Evaluation of Ad-RTS-hIL-12 + Veledimex in Subjects With Recurrent or Progressive Glioblastoma, a Substudy to ATI001-102

Study Overview
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Brief Summary
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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 intratumoral injection of Ad-RTS-hIL-12 given with oral veledimex.

Detailed Description
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Patients who are scheduled for 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. The study is divided into three periods: the screening period, the treatment period and the follow-up period.

Official Title
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Protocol ATI001-102 Expansion Substudy: Evaluation of Ad-RTS-hIL-12 + Veledimex in Subjects With Recurrent or Progressive Glioblastoma

Conditions
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Glioblastoma

Intervention / Treatment
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* Biological: Ad-RTS-hIL-12
* Drug: veledimex


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subject ≥18 and ≤75 years of age Provision of written informed consent for tumor resection, tumor biopsy, samples collection, and treatment with investigational products prior to undergoing any study specific procedures Histologically confirmed glioblastoma Evidence of supratentorial tumor recurrence/progression by magnetic resonance imaging (MRI) according to Response Assessment in Neuro-Oncology (RANO) criteria after standard initial therapy Previous standard-of-care antitumor treatment including surgery and/or biopsy and chemoradiation. At the time of registration, subjects must have recovered from the toxic effects of previous treatments as determined by the treating physician. The washout periods from prior therapies are intended as follows: (windows other than what is listed below should be allowed only after consultation with the Medical Monitor) Nitrosureas: 6 weeks Other cytotoxic agents: 4 weeks Antiangiogenic agents: 4 weeks (NOTE: short use (< 4 doses) of bevacizumab for controlling edema is allowed) Targeted agents, including small molecule tyrosine kinase inhibitors: 2 weeks Vaccine-based therapy: 3 months Able to undergo standard MRI scans with contrast agent before enrollment and after treatment Karnofsky Performance Status ≥70 Adequate bone marrow reserves and liver and kidney function, as assessed by the following laboratory requirements: Hemoglobin ≥9 g/L Lymphocytes >500/mm3 Absolute neutrophil count ≥1500/mm3 Platelets ≥100,000/mm3 Serum creatinine ≤1.5 x upper limit of normal (ULN) Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x ULN. For subjects with documented liver metastases, ALT and AST ≤5 x ULN Total bilirubin <1.5 x ULN International normalized ratio (INR) and activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) within normal institutional limits Male and female subjects must agree to use a highly reliable method of birth control (expected failure rate <5% per year) from the Screening Visit through 28 days after the last dose of study drug. Women of childbearing potential (perimenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential) must have a negative pregnancy test at screening Exclusion Criteria: Previous treatment with bevacizumab for their disease (NOTE: short use (< 4 doses) of bevacizumab for controlling edema is allowed) Subjects receiving systemic corticosteroids during the previous 4 weeks Radiotherapy treatment within 4 weeks of starting veledimex Subjects with clinically significant increased intracranial pressure (eg, impending herniation or requirement for immediate palliative treatment) or uncontrolled seizures Known immunosuppressive disease, or autoimmune conditions, and/or chronic viral infections (eg, human immunodeficiency virus [HIV], hepatitis) Use of systemic antibacterial, antifungal, or antiviral medications 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 allowed perioperatively Use of enzyme-inducing antiepileptic drugs (EIAED) within 7 days prior to the first dose of study drug. Note: Levetiracetam (Keppra®) is not an EIAED and is allowed 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 nonmetastatic prostate cancer Nursing or pregnant females Prior exposure to veledimex Use of medications that induce, inhibit, or are substrates of CYP4503A4 within 7 days prior to veledimex dosing without consultation with the Medical Monitor Presence of any contraindication for a neurosurgical procedure 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. Examples may include, but are not limited to, colitis, pneumonitis, unstable angina, congestive heart failure, myocardial infarction within 2 months of screening, and ongoing maintenance therapy for life-threatening ventricular arrhythmia or uncontrolled asthma

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ad-RTS-hIL-12 + veledimex<br>Intratumoral Ad-RTS-hIL-12 and oral veledimex | Biological: Ad-RTS-hIL-12<br>* 2.0 x 10^11 viral particles (vp) per injection intratumoral injection of Ad-RTS-hIL-12<br>Drug: veledimex<br>* 20mg/day 15 oral daily doses of veledimex<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of intratumoral Ad-RTS-hIL-12 and oral veledimex in subjects with recurrent or progressive glioblastoma based on evaluation of adverse events summarized by incidence, intensity and type of adverse event. | Evaluation of adverse events as assessed by CTCAE v4.03. Adverse events will be summarized based on the incidence, intensity and type of adverse event. | 3 years | 
| Tolerability of intratumoral Ad-RTS-hIL-12 and oral veledimex in subjects with recurrent or progressive glioblastoma will be assessed based on expected dose compliance | Evaluation will be based on expected dose compliance | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the overall survival (OS) of Ad-RTS-hIL-12 + veledimex |  | 3 years | 
| Veledimex pharmacokinetic profile: maximum plasma concentration (Cmax) | The maximum plasma concentration (Cmax) | 3 years | 
| Veledimex pharmacokinetic profile: Time to maximum plasma concentration (Tmax) | Time to maximum plasma concentration (Tmax) | 3 years | 
| Veledimex pharmacokinetic profile: Half-life (t1/2) | Half-life (t1/2) | 3 years | 
| Veledimex pharmacokinetic profile: Area-under-the-concentration versus time curve (AUC) | Area-under-the-concentration versus time curve (AUC) | 3 years | 
| Veledimex pharmacokinetic profile: Volume of distribution (Vd) | Volume of distribution (Vd) | 3 years | 
| Veledimex pharmacokinetic profile: Clearance (CL) | Clearance (CL) | 3 years | 
| Veledimex concentration ratio between the brain tumor and the blood |  | 3 years | 
| Tumor objective response rate (ORR) |  | 3 years | 
| Progression free survival (PFS) |  | 3 years | 
| Rate of pseudo-progression (PSP) |  | 3 years | 
| Changes from baseline in cellular responses elicited by Ad-RTS-hIL-12 and veledimex | Evaluation in changes in immune cell population markers, such as, but not limited to CD3, CD4 and CD8 in peripheral blood and tumor | 3 years | 
| Changes from baseline in humoral immune responses elicited by Ad-RTS-hIL-12 and veledimex | Evaluation of changes in levels of immunological and biological markers, such as, but not limited to IL-12 and IFN-gamma in peripheral serum samples | 3 years |