GlioblastomaPhase 1NCT02658981

Anti-LAG-3 Alone & in Combination w/ Nivolumab Treating Patients w/ Recurrent GBM (Anti-CD137 Arm Closed 10/16/18)

A Phase 1 study testing Anti-LAG-3 Monoclonal Antibody BMS 986016, Anti-PD-1 and Pharmacological Study in people with Glioblastoma and Gliosarcoma, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 11 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Glioblastoma, Gliosarcoma, Recurrent Brain Neoplasm
What is being tested?: Anti-LAG-3 Monoclonal Antibody BMS 986016, Anti-PD-1 and Pharmacological Study
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 63 participants
Where: 11 sitesUnited States
Study dates: 24 Aug 2016to 3 Oct 2023
Phase: Phase 1
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Patients must have histologically proven glioblastoma or gliosarcoma which is progressive or recurrent following radiation therapy and temozolomide
Tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) methylation status must be available; results of routinely used methods for MGMT methylation testing (e.g. mutagenically separated polymerase chain reaction [MSPCR] or quantitative polymerase chain reaction [PCR]) are acceptable
Patients must have measurable contrast-enhancing disease (defined as at least 1 cm x 1 cm) by magnetic resonance imaging (MRI) imaging within 21 days of starting treatment (patients may have gross total resection, but should have measurable disease post-operatively); patients must be able to undergo MRI of the brain with gadolinium; patients must be maintained on a stable corticosteroid regimen (no increase for 5 days) prior to this baseline MRI
Patients must be in first recurrence of glioblastoma following radiation therapy and temozolomide
Patients must have recovered from severe toxicity of prior therapy; an interval of at least 12 weeks must have elapsed since the completion of radiation therapy or placement of Gliadel wafers, and at least 6 weeks must have elapsed from the last dose of temozolomide (TMZ); no prior therapies are allowed other than radiation, temozolomide, and Gliadel wafers (placed during the first surgery at diagnosis of GBM)
Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be able to care for himself/herself with occasional help from others)

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Absolute lymphocyte count >= 1000/ul
Absolute neutrophil count >= 1,500/ul
Platelets >= 100,000/ul
Hemoglobin >= 9 g/dl
Total bilirubin =< institutional upper limit of normal
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60 ml/min/1.73m^2 for patients with creatinine levels above institutional normal
Activated partial thromboplastin time (APTT) or partial thromboplastin time (PTT) =< 1.5 x institutional upper limit of normal
Patients must be able to provide written informed consent
Women of childbearing potential must have a negative serum pregnancy test within 24 hours prior to treatment start; women of childbearing potential must agree to use two methods of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment, and through 23 weeks after the last dose of study drug; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and through 31 weeks after the last dose of study drug
Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder; patients with prior malignancies must be disease-free for >= five years

Who cannot join

Patients receiving any other investigational agents are ineligible
Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to anti-LAG-3, anti-CD137, and anti-PD1 are ineligible; the investigator brochures can be referenced for more information
Patients with active or recent history of known or suspected autoimmune disease are ineligible; subjects with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, and skin disorders (vitiligo, psoriasis, or alopecia) not requiring systemic treatment, are permitted to enroll
Patients with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of study entry are ineligible
Patients must not be receiving greater than 1 mg dexamethasone/day (or an equivalent amount of an alternative corticosteroid) for at least 1 week prior to treatment start
Patients must have no evidence of mass effect and no midline shift

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Patients must have no evidence of significant hematologic, renal, or hepatic dysfunction; patients with underlying hepatocellular disease should be given careful risk/benefit consideration prior to enrollment; patients with a history of any chronic hepatitis as evidenced by the following are ineligible:
Positive test for hepatitis B surface antigen (HBsAg)
Positive test for qualitative hepatitis C viral load (by PCR) (Note: subjects with positive hepatitis C antibody and negative quantitative hepatitis C by PCR are eligible; history of resolved hepatitis A virus infection is not an exclusion criterion)
History of alcoholic or non-alcoholic steatohepatitis (NASH), auto-immune hepatitis, or previous grade 3-4 drug-related hepatitis, or any form of chronic liver disease
Patients must be hepatitis C virus (HCV) negative (by quantitative PCR [qPCR]) and hepatitis B virus core antibody (HBcAb) negative (no prior hepatitis B infection)
Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, clinically significant cardiac disease, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible
Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with these agents
Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

Trial locations and contacts

11 sites in 1 country.

