human stem cell derived neurons

Study of Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab in Subjects With Recurrent or Progressive Glioblastoma

Summary

This phase II clinical trial will evaluate the safety and efficacy of a single tumoral injection of Ad-RTS-hIL-12 in combination with veledimex and cemiplimab-rwlc for treating 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.

Cemiplimab-rwlc (also called Libtayo) is an antibody-based drug that targets the immune system and activates it to stop cancer growth and/or kill cancer cells. More specifically, cemiplimab works by binding and inhibiting PD-1, a protein that normally protects the body from attacking itself. Normally, PD-1 works by detecting a molecular signal (called PDL-1) made by various cells across the body. Some cancer cells take advantage of this protection mechanism making the protective signal themselves. Blocking PD-1 with cemiplimab-rwlc allows the immune system to activate its T-cells and recognize these tumors as cells to be attacked; this may enhance the effect of Ad-RTS-hIL-12 and veledimex. Cemiplimab-rwlc is currently FDA approved for some cancers, but not yet approved in glioblastoma. 

This phase II study will evaluate Ad-RTS-hIL-12 and veledimex in combination with cemiplimab-rwlc for treating patients with recurrent glioblastoma. All eligible participants will receive the following treatment: 

  • Experimental Group: Ad-RTS-hIL-12 + veledimex + cemiplimab-rwlc 

 

Inclusion Criteria
  1. Male or female subject ≥18 and ≤75 years of age
  2. Provision of written informed consent for tumor resection (subtotal allowed), tumor biopsy, samples collection, and treatment with investigational products prior to undergoing any study-specific procedures
  3. Histologically confirmed glioblastoma from archival tissue
  4. Evidence of tumor recurrence/progression by magnetic resonance imaging (MRI) according to Response Assessment in Neuro-Oncology (RANO) criteria after standard initial therapy. Multifocal disease is allowed.
  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. Nitrosoureas: 6 weeks
    2. Other cytotoxic agents: 4 weeks
    3. Antiangiogenic agents: 4 weeks
    4. Targeted agents, including small molecule tyrosine kinase inhibitors: 2 weeks
    5. Vaccine-based or CAR-T 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
    7. Total bilirubin <1.5 x ULN
    8. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) within normal institutional limits
  9. Female of child bearing potential* and sexually active male subjects must agree to practice highly effective contraception prior to the start of the first treatment, during the study, and for at least 4 months after the last dose. Highly effective contraceptive measures include stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal ligation; vasectomized partner; and or sexual abstinence**.
  10. * Postmenopausal women must be amenorrhoeic for at least 12 months in order not to be considered of childbearing potential. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.
  11. ** Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.

  12. Normal cardiac and pulmonary function as evidenced by a normal ECG with QTc ≤450 msec and peripheral oxygen saturation (SpO2) ≥92% on room air by pulse oximetry

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

Exclusion Criteria
  1. Radiotherapy treatment within 4 weeks of starting veledimex
  2. Prior treatment of disease with bevacizumab (NOTE: short use (< 4 doses) of bevacizumab for controlling edema is allowed)
  3. Subjects receiving systemic corticosteroids for treatment of disease-related symptoms during the 4 weeks prior to Day -7
  4. Subjects with clinically significant increased intracranial pressure (e.g., impending herniation or requirement for immediate palliative treatment) or uncontrolled seizures
  5. Uncontrolled infection with human immunodeficiency virus, hepatitis B or hepatitis C infection; or diagnosis of immunodeficiency. NOTE:
    1. Subjects with known HIV infection who have controlled infection (undetectable viral load (HIV RNA PCR) and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted. For Subjects with controlled HIV infection, monitoring will be performed per local standards.
    2. Subjects with hepatitis B (HBsAg+) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted. Subjects with controlled infections must undergo periodic monitoring of HBV DNA. Patients must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug.
    3. Subjects who are hepatitis C virus antibody positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted.
  6. 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.
  7. 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.
  8. Other concurrent clinically active malignant disease, requiring treatment, except for non-melanoma cancers of the skin or carcinoma in situ of the cervix or non-metastatic prostate cancer
  9. Nursing or pregnant females
  10. Prior exposure to veledimex
  11. Use of an investigational product within prior 30 days.
  12. Prior exposure to inhibitors of immuno-checkpoint pathways (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody) or other agents specifically targeting T cells
  13. Use of medications that induce, inhibit, or are substrates of CYP450 3A4 prior to veledimex dosing without consultation with the Medical Monitor
  14. Presence of any contraindication for a neurosurgical procedure
  15. Use of heparin or other anti-coagulation therapy, or acetylsalicylic acid (ASA), or anti-platelet drug within Day -7 to Day 21 should not be used unless necessary to treat a life-threatening illness. Prophylactic subcutaneous heparin per institutional protocol for prevention of deep vein thrombosis (DVT) may be allowed based on discussion with the Medical Monitor. Concomitant medications should continue to be reviewed in consultation with the Medical Monitor.
  16. Unstable or clinically significant 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, a history of myocarditis or congestive heart failure (as defined by New York Heart Association Functional Class III or IV), unstable angina, serious uncontrolled cardiac arrythmia, myocardial infarction within 6 months of screening, active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids uncontrolled asthma, or colitis.

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

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