An Investigational Immuno-therapy Study to Investigate the Safety and Effectiveness of Nivolumab, and Nivolumab Combination Therapy in Virus-associated Tumors (CheckMate358)

• ClinicalTrials.gov Identifier: NCT02488759
• Recruitment Status: Completed
• First Posted: July 2, 2015
• Results First Posted: April 12, 2022
• Last Update Posted: December 13, 2022
• Sponsor: Bristol-Myers Squibb
• Collaborator: Ono Pharmaceutical Co. Ltd
• Information provided by (Responsible Party): Bristol-Myers Squibb

Tracking Information

• First Submitted Date: June 30, 2015
• First Posted Date: July 2, 2015
• Results First Submitted Date: March 17, 2022
• Results First Posted Date: April 12, 2022
• Last Update Posted Date: December 13, 2022
• Actual Study Start Date: October 13, 2015
• Actual Primary Completion Date: March 19, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 4, 2022)

• Neoadjuvant: Number of Participants With Drug-Related Select Adverse Events (AEs) [ Time Frame: From first dose to 30 days post last dose (Up to 2 months) ]
  Number of participants with any grade of drug-related select adverse events (AEs) including endocrine, gastrointestinal, hepatic, pulmonary, renal, skin, and hypersensitivity AEs in Neoadjuvant cohort
• Neoadjuvant: Number of Participants With Drug-Related Serious Adverse Events (SAEs) [ Time Frame: From first dose to 30 days post last dose (Up to 2 months) ]
  Number of participants with any grade of drug-related serious adverse events (SAEs) in Neoadjuvant cohort
• Neoadjuvant: Rate of Surgery Delay [ Time Frame: Day 29 ]
  Rate of surgery delay is defined as the percentage of participants in the neoadjuvant cohort with surgery delayed > 4 weeks from the planned surgery date or planned start date for chemoradiation due to a drug-related adverse event
• Metastatic: Investigator-Assessed Objective Response Rate (ORR) [ Time Frame: Up to 72 months ]
  Objective response rate (ORR) is defined as the the number of participants with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) divided by the number of treated participants using RECIST 1.1 criteria. An ORR in excess of 10% will be considered of clinical interest, and an ORR of 25% or greater will be considered of strong clinical interest. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants with the following diseases will be assessed:

  1. EBV positive related gastric cancer;
  2. HPV positive SCCHN;
  3. Other anogenital HPV associated cancers;
  4. GYN (Cervical, Vaginal, Vulvar) carcinoma;
  5. Merkel cell carcinoma (MCC);
  6. Nasopharyngeal carcinoma (NPC)

Original Primary Outcome Measures (submitted: June 30, 2015)

• The safety and tolerability will be measured by the incidence of drug-related adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: 6 months after the last patient receives their first dose ]
• The investigator-assessed objective response rate (ORR) of nivolumab monotherapy in subjects in the metastatic cohort [ Time Frame: 6 months after the last patient receives their first dose ]
• Rate of surgery delay [ Time Frame: 6 months after the last patient receives their first dose ]
  Rate of surgery delay which is defined as the proportion of subjects in the neoadjuvant cohort with surgery delayed > 4 weeks due to a drug related AE

Current Secondary Outcome Measures (submitted: May 4, 2022)

• Metastatic: Investigator-Assessed Duration of Response (DoR) [ Time Frame: Up to 72 months ]
  Duration of response (DoR) is defined as the time from first confirmed response (complete response or partial response) to the date of the initial objectively documented tumor progression as determined per investigator assessment using RECIST 1.1 criteria or death due to any cause, whichever occurs first. Participants with the following diseases will be assessed:

  1. EBV positive related gastric cancer;
  2. HPV positive SCCHN;
  3. Other anogenital HPV associated cancers;
  4. GYN (Cervical, Vaginal, Vulvar) carcinoma;
  5. Merkel cell carcinoma (MCC);
  6. Nasopharyngeal carcinoma (NPC)
• Metastatic: Overall Survival (OS) [ Time Frame: Up to 72 months ]
  Overall survival (OS) is defined as the time from first dosing date to the date of death. A participant who has not died will be censored at last known date alive. Participants with the following diseases will be assessed:

