An Exploratory Study of Nivolumab with or without Ipilimumab According to the Percentage of Tumoral CD8 Cells in Participants with Advanced Metastatic Cancer

Protocol # :
Advanced Metastatic Cancer
Advanced Prostate Cancer
Feasibility / Pilot
Disease Sites
Gastroesophageal Junction
Lip, Oral Cavity and Pharynx
Small Intestine
Other Digestive Organ
Other Respiratory and Intrathoracic Organs
Bones and Joints
Soft Tissue
Mycosis Fungoides
Other Skin
Corpus Uteri
Other Female Genital
Other Male Genital
Urinary Bladder
Other Urinary
Eye and Orbit
Brain and Nervous System
Other Hematopoietic
Unknown Sites
Ill-Defined Sites
Other Endocrine System
Non-Hodgkin's Lymphoma
Hodgkin's Lymphoma
Multiple Myeloma
Lymphoid Leukemia
Myeloid and Monocytic Leukemia
Leukemia, other
Kaposi's Sarcoma
Melanoma, Skin
Principal Investigator
Hodi, Frank, Stephen
Site Research Nurses
Baylies, Rosemarie
Carey, Margaret, M.
Gillen Mckay, Christine, A.
Kelley, Kristina
Rang, Bethany
Rowan, Jennifer, M.

Trial Description

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.

Eligibility Requirements

Inclusion Criteria:

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.

17. Evidence of stage IV prostate cancer (as defined by American Joint Committee of Cancer
criteria) on previous bone, CT and/or MRI scan.

18. 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).

19. 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.

20. Participants must have measurable disease per RECIST v 1.1.

21. Have received and progressed on prior secondary androgen receptor signaling inhibitor
therapy (eg, abiraterone, enzalutamide, apalutamide).

Exclusion Criteria:

1. 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.

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
study requirements.

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
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.

13. Anticancer chemotherapy, radiotherapy, immunotherapy, or investigational agents within
14 days of first dose of study intervention, provided that all treatment-related AEs
have resolved.