The purpose of this phase 2 multi-site trial is to evaluate the safety and efficacy of adding Gene Mediated Cytotoxic Immunotherapy (GMCI™) to standard of care in patients with stage III/IV NSCLC that are not responding to a first line immune checkpoint inhibitor (ICI). GMCI kills tumor cells and creates an immune stimulatory environment in the tumor. Killing tumor cells in an immune stimulatory environment induces the body's immune system to detect and destroy cancer cells. Patients will receive two courses of GMCI with aglatimagene besadenovec injected into an accessible involved tumor site followed by 14 days of oral valacyclovir. Patients will continue with standard of care ICI, plus chemotherapy if indicated. The hypothesis is that the combination of GMCI and ICI may improve the response rate and overall clinical long-term benefit for NSCLC patients.
Full Title of Study: “GMCI Plus Standard of Care Immune Checkpoint Inhibitor for Stage III/IV NSCLC Patients”
- Study Type: Interventional
- Study Design
- Allocation: N/A
- Intervention Model: Single Group Assignment
- Primary Purpose: Treatment
- Masking: None (Open Label)
- Study Primary Completion Date: June 2022
This trial seeks to add GMCI to stage III/IV NSCLC patients who are on standard of care first line ICI with evidence that the treatment may not be optimal but have the potential for delayed clinical benefit such that continuing the ICI is indicated. Studies of first line ICI have shown that most patients that will respond, respond in the first few weeks of treatment. However, a small percentage of patients have a delayed response with ICI. GMCI has been shown to increase the response rate to ICI in animal studies. Safety and potential efficacy of GMCI has been seen in clinical trials in over 650 patients with cancer (lung, pancreas, brain and ovarian). The goal of this study is to evaluate if adding GMCI can increase the percentage of patients that respond to the continued ICI. Patients may receive whatever standard of care therapy is indicated for their disease, such as maintenance chemotherapy, bevacizumab or focal radiation, in addition to continuing ICI. The eligibility criterion for determining that the ICI may not be working is based on time on ICI and response status with 3 cohorts as follows:
Cohort 1 is for patients with stable disease at least 18 weeks after starting ICI treatment, thus they have radiographic stable disease and clinically are stable but appear to have disease that is not responding further.
Cohort 2 is for patients with evidence of radiographic progression at least 18 weeks after starting ICI treatment but who are clinically stable. Examples that would fit this cohort would be patients that have disease that decreased or was stable with initial ICI therapy, and then is slowly progressing or a new distant lesion appears on imaging, but the patient is otherwise clinically stable.
Cohort 3 is for patients who have new lesions or progression of existing lesions at least 9 weeks after starting ICI but who are clinically stable.
The specific ICI treatment regimen on this protocol is not specified to allow for different standard of care options with or without chemotherapy; for example, pembrolizumab alone, pembrolizumab plus chemotherapy, atezolizumab or atezolizumab plus chemotherapy. In addition, it allows stage III patients after chemoradiation who may be on durvalumab as their standard of care. For example, a stage III patient may be eligible for cohort 2 if they have radiographic progression but are clinically stable 18 weeks after starting durvalumab or cohort 3 if they develop a new lesion at 12 weeks after starting durvalumab.
- Biological: GMCI
- Two courses of GMCI each involving AdV-tk injection into an accessible involved tumor site followed by 14 days of oral valacyclovir.
Arms, Groups and Cohorts
- Other: Cohorts
- Cohort 1 – persistent but stable disease at least 18 weeks after starting ICI treatment Cohort 2 – radiographic progressive disease at least 18 weeks after starting ICI treatment Cohort 3 – refractory disease defined as progressed by imaging at least 9 weeks after starting ICI treatment
Clinical Trial Outcome Measures
- Response rate
- Time Frame: 12 months
- Tumor response as measured by RECIST criteria
- Safety graded by CTCAE version 5.0
- Time Frame: 12 weeks
- Frequency of adverse events
- Changes in quantity of CD8 T cell subsets
- Time Frame: 6 months
- Blood and tumor will be evaluated for changes in immune response before and after GMCI
- Overall Survival (OS)
- Time Frame: 3 years
- The OS curves will be estimated using the Kaplan-Meier method.
- Progression Free Survival (PFS)
- Time Frame: 3 years
- The PFS curves will be estimated using the Kaplan-Meier method.
- Changes in patient-reported symptoms using the NSCLC-SAQ
- Time Frame: 12 months
- NSCLC Symptoms Assessment Questionnaire (NSCLC-SAQ) score after compared to before treatment. Higher score indicates more severe symptoms.
Participating in This Clinical Trial
1. Patients with Stage III/IV NSCLC on treatment with anti-PD-1/PD-L1 (ICI) +/ chemotherapy and a) have persistent but stable disease at least 18 weeks after starting ICI treatment, b) have radiographic progressive disease at least 18 weeks after starting ICI treatment, or c) have refractory disease defined as progressed by imaging at least 9 weeks after starting ICI treatment
2. Measurable disease including a lesion that is amenable to injection
3. Able and willing to undergo a pre-treatment and on-treatment biopsy
4. ECOG Performance status of 0 or 1
5. 18 years of age or older
6. Granulocyte count (ANC) ≥ 1,000/mm3
7. Peripheral lymphocyte count ≥ 500/mm3
8. Hemoglobin ≥ 8 g/dl (patients may be transfused to meet this criterion)
9. Platelets ≥ 75,000/mm3
10. Total bilirubin ≤ 1.5 x upper limit of normal, except for patients with known Gilbert disease who must have total bilirubin ≤ 3 x upper limit of normal
11. SGOT (AST) ≤ 5x upper limit of normal and if elevated, not clinically significant such that ICI can continue
12. INR/aPTT within normal limits or, if on anti-coagulation, it must be clinically acceptable to hold anti-coagulation for the injection procedures as appropriate
13. Serum creatinine < 2mg/dl and calculated creatinine clearance > 30ml/min
14. Clinically eligible and willing to continue ICI
15. Patients must give study specific informed consent prior to enrollment
1. Patients with a history of severe hypersensitivity reaction to ICI
2. Patients who require ongoing therapy with systemic immunosuppressive drugs including systemic corticosteroids (>10 mg prednisone per day or equivalent) – premedication for ICI or chemotherapy is allowed
3. Patients with a history of active autoimmune disease requiring treatment in the past 2 years
4. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active hepatitis, or psychiatric illness/social situations that would limit compliance with study requirements
5. Women who are pregnant, lactating or intend to become pregnant during the study
6. Patients who are known to be HIV positive
7. Patients with a history of hypersensitivity or allergic reactions to valacyclovir or acyclovir
8. Patients with significant heart disease (New York Heart Association Functional Classification III or IV)
9. Patients with oxygen dependence (daily use)
10. Tumor impinging on a neurovascular structure such that inflammation in the site may put patient at risk of compromise as determined by the investigator
Gender Eligibility: All
Minimum Age: 18 Years
Maximum Age: N/A
Are Healthy Volunteers Accepted: No
- Lead Sponsor
- Advantagene, Inc. d.b.a. Candel Therapeutics
- NYU Langone Health
- Provider of Information About this Clinical Study
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