Please select the eligibility criteria that correspond to the clinical trial below.
Title: Neoadjuvant Combination Biotherapy With Ipilimumab and Nivolumab or Nivolumab Alone in Patients With Locally/Regionally Advanced/Recurrent Melanoma: A Randomized Efficacy, Safety and Biomarker Study
Brief Summary: This study plans to test the pathologic complete response (pCR) rate of the combination biotherapy regimen consisting of nivolumab plus ipilimumab versus nivolumab alone in patients with advanced but operable melanoma. Evaluation of the presence of tumor-infiltrating CD8+ T cells as well as that of PDL1 expression and IDO expression will be associated with clinical response (pathologic and/or radiologic). The study will test the radiologic/clinical preoperative response rate, recurrence free survival (RFS) and overall survival (OS). It will evaluate the safety of neoadjuvant nivolumab and neoadjuvant nivolumab-ipilimumab. Up to 66 patients will be randomized in 1:1 ratio.


Options:
A: Inclusion Criteria:

* Histologically-confirmed diagnosis of unresectable Stage III or metastatic melanoma not amenable to local therapy (excluding uveal or ocular melanoma)
* At least one measurable lesion
* No prior systemic treatment (excluding adjuvant or neoadjuvant therapy) for melanoma (first line) or one prior systemic treatment (excluding adjuvant or neoadjuvant therapy) for melanoma (second line)
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
* Archived tissue sample or new biopsy sample
* Female participants of childbearing potential must agree to use effective contraception from Visit 1 to 120 days after the last dose of study drug; male participants must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug

Exclusion criteria:

* Prior treatment with ipilimumab or other anti-cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) agent or any anti-programmed cell death (PD-1 or PD-L2) agent
* Chemotherapy, radioactive, or biological cancer therapy within four weeks prior to the first dose of study drug, or not recovered from adverse events caused by cancer therapeutics administered more than four weeks earlier
* Currently 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
* On any systemic steroid therapy within one week before the planned date for first dose of randomized treatment or on any other form of immunosuppressive medication
* History of a malignancy (other than the disease under treatment in the study) within 5 years prior to first study drug administration, excluding adequately treated Stage 1 or Stage 2 basal/squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other in situ cancers.
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; participants with previously treated brain metastases are eligible
* Severe hypersensitivity reaction to treatment with another monoclonal antibody
* Active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents
* Active infection requiring systemic therapy
* Known history of Human Immunodeficiency Virus (HIV)
* Known history of or positive for Hepatitis B or C
* Known psychiatric or substance abuse disorder
* 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
* Received a live vaccine within 30 days prior to first dose of study drug
B: Inclusion Criteria:

* Men and women at least 18 years of age
* Willing and able to give written informed consent
* Performance status Eastern Cooperative Oncology Group (ECOG) zero or 1
* Histologic diagnosis of melanoma belonging to the following AJCC Tumor Node and Metastasis (TNM) stages: Tx or T1-4 and N1b or N2 or N2c or N3 and/or M0 or M1 (if considered surgically operable)
* Patients are eligible for this trial either at presentation for primary melanoma with concurrent regional nodal and/or in-transit metastasis and/or distant metastasis, or at the time of clinically detected nodal and/or in-transit recurrence and/or distant metastasis and may belong to any of the following groups: Primary melanoma with clinically apparent (overt) regional lymph node metastases.
* Clinically detected recurrence of melanoma at the proximal regional lymph node(s) basin.
* Clinically detected primary melanoma involving multiple regional nodal groups.
* Clinically detected site of nodal metastatic melanoma arising from an unknown primary.
* Patients with intransit or satellite metastases with or without lymph node involvement are allowed if they are considered surgically resectable at baseline.
* Patients with distant metastases with or without intransit or lymph node involvement are allowed if they are considered potentially surgically resectable at baseline. NOTE: All patients must be determined to be surgically resectable at baseline to be eligible for this neoadjuvant study.
* Have measurable disease based on RECIST 1.1.
* Have provided tumor tissue from a newly obtained core, punch, incisional or excisional tumor biopsy. Patients must undergo biopsy (core, punch) or open incisional/excisional biopsy (if done as part of a clinically indicated baseline diagnostic procedure) within 4 weeks of registration on the study.
* Patients must have been evaluated by standard-of-care full body imaging studies (CT, PET/CT or MRI) as part of the initial clinical work-up at baseline (no more than 4 weeks prior to study enrollment) and after completion of induction nivolumab-ipilimumab or nivolumab alone (at 6-8 weeks after the first dose of induction and prior to the definitive surgery procedure).
* Required values for initial laboratory tests:

  * White blood cell (WBC) 3000/uL
  * Absolute neutrophil count (ANC) 1500/uL
  * Platelets 100 x 103/uL
  * Hemoglobin 10 g/dL
  * Aspartate transaminase/alanine transaminase (AST/ALT) 2.5 x unique learner number (ULN)
  * Bilirubin 1.5 ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
  * Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):

Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL

• No active or chronic infection with HIV, Hepatitis B, or Hepatitis C

Exclusion Criteria:

* Subject will be excluded from participating in the trial if they meet any of the following criteria:
* Patients are excluded if they have a history of central nervous system (CNS)metastases.
* Patients who have had a history of acute diverticulitis, intra-abdominal abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation.
* Any other malignancy from which the patient has been disease-free for less than 3 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 will be excluded if they have an active, known or suspected autoimmune disease. Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded from this study, as are patients with a history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis e.g., Wegener's Granulomatosis); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome).
* Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
* Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
* Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
* As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen.
* Has an active infection requiring systemic therapy.
* Has received a live vaccine within 30 days prior to the first dose of trial treatment.
* Any underlying medical or psychiatric condition, which in the opinion of the Investigator/Sub-Investigator will make the administration of ipilimumab or nivolumab hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea.
* Patients with underlying heart conditions who are deemed ineligible for surgery by cardiology consult.
* A history of prior treatment with ipilimumab, nivolumab or other cytotoxic T-lymphocyte-associated protein (CTLA-4), progressive disease (PD1) or PD-L1 inhibitor.
* Prior treatment with interferon alfa is allowed.
* A history of prior radiotherapy, chemotherapy, including infusion or perfusion therapy for current disease or any immunotherapy including tumor vaccines, interferon-alfa, interleukins, levamisole or other biologic response modifiers within the past 4 weeks.
* Concomitant therapy with any of the following: IL 2 or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids; unless discontinued ≥ 4 weeks. A history of occasional use of steroid inhalers is allowed.
* Women of childbearing potential (WOCBP), defined above in Section 3.3, who are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 23 weeks after cessation of study drug, or have a positive pregnancy test at baseline, or are pregnant or breastfeeding.
* Melanoma of Uveal Origin
C: Inclusion Criteria:

* adult patients \>/=18 years of age
* histologically confirmed metastatic melanoma (Stage IV, AJCC)
* patients must have completed and failed at least one prior standard of care regimen (e.g. DTIC, temozolomide, etc.)
* BRAF V600E positive mutation (by Roche CoDx BRAF mutation assay)
* 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 CNS metastases on CT/MRI within 28 days prior to enrollment
* history of or known carcinomatous meningitis
* previous treatment with BRAF (sorafenib allowed) or MEK inhibitor
* cardiac dysrhythmias \>2 NCI CTCAE or treatment with drugs with dysrhythmic potential
* uncontrolled hypertension(\>150/100mmHg) despite optimal medical therapy
* infectious disease including HIV, HBV and HCV
D: Inclusion Criteria:

* ≥18 years of age
* Written informed consent.
* Histologically confirmed, resectable American Joint Committee on Cancer (AJCC, 8th edition) stage IIIB, IIIC (Tx, T0, T1-4, N1b, N2b, N3b, M0) cutaneous melanoma or unknown primary melanoma with sufficient cutaneous and/or nodal disease to enable multiple excisional or core biopsies (at baseline, week 1 and week 2). 'Resectable' tumours are defined as having no significant vascular, central nervous system or bony involvement. Only cases where a complete surgical resection with tumour-free margins can safely be achieved are defined as resectable. Patients who may not have sufficient disease to enable multiple biopsies at weeks 1 and 2 will not be excluded, however the intention of the study is that at least one biopsy at these time points is required.
* Measurable disease according to RECIST version 1.1 criteria (≥ 10mm longest diameter for non-nodal lesions and / or ≥ 15mm in shortest diameter for lymph nodes) within 4 weeks of randomisation. 'Measurable' disease may be ascertained by CT or for cutaneous and superficial lesions, by caliper measurement with digital photography. CT preferred for all lesions where possible. PET imaging will be performed, but not used for the primary purpose of measuring response.
* BRAF V600 mutation positive on immunohistochemistry or a local molecular test (e.g. Oncofocus): a. A positive V600E immunohistochemistry stain at study entry should be formally quantified with a local molecular test following study entry (e.g. Oncofocus); b. Molecular BRAF mutation status should preferentially be confirmed using tissue taken from the presenting stage III / IV disease. Alternatively, archival primary tissue is also acceptable to confirm BRAF mutation status.
* Able to swallow and retain oral medication
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
* Demonstrated adequate organ function as defined:

  1. Absolute neutrophil count (ANC) ≥1.5 109/L
  2. Platelets ≥100 109/L
  3. Haemoglobin ≥90g/L
  4. Serum creatinine OR measured or calculated creatinine clearance (CrCl) (Glomerular filtration rate \[GFR\] can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for patient with creatinine levels \> 1.5 X institutional ULN.
  5. Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 ULN.
  6. Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 2.5 X ULN OR ≤ 5 X ULN for patients with liver metastases.
  7. Albumin \>25 g/L
  8. International Normalized Ratio (INR) or Prothrombin Time (PT)
  9. Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. ≤1.5 X ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
* Anticipated life expectancy of \> 12 months.
* Women of childbearing potential: a negative serum pregnancy test within 72 hours of first dose of study treatment and effective contraception from 14 days prior to study treatment until 4 months after the last dose.
* Men with a female partner of childbearing potential to use effective contraception from 14 days prior to study treatment until 4 months after the last dose.

