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

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ClinicalTrials.gov Identifier: NCT04006119
Recruitment Status : Recruiting
First Posted : July 2, 2019
Last Update Posted : August 15, 2019
Sponsor:
Information provided by (Responsible Party):
Ziopharm

Tracking Information
First Submitted Date  ICMJE June 28, 2019
First Posted Date  ICMJE July 2, 2019
Last Update Posted Date August 15, 2019
Actual Study Start Date  ICMJE August 1, 2019
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 1, 2019)
  • 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 ]
    Evaluation of adverse events as assessed by CTCAE v5.0 will be based on the incidence, intensity and type of adverse event.
  • Efficacy 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 ]
    Overall Survival
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT04006119 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 1, 2019)
  • To determine the survival rates at 6, 12, 18 and 24 months [ Time Frame: 6, 12, 18 and 24 months after completion of enrollment ]
  • To determine the progression free survival (PFS) [ Time Frame: 3.5yrs ]
  • 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 ]
  • 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 ]
  • 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 ]
  • Changes from baseline in cellular responses elicited by Ad-RTS-hIL-12 and veledimex in combination with cemiplimab-rwlc [ Time Frame: 3.5yrs ]
  • Changes from baseline in humoral immune responses elicited by Ad-RTS-hIL-12 and veledimex in combination with cemiplimab-rwlc [ Time Frame: 3.5yrs ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab in Subjects With Recurrent or Progressive Glioblastoma
Official Title  ICMJE A Phase II Study of Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc (Libtayo®) in Subjects With Recurrent or Progressive Glioblastoma
Brief Summary

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma
Intervention  ICMJE
  • Biological: Ad-RTS-hIL-12
    • intratumoral injection of Ad-RTS-hIL-12
    • 2.0 x 10^11 viral particles (vp) per injection
  • Drug: Veledimex
    20mg/day 15 oral daily doses of veledimex
  • Drug: Cemiplimab-Rwlc
    Infusion every 3 weeks (350mg)
    Other Names:
    • Libtayo
    • REGN2810
Study Arms  ICMJE Experimental: Ad-RTS-hIL-12 + veledimex in combination with cemiplimab-rwlc
Intratumoral Ad-RTS-hIL-12 and oral veledimex (activator ligand, 20mg) given in combination with cemiplimab-rwlc via infusion.
Interventions:
  • Biological: Ad-RTS-hIL-12
  • Drug: Veledimex
  • Drug: Cemiplimab-Rwlc
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 1, 2019)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 2022
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Nathan Demars 617-778-1081 ndemars@ziopharm.com
Contact: Erin Walsh 617-502-1883 ewalsh@ziopharm.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04006119
Other Study ID Numbers  ICMJE ATI001-204
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ziopharm
Study Sponsor  ICMJE Ziopharm
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Arnold Gelb, M.D. Ziopharm
PRS Account Ziopharm
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP