Clinical Trials /

Biomarker-Driven Therapy Using Immune Activators With Nivolumab in Patients With First Recurrence of Glioblastoma

NCT03707457

Description:

This research is being done to test if it is safe to give nivolumab with targeted immunotherapy drugs for recurrent glioblastoma (GBM), a type of brain tumor. The study doctors believe that giving immunotherapy drugs that match the biomarkers in a tumor will help the immune system fight the tumor. Tumor tissue collected during surgery will be tested for certain biomarkers to determine which immunotherapy might best target the tumor. The combination immunotherapy arms include: Arm A: Nivolumab + anti-GITR Arm B: Nivolumab + IDO1 inhibitor Arm C: Nivolumab + Ipilimumab

Related Conditions:
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Biomarker-Driven Therapy Using Immune Activators With Nivolumab in Patients With First Recurrence of Glioblastoma
  • Official Title: Phase I Protocol to Assess Safety of Biomarker-Driven Therapy Using Selective Immune Activators in Combination With Anti-PD-1 (Nivolumab) in Patients With First Recurrence of Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: J17154
  • SECONDARY ID: IRB00129944
  • NCT ID: NCT03707457

Conditions

  • Glioblastoma
  • Glioblastoma Multiforme

Interventions

DrugSynonymsArms
Nivolumabanti-PD1Arm A: Nivolumab + anti-GITR
Anti-GITR Monoclonal Antibody MK-4166anti-GITRArm A: Nivolumab + anti-GITR
IDO1 inhibitor INCB024360Arm B: Nivolumab + IDO1 inhibitor
IpilimumabArm C: Nivolumab + Ipilimumab

Purpose

This research is being done to test if it is safe to give nivolumab with targeted immunotherapy drugs for recurrent glioblastoma (GBM), a type of brain tumor. The study doctors believe that giving immunotherapy drugs that match the biomarkers in a tumor will help the immune system fight the tumor. Tumor tissue collected during surgery will be tested for certain biomarkers to determine which immunotherapy might best target the tumor. The combination immunotherapy arms include: Arm A: Nivolumab + anti-GITR Arm B: Nivolumab + IDO1 inhibitor Arm C: Nivolumab + Ipilimumab

Detailed Description

      PRIMARY OBJECTIVE

      1. To determine safety of each of the following study agents, anti-GITR, IDO1 inhibitor, and
      ipilimumab, in combination with nivolumab (BMS-936558) flat dose in patients with first
      recurrence of GBM.

      SECONDARY OBJECTIVES

        1. To estimate toxicity

        2. To estimate progression-free survival

        3. To estimate overall survival

        4. To evaluate pain for patients undergoing the treatment of anti-GITR, IDO1 inhibitor, and
           ipilimumab, in combination with nivolumab.

      EXPLORATORY OBJECTIVES

        1. To characterize the immune response during and after treatment as measured by
           immunohistochemistry, and other T cells etc. in peripheral blood

        2. To characterize the pharmacodynamic and genomic activity in tumor tissue as target
           inhibition

        3. To characterize radiographic response

        4. Genetic characterization of correlative samples
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: Nivolumab + anti-GITRExperimentalPatients receive nivolumab intravenously (IV) over 30 minutes and anti-GITR intravenously (IV) over 30 minutes on Day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Nivolumab
  • Anti-GITR Monoclonal Antibody MK-4166
Arm B: Nivolumab + IDO1 inhibitorExperimentalPatients receive nivolumab intravenously (IV) over 30 minutes on Day 1 and IDO1 inhibitor daily by mouth. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Nivolumab
  • IDO1 inhibitor INCB024360
Arm C: Nivolumab + IpilimumabExperimentalPatients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab intravenously (IV) over 90 minutes on Day 1. Courses repeat every 21 days for up to 4 doses. After ipilimumab is discontinued, courses of nivolumab repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Nivolumab
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically proven glioblastoma or gliosarcoma which is
             progressive or recurrent following radiation therapy with or without temozolomide.

          -  Patients must be in first recurrence of glioblastoma following radiation therapy with
             or without temozolomide. Patients with previously grade 3 astrocytoma who after first
             recurrence after radiotherapy with or without temozolomide are found to have GBM are
             eligible. Patients who have received Gliadel wafers during their initial surgery are
             eligible.

          -  Patients 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.

          -  Patients must consent to our acquiring tumor tissue removed before, during, or after
             the study, if it becomes available.

          -  Patients must be able to undergo MRI of the brain with gadolinium.

