Glioblastoma
Conditions
Brief summary
This research study involves an investigational product: Ad-RTS-hIL-12 given with veledimex for production of human IL-12. IL-12 is a protein that can improve the body's natural response to disease by enhancing the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor. Cemiplimab-rwlc (Libtayo) 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. Libtayo (cemiplimab-rwlc) is currently FDA approved in the United States for metastatic cutaneous cell carcinoma (CSCC), but is not approved in glioblastoma. Cemiplimab-rwlc may help your immune system detect and attack cancer cells. Ad-RTS-hIL-12 and veledimex will be given in combination with cemiplimab-rwlc to enhance the IL-12 mediated effect observed to date. The main purpose of this study is to evaluate the safety and efficacy of a single tumoral injection of Ad-RTS-hIL-12 given with oral veledimex in combination with cemiplimab-rwlc.
Detailed description
Eligible patients will receive one dose of cemiplimab-rwlc, 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 cemiplimab-rwlc via infusion every three weeks. The study is divided into three periods: the screening period, the treatment period and the follow-up period.
Interventions
BIOLOGICALAd-RTS-hIL-12
* intratumoral injection of Ad-RTS-hIL-12 * 2.0 x 10\^11 viral particles (vp) per injection
DRUGVeledimex
20mg/day 15 oral daily doses of veledimex
DRUGCemiplimab-Rwlc
Infusion every 3 weeks (350mg)
Sponsors
Alaunos Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male or female subject ≥18 and ≤75 years of age * Provision of written informed consent for tumor resection (subtotal allowed), tumor biopsy, samples collection, and treatment with investigational products prior to undergoing any study-specific procedures * Histologically confirmed glioblastoma from archival tissue * Evidence of tumor recurrence/progression by magnetic resonance imaging (MRI) according to Response Assessment in Neuro-Oncology (RANO) criteria after standard initial therapy. Multifocal disease is allowed. * 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. Nitrosoureas: 6 weeks 2. Other cytotoxic agents: 4 weeks 3. Antiangiogenic agents: 4 weeks 4. Targeted agents, including small molecule tyrosine kinase inhibitors: 2 weeks 5. Vaccine-based or CAR-T 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 7. Total bilirubin \<1.5 x ULN 8. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) within normal institutional limits * Female of child bearing potential\* and sexually active male subjects must agree to practice highly effective contraception prior to the start of the first treatment, during the study, and for at least 4 months after the last dose. Highly effective contraceptive measures include stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal ligation; vasectomized partner; and or sexual abstinence\*\*. \* Postmenopausal women must be amenorrhoeic for at least 12 months in order not to be considered of childbearing potential. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation. \*\* Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. * Normal cardiac and pulmonary function as evidenced by a normal ECG with QTc ≤450 msec and peripheral oxygen saturation (SpO2) ≥92% on room air by pulse oximetry
Exclusion criteria
* Radiotherapy treatment within 4 weeks of starting veledimex * Prior treatment of disease with bevacizumab (NOTE: short use (\< 4 doses) of bevacizumab for controlling edema is allowed) * Subjects receiving systemic corticosteroids for treatment of disease-related symptoms during the 4 weeks prior to Day -7 * Subjects with clinically significant increased intracranial pressure (e.g., impending herniation or requirement for immediate palliative treatment) or uncontrolled seizures * Uncontrolled infection with human immunodeficiency virus, hepatitis B or hepatitis C infection; or diagnosis of immunodeficiency. NOTE: * Subjects with known HIV infection who have controlled infection (undetectable viral load (HIV RNA PCR) and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted. For Subjects with controlled HIV infection, monitoring will be performed per local standards. * Subjects with hepatitis B (HBsAg+) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted. Subjects with controlled infections must undergo periodic monitoring of HBV DNA. Patients must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug. * Subjects who are hepatitis C virus antibody positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted. * 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, except for non-melanoma cancers of the skin or carcinoma in situ of the cervix or non-metastatic prostate cancer * Nursing or pregnant females * Prior exposure to veledimex * Use of an investigational product within prior 30 days. * Prior exposure to inhibitors of immuno-checkpoint