QUILT 2.023: A Study of N-803 in Combination With Current Standard of Care vs Standard of Care as First-Line Treatment for Patients With Stage 3 or 4 NSCLC.

This is a phase 3, open-label, 4-cohort study (3 randomized cohorts and 1 single-arm cohort). Participants enrolled in each cohort will be treated as detailed below. Each study cohort will be analyzed separately. Treatment will continue for up to 2 years, or until the patient experiences confirmed progressive disease or unacceptable toxicity, withdraws consent, or if the investigator feels that it is no longer in the patient's best interest to continue treatment. Patients will be followed for disease progression, post-therapies, and survival through 24 months after the first dose of study drug.

Participant enrollment will only occur for Cohort D. Cohort D will evaluate the efficacy and safety of N-803 in combination with chemoimmunotherapy containing approved CPIs (nivolumab plus ipilimumab) as first-line treatment for participants with stage III or IV squamous or nonsquamous NSCLC.

Eligibility Criteria:
Cohorts A, B, C Inclusion Criteria:

1. Age ≥ 18 years old.
2. Able to understand and provide a signed informed consent that fulfills the relevant IRB or Independent Ethics Committee (IEC) guidelines.
3. Histologically-confirmed stage 3 or 4 NSCLC disease. Subjects with stage 3 disease must not be candidates for treatment with surgical resection or chemoradiation.
4. Subjects must not have received prior systemic chemotherapy for advanced or metastatic NSCLC. Previous neoadjuvant/adjuvant chemotherapy is allowed if completed ≥ 6 months before diagnosis of metastatic disease. Subject's with newly-diagnosed stage 4 NSCLC may have previously received systemic chemotherapy for stage 3 NSCLC.
5. For Cohort A only: NSCLC tumors must have PD-L1 expression (i.e. a TPS ≥1%) as determined by an FDA-approved test.
6. The subject's tumor must not harbor an EGFR sensitizing (activating) mutation or ALK translocation or targetable genomic aberration in BRAF, ROS1 or NTRK. EGFR sensitizing mutations are those mutations that are amenable to treatment with tyrosine kinase inhibitors including erlotinib, gefitinib, or afatinib. Investigators must be able to produce the source documentation of the EGFR mutation, ALK translocation, and BRAF, ROS1, and NTRK status. If any of the genomic changes described above are detected, additional information regarding the mutation status of other molecules is not required. If unable to test for these molecular changes, formalin fixed paraffin embedded tumor tissue of any age should be submitted to a central laboratory designated by the Sponsor for such testing. Subjects will not be randomized until the EGFR , BRAFT, ROS1, and NTRK mutation status and ALK translocation status is available in source documentation at the site.
7. ECOG performance status of 0 or 1.
8. Measurable tumor lesions according to RECIST 1.1.
9. Must be willing to release tumor biopsy specimen used for diagnosis of advanced or metastatic NSCLC (if available) for exploratory tumor molecular profiling. If tumor biopsy specimen is not available, subjects can still be enrolled.
10. Must be willing to provide blood samples prior to the start of treatment on this study for exploratory tumor molecular profiling analysis.
11. Must be willing to provide a tumor biopsy specimen 9 weeks after the start of treatment for exploratory analyses, if considered safe by the Investigator.
12. Ability to attend required study visits and return for adequate follow-up, as required by this protocol
13. Agreement to practice effective contraception for female subjects of child-bearing potential and non-sterile males. Female subjects of child-bearing potential must agree to use effective contraception for up to 1 year after completion of therapy, and non-sterile male subjects must agree to use a condom for up to 4 months after treatment. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), two forms of barrier methods (eg, condom, diaphragm) used with spermicide, intrauterine devices (IUDs), hormonal therapy, and abstinence.

Cohorts A, B, C Exclusion Criteria:

1. Serious uncontrolled concomitant disease that would contraindicate the use of the investigational drug used in this study or that would put the subject at high risk for treatment-related complications.
2. A history of prior malignancy with the following exceptions: cancer treated with curative therapy with no disease recurrence for \>3 years, non-metastatic prostate cancer controlled with hormonal therapy, or under observation; non-metastatic thyroid cancer; basal or squamous cell carcinoma of the skin, superficial bladder cancer, or in situ cervical cancer that has undergone successful definitive resection.
3. Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's disease, or autoimmune disease associated with lymphoma).
4. History of organ transplant requiring immunosuppression; or history of pneumonitis or interstitial lung disease requiring treatment with systemic steroids; or a history of receiving systemic steroid therapy or any other immunosuppressive medication ≤ 3 days prior to study initiation. Daily steroid replacement therapy (eg, prednisone or hydrocortisone) and corticosteroid use to manage AEs are permitted.
5. Prior systemic chemotherapy, major surgery, or thoracic radiation within 3 weeks of study initiation.
6. Requirement for other forms of anticancer treatment while on trial, including maintenance therapy, other radiation therapy, and/or surgery. Palliative radiation is permitted.
7. Known CNS metastases or carcinomatous meningitis. Subjects with previously treated, stable CNS metastases (no evidence of progression for ≥ 4 weeks, and resolution of neurologic symptoms to baseline state) are permitted in this study.
8. History of receiving a live vaccine 30 days prior to study treatment.
9. History of human immunodeficiency virus (HIV), or known active hepatitis B or C infection.
10. An active infection requiring systemic IV therapy.
11. History of or active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis).
12. Inadequate organ function, evidenced by the following laboratory results:

