Combination Adenovirus + Pembrolizumab to Trigger Immune Virus Effects

NCT ID: NCT02798406

Last Updated: 2021-07-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 49 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-10-06
• Study Completion Date: 2021-06-30

Brief Summary

Glioblastoma (GBM) and gliosarcoma (GS) are the most common and aggressive forms of malignant brain tumor in adults and can be resistant to conventional therapies. The purpose of this Phase II study is to evaluate how well a recurrent glioblastoma or gliosarcoma tumor responds to one injection of DNX-2401, a genetically modified oncolytic adenovirus, when delivered directly into the tumor followed by the administration of intravenous pembrolizumab (an immune checkpoint inhibitor) given every 3 weeks for up to 2 years or until disease progression.

Funding Source-FDA OOPD

Detailed Description

In the initial phase of the study, up to 12 evaluable subjects will be enrolled in 3 dose cohorts to determine the best dose of DNX-2401, as follows:

• Cohort 1: Single dose DNX-2401 (5e8 vp) delivered intratumorally by cannula, followed by intravenous pembrolizumab every 3 weeks (Q3W)
• Cohort 2: Single dose DNX-2401(5e9 vp) delivered intratumorally by cannula, followed by intravenous pembrolizumab every 3 weeks (Q3W)
• Cohort 3: Single dose DNX-2401 (5e10 vp) delivered intratumorally by cannula, followed by intravenous pembrolizumab every 3 weeks (Q3W)

Following the initial phase, up to 36 additional subjects diagnosed with recurrent glioblastoma or gliosarcoma will be enrolled to receive a single of DNX-2401 determined in the initial phase administered intratumorally followed by intravenous pembrolizumab every 3 weeks.

All subjects will return to the clinic for study follow-up visits at regular intervals for safety monitoring, MRI scans and other assessments, for up to 2 years or until disease progression. All subjects will be followed closely for safety and survival.

Conditions

Brain Cancer; Brain Neoplasm; Glioma; Glioblastoma; Gliosarcoma; Malignant Brain Tumor; Neoplasm, Neuroepithelial; Neuroectodermal Tumors; Neoplasm by Histologic Type; Neoplasm, Nerve Tissue; Nervous System Diseases

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

DNX-2401 + pembrolizumab

Intratumoral dose (1.0 mL) of DNX-2401 followed 7-9 days later by intravenous pembrolizumab, 200 mg, given every three weeks through 105 weeks (2 yrs.) or until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

DNX-2401

Intervention Type: BIOLOGICAL

On Day 0, following brain tumor biopsy and confirmation of recurrent tumor, a single injection of DNX-2401 is administered directly into the brain tumor.

pembrolizumab

Intervention Type: BIOLOGICAL

Sequential intravenous administration every three weeks beginning 7-9 days after Day 0/DNX-2401

Interventions

DNX-2401

On Day 0, following brain tumor biopsy and confirmation of recurrent tumor, a single injection of DNX-2401 is administered directly into the brain tumor.

Intervention Type: BIOLOGICAL

pembrolizumab

Sequential intravenous administration every three weeks beginning 7-9 days after Day 0/DNX-2401

Intervention Type: BIOLOGICAL

Other Intervention Names

Oncolytic virus; Genetically-modified adenovirus; Delta-24; Delta-24-RGD; KEYTRUDA; lambrolizumab; MK-3475; SCH 900475; Checkpoint inhibitor; monoclonal antibody; anti-PD1/PD-L1

Eligibility Criteria

Inclusion Criteria

• A single glioblastoma or gliosarcoma tumor with histopathological confirmation for first or presenting second recurrence of glioblastoma or gliosarcoma at the time of consent
• Gross total or partial tumor resection is not possible or not planned
• A single measurable tumor that is at least 10.0 mm longest diameter (LDi) X 10.0 mm shortest diameter (SDi) and this tumor does not exceed 40.0 mm in LDi or SDi on Screening MRI
• Tumor recurrence or progression documented after previously failing surgical resection, chemotherapy or radiation
• Karnofsky performance status ≥ 70 %
• Prior anti-tumor therapies must have been completed within time periods specified in the protocol prior to DNX-2401 injection and toxic side effects must be mild, if present
• Demonstrate adequate organ function via specified laboratory test results

Exclusion Criteria

• Multiple (≥ 2) separate enhancing tumors
• Tumor location on both sides of the brain and/or involvement that would present the risk of injecting DNX-2401 into the ventricles of the brain
• Tumor location in the brain stem
• Requires or, based upon history, may require treatment with high-dose systemic corticosteroids within 2 weeks of the start of intravenous pembrolizumab infusions and within 2 weeks following the first infusion of pembrolizumab
• Uncontrolled blood-sugar levels defined as HbA1c > 7%
• Previous treatment with any checkpoint inhibitor such as anti-PD1 or PD-L1 agents including pembrolizumab (KEYTRUDA) or any other checkpoint inhibitor(s) (e.g., ipilimumab, nivolumab, etc.)
• History of (non-infectious) or current active pneumonitis that required steroids and/or a history of interstitial lung disease
• Prior gene transfer therapy or prior therapy with a cytolytic virus of any type
• Brain tumor that is not measurable on MRI or persons who are unable to have MRIs
• Pregnant or nursing females

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

DNAtrix, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nancy Gady, BS

Role: STUDY_DIRECTOR

DNAtrix, Inc.

Locations

University of Arkansas for Medical Sciences (UAMS)

Little Rock, Arkansas, United States

UCLA Medical Center

Los Angeles, California, United States

Northwestern University

Chicago, Illinois, United States

University of Minnesota Neurosurgery

Minneapolis, Minnesota, United States

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Weill-Cornell Medicine New York-Presbyterian

New York, New York, United States

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, United States

Cleveland Clinic

Cleveland, Ohio, United States

Ohio State University James Cancer Center

Columbus, Ohio, United States

Lehigh Valley Health Network

Allentown, Pennsylvania, United States

Texas Oncology Austin-Midtown

Austin, Texas, United States

MD Anderson Cancer Center

Houston, Texas, United States

Huntsman Cancer Institute

Salt Lake City, Utah, United States

University Health Network

Toronto, Ontario, Canada

Countries

United States; Canada

References

Nassiri F, Patil V, Yefet LS, Singh O, Liu J, Dang RMA, Yamaguchi TN, Daras M, Cloughesy TF, Colman H, Kumthekar PU, Chen CC, Aiken R, Groves MD, Ong SS, Ramakrishna R, Vogelbaum MA, Khagi S, Kaley T, Melear JM, Peereboom DM, Rodriguez A, Yankelevich M, Nair SG, Puduvalli VK, Aldape K, Gao A, Lopez-Janeiro A, de Andrea CE, Alonso MM, Boutros P, Robbins J, Mason WP, Sonabend AM, Stupp R, Fueyo J, Gomez-Manzano C, Lang FF, Zadeh G. Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial. Nat Med. 2023 Jun;29(6):1370-1378. doi: 10.1038/s41591-023-02347-y. Epub 2023 May 15.

Reference Type: DERIVED

PMID: 37188783 (View on PubMed)

Other Identifiers

2401BT-002P

Identifier Type: -

Identifier Source: org_study_id