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

Primary Purpose

Malignant Melanoma

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

BMS-936558 (MDX1106-04)

Ipilimumab

About this trial

This is an interventional treatment trial for Malignant Melanoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Yale University School Of Medicine
Medstar Georgetown-Lombardi Comprehensive Cancer Center
Memorial Sloan Kettering Nassau
Hillman Cancer Research Pavilion

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm Type

Experimental

Arm Label

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

Cohort 2: BMS-936558 (1 mg/kg)+Ipilimumab (3 mg/kg)

Cohort 3: BMS-936558 (3 mg/kg)+Ipilimumab (3 mg/kg)

Cohort 4: BMS-936558 (10 mg/kg)+Ipilimumab (3 mg/kg)

Cohort 5: BMS-936558 (10 mg/kg)+Ipilimumab (10 mg/kg)

Cohort 6: BMS-936558 (1 mg/kg)

Cohort 7: BMS-936558 (3 mg/kg)

Cohort 8: Nivolumab+Ipilimumab

Arm Description

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

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

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

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

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

BMS-936558 (MDX1106-04) 1 mg/kg solution, 60 minutes intravenous infusion, once q2 weeks for a total maximal duration of 96 weeks

BMS-936558 (MDX1106-04) 3 mg/kg solution, 60 minutes intravenous infusion, once q2 weeks for a total maximal duration of 96 weeks

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

Outcomes

Primary Outcome Measures

Number of Participants With an Adverse Event (AE)

incidence of all cause and treatment related adverse events

Number of Participants With a Serious Adverse Event (AE)

incidence of all cause and treatment related serious adverse events

Number of Participants With an Adverse Event (AE) Which Lead to Discontinuation

incidence of all cause and treatment related adverse events which lead to discontinuation

Number of Deaths

incidence of all cause and treatment related deaths

Number of Participants With Select AEs

incidence of all cause and treatment related Adverse events in certain organ systems

Laboratory Abnormalities: Specific Liver Tests

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

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

Objective Response Rate

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

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

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

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)

Serum samples will be collected to evaluate the development of antibodies to BMS-936558 and to ipilimumab.

Peak and Trough Concentrations

The peak and trough concentrations of BMS-936558 (MDX-1106) and ipilimumab in participants with quantifiable data

Full Information

NCT ID

NCT01024231

First Posted

December 1, 2009

Last Updated

March 19, 2021

Sponsor

Bristol-Myers Squibb

Collaborators

Medarex, Ono Pharma USA Inc

1. Study Identification

Unique Protocol Identification Number

NCT01024231

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2021

Overall Recruitment Status

Completed

Study Start Date

December 14, 2009 (Actual)

Primary Completion Date

February 4, 2014 (Actual)

Study Completion Date

April 1, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Bristol-Myers Squibb

Collaborators

Medarex, Ono Pharma USA Inc

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Malignant Melanoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

127 (Actual)

8. Arms, Groups, and Interventions

Arm Title

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

Arm Type

Experimental

Arm Description

Arm Title

Cohort 2: BMS-936558 (1 mg/kg)+Ipilimumab (3 mg/kg)

Arm Type

Experimental

Arm Description

Arm Title

Cohort 3: BMS-936558 (3 mg/kg)+Ipilimumab (3 mg/kg)

Arm Type

Experimental

Arm Description

Arm Title

Cohort 4: BMS-936558 (10 mg/kg)+Ipilimumab (3 mg/kg)

Arm Type

Experimental

Arm Description

Arm Title

Cohort 5: BMS-936558 (10 mg/kg)+Ipilimumab (10 mg/kg)

Arm Type

Experimental

Arm Description

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

Arm Title

Cohort 6: BMS-936558 (1 mg/kg)

Arm Type

Experimental

Arm Description

BMS-936558 (MDX1106-04) 1 mg/kg solution, 60 minutes intravenous infusion, once q2 weeks for a total maximal duration of 96 weeks

