An Open Label, Multicenter Phase 2 Study of Durvalumab (MEDI4736) + Olaparib as Maintenance Therapy in Chinese

Inclusion Criteria:

1. Male or female ≥18 years at the time of screening.
2. Capable of giving signed informed consent which includes compliance with therequirements and restrictions listed in the informed consent form (ICF) and in thisprotocol.
3. Written informed consent and any locally required authorization obtained from thepatient/legal representative prior to performing any protocol-related procedures,including screening evaluations.
4. Histologically or cytologically documented extensive disease (American Joint Committeeon Cancer Stage (7th edition) IV SCLC [T any, N any, M1 a/b]), or T3-4 due to multiplelung nodules that are too extensive or have tumor/nodal volume that is too large to beencompassed in a tolerable radiation plan. Brain metastases; must be asymptomatic or treated and stable off steroids andanti-convulsants for at least 1 month prior to study treatment. Patients withsuspected brain metastases at screening should have a CT/MRI of the brain prior tostudy entry.
5. Provision of an archived tumor tissue block (or at least 15 newly cut unstainedslides) where such samples exist.
6. Patients must be considered suitable to receive a platinum based chemotherapy regimenas 1st line treatment for the ED-SCLC. Chemotherapy must contain either cisplatin orcarboplatin in combination with etoposide.
7. Life expectancy ≥16 weeks at Day 1.
8. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) PerformanceStatus of 0 to 2 at enrollment. PS2 patients are permitted to receive first-linetreatment, and PS score should be reassessed after first-line treatment. Then patientswho are assessed as PS2 at the completion of chemotherapy+durvalumab will be excluded.
9. Body weight >30 kg.
10. At least 1 lesion, not previously irradiated, that can be accurately measured atbaseline as ≥10 mm in the longest diameter (except lymph nodes which must have a shortaxis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) andthat is suitable for accurate repeated measurements as per RECIST 1.1 guidelines.
11. No prior exposure to immune-mediated therapy including, but not limited to, other PARPinhibitor, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 (anti-PD-L2)antibodies, excluding therapeutic anticancer vaccines.
12. Adequate organ and marrow function which is measured within 28 days prior toadministration of study treatment as defined below: Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days Absoluteneutrophil count ≥1.5 × 109/L (use of granulocyte colony-stimulating factor is notpermitted at screening). Platelet count ≥100 × 109/L. Serum bilirubin ≤1.5 × the upper limit of normal (ULN).This will not apply to patients with confirmed Gilbert's syndrome, who will be allowedin consultation with their physicians. In patients without hepatic metastasis: ALT and AST ≤2.5 × ULN. In patients withhepatic metastases, ALT and AST ≤5 × ULN. Measured or calculated creatinine clearance: >60mL/min for patients on cisplatin and >51mL/min for patients on carboplatin, as determined by Cockcroft-Gault (using actualbody weight) or based on a 24 hour urine test: Males: Creatinine CL (mL/min) = [Weight (kg) × (140 - Age)] / [72 × Serum creatinine (mg/dL)] Females: Creatinine CL (mL/min) = {[Weight (kg) × (140 - Age)] / [72 × Serum creatinine (mg/dL)]}*0.85
13. 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. The followingage-specific requirements apply: Women <50 years of age would be considered post-menopausal if they have beenamenorrhoeic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulating hormonelevels in the post-menopausal range for the institution or underwent surgicalsterilization (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 underwent surgicalsterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
14. Male patients must use a condom during treatment and for 3 months after the last doseof olaparib when having sexual intercourse with a pregnant woman or with a woman ofchildbearing potential. Female partners of male patients should also use a highlyeffective form of contraception

Exclusion Criteria:

1. Previous IP assignment in the present study.
2. Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow up period of an interventionalstudy.
3. Participation in another clinical study with an IP during the last 4 weeks.
4. Patients unable to swallow orally administered medication and patients withgastrointestinal disorders likely to interfere with absorption of the studymedication.
5. Medical contraindication to etoposide platinum (carboplatin or cisplatin) basedchemotherapy.
6. Any history of radiotherapy to the chest prior to systemic therapy or plannedconsolidation chest radiation therapy. Radiation therapy outside of the chest forpalliative care (ie, bone metastasis) is allowed but must be completed before firstdose of the study medication.
7. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.Concurrent use of hormonal therapy for non-cancer related conditions (eg, hormonereplacement therapy) is acceptable.
8. 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.
9. History of allogeneic organ transplantation.
10. Has a paraneoplastic syndrome (PNS) of autoimmune nature, requiring systemic treatment (systemic steroids or immunosuppressive agents) or has a clinical symptomatologysuggesting worsening of PNS.
11. Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis with theexception of diverticulosis, systemic lupus erythematosus, sarcoidosis syndrome, orWegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoidarthritis, hypophysitis, and uveitis, etc]). The following are exceptions to thiscriterion: Patients with vitiligo or alopecia Patients with hypothyroidism (eg, followingHashimoto syndrome) and stable on hormone replacement Any chronic skin condition thatdoes not require systemic therapy Patients without active disease in the last 5 yearsmay be included but only after consultation with the investigator Patients with celiacdisease controlled by diet alone
12. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, interstitial lung disease, symptomatic congestive heart failure,uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, 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.
13. History of another primary malignancy except for Malignancy treated with curativeintent and with no known active disease ≥5 years before the first dose of IP and oflow potential risk for recurrence Adequately treated non-melanoma skin cancer orlentigo maligna without evidence of disease Adequately treated carcinoma in situwithout evidence of disease
14. History of leptomeningeal carcinomatosis.
15. History of active primary immunodeficiency.
16. Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and tuberculosis testing inline with local practice), hepatitis B (known positive HBV surface antigen [HbsAg]result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies).Patients with a past or resolved HBV infection (defined as the presence of hepatitis Bcore antibody [anti-HBc] and absence of HbsAg) are eligible. Patients positive forhepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction isnegative for HCV RNA.
17. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab or olaparib. The following are exceptions to this criterion: Intranasal, inhaled, topical steroids or local steroid injections (eg, intra articularinjection). Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone orits equivalent. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).Premedication with steroids for chemotherapy is acceptable.
18. 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.
19. 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 or 180 days afterthe last dose of durvalumab + olaparib combination therapy.
20. Known allergy or hypersensitivity to durvalumab, olaparib, etoposide, carboplatin,cisplatin, or any of their excipients
21. Prior randomization or treatment in a previous durvalumab and/or olaparib clinicalstudy regardless of treatment arm assignment.
22. *Other malignancy unless curatively treated with no evidence of disease for ≥5 yearsexcept: adequately treated non-melanoma skin cancer, curatively treated in situ cancerof the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrialcarcinoma.
23. *Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, asjudged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia,congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), orpatients with congenital long QT syndrome.

24. *Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2)caused by previous cancer therapy, excluding alopecia.
25. *Patients with myelodysplastic syndrome/acute myeloid leukaemia or with featuressuggestive of MDS/AML.
26. *Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washoutperiod prior to starting olaparib is 2 weeks.
27. *Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ) ormoderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout periodprior to starting Olaprrib is 5 weeks for enzalutamide or phenobarbital and 3 weeks forother agents.
28. *Previous allogenic bone marrow transplant or double umbilical cord bloodtransplantation (dUCBT).
29. *Breast feeding women. 30) Patients with a known hypersensitivity to thecombination/comparator agent. 31) As judged by the investigator, any evidence of which inthe investigator's opinion makes it undesirable for the patient to participate in thetrial.