Treatment With Nivolumab and Ipilimumab or Nivolumab Alone According to the Percentage of Tumoral CD8 Cells in Advanced Metastatic Cancer

Study Overview
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Brief Summary
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This is an open-label, exploratory study to evaluate nivolumab with or without ipilimumab based on percentage of tumoral CD8 cells at the time of treatment in participants with varying advanced solid tumors. Participants who have a tumor with ≥ 15% CD8 cells (classified as CD8 high) will receive nivolumab monotherapy, and participants who have a tumor with < 15% CD8 cells (classified as CD8 low) will receive ipilimumab in combination with nivolumab.

Detailed Description
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The aim of this study is to provide a prospective classification of CD8 high (immunologically hot) versus CD8 low (immunologically cold) tumors at the time of treatment, based on the percentage of CD8 cells in a tumor biopsy, and to address the predictive value of the CD8 biomarker for selecting patients for treatment with nivolumab with or without ipilimumab. A total of up to approximately 200 participants with advanced metastatic cancer will be enrolled. Ongoing monitoring for safety and futility will be implemented based on the method of Thall and colleagues (Thall et al, 1995) separately in the CD8 high and CD8 low tumor groups. Single-agent nivolumab will be administered at 360 mg intravenously (IV) every 3 weeks (Q3W). Participants who continue to show clinical benefit after the first disease assessment will receive nivolumab 480 mg IV every 4 weeks (Q4W) until progressive disease (PD) or intolerable toxicity. At PD, participants will be allowed to add ipilimumab. For nivolumab and ipilimumab combination therapy, nivolumab will be administered at 360 mg IV Q3W, and ipilimumab will be administered at 1 mg/kg IV Q3W for the first 2 doses and then every 6 weeks for the 3rd and 4th doses, followed by nivolumab 480 mg IV Q4W until PD or intolerable toxicity. After receipt of the first dose of ipilimumab, the Investigator may determine (based on clinical symptoms) the number of future doses of ipilimumab the participant will receive, for a maximum of 4 doses. Participants who stop ipilimumab dosing early due to toxicities, may start nivolumab maintenance (ie, 4 doses [12 weeks] of nivolumab following the first dose). Advanced prostate cancer participants with tumoral CD8 ≥ 15% will be enrolled in the nivolumab monotherapy arm. A total of approximately 20 participants with Advanced Prostate Cancer and tumoral CD8 < 15% will be allocated to 1 of 2 cohorts using combinations of ipilimumab and nivolumab.

Official Title
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An Exploratory Study of Nivolumab With or Without Ipilimumab According to the Percentage of Tumoral CD8 Cells in Participants With Advanced Metastatic Cancer

Conditions
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Advanced Metastatic Cancer, Advanced Prostate Cancer

Intervention / Treatment
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* Biological: Nivolumab Monotherapy
* Biological: Nivolumab and Ipilimumab and Combination for Metastatic Cancer
* Biological: Nivolumab and Ipilimumab (3 mg/kg) Combination for Prostate Cancer
* Biological: Nivolumab and Ipilimumab (5 mg/kg) Combination for Prostate Cancer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be ≥ 18 years of age inclusive, at the time of signing the informed consent. Male or female participants of child-producing potential must agree to use contraception or avoidance of pregnancy measures during the study and for 7 and 5 months, respectively, after the last dose. Females of childbearing potential must have a negative serum or urine pregnancy test. Histologically or cytologically confirmed cancer that is metastatic, unresectable, or recurrent and are responsive to immunomodulation (ie, with US Prescribing Information [USPI]). Participants who have failed or refused available approved treatment options are eligible to participate. Participants who have received prior immunotherapy, including prior anti-PD-1 or anti-PD-L1 therapies, will be allowed to participate in this study. Participants who received prior anti-PD-1 or anti-PD-L1 may participate only if their prior anti-PD-1 or anti-PD-L1 monotherapy or combination therapy were NOT the last treatment prior to participation on this study. Participants who had prior immunotherapies and experienced Grade 1-2 immune-related adverse event (irAE) must have documentation that their irAEs are ≤ Grade 1 or baseline using current Common Terminology Criteria for Adverse Events v5.0 (CTCAE v5.0) and participants must be off steroid therapy and/or other immunosuppressive therapy, as treatment for irAEs, for ≥ 14 days from Cycle 1, Day 1. Participants who experienced Grade 3 irAEs consisting of laboratory abnormalities that were asymptomatic and have now resolved to ≤ Grade 1 or baseline and participants who have been off steroid and/or other immunosuppressive therapy, as treatment for irAEs, for ≥ 30 days from Cycle 1, Day 1. Concurrent malignancies are permitted if any one of the following applies: Previously treated malignancy for which all treatment of that malignancy was completed at least 2 years before enrollment and no evidence of disease exists, or With agreement from the Sponsor and Principal Investigator (PI), participants who have a concurrent malignancy that is clinically stable and does not require tumor-directed treatment are eligible to participate if the risk of the prior malignancy interfering with either safety or efficacy endpoints is very low, or With agreement from the Sponsor and PI, other malignancies may be permitted if the risk of the prior malignancy interfering with either safety or efficacy end points is very low. Provide newly obtained core needle or incisional biopsy of a tumor lesion not previously irradiated. Fine needle aspiration is not acceptable. a. Biopsies should be obtained from sites that do not pose significant risk to the participant based on the tumor site and the procedure used. Biopsy sites/procedures including, but not limited to, the brain, open lung/mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach, or bowel would be considered to pose a significant risk to the participant. Procedures to areas that are deemed by the Investigator to be of non-significant risk based on individual clinical scenarios will be permitted. Measurable disease as defined by RECIST v1.1. a. Participants who do not have measurable disease by RECIST criteria but whose disease can be objectively measured through tumor markers or another disease specific standard are considered eligible. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN). Participants who have liver lesions may be eligible if they have AST and ALT ≤ 3.0 x ULN. Participants with hepatocellular carcinoma (HCC) may be eligible provided they have AST and ALT that are ≤ 5.0 x ULN. Hemoglobin ≥ 9 g/dL. Total bilirubin ≤ 1.5 × ULN. Participants with liver lesions who do not have HCC and who have a total bilirubin < 2.0 x ULN may be eligible. Participants with HCC are eligible provided they have total bilirubin < 3.0 x ULN and are considered Child-Pugh Class A or Child-Pugh Class B7 (Child-Pugh Class B with a total Child-Pugh score not to exceed 7). Participants with Gilbert syndrome must have ≤ 3 x ULN and no liver lesions. Creatinine clearance should be ≥ 30 mL/min as estimated by the Cockcroft-Gault equation. Absolute neutrophil count ≥ 1.0 x 109/L. Platelets count ≥ 75 x 109/L. Participants must be capable of giving signed informed consent. Evidence of stage IV prostate cancer (as defined by American Joint Committee of Cancer criteria) on previous bone, CT and/or MRI scan. Ongoing androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone (GnRH) analogue or a surgical/medical castration with testosterone level of ≤ 1.73 nmol/L (< 50 ng/dL). Participants with skeletal system symptoms who are already on medications (eg, bisphosphonates and/or RANK ligand inhibitors) to strengthen bones are allowed if they were started ˃ 28 days before the first dose of study treatment. Participants must have measurable disease per RECIST v 1.1. Have received and progressed on prior secondary androgen receptor signaling inhibitor therapy (eg, abiraterone, enzalutamide, apalutamide). Exclusion Criteria: Participants who had a medical condition that required a surgical procedure and were subject to general anesthesia within 4 weeks prior to beginning protocol therapy are excluded except the use of general anesthesia during biopsy procedures, indicated for patient comfort and or safety will be permitted. Pregnant or breastfeeding. Significant gastrointestinal disorder(s) (eg, active Crohn disease or ulcerative colitis or a history of extensive gastric resection and/or small intestinal resection). Has interstitial lung disease or active, noninfectious pneumonitis. Has a transplanted organ or has undergone allogeneic bone marrow transplant. Has received a live vaccine within 30 days prior to first dose. Known hypersensitivity to a component of protocol therapy. a. Participants with known hypersensitivity to ipilimumab and/or nivolumab are excluded. Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or on mild exertion), uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements. Abnormal electrocardiograms (ECGs) that are clinically significant, clinically significant cardiac enlargement or hypertrophy, new bundle branch block or existing left bundle branch block, or signs of new, active ischemia. a. Participants with evidence of prior infarction who are New York Heart Association (NYHA) functional class II, III, or IV are excluded, as are participants with marked arrhythmia such as Wolff Parkinson White pattern or complete atrioventricular dissociation.* *Participants with complete or incomplete atrioventricular dissociation who have a pacemaker may be eligible for enrollment provided they are NYHA functional class I: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath). Participants who experienced any ≥ Grade 3 symptomatic irAE on a prior immunotherapy study will be excluded from this study regardless of resolution of the irAE. Any known, untreated, brain metastases. Treated participants must be stable 4 weeks after completion of treatment for brain metastases, and image-documented stability is required. Participants must have no clinical symptoms from brain metastases and have not required systemic corticosteroids > 10 mg/day prednisone or equivalent for ≥ 2 weeks prior to first dose of study intervention. Has an active autoimmune disease requiring immunosuppression except for participants with isolated vitiligo, resolved childhood asthma or atopic dermatitis, controlled hypoadrenalism or hypopituitarism, and euthyroid participants with a history of Graves' disease. a. Participants with controlled hyperthyroidism must be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid-stimulating immunoglobulin prior to study intervention administration. Anticancer chemotherapy, radiotherapy, immunotherapy, or investigational agents within 14 days of first dose of study intervention, provided that all treatment-related AEs have resolved.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hot tumors for Advanced Metastatic Cancer<br>Participants with ≥ 15% CD8 cells in their tumor biopsies (ie, CD8 high tumors) will be treated with single-agent nivolumab. At PD, participants will be allowed to add ipilimumab. | Biological: Nivolumab Monotherapy<br>* Single-agent nivolumab will be administered at 360 mg IV Q3W. Participants who continue to show clinical benefit after the first disease assessment will receive nivolumab 480 mg IV Q4W until PD or intolerable toxicity.<br>|
| Experimental: Cold tumors for Advanced Metastatic Cancer<br>Participants with < 15% CD8 cells in their tumor biopsies (ie, CD8 low tumors) will be treated with nivolumab in combination with ipilimumab. | Biological: Nivolumab and Ipilimumab and Combination for Metastatic Cancer<br>* For nivolumab and ipilimumab combination therapy, nivolumab will be administered at 360 mg IV Q3W, and ipilimumab will be administered at 1 mg/kg IV Q3W for the first 2 doses and then Q6W for the 3rd and 4th doses, followed by single-agent nivolumab 480 mg IV Q4W until PD or intolerable toxicity.<br>|
| Experimental: Hot tumors for Advanced Prostate Cancer<br>Participants with ≥ 15% CD8 cells in their tumor biopsies (ie, CD8 high tumors) will be treated with single-agent nivolumab. At PD, participants will be allowed to add ipilimumab. | Biological: Nivolumab Monotherapy<br>* Single-agent nivolumab will be administered at 360 mg IV Q3W. Participants who continue to show clinical benefit after the first disease assessment will receive nivolumab 480 mg IV Q4W until PD or intolerable toxicity.<br>|
| Experimental: Cold tumors for Advanced Prostate Cancer Cohort A<br>Participants with < 15% CD8 cells in their tumor biopsies (ie, CD8 low tumors) will be treated with nivolumab in combination with ipilimumab. | Biological: Nivolumab and Ipilimumab (3 mg/kg) Combination for Prostate Cancer<br>* For nivolumab and ipilimumab combination therapy, CD8 low arm, approximately 10 participants will be randomly allocated into 1 of 2 cohorts, using different doses of ipilimumab administered in 6-week cycles. Participants assigned to Prostate Cohort A will receive nivolumab 1 mg/kg Q3W and ipilimumab 3 mg/kg every 6 weeks (Q6W) for 2 cycles, then nivolumab maintenance 480 mg Q4W until PD or intolerable toxicity. If the safety profile of Prostate Cohort B is deemed unacceptable, an additional 10 participants will be enrolled in Prostate Cohort A.<br>|
| Experimental: Cold tumors for Advanced Prostate Cancer Cohort B<br>Participants with < 15% CD8 cells in their tumor biopsies (ie, CD8 low tumors) will be treated with nivolumab in combination with ipilimumab. | Biological: Nivolumab and Ipilimumab (5 mg/kg) Combination for Prostate Cancer<br>* For nivolumab and ipilimumab combination therapy, CD8 low arm, approximately 10 participants will be randomly allocated into 1 of 2 cohorts, using different doses of ipilimumab administered in 6-week cycles. Participants assigned to Prostate Cohort B will receive nivolumab 1 mg/kg Q3W and ipilimumab 5 mg/kg Q6W for 2 cycles, then nivolumab maintenance 480 mg Q4W until PD or intolerable toxicity. If Prostate Cohort B is determined to have a tolerable safety profile, an additional 10 participants will be enrolled to receive nivolumab 1 mg/kg Q3W and ipilimumab 5 mg/kg Q6W for 2 cycles, then nivolumab maintenance 480 mg Q4W until PD or intolerable toxicity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical benefit rate (CBR) of nivolumab with or without ipilimumab | The proportion of participants who show clinical benefit, defined as complete response (CR), partial response (PR), or stable disease (SD) for ≥ 6 months as best response by RECIST v1.1 | 2 years | 
| Percentage of CD8 cells in on-treatment biopsies | Proportion of participants in the nivolumab plus ipilimumab arm whose tumors will change from CD8 low to CD8 high as measured by a change in the percentage of tumoral CD8 cells | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of nivolumab with or without ipilimumab measured by AEs based on CTCAE v5.0 | Number and percentage of subjects with adverse events (AEs), serious adverse events (SAEs), and trial-limiting toxicity (TOX) | 2 years | 
| Objective response rate (ORR) of nivolumab with or without ipilimumab in participants | ORR defined as CR or PR as best response by RECIST v1.1 assessment | 2 years | 
| The association of the percentage of CD8 cells in tumor samples with clinical outcomes | Percentage of CD8 cells in tumor tissue will be measured at baseline for treatment assignment and again after 2 doses | 2 years |