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 (CheckMate204)

• ClinicalTrials.gov Identifier: NCT02320058
• Recruitment Status: Completed
• First Posted: December 19, 2014
• Results First Posted: October 5, 2021
• Last Update Posted: October 5, 2021
• Sponsor: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

Tracking Information

• First Submitted Date: December 16, 2014
• First Posted Date: December 19, 2014
• Results First Submitted Date: September 8, 2021
• Results First Posted Date: October 5, 2021
• Last Update Posted Date: October 5, 2021
• Actual Study Start Date: March 5, 2015
• Actual Primary Completion Date: September 8, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 8, 2021)

Intracranial Clinical Benefit Rate (CBR) [ Time Frame: Up to 66 months ]

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.

Original Primary Outcome Measures (submitted: December 16, 2014)

CNS clinical benefit rate (CBR) [ Time Frame: approximately 6 months ]

It is defined as the proportion of all treated subjects whose best overall response is either a Complete Response (CR) or Partial Response (PR) or whose best overall response was standard deviation (SD) with duration of approximately 6 months, as determined by protocol-defined criteria for index lesions of 0.5 cm or greater based on central review according to the protocol-defined response criteria for CNS

Current Secondary Outcome Measures (submitted: September 8, 2021)

• Intracranial Objective Response Rate (ORR) [ Time Frame: Up to 66 months ]
  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.
• Intracranial Progression Free Survival (PFS) [ Time Frame: Up to 66 months ]
  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.
• Extracranial Clinical Benefit Rate (CBR) [ Time Frame: Up to 66 months ]
  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.
• Extracranial Objective Response Rate (ORR) [ Time Frame: Up to 66 months ]
  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.
• Extracranial Progression Free Survival (PFS) [ Time Frame: Up to 66 months ]
  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.
• Global Clinical Benefit Rate (CBR) [ Time Frame: Up to 66 months ]
  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
• Global Objective Response Rate (ORR) [ Time Frame: Up to 66 months ]
  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.
• Global Progression Free Survival (PFS) [ Time Frame: Up to 66 months ]
  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.
• Overall Survival (OS) [ Time Frame: Up to 66 months ]
  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.
• Number of Participants With Adverse Events (AEs) [ Time Frame: From first dose to 30 days post last dose (Up to 66 months) ]
  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)
• Number of Participants Deaths [ Time Frame: Up to 66 months ]
  Number of participants who died due to any cause.
• Number of Participants With Laboratory Abnormalities in Specific Liver Tests [ Time Frame: From first dose to 30 days post last dose (Up to 66 months) ]
  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
• Number of Participants With Laboratory Abnormalities in Specific Thyroid Tests [ Time Frame: From first dose to 30 days post last dose (Up to 66 months) ]
  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

Original Secondary Outcome Measures (submitted: December 16, 2014)

• Extracranial CBR will be calculated using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [ Time Frame: approximately 6 months ]
• Global CBR will be calculated using modified Response Evaluation Criteria in Solid Tumors (mRECIST 1.1), allowing for 0.5 cm index lesions in CNS and will encompass all index lesions in CNS and systemic compartments [ Time Frame: approximately 6 months ]
  CNS, extracranial and global CBR will also be calculated using Immune-related Response Criteria (irRC)
• Overall survival, defined as the time from first dosing date to the date of death, will be estimated using the Kaplan-Meier product-limit method, with subjects censored at their last known date alive [ Time Frame: 5 Years ]
• Safety and tolerability will be measured by the incidence of adverse events, serious adverse events, deaths and laboratory abnormalities [ Time Frame: 3 Years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Melanoma

Intervention

• Drug: Ipilimumab
  Other Name: Yervoy
• Drug: Nivolumab
  Other Names:

  • Opdivo
  • BMS-936558

Study Arms

Experimental: Nivolumab and Ipilimumab

Induction Phase: Nivolumab + Ipilimumab infusion intravenously

Maintenance Phase: Nivolumab infusion intravenously

Interventions:

• Drug: Ipilimumab
• Drug: Nivolumab

Publications *

• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 22, 2018): 119
• Original Estimated Enrollment (submitted: December 16, 2014): 148
• Actual Study Completion Date: September 8, 2020
• Actual Primary Completion Date: September 8, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02320058
• Other Study ID Numbers: CA209-204
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bristol-Myers Squibb
• Original Responsible Party: Same as current
• Current Study Sponsor: Bristol-Myers Squibb
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Bristol-Myers Squibb
• Verification Date: September 2021