Glioblastoma
Conditions
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.
Interventions
BIOLOGICALAd-RTS-hIL-12
* 2.0 x 10\^11 viral particles (vp) per injection * intratumoral injection of Ad-RTS-hIL-12
DRUGveledimex
* 20mg/day * 15 oral daily doses of veledimex
Sponsors
Alaunos Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | From the first dose of study treatment until 30 days after the last dose of veledimex, lasting approximately 5 months. | 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. |
| 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 | Days 1 through 14 of each 21-day treatment cycle, over a total treatment period of up to 6 cycles (approximately 4 months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Determine the Overall Survival (OS) of Ad-RTS-hIL-12 + Veledimex | From the first dose of study drug for up to 2 years. | 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. |
| Veledimex Pharmacokinetic Profile: Maximum Plasma Concentration (Cmax) | 15 days | The maximum plasma concentration (Cmax) of veledimex |
| Veledimex Pharmacokinetic Profile: Area-under-the-concentration Versus Time Curve (AUC) | 15 days | 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. |
| Veledimex Pharmacokinetic Profile: Volume of Distribution (Vd) | 15 days | Volume of distribution (Vd) of veledimex. Vd was calculated using AUC approximated as described in the Outcome Measure Description for Outcome Measure 6. |
| Veledimex Pharmacokinetic Profile: Clearance (CL) | 15 days | Clearance (CL) of veledimex. CL was calculated using AUC approximated as described in the Outcome Measure Description for Outcome Measure 6. |
| Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Day 0 (at the time of tumor resection) | Veledimex concentration ratio was calculated based on the Day 0 tumor and plasma PK results. |
| Veledimex Pharmacokinetic Profile: Time to Maximum Plasma Concentration (Tmax) | 15 days | 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). |
| Progression Free Survival (PFS) | From the first dose of study drug for up to 2 years. | 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. |
| Rate of Pseudo-progression (PSP) | From the first dose of study drug for up to 2 years. | PSP Progression free survival was originally defined for determination of PSP requiring confirmation of progression based on RANO/iRANO criteria guidelines. |
| Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex | Baseline and Week 6. | Evaluation in changes in immune cell population markers, such as CD3 and CD8 in tumor |
| Peak Serum Concentration of Interleukin-12 (IL-12) | 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. | 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. |
| Peak Serum Concentration of Interferon-gamma (IFN-γ) | 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 | 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. |
| Tumor Objective Response Rate (ORR) | 48 weeks | 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. |
| Veledimex Pharmacokinetic Profile: Half-life (t1/2) | 15 days | Half-life (t1/2) of veledimex |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ad-RTS-hIL-12 + Veledimex Intratumoral Ad-RTS-hIL-12 and oral veledimex
Ad-RTS-hIL-12:
\- intratumoral injection of Ad-RTS-hIL-12
veledimex: - 20mg/day
\- 15 oral daily doses of veledimex | 36 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Investigator request | 1 |
Baseline characteristics
| Characteristic | Ad-RTS-hIL-12 + Veledimex |
|---|---|
| Age, Continuous | 52.1 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Height | 172.70 cm |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 28 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 22 Participants |
| Weight | 76.6 kg |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 36 |
| other Total, other adverse events | 36 / 36 |
| serious Total, serious adverse events | 10 / 36 |
Outcome results
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.
Time frame: From the first dose of study treatment until 30 days after the last dose of veledimex, lasting approximately 5 months.
Population: The Full Analysis Set (FAS): Overall Safety Population (OSP) includes all subjects who have received at least one dose of veledimex (pretumor resection and) and/or all subjects who received Ad-RTS-hIL-12.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex | 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. | Any TEAEs with Toxicity Grade ≥ 3 | 16 participants |
| Ad-RTS-hIL-12 + Veledimex | 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. | Any TEAEs | 36 participants |
| Ad-RTS-hIL-12 + Veledimex | 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. | Any Serious TEAEs | 10 participants |
| Ad-RTS-hIL-12 + Veledimex | 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. | Any TEAEs Leading to Treatment Dose Modification | 11 participants |
| Ad-RTS-hIL-12 + Veledimex | 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. | Any TEAEs Leading to Treatment Discontinuations | 1 participants |
| Ad-RTS-hIL-12 + Veledimex | 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. | Any TEAEs Leading to Death | 0 participants |
| Ad-RTS-hIL-12 + Veledimex | 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. | Any Drug-Related TEAEs | 24 participants |
| Ad-RTS-hIL-12 + Veledimex | 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. | Any Drug-Related Serious TEAEs | 4 participants |
| Ad-RTS-hIL-12 + Veledimex | 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. | Any Drug-Related TEAEs with Toxicity Grade ≥ 3 | 8 participants |
| Ad-RTS-hIL-12 + Veledimex | 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. | Any Drug-Related TEAEs Leading to Treatment Dose Modification | 9 participants |
| Ad-RTS-hIL-12 + Veledimex | 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. | Any Drug-Related TEAEs Leading to Treatment Discontinuations | 1 participants |
| Ad-RTS-hIL-12 + Veledimex | 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. | Any Drug-Related TEAEs Leading to Death | 0 participants |
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
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)
Population: The Full Analysis Set (FAS): Overall Safety Population (OSP) includes all subjects who have received at least one dose of veledimex (pretumor resection and) and/or all subjects who received Ad-RTS-hIL-12.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex | 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 | 100% Compliance | 22 Participants |
| Ad-RTS-hIL-12 + Veledimex | 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 | Less than 100% Compliance | 14 Participants |
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 CD3 and CD8 in tumor
Time frame: Baseline and Week 6.
