Clinical trial NCT02320058: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Melanoma
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2014-12-19
Enrollment: 119
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

1. Target Population

1. Histologically confirmed malignant melanoma with measurable metastases in the brain. Both asymptomatic and symptomatic patients.
2. 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.
3. 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
4. Must have tumor tissue available for biomarker analysis. Biopsy should be excisional, incisional, punch, or core needle
5. 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.
6. Allowable prior therapy:

   1. 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
   2. 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
   3. Steroids for physiological replacement are allowed.
7. Cohort A (asymptomatic): ECOG performance status ≤1 Cohort B (symptomatic): ECOG performance status ≤2

Exclusion Criteria:

2. Target Disease Exceptions

1. History of known leptomeningeal involvement (lumbar puncture not required)
2. 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)
3. Brain lesions \>3 lesions which were previously treated with SRT
4. 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

1. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
2. 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

1. Prisoners or subjects who are involuntarily incarcerated
2. 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

Primary outcomes:
measure: Intracranial Clinical Benefit Rate (CBR)
timeFrame: Up to 66 months
Secondary outcomes:
measure: Intracranial Objective Response Rate (ORR)
timeFrame: Up to 66 months
measure: Intracranial Progression Free Survival (PFS)
timeFrame: Up to 66 months
measure: Extracranial Clinical Benefit Rate (CBR)
timeFrame: Up to 66 months
measure: Extracranial Objective Response Rate (ORR)
timeFrame: Up to 66 months
measure: Extracranial Progression Free Survival (PFS)
timeFrame: Up to 66 months
measure: Global Clinical Benefit Rate (CBR)
timeFrame: Up to 66 months
measure: Global Objective Response Rate (ORR)
timeFrame: Up to 66 months
measure: Global Progression Free Survival (PFS)
timeFrame: Up to 66 months
measure: Overall Survival (OS)
timeFrame: Up to 66 months
measure: Number of Participants With Adverse Events (AEs)
timeFrame: From first dose to 30 days post last dose (Up to 66 months)
measure: Number of Participants Deaths
timeFrame: Up to 66 months
measure: Number of Participants With Laboratory Abnormalities in Specific Liver Tests
timeFrame: From first dose to 30 days post last dose (Up to 66 months)
measure: Number of Participants With Laboratory Abnormalities in Specific Thyroid Tests
timeFrame: From first dose to 30 days post last dose (Up to 66 months)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: Angeles Clinic and Research Institute
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Hematology and Oncology
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Francisco
country: United States
facility: The California Pacific Medical Research Institute
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: University of Colorado - Cancer Center - PPDS
state: Colorado
city: Washington
country: United States
facility: Washington Cancer Inst at MedStar Washington Hospital Ctr
state: District of Columbia
city: Washington
country: United States
facility: Weinberg Cancer Institute At Franklin Square
state: District of Columbia
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center
state: Florida
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Weston
country: United States
facility: The Cleveland Clinic Foundation
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute, Emory University
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Boston
country: United States
facility: Dana Farber Cancer Institute.
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: New Brunswick
country: United States
facility: Cancer Institute of New Jersey
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Case School of Medicine University Hospitals of Cleveland
state: Ohio
city: Allentown
country: United States
facility: Lehigh Valley Health Network
state: Pennsylvania
city: Easton
country: United States
facility: St Luke's Health Network
state: Pennsylvania
city: Philadelphia
country: United States
facility: Abramson Cancer Center of The University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah - Huntsman Cancer Institute - PPDS
state: Utah
city: Fairfax
country: United States
facility: Inova Melanoma and Skin Cancer Center
state: Virginia
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: Johannet P, Simons M, Qian Y, Azmy N, Mehnert JM, Weber JS, Zhong J, Osman I. Risk and tropism of central nervous system (CNS) metastases in patients with stage II and III cutaneous melanoma. Cancer. 2022 Oct;128(20):3620-3629. doi: 10.1002/cncr.34435. Epub 2022 Aug 25.
citation: Tawbi HA, Forsyth PA, Hodi FS, Algazi AP, Hamid O, Lao CD, Moschos SJ, Atkins MB, Lewis K, Postow MA, Thomas RP, Glaspy J, Jang S, Khushalani NI, Pavlick AC, Ernstoff MS, Reardon DA, Kudchadkar R, Tarhini A, Chung C, Ritchings C, Durani P, Askelson M, Puzanov I, Margolin KA. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Lancet Oncol. 2021 Dec;22(12):1692-1704. doi: 10.1016/S1470-2045(21)00545-3. Epub 2021 Nov 10.
citation: Tawbi HA, Forsyth PA, Hodi FS, Lao CD, Moschos SJ, Hamid O, Atkins MB, Lewis K, Thomas RP, Glaspy JA, Jang S, Algazi AP, Khushalani NI, Postow MA, Pavlick AC, Ernstoff MS, Reardon DA, Puzanov I, Kudchadkar RR, Tarhini AA, Sumbul A, Rizzo JI, Margolin KA. Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204). Neuro Oncol. 2021 Nov 2;23(11):1961-1973. doi: 10.1093/neuonc/noab094.
citation: Tawbi HA, Forsyth PA, Algazi A, Hamid O, Hodi FS, Moschos SJ, Khushalani NI, Lewis K, Lao CD, Postow MA, Atkins MB, Ernstoff MS, Reardon DA, Puzanov I, Kudchadkar RR, Thomas RP, Tarhini A, Pavlick AC, Jiang J, Avila A, Demelo S, Margolin K. Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N Engl J Med. 2018 Aug 23;379(8):722-730. doi: 10.1056/NEJMoa1805453.