A Study of Ad-RTS-hIL-12 With Veledimex in Combination With Nivolumab in Subjects With Glioblastoma; a Substudy to ATI001-102

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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03636477

Enrollment

Registered

2018-08-17

Start date

2018-06-18

Completion date

2021-06-30

Last updated

2025-08-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Glioblastoma

Brief summary

This research study involves an investigational product: Ad-RTS-hIL-12 given with veledimex for production of human interleukin-12 (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. Nivolumab is an antibody (a kind of human protein) that is being tested to see if it will allow the body's immune system to work against glioblastoma tumors. Opdivo (Nivolumab) is currently FDA approved in the United States for melanoma (a type of skin cancer), non-small cell lung cancer, renal cell cancer (a type of kidney cancer), Hodgkin's lymphoma but is not approved in glioblastoma. Nivolumab may help your immune system detect and attack cancer cells. Ad-RTS-hIL-12 and veledimex will be given in combination with Nivolumab to enhance the IL-12 mediated effect observed to date. The main purpose of this substudy is to evaluate the safety and tolerability of a single tumoral injection of Ad-RTS-hIL-12 given with oral veledimex in combination with nivolumab.

Detailed description

Eligible patients will receive one dose of nivolumab, via infusion, one week prior to standard of care craniotomy and tumor resection (subtotal or total). On the day of surgery, patients 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. Following veledimex, patients will receive nivolumab via infusion every two weeks. 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

* 2 doses (10mg/day, 20mg/day) * 15 oral daily doses of veledimex

DRUGNivolumab

* 2 doses (1mg/kg, 3mg/kg) * Every 2 weeks

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Inclusion criteria

* Male or female subject ≥18 and ≤75 years of age * Provision of written informed consent for tumor resection, stereotactic surgery, tumor biopsy, samples collection, and treatment with investigational products prior to undergoing any study specific procedures * Histologically confirmed supratentorial glioblastoma * Evidence of 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, including bevacizumab: 4weeks 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) 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. * Normal cardiac and pulmonary function as evidenced by a normal electrocardiogram (ECG) and peripheral oxygen saturation (SpO2) ≥90% by pulse oximetry

