Clinical Trials /

Treatment With Nivolumab and Ipilimumab or Nivolumab Alone According to the Percentage of Tumoral CD8 Cells in Advanced Metastatic Cancer

NCT03651271

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Treatment With Nivolumab and Ipilimumab or Nivolumab Alone According to the Percentage of Tumoral CD8 Cells in Advanced Metastatic Cancer
  • 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

Clinical Trial IDs

  • ORG STUDY ID: PICI0025
  • NCT ID: NCT03651271

Conditions

  • Advanced Metastatic Cancer

Interventions

DrugSynonymsArms
NivolumabOpdivo"Hot" tumors
IpilimumabYervoy"Cold" tumors

Purpose

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 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).
    

Trial Arms

NameTypeDescriptionInterventions
"Hot" tumorsExperimentalParticipants 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.
  • Nivolumab
"Cold" tumorsExperimentalParticipants with < 15% CD8 cells in their tumor biopsies (ie, CD8 low tumors) will be treated with nivolumab in combination with ipilimumab.
  • Nivolumab
  • Ipilimumab

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.

        Exclusion Criteria:

          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
             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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Clinical benefit rate (CBR) of nivolumab with or without ipilimumab
Time Frame:2 years
Safety Issue:
Description:The proportion of participants who show clinical benefit, defined as complete response (CR), partial response (PR), or stable disease (SD) for ≥ 6 months as best response by RECIST v1.1

Secondary Outcome Measures

Measure:Safety of nivolumab with or without ipilimumab measured by AEs based on CTCAE v5.0
Time Frame:2 years
Safety Issue:
Description:Number and percentage of subjects with adverse events (AEs), serious adverse events (SAEs), and trial-limiting toxicity (TOX)
Measure:Objective response rate (ORR) of nivolumab with or without ipilimumab in participants
Time Frame:2 years
Safety Issue:
Description:ORR defined as CR or PR as best response by RECIST v1.1 assessment
Measure:The association of the percentage of CD8 cells in tumor samples with clinical outcomes
Time Frame:2 years
Safety Issue:
Description:Percentage of CD8 cells in tumor tissue will be measured at baseline for treatment assignment and again after 2 doses

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Parker Institute for Cancer Immunotherapy

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