pathways (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody) or other agents specifically targeting T cells * Use of medications that induce, inhibit, or are substrates of CYP450 3A4 prior to veledimex dosing without consultation with the Medical Monitor * Presence of any contraindication for a neurosurgical procedure * Use of heparin or other anti-coagulation therapy, or acetylsalicylic acid (ASA), or anti-platelet drug within Day -7 to Day 21 should not be used unless necessary to treat a life-threatening illness. Prophylactic subcutaneous heparin per institutional protocol for prevention of deep vein thrombosis (DVT) may be allowed based on discussion with the Medical Monitor. Concomitant medications should continue to be reviewed in consultation with the Medical Monitor. * Unstable or clinically significant 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, a history of myocarditis or congestive heart failure (as defined by New York Heart Association Functional Class III or IV), unstable angina, serious uncontrolled cardiac arrythmia, myocardial infarction within 6 months of screening, active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids uncontrolled asthma, or colitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | 2.0 yrs | Evaluation of adverse events as assessed by CTCAE v5.0 will be based on the incidence, intensity and type of adverse event. Safety evaluations included the observed incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs of toxicity Grade \>3, TEAEs leading to treatment dose modification, discontinuation, and death. Drug-related TEAEs were also assessed. |
| Efficacy of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | 2.0 yrs | Overall Survival (OS) OS is defined as the duration of time from the first dose of study drug (i.e., cemiplimab at Day -7) to the date of death from any cause. Censoring will be considered as below: * Subjects who discontinue study will be censored at date of discontinuation. * Subjects who are lost to follow-up will be censored at last follow-up contact date. * If the subject has not died, the subject is censored if still alive up to 2 years from the first dose of study drug received. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Determine the Rate of Pseudoprogression (PSP) at 6, 12, 18 and 24 Months | 2 years | Given the early closure of the study complete assessment of efficacy could not be determined. Reported below is the PSP at anytime while on study. |
| To Determine the Investigator's Assessment of Response, Including Tumor Objective Response Rate (ORR) at 6, 12, 18 and 24 Months | 2 years | Tumor response will be defined by radiographic and clinical criteria. Complete response (CR) or partial response (PR) will be first assessed by radiographic changes that indicate a reduction of bi-dimensional tumor size as per Recist 1.1 criteria. In addition, changes in neurologic function and steroid use will be considered to determine stable disease (SD).Given the early closure of the study complete assessment of efficacy could not be determined. The results below report response at anytime while on study. |
| To Determine the Survival Rates at 6, 12, and 18 Months | From Day 0 through 18 months post first dose of study treatment | Given the early closure of the study and survival follow-up data limited to one year post last patient in, complete assessment of efficacy could not be determined. Number of participants with death prior to each time point (6, 12, and 18 months) is reported here. |
| Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | Screening through Day 28 (assessed at Screening and Days 0, 1, 3, 7, 14, and 28) | Immune cell population markers, such as cluster of differentiation (CD) antigens CD3+CD4+ and CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo-, were assessed. |
| Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | Screening through Day 28 (assessed at Screening and Days 0, 1, 3, 7, 14, and 28) | Immunological and biological markers, such as levels of interleukin-12 (IL-12) and interferon gamma (IFN-γ) were assessed in serum samples. |
| To Determine the Tumor Response Rates at 6, 12, 18 and 24 Months | 2 years | Given the early closure of the study and survival follow-up data limited to one year post last patient in, complete assessment of efficacy could not be determined. The IRANO results below report response at anytime while on study. |
| To Determine the Progression Free Survival (PFS) | 2.0 yrs | Given the early closure of the study, formal assessment of PFS using Kaplan Meier Product-Line method was not performed. Mean time to disease progression (or participant's last scan) is reported here. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc Intratumoral Ad-RTS-hIL-12 and oral veledimex (activator ligand, 20mg) given in combination with cemiplimab-rwlc via infusion.
