Durvalumab(MEDI4736) After chemoRadioTherapy(DART) for NSCLC-a Translational and Biomarker Study

Inclusion Criteria:

1. Locally-advanced, unresectable, stage III NSCLC (including PET-CT and MRI-brain in thediagnostic work-up).
2. Capable of giving signed informed consent which includes compliance with therequirements and restrictions listed in the informed consent form (ICF) and in thisprotocol. Written informed consent and any locally required authorization (EuropeanUnion [EU] Data Privacy Directive in the EU) obtained from the patient/legalrepresentative prior to performing any protocol-related procedures, includingscreening evaluations.
3. Diagnostic biopsy with PD-L1 <1% in 50 patients PD-L1 ≥1% in 50 patients
4. Adequate core or excisional biopsy for tumor assessment
5. Age > 18 years at time of study entry
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. Life expectancy of at least 12 weeks
8. Body weight >30 kg
9. Adequate normal organ and marrow function as defined below:

• Haemoglobin ≥9.0 g/dL
• Absolute neutrophil count (ANC) 1.5 x (> 1500 per mm3)
• Platelet count ≥100 x 109/L (>75,000 per mm3)
• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).
• AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless livermetastases are present, in which case it must be ≤5x ULN
• Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hoururine collection for determination of creatinine clearance: Males:
• Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL) Females:
• Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)

10. Evidence of post-menopausal status or negative urinary or serum pregnancy test forfemale pre-menopausal patients. Women will be considered post-menopausal if they havebeen amenorrheic for 12 months without an alternative medical cause.
11. Women of childbearing potential (WOCBP) should have a negative urine or serumpregnancy within 7 days prior to receiving the firs dose of study medication. If theurine test is positive or cannot be confirmed as negative, a serum pregnancy test willbe required. A woman is considered as WOCBP, i.e. fertile, following menarche anduntil becoming post-menopausal unless permanently sterile. Permanent sterilisationmethods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
12. WOCBP should use an adequate method to avoid pregnancy
13. males who are sexually active with women of childbearing potential must agree tofollow instructions for method(s) of contraception for a period of 90 days (durationof sperm turnover) / the time required for the investigational drug to undergo fivehalf-lives
14. Patient is willing and able to comply with the protocol for the duration of the studyincluding undergoing treatment and scheduled visits and examinations including followup.

Exclusion Criteria:

1. Non-small cell lung cancer disease suitable for curative surgery
2. Significant cardiac, pulmonary or other medical illness that would limit activity orsurvival
3. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of aninterventional study during the last 2 weeks.
4. Any concurrent chemotherapy, Investigational Product (IP), biologic, or hormonaltherapy for cancer treatment. Concurrent use of hormonal therapy fornon-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
5. Major surgical procedure (as defined by the Investigator) within 28 days prior to thefirst dose of IP. Note: Local surgery of isolated lesions for palliative intent isacceptable.
6. History of allogenic organ transplantation.
7. Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoidarthritis, hypophysitis, uveitis, etc]). The following are exceptions to thiscriterion:

• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stableonhormone replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician
• Patients with celiac disease controlled by diet alone i. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstable anginapectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinalconditions associated with diarrhea, or psychiatric illness/social situations that wouldlimit compliance with study requirement, substantially increase risk of incurring AEs orcompromise the ability of the patient to give written informed consent j. History ofanother primary malignancy except for
• Malignancy treated with curative intent and with no known active disease ≥5 yearsbefore the first dose of IP and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence ofdisease
• Adequately treated carcinoma in situ without evidence of disease k. History of activeprimary immunodeficiency or medical condition requiring high doses (>30 mgprednisolone daily) of systemic steroids or other forms of immunosuppressive therapy l. Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and TB testing in line withlocal practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), andhepatitis C. Patients with a past or resolved HBV infection (defined as the presenceof hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patientspositive for hepatitis C (HCV) antibody are eligible only if polymerase chain reactionis negative for HCV RNA. m. Current or prior use of immunosuppressive medication within 14 days before thefirst dose of durvalumab. The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone orits equivalent
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP. n. Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ effective birth control fromscreening to 90 days after the last dose of durvalumab monotherapy. o. Known allergy or hypersensitivity to any of the study drugs or any of the studydrug excipients. p. Prior randomisation or treatment in a previous durvalumab clinical study regardlessof treatment arm assignment. q. Judgement by the investigator that the patient is unsuitable to participate in thestudy and the patient is unlikely to comply with study procedures, restrictions andrequirements. r. Patients with grade ≥2 neuropathy will be evaluated on a case-by-case basis afterconsultation with the Study physician. s. Patients with irreverible toxicity not reasonably expected to be exacerbated bytreatment with durvalumab may be included only after consulation with the StudyPhysician.