          -  Patients receiving corticosteroid to treat cerebral edema or hypothalamic-pituitary
             insufficiency are eligible.

          -  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 high
             grade glioma (HGG)).

          -  Patients must be 18 years of age or older.

          -  Patients must have a Karnofsky Performance Status (KPS) ≥ 60% (i.e. the patient must
             be able to care for himself/herself with occasional help from others).

          -  Patients must have the following organ and marrow function:

          -  Absolute lymphocyte count ≥ 750/mcl

          -  Absolute neutrophil count ≥ 1,500/mcl

          -  Platelets ≥ 100,000/mcl

          -  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 glutamic pyruvic transaminase [SGPT]) ≤
             3 × institutional upper limit of normal

          -  Creatinine ≤ institutional upper limit of normal OR Creatinine clearance ≥ 60
             ml/min/1.73m2 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 (WOCBP) must agree to have a negative serum pregnancy
             test within -7 days prior to treatment start. Women of childbearing potential must
             agree to use non-hormonal (due to induction of Cyp3a4) (barrier method of birth
             control; abstinence) prior to study entry, for the duration of study treatment, and
             through at least 5 months 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. Males who are sexually active with WOCBP
             must agree to use a condom during penile vaginal intercourse for the duration of
             treatment with study treatment plus 7 months after the last dose of the study
             treatment (i.e., 90 days [duration of sperm turnover] plus the time required for
             nivolumab to undergo approximately 5 half-lives). This criteria applies to azoospermic
             males as well.

          -  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 IO agents used in this study 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
             (other than for cerebral edema or hypothalamic-pituitary dysfunction) or other
             immunosuppressive medications within 14 days of study entry are ineligible.

          -  Patients must not have evidence of significant 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 known 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 with a confirmed history of encephalitis or meningitis 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)

               -  QTc prolongation > 480 msec

               -  History of other clinically significant cardiovascular disease (i.e.,
                  cardiomyopathy, myocarditis, congestive heart failure with New York Heart
                  Association (NYHA) functional classification III-IV, pericarditis, significant
                  pericardial effusion, significant coronary stent occlusion, deep venous
                  thrombosis, etc.)

               -  Cardiovascular disease-related requirement for daily supplemental oxygen Patients
                  with other uncontrolled intercurrent illness including, but not limited to,
                  ongoing or active infection that requires systemic antibacterial, antiviral or
                  antifungal therapy < 7 days prior to the first dose of study drug, or psychiatric
                  illness/social situations that would limit compliance with study requirements,
                  are ineligible.

          -  Pregnant women are excluded from this study because the study agents have potential
             for teratogenic or abortifacients effects. Because there is an unknown but potential
             risk for adverse events in nursing infants secondary to treatment of the mother with
             IO agents used in 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), hepatitis C (HCV) negative
             (by qPCR) and HBcAb negative (no prior Hepatitis B infection)) are ineligible.

          -  Participants with a personal or family (i.e., in a first-degree relative) history of
             cytochrome b5 reductase deficiency (previously called methemoglobin reductase
             deficiency) or other diseases that put them at risk of methemoglobinemia. All
             participants will be screened for methemoglobin levels prior to randomization.

          -  Participants with a history of glucose-6-phosphate dehydrogenase (G6PD) deficiency or
             other congenital or autoimmune hemolytic disorders. All participants will be screened
             for G6PD levels prior to arm assignment.

          -  Patients with prior organ or tissue allograft are ineligible.

          -  Patients with a history of life-threatening toxicity related to prior immune therapy
             are ineligible.

          -  Quantitative or qualitative G6PD assay results suggesting underlying G6PD deficiency.

          -  Blood methemoglobin > upper limit of normal (ULN), assessed in an arterial or venous
             blood sample or by co-oximetry.

          -  History or presence of hypersensitivity or idiosyncratic reaction to methylene blue.

          -  Prior history of serotonin syndrome

          -  Participants with active interstitial lung disease (ILD) or pneumonitis or with recent
             history of ILD or pneumonitis requiring steroids (excluding radiation pneumonitis)

          -  Participants with conditions known to interfere significantly with the absorption of
             oral medication, as per investigator judgement.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of subjects with dose limiting toxicities evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time Frame:Up to 9 weeks after the initial dose of combination therapy
Safety Issue:
Description:The proportion of subjects who experienced grade ≥3 toxicities will be estimated, along with 95% confidence intervals by each type of toxicity.

Details

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

Last Updated