Ad-RTS-hIL-12: - intratumoral injection of Ad-RTS-hIL-12
\- 2.0 x 10\^11 viral particles (vp) per injection
Veledimex: 20mg/day 15 oral daily doses of veledimex
Cemiplimab-Rwlc: Infusion every 3 weeks (350mg) | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Adjuvant Cemiplimab Period | Adverse Event | 3 |
| Adjuvant Cemiplimab Period | Lack of Efficacy | 28 |
| Adjuvant Cemiplimab Period | Sponsor Study Termination rollover to Compassionate Use | 2 |
| Adjuvant Cemiplimab Period | Withdrawal by Subject | 4 |
| End of Treatment Veledimex | Adverse Event | 2 |
| Run in Cemiplimab Period | Lack of Efficacy | 1 |
Baseline characteristics
| Characteristic | Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc |
|---|---|
| Age, Continuous | 58 Years |
| Isocitrate Dehydrogenase wild type (WT) | 37 Participants |
| Karnofsky performance score (KPS) ≥90 | 25 Participants |
| O6-methlyguanine-DNA methyltransferase (MGMT) unmethylated | 28 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants |
| Race/Ethnicity, Customized Caucasian | 35 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants |
| Region of Enrollment United States | 40 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 25 Participants |
| Unifocal Disease | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 24 / 40 |
| other Total, other adverse events | 39 / 40 |
| serious Total, serious adverse events | 30 / 40 |
Outcome results
Primary
Efficacy of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma.
Overall Survival (OS) OS is defined as the duration of time from the first dose of study drug (i.e., cemiplimab at Day -7) to the date of death from any cause. Censoring will be considered as below: * Subjects who discontinue study will be censored at date of discontinuation. * Subjects who are lost to follow-up will be censored at last follow-up contact date. * If the subject has not died, the subject is censored if still alive up to 2 years from the first dose of study drug received.
Time frame: 2.0 yrs
Population: The per protocol population will comprise subjects who have received Day -7 of cemiplimab, the injection of Ad-RTS-hIL-12 with at least one post IL-12 dose of veledimex, at least one post IL-12 dose of cemiplimab (e.g. Day 15), and who have not had a major protocol deviation for which the key efficacy endpoints could be regarded as confounded or uninterpretable. Subjects who have had minor protocol deviation(s) that are thought not to impact efficacy will be included in this analysis population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Efficacy of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | 12.09 Months |
Primary
Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma.
Evaluation of adverse events as assessed by CTCAE v5.0 will be based on the incidence, intensity and type of adverse event. Safety evaluations included the observed incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs of toxicity Grade \>3, TEAEs leading to treatment dose modification, discontinuation, and death. Drug-related TEAEs were also assessed.
Time frame: 2.0 yrs
Population: The Full Analysis Set (FAS) includes every subject who received at least one dose of any study drug recorded in the Data Management database excluding screen failures.~The Evaluable Safety Population (ESP) is a subset of the FAS. Regardless of major protocol deviations, these subjects have received at least one of the following:~* Day -7 of cemiplimab,~* the injection of Ad-RTS-hIL-12 with at least one post IL-12 dose of veledimex,~* and at least one post IL-12 dose of cemiplimab (Day 15).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Any TEAE | 39 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Any Serious TEAE | 28 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Any TEAE with Toxicity Grade >/= 3 | 32 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Any TEAE Leading to Treatment Discontinuation | 5 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Any TEAE Leading to Death (Progressive Disease) | 8 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Any Drug-Related TEAE | 39 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Any Drug-Related Serious TEAE | 10 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Any Drug-Related TEAE with Toxicity Grade >/=3 | 20 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Any Drug-Related TEAE Leading to Treatment Dose Modification | 11 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Any Drug-Related TEAE Leading to Treatment Discontinuation | 3 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Ad-RTS-hIL-12 + Veledimex Related TEAEs | 35 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Ad-RTS-hIL-12 + Veledimex Related Serious TEAEs | 9 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Ad-RTS-hIL-12 + Veledimex Related TEAEs with Toxicity Grade >/= 3 | 17 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Ad-RTS-hIL-12 + Veledimex TEAEs Leading to Treatment Dose Modification | 8 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Ad-RTS-hIL-12 + Veledimex TEAEs Leading to Treatment Discontinuation | 2 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Ad-RTS-hIL-12 + Veledimex Related TEAEs Leading to Death | 0 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Cemiplimab Related TEAEs | 34 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Cemiplimab Related Serious TEAEs | 6 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Cemiplimab Related TEAEs with Toxicity Grade >/= 3 | 17 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Cemiplimab Related TEAEs Leading to Treatment Dose Modification | 3 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Cemiplimab Related TEAEs Leading to Treatment Discontinuation | 1 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Cemiplimab Related TEAEs Leading to Death | 0 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Safety of Intratumoral Ad-RTS-hIL-12 and Oral Veledimex in Combination With Cemiplimab-rwlc in Subjects With Recurrent or Progressive Glioblastoma. | Any Drug-Related TEAE Leading to Death | 0 participants |
Secondary
Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc
Immune cell population markers, such as cluster of differentiation (CD) antigens CD3+CD4+ and CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo-, were assessed.
Time frame: Screening through Day 28 (assessed at Screening and Days 0, 1, 3, 7, 14, and 28)
Population: The biomarker-evaluable population includes all ESP subjects who have adequate biomarker sample(s) at screening (baseline) and at least one follow-up assessment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | CD3+CD4+ at Screening | 40.85 % of total lymphocytes | Standard Deviation 10.42 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | CD3+CD4+ at Day 0 | 40.26 % of total lymphocytes | Standard Deviation 11.28 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | CD3+CD4+ at Day 1 | 35.36 % of total lymphocytes | Standard Deviation 12.38 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | CD3+CD4+ at Day 3 | 46.85 % of total lymphocytes | Standard Deviation 12.38 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | CD3+CD4+ at Day 7 | 39.96 % of total lymphocytes | Standard Deviation 7.81 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | CD3+CD4+ at Day 14 | 33.00 % of total lymphocytes | Standard Deviation 12.28 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | CD3+CD4+ at Day 28 | 37.17 % of total lymphocytes | Standard Deviation 11.54 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- at Screening | 0.67 % of total lymphocytes | Standard Deviation 0.6 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- at Day 0 | 0.82 % of total lymphocytes | Standard Deviation 0.64 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- at Day 1 | 0.44 % of total lymphocytes | Standard Deviation 0.46 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- at Day 3 | 1.02 % of total lymphocytes | Standard Deviation 0.81 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- at Day 7 | 0.55 % of total lymphocytes | Standard Deviation 0.51 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- at Day 14 | 0.50 % of total lymphocytes | Standard Deviation 0.49 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Cellular Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | CD3+/ CD4+/ CD25hi/ Foxp3+/ CD127lo- at Day 28 | 0.48 % of total lymphocytes | Standard Deviation 0.47 |
Secondary
Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc
Immunological and biological markers, such as levels of interleukin-12 (IL-12) and interferon gamma (IFN-γ) were assessed in serum samples.
Time frame: Screening through Day 28 (assessed at Screening and Days 0, 1, 3, 7, 14, and 28)
Population: The biomarker-evaluable population includes all Evaluable Safety Population (ESP) subjects who have adequate biomarker sample(s) at screening (baseline) and at least one follow-up assessment. Individual samples that were below the limit of quantitation were considered 0.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | IFN-gamma at Screening | 0.00 pg/mL | Standard Deviation 0 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | IFN-gamma at Day 0 | 0.11 pg/mL | Standard Deviation 0.58 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | IFN-gamma at Day 1 | 0.18 pg/mL | Standard Deviation 0.83 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | IFN-gamma at Day 3 | 10.53 pg/mL | Standard Deviation 20.34 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | IFN-gamma at Day 7 | 6.43 pg/mL | Standard Deviation 13.12 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | IFN-gamma at Day 14 | 0.74 pg/mL | Standard Deviation 2.04 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | IFN-gamma at Day 28 | 10.07 pg/mL | Standard Deviation 42.86 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | IL-12 at Screening | 0.00 pg/mL | Standard Deviation 0 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | IL-12 at Day 0 | 0.09 pg/mL | Standard Deviation 0.48 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | IL-12 at Day 1 | 0.28 pg/mL | Standard Deviation 0.73 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | IL-12 at Day 3 | 29.65 pg/mL | Standard Deviation 49.96 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | IL-12 at Day 7 | 15.56 pg/mL | Standard Deviation 23.09 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | IL-12 at Day 14 | 6.80 pg/mL | Standard Deviation 12.24 |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | Changes From Baseline in Humoral Immune Responses Elicited by Ad-RTS-hIL-12 and Veledimex in Combination With Cemiplimab-rwlc | IL-12 at Day 28 | 31.06 pg/mL | Standard Deviation 131.49 |
Secondary
To Determine the Investigator's Assessment of Response, Including Tumor Objective Response Rate (ORR) at 6, 12, 18 and 24 Months
Tumor response will be defined by radiographic and clinical criteria. Complete response (CR) or partial response (PR) will be first assessed by radiographic changes that indicate a reduction of bi-dimensional tumor size as per Recist 1.1 criteria. In addition, changes in neurologic function and steroid use will be considered to determine stable disease (SD).Given the early closure of the study complete assessment of efficacy could not be determined. The results below report response at anytime while on study.
