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

Phase 1

Completed

• Conditions: Malignant Melanoma
• Interventions: Drug: BMS-936558 (MDX1106-04); Drug: Ipilimumab

• Registration Number: NCT01024231
• Lead Sponsor: Bristol-Myers Squibb

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 available

Study Timeline

• Study First Submitted: 2009-12-01
• Study First Submitted QC: 2009-12-01
• Study First Posted: 2009-12-02
• Study Start: 2009-12-14
• Primary Completion: 2014-02-04
• Study Completion: 2019-04-01
• Results First Submitted: 2020-08-28
• Status Verified: 2021-03
• Results First Submitted QC: 2021-03-19
• Last Update Submitted: 2021-03-19
• Results First Posted: 2021-03-22
• Last Update Posted: 2021-03-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 127

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort 1: BMS-936558 (0.3 mg/kg)+Ipilimumab (3 mg/kg)	BMS-936558 (MDX1106-04)	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
Cohort 1: BMS-936558 (0.3 mg/kg)+Ipilimumab (3 mg/kg)	Ipilimumab	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
Cohort 2: BMS-936558 (1 mg/kg)+Ipilimumab (3 mg/kg)	BMS-936558 (MDX1106-04)	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
Cohort 3: BMS-936558 (3 mg/kg)+Ipilimumab (3 mg/kg)	BMS-936558 (MDX1106-04)	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
Cohort 4: BMS-936558 (10 mg/kg)+Ipilimumab (3 mg/kg)	BMS-936558 (MDX1106-04)	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
Cohort 5: BMS-936558 (10 mg/kg)+Ipilimumab (10 mg/kg)	BMS-936558 (MDX1106-04)	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
Cohort 6: BMS-936558 (1 mg/kg)	BMS-936558 (MDX1106-04)	BMS-936558 (MDX1106-04) 1 mg/kg solution, 60 minutes intravenous infusion, once q2 weeks for a total maximal duration of 96 weeks
Cohort 7: BMS-936558 (3 mg/kg)	BMS-936558 (MDX1106-04)	BMS-936558 (MDX1106-04) 3 mg/kg solution, 60 minutes intravenous infusion, once q2 weeks for a total maximal duration of 96 weeks
Cohort 8: Nivolumab+Ipilimumab	BMS-936558 (MDX1106-04)	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
Cohort 8: Nivolumab+Ipilimumab	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
Cohort 2: BMS-936558 (1 mg/kg)+Ipilimumab (3 mg/kg)	Ipilimumab	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
Cohort 3: BMS-936558 (3 mg/kg)+Ipilimumab (3 mg/kg)	Ipilimumab	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
Cohort 4: BMS-936558 (10 mg/kg)+Ipilimumab (3 mg/kg)	Ipilimumab	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
Cohort 5: BMS-936558 (10 mg/kg)+Ipilimumab (10 mg/kg)	Ipilimumab	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

Primary Outcome Measures

Name	Time	Method
Number of Participants With a Serious Adverse Event (AE)	Up to 3 years	incidence of all cause and treatment related serious adverse events
Number of Participants With Select AEs	Up to 3 years	incidence of all cause and treatment related Adverse events in certain organ systems
Number of Participants With an Adverse Event (AE)	Up to 3 years	incidence of all cause and treatment related adverse events
Number of Participants With an Adverse Event (AE) Which Lead to Discontinuation	Up to 3 years	incidence of all cause and treatment related adverse events which lead to discontinuation
Number of Deaths	Up to 3 years	incidence of all cause and treatment related deaths
Laboratory Abnormalities: Specific Liver Tests	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	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)

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate	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	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	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	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)	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	Up to 64 Weeks	The peak and trough concentrations of BMS-936558 (MDX-1106) and ipilimumab in participants with quantifiable data

Trial Locations

Locations (4)

Memorial Sloan Kettering Nassau; 🇺🇸 New York, New York, United States

Medstar Georgetown-Lombardi Comprehensive Cancer Center; 🇺🇸 Washington, District of Columbia, United States

Hillman Cancer Research Pavilion; 🇺🇸 Pittsburgh, Pennsylvania, United States

Yale University School Of Medicine; 🇺🇸 New Haven, Connecticut, United States