GMCI Plus Standard of Care Immune Checkpoint Inhibitor for Stage III/IV NSCLC
- Interventional
- Recruiting
- NCT04495153
Contact Information
GMCI Plus Standard of Care Immune Checkpoint Inhibitor for Stage III/IV NSCLC Patients
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.
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 700 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 radiographically at least 18 weeks after starting ICI treatment and are clinically 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.
Cohort 1 is for patients with stable disease radiographically at least 18 weeks after starting ICI treatment and are clinically 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.
Gender
All
Age Group
18 Years and up
Accepting Healthy Volunteers?
No
Inclusion Criteria:
1. Patients with Stage III/IV NSCLC on first line treatment with anti-PD-1/PD-L1 (ICI) +/- chemotherapy for their current stage of disease and fits into one of the following three cohorts as determined by investigator, preferably as per RECIST 1.1: Cohort 1) have persistent but stable disease at least 18 weeks after starting ICI treatment, Cohort 2) have radiographic progressive disease at least 18 weeks after starting ICI treatment, or Cohort 3) have refractory disease defined as progressed by imaging at least 9 weeks after starting ICI treatment
2. RECIST evaluable disease including a lesion that is amenable to injection
3. Able and willing to undergo a pre-treatment and on-treatment biopsy, if feasible
4. ECOG Performance status of 0 or 1
5. 18 years of age or older
6. Granulocyte count (ANC) ≥ 1,000/mm3
7. Hemoglobin ≥ 8 g/dl (patients may be transfused to meet this criterion)
8. Platelets ≥ 75,000/mm3
9. 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
10. SGOT (AST) ≤ 5x upper limit of normal and if elevated, not clinically significant such that ICI can continue
11. INR no more than 0.2 above upper limit of normal and aPTT not >1.2 x upper limit of normal, and value is acceptable for patient to undergo injection procedure. If on anti-coagulation, it must be clinically acceptable to hold anti-coagulation for the injection procedures per investigator discretion
12. Serum creatinine < 2mg/dl and calculated creatinine clearance > 30ml/min
13. Clinically eligible and willing to continue ICI for at least the 12-week treatment period
14. Patients must give study specific informed consent prior to enrollment and any study specific procedures
Exclusion Criteria:
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 continuous oxygen dependence >2L/min at rest
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
11. Patients with uncontrolled brain metastases as per investigator
12. Patients with liver metastases involving more than half of the liver
1. Patients with Stage III/IV NSCLC on first line treatment with anti-PD-1/PD-L1 (ICI) +/- chemotherapy for their current stage of disease and fits into one of the following three cohorts as determined by investigator, preferably as per RECIST 1.1: Cohort 1) have persistent but stable disease at least 18 weeks after starting ICI treatment, Cohort 2) have radiographic progressive disease at least 18 weeks after starting ICI treatment, or Cohort 3) have refractory disease defined as progressed by imaging at least 9 weeks after starting ICI treatment
2. RECIST evaluable disease including a lesion that is amenable to injection
3. Able and willing to undergo a pre-treatment and on-treatment biopsy, if feasible
4. ECOG Performance status of 0 or 1
5. 18 years of age or older
6. Granulocyte count (ANC) ≥ 1,000/mm3
7. Hemoglobin ≥ 8 g/dl (patients may be transfused to meet this criterion)
8. Platelets ≥ 75,000/mm3
9. 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
10. SGOT (AST) ≤ 5x upper limit of normal and if elevated, not clinically significant such that ICI can continue
11. INR no more than 0.2 above upper limit of normal and aPTT not >1.2 x upper limit of normal, and value is acceptable for patient to undergo injection procedure. If on anti-coagulation, it must be clinically acceptable to hold anti-coagulation for the injection procedures per investigator discretion
12. Serum creatinine < 2mg/dl and calculated creatinine clearance > 30ml/min
13. Clinically eligible and willing to continue ICI for at least the 12-week treatment period
14. Patients must give study specific informed consent prior to enrollment and any study specific procedures
Exclusion Criteria:
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 continuous oxygen dependence >2L/min at rest
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
11. Patients with uncontrolled brain metastases as per investigator
12. Patients with liver metastases involving more than half of the liver