Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized Phase II Neoadjuvant Study of Temozolomide Alone or With Pegylated Interferon-alpha 2b in Patients With Resectable American Joint Committee on Cancer (AJCC) Stage IIIB/IIIC or Stage IV (M1a) Metastatic Melanoma
Brief Summary: The goal of this clinical research study is to learn if temozolomide alone or given with pegylated interferon alpha-2b can help to control metastatic melanoma. Researchers also want to study the safety of these 2 treatments.

Objectives:

1. To determine the anti-tumor activity (pathological response CR+PR) and toxicity of temozolomide (TMZ) alone or in combination with pegylated interferon alpha-2b (PGI) in patients with resectable stage IIIC or stage IV (M1a) metastatic melanoma prior to definitive surgical resection.
2. To determine the relapse-free survival, overall survival and the impact of tumor response to chemotherapy in these patients.
3. To differentiate the in vivo treatment effects of TMZ alone vs.TMZ plus PGI and correlate with clinical outcome by analysis the pre- and post-treatment tumors and peripheral blood mononuclear cells with respect to:

1) Known cellular and molecular markers of apoptosis and cell proliferation, 2) Promotor methylation status of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), 3) DNA sequence variability of tumor suppressor genes and DNA repair enzymes, 4) Tumor genomic expression profiles analysis by complementary DNA (cDNA) microarray and protein array


Options:
A: Inclusion Criteria:

1. Histologically documented diagnosis of melanoma metastases.
2. Stage IIIB/IIIC (N2b, N2c and N3) or stage IV (M1a) melanoma patients with measurable and potentially resectable metastases without clinical and radiological evidence of other distant metastases.
3. An Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
4. Age 18 or older.
5. Adequate organ function defined as follows: a.) Absolute granulocytes greater than or equal to 1,000/mm\^3 and Platelets greater than or equal to 100,000/mm\^3, b.) Serum bilirubin and serum creatinine of less than or equal to 1.5 times upper limit of laboratory normal. If serum creatinine is greater than 1.5 times upper limit of laboratory normal, the urine creatinine clearance must be greater than 60 ml/min., c.) serum glutamate oxaloacetate transaminase (SGOT) (AST), serum glutamate pyruvate transaminase (SGPT) (ALT) and alkaline phosphatase less than or equal to 3 times upper limit of laboratory normal.
6. Patients have not had any previous systemic chemotherapy for metastatic melanoma. Prior biologic therapy, targeted therapy or immunotherapy are allowable, but must be at least 2 weeks since prior therapy before starting study drugs. No other concurrent chemotherapy, immunotherapy, or radiotherapy.
7. Prior radiation therapy used to enhance local regional control is permitted, but must be at least 2 weeks since prior therapy before starting study drugs. In addition, the patient must have unirradiated metastatic sites for response evaluation and has fully recovered from its toxicity. Lesions within the prior field of radiation may only be used as indicator lesions if there has been recent evidence of disease progression after .
8. Ability to understand and sign an informed consent form, indicating awareness of the investigational nature of this study.

Exclusion Criteria:

1. Significant cardiac or pulmonary dysfunction, such as a history of severe cardiovascular disease, myocardial infarction within 6 months of the start of treatment, unstable angina, Class III or Class IV congestive heart failure, ventricular arrhythmia, or any uncontrolled arrhythmia.
2. Current significant psychiatric illness.
3. Serious infection requiring intravenous antibiotics, or any non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by complications of this therapy.
4. Frequent vomiting or any medical condition (e.g. partial bowel obstruction) that could interfere with oral medication intake.
5. Autoimmune or immunosuppressive disorders (e.g. HIV or AIDS-related illness).
6. Patients who require therapy with systemic corticosteroids.
7. No evidence of active secondary malignancy that requires chemotherapy within the past 2 years (excluding non-melanoma skin cancer, and/or all carcinoma in-situ)
8. Pregnant or lactating women are ineligible. Women of childbearing potential must have a negative urine pregnancy test within a week of initiation of therapy. All patients must agree to use medically approved contraceptive measures to prevent pregnancy during treatment.
9. Any other medical condition or reason that, in the principal investigator's opinion, makes the patient unsuitable to participate in a clinical trial.
B: Inclusion Criteria:

* Adults at least 18 years of age
* Has advanced (unresectable Stage III) or metastatic (Stage IV) melanoma that is BRAF mutation positive (V600E)
* Is treatment naive for advanced (unresectable) or metastatic melanoma, with the exception of Interleukin 2 (IL-2) which is allowed.
* Has measurable disease according to RECIST 1.1 criteria.
* Women of child-bearing potential must have a negative pregnancy test within 14 days prior to the first dose of study treatment.
* Women with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 4 weeks after the last dose of study medication.
* Men with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 16 weeks after the last dose of study medication.
* Must have adequate organ function.
* Must have Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.

