A Study of Two Different Dose Combinations of Nivolumab in Combination With Ipilimumab in Subjects With Previously Untreated, Unresectable or Metastatic Melanoma

Phase IIIb/IV, Randomized, Double Blinded, Study of Nivolumab 3 mg/kg in Combination With Ipilimumab 1 mg/kg vs Nivolumab 1 mg/kg in Combination With Ipilimumab 3 mg/kg in Subjects With Previously Untreated, Unresectable or Metastatic Melanoma

The purpose of this study is to evaluate two different dose combinations of nivolumab and ipilimumab in the treatment of melanoma.

Study Overview

• Status: Completed
• Conditions: Melanoma
• Intervention / Treatment: Biological: Nivolumab 3 mg/kg IV; Biological: Ipilimumab 1 mg/kg IV; Biological: Nivolumab 1 mg/kg IV; Biological: Ipilimumab 3 mg/kg IV; Biological: Nivolumab 6 mg/kg IV

• Study Type: Interventional
• Enrollment (Actual): 387
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • North Sydney, New South Wales, Australia, 2060
      • Local Institution
    • Waratah, New South Wales, Australia, 2298
      • Local Institution - 0045
  • Queensland
    • Greenslopes, Queensland, Australia, 4120
      • Local Institution
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Local Institution
• Canada
  • Quebec, Canada, G1R 2J6
    • CHU de Québec - Université Laval
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Local Institution - 0007
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
• Denmark
  • Aarhus N, Denmark, 8200
    • Local Institution - 0063
  • Herlev, Denmark, 2730
    • Local Institution - 0065
  • Odense, Denmark, 5000
    • Local Institution - 0064
• France
  • Bordeaux, France, 33075
    • Hopital Saint André
  • Lille, France, 59037
    • CHRU de Lille
  • Marseille Cedex 5, France, 13385
    • Hopital de la Timone
  • Nantes Cedex, France, 44093
    • Hôpital Hôtel Dieu
  • Paris, France, 75475
    • Hopital Saint Louis
  • Pierre Benite, France, 69310
    • Centre Hospitalier Lyon Sud
  • Toulouse Cedex 9, France, 31059
    • Institut Claudius Regaud
  • Villejuif, France, 94805
    • Local Institution - 0019
• Germany
  • Essen, Germany, 45147
    • Universitaetsklinikum Essen
  • Heidelberg, Germany, 69120
    • Universitaetsklinikum Heidelberg
  • Muenchen, Germany, 80337
    • Ludwig-Maximilians-Universitaet
  • Tuebingen, Germany, 72076
    • Universitaetsklinikum Tuebingen
• Israel
  • Ramat Gan, Israel, 5262100
    • Local Institution
• Italy
  • Bergamo, Italy, 24127
    • Local Institution - 0039
  • Milano, Italy, 20133
    • Local Institution - 0042
  • Napoli, Italy, 80131
    • Local Institution - 0040
  • Padova, Italy, 35128
    • Istituto Oncologico Veneto IOV
  • Siena, Italy, 53100
    • Local Institution - 0041
  • Taormina, Italy, 98039
    • Ospedale San Vincenzo
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Local Institution
  • Amsterdam, Netherlands, 1066 CX
    • Local Institution - 0052
  • Groningen, Netherlands, 9700RB
    • University Medical Center Groningen (UMCG)
• Poland
  • Gdansk, Poland, 80-214
    • Uniwersyteckie Centrum Kliniczne Klinika Onkologii I Radiote
  • Krakow, Poland, 31-115
    • Klinika Nowotworow Ukladowych i Uogolnionych
  • Warszawa, Poland, 02-781
    • Klinika Nowotworów Tkanek Miękkich, Kości i Czerniaków
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Local Institution
• Spain
  • Badalona-barcelona, Spain, 08916
    • Local Institution
  • Barcelona, Spain, 08036
    • Local Institution - 0024
  • Madrid, Spain, 28007
    • Local Institution
  • Madrid, Spain, 28034
    • Local Institution - 0027
  • San Sabastian Gipuzkoa, Spain, 20014
    • Local Institution
  • Valencia, Spain, 46014
    • Local Institution
• United Kingdom
  • Guildford, United Kingdom, GU2 7XX
    • Local Institution
  • London, United Kingdom, SW3 6JJ
    • Local Institution
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M20 4XB
      • Local Institution
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 7LJ
      • Local Institution
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University Of Colorado Cancer Center
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center
  • Minnesota
    • Fridley, Minnesota, United States, 55432
      • Allina Health
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nevada
    • Las Vegas, Nevada, United States, 89148
      • Comprehensive Cancer Centers of Nevada
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center at Hackensack University Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Health Network
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington - Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Subject must have been diagnosed with stage III or/and stage IV histologically confirmed melanoma [per American Joint Committee on Cancer (AJCC) staging system] that is unresectable or metastatic
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Subject has not been treated by systemic anticancer therapy for unresectable or metastatic melanoma

Exclusion Criteria:

• Subjects with active brain metastases or leptomeningeal metastases
• Subjects with ocular melanoma
• Subjects with active, known or suspected autoimmune disease

