Nivolumab With or Without Ipilimumab in Advanced Metastatic Cancer

NCT03651271 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: PICI0025
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 6

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.

Conditions

Advanced Metastatic Cancer; Advanced Prostate Cancer

Outcome Measures

Primary Outcomes (2)

• Clinical Benefit Rate (CBR) of Nivolumab With or Without Ipilimumab

  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.

  Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy, whichever occurred first, up to 43 months

• Percentage of Participants Whose Tumors Convert From CD8 Low (<15% Tumoral CD8) to CD8 High (>=15%).

  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).

  From initiation of study intervention through the 2nd on-treatment tumor biopsy, up to 8 months

Secondary Outcomes (4)

• 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

• 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

• Overall Survival (OS)

  From initiation of study drug until death due to any cause, up to 43 months

Study Arms (5)

"Hot" tumors for Advanced Metastatic Cancer

EXPERIMENTAL

Participants 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.

Biological: Nivolumab Monotherapy

"Cold" tumors for Advanced Metastatic Cancer

EXPERIMENTAL

Participants with \< 15% CD8 cells in their tumor biopsies (ie, CD8 low tumors) will be treated with nivolumab in combination with ipilimumab.

Biological: Nivolumab and Ipilimumab and Combination for Metastatic Cancer

"Hot" tumors for Advanced Prostate Cancer

EXPERIMENTAL

Participants 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.

Biological: Nivolumab Monotherapy

"Cold" tumors for Advanced Prostate Cancer Cohort A

EXPERIMENTAL

Participants with \< 15% CD8 cells in their tumor biopsies (ie, CD8 low tumors) will be treated with nivolumab in combination with ipilimumab.

Biological: Nivolumab and Ipilimumab (3 mg/kg) Combination for Prostate Cancer

"Cold" tumors for Advanced Prostate Cancer Cohort B

EXPERIMENTAL

Participants with \< 15% CD8 cells in their tumor biopsies (ie, CD8 low tumors) will be treated with nivolumab in combination with ipilimumab.

Biological: Nivolumab and Ipilimumab (5 mg/kg) Combination for Prostate Cancer

Interventions

Nivolumab Monotherapy BIOLOGICAL

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.

"Hot" tumors for Advanced Metastatic Cancer; "Hot" tumors for Advanced Prostate Cancer

Nivolumab and Ipilimumab and Combination for Metastatic Cancer BIOLOGICAL

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.

"Cold" tumors for Advanced Metastatic Cancer

Nivolumab and Ipilimumab (3 mg/kg) Combination for Prostate Cancer BIOLOGICAL

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.

"Cold" tumors for Advanced Prostate Cancer Cohort A

Nivolumab and Ipilimumab (5 mg/kg) Combination for Prostate Cancer BIOLOGICAL

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.

"Cold" tumors for Advanced Prostate Cancer Cohort B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 1.
• 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.
• 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
• 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
• 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.
• 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.
• Measurable disease as defined by RECIST v1.1.

You may not qualify if:

• 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.
• 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)."
• 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.
• 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.
• 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.

Sponsors & Collaborators

• Parker Institute for Cancer Immunotherapy: lead
• Bristol-Myers Squibb: collaborator
• Cancer Research Institute, New York City: collaborator

Study Sites (6)

University of California, Los Angeles

Los Angeles, California, 90095, United States

Location

Stanford University

Palo Alto, California, 94304, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

M.D. Anderson Cancer Center

Houston, Texas, 77030, United States

Location

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Related Links

• Yervoy (ipilimumab) US Prescribing Information (USPI), April 2018
• Opdivo (nivolumab) US Prescribing Information (USPI), April 2018

MeSH Terms

Interventions

Nivolumab; Ipilimumab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Ute Dugan
• Organization: Parker Institute for Cancer Immunotherapy

udugan@parkerici.org

203-379-6757

Study Officials

• Parker Institute for Cancer Immunotherapy

  Parker Institute for Cancer Immunotherapy

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 27, 2018
• First Posted: August 29, 2018
• Study Start: October 17, 2018
• Primary Completion: June 30, 2023
• Study Completion: June 30, 2023
• Last Updated: February 7, 2024
• Results First Posted: January 17, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)