PVSRIPO for Recurrent Glioblastoma (GBM)

NCT01491893 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: Pro00031169NS20023
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 1

Brief Summary

Purpose of the Study: To determine the maximally tolerated dose (MTD) and the Recommended Phase 2 Dose (RP2D) of PVSRIPO when delivered intracerebrally by convection-enhanced delivery (CED). To obtain correlative mechanistic evidence of PVSRIPO's effects on infected WHO Grade IV malignant glioma tumors and to estimate progression-free survival (PFS) and overall survival (OS) in recurrent WHO Grade IV malignant glioma patients. To obtain information about clinical response rates to intratumoral inoculation of PVSRIPO. To estimate the efficacy of PVSRIPO administered at the optimal dose.

Conditions

GBM; Glioblastoma; Glioma; Malignant Glioma

Keywords

GBM; Brain Tumor; Poliovirus Vaccine; WHO Grade IV Malignant Glioma

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Dose (MTD)

  The MTD will be the highest dose level for which the probability that a dose escalation patient experiences a dose-limiting toxicity (DLT) is estimated to be less than 20%. Any Grade 3 or 4 toxicity that is not reversible within 2 weeks, or any life-threatening event, or treatment-related death will be considered a DLT. Any grade 2 or higher serious autoimmune toxicities particularly those affecting vital organs (e.g. cardiac, renal, CNS) will be considered a DLT. 50% Tissue Culture Infective Dose (TCID50) is the unit of measure of infectious virus titer. The MTD was determined based on the first 9 patients treated with PVSRIPO- 1 at dose level 1 (1.0 x 10e8 TCID50 (50% Tissue Culture Infectious Dose)), 1 at dose level 2 (3.3 x 10e8 TCID50), 1 at dose level 3 (1.0 x 10e9 TCID50), 2 at dose level 4 (3.3 x 10e9 TCID50), and 4 at dose level 5 (1.0 x 10e10 TCID50).

  28 days after administration of PVSRIPO

• Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)

  The number of dose escalation patients experiencing a dose-limiting toxicity (DLT) will be reported. Any grade 3 or any Grade 4 toxicity that is not reversible within 2 weeks, or any life-threatening event, or treatment-related death will be considered a DLT. Any grade 2 or higher serious autoimmune toxicities particularly those affecting vital organs (e.g. cardiac, renal, CNS) will also be considered a DLT.

  28 days after administration of PVSRIPO

• Recommended Phase 2 Dose (RP2D)

  The RP2D of PVSRIPO is the safe, therapeutic dose where patients have not experienced undue side effects from PVSRIPO or from the management of cerebral inflammation secondary to PVSRIPO administration. 50% Tissue Culture Infective Dose (TCID50) is the unit of measure of infectious virus titer.

  5 years

Study Arms (10)

Dose Level 1 (dose escalation)

EXPERIMENTAL

Participants received a single intratumoral infusion of 1.0 x 10\^8 TCID50 Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO), via convection-enhanced delivery to the brain tumor, with 4 weeks of monitoring for toxicities after infusion.

Biological: Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO)

Dose Level 2 (dose escalation)

EXPERIMENTAL

Participants received a single intratumoral infusion of 3.3 x 10\^8 TCID50 Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO), via convention-enhanced delivery to the brain tumor, with 4 weeks of monitoring for toxicities after infusion.

Biological: Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO)

Dose Level 3 (dose escalation)

EXPERIMENTAL

Participants received a single intratumoral infusion of 1.0 x 10\^9 TCID50 Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO), via convection-enhanced delivery to the brain tumor, with 4 weeks of monitoring for toxicities after infusion.

Biological: Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO)

Dose Level 4 (dose escalation)

EXPERIMENTAL

Participants received a single intratumoral infusion of 3.3 x 10\^9 TCID50 Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO), via convection-enhanced delivery to the brain tumor, with 4 weeks of monitoring for toxicities after infusion.

Biological: Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO)

Dose Level 5 (dose escalation)

EXPERIMENTAL

Participants received a single intratumoral infusion of 1.0 x 10\^10 TCID50 Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO), via convection-enhanced delivery to the brain tumor, with 4 weeks of monitoring for toxicities after infusion.