Exclusion Criteria:

* Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy or surgery).
* Evidence of active central nervous system (CNS) disease.
* Previous treatment for metastatic melanoma, including treatment with BRAF or MEK inhibitor.
* A history of other malignancy. Subjects who have been disease-free for 5 years or subjects with a history of complete resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
* History of Human Immunodeficiency Virus (HIV) infection.
* Certain cardiac abnormalities
C: Inclusion Criteria:

* adults, \>/=18 years of age
* metastatic melanoma, stage IIIC or IV (AJCC)
* treatment-naïve (no prior systemic anticancer therapy)
* positive for BRAF V600E mutation
* measurable disease by RECIST criteria
* negative pregnancy test and, for fertile men and women, effective contraception during treatment and for 6 months after completion

Exclusion Criteria:

* active central nervous system metastases
* history of carcinomatous meningitis
* severe cardiovascular disease within 6 months prior to study drug administration
* previous malignancy within 5 years prior to study, except for basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma in-situ of the cervix
D: Inclusion Criteria:

1. Signed ICF
2. Age ≥ 18 years
3. Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIC (locally advanced) melanoma, as defined by the AJCC, 7th revised edition

   1. Naïve to prior systemic anti-cancer therapy for melanoma, with the following exceptions: Adjuvant treatment with IFN, IL-2, or vaccine therapies, if discontinued at least 28 days prior to initiation of study treatment
   2. Adjuvant treatment with herbal therapies, if discontinued at least 7 days prior to initiation of study treatment
4. Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue (archival or newly obtained) through use of a clinical mutation test approved by the local health authority
5. ECOG of 0 or 1
6. Decision of eligibility for neoadjuvant combined vem+cobi+atezo treatment by in-terdisciplinary tumor board. Patient with limited numbers of metastases and few organ systems involved should be selected, making surgical resection after neo-adjuvant treatment probable.
7. Measurable disease by RECIST V1.1 criteria (must be outside the CNS)
8. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment, with the exception of amylase, lipase, and LDH where up to 28 days is acceptable

   * ANC ≥ 1.5 × 109/L without granulocyte colony-stimulating factor support
   * WBC count ≥ 2.5 × 109/L
   * Lymphocyte count ≥ 0.5 × 109/L
   * Platelet count ≥ 100 × 109/L without transfusion
   * Hemoglobin ≥ 9 g/dL without transfusion
   * Serum albumin ≥ 2.5 g/dL
   * Total bilirubin ≤ 1.5 × ULN
   * AST and ALT ≤ 2.0 x ULN
   * Amylase and lipase ≤ 1.5 x ULN
   * ALP ≤ 2.5 × ULN or, for patients with documented liver or bone metastases, ALP ≤ 5 × ULN
   * Serum creatinine ≤ 1.5 × ULN or CrCl ≥ 40mL/min on the basis of measured CrCl from a 24-hour urine collection or Crockcroft-Gault glomerular filtration rate estimation:
   * CrCL= ((140-age) x (weight in kg) x (72 x (serum creatinine in mg/dL)-1) (x 0.85 if female)
   * For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 × ULN within 28 days prior to initiation of study treatment
   * For patients receiving therapeutic anticoagulation: stable anticoagulant regi-men and stable INR during the 28 days immediately preceding initiation of study treatment
9. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:

   1. With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of \< 1% per year during the treatment period and for at least 6 months after the last dose of study treatment. Men must refrain from donating sperm during this same period.
   2. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 6 months after the last dose of study treatment to avoid exposing the embryo.
   3. The reliability of sexual abstinence should be evaluated in relation to the dura-tion of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence and withdrawal are not acceptable methods of contraception
10. For WOCBP: agreement to remain abstinent (refrain from heterosexual inter-course) or use a contraceptive method with a failure rate of \<1% per year during the treatment period and for 6 months after the last dose of study treatment

    1. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state, and has not undergone surgical sterilization
    2. Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices (IUD), and copper IUDs.
    3. Hormonal contraceptive methods must be supplemented by a barrier method. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence and withdrawal are not acceptable methods of contraception.
11. Female subjects who are lactating have to discontinue nursing prior to the first dose of study drug and must refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.

Exclusion Criteria:

1. Candidates for direct surgery: patients with single site easily resectable metasta-sis
2. Major surgical procedure or significant traumatic injury within 2 weeks prior to first dose of study drug treatment
3. Palliative radiotherapy within 14 days prior to initiation of study treatment
4. Active malignancy (other than BRAFV600 mutation-positive melanoma) or malig-nancy within 3 years prior to screening are excluded, with the exception of resected melanoma, resected BCC, resected cuSCC, resected carcinoma in situ of the cervix, resected carcinoma in situ of the breast, in situ prostate cancer, limited-stage bladder cancer, or any other curatively treated malignancies from which the patient has been disease-free for at least 3 years

   a. Patients with a history of isolated elevation in prostate-specific antigen in the absence of radiographic evidence of metastatic prostate cancer are eligible for the study.
5. A history of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, CSCR, RVO, or ne-ovascular macular degeneration

   a. Patients will be excluded from study participation if they currently are known to have any of the following risk factors for RVO: i. History of serous retinopathy ii. History of RVO iii. Evidence of ongoing serous retinopathy or RVO at baseline
6. History of clinically significant cardiac dysfunction, including the following:

