Clinical trial NCT01968109: An Investigational Immuno-therapy Study to Assess the Safety, Tolerability and Effectiveness of Anti-LAG-3 With and Without Anti-PD-1 in the Treatment of Solid Tumors
Official title: A Phase I/2a Dose Escalation and Cohort Expansion Study of the Safety, Tolerability, and Efficacy of Anti-LAG-3 Monoclonal Antibody (BMS-986016) Administered Alone and in Combination With Anti-PD-1 Monoclonal Antibody (Nivolumab, BMS-936558) in Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Neoplasms by Site
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2013-10-23
Enrollment: 1499
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to assess the safety, tolerability and effectiveness of experimental medication BMS-986016 administered alone and in combination with nivolumab in patients with solid tumors that have spread and/or cannot be removed by surgery.

The following tumor types are included in this study:

Non-Small Cell Lung Cancer (NSCLC), gastric cancer, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, squamous cell carcinoma of the head and neck, and melanoma, that have NOT previously been treated with immunotherapy. NSCLC and melanoma that HAVE previously been treated with immunotherapy.


Eligibility criteria: Inclusion Criteria:

* For Dose escalation: subjects with cervical, ovarian, bladder and colorectal cancer (CRC), head and neck, gastric and hepatocellular cancer naive to immuno-oncology agents; 1st line melanoma and 1st line/2nd line NSCLC; Renal Cell Carcinoma naive to IO; NSCLC progressing while on or after therapy with anti-PD1/anti-PDL-1 and melanoma subjects progressed while-on or after treatment with anti-PD1 or anti-PDL1 with or without anti-CTLA-4.
* For Dose Expansion: all of the above in escalation except for cervical, ovarian, and CRC
* Progressed, or been intolerant to, at least one standard treatment regimen, except for participants in 1st line cohorts.
* ECOG performance status between 0 and 2
* At least 1 lesion with measurable disease at baseline
* Availability of an existing tumor biopsy sample (and consent to allow pre-treatment tumor biopsy)

Exclusion Criteria:

* Primary central nervous system (CNS) tumors or solid tumors with CNS metastases as the only site of active disease
* Autoimmune disease
* Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
* Uncontrolled CNS metastases

