Combination Adenovirus + Pembrolizumab to Trigger Immune Virus Effects (CAPTIVE)

A Phase II, Multi-center, Open-label Study of a Conditionally Replicative Adenovirus (DNX-2401) With Pembrolizumab (KEYTRUDA®) for Recurrent Glioblastoma or Gliosarcoma (CAPTIVE/KEYNOTE-192)

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

Study Overview

• Status: Completed
• Conditions: Nervous System Diseases; Glioma; Glioblastoma; Neuroectodermal Tumors; Brain Cancer; Gliosarcoma; Brain Neoplasm; Malignant Brain Tumor; Neoplasm, Neuroepithelial; Neoplasm by Histologic Type; Neoplasm, Nerve Tissue
• Intervention / Treatment: Biological: DNX-2401; Biological: pembrolizumab

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.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 2S8
      • University Health Network
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences (UAMS)
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Neurosurgery
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10065
      • Weill-Cornell Medicine New York-Presbyterian
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • UNC Lineberger Comprehensive Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • Ohio State University James Cancer Center
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Health Network
  • Texas
    • Austin, Texas, United States, 78705
      • Texas Oncology Austin-Midtown
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Note: Other protocol-defined inclusion and exclusion criteria may apply as outlined in the relevant protocol version

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Biological: 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.; Other Names: Oncolytic virus; Genetically-modified adenovirus; Delta-24; Delta-24-RGD; Biological: pembrolizumab; Sequential intravenous administration every three weeks beginning 7-9 days after Day 0/DNX-2401; Other Names: KEYTRUDA; lambrolizumab; MK-3475; SCH 900475; Checkpoint inhibitor; monoclonal antibody; anti-PD1/PD-L1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	Interval tumor size reduction as measured from periodic MRI	3.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Months alive following treatment as measured during periodic study visits	3.5 years
Time to tumor response	Months to response following treatment as measured during periodic MRIs	3.5 years
Duration of response	Months of sustained response as measured during periodic study visits	3.5 years

Collaborators and Investigators

• Sponsor: DNAtrix, Inc.
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Study Director: Nancy Gady, BS, DNAtrix, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2016
• Primary Completion (Actual): March 17, 2021
• Study Completion (Actual): June 30, 2021

Study Registration Dates

• First Submitted: June 9, 2016
• First Submitted That Met QC Criteria: June 13, 2016
• First Posted (Estimate): June 14, 2016

Study Record Updates

• Last Update Posted (Actual): July 15, 2021
• Last Update Submitted That Met QC Criteria: July 13, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: immunotherapy; Checkpoint inhibitor; monoclonal antibody; brain; pembrolizumab; CNS; MK-3475; cannula; Central Nervous System (CNS) diseases; Central Nervous System (CNS) neoplasms; conditionally replicative adenovirus; DNX-2401; KEYTRUDA; SCH 900475; lambrolizumab; neoplasm, germ cell and embryonal; neoplasm, granular and epithelial; Alcyone; Alcyone Lifesciences; AMC; MEMS cannula; DNX-2401 + pembrolizumab; Delta-24; Delta-24-RGD; anti-PD1/PD-L1; KEYNOTE-192
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Virus Diseases; Infections; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Germ Cell and Embryonal; DNA Virus Infections; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms; Glioblastoma; Nervous System Diseases; Brain Neoplasms; Gliosarcoma; Adenoviridae Infections; Neoplasms by Histologic Type; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neoplasms, Nerve Tissue; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: 2401BT-002P

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Plan to share aggregate data at completion of study