Other protocol defined inclusion/exclusion criteria could apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV; Specified dose on specified days	Biological: Nivolumab 3 mg/kg IV; Followed by Nivolumab monotherapy; Biological: Ipilimumab 1 mg/kg IV; Followed by Nivolumab monotherapy
Experimental: Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV; Specified dose on specified days	Biological: Nivolumab 1 mg/kg IV; Biological: Ipilimumab 3 mg/kg IV
Experimental: Nivolumab 6 mg/kg IV + Ipilimumab 1 mg/kg; Specified dose on specified days	Biological: Ipilimumab 1 mg/kg IV; Followed by Nivolumab monotherapy; Biological: Nivolumab 6 mg/kg IV; A dose of 240mg is identical to a dose of 3mg/kg, therefore 6mg/kg is approximately equal to ~ 480mg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Percentage of Participants With Drug-Related Grade 3 - 5 Adverse Events (AEs)	The percentage of participants who experienced at least 1 AE of Grade 3 or higher, judged to be related to study drug by the investigator, and with onset on or after the first dose of study treatment and within 30 days of the last dose of study treatment. AE grade was defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria.	From first dose of study treatment up to primary completion date 20-Apr-2017 (up to approximately 12 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	The percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). BOR is defined as the best response, as determined by the investigator, recorded between the date of randomization and the date of progression per RECIST 1.1 or the date of subsequent anticancer therapy, whichever occurred first. For subjects without documented progression or subsequent therapy, all available response designations will contribute to the BOR assessment. Tumor assessments are scheduled at Week 12 following randomization, every 8 weeks for the first 12 months and then every 12 weeks until disease progression. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.	From date of randomization to date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (up to approximately 5 years)
Overall Survival (OS)	The time between the date of randomization and the date of death due to any cause. A participant who has not died will be censored at the last known alive date. OS will be followed continuously while participants are on the study drug and every 3 months via in-person or phone contact after participants discontinue the study drug. Based on Kaplan-Meier Estimates.	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first (up tp approximately 5 years)
Progression Free Survival (PFS)	The time between the date of randomization and the first date of documented progression, determined by the investigator, or death due to any cause, whichever occurs first. Participants who die without a reported progression will be considered to have progressed on the date of their death. Those who did not progress or die will be censored on the date of their last evaluable tumor assessment. Participants without on study tumor assessments and who did not die will be censored on their date of randomization. Participants who started anti-cancer therapy without a prior reported progression will be censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy. Based on Kaplan-Meier Estimates. Progression is defined as at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).	From randomization to the first date of documented progression or death due to any cause, whichever occurs first (up to approximately 5 years)
Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Physical Functioning Scale	Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Physical Functioning Scale sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.	Weeks 7, 16, 20, 24, 28, 32, 36, 40
Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Role Functioning Scale	Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Role Functioning Scale sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.	Weeks 7, 16, 20, 24, 28, 32, 36, 40
Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Emotional Functioning Scale	Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Emotional Functioning Scale sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.	Weeks 7, 16, 20, 24, 28, 32, 36, 40
Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Cognitive Functioning Scale	Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Cognitive Functioning Scale sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.	Weeks 7, 16, 20, 24, 28, 32, 36, 40
Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Social Functioning Scale	Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Social Functioning Scale sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.	Weeks 7, 16, 20, 24, 28, 32, 36, 40
Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Global Health Status	Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 comprises 6 functional scales (role function, physical functioning, cognitive functioning, emotional functioning, social functioning and global quality of life) as well as nine symptom scales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline.	Weeks 7, 16, 20, 24, 28, 32, 36, 40
Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Dyspnea	Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Dyspnea sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.	Weeks 7, 16, 20, 24, 28, 32, 36, 40
Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Insomnia	Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Insomnia sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.	Weeks 7, 16, 20, 24, 28, 32, 36, 40
Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Appetite Loss	Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Appetite loss sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.	Weeks 7, 16, 20, 24, 28, 32, 36, 40
Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Constipation	Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Constipation sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points	Weeks 7, 16, 20, 24, 28, 32, 36, 40
Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Diarrhea	Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Diarrhea sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.	Weeks 7, 16, 20, 24, 28, 32, 36, 40
Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Financial Difficulties	Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Financial difficulties sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points	Weeks 7, 16, 20, 24, 28, 32, 36, 40
Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Fatigue	Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Fatigue sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points	Weeks 7, 16, 20, 24, 28, 32, 36, 40
Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Nausea and Vomiting	Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Nausea and Vomiting sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points for the various scales of the EORTC QLQ-C30	Weeks 7, 16, 20, 24, 28, 32, 36, 40
Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Pain	Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Pain sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points	Weeks 7, 16, 20, 24, 28, 32, 36, 40

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Lebbe C, Meyer N, Mortier L, Marquez-Rodas I, Robert C, Rutkowski P, Menzies AM, Eigentler T, Ascierto PA, Smylie M, Schadendorf D, Ajaz M, Svane IM, Gonzalez R, Rollin L, Lord-Bessen J, Saci A, Grigoryeva E, Pigozzo J. Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. J Clin Oncol. 2019 Apr 10;37(11):867-875. doi: 10.1200/JCO.18.01998. Epub 2019 Feb 27.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2016
• Primary Completion (Actual): April 20, 2017
• Study Completion (Actual): May 28, 2021

Study Registration Dates

• First Submitted: March 16, 2016
• First Submitted That Met QC Criteria: March 18, 2016
• First Posted (Estimate): March 21, 2016

Study Record Updates

• Last Update Posted (Actual): June 24, 2022
• Last Update Submitted That Met QC Criteria: June 17, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Ipilimumab
• Other Study ID Numbers: CA209-511

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No