Durvalumab With Consolidative Radiochemotherapy and Ablative Stereotactic Radiotherapy in Oligometastatic ES-SCLC

Inclusion Criteria: For inclusion in the study patients must fulfill all of the following criteria:

1. Histologically confirmed first diagnosis of ES-SCLC according to the VeteransAdministration Lung Study Group (VALG) Staging System for SCLC1 (disease extensionthat cannot be treated within one radiation field).
2. Oligometastatic disease defined as follows:

• Primary tumor with or without mediastinal or supraclavicular lymph nodemetastases (counts as one lesion if it can be treated within one radiationfield).
• Up to four distant tumor lesions/metastases that can be treated with stereotacticradiotherapy (stereotactic radiotherapy of lung metastases in addition toradiochemotherapy of primary tumor should previously be discussed with theprincipal investigator).
• No cytologically confirmed malignant pleural effusion (in case of suspectedmalignant pleural effusion in imaging, pleurocentesis for cytological assessmentis required).

3. Stable disease (SD) or partial response (PR) according to RECIST 1.1 criteria afterprevious treatment with two cycles of platinum/etoposide/durvalumab.
4. Adequate lung function defined as forced expiratory volume in the first second (FEV1) ≥1.3 liter in spirometry.
5. 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 including European Union Data Privacy Directiveobtained from the patient prior to performing any protocol-related procedures,including screening evaluations.
6. Age > 18 years at time of study entry.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Body weight >30 kg.
9. Adequate normal organ and marrow function as defined below:

• Hemoglobin ≥9.0 g/dL
• White Blood Cells (WBC) ≥ 3,000 per mm3
• Platelet count >100,000 per mm3
• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will notapply to patients with confirmed Gilbert's syndrome (persistent or recurrenthyperbilirubinemia that is predominantly unconjugated in the absence of hemolysisor 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
• Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula

10. Patient is willing and able to comply with the protocol for the duration of the studyincluding undergoing treatment and scheduled visits and examinations includingfollow-up.
11. Must have a life expectancy of at least 12 weeks.

Exclusion Criteria: Patients should not enter the study if any of the following exclusion criteria arefulfilled:

1. Participation in another clinical study with an investigational product during thelast 4 weeks.
2. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of aninterventional study.
3. Prior systemic anticancer therapy (chemotherapy, immunotherapy, targeted therapy),apart from two cycles of etoposide/platinum + durvalumab (prior chemotherapy/immunotherapy/ targeted therapy for other malignancy treated with curative intent ≥5years ago is no exclusion criterion).
4. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous chemo-immunotherapy (2 cyclesof platinum/etoposide + durvalumab) with the exception of alopecia, vitiligo, and thelaboratory values defined in the inclusion criteria
5. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis afterconsultation with the Study Physician.
6. Patients with irreversible toxicity not reasonably expected to be exacerbated bytreatment with durvalumab may be included only after consultation with the StudyPhysician.
7. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormonereplacement therapy) is acceptable.
8. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field ofradiation within 4 weeks of the first dose of study drug.
9. 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.
10. History of allogenic organ transplantation.
11. 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:
12. Patients with vitiligo or alopecia
13. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement
14. Any chronic skin condition that does not require systemic therapy
15. Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician
16. Patients with celiac disease controlled by diet alone
17. Uncontrolled intercurrent illness, including but not limited to, ongoing or activesymptomatic infection, symptomatic congestive heart failure, uncontrolledhypertension, unstable angina pectoris, cardiac arrhythmia, QTcF (QT interval on ECGcorrected using the Frederica's formula) >470 ms, interstitial lung disease, seriouschronic gastrointestinal conditions associated with diarrhea, or psychiatricillness/social situations that would limit compliance with study requirement,substantially increase risk of incurring AEs or compromise the ability of the patientto give written informed consent.
18. History of another primary malignancy except for
19. 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
20. Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease
21. Adequately treated carcinoma in situ without evidence of disease
22. History of leptomeningeal carcinomatosis.
23. History of active primary immunodeficiency.
24. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitisB virus (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.
25. Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2antibodies) or active tuberculosis infection (clinical evaluation that may includeclinical history, physical examination and radiographic findings).
26. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab. The following are exceptions to this criterion:
27. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)
28. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent
29. Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication)
30. 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.
31. 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.
32. Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients.
33. Prior randomization or treatment in a previous durvalumab clinical study regardless oftreatment arm assignment.
34. Judgment by the investigator that the patient is unsuitable to participate in thestudy and the patient is unlikely to comply with study procedures, restrictions andrequirements.
35. Known allergy or hypersensitivity to IP or any excipient.