Phase I Biomarker Study (BMS-936558)

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

Detailed Description
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Intervention Model: Parallel Dose Comparison

Official Title
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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).

Conditions
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Renal Cell Carcinoma

Intervention / Treatment
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* Drug: BMS-936558 (Anti-PD-1)
* Drug: BMS-936558 (Anti-PD-1)
* Drug: BMS-936558 (Anti-PD-1)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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. |