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

NCT02658981 | Completed Phase 1 DMC

• 3 other identifiers: ABTC 1501IRB00095527UM1CA137443
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 11

Brief Summary

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.)

Conditions

Glioblastoma; Gliosarcoma; Recurrent Brain Neoplasm

Outcome Measures

Primary Outcomes (4)

• 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).

  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).

  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).

  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).

  4 weeks

Secondary Outcomes (6)

• Overall Survival

  2 years or until time of death, whichever occurs first

• Progression-free survival rate

  1 year

• Overall Response, assessed by RANO and iRANO

  up to 2 years

• Overall Response to anti-LAG-3 monoclonal antibody BMS-98601, assessed by RANO and iRANO

  up to 2 years

• Overall Response to anti-CD137 as monotherapy, assessed by RANO and iRANO

  up to 2 years

Study Arms (5)

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

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

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

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

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.)

Biological: Anti-LAG-3 Monoclonal Antibody BMS 986016; Biological: Anti-PD-1; Other: Pharmacological Study; Other: Laboratory Biomarker Analysis; Biological: Anti-CD137

Interventions

Anti-LAG-3 Monoclonal Antibody BMS 986016 BIOLOGICAL

Given IV

A1 Anti-LAG-3; B1 Anti-LAG3 + Anti-PD-1 (nivolumab); Intratumoral Studies

Anti-PD-1 BIOLOGICAL

Given IV

Also known as: BMS-936558, Nivolumab

B1 Anti-LAG3 + Anti-PD-1 (nivolumab); B2 Anti-CD137 + Anti-PD-1; Intratumoral Studies

Pharmacological Study OTHER

Correlative Studies

A1 Anti-LAG-3; B2 Anti-CD137 + Anti-PD-1; Intratumoral Studies

Laboratory Biomarker Analysis OTHER

Correlative Studies

A1 Anti-LAG-3; A2 Anti-CD137 (Urelumab); B1 Anti-LAG3 + Anti-PD-1 (nivolumab); B2 Anti-CD137 + Anti-PD-1; Intratumoral Studies

Anti-CD137 BIOLOGICAL

Given IV

Also known as: urelumab

A2 Anti-CD137 (Urelumab); B2 Anti-CD137 + Anti-PD-1; Intratumoral Studies

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• 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

You may not qualify if:

• 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
• 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)
• 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

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• National Cancer Institute (NCI): collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (11)

UAB Comprehensive Cancer Center

Birmingham, Alabama, 35294-3410, United States

Location

Jonsson Comprehensive Cancer Center at UCLA

Los Angeles, California, 90095, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231, United States

Location

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

Location

Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10021, United States

Location

Wake Forest University Comprehensive Cancer Center

Winston-Salem, North Carolina, 27157-1096, United States

Location

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, 44195, United States

Location

Abrams Cancer Center of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Hillman Cancer Center at University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Conditions

Glioblastoma; Gliosarcoma; Brain Neoplasms

Interventions

spartalizumab; Nivolumab; urelumab

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Micheal Lim, MD

  Johns Hopkins/ABTC

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 15, 2016
• First Posted: January 20, 2016
• Study Start: August 24, 2016
• Primary Completion: April 30, 2022
• Study Completion: October 3, 2023
• Last Updated: October 6, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (11)