This study will evaluate how safe the study drug is, how well patients tolerate it, how it works in the body, and the disease's response to the drug. The study drug being tested is sarilumab, when given with the combination of ipilimumab, nivolumab, and relatlimab in patients like yourself, with stage III or stage IV melanoma that cannot be removed by surgery. Previous studies have provided a strong rationale for combining sarilumab, with ipilimumab, nivolumab and relatlimab in metastatic melanoma to reduce side effects and potentially work better for your type of cancer. Sarilumab is an FDA-approved inhibitor of the receptor for the cytokine IL-6, currently approved for the treatment of rheumatoid arthritis, but it is not FDA-approved to treat melanoma. This means that the use of Sarilumab to treat melanoma is considered investigational. The other drugs which will be administered in this study, ipilimumab and nivolumab, are also monoclonal antibodies, but they target different proteins. Ipilimumab and nivolumab are both approved by the FDA to treat advanced stage III and IV melanomas. The nivolumab + relatlimab FDC (fixed dose combination) being used in this study is considered investigational, meaning it is not approved by the FDA. The combination of sarilumab, ipilimumab, nivolumab and relatlimab is considered investigational because it has not yet been approved by the FDA. The FDA has given its permission to study the investigational combination of these drugs in this research study.
This is a Phase II study conducted in two stages. In the first stage, up to 33 patients will be treated with all four drugs in a single arm open label trial. In the second stage, 72 patients will be randomized 1:1 to receive ipilimumab, nivolumab and relatlimab with or without sarilumab for up to 24 weeks. The study will include an assessment of the safety and tolerability and overall response rates of sarilumab administered concurrently at 150 mg flat dose every 2 weeks for 12 doses in combination with ipilimumab for three doses given every 8 weeks, and fixed dose nivolumab and relatlimab given every 4 weeks for six doses to week 24, then maintenance nivolumab and relatlimab every 4 weeks and ipilimumab every 8 weeks for up to a total of two years to patients with advanced melanoma in the first stage, and a comparison of the co-primary endpoints in the second randomized stage of the trial. Treatment will be divided into an 8-week induction and subsequent maintenance phases.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
105
Injectable solutions of sarilumab are formulated in 2 mL of aqueous solution in a 5 mL vial containing 175 mg/ml of sarilumab arginine (8.94 mg), histidine (3.71 mg), polysorbate 20 (2.28 mg), sucrose (57 mg) and Water for Injection USP.Patients will be administered sarilumab at a dose of 150 mg subcutaneously in combination with ipilimumab, nivolumab and relatlimab given intravenously, with nivolumab/relatlimab given intravenously, or sarilumab at a dose of 150 mg subcutaneously given alone.
Ipilimumab injection is a sterile, nonpyrogenic, clear to slightly opalescent, colorless to pale yellow solution, single-use, preservative-free, isotonic aqueous solution that may contain particles. It is formulated at a concentration of 5 mg/mL ipilimumab in TRIS hydrochloride (also known as 2-amino-2-hydroxymethyl-1,3-propanediol hydrochloride), sodium chloride, mannitol, pentetic acid (also known as diethylenetriaminepentaacetic acid or DTPA), polysorbate 80, and water at pH 7.0. Sodium hydroxide and/or hydrochloric acid may be used to adjust the pH of the solution. Ipilimumab Injection 200 mg/40 mL (5 mg/mL) is packaged in a 50-cc Type I flint molded glass vials.
The FDC drug product, referred to as nivolumab/relatlimab, contains relatlimab and nivolumab in a single vial in a kit of 2 vials. The product is a sterile, non-pyrogenic, single-use, isotonic aqueous solution for IV infusion. It is formulated at a total protein concentration of 16 mg/mL (4 mg/mL relatlimab and 12 mg/mL nivolumab) and is packaged in a 20-cc glass vial in a kit of two vials. Each vial contains 80 mg of relatlimab and 240 mg of nivolumab.
The Angeles Clinic at Cedars Sinai
Los Angeles, California, United States
RECRUITINGMassachusetts General Hospital
Boston, Massachusetts, United States
RECRUITINGDana Farber Cancer Institute
Boston, Massachusetts, United States
RECRUITINGNYU Langone Health
New York, New York, United States
RECRUITINGNumber of Grades 3-5 Treatment-Related Immune-Related Adverse Events (irAE) per NCI CTCAE v 5.0 Criteria
The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v 5.0) grades adverse events by the following scale: Grade 1 - Mild, Grade 2 - Moderate, Grade 3 - Severe, Grade 4 - Life-threatening, Grade 5 - Death Safety will be measured by physical examinations, vital sign measurements, Eastern Cooperative Oncology Group (ECOG) performance status evaluations, AE assessments, laboratory testing, electrocardiograms (ECGs), oxygen saturation, and concomitant medications.
Time frame: week 24 (+/- 7 days)
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) Category
Each patient will be assigned one of the following categories: 1. = Complete Response (CR) = Disappearance of all target lesions; 2. = Partial Response (PR) = At least a 30% decrease in the sum of the longest diameter (LD) of target lesions. 3. = Stable Disease (SD) = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum LD since treatment started. 4. = Progressive Disease (PD) = At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. 5. = Early death from malignant disease 6. = Early death from toxicity 7. = early death because of other cause 9 = Unknown (not assessable, insufficient data)
Time frame: week 24 (+/- 7 days)
Progression-free survival (PFS)
Progression-Free Survival (PFS) will be reported as the time from first dosing to the first observation of disease progression or death due to any cause. If a patient has not progressed or died at the time of analysis, PFS will be censored on the date of the last disease assessment. Patients who do not have any tumor assessment on treatment will be censored on the day of the first dose.
Time frame: Up to Month 31
Overall survival (OS)
Overall Survival will be reported as the time from first dosing to death due to any cause. If a patient has not died at the time of analysis, OS will be censored as of their last known date alive (i.e., last time patient was contacted for any reason in the study). Patients who do not have any tumor assessment on treatment will be followed up for OS, and their date of death will be incorporated into the OS analysis.
Time frame: Up to Month 31
Best overall response (iBOR)
iBOR will be reported as the best timepoint response recorded from the time the measurement criteria are met for partial response (PR) or complete (CR), whichever is recorded first, until the date of documented PD or death.
Time frame: week 24 (+/- 7 days)
Disease Control Rate (DCR)
Total number of patients whose best response outcome is a Complete Response (CR), Partial Response (PR) or Stable Disease (SD), divided by the total number of evaluable patients. Per Response Evaluation Criteria in Solid Tumors (RECIST v 1.1): CR = Disappearance of all target lesions; PR = At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD; SD = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum LD since treatment started.
Time frame: Month 31
Duration of Overall Response
Among patients whose best response to treatment is a Complete Response (CR) or Partial Response (PR): The time between the date measurement criteria are met for PR or CR, whichever is recorded first, and the date of documented Progressive Disease (PD) or death. Per Response Evaluation Criteria in Solid Tumors (RECIST v 1.1): CR = Disappearance of all target lesions; PR = At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD PD = At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Time frame: Month 31
Duration of disease control
Among patients who had an Overall Response Rate (ORR) outcome of Complete Response (CR), Partial Response (PR), or Stable Disease (SD): The time from first dosing to documented disease progression. Per Response Evaluation Criteria in Solid Tumors (RECIST v 1.1): CR = Disappearance of all target lesions; PR = At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD; SD = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum LD since treatment started.
Time frame: Up to Month 31
Immune-related Response Rate (irRR) per irRC criteria
The highest Immune-Related Response Criteria (irRC) designation given over 24 weeks, where: 1. = Immune related complete response (irCR) = Complete disappearance of all tumor lesions 2. = Immune related partial response (irPR) = A decrease relative to baseline of the immune related sum of products of diameters (irSPD) of 50% or greater 3. = Immune related stable disease (irSD) = An evaluable response that fails to meet criteria for irCR or irPR, in the absence of progressive disease 4. = Immune related progressive disease (irPD) = At least a 25% increase in the irSPD over the lowest irSPD 5. = Immune related unknown response (irUN) = Tumor assessments that cannot be evaluated
Time frame: Week 24
Immune-related Response Rate (irRR) per irRC criteria
The total number of response-evaluable patients whose Immune Related Best Overall Response (irBOR) outcome is immune related complete response (irCR) or immune related partial response (irPR), per Immune-Related Response Criteria (irRC): irCR = Complete disappearance of all tumor lesions irPR = A decrease relative to baseline of the immune related sum of products of diameters (irSPD) of 50% or greater
Time frame: Month 31
Immune-related Disease Control Rate per irRC criteria
The total number of the response-evaluable patients whose Immune Related Best Overall Response (irBOR) outcome is immune related complete response (irCR), immune related partial response (irPR) or immune-related stable disease (irSD), per Immune-Related Response Criteria (irRC): irCR = Complete disappearance of all tumor lesions irPR = A decrease relative to baseline of the immune related sum of products of diameters (irSPD) of 50% or greater irSD = An evaluable response that fails to meet criteria for irCR or irPR, in the absence of progressive disease
Time frame: Month 31
Immune-related Progression-Free Survival (irPFS)
The time between first dosing and the date of immune-related progressive disease (irPD) or death, whichever occurs first. For patients with no recorded post-baseline tumor assessment, irPFS will be censored at the day of first dose. A patient who dies without reported irPD will be considered to have progressed on the date of death. For those who remain alive and have no irPD, irPFS will be censored on the date of last evaluable tumor assessment. Patients who do not have any tumor assessment on treatment will be censored on the day of the first dose. Per Immune-Related Response Criteria (irRC): irPD = At least a 25% increase in the irSPD over the lowest immune related sum of products of diameters
Time frame: Month 31
Duration of Immune-related Overall Response
Duration of Immune-related Overall Response will be computed for all patients whose irBOR outcome is either an irPR or irCR and is calculated from the time the measurement criteria are met for irPR or irCR, whichever is recorded first, until the date of documented PD or death by irRC
Time frame: Month 31
Duration of Immune-related Disease Control
Among patients with Immune-related Overall Response outcome of immune related complete response (irCR), immune related partial response (irPR), or immune-related stable disease (irSD): The time between the date treatment began and the date of documented disease progression. Per Immune-Related Response Criteria (irRC): irCR = Complete disappearance of all tumor lesions irPR = A decrease relative to baseline of the immune related sum of products of diameters (irSPD) of 50% or greater irSD = An evaluable response that fails to meet criteria for irCR or irPR, in the absence of progressive disease
Time frame: Month 31
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.