Exclusion criteria

* Previous treatment with inhibitors of immunocheckpoint pathways (eg, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody) or other agents specifically targeting T cells * Radiotherapy treatment within 4 weeks or less prior to veledimex dosing * 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 cytochrome p450 (CYP450) 3A4 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 include, but are not limited to: unstable angina, congestive heart failure, myocardial infarction within 2 months of screening, ongoing maintenance therapy for life-threatening ventricular arrhythmia or uncontrolled asthma. * History of myocarditis or congestive heart failure (as defined by New York Heart Association Functional Classification III or IV), as well as unstable angina, serious uncontrolled cardiac arrhythmia, uncontrolled infection, or myocardial infarction 6 months prior to study entry.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Adverse Events (AEs)	2 years and 4 months	Evaluation of adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.03 will be based on the incidence, intensity and type of adverse event. AEs will be regarded as treatment-emergent adverse events (TEAEs) during the treatment period regardless of relationship to study drug if: • The AE occurred or worsened from baseline during or after administration of the first dose of study drug (on or after Day 0).
Number of Participants With Veledimex Dose Compliance	From Day 0 through Day 14 for each participant	Evaluation will be based on expected dose compliance. Subjects were instructed to document veledimex dosing compliance in a subject diary, including the time each dose was taken, the time of 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
Progression Free Survival (PFS)	2 years and 4 months	PFS is the time in days 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 (per Response Assessment in Neuro-Oncology \[RANO\] or Immunotherapy Response Assessment in Neuro-Oncology \[iRANO\] criteria). 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)	2 years and 4 months	PSP -- Progression free survival was originally defined for determination of PSP requiring confirmation of progression (per Response Assessment in Neuro-Oncology \[RANO\] or Immunotherapy Response Assessment in Neuro-Oncology \[iRANO\] criteria).
Overall Survival (OS)	Up to 24 months	The percentage of participants alive at each time point (6, 9, 12, 15, 18, and 24 months) are reported.
Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	From Screening through Day 28, assessed at Screening and Days 0, 1, 3, 7, 14, and 28	Blood samples for pharmacodynamic biomarker evaluation were collected at screening, during treatment, and post-treatment. The immunological and biological response markers include serum cytokines (IL-12 and IFNℽ), and T and B cell subpopulations. Serum IL-12 and downstream IFNℽ expressions are reported by time point.
Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	From Screening through Day 28, assessed at Screening, Days 0, 14, and 28	Blood samples for pharmacodynamic biomarker evaluation were collected at screening, during treatment, and post-treatment. Whole blood flow cytometry was used to assess the circulating blood cell subpopulations (e.g., T-reg and T cell panels).
Veledimex Pharmacokinetic Profile: Maximum Plasma Concentration (Cmax)	Day 0 to Day 15 (Day 14 24-hour post dose)	Cmax was 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.
Number of Participants With a Dose-Limiting Toxicity (DLT)	The first treatment cycle (21 days).	The primary objective was to determine the Maximum Tolerated Dose (MTD), defined as the dose at which fewer than 33% of subjects experience a Dose-Limiting Toxicity (DLT). The MTD was not reached; a Maximum Administered Dose (MAD) of 20mg veledimex and 3mg/kg nivolumab was determined. This measure reports the number of subjects who experienced a DLT during the first treatment cycle in each dose cohort.
Veledimex Pharmacokinetic Profile: Half-life (t1/2)	Day 0 to Day 15 (24 hours post Day 14 dose)	t1/2 was determined from the plasma concentrations measured from Day 0 (post veledimex and resection/craniotomy) through Day 15 (24 hours post Day 14 dose)
Veledimex Pharmacokinetic Profile: Area Under the Concentration-versus-time Curve (AUC)	Day 0 to Day 15 (Day 14 24-hour post dose)	AUC was determined from the plasma concentrations measured from Day 0 (post veledimex and resection/craniotomy) through Day 15 (24 hours post Day 14 dose)
Veledimex Pharmacokinetic Profile: Volume of Distribution (Vd)	Day 0 to Day 15 (Day 14 24-hour post dose)	Vd was determined from the plasma concentrations measured from Day 0 (post veledimex and resection/craniotomy) through Day 15 (24 hours post Day 14 dose).
Veledimex Pharmacokinetic Profile: Clearance (CL)	Day 0 to Day 15 (Day 14 24-hour post dose)	CL was determined from the plasma concentrations measured from Day 0 (post veledimex and resection/craniotomy) through Day 15 (24 hours post Day 14 dose).
Veledimex Concentration Ratio Between the Brain Tumor and the Blood.	1 day (Day 0 at time of resection)	Tumor/plasma ratio at Day 0 by cohort
Cumulative Dexamethasone Use During Days 0-14	Days 0 through 14	To assess concomitant corticosteroid use during the first treatment cycle, the cumulative dose of dexamethasone administered to each subject from Day 0 to Day 14 was calculated. This measure reports the mean cumulative dose in milligrams (mg) for each cohort
Veledimex Pharmacokinetic Profile: Time to Maximum Plasma Concentration (Tmax)	Day 0 to Day 15 (Day 14 24-hour post dose)	Tmax was determined from the time of 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.
Tumor Objective Response Rate (ORR)	2 years and 4 months	To determine investigator assessment of response including tumor ORR of Ad-RTS-hIL-12 + veledimex when administered in combination with nivolumab. Investigator assessment of ORR was determined according to Immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria. iRANO is a set of criteria built on RANO criteria but adapts them for immune-related effects to evaluate treatment response in brain tumor patients receiving immunotherapy. It addresses unique challenges like pseudoprogression, where immune-related inflammation mimics tumor growth on imaging allowing continued treatment despite early radiographic worsening if the patient is clinically stable. This criteria requires confirmation of progression with follow-up imaging ≥3 months later, especially within the first 6 months of immunotherapy.

Countries

United States

Participant flow

Recruitment details

Subject enrollment and dose escalation followed a 3+3 design. Each subject in the 1st cohort, Cohort S1, was monitored through Day 28 before next subject was dosed. The first subjects in the subsequent cohorts, Cohorts S2 and S3, were monitored through Day 28. After completion of Cohort S3, the Safety Review Committee (SRC) and Data Safety Monitoring Board (DSMB )recommended expanding accrual, and additional 12 subjects were enrolled in an expansion cohort (20mg veledimex and 3mg/kg nivolumab).

Participants by arm

Arm	Count
Veledimex 10mg Dose Level + Nivolumab 1mg/kg Cohort S1: Ad-RTS-hIL-12 on Day 0 Veledimex 10 mg QD on Days 0-14 Nivolumab 1 mg/kg IV over 60 minutes on Day -7, Day 15, and approx every 2 weeks	3
Veledimex 10mg Dose Level + Nivolumab 3mg/kg Cohort S2: Ad-RTS-hIL-12 on Day 0 Veledimex 10 mg QD on Days 0-14 Nivolumab 3 mg/kg IV over 60 minutes on Day -7, Day 15, and approx every 2 weeks	3
Veledimex 20mg Dose Level + Nivolumab 3mg/kg Cohort S3: Ad-RTS-hIL-12 on Day 0 Veledimex 20 mg QD on Days 0-14 Nivolumab 3 mg/kg IV over 60 minutes on Day -7, Day 15, and approx every 2 weeks	15
Total	21

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	0	0	1

Baseline characteristics

Characteristic	Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Total	Veledimex 20mg Dose Level + Nivolumab 3mg/kg
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	1 Participants	8 Participants	7 Participants
Age, Categorical Between 18 and 65 years	3 Participants	2 Participants	13 Participants	8 Participants
Age, Continuous	42.90 years STANDARD_DEVIATION 17.34	59.37 years STANDARD_DEVIATION 7.21	57.29 years STANDARD_DEVIATION 14.14	59.75 years STANDARD_DEVIATION 13.54
Disease Status at Entry Missing	0 Participants	0 Participants	0 Participants	0 Participants
Disease Status at Entry Multifocal	1 Participants	0 Participants	6 Participants	5 Participants
Disease Status at Entry Unifocal	2 Participants	3 Participants	15 Participants	10 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	1 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants	3 Participants	20 Participants	14 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Height	178.67 cm STANDARD_DEVIATION 8.93	175.27 cm STANDARD_DEVIATION 14.17	175.52 cm STANDARD_DEVIATION 10.1	147.94 cm STANDARD_DEVIATION 10.15
Isocitrate Dehydrogenase (IDH) Mutation Status at Diagnosis Missing	0 Participants	0 Participants	0 Participants	0 Participants
Isocitrate Dehydrogenase (IDH) Mutation Status at Diagnosis Mutated	1 Participants	0 Participants	2 Participants	1 Participants
Isocitrate Dehydrogenase (IDH) Mutation Status at Diagnosis Wild-Type	2 Participants	3 Participants	19 Participants	14 Participants
Karnofsky Performance Score (KPS) at Screening >= 70-90	0 Participants	0 Participants	4 Participants	4 Participants
Karnofsky Performance Score (KPS) at Screening >= 90	3 Participants	3 Participants	17 Participants	11 Participants
Karnofsky Performance Score (KPS) at Screening Missing	0 Participants	0 Participants	0 Participants	0 Participants
MGMT Status at Diagnosis Methylated	2 Participants	1 Participants	8 Participants	5 Participants
MGMT Status at Diagnosis Missing	0 Participants	0 Participants	2 Participants	2 Participants
MGMT Status at Diagnosis Unmethylated	1 Participants	2 Participants	11 Participants	8 Participants
Number of Recurrences 1st recurrence	2 Participants	3 Participants	15 Participants	10 Participants
Number of Recurrences >=2 recurrence	1 Participants	0 Participants	5 Participants	4 Participants
Number of Recurrences Missing	0 Participants	0 Participants	1 Participants	1 Participants
Prior Lines of Treatment Greater Than One	0 Participants	0 Participants	5 Participants	5 Participants
Prior Lines of Treatment One	3 Participants	3 Participants	16 Participants	10 Participants
Prior Steroid Use Missing	0 Participants	0 Participants	0 Participants	0 Participants
Prior Steroid Use No	3 Participants	3 Participants	18 Participants	12 Participants
Prior Steroid Use Yes	0 Participants	0 Participants	3 Participants	3 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	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
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) White	3 Participants	3 Participants	20 Participants	14 Participants
Sex: Female, Male Female	1 Participants	1 Participants	9 Participants	7 Participants
Sex: Female, Male Male	2 Participants	2 Participants	12 Participants	8 Participants
Weight	74.33 kg STANDARD_DEVIATION 11.62	82.83 kg STANDARD_DEVIATION 29.11	83.30 kg STANDARD_DEVIATION 19.71	85.19 kg STANDARD_DEVIATION 19.84

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	3 / 3	3 / 3	15 / 15
other Total, other adverse events	3 / 3	3 / 3	15 / 15
serious Total, serious adverse events	1 / 3	2 / 3	6 / 15

Outcome results

Primary

Number of Participants With Adverse Events (AEs)

Evaluation of adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.03 will be based on the incidence, intensity and type of adverse event. AEs will be regarded as treatment-emergent adverse events (TEAEs) during the treatment period regardless of relationship to study drug if: • The AE occurred or worsened from baseline during or after administration of the first dose of study drug (on or after Day 0).

Time frame: 2 years and 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	Group	Value (NUMBER)
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related TEAEs Leading to Death	0 participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related TEAEs with Toxicity Grade ≥ 3	2 participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Adverse Events (AEs)	Any TEAEs Leading to Death	0 participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Adverse Events (AEs)	Any TEAEs with Toxicity Grade ≥ 3	3 participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related Serious TEAEs	1 participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related TEAEs	3 participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Adverse Events (AEs)	Any TEAEs	3 participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related TEAEs Leading to Treatment Discontinuations	0 participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Adverse Events (AEs)	Any TEAEs Leading to Treatment Dose Modification	2 participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Adverse Events (AEs)	Any Serious TEAEs	1 participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related TEAEs Leading to Treatment Dose Modification	2 participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Adverse Events (AEs)	Any TEAEs Leading to Treatment Discontinuations	0 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any Serious TEAEs	2 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any TEAEs	3 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any TEAEs with Toxicity Grade ≥ 3	3 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any TEAEs Leading to Treatment Dose Modification	2 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any TEAEs Leading to Treatment Discontinuations	2 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any TEAEs Leading to Death	0 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related TEAEs	3 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related Serious TEAEs	1 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related TEAEs with Toxicity Grade ≥ 3	3 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related TEAEs Leading to Treatment Dose Modification	1 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related TEAEs Leading to Treatment Discontinuations	1 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related TEAEs Leading to Death	0 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any Serious TEAEs	6 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related TEAEs with Toxicity Grade ≥ 3	7 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any TEAEs Leading to Treatment Dose Modification	4 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any TEAEs	15 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related TEAEs Leading to Treatment Dose Modification	4 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any TEAEs with Toxicity Grade ≥ 3	11 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related TEAEs Leading to Death	0 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related TEAEs	15 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any TEAEs Leading to Death	1 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related TEAEs Leading to Treatment Discontinuations	2 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any Drug-Related Serious TEAEs	3 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Adverse Events (AEs)	Any TEAEs Leading to Treatment Discontinuations	2 participants

Primary

Number of Participants With Veledimex Dose Compliance

Evaluation will be based on expected dose compliance. Subjects were instructed to document veledimex dosing compliance in a subject diary, including the time each dose was taken, the time of 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: From Day 0 through Day 14 for each participant

Arm	Measure	Group	Value (NUMBER)
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Veledimex Dose Compliance	100% compliance	2 participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Veledimex Dose Compliance	Less than 100%	1 participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Veledimex Dose Compliance	80% or more	3 participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With Veledimex Dose Compliance	Less than 80%	0 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Veledimex Dose Compliance	Less than 80%	0 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Veledimex Dose Compliance	100% compliance	3 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Veledimex Dose Compliance	80% or more	3 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Veledimex Dose Compliance	Less than 100%	0 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Veledimex Dose Compliance	Less than 80%	0 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Veledimex Dose Compliance	Less than 100%	4 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Veledimex Dose Compliance	80% or more	15 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With Veledimex Dose Compliance	100% compliance	11 participants

Secondary

Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.

