Ensayos clínicos

Inclusion Criteria:

• Participants must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal patient care.
• Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
• Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 1/Lansky Performance Score ≥ 80% for minors (ages 12-17) ONLY.
• Participants must have histologically confirmed Stage III (unresectable) or Stage IV melanoma, per the AJCC staging system.
• Participants must not have had prior systemic anticancer therapy for unresectable or metastatic melanoma.
  • Note that the following prior adjuvant or neoadjuvant melanoma therapies are allowed if all related adverse events have either returned to baseline or stabilized:
    • Anti-PD-1 or anti-CTLA-4 therapy with at least 6 months between the last dose and date of recurrence;
    • Interferon therapy with the last dose at least 6 weeks prior to randomization;
    • BRAF- or MEK-inhibitor-containing regimens with at least 6 months between the last dose and date of recurrence.
• Participants must have measurable disease by CT or MRI per RECIST v1.1 criteria.
• Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. Either a recent archival sample obtained within 3 months prior to enrollment (with no intervening treatment between time of acquisition and enrollment) or a fresh pre-treatment biopsy is to be submitted as a FFPE tissue block or unstained tumor tissue sections, to the analytical laboratory for inclusion. In order to be randomized, a participant must be classified as PD-L1 positive or PD-L1 negative, as well as LAG-3 positive or LAG-3 negative. Participants with indeterminate or unevaluable PD-L1 or LAG-3 status results will not be permitted to randomize to a treatment arm. If an insufficient amount of tumor tissue from an unresectable or metastatic site is available prior to the start of the screening phase, participants must consent to allow the acquisition of additional tumor tissue during the screening period for performance of biomarker analyses.  The biopsy should be a core biopsy, a punch biopsy, an excisional biopsy, or a surgical specimen. Fine needle aspiration is unacceptable for submission. The analytical laboratory must provide IRT with the related results prior to randomization.
• Participants must have known BRAF V600 mutation status or consent to BRAF V600 mutation testing per local institutional standards during the screening period.
• Prior radiotherapy must have completed at least 2 weeks prior to study treatment administration.
• Participant Re-enrollment: This study permits the re-enrollment of a participant that has discontinued the study as a pre-treatment failure (i.e., participant has not been randomized).  If re-enrolled, the participant must re-consent.
• Male and female participants must be ≥ 12 years at the time of informed consent if local regulations and/or institutional policies allow for participants < 18 years of age (pediatric population). If pediatric population is not allowed to participate, then ≥ 18 years applies.
• WOCBP 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 study treatment.
• Women must not be pregnant or breastfeeding.
• WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study treatment(s) plus 24 weeks after the last dose of study treatment (i.e., 30 days [duration of ovulatory cycle] plus the time required for nivolumab and relatlimab to undergo approximately 5 half-lives).
• Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study treatment(s) plus 33 weeks after the last dose of the study treatment (i.e., 90 days [duration of sperm turnover] plus the time required for nivolumab and relatlimab to undergo approximately 5 half-lives). In addition, male participants must be willing to refrain from sperm donation during this time.
• WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements, and still must undergo pregnancy testing as described in this section.  Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, on the importance of pregnancy prevention and the implications of an unexpected pregnancy.  Investigators shall advise on the use of highly effective methods of contraception which have a failure rate of < 1% when used consistently and correctly.

Exclusion Criteria:

• Participants must not have active brain metastases or leptomeningeal metastases.  Participants with brain metastases are eligible if these have been treated and there is no MRI evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to first dose of study treatment administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study treatment administration.  Participants with brain disease treated with whole brain radiation are not eligible.
• Participants must not have uveal melanoma.
• Participants must not have an active, known or suspected autoimmune disease. Participants may enroll with the following conditions:
  • with type 1 diabetes mellitus;
  • hypothyroidism only requiring hormone replacement;
  • skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment;
  • conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Participants must not have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Participants must not have a history of myocarditis.
• Participants must not have any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study treatment administration, impair the ability of the participant to receive protocol therapy, or interfere with the interpretation of study results.
• Participants must not have had a prior malignancy active within the previous 3 years except for locally 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.
• Participants must not have had prior treatment with an anti-PD-1 (except if given as adjuvant or neoadjuvant therapy for melanoma), anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody (except if given as adjuvant or neoadjuvant therapy for melanoma), or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways (except for interferon given as adjuvant or neoadjuvant therapy for melanoma).
• Participants must not have a history of life-threatening toxicity related to prior immune therapy (e.g., anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (e.g., hormone replacement after adrenal crisis).
• Participants must not have had prior treatment with relatlimab or any other LAG-3 targeted agent.
• Participants must not have treatment with botanical preparations (e.g., herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to randomization/treatment. 
• Participants must not have received a live / attenuated vaccine within 30 days of first treatment (inactivated vaccines are permitted).
• The following lab criteria must be met:
  • WBC < 2000/µL;
  • Neutrophils < 1500/µL;
  • Platelets < 100*103/µL;
  • Hemoglobin < 9.0 g/dL;
  • Serum creatinine > 1.5x ULN or calculated creatinine clearance < 40 mL/min (using the Cockcroft-Gault formula):
  • Female CrCl = (140- age in years) x weight in kg x 0.85
    72 x serum creatinine in mg/dL
  • Male CrCl = (140- age in years) x weight in kg x 1.00
    72 x serum creatinine in mg/dL;
  • AST/ALT > 3.0x ULN;
  • Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have a total bilirubin level of < 3.0 x ULN);
  • Troponin T (TnT) or I (TnI) > 2 × institutional ULN. Between > 1 to 2 × ULN will be permitted if a repeat assessment remains ≤ 2 × ULN and patient undergoes a cardiac evaluation.
• Participants must not have 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).
• Participants must not have a known history of a positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
  • NOTE: Testing for HIV must be performed at sites where mandated locally.
• Participants must not have a positive pregnancy test at enrollment or prior to administration of study medication.
• Participants must not have a history of allergy or hypersensitivity to study treatment components.

Other Exclusion Criteria:

• Participants must not be prisoners or involuntarily incarcerated.
  • Note: Under certain specific circumstances, a person who has been imprisoned may be included or permitted to continue as a participant. Strict conditions apply and BMS approval is required.
• Participants must not be compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.  Eligibility criteria for this study have been carefully considered to ensure the safety of the study participants and that the results of the study can be used. It is imperative that participants fully meet all eligibility criteria.