PH 1 Biomarker Study of Nivolumab and Ipilimumab and Nivolumab in Combination With Ipilimumab in Advanced Melanoma

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• Melanoma 3,006

Melanoma

3,006 studies on the registry are indexed under Melanoma; 520 are open to participants now.

This study's enrollment of 170 is above the median of 38 across 2,351 interventional studies indexed under Melanoma.

Lead sponsor

Bristol-Myers Squibb is the lead sponsor of 1,538 studies on the registry; 116 are open to participants now.

Of its 429 completed or terminated interventional studies of FDA-regulated products, 223 (52%) have results posted.

Eligibility criteria

Study arms

• Experimental
  Part 1-Cohort 1 and 2: Nivolumab

  Nivolumab 3 mg/kg solution intravenously Every 2 weeks, Up to 2 years depending on response

  Biological: Nivolumab

• Experimental
  Part 2-Arm A: Nivolumab + Ipilimumab

  Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified

  Biological: Nivolumab · Drug: Ipilimumab

• Experimental
  Part 3-Arm A: Nivolumab + Ipilimumab

  Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified

  Biological: Nivolumab · Drug: Ipilimumab

• Experimental
  Part 3-Arm B: Nivolumab

  Nivolumab 3 mg/kg solution intravenously as specified

  Biological: Nivolumab

• Experimental
  Part 4-Arm D: Nivolumab + Ipilimumab

  Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified

  Biological: Nivolumab · Drug: Ipilimumab

• Experimental
  Part 4-Arm E: Nivolumab

  Nivolumab 3 mg/kg solution intravenously as specified

  Biological: Nivolumab

Interventions

• BiologicalNivolumab

  Also known as: BMS-936558 (MDX1106)

• DrugIpilimumab

  Also known as: BMS734016, Yervoy

Primary outcomes

1. Median Change From Baseline to Week 7, of Interferon (IFN) and Interferon Gamma (IFN-gamma) Inducible Factors

   Baseline and post-treatment modulation of serum levels of chemokines, cytokines and other immune mediators were assessed by techniques that included ELISA or other multiplex-based assay methods. Primary analysis included IFN-gamma and IFN-gamma inducible factors, including chemokine \[C-X-C motif\] ligand 9 (CXCL9) and CXCL10

   Time frame: From last non-missing value prior to first dose to week 7 day 1

2. Tumor Infiltrating Lymphocytes (TILs) as Measured by Medians in Percent Positive CD8 and Positive CD4 at Baseline and On-treatment Biopsy, Both Using the Mosaic Singleplex IHC Assay

   Biomarkers examined were percent positive CD8 and percent positive CD4, both using the Mosaic Singleplex IHC assay. Analyses are presented with the medians at baseline and on-treatment, rather than the median change because the baseline values differed across groups. Baseline was defined as the last non-missing value on or prior to the first dose of study therapy. Biopsies were also collected on treatment.

   Time frame: From last non-missing value prior to first dose to week 4 day 1

Secondary outcomes

1. Frequency of Adverse Events or Death

   The assessment of safety was based on frequency of deaths and adverse events (AEs). AEs were graded for severity according to the NCI CTCAE version 4.0.

   Time frame: Includes events reported between first dose and up to 100 days after last dose of study medication (up to approximately 73 months).

2. Frequency of AEs Leading to Discontinuation of Study Drug and SAEs

   The assessment of safety was based on frequency of serious adverse events (SAEs) and adverse events (AEs) leading to discontinuation of study drug. AEs were graded for severity according to the NCI CTCAE version 4.0.

   Time frame: From enrollment to 100 days after the last dose date (up to approximately 73 months)

3. Number of Laboratory Abnormalities in Specific Liver Tests

   Abnormalities in hepatic parameters measured included those in aspartate aminotransferase (AST), alanine aminotransferase (ALT)and total bilirubin, with respect to upper limit of normal (ULN)

   Time frame: 101-120 days after last dose.

4. Number of Laboratory Abnormalities in Specific Thyroid Tests

   Abnormalities in thyroid parameters measured included those in thyroid stimulating hormone (TSH) levels with respect to upper limit of normal (ULN) and lower limit of normal (LLN)

   Time frame: 101-120 days after last dose.

5. Objective Response Rate (ORR)

   The objective response rate (ORR) was defined as the percentage of participants with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized participants in the population of interest. The BOR was defined as 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 RECIST 1.1, with subsequent confirmation, or date of subsequent anti-cancer therapy, whichever occurred first in the study.

   Time frame: Approximately every 8 weeks until disease progression and in follow-up if no progression (up to approximately 73 months)

6. Median Duration of Response (mDOR)

   Median duration of response (mDOR) was calculated for subjects with BOR of CR or PR only, and is defined as time between the date of first documented objective response and the date of the first subsequent disease progression or death, whichever occurred first, if death occurred within 100 days after last dose of study medication.

   Time frame: From date of first documented objective response to date of disease progression or death, up to approximately 27 months

7. Median Time to Response (mTTR)

   Median time to response (mTTR) for a participant with a BOR of CR or PR is defined as the time from the first dosing date to the date of the first documented objective response (CR or PR).

   Time frame: From the first dosing date to the date of the first documented objective response, up to approximately 15 months

8. Progression Free Survival (PFS)

   Progression free survival (PFS) for a participant was defined as the time from the date of first dose of study medication to the date of the first documented disease progression, or death due to any cause, whichever occurred first, if death occurred within 100 days after last dose of study medication.

   Time frame: From first dose of study medication to the date of progression or death, whichever occurs first, up to approximately 29 months

9. Immunogenicity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Number of Serum Anti-drug Antibody (ADA) Positive Participants and the Number of Neutralizing ADA Positive Participants

   Time Frame: Part 1: Day 1, Day 15, Day 43 of cycle 1, Day 1 of cycle 2, Day 15 of cycle 3, every 16 weeks after cycle 3 up to 2 years, follow-up visit 1 (40-60 days after last treatment), and follow-up visit 2 (101-120 days since last treatment) Part 2, 3 and 4: Weeks 1, 3, 4, 7, 9, 10, 13, 25, 53, 79, 95 follow-up visit 1 (40-60 days after last treatment), and follow-up visit 2 (101-120 days since last treatment)

   Time frame: Up to follow-up visit 2 (101-120 days since last treatment)

10. Objective Response Rate (ORR) by PD-L1 Expression

    For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels \>= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The objective response rate (ORR) was defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects in the population of interest (all response-evaluable participants).

    Time frame: Approximately every 8 weeks until disease progression and in follow-up if no progression (up to approximately 73 months)

11. Duration of Response (DOR) by PD-L1 Expression

    For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels \>= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. Median duration of response (mDOR) was calculated for all response-evaluable participants with best overall response of CR or PR only, and is defined as time between the date of first documented objective response and the date of the first subsequent disease progression or death, whichever occurred first, if death occurred within 100 days after last dose of study medication.

    Time frame: From the date of first documented objective response and the date of the first subsequent disease progression or death, whichever occurred first, up to approximately 73 months

12. Progression Free Survival (PFS) by PD-L1 Expression

    For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels \>= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The progression free survival rate (PFSR) for a subject was defined as the time from the date of first dose of study medication to the date of the first documented disease progression, or death due to any cause, whichever occurred first, if death occurred within 100 days after last dose of study medication.

    Time frame: From first dose of study medication to the date of progression or death, whichever occurs first, up to approximately 29 months

13. Overall Survival Rate (OSR)

    The percentage of participants surviving to time t, where t is a specific length of time, eg, 12 months, which was determined by the available data for final analysis and was documented in the DPP. The percentage was calculated by the product-limit method (Kaplan-Meier estimate), which takes into account censored data. The overall survival rate (OSR) for a participant was defined as the time from the date of first dose of study medication to the date of death for any cause. A participant who had not died was censored at last known date alive.

    Time frame: From first dose of study medication to the date of death for any cause, up to approximately 73 months

14. Percent Probability for Progression Free Survival Rate (PFSR)

    The Progression Free Survival Rate (PFSR) is defined as the probability of a participant remaining progression free or survival to time t, where t is equal to the specified timepoints. This probability will be calculated by the product limit method (Kaplan-Meier estimates) which takes into account censored data. Medians and 95% confidence interval are estimated using the Kaplan-Meier method. If there is an insufficient number of events, the median and confidence intervals cannot be calculated.

    Time frame: From first dose up to the specified timepoints of 3, 6, 9, 12, and 24 months

Baseline characteristics

Publications

• Kim YJ, Sheu KM, Tsoi J, Abril-Rodriguez G, Medina E, Grasso CS, Torrejon DY, Champhekar AS, Litchfield K, Swanton C, Speiser DE, Scumpia PO, Hoffmann A, Graeber TG, Puig-Saus C, Ribas A. Melanoma dedifferentiation induced by IFN-gamma epigenetic remodeling in response to anti-PD-1 therapy. J Clin Invest. 2021 Jun 15;131(12):e145859. doi: 10.1172/JCI145859. PubMed 33914706 ↗
• Anagnostou V, Bruhm DC, Niknafs N, White JR, Shao XM, Sidhom JW, Stein J, Tsai HL, Wang H, Belcaid Z, Murray J, Balan A, Ferreira L, Ross-Macdonald P, Wind-Rotolo M, Baras AS, Taube J, Karchin R, Scharpf RB, Grasso C, Ribas A, Pardoll DM, Topalian SL, Velculescu VE. Integrative Tumor and Immune Cell Multi-omic Analyses Predict Response to Immune Checkpoint Blockade in Melanoma. Cell Rep Med. 2020 Nov 17;1(8):100139. doi: 10.1016/j.xcrm.2020.100139. eCollection 2020 Nov 17. PubMed 33294860 ↗
• Stein JE, Soni A, Danilova L, Cottrell TR, Gajewski TF, Hodi FS, Bhatia S, Urba WJ, Sharfman WH, Wind-Rotolo M, Edwards R, Lipson EJ, Taube JM. Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response. Ann Oncol. 2019 Apr 1;30(4):589-596. doi: 10.1093/annonc/mdz019. PubMed 30689736 ↗

Related links

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

Study documents

• Study protocol · Oct 25, 2016
• Statistical analysis plan · Mar 27, 2016

Documents are hosted by the registry — open the source record to download them.