   1. Poorly controlled hypertension, defined as sustained, uncontrolled, non-episodic baseline hypertension consistently above 159/99mmHg despite opti-mal medical management
   2. Unstable angina, or new-onset angina within 3 months prior to initiation of study treatment
   3. Symptomatic congestive heart failure, defined as NYHA Class II or higher
   4. Myocardial infarction within 3 months prior to initiation of study treatment
   5. Unstable arrhythmia
   6. History of congenital long QT syndrome
   7. QTcF ≥480 ms at screening, or uncorrectable abnormalities in serum electro-lytes
   8. LVEF below the institutional lower limit of normal or below 50%, whichever is lower
7. Untreated or actively progressing CNS lesions (carcinomatous meningitis)
8. Patients with a history of CNS lesions are eligible, provided that all of the following criteria are met:

   1. Measurable disease, per RECIST v1.1, must be present outside the CNS
   2. All known CNS lesions have been treated with radiotherapy or surgery
   3. CNS lesions have not been treated with whole-brain radiotherapy, except in patients who underwent definitive resection of or stereotactic therapy for all radiologically detectable parenchymal brain lesions
   4. Absence of interim progression must be confirmed by radiographic study within 4 weeks prior to initiation of study treatment. If new CNS metastases are suspected during the screening period, a confirmatory radiographic study is required prior to initiation of study treatment
   5. Any radiotherapy or surgery must be completed ≥ 4 weeks prior to initiation of study treatment
   6. There is no ongoing requirement for corticosteroids, and any prior corticosteroid treatment must be discontinued ≥ 2 weeks prior to initiation of study treatment. Treatment with an anticonvulsant at a stable dose is allowed
   7. No history of intracranial hemorrhage from CNS lesions
9. History of metastases to brain stem, midbrain, pons, or medulla, or within 10 mm of the optic apparatus
10. History of leptomeningeal metastatic disease
11. Anticipated use of any concomitant medication during or within 7 days prior to initiation of study treatment that is known to cause QT prolongation. Patients with regular amiodaron intake in the last 365 days cannot be included.
12. Uncontrolled diabetes or symptomatic hyperglycemia
13. History of malabsorption or other clinically significant metabolic dysfunction that may interfere with absorption of oral study treatment
14. Pregnancy or lactation period or intention to become pregnant during the study.

    a. WOCBP must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment
15. Prior allogeneic stem cell or solid organ transplantation
16. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan

    a. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
17. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus ery-thematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:

    a. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone may be eligible for the study after discussion with and approval by the Medical Monitor b. Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible for the study after discussion with and approval by the Medical Monitor c. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with der-matologic manifestations only are eligible for the study provided all of following conditions are met: i. Rash must cover \< 10% of body surface area ii. Disease is well controlled at baseline and requires only low-potency topical corticosteroids iii. No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral cor-ticosteroids within the previous 12 months
18. Known clinically significant liver disease, including alcoholism, cirrhosis, fatty liver, and other inherited liver disease as well as active viral disease including:

    1. Positive HIV test at screening
    2. Active HBV infection, defined as having a positive HBsAg test at screening Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total HBcAb test at screening, are eligible for the study
    3. Active HCV infection, defined as having a positive HCV antibody test and a positive HCV RNA test at screening
19. Active tuberculosis
20. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
21. Any Grade ≥ 3 hemorrhage or bleeding event within 4 weeks prior to initiation of study treatment
22. History of stroke, reversible ischemic neurological defect, or transient ischemic at-tack within 6 months prior to initiation of study treatment
23. Current severe, uncontrolled systemic disease or any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or could jeopardize the safety of the patient and their compliance in the study
24. Signs or symptoms of clinically relevant infection and/or treatment with therapeutic systemic antibiotics within 2 weeks prior to initiation of study treatment

    a. Patients receiving prophylactic antibiotics are eligible for the study
25. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study
26. Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the study

    1. Patients who have received acute, low-dose systemic immunosuppressant medication ≥ 4 weeks prior to ini-tiation of study treatment or a one-time pulse dose of systemic immunosup-pressant medication are eligible for the study.
    2. The use of inhaled corticosteroids for chronic obstructive pulmonary disease or asthma, mineralocorticoids , or low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.
27. Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells
28. Known hypersensitivity to any component of the atezo, cobi, or vem formulations
29. History of severe allergic, anaphylactic or other hypersensitivity reactions to chi-meric or humanized antibodies or fusion proteins
30. Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 4 weeks of the start of study treatment.
31. Inability or unwillingness to swallow pills
32. Any psychological, familial, sociological, or geographical conditions that may hamper compliance with the protocol and follow-up after treatment discontinuation
33. Requirement for concomitant therapy or food that is prohibited during the study, as described in Sections 10.10 and 10.11.
34. Patient is unable to comply with the study protocol for any other reason

Answer: A