This phase I trial investigates the best dose and side effects of NBTXR3 when given together with radiation therapy for the treatment of non-small cell lung cancer that cannot be treated by surgery (inoperable) and has come back (recurrent). NBTXR3 is a radio-enhancer designed to increase the radiotherapy energy dose deposition inside tumor cells. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving NBTXR3 and radiation therapy may increase radiation-dependent tumor cell killing without increasing the radiation exposure of healthy surrounding tissues.

PRIMARY OBJECTIVE:

I. To assess the safety of 45 Gy in 15 fractions in patients with inoperable, locoregional recurrent NSCLC, previously treated with definitive radiation therapy.

II. To determine the recommended phase II dose (RP2D) of NBTXR3 activated by radiotherapy in patients with inoperable, locoregional recurrent NSCLC, previously treated with definitive radiation therapy.

SECONDARY OBJECTIVES:

I. To evaluate the safety and feasibility of reirradiation with NBTXR3 in patients with inoperable, locoregionally recurrent NSCLC.

II. To evaluate the anti-tumor response of reirradiation with NBTXR3 in patients with inoperable, locoregionally recurrent NSCLC.

III. To evaluate time-to-event outcomes after reirradiation with NBTXR3 in patients with inoperable, locoregionally recurrent NSCLC

EXPLORATORY OBJECTIVE:

I. To assess biomarkers of response in patients treated with NBTXR3/radiation therapy (RT).

OUTLINE: This is a dose-escalation and dose-expansion study of NBTXR3.

Patients receive NBTXR3 intratumorally (IT) or intranodally on day 1. Within 15 days, patients undergo RT 5 times weekly (Monday-Friday) over 3 weeks for a total of 10-15 fractions.

After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for up to 5 years.

Inclusion Criteria:

1. Biopsy proven locoregionally recurrent NSCLC after prior definitive radiation therapy, or patients that have imaging characteristics highly suggestive of recurrence but no pathologic or cytologic diagnosis. Pathologic diagnosis will be confirmed during the procedure to inject NBTXR3, prior to injecting the drug. If pathologic diagnosis cannot be established, the procedure will be aborted and the patient will be considered a screening failure. For stage IV patients, oligometastatic disease should be confirmed at screening. Oligometastatic disease is defined as ≤ 3 cancer lesions, not including the primary tumor.

2. Participant deemed medically inoperable by the investigator or treating physician.

3. Overlap between recurrent disease in need of treatment and prior radiation treatment field as determined by treating Radiation Oncologist.

   1. As a general reference, recurrent disease within 50% isodose line of prior radiation treatment field would be considered significant.
   2. Radiation treatment received more than 6 months prior to enrollment.

4. Amenable to undergo bronchoscopic (EBUS, CBCT) or CT-guided injection of NBTXR3 as per investigator or treating physician.

   1. Up to 4 lung lesions may be injected with NBTXR3, including the primary tumor, involved lymph node(s), and/or metastatic lesion(s).
   2. At least 1 injected lesion should be located within a reirradiation field.
   3. All injected lesions must be radiated.

5. The target lesion(s) should be measurable on cross sectional imaging (RECIST 1.1).

   a. Nodal target lesions must be ≥15 mm (short axis) based on CT (slice thickness of 5 mm or less) or MRI.

6. Age ≥ 18 years

7. ECOG Performance Status 0-2

8. For cohort 1, adequate laboratory values to receive radiation as determined by the principal investigator or treating physician.

9. For cohort 2 laboratory values at screening:

   1. Hemoglobin ≥ 8.0 g/dL
   2. Absolute Neutrophil Count (ANC) ≥ 1,500/mm3
   3. Platelet Count ≥ 100,000/mm3
   4. Creatinine ≤ 1.5 x upper limit of normal (ULN)
   5. Calc. Creatinine Clearance ≥ 30 mL/min
   6. Total Bilirubin ≤ 2.0 mg/dL
   7. AST / ALT ≤ 3.0 x upper limit of normal (ULN) or 5.0 x ULN if known liver metastases
   8. Serum albumin ≥ 3.0 g/dL

10. Negative urine or serum pregnancy test ≤ 7 days of NBTXR3 injection in all female of child-bearing potential.

11. Signed informed consent form (ICF) indicating that participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.

12. English speaking or Non-English Speaking subjects

Exclusion Criteria:

1. At screening, past medical history of:

   1. Interstitial lung disease, excluding drug-induced ILD, speficially immunotherapy-induced pneumonitis that has been resolved
   2. Any Grade 4 thoracic radiation related toxicity
   3. Unresolved radiation related

   i. Esophagitis ii. Pneumonitis iii. Bronchopulmonary hemorrhage d. Any Grade i. Esophageal perforation ii. Radiation associated airway necrosis iii. Bronchoesophageal fistula e. Any Grade i. Esophageal perforation ii. Radiation associated airway necrosis iii. Bronchoesophageal fistula iv. Tracheoesophageal fistula v. Spinal cord myelopathy

2. Has received any approved or investigational anti-neoplastic or immunotherapy agent within 2 weeks prior to NBTXR3 injection

3. Use of concurrent systemic therapy (chemotherapy, immunotherapy, targeted therapy) or patient participation on another therapeutic clinical trial.

4. Active malignancy, in addition to locoregionally recurrent NSCLC, with the exception of definitively treated and relapse free within 1 year from diagnosis of non-melanoma skin cancer or cervical cancer in situ; definitively treated non-metastatic prostate cancer; or patients with another primary malignancy who are definitively treated and relapse free with at least 2 years elapsed since the diagnosis of the other primary malignancy.

5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, renal failure, cardiac arrhythmia, or psychiatric illness that would limit compliance with treatment.

6. Known active, uncontrolled (high viral load) HIV or hepatitis B or hepatitis C infection

7. Female patients who are pregnant or breastfeeding.

8. Women of child-bearing potential and their male partners who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period. Acceptable methods of contraception are those that, alone or in combination, result in a failure rate of < 1% per year when used consistently and correctly.

9. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

10. Cognitively impaired subjects