A Study of Ad-RTS-hIL-12 With Veledimex in Subjects With Glioblastoma or Malignant Glioma

A Phase I Study of Ad-RTS-hIL-12, an Inducible Adenoviral Vector Engineered to Express hIL-12 in the Presence of the Activator Ligand Veledimex in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma

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.

The main purpose of this study is to evaluate the safety and tolerability of a single tumor injection of Ad-RTS-hIL-12 given with oral veledimex.

Study Overview

• Status: Completed
• Conditions: Glioblastoma Multiforme; Anaplastic Oligoastrocytoma
• Intervention / Treatment: Biological: Ad-RTS-hIL-12; Drug: veledimex

Detailed Description

Eligible patients will be stratified to one of two groups, according to clinical indication for tumor resection. Patients who are scheduled for a standard of care craniotomy and tumor resection 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.

Patients not scheduled for tumor resection will receive Ad-RTS-hIL-12 by stereotactic injection and then will continue on oral veledimex for 14 days.

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

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai
    • San Francisco, California, United States, 94143
      • University of California - San Francisco
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women's
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female subjects ≥ 18 and ≤ 75 years of age
2. Provision of written informed consent for tumor resection, stereotactic surgery, tumor biopsy, samples collection and treatment with investigational products prior to undergoing any study procedures
3. Histologically confirmed supratentorial glioblastoma or other WHO grade III or IV malignant glioma from archival tissue.
4. Evidence of tumor recurrence/progression by MRI (RANO criteria) post standard initial therapy.

5. Previous standard of care anti-tumor treatment including surgery and/or biopsy and chemoradiation. The washout periods from prior therapies are intended as follows:

   1. Nitrosoureas: 6 weeks
   2. Other cytotoxic agents: 4 weeks
   3. Anti-angiogenic agents including bevacizumab: 4 weeks
   4. Targeted agents including small-molecule tyrosine kinase inhibitors: 2 weeks
   5. Experimental immunotherapies: 3 months
   6. Vaccine based therapy: 3 months
6. Able to undergo standard MRI scans with contrast agent
7. Karnofsky Performance Status ≥ 70

8. 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 ULN
   6. AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN. For subjects with documented liver metastases, ALT and AST ≤ 5 × ULN
   7. Total bilirubin < 1.5 x ULN
   8. International Normalized Ratio (INR) and activated Partial Thromboplastin Time [PTT] within normal institutional limits
9. Male and female subjects must agree to use a highly reliable method of birth control (expected failure rate less than 5% per year) from the screening visit through 28 days after the last dose of study drug. Women of childbearing potential must have a negative pregnancy test at screening.

Exclusion Criteria:

1. Radiotherapy within 4 weeks or less prior to starting first veledimex dose
2. Subjects with clinically significant increased intracranial pressure or uncontrolled seizures.
3. Known immunosuppressive disease, autoimmune conditions, and /or chronic viral infections
4. Use of systemic antibacterials, antifungals or antivirals 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 permitted perioperatively.
5. Use of enzyme-inducing anti-epileptic drugs (EIAED) within 7 days prior to the first dose of study drug.
6. 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 non-metastatic prostate cancer.
7. Nursing or pregnant females
8. Prior exposure to veledimex
9. Use of medications that induce, inhibit or are substrates of CYP450 3A4 within 7 days prior to the first veledimex dosing
10. Presence of any contra-indication for a neurosurgical procedure
11. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ad-RTS-hIL-12+veledimex; varying doses of intratumoral Ad-RTS-hIL-12 (INXN-2001) and oral veledimex (activator ligand).	Biological: Ad-RTS-hIL-12; 2.0 x 10^11 viral particles (vp) per injection or 1.0 x 10^12 viral particles (vp) per injection; one intratumoral injection of Ad-RTS-hIL-12; Other Names: INXN-2001; Drug: veledimex; 4 doses (20mg/day, 40mg/day, 80mg/day, and 120mg/day); 14 oral daily doses of veledimex; 1 Expansion cohort at a single dose level at or below MTD; Other Names: INXN-1001; Activator Ligand

