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Trial of C134 in Patients With Recurrent GBM (C134-HSV-1)

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ClinicalTrials.gov Identifier: NCT03657576
Recruitment Status : Not yet recruiting
First Posted : September 5, 2018
Last Update Posted : July 18, 2019
Sponsor:
Collaborators:
Gateway for Cancer Research
National Cancer Institute (NCI)
Information provided by (Responsible Party):
James Markert, MD, University of Alabama at Birmingham

Brief Summary:
The purpose of this project is to obtain safety information in small groups of individuals, scheduled to receive escalating doses of C134, a cancer killing virus (HSV-1) that has been genetically engineered to safely replicate and kill glioma tumor cells. Safety will be assessed at each dose level before proceeding to the next dose level. A special statistical technique called the Continual Reassessment Method (CRM) will be used to determine when higher doses of virus can be administered. Other objectives of the study include characterization of the activity of C134 after inoculation into the tumor and of the local and systemic immune responses to C134. Patients will also be followed with MRI scans for potential clinical response to C134. The clinical strategy takes advantage of the virus' ability to infect and kill tumor cells while making new virus within the tumors cells; a critical enhancement of this effect is accomplished by the induction of an anti-tumor immune response; both effects are produced by the IRS-1 gene that was placed into the virus by genetic engineering. An additional important component of the research are systematic assessments of the quality of life on treated patients.

Condition or disease Intervention/treatment Phase
Glioblastoma Multiforme of Brain Anaplastic Astrocytoma of Brain Gliosarcoma of Brain Biological: C134 Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Sequential Assignment
Intervention Model Description: Modified continuous reassessment model (mCRM). Using this statistical method, dose changes occur based upon toxicities (or lack thereof) observed after a 24 day observation period for the initial dose level. If toxicities occurring at any dose were acceptable, doses for subsequent cohorts can be increased by up to 1 log until a maximum tolerated dose is reached. If toxicities are unacceptable then dose de-escalation occurs until a safe acceptable maximum tolerated dosage is defined. However, it should be noted that the dose alterations are not predictable and cannot be predefined, they are statistically determined after each patient using mCRM software.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial of IRS-1 HSV C134 Administered Intratumorally in Patients With Recurrent Malignant Glioma
Estimated Study Start Date : September 2019
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : September 2024


Arm Intervention/treatment
Experimental: C134 Treatment
All patients who enroll will receive C134 inoculation into their tumor (one time procedure with 1-5 inoculation sites)
Biological: C134
C134 is a virus that was created from an oncolytic Herpes Simplex Virus (oHSV) known to infect and kill tumor cells. The Investigators have made changes to the original virus to make C134. It efficiently infects tumor cells (not normal healthy cells) and induces an immune response to fight the cancer as well.




Primary Outcome Measures :
  1. Measure of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: from baseline through month 12 ]
    Adverse events will be monitored and any changes in status will be recorded for each patient as outlined in CTCAE v4.0 reporting requirements.


Secondary Outcome Measures :
  1. Measure of Progression Free Survival [ Time Frame: pre-study, day 3, day 28, month 3, month 6, month 12 ]
    Patients will receive contrast-enhanced MRI to monitor progression (changes in tumor volume or tumor enhancement assessed by the iRANO criteria). As indicated in the criteria, biopsy and/or resection may be performed in instances of uncertainty. Determination of time to progression (in months) will be recorded for each patient and median progression-free survival will be calculated for the entire cohort (Kaplan-Meier).

  2. Measure Overall Survival [ Time Frame: day 0, day 1, day 2, day 3, day 7, day 28, month 3, month 6, month 12 ]
    Patients survival will be recorded (Kaplan-Meier).

  3. Measurement of HSV titer [ Time Frame: pre-study, day 28, month 3, month 6, month 12 ]
    Detection and quantification of HSV antibody titer via ELISA, pfu/mL.

  4. Composition of the white blood cells [ Time Frame: pre-study, day 2, day 7, day 28, month 3, month 6, month 12 ]
    White blood cell subset analysis by FACS, as a percent of total white blood cell number.

  5. Measure interferon levels [ Time Frame: pre-study, day 2, day 7, day 28, month 3, month 6, month 12 ]
    Intracellular lymphocyte interferon levels will be assessed by FACS analysis ng/mL



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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:

  • Patients must have histologically or cytologically confirmed recurrent/progressive glioblastoma multiforme, anaplastic astrocytoma, or gliosarcoma.
  • Prior therapy. Patients must have failed external beam radiotherapy 5,000 CGy to the brain at least 4 weeks prior to enrollment.
  • Age 18 years or older, because no dosing or adverse event data are currently available on the use of IRSl-chimeric HSVl in patients below 18 years of age, children are excluded from this study but will be eligible for future pediatric phase 1 single-agent trials. Note: 18 is the age of majority in the state of Alabama for participation in clinical 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/uL
    • absolute neutrophil count ≥1,500/uL
    • platelets ≥100,000/uL
    • total bilirubin within normal institutional limits
    • AST(SGOT)/ ALT(SGPT) ≤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
  • Residual lesion must be ≥1.0 cm in diameter as determined by MRI.
  • The effects of IRS1-chimeric HSV1 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 IRS1-chimeric HSVl. Because it is currently unknown if IRS1-chimeric HSV1 can be transmitted by sexual contact, a barrier method of birth control should be employed. Should a woman become pregnant while participating in this study, she should inform her treating physician immediately.
  • Ability to understand and the willingness to sign a written informed consent document (Informed consent document in Appendix E).
  • 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 C134 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 or gene therapy within 6 weeks prior to entering the study, surgical resection within 4 weeks prior to entering the study, or have received experimental viral therapy at any time (e.g., adenovirus, retrovirus or herpesvirus * protocol). Also, those 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 compound of similar biologic composition to IRS1-chimeric HSVl.
  • 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.
  • Prior history of encephalitis, multiple sclerosis, or other CNS infection.
  • Required steroid increase within 2 weeks of scheduled IRS1-chimeric HSV1 administration.
  • Active oral herpes lesion.
  • Concurrent therapy with any drug active against HSV (acyclovir, valaciclovir, penciclovir, famciclovir, ganciclovir, 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.
  • Required steroid increase within 2 weeks of scheduled C134 administration. When possible, the patient should be on a dexamethasone equivalent dose of ≤2mg daily at the time of treatment.
  • Excluded patient groups

    • Pregnant women are excluded from this study because IRS1-chimeric HSV1 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 IRS1-chimeric HSV1, breastfeeding should be discontinued if the mother is treated with IRS1-chimeric HSVl.
    • 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.

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): NCT03657576


Contacts
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Contact: Norma Miller, RN (205) 996-6169 ncmiller@uabmc.edu

Locations
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United States, Alabama
University of Alabama at Birmingham Not yet recruiting
Birmingham, Alabama, United States, 35294
Contact: Norma Miller, RN    205-996-6169    ncmiller@uabmc.edu   
Sponsors and Collaborators
University of Alabama at Birmingham
Gateway for Cancer Research
National Cancer Institute (NCI)
Investigators
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Principal Investigator: James 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: NCT03657576     History of Changes
Other Study ID Numbers: IRB-3000000571
R01CA222903 ( U.S. NIH Grant/Contract )
First Posted: September 5, 2018    Key Record Dates
Last Update Posted: July 18, 2019
Last Verified: July 2019
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 James Markert, MD, University of Alabama at Birmingham:
oncolytic virus
glioma
glioblastoma
GBM
HSV
immunotherapy

Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Gliosarcoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue