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.
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
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
36
* 2.0 x 10\^11 viral particles (vp) per injection * intratumoral injection of Ad-RTS-hIL-12
* 20mg/day * 15 oral daily doses of veledimex
Cedars-Sinai Medical Center
Los Angeles, California, United States
Northwestern Memorial Hospital
Chicago, Illinois, United States
NYU - Langone Health
New York, New York, United States
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
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.
Time frame: From the first dose of study treatment until 30 days after the last dose of veledimex, lasting approximately 5 months.
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
The Day 0 (as applicable), and Day 1 doses of veledimex were administered by study personnel at the study center. Thereafter, subjects could self-administer the remaining once daily dose of veledimex. Subjects were instructed to document veledimex dosing compliance in a subject diary, including the time each dose was taken, the time the subject ate the last meal prior to administration of veledimex, the number of capsules taken, whether the subject missed any veledimex doses, and reason for any missed doses. Investigational product container(s) with any remaining capsules were returned to the study staff on Day 15, and staff assessed dose compliance.
Time frame: Days 1 through 14 of each 21-day treatment cycle, over a total treatment period of up to 6 cycles (approximately 4 months)
Determine the Overall Survival (OS) of Ad-RTS-hIL-12 + Veledimex
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.
Time frame: From the first dose of study drug for up to 2 years.
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Veledimex Pharmacokinetic Profile: Maximum Plasma Concentration (Cmax)
The maximum plasma concentration (Cmax) of veledimex
Time frame: 15 days
Veledimex Pharmacokinetic Profile: Time to Maximum Plasma Concentration (Tmax)
Time to maximum plasma concentration (Tmax) of veledimex. Tmax was estimated based on time of maximum concentration (Cmax) from predose (Day 0 or 14) to predose the following day (Day 1 or 15).
Time frame: 15 days
Veledimex Pharmacokinetic Profile: Half-life (t1/2)
Half-life (t1/2) of veledimex
Time frame: 15 days
Veledimex Pharmacokinetic Profile: Area-under-the-concentration Versus Time Curve (AUC)
Area-under-the-concentration versus time curve (AUC) of veledimex from Day 14 predose to Day 15 predose. AUC was estimated using the elimination rate constant k, where k = ln(Cmax/Ctrough)/time difference and AUC is approximately Cmax/k.
Time frame: 15 days
Veledimex Pharmacokinetic Profile: Volume of Distribution (Vd)
Volume of distribution (Vd) of veledimex. Vd was calculated using AUC approximated as described in the Outcome Measure Description for Outcome Measure 6.
Time frame: 15 days
Veledimex Pharmacokinetic Profile: Clearance (CL)
Clearance (CL) of veledimex. CL was calculated using AUC approximated as described in the Outcome Measure Description for Outcome Measure 6.
Time frame: 15 days
Veledimex Concentration Ratio Between the Brain Tumor and the Blood
Veledimex concentration ratio was calculated based on the Day 0 tumor and plasma PK results.
Time frame: Day 0 (at the time of tumor resection)
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. Overall Response was assessed at multiple timepoints (day 56, week 16, week 24, and week 48) by the study investigators. Changes to the original plan for exploration of estimates of efficacy are summarized below. • The best overall response (BOR) endpoint was added to the efficacy assessment and reported here.
Time frame: 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.
Time frame: From the first dose of study drug for up to 2 years.
Rate of Pseudo-progression (PSP)
PSP Progression free survival was originally defined for determination of PSP requiring confirmation of progression based on RANO/iRANO criteria guidelines.
Time frame: From the first dose of study drug for up to 2 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 CD3 and CD8 in tumor
Time frame: Baseline and Week 6.
Peak Serum Concentration of Interleukin-12 (IL-12)
Serum concentrations of IL-12 were measured at multiple timepoints post-dose. For each participant, the peak (maximum) concentration observed from Day 3 through the 30-day follow-up visit was identified. This measure summarizes the mean of those individual peak concentrations.
Time frame: Samples were collected at Baseline (Day 1), Day 3, Day 8, and Day 15 of Cycle 1, and at the 30-day follow-up visit.
Peak Serum Concentration of Interferon-gamma (IFN-γ)
Serum concentrations of IFN-γ were measured at multiple timepoints post-dose. For each participant, the peak (maximum) concentration observed from Day 3 through the 30-day follow-up visit was identified. This measure summarizes the mean of those individual peak concentrations.
Time frame: Samples were collected at Baseline (Day 1), Day 3, Day 8, and Day 15 of Cycle 1, and at the 30-day follow-up visit