Anaplastic Oligoastrocytoma, Glioblastoma Multiforme
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 tumor injection of Ad-RTS-hIL-12 given with oral veledimex.
Detailed description
Eligible patients will be stratified to one of two groups, according to clinical indication for tumor resection. Patients who are scheduled for a standard of care 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. Patients not scheduled for tumor resection will receive Ad-RTS-hIL-12 by stereotactic injection and then 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 or 1.0 x 10\^12 viral particles (vp) per injection * one intratumoral injection of Ad-RTS-hIL-12
DRUGveledimex
* 4 doses (20mg/day, 40mg/day, 80mg/day, and 120mg/day) * 14 oral daily doses of veledimex * 1 Expansion cohort at a single dose level at or below MTD
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
1. Male or female subjects ≥ 18 and ≤ 75 years of age 2. Provision of written informed consent for tumor resection, stereotactic surgery, tumor biopsy, samples collection and treatment with investigational products prior to undergoing any study procedures 3. Histologically confirmed supratentorial glioblastoma or other WHO grade III or IV malignant glioma from archival tissue. 4. Evidence of tumor recurrence/progression by MRI (RANO criteria) post standard initial therapy. 5. Previous standard of care anti-tumor treatment including surgery and/or biopsy and chemoradiation. The washout periods from prior therapies are intended as follows: 1. Nitrosoureas: 6 weeks 2. Other cytotoxic agents: 4 weeks 3. Anti-angiogenic agents including bevacizumab: 4 weeks 4. Targeted agents including small-molecule tyrosine kinase inhibitors: 2 weeks 5. Experimental immunotherapies: 3 months 6. Vaccine based therapy: 3 months 6. Able to undergo standard MRI scans with contrast agent 7. Karnofsky Performance Status ≥ 70 8. 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 ULN 6. AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN. For subjects with documented liver metastases, ALT and AST ≤ 5 × ULN 7. Total bilirubin \< 1.5 x ULN 8. International Normalized Ratio (INR) and activated Partial Thromboplastin Time \[PTT\] within normal institutional limits 9. Male and female subjects must agree to use a highly reliable method of birth control (expected failure rate less than 5% per year) from the screening visit through 28 days after the last dose of study drug. Women of childbearing potential must have a negative pregnancy test at screening.
Exclusion criteria
1. Radiotherapy within 4 weeks or less prior to starting first veledimex dose 2. Subjects with clinically significant increased intracranial pressure or uncontrolled seizures. 3. Known immunosuppressive disease, autoimmune conditions, and /or chronic viral infections 4. Use of systemic antibacterials, antifungals or antivirals 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 permitted perioperatively. 5. Use of enzyme-inducing anti-epileptic drugs (EIAED) within 7 days prior to the first dose of study drug. 6. 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 non-metastatic prostate cancer. 7. Nursing or pregnant females 8. Prior exposure to veledimex 9. Use of medications that induce, inhibit or are substrates of CYP450 3A4 within 7 days prior to the first veledimex dosing 10. Presence of any contra-indication for a neurosurgical procedure 11. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | 3 years | Evaluation will be based on the incidence, intensity, and type of Adverse Events (AEs). Clinically significant changes in the subjects' physical examinations, vital signs, and ECG evaluations, and clinical manifestations relevant to abnormal laboratory values will be captured as AEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | 15 days | From the protocol: Veledimex PK parameters to be determined will include, but are not limited to, the maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), half-life (t1/2), area-under-the-concentration versus time curve (AUC), volume of distribution (Vd), and clearance (CL). From the SAP: 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. Veledimex concentration ratio between brain tumor and blood will be assessed on Day 0 samples. 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). Cmax will be determined from the maximum plasma concentration from Day 0 (post veledimex and resection/craniotomy), 3-5 hours after the veledimex dose on Day 1, and 3-5 hours after the veledimex dose on Day 14. |
| Cellular and Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex | 28 days | Peak serum IL-12 and I downstream IFN-gamma expressions between Day 3 to Day 28 are reported by dose cohort. |
| 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. The ORR is reported overall by treatment arm based on the investigator response at timepoints 56 days, Week 16, Week 24, and Week 48. |
| Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | 3 years | The protocol defined the MTD as the dose level below at which less than 33% of subjects, of the same cohort in a group, experienced DLTs, with an independent assessment of Group 1 and Group 2 subjects. • The number of DLTs and the proportion of subjects with any DLT and each type of DLT were summarized by veledimex dose within each group. |
