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

Phase 2

Terminated

• Conditions: Glioblastoma
• Interventions: Biological: Ad-RTS-hIL-12; Drug: Veledimex; Drug: Cemiplimab-Rwlc

• Registration Number: NCT04006119
• Lead Sponsor: Alaunos Therapeutics

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 Timeline

• Study First Submitted: 2019-06-28
• Study First Submitted QC: 2019-07-01
• Study First Posted: 2019-07-02
• Study Start: 2019-08-01
• Primary Completion: 2021-08-05
• Study Completion: 2021-08-05
• Results First Submitted: 2025-02-21
• Status Verified: 2025-03
• Results First Submitted QC: 2025-03-31
• Last Update Submitted: 2025-03-31
• Results First Posted: 2025-04-18
• Last Update Posted: 2025-04-18

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 40

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Efficacy of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma.	2.0 yrs	Overall Survival (OS); OS is defined as the duration of time from the first dose of study drug (i.e., cemiplimab at Day -7) to the date of death from any cause. Censoring will be considered as below: * Subjects who discontinue study will be censored at date of discontinuation.; * Subjects who are lost to follow-up will be censored at last follow-up contact date.; * If the subject has not died, the subject is censored if still alive up to 2 years from the first dose of study drug received.
Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma.	2.0 yrs	Evaluation of adverse events as assessed by CTCAE v5.0 will be based on the incidence, intensity and type of adverse event. Safety evaluations included the observed incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs of toxicity Grade \>3, TEAEs leading to treatment dose modification, discontinuation, and death. Drug-related TEAEs were also assessed.

Secondary Outcome Measures

Name	Time	Method
To Determine the Survival Rates at 6, 12, and 18 Months	From Day 0 through 18 months post first dose of study treatment	Given the early closure of the study and survival follow-up data limited to one year post last patient in, complete assessment of efficacy could not be determined. Number of participants with death prior to each time point (6, 12, and 18 months) is reported here.
To Determine the Progression Free Survival (PFS)	2.0 yrs	Given the early closure of the study, formal assessment of PFS using Kaplan Meier Product-Line method was not performed. Mean time to disease progression (or participant's last scan) is reported here.
To Determine the Rate of Pseudoprogression (PSP) at 6, 12, 18 and 24 Months	2 years	Given the early closure of the study complete assessment of efficacy could not be determined. Reported below is the PSP at anytime while on study.
To Determine the Investigator's Assessment of Response, Including Tumor Objective Response Rate (ORR) at 6, 12, 18 and 24 Months	2 years	Tumor response will be defined by radiographic and clinical criteria. Complete response (CR) or partial response (PR) will be first assessed by radiographic changes that indicate a reduction of bi-dimensional tumor size as per Recist 1.1 criteria. In addition, changes in neurologic function and steroid use will be considered to determine stable disease (SD).Given the early closure of the study complete assessment of efficacy could not be determined. The results below report response at anytime while on study.
To Determine the Tumor Response Rates at 6, 12, 18 and 24 Months	2 years	Given the early closure of the study and survival follow-up data limited to one year post last patient in, complete assessment of efficacy could not be determined. The IRANO results below report response at anytime while on study.
Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc	Screening through Day 28 (assessed at Screening and Days 0, 1, 3, 7, 14, and 28)	Immune cell population markers, such as cluster of differentiation (CD) antigens CD3+CD4+ and CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo-, were assessed.
Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc	Screening through Day 28 (assessed at Screening and Days 0, 1, 3, 7, 14, and 28)	Immunological and biological markers, such as levels of interleukin-12 (IL-12) and interferon gamma (IFN-γ) were assessed in serum samples.

Trial Locations

Locations (7)

Cedars Sinai; 🇺🇸 Los Angeles, California, United States

Baptist MD Anderson Cancer Center; 🇺🇸 Jacksonville, Florida, United States

University of California - San Francisco; 🇺🇸 San Francisco, California, United States

Northwestern Memorial Hospital; 🇺🇸 Chicago, Illinois, United States

Brigham and Women's; 🇺🇸 Boston, Massachusetts, United States

JFK Medical Center; 🇺🇸 Edison, New Jersey, United States

NYU Langone Health; 🇺🇸 New York, New York, United States