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

NCT03707457 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: J17154IRB00129944
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

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

Conditions

Glioblastoma; Glioblastoma Multiforme

Outcome Measures

Primary Outcomes (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

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

  Up to 9 weeks after the initial dose of combination therapy

Study Arms (3)

Arm A: Nivolumab + anti-GITR

EXPERIMENTAL

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; Drug: Anti-GITR Monoclonal Antibody MK-4166

Arm B: Nivolumab + IDO1 inhibitor

EXPERIMENTAL

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; Drug: IDO1 inhibitor INCB024360

Arm C: Nivolumab + Ipilimumab

EXPERIMENTAL

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; Drug: Ipilimumab

Interventions

Nivolumab DRUG

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.

Also known as: anti-PD1

Arm A: Nivolumab + anti-GITR; Arm B: Nivolumab + IDO1 inhibitor; Arm C: Nivolumab + Ipilimumab

Anti-GITR Monoclonal Antibody MK-4166 DRUG

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.

Also known as: anti-GITR

Arm A: Nivolumab + anti-GITR

IDO1 inhibitor INCB024360 DRUG

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.

Arm B: Nivolumab + IDO1 inhibitor

Ipilimumab DRUG

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.

Arm C: Nivolumab + Ipilimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must have histologically proven glioblastoma or gliosarcoma which is progressive or recurrent following radiation therapy with or without temozolomide.
• Patient 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 with previously grade 3 glioma found to have conclusively progressed to GBM at the time screening tissue is taken are eligible. Patients who have received Gliadel wafers during their initial surgery are eligible.
• Patient 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.
• Patient must consent to our acquiring tumor tissue removed before, during, or after the study, if it becomes available.
• Patient must be able to undergo MRI of the brain with gadolinium.
• Patient 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) before starting Nivolumab. Patients must stop using the Optune device prior to starting nivolumab. No prior therapies are allowed other than radiation, temozolomide, Optune device, 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 ≥ 500/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

You may not qualify if:

• Patient is/has received any other investigational agent(s).
• Patient has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to IO agents used in this study.
• Patient has active or a known history of known or suspected autoimmune disease. (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.
• Patient has a condition requiring systemic treatment with either corticosteroids (other than for brain tumor management, cerebral edema or hypothalamic-pituitary dysfunction) or other immunosuppressive medications within 14 days of study entry.
• Patient has evidence of significant mass effect.
• Patient has evidence of significant hematologic, renal, or hepatic dysfunction. (NOTE: Patients with underlying hepatocellular disease should be given careful risk/benefit consideration prior to enrollment).
• Patient has a known history of any chronic hepatitis as evidenced by the following:
• Positive test for hepatitis B surface antigen (HBsAg)
• 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.
• Patient has a confirmed history of encephalitis or meningitis in the year prior to signing informed consent.
• 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

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

Nivolumab; spartalizumab; MK-4166; epacadostat; Ipilimumab

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Michael Lim, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 10, 2018
• First Posted: October 16, 2018
• Study Start: March 22, 2019
• Primary Completion: November 30, 2019
• Study Completion: June 18, 2020
• Last Updated: July 2, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)