ALT-803 Plus Nivolumab in Patients With Pretreated, Advanced or Metastatic Non-Small Cell Lung Cancer

The purpose of the study is to define the safety and tolerability of this drug combination. The study will also define the response rate of patients with advanced and unresectable NSCLC.

This study has a dose escalation (Ib) and dose expansion phase (II). The ALT-803 treatment in the Phase Ib portion of the study will escalate until a recommended dose level is decided. This dose level will be used in the phase II portion of the study. The Phase II potion of the study will include two groups: Nivolumab naive and Nivolumab progressing. Patients will be enrolled to one of the arms based on their previous treatment with Nivolumab.

Eligibility Criteria:
Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of NSCLC who present with Stage IIIB/Stage IV disease (according to version 7 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology) or recurrent disease following radiation therapy or surgical resection.
2. Patient must be eligible for treatment with nivolumab. Patients previously treated with nivolumab, pembrolizumab or atezolizumab, and who have progressed are eligible.

   Patients with targetable with EGFR or ALK mutations are eligible after disease recurrence or progression after at least one targeted therapy for advanced or metastatic disease.
3. Measurable disease as defined by RECIST 1.1 criteria.
4. Age ≥ 18 years
5. Performance status: ECOG performance status of ≤1 (Appendix A)
6. Adequate organ system function within 14 days of registration:

   ANC ≥ 750/μL (≥0.75 X 109/L) PLT ≥ 100,000/μL (≥ 30 X 109/L) HGB \> 8g/dL Total bilirubin \< 2.0 x ULN AST \< 3.0 X ULN ALT \< 3.0 X ULN eGFR\* \> 45mL/min

   \*using Cockcroft \& Gault equation (see Appendix B)
7. Negative serum pregnancy test if WOCBP (non-childbearing is defined as greater than one year postmenopausal or surgically sterilized).
8. Female participants of childbearing potential must adhere to using a medically accepted method of birth control up to 28 days prior to screening and agree to continue its use during the study or be surgically sterilized (e.g., hysterectomy or tubal ligation) and males must agree to use barrier methods of birth control while on study. WOCBP must agree to use effective contraception during treatment and for at least 5 months following the last dose of study treatment.
9. Prior to any study specific activities, the patient must be aware of the nature of his/her disease and willingly consent to the study after being informed of study procedures, the experimental therapy, possible alternatives, risks and potential benefits.

Exclusion Criteria:

1. While prior therapy with nivolumab, pembrolizumab, or atezolizumab is allowed, any prior therapy with other anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) is not allowed.
2. NYHA Class III or IV heart failure (Appendix C), uncontrollable supraventricular arrhythmias, any history of a ventricular arrhythmia, or other clinical signs of severe cardiac dysfunction.
3. Symptomatic congestive heart failure, unstable angina pectoris, or myocardial infarction within 6 months of registration.
4. Marked baseline prolongation of QT/QTc interval (e.g. demonstration of a QTc interval greater than 500 milliseconds).
5. Patients with CNS metastases with the following exceptions: Patient untreated CNS metastases with 5 or fewer sites of disease, with no single site larger than 20mm, are eligible if they are asymptomatic and not requiring steroids at any dose. Patients with asymptomatic CNS metastases may be treated with radiosurgery before or during therapy on trial without treatment delays. Patients with treated, symptomatic CNS metastases are eligible if they are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to registration AND either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent).
6. Known autoimmune disease requiring active treatment. Subjects with a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of registration are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses \< 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
7. Subjects with a history of interstitial lung disease and/or pneumonitis.
8. Known HIV-positive.
9. Active systemic infection requiring parenteral antibiotic therapy. All prior infections must have resolved following optimal therapy.
10. Positive hepatitis C serology or active hepatitis B infection. Chronic asymptomatic viral hepatitis is allowed.
11. Women who are pregnant or nursing.
12. Psychiatric illness/social situations that would limit compliance with study requirements.
13. Any ongoing toxicity from prior anti-cancer treatment that, in the judgment of the investigator, may interfere with study treatment. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must resolve to grade 1 (NCI CTCAE version 4) or baseline prior to registration.
14. Anti-cancer treatment including surgery, radiotherapy, chemotherapy, other immunotherapy, or investigational therapy within 14 days of registration.
15. Other illness that in the opinion of the investigator would exclude the patient from participating in this study, including uncontrolled diabetes mellitus, cardiac disease.