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

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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Various Advanced Cancer

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Ipilimumab
* Drug: Relatlimab
* Drug: Daratumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathologic confirmation of the following tumor types (please refer to protocol for full details pertaining to eligible tumor types): Merkel Cell Carcinoma Gastric or Gastro-Esophageal junction carcinoma (No longer enrolling this tumor type) Nasopharyngeal Carcinoma Squamous cell carcinoma (SCC) of the cervix, vagina, or vulva Squamous cell carcinoma of the Head and Neck Squamous cell carcinoma of the anal canal and penis 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

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant Cohort<br>Nivolumab intravenous infusion as specified **Not participating: Japan, Korea, and Taiwan | Drug: Nivolumab<br> <br> |
| Experimental: Metastatic Monotherapy Cohort<br>Nivolumab intravenous infusion as specified | Drug: Nivolumab<br> <br> |
| Experimental: Nivolumab plus Ipilimumab Cohort<br>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 | Drug: Nivolumab<br> <br> Drug: Ipilimumab<br> <br> |
| Experimental: Nivolumab plus Relatlimab Cohort<br>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 | Drug: Nivolumab<br> <br> Drug: Relatlimab<br> <br> * Other names: Anti-LAG 3;|
| Experimental: Nivolumab plus Daratumumab Cohort<br>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 | Drug: Nivolumab<br> <br> Drug: Daratumumab<br> <br> * Other names: Darzalex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neoadjuvant: Number of Participants With Drug-Related Select Adverse Events (AEs) | 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 | From first dose to 30 days post last dose (Up to 2 months) | 
| Neoadjuvant: Number of Participants With Drug-Related Serious Adverse Events (SAEs) | Number of participants with any grade of drug-related serious adverse events (SAEs) in Neoadjuvant cohort | From first dose to 30 days post last dose (Up to 2 months) | 
| Neoadjuvant: Rate of Surgery Delay | 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. Participants with the following diseases will be assessed: HPV positive squamous cell carcinoma of the Head and Neck (SCCHN); HPV negative SCCHN; Cervical Carcinoma; Vaginal/Vulvar Carcinoma; Merkel Cell Carcinoma | Day 29 | 
| Metastatic: Investigator-Assessed Objective Response Rate (ORR) | Objective response rate (ORR) is defined as the percentage of participants with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) 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: EBV positive related gastric cancer; HPV positive SCCHN; Other anogenital HPV associated cancers; GYN (Cervical, Vaginal, Vulvar) carcinoma; Merkel cell carcinoma (MCC); Nasopharyngeal carcinoma (NPC) | From the date of first dose to the date of the initial objectively documented tumor progression or the date of the last tumor assessment prior to subsequent therapy (Up to 65 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metastatic: Investigator-Assessed Duration of Response (DoR) | 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: EBV positive related gastric cancer; HPV positive SCCHN; Other anogenital HPV associated cancers; GYN (Cervical, Vaginal, Vulvar) carcinoma; Merkel cell carcinoma (MCC); Nasopharyngeal carcinoma (NPC) NOTE: Cervical, Randomized and Cervical, Pooled are not mutually exclusive categories. | From first confirmed response (complete response or partial response) to the date of the initial objectively documented tumor progression or death due to any cause, whichever occurs first (Up to 83 months) | 
| Metastatic: Overall Survival (OS) | 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: EBV positive related gastric cancer; HPV positive SCCHN; Other anogenital HPV associated cancers; GYN (Cervical, Vaginal, Vulvar) carcinoma; Merkel cell carcinoma (MCC); Nasopharyngeal carcinoma (NPC) Note: Cervical, Randomized and Cervical, Pooled are not mutually exclusive categories | From the first dosing date to the date of death (Up to 83 months) | 
| Metastatic: Investigator-Assessed Progression-Free Survival (PFS) | 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 cause, whichever occurs first. Participants with the following diseases will be assessed: EBV positive related gastric cancer; HPV positive SCCHN; Other anogenital HPV associated cancers; GYN (Cervical, Vaginal, Vulvar) carcinoma; Merkel cell carcinoma (MCC); Nasopharyngeal carcinoma (NPC) Note: Cervical, Randomized and Cervical, Pooled are not mutually exclusive categories | From the first dosing date to the date of the first documented tumor progression or death due to any cause, whichever occurs first (Up to 83 months) |