A Study of Ad-RTS-hIL-12 With Veledimex in Subjects With Glioblastoma or Malignant Glioma

A Phase I Study of Ad-RTS-hIL-12, an Inducible Adenoviral Vector Engineered to Express hIL-12 in the Presence of the Activator Ligand Veledimex in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma

This research study involves an investigational product: Ad-RTS-hIL-12 given with veledimex for production of human IL-12. IL-12 is a protein that can improve the body's natural response to disease by enhancing the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor.

The main purpose of this study is to evaluate the safety and tolerability of a single tumor injection of Ad-RTS-hIL-12 given with oral veledimex.

Eligible patients will be stratified to one of two groups, according to clinical indication for tumor resection. Patients who are scheduled for a standard of care craniotomy and tumor resection will receive one dose of veledimex before the resection procedure. Ad-RTS-hIL-12 will be administered by free-hand injection. Patients will continue on oral veledimex for 14 days.

Patients not scheduled for tumor resection will receive Ad-RTS-hIL-12 by stereotactic injection and then will continue on oral veledimex for 14 days.

The study is divided into three periods: the screening period, the treatment period and the follow-up period.

Inclusion Criteria:

1. Male or female subjects ≥ 18 and ≤ 75 years of age

2. Provision of written informed consent for tumor resection, stereotactic surgery, tumor biopsy, samples collection and treatment with investigational products prior to undergoing any study procedures

3. Histologically confirmed supratentorial glioblastoma or other WHO grade III or IV malignant glioma from archival tissue.

4. Evidence of tumor recurrence/progression by MRI (RANO criteria) post standard initial therapy.

5. Previous standard of care anti-tumor treatment including surgery and/or biopsy and chemoradiation. The washout periods from prior therapies are intended as follows:

   1. Nitrosoureas: 6 weeks
   2. Other cytotoxic agents: 4 weeks
   3. Anti-angiogenic agents including bevacizumab: 4 weeks
   4. Targeted agents including small-molecule tyrosine kinase inhibitors: 2 weeks
   5. Experimental immunotherapies: 3 months
   6. Vaccine based therapy: 3 months

6. Able to undergo standard MRI scans with contrast agent

7. Karnofsky Performance Status ≥ 70

8. Adequate bone marrow reserves and liver and kidney function, as assessed by the following laboratory requirements:

   1. Hemoglobin ≥ 9 g/L
   2. Lymphocytes > 500/ mm3
   3. Absolute Neutrophil Count ≥ 1500/ mm3
   4. Platelets ≥ 100,000/ mm3
   5. Serum creatinine ≤ 1.5 x ULN
   6. AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN. For subjects with documented liver metastases, ALT and AST ≤ 5 × ULN
   7. Total bilirubin < 1.5 x ULN
   8. International Normalized Ratio (INR) and activated Partial Thromboplastin Time [PTT] within normal institutional limits

9. Male and female subjects must agree to use a highly reliable method of birth control (expected failure rate less than 5% per year) from the screening visit through 28 days after the last dose of study drug. Women of childbearing potential must have a negative pregnancy test at screening.

Exclusion Criteria:

1. Radiotherapy within 4 weeks or less prior to starting first veledimex dose
2. Subjects with clinically significant increased intracranial pressure or uncontrolled seizures.
3. Known immunosuppressive disease, autoimmune conditions, and /or chronic viral infections
4. Use of systemic antibacterials, antifungals or antivirals for the treatment of acute clinically significant infection within 2 weeks of first veledimex dose. Concomitant therapy for chronic infections is not allowed. Subjects must be afebrile prior to Ad-RTS-hIL-12 injection; only prophylactic antibiotic use is permitted perioperatively.
5. Use of enzyme-inducing anti-epileptic drugs (EIAED) within 7 days prior to the first dose of study drug.
6. Other concurrent clinically active malignant disease, requiring treatment, with the exception of non-melanoma cancers of the skin or carcinoma in-situ of the cervix or non-metastatic prostate cancer.
7. Nursing or pregnant females
8. Prior exposure to veledimex
9. Use of medications that induce, inhibit or are substrates of CYP450 3A4 within 7 days prior to the first veledimex dosing
10. Presence of any contra-indication for a neurosurgical procedure
11. Unstable or clinically significant concurrent medical condition that would, in the opinion of the investigator or medical monitor, jeopardize the safety of a subject and/or their compliance with the protocol.