Interleukin-6 Receptor Inhibitor Sarilumab in Combination With Ipilimumab, Nivolumab and Relatlimab in Patients With Unresectable Stage III or Stage IV Melanoma

Study Overview
=================
Brief Summary
-----------------
The study will evaluate how safe the study drug is, how well you tolerate it, and 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 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 this 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.

Detailed Description
-----------------
In this Phase II, open-label study, the treatment period will consist of an induction phase and a maintenance phase. The induction phase consists of an induction treatment cycle of 8 weeks which is the DLT period. The maintenance phase consists of treatment cycles of 56 days (8 weeks) each, and may extend up to 2 years. During the induction phase, ipilimumab will be administered on day 1 at a dose of 1 mg/kg intravenously (IV) during the 8-week induction period, concurrent with nivolumab 480 mg/relatlimab at 160 mg, fixed dose, administered at a 4 week interval on days 1 and 29 with a 30 minute rest period between the two infusions on day 1 and 29. On days administered in combination, nivolumab/relatlimab will be administered first at a dose of 480 mg/160 mg, followed by ipilimumab at 1 mg/kg, and immediately followed by sarilumab at 150 mg given subcutaneously. Nivolumab/relatlimab and ipilimumab will be each administered IV over 30 minutes consecutively with a 30-minute rest period between infusions, on day 1 of the first and all subsequent 56-day maintenance treatment cycles and nivolumab/relatlimab will be administered on day 29 of each cycle. Sarilumab will be administered subcutaneously every 2 weeks during the 56-day induction treatment cycle and the first two 56-day maintenance cycles only for a total of 24 weeks

Official Title
-----------------
A Phase II Study of the Interleukin-6 Receptor Inhibitor Sarilumab in Combination With Ipilimumab, Nivolumab and Relatlimab in Patients With Unresectable Stage III or Stage IV Melanoma

Conditions
-----------------
Melanoma, Unresectable Melanoma

Intervention / Treatment
-----------------
* Drug: Sarilumab
* Drug: Ipilimumab Injection
* Drug: Nivolumab/Relatlimab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have signed and dated an Institutional Review Board/Independent Ethics Committee -approved written informed consent form 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 according to the American Joint Committee on Cancer (AJCC) (8th edition) and have histologically-confirmed melanoma that is felt to be surgically unresectable in order to be eligible. Please refer to the AJCC Cancer Staging Manual, 8th edition 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; 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). oExceptions: Surgery for melanoma and/or post-resection brain radiotherapy (RT) if central nervous system (CNS) metastases and local radiation for locoregional disease and/or prior treatment with adjuvant nivolumab, dabrafenib and trametinib, pembrolizumab, interferon (IFN) or ipilimumab (IPI) (as described in Exclusion Criterion 8,4 full protocol below). All patients must have their disease status documented by a complete physical examination and imaging studies within 4 weeks prior to the first dose of study drug. Imaging studies must include 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). Disease must be measurable by RECIST 1.1 The complete set of baseline radiographic images must be available before treatment initiation. Exclusion Criteria: Patients with untreated brain metastases, carcinomatosis meningitis or current ocular/uveal melanoma are excluded. Patients with previous non-melanoma 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, non-melanoma 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 14 days of study drug administration. Inhaled or topical steroids are permitted in the absence of active autoimmune disease

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Group<br>Participants receive sarilumab at 150 mg flat dose is administered subcutaneously every 2 weeks for 12 doses from day 1, cycle 1 in combination with a regimen of ipilimumab at 1 mg/kg every 8 weeks and fixed dose nivolumab at 480 mg and relatlimab at 160 mg flat dose every 4 weeks two times during the 8-week induction period, then the same regimen again up to week 16, and up to week 24 in maintenance. After week 24 the regimen will be ipilimumab at 1 mg/kg every 8 weeks and fixed dose nivolumab at 480 mg with relatlimab at 160 mg flat dose every 4 weeks for 8 week cycles for up to a total of 2 years in patients with unresectable Stage III/Stage IV melanoma. | Drug: Sarilumab<br>* 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.<br>* Other names: REGN88;Drug: Ipilimumab Injection<br>* 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.<br>* Other names: MDX-CTLA4;Drug: Nivolumab/Relatlimab<br>* 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.<br>* Other names: BMS-986213;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number 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. | week 24 (+/- 7 days) | 
| Response Evaluation Criteria in Solid Tumors (RECIST 1.1) Category | Each patient will be assigned one of the following categories: = Complete Response (CR) = Disappearance of all target lesions; = Partial Response (PR) = At least a 30% decrease in the sum of the longest diameter (LD) of target lesions. = 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. = 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. = Early death from malignant disease = Early death from toxicity = early death because of other cause 9 = Unknown (not assessable, insufficient data) | week 24 (+/- 7 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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: = Immune related complete response (irCR) = Complete disappearance of all tumor lesions = Immune related partial response (irPR) = A decrease relative to baseline of the immune related sum of products of diameters (irSPD) of 50% or greater = Immune related stable disease (irSD) = An evaluable response that fails to meet criteria for irCR or irPR, in the absence of progressive disease = Immune related progressive disease (irPD) = At least a 25% increase in the irSPD over the lowest irSPD = Immune related unknown response (irUN) = Tumor assessments that cannot be evaluated | 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 | 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 | 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 | 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 | 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 | Month 31 |