Nivolumab With or Without Ipilimumab in Advanced Metastatic Cancer

Phase 2

Completed

Conditions: Advanced Metastatic Cancer
Advanced Prostate Cancer

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

Registration Number: NCT03651271

Lead Sponsor: Parker Institute for Cancer Immunotherapy

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 100

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.
1. 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.
2. 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.
3. 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:
1. 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
2. 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
3. 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).
1. Participants who have liver lesions may be eligible if they have AST and ALT
  
  ≤ 3.0 x ULN.
2. 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.
1. 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).
2. 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
"Hot" tumors for Advanced Metastatic Cancer	Nivolumab Monotherapy	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.
"Hot" tumors for Advanced Prostate Cancer	Nivolumab Monotherapy	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.
"Cold" tumors for Advanced Prostate Cancer Cohort B	Nivolumab and Ipilimumab (5 mg/kg) Combination for Prostate Cancer	Participants with \< 15% CD8 cells in their tumor biopsies (ie, CD8 low tumors) will be treated with nivolumab in combination with ipilimumab.
"Cold" tumors for Advanced Metastatic Cancer	Nivolumab and Ipilimumab and Combination for Metastatic Cancer	Participants with \< 15% CD8 cells in their tumor biopsies (ie, CD8 low tumors) will be treated with nivolumab in combination with ipilimumab.
"Cold" tumors for Advanced Prostate Cancer Cohort A	Nivolumab and Ipilimumab (3 mg/kg) Combination for Prostate Cancer	Participants with \< 15% CD8 cells in their tumor biopsies (ie, CD8 low tumors) will be treated with nivolumab in combination with ipilimumab.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Whose Tumors Convert From CD8 Low (<15% Tumoral CD8) to CD8 High (>=15%).	From initiation of study intervention through the 2nd on-treatment tumor biopsy, up to 8 months	Percentage of participants in the nivolumab plus ipilimumab ("CD8 low") arm whose tumors convert from CD8 low (\<15%) to CD8 high (\>=15%) as measured by the percentage of tumoral CD8 cells. Participants in the CD8 high arms are not evaluated for this outcome. On-treatment biopsies for the advanced metastatic cancer cohort were scheduled for as early as possible after the 2nd and 4th doses of ipilimumab (Day 2 - 10 of Cycle 2 and Cycle 6, respectively). On-treatment biopsies for the advanced prostate cancer cohort were scheduled for within 3 days (+/-) of the 2nd and 4th doses of nivolumab (Day 22 of Cycle 1 and Cycle 2, respectively).
Clinical Benefit Rate (CBR) of Nivolumab With or Without Ipilimumab	Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy, whichever occurred first, up to 43 months	CBR is defined as the percentage of participants who show clinical benefit, defined as obtaining a complete response (CR; disappearance of all target and non-target lesions), partial response (PR; ≥ 30% decrease in the sum of the longest diameter of target lesions), or stable disease (SD) for ≥ 6 months, as determined by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	Initiation of study drug through death, radiographic progression or initiation of new anti-cancer therapy, whichever occurred first, up to 43 months	PFS is defined as the time from initiation of study intervention to the date of first documented radiographic progression of disease or date of death due to any cause, whichever occurred first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Number of Participants With Treatment-related Adverse Events (TRAE)	From signing informed consent (prior to Screening) through 100 days after last dose, up to 43 months.	Investigators recorded adverse events (AEs) during each participant encounter. AE severity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, which grades AEs on a 1 to 5 scale: Grades 1 and 2 indicate mild to moderate events; Grade 3 denotes severe events; Grades 4 and 5 signify life-threatening or fatal outcomes. A TRAE is defined as any event that either occurs after the initiation of study intervention, having been absent at baseline, or, if present at baseline, appears to have worsened in severity or frequency, that is deemed 'Possibly', 'Probably', or 'Definitely' related to the intervention by the Investigator. All TRAEs were collected from the time the participant signed informed consent until 100 days after the last dose of study intervention. Prior to initiation of study intervention, only TRAEs that were related to a protocol mandated intervention, including those that occurred prior to being assigned to a study arm, were reported.
Objective Response Rate (ORR)	Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy, whichever occurred first, up to 43 months	Objective Response Rate (ORR) is defined as the percentage of participants who attain a best overall response of complete response (CR; disappearance of all target and non-target lesions) or partial response (PR; \>= 30% decrease in the sum of the longest diameter of target lesions), as determined by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
Overall Survival (OS)	From initiation of study drug until death due to any cause, up to 43 months	OS is defined as the time from initiation of study intervention until death due to any cause. Participants not reported as having died at the time of analysis were censored at the most recent contact date they were known to be alive.

Trial Locations

Locations (6): University of California, Los Angeles
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Los Angeles, California, United States
University of California, San Francisco
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San Francisco, California, United States
Dana-Farber Cancer Institute
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Boston, Massachusetts, United States
Memorial Sloan Kettering Cancer Center
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New York, New York, United States
M.D. Anderson Cancer Center
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Houston, Texas, United States
Stanford University
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Palo Alto, California, United States