Nivolumab With or Without Ipilimumab in Advanced Metastatic Cancer

Not Recruiting

Trial ID: NCT03651271


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.

Official Title

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

Stanford Investigator(s)

Saad A. Khan, MD
Saad A. Khan, MD

Associate Professor of Medicine (Oncology)


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.


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

Not Recruiting

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Aja Macias

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