Ensayos clínicos

Inclusion Criteria:

• Age ≥ 18 years of age on the day of registration.
• Histological or cytologically confirmed diagnosis of unresectable stage III or metastatic melanoma (stage IV) not amenable to curative local therapy.
• Lack of response to therapy with a PD-1- or PD-L1-targeting monoclonal antibody (pembrolizumab, nivolumab, etc.) after at least 18 weeks of therapy OR documented progression of disease at any time after initiation of therapy with a PD-1- or PD-L1-targeting monoclonal antibody.
  • NOTE: This treatment could have been at any time prior to registration. If given in the adjuvant setting, progression must have been ≤26 weeks after the last dose of therapy.
• ECOG Performance Status (PS) 0 or 1.
• Minimum of 3 radiographically apparent lesions such that there is:
  • Minimum of one lesion in areas that have not been previously irradiated that is considered measurable by RECIST 1.1 criteria; AND
  • Minimum of two lesions in areas that have not been previously irradiated that are determined by Interventional Radiology to be of a size and in a location that a single probe could ablate at least 75% of the lesion.
    • Note: Hepatic lesions measuring ≤3cm may be treated, as determined by Interventional Radiology.
    • Note: Brain metastases are not acceptable as lesions defining measurable disease, nor are they candidate lesions for cryoablation.
• Adequate venous access for apheresis as assessed by apheresis team.
  • NOTE: If a central venous catheter is required for apheresis, the patient is not eligible.
• The following laboratory values obtained ≤ 14 days prior to registration:
  • Absolute neutrophil count (ANC) ≥ 1000/mm3;
  • Absolute lymphocyte count ≥ 500/mm3;
  • Platelet count ≥ 100,000/mm3;
  • Hemoglobin ≥ 10 g/dL;
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN), unless due to Gilbert’s disease;
  • Aspartate transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT) ≤ 2.5 x ULN;
  • Creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min for subject with creatinine ˃ 1.5 x institutional ULN.
• Negative serum pregnancy test for persons of childbearing potential ≤ 7 days prior to registration.
• Provide written informed consent.
• Willing to return to the enrolling institution for follow-up (during active treatment and active monitoring phase of the study).
• Willing to provide tissue and blood samples for research purposes.
• Willing to use adequate contraception while on the study and until 120 days after the last dose of study drug.

Exclusion Criteria:

• Choroidal  melanoma.
• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant persons;
  • Nursing persons.
• History of HIV, hepatitis B, or hepatitis C.
• Active tuberculosis or active, non-infectious pneumonitis.
• Evidence of interstitial lung disease.
• Active infection requiring the use of systemic antibiotics.
• Symptomatic congestive heart failure (New York Heart Association Classification III or IV cardiovascular disease, myocardial infarction ≤6 months prior to registration, unstable angina pectoris or cardiac arrhythmia ≤ 3 months prior to registration, or cardiac arrhythmia.
• Currently receiving or have received any other investigational agent considered as a treatment for the primary neoplasm ≤ 21 days prior to registration.
• History of other primary malignancy requiring systemic treatment ≤ 3 years prior to registration. Patients must not be receiving chemotherapy or immunotherapy for another cancer. Patients must not have another active malignancy requiring active treatment.
  • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.
• Failure to recover from prior side effects of immune checkpoint inhibitor therapy to ≤ Grade 1.
  • NOTE: Patients will not be excluded for adrenal insufficiency or hypothyroidism secondary to immunotherapy provided they are receiving hormonal replacement.
• Major surgery ≤ 4 weeks prior to registration.
• Prior chemotherapy, targeted therapy, or radiation therapy ≤ 2 weeks prior to registration or who has not recovered (i.e., to ≤ Grade 1 or baseline) from an adverse event due to the previously administered therapy.
• History of hypersensitivity and anaphylactoid reactions to pneumococcal vaccine or any component of the formulation, including diphtheria toxoid.
• Active autoimmune disease such as Crohn’s disease, rheumatoid arthritis, Sjögren’s disease, systemic lupus erythematosus, or similar conditions requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease/syndrome difficult to control in the past.
• EXCEPTIONS (the following are allowed):
  • Vitiligo or resolved childhood asthma/atopy;
  • Intermittent use of bronchodilators or local steroid injections;
  • Non-immunosuppressive maintenance treatments in the setting of clinically asymptomatic disease (e.g., sulfasalazine for ulcerative colitis);
  • Hypothyroidism stable on hormone replacement;
  • Diabetes stable with current management;
  • History of positive Coombs test but no evidence of hemolysis;
  • Psoriasis not requiring systemic treatment;
  • Conditions not expected to recur in the absence of an external trigger;
  • Secondary adrenal insufficiency from previous hypophysitis, currently on physiologic replacement steroid dosing only.
• Coagulopathy, including the use of therapeutic anticoagulants that cannot be discontinued for the cryoablation procedure.
  • NOTE: Heparin for line patency without detectable lab abnormalities for coagulation will be allowed.
• Corticosteroid use ≤ 14 days prior to registration.
  • NOTE: Patients must be off systemic corticosteroids for at least 2 weeks prior to registration. This includes oral or IV route of administration. Patients on chronic corticosteroids for adrenal insufficiency or other reasons may enroll if they receive less than 10 mg/day of prednisone (or equivalent). Patients receiving inhaled or intranasal or intra-articular steroids are not excluded.
• Active CNS metastasis.
  • NOTE: Patients with prior brain metastases that are asymptomatic without corticosteroid use and stable or improved ≥ 90 days after treatment with surgery or radiation are not excluded.
• Receipt of a live vaccine ≤ 30 days prior to registration.