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

Glioblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03679754
• Other study ID #: ATI001-102 EXP Substudy 2.0
• Status: Completed
• Phase: Phase 1
• Start date: September 5, 2018
• Est. completion date: January 19, 2021

Study information

• Verified date: September 2021
• Source: Ziopharm
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: January 19, 2021
• Est. primary completion date: April 2, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Glioblastoma

Intervention

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

Locations

Country	Name	City	State
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	NYU - Langone Health	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Ziopharm

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Determine the overall survival (OS) of Ad-RTS-hIL-12 + veledimex		3 years
Secondary	Veledimex pharmacokinetic profile: maximum plasma concentration (Cmax)	The maximum plasma concentration (Cmax)	3 years
Secondary	Veledimex pharmacokinetic profile: Time to maximum plasma concentration (Tmax)	Time to maximum plasma concentration (Tmax)	3 years
Secondary	Veledimex pharmacokinetic profile: Half-life (t1/2)	Half-life (t1/2)	3 years
Secondary	Veledimex pharmacokinetic profile: Area-under-the-concentration versus time curve (AUC)	Area-under-the-concentration versus time curve (AUC)	3 years
Secondary	Veledimex pharmacokinetic profile: Volume of distribution (Vd)	Volume of distribution (Vd)	3 years
Secondary	Veledimex pharmacokinetic profile: Clearance (CL)	Clearance (CL)	3 years
Secondary	Veledimex concentration ratio between the brain tumor and the blood		3 years
Secondary	Tumor objective response rate (ORR)		3 years
Secondary	Progression free survival (PFS)		3 years
Secondary	Rate of pseudo-progression (PSP)		3 years
Secondary	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
Secondary	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