Evaluation of Ad-RTS-hIL-12 + Veledimex in Subjects With Recurrent or Progressive Glioblastoma, a Substudy to ATI001-102

Protocol ATI001-102 Expansion Substudy: Evaluation of Ad-RTS-hIL-12 + Veledimex in Subjects With Recurrent or Progressive Glioblastoma

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 intratumoral injection of Ad-RTS-hIL-12 given with oral veledimex.

Study Overview

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

Detailed Description

Patients who are scheduled for 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.

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

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
  • New York
    • New York, New York, United States, 10016
      • NYU - Langone Health
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female subject ≥18 and ≤75 years of age
• Provision of written informed consent for tumor resection, tumor biopsy, samples collection, and treatment with investigational products prior to undergoing any study specific procedures
• Histologically confirmed glioblastoma
• Evidence of supratentorial 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: 4 weeks (NOTE: short use (< 4 doses) of bevacizumab for controlling edema is allowed)
  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 activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) 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

Exclusion Criteria:

• Previous treatment with bevacizumab for their disease (NOTE: short use (< 4 doses) of bevacizumab for controlling edema is allowed)
• Subjects receiving systemic corticosteroids during the previous 4 weeks
• Radiotherapy treatment within 4 weeks of starting veledimex
• 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 CYP4503A4 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 may include, but are not limited to, colitis, pneumonitis, unstable angina, congestive heart failure, myocardial infarction within 2 months of screening, and ongoing maintenance therapy for life-threatening ventricular arrhythmia or uncontrolled asthma

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Ad-RTS-hIL-12 + veledimex; Intratumoral Ad-RTS-hIL-12 and oral veledimex	Biological: Ad-RTS-hIL-12; 2.0 x 10^11 viral particles (vp) per injection; intratumoral injection of Ad-RTS-hIL-12; Drug: veledimex; 20mg/day; 15 oral daily doses of veledimex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of intratumoral Ad-RTS-hIL-12 and oral veledimex in subjects with recurrent or progressive glioblastoma based on evaluation of adverse events summarized by incidence, intensity and type of adverse event.	Evaluation of adverse events as assessed by CTCAE v4.03. Adverse events will be summarized based on the incidence, intensity and type of adverse event.	3 years
Tolerability of intratumoral Ad-RTS-hIL-12 and oral veledimex in subjects with recurrent or progressive glioblastoma will be assessed based on expected dose compliance	Evaluation will be based on expected dose compliance	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the overall survival (OS) of Ad-RTS-hIL-12 + veledimex		3 years
Veledimex pharmacokinetic profile: maximum plasma concentration (Cmax)	The maximum plasma concentration (Cmax)	3 years
Veledimex pharmacokinetic profile: Time to maximum plasma concentration (Tmax)	Time to maximum plasma concentration (Tmax)	3 years
Veledimex pharmacokinetic profile: Half-life (t1/2)	Half-life (t1/2)	3 years
Veledimex pharmacokinetic profile: Area-under-the-concentration versus time curve (AUC)	Area-under-the-concentration versus time curve (AUC)	3 years
Veledimex pharmacokinetic profile: Volume of distribution (Vd)	Volume of distribution (Vd)	3 years
Veledimex pharmacokinetic profile: Clearance (CL)	Clearance (CL)	3 years
Veledimex concentration ratio between the brain tumor and the blood		3 years
Tumor objective response rate (ORR)		3 years
Progression free survival (PFS)		3 years
Rate of pseudo-progression (PSP)		3 years
Changes from baseline in cellular responses elicited by Ad-RTS-hIL-12 and veledimex	Evaluation in changes in immune cell population markers, such as, but not limited to CD3, CD4 and CD8 in peripheral blood and tumor	3 years
Changes from baseline in humoral immune responses elicited by Ad-RTS-hIL-12 and veledimex	Evaluation of changes in levels of immunological and biological markers, such as, but not limited to IL-12 and IFN-gamma in peripheral serum samples	3 years

Collaborators and Investigators

• Sponsor: Alaunos Therapeutics
• Investigators: Study Director: Arnold Gelb, MD, Ziopharm Oncology Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 5, 2018
• Primary Completion (ACTUAL): April 2, 2019
• Study Completion (ACTUAL): January 19, 2021

Study Registration Dates

• First Submitted: August 29, 2018
• First Submitted That Met QC Criteria: September 19, 2018
• First Posted (ACTUAL): September 20, 2018

Study Record Updates

• Last Update Posted (ACTUAL): September 22, 2021
• Last Update Submitted That Met QC Criteria: September 21, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma
• Other Study ID Numbers: ATI001-102 EXP Substudy 2.0

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No