Arm Title

Cohort 7: BMS-936558 (3 mg/kg)

Arm Type

Experimental

Arm Description

BMS-936558 (MDX1106-04) 3 mg/kg solution, 60 minutes intravenous infusion, once q2 weeks for a total maximal duration of 96 weeks

Arm Title

Cohort 8: Nivolumab+Ipilimumab

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

BMS-936558 (MDX1106-04)

Other Intervention Name(s)

Nivolumab

Intervention Type

Drug

Intervention Name(s)

Ipilimumab

Other Intervention Name(s)

BMS-734016

Primary Outcome Measure Information:

Title

Number of Participants With an Adverse Event (AE)

Description

incidence of all cause and treatment related adverse events

Time Frame

Up to 3 years

Title

Number of Participants With a Serious Adverse Event (AE)

Description

incidence of all cause and treatment related serious adverse events

Time Frame

Up to 3 years

Title

Number of Participants With an Adverse Event (AE) Which Lead to Discontinuation

Description

incidence of all cause and treatment related adverse events which lead to discontinuation

Time Frame

Up to 3 years

Title

Number of Deaths

Description

incidence of all cause and treatment related deaths

Time Frame

Up to 3 years

Title

Number of Participants With Select AEs

Description

incidence of all cause and treatment related Adverse events in certain organ systems

Time Frame

Up to 3 years

Title

Laboratory Abnormalities: Specific Liver Tests

Description

Number of Participants with On-Treatment Laboratory Abnormalities in Specific Liver Tests Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN)

Time Frame

Up to 3 years

Title

Laboratory Abnormalities: Specific Thyroid Tests

Description

Number of Participants with On-Treatment Laboratory Abnormalities in Specific Thyroid Tests Free T3 (FT3) Free T4 (FT4) Lower Limit of Normal (LLN)

Time Frame

Up to 3 years

Secondary Outcome Measure Information:

Title

Objective Response Rate

Description

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 Frame

Up to 3 years

Title

Time to Response

Description

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

Time Frame

Up to 3 Years

Title

Duration of Response

Description

Time Frame

from the first documented response (irCR or irPR) until progression or death

Title

Progression Free Survival

Description

Time Frame

156 weeks

Title

Number of Participants With an Anti-Drug Antibody (ADA) Response for Nivolumab (Nivo) and Ipilimumab (Ipi)

Description

Serum samples will be collected to evaluate the development of antibodies to BMS-936558 and to ipilimumab.

Time Frame

Up to 3 years

Title

Peak and Trough Concentrations

Description

The peak and trough concentrations of BMS-936558 (MDX-1106) and ipilimumab in participants with quantifiable data

Time Frame

Up to 64 Weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bristol-Myers Squibb

Organizational Affiliation

Bristol-Myers Squibb

Official's Role

Study Director

Facility Information:

Facility Name

Yale University School Of Medicine

City

New Haven

State/Province

Connecticut

ZIP/Postal Code

06520

Country

United States

Facility Name

Medstar Georgetown-Lombardi Comprehensive Cancer Center

City

Washington

State/Province

District of Columbia

ZIP/Postal Code

20007

Country

United States

Facility Name

Memorial Sloan Kettering Nassau

City

New York

State/Province

New York

ZIP/Postal Code

11065

Country

United States

Facility Name

Hillman Cancer Research Pavilion

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15232

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

29040030

Citation

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.

Results Reference

derived

PubMed Identifier

26771550

Citation

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.

Results Reference

derived

PubMed Identifier

23724867

Citation

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.

Results Reference

derived

Links:

URL

https://www.bms.com/researchers-and-partners/clinical-trials-and-research.html

Description

BMS Clinical Trial Information

URL

https://www.bmsstudyconnect.com/s/US/English/USenHome

Description

BMS Clinical Trial Patient Recruiting

URL

https://www.fda.gov/Safety/MedWatch/SafetyInformation/default.htm

Description

FDA Safety Alerts and Recalls

Learn more about this trial

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

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