Nivolumab and Relatlimab in Treating Patients with Stage IIIB-IV Melanoma
- American Joint Committee on Cancer (AJCC) 8th edition criteria for unresectable stage IIIB, stage IIIC, stage IIID, or stage IV melanoma who have not received prior immunotherapy treatment in the metastatic setting (defined as prior treatment with anti-PD1, anti-PDL1, anti-PDL2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint); or chemotherapy * Subjects who have received prior adjuvant treatment with anti-PD1, anti-PDL1, and/or anti-LAG3 antibody would be excluded. Note that prior adjuvant treatment with targeted therapy (e.g. BRAF/MEK inhibition), anti-CTLA4, or treatment not otherwise specified would be permitted.
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 80%.)
- Leukocytes: >= 3,000/mcL.
- Absolute neutrophil count >= 1,500/mcL.
- Platelets >= 100,000/mcL.
- Total bilirubin =< 1.5 x institutional upper limit of normal (except in subjects with Gilbert’s syndrome who must have a normal direct bilirubin).
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal.
- Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.
- Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 10 mm (>= 1 cm) with CT scan, magnetic resonance imaging (MRI), or calipers by clinical exam. If subjects have a single lesion, the lesion must be amenable to biopsy without interfering with radiographic assessment as determined by principal investigator (PI).
- The effects of relatlimab and nivolumab on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 24 weeks following last dose.
- Ability to understand and the willingness to sign a written informed consent document.
- Known or suspected central nervous system (CNS) metastases, with the following exceptions: * Subjects with controlled brain metastases will be allowed to enroll. Controlled brain metastases are defined as no radiographic progression for at least 4 weeks following radiation and/or surgical treatment at the time of randomization. * Subjects must be off steroids for at least 2 weeks prior to randomization. * Subjects with signs or symptoms of brain metastases are not eligible unless brain metastases are ruled out by computed tomography or magnetic resonance imaging.
- Ocular melanoma.
- Patients who are receiving any other investigational agents.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab or relatlimab.
- 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.
- Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following: * Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6 months prior to consent * Uncontrolled angina within the 3 months prior to consent * Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, torsades de pointes, or poorly controlled atrial fibrillation) * History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, poorly controlled deep venous thrombosis, etc.) * Cardiovascular disease-related requirement for daily supplemental oxygen * History of two or more MIs OR two or more coronary revascularization procedures * Subjects with history of myocarditis, regardless of etiology.
- A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent.
- Subjects with history of life-threatening toxicity related to prior immune therapy (e.g. anti-CTLA-4 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 endocrinopathy).
- Troponin T (TnT) or I (TnI) > 2 x institutional ULN. Subjects with TnT or TnI levels between > 1 to 2 x ULN will be permitted if repeat levels within 24 hours are =< 1 x ULN. If TnT or TnI levels are > 1 to 2 x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment based on the discretion of the PI. 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 subject may undergo a cardiac evaluation and be considered for treatment, based on the discretion of the PI.
- Prior treatment with LAG-3 targeted agents.
- Subject has been administered prior chemotherapy or immunotherapy for melanoma at any time, and any with radiation therapy within 4 weeks prior to time of consent or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to previously administered agent. * Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study. * If subject underwent major surgery, subject must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- Subject has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
- A known or underlying medical condition that, in the opinion of the investigator could make the administration of study drug hazardous to the subject or could adversely affect the ability of the subject to comply with or tolerate study therapy.
- Pregnant women are excluded from this study because relatlimab has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued if the mother is treated with relatlimab.
- Subjects who are unable to undergo venipuncture and/or tolerate venous access.
- Evidence of active infection that requires systemic antibacterial, antiviral, or antifungal therapy =< 7 days prior to initiation of study drug therapy
- Prisoners or subjects who are involuntarily incarcerated.
- Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
- Inability to comply with restrictions and prohibited activities and treatments.
I. Assess change in immune biomarkers by analysis of peripheral blood and tumor biopsy samples taken serially from patients receiving treatment with relatlimab alone, nivolumab alone, and the combination of nivolumab + relatlimab. (Lead-in phase)
II. Estimate association between change in immune biomarkers and change in tumor size. (Lead-in phase)
III. Computed tomography (CT) assessment of objective response rate relative to the beginning of the combination phase by comparing CT measurements obtained 12 weeks after beginning of combination phase and subsequently at 12 week intervals with reference to CT measurements obtained at completion of initial 4 week lead-in phase. (Combination phase)
I. To assess the potential clinical benefit of the combination therapy.
II. To assess the duration of response.
III. To assess progression-free survival and overall survival.
IV. To assess the safety of the combination of nivolumab and relatlimab.
V. To evaluate for a correlation between LAG3 expression as assessed by immunohistochemistry (IHC) and/or multiplexed immunofluorescence (IF) at baseline and response to the study treatment.
VI. To assess the change in immune biomarkers by analysis of peripheral blood and tumor biopsies obtained prior to initiating treatment, following 1 cycles (4 weeks) of lead-in treatment, and following 3 cycles of combination treatment in all three groups (12 weeks after initiating combination phase), and at the time of disease progression.
VII. To estimate and compare tumor response profiles that combine both the lead-in and combination phases.
I. Assessment of clinical response at 4 weeks following 1 cycle of assigned lead-in treatment with relatlimab, nivolumab, or the combination of nivolumab + relatlimab.
II. Assessment of matching peripheral blood lymphocytes and tumor biopsies by single cell ribonucleic acid sequencing (RNAseq) on 9 subjects.
Patients receive nivolumab intravenously (IV) over 30 minutes and relatlimab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 48 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for up to 5 years.
Trial Phase Phase II
Trial Type Treatment
University of Pittsburgh Cancer Institute (UPCI)
John Munn Kirkwood
- Primary ID 18-071
- Secondary IDs NCI-2019-02780
- Clinicaltrials.gov ID NCT03743766