untitled h1
o hepatitis serologies

11.1.4 Treatment phase Procedures to be conducted during the treatment phase of the study are presented in the SoAs. Screening procedures performed within 5 days of Day 1 of the first chemoimmunotherapy course do not need to be repeated before study treatment commences. 11.1.5 End of treatment Assessments for patients who have completed durvalumab treatment and achieved disease control or have discontinued durvalumab due to toxicity in the absence of confirmed progressive disease, and for those who have progressed are provided below the schedule of events on page 11.  
All patients will be followed for survival until the end of the study regardless of further treatments, or until the sponsor ends the study.  
11.2 Patient reported outcomes (PRO)
11.2.1 Assessment of health-related quality of life (HRQoL)
HRQoL will be assessed using the European Organisation for Research and Treatment of Cancer (EORTC)
Quality of Life Questionnaire (QLQ) C30 and the lung cancer specific module LC13. The QLQ-C30 measures fundamental aspects of HRQoL and symptoms commonly reported by cancer patients in general, the LC13 measures symptoms commonly associated with lung cancer and its treatment.61,62 Patients will complete the questionnaires on paper. The questionnaires are either handed patients by local study personnel or mailed them from the central trial office in Trondheim. Patients will return the completed questionnaires in enclosed, prepaid envelopes provided by the central trial office. If patients who receive the questionnaires via mail do not return a completed questionnaire within 14 days, a reminder will be mailed.  
When questionnaires are handed to patients by local study personnel, the study personnel will check that the questionnaire is completed correctly before they are stored locally. All questionnaires are mailed to the central trial office by completion of the trial or upon request from the trial office. If the questionnaires may not be mailed to the central trial office due to local laws or regulations, the local study personnel will enter the responses in the CRF.  
11.3 Assessment of cognitive function Cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA).63 The assessment will be performed by trained study personnel. The training is performed online at mocatest.org. Study personnel will enter the results in the CRF.  
11.4 Biological sampling procedures 11.4.1 Collection of biological material for translational research We will collect tumor samples, blood samples (whole blood, plasma, serum) and stool for biomarker analyses.  
11.4.2 Tissue samples We will collect diagnostic tissue samples and biopsies collected at relapse when possible to collect. We will collect formalin-fixed, paraffin-embedded and not fresh frozen tissue.  
It is recommended that tissue samples are placed immediately (within 30 min of excision) into an adequate volume of 10% v/v neutral buffered formalin (NBF). Samples should remain in fixative for 24 - 48 hours at room temperature. It is vital that there is an adequate volume of fixative relevant to the tissue (at least a 10-volume excess) and that large specimens (if any) are incised prior to fixation to promote efficient tissue preservation. An overnight processing schedule into paraffin wax is recommended, and FFPE blocks should be stored at ambient temperature and protected from light until shipment by courier at ambient temperature.  
FFPE blocks are stable under these conditions for an indefinite period. The samples are to be shipped to the central trial office in Trondheim when enrollment of patients has  
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been completed or upon request. Blocks of formalin-fixed, paraffin-embedded tissue is preferred, but slides are also welcome. Slides should be cut immediately before shipping, and the time point for shipping will be agreed upon with each site. Details on how to cut slides will be provided when shipping of blocks or slides is requested.  
11.4.3 Blood samples The following blood samples for biomarker analyses will be collected:
We are aware that not all sites have access to centrifuges with the descried capacity. The impact of centrifuge speed on the material quality is undetermined, and we will collect samples regardless of equipment. All sites will report the capacity of the centrifuges used for processing of blood samples. Labels for the tubes will be supplied from the central trial office in Trondheim.  
Serum  **18 ml blood should be collected in 3 x 6 ml serum tubes (e.g. Vacuette Z serum clot activator tubes or**
similar) for isolation of serum.  **The tubes should be turned gently 8-10 times and left in a standing position at room temperature for**
30-60 minutes.  Centrifuge the tubes at 2500 g at room temperature for 10 minutes.  **After centrifugation, the serum should be aliquoted into 4 cryotubes, 1.5 ml in each. If more serum is**
available, increase the aliquots to 1.8 ml.  **All tubes should be labeled and stored at -80°C until shipment.**
Plasma  30 ml blood should be collected in 5 x 6 ml EDTA tubes for isolation of plasma.  The tubes should be turned gently 8-10 times to dissolve the anticoagulant.  **Centrifuge the tubes as soon as possible and within 60 minutes in a horizontal rotor (both swing-out**
and fixed rotors are ok) at 1600 g at 4°C for 15 minutes.  **After centrifugation, the plasma layer will be at the top of the tube. Mononuclear cells and platelets**
will be in a whitish layer, called the "buffy coat", below the plasma and above the red blood cells.  **Carefully collect the plasma with a sterile pipette (in a sterile hood) without disturbing the buffy coat** layer and transfer the plasma to Eppendorf tubes.  **Centrifuge the Eppendorf tubes at 10000 g at 4°C for 10 minutes, then transfer plasma into 4 x 4.5 ml**
cryotubes, up to 4 mL in each.  Collect the buffy coat from all tubes and transfer to two cryotubes.  **All tubes should be labeled and stored at -80°C until shipment.**
EDTA whole blood (only at inclusion)  6 ml blood should be collected in one EDTA tube for genetic analysis.  **The tube should be turned gently 8-10 times to dissolve the anticoagulant and aliquoted into 4 x 1.8 ml**
cryotubes with a minimum of 1 ml in each.  **All tubes should be labeled and stored at -80°C until shipment.**
PAX tube  2.5 ml blood should be collected in one 10 ml PAX-tube.  **The tube should be turned gently 8-10 times and left in a standing position in room temperature for 2-3**
hours before placed in freezer at -20°C for 24 hours. Do not store tubes in Styrofoam trays, as it could cause the tubes to crack.  Transfer the tube to -80°C after 24 hours.  **All tubes should be labeled and stored at -80°C until shipment.**  
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Patients will be handed a kit for stool sampling including instructions for sampling. Patients will apply a sample on an appropriate medium and deliver at the study site in an envelope designed for this purpose.  
The stool samples should be labeled and stored at -80°C until shipment. Labels will be supplied from the central trial office in Trondheim. Details on stool sampling will be provided in the study procedure manual.  
11.4.5 Proposed biomarker analyses There are no established predictive markers for effect of ICI, chemotherapy or RT in SCLC. PD-L1 and TMB,
the most relevant predictive markers in other types of cancer, do not appear to be clinically relevant in SCLC.  
A molecular classification of SCLC based on RNA-sequencing has been proposed,64 and there are indications that such classification might be used to predict treatment response.65 Recently, a study found that germline genotype was associated with recurrence-free survival after platinum chemotherapy.66 Thus, we will investigate the prognostic and predictive role of these molecular profiles in this trial.  
Few have investigated the clinical role of ctDNA in SCLC, but data from NSCLC studies suggest that changes in ctDNA occur before response to immunotherapy can be evaluated on CT scans.67 Thus, we will investigate the prognostic value of baseline ctDNA analyses (presence of detectable mutations and quantification), and associations between dynamics of known SCLC-related mutations in ctDNA are associated with response to therapy and treatment outcomes, especially long-term survival.  
miRNA-profile is a highly relevant marker associated with extent of disease, tumor biology and prognosis.68 Few have investigated whether this is the case in SCLC. We will investigate associations between miRNA profile and the outcomes as described above - both for miRNA alone, and as part of an integrative model including both sequencing data from tissue, ctDNA and miRNA-analyses.  
There are strong indications of associations between gut microbiome and response to ICI,69,70 but this is scarcely investigated in SCLC. We assess the microbiome through sequencing, and investigate whether there are associations with the tumor, ctDNA or miRNA-profile - or treatment outcomes. To facilitate a correct interpretation, we will collect information about concomitant medication and use of antibiotics the last 6 months before study enrolment from all patients, since antibiotics are known to influence the gut microbiome.  
We plan to start the biomarker analyses one year after enrolment in the trial has been completed. There is a lot of ongoing research on prognostic and predictive factors in patients who receive ICI, and based on research results published until then, other markers may be added to the analyses plan. A final plan describing analyses and techniques will be defined when enrolment is close to complete.  
11.4.6 Withdrawal of informed consent for donated biological samples If a patient withdraws, collection of data and biological material will stop, but according to Norwegian legislation, already collected data and material will be included in the analyses.  
12. **Disease evaluation and methods**
The response to immunotherapy may differ from the typical responses observed with cytotoxic chemotherapy including the following (Wolchok et al 2009, Nishino et al 2013):  Response to immunotherapy may be delayed  Response to immunotherapy may occur after PD by conventional criteria  The appearance of new lesions may not represent PD with immunotherapy  **SD while on immunotherapy may be durable and represent clinical benefit.**
Based on the above-described unique response to immunotherapy and based on guidelines from regulatory agencies, e.g., European Medicines Agency's "Guideline on the evaluation of anticancer medicinal products in man" (EMA/CHMP/205/95/Rev.4) for immune modulating anticancer compounds, the study implements the following in addition to standard RECIST 1.1 criteria:  
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**PD must be confirmed after 4-6 weeks if study treatment continues beyond PD. If clinically significant**
deterioration occurs, a new CT scan should be performed earlier to ensure that patients are offered relapse treatment at a time when they still may benefit from other therapies.  **Patients may continue to receive durvalumab beyond confirmed PD in the absence of clinically**
significant deterioration and if investigators consider that patients continue to receive benefit from treatment.