| Overall Survival (OS) | 6, 9, 12, 15, 18, and 24 months | 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 Concentration Ratio Between the Brain Tumor and the Blood | 15 days | From the protocol: Veledimex PK parameters to be determined will include, but are not limited to, the maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), half-life (t1/2), area-under-the-concentration versus time curve (AUC), volume of distribution (Vd), and clearance (CL). From the SAP: 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. Veledimex concentration ratio between brain tumor and blood will be assessed on Day 0 samples. 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). Cmax will be determined from the maximum plasma concentration from Day 0 (post veledimex and resection/craniotomy), 3-5 hours after the veledimex dose on Day 1, and 3-5 hours after the veledimex dose on Day 14. |
| Progression-free Survival (PFS) | 3 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. |
Countries
United States
Participant flow
Pre-assignment details
Plan: 4 Veledimex (V) doses (20, 40, 80, 120 mg QD) and 2 AdRTShIL12 doses (2x10\^11vp, 1x10\^12vp). Actual: V 10, 20, 30, 40 mg and AdRTShIL12 2x10\^11vp. Grp 1: After 20mg cohort, SRC approved 40mg which was deemed the MAD due to DLTs. SRC approved 30mg cohort to determine MTD, but due to compliance SRC opened a 20mg exp cohort then inter 10mg cohort. Based on V compliance and OS, 20mg was determined as the optimal dose. Grp 2: Spnsr decided not to escalate post Cohort 1 (not safety based).
Participants by arm
| Arm | Count |
|---|---|
| Group 1 (Intracranial) 10 mg/Day Veledimex Group 1: Subjects scheduled for craniotomy and tumor resection: Subjects with a clinical indication for tumor resection will receive veledimex 10 mg/day 3 (± 2) hours before the craniotomy procedure. | 6 |
| Group 1 (Intracranial) 20 mg/Day Veledimex Group 1: Subjects scheduled for craniotomy and tumor resection: Subjects with a clinical indication for tumor resection will receive veledimex 20 mg/day 3 (± 2) hours before the craniotomy procedure. | 16 |
| Group 1 (Intracranial) 30 mg/Day Veledimex Group 1: Subjects scheduled for craniotomy and tumor resection: Subjects with a clinical indication for tumor resection will receive veledimex 30 mg/day 3 (± 2) hours before the craniotomy procedure. | 4 |
| Group 1 (Intracranial) 40 mg/Day Veledimex Group 1: Subjects scheduled for craniotomy and tumor resection: Subjects with a clinical indication for tumor resection will receive veledimex 40 mg/day 3 (± 2) hours before the craniotomy procedure. | 6 |
| Group 2 (Stereotactic) 20 mg/Day Veledimex Subjects who will not undergo tumor resection will receive Ad-RTS-hIL-12 by standard stereotactic surgery on Day 0. After the Ad-RTS-hIL-12 injection, veledimex 20 mg/day will be administered orally for 14 days. | 7 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 | 2 | 3 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Group 1 (Intracranial) 20 mg/Day Veledimex | Group 1 (Intracranial) 30 mg/Day Veledimex | Group 1 (Intracranial) 40 mg/Day Veledimex | Group 2 (Stereotactic) 20 mg/Day Veledimex | Total | Group 1 (Intracranial) 10 mg/Day Veledimex |
|---|---|---|---|---|---|---|
| Age, Continuous | 46.90 years STANDARD_DEVIATION 13.22 | 60.40 years STANDARD_DEVIATION 15.12 | 48.12 years STANDARD_DEVIATION 9.32 | 51.71 years STANDARD_DEVIATION 17.16 | 49.64 years STANDARD_DEVIATION 13.48 | 48.87 years STANDARD_DEVIATION 12.39 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 4 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 3 Participants | 6 Participants | 5 Participants | 35 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height (cm) | 174.69 centimeters STANDARD_DEVIATION 8.75 | 169.53 centimeters STANDARD_DEVIATION 15.96 | 176.08 centimeters STANDARD_DEVIATION 12.11 | 175.64 centimeters STANDARD_DEVIATION 7.16 | 174.25 centimeters STANDARD_DEVIATION 9.71 | 172.75 centimeters STANDARD_DEVIATION 9.92 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 4 Participants | 6 Participants | 6 Participants | 36 Participants | 5 Participants |
| Region of Enrollment United States | 16 participants | 4 participants | 6 participants | 7 participants | 39 participants | 6 participants |
| Sex: Female, Male Female | 11 Participants | 2 Participants | 4 Participants | 5 Participants | 25 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 2 Participants | 2 Participants | 2 Participants | 14 Participants | 3 Participants |
| Weight (kg) | 81.11 kilograms STANDARD_DEVIATION 18.78 | 73.70 kilograms STANDARD_DEVIATION 25.99 | 86.84 kilograms STANDARD_DEVIATION 20.26 | 83.66 kilograms STANDARD_DEVIATION 6.22 | 81.49 kilograms STANDARD_DEVIATION 16.61 | 79.86 kilograms STANDARD_DEVIATION 9.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 6 | 12 / 16 | 4 / 4 | 5 / 6 | 5 / 7 |
| other Total, other adverse events | 6 / 6 | 16 / 16 | 4 / 4 | 5 / 6 | 7 / 7 |
| serious Total, serious adverse events | 2 / 6 | 10 / 16 | 3 / 4 | 4 / 6 | 4 / 7 |
Outcome results
Primary
Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma
Evaluation will be based on the incidence, intensity, and type of Adverse Events (AEs). Clinically significant changes in the subjects' physical examinations, vital signs, and ECG evaluations, and clinical manifestations relevant to abnormal laboratory values will be captured as AEs.
Time frame: 3 years
