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 will be enrolled. However, to account for
unexpected challenges in obtaining information on the percentage of tumoral CD8 cells,
enrollment to initial biopsy may be about 10% higher (ie, ~220 participants). 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).
1. Participant must be ≥ 18 years of age inclusive, at the time of signing the informed
2. 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.
3. Females of childbearing potential must have a negative serum or urine pregnancy test.
4. 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.
5. 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.
6. 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,
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.
7. 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.
8. 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.
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
10. 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.
11. Hemoglobin ≥ 9 g/dL.
12. 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.
13. Creatinine clearance should be ≥ 30 mL/min as estimated by the Cockcroft-Gault
14. Absolute neutrophil count ≥ 1.0 x 109/L.
15. Platelets count ≥ 75 x 109/L.
16. Participants must be capable of giving signed informed consent.
1. Had a surgical procedure requiring general anesthesia within 4 weeks prior to
beginning protocol therapy.
2. Pregnant or breastfeeding.
3. Significant gastrointestinal disorder(s) (eg, active Crohn disease or ulcerative
colitis or a history of extensive gastric resection and/or small intestinal
4. Has interstitial lung disease or active, noninfectious pneumonitis.
5. Has a transplanted organ or has undergone allogeneic bone marrow transplant.
6. Has received a live vaccine within 30 days prior to first dose.
7. Known hypersensitivity to a component of protocol therapy.
a. Participants with known hypersensitivity to ipilimumab and/or nivolumab are
8. 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
9. 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
*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)."
10. 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.
11. 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.
12. 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
a. Participants with controlled hyperthyroidism must be negative for thyroglobulin and
thyroid peroxidase antibodies and thyroid-stimulating immunoglobulin prior to study
13. Anticancer chemotherapy, radiotherapy, immunotherapy, or investigational agents within
14 days of first dose of study intervention, provided that all treatment-related AEs