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

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03152318
Recruitment Status : Recruiting
First Posted : May 15, 2017
Last Update Posted : August 8, 2023
Sponsor:
Collaborators:
National Institutes of Health (NIH)
Candel Therapeutics, Inc.
Information provided by (Responsible Party):
E. Antonio Chiocca, MD, PhD, Dana-Farber Cancer Institute

Study Description
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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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 62 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Phase I, open-label, single center, dose-escalation, triple-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 : December 2024
Estimated Study Completion Date : December 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 Names:
  • rQNestin34.5v.2
  • CAN-3110

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 Names:
  • rQNestin34.5v.2
  • CAN-3110

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.
Experimental: Arm C- Multiple Dose rQNestin

Arm C includes up to 6 intratumoral repeated doses of rQNestin34.5v.2, first in a cohort receiving 10^8 pfus per time point, followed by a cohort receiving 10^9 or 10^7 pfus per time point.

  • Arm C adds 2 cohorts of 12 subjects in an open-label clinical trial of rQNestin34.5v.2 administered at two dose levels
  • The injections are planned for days 0, 15, 30, 60, 90, and 120
  • 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.
 Drug: rQNestin
rQNestin is an oncolytic viral vector. It is administered via intratumoral injection during biopsy surgery.
Other Names:
  • rQNestin34.5v.2
  • CAN-3110

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.


Outcome Measures
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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


Eligibility Criteria
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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.


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

Inclusion Criteria:

  • Frozen biopsy consistent with glioma by neuropathologist at the time of the first surgery in this longitudinal trial. Biopsy confirmation of glioma or infiltrative glioma at time of surgery will be acceptable, provided the subject has prior pathology confirmation of IDH wild-type glioma. Patients with reactive changes, gliosis or normal brain tissue only, without evidence of glioma at initial study surgery only will not receive study rQNestin34.5v.2 therapy and will be replaced. Confirmation of glioma at subsequent neurosurgical procedures beyond the initial surgery will not be required.
  • Participants must have prior diagnosis of IDH wild-type glial tumor including GBM, grade 3 anaplastic astrocytoma or oligodendroglioma or or grade 2 astrocytoma with genetic features consistent with GBM, as confirmed by a neuropathologist or by a previous local pathology report. IDH wild-type designation may be based on negative immunohistochemistry (IDH1 R132H mutation) or next generation sequencing for patients with grade 4 tumor and by negative next-generation sequencing for those with grade 2 or 3 tumors. Patients with negative immunohistochemistry study for IDH1 R132H who are identified to have an alternative mutation of IDH1 or 2 are also not eligible.
  • Prior history of external beam radiotherapy ≥ 5,000 cGy delivered to the tumor at least 4 weeks prior to OHRS 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 with external beam radiotherapy and after as per current standard of care. However, temozolomide is not required to have been provided concomitantly or after radiation if the patient had unmethylated MGMT promoter. At least 23 days must have passed from the last dose of temozolomide and first dose of rQNestin34.5v.2.
  • For use of other investigational drug or other anti-tumor treatment, the following time periods must have elapsed from the projected start of scheduled study treatment: 4 weeks or 5 half-lives (whichever is shorter) from any investigational agent; 4 weeks from cytotoxic therapy (except 23 days for TMZ; 6 weeks from last dose for nitrosoureas); 12 weeks from completion of prior radiation therapy; 6 weeks from antibodies treatment; 4 weeks or 5 half-lives (whichever is shorter) from other anti-tumor therapies; 1 day from NOVO-TTF (Optune®) or prior cancer vaccine therapy
  • The initial recurrent or residual gadolinium-enhancing lesion to be treated must be at least 1.0 cm in diameter and less than or equal to 2 cm in greatest maximal diameter, as determined by MRI. The initially treated lesion must be located in non-eloquent cortex, defined as non-dominant temporal, frontal, or occipital lobe. If located in the dominant cortex, the lesion must be in the occipital lobe. For lesions in dominant or non-dominant lobes, there should be a judgment that the subject will be able to tolerate multiple injections and biopsies, based on sufficient distance from the enhancing edge and eloquent cortex defined as speech (dominant mid-to posterior temporal lobe, parietal lobe and frontal lobe: Broca's area), memory (hippocampus and mesial dominant temporal lobe), or sensorimotor cortex. Subsequent injections (injections at day 15, 30, 60, 90, 120) will not be subject to the limitations of the initially treated lesion detailed above.
  • Normal hematological, renal and liver function as defined below before first injection: ANC ≥ 1000/mcL, platelets ≥100,000/mcL, PT or PTT <1.5 x institutional upper limit, Hemoglobin >9.0 g/dL, Total serum bilirubin ≤ 1.5 upper normal institutional limits, AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal, and Serum creatinine ≤ 1.5 upper normal institutional limits OR Creatinine clearance ≥60 mL/min/1.73 m^2 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.
  • No dexamethasone therapy for at least 14 days prior to the first rQNestin34.5v.2 inoculation. Patients who are on physiologic doses of corticosteroids for the treatment of adrenal insufficiency will be allowed to enroll.
  • Ability to undergo MRI scanning with contrast;
  • Have residual tumor or be at first or second relapse. Note: Relapse is defined as progression following initial therapy (i.e., radiation ± chemotherapy). For participants who had prior therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be considered the first relapse. Residual tumor is defined as contrast-enhancing tumor that is present after the initial surgery, radiation, and chemotherapy.
  • Participants must have recovered to grade 0 or 1 or pre-treatment baseline from clinically significant toxic effects of prior therapy (exceptions include but not limited to alopecia, laboratory values not listed per inclusion criteria, and lymphopenia which is common after therapy with temozolomide).

