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

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ClinicalTrials.gov Identifier: NCT03152318
Recruitment Status : Recruiting
First Posted : May 15, 2017
Last Update Posted : July 19, 2018
Sponsor:
Collaborators:
National Institutes of Health (NIH)
Advantagene, Inc.
Information provided by (Responsible Party):
E. Antonio Chiocca, Dana-Farber Cancer Institute

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: rQNestin Drug: Cyclophosphamide Procedure: Stereotactic biopsy Phase 1

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 108 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: phase I, open-label, single center, dose-escalation, double arm clinical trial of an oncolytic virus called rQNestin
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 18, 2017
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : July 2022


Arm Intervention/treatment
Experimental: Arm A- rQNestin

Arm 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
Drug: rQNestin
rQNestin is an oncolytic viral vector. It is administered via intratumoral injection during biopsy surgery.
Other Name: rQNestin34.5v.2

Procedure: Stereotactic biopsy
In both arms, subjects will undergo standard of care stereotactic biopsy in the intraoperative MRI operating room. The stereotactic needle will be placed stereotactically into the tumor bed using intraoperative MRI guidance to collect the biopsy, and again to administer the rQNestin oncolytic virus.

Experimental: Arm B- rQNestin+CPA

Arm 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
Drug: rQNestin
rQNestin is an oncolytic viral vector. It is administered via intratumoral injection during biopsy surgery.
Other Name: rQNestin34.5v.2

Drug: Cyclophosphamide
Cyclophosphamide is an immunomodulating agent. It is administered intravenously in a single dose 2 days (+/- 6 hrs) before surgery.
Other Names:
  • Cytoxan®
  • Neosar®

Procedure: Stereotactic biopsy
In both arms, subjects will undergo standard of care stereotactic biopsy in the intraoperative MRI operating room. The stereotactic needle will be placed stereotactically into the tumor bed using intraoperative MRI guidance to collect the biopsy, and again to administer the rQNestin oncolytic virus.




Primary Outcome Measures :
  1. Maximum Tolerated Dose [ Time Frame: Minimum of 21 Days ]
    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 :
  1. MRI Changes in Permeability [ Time Frame: Evaluated every 2 months for 1 year ]
    Determine MRI alterations of permeability in injected sites using standard perfusion sequences.

  2. MRI Changes in Volume [ Time Frame: Evaluated every 2 months for 1 year ]
    Determine MRI alterations of cerebral blood volume in injected sites using standard sequences.

  3. MRI Changes in Flow [ Time Frame: Evaluated every 2 months for 1 year ]
    Determine MRI alterations of cerebral blood flow in injected sites using standard sequences.

  4. Viral Shedding in Saliva [ Time Frame: Evaluated up to day 56 for each subject ]
    Assess the shedding of rQNestin34.5v.2 in the saliva of subjects treated with rQNestin34.5v.2

  5. HSV1 Viremia [ Time Frame: Evaluated up to day 56 for each subject ]
    Assess the degree of HSV-1 viremia post rQNestin34.5v.2 administration

  6. HSV1 Antibody Response [ Time Frame: Evaluated up to day 56 for each subject ]
    Identify changes in HSV1 antibody response



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • At the time of surgery, frozen biopsy confirmation of high grade or malignant glioma by neuropathologist. 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;
  • 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 8 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 of the investigational agent.
  • 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 (6 weeks for nitrosoureas or mitomycin C) 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.

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): NCT03152318


Contacts
Contact: E. Antonio Chiooca, MD, PhD 617-732-6939 echiocca@partners.org

Locations
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Principal Investigator: E.Antonio Chiocca, MD, PhD         
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02215
Contact: E. Antonio Chiocca, MD, PhD    617-732-6939    echiocca@partners.org   
Principal Investigator: E. Antonio Chiocca, MD, PhD         
Sponsors and Collaborators
Dana-Farber Cancer Institute
National Institutes of Health (NIH)
Advantagene, Inc.
Investigators
Principal Investigator: E. Antonio Chiocca, MD, PhD Brigham and Women's Hospital

Responsible Party: E. Antonio Chiocca, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT03152318     History of Changes
Other Study ID Numbers: 16-557
First Posted: May 15, 2017    Key Record Dates
Last Update Posted: July 19, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Keywords provided by E. Antonio Chiocca, Dana-Farber Cancer Institute:
Malignant Glioma
Brain Tumor
Glioblastoma

Additional relevant MeSH terms:
Glioblastoma
Glioma
Brain Neoplasms
Astrocytoma
Ependymoma
Oligodendroglioma
Ganglioglioma
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
Cyclophosphamide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists