Trial of C134 in Patients With Recurrent GBM

Study Overview
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Brief Summary
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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.

Detailed Description
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The efficacy of herpes simplex virus (HSV) as a treatment for brain tumors has been demonstrated experimentally. The earliest studies used an HSV that was genetically engineered so that the gene for an important enzyme, thymidine kinase (tk) was deleted. This engineered virus still killed tumor cells but was not toxic. Martuza and colleagues demonstrated that tumors implanted in mice shrank following treatment with varying doses of this virus. Additional modified viruses based on the HSV backbone have been developed and tested with encouraging results.Viruses containing deletions in other important viral genes (e.g., DNA polymerase and the gene which can make the virus neurotoxic, γ134.5), also retained the capability of killing cultured human tumors but did not injure mice; in particular, they were safe for use in the brain. These viruses retained the viral tk gene, and so are susceptible to the antiviral drug acyclovir which is routinely used to treat HSV Infection, making them even more safe . Martuza and colleagues generated G207, a modified HSV that contains (1) deletions of both copies of γ134.5 and (2) another gene called ribonucleotide reductase, was disabled secondary to disruption of the U139 gene by insertion of the E. coli LacZ coding region . G207 significantly prolonged survival of nude mice bearing human tumors. In addition, virus injected into the brains of the HSV sensitive primates (Aotus) did not produce any deleterious side effects. G207 and 1716 have both been used in human trials. A dose-escalating phase 1 study of G207 was completed in patients with recurrent, progressive malignant glioma . The trial was conducted at University of Alabama at Birmingham and Georgetown University Medical Center. Twenty-one patients were enrolled in a total of seven dose-escalating cohorts, with three patients per cohort. Patients were stereotactically inoculated with G207 in the enhancing portions of their tumors. Five separate loci were inoculated in the final cohort; all previous cohorts were inoculated in a single locus within the enhancing tissue only. No toxicity definitively related to G207 was observed at doses up to 3 x 109 plaque forming units (pfu-these are active viral particles). In fact, a toxic dose level was not attained during this trial. This was due to viral processing techniques, limiting the total dose that could be administered. In a Phase IB study, six patients with recurrent, resectable malignant glioma were enrolled at the University of Alabama at Birmingham, in a trial examining a split dose administration strategy of G207. Patients underwent inoculation of G207 into their tumors, followed two to five days later by resection of the tumor and reinoculation of G207 into the tumor cavity. No dose limiting toxicities were seen in the trial, although one patient suffered a twelve hour period of mental status changes, weakness, and an elevated temperature when a protocol deviation resulted in an inadvertent partial dose of virus being administered intraventricularly, into the cerebrospinal fluid chamber of the brain. The patient fully recovered quickly and fully. One of the six patients went nearly two years before remote recurrence of her glioblastoma multiforme resulted in her death. A third study in 9 patients with recurrent malignant glioma was completed in which G207 was being administered followed by a single small dose of 5Gy of radiation. Nine patients were followed without any dose limiting toxicity, and some patients had remarkable responses to treatment. Currently, two clinical studies of oncolytic HSV are underway that examine G207 in pediatric patients as well as a novel oncolytic HSV expressing IL- 12, in adult patients. No findings of these two studies have yet been reported. C134 was designed to replicate better than 1st gen HSVs. C134 is created by by inserting the PKR evasion gene, IRS1. from an evolutionary distant herpesvirus HCMV, which allows the virus to replicate much better but does not produce toxicity. The described G207 trials clearly demonstrate that increased immune cell infiltrates within MG are associated with better outcomes. C134 elicits a robust immune response that contributes greatly to its antitumor effects. C134 combines advantages of both wild-type and Δγ134.5 HSV and is an improvement over 1st generation viruses. C134 replicates and lyses tumor cells like a wild-type HSV in the IFN aberrant tumor environment, but is safe in normal cells. C134 induces immune responses which exceed those produced by 1st generation viruses. The study is designed to use all the information from any patients already treated to determine what the best dose for the next patient should be.

Official Title
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A Phase I Trial of IRS-1 HSV C134 Administered Intratumorally in Patients With Recurrent Malignant Glioma

Conditions
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Glioblastoma Multiforme of Brain, Anaplastic Astrocytoma of Brain, Gliosarcoma of Brain

Intervention / Treatment
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* Biological: C134


Participation Criteria
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Eligibility Criteria
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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 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 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 criteria, the patient will not undergo catheter implantation or treatment with C134. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: C134 Treatment<br>All patients who enroll will receive C134 inoculation into their tumor (one time procedure with 1-5 inoculation sites) | Biological: C134<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of Progression Free Survival | 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). | pre-study, day 3, day 28, month 3, month 6, month 12 | 
| Measure Overall Survival | Patients survival will be recorded (Kaplan-Meier). | day 0, day 1, day 2, day 3, day 7, day 28, month 3, month 6, month 12 | 
| Measurement of HSV titer | Detection and quantification of HSV antibody titer via ELISA, pfu/mL. | pre-study, day 28, month 3, month 6, month 12 | 
| Composition of the white blood cells | White blood cell subset analysis by FACS, as a percent of total white blood cell number. | pre-study, day 2, day 7, day 28, month 3, month 6, month 12 | 
| Measure interferon levels | Intracellular lymphocyte interferon levels will be assessed by FACS analysis ng/mL | pre-study, day 2, day 7, day 28, month 3, month 6, month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oncolytic virus, glioma, glioblastoma, HSV, immunotherapy, Brain Tumors, GBM