Biological: Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO)

Dose Level 4 (dose de-escalation)

EXPERIMENTAL

Participants received a single intratumoral infusion of 3.3 x 10\^9 TCID50 Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO), via convection-enhanced delivery to the brain tumor, with 4 weeks of monitoring for toxicities after infusion.

Biological: Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO)

Dose Level 2 (dose expansion)

EXPERIMENTAL

Participants received a single intratumoral infusion of 3.3 x 10\^8 TCID50 of PVSRIPO, via convection-enhanced delivery to the brain tumor, with 4 weeks of monitoring for toxicities after infusion.

Biological: Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO)

Dose Level -1 (dose expansion)

EXPERIMENTAL

Participants received a single intratumoral infusion of 5.0 x 10\^7 TCID50 Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO), via convection-enhanced delivery to the brain tumor, with 4 weeks of monitoring for toxicities after infusion.

Biological: Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO)

Dose Level -2 (dose expansion)

EXPERIMENTAL

Participants received a single intratumoral infusion of 1.0 x 10\^7 TCID50 Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO), via convection-enhanced delivery to the brain tumor, with 4 weeks of monitoring for toxicities after infusion.

Biological: Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO)

Dose Level -1 (selected dose expansion)

EXPERIMENTAL

Participants received a single intratumoral infusion of 5.0 x 10\^7 TCID50 Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO), via convection-enhanced delivery to the brain tumor, with 4 weeks of monitoring for toxicities after infusion.

Biological: Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO)

Interventions

Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO) BIOLOGICAL

Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO)

Also known as: Live attenuated, oral (Sabin) serotype 1 poliovirus vaccine

Dose Level -1 (dose expansion); Dose Level -1 (selected dose expansion); Dose Level -2 (dose expansion); Dose Level 1 (dose escalation); Dose Level 2 (dose escalation); Dose Level 2 (dose expansion); Dose Level 3 (dose escalation); Dose Level 4 (dose de-escalation); Dose Level 4 (dose escalation); Dose Level 5 (dose escalation)

Eligibility Criteria

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

You may qualify if:

• Disease Status. Patients must have a recurrent supratentorial WHO Grade IV malignant glioma based on imaging studies with measurable disease (≥ 1 cm or ≤ 5.5 cm of contrast-enhancing tumor). Prior histopathology consistent with a World Health Organization (WHO) Grade IV malignant glioma confirmed by the study pathologist, Roger McLendon, or his designate.
• Age. Due to the potential implications of the treatment on the developing CNS, all patients must be ≥ 18 years of age at the time of entry into the study.
• Performance Status. The patient must have a Karnofsky Performance Score (KPS) of ≥ 70% at the time of entry.
• Laboratory Studies
• Platelet count ≥ 125,000/microliter prior to biopsy. Platelets ≥ 100,000/microliter prior to infusion
• Prothrombin and Partial Thromboplastin Times ≤ 1.2 x normal prior to biopsy
• Positive serum anti-poliovirus titer prior to biopsy (except for retreatment)
• Creatinine ≤ 1.2 x normal prior to biopsy
• Total bilirubin, SGOT, SGPT, alkaline phosphatase ≤ 2.5 x normal prior to biopsy
• Neutrophil count ≥ 1000 prior to biopsy
• Hemoglobin ≥ 9 prior to biopsy
• Poliovirus Immunization Booster. The subject must have received a boost immunization with trivalent inactivated IPOL™ (Sanofi-Pasteur) at least 1 week prior to administration of the study agent.
• Disease Confirmation. At the time of biopsy, prior to administration of virus, the presence of recurrent tumor must be confirmed by histopathological analysis.
• Informed Consent. A signed informed consent form approved by the Duke University Institutional Review Board (IRB) will be required for patient enrollment into the study. Patients must be able to read and understand the informed consent document and must sign the informed consent indicating that they are aware of the investigational nature of this study.
• Brain MRI. Able to undergo brain MRI with and without contrast

You may not qualify if:

• Pregnancy. Because of the unknown risk of virus administration potentially affecting a developing fetus or growing infant, females who are pregnant or breast-feeding during the study period will be excluded. Adults of reproductive potential not employing an effective method of birth control will be excluded. Sexually active women of child bearing potential, whose partner is male, must use medically accepted birth control. Sexually active men, whose partner is a female of child bearing potential, must use a medically accepted birth control.
• Disease Status. Because patients will receive drug intracerebrally, patients with an impending, life-threatening cerebral herniation syndrome, based on the assessment of the study neurosurgeons, Allan Friedman, John Sampson, or Peter Fecci, or their designate, will be excluded.
• Medical Conditions. Because the potential toxicities from the agent being studied in this protocol may be similar to some known diseases or may be more dangerous in the context of certain known diseases, the following patients will be excluded to avoid confounding the study results:
• Patients with an active infection requiring intravenous treatment or having an unexplained febrile illness (Tmax \> 99.5 F/37.5 C).
• Patients with known immunosuppressive disease or known human immunodeficiency virus infection.
• Unstable or severe intercurrent medical conditions such as severe heart (New York Heart Association Class 3 or 4) or known lung (FEV1 \< 50%) disease, uncontrolled diabetes mellitus.
• Albumin allergy. Albumin is added to the agent as a stabilizer. Patients with a known allergy will be excluded.
• Current or history of anaphylactic reaction to gadolinium. Gadolinium is used as contrast for the MRI.
• Previous Poliomyelitis. A history of neurological complications due to poliovirus infection would imply previous virus replication in the CNS. Based on animal studies, previous exposure to poliovirus administered intracerebrally can reduce subsequent virus replication in the CNS.
• Prior Therapy. Patients who have not recovered from the toxic effects of prior chemotherapy and/or radiation therapy will be excluded. Guidelines for this recovery period are dependent upon the specific therapeutic agent being used:
• Patients may not have received chemotherapy or bevacizumab ≤ 4 weeks \[except for nitrosourea (6 weeks) or metronomic dosed chemotherapy such as daily etoposide or cyclophosphamide (1 week)\] prior to starting the study drug unless patients have recovered from side effects of such therapy.
• Patients may not have received immunotherapy ≤ 4 weeks prior to starting the study drug unless patients have recovered from side effects of such therapy.
• Patients may not be less than 12 weeks from radiation therapy, unless progressive d disease outside of the radiation field or 2 progressive scans at least 4 weeks apart or histopathologic confirmation
• Patients must have completed all standard of care treatments including surgical procedure and radiation therapy (at least 59Gy):
• If the MGMT promoter in their tumor is known to be unmethylated, patients are not mandated to have received chemotherapy prior to participating in this trial.

Sponsors & Collaborators

• Istari Oncology, Inc.: lead
• National Cancer Institute (NCI): collaborator
• Brain Tumor Research Charity Grant: collaborator
• Duke University: collaborator

Study Sites (1)

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Related Publications (2)

• Brown MC, Beasley GM, McKay ZP, Yang Y, Desjardins A, Randazzo DM, Landi D, Ashley DM, Bigner DD, Nair SK, Gromeier M. Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils. J Immunother Cancer. 2023 Apr;11(4):e006463. doi: 10.1136/jitc-2022-006463.

  PMID: 37072349 DERIVED

• Desjardins A, Gromeier M, Herndon JE 2nd, Beaubier N, Bolognesi DP, Friedman AH, Friedman HS, McSherry F, Muscat AM, Nair S, Peters KB, Randazzo D, Sampson JH, Vlahovic G, Harrison WT, McLendon RE, Ashley D, Bigner DD. Recurrent Glioblastoma Treated with Recombinant Poliovirus. N Engl J Med. 2018 Jul 12;379(2):150-161. doi: 10.1056/NEJMoa1716435. Epub 2018 Jun 26.

  PMID: 29943666 DERIVED

Related Links

• The Preston Robert Tisch Brain Tumor Center at Duke
• Duke Cancer Institute Clinical Trials

MeSH Terms

Conditions

Glioblastoma; Glioma; Brain Neoplasms

Condition Hierarchy (Ancestors)

Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Results Point of Contact

• Title: Garrett Nichols, MD
• Organization: Istari Oncology

gnichols@istarioncology.com

(919) 245.7662

Study Officials

• Daniel Landi, MD

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

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

Study Record Dates

• First Submitted: December 1, 2011
• First Posted: December 14, 2011
• Study Start: April 25, 2012
• Primary Completion: June 27, 2017
• Study Completion: October 1, 2021
• Last Updated: September 28, 2023
• Results First Posted: September 28, 2018

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)