  1. EBV positive related gastric cancer;
  2. HPV positive SCCHN;
  3. Other anogenital HPV associated cancers;
  4. GYN (Cervical, Vaginal, Vulvar) carcinoma;
  5. Merkel cell carcinoma (MCC);
  6. Nasopharyngeal carcinoma (NPC)
• Metastatic: Investigator-Assessed Progression-Free Survival (PFS) [ Time Frame: Up to 72 months ]
  Investigator-assessed progression free survival (PFS) is defined as the time from first dosing date to the date of the first documented tumor progression, as determined by investigators (per RECIST 1.1), or death due to any. Participants with the following diseases will be assessed:

  1. EBV positive related gastric cancer;
  2. HPV positive SCCHN;
  3. Other anogenital HPV associated cancers;
  4. GYN (Cervical, Vaginal, Vulvar) carcinoma;
  5. Merkel cell carcinoma (MCC);
  6. Nasopharyngeal carcinoma (NPC)

Original Secondary Outcome Measures (submitted: June 30, 2015)

• The percent change from baseline of immune cells of viral specific T cells in tumor specific subsets of nivolumab treated subjects [ Time Frame: Approximately 3 years ]
• The percent change from baseline of select immune activation/inhibitory molecules of viral specific T cells in tumor specific subsets of nivolumab treated subjects [ Time Frame: Approximately 3 years ]
• Progression-free survival in subjects with nivolumab monotherapy [ Time Frame: Approximately 3 years ]
• Overall survival in subjects with nivolumab monotherapy [ Time Frame: Approximately 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 Investigate the Safety and Effectiveness of Nivolumab, and Nivolumab Combination Therapy in Virus-associated Tumors
• Official Title: Non-Comparative, Open-Label, Multiple Cohort, Phase 1/2 Study of Nivolumab Monotherapy and Nivolumab Combination Therapy in Subjects With Virus-Positive and Virus-Negative Solid Tumors

Brief Summary

The purpose of this study to investigate the safety and effectiveness of nivolumab, and nivolumab combination therapy, to treat patients who have virus-associated tumors. Certain viruses have been known to play a role in tumor formation and growth. This study will investigate the effects of the study drugs, in patients who have the following types of tumors:

• Anal canal cancer-No longer enrolling this tumor type
• Cervical cancer
• Epstein Barr Virus (EBV) positive gastric cancer-No longer enrolling this tumor type
• Merkel Cell Cancer
• Penile cancer-No longer enrolling this tumor type
• Vaginal and vulvar cancer-No longer enrolling this tumor type
• Nasopharyngeal Cancer - No longer enrolling this tumor type
• Head and Neck Cancer - No longer enrolling this tumor type

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Various Advanced Cancer

Intervention

• Drug: Nivolumab
• Drug: Ipilimumab
• Drug: Relatlimab
  Other Names:

  • BMS-986016
  • Anti-LAG 3
• Drug: Daratumumab
  Other Name: Darzalex

Study Arms

• Experimental: Neoadjuvant Cohort

  Nivolumab intravenous infusion as specified

  **Not participating: Japan, Korea, and Taiwan

  Intervention: Drug: Nivolumab
• Experimental: Metastatic Monotherapy Cohort
  Nivolumab intravenous infusion as specified
  Intervention: Drug: Nivolumab
• Experimental: Nivolumab plus Ipilimumab Cohort

  Nivolumab intravenous infusion as specified with Ipilimumab intravenous infusion as specified

  **Not participating: Belgium, France and Germany

  Cohort expansion participating countries: Spain, US, UK, Netherlands, Japan and Mexico

  **Not participating in cohort expansion: France, Germany, Korea and Taiwan

  Interventions:

  • Drug: Nivolumab
  • Drug: Ipilimumab
• Experimental: Nivolumab plus Relatlimab Cohort

  Nivolumab intravenous infusion as specified with Relatlimab intravenous infusion as specified

  ** Not Participating: Belgium, Germany, France, Japan, Korea, Taiwan, UK, and Netherlands

  Enrollment is closed for this cohort

  Interventions:

  • Drug: Nivolumab
  • Drug: Relatlimab
• Experimental: Nivolumab plus Daratumumab Cohort

