Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

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.
 
ClinicalTrials.gov Identifier: NCT03707457
Recruitment Status : Recruiting
First Posted : October 16, 2018
Last Update Posted : July 3, 2019
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:

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


Condition or disease Intervention/treatment Phase
Glioblastoma Glioblastoma Multiforme Drug: Nivolumab Drug: Anti-GITR Monoclonal Antibody MK-4166 Drug: IDO1 inhibitor INCB024360 Drug: Ipilimumab Phase 1

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

Layout table for study information
Study Type : Interventional
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 22, 2019
Estimated Primary Completion Date : February 2022
Estimated Study Completion Date : February 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Arm A: Nivolumab + anti-GITR
Patients 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.
Drug: Nivolumab
Patients receive nivolumab intravenously (IV) over 30 minutes on Day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other Name: anti-PD1

Drug: Anti-GITR Monoclonal Antibody MK-4166
Patients receive anti-GITR intravenously (IV) over 30 minutes on Day 1 of the first cycle of nivolumab after arm assignment. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other Name: anti-GITR

Experimental: Arm B: Nivolumab + IDO1 inhibitor
Patients 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.
Drug: Nivolumab
Patients receive nivolumab intravenously (IV) over 30 minutes on Day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other Name: anti-PD1

Drug: IDO1 inhibitor INCB024360
Patients receive IDO1 inhibitor by mouth daily beginning on Day 1 of the first cycle of nivolumab after arm assignment. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Experimental: Arm C: Nivolumab + Ipilimumab
Patients 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.
Drug: Nivolumab
Patients receive nivolumab intravenously (IV) over 30 minutes on Day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other Name: anti-PD1

Drug: Ipilimumab
Patients receive ipilimumab intravenously (IV) over 90 minutes on Day 1 of the first cycle of nivolumab after arm assignment. Courses repeat every 21 days for up to 4 doses in the absence of disease progression or unacceptable toxicity.




Primary Outcome Measures :
  1. 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 ]
    The proportion of subjects who experienced grade ≥3 toxicities will be estimated, along with 95% confidence intervals by each type of toxicity.



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.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
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 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.

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): NCT03707457


Contacts
Layout table for location contacts
Contact: Kelly Szajna, BSN 410-502-4081 kszajna1@jhmi.edu
Contact: Whitney Webb, MSN 410-955-7008 wwebb10@jhmi.edu

Locations
Layout table for location information
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Kelly K. Szajna, RN, BSN    410-502-4081    kszajna1@jhmi.edu   
Contact: Whitney Webb, RN, MSN    4109557008    wwebb10@jhmi.edu   
Principal Investigator: Michael K. Lim, MD         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Bristol-Myers Squibb
Investigators
Layout table for investigator information
Principal Investigator: Michael Lim, MD Johns Hopkins University

Layout table for additonal information
Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT03707457     History of Changes
Other Study ID Numbers: J17154
IRB00129944 ( Other Identifier: JHM IRB )
First Posted: October 16, 2018    Key Record Dates
Last Update Posted: July 3, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Glioma
Glioblastoma
Recurrence
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Disease Attributes
Pathologic Processes
Nivolumab
Ipilimumab
Antibodies
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents