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 informed consent.
• •Patient must have a histologically confirmed diagnosis of locally advanced unresectable stage III/IV or metastatic stage IV cutaneous or mucosal melanoma that has progressed on PD-1/PD-L1 therapy:
• •o For Cohort A, the patient's melanoma must have progressed on prior PD-1 monotherapy
• •* For Cohort B, the patient's melanoma must have progressed on prior combination PD-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 therapy and the start of study therapy
• •* Note: For cohort A, peptide and mRNA vaccines may have been combined with PD-1 monotherapy as long as no other checkpoint inhibitors were concomitantly administered. For cohort B, peptide and mRNA vaccines may have been combined with combined PD-1 + LAG-3 blockade as long as no other checkpoint inhibitors were concomitantly administered Note: Prior PD-1 monotherapy (Cohort A) or PD-1 and LAG-3 blockade (Cohort B) may have been given in the neoadjuvant or adjuvant setting as long as progression is documented within 3 months of the final dose neoadjuvant/adjuvant therapy
• •Patients must have measurable disease as defined by RECIST v1.1 o Note: Lesions previously injected with Talimogene laherparepvec or other local therapies may not be selected as target lesions unless they have demonstrated subsequent growth after injection
• •If a suitable archival tissue sample is available, the patient must be willing to have 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 be made 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 \< 3 mg/dL for subjects with Gilbert's disease)
• •No signs of active coronary ischemia, including ECG changes or elevated troponin if clinically indicated
• •Calculated creatinine clearance (CrCl) ≥30 mL/min based on the Cockcroft-Gault equation
• •All immune-related adverse events (irAE's) from prior ICI based therapy must have improved to Grade 1 or lower with the following exception. Patients with stable adrenal insufficiency are eligible as long as 1) they are asymptomatic at the time of consent on a stable steroid replacement regimen and 2) are on daily steroid replacement of 7.5mg prednisone equivalent or less.
• •All women of childbearing potential (WOCBP)\* or sexually active men must practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose. Highly effective contraceptive measures in women include
• •o Stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation 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 they are vasectomized† or practice sexual abstinence.‡,§
• •\* WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to Clinical Trial Facilitation Group (CTFG) guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
• •* Vasectomized partner or vasectomized study participant must have received medical assessment of the surgical success.
• •* Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.
• •* Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.