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

NCT03636477

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. 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.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of Ad-RTS-hIL-12 With Veledimex in Combination With Nivolumab in Subjects With Glioblastoma; a Substudy to ATI001-102
  • Official Title: Protocol ATI001-102 Substudy: Evaluation of Ad-RTS-hIL-12 + Veledimex in Combination With Nivolumab in Subjects With Recurrent or Progressive Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: ATI001-102 CPI Substudy 1.0
  • NCT ID: NCT03636477

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
Ad-RTS-hIL-12Ad-RTS-hIL-12 + veledimex in combination with nivolumab
veledimexAd-RTS-hIL-12 + veledimex in combination with nivolumab
NivolumabOpdivoAd-RTS-hIL-12 + veledimex in combination with nivolumab

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. 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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Ad-RTS-hIL-12 + veledimex in combination with nivolumabExperimentalIntratumoral Ad-RTS-hIL-12 and varying doses of oral veledimex (activator ligand) given in combination with nivolumab via infusion.
  • Ad-RTS-hIL-12
  • veledimex
  • Nivolumab

Eligibility Criteria

        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)

               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

          -  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. 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

          -  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.
      
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 doses in combination with nivolumab in subjects with recurrent or progressive glioblastoma.
Time Frame:3.5 years
Safety Issue:
Description:Evaluation of adverse events as assessed by CTCAE v4.03 will be based on the incidence, intensity and type of adverse event.

Secondary Outcome Measures

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

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Ziopharm

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