Quaratusugene Ozeplasmid (Reqorsa) in Combination With Pembrolizumab in Previously Treated Non-Small Lung Cancer

Patients will have their most recent archival tumor biopsy submitted to a central laboratory for IHC analysis.

Inclusion Criteria:

1. Age ≥18 years.

2. Voluntarily signed an informed consent in accordance with institutional policies.

3. Histologically or cytologically documented NSCLC (SQ, NSQ, or mixed (adenosquamous)histology) with locally advanced or metastatic disease. Note: Any level of PD-L1 TPSis allowed.

4. Achieved clinical benefit to prior pembrolizumab or pembrolizumab/platinum-basedchemotherapy for at least 3 months and subsequently progressed as confirmed byradiological tumor assessment per RECIST 1.1. Patients receiving pembrolizumab as asingle agent must have additional therapy with a platinum-based chemotherapy priorto enrolling, but patients receiving pembrolizumab in combination with aplatinum-based chemotherapy should have enrollment in this trial as the nexttreatment regimen. Chemotherapy is to be limited such that study treatment will be 2nd or 3rd line.

5. For Phase 2, patients must have measurable disease per RECIST 1.1.

6. Patients with genetic alterations with FDA-approved therapy (such as EGFR oranaplastic lymphoma kinase [ALK] mutations) must have disease progression aftertreatment with appropriate targeted therapy and must be eligible for immunotherapyas determined by the investigator.

7. ECOG performance status score from 0 to 1.

8. Must be ≥28 days beyond major surgical procedures such as thoracotomy, laparotomy,or joint replacement, and must be ≥10 days beyond minor surgical procedures such asbiopsy of subcutaneous tumors, pleuroscopy, etc., and must not have evidence ofwound dehiscence, active wound infection, or comparable major residual complicationsof the surgery. Note: Placement of pleural catheter despite being a minor surgicalprocedure, may be performed <10 days prior to study enrollment.

9. Demonstrate adequate organ function, as determined by the following laboratoryvalues obtained within 21 days prior to enrollment:

10. Absolute neutrophil count (ANC) ≥1,500/μL,

11. Platelets ≥ 100,000/μL,

12. Hemoglobin ≥8.0 g/dL ≥2 weeks without transfusions,

13. International normalized ratio (INR) or prothrombin time (PT): ≤1.5 × upperlimit of normal (ULN) unless the patient is receiving anticoagulant therapy aslong as PT is within therapeutic range of intended use of anticoagulants,

14. Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT): ≤1.5 × ULN unless the patient is receiving anticoagulant therapy as longas aPTT is within therapeutic range of intended use of anticoagulants,

15. Creatinine ≤1.5 × ULN OR calculated creatinine clearance (CrCl) ≥60 mL/min forpatients with creatinine levels >1.5 × ULN,

16. Serum total bilirubin ≤1.0 × ULN,

17. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 × ULN,

18. Alkaline phosphatase ≤2.5 x ULN.

19. Stable cardiac condition with a left ventricular ejection fraction >40% within ≤21days prior to enrollment.

20. Asymptomatic brain metastases, must meet ALL of the following criteria (a-d):

21. No history of seizures in the preceding 6 months,

22. Definitive treatment must be completed ≥4 weeks prior to enrollment,

23. Stopped corticosteroid treatments administered because of brain metastases orrelated symptoms for ≥2 weeks prior to enrollment,

24. Post-treatment imaging must demonstrate stability or regression of the brainmetastases.

25. Female patients of childbearing potential (FOCBP) must have a negative serumpregnancy test at screening (within 7 days of enrollment). Note: Non-childbearingpotential is defined as greater than 1 year postmenopausal or surgically sterilized.

26. FOCBP and non-sterile male patients with female partner(s) of childbearing potentialmust agree to use 2 forms of contraception including 1 highly effective and 1effective method beginning ≥2 weeks prior to enrollment through 4 months followingthe last dose of study treatment.

27. Male patients must agree to no sperm donation during study treatment and for anadditional 4 months following the last dose of study treatment.

Exclusion Criteria:

1. Unable to tolerate pembrolizumab treatment, leading to early treatmentdiscontinuation or prolonged/frequent dosage modifications as determined by theinvestigator.

2. Hypersensitivity to docetaxel or polysorbate 80 (Phase 2 only).

3. Patients at risk of tumor lysis syndrome (e.g., renal impairment, hyperuricemia,bulky tumor [Phase 2 randomized portion only]).

4. Received prior systemic chemotherapy or monoclonal antibodies for the treatment ofthe participant's advanced or metastatic disease within 21 days of study enrollment.

5. Received prior gene therapy.

6. Received any radiotherapy to the skull, spine, thorax, or pelvis within 1 month ofstudy enrollment. Note: Patients are permitted to have received palliativeradiotherapy to an extremity provided at least 14 days has elapsed since completionof therapy, provided the patient received no more than 10 radiotherapy fractions anda dose no higher than 30 Gy to that site.

7. Expected to require any other form of antineoplastic therapy while participating inthe study.

8. Received a live-virus vaccination within 1 month of enrollment. Seasonal fluvaccines that do not contain live virus are permitted.

9. Has known active, symptomatic CNS metastases and/or carcinomatous meningitis.

10. Active, known, or suspected autoimmune disease.

11. Active systemic viral, bacterial, or fungal infections(s) requiring treatment.

12. Serious concurrent illness or psychological, familial, sociological, geographical,or other condition that, in the opinion of the investigator, would prevent adequatefollow-up and compliance with the study protocol.

13. A condition requiring systemic treatment with either corticosteroids (>10 mg dailyprednisone equivalents) or other immunosuppressive medications within 14 days ofstudy enrollment. Inhaled or topical steroids and adrenal replacement doses ≤10 mgdaily prednisone equivalents are permitted in the absence of active autoimmunedisease.

14. Active concurrent malignancies, i.e., cancers other than NSCLC.

15. Has a second, concurrent, untreated malignancy.

16. History of symptomatic interstitial lung disease or pneumonitis that required oral (PO) or IV glucocorticoids to assist with management. Note: Lymphangitic spread ofthe NSCLC is not an exclusion criterion.

17. History of myocardial infarction or unstable angina within 6 months prior toenrollment.

18. Presence of pre-existing peripheral neuropathy that is ≥Grade 2 by NCI-CTCAE v5.0criteria.

19. Is, at the time of signing informed consent, a regular user (including "recreationaluse") of any illicit drugs or has a recent history (within the last year) ofsubstance abuse (including alcohol) requiring medical intervention.

20. Known human immunodeficiency virus (HIV) infection or has active hepatitisinfection.

21. Female patients who are pregnant or breastfeeding.