Overview

The purpose of this randomized study is to determine the safety and efficacy of quaratusugene ozeplasmid (Reqorsa) added to osimertinib in NSCLC patients with activating EGFR mutations who have progressed while on treatment with osimertinib. Quaratusugene ozeplasmid consists of non-viral lipid nanoparticles that encapsulate a DNA plasmid with the TUSC2 tumor suppressor gene and is the first systemic gene therapy for cancer.

The study will comprise of a Phase 1 dose escalation and Phase 2 evaluations of safety and efficacy. In the Phase 1 dose escalation, patients will be enrolled in sequential cohorts treated with successively higher doses of quaratusugene ozeplasmid in combination with osimertinib. When the recommended Phase 2 dose (RP2D) is determined in Phase 1, Phase 2a will be initiated and patients will be enrolled in 2 parallel, non-randomized cohorts treated with quaratusugene ozeplasmid at the RP2D in combination with osimertinib. In Phase 2b, patients will be randomized to receive either quaratusugene ozeplasmid plus osimertinib or platinum-based chemotherapy.

Eligibility

Inclusion Criteria:

1. Age ≥18 years.
2. Histologically or cytologically documented NSCLC.
3. Stage III or IV NSCLC or recurrent NSCLC that is not potentially curable by radiotherapy or surgery.
4. EGFR mutation-positive, based on results of most recent lung cancer tissue biopsy or evaluation of circulating tumor DNA. If the most recent EGFR mutation evaluation is by circulating tumor DNA, a previous lung cancer tissue biopsy must have demonstrated EGFR mutation.
5. Achieved clinical response to osimertinib for ≥4 months, which can be a response of stable disease. Must have a minimum of a 10-day osimertinib washout completed at the time of enrollment.
6. Must have radiological progression on osimertinib treatment and measurable disease per RECIST 1.1. Patients can have either asymptomatic disease or symptomatic disease. In addition, the following criteria must be met based on trial phase enrollment:

   Phase 2a:

   1. Cohort 1 must have progression on osimertinib treatment which must be the only systemic treatment for NSCLC.
   2. Cohort 2 must either have 1) progression on osimertinib in combination with pemetrexed and a platin (carboplatin or cisplatin) administered as initial treatment for metastatic NSCLC, or 2) have progression on single agent osimertinib administered as initial treatment for metastatic NSCLC, and then progression on pemetrexed and a platin (carboplatin or cisplatin), administered with or without osimertinib.

      Phase 2b:

   3. Must have progression on osimertinib treatment which must be the only systemic treatment for NSCLC.
7. Eastern Cooperative Oncology Group performance status (ECOG PS) 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 as biopsy of subcutaneous tumors, pleuroscopy, etc., and must not have evidence of wound dehiscence, active wound infection, or comparable major residual complications of the surgery per Investigator assessment.
9. Asymptomatic brain metastases must meet ALL criteria of the following (a-d):
   1. No history of seizures in the preceding 6 months.
   2. Definitive treatment must be completed ≥21 days.
   3. Must be off steroids administered because of brain metastases or related symptoms for ≥7 days.
   4. Post-treatment imaging must demonstrate stability or regression of the brain metastases.
10. Patient must have and be willing to submit archival tumor biopsy for submissions to

    central laboratory for IHC analysis.

11. Absolute neutrophil count (ANC) >1500/mm3, platelet count >100,000/mm3 within ≤21 days.
12. Adequate renal function documented by serum creatinine of ≤1.5 mg/dL or calculated creatinine clearance >50 ml/min within ≤21 days.
13. Adequate hepatic function as documented by serum bilirubin <1.5 mg/dL and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 X upper limit of normal (ULN) within ≤21 days.
14. Stable cardiac condition with a left ventricular ejection fraction ≥40% within ≤21 days.
15. If female of childbearing potential (FOCBP), must have negative serum pregnancy test (serum beta-human chorionic gonadotropin [β-hCG]) within ≤7 days.
16. FOCBP and non-sterile male patients with female partner(s) of childbearing potential must agree to use 2 forms of contraception including 1 highly effective and 1 effective method beginning ≥2 weeks prior to enrollment through 4 months following the last dose of study treatment.
17. If male, must agree to no sperm donation during study treatment and for an additional 4 months following the last dose of study treatment.
18. Must have voluntarily signed an informed consent in accordance with institutional policies.

Exclusion Criteria:

1. Unable to tolerate osimertinib treatment, leading to early treatment discontinuation or prolonged/frequent dosage modifications as determined by the Investigator.
2. Received standard chemotherapy or monoclonal antibodies to treat NSCLC within ≤21 days.
3. Received prior gene therapy.
4. Other genetic characteristics (such as ALK, ROS, BRAF V600E mutations) which makes them a candidate for treatment with other approved targeted therapies.
5. Received radiotherapy to the skull, spine, thorax, or pelvis within ≤30 days.
6. Active systemic viral, bacterial, or fungal infection(s) requiring treatment.
7. Serious concurrent illness or psychological, familial, sociological, geographical, or other concomitant conditions that, in the opinion of the Investigator, would not permit adequate follow-up and compliance with the study protocol.
8. History of myocardial infarction or unstable angina within ≤6 months.
9. Known human immunodeficiency virus (HIV) infection or has active hepatitis infection.
10. Female who is pregnant or breastfeeding.