  Nivolumab intravenous infusion as specified with Daratumumab intravenous infusion as specified

  **Not Participating: Belgium, Germany, France, Japan, Korea, Taiwan, UK, and Netherlands

  Enrollment is closed for this cohort

  Interventions:

  • Drug: Nivolumab
  • Drug: Daratumumab

Publications *

• Ferris RL, Spanos WC, Leidner R, Goncalves A, Martens UM, Kyi C, Sharfman W, Chung CH, Devriese LA, Gauthier H, Chiosea SI, Vujanovic L, Taube JM, Stein JE, Li J, Li B, Chen T, Barrows A, Topalian SL. Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial. J Immunother Cancer. 2021 Jun;9(6):e002568. doi: 10.1136/jitc-2021-002568. Erratum In: J Immunother Cancer. 2021 Aug;9(8):
• Topalian SL, Bhatia S, Amin A, Kudchadkar RR, Sharfman WH, Lebbe C, Delord JP, Dunn LA, Shinohara MM, Kulikauskas R, Chung CH, Martens UM, Ferris RL, Stein JE, Engle EL, Devriese LA, Lao CD, Gu J, Li B, Chen T, Barrows A, Horvath A, Taube JM, Nghiem P. Neoadjuvant Nivolumab for Patients With Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial. J Clin Oncol. 2020 Aug 1;38(22):2476-2487. doi: 10.1200/JCO.20.00201. Epub 2020 Apr 23.
• Naumann RW, Hollebecque A, Meyer T, Devlin MJ, Oaknin A, Kerger J, Lopez-Picazo JM, Machiels JP, Delord JP, Evans TRJ, Boni V, Calvo E, Topalian SL, Chen T, Soumaoro I, Li B, Gu J, Zwirtes R, Moore KN. Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial. J Clin Oncol. 2019 Nov 1;37(31):2825-2834. doi: 10.1200/JCO.19.00739. Epub 2019 Sep 5.
• Appelbaum J, Wells D, Hiatt JB, Steinbach G, Stewart FM, Thomas H, Nghiem P, Kapur RP, Thompson JA, Bhatia S. Fatal enteric plexus neuropathy after one dose of ipilimumab plus nivolumab: a case report. J Immunother Cancer. 2018 Aug 31;6(1):82. doi: 10.1186/s40425-018-0396-9.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 17, 2022): 578
• Original Estimated Enrollment (submitted: June 30, 2015): 200
• Actual Study Completion Date: October 24, 2022
• Actual Primary Completion Date: March 19, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histopathologic confirmation of the following tumor types (please refer to protocol for full details pertaining to eligible tumor types):

  1. Merkel Cell Carcinoma
  2. Gastric or Gastro-Esophageal junction carcinoma (No longer enrolling this tumor type)
  3. Nasopharyngeal Carcinoma
  4. Squamous cell carcinoma (SCC) of the cervix, vagina, or vulva
  5. Squamous cell carcinoma of the Head and Neck
  6. Squamous cell carcinoma of the anal canal and penis
  7. Recurrent/metastatic SCC of the cervix not amenable to curative treatment with surgery and/or radiation therapy who are unsuitable for platinum-based therapy may enroll in the cervical cancer Combination B expansion cohort
• Measurable disease by CT or MRI
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Patient willing to comply to provide tumor tissue (archival or fresh biopsy specimen)
• Men and women of age 18 or older

Exclusion Criteria:

• Active brain metastases or leptomeningeal metastases
• Patients with active, known or suspected autoimmune disease
• Patients with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications
• Patients with hepatitis
• Patients with HIV
• Pregnant or breastfeeding women

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: Belgium, France, Germany, Japan, Korea, Republic of, Mexico, Netherlands, Spain, Taiwan, United Kingdom, United States
• Removed Location Countries: Argentina, Romania

Administrative Information

• NCT Number: NCT02488759
• Other Study ID Numbers: CA209-358; 2015-000230-29 ( EudraCT Number )
• 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: Ono Pharmaceutical Co. Ltd

Investigators

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

• PRS Account: Bristol-Myers Squibb
• Verification Date: November 2022