Ensayos clínicos

Inclusion Criteria

• Age ≥ 18 years
• Written informed consent must be obtained prior to any study procedures
• Has advanced cutaneous melanoma defined as unresectable stage III or metastatic stage IV disease 
  • Non-cutaneous (uveal, acral or mucosal) melanoma is excluded
• Phase II PD-1/PD-L1 refractory subset
  • Must have measurable disease according to RECIST v.1.1 criteria
  • Must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines
  • Confirmed disease progression within 1 year following initiation of PD-1/PD-L1 inhibitor therapy (must have received at least 2 doses of the PD-1/PD-L1 inhibitor)
  • No prior cytotoxic therapy in the advanced setting is permitted
  • BRAF inhibition therapy is acceptable before immunotherapy where clinically indicated
  • CTLA-4-inhibition therapy is acceptable as a prior line of therapy or in combination with anti-PD-1 therapy
• Phase II IMT naive cohort
  • Must have measurable disease according to RECIST v.1.1 criteria
  • Must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines
  • Has not received systemic cytotoxic or immune-based therapy for advanced melanoma
  • BRAF and/or MEK inhibition therapy is acceptable before immunotherapy where clinically indicated
  • Other systemic cytotoxic or targeted therapy in the advanced setting is not permitted in this subset
• Phase Ib
  • Must have evaluable disease
  • Need not have disease accessible to biopsy
  • No restriction on prior therapy
• HLA-A2 positive
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Life expectancy of at least 3 months
• Those receiving prior immunotherapy must meet all of the following conditions
  • Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy
  • All AEs while receiving prior immunotherapy must have resolved to ≤ grade 1 or baseline prior to screening for this study
  • Must not have experienced a ≥ grade 3 immune-related AE within the past 16 weeks or any grade 4 immune related AE (regardless of duration) or neurologic or ocular AE of any grade while receiving prior immunotherapy 
  • Endocrine AE of any grade permitted to enroll if stably maintained on appropriate replacement therapy, but must have no history of adrenal crisis and be asymptomatic
  • Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, and not have experienced recurrence of an AE if re-challenged
    • If currently receiving chronic corticosteroid treatment (longer than 8 weeks duration) for management of pre-existing adverse events, or has a history of chronic corticosteroid treatment longer than 8 weeks' duration for AEs within 6 months of screening is excluded