City, postcode or hospital

11 sites in 1 country

United States11 sites

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, 21231
UAB Comprehensive Cancer Center
Birmingham, Alabama, 35294-3410
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, 02114
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
Boston, Massachusetts, 02115
Cleveland Clinic Taussig Cancer Center
Cleveland, Ohio, 44195
Henry Ford Hospital
Detroit, Michigan, 48202
Jonsson Comprehensive Cancer Center at UCLA
Los Angeles, California, 90095
Memorial Sloan-Kettering Cancer Center
New York, New York, 10021
Abrams Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Hillman Cancer Center at University of Pittsburgh Cancer Institute
Pittsburgh, Pennsylvania, 15232
Wake Forest University Comprehensive Cancer Center
Winston-Salem, North Carolina, 27157-1096

Other trials in United States

About this study

Official title: A Phase I Trial of Anti-LAG-3 or Anti-CD137 Alone and in Combination With Anti-PD-1 in Patients With Recurrent GBM

This phase I trial studies the safety and best dose of anti-LAG-3 (anti-LAG-3 monoclonal antibody BMS-986016) or urelumab alone and in combination with nivolumab in treating patients with glioblastoma that has returned (recurrent). Anti-LAG-3 monoclonal antibody BMS-986016, urelumab, and nivolumab are antibodies (a type of protein) that may stimulate the cells in the immune system to attack tumor cells. It is not yet known whether anti-LAG-3 monoclonal antibody BMS-986016 or urelumab alone or in combination with nivolumab may kill more tumor cells. (The Anti-CD137 antibody (BMS-663513 - urelumab) treatment arm closed by BMS on 10/16/18 due to closure of BMS Urelumab development program. Subjects currently on treatment may continue.)

Read the detailed description

PRIMARY OBJECTIVES:

To determine a maximum tolerated dose or maximum administrated dose of anti-lymphocyte activation gene-3 (LAG-3) antibody (BMS-986016) (anti-LAG-3 monoclonal antibody BMS-986016) and anti-cluster of differentiation 137 (CD137) antibody (BMS- 663513) (urelumab) given independently and in combination with anti-programmed death-1 (PD-1) antibody (nivolumab, BMS-936558) safely in patients with recurrent glioblastoma multiforme (GBM).

SECONDARY OBJECTIVES:

To estimate overall survival. II. To estimate 1 year progression-free survival (PFS) rate. III. To estimate radiographic response (radiographic assessment in neuro-oncology [RANO] and immunotherapy response assessment for neuro-oncology [iRANO]).

TERTIARY OBJECTIVES:

To assess the pharmacodynamic effects of anti-LAG-3 antibody (BMS-986016), anti-CD137 antibody (BMS- 663513), and/or anti-PD-1 antibody (BMS-936558) on biomarkers in peripheral blood, including the T cell compartments, and serum proteins (cytokines and other immune modulators).

II. To assess the pharmacodynamic activity in tumor tissue and peripheral blood in treated subjects who undergo optional tumor biopsies.

III. To explore potential associations between biomarker measures and anti-tumor activity by analyzing markers of inflammation, immune activation, host tumor growth factors, and tumor-derived proteins in the pre-treatment and on-treatment setting.

IV. To further characterize the occupancy and immune cell function at multiple dose levels of anti-LAG-3 antibody (BMS-986016), anti-CD137 antibody (BMS-663513), and/or anti-PD-1 antibody (BMS-936558).

To explore characteristics of tumor immune microenvironment changes after the treatment of anti-LAG-3, anti-CD137, and its combination treatment with anti- PD-1 in surgically indicated patients undergoing tumor resection

OUTLINE:

PART A: This is a dose-escalation study of the monotherapy of Anti-LAG-3 monoclonal antibody BMS-986016 and Anti-CD137 (urelumab). Patients are assigned to 1 of 2 arms.

