A Phase I/II Study of Pembrolizumab and M032 (NSC 733972), a Genetically Engineered HSV-1 Expressing IL-12, in Patients With Recurrent/Progressive and Newly Diagnosed Glioblastoma Multiforme, Anaplastic Astrocytoma, or Gliosarcoma

This Phase I (Cohort I and Cohort II) and Phase II trial is designed to confirm the safety and tolerability of Pembrolizumab when given in conjunction with M032, an Oncolytic Herpes Simplex Virus (oHSV) that expresses IL-12 and perform the Phase II portion using a Recommended Phase 2 Dose (RP2D) of M032 (provided by the Phase I) when given in conjunction with Pembrolizumab for recurrent malignant glioma (glioblastoma multiforme, anaplastic astrocytoma, or glio-sarcoma).

Start Date25 Feb 2022

Sponsor / Collaborator

The University of Alabama at Birmingham

NCT02062827 / Active, not recruitingPhase 1IIT

A Phase 1 Study of M032 (NSC 733972), a Genetically Engineered HSV-1 Expressing IL-12, in Patients With Recurrent/Progressive Glioblastoma Multiforme, Anaplastic Astrocytoma, or Gliosarcoma

To determine the safety and tolerability of the maximum dose for laboratory engineered Herpes Simplex Virus-1 in patients who would not be eligible for surgical resection of recurrent glioma To determine the safety and tolerability of the maximum dose for laboratory engineered Herpes Simples Virus-1 in patients who would benefit from surgical resection of recurrent glioma

Start Date25 Nov 2013

Sponsor / Collaborator

The University of Alabama at Birmingham

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100 Clinical Results associated with NSC-733972

100 Translational Medicine associated with NSC-733972

100 Patents (Medical) associated with NSC-733972

Literatures (Medical) associated with NSC-733972

01 Feb 2021·Neurosurgical FocusQ2 · MEDICINE

Safety and interim survival data after intracranial administration of M032, a genetically engineered oncolytic HSV-1 expressing IL-12, in pet dogs with sporadic gliomas

Q2 · MEDICINE

Article

Author: Koehler, Jennifer W. ; Omar, Nidal B. ; Bentley, R. Timothy ; Gillespie, G. Yancey ; Sorjonen, Donald ; Rissi, Daniel R. ; Crossman, David K. ; Platt, Simon R. ; Yanke, Amy B. ; Shores, Andy ; Chambers, Melissa R. ; Markert, James M. ; Foote, Jeremy B.

OBJECTIVEThe diagnosis of glioma remains disheartening in the clinical realm. While a multitude of studies and trials have shown promise, improvements in overall survival have been disappointing. Modeling these tumors in the laboratory setting has become increasingly challenging, given their complex in situ behavior and interactions for therapeutic evasion. Dogs, particularly brachycephalic breeds, are known to spontaneously develop gliomas that resemble human gliomas both clinically and pathophysiologically, making canines with sporadic tumors promising candidates for study. Typically, survival among these dogs is approximately 2 months with palliation alone.METHODSThe authors have completed the first stage of a unique phase I dose-escalating canine clinical trial in which the safety and tolerability of M032, a nonneurovirulent oncolytic herpes simplex virus–1 vector genetically engineered to express interleukin-12, are being studied in pet dogs with gliomas undergoing maximum safe tumor resection and inoculation of the cavity with the viral infusate.RESULTSTwenty-five canine patients were enrolled between January 2018 and August 2020. One patient was electively withdrawn from the trial by its owner, and 3 did not receive the virus. For the 21 dogs that remained, 13 had high-grade gliomas, 5 had low-grade gliomas, and 3 were undetermined. According to histopathological analysis, 62% of the tumors were oligodendrogliomas. At the time of this report, the median overall survival from the date of treatment was 151 days (± 78 days). No significant adverse events attributable to M032 or dose-limiting toxicities have been observed to date.CONCLUSIONSIn this largest study of oncolytic viral therapy for canine brain tumors to date, treatment with M032 did not cause harm and the combination of surgery and oncolytic viral therapy may have contributed to prolonged survival in pet dogs with spontaneous gliomas. Forthcoming in-depth radiographic, immunohistochemical, and genetic analyses will afford a more advanced understanding of how this treatment impacts these tumors and the immune system. Our goal is to utilize these findings bitranslationally to inform human studies and refine therapies that will improve outcomes in both humans and pet dogs with gliomas.

01 Jun 2016·Human Gene Therapy Clinical DevelopmentQ3 · MEDICINE

Design of a Phase I Clinical Trial to Evaluate M032, a Genetically Engineered HSV-1 Expressing IL-12, in Patients with Recurrent/Progressive Glioblastoma Multiforme, Anaplastic Astrocytoma, or Gliosarcoma

Q3 · MEDICINE

Article

Author: Gillespie, G. Yancey ; Foreman, Paul M. ; Riley, Kristen O. ; Nabors, L. Burt ; Patel, Daxa M. ; Markert, James M.

M032 is a second-generation oncolytic herpes simplex virus (oHSV) that selectively replicates in tumor cells. M032 kills tumor cells directly through oncolytic replication and then proceeds to infect tumor cells in proximity, continuing the process of tumor destruction. In addition to this direct oncolytic activity, the virus carries a therapeutic payload-thus acting as a gene therapy vector-and causes the tumor cell to synthesize and secrete the immunity-stimulating protein interleukin-12 (IL-12) before cell death. (1) Human IL-12 is expressed and promotes an immune response against surviving tumor cells, increasing the antitumor effect of the therapy. IL-12 also produces an antiangiogenic effect, by interfering with the production of new tumor blood vessels necessary for tumor growth. Thus, M032 oHSV exerts antitumor effects through three distinct potential mechanisms. The virus has also been genetically engineered to minimize toxic effects for the patient. Preclinical animal models support the safety of intracranial inoculation with M032 in two relevant species (mouse and nonhuman primate). This clinical protocol outlines the dose-escalating phase I study for evaluation of M032 in patients with recurrent or progressive malignant glioma.

01 Mar 2014·Human Gene Therapy Clinical DevelopmentQ3 · MEDICINE

Evaluation of the Safety and Biodistribution of M032, an Attenuated Herpes Simplex Virus Type 1 Expressing hIL-12, After Intracerebral Administration toAotusNonhuman Primates

Q3 · MEDICINE

Article

Author: Peggins, James O. ; Whitley, Richard J. ; Grimes, Sheila D. ; Parker, Jackie N. ; Price, Kathleen H. ; Markert, James M. ; Cody, James J. ; Coleman, Jennifer M. ; Roth, Justin C. ; Noker, Patricia E. ; Powers, Nicholas W. ; Cassady, Kevin A. ; Carroll, Steven L. ; Gillespie, G. Yancey

Herpes simplex virus type 1 (HSV-1) mutants lacking the γ(1)34.5 neurovirulence loci are promising agents for treating malignant glioma. Arming oncolytic HSV-1 to express immunostimulatory genes may potentiate therapeutic efficacy. We have previously demonstrated improved preclinical efficacy, biodistribution, and safety of M002, a γ(1)34.5-deleted HSV-1 engineered to express murine IL-12. Herein, we describe the safety and biodistribution of M032, a γ(1)34.5-deleted HSV-1 virus that expresses human IL-12 after intracerebral administration to nonhuman primates, Aotus nancymae. Cohorts were administered vehicle, 10(6), or 10(8) pfu of M032 on day 1 and subjected to detailed clinical observations performed serially over a 92-day trial. Animals were sacrificed on days 3, 31, and 91 for detailed histopathologic assessments of all organs and to isolate and quantify virus in all organs. With the possible exception of one animal euthanized on day 16, neither adverse clinical signs nor sex- or dose-related differences were attributed to M032. Elevated white blood cell and neutrophil counts were observed in virus-injected groups on day 3, but no other significant changes were noted in clinical chemistry or coagulation parameters. Minimal to mild inflammation and fibrosis detected, primarily in meningeal tissues, in M032-injected animals on days 3 and 31 had mostly resolved by day 91. The highest viral DNA levels were detected at the injection site and motor cortex on day 3 but decreased in central nervous system tissues over time. These data demonstrate the requisite safety of intracerebral M032 administration for consideration as a therapeutic for treating malignant brain tumors.

100 Deals associated with NSC-733972

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma Multiforme	Phase 2	US	The University of Alabama at Birmingham	25 Feb 2022
Gliosarcoma	Phase 2	US	The University of Alabama at Birmingham	25 Feb 2022
Recurrent Glioblastoma	Phase 1	US	National Cancer Institute	25 Nov 2013
Recurrent Malignant Glioma	Phase 1	US	National Cancer Institute	25 Nov 2013
Glioma	Phase 1	-	The University of Alabama at Birmingham	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


AACR2020	Phase 1	Glioma	-	M032 alone	(nbrtgswbgn) = bcbmnjlcko oixvzagdze (csvmlaxjff, 83.2 - 292.8)	-	15 Aug 2020

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