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Participants that have completed the study "Trial of C134 in Patients With Recurrent GBM (C134-HSV-1)"

Administration of a second dose of C134 to participants that have completed the study Trial of C134 in Patients With Recurrent GBM (C134-HSV-1).

C134 Re-Administration

Norma Miller, RN

James Markert, MD

The purpose of this study is to determine how safe and how well-tolerated the experimental study drug, C134 is when re-administered into the brain where the tumor is located.

C134 is a genetically engineered herpes simplex virus or "HSV" (the virus that usually causes cold sores and rarely, a severe infection of the brain). It has been known that viruses may kill tumor cells. When tumor cells are mixed with certain viruses in the laboratory, the tumor cells die. The DNA of the (HSV) virus has been modified so that tumor cells may be killed when infected by C134. The changes made to the virus (HSV) should help prevent the (C134) virus from infecting normal brain tissue. Extensive testing in both mice and monkeys has demonstrated that C134 is not able to cause HSV when injected directly into the brain. C134 may also be able to help kill tumor cells because it can prevent tumor cells from killing it more effectively than other, similar viruses can. This allows it to infect and kill more brain tumor cells. C134 has been tested in more than ten patients previously. The virus has had only two instances of known significant toxicities. In one patients with extensive disease present on both sides of the brain, the virus traveled throughout the brain and as a result, caused extensive inflammation that required treatment with an antiviral drug. The patient recovered partially, but eventually succumbed to their tumor. A second patient developed an infection of the retina (back of the eye) apparently as a result of the virus migrating to that area from the site of inoculation in the occipital lobe.

Based on these findings the investigators have amended the protocol to protect future patients from these toxicities as follows: 1) The dose of the virus being administered has been lowered; 2) patients with enhancing tumor on both sides of the brain are not eligible for the trial and 3) patients with disease in the occipital lobe which has connections to the retina are not eligible for the trial

Based on laboratory testing, the investigators believe multiple doses of C134 viral therapy in cases such as the patients, could potentially benefit from repeat treatment as this has been seen in preclinical studies, since the patients have received C134, the patients are thus eligible for retreatment under this protocol.

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

A Phase IB (Repeat Dosing) Trial of Second Dose Oncolytic HSV Administered Intratumorally in Patients With Recurrent Malignant Glioma.

Adverse events will be monitored and any changes in status will be recorded for each patient as outlined in CTCAE v4.0 reporting requirements.

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).

Patients survival will be recorded (Kaplan-Meier)

Detection and quantification of HSV antibody titer via ELISA, pfu/mL.

White blood cell subset analysis by FACS, as a percent of total white blood cell number.

Intracellular lymphocyte interferon levels will be assessed by FACS analysis ng/mL

University of Alabama at Birmingham

Chair, Department of Neurosurgery

Infections

Virus Diseases

All Drugs and Chemicals

Immunomodulating Agents

All patients who enroll will receive C134 inoculation into their tumor (one time procedure with 1-5 inoculation sites)

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.

C134

Natalie Lane, RN

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.

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.

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.

Trial of C134 in Patients With Recurrent GBM

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

Patients survival will be recorded (Kaplan-Meier).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Re-Administration of C134 in Patients With Recurrent GBM (C134-HSV-1)	NCT06193174	Recurrent Malig... Glioblastoma Mu... Gliosarcoma of ... Anaplastic Astr...	C134 Re-Adminis...	18 Years -	University of Alabama at Birmingham
Trial of C134 in Patients With Recurrent GBM	NCT03657576	Glioblastoma Mu... Anaplastic Astr... Gliosarcoma of ...	C134	18 Years -	University of Alabama at Birmingham

Spots Global Cancer Trial Database for gliosarcoma of brain