A Study of Fianlimab, Cemiplimab, and Ipilimumab in People With Melanoma

Inclusion Criteria:

• Age ≥ 18 years at the time of informed consent

• Patient/legal authorized representative (LAR) must be able to provide informedconsent.

• Patient must have a histologically confirmed diagnosis of locally advancedunresectable stage III/IV or metastatic stage IV cutaneous or mucosal melanoma thathas progressed on PD-1/PD-L1 therapy: o For Cohort A, the patient's melanoma must have progressed on prior PD-1monotherapy

• For Cohort B, the patient's melanoma must have progressed on prior combinationPD-1 + LAG-3 blockade

• Note: Intervening lines of targeted therapy, chemotherapy, bispecific (e.g.IMCgp100) and cell-based therapies are permitted between last ICI-based therapyand the start of study therapy

• Note: For cohort A, peptide and mRNA vaccines may have been combined with PD-1monotherapy as long as no other checkpoint inhibitors were concomitantlyadministered. For cohort B, peptide and mRNA vaccines may have been combinedwith combined PD-1 + LAG-3 blockade as long as no other checkpoint inhibitorswere concomitantly administered Note: Prior PD-1 monotherapy (Cohort A) or PD-1and LAG-3 blockade (Cohort B) may have been given in the neoadjuvant oradjuvant setting as long as progression is documented within 3 months of thefinal dose neoadjuvant/adjuvant therapy

• Patients must have measurable disease as defined by RECIST v1.1 o Note: Lesionspreviously injected with Talimogene laherparepvec or other local therapies may notbe selected as target lesions unless they have demonstrated subsequent growth afterinjection

• If a suitable archival tissue sample is available, the patient must be willing tohave this specimen submitted for research. If an archival sample is not available,the patient is still a candidate for the trial, and every reasonable effort will bemade to obtain a biopsy if deemed safe

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

° Adequate laboratory function at screening, defined as:

° Hemoglobin ≥ 10 gm/dL (≥ 6.2 mmol/L)

° Platelet count ≥ 100 × 10^9 /L

°Serum direct bilirubin ≤ 1.5 × ULN; AST and ALT ≤ 2.5 × ULN. (Total bilirubin < 3mg/dL for subjects with Gilbert's disease)

• No signs of active coronary ischemia, including ECG changes or elevated troponin ifclinically indicated

• Calculated creatinine clearance (CrCl) ≥30 mL/min based on the Cockcroft-Gaultequation

• All immune-related adverse events (irAE's) from prior ICI based therapy must haveimproved to Grade 1 or lower

• All women of childbearing potential (WOCBP)* or sexually active men must practicehighly effective contraception prior to the initial dose/start of the firsttreatment, during the study, and for at least 6 months after the last dose. Highlyeffective contraceptive measures in women include o Stable use of combined (estrogen and progestogen containing) hormonalcontraception (oral, intravaginal, transdermal) or progestogen-only hormonalcontraception (oral, injectable, implantable) associated with inhibition ofovulation initiated 2 or more menstrual cycles prior to screening,

• Intrauterine device (IUD),

• Intrauterine hormone-releasing system (IUS),

• Bilateral tubal ligation,

• Vasectomized partner,† and/or

• Sexual abstinence.‡,§

• Male study participants with WOCBP partners are required to use condoms unless theyare vasectomized† or practice sexual abstinence.‡,§

• • WOCBP are defined as women who are fertile following menarche until becomingpostmenopausal, unless permanently sterile. A postmenopausal state is defined as nomenses for 12 months without an alternative medical cause. A high folliclestimulating hormone (FSH) level in the postmenopausal range may be used to confirm apostmenopausal state in women not using hormonal contraception or hormonalreplacement therapy. However, in the absence of 12 months of amenorrhea, a singleFSH measurement is insufficient to determine the occurrence of a postmenopausalstate. The above definitions are according to Clinical Trial Facilitation Group (CTFG) guidance. Pregnancy testing and contraception are not required for women withdocumented hysterectomy or tubal ligation. Permanent sterilization methods includehysterectomy, bilateral salpingectomy, and bilateral oophorectomy.

• Vasectomized partner or vasectomized study participant must have receivedmedical assessment of the surgical success.

• Sexual abstinence is considered a highly effective method only if definedas refraining from heterosexual intercourse during the entire period ofrisk associated with the study drugs. The reliability of sexual abstinenceneeds to be evaluated in relation to the duration of the clinical trialand the preferred and usual lifestyle of the patient.

• Periodic abstinence (calendar, symptothermal, post-ovulationmethods), withdrawal (coitus interruptus), spermicides only, andlactational amenorrhea method (LAM) are not acceptable methods ofcontraception. Female condom and male condom should not be usedtogether.

Exclusion Criteria:

• Uveal melanoma

• Untreated central nervous system (CNS) metastases or leptomeningeal involvement;patients with brain metastases definitively treated with surgery or stereotacticradiosurgery (SRS) are permitted

• Receipt of the following prior therapies:

• For Cohort A: Any prior anti-LAG-3 (e.g., relatlimab) or CTLA-4 (e.g.,ipilimumab) directed therapy, unless it was given in the adjuvant orneoadjuvant setting and the last dose was given more than three months prior todisease recurrence

• For Cohort B: Any prior CTLA-directed therapy (e.g., ipilimumab), unless it wasgiven in the adjuvant or neoadjuvant setting and the last dose was given morethan three months prior to disease recurrence

• Prior Grade 3 or greater neurologic toxicity associated with a prior line of ICItherapy

• Any prior myocarditis associated with ICI therapy

• Concurrent systemic steroid therapy higher than physiologic dose steroid replacement (>7.5 mg/day of prednisone or equivalent), given within 14 days of startingtreatment, or other immunosuppressive medications within 14 days of the start oftreatment. Inhaled or topical steroids are permitted in the absence of activeautoimmune disease.

• Receipt of a live vaccine within 30 days of planned start of study medication

• Significant infection requiring systemic antibiotics within 2 weeks of the plannedstart of study medication (e.g., pneumonia, cellulitis)

• Uncontrolled (i.e., unstable) concomitant medical condition or organ systemdysfunction which, in the treating Investigator's opinion, could compromise thepatient's safety or compliance with the study procedures.

• Other active, concurrent malignancy that requires ongoing systemic treatment orinterferes with radiographic assessment of melanoma response as determined by thetreating investigator

• History of severe hypersensitivity reactions to any unknown allergens or anycomponents of the study drugs (active ingredients or excipients)

• Has uncontrolled infection with human immunodeficiency virus, hepatitis B, orhepatitis C infection; or has a diagnosis of immunodeficiency. Notes:

• Patients will be tested for hepatitis C virus (HCV) and hepatitis B virus (HBV)at screening.

• Patients with known HIV infection who have controlled infection (undetectableviral load (HIV RNA PCR) and CD4 count above 350 either spontaneously or on astable antiviral regimen) are permitted. For patients with controlled HIVinfection, monitoring will be performed per local standards.

• Patients with hepatitis B (HBsAg+) who have controlled infection (serumhepatitis B virus DNA PCR that is below the limit of detection and receivinganti-viral therapy for hepatitis B) are permitted. Patients with controlledinfections must undergo periodic monitoring of HBV DNA. Patients must remain onanti-viral therapy for at least 6 months beyond the last dose ofinvestigational study drug.

• Patients who are hepatitis C virus antibody positive (HCV Ab+) who havecontrolled infection (undetectable HCV RNA by PCR either spontaneously or inresponse to a successful prior course of anti-HCV therapy) may be enrolled intothe study.

• Patients who are breastfeeding or who are pregnant as evidenced by a positive serumpregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) performedwithin 14 days of the first dose of study drug.

• Prisoners or participants who are involuntarily incarcerated. (Note: Under certainspecific circumstances where local regulations permit, a person who has beenimprisoned may be permitted to continue as a participant.)

• Participants who are compulsorily detained for treatment of either a psychiatric orphysical illness (e.g., transmissible infection)