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 is comprised of a Phase 1 dose escalation portion and two Phase 2 portions evaluating safety and efficacy. Enrollment in the Phase 1 dose escalation portion is complete and the recommended Phase 2 dose (RP2D) was determined. Phase 2a has initiated and enrolled patients are 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.

Acclaim-1 is an open-label, multi-center, Phase 1/2 study evaluating quaratusugene ozeplasmid (Reqorsa) plus osimertinib (investigational arm) versus platinum-based chemotherapy (control arm) in patients with advanced metastatic or recurrent NSCLC.

Toxicities will be assessed by the Investigator using United States National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Serious Adverse Events and Dose Limiting Toxicities (DLT) will be reviewed by a Safety Review Committee.

Phase 1 - Dose Escalation: The RP2D of quaratusugene ozeplasmid when given in combination with osimertinib has been identified.

Phase 2a: This expansion cohort will be enrolled to better characterize safety, tolerability, and preliminary anti-tumor activity of the combination therapy.

Phase 2b: Quaratusugene ozeplasmid in combination with osimertinib will be further evaluated using the RP2D identified in Phase 1. Patients may receive local therapy, such as radiation therapy, to progressing lesions prior to enrollment. Patients will be randomized to receive either the investigational arm or the control arm in a 1 to 1 ratio and stratified based on prior local radiotherapy.

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. The NSCLC must be epidermal growth factor receptor (EGFR) mutation positive-positive based on results from most recent tissue biopsy or most recent evaluation of circulating tumor DNA.

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 can have either asymptomatic disease or symptomatic disease. In addition:

   1. Must have measurable disease per RECIST 1.1.
   2. Must have progression on osimertinib treatment as a single agent or in combination with other anti-cancer agents as their most recent treatment.

   Notes:

   • Patients may have had treatment with other EGFR inhibitors as single agents prior to osimertinib.
   • Patients may have progression on osimertinib treatment being used for adjuvant therapy after surgery.

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 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 six 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. Must have and be willing to submit a prior tumor biopsy or undergo a biopsy during Screening to obtain tumor tissue for submission to a central laboratory for IHC analysis and FISH or qPCR testing.

11. Absolute neutrophil count (ANC) >1500/mm3, platelet count >100,000/mm3 within ≤28 days.

12. Adequate renal function documented by serum creatinine of ≤1.5 mg/dL or calculated creatinine clearance >50 ml/min within ≤28 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 ≤28 days.

14. Stable cardiac condition with a left ventricular ejection fraction ≥40% within ≤28 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 two forms of contraception including one highly effective and one effective method beginning ≥2 weeks prior to enrollment through four months following the last dose of study treatment.

17. If male, must agree to no sperm donation during study treatment and for an additional four 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 prior gene therapy.
3. Other genetic characteristics (such as ALK, ROS, BRAF V600E mutations) which make them a candidate for treatment with other approved targeted therapies.
4. Received radiotherapy to the skull, spine, thorax, or pelvis within ≤30 days.
5. Active concurrent malignancies, i.e., cancers other than NSCLC that require systemic therapy.
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.