Nivolumab With or Without Ipilimumab in Advanced Metastatic Cancer
Condition: Advanced Metastatic Cancer; Advanced Prostate Cancer
MeSH terms: Neoplasm Metastasis; Neoplasms; Neoplasms, Second Primary
Intervention: Nivolumab Monotherapy; Nivolumab and Ipilimumab and Combination for Metastatic Cancer; Nivolumab and Ipilimumab (3 mg/kg) Combination for Prostate Cancer; Nivolumab and Ipilimumab (5 mg/kg) Combination for Prostate Cancer
Intervention description: 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.; 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.; 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.; 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.
Intervention MeSH terms: Nivolumab; Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 100.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Participant must be ≥ 18 years of age inclusive, at the time of signing the informed
             consent.

          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,
                  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.

          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
             equation.

         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
             resection).

          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
             excluded.

          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
             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)."

         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.