Ensayos clínicos

Inclusion Criteria:

• Provide written, informed consent to participate in the study and follow the study procedures. The Investigator takes responsibility for ensuring that all vulnerable patients are protected and participate voluntarily in an environment free from coercion or undue influence.
• Male or female patients ≥ 12 years of age at the time of signing the informed consent form (ICF), except where local regulations, countries, and/or institutional policies do not allow for patients < 18 years of age (adolescents) to participate. In regions where adolescents are not allowed to participate in the study due to age restrictions, enrolled patients must be ≥ 18 years of age.
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (≥ 17 years of age)/Lansky Performance Score ≥ 80% (12 to 16 years of age, inclusive).
• Histologically confirmed Stage IIIA (LN metastasis > 1 mm [i.e., at least one LN metastasis measuring > 1 mm at greatest diameter]), IIIB/C/D, or IV (M1a/b/c/d) cutaneous melanoma by AJCC (8th edition) at study entry:
  • Patient must be completely surgically resected within 12 weeks prior to randomization;
  • Patients with in-transit or microsatellite disease will be allowed if disease has been completely surgically resected;
  • Patients must have been surgically rendered free of disease with negative surgical margins documented, as applicable.
• Prior treated central nervous system (CNS) metastases must have magnetic resonance imaging (MRI) evidence of no recurrence for at least 4 weeks after treatment, subjects must be off immunosuppressive doses of systemic steroids (> 10 mg/day or equivalent) for at least 14 days prior to study drug administration and must have returned to neurologic baseline post-operatively. (The 4-week period of stability is measured after the completion of the neurologic interventions [i.e., surgery and/or radiation]).
  • Note: Leptomeningeal disease is excluded.
• In addition to neurosurgery to treat CNS metastases, adjuvant radiation after the resection of CNS metastasis is allowed. Immunosuppressive doses of systemic steroids (doses > 10 mg/day prednisone or equivalent) must be discontinued at least 14 days before study drug administration.
• Tumor tissue available from biopsy or resected disease must be provided to central laboratory for biomarker and PD-L1 status analysis. Must have PD-L1 expression classification (≥ 1%, < 1%, indeterminate, or not evaluable) prior to randomization.
• Disease-free status documented by a complete physical examination and imaging studies within 28 days prior to randomization.
• Demonstrated adequate organ function, as defined below:
  • White blood cells ≥ 2000/μL;
  • Absolute neutrophil count ≥ 1500/μL (1.5 × 109 /L);
  • Hemoglobin ≥ 9.0 g/dL (90 g/L);
  • Platelet count ≥ 100 × 109 /L;
  • Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (except patients with Gilbert Syndrome, who must have total bilirubin < 3.0 mg/dL);
  • Alanine aminotransferase (ALT) ≤ 3 × ULN;
  • Aspartate aminotransferase (AST) ≤ 3 × ULN;
  • Serum creatinine ≤ 1.5 × ULN (133 μmol/L) OR calculated creatinine clearance ≥ 50 mL/min (using Cockcroft-Gault formula and actual body weight).
• A documented left ventricular ejection fraction (LVEF) > 45% using standard echocardiogram or multigated acquisition (MUGA) scan test.
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 14 days prior to the start of study treatment.
• Women must not be breastfeeding.
• WOCBP must agree to follow instructions for methods of contraception for the duration of treatment with study treatment and for 5 months after bempegaldesleukin and/or nivolumab treatment completion. WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements, and still must undergo pregnancy testing as described in this protocol.
• Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with bempegaldesleukin and 3 months after bempegaldesleukin treatment completion. In addition, male patients must be willing to refrain from sperm donation during this time.
• Patients must be able and willing to comply with the study visit schedule and study procedures.

Exclusion Criteria:

• Use of an investigational agent or an investigational device within 28 days before randomization.
• Female patients who are pregnant or lactating, who plan to get pregnant, or who have a positive serum or urine pregnancy test.
• History of ocular/uveal melanoma or mucosal melanoma.
• Active, known or suspected autoimmune disease. Patients with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Conditions requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 30 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Prior therapy for melanoma.
  • Exceptions include surgery for the melanoma lesion(s) and/or adjuvant radiation therapy for CNS lesions at least 28 days prior to randomization. Patients must have recovered from all Grade ≥ 2 radiation-related toxicities.
• Prior therapy with interferon, talimogene laherparepvec (Imlygic®), IL-2 directed therapy, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways).
• History of leptomeningeal disease.
• History of hypersensitivity or allergy to study drug components (for nivolumab, bempegaldesleukin, or any of their excipients).
• History of severe hypersensitivity reaction to any monoclonal antibody.
• Prior malignancy active within the previous 3 years except for locally potentially curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. Consult with the Medical Monitor about prior melanoma or other potential exceptions.
• History of allogeneic stem cell transplant; history of solid organ or tissue transplant that requires systemic use of immune suppressive agents.
• Prior surgery that required general anesthesia within 28 days before the first dose of study treatment; surgery requiring local/epidural anesthesia within 72 hours before first dose.
• Active infection requiring systemic therapy within 14 days prior to randomization.
• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on Screening chest computed tomography (CT) scan.
• Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus (e.g., hepatitis B surface antigen [HBsAg, Australia antigen] positive, or hepatitis C antibody [anti-HCV] positive [except if HCV-RNA negative]).
• Any positive test result for immunodeficiency or active human immunodeficiency virus (HIV-1/2 antibodies).
• Prolonged Fridericia’s corrected QT interval (QTcF) > 450 ms for men and > 470 ms for women at Screening.
• Unstable or deteriorating cardiovascular disease within the previous 12 months prior to Screening including, but not limited to, the following:
  • Unstable angina or myocardial infarction;
  • Congestive heart failure (New York Heart Association Class III or IV);
  • Uncontrolled clinically significant arrhythmias.
• Transient ischemic attack (TIA) or CVA within 12 months prior to Screening.
• Need for > 2 antihypertensive medications for management of hypertension (including diuretics). Patients with hypertension must be on a stable antihypertensive regimen for the 14 days prior to randomization.
  • Note: An antihypertensive medication that contains 2 drugs under one formulation is counted as 2 antihypertensive medications (e.g., angiotensin-converting-enzyme [ACE] inhibitor plus diuretic, calcium channel blocker plus ACE inhibitor).
• History of pulmonary embolism, deep vein thrombosis, or prior clinically significant venous or non-CVA/TIA arterial thromboembolic event (e.g., internal jugular vein thrombosis) within 3 months prior to randomization. Note: Patients with a history of a venous or arterial thromboembolic event must be asymptomatic for at least 2 weeks prior to randomization and must be receiving a stable regimen of therapeutic anticoagulation (preferably low molecular weight heparin [LMWH] or direct oral anticoagulation [DOAC].
  • Note: Unless there is a new medical contraindication observed after Cycle 1 Day 1, a patient with a history of venous or arterial thromboembolic event must be maintained on therapeutic anticoagulation throughout participation on the treatment phase of the study.
• Patients with inadequately treated adrenal insufficiency.
• Patients who have received a live/attenuated vaccine within 30 days of randomization.
• Known current drug or alcohol abuse.
• Receiving any medication prohibited in combination with study treatments as described in the respective product labels, unless medication was stopped within 7 days prior to randomization.
• Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of the Investigator, would preclude the patient from adhering to the protocol or would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results (e.g., a condition associated with diarrhea or acute diverticulitis).

Eligibility last updated 9/9/21.  Questions regarding updates should be directed to the study team contact.