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

Alaunos Therapeutics21 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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

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

Secondary Outcomes

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).

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

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

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

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

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

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

Veledimex Pharmacokinetic Profile: Maximum Plasma Concentration (Cmax)

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.