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma	Evaluation will be based on the incidence, intensity, and type of Adverse Events (AEs). Clinically significant changes in the subjects' physical examinations, vital signs, and ECG evaluations, and clinical manifestations relevant to abnormal laboratory values will be captured as AEs.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12	The protocol defined the MTD as the dose level below at which less than 33% of subjects, of the same cohort in a group, experienced DLTs, with an independent assessment of Group 1 and Group 2 subjects. • The number of DLTs and the proportion of subjects with any DLT and each type of DLT were summarized by veledimex dose within each group.	3 years
Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood	From the protocol: Veledimex PK parameters to be determined will include, but are not limited to, the maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), half-life (t1/2), area-under-the-concentration versus time curve (AUC), volume of distribution (Vd), and clearance (CL). From the SAP: The PK blood sample collection was performed either pre-dose or 3-5 hours post-dose, therefore only Cmax and Ctrough will be summarized and plotted. Veledimex concentration ratio between brain tumor and blood will be assessed on Day 0 samples. There will be no parameters including time to maximum plasma concentration (Tmax), half-life (t1/2), area under the curve (AUC), volume of distribution (Vd), and clearance (CL). Cmax will be determined from the maximum plasma concentration from Day 0 (post veledimex and resection/craniotomy), 3-5 hours after the veledimex dose on Day 1, and 3-5 hours after the veledimex dose on Day 14.	15 days
Cellular and Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex	Peak serum IL-12 and I downstream IFN-gamma expressions between Day 3 to Day 28 are reported by dose cohort.	28 days
Tumor Objective Response Rate (ORR)	For the ORR calculation, responders are defined as those experiencing a confirmed complete response or confirmed partial response. Non-responders are those either with stable or progressive disease. Those subjects that cannot be assessed will be treated as non-responders for the purposes of deriving the percentage of responders and confidence intervals. The ORR is reported overall by treatment arm based on the investigator response at timepoints 56 days, Week 16, Week 24, and Week 48.	48 weeks
Progression-free Survival (PFS)	PFS (progression free survival) is the time in months from the first treatment (either veledimex or Ad-RTS-hIL-12) to the first assessment on which the overall response is reported as disease progression. Subjects withdrawing from the study will be censored at their last non progressive disease response assessment. If a subject does not have a non-progressive disease response assessment, the subject will be censored on the date of the first treatment as described above.	3 years
Overall Survival (OS)	OS is defined as the duration of time from the first dose of study drug (Day 0) to the date of death from any cause in days or months. Subjects are censored based on the last date known to be alive. For example: Subjects who discontinue the study without documentation of additional follow-up will be censored at the date of discontinuation.; Subjects who are lost to follow-up will be censored at last follow-up contact date.; Subjects still alive up to 2 years from the first dose of study drug are classified as censored and as having completed all follow-up scheduling.	6, 9, 12, 15, 18, and 24 months
Veledimex Concentration Ratio Between the Brain Tumor and the Blood	From the protocol: Veledimex PK parameters to be determined will include, but are not limited to, the maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), half-life (t1/2), area-under-the-concentration versus time curve (AUC), volume of distribution (Vd), and clearance (CL). From the SAP: The PK blood sample collection was performed either pre-dose or 3-5 hours post-dose, therefore only Cmax and Ctrough will be summarized and plotted. Veledimex concentration ratio between brain tumor and blood will be assessed on Day 0 samples. There will be no parameters including time to maximum plasma concentration (Tmax), half-life (t1/2), area under the curve (AUC), volume of distribution (Vd), and clearance (CL). Cmax will be determined from the maximum plasma concentration from Day 0 (post veledimex and resection/craniotomy), 3-5 hours after the veledimex dose on Day 1, and 3-5 hours after the veledimex dose on Day 14.	15 days

Collaborators and Investigators

• Sponsor: Alaunos Therapeutics
• Investigators: Study Director: Jaymes Holland, Alaunos Therapeutics

Publications and helpful links

General Publications

• Chiocca EA, Yu JS, Lukas RV, Solomon IH, Ligon KL, Nakashima H, Triggs DA, Reardon DA, Wen P, Stopa BM, Naik A, Rudnick J, Hu JL, Kumthekar P, Yamini B, Buck JY, Demars N, Barrett JA, Gelb AB, Zhou J, Lebel F, Cooper LJN. Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial. Sci Transl Med. 2019 Aug 14;11(505):eaaw5680. doi: 10.1126/scitranslmed.aaw5680.

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): August 1, 2019
• Study Completion (Actual): August 1, 2019

Study Registration Dates

• First Submitted: December 16, 2013
• First Submitted That Met QC Criteria: December 30, 2013
• First Posted (Estimated): January 1, 2014

Study Record Updates

• Last Update Posted (Actual): April 16, 2025
• Last Update Submitted That Met QC Criteria: March 27, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Glioma
• Other Study ID Numbers: ATI001-102

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No