Blood samples for pharmacodynamic biomarker evaluation were collected at screening, during treatment, and post-treatment. The immunological and biological response markers include serum cytokines (IL-12 and IFNℽ), and T and B cell subpopulations. Serum IL-12 and downstream IFNℽ expressions are reported by time point.

Time frame: From Screening through Day 28, assessed at Screening and Days 0, 1, 3, 7, 14, and 28

Population: Evaluable Safety Population (ESP) includes subjects who have received nivolumab, Ad-RTS-hIL-12, and at least one dose of veledimex. Pharmacodynamic Population (PDP) refers to ESP.

Arm	Measure	Group	Value (MEAN)	Dispersion
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 3	NA pg/mL	—
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 14	5.41 pg/mL	Standard Deviation 4.75
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 1	2.16 pg/mL	Standard Deviation 2.03
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 1	NA pg/mL	—
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 28	1.32 pg/mL	Standard Deviation 0.5
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 0	0.93 pg/mL	Standard Deviation 0.26
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 0	8.1 pg/mL	Standard Deviation 0.17
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Screening	8.93 pg/mL	Standard Deviation 1.62
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 7	NA pg/mL	—
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 3	6.05 pg/mL	Standard Deviation 3.7
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 28	NA pg/mL	—
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Screening	1.19 pg/mL	Standard Deviation 0.2
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 7	1.98 pg/mL	Standard Deviation 0
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 14	13.9 pg/mL	Standard Deviation 8.34
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 3	NA pg/mL	—
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Screening	0.73 pg/mL	Standard Deviation 0.15
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 0	1.12 pg/mL	Standard Deviation 0.69
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 1	0.90 pg/mL	Standard Deviation 0.36
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 3	2.22 pg/mL	Standard Deviation 1.34
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 7	3.84 pg/mL	Standard Deviation 0.42
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 14	1.01 pg/mL	Standard Deviation 0.29
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 28	0.84 pg/mL	Standard Deviation 0.23
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Screening	NA pg/mL	—
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 0	NA pg/mL	—
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 1	NA pg/mL	—
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 7	NA pg/mL	—
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 14	NA pg/mL	—
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 28	8.70 pg/mL	Standard Deviation 1.21
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Screening	0.40 pg/mL	Standard Deviation 0.32
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 1	NA pg/mL	—
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 7	4.32 pg/mL	Standard Deviation 3.82
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 3	9.00 pg/mL	Standard Deviation 11.57
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 1	0.82 pg/mL	Standard Deviation 0.38
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 3	2.12 pg/mL	Standard Deviation 5.4
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 7	5.46 pg/mL	Standard Deviation 7.22
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 0	0.64 pg/mL	Standard Deviation 0.34
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 28	3.52 pg/mL	Standard Deviation 12.67
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Screening	NA pg/mL	—
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 28	0.64 pg/mL	Standard Deviation 0.33
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 14	7.68 pg/mL	Standard Deviation 28.73
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IFN gamma Day 0	NA pg/mL	—
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	Serum IL12 Day 14	2.58 pg/mL	Standard Deviation 2.49

Secondary

Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.

Blood samples for pharmacodynamic biomarker evaluation were collected at screening, during treatment, and post-treatment. Whole blood flow cytometry was used to assess the circulating blood cell subpopulations (e.g., T-reg and T cell panels).

Time frame: From Screening through Day 28, assessed at Screening, Days 0, 14, and 28

Population: Evaluable Safety Population (ESP) includes subjects who have received nivolumab, Ad-RTS-hIL-12, and at least one dose of veledimex. Pharmacodynamic Population (PDP) refers to ESP.