    1. Absolute neutrophil count \< 1,500 cells/mm3.
    2. Platelet count \< 100,000 cells/mm3.
    3. Total bilirubin greater the upper limit of normal (ULN; unless the subject has documented Gilbert's syndrome).
    4. Aspartate aminotransferase (AST \[SGOT\]) or alanine aminotransferase (ALT \[SGPT\]) \> 1.5 × ULN.
    5. Alkaline phosphatase (ALP) levels \> 2.5 × ULN.
    6. Serum creatinine \> 2.0 mg/dL or 177 μmol/L or creatinine clearance \< 40 mL/min (using the Cockcroft-Gault formula)
13. Uncontrolled hypertension (systolic \> 160 mm Hg and/or diastolic \> 110 mm Hg) or clinically significant (ie, active) cardiovascular disease, cerebrovascular accident/stroke, or myocardial infarction within 6 months prior to first study medication; unstable angina; congestive heart failure of New York Heart Association grade 2 or higher; or serious cardiac arrhythmia requiring medication. Subjects with uncontrolled hypertension should be medically managed on a stable regimen to control hypertension prior to study entry.
14. Dyspnea at rest due to complications of advanced malignancy or other disease requiring continuous oxygen therapy.
15. Known hypersensitivity to any component of the study medication(s).
16. Subjects taking any medication(s) (herbal or prescribed) known to have an adverse drug reaction with any of the study medications.
17. Participation in an investigational drug study or history of receiving any investigational treatment within 30 days prior to screening for this study, except for testosterone-lowering therapy in men with prostate cancer.
18. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol.
19. Concurrent participation in any interventional clinical trial.
20. Pregnant and nursing women.

Cohort D Inclusion criteria

1. Age ≥ 18 years old.
2. Able to understand and provide a signed informed consent that fulfills the relevant IRB or IEC guidelines
3. Histologically-confirmed stage III or IV NSCLC disease. Participants with stage III disease must not be candidates for treatment with surgical resection or definitive chemoradiation.
4. ECOG performance status of 0 to 2.
5. Measurable tumor lesions according to RECIST v1.1.
6. Ability to attend required study visits and return for adequate follow-up, as required by this protocol.
7. Agreement to practice effective contraception for female participants of childbearing potential and non-sterile males. Female participants of childbearing potential must agree to use effective contraception for up to 7 months after completion of therapy, and nonsterile male participants must agree to use a condom for up to 7 months after treatment. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), orals, injectables. two forms of barrier methods (eg, condom, diaphragm) used with spermicide, intrauterine devices (IUDs), and hormonal therapy.

Cohort D Exclusion criteria

1. Prior systemic therapy or radiation therapy for treatment of current advanced or metastatic NSCLC.
2. Have known EGFR mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 \[L858R\] substitution mutations). All participants with nonsquamous histology must have been tested for EGFR mutation status; use of an approved test is strongly encouraged. Participants with nonsquamous histology and unknown or indeterminate EGFR status are excluded.
3. Have known ALK translocations which are sensitive to available targeted inhibitor therapy are excluded. If tested, use of an approved test is strongly encouraged.

   Participants with unknown or indeterminate ALK status may be enrolled.
4. Systemic autoimmune disease currently requiring treatment (eg, lupus erythematosus, rheumatoid arthritis, Addison's disease, or autoimmune disease associated with lymphoma). Participants must have been off treatment for 180 days.
5. History of organ transplant requiring immunosuppression; or history of pneumonitis or interstitial lung disease requiring treatment with systemic steroids; or a history of receiving systemic steroid therapy or any other immunosuppressive medication ≤ 3 days prior to study initiation. Daily steroid replacement therapy (eg, prednisone or hydrocortisone) and corticosteroid use to manage AEs are permitted.
6. Requirement for other forms of anticancer treatment while on trial, including maintenance therapy, radiation therapy, and/or surgery. Palliative radiation is permitted.
7. Participants with untreated CNS metastases and carcinomatous meningitis are excluded.

   Participants are eligible if CNS metastases are adequately treated and participants are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to first treatment. In addition, participants must be either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisone.
8. Active infection requiring systemic IV therapy.
9. History of or active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis).
10. Inadequate organ function, evidenced by the following laboratory results:

    1. Absolute lymphocyte count \< institutional ULN.
    2. Absolute neutrophil count \< 1,500 cells/mm3.
    3. Platelet count \< 100,000 cells/mm3.
    4. Total bilirubin greater than the upper limit of normal (ULN; unless the participant has documented Gilbert's syndrome).
    5. Aspartate aminotransferase (AST \[SGOT\]) or alanine aminotransferase (ALT \[SGPT\]) \> 1.5 × ULN.
    6. ALP levels \> 2.5 × ULN.
    7. Hemoglobin \< 9.0 g/dL.
    8. Serum creatinine \> 2.0 mg/dL or 177 μmol/L or creatinine clearance \< 40 mL/min (using the Cockcroft-Gault formula below). Female = \[(140 - age in years) × weight in kg x 0.85\] / \[72 × serum creatinine in mg/dL\] Male = \[(140 - age in years) × weight in kg × 1.00\] / \[72 × serum creatinine in mg/dL\].
11. Participants taking any medication(s) (herbal or prescribed) known to have an adverse drug reaction with any of the study medications.
12. Participation in an investigational drug study or history of receiving any investigational treatment within 30 days prior to the start of treatment on this study, except for hormone-lowering therapy in participants with hormone-sensitive cancer.
13. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol.
14. Pregnant and nursing women.