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Genetically Engineered HSV-1 Phase 1 Study for the Treatment of Recurrent Malignant Glioma (M032-HSV-1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02062827
Recruitment Status : Active, not recruiting
First Posted : February 14, 2014
Last Update Posted : September 16, 2022
Information provided by (Responsible Party):
James Markert, MD, University of Alabama at Birmingham

Brief Summary:
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

Condition or disease Intervention/treatment Phase
Recurrent Glioblastoma Multiforme Progressive Glioblastoma Multiforme Anaplastic Astrocytoma or Gliosarcoma Biological: M032 (NSC 733972) Phase 1

Detailed Description:
M032 is a second-generation oncolytic herpes simplex virus (oHSV) that is conditionally replication competent; that is, similar to G207, a first generation oHSV, it can replicate in tumor cells, but not in normal cells, thus killing the tumor cells directly through this process. Replication of M032 in the tumor itself not only kills the infected tumor cells, but causes the tumor cell to act as a factory to produce new virus. These virus particles are released as the tumor cell dies, and can then proceed to infect other tumor cells in the vicinity, and continue the process of tumor kill. In addition to this direct oncolytic activity, the virus carries a therapeutic payload--acting as a gene therapy vector, too--and causes the tumor cell to synthesize and secrete an immunity-stimulating protein called Interleukin-12 (IL-12) before it is killed. This IL-12 is released and promotes an immune response against surviving tumor cells, which increases the antitumor effect of the therapy. The IL-12 that is expressed can also produce an anti-angiogenic effect, by interfering with the production of new tumor blood vessels necessary to allow tumor growth. Anti-angiogenic therapies potentially starve the tumor of necessary oxygen and nutrients. Thus, the M032 oHSV produces three different potential mechanisms for antitumor effects. The virus has also been genetically-engineered to minimize the production of any toxic effects for the patient receiving the therapy.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : November 25, 2013
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : September 2024

Arm Intervention/treatment
Experimental: Group A single dose of HSV-1 (M032)
single dose of HSV-1 (M032) infused through catheters into region(s) of tumor defined by MRI
Biological: M032 (NSC 733972)
A single dose of HSV-1 (M032) infused through catheters into region(s) of tumor defined by MRI

Primary Outcome Measures :
  1. Highest safe dose/MTD (maximum tolerated dose) or maximally planned dose if no dose-limiting toxicity observed [ Time Frame: baseline to12 months ]

Secondary Outcome Measures :
  1. Time to progression assessment [ Time Frame: baseline to 12 months ]
  2. The time of survival assessment [ Time Frame: baseline to 12 months ]
  3. The time of biologic assessment [ Time Frame: baseline to 12 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria

  • Patients must have histologically or cytologically confirmed glioblastoma multiforme, anaplastic astrocytoma, or gliosarcoma.
  • Prior therapy: Patients must have failed external beam radiotherapy to the brain, and if eligible and tolerated, undergone appropriate treatment with temozolomide chemotherapy. All radiation and additional chemotherapies must have been completed at least 4 weeks prior to enrollment. Prior therapy with nitrosoureas must have been completed at least 6 weeks prior to enrollment.
  • Age ≥18 years (age of majority for clinical trials in Alabama). Because no dosing or adverse event data are currently available on the use of M032 in patients <18 years of age, children are excluded from this study but will be eligible for future pediatric phase 1 single-agent trials.
  • Karnofsky Performance Status ≥70%
  • Life expectancy of greater than 4 weeks.
  • Patients must have normal organ and marrow function as defined below:

