An Investigational Immuno-therapy Study to Evaluate Safety and Effectiveness in Patients With Melanoma That Has Spread to the Brain, Treated With Nivolumab in Combination With Ipilimumab, Followed by Nivolumab by Itself

Study Overview
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Brief Summary
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This is a study of Nivolumab combined with Ipilimumab followed by Nivolumab by itself for the treatment of patients with Melanoma that has spread to the brain. Patients with histologically confirmed Malignant Melanoma and asymptomatic brain metastases are eligible for the study.

Official Title
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A Multi-Center Phase 2 Open-Label Study to Evaluate Safety and Efficacy in Subjects With Melanoma Metastatic to the Brain Treated With Nivolumab in Combination With Ipilimumab Followed by Nivolumab Monotherapy

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Ipilimumab
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: 1. Target Population Histologically confirmed malignant melanoma with measurable metastases in the brain. Both asymptomatic and symptomatic patients. Cohort A (asymptomatic patients): At least 1 measurable brain metastasis ≥ 0.5 cm in and ≤ 3 cm in longest diameter that has not been previously irradiated. No clinical requirement for local intervention (surgery, radiosurgery, corticosteroid therapy) or other systemic therapy Cohort B (symptomatic patients): Subjects with neurologic signs and symptoms related to metastatic brain lesions are eligibile. Subjects must have at least 1 measurable brain metastasis ≥ 0.5 cm in and ≤ 3 cm in longest diameter that has not been previously irradiated. No immediate requirement (within 3 weeks prior to first treatment) for local intervention (surgery, radiosurgery, corticosteroid therapy). Steroid use is permitted as defined in the protocol. Prior stereotactic radiotherapy (SRT) and prior excision of up to 3 melanoma brain metastases is permitted if there has been complete recovery, with no neurologic sequelae, and measurable lesions remain. Growth or change in a lesion previously irradiated will not be considered measurable. Regrowth in cavity of previously excised lesion will not be considered measurable. lesions or prior excision must have occurred ≥ 3 weeks before the start of dosing for this study Must have tumor tissue available for biomarker analysis. Biopsy should be excisional, incisional, punch, or core needle Cohort A (asymptomatic): Subjects must be free of neurologic signs and symptoms related to metastatic brain lesions and must not have required or received systemic corticosteroid therapy within 10 days prior to first treatment. Cohort B (symptomatic): Subjects with neurologic signs and symptoms related to metastatic brain lesions are eligible per Amendment 02. Subjects with neurologic signs and symptoms may be treated with a total daily dose of no more than 4 mg of dexamethasone that is stable or tapering for 10 days prior to first treatment. Subjects with neurologic signs and symptoms who are not being treated with steroids are eligible for Cohort B and should have no experience of seizure within 10 days prior to first treatment. Allowable prior therapy: Approved adjuvant therapies, which may include molecularly-targeted agents, IFN α, and ipilimumab. Patients who received ipilimumab as adjuvant therapy must have a 6 month washout before receiving any dosing on this study For advanced disease, interleukin-2 at any dose and/or IFN-α (any formulation, no washout required); MEK and BRAF inhibitors: washout for at least 4 weeks prior to the start of dosing in this study Steroids for physiological replacement are allowed. Cohort A (asymptomatic): ECOG performance status ≤1 Cohort B (symptomatic): ECOG performance status ≤2 Exclusion Criteria: 2. Target Disease Exceptions History of known leptomeningeal involvement (lumbar puncture not required) Previous stereotactic or highly conformal radiotherapy within 3 weeks before the start of dosing for this study. Note the stereotactic radiotherapy field must not have included the brain index lesion(s) Brain lesions >3 lesions which were previously treated with SRT Brain lesion size > 3cm 3. Medical History and Concurrent Diseases a) History of whole brain irradiation b) Subjects with an active, known or suspected autoimmune disease c) Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled d) Any concurrent malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix. For any prior invasive malignancy, at least 5 years must have elapsed since curative therapy and patients must have no residual sequelae of prior therapy e) Cohort A (asymptomatic): The use of corticosteroids is not allowed within 10 days prior to first treatment (based upon 5 times the expected half life of dexamethasone) except patients who are taking steroids for physiological replacement. If alternative corticosteroid therapy has been used, consultation with the sponsor Medical Monitor is required to determine the washout period prior to initiating study treatment Cohort B (symptomatic): Subjects with neurologic sign and symptoms related to brain metastases who are being treated with a total daily dose of higher than 4 mg dexamethasone or equivalent within 10 prior to the start of treatment with study drug are excluded. 4. Physical and Laboratory Test Findings Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on ART-due to the unknown effects of HIV on the immune response to combined nivolumab plus ipilimumab or the unique toxicity spectrum of these drugs in patients with HIV 5. Allergies and Adverse Drug Reaction a) History of allergy to study drug components b) History of severe hypersensitivity reaction to any monoclonal antibody 6. Other Exclusion Criteria 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 Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria Other protocol defined inclusion/exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab and Ipilimumab<br>Induction Phase: Nivolumab + Ipilimumab infusion intravenously Maintenance Phase: Nivolumab infusion intravenously | Drug: Ipilimumab<br> <br> * Other names: Yervoy;Drug: Nivolumab<br> <br> * Other names: BMS-936558;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial Clinical Benefit Rate (CBR) | Intracranial Clinical Benefit Rate (CBR) is defined as the percentage of all treated participants whose best overall response is either a complete response (CR) or partial response (PR) or whose best overall response was Stable Disease (SD) with duration of >6 months, as determined by modified RECIST 1.1 criteria for index intracranial lesions based on investigator review. | Up to 66 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial Objective Response Rate (ORR) | Investigator-Assessed Intracranial Objective Response Rate (ORR) per modified RECIST 1.1 criteria is defined as the number of participants who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of treated participants. | Up to 66 months | 
