Personalized Escalation of Consolidation Treatment Following Chemoradiotherapy and Immunotherapy in Stage III NSCLC in Stage III NSCLC

Inclusion Criteria:

1. Histologically- or cytologically-documented NSCLC presenting with locally-advanced,unresectable stage III disease (Version 8 of AJCC Staging Manual) or NSCLC withlocoregional recurrence after previous definitive treatment.

2. For stage III or recurrent disease, must have completed platinum-based chemotherapyand radiation therapy to all known tumor sites (60 Gy +/- 10%). Must not have knownprogression of disease.

3. Must be receiving consolidation durvalumab following completion of radiation andchemotherapy, and less than 32 weeks has elapsed from their first dose ofdurvalumab. (Patients may sign consent for study before start of durvalumab, butconfirm eligibility and enroll only after first dose of durvalumab is received).

4. Able to potentially receive further consolidation chemotherapy plus durvalumab andtremelimumab, but not be currently intended to receive additional systemicconsolidation chemotherapy apart from this durvalumab.

5. Pre-treatment tumor tissue or tumor DNA sample is believed to be available foranalysis

6. Aged 18 years or older

7. Weight > 30kg

8. Life expectancy ≥ 12 weeks

9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

10. Absolute neutrophil count > 1.0 x 109/L (1000/mm3)

11. Platelets > 75 x 109/L (100,000/mm3)

12. Hemoglobin ≥ 9.0 g/dL (5.59 mmol/L)

13. Measured creatinine clearance > 40 mL/min, by either 24 hour urine collection or theCockcroft Gault formula Males: Mass(kg) x (140-Age) / 72 x serum creatinine (mg/dL) Females: Mass(kg) x (140-Age) x 0.85 / 72 x serum creatinine (mg/dL)

14. Serum bilirubin ≤ 1.5 x upper limit of normal (ULN). This will not apply to subjectswith confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia thatis predominantly unconjugated in the absence of evidence of hemolysis or hepaticpathology) who will be allowed in consultation with their physician.

15. aspartate aminotransferase (AST) (SGOT)/Alanine Aminotransferase (ALT) (SGPT) ≤ 2.5x institutional upper limit of normal (ULN) unless liver metastases are present, inwhich case it must be ≤ 5 x ULN

16. Ability to understand and the willingness to sign the written IRB approved informedconsent document.

Exclusion Criteria:

Involvement in the planning and/or conduct of the study

2. Previous enrollment or randomization in the present study

3. Received Investigational product as part of another clinical study

4. Mixed small cell and non small cell lung cancer histology

5. History of another primary malignancy and currently undergoing active treatment.

Exception: May participate if receiving adjuvant endocrine therapy for breast or prostate cancer.

6. Current or prior use of immunosuppressive medication within 14 days beforeenrollment, with the exceptions of intranasal and inhaled corticosteroids orsystemic corticosteroids at physiological doses, which are not to exceed 10 mg/dayof prednisone, or an equivalent corticosteroid. Systemic steroid administrationrequired to manage toxicities arising from radiation therapy delivered as part ofthe chemoradiation therapy for locally advanced NSCLC is allowed.

7. Any unresolved toxicity CTCAE > Grade 2 from the prior chemoradiation therapy withthe exception of alopecia, vitiligo, and the laboratory values defined in theinclusion criteria.

• Subjects with Grade ≥ 2 neuropathy will be evaluated on a case by case basis afterconsultation with the Protocol Director / Principal Investigator

• Subjects with irreversible toxicity that is not reasonably expected to beexacerbated by treatment with durvalumab may be included (ie, hearing loss) onlyafter consultation with the Protocol Director / Principal Investigator.

8. Any prior Grade ≥ 3 immune related adverse event (irAE) while receiving anyprevious immunotherapy agent, or any unresolved irAE > Grade 1) that may limitsubject from continuing durvalumab during the study

9. Recent major surgery within 4 weeks prior to entry into the study (excludingthe placement of vascular access) that would prevent administration of studydrug.

10. Active or prior documented autoimmune or inflammatory disorders which is likelyto limit the subjects ability to continue durvalumab on the study (includinginflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus,Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis;Graves' disease; rheumatoid arthritis; hypophysitis; uveitis; etc]). Those withhistory of autoimmune or inflammatory disorders who are currently toleratingdurvalumab may be eligible to participate with approval from the PI. Thefollowing are also exceptions to this criterion:

11. Vitiligo or alopecia

12. Hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement

13. Chronic skin condition not requiring systemic therapy

14. Celiac disease controlled by diet alone

15. History of primary immunodeficiency

16. History of organ transplant requiring therapeutic immunosuppression

17. History of hypersensitivity to carboplatin, pemetrexed, paclitaxel, ornab-paclitaxel that is likely to prevent re-administration of these agents

18. Active infection including but not limited to:

• Grade 3 or higher clinically significant infection

• Active known Hepatitis B [known positive results for HBV surface antigen (HBsAg)within 2 months prior to enrollment]. EXCEPTION: Subjects with a past or resolvedHBV infection, defined as the presence of hepatitis B core antibody (anti-HBc) andabsence of HBsAg are eligible

• Active known Hepatitis C (HCV). EXCEPTION: Subjects positive for HCV antibody areeligible only if polymerase chain reaction is negative for HCV RNA

• Active known tuberculosis infection (clinical evaluation that may include clinicalhistory, physical examination and radiographic findings, or tuberculosis testing inline with local practice).

• Active known HIV infection

15. Receipt of live attenuated vaccine within 30 days prior to the first dose ofconcurrent chemotherapy and durvalumab. Note: Subjects, if enrolled, should notreceive live vaccine through 30 days after the last dose of chemotherapyconcurrent with durvalumab.

16. Uncontrolled intercurrent illness, including but not limited to:

• Ongoing or active infection

• Symptomatic congestive heart failure

• Uncontrolled hypertension

• Unstable angina pectoris

• Cardiac arrhythmia

• Interstitial lung disease

• Serious chronic gastrointestinal conditions associated with diarrhea

• Psychiatric illness/social situations that would limit compliance with studyrequirement, substantially increase risk of incurring AEs or compromise theability of the subject to give written informed consent.

17. Female subjects who are pregnant or breast feeding; or subjects ofreproductive potential of any gender who are not employing or who do notagree to employ an effective method of birth control prior to trialenrollment.ollment.