Time frame: 2 years
Population: The per protocol population will comprise subjects who have received Day -7 of cemiplimab, the injection of Ad-RTS-hIL-12 with at least one post IL-12 dose of veledimex, at least one post IL-12 dose of cemiplimab (e.g., Day 15), and who have not had a major protocol deviation for which the key efficacy endpoints could be regarded as confounded or uninterpretable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | To Determine the Investigator's Assessment of Response, Including Tumor Objective Response Rate (ORR) at 6, 12, 18 and 24 Months | 3 Participants |
Secondary
To Determine the Progression Free Survival (PFS)
Given the early closure of the study, formal assessment of PFS using Kaplan Meier Product-Line method was not performed. Mean time to disease progression (or participant's last scan) is reported here.
Time frame: 2.0 yrs
Population: The per protocol population comprised subjects who had received Day -7 of cemiplimab, the injection of Ad-RTS-hIL-12 with at least 1 post IL-12 dose of veledimex, at least 1 post IL-12 dose of cemiplimab (e.g., Day 15), and who had not had a major protocol deviation for which the key efficacy endpoints could be regarded as confounded or uninterpretable. Subjects who have had minor protocol deviation(s) that are thought not to impact efficacy were included in this analysis population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | To Determine the Progression Free Survival (PFS) | 89.0 Days | Standard Deviation 95.6 |
Secondary
To Determine the Rate of Pseudoprogression (PSP) at 6, 12, 18 and 24 Months
Given the early closure of the study complete assessment of efficacy could not be determined. Reported below is the PSP at anytime while on study.
Time frame: 2 years
Population: Given the early closure of the study complete assessment of efficacy could not be determined. The per protocol population will comprise subjects who have received Day -7 of cemiplimab, the injection of Ad-RTS-hIL-12 with at least one post IL-12 dose of veledimex, at least one post IL-12 dose of cemiplimab (e.g., Day 15), and who have not had a major protocol deviation for which the key efficacy endpoints could be regarded as confounded or uninterpretable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | To Determine the Rate of Pseudoprogression (PSP) at 6, 12, 18 and 24 Months | 5 Participants |
Secondary
To Determine the Survival Rates at 6, 12, and 18 Months
Given the early closure of the study and survival follow-up data limited to one year post last patient in, complete assessment of efficacy could not be determined. Number of participants with death prior to each time point (6, 12, and 18 months) is reported here.
Time frame: From Day 0 through 18 months post first dose of study treatment
Population: The population will comprise subjects who have received Day -7 of cemiplimab, the injection of Ad-RTS-hIL-12 with at least one post IL-12 dose of veledimex, at least one post IL- 12 dose of cemiplimab (e.g., Day 15), and who have not had a major protocol deviation for which the key efficacy endpoints could be regarded as confounded or uninterpretable. Estimates of the OS at prespecified timepoints will be based on the per protocol (PP) population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | To Determine the Survival Rates at 6, 12, and 18 Months | Death prior to 6 months | 8 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | To Determine the Survival Rates at 6, 12, and 18 Months | Death prior to 12 months | 19 participants |
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | To Determine the Survival Rates at 6, 12, and 18 Months | Death prior to 18 months | 24 participants |
Secondary
To Determine the Tumor Response Rates at 6, 12, 18 and 24 Months
Given the early closure of the study and survival follow-up data limited to one year post last patient in, complete assessment of efficacy could not be determined. The IRANO results below report response at anytime while on study.
Time frame: 2 years
Population: Given the early closure of the study and survival follow-up data limited to one year post last patient in, complete assessment of efficacy could not be determined.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab-rwlc | To Determine the Tumor Response Rates at 6, 12, 18 and 24 Months | 3 Participants |