Clinical Trials /

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

NCT04006119

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.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab in Subjects With Recurrent or Progressive Glioblastoma
  • Official Title: A Phase II Study of Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc (Libtayo®) in Subjects With Recurrent or Progressive Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: ATI001-204
  • NCT ID: NCT04006119

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
Ad-RTS-hIL-12Ad-RTS-hIL-12 + veledimex in combination with cemiplimab-rwlc
VeledimexAd-RTS-hIL-12 + veledimex in combination with cemiplimab-rwlc
Cemiplimab-RwlcLibtayo, REGN2810Ad-RTS-hIL-12 + veledimex in combination with cemiplimab-rwlc

Purpose

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.

Detailed Description

      Eligible patients will receive one dose of cemiplimab-rwlc, 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 cemiplimab-rwlc via infusion every three
      weeks.

      The study is divided into three periods: the screening period, the treatment period and the
      follow-up period.
    

Trial Arms

NameTypeDescriptionInterventions
Ad-RTS-hIL-12 + veledimex in combination with cemiplimab-rwlcExperimentalIntratumoral Ad-RTS-hIL-12 and oral veledimex (activator ligand, 20mg) given in combination with cemiplimab-rwlc via infusion.
  • Ad-RTS-hIL-12
  • Veledimex
  • Cemiplimab-Rwlc

Eligibility Criteria

        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
             treatment

          -  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
             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, 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.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety of intratumoral Ad-RTS-hIL-12 and oral veledimex in combination with cemiplimab-rwlc in subjects with recurrent or progressive glioblastoma.
Time Frame:3.5yrs
Safety Issue:
Description:Evaluation of adverse events as assessed by CTCAE v5.0 will be based on the incidence, intensity and type of adverse event.

Secondary Outcome Measures

Measure:To determine the survival rates at 6, 12, 18 and 24 months
Time Frame:6, 12, 18 and 24 months after completion of enrollment
Safety Issue:
Description:
Measure:To determine the progression free survival (PFS)
Time Frame:3.5yrs
Safety Issue:
Description:
Measure:To determine the rate of pseudoprogression (PSP) at 6, 12, 18 and 24 months
Time Frame:6, 12, 18 and 24 months after completion of enrollment
Safety Issue:
Description:
Measure:To determine the Investigator's assessment of response, including tumor objective response rate (ORR) at 6, 12, 18 and 24 months
Time Frame:6, 12, 18 and 24 months after completion of enrollment
Safety Issue:
Description:
Measure:To determine the tumor response rates at 6, 12, 18 and 24 months
Time Frame:6, 12, 18 and 24 months after completion of enrollment
Safety Issue:
Description:
Measure:Changes from baseline in cellular responses elicited by Ad-RTS-hIL-12 and veledimex in combination with cemiplimab-rwlc
Time Frame:3.5yrs
Safety Issue:
Description:
Measure:Changes from baseline in humoral immune responses elicited by Ad-RTS-hIL-12 and veledimex in combination with cemiplimab-rwlc
Time Frame:3.5yrs
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Ziopharm

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