    • Leukocytes: >3,000/μl
    • absolute neutrophil count: >1,500/μl
    • platelets: >100,000/μl
    • total bilirubin within normal institutional limits
    • AST(SGOT)(aspartate aminotransferase)/ALT(SGPT)(alanine aminotransferase): <2.5 X institutional upper limit of normal
    • creatinine within normal institutional limits OR
    • creatinine clearance: >60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
  • Residual lesion must be ≥1.0 cm and < 5.5 cm in diameter without bilateral extension through the corpus callosum as determined by MRI as this is a locally delivered treatment. These parameters will be re-evaluated on imaging done on the day of catheter implantation and if the lesion no longer meets.
  • The effects of M032 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the first six months after receiving M032. Because it is currently unknown if M032 can be transmitted by sexual contact, a barrier method of birth control must be employed and for six (6) months following the administration of the study drug. Should a woman become pregnant while participating in this study, she should inform her treating physician immediately. For two weeks after receiving M032, subjects should avoid intimate contact with pregnant women, infants and young children and individuals with decreased immunity (ability to fight infection). Subjects should also refrain from donating blood during the trial
  • Ability to understand and the willingness to sign a written informed consent document.
  • Females of childbearing potential must not be pregnant; this will be confirmed by a negative serum pregnancy test within 14 days prior to starting study treatment.
  • Steroid use is allowed as long as dose has not increased within 2 weeks of scheduled M032 administration. Whenever possible, the patient should be on a steroid dose that is equivalent to a dexamethasone dose of ≤ 2mg daily at the time of treatment.

Exclusion Criteria

  • Patients who have had chemotherapy, cytotoxic therapy, immunotherapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas), surgical resection within 4 weeks prior to entering the study, or have received experimental viral therapy or gene therapy at any time (e.g., adenovirus, retrovirus or herpes virus protocol). However, this does not preclude re-treatment with M032 at a later date.
  • Patients who have not recovered from adverse events due to therapeutic interventions administered more than 4 weeks earlier.
  • Patients may not be receiving any other investigational agents.
  • History of allergic reactions attributed to compounds of similar biologic composition to M032 or to IL-12.
  • Tumor involvement which would require ventricular, brainstem, basal ganglia, or posterior fossa inoculation or would require access through a ventricle in order to deliver treatment. Also, since M032 is a local treatment, patients whose tumors have bilateral extension through the corpus callosum, those with actively growing multifocal disease by MRI, and/or CSF dissemination/ leptomeningeal disease, are ineligible.
  • Prior history of encephalitis, multiple sclerosis, or other CNS infection.
  • Required steroid increase within 2 weeks of scheduled M032 administration. When possible, the patient should be on a dexamethasone equivalent dose of ≤ 2mg daily at the time of treatment.
  • Active oral herpes lesion.
  • Concurrent therapy with any drug active against HSV (acyclovir, valacyclovir, penciclovir, famciclovir, gancyclovir, foscarnet, cidofovir).
  • Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or any other medical condition that precludes surgery. Also, psychiatric illness/social situations that would limit compliance with study requirements.
  • Excluded patient groups

    • Pregnant women are excluded from this study because M032 is a viral oncolytic therapy with unknown potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M032, breastfeeding women will not be included in the study.
    • Because patients with immune deficiency will be unable to mount the anticipated immune response underlying this therapeutic rationale, HIV-seropositive patients are excluded from this study. Other treatment studies for this disease that are less dependent on the patients' immune response are more appropriate for HIV-seropositive patients.
  • Patients with known history of allergic reaction to IV contrast material that is not amenable to pre-treatment by University of Alabama at Birmingham protocol.
  • Patients with pacemakers, ferro-magnetic aneurysm clips, metal infusion pumps, metal or shrapnel fragments or certain types of stents.
  • Receipt of Gliadel Therapy.
  • (Receipt of Bevacizumab (Avastin) therapy within 4 weeks of scheduled M032 administration. (Receipt of Bevacizumab (Avastin) greater than 4 weeks of scheduled M032 administration does not exclude patient.)
  • Any other reason the investigator deems subject is unfit for participation in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02062827

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United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
Sponsors and Collaborators
University of Alabama at Birmingham
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Principal Investigator: James M. Markert, MD University of Alabama at Birmingham
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Responsible Party: James Markert, MD, Principal Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT02062827    
Other Study ID Numbers: UAB-1317
First Posted: February 14, 2014    Key Record Dates
Last Update Posted: September 16, 2022
Last Verified: September 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by James Markert, MD, University of Alabama at Birmingham:
Oncolytic virus
Gene therapy
Brain Tumors
Additional relevant MeSH terms:
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Disease Attributes
Pathologic Processes
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue