A Phase II Study of Ad-RTS-hIL-12 + Veledimex in Combination with Cemiplimab-rwlc (Libtayo®) in Subjects with Recurrent or Progressive Glioblastoma

Protocol # :
Disease Sites
Brain and Nervous System
Principal Investigator
Chiocca, Ennio, A
Site Investigator
Alterman, Ron
Site Research Nurses
Anketell, Mary Beth
Bowers, Mary, Ellen
Chau, Johny, E.
Doherty, Lisa
Donohoe, Aisling
Iuliano, Sherry
Triggs, Daniel

Trial Description

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.

Cemiplimab-rwlc (Libtayo) 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. Libtayo
(cemiplimab-rwlc) is currently FDA approved in the United States for metastatic cutaneous
cell carcinoma (CSCC), but is not approved in glioblastoma. Cemiplimab-rwlc may help your
immune system detect and attack cancer cells. Ad-RTS-hIL-12 and veledimex will be given in
combination with cemiplimab-rwlc to enhance the IL-12 mediated effect observed to date.

The main purpose of this study is to evaluate the safety and efficacy of a single tumoral
injection of Ad-RTS-hIL-12 given with oral veledimex in combination with cemiplimab-rwlc.

Eligibility Requirements

Inclusion Criteria:

- Male or female subject ≥18 and ≤75 years of age

- 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

- Histologically confirmed glioblastoma from archival tissue

- 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.

- 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

- Able to undergo standard MRI scans with contrast agent before enrollment and after

- Karnofsky Performance Status ≥70

- 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

- 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**.

* 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.

** 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.

- 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

Exclusion Criteria:

- Radiotherapy treatment within 4 weeks of starting veledimex

- Prior treatment of disease with bevacizumab (NOTE: short use (< 4 doses) of
bevacizumab for controlling edema is allowed)

- Subjects receiving systemic corticosteroids for treatment of disease-related symptoms
during the 4 weeks prior to Day -7

- Subjects with clinically significant increased intracranial pressure (e.g., impending
herniation or requirement for immediate palliative treatment) or uncontrolled seizures

- Uncontrolled infection with human immunodeficiency virus, hepatitis B or hepatitis C
infection; or diagnosis of immunodeficiency. NOTE:

- 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.

- 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.

- 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.

- 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

- 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, except for
non-melanoma cancers of the skin or carcinoma in situ of the cervix or non-metastatic
prostate cancer

- Nursing or pregnant females

- Prior exposure to veledimex

- Use of an investigational product within prior 30 days.

- 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

- Use of medications that induce, inhibit, or are substrates of CYP450 3A4 prior to
veledimex dosing without consultation with the Medical Monitor

- Presence of any contraindication for a neurosurgical procedure

- 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.

- 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.