Exclusion Criteria:

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

  • Prior systemic malignancy requiring or expected to require more than surgical therapy within the past 24 months.
  • 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 HSV-1 infection on current valacyclovir, acyclovir or ganciclovir therapy must be off treatment with any of these agents at least 7 days prior to surgery.
  • Active, known, or suspected immunosuppressive disorders, such as acquired or congenital immune deficiency syndromes and autoimmune diseases.
  • Unacceptable anesthesia risk
  • Pregnant or lactating females who are breastfeeding.
  • Participants who are receiving other investigational agents or immunotherapeutic agents during the period of rQNestin34.5v.2 longitudinal injections.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, significant active hepatic or renal disease, an active infection requiring systemic therapy, need for continuous systemic anticoagulation that cannot be stopped or psychiatric illness/social situations that would limit compliance with study requirements.
  • Certain tumor sizes and locations are exclusionary: 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 could lead to spillage into the ventricles regardless of where the tumor is located; Participants whose initial tumor size, location and rate of growth are deemed by the treating neurosurgeons and the CAC to not be able to tolerate the time period of expected longitudinal injections with biopsies, which could be as short as 15 days and as long as 120 days. This category would include tumors located in: a) dominant and non-dominant locations close to eloquent cortices (sensorimotor strip, speech and memory cortices), b) deep nuclear structures (caudate, putamen, thalamus), c) close proximity to corticospinal tracts (based on consensus of Clinical Advisory Committee); Participants with multifocal or multicentric tumors or tumors arising in the brain stem or spinal cord or diffuse leptomeningeal disease.
  • Has received systemic immunosuppressive treatments, aside from systemic corticosteroids (such as methotrexate, chloroquine, azathioprine, etc.) within six months of registration.
  • Has received anti-VEGF or anti-VEGFR targeted agents (e.g. bevacizumab, cediranib, aflibercept, vandetanib, XL-184, sunitinib, etc.)
  • Has history of known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of registration.
  • Has a known history of active TB (Bacillus Tuberculosis).
  • Has gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3 within 6 months of registration.
  • Requires systemic anti-coagulation that cannot be halted for each intraoperative and peri-operative biopsy time period.
Contacts and Locations
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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
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Contact: E. Antonio Chiocca, MD, PhD 617-732-6939 echiocca@partners.org

Locations
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United States, Maryland
Johns Hopkins University Medical Center Not yet recruiting
Baltimore, Maryland, United States, 21287
Contact: Chetan Bettegowda, MD, PhD    410-955-8620    cbetteg1@jhmu.edu   
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         
United States, New York
Memorial Sloan Kettering Cancer Center Not yet recruiting
New York, New York, United States, 10065
Contact: Cameron W. Brennan, MD    212-639-8268    brennac2@mskcc.org   
United States, Texas
MD Anderson Cancer Center Not yet recruiting
Houston, Texas, United States, 77030
Contact: Betty YS Kiim, MD, PhD    713-834-6232    BYKim@mdanderson.org   
Sponsors and Collaborators
Dana-Farber Cancer Institute
National Institutes of Health (NIH)
Candel Therapeutics, Inc.
Investigators
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Principal Investigator: E. Antonio Chiocca, MD, PhD Brigham and Women's Hospital
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: E. Antonio Chiocca, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT03152318    
Other Study ID Numbers: 16-557
First Posted: May 15, 2017    Key Record Dates
Last Update Posted: August 8, 2023
Last Verified: August 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 E. Antonio Chiocca, MD, PhD, Dana-Farber Cancer Institute:
Malignant Glioma
Brain Tumor
Glioblastoma
CAN-3110
Additional relevant MeSH terms:
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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