Phase I Biomarker Study (BMS-936558)

An Exploratory Study to Investigate the Immunomodulatory Activity of Various Dose Levels of Anti Programmed-Death-1 (PD-1) Antibody (BMS-936558) in Subjects With Metastatic Clear Cell Renal Cell Carcinoma (RCC).

The purpose of this study is to evaluate the pharmacodynamic and biologic properties of BMS-936558 in subjects with metastatic renal cell carcinoma.

Study Overview

• Status: Completed
• Conditions: Renal Cell Carcinoma
• Intervention / Treatment: Drug: BMS-936558 (Anti-PD-1); Drug: BMS-936558 (Anti-PD-1); Drug: BMS-936558 (Anti-PD-1)

Detailed Description

Intervention Model: Parallel Dose Comparison

• Study Type: Interventional
• Enrollment (Actual): 119
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Villejuif Cedex, France, 94805
    • Local Institution
• Spain
  • Pamplona, Spain, 31192
    • Local Institution
• United States
  • California
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • The Bunting-Blaustein Cancer Research Building
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Inst
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Portland Med Ctr
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Cancer Pavilion
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin Carbone Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Women and men ≥ 18 years of age.
• Histologic confirmation of renal cell carcinoma with a clear cell component.
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST).
• Tumor sites that can be accessed for repeat biopsies at acceptable clinical risk.
• Previously treated subjects must have failed at least 1 prior anti-angiogenic agent and can have a maximum of 3 prior systemic treatments for renal cell cancer.
• Subjects in the treatment naive arm cannot have received prior systemic therapy for their renal cell carcinoma.

Exclusion Criteria:

• Active or progressing brain metastases.
• Active concomitant.
• Active or history of autoimmune disease.
• Active use of systemic corticosteroids.
• Prior therapy with Cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA4), anti Programmed death-1 (anti-PD1), anti Programmed death ligand 1 (anti-PD-L1), anti Programmed death ligand 2 (anti-PD-L2), anti-CD137, anti-CD40, anti-OX40 antibodies.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: BMS-936558	Drug: BMS-936558 (Anti-PD-1); Solution, Intravenous infusion, 0.3 mg/kg, Every 3 weeks, Indefinitely depending on response; Drug: BMS-936558 (Anti-PD-1); Solution, Intravenous infusion, 2 mg/kg, Every 3 weeks, Indefinitely depending on response; Drug: BMS-936558 (Anti-PD-1); Solution, Intravenous infusion, 10 mg/kg, Every 3 weeks, Indefinitely depending on response
Experimental: Arm 2: BMS-936558	Drug: BMS-936558 (Anti-PD-1); Solution, Intravenous infusion, 0.3 mg/kg, Every 3 weeks, Indefinitely depending on response; Drug: BMS-936558 (Anti-PD-1); Solution, Intravenous infusion, 2 mg/kg, Every 3 weeks, Indefinitely depending on response; Drug: BMS-936558 (Anti-PD-1); Solution, Intravenous infusion, 10 mg/kg, Every 3 weeks, Indefinitely depending on response
Experimental: Arm 3: BMS-936558	Drug: BMS-936558 (Anti-PD-1); Solution, Intravenous infusion, 0.3 mg/kg, Every 3 weeks, Indefinitely depending on response; Drug: BMS-936558 (Anti-PD-1); Solution, Intravenous infusion, 2 mg/kg, Every 3 weeks, Indefinitely depending on response; Drug: BMS-936558 (Anti-PD-1); Solution, Intravenous infusion, 10 mg/kg, Every 3 weeks, Indefinitely depending on response
Experimental: Arm 4: BMS-936558; (treatment naive)	Drug: BMS-936558 (Anti-PD-1); Solution, Intravenous infusion, 0.3 mg/kg, Every 3 weeks, Indefinitely depending on response; Drug: BMS-936558 (Anti-PD-1); Solution, Intravenous infusion, 2 mg/kg, Every 3 weeks, Indefinitely depending on response; Drug: BMS-936558 (Anti-PD-1); Solution, Intravenous infusion, 10 mg/kg, Every 3 weeks, Indefinitely depending on response

