A Study of Ad-RTS-hIL-12 With Veledimex in Combination With Nivolumab in Subjects With 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. Nivolumab is an antibody (a kind of human protein) that is being tested to see if it will allow the body's immune system to work against glioblastoma tumors. Opdivo (Nivolumab) is currently FDA approved in the United States for melanoma (a type of skin cancer), non-small cell lung cancer, renal cell cancer (a type of kidney cancer), Hodgkin's lymphoma but is not approved in glioblastoma. Nivolumab may help your immune system detect and attack cancer cells. Ad-RTS-hIL-12 and veledimex will be given in combination with Nivolumab to enhance the IL-12 mediated effect observed to date. The main purpose of this substudy is to evaluate the safety and tolerability of a single tumoral injection of Ad-RTS-hIL-12 given with oral veledimex in combination with nivolumab.

Detailed Description
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Eligible patients will receive one dose of nivolumab, via infusion, one week prior to standard of care craniotomy and tumor resection (subtotal or total). On the day of surgery, patients 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. Following veledimex, patients will receive nivolumab via infusion every two weeks. 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 Substudy: Evaluation of Ad-RTS-hIL-12 + Veledimex in Combination With Nivolumab 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
* Drug: Nivolumab


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, stereotactic surgery, tumor biopsy, samples collection, and treatment with investigational products prior to undergoing any study specific procedures Histologically confirmed supratentorial glioblastoma Evidence of 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, including bevacizumab: 4weeks 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 aPTT 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. Normal cardiac and pulmonary function as evidenced by a normal ECG and peripheral oxygen saturation (SpO2) ≥90% by pulse oximetry Exclusion Criteria: Previous treatment with inhibitors of immunocheckpoint pathways (eg, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody) or other agents specifically targeting T cells Radiotherapy treatment within 4 weeks or less prior to veledimex dosing 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 cytochrome p450 (CYP450) 3A4 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 include, but are not limited to: unstable angina, congestive heart failure, myocardial infarction within 2 months of screening, ongoing maintenance therapy for life-threatening ventricular arrhythmia or uncontrolled asthma. History of myocarditis or congestive heart failure (as defined by New York Heart Association Functional Classification III or IV), as well as unstable angina, serious uncontrolled cardiac arrhythmia, uncontrolled infection, or myocardial infarction 6 months prior to study entry.

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 in combination with nivolumab<br>Intratumoral Ad-RTS-hIL-12 and varying doses of oral veledimex (activator ligand) given in combination with nivolumab via infusion. | 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>* 2 doses (10mg/day, 20mg/day) 15 oral daily doses of veledimex<br>Drug: Nivolumab<br>* 2 doses (1mg/kg, 3mg/kg) Every 2 weeks<br>* Other names: Opdivo;|

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 doses in combination with nivolumab in subjects with recurrent or progressive glioblastoma. | Evaluation of adverse events as assessed by CTCAE v4.03 will be based on the incidence, intensity and type of adverse event. | 3.5 years | 
| Tolerability of intratumoral Ad-RTS-hIL-12 and oral veledimex doses in combination with nivolumab in subjects with recurrent or progressive glioblastoma. | Evaluation will be based on expected dose compliance. | 3.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Optimal dose of Ad-RTS-hIL-12 and veledimex given in combination with nivolumab |  | 3.5 years | 
| Tumor objective response rate (ORR) |  | 3.5 years | 
| Progression free survival (PFS) |  | 3.5 years | 
| Rate of pseudo-progression (PSP) |  | 3.5 years | 
| Overall survival (OS) |  | 3.5 years | 
| Changes from baseline in cellular responses elicited by Ad-RTS-hIL-12 and veledimex in combination with nivolumab. |  | 3.5 years | 
| Changes from baseline in humoral immune responses elicited by Ad-RTS-hIL-12 and veledimex in combination with nivolumab. |  | 3.5 years | 
| Veledimex pharmacokinetic profile between the brain tumor and the blood. | Evaluation: maximum plasma concentration (Cmax) | 3.5 years | 
| Veledimex pharmacokinetic profile between the brain tumor and the blood. | Evaluation: time to maximum plasma concentration (Tmax) | 3.5 years | 
| Veledimex pharmacokinetic profile between the brain tumor and the blood. | Evaluation: half-life (t1/2) | 3.5 years | 
| Veledimex pharmacokinetic profile between the brain tumor and the blood. | Evaluation: area-under-the-concentration versus time curve (AUC) | 3.5 years | 
| Veledimex pharmacokinetic profile between the brain tumor and the blood. | Evaluation: volume of distribution (Vd) | 3.5 years | 
| Veledimex pharmacokinetic profile between the brain tumor and the blood. | Evaluation: clearance (CL) | 3.5 years | 
| Veledimex concentration ratio between the brain tumor and the blood. |  | 3.5 years |