ARM I: Patients receive anti-LAG-3 monoclonal antibody BMS-986016 intravenously (IV) on days 1 and 15. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive anti-CD137 (urelumab) IV on day 1. Treatment repeats every 21 days for up to 15 courses in the absence of disease progression or unacceptable toxicity.

PART B: This is the dose-escalation combination therapy portion study of Anti-LAG-3 monoclonal antibody BMS-986016 plus Anti-PD-1(nivolumab) and Anti-CD137 (urelumab) plus Anti-PD-1 (nivolumab). Patients are assigned to 1 of 2 arms.

ARM I: Patients receive Anti-PD-1 (nivolumab) IV over 60 minutes and anti-LAG-3 monoclonal antibody BMS-986016 IV on days 1 and 15. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive Anti-PD-1 (nivolumab) IV over 60 minutes on days 1 and 15 and urelumab IV on day 1. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

(2pts enrolled before the Anti-CD137 antibody (BMS-663513 - urelumab) treatment arm closed by BMS on 10/16/18 due to closure of BMS Urelumab development program. Subjects currently on treatment may continue.)

INTRATUMORAL STUDIES: Patients enrolled on the Intratumoral Studies surgical arm pre-operatively receive either anti-LAG-3 monoclonal antibody BMS-986016 as in Part A Arm I, urelumab as in as in Part A Arm II, nivolumab and anti-LAG-3 monoclonal antibody BMS-986016 as in Part B Arm I, or nivolumab and urelumab as in Part B Arm II. Within 45 days of surgical resection, patients post-operatively receive either anti-LAG-3 monoclonal antibody BMS-986016 as in Part A Arm I, urelumab as in as in Part A Arm II, nivolumab and anti-LAG-3 monoclonal antibody BMS-986016 as in Part B Arm I, or nivolumab and urelumab as in Part B Arm II.

(3pts enrolled before the Anti-CD137 antibody (BMS-663513 - urelumab) treatment arm closed by BMS on 10/16/18 due to closure of BMS Urelumab development program. Subjects currently on treatment may continue.)

After completion of study treatment, patients are followed up at 60 days, every 2 months for 2 years, and then every 6 months thereafter. Patients taken off treatment for other reasons than disease progression are followed up every 2 months for 1 year.

Conditions: Glioblastoma, Gliosarcoma, Recurrent Brain Neoplasm
Being tested: Anti-LAG-3 Monoclonal Antibody BMS 986016, Anti-PD-1, Pharmacological Study, Laboratory Biomarker Analysis, Anti-CD137
Medical subject headings: Glioblastoma, Gliosarcoma, Brain Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Anti-LAG-3 Monoclonal Antibody BMS 986016Biological
Given IV
Anti-PD-1Biological
Also called BMS-936558, Nivolumab
Given IV
Pharmacological StudyOther
Correlative Studies
Laboratory Biomarker AnalysisOther
Correlative Studies
Anti-CD137Biological
Also called urelumab
Given IV

Study groups in NCT02658981
Study group	Role	What they receive
A1 Anti-LAG-3	Experimental	Patients receive Anti-LAG-3 monoclonal antibody BMS-986016 IV over 60 minutes and on days 1 and 15. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Pharmacological Study Laboratory Biomarker Analysis Receives: Biological: Anti-LAG-3 Monoclonal Antibody BMS 986016; Other: Pharmacological Study; Other: Laboratory Biomarker Analysis
A2 Anti-CD137 (Urelumab)	Experimental	Patients receive Anti-CD137 (Urelumab) IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 15 courses in the absence of disease progression or unacceptable toxicity Pharmacological Study Laboratory Biomarker Analysis Receives: Other: Laboratory Biomarker Analysis; Biological: Anti-CD137
B1 Anti-LAG3 + Anti-PD-1 (nivolumab)	Experimental	Patients receive Anti-PD-1 (nivolumab) IV over 60 minutes and anti-LAG-3 monoclonal antibody BMS-986016 IV on days 1 and 15. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Pharmacological Study Laboratory Biomarker Analysis Receives: Biological: Anti-LAG-3 Monoclonal Antibody BMS 986016; Biological: Anti-PD-1; Other: Laboratory Biomarker Analysis
B2 Anti-CD137 + Anti-PD-1	Experimental	Patients receive Anti-PD-1 (nivolumab) IV over 60 minutes on days 1 and 15 and Anti-CD137 (urelumab) IV on day 1. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. (2pts enrolled before the Anti-CD137 antibody (BMS-663513 - urelumab) treatment arm closed by BMS on 10/16/18 due to closure of BMS Urelumab development program. Subjects currently on treatment may continue.) Pharmacological Study Laboratory Biomarker Analysis Receives: Biological: Anti-PD-1; Other: Pharmacological Study; Other: Laboratory Biomarker Analysis; Biological: Anti-CD137
Intratumoral Studies	Experimental	Patients pre-operatively receive either anti-LAG-3 monoclonal antibody BMS-986016 (Arm A1), or urelumab (Arm A2), or nivolumab and anti-LAG-3 monoclonal antibody BMS-986016 as in Part B (B1)), or nivolumab and urelumab as in Part B (B2). Within 45 days of surgical resection, patients post-operatively receive drug from one of the four arms. (3pts enrolled before the Anti-CD137 antibody (BMS-663513 - urelumab) treatment arm closed by BMS on 10/16/18 due to closure of BMS Urelumab development program. Subjects currently on treatment may continue.) Receives: Biological: Anti-LAG-3 Monoclonal Antibody BMS 986016; Biological: Anti-PD-1; Other: Pharmacological Study; Other: Laboratory Biomarker Analysis; Biological: Anti-CD137

What is being measured

The primary outcome is the main question the study is designed to answer.

Maximum tolerated dose (MTD) of anti-LAG-3 monoclonal antibody BMS-986016 as monotherapy as determined by frequency of toxicity
The frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experienced grade 3 or above toxicities (as defined by CTCAE v. 5.0 [Common Terminology Criteria for Adverse Events]) will be estimated, along with 95% confidence interval. MTD will be confirmed as the maximum dose level at which ≤ 33% of participants experience a dose-limiting toxicity (DLT).
Measured: 4 weeks
Maximum tolerated dose (MTD) of anti-CD137 as monotherapy as determined by frequency of toxicity
The frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experienced grade 3 or above toxicities (as defined by CTCAE v. 5.0 [Common Terminology Criteria for Adverse Events]) will be estimated, along with 95% confidence interval. MTD will be confirmed as the maximum dose level at which ≤ 33% of participants experience a dose-limiting toxicity (DLT).
Measured: 4 weeks
MTD of Anti-LAG-3 + Anti-PD-1 as determined by frequency of toxicity
The frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experienced grade 3 or above toxicities (as defined by CTCAE v. 5.0 [Common Terminology Criteria for Adverse Events]) will be estimated, along with 95% confidence interval. MTD will be confirmed as the maximum dose level at which ≤ 33% of participants experience a dose-limiting toxicity (DLT).
Measured: 4 weeks
MTD of Anti-CD137 + Anti-PD-1 as determined by frequency of toxicity
The frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experienced grade 3 or above toxicities (as defined by CTCAE v. 5.0 [Common Terminology Criteria for Adverse Events]) will be estimated, along with 95% confidence interval. MTD will be confirmed as the maximum dose level at which ≤ 33% of participants experience a dose-limiting toxicity (DLT).
Measured: 4 weeks

Secondary outcomes (6)