Arm	Measure	Group	Value (MEAN)	Dispersion
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- [Treg] at Day 0	0.97 percentage	Standard Deviation 0.38
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD8+ [Tcytotoxic] at Screening	21 percentage	Standard Deviation 2.83
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD45+ [pan-T] at Day 0	58.67 percentage	Standard Deviation 8.39
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD8+ [Tcytotoxic] at Day 28	29 percentage	Standard Deviation 10.15
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD8+ [Tcytotoxic] at Day 0	24 percentage	Standard Deviation 3.61
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD45+ [pan-T] at Screening	62 percentage	Standard Deviation 15.56
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD8+ [Tcytotoxic] at Day 14	31.67 percentage	Standard Deviation 9.5
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD45+ [pan-T] at Day 14	71.33 percentage	Standard Deviation 7.37
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- [Treg] at Screening	1.1 percentage	Standard Deviation 0.57
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- [Treg] at Day 14	0.8 percentage	Standard Deviation 0.78
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD45+ [pan-T] at Day 28	69 percentage	Standard Deviation 7.55
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- [Treg] at Day 28	1.27 percentage	Standard Deviation 1.24
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- [Treg] at Day 28	2.9 percentage	Standard Deviation 2.26
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD45+ [pan-T] at Screening	78 percentage	Standard Deviation 7.07
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD45+ [pan-T] at Day 0	74.33 percentage	Standard Deviation 7.51
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD45+ [pan-T] at Day 14	73.67 percentage	Standard Deviation 9.08
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD45+ [pan-T] at Day 28	77.33 percentage	Standard Deviation 9.29
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD8+ [Tcytotoxic] at Screening	30.5 percentage	Standard Deviation 0.71
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD8+ [Tcytotoxic] at Day 0	31 percentage	Standard Deviation 5
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD8+ [Tcytotoxic] at Day 14	30.33 percentage	Standard Deviation 1.15
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD8+ [Tcytotoxic] at Day 28	30.67 percentage	Standard Deviation 4.62
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- [Treg] at Screening	1.8 percentage	Standard Deviation 0.99
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- [Treg] at Day 0	0.85 percentage	Standard Deviation 0.49
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- [Treg] at Day 14	1.70 percentage	Standard Deviation 1.5
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD8+ [Tcytotoxic] at Day 28	31 percentage	Standard Deviation 0
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD45+ [pan-T] at Screening	75 percentage	Standard Deviation 14.14
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- [Treg] at Screening	0.35 percentage	Standard Deviation 0.49
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD45+ [pan-T] at Day 28	73 percentage	Standard Deviation 2.83
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD45+ [pan-T] at Day 0	75.5 percentage	Standard Deviation 3.54
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- [Treg] at Day 0	1.1 percentage	Standard Deviation 0.99
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD45+ [pan-T] at Day 14	78 percentage	Standard Deviation 3.83
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD8+ [Tcytotoxic] at Day 0	30 percentage	Standard Deviation 4.24
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- [Treg] at Day 28	0.95 percentage	Standard Deviation 0.92
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD8+ [Tcytotoxic] at Day 14	29.5 percentage	Standard Deviation 6.36
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+ CD8+ [Tcytotoxic] at Screening	32.5 percentage	Standard Deviation 2.12
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Nivolumab.	CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- [Treg] at Day 14	0.35 percentage	Standard Deviation 0.35

Secondary

Cumulative Dexamethasone Use During Days 0-14

To assess concomitant corticosteroid use during the first treatment cycle, the cumulative dose of dexamethasone administered to each subject from Day 0 to Day 14 was calculated. This measure reports the mean cumulative dose in milligrams (mg) for each cohort

Time frame: Days 0 through 14

Population: The Overall Safety Population (OSP) includes all subjects who have received at least one dose of veledimex and/or Ad-RTS-hIL-12

Arm	Measure	Value (MEAN)	Dispersion
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Cumulative Dexamethasone Use During Days 0-14	82.7 mg	Standard Deviation 88.6
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Cumulative Dexamethasone Use During Days 0-14	20 mg	Standard Deviation 0
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Cumulative Dexamethasone Use During Days 0-14	60.1 mg	Standard Deviation 100.2

Secondary

Number of Participants With a Dose-Limiting Toxicity (DLT)

The primary objective was to determine the Maximum Tolerated Dose (MTD), defined as the dose at which fewer than 33% of subjects experience a Dose-Limiting Toxicity (DLT). The MTD was not reached; a Maximum Administered Dose (MAD) of 20mg veledimex and 3mg/kg nivolumab was determined. This measure reports the number of subjects who experienced a DLT during the first treatment cycle in each dose cohort.

