Clinical trial NCT03679754: Evaluation of Ad-RTS-hIL-12 + Veledimex in Subjects With Recurrent or Progressive Glioblastoma, a Substudy to ATI001-102
Official title: Protocol ATI001-102 Expansion Substudy: Evaluation of Ad-RTS-hIL-12 + Veledimex in Subjects With Recurrent or Progressive Glioblastoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Glioblastoma
Lead sponsor: Alaunos Therapeutics
Sponsor class: INDUSTRY
First posted: 2018-09-20
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: 3 years
measure: 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
timeFrame: 3 years
Secondary outcomes:
measure: Determine the overall survival (OS) of Ad-RTS-hIL-12 + veledimex
timeFrame: 3 years
measure: Veledimex pharmacokinetic profile: maximum plasma concentration (Cmax)
timeFrame: 3 years
measure: Veledimex pharmacokinetic profile: Time to maximum plasma concentration (Tmax)
timeFrame: 3 years
measure: Veledimex pharmacokinetic profile: Half-life (t1/2)
timeFrame: 3 years
measure: Veledimex pharmacokinetic profile: Area-under-the-concentration versus time curve (AUC)
timeFrame: 3 years
measure: Veledimex pharmacokinetic profile: Volume of distribution (Vd)
timeFrame: 3 years
measure: Veledimex pharmacokinetic profile: Clearance (CL)
timeFrame: 3 years
measure: Veledimex concentration ratio between the brain tumor and the blood
timeFrame: 3 years
measure: Tumor objective response rate (ORR)
timeFrame: 3 years
measure: Progression free survival (PFS)
timeFrame: 3 years
measure: Rate of pseudo-progression (PSP)
timeFrame: 3 years
measure: Changes from baseline in cellular responses elicited by Ad-RTS-hIL-12 and veledimex
timeFrame: 3 years
measure: Changes from baseline in humoral immune responses elicited by Ad-RTS-hIL-12 and veledimex
timeFrame: 3 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: New York
country: United States
facility: NYU - Langone Health
state: New York
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Ziopharm Oncology Inc.
name: Arnold Gelb, MD
role: STUDY_DIRECTOR
References: