Durvalumab and Ablative Radiation in Small Cell Lung Cancer (DARES)

Inclusion Criteria:

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

1. Capable of giving signed informed consent which includes compliance with therequirements and restrictions listed in the informed consent form (ICF) and in thestudy protocol.

2. Age > 18 years at time of study entry.

3. Have a histologic/clinically confirmed diagnosis of small cell lung cancer withknown metastatic disease.

4. Patient is suitable to receive a platinum-based chemotherapy regimen as first linetreatment for extensive stage small cell lung cancer.

5. Brain metastases must be asymptomatic or treated and stable off steroids andanti-convulsant for at least 2 weeks prior to study treatment.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

7. Life expectancy of at least 12 weeks

8. Body weight >30 kg

9. Adequate normal organ and marrow function as defined by lab values the study doctorwill review.

10. 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.

11. Have measurable disease based on Response Evaluation Criteria in Solid Tumor (RECIST 1.1) including at least ONE lesion that meets criteria for ablative radiation,including 0.25 cc to 65 cc of viable tumor (i.e. primary disease or metastases)approximately 5cm in maximal dimension. Tumors larger than 65 cc can be partiallytreated.

12. Female subject of childbearing potential should have a negative urine or serumpregnancy within 24 hours prior to receiving the first dose of study medication. Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required.

13. Female subjects of childbearing potential should be willing to use 2 methods ofbirth control or be surgically sterile, or abstain from heterosexual activity forthe course of the study through 120 days after the last dose of study medication.Subjects of childbearing potential are those who have not been surgically sterilizedor have not been free from menses for > 1 year.

14. Male subjects should agree to use an adequate method of contraception starting withthe first dose of study therapy through 120 days after the last dose of studytherapy.

Exclusion Criteria:

Patients should not enter the study if any of the following exclusion criteria are fulfilled:

1. Participation in another clinical study with an investigational product during thelast 2 weeks.

2. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of aninterventional study

3. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria:

4. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basisafter consultation with the Study Physician.

5. Patients with irreversible toxicity not reasonably expected to be exacerbatedby treatment with durvalumab may be included only after consultation with theStudy Physician.

6. Any concurrent chemotherapy, investigational product (IP), biologic, or hormonaltherapy for cancer treatment, outside of those specified as part of this clinicaltrial. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g.,hormone replacement therapy) is acceptable.

7. 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

8. Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of IP. Note: Local surgery of isolated lesions for palliative intentis acceptable.

9. History of allogenic organ transplantation.

10. 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 tothis criterion:

11. Patients with vitiligo or alopecia

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

13. Any chronic skin condition that does not require systemic therapy

14. Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician

15. Patients with celiac disease controlled by diet alone

16. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantiallyincrease risk of incurring AEs or compromise the ability of the patient to givewritten informed consent

17. History of another primary malignancy except for

18. 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

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

20. Adequately treated carcinoma in situ without evidence of disease

21. History of leptomeningeal carcinomatosis

22. Has a paraneoplastic syndrome (PNS) of autoimmune nature, requiring systemictreatment (systemic steroids or immunosuppressive agents) or has a clinicalsymptomatology suggesting worsening of PNS.

23. All patients at screening should have an MRI (preferred) or CT each preferably withIV contrast of the brain prior to study entry. Patients whose brain metastases havebeen treated may participate provided they show radiographic stability (defined as 2brain images, both of which are obtained after treatment to the brain metastases.These imaging scans should both be obtained at least two weeks apart and show noevidence of intracranial progression). In addition, any neurologic symptoms thatdeveloped either as a result of the brain metastases or their treatment must haveresolved or be stable either, without the use of steroids, or are stable on asteroid dose of ≤10mg/day of prednisone or its equivalent for at least 14 days priorto the start of treatment. Brain metastases will not be recorded as RECIST TargetLesions at baseline.

24. History of active primary immunodeficiency

25. Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and tuberculosis (TB)testing in line with local practice), hepatitis B (known positive HBV surfaceantigen (HBsAg) result), hepatitis C, or HIV. Patients with a past or resolved HBVinfection (defined as the presence of hepatitis B core antibody [anti-HBc] andabsence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody areeligible only if polymerase chain reaction is negative for hepatitis C (HCV)ribonucleic acid (RNA).

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 andup 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 randomisation or treatment in a previous durvalumab clinical study regardlessof treatment arm assignment.

34. Has received prior chemotherapy, immunotherapy or thoracic radiation for small celllung cancer.

35. Has prior exposure to anti-PD (Programmed death-ligand 1) 1/PD-L1 or anti- cytotoxicT lymphocyte-associated antigen (CTLA4) therapy.

36. Has had prior radiation therapy (defined as >10% of prior prescription dose) to thearea planning to be treated with trial RT.

Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.3