Sarilumab in Combination with Ipilimumab, Nivolumab, and Relatlimab for the Treatment of Unresectable Stage IIIB/C/D or Stage IV Melanoma

Inclusion Criteria

• Patients must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written informed consent form (ICF) 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
• Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study
• All patients must be either stage IIIb/c/d or stage IV melanoma according to the American Joint Committee on Cancer (AJCC) (8th edition) and have histologically-confirmed melanoma that is felt to be surgically unresectable or metastatic in order to be eligible. Please refer to the AJCC 8th edition Cancer Staging Manual for a description of tumor, lymph node, metastasis, and staging * All melanomas, except ocular/uveal melanoma, regardless of primary site of disease will be allowed; acral and mucosal melanomas are eligible * Patients must not have received prior anticancer treatment for metastatic disease (for example, but not limited to, systemic, local, radiation, radiopharmaceutical) * Exceptions: Surgery for melanoma and/or post-resection brain radiotherapy (RT) if central nervous system (CNS) metastases and adjuvant radiation therapy (RT) for locoregional disease after resection and/or prior treatment with adjuvant interferon (IFN)-alpha, dabrafenib and trametinib, pembrolizumab, ipilimumab or nivolumab * All patients must have their disease status documented by a complete physical examination and imaging studies within 28 days prior to the first dose of study drug. Imaging studies must include contrast-enhanced (unless contrast contraindicated) computerized tomography (CT) scan of chest, abdomen, pelvis, and all known sites of resected disease in the setting of stage IIIb/c/d or stage IV disease, and brain magnetic resonance imaging ([MRI]; brain CT is allowable if MRI is contraindicated) * The complete set of baseline radiographic images must be available before treatment initiation * Patients must have at least one measurable lesion by RECIST 1.1
• Prior treatment with adjuvant IFN-alpha, adjuvant ipilimumab and/or nivolumab or pembrolizumab or dabrafenib and trametinib are allowed if recurrence of disease occurred more than 6 months from the last dose of adjuvant therapy; that is, a patient must have recurred with unresectable disease at least 6 months or more after finishing adjuvant therapy; combination adjuvant therapies with nivolumab or pembrolizumab are also allowed (vaccines, bempegaldesleukin, relatlimab, cemiplimab with fianlimab, etc)
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
• Tumor tissue from the resected site of disease must be provided for biomarker analyses. In order to be treated, a patient must have tissue available for PD-L1 and LAG3 expression analysis by immunohistochemistry (IHC) and other assays obtained within 6 months of starting treatment; a minimum of 8 slides is required. If insufficient tumor tissue content is provided for analysis, acquisition of additional archived tumor tissue (block and/or slides) for the biomarker analysis is required
• Prior treated CNS metastases must be without MRI evidence of recurrence for at least 4 weeks after treatment. Patients must be off immunosuppressive doses of systemic steroids (> 10 mg/day prednisone or equivalent) for at least 14 days prior to study drug administration, and must have returned to neurologic baseline status postoperatively * The 4-week period of stability is measured after the completion of the neurologic interventions (i.e., surgery and/or radiation)
• 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 7 days before study drug administration
• Prior surgery that required general anesthesia must be completed at least 2 weeks before study drug administration. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration
• White blood cells (WBCs) >= 2000/uL (within 14 days of the first dose of study drug)
• Neutrophils >= 1500/uL (within 14 days of the first dose of study drug)
• Platelets >= 100 x 10^3/uL (within 14 days of the first dose of study drug)
• Hemoglobin ≥ 9.0 g/dL (within 14 days of the first dose of study drug)
• Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance > 40 mL/minute (using Cockcroft/Gault formula) (within 14 days of the first dose of study drug)
• Aspartate aminotransferase (AST) =< 2.5 x ULN (within 14 days of the first dose of study drug)
• Alanine aminotransferase (ALT) =< 2.5 x ULN (within 14 days of the first dose of study drug)
• Total bilirubin =< 1.5 x ULN (except patients with Gilbert Syndrome who must have total bilirubin < 3.5 mg/dL) (within 14 days of the first dose of study drug)
• Patient Re-enrollment: This study permits the re-enrollment of a patient that has discontinued the study as a screen failure (i.e., patient has not been dosed/has not been treated). If re-enrolled, the patient must be re-consented and satisfy all eligibility criteria
• Males and females >= 18 years of age
• Women of childbearing potential (WOCBP); A woman is considered fertile following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy * Women in the following categories are not considered WOCBP ** Premenarchal ** Premenopausal woman with 1 of the following: ** Documented hysterectomy ** Documented bilateral salpingectomy ** Documented bilateral oophorectomy * Note: Documentation can come from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview * Postmenopausal woman ** A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes. In addition, women under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 mIU/mL to confirm menopause * Note: Women treated with hormone replacement therapy (HRT) are likely to have artificially suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH level. The duration of the washout period is a function of the type of HRT used. The duration of the washout periods indicated below are suggested guidelines, and the investigators should use their judgement in checking serum FSH levels ** 1 week minimum for vaginal hormonal products (rings, creams, gels) ** 4 week minimum for transdermal products ** 8 week minimum for oral products * Other parenteral products may require washout periods as long as 6 months. If the serum FSH level is > 40 mIU/ml at any time during the washout period, the woman can be considered postmenopausal * WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG] hormone) within 24 hours prior to the start of study drug during induction phase at each scheduled visit and during the maintenance phase every 4 weeks while on treatment
• Women of childbearing potential must agree to follow one of the highly effective methods of contraception listed below during study duration and until the end of relevant systemic exposure, which is defined as 5 months after the last dose of study drug * Highly effective contraceptive methods that are user dependent. Failure rate of < 1% per year when used consistently and correctly ** Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (This method of contraception cannot be used by WOCBP participants in studies where hormonal contraception is prohibited) *** oral *** intravaginal *** transdermal ** Progestogen-only hormonal contraception associated with inhibition of ovulation (This method of contraception cannot be used by WOCBP participants in studies where hormonal contraception is prohibited) *** oral *** injectable * Highly effective methods that are user independent ** Implantable progestogen-only hormonal contraception associated with inhibition of ovulation ** Intrauterine device ** Intrauterine hormone-releasing system (IUS) (This method of contraception cannot be used by WOCBP participants in studies where hormonal contraception is prohibited) ** Bilateral tubal occlusion ** Vasectomized partner *** A vasectomized partner is a highly effective contraceptive method provided that the partner is the sole male sexual partner of the WOCBP, and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used ** Sexual abstinence *** Sexual abstinence is considered a highly effective contraceptive method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant * It is not necessary to use any other method of contraception when complete abstinence is elected. * WOCBP participants who choose complete abstinence must continue to have pregnancy tests * Acceptable alternate methods of highly effective contraceptive methods must be discussed in the event that the WOCBP participants chooses to forego complete abstinence * NOTES: ** Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for participants participating in clinical studies ** Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient evidence that the investigational medicinal product and other study medications will not alter hormonal exposures such that contraception would be ineffective or result in increased exposures that could be potentially hazardous. In this case, alternative methods of contraception should be utilized ** Intrauterine devices and intrauterine hormone-releasing systems are acceptable methods of contraception in the absence of definitive drug interaction studies or when hormone exposures from intrauterine devices do not alter contraception effectiveness * Less than highly effective contraceptive methods that are user dependent. Failure rate of > 1% per year when used consistently and correctly ** Male or female condom with or without spermicide. Male and female condoms cannot be used simultaneously ** Diaphragm with spermicide ** Cervical cap with spermicide ** Vaginal sponge with spermicide ** Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mechanism of action (This method of contraception cannot be used by WOCBP participants in studies where hormonal contraception is prohibited) * Unacceptable methods of contraception ** Periodic abstinence (calendar, symptothermal, post-ovulation methods) ** Withdrawal (coitus interruptus) ** Spermicide only ** Lactation amenorrhea method (LAM)
• WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, they must still undergo pregnancy testing. Investigators shall counsel WOCBP and male patients who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise WOCBP and male patients who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly * Male participants: Contraception is required
• Prior uveitis and myocarditis of grade 2 or more

Exclusion Criteria

• Patients with active or history of steroid-requiring non-infectious pneumonitis
• Patients who have previously discontinued adjuvant immunotherapy due to an immune-mediated adverse reaction of grade 4
• Patients with ongoing immune-related toxicity attributed to prior therapy that has not returned to baseline or stabilized at grade 1 or less
• Patients with untreated brain metastases, carcinomatosis meningitis or a history of current ocular/uveal melanoma are excluded
• Patients with previous nonmelanoma malignancies are excluded unless a complete resection or remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period (exceptions include, but are not limited to, nonmelanoma skin cancers, in situ bladder cancer, in situ gastric cancer or gastrointestinal stromal tumor, in situ colon cancers, in situ cervical cancers/dysplasia, or breast carcinoma in situ)
• Patients with active, known, or suspected autoimmune disease. Patients with type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll. For any cases of uncertainty, it is recommended that the Principal Investigator be consulted prior to signing informed consent
• Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 7 days of study drug administration. Inhaled or topical steroids are permitted in the absence of active autoimmune disease
• Prior therapy for melanoma with the following exceptions which are allowed: 1) surgery for the melanoma lesion(s), 2) adjuvant RT after neurosurgical resection for CNS lesions or for resected locoregional disease, and 3) prior adjuvant IFN-alpha, dabrafenib/trametinib, ipilimumab, pembrolizumab and nivolumab (see qualifier above). Prior treatment with a LAG3 antibody as adjuvant or metastatic therapy will be an exclusion
• Treatment directed against the melanoma (e.g., chemotherapy, targeted agents, biotherapy, limb perfusion) that is administered after a prior complete resection other than adjuvant radiation after neurosurgical resection or resection of locoregional disease and IFN-alpha, ipilimumab and/or nivolumab, pembrolizumab and dabrafenib and trametinib for resected melanoma; adjuvant therapy must have been finished 6 months or more prior to starting
• ANC < 1,500/uL
• WBC < 2,000 uL
• Platelet count < 100,000/uL
• Hematologic growth factors are not allowed at screening or during the first cycle of treatment
• Hemoglobin < 9 g/dL (< 5.5 mmol/L; previous red blood cell (RBC) transfusion is permitted)
• Creatinine > 2.5 x ULN
• AST or ALT > 2.5 x ULN. For patients with liver metastasis AST or ALT > 3 x ULN
• Serum total bilirubin > 1.5 mg/dL or > 3 x ULN for patients with hereditary benign hyperbilirubinemia
• 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 evaluation and be considered for treatment, based on a favorable benefit-risk assessment by the Investigator. 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 evaluation and be considered for treatment, based on a favorable benefit-risk assessment by the Investigator
• Congestive heart failure (New York Heart Association Class III or IV), documented cardiomyopathy, myocarditis regardless of etiology, myocardial infarction within 12 months before starting study treatment, or unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris
• Any serious or uncontrolled medical disorder or active infection that, in the opinion of the Investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the patient to receive protocol therapy
• Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections
• Any positive test result for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
• Positive QuantiFERON tuberculosis (TB) test, history of tuberculosis, or active TB infection without at least 4 weeks of adequate therapy for TB
• Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease (including complicated diverticulitis, ulcerative colitis, or Crohn’s disease). Such cases should be discussed with the medical monitor prior to accrual
• Immunization with a live or attenuated vaccine within 4 weeks of baseline
• Clinically significant, active, uncontrolled infection including human immunodeficiency virus (HIV), or hepatitis B or C virus (HBV; HCV). To have a controlled infection: * Patients with HIV must be on effective antiretroviral therapy for >= 4 weeks prior to enrollment and have HIV viral load < 400 copies/uL, have had no acquired immunodeficiency syndrome-defining opportunistic infections in the past 12 months, and have CD4+ count >= 350 cells/uL * Patients with chronic HBV must be on antiviral therapy and have an HBV viral load below the limit of detection. Patients with HCV must have completed antiviral therapy and have an HCV viral load below the limit of detection
• Known hypersensitivity to monoclonal antibodies
• History of acute diverticulitis in the last 3 years
• Prisoners or patients who are involuntarily incarcerated
• Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
• Pregnant or nursing women
• Psychological, familial, sociological, or geographical conditions that potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial