Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase II, Randomised, Open Label Study of Neoadjuvant Dabrafenib, Trametinib and / or Pembrolizumab in BRAF V600 Mutant Resectable Stage IIIB/C Melanoma
Brief Summary: This study aims to determine which of 3 drug combinations best reduces the size of tumour prior to surgery for advanced melanoma and prevents the recurrence of melanoma after surgery.


Options:
A: Inclusion Criteria:

* Histologic diagnosis of malignant melanoma
* Stage III (unresectable) or Stage IV melanoma
* Maximum 1 line of chemotherapy for advanced disease allowed
* No prior chemotherapy within 4 weeks from treatment start (6 weeks in case of nitrosourea)
* No previous systemic corticosteroid therapy within 10 days
* Prior adjuvant treatment with IFN or other immunotherapy allowed
* Asymptomatic brain metastases allowed
* Measurable disease
* Prior treatment of brain metastases. In case stereotactic radiotherapy (or surgery) was not applicable, whole brain radiotherapy should have been performed
* Life expectancy \>= 16 weeks
* ECOG performance status of 0 or 1
* Normal laboratory tests were required
* Negative screening tests for HIV, Hepatitis B, and Hepatitis C.
* Men and women, of and over 18 years old. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the study in such a manner that the risk of pregnancy is minimized.

Exclusion Criteria:

* Any malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix;
* Primary ocular or mucosal melanoma. Medical History and Concurrent Diseases
* Symptomatic brain metastases requiring immediate local intervention (radiotherapy (RT) and/or surgery)
* Autoimmune disease
* Any underlying medical 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.

Prohibited Treatments and/or Therapies

* Concomitant therapy with any anti-cancer agent
* Immunosuppressive agents
* Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month prior to or after any dose of study drug); surgery or radiotherapy ; other investigational anti-cancer therapies; or chronic use of systemic corticosteroids ;
* Previous treatment with other investigational products, including cancer immunotherapy, within 30 days;
* Previous enrollment in another clinical trial or prior treatment with a CD137 agonist or anti-CTLA-4 and/or fotemustine.

Sex and Reproductive Status

* WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 8 weeks after the study;
* Women who are pregnant or breastfeeding;
* Women with a positive pregnancy test on enrollment or prior to investigational product administration;
* Sexually active fertile men not using effective birth control if their partners are WOCBP.

Other Exclusion Criteria

* Prisoners or subjects who are involuntarily incarcerated;
* Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.
B: 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.
C: 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).
D: 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

Answer: C