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) |
|---|---|---|---|
| Group 1 (Intracranial) 10 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs | 6 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs | 6 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related Serious TEAEs | 1 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs Leading to Treatment Dose Modification | 3 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs Leading to Treatment Dose Modification | 3 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Serious TEAEs | 2 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs Leading to Death | 1 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs Leading to Treatment Discontinuations | 2 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs with Toxicity Grade ≥ 3 | 4 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs Leading to Treatment Discontinuations | 2 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs with Toxicity Grade ≥ 3 | 4 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs Leading to Death | 0 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs with Toxicity Grade ≥ 3 | 11 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs Leading to Death | 2 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs | 10 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Serious TEAEs | 10 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs | 16 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs Leading to Treatment Discontinuations | 2 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related Serious TEAEs | 7 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs Leading to Treatment Dose Modification | 4 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs Leading to Treatment Dose Modification | 4 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs Leading to Death | 0 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs with Toxicity Grade ≥ 3 | 6 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs Leading to Treatment Discontinuations | 3 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs Leading to Treatment Discontinuations | 2 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs | 4 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Serious TEAEs | 3 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs with Toxicity Grade ≥ 3 | 4 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs Leading to Treatment Dose Modification | 2 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs Leading to Treatment Discontinuations | 2 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs Leading to Death | 1 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs | 4 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related Serious TEAEs | 2 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs with Toxicity Grade ≥ 3 | 2 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs Leading to Treatment Dose Modification | 2 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs Leading to Death | 1 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs Leading to Treatment Dose Modification | 2 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs Leading to Treatment Discontinuations | 3 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs with Toxicity Grade ≥ 3 | 4 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Serious TEAEs | 4 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related Serious TEAEs | 3 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs Leading to Treatment Discontinuations | 3 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs | 5 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs Leading to Treatment Dose Modification | 2 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs Leading to Death | 0 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs with Toxicity Grade ≥ 3 | 5 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs | 5 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs Leading to Death | 0 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs | 4 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related Serious TEAEs | 2 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs Leading to Treatment Dose Modification | 2 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs Leading to Death | 0 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs with Toxicity Grade ≥ 3 | 2 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs with Toxicity Grade ≥ 3 | 4 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs Leading to Treatment Dose Modification | 2 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Serious TEAEs | 4 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any Drug-Related TEAEs Leading to Treatment Discontinuations | 0 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs Leading to Death | 3 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs | 7 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Safety and Tolerability of Varying Doses of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex Doses in Subjects With Recurrent or Progressive Glioblastoma or Grade III Malignant Glioma | Any TEAEs Leading to Treatment Discontinuations | 0 participants |
Secondary
Cellular and Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex
Peak serum IL-12 and I downstream IFN-gamma expressions between Day 3 to Day 28 are reported by dose cohort.
