade 2 (patients with a history of hypertension controlled with anti-hypertensives to ≤ Grade 1 are eligible).
    5. Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%, whichever is lower.

17. Palliative radiotherapy or major surgery within 14 days prior to first dose of study treatment.
D: Inclusion Criteria:

* All sites of disease must be evaluated within 4 weeks prior to randomization; patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)
* No more than one prior systemic therapeutic regimen for unresectable stage III or stage IV melanoma; this includes chemotherapy, biologic therapy, biochemotherapy, or investigational treatment; this does not include any therapies given in the adjuvant setting
* Histologic diagnosis of metastatic melanoma; for unknown primary disease, diagnosis of metastatic disease by cytology fine needle aspiration (FNA) is not acceptable
* Women must not be pregnant or breast-feeding due to unknown effects of ipilimumab and GM-CSF on the unborn fetus; all women of childbearing potential must have a blood test within 72 hours prior to randomization to rule out pregnancy; women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception; women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized; sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be of childbearing potential; women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential
* White blood cells (WBC) \>= 2000/uL (obtained =\< 4 weeks prior to randomization)
* Absolute neutrophil count (ANC) \>= 1500/mcL (obtained =\< 4 weeks prior to randomization)
* Platelets \>= 100,000/mcL (obtained =\< 4 weeks prior to randomization)
* Hemoglobin \>= 8 g/dL (obtained =\< 4 weeks prior to randomization)
* Creatinine =\< 3.0 x upper limit of normal (ULN) (obtained =\< 4 weeks prior to randomization)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x ULN (obtained =\< 4 weeks prior to randomization)
* Bilirubin =\< 3.0 x ULN, (except patients with Gilbert's syndrome, who must have a total bilirubin less than 3.0 mg/dL) (obtained =\< 4 weeks prior to randomization)
* No concomitant therapy with any of the following: interleukin (IL) 2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids; must have been discontinued \>= 4 weeks
* No infection with human immunodeficiency virus (HIV); due to the mechanism of action of ipilimumab and GM-CSF, activity and side effects in an immune compromised patient are unknown
* No active infection with hepatitis B
* No active or chronic infection with hepatitis C
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

Exclusion Criteria:

* Patients with any history of central nervous system (CNS) metastases are excluded
* Patients are excluded if they have a history of any other malignancy from which the patient has been disease-free for less than 2 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix
* Patients are excluded if they have a history of any autoimmune disease; patients with a history of autoimmune thyroiditis are eligible if their current thyroid disorder is treated and stable with replacement or other medical therapy
* Patients are excluded for any underlying medical or psychiatric condition, which in the opinion of the investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea
* Patients are excluded for receiving any non-oncology vaccine therapy used for prevention of infectious diseases for up to four weeks (28 days) prior to or after any dose of ipilimumab
* Patients are excluded if they have a history of prior treatment with ipilimumab or prior cluster of differentiation (CD)137 agonist or cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor or agonist
* Any concurrent medical condition requiring the use of systemic steroids is not permitted (the use of inhaled or topical steroids is permitted)

Answer: C