Exclusion Criteria

• Presence of untreated or symptomatic central nervous system metastases, or central nervous system metastases that currently require local therapy (such as radiotherapy or surgery), or require doses of corticosteroids within the prior 4 weeks
• History of severe hypersensitivity reactions to other mAbs
• History of treatment-related interstitial lung disease/pneumonitis
• Any out-of-range laboratory values defined as
  • Serum creatinine ≤ 1.5 x ULN and/or creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 50 mL/min
  • Total bilirubin > 1.5 x ULN
    • Except for patients with Gilbert's syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
  • Alanine aminotransferase (ALT) > 3 x ULN
  • Aspartate aminotransferase (AST) > 3 x ULN
  • Absolute neutrophil count (ANC) < 1.0 x 10^9/L
  • Absolute lymphocyte count < 0.5 x 10^9/L
  • Platelet count < 75 x 10^9/L
  • Hemoglobin (Hgb) < 8 g/dL
  • Potassium, magnesium, corrected calcium or phosphate abnormality of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) > grade 1
• Clinically significant cardiac disease or impaired cardiac function, including any of the following
  • Clinically significant and/or uncontrolled heart disease such as congestive heart failure (New York Heart Association [NYHA] grade ≥ 2), uncontrolled hypertension or clinically significant arrhythmia currently requiring medical treatment
  • QTcF >470 msec on screening ECG or congenital long QT syndrome
  • Acute myocardial infarction or unstable angina pectoris < 6 months prior to screening
• Active autoimmune disease or a documented history of autoimmune disease within 3 years before screening (or as indicated below), including the following
  • A documented history of inflammatory bowel disease (ulcerative colitis or Crohn's disease, within three years)
    • Vitiligo, alopecia, managed hypothyroidism (on stable replacement doses), psoriasis, resolved childhood asthma/atopy, well-controlled asthma and type I diabetes mellitus are NOT excluded
• Recent (< 12 months) active diverticulitis
• Active infection requiring systemic antibiotic therapy
  • Must have completed therapy before screening is initiated
• Known history of human immunodeficiency virus (HIV) infection
  • Testing for HIV status is not necessary unless clinically indicated
• Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, currently requiring medical intervention, per institutional protocol
  • Testing for HBV or HCV status is not necessary unless clinically indicated or a history of HBV or HCV infection requiring treatment with currently an unknown status
  • History of treated hepatitis is not exclusionary
• Malignant disease, other than that being treated in this study
  • Exceptions to this exclusion include 
    • Malignancies that were treated curatively and have not recurred within 2 years after completion of treatment
    • Completely resected basal cell and squamous cell skin cancers
    • Any malignancy considered to be indolent and that has never required therapy
    • Completely resected carcinoma in situ of any type
• Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results
• Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment
  • For cytotoxic agents that have major delayed toxicity and any prior immunotherapy approach, 4 weeks is indicated as washout period
• Presence of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) ≥ grade 2 toxicity (except alopecia, peripheral neuropathy and ototoxicity, which are excluded if ≥ NCI CTCAE grade 3) due to prior cancer therapy
• Chronic systemic corticosteroid use (ie, prednisone > 10 mg QD or the equivalent of longer duration than 8 weeks for any medical condition) 
• History of chronic corticosteroid use (longer than 8 weeks duration) within the past 6 months
  • Treatment for well-controlled and asymptomatic adrenal insufficiency is permitted, but replacement dosing is limited to prednisone ≤ 10 mg QD or the equivalent, and must be no history of adrenal crisis
  • Local steroid therapies (eg, otic, ophthalmic, intra-articular or inhaled medications) are acceptable
• Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment
  • Non-live vaccination (eg, influenza) are permitted anytime during treatment
• Major surgery as defined by the investigator within 2 weeks of the first dose of study treatment
  • Minimally invasive procedures such as bronchoscopy, tumor biopsy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery
• Radiotherapy within 2 weeks of the first dose of study drug 
  • Exception of palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass
• Use of hematopoietic colony-stimulating growth factors (eg, G-CSF, GMCSF, M-CSF) ≤ 2 weeks prior to start of study drug
  • Must have completed therapy at least 2 weeks before the screening period begins with any hematopoietic colony-stimulating growth factors
  • An erythroid stimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose of study treatment and patient is not red blood cell transfusion dependent
• Pregnant or lactating, defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test
• Women of child-bearing potential who are sexually active with a non-sterilized male partner defined as
  • Any female physiologically capable of becoming pregnant, unless they are using highly effective contraception from screening throughout study treatment
    • Must agree to continue using such precautions for 6 months after the final dose of investigational product
    • Cessation of birth control after this point should be discussed with a responsible physician
  • Highly effective methods of contrception include the combination of any 2 of the following methods when both are used simultaneously
    • Barrier methods of contraception, such as condom or occlusive cap (diaphragm or cervical/vault caps) when used with spermicidal foam, gel, film, cream, or use of a spermicidal vaginal suppository
    • Placement of an intrauterine device or intrauterine system
    • Use of oral, injected, or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception
    • Is post-menopausal (no menstrual period for at least 12 months prior to screening), or surgically sterile
      • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least 6 weeks before taking study treatment
      • In case of oophorectomy alone, this applies only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
    • Total abstinence from sexual relations for the duration of the treatment when applicable to the lifestyle of the patient.
    • Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Male patients not surgically sterile for at least 6 months prior to screening 
  • Or use double barrier contraception method from enrollment through treatment and for 6 months following administration of the last dose of study drug
    • For female patients on the study the vasectomized male partner should be the sole partner for that patient