Exclusion Criteria:

* In transit disease
* Uveal or mucosal melanoma.
* Prior anti-cancer treatment for melanoma, except for the following:

  1. surgery for a primary melanoma or previous stage III melanoma,
  2. adjuvant radiotherapy to the primary melanoma resected site or to lymph nodes for previous Stage III disease,
  3. previous adjuvant interferon or ipilimumab for resected stage II or III melanoma, Previous adjuvant treatment with PD-1 inhibitors or BRAF/MEK inhibitors is not permitted.
* Received any investigational drug within 28 days or 5 half-lives of the planned first dose of this study treatment.
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients and / or dimethyl sulfoxide (DMSO).
* Active infection requiring systemic therapy.
* Current use of any prohibited medication as described in protocol.
* Active autoimmune disease or a documented history of autoimmune disease or a syndrome requiring systemic steroids or immunosuppressive agents. Patients with the following are permitted to enrol:

  1. vitiligo,
  2. type I diabetes mellitus,
  3. residual hypothyroidism due to an autoimmune condition only requiring, and stable on hormone replacement,
  4. psoriasis not requiring systemic treatment,
  5. resolved childhood asthma or atopy,
  6. or conditions not expected to recur in the absence of an external trigger.
* A requirement for chronic systemic steroid therapy (\> 10mg/kg per day of prednisone or equivalent) within two weeks before the planned first dose of study treatment or any on any other form of immunosuppressive treatment. Patients who require inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if the patient is on a stable dose. Non-absorbed intra-articular steroid injections will also be permitted.
* A known history of another malignancy or concurrent malignancy unless the patient is disease-free for a minimum of 1 year, is completely treated and at low-risk of recurrence. The time requirement does not apply for patients with successful definitive resection or curative treatment of:

  1. Non-melanoma skin cancer (e.g. basal cell or squamous cell carcinoma of the skin),
  2. superficial bladder cancer,
  3. in situ carcinoma of the cervix,
  4. in situ breast cancer,
  5. atypical melanocytic hyperplasia or melanoma in situ
  6. other in situ carcinomas,
  7. multiple primary melanomas, or other treated low risk tumours.
* Known HIV, hepatitis B or C virus positive status or history of active tuberculosis (testing prior to randomisation is not required).
* Administration of a live vaccine with 30 days of planned first dose of study treatment. Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed, however intranasal influenza vaccines (e.g., Fluad®) are live attenuated vaccines, and are not allowed. Any vaccine is cautionary within 30 days.
* Patients with a history or evidence of cardiovascular risk including any of the following:

  1. QT interval corrected for heart rate using the Bazett formula ≥480 msec, a diagnosis of long QT syndrome (Roman-Ward or Jervell Lange-Nielsen syndromes)
  2. Taking medications known to prolong the QT interval.
  3. Uncorrectable electrolyte abnormal abnormality (e.g. hypo- or hyperkalaemia, hypomagnesaemia, hypocalcaemia)
  4. Uncontrolled arrhythmias, with the exception of atrial fibrillation which is controlled for \> 30 days prior to randomisation.
  5. Patients with implanted cardioverter/defibrillators.
  6. Acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty or stenting within 6 months prior to randomisation.
  7. A history or current evidence of New York Heart Association (NYHA) ≥Grade 2 congestive heart failure
  8. A current left ventricular ejection fraction (LVEF) below than the lower limit of normal (LLN).
  9. Any abnormal cardiac valve morphology documented by echocardiogram which in the opinion of the investigator could interfere with the patient's safety.
  10. Treatment-refractory hypertension defined as a systolic blood pressure of \>140 mm Hg and/or a diastolic pressure of \>90 mm Hg, which cannot be controlled by anti-hypertensive treatment.
* Evidence or a risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR), including:

  1. Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes).
  2. Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR, such as evidence of new optic disc cupping.
  3. Intraocular pressure \> 21 mm Hg as measured by tonography.
  4. Evidence of new visual field defects on automated perimetry.
* History or evidence of interstitial lung disease or active non-infectious pneumonitis.
* Serious or unstable pre-existing medical conditions or other conditions that could interfere with the patient's safety, consent, or compliance.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or an agent directed to another co-inhibitory T-cell receptor (i.e. OX-40, CTLA-4).

Answer: B