human stem cell derived neurons

A Study of Ad-RTS-hIL-12 With Veledimex in Combination With Nivolumab in Subjects With Glioblastoma (Substudy to ATI001-102)

 

Summary

This phase I clinical trial will evaluate the safety and tolerability of a single tumor injection of Ad-RTS-hIL-12 given with veledimex and nivolumab, for patients with recurrent glioblastoma

Ad-RTS-hiL-12 is a genetically engineered, non-pathogenic form of an adenovirus that encodes the protein called interleukin 12 (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. It may also interfere with blood flow to the tumor.

When Ad-RTS-hiL-12 is administered to the tumor site, the modified adenovirus will infect the tumor cells and begin using host cell machinery to produce IL-12. Additional modifications ensure that Ad-RTS-hIL-12 will only initiate production of IL-12 protein if administered with veledimex, an oral drug.

Nivolumab is an antibody-based immunotherapy that helps energize a patient’s immune system against tumor cells. It’s been approved for use in several cancers, and is currently being investigated for glioblastoma. 

Nivolumab is designed to block the activity of PD-1, a protein that normally protects the body from attacking itself. PD-1 prevents immune cells from attacking by detecting a molecular signal (called PD-L1) made by various cells across the body. Some cancer cells take advantage of this protection mechanism making the protective signal themselves. Nivolumab directly binds PD-L1, thus blocking the activity of PD-1. This allows the immune system to activate its T-cells and recognize the tumor as cells to be attacked.

In this phase I study, Ad-RTS-hIL-12 will be injected to the tumor site during surgical resection, along with veledimex (administered orally) and nivolumab (administered intravenously). Eligible participants will receive the following:

  • Experimental Group: Ad-RTS-hIL-12 + veledimex + nivolumab

 

* This is a substudy of another Ad-RTS-hIL-12 trial for patients with recurrent high-grade glioma.

 

Inclusion Criteria
  1. Male or female subject ≥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 specific procedures
  3. Histologically confirmed supratentorial glioblastoma
  4. Evidence of tumor recurrence/progression by magnetic resonance imaging (MRI) according to response assessment in neuro-oncology (RANO) criteria after standard initial therapy
  5. 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)
    1. Nitrosureas: 6 weeks
    2. Other cytotoxic agents: 4 weeks
    3. Antiangiogenic agents, including bevacizumab: 4weeks
    4. Targeted agents, including small molecule tyrosine kinase inhibitors: 2 weeks
    5. Vaccine-based therapy: 3 months
  6. Able to undergo standard MRI scans with contrast agent before enrollment and after treatment
  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 upper limit of normal (ULN)
    6. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x ULN. For subjects with documented liver metastases, ALT and AST ≤5 x ULN
    7. Total bilirubin < 1.5 x ULN
    8. International normalized ratio (INR) and aPTT within normal institutional limits
  9. 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.
  10. Normal cardiac and pulmonary function as evidenced by a normal ECG and peripheral oxygen saturation (SpO2) ≥90% by pulse oximetry

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Exclusion Criteria
  1. 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
  2. Radiotherapy treatment within 4 weeks or less prior to veledimex dosing
  3. Subjects with clinically significant increased intracranial pressure (eg, impending herniation or requirement for immediate palliative treatment) or uncontrolled seizures
  4. Known immunosuppressive disease, or autoimmune conditions, and/or chronic viral infections (eg, human immunodeficiency virus [HIV], hepatitis)
  5. 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.
  6. 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.
  7. 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
  8. Nursing or pregnant females
  9. Prior exposure to veledimex
  10. 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
  11. Presence of any contraindication for a neurosurgical procedure
  12. 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.
  13. 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.
     

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Stay Informed