Time frame: The first treatment cycle (21 days).

Arm	Measure	Value (NUMBER)
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Number of Participants With a Dose-Limiting Toxicity (DLT)	0 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Number of Participants With a Dose-Limiting Toxicity (DLT)	1 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Number of Participants With a Dose-Limiting Toxicity (DLT)	2 participants

Secondary

Overall Survival (OS)

The percentage of participants alive at each time point (6, 9, 12, 15, 18, and 24 months) are reported.

Time frame: Up to 24 months

Population: The Overall Safety Population (OSP) included all subjects who received at least one dose of any study drug.

Arm	Measure	Group	Value (NUMBER)
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Overall Survival (OS)	OS at Month 6	100 Percentage of participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Overall Survival (OS)	OS at Month 9	66.7 Percentage of participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Overall Survival (OS)	OS at Month 12	33.3 Percentage of participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Overall Survival (OS)	OS at Month 15	33.3 Percentage of participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Overall Survival (OS)	OS at Month 18	33.3 Percentage of participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Overall Survival (OS)	OS at Month 24	0 Percentage of participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Overall Survival (OS)	OS at Month 24	33.3 Percentage of participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Overall Survival (OS)	OS at Month 6	66.7 Percentage of participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Overall Survival (OS)	OS at Month 15	66.7 Percentage of participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Overall Survival (OS)	OS at Month 18	66.7 Percentage of participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Overall Survival (OS)	OS at Month 9	66.7 Percentage of participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Overall Survival (OS)	OS at Month 12	66.7 Percentage of participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Overall Survival (OS)	OS at Month 9	46.7 Percentage of participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Overall Survival (OS)	OS at Month 12	40 Percentage of participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Overall Survival (OS)	OS at Month 24	0 Percentage of participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Overall Survival (OS)	OS at Month 15	26.7 Percentage of participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Overall Survival (OS)	OS at Month 6	60.0 Percentage of participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Overall Survival (OS)	OS at Month 18	13.3 Percentage of participants

Secondary

Progression Free Survival (PFS)

PFS is the time in days 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 (per Response Assessment in Neuro-Oncology \[RANO\] or Immunotherapy Response Assessment in Neuro-Oncology \[iRANO\] criteria). 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: 2 years and 4 months

Arm	Measure	Value (MEAN)	Dispersion
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Progression Free Survival (PFS)	38.0 Days	Standard Deviation 41.6
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Progression Free Survival (PFS)	88.0 Days	Standard Deviation 98.8
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Progression Free Survival (PFS)	36.9 Days	Standard Deviation 29

Secondary

Rate of Pseudo-progression (PSP)

PSP -- Progression free survival was originally defined for determination of PSP requiring confirmation of progression (per Response Assessment in Neuro-Oncology \[RANO\] or Immunotherapy Response Assessment in Neuro-Oncology \[iRANO\] criteria).

Time frame: 2 years and 4 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. The ESP is denoted as the PP population in this uncontrolled setting.

Arm	Measure	Value (NUMBER)
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Rate of Pseudo-progression (PSP)	0 participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Rate of Pseudo-progression (PSP)	1 participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Rate of Pseudo-progression (PSP)	0 participants

Secondary

Tumor Objective Response Rate (ORR)

To determine investigator assessment of response including tumor ORR of Ad-RTS-hIL-12 + veledimex when administered in combination with nivolumab. Investigator assessment of ORR was determined according to Immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria. iRANO is a set of criteria built on RANO criteria but adapts them for immune-related effects to evaluate treatment response in brain tumor patients receiving immunotherapy. It addresses unique challenges like pseudoprogression, where immune-related inflammation mimics tumor growth on imaging allowing continued treatment despite early radiographic worsening if the patient is clinically stable. This criteria requires confirmation of progression with follow-up imaging ≥3 months later, especially within the first 6 months of immunotherapy.

Time frame: 2 years and 4 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. The ESP will be evaluated for investigator assessment of objective response rate (ORR).

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Tumor Objective Response Rate (ORR)	No Response	0 Participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Tumor Objective Response Rate (ORR)	Partial Response	0 Participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Tumor Objective Response Rate (ORR)	Progressive Disease	1 Participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Tumor Objective Response Rate (ORR)	Complete Response	0 Participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Tumor Objective Response Rate (ORR)	Not Evaluable	0 Participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Tumor Objective Response Rate (ORR)	Missing	0 Participants
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Tumor Objective Response Rate (ORR)	Stable Disease	2 Participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Tumor Objective Response Rate (ORR)	Missing	0 Participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Tumor Objective Response Rate (ORR)	Complete Response	0 Participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Tumor Objective Response Rate (ORR)	Partial Response	1 Participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Tumor Objective Response Rate (ORR)	Stable Disease	1 Participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Tumor Objective Response Rate (ORR)	Progressive Disease	1 Participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Tumor Objective Response Rate (ORR)	Not Evaluable	0 Participants
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Tumor Objective Response Rate (ORR)	No Response	0 Participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Tumor Objective Response Rate (ORR)	Not Evaluable	0 Participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Tumor Objective Response Rate (ORR)	Stable Disease	11 Participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Tumor Objective Response Rate (ORR)	Complete Response	0 Participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Tumor Objective Response Rate (ORR)	No Response	0 Participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Tumor Objective Response Rate (ORR)	Partial Response	0 Participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Tumor Objective Response Rate (ORR)	Progressive Disease	4 Participants
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Tumor Objective Response Rate (ORR)	Missing	0 Participants

Secondary

Veledimex Concentration Ratio Between the Brain Tumor and the Blood.

Tumor/plasma ratio at Day 0 by cohort

Time frame: 1 day (Day 0 at time of resection)

Population: All subjects with available tumor concentration data are included in the PK Population for determination of tumor/plasma concentration ratio.

Arm	Measure	Value (MEAN)	Dispersion
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Veledimex Concentration Ratio Between the Brain Tumor and the Blood.	0.561 ratio	Standard Deviation 0.212
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Veledimex Concentration Ratio Between the Brain Tumor and the Blood.	0.404 ratio	Standard Deviation 0.87
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Veledimex Concentration Ratio Between the Brain Tumor and the Blood.	0.632 ratio	Standard Deviation 0.446

Secondary

Veledimex Pharmacokinetic Profile: Area Under the Concentration-versus-time Curve (AUC)

AUC was determined from the plasma concentrations measured from Day 0 (post veledimex and resection/craniotomy) through Day 15 (24 hours post Day 14 dose)

Time frame: Day 0 to Day 15 (Day 14 24-hour post dose)

Population: All Subjects with available plasma-time concentration data are included in the PK Population.

Arm	Measure	Value (MEAN)	Dispersion
Veledimex 10mg Dose Level + Nivolumab 1mg/kg	Veledimex Pharmacokinetic Profile: Area Under the Concentration-versus-time Curve (AUC)	24.85 ng*hr/mL	Standard Deviation 13.82
Veledimex 10mg Dose Level + Nivolumab 3mg/kg	Veledimex Pharmacokinetic Profile: Area Under the Concentration-versus-time Curve (AUC)	30.76 ng*hr/mL	Standard Deviation 5.42
Veledimex 20mg Dose Level + Nivolumab 3mg/kg	Veledimex Pharmacokinetic Profile: Area Under the Concentration-versus-time Curve (AUC)	185.34 ng*hr/mL	Standard Deviation 215.77

Secondary

Veledimex Pharmacokinetic Profile: Clearance (CL)

CL was determined from the plasma concentrations measured from Day 0 (post veledimex and resection/craniotomy) through Day 15 (24 hours post Day 14 dose).

Time frame: Day 0 to Day 15 (Day 14 24-hour post dose)