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Anti-LAG-3 or Urelumab Alone and in Combination With Nivolumab in Treating Patients With Recurrent Glioblastoma

This study is currently recruiting participants.
Verified November 2017 by Sidney Kimmel Comprehensive Cancer Center
Sponsor:
ClinicalTrials.gov Identifier:
NCT02658981
First Posted: January 20, 2016
Last Update Posted: November 14, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
National Cancer Institute (NCI)
Bristol-Myers Squibb
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
  Purpose
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.

Condition Intervention Phase
Glioblastoma Gliosarcoma Recurrent Brain Neoplasm Biological: Anti-LAG-3 Monoclonal Antibody BMS 986016 Biological: Anti-PD-1 Other: Pharmacological Study Other: Laboratory Biomarker Analysis Biological: Anti-CD137 Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) of anti-LAG-3 monoclonal antibody BMS-986016 as monotherapy [ Time Frame: 4 weeks ]
    If no more than two of the six patients at that dose level experience a dose-limiting toxicity (DLT), then that dose level will be confirmed as the MTD. The target DLT rate is =< 33%. The severity and 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 will be estimated, along with 95% confidence

  • Maximum tolerated dose (MTD) of anti-CD137 as monotherapy [ Time Frame: 4 weeks ]
    If no more than two of the six patients at that dose level experience a dose-limiting toxicity (DLT), then that dose level will be confirmed as the MTD. The target DLT rate is =< 33%. The severity and 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 will be estimated, along with 95% confidence

  • MTD of Anti-LAG-3 + Anti-PD-1 [ Time Frame: 4 weeks ]
    If no more than two of the six patients at that dose level experience a dose-limiting toxicity (DLT), then that dose level will be confirmed as the MTD. The target DLT rate is =< 33%. The severity and 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 will be estimated, along with 95% confidence

  • MTD of Anti-CD137 + Anti-PD-1 [ Time Frame: 4 weeks ]
    If no more than two of the six patients at that dose level experience a dose-limiting toxicity (DLT), then that dose level will be confirmed as the MTD. The target DLT rate is =< 33%. The severity and 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 will be estimated, along with 95% confidence


Secondary Outcome Measures:
  • Overall Survival [ Time Frame: Start of treatment to the date of death, 2 years ]
    The Kaplan-Meier method will be used to estimate overall survival probability and median time of survival along with a 95% confidence interval.

  • Progression-free survival rate [ Time Frame: 1 year ]
    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.

  • Response, assessed by RANO and iRANO [ Time Frame: up to 2 years ]
    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. The proportion of tumor response also will be estimated per dose level, single agent or combination treatment independently along with 95% confidence interval.


Estimated Enrollment: 68
Study Start Date: August 2016
Estimated Study Completion Date: December 2019
Estimated Primary Completion Date: August 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A1 Anti-LAG-3

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
Given IV
Other: Pharmacological Study
Correlative Studies
Other: Laboratory Biomarker Analysis
Correlative Studies
Experimental: A2 Anti-CD137 (Urelumab)

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
Correlative Studies
Biological: Anti-CD137
Given IV
Other Name: urelumab
Experimental: B1 Anti-LAG3 + Anti-PD-1 (nivolumab)

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
Given IV
Biological: Anti-PD-1
Given IV
Other Names:
  • BMS-936558
  • Nivolumab
Other: Laboratory Biomarker Analysis
Correlative Studies
Experimental: B2 Anti-CD137 + Anti-PD-1

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.

Pharmacological Study

Laboratory Biomarker Analysis

Biological: Anti-PD-1
Given IV
Other Names:
  • BMS-936558
  • Nivolumab
Other: Pharmacological Study
Correlative Studies
Other: Laboratory Biomarker Analysis
Correlative Studies
Biological: Anti-CD137
Given IV
Other Name: urelumab

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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
    • 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

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 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)
      • 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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02658981


Contacts
Contact: Stuart Grossman, MD 410-955-8837 grossman@jhmi.edu
Contact: Joy Fisher, MA 410-955-3657 jfisher@jhmi.edu

Locations
United States, Alabama
UAB Comprehensive Cancer Center Recruiting
Birmingham, Alabama, United States, 35294-3410
Contact: Thiru Pillay, RN    205-934-1842    thiru@uab.edu   
Principal Investigator: Burt Nabors, MD         
United States, California
Jonsson Comprehensive Cancer Center at UCLA Not yet recruiting
Los Angeles, California, United States, 90095
Contact: Timothy Cloughesy, MD    310-825-5321    TCloughesy@mednet.ucla.edu   
Principal Investigator: Timothy Cloughesy, MD         
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21231
Contact: Quinn Alexopulos, RN    410-955-8837    qta@jhmi.edu   
Principal Investigator: Michael Lim, MD         
Sub-Investigator: Stuart Grossman, MD         
United States, Massachusetts
Massachusetts General Hospital Cancer Center Recruiting
Boston, Massachusetts, United States, 02114
Contact: Clinical Trials Office - Massachusetts General Hospital Cancer    877-726-5130      
Contact: , MD         
Principal Investigator: Elizabeth Gerstner, MD         
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Clinical Trials Office - Dana-Farber/Harvard Cancer Center    617-632-2166      
Contact: Wen         
Principal Investigator: Patrick Wen, MD         
United States, Michigan
Henry Ford Hospital Recruiting
Detroit, Michigan, United States, 48202
Contact: Amy Williamson, RN       awillia12@hfhs.org   
Contact: Emily Krozek, MHSA       ekrozek1@hfhs.org   
Principal Investigator: Tobias Walbert, MD         
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10021
Contact: Tom Kaley, MD    212-639-5122      
Principal Investigator: Tom Kaley, MD         
United States, North Carolina
Wake Forest University Comprehensive Cancer Center Recruiting
Winston-Salem, North Carolina, United States, 27157-1096
Contact: Clinical Trials Office - Wake Forest University CCC    336-713-6771      
Principal Investigator: Glenn Lesser, MD         
United States, Ohio
Cleveland Clinic Taussig Cancer Center Recruiting
Cleveland, Ohio, United States, 44195
Contact: Cancer Center-Cares    216-444-7923      
Principal Investigator: Manmeet Ahluwalia, MD         
Sub-Investigator: David Peereboom, MD         
United States, Pennsylvania
Abrams Cancer Center of the University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Scott Levy    215-662-6832    NCRD-BTC@uphs.upenn.edu   
Principal Investigator: Arati Desai, MD         
Hillman Cancer Center at University of Pittsburgh Cancer Institute Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Clinical Trials Office - Hillman Cancer Center    412-647-8073      
Principal Investigator: Frank Lieberman, MD         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
National Cancer Institute (NCI)
Bristol-Myers Squibb
Investigators
Study Chair: Micheal Lim, MD Johns Hopkins/ABTC
  More Information

Responsible Party: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT02658981     History of Changes
Other Study ID Numbers: ABTC 1501
UM1CA137443 ( U.S. NIH Grant/Contract )
First Submitted: January 15, 2016
First Posted: January 20, 2016
Last Update Posted: November 14, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Glioblastoma
Gliosarcoma
Brain Neoplasms
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
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Nivolumab
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents