Ipilimumab in Combination with Relatlimab and Nivolumab for the First Line Therapy in Patients with Stage III-IV Unresectable or Metastatic Melanoma, TRINITY Trial

Inclusion Criteria

• Age ≥ 18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Subjects must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (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 subject care. * Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
• Histologically confirmed unresectable stage III or stage IV malignant melanoma (stage IV).
• At least one measurable target lesion according to RECIST 1.1, which previously was not treated. * Growth or change in a lesion previously irradiated will not be considered measurable. Regrowth in cavity of previously excised lesion will not be considered measurable.
• Tumor tissue from an unresectable or metastatic site of disease must be available for 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 * For Phase I participants: Pretreatment tissue must be available through either an archival sample obtained within at most 6 months and submitted as an formalin-fixed paraffin-embedded (FFPE) tissue block or 30 unstained tumor tissue slides or a fresh pretreatment biopsy. Subsequent tumor biopsies will be optional. * For Phase IIa participants: Either an archival sample submitted as an FFPE tissue block or unstained tumor tissue slides or a fresh pretreatment biopsy from safely biopsiable lesion. Note that if the patient has archival tissue available from a biopsy within 90 days of cycle 1 day 1 (C1D1) and there has been no systemic treatment since that time then that tissue can be used in place of a fresh pre-treatment biopsy. Patients must also agree to undergo post treatment, cycle 2, tumor biopsies for research purposes. Subsequent biopsies will be optional.
• No prior systemic lines of treatment for metastatic melanoma. Prior adjuvant or neo-adjuvant therapy will be permitted as long as it did not contain ipilimumab and the last dose has been > 6 months.
• Prior radiation is allowed with a two week wash out period prior to initiation of treatment.
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L.
• Platelets ≥ 100 x 10^9/L (≥ 60 for hepatocellular cancer [HCC]).
• Hemoglobin ≥ 8.0 g/dL.
• Creatinine ≤ 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) ≥ 40 mL/min for participant with creatinine levels >1.5 x institutional ULN. * Creatinine clearance (CrCl) should be calculated per institutional standard.
• Total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 x ULN.
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) ≤ 3.0 x ULN (≤ 5 x ULN for participants with liver metastases).
• International normalized ratio (INR) OR or prothrombin time (PTT) activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.
• Women of child-bearing potential (WOCBP) must not be breastfeeding and must have a negative pregnancy test within 3 days prior to initiation of dosing. She must agree to use an acceptable method of birth control from the time of the negative pregnancy test, through the duration of treatment with the study combination plus 5 half-lives of study treatment for a total of 5 months post -treatment completion. WOCBP must agree to adhere to the contraceptive guidance. NOTE: A female participant is eligible to participate if she is not a woman of childbearing potential.
• All associated toxicity from previous or concurrent cancer therapy must be resolved (to ≤ grade 1 or baseline) prior to study treatment administration. This excludes low grade or non-serious toxicities. However, stable endocrinopathies requiring replacement therapy will be allowed.
• Steroids for physiological replacement are allowed as long as it does not exceed 10 mg/day prednisone equivalents.
• Participants must have known BRAF V600 mutation status or consent to BRAF V600 mutation testing per local institutional standards during the screening period. BRAF V600 results need not be available at the time of study start.
• Participants with asymptomatic brain metastases are eligible. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 10 days prior to study treatment administration. Patients with brain metastases treated with stereotactic radiosurgery (SRS) will be allowed, as long as last radiation therapy is > 1 week.

Exclusion Criteria

• Patients with ocular melanoma.
• Patients with symptomatic central nervous system (CNS) metastases and/or requiring corticosteroid treatment.
• History of known leptomeningeal involvement (lumbar puncture not required).
• Patients who experienced grade 3/4 immune-related adverse events with checkpoint inhibitor therapy, except those that are unlikely to re-occur with standard countermeasures (e.g. hypothyroidism).
• Subjects with an active, known or suspected autoimmune disease. Subjects 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.
• Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled.
• Subject has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. Note: The time requirement does not apply to participants who underwent successful treatment of superficial bladder cancer, in situ cervical cancer, or other in-situ cancers. Subjects with a completely treated prior malignancy and no evidence of disease for ≥ 2 years are eligible. * Skin Cancer Exclusion: Please note that basal cell carcinoma and squamous cell carcinoma is exempt from needing resection prior to treatment. (Resection can be completed after the start of treatment).
• History of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] ribonucleic acid (RNA) [qualitative] is detected). * NOTE: Without known history, testing needs to be performed to determine eligibility. Hepatitis C antibody (Ab) testing is allowed for screening purposes in countries where HCV RNA is not part of standard of care.
• History of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
• The use of corticosteroids is not allowed for 14 days prior to initiation of therapy (based upon 5 times the expected half-life of dexamethasone) except patients who are taking steroids for physiological replacement or in the case of Inhaled or topical steroids or other immunosuppressive medications. If alternative corticosteroid therapy has been used, consultation with the principal investigator (PI) is required to determine the washout period prior to initiating study treatment.
• Major surgical procedure, open biopsy (excluding skin cancer resection), or significant traumatic injury within 14 days of initiating study drug (unless the wound has healed) or anticipation of the need for major surgery during the study.
• Non-healing wound, ulcer, or bone fracture.
• Women who are breast-feeding or pregnant.
• Uncontrolled intercurrent illness (i.e., active infection ≥ grade 2) or concurrent condition that, in the opinion of the Investigator, would interfere with the study endpoints or the subject's ability to participate.
• History of clinically significant cardiac disease or congestive heart failure > New York Heart Association (NYHA) class 2. Subjects must not have unstable angina (anginal symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months or a history of myocarditis. Also, * Prior myocarditis of any etiology. * Left ventricular ejection fraction (LVEF) assessment with documented LVEF < 50% by either transthoracic echocardiogram (TTE) or multigated acquisition scan (TTE preferred test) within 6 months prior to the start of study treatment.
• Troponin T (TnT) or I (TnI) > 2 x institutional ULN. Participants with TnT or TnI levels between > 1 to 2 x ULN will be permitted if repeat levels within 24 hours are ≤1 ULN. If TnT or TnI levels are between > 1 to 2 x ULN within 24 hours, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. Notification of the decision to enroll the participant following cardiologist recommendation has to be made to the principal investigator.
• Investigational drug use within 14 days (or 5 half-lives, whichever is shorter) of the first dose of the triplet therapy.
• The use of herbal supplements within 7 days.
• History of non-infectious pneumonitis that required steroids or current pneumonitis.