Anti-LAG-3 Monoclonal Antibody BMS-986016 or Urelumab Alone and in Combination with Nivolumab in Treating Patients with Recurrent Glioblastoma

Status: Active

Description

This phase I trial studies the safety and best dose of anti-lymphocyte activation gene-3 (LAG-3) monoclonal antibody BMS-986016 or urelumab alone and in combination with nivolumab in treating patients with glioblastoma that has returned (recurrent). Monoclonal antibodies, such as anti-LAG-3 monoclonal antibody BMS-986016, urelumab, and nivolumab may interfere with the ability of tumor cells to grow and spread.

Eligibility Criteria

Inclusion Criteria

  • Patients must have histologically proven glioblastoma or gliosarcoma which is progressive or recurrent (per RANO criteria) 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 a tumor tissue form indicating availability of archived tissue from initial resection at diagnosis of glioblastoma completed and signed by a pathologist; availability of tissue is not a requirement for study participation
  • Phase I 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 prior to 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
  • Phase I patients must be maintained on a stable corticosteroid regimen (no increase for 5 days) prior to the 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 (except for patients with Gilberts' syndrome who must have normal direct bilirubin)
  • 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/1.73 m^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 agree to 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 at least 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; sexually active men of reproductive potential who are partners of women with reproductive potential must also agree to use adequate contraception prior to the study, for the duration of study participation, and through at least 32 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
  • INTRATUMORAL STUDIES PATIENTS:
  • Patients on the Intratumoral Studies surgical arm must be undergoing repeat surgery that is clinically indicated as determined by their care providers, where a significant debulking or a gross total surgical resection of the contrast-enhancing area is intended

Exclusion Criteria

  • 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 a known 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
  • Phase I 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 significant mass effect, no midline shift, and no uncontrolled clinical signs of mass effect
  • 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 a confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to signing informed consent are ineligible
  • Patients with uncontrolled or significant cardiovascular disease including, but not limited to, any of the following are ineligible: * Myocardial infarction or stroke/transient ischemic attack (TIA) within the 6 months prior to consent * Uncontrolled angina within the 3 months prior to consent * Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes) * History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III-IV, myocarditis and pericarditis, significant pericardial effusion, significant coronary stent occlusion, deep venous thrombosis, etc.) * Cardiovascular disease-related requirement for daily supplemental oxygen
  • Corrected QT interval (QTc) prolongation > 480 msec
  • Patients with other uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 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
  • Patients with a known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) are ineligible

Locations & Contacts

Alabama

Birmingham
University of Alabama at Birmingham Cancer Center
Status: Temporarily closed to accrual
Contact: Site Public Contact
Phone: 205-934-0220
Email: tmyrick@uab.edu

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: Active
Contact: Site Public Contact
Phone: 410-955-8804
Email: jhcccro@jhmi.edu

Massachusetts

Boston
Dana-Farber Cancer Institute
Status: Temporarily closed to accrual
Contact: Site Public Contact
Phone: 877-442-3324

Michigan

Detroit
Henry Ford Hospital
Status: Active
Contact: Site Public Contact
Phone: 313-916-3721
Email: CTOResearch@hfhs.org

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: Active
Contact: Site Public Contact
Phone: 212-639-7592

New York

Commack
Memorial Sloan Kettering Commack
Status: Active
Contact: Site Public Contact
Phone: 212-639-7592
New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Site Public Contact
Phone: 212-639-7592
West Harrison
Memorial Sloan Kettering Westchester
Status: Active
Contact: Site Public Contact
Phone: 212-639-7592

North Carolina

Winston-Salem
Wake Forest University Health Sciences
Status: Active
Contact: Site Public Contact
Phone: 336-713-6771

Ohio

Cleveland
Case Western Reserve University
Status: Temporarily closed to accrual
Contact: Site Public Contact
Phone: 800-641-2422
Email: CTUReferral@UHhospitals.org
Cleveland Clinic Foundation
Status: Temporarily closed to accrual
Contact: Site Public Contact
Phone: 866-223-8100
Email: CancerAnswer@ccf.org

Pennsylvania

Philadelphia
University of Pennsylvania / Abramson Cancer Center
Status: Temporarily closed to accrual
Contact: Site Public Contact
Phone: 800-474-9892
Pittsburgh
University of Pittsburgh Cancer Institute (UPCI)
Status: Active
Contact: Site Public Contact
Phone: 412-647-8073

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine a maximum tolerated dose or maximum administrated dose of anti-LAG-3 monoclonal antibody BMS-986016 (anti-LAG-3 antibody [BMS-986016]) and urelumab (anti-CD137 antibody [BMS- 663513]) given independently and in combination with anti-PD-1 antibody (nivolumab, BMS-936558) safely in patients with recurrent glioblastoma multiforme (GBM).

SECONDARY OBJECTIVES:

I. 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:

I. 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 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).

V. 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 anti-LAG-3 monoclonal antibody BMS-986016 and 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 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 a dose-escalation study of anti-LAG-3 monoclonal antibody BMS-986016 and urelumab. Patients are assigned to 1 of 2 arms.

ARM I: Patients receive 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 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.

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.

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.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Adult Brain Tumor Consortium

Principal Investigator
Michael Lim

Trial IDs

Primary ID ABTC-1501
Secondary IDs NCI-2015-01914, ABTC 1501, 1501, ABTC # 1501
Clinicaltrials.gov ID NCT02658981