| Intracranial Progression Free Survival (PFS) | Intracranial progression-free survival (PFS) per modified RECIST 1.1 criteria is defined as the time between the date of first dose of study drug and the first date of documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. Participant who die without a reported progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die will be censored on the date of first dose of study drug. Participants who started anti-cancer therapy without a prior reported progression will be censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy. | Up to 66 months | 
| Extracranial Clinical Benefit Rate (CBR) | Extracranial Clinical Benefit Rate (CBR) is defined as the percentage of all treated participants whose best overall response is either a complete response (CR) or partial response (PR) or whose best overall response was Stable Disease (SD) with duration of >6 months, as determined by RECIST 1.1 criteria for index extracranial lesions based on investigator review. | Up to 66 months | 
| Extracranial Objective Response Rate (ORR) | Extracranial Objective Response Rate (ORR) per RECIST 1.1 criteria is defined as the number of participants who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of treated participants. | Up to 66 months | 
| Extracranial Progression Free Survival (PFS) | Extracranial progression-free survival (PFS) per RECIST 1.1 criteria is defined as the time between the date of first dose of study drug and the first date of documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. Participant who die without a reported progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die will be censored on the date of first dose of study drug. Participants who started anti-cancer therapy without a prior reported progression will be censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy. | Up to 66 months | 
| Global Clinical Benefit Rate (CBR) | Investigator-assessed global (intracranial + extracranial) clinical benefit rate (CBR) per a combination of modified RECIST 1.1 criteria for intracranial lesions and RECIST 1.1 for extracranial disease is defined as the percentage of all treated participants whose best overall response is either a complete response (CR) or partial response (PR) or whose best overall response was Stable Disease (SD) with duration of >6 months | Up to 66 months | 
| Global Objective Response Rate (ORR) | Investigator-assessed global objective response rate (ORR) per a combination of modified RECIST 1.1 criteria for intracranial lesions and RECIST 1.1 for extracranial disease is defined as the number of participants who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of treated participants. | Up to 66 months | 
| Global Progression Free Survival (PFS) | Investigator-assessed global progression free survival (PFS) per a combination of modified RECIST 1.1 criteria for intracranial lesions and RECIST 1.1 for extracranial disease is defined as the time between the date of first dose of study drug and the first date of documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. Participant who die without a reported progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die will be censored on the date of first dose of study drug. Participants who started anti-cancer therapy without a prior reported progression will be censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy. | Up to 66 months | 
| Overall Survival (OS) | Overall Survival (OS) is defined as the time from the date of the start of treatment until the date of death. For participants who have not died, OS will be censored at the recorded last date of participant contact, and participants with a missing recorded last date of contact will be censored at the last date the participant was known to be alive. | Up to 66 months | 
| Number of Participants With Adverse Events (AEs) | Number of participants with any grade of adverse events (AEs) and any grade of serious adverse events (SAEs) graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v4.0) | From first dose to 30 days post last dose (Up to 66 months) | 
| Number of Participants Deaths | Number of participants who died due to any cause. | Up to 66 months | 
| Number of Participants With Laboratory Abnormalities in Specific Liver Tests | Number of participants with laboratory abnormalities in specific liver tests based on US conventional units to determine the safety and tolerability of Nivolumab and Daratumumab. The number of participants with the following laboratory abnormalities from on-treatment evaluations will be summarized: ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN Total bilirubin > 2 x ULN Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN | From first dose to 30 days post last dose (Up to 66 months) | 
| Number of Participants With Laboratory Abnormalities in Specific Thyroid Tests | Number of participants with laboratory abnormalities in specific thyroid tests based on US conventional units to determine the safety and tolerability of Nivolumab and Daratumumab. The number of subjects with the following laboratory abnormalities from on-treatment evaluations will be summarized: TSH value > ULN and with baseline TSH value <= ULN with at least one FT3/FT4 test value < LLN within 2-week window after the abnormal TSH test with all FT3/FT4 test values >= LLN within 2-week window after the abnormal TSH test with FT3/FT4 missing within 2-week window after the abnormal TSH test. TSH < LLN and with baseline TSH value >= LLN with at least one FT3/FT4 test value > ULN within 2-week window after the abnormal TSH test with all FT3/FT4 test values <= ULN within 2-week window after the abnormal TSH test with FT3/FT4 missing within 2-week window after the abnormal TSH test | From first dose to 30 days post last dose (Up to 66 months) |