Population: Due to the study's early termination and limited enrollment, a decision was made not to perform the planned immunohistochemistry (IHC) analyses on collected tumor biopsies. Therefore, no data are available for this endpoint, and zero subjects were analyzed. These analyses will not be performed in the future, and data for this outcome measure will not be reported.
Secondary
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.
Population: The Evaluable Safety Population (ESP) includes subjects who have received Ad-RTS-hIL-12 and at least one dose of veledimex after Ad-RTS-hIL-12 administration. The ESP is used for analysis of overall survival.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ad-RTS-hIL-12 + Veledimex | Determine the Overall Survival (OS) of Ad-RTS-hIL-12 + Veledimex | 10.68 Months |
Secondary
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
Population: The Evaluable Safety Population (ESP) includes subjects who have received Ad-RTS-hIL-12 and at least one dose of veledimex after Ad-RTS-hIL-12 administration. The ESP is denoted as the Per Protocol population in this uncontrolled setting.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex | Peak Serum Concentration of Interferon-gamma (IFN-γ) | 39.3 pg/mL | Standard Error 27.3 |
Secondary
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.
Population: The Evaluable Safety Population (ESP) includes subjects who have received Ad-RTS-hIL-12 and at least one dose of veledimex after Ad-RTS-hIL-12 administration. The ESP is denoted as the Per Protocol population in this uncontrolled setting.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex | Peak Serum Concentration of Interleukin-12 (IL-12) | 20.3 pg/mL | Standard Error 5.4 |
Secondary
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.
Population: The Evaluable Safety Population (ESP) includes subjects who have received Ad-RTS-hIL-12 and at least one dose of veledimex after Ad-RTS-hIL-12 administration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex | Progression Free Survival (PFS) | 52.17 Days | Standard Deviation 39.1 |
Secondary
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.
Population: The Evaluable Safety Population (ESP) includes subjects who have received Ad-RTS-hIL-12 and at least one dose of veledimex after Ad-RTS-hIL-12 administration. The ESP is denoted as the PP population in this uncontrolled setting.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ad-RTS-hIL-12 + Veledimex | Rate of Pseudo-progression (PSP) | 0 Participants |
Secondary
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
Population: The Evaluable Safety Population (ESP) includes subjects who have received Ad-RTS-hIL-12 and at least one dose of veledimex after Ad-RTS-hIL-12 administration. The Evaluable Safety Population (ESP) includes subjects who have received Ad-RTS-hIL-12 and at least one dose of veledimex after Ad-RTS-hIL-12 administration. The ESP is to be used for analysis of dose limiting toxicities, overall survival and progression free survival and finding the maximum tolerated dose.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex | Tumor Objective Response Rate (ORR) | No Response | 1 Participants |
| Ad-RTS-hIL-12 + Veledimex | Tumor Objective Response Rate (ORR) | Complete Response | 1 Participants |
| Ad-RTS-hIL-12 + Veledimex | Tumor Objective Response Rate (ORR) | Partial Response | 1 Participants |
| Ad-RTS-hIL-12 + Veledimex | Tumor Objective Response Rate (ORR) | Stable Disease | 27 Participants |
| Ad-RTS-hIL-12 + Veledimex | Tumor Objective Response Rate (ORR) | Progressive Disease | 6 Participants |
| Ad-RTS-hIL-12 + Veledimex | Tumor Objective Response Rate (ORR) | Not Evaluable | 0 Participants |
| Ad-RTS-hIL-12 + Veledimex | Tumor Objective Response Rate (ORR) | Missing | 0 Participants |
Secondary
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)
Population: All Subjects with available serum-time concentration data are included in the PK Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex | Veledimex Concentration Ratio Between the Brain Tumor and the Blood | 0.63 ratio | Standard Deviation 0.54 |
Secondary
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
Population: All subjects with available plasma-time concentration data post dose (steady state) on Day 14 and predose on Day 15 are included in the PK Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex | Veledimex Pharmacokinetic Profile: Area-under-the-concentration Versus Time Curve (AUC) | 771.4 ng*hr/mL | Standard Deviation 364.5 |
Secondary
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
Population: All Subjects with available plasma-time concentration data post dose on Day 14 and predose on Day 15 are included in the PK Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex | Veledimex Pharmacokinetic Profile: Clearance (CL) | 32.6 mL/hr | Standard Deviation 16.2 |
Secondary
Veledimex Pharmacokinetic Profile: Half-life (t1/2)
Half-life (t1/2) of veledimex
Time frame: 15 days
Population: All subjects with available plasma-time concentration data post dose (steady state) on Day 14 and predose on Day 15 are included in the PK Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex | Veledimex Pharmacokinetic Profile: Half-life (t1/2) | 16.4 hr | Standard Deviation 19.4 |
Secondary
Veledimex Pharmacokinetic Profile: Maximum Plasma Concentration (Cmax)
The maximum plasma concentration (Cmax) of veledimex
Time frame: 15 days
Population: All Subjects with available plasma-time concentration data post dose on Day 14 and predose on Day 15 are included in the PK Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex | Veledimex Pharmacokinetic Profile: Maximum Plasma Concentration (Cmax) | 68.69 ng/mL | Standard Deviation 41.95 |
Secondary
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
Population: All Subjects with available plasma-time concentration data post dose on Day 14 and predose on Day 15 are included in the PK Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex | Veledimex Pharmacokinetic Profile: Time to Maximum Plasma Concentration (Tmax) | 4.00 hr | Standard Deviation 1.16 |
Secondary
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
Population: 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. 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).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex | Veledimex Pharmacokinetic Profile: Volume of Distribution (Vd) | 683 mL | Standard Deviation 613 |