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Activated and Memory T Cells	The objective of the study was to investigate the pharmacodynamic immunomodulatory activity of anti-PD-1 antibody in activated and memory T cells with metastatic clear-cell Renal Cell Carcinoma (RCC)	Baseline, Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 8, Cycle 2 Day 8, Cycle 4 Day 1
Mean Serum Cytokines: CXCL9	Objective is to investigate the pharmacodynamic immunomodulatory activity of serum chemokines (CXCL9, CXCL10)	Baseline, Cycle 1 Day 1 3 Hrs Post, Cycle 1 Day 1 7 Hr Post, Cycle 1 Day 2 24 Hr Post, Cycle 2 Day 1 0 Hr Pre, Cycle 2 Day 8 168 Hrs Post, Cycle 4 Day 1 O Hr Pre (~39 months)
Mean Serum Cytokines CXCL10 (IP10)	Objective is to investigate the pharmacodynamic immunomodulatory activity of serum chemokines (CXCL9, CXCL10)	Baseline, Cycle 1 Day 1 3 Hrs Post, Cycle 1 Day 1 7 Hr Post, Cycle 1 Day 2 24 Hr Post, Cycle 2 Day 1 0 Hr Pre, Cycle 2 Day 8 168 Hrs Post, Cycle 4 Day 1 O Hr Pre (~39 months)
Mean CD4 T Cell Infiltration	The objective of the study was to investigate the pharmacodynamic immunomodulatory activity of anti-PD-1 antibody on circulating CD4 infiltrations in tumors in participants with metastatic clear-cell Renal Cell Carcinoma (RCC).	Cycle 2 Day 8 168 Hr post dose
Mean CD8 T Cell Infiltration	The objective of the study was to investigate the pharmacodynamic immunomodulatory activity of anti-PD-1 antibody on circulating CD8 infiltrations in tumors in participants with metastatic clear-cell Renal Cell Carcinoma (RCC).	168 hour post does Cycle 2 Day 8 in evaluable participates (First active dose of study medication to cycle two day eight post injection)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Overall Response in the BMS-936558 Arms	Baseline and post-nivolumab treatment modulation of serum levels of interferon-gamma stimulated chemokines CXCL9 and CXCL10 (IP10) were assessed. The participant's best response designation over the study as a whole, recorded between the date of first study drug administration and the date of objectively documented progression per Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR	Assessed at a minimum of every 3 weeks up to 70 days following discontinuation of study drug (up to approximately 39 months)
Progression Free Survival Rate in BMS-936558	PFS is defined as the time from treatment arm assignment to the date of first documented disease progression. Participants who die without a reported prior progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last tumor assessment. Participants who did not have any on study tumor assessments will be censored on the date they were assigned a treatment arm. PFS rate is the percentage of participants who did not have disease progression at particular time points (16 weeks, 24 weeks, 48 weeks)	Progression free survival rate will be assessed in each individual treatment arm by tumor assessments at 16, 24, and 48 weeks. From initial dose to end of study (assessed up to 39 months)
Objective Response Rate in BMS-936558	The total number of subjects whose best overall response (BOR) is either a complete response (CR) or partial response (PR) divided by the total number of participants in the population of interest, and expressed as a percentage.	Up to 22 months after study start
Duration of Objective Response for BMS-936558	The duration of response is defined as the time when the measurement criteria are first met for PR or CR (whichever is reported first) until the date of documented disease progression or death. For subjects who neither progress nor die, the duration of response will be censored at the date of their last tumor assessment.	The time when the measurement criteria are first met for PR or CR (whichever is reported first) until the date of documented disease progression or death (assessed up to 39 months)
Duration of Stable Disease for BMS-936558 as Measured in Participants Whose Best Overall Response is Stable Disease as the Time From Baseline Until the Date of Documented Disease Progression or Death	Duration of stable disease (SD) is defined in participants whose BOR is SD at the time from treatment arm assignment until the criteria for progression are met or death (whichever occurs first). Participants who die without a reported prior progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last tumor assessment	The time from treatment arm assignment until the criteria for progression are met or death (whichever occurs first)(assessed up to 39 months)
Immunogenicity of BMS-936558 as Measured by the Detection of Human Antibodies Against BMS-936558	Blood samples to evaluate the development of a positive anti-drug antibodies (ADA) response at the doses tested will be collected at time-points pre-dose, C4D1, C8D1 and during follow-up.	Pre-dose, Cycle 4 Day 1, Cycle 8 Day 1 and during follow-up.

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Collaborators: Ono Pharma USA Inc

Publications and helpful links

General Publications

• Ross-Macdonald P, Walsh AM, Chasalow SD, Ammar R, Papillon-Cavanagh S, Szabo PM, Choueiri TK, Sznol M, Wind-Rotolo M. Molecular correlates of response to nivolumab at baseline and on treatment in patients with RCC. J Immunother Cancer. 2021 Mar;9(3):e001506. doi: 10.1136/jitc-2020-001506.
• Zhou Q, Qi Y, Wang Z, Zeng H, Zhang H, Liu Z, Huang Q, Xiong Y, Wang J, Chang Y, Bai Q, Xia Y, Wang Y, Liu L, Xu L, Dai B, Guo J, Zhu Y, Zhang W, Xu J. CCR5 blockade inflames antitumor immunity in BAP1-mutant clear cell renal cell carcinoma. J Immunother Cancer. 2020 Apr;8(1):e000228. doi: 10.1136/jitc-2019-000228.

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• Investigator Inquiry Form
• FDA Safety Alerts and Recalls

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2011
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): May 22, 2019

Study Registration Dates

• First Submitted: May 20, 2011
• First Submitted That Met QC Criteria: May 20, 2011
• First Posted (Estimate): May 24, 2011

Study Record Updates

• Last Update Posted (Actual): October 28, 2021
• Last Update Submitted That Met QC Criteria: October 13, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Carcinoma, Renal Cell; Carcinoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: CA209-009; 2011-005379-18 (EudraCT Number)