Please select the eligibility criteria that correspond to the clinical trial below.
Title: Multicenter Phase 2 Study to Identify of the Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo)
Brief Summary: This is an open-label three-arm phase 2 trial (including a Simon stage 2 design) consisting of 90 stage III melanoma patients randomized 1:1:1 to receive either 2 courses 3 mg/kg ipilimumab + 1 mg/kg nivolumab every 3 weeks (Arm A), 2 courses 1 mg/kg ipilimumab + 3 mg/kg nivolumab every 3 weeks (Arm B), or 2 courses ipilimumab 3 mg/kg, directly followed by 2 courses nivolumab 3 mg/kg every 2 weeks (Arm C). All three treatment arms are applied prior to surgery at week 6, 30 patients per arm. Patients will be stratified according to treatment center. An interim analysis will be performed after 13 patients have been included in each arm, thus in total 39 patients have been included.

PRADO extension cohort The trial will enroll in total about 100-110 melanoma patients with macroscopic stage III disease (RECIST measurable disease); inclusion will stop when 50 patients have achieved a pCR or pnCR. All patients will be treated (after marker placement into the largest lymph node metastasis) with the winner combination identified in the first part of the OpACIN-neo study which is 2 courses ipilimumab 1mg/kg + nivolumab 3mg/kg, q3wks. After 6 weeks of treatment, the patients will undergo only surgical resection of the marked index lymph node. Thereafter subsequent surgery and adjuvant therapy will be performed according to the achieved pathologic response.


Options:
A: 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).
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 at least 18 years of age
* World Health Organization (WHO) Performance Status 0 or 1
* Cytologically or histologically confirmed resectable stage III melanoma with one or more macroscopic lymph node metastases (measurable according to RECIST 1.1), that can be biopsied, and no history of in-transit metastases within the last 6 months
* No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years
* Patient willing to undergo triple tumor biopsies and extra blood withdrawal during screening and in case of relapse
* No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1
* No immunosuppressive medications within 6 months prior study inclusion
* Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.5x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN
* Normal LDH
* Women of childbearing potential (WOCBP) must use appropriate method(s) of contra-ception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug
* Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of ipilimumab + nivolumab
* Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product
* Women who are not of childbearing potential (i.e., who are postmenopausal), or surgically sterile as well as azoospermic men do not require contraception
* Patient is capable of understanding and complying with the protocol requirements and has signed the Informed Consent document.

Exclusion Criteria:

* Distantly metastasized melanoma
* History of in-transit metastases within the last 6 months
* No measurable lesion according to RECIST 1.1
* Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy
* Prior CTLA-4 or PD-1/PD-L1 targeting immunotherapy
* Radiotherapy prior or post-surgery
* Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection
* Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
* Allergies and Adverse Drug Reaction

  * History of allergy to study drug components
  * History of severe hypersensitivity reaction to any monoclonal antibody
* Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events;
* Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids;
* Use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion
* Pregnant or nursing
D: Inclusion Criteria:

* Histologically confirmed diagnosis of stage IIIB, IIIC or IVM1a melanoma eligible for complete surgical resection.
* Prior systemic, regional and radiation anticancer therapies for melanoma must have been completed at least 3 months prior to randomization.
* Subject must have measurable disease and must be a candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
* Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and must have a serum lactate dehydrogenase (LDH) ≤ 1.0 X upper limit of normal and adequate hematologic, hepatic, renal, and coagulation organ function- Other criteria may apply

Exclusion Criteria:

* Subject must not have primary ocular or mucosal melanoma, or history or evidence of melanoma associated with immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia).
* Subject must not have history or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, or other symptomatic autoimmune disease.
* Subject must not have evidence of clinically significant immunosuppression or active herpetic skin lesions or prior complications of herpes simplex type 1 (HSV-1) infection (eg, herpetic keratitis or encephalitis) and must not require intermittent or chronic systemic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.
* Subject known to have acute or chronic active hepatitis B, hepatitis C, or human immunodeficiency virus infection will also be excluded.
* Subject must not have been treated previously with talimogene laherparepvec or tumor vaccine.

Other criteria may apply

Answer: C