Dose-escalation Study of Combination BMS-936558 (MDX-1106) and Ipilimumab in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma

• ClinicalTrials.gov Identifier: NCT01024231
• Recruitment Status: Completed
• First Posted: December 2, 2009
• Results First Posted: March 22, 2021
• Last Update Posted: March 22, 2021
• Sponsor: Bristol-Myers Squibb
• Collaborators: Medarex; Ono Pharma USA Inc
• Information provided by (Responsible Party): Bristol-Myers Squibb

Tracking Information

• First Submitted Date: December 1, 2009
• First Posted Date: December 2, 2009
• Results First Submitted Date: August 28, 2020
• Results First Posted Date: March 22, 2021
• Last Update Posted Date: March 22, 2021
• Actual Study Start Date: December 14, 2009
• Actual Primary Completion Date: February 4, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 19, 2021)

• Number of Participants With an Adverse Event (AE) [ Time Frame: Up to 3 years ]
  incidence of all cause and treatment related adverse events
• Number of Participants With a Serious Adverse Event (AE) [ Time Frame: Up to 3 years ]
  incidence of all cause and treatment related serious adverse events
• Number of Participants With an Adverse Event (AE) Which Lead to Discontinuation [ Time Frame: Up to 3 years ]
  incidence of all cause and treatment related adverse events which lead to discontinuation
• Number of Deaths [ Time Frame: Up to 3 years ]
  incidence of all cause and treatment related deaths
• Number of Participants With Select AEs [ Time Frame: Up to 3 years ]
  incidence of all cause and treatment related Adverse events in certain organ systems
• Laboratory Abnormalities: Specific Liver Tests [ Time Frame: Up to 3 years ]
  Number of Participants with On-Treatment Laboratory Abnormalities in Specific Liver Tests Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN)
• Laboratory Abnormalities: Specific Thyroid Tests [ Time Frame: Up to 3 years ]
  Number of Participants with On-Treatment Laboratory Abnormalities in Specific Thyroid Tests Free T3 (FT3) Free T4 (FT4) Lower Limit of Normal (LLN)

• Original Primary Outcome Measures (submitted: December 1, 2009): Maximum tolerated dose [ Time Frame: Completion of each dosing cohort ]

Current Secondary Outcome Measures (submitted: March 19, 2021)

• Objective Response Rate [ Time Frame: Up to 3 years ]
  the total number of participants whose best overall response (BOR) is either irCR or irPR divided by the total number of response-evaluable participants.
• Time to Response [ Time Frame: Up to 3 Years ]
  the time from the first dose of study drug until the first documentation of irCR or irPR, as related to current database lock date or most current tumor measurement
• Duration of Response [ Time Frame: from the first documented response (irCR or irPR) until progression or death ]
  the time from the first documented response (irCR or irPR) until progression or death, whichever occurs first. For participants who did not progress or die, duration of response will be censored on the date of the last tumor assessment.
• Progression Free Survival [ Time Frame: 156 weeks ]
  the time from the first dose to the first observation of disease progression or death due to any cause. If a participant has not progressed or died at the time of analysis, PFS will be censored on the date of the last disease assessment. Participants who did not have any on-study tumor assessments and did not die will be censored on the date of the first dose of study medication.
• Number of Participants With an Anti-Drug Antibody (ADA) Response for Nivolumab (Nivo) and Ipilimumab (Ipi) [ Time Frame: Up to 3 years ]
  Serum samples will be collected to evaluate the development of antibodies to BMS-936558 and to ipilimumab.
• Peak and Trough Concentrations [ Time Frame: Up to 64 Weeks ]
  The peak and trough concentrations of BMS-936558 (MDX-1106) and ipilimumab in participants with quantifiable data

Original Secondary Outcome Measures (submitted: December 1, 2009)