Overall Survival
The Kaplan-Meier method will be used to estimate overall survival probability and median time of survival along with a 95% confidence interval.
Measured: 2 years or until time of death, whichever occurs first
Progression-free survival rate
To estimate PFS rate at one year, all patients with non-progressive disease and alive at one year will be evaluated by RANO and iRANO at one year to confirm non-progressive status. The proportion of patients who achieve PFS at one year will be estimated along with a 90% confidence interval, assuming underlying binomial distribution.
Measured: 1 year
Overall Response, assessed by RANO and iRANO
To estimate an overall tumor response rate: the proportion of patients who have objective partial response or complete response during the course of treatment will be estimated, along with 95% confidence intervals using the exact binomial method regardless of dosage, single or combination treatment.
Measured: up to 2 years
Overall Response to anti-LAG-3 monoclonal antibody BMS-98601, assessed by RANO and iRANO
The proportion of patients who have objective partial response or complete response to anti-LAG-3 monoclonal antibody BMS-98601 during the course of treatment will be estimated per dose level with 95% confidence interval.
Measured: up to 2 years
Overall Response to anti-CD137 as monotherapy, assessed by RANO and iRANO
The proportion of patients who have objective partial response or complete response to anti-CD137 as monotherapy during the course of treatment will be estimated per dose level with 95% confidence interval.
Measured: up to 2 years
Overall Response to Anti-LAG-3 + Anti-PD-1, assessed by RANO and iRANO
The proportion of patients who have objective partial response or complete response to Anti-LAG-3 + Anti-PD-1 combination therapy, during the course of treatment will be estimated per dose level with 95% confidence interval.
Measured: up to 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

24 Aug 20163 Oct 2023

First posted20 Jan 2016 (estimated)
Study start24 Aug 2016
Primary completion30 Apr 2022
Study completion3 Oct 2023

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (1)Papers the sponsor has linked to this study.
Other trials for GlioblastomaStudies of the same condition, open and under way.
More trials run by Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 63 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02658981
Sponsor's protocol ID: ABTC 1501
Other IDs: IRB00095527, UM1CA137443
Status last verified: Oct 2023
First submitted: 15 Jan 2016
Last updated: 6 Oct 2023
Results posted: No
Data monitoring committee: Yes
Individual data sharing: No

Publications

Lim M, Ye X, Piotrowski AF, Desai A, Ahluwalia MS, Walbert T, Lesser G, Ellingson BM, Peereboom DM, Fisher JD, Desideri S, Jackson C, Pant A, Jain A, Verma R, Oberlton B, Piyadasa H, Bettegowda C, Engle L, Taube J, Bendall SC, Choi J, Drappatz J, Lieberman FS, Kleinberg LR, Pardoll DM, Nabors LB, Wen PY, Grossman SA. Anti-LAG-3 with or without anti-PD-1 in recurrent glioblastoma: a phase 1 trial. Nat Med. 2026 Jul;32(7):2449-2460. doi: 10.1038/s41591-026-04475-7. Epub 2026 Jul 10.
PubMed 42432293

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 6 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase I Trial of Anti-LAG-3 or Anti-CD137 Alone and in Combination With Anti-PD-1 in Patients With Recurrent GBM
ClinicalTrials.gov ID: NCT02658981
Acronym / sponsor ID: ABTC 1501
Conditions: Glioblastoma, Gliosarcoma, Recurrent Brain Neoplasm
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 63 participants (actual)
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsUniversity, hospital or other
Collaborators: National Cancer Institute (NCI), Bristol-Myers Squibb
Study start: 24 Aug 2016 (actual)
Primary completion: 30 Apr 2022 (actual)
Study completion: 3 Oct 2023 (actual)
First posted: 20 Jan 2016 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

PRIMARY OBJECTIVES:

To determine a maximum tolerated dose or maximum administrated dose of anti-lymphocyte activation gene-3 (LAG-3) antibody (BMS-986016) (anti-LAG-3 monoclonal antibody BMS-986016) and anti-cluster of differentiation 137 (CD137) antibody (BMS- 663513) (urelumab) given independently and in combination with anti-programmed death-1 (PD-1) antibody (nivolumab, BMS-936558) safely in patients with recurrent glioblastoma multiforme (GBM).

SECONDARY OBJECTIVES:

To estimate overall survival. II. To estimate 1 year progression-free survival (PFS) rate. III. To estimate radiographic response (radiographic assessment in neuro-oncology [RANO] and immunotherapy response assessment for neuro-oncology [iRANO]).

TERTIARY OBJECTIVES:

To assess the pharmacodynamic effects of anti-LAG-3 antibody (BMS-986016), anti-CD137 antibody (BMS- 663513), and/or anti-PD-1 antibody (BMS-936558) on biomarkers in peripheral blood, including the T cell compartments, and serum proteins (cytokines and other immune modulators).

II. To assess the pharmacodynamic activity in tumor tissue and peripheral blood in treated subjects who undergo optional tumor biopsies.

To explore characteristics of tumor immune microenvironment changes after the treatment of anti-LAG-3, anti-CD137, and its combination treatment with anti- PD-1 in surgically indicated patients undergoing tumor resection

OUTLINE:

PART A: This is a dose-escalation study of the monotherapy of Anti-LAG-3 monoclonal antibody BMS-986016 and Anti-CD137 (urelumab). Patients are assigned to 1 of 2 arms.

ARM II: Patients receive anti-CD137 (urelumab) IV on day 1. Treatment repeats every 21 days for up to 15 courses in the absence of disease progression or unacceptable toxicity.

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 5

Arm	Type	Receives
A1 Anti-LAG-3	Experimental	Biological: Anti-LAG-3 Monoclonal Antibody BMS 986016, Other: Pharmacological Study, Other: Laboratory Biomarker AnalysisPatients receive Anti-LAG-3 monoclonal antibody BMS-986016 IV over 60 minutes and on days 1 and 15. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Pharmacological Study Laboratory Biomarker Analysis
A2 Anti-CD137 (Urelumab)	Experimental	Other: Laboratory Biomarker Analysis, Biological: Anti-CD137Patients receive Anti-CD137 (Urelumab) IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 15 courses in the absence of disease progression or unacceptable toxicity Pharmacological Study Laboratory Biomarker Analysis
B1 Anti-LAG3 + Anti-PD-1 (nivolumab)	Experimental	Biological: Anti-LAG-3 Monoclonal Antibody BMS 986016, Biological: Anti-PD-1, Other: Laboratory Biomarker AnalysisPatients receive Anti-PD-1 (nivolumab) IV over 60 minutes and anti-LAG-3 monoclonal antibody BMS-986016 IV on days 1 and 15. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Pharmacological Study Laboratory Biomarker Analysis
B2 Anti-CD137 + Anti-PD-1	Experimental	Biological: Anti-PD-1, Other: Pharmacological Study, Other: Laboratory Biomarker Analysis, Biological: Anti-CD137Patients receive Anti-PD-1 (nivolumab) IV over 60 minutes on days 1 and 15 and Anti-CD137 (urelumab) IV on day 1. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. (2pts enrolled before the Anti-CD137 antibody (BMS-663513 - urelumab) treatment arm closed by BMS on 10/16/18 due to closure of BMS Urelumab development program. Subjects currently on treatment may continue.) Pharmacological Study Laboratory Biomarker Analysis
Intratumoral Studies	Experimental	Biological: Anti-LAG-3 Monoclonal Antibody BMS 986016, Biological: Anti-PD-1, Other: Pharmacological Study, Other: Laboratory Biomarker Analysis, Biological: Anti-CD137Patients pre-operatively receive either anti-LAG-3 monoclonal antibody BMS-986016 (Arm A1), or urelumab (Arm A2), or nivolumab and anti-LAG-3 monoclonal antibody BMS-986016 as in Part B (B1)), or nivolumab and urelumab as in Part B (B2). Within 45 days of surgical resection, patients post-operatively receive drug from one of the four arms. (3pts enrolled before the Anti-CD137 antibody (BMS-663513 - urelumab) treatment arm closed by BMS on 10/16/18 due to closure of BMS Urelumab development program. Subjects currently on treatment may continue.)

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (17 listed)

Patients must have histologically proven glioblastoma or gliosarcoma which is progressive or recurrent following radiation therapy and temozolomide

Key exclusion criteria (14 listed)

Patients receiving any other investigational agents are ineligible

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Anti-LAG-3 Monoclonal Antibody BMS 986016Given IV	Biological	A1 Anti-LAG-3, B1 Anti-LAG3 + Anti-PD-1 (nivolumab), Intratumoral Studies
Anti-PD-1Also: BMS-936558, NivolumabGiven IV	Biological	B1 Anti-LAG3 + Anti-PD-1 (nivolumab), B2 Anti-CD137 + Anti-PD-1, Intratumoral Studies
Pharmacological StudyCorrelative Studies	Other	A1 Anti-LAG-3, B2 Anti-CD137 + Anti-PD-1, Intratumoral Studies
Laboratory Biomarker AnalysisCorrelative Studies	Other	A1 Anti-LAG-3, A2 Anti-CD137 (Urelumab), B1 Anti-LAG3 + Anti-PD-1 (nivolumab), B2 Anti-CD137 + Anti-PD-1, Intratumoral Studies
Anti-CD137Also: urelumabGiven IV	Biological	A2 Anti-CD137 (Urelumab), B2 Anti-CD137 + Anti-PD-1, Intratumoral Studies

Primary outcome

Maximum tolerated dose (MTD) of anti-LAG-3 monoclonal antibody BMS-986016 as monotherapy as determined by frequency of toxicity
Time frame: 4 weeks
The frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experienced grade 3 or above toxicities (as defined by CTCAE v. 5.0 [Common Terminology Criteria for Adverse Events]) will be estimated, along with 95% confidence interval. MTD will be confirmed as the maximum dose level at which ≤ 33% of participants experience a dose-limiting toxicity (DLT).
Maximum tolerated dose (MTD) of anti-CD137 as monotherapy as determined by frequency of toxicity
Time frame: 4 weeks
The frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experienced grade 3 or above toxicities (as defined by CTCAE v. 5.0 [Common Terminology Criteria for Adverse Events]) will be estimated, along with 95% confidence interval. MTD will be confirmed as the maximum dose level at which ≤ 33% of participants experience a dose-limiting toxicity (DLT).
MTD of Anti-LAG-3 + Anti-PD-1 as determined by frequency of toxicity
Time frame: 4 weeks
The frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experienced grade 3 or above toxicities (as defined by CTCAE v. 5.0 [Common Terminology Criteria for Adverse Events]) will be estimated, along with 95% confidence interval. MTD will be confirmed as the maximum dose level at which ≤ 33% of participants experience a dose-limiting toxicity (DLT).
MTD of Anti-CD137 + Anti-PD-1 as determined by frequency of toxicity
Time frame: 4 weeks
The frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experienced grade 3 or above toxicities (as defined by CTCAE v. 5.0 [Common Terminology Criteria for Adverse Events]) will be estimated, along with 95% confidence interval. MTD will be confirmed as the maximum dose level at which ≤ 33% of participants experience a dose-limiting toxicity (DLT).

6 secondary outcomes

Overall Survival
Time frame: 2 years or until time of death, whichever occurs first
Progression-free survival rate
Time frame: 1 year
Overall Response, assessed by RANO and iRANO
Time frame: up to 2 years
Overall Response to anti-LAG-3 monoclonal antibody BMS-98601, assessed by RANO and iRANO
Time frame: up to 2 years
Overall Response to anti-CD137 as monotherapy, assessed by RANO and iRANO
Time frame: up to 2 years
Overall Response to Anti-LAG-3 + Anti-PD-1, assessed by RANO and iRANO
Time frame: up to 2 years

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 6 Oct 2023.
Derived from this study: PubMed 42432293Lim M, Ye X, Piotrowski AF, Desai A, Ahluwalia MS, Walbert T, Lesser G, Ellingson BM, Peereboom DM, Fisher JD, Desideri S, Jackson C, Pant A, Jain A, Verma R, Oberlton B, Piyadasa H, Bettegowda C, Engle L, Taube J, Bendall SC, Choi J, Drappatz J, Lieberman FS, Kleinberg LR, Pardoll DM, Nabors LB, Wen PY, Grossman SA. Anti-LAG-3 with or without anti-PD-1 in recurrent glioblastoma: a phase 1 trial. Nat Med. 2026 Jul;32(7):2449-2460. doi: 10.1038/s41591-026-04475-7. Epub 2026 Jul 10.
Individual participant dataSharing planned: No

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Micheal Lim, MD study chair

Johns Hopkins/ABTC

11 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated dose (MTD) of anti-LAG-3 monoclonal antibody BMS-986016 as monotherapy as determined by frequency of toxicity (time frame: 4 weeks). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02658981, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Oct 2023.