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

• ClinicalTrials.gov Identifier: NCT02062827
• Recruitment Status: Active, not recruiting
• First Posted: February 14, 2014
• Results First Posted: February 2, 2024
• Last Update Posted: February 2, 2024
• Sponsor: University of Alabama at Birmingham
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): James Markert, MD, University of Alabama at Birmingham

Tracking Information

• First Submitted Date: February 9, 2014
• First Posted Date: February 14, 2014
• Results First Submitted Date: October 5, 2023
• Results First Posted Date: February 2, 2024
• Last Update Posted Date: February 2, 2024
• Actual Study Start Date: November 25, 2013
• Actual Primary Completion Date: September 2022 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 1, 2024): Maximum Tolerated Dose (MTD) of M032 [ Time Frame: baseline to12 months ]
• Original Primary Outcome Measures (submitted: February 12, 2014): Highest safe dose/MTD (maximum tolerated dose) or maximally planned dose if no dose-limiting toxicity observed [ Time Frame: baseline to12 months ]

Current Secondary Outcome Measures (submitted: February 1, 2024)

• Time to Progression Assessment [ Time Frame: baseline to 12 months ]
• The Time of Survival Assessment [ Time Frame: baseline to 12 months ]
• The Time of Biologic Assessment [ Time Frame: baseline to 12 months ]

Original Secondary Outcome Measures (submitted: February 12, 2014)

• Time to progression assessment [ Time Frame: baseline to 12 months ]
• The time of survival assessment [ Time Frame: baseline to 12 months ]
• The time of biologic assessment [ Time Frame: baseline to 12 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Genetically Engineered HSV-1 Phase 1 Study for the Treatment of Recurrent Malignant Glioma
• 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
• 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Recurrent Glioblastoma Multiforme
• Progressive Glioblastoma Multiforme
• Anaplastic Astrocytoma or Gliosarcoma

Intervention

Biological: M032 (NSC 733972)

A single dose of HSV-1 (M032) infused through catheters into region(s) of tumor defined by MRI

Study Arms

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

Intervention: Biological: M032 (NSC 733972)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 1, 2024): 29
• Original Estimated Enrollment (submitted: February 12, 2014): 36
• Estimated Study Completion Date: September 2024
• Actual Primary Completion Date: September 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02062827
• Other Study ID Numbers: UAB-1317; R01CA217179 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: James Markert, MD, University of Alabama at Birmingham
• Original Responsible Party: University of Alabama at Birmingham
• Current Study Sponsor: University of Alabama at Birmingham
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: James M. Markert, MD; University of Alabama at Birmingham

• PRS Account: University of Alabama at Birmingham
• Verification Date: February 2024