Clinical Trials /

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

NCT02658981

Description:

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.)

Related Conditions:
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: ABTC 1501
  • SECONDARY ID: IRB00095527
  • SECONDARY ID: UM1CA137443
  • NCT ID: NCT02658981

Conditions

  • Glioblastoma
  • Gliosarcoma
  • Recurrent Brain Neoplasm

Interventions

DrugSynonymsArms
Anti-LAG-3 Monoclonal Antibody BMS 986016A1 Anti-LAG-3
Anti-PD-1BMS-936558, NivolumabB1 Anti-LAG3 + Anti-PD-1 (nivolumab)
Anti-CD137urelumabA2 Anti-CD137 (Urelumab)

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. (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.)

Detailed Description

      PRIMARY OBJECTIVES:

      I. 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:

      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 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).

      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 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.
    

Trial Arms

NameTypeDescriptionInterventions
A1 Anti-LAG-3ExperimentalPatients 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
  • Anti-LAG-3 Monoclonal Antibody BMS 986016
A2 Anti-CD137 (Urelumab)ExperimentalPatients 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
  • Anti-CD137
B1 Anti-LAG3 + Anti-PD-1 (nivolumab)ExperimentalPatients 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
  • Anti-LAG-3 Monoclonal Antibody BMS 986016
  • Anti-PD-1
B2 Anti-CD137 + Anti-PD-1ExperimentalPatients 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
  • Anti-PD-1
  • Anti-CD137
Intratumoral StudiesExperimentalPatients 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.)
  • Anti-LAG-3 Monoclonal Antibody BMS 986016
  • Anti-PD-1
  • Anti-CD137

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:2 years or until time of death, whichever occurs first
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate overall survival probability and median time of survival along with a 95% confidence interval.
Measure:Progression-free survival rate
Time Frame:1 year
Safety Issue:
Description: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.
Measure:Overall Response, assessed by RANO and iRANO
Time Frame:up to 2 years
Safety Issue:
Description: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.
Measure:Overall Response to anti-LAG-3 monoclonal antibody BMS-98601, assessed by RANO and iRANO
Time Frame:up to 2 years
Safety Issue:
Description: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.
Measure:Overall Response to anti-CD137 as monotherapy, assessed by RANO and iRANO
Time Frame:up to 2 years
Safety Issue:
Description: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.
Measure:Overall Response to Anti-LAG-3 + Anti-PD-1, assessed by RANO and iRANO
Time Frame:up to 2 years
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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