Time frame: 28 days
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 | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 (Intracranial) 10 mg/Day Veledimex | Cellular and Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex | Peak serum IL-12 | 51.2 pg/mL | Standard Error 31.3 |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Cellular and Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex | Peak serum IFN-gamma | 14.6 pg/mL | Standard Error 7.1 |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Cellular and Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex | Peak serum IL-12 | 25.8 pg/mL | Standard Error 7.1 |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Cellular and Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex | Peak serum IFN-gamma | 57.0 pg/mL | Standard Error 26.5 |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Cellular and Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex | Peak serum IL-12 | 65.7 pg/mL | Standard Error 45.5 |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Cellular and Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex | Peak serum IFN-gamma | 57.3 pg/mL | Standard Error 46.5 |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Cellular and Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex | Peak serum IFN-gamma | 125.5 pg/mL | Standard Error 60.4 |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Cellular and Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex | Peak serum IL-12 | 108.8 pg/mL | Standard Error 41 |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Cellular and Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex | Peak serum IL-12 | 25.1 pg/mL | Standard Error 7.2 |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Cellular and Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex | Peak serum IFN-gamma | 69.8 pg/mL | Standard Error 48.8 |
Secondary
Overall Survival (OS)
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: 6, 9, 12, 15, 18, and 24 months
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. Overall survival was reported by time point for the following set of subjects of the ESP: ATI001-102 Main Group 1: Craniotomy (treated at 20 mg veledimex: n=15).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 (Intracranial) 20 mg/Day Veledimex | Overall Survival (OS) | Month 6 | 73.3 percentage of participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Overall Survival (OS) | Month 9 | 66.7 percentage of participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Overall Survival (OS) | Month 12 | 60.0 percentage of participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Overall Survival (OS) | Month 15 | 40.0 percentage of participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Overall Survival (OS) | Month 18 | 26.7 percentage of participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Overall Survival (OS) | Month 24 | 6.7 percentage of participants |
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: 3 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 (MEDIAN) |
|---|---|---|
| Group 1 (Intracranial) 10 mg/Day Veledimex | Progression-free Survival (PFS) | 4 Months |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Progression-free Survival (PFS) | 2 Months |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Progression-free Survival (PFS) | 0.25 Months |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Progression-free Survival (PFS) | 1.5 Months |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Progression-free Survival (PFS) | 1.75 Months |
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. The ORR is reported overall by treatment arm based on the investigator response at timepoints 56 days, Week 16, Week 24, and Week 48.
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 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 | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 (Intracranial) 10 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Complete Response | 0 Participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Missing | 0 Participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | No Response | 0 Participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Stable Disease | 3 Participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Partial Response | 1 Participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Progressive Disease | 2 Participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Not Evaluable | 0 Participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Not Evaluable | 0 Participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Progressive Disease | 4 Participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Partial Response | 0 Participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Complete Response | 1 Participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | No Response | 0 Participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Stable Disease | 10 Participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Missing | 0 Participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Progressive Disease | 1 Participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Complete Response | 0 Participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Partial Response | 0 Participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Stable Disease | 1 Participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Not Evaluable | 1 Participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | No Response | 1 Participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Missing | 0 Participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Stable Disease | 3 Participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Not Evaluable | 0 Participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Partial Response | 1 Participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Missing | 0 Participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | No Response | 0 Participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Complete Response | 0 Participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Progressive Disease | 2 Participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Stable Disease | 4 Participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Missing | 0 Participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | No Response | 2 Participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Not Evaluable | 0 Participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Partial Response | 0 Participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Complete Response | 0 Participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Tumor Objective Response Rate (ORR) | Progressive Disease | 1 Participants |
Secondary
Veledimex Concentration Ratio Between the Brain Tumor and the Blood
From the protocol: Veledimex PK parameters to be determined will include, but are not limited to, the maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), half-life (t1/2), area-under-the-concentration versus time curve (AUC), volume of distribution (Vd), and clearance (CL). From the SAP: 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. Veledimex concentration ratio between brain tumor and blood will be assessed on Day 0 samples. 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). Cmax will be determined from the maximum plasma concentration from Day 0 (post veledimex and resection/craniotomy), 3-5 hours after the veledimex dose on Day 1, and 3-5 hours after the veledimex dose on Day 14.
Time frame: 15 days
Population: The Pharmacokinetic Population (PKP) includes all subjects who received veledimex and have PK samples to be measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 (Intracranial) 10 mg/Day Veledimex | Veledimex Concentration Ratio Between the Brain Tumor and the Blood | 0.42 ratio | Standard Deviation 0.21 |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Veledimex Concentration Ratio Between the Brain Tumor and the Blood | 0.35 ratio | Standard Deviation 0.3 |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Veledimex Concentration Ratio Between the Brain Tumor and the Blood | 0.51 ratio | Standard Deviation 0 |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Veledimex Concentration Ratio Between the Brain Tumor and the Blood | 0.60 ratio | Standard Deviation 0.33 |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Veledimex Concentration Ratio Between the Brain Tumor and the Blood | 0.63 ratio | Standard Deviation 0.54 |
Secondary
Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12
The protocol defined the MTD as the dose level below at which less than 33% of subjects, of the same cohort in a group, experienced DLTs, with an independent assessment of Group 1 and Group 2 subjects. • The number of DLTs and the proportion of subjects with any DLT and each type of DLT were summarized by veledimex dose within each group.
Time frame: 3 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 was used for analysis of DLTs.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 (Intracranial) 10 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Liver Function Test Increased | 0 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Meningitis Aseptic | 0 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Thrombocytopenia | 0 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | Total participants with DLTs | 2 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Aspartate Aminotransferase Increased | 0 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Leukopenia | 0 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Alanine Aminotransferase Increased | 2 participants |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Cytokine Release Syndrome | 0 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Alanine Aminotransferase Increased | 0 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Aspartate Aminotransferase Increased | 0 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Leukopenia | 1 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Thrombocytopenia | 1 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Meningitis Aseptic | 1 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Liver Function Test Increased | 1 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Cytokine Release Syndrome | 0 participants |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | Total participants with DLTs | 4 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | Total participants with DLTs | 0 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Leukopenia | 0 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Alanine Aminotransferase Increased | 0 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Cytokine Release Syndrome | 0 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Meningitis Aseptic | 0 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Aspartate Aminotransferase Increased | 0 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Liver Function Test Increased | 0 participants |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Thrombocytopenia | 0 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Cytokine Release Syndrome | 2 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Meningitis Aseptic | 0 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Leukopenia | 0 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Liver Function Test Increased | 0 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Aspartate Aminotransferase Increased | 1 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Alanine Aminotransferase Increased | 0 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | Total participants with DLTs | 3 participants |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Thrombocytopenia | 0 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Meningitis Aseptic | 0 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Aspartate Aminotransferase Increased | 0 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Leukopenia | 0 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Thrombocytopenia | 0 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Liver Function Test Increased | 0 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Cytokine Release Syndrome | 0 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | DLT of Alanine Aminotransferase Increased | 0 participants |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Veledimex Maximum Tolerated Dose (MTD) When Given With Varying Doses of Intratumoral Ad-RTS-hIL-12 | Total participants with DLTs | 0 participants |
Secondary
Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood
From the protocol: Veledimex PK parameters to be determined will include, but are not limited to, the maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), half-life (t1/2), area-under-the-concentration versus time curve (AUC), volume of distribution (Vd), and clearance (CL). From the SAP: 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. Veledimex concentration ratio between brain tumor and blood will be assessed on Day 0 samples. 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). Cmax will be determined from the maximum plasma concentration from Day 0 (post veledimex and resection/craniotomy), 3-5 hours after the veledimex dose on Day 1, and 3-5 hours after the veledimex dose on Day 14.
Time frame: 15 days
Population: The Pharmacokinetic Population (PKP) includes all subjects who received veledimex and have PK samples to be measured.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 (Intracranial) 10 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex Plasma Cmax | 16.27 ng/mL | Standard Deviation 8.68 |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex Plasma Ctrough | 3.60 ng/mL | Standard Deviation 0.95 |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116041 Plasma Cmax | 4.50 ng/mL | Standard Deviation 2.38 |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116041 Plasma Ctrough | 0.16 ng/mL | Standard Deviation 0.19 |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116043 Plasma Cmax | 0.83 ng/mL | Standard Deviation 1.31 |
| Group 1 (Intracranial) 10 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116043 Plasma Ctrough | 0 ng/mL | Standard Deviation 0 |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116043 Plasma Cmax | 1.55 ng/mL | Standard Deviation 2.11 |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116043 Plasma Ctrough | 0.05 ng/mL | Standard Deviation 0.18 |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex Plasma Cmax | 41.77 ng/mL | Standard Deviation 54.5 |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116041 Plasma Cmax | 8.57 ng/mL | Standard Deviation 10.88 |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116041 Plasma Ctrough | 0.50 ng/mL | Standard Deviation 0.73 |
| Group 1 (Intracranial) 20 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex Plasma Ctrough | 5.49 ng/mL | Standard Deviation 2.57 |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116041 Plasma Ctrough | 0.45 ng/mL | Standard Deviation 0.79 |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116043 Plasma Cmax | 3.62 ng/mL | Standard Deviation 1.76 |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex Plasma Cmax | 87.5 ng/mL | Standard Deviation 35.86 |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116041 Plasma Cmax | 16.27 ng/mL | Standard Deviation 9.39 |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex Plasma Ctrough | 11.72 ng/mL | Standard Deviation 2.67 |
| Group 1 (Intracranial) 30 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116043 Plasma Ctrough | 0 ng/mL | Standard Deviation 0 |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116041 Plasma Ctrough | 2.44 ng/mL | Standard Deviation 1.39 |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex Plasma Ctrough | 23.42 ng/mL | Standard Deviation 15.51 |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116041 Plasma Cmax | 10.17 ng/mL | Standard Deviation 7.68 |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116043 Plasma Ctrough | 0.26 ng/mL | Standard Deviation 0.37 |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116043 Plasma Cmax | 3.52 ng/mL | Standard Deviation 2.8 |
| Group 1 (Intracranial) 40 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex Plasma Cmax | 52.76 ng/mL | Standard Deviation 47.12 |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116043 Plasma Cmax | 1.93 ng/mL | Standard Deviation 2.78 |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116041 Plasma Cmax | 8.58 ng/mL | Standard Deviation 5.96 |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex Plasma Ctrough | 4.39 ng/mL | Standard Deviation 4.77 |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116043 Plasma Ctrough | 0.06 ng/mL | Standard Deviation 0.15 |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex metabolite: RG-116041 Plasma Ctrough | 0.14 ng/mL | Standard Deviation 0.24 |
| Group 2 (Stereotactic) 20 mg/Day Veledimex | Veledimex Pharmacokinetic Profile and Veledimex Concentration Ratio Between the Brain Tumor and the Blood | Veledimex Plasma Cmax | 39.43 ng/mL | Standard Deviation 35.18 |