• Safety assessment based on Adverse Event reports, results of clinical laboratory tests, immune safety tests, physical exam, vital signs, ECG evaluation and ECOG [ Time Frame: Safety is assessed at all study timepoints ]
• Tumor response evaluations [ Time Frame: Tumor response is assessed at weeks 12, 18, 24, 30, 36, 48, 60, 72, 84, 96 and 108 ]
• Pharmacokinetic peak and trough concentration of each study drug when given in combination compared to historical monotherapy data [ Time Frame: PK is collected pre and post dose ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Dose-escalation Study of Combination BMS-936558 (MDX-1106) and Ipilimumab in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma
• Official Title: A Phase 1b, Open-label, Multicenter, Multidose, Dose-escalation Study of BMS-936558 (MDX-1106) in Combination With Ipilimumab in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma
• Brief Summary: The purpose of this study is to determine the safety and tolerability of treatment with BMS-936558 (MDX-1106) in combination with Ipilimumab (BMS-734016) when given at the same time or as a sequenced regimen in subjects with unresectable Stage III or Stage IV malignant melanoma (MEL)
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Malignant Melanoma

Intervention

• Drug: BMS-936558 (MDX1106-04)
  Other Name: Nivolumab
• Drug: Ipilimumab
  Other Name: BMS-734016

Study Arms

• Experimental: Cohort 1: BMS-936558 (0.3 mg/kg)+Ipilimumab (3 mg/kg)

  BMS-936558 (MDX1106-04) 0.3 mg/kg solution, 60 minutes intravenous infusion every 3 (q3) weeks for 21 weeks in induction and every 12 (q12) weeks for 84 weeks in maintenance

  Ipilimumab (BMS-734016) 3 mg/kg solution, 90 minutes intravenous infusion q3 weeks for 9 weeks in induction and q12 weeks for 84 weeks in maintenance

  Interventions:

  • Drug: BMS-936558 (MDX1106-04)
  • Drug: Ipilimumab
• Experimental: Cohort 2: BMS-936558 (1 mg/kg)+Ipilimumab (3 mg/kg)

  Ipilimumab (BMS-734016) 3 mg/kg solution, 90 minutes intravenous infusion, q3 weeks for 9 weeks in induction and q12 weeks for 84 weeks in maintenance

  BMS-936558 (MDX1106-04) 1 mg/kg solution, 60 minutes intravenous infusion, q3 weeks for 21 weeks in induction and q12 weeks for 84 weeks in maintenance

  Interventions:

  • Drug: BMS-936558 (MDX1106-04)
  • Drug: Ipilimumab
• Experimental: Cohort 3: BMS-936558 (3 mg/kg)+Ipilimumab (3 mg/kg)

  Ipilimumab (BMS-734016) 3 mg/kg solution, 90 minutes intravenous infusion, q3 weeks for 9 weeks in induction and q12 weeks for 84 weeks in maintenance

  BMS-936558 (MDX1106-04) 3 mg/kg solution, 60 minutes intravenous infusion, q3 weeks for 21 weeks in induction and q12 weeks for 84 weeks in maintenance

  Interventions:

  • Drug: BMS-936558 (MDX1106-04)
  • Drug: Ipilimumab
• Experimental: Cohort 4: BMS-936558 (10 mg/kg)+Ipilimumab (3 mg/kg)

  BMS-936558 (MDX1106-04) 10 mg/kg solution, 60 minutes intravenous infusion, q3 weeks for 21 weeks in induction and q12 weeks for 84 weeks in maintenance

  Ipilimumab (BMS-734016) 3 mg/kg solution, 90 minutes intravenous infusion, q3 weeks for 9 weeks in induction and q12 weeks for 84 weeks in maintenance

  Interventions:

  • Drug: BMS-936558 (MDX1106-04)
  • Drug: Ipilimumab
• Experimental: Cohort 5: BMS-936558 (10 mg/kg)+Ipilimumab (10 mg/kg)

  BMS-936558 (MDX1106-04) 10 mg/kg solution, 60 minutes intravenous infusion, q3 weeks for 21 weeks in induction and q12 weeks for 84 weeks in maintenance

  Ipilimumab (BMS-734016) 10 mg/kg solution, 90 minutes intravenous infusion, q3 weeks for 9 weeks in induction and q12 weeks for 84 weeks in maintenance

  Interventions:

  • Drug: BMS-936558 (MDX1106-04)
  • Drug: Ipilimumab
• Experimental: Cohort 6: BMS-936558 (1 mg/kg)
  BMS-936558 (MDX1106-04) 1 mg/kg solution, 60 minutes intravenous infusion, once q2 weeks for a total maximal duration of 96 weeks
  Intervention: Drug: BMS-936558 (MDX1106-04)
• Experimental: Cohort 7: BMS-936558 (3 mg/kg)
  BMS-936558 (MDX1106-04) 3 mg/kg solution, 60 minutes intravenous infusion, once q2 weeks for a total maximal duration of 96 weeks
  Intervention: Drug: BMS-936558 (MDX1106-04)
• Experimental: Cohort 8: Nivolumab+Ipilimumab

  Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg solution intravenously q3 weeks, 4 doses for 12 weeks

  Followed by Nivolumab 3 mg/kg solution alone intravenously q2 weeks, 48 doses for a maximum of 96 weeks

  Interventions:

  • Drug: BMS-936558 (MDX1106-04)
  • Drug: Ipilimumab

Publications *

• Callahan MK, Kluger H, Postow MA, Segal NH, Lesokhin A, Atkins MB, Kirkwood JM, Krishnan S, Bhore R, Horak C, Wolchok JD, Sznol M. Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study. J Clin Oncol. 2018 Feb 1;36(4):391-398. doi: 10.1200/JCO.2017.72.2850. Epub 2017 Oct 17.
• Nguyen AT, Elia M, Materin MA, Sznol M, Chow J. Cyclosporine for Dry Eye Associated With Nivolumab: A Case Progressing to Corneal Perforation. Cornea. 2016 Mar;35(3):399-401. doi: 10.1097/ICO.0000000000000724.
• Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. doi: 10.1056/NEJMoa1302369. Epub 2013 Jun 2. Erratum In: N Engl J Med. 2018 Nov 29;379(22):2185.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 19, 2021): 127
• Original Estimated Enrollment (submitted: December 1, 2009): 50
• Actual Study Completion Date: April 1, 2019
• Actual Primary Completion Date: February 4, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Inclusion Criteria:

• Histologic diagnosis of malignant melanoma (MEL)
• Measurable unresectable Stage III or IV MEL
• ECOG performance status score of 0 or 1
• Life expectancy ≥4 months
• For those enrolled in amendment 5 and later, tumor tissue (archival or recent acquisition) must be available
• For Cohorts 1-5, subjects may have been treated with up to 3 prior systemic standard treatments for metastatic melanoma not including any post-incisional adjuvant therapy. Subjects may be treatment naïve. All metastatic melanoma regardless of primary site of disease will be allowed
• For Cohorts 6-7, subjects may have been treated with up to 3 prior systemic standard treatments for metastatic melanoma; this does not include any post-incisional adjuvant therapy. Specifically, subjects must have received ≥3 doses of Ipilimumab therapy and the last dose having been administered within 4-12 weeks of initiation of study treatment

Exclusion Criteria:

• History of severe hypersensitivity reactions to other mAbs
• Prior malignancy active within the previous 2 years except for localized cancers that are considered to have been cured and in the opinion of the investigator present a low risk for recurrence
• Active autoimmune disease or a history of known or suspected autoimmune disease
• History of recently active diverticulitis or symptomatic peptic ulcer disease and history of adrenal insufficiency
• Regular narcotic analgesia
• Active, untreated central nervous system metastasis
• For subjects enrolled in Cohorts 1-5, prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti-CTLA-4 antibody
• For subjects enrolled in Cohorts 6-7, prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CD137 antibodies
• Any non-oncology vaccine therapy used for prevention of infectious disease
• Concomitant therapy with any other anti-cancer therapy, concurrent medical conditions requiring use of immunosuppressive medications or use of other investigational drugs
• Positive tests for human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), hepatitis B, hepatitis C
• Subjects weighing ≥125 kg are excluded from Cohort 5
• Subjects in Cohorts 6 and 7 must have received Ipilimumab monotherapy immediately prior to study entry, but must not have received that Ipilimumab as part of a clinical trial
• Subjects with ocular melanoma are excluded from Cohort 8

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01024231
• Other Study ID Numbers: CA209-004; (MDX1106-04) ( Other Identifier: Medarex )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bristol-Myers Squibb
• Original Responsible Party: Study Director, Bristol-Myers Squibb
• Current Study Sponsor: Bristol-Myers Squibb
• Original Study Sponsor: Same as current

Collaborators

• Medarex
• Ono Pharma USA Inc

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Bristol-Myers Squibb
• Verification Date: March 2021