Clinical Trials /

A Study of the Treatment of Recurrent Malignant Glioma With rQNestin34.5v.2

NCT03152318

Description:

This research study is evaluating an investigational drug, an oncolytic virus called rQNestin34.5v.2. This research study is a Phase I clinical trial, which tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug as a possible treatment for this diagnosis of recurrent or progressive brain tumor.

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of the Treatment of Recurrent Malignant Glioma With rQNestin34.5v.2
  • Official Title: A Phase I Study of the Treatment of Recurrent Malignant Glioma With rQNestin34.5v.2, a Genetically Engineered HSV-1 Virus, and Immunomodulation With Cyclophosphamide

Clinical Trial IDs

  • ORG STUDY ID: 16-557
  • NCT ID: NCT03152318

Conditions

  • Malignant Glioma of Brain
  • Astrocytoma
  • Malignant Astrocytoma
  • Oligodendroglioma
  • Anaplastic Oligodendroglioma of Brain (Diagnosis)
  • Mixed Oligo-Astrocytoma
  • Ependymoma
  • Ganglioglioma
  • Pylocytic/Pylomyxoid Astrocytoma
  • Brain Tumor
  • Glioma
  • Brain Cancer
  • Glioblastoma
  • Glioblastoma Multiforme

Interventions

DrugSynonymsArms
rQNestinrQNestin34.5v.2Arm A- rQNestin
CyclophosphamideCytoxan®, Neosar®Arm B- rQNestin+CPA

Purpose

This research study is evaluating an investigational drug, an oncolytic virus called rQNestin34.5v.2. This research study is a Phase I clinical trial, which tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug as a possible treatment for this diagnosis of recurrent or progressive brain tumor.

Detailed Description

      This research study is a Phase I clinical trial, which tests the safety of an investigational
      drug and also tries to define the appropriate dose of the investigational drug as a possible
      treatment for this diagnosis. "Investigational" means that the intervention is being studied.

      The FDA (the U.S. Food and Drug Administration) has not approved rQNestin34.5v.2 as a
      treatment for any disease. This is the first time that rQnestin34.5v.2 will be given to
      humans.

      The research drug, rQNestin34.5v.2, is an oncolytic viral vector made from the herpes simplex
      virus type 1 (HSV1). The large majority of humans already have regular HSV1 in their nervous
      system. Normally, this virus can cause cold sores in areas like the lips, fingers and
      genitals in humans by making copies of itself in normal healthy cells. In some cases, HSV1
      can cause severe infection of the brain and liver and/or death. However, scientists have
      removed or changed parts of the rQNestin virus being used on this study so it can only make
      copies of itself in glioma cells and not normal healthy cells.

      If it is effective, the rQNestin34.5v.2 drug will spread to a glioma cell, kill it, and then
      make a copy of itself and spread again. This should be repeated over and over until all
      glioma cells are reached. If rQNestin34.5v.2 moves into a normal brain cell, it should not
      grow and make copies, and therefore should not spread to other normal brain cells.

      The purpose of this research study is to test if rQnestin34.5v.2 is safe to use in humans,
      and if it is effective in treating malignant glioma. This study is also looking for the
      highest dose of rQNestin34.5v.2 that can be given safely to people with malignant brain
      tumors.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A- rQNestinExperimentalArm A is rQNestin34.5v.2 treatment This study follows a standard 3+3 dose escalation design. Participants will not enroll to Arm B until the MTD or HTD has been met for Arm A. Subjects with presumed radiologic evidence of recurrent malignant glioma will undergo stereotactic biopsy under monitored general or local anesthesia. Evidence of recurrent high grade or malignant must be found on frozen section for the person to receive administration of the agent. rQNestin34.5v.2 Indicated dose as per cohort, Intratumor administration during surgery, single dose
  • rQNestin
Arm B- rQNestin+CPAExperimentalArm B is rQNestin34.5v.2 treatment with Cyclophosphamide (CPA) pre-treatment This study follows a standard 3+3 dose escalation design. Participants will not enroll to Arm B until the MTD or HTD has been met for Arm A. Cyclophosphamide one intravenous injection 2 days prior to procedure. Subjects with presumed radiologic evidence of recurrent malignant glioma will undergo stereotactic biopsy under monitored general or local anesthesia. Evidence of recurrent high grade or malignant must be found on frozen section for the person to receive administration of the agent. rQNestin34.5v.2 Indicated dose as per cohort, Intratumor administration during surgery, single dose
  • rQNestin
  • Cyclophosphamide

Eligibility Criteria

        Inclusion Criteria:

          -  At the time of surgery, frozen biopsy confirmation of high grade or malignant glioma
             by neuropathologist. Biopsy confirmation of glioma or infiltrative glioma at time of
             surgery will be acceptable, provided that subject has prior pathology confirmation of
             high-grade glioma. If subject had previous diagnosis of low grade glioma, then the
             biopsy must show high grade glioma. To be confirmed at time of surgery, after
             registration in OnCore.

          -  Participants must have prior diagnosis of glioma (astrocytoma, malignant astrocytoma,
             oligodendroglioma, anaplastic oligodendroglioma, mixed oligo-astrocytoma), exclusive
             of ependymoma, ganglioglioma, pylocytic/pylomyxoid astrocytoma as confirmed by a
             neuropathologist or by a previous local pathology report.

          -  Prior history of external beam radiotherapy ≥ 5,000 cGy delivered to the tumor at
             least 4 weeks prior to registration. Participants over the age of 70 with prior
             history of hypofractionated external beam radiotherapy will also be accommodated, in
             accordance with NCCN guidelines.

          -  Prior history of temozolomide chemotherapy provided concurrent to external beam
             radiotherapy and after as per current standard of care. However, temozolomide would
             not be required to have been provided concomitantly or after radiation if the patient
             had unmethylated MGMT promoter or if the patient initially was diagnosed with a low
             grade glioma. At least 4 weeks must have passed from the last dose of temozolomide and
             first dose of cyclophosphamide and/or rQNestin34.5v.2;

          -  If participant was treated with bevacizumab, at least 4 weeks must elapse before
             treatment with either agent (Cyclophosphamide or rQNestin34.5v.2);

          -  Recurrent lesion must be ≥ 1.0 cm in diameter as determined by MRI;

          -  Normal hematological, renal and liver function as defined below: Leukocytes
             ≥3,000/mcL; Absolute lymphocyte count > 500/ mcL; Absolute neutrophil count
             ≥1,500/mcL; platelets ≥100,000/mcL; PT or PTT <1.5 x institutional upper limit;
             Hemoglobin >10.0 g/dL; Total serum bilirubin within normal institutional limits;
             AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal; Serum creatinine
             within normal institutional limits OR Creatinine clearance ≥60 mL/min/1.73 m2 for
             participants with creatinine levels above institutional normal;

          -  Karnofsky Performance Score ≥70.

          -  Age ≥ 18 years;

          -  Ability to understand and the willingness to sign a written informed consent document;

          -  The effects of rQNestin34.5v.2 and cyclophosphamide on the developing human fetus are
             unknown. For this reason and because cytotoxic & immunomodulating agents as well as
             other therapeutic agents used in this trial are known to be teratogenic, women of
             child-bearing potential and men must agree to use adequate contraception (hormonal or
             barrier method of birth control; abstinence) prior to study entry and for the duration
             of study participation including 3 months following the study. Should a woman become
             pregnant or suspect she is pregnant while she or her partner is participating in this
             study, she should inform her treating physician immediately. Men treated or enrolled
             on this protocol must also agree to use adequate contraception prior to the study and
             for the duration of study participation including 3 months following the study. Women
             of child-bearing potential must have a negative serum pregnancy test within 48 hours
             of study registration.

          -  Steroid regimen stable or decreasing for at least 7 days prior to inoculation;

          -  Ability to undergo MRI scanning with contrast;

          -  Subjects with any recurrence (first, second, third, etc recurrence) will be able to be
             enrolled.

        Exclusion Criteria:

        Participants who exhibit any of the following conditions prior to initiating study
        treatment will not be eligible for this study:

          -  Participants with significant renal or liver disease

          -  Participants with progressive systemic malignancy.

          -  Known chronic infections with HIV, hepatitis B or C; participants with a history of
             resolved Hepatitis A may be included in the trial.

          -  Participants with active viral, bacterial or fungal infection requiring concurrent
             antiviral or antibiotics.

          -  Subjects with active HSV1 infection on current valacyclovir, acyclovir or ganciclovir
             therapy must be off treatment with any of these agents at least 7 days prior to
             surgery.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to cyclophosphamide (only for arm B).

          -  Active, known, or suspected immunosuppressive disorders, such as acquired or
             congenital immune deficiency syndromes and autoimmune diseases

          -  Unacceptable anesthesia risk

          -  Serious cardiopulmonary medical condition

          -  Pregnant or lactating females

          -  Recurrent glioma where injection in either arm A or B of the biologic agent would
             require access and/or considerable spillage into the ventricular system.

          -  Prior participant in another protocol using an investigational agent or device within
             5 half-lives or 4 weeks of the investigational agent, whichever is shorter.

          -  Known HIV seropositivity.

          -  Concurrent therapy with drugs active against HSV (acyclovir, valaciclovir,
             penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir). Participants must be off
             treatment with these agents for at least 7 days prior to surgery.

          -  Active oral or genital herpes lesions.

          -  Participants who have had chemotherapy or radiotherapy within 4 weeks prior to
             entering the study or those who have not recovered from adverse events due to agents
             administered more than 4 weeks earlier.

          -  Participants who are receiving any other investigational agents.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  Participants with tumor ≤ 1 cm proximity to the ventricles will be allowed to enroll.
             However the study agent (rQNestin34.5v.2) may not be injected in any area that is
             within 1 cm of the ventricle regardless of where the tumor is located.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose
Time Frame:Minimum of 21 Days
Safety Issue:
Description:The primary objective is to determine the maximum tolerated dose of rQNestin34.5v.2 injected into recurrent malignant gliomas, with or without previous immunomodulation with cyclophosphamide.

Secondary Outcome Measures

Measure:MRI Changes in Permeability
Time Frame:Evaluated every 2 months for 1 year
Safety Issue:
Description:Determine MRI alterations of permeability in injected sites using standard perfusion sequences.
Measure:MRI Changes in Volume
Time Frame:Evaluated every 2 months for 1 year
Safety Issue:
Description:Determine MRI alterations of cerebral blood volume in injected sites using standard sequences.
Measure:MRI Changes in Flow
Time Frame:Evaluated every 2 months for 1 year
Safety Issue:
Description:Determine MRI alterations of cerebral blood flow in injected sites using standard sequences.
Measure:Viral Shedding in Saliva
Time Frame:Evaluated up to day 56 for each subject
Safety Issue:
Description:Assess the shedding of rQNestin34.5v.2 in the saliva of subjects treated with rQNestin34.5v.2
Measure:HSV1 Viremia
Time Frame:Evaluated up to day 56 for each subject
Safety Issue:
Description:Assess the degree of HSV-1 viremia post rQNestin34.5v.2 administration
Measure:HSV1 Antibody Response
Time Frame:Evaluated up to day 56 for each subject
Safety Issue:
Description:Identify changes in HSV1 antibody response

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Malignant Glioma
  • Brain Tumor
  • Glioblastoma

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