An Exploratory Study of Nivolumab With or Without Ipilimumab According to the Percentage of Tumoral CD8 Cells in Participants With Advanced Metastatic Cancer
Overview
- Phase
- Phase 2
- Intervention
- Not specified
- Conditions
- Advanced Metastatic Cancer
- Sponsor
- Parker Institute for Cancer Immunotherapy
- Enrollment
- 100
- Locations
- 6
- Primary Endpoint
- Percentage of Participants Whose Tumors Convert From CD8 Low (<15% Tumoral CD8) to CD8 High (>=15%).
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief 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.
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 with advanced metastatic cancer will be enrolled. 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). Advanced prostate cancer participants with tumoral CD8 ≥ 15% will be enrolled in the nivolumab monotherapy arm. A total of approximately 20 participants with Advanced Prostate Cancer and tumoral CD8 \< 15% will be allocated to 1 of 2 cohorts using combinations of ipilimumab and nivolumab.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participant must be ≥ 18 years of age inclusive, at the time of signing the informed consent.
- •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.
- •Females of childbearing potential must have a negative serum or urine pregnancy test.
- •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.
- •Participants who have received prior immunotherapy, including prior anti-PD-1 or anti-PD-L1 therapies, will be allowed to participate in this study.
- •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.
- •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
- •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
- •Concurrent malignancies are permitted if any one of the following applies:
- •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
Exclusion Criteria
- •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.
- •Pregnant or breastfeeding.
- •Significant gastrointestinal disorder(s) (eg, active Crohn disease or ulcerative colitis or a history of extensive gastric resection and/or small intestinal resection).
- •Has interstitial lung disease or active, noninfectious pneumonitis.
- •Has a transplanted organ or has undergone allogeneic bone marrow transplant.
- •Has received a live vaccine within 30 days prior to first dose.
- •Known hypersensitivity to a component of protocol therapy.
- •a. Participants with known hypersensitivity to ipilimumab and/or nivolumab are excluded.
- •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.
- •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.
Outcomes
Primary Outcomes
Percentage of Participants Whose Tumors Convert From CD8 Low (<15% Tumoral CD8) to CD8 High (>=15%).
Time Frame: From initiation of study intervention through the 2nd on-treatment tumor biopsy, up to 8 months
Percentage of participants in the nivolumab plus ipilimumab ("CD8 low") arm whose tumors convert from CD8 low (\<15%) to CD8 high (\>=15%) as measured by the percentage of tumoral CD8 cells. Participants in the CD8 high arms are not evaluated for this outcome. On-treatment biopsies for the advanced metastatic cancer cohort were scheduled for as early as possible after the 2nd and 4th doses of ipilimumab (Day 2 - 10 of Cycle 2 and Cycle 6, respectively). On-treatment biopsies for the advanced prostate cancer cohort were scheduled for within 3 days (+/-) of the 2nd and 4th doses of nivolumab (Day 22 of Cycle 1 and Cycle 2, respectively).
Clinical Benefit Rate (CBR) of Nivolumab With or Without Ipilimumab
Time Frame: Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy, whichever occurred first, up to 43 months
CBR is defined as the percentage of participants who show clinical benefit, defined as obtaining a complete response (CR; disappearance of all target and non-target lesions), partial response (PR; ≥ 30% decrease in the sum of the longest diameter of target lesions), or stable disease (SD) for ≥ 6 months, as determined by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.
Secondary Outcomes
- Progression-free Survival (PFS)(Initiation of study drug through death, radiographic progression or initiation of new anti-cancer therapy, whichever occurred first, up to 43 months)
- Number of Participants With Treatment-related Adverse Events (TRAE)(From signing informed consent (prior to Screening) through 100 days after last dose, up to 43 months.)
- Objective Response Rate (ORR)(Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy, whichever occurred first, up to 43 months)
- Overall Survival (OS)(From initiation of study drug until death due to any cause, up to 43 months)