FIRST-NEC (GFPC 01-2022) - Combination of Durvalumab With Etoposide and Platinum

Inclusion Criteria:

1. Age ≥ 18 years at the time of study entry;

2. Locally documented histological diagnosis of Large-Cell NeuroEndocrine Carcinoma ofthe lung (2021 WHO classification of Lung Tumors );

3. Patient must have sufficient material to achieve central histological confirmationand exploratory analyses (1 representative FFPE block or at least 10 unstainedslides);

4. Setting of the disease: locally advanced (Stage III) not eligible for loco-regionaltherapy or metastatic (Stage IV) in first line treatment (8th TNM classification). Nota Bene: patients with recurrence of local or locally advanced LCNEC are eligibleto the trial provided that recurrence occurs beyond 3 months after the lastchemotherapy administration. For relapsing patients, tumor material collected at diagnosis can be used for theFIRST-NEC trial if relapse occurs within two years of initial management and ifinitial histologic tumor material is available.

5. Measurable disease as per the RECIST 1.1;

6. Performance Status (PS) of the Eastern Cooperative Oncology Group (ECOG): 0 or 1 ;

7. Body weight > 30Kg;

8. Must have a life expectancy of at least 12 weeks;

9. Adequate normal organ and marrow function as defined below:

• Haemoglobin ≥8.0 g/dL (with or without transfusion)

• Absolute neutrophil count (ANC) ≥1.5 × 109 /L

• Platelet count ≥100 × 109/L

• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN)), or ≤3.0xULNin case of liver metastases. Note: this will not apply to patients with confirmed Gilbert's syndrome (persistentor recurrent hyperbilirubinemia that is predominantly unconjugated in the absence ofhemolysis or hepatic pathology), who will be allowed only in consultation with theirphysician.

• AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless livermetastases are present, in which case it must be ≤5x ULN

• For patients undergoing a treatment by cisplatin: measured creatinine clearance (CrCl) ≥60 mL/min or Calculated creatinine CrCl ≥60 mL/min by the CKD-EPIequation or by 24-hour urine collection for determination of creatinineclearance (CrCl). Nota Bene: if creatinine clearance is <60 ml/min, patients must be treated withcarboplatin rather than cisplatin.

10. Evidence of post-menopausal status or negative urinary or serum pregnancy test forfemale pre-menopausal patients. Women will be considered post-menopausal if theyhave been amenorrheic for 12 months without an alternative medical cause. Thefollowing age-specific requirements apply:

• Women <50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulatinghormone levels in the post-menopausal range for the institution or underwentsurgical sterilization (bilateral oophorectomy or hysterectomy).

• Women ≥50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation induced menopause with last menses >1 year ago, hadchemotherapy-induced menopause with last menses >1 year ago, or underwentsurgical sterilization (bilateral oophorectomy, bilateral salpingectomy orhysterectomy).

11. Patient (male or female) using a highly effective contraception as defined in duringthe treatment period and at least up to 6 months after the last administration ofchemotherapy or 90 days after the last administration of durvalumab, whichever islonger. Prior to dispensing study drugs, the investigator must confirm and documentthe patient's (and his/her partner) use of highly effective contraceptive methods,dates of negative pregnancy tests, and confirm the patient's understanding of theteratogenic potential of study drugs;

12. Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations includingfollow up.

13. Affiliation to a social security system;

14. 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 obtained from the patient prior to performing anyprotocol-related procedures, including screening evaluations.

Exclusion Criteria:

1. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of aninterventional study (wash-out period of 28 days);

2. Patient previously treated for a LCNEC in a metastatic setting;

3. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab;

4. Any concurrent chemotherapy, Investigational product, biologic, or hormonal therapyfor cancer treatment. Concurrent use of hormonal therapy for non-cancer-relatedconditions (e.g., hormone replacement therapy) is acceptable;

5. Major surgical procedure (as defined by the Investigator) within 21 days prior tothe first dose of study drugs; Note: Local surgery or radiotherapy of isolatedlesions for palliative intent is acceptable.

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, Sarcoidosissyndrome, or Wegener syndrome [granulomatosis with polyangiitis], Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, etc). The following are exceptions to this criterion:

• Patients with vitiligo or alopecia

• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone 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

8. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, unstable cardiac arrhythmia, interstitial lung disease, peripheralneuropathy > grade II, serious chronic gastrointestinal conditions associated withdiarrhea, or psychiatric illness/social situations that would limit compliance withstudy requirement, substantially increase risk of incurring AEs or compromise theability of the patient to give written informed consent;

9. History of another primary malignancy except for:

• Malignancy treated with curative intent and with no known active disease ≥5years before the first dose of IP and of low potential risk for recurrence

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease

• Adequately treated carcinoma in situ without evidence of disease, or Gleason ≤6prostate cancer.

10. Central Nervous System metastases, unless asymptomatic (including patients treatedwith anticonvulsants) or previously treated (surgery or radiation therapy combinedwith corticosteroids ≤10 mg per day) and stable at the time of randomization for atleast 15 days;

11. Carcinomatous meningitis;

12. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms;

13. History of active primary immunodeficiency;

14. Active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis Bvirus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening.Participants with a past or resolved HBV infection (defined as the presence of antiHBc and absence of HBsAg) are eligible. Participants positive for HCV antibody areeligible only if polymerase chain reaction is negative for HCV RNA;

15. Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection;

16. Current or prior use of immunosuppressive medication within 14 days before the firstdose 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" ofprednisone or its equivalent

• Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication)

17. 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 receivingdurvalumab and up to 30 days after the last dose of durvalumab.

18. Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients;

19. Pregnant or breast-feeding woman