Other protocol defined inclusion/exclusion criteria could apply

Primary outcomes:
measure: Proportion of participants with Adverse Events (AEs)
timeFrame: Approximately Up to 3 years
measure: Proportion of participants with Serious Adverse Events (SAEs)
timeFrame: Approximately Up to 3 years
measure: Proportion of Deaths
timeFrame: Approximately Up to 3 years
measure: Proportion of participants with laboratory abnormalities in blood
timeFrame: Approximately Up to 3 years
measure: Proportion of participants with laboratory abnormalities in blood serum
timeFrame: Approximately Up to 3 years
measure: Proportion of participants with laboratory abnormalities in urine
timeFrame: Approximately Up to 3 years
measure: Objective response rate (ORR)
timeFrame: Approximately 3 years
measure: Disease control rate (DCR)
timeFrame: Approximately 3 years
measure: Duration of response (DOR)
timeFrame: Approximately 3 years
measure: Number of AEs in the Broad Scope MedDRA Anaphylactic Reaction SMQ
timeFrame: Approximately 3 years
measure: Proportion of participants with AEs leading to discontinuation of treatment
timeFrame: Approximately up to 3 years
Secondary outcomes:
measure: Maximum observed serum concentration (Cmax) of BMS-986016 administered both alone and in combination with nivolumab
timeFrame: Approximately 2.3 years
measure: Time of maximum observed serum concentration (Tmax) of BMS-986016 administered both alone and in combination with nivolumab
timeFrame: Approximately 2.3 years
measure: Trough observed serum concentration (Ctrough) of BMS-986016 administered both alone and in combination with nivolumab
timeFrame: Approximately 2.3 years
measure: Concentration at the end of a dosing interval (Ctau) [Eg: concentration at 336 hours] of BMS-986016 administered both alone and in combination with nivolumab
timeFrame: Approximately 2.3 years
measure: Area under the concentration-time curve in one dosing interval [AUC(TAU)] of BMS-986016 administered both alone and in combination with nivolumab
timeFrame: Approximately 2.3 years
measure: Total body clearance (CLT) of BMS-986016 administered both alone and in combination with nivolumab
timeFrame: Approximately 2.3 years
measure: Volume of distribution at steady state (Vss) of BMS-986016 administered both alone and in combination with nivolumab
timeFrame: Approximately 2.3 years
measure: Effective elimination half-life that explains the degree of area under the concentration-time curve (AUC) accumulation observed (T-HALFeff AUC) of BMS-986016 administered both alone and in combination with nivolumab
timeFrame: Approximately 2.3 years
measure: Effective elimination half-life that explains the degree of Cmax accumulation observed (T-HALFeff Cmax) of BMS-986016 administered both alone and in combination with nivolumab
timeFrame: Approximately 2.3 years
measure: Accumulation index; ratio of AUC(TAU) at steady state to AUC(TAU) after the first dose (AI_AUC) of BMS-986016 administered both alone and in combination with nivolumab
timeFrame: Approximately 2.3 years
measure: Cmax accumulation index; ratio of Cmax at steady state to Cmax after the first dose (AI_Cmax) of BMS-986016 administered both alone and in combination with nivolumab
timeFrame: Approximately 2.3 years
measure: Ctau accumulation index; ratio of Ctau at steady state to Ctau after the first dose (AI_Ctau) of BMS-986016 administered both alone and in combination with nivolumab
timeFrame: Approximately 2.3 years
measure: Degree of fluctuation (DF) or fluctuation index ([Cmax - Ctau]/Css,avg]) of BMS-986016 administered both alone and in combination with nivolumab
timeFrame: Approximately 2.3 years
measure: Immunogenicity measured by anti-drug antibody (ADA) for BMS-986016 (all participants) and nivolumab
timeFrame: Approximately 2.3 years
measure: QTc interval from centrally read electrocardiograms (ECGs)
timeFrame: Approximately 2.3 years
measure: Best overall response (BOR)
timeFrame: Approximately 3 years
measure: ORR
timeFrame: Approximately 3 years
measure: DCR
timeFrame: Approximately 3 years
measure: Duration of response (DOR)
timeFrame: Approximately 3 years
measure: Progression-free survival (PFS) rates
timeFrame: Up to approximately 3 years
measure: Overall survival (OS)
timeFrame: Approximately 2 years
measure: Number of AEs in the Narrow Scope MedDRA Anaphylactic Reaction SMQ
timeFrame: Approximately 3 years
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Local Institution - 0043
state: California
city: Aurora
country: United States
facility: Local Institution - 0053
state: Colorado
city: Tampa
country: United States
facility: Local Institution - 0058
state: Florida
city: Chicago
country: United States
facility: Local Institution - 0003
state: Illinois
city: Niles
country: United States
facility: Local Institution - 0048
state: Illinois
city: Baltimore
country: United States
facility: Local Institution - 0004
state: Maryland
city: Boston
country: United States
facility: Local Institution - 0001
state: Massachusetts
city: Detroit
country: United States
facility: Local Institution - 0011
state: Michigan
city: Rochester
country: United States
facility: Local Institution - 0051
state: Minnesota
city: Saint Louis
country: United States
facility: Local Institution - 0044
state: Missouri
city: New York
country: United States
facility: Local Institution - 0005
state: New York
city: Portland
country: United States
facility: Local Institution - 0002
state: Oregon
city: Allentown
country: United States
facility: Local Institution - 0047
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Local Institution - 0010
state: Pennsylvania
city: Dallas
country: United States
facility: Local Institution - 0057
state: Texas
city: Houston
country: United States
facility: Local Institution - 0045
state: Texas
city: Seattle
country: United States
facility: Local Institution - 0008
state: Washington
city: North Sydney
country: Australia
facility: Local Institution - 0029
state: New South Wales
city: Brisbane
country: Australia
facility: Local Institution - 0031
state: Queensland
city: Southport
country: Australia
facility: Local Institution - 0039
state: Queensland
city: Melbourne
country: Australia
facility: Local Institution - 0033
state: Victoria
city: Nedlands
country: Australia
facility: Local Institution - 0032
state: Western Australia
city: Wien
country: Austria
facility: Local Institution - 0023
city: Wien
country: Austria
facility: Local Institution - 0024
city: Toronto
country: Canada
facility: Local Institution - 0049
state: Ontario
city: Quebec City
country: Canada
facility: Local Institution - 0050
state: Quebec
city: Copenhagen
country: Denmark
facility: Local Institution - 0028
city: Herlev
country: Denmark
facility: Local Institution - 0020
city: Helsinki
country: Finland
facility: Local Institution - 0021
state: Uusimaa
city: Marseille Cedex 5
country: France
facility: Local Institution - 0038
city: Nantes Cedex 01
country: France
facility: Local Institution - 0037
city: Pierre Benite Cedex
country: France
facility: Local Institution - 0036
city: Toulouse Cedex 9
country: France
facility: Local Institution - 0026
city: Villejuif
country: France
facility: Local Institution - 0018
city: Essen
country: Germany
facility: Local Institution - 0007
city: Heilbronn
country: Germany
facility: Local Institution - 0040
city: Wuerzburg
country: Germany
facility: Local Institution - 0041
city: Milano
country: Italy
facility: Local Institution - 0014
city: Napoli
country: Italy
facility: Local Institution - 0013
city: Padova
country: Italy
facility: Local Institution - 0035
city: Nagoya-shi
country: Japan
facility: Local Institution - 0055
state: Aichi
city: Sapporo-shi
country: Japan
facility: Local Institution - 0059
state: Hokkaido
city: Sunto-gun
country: Japan
facility: Local Institution - 0054
state: Shizuoka
city: Chuo-ku
country: Japan
facility: Local Institution - 0052
state: Tokyo
city: Amsterdam
country: Netherlands
facility: Local Institution - 0025
state: Noord-Holland
city: Oslo
country: Norway
facility: Local Institution - 0019
city: Barcelona
country: Spain
facility: Local Institution - 0015
city: Malaga
country: Spain
facility: Local Institution - 0046
city: Pamplona
country: Spain
facility: Local Institution - 0006
city: Lausanne
country: Switzerland
facility: Local Institution - 0017
city: Zuerich
country: Switzerland
facility: Local Institution - 0016
city: London
country: United Kingdom
facility: Local Institution - 0027
state: Greater London
city: London
country: United Kingdom
facility: Local Institution - 0022
state: Greater London
city: Manchester
country: United Kingdom
facility: Local Institution - 0034
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: Nielsen M, Presti M, Sztupinszki Z, Jensen AWP, Draghi A, Chamberlain CA, Schina A, Yde CW, Wojcik J, Szallasi Z, Crowther MD, Svane IM, Donia M. Coexisting Alterations of MHC Class I Antigen Presentation and IFNgamma Signaling Mediate Acquired Resistance of Melanoma to Post-PD-1 Immunotherapy. Cancer Immunol Res. 2022 Oct 4;10(10):1254-1262. doi: 10.1158/2326-6066.CIR-22-0326.