Modification of RECIST as described may discourage the early discontinuation of durvalumab and provide a more complete evaluation of its antitumor activity than would be seen with conventional response criteria. Nonetheless, the efficacy analysis will be conducted based on the RECIST 1.1 criteria. Of note, clinically significant deterioration which is not due to another known condition or intercurrent disease is considered to reflect a rapid tumor progression that necessitates treatment with anticancer therapy other than durvalumab or with symptomatic progression that requires urgent medical intervention (e.g. CNS metastasis, respiratory failure due to tumor compression, spinal cord compression).  
12.1 Sensitivity analyses One reason TRT is debated in ES SCLC, is that it may be problematic to offer palliative TRT for local relapse if patients receive TRT as part of their primary therapy. Thus, assessing the local relapse rate and time to local relapse is of great interest in this trial, since the survival benefit of TRT alone is limited, and that adding immunotherapy to chemotherapy may prolong local control. Another clinical setting of great interest is the timing and number of brain metastases. There are different policies with respect of timing of brain irradiation for brain metastases and the benefit of PCI in ES SCLC is debated.  
Per RECIST 1.1 definition, irradiated lesions are not considered measurable. However, for this trial, we will perform sensitivity analyses including irradiated lesions for assessment of progression since these analyses will provide important information on how to care for ES SCLC patients. In these sensitivity analyses, irradiated lesions will be classified and measured similar to non-irradiated lesions according to RECIST 1.1.  
13. **Assessment of safety**
13.1 Clinical laboratory tests Blood samples for determination of clinical chemistry and hematology will be taken at the times indicated in the SoAs and as clinically indicated. Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a licensed clinical laboratory according to local standard procedures. Sample tubes and sample sizes may vary depending on the laboratory method used and routine practice at the site. Pregnancy tests may be performed at the site using a licensed test (urine or serum pregnancy test). Abnormal clinically significant laboratory results should be repeated as soon as possible (preferably within 24 to 48 hours).  
The laboratory variables to be measured are:  
| Table 4 Hematology laboratory tests                                                 |                                   |                                |                |
|-------------------------------------------------------------------------------------|-----------------------------------|--------------------------------|----------------|
| Absolute neutrophile count                                                          | Hemoglobine                       | Leukocytes                     | Platelet count |
| Table 5 Clinical chemistry (serum or plasma) laboratory tests                       |                                   |                                |                |
| Bilirubin                                                                           | Aspartate aminotransferase (AST)  | Alanine aminotransferase (ALT) |                |
| Alkaline phosphatase (ALP)                                                          | Creatinine                        | Sodium (Na)                    |                |
| Potassium (K)                                                                       | Thyroid stimulating hormone (TSH) | Free thyroxine (FT4)           |                |
| Erythrocyte sedimentation rate Glucose                                              | Lactate dehydrogenase (LDH)       |                                |                |
| Tri-iodothyronine (T3) if abnormal thyroid function is suspected and FT4 is normal. |                                   |                                |                |  
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Other safety tests to be performed at screening include assessment for hepatitis B surface antigen (HBsAg),
hepatitis C antibodies (HCV Ab), and HIV antibodies. If a patient shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN, refer to Section 13.15.2 for further instructions on cases of increases in liver biochemistry and evaluation of Hy's Law. These cases should be reported as SAEs if, after evaluation, they meet the criteria for a Hy's law case or if any of the individual liver test parameters fulfill any of the SAE criteria. All patients should have further chemistry profiles performed at 30 days after permanent discontinuation of IP if the reason is an AE.  
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation from IP must have further tests performed until the laboratory values have returned to Grade 1 or 2, unless these values are not likely to improve because of the underlying disease.  
13.1.1 Physical examinations Physical examinations will be performed according to the assessment schedules (see the SoAs). Full physical examinations will include assessments of the head, eyes, ears, nose, and throat and the respiratory, cardiovascular, gastrointestinal, urogenital, musculoskeletal, neurological, dermatological, hematologic/lymphatic, and endocrine systems. Height will be measured at screening only. Targeted physical examinations are to be utilized by the Investigator on the basis of clinical observations and symptomatology. Situations in which physical examination results should be reported as AEs are described in Section 13.4.1.  
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the study.  
ECGs should be obtained after the patient has been in a supine position for 5 minutes and recorded while the patient remains in that position.  
At screening, a single ECG will be obtained on which QTcF must be <470 ms. In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm the finding before a patient in deemed ineligible.  
First infusion BP and pulse should be monitored: - Prior to the beginning of the infusion (measured once from approximately 30 minutes before up to 0 minutes [i.e., the beginning of the infusion])
- Approximately 30 minutes during the infusion (halfway **through infusion)**
- At the end of the infusion (approximately 60 minutes ±5 minutes) - If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow the principles as described above or be taken more frequently if clinically indicated.  
A 1-hour observation period is recommended after the first infusion of durvalumab.  
Subsequent infusions Patients should be carefully monitored with respect to BP and other vital signs prior to, during and post infusion as per institution standard and as clinically indicated.  
13.2 WHO/ECOG performance status ECOG performance status will be assessed at the times specified in the SoAs based on the following:  
0 Fully active; able to carry out all usual activities without restrictions 1 Restricted in strenuous activity, but ambulatory and able to carry out light work or work of a sedentary nature (e.g., light housework or office work) 2 Ambulatory and capable of self-care, but unable to carry out any work activities; up and about more than 50% of waking hours.  
3 Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 4 Completely disabled; unable to carry out any self-care and totally confined to bed or chair
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13.3 Other safety assessments If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormality suggestive of pneumonitis/ILD is observed, toxicity management as described in detail in the Toxicity Management Guidelines (see Appendix 1) will be applied. It is strongly recommended to perform a full diagnostic workup
(including high-resolution computed tomography [HRCT], blood and sputum culture, hematological parameters, etc.), to exclude alternative causes such as lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage. In the presence of confirmatory HRCT scans where other causes of respiratory symptoms have been excluded, a diagnosis of pneumonitis/ILD should be considered and the Dosing Modification and Toxicity Management Guidelines should be followed.  
The Principal Investigator is responsible for ensuring that all staff involved in the study is familiar with the content of this section.  
13.4 Safety parameters 13.4.1 Definition of adverse events (AEs)
The International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) E6(R2) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding),
symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.  
An AE includes but is not limited to any clinically significant worsening of a patient's pre-existing condition. An abnormal laboratory finding (including ECG finding) that requires an action or intervention by the investigator, or a finding judged by the investigator to represent a change beyond the range of normal physiologic fluctuation, should be reported as an AE. AEs may be treatment emergent (i.e., occurring after initial receipt of investigational product) or nontreatment emergent. A non-treatment-emergent AE is any new sign or symptom, disease, or other untoward medical event that begins after written informed consent has been obtained but before the patient has received investigational product. Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the patient being enrolled into the study) for a documented pre-existing condition, that did not worsen from baseline, is not considered an AE (serious or nonserious). An untoward medical event occurring during the prescheduled elective procedure or routinely scheduled treatment should be recorded as an AE or SAE. The term AE is used to include both serious and non-serious AEs.  
13.4.2 Definition of serious adverse events (SAEs) An SAE is an AE occurring during any study phase (i.e., screening, run-in, treatment, wash-out, follow-up),
at any dose of the study drugs that fulfils one or more of the following criteria:  Results in death  Is immediately life-threatening  Requires in-patient hospitalization or prolongation of existing hospitalization  Results in persistent or significant disability or incapacity  Is a congenital abnormality or birth defect in offspring of the patient  **Is an important medical event that may jeopardize the patient or may require medical intervention to**
prevent one of the outcomes listed above.  
Medical or scientific judgment should be exercised in deciding whether expedited reporting is appropriate in this situation. Examples of medically important events are intensive treatment in an emergency room or  
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at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalizations, or development of drug dependency or drug abuse.  
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by the investigator(s) and immediately reported to the central trial office on the SAE form (i.e. no more than 24 hours after learning of the event) by emailing the completed SAE-form to triplex@stolav.no.  
Exception **An event that leads to hospitalization under the following circumstances should not be reported**
as an adverse event or a serious adverse event: - Hospitalization for respite care - **Planned hospitalization required by the protocol (e.g., for study treatment administration or**
performance of an efficacy measurement for the study) or to perform study procedures - **Hospitalization for pre-existing conditions, provided that the hospitalization was planned prior to the**
study and the patient has not experienced an adverse event - **Hospitalization due solely to progression or suspicion of progression of the underlying cancer**
13.4.3 Definition of adverse events of special interest (AESI) An adverse event of special interest (AESI) is one of scientific and medical interest specific to understanding of durvalumab and may require close monitoring. An AESI may be serious or non-serious. If the Investigator has any questions regarding an event being an immune-mediated AE (imAE), the investigator should promptly contact the Chief Investigator.  
AESIs observed with durvalumab include:  Diarrhea / Colitis and intestinal perforation  Pneumonitis / ILD  Hepatitis / transaminase increases  **Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper- and**
hypothyroidism and type I diabetes mellitus)  Rash / Dermatitis  Nephritis / Blood creatinine increases  Pancreatitis / serum lipase and amylase increases  Myocarditis  Myositis / Polymyositis  Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis)  **Intestinal Perforations**
Other inflammatory responses that are rare/less frequent with a potential immune-mediated etiology include, but are not limited to:  Pericarditis  Sarcoidosis  Uveitis  Other events involving the eye and skin  Hematological events  Rheumatological events  Vasculitis  Non-infectious meningitis  **Non-infectious encephalitis**
It is possible that events with an inflammatory or immune mediated mechanism could occur in nearly all organs. In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different underlying pharmacological etiology are also considered AESIs.  
Further information on these risks (e.g. presenting symptoms) can be found in the current version of the durvalumab Investigator's Brochure. More specific guidelines for their evaluation and treatment are  
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described in detail in the Dosing Modification and Toxicity Management Guidelines (please see Appendix 1). These guidelines have been prepared by the Sponsor to assist the Investigator in the exercise of his/her clinical judgment in treating these types of toxicities. These guidelines apply to AEs considered causally related to the study drug/study regimen by the reporting investigator.  
13.4.4 Pneumonitis/ILD investigation The following assessments, and additional assessments if required, will be performed to enhance the investigation and diagnosis of potential cases of pneumonitis.  **Physical examination: Signs and symptoms (cough, shortness of breath and pyrexia, etc.) including**
auscultation for lung field will be assessed.  SpO2Saturation of peripheral oxygen (SpO2)  **When pneumonitis/ILD is suspected during study treatment, the following markers should be**
measured where possible: ILD Markers (KL-6, SP-D) and β-D-glucan  Tumor markers: Particular tumor markers which are related to disease progression.  **Additional Clinical chemistry: CRP, LDH**
13.5 Assessment of safety parameters 13.5.1 Assessment of severity Assessment of severity is one of the responsibilities of the investigator in the evaluation of AEs and SAEs. Severity will be graded according to the NCI CTCAE v5.0. The determination of severity for all other events not listed in the CTCAE should be made by the investigator based upon medical judgment and the severity categories of Grade 1 to 5 as defined below.  
| Grade 1 (mild)                                                                     | An event that is usually transient and may require only minimal treatment   |
|------------------------------------------------------------------------------------|-----------------------------------------------------------------------------|
| or therapeutic intervention. The event does not generally interfere with           |                                                                             |
| usual activities of daily living.                                                  |                                                                             |
| Grade 2 (moderate)                                                                 | An event that is usually alleviated with additional specific therapeutic    |
| intervention. The event interferes with usual activities of daily living,          |                                                                             |
| causing discomfort but poses no significant or permanent risk of harm to           |                                                                             |
| the patient.                                                                       |                                                                             |
| Grade 3 (severe)                                                                   | An event that requires intensive therapeutic intervention. The event        |
| interrupts usual activities of daily living, or significantly affects the clinical |                                                                             |
| status of the patient.                                                             |                                                                             |
| Grade 4 (life-threatening)                                                         | An event, and/or its immediate sequelae, that is associated with an         |
| imminent risk of death or with physical or mental disabilities that affect or      |                                                                             |
| limit the ability of the patient to perform activities of daily living (eating,    |                                                                             |
| ambulation, toileting, etc.).                                                      |                                                                             |
| Grade 5 (fatal)                                                                    | Death (loss of life) as a result of an event.                               |  
It is important to distinguish between serious criteria and severity of an AE. Severity is a measure of intensity whereas seriousness is defined by the criteria in Section 13.4.1. A Grade 3 AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists for several hours may not meet the regulatory definition of an SAE and would be considered a nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be considered an SAE.  
13.6 Recording of adverse events and serious adverse events AEs and SAEs will be collected from the time of the patient signing the ICF until the follow-up period is completed or 90 days after the last dose of study treatment. If an event that starts later is considered to be a late onset toxicity to study treatment, it should still be reported as an AE or SAE. During study participation, all AEs and SAEs should be proactively followed up for each patient for  
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as long as the event is ongoing. Every effort should be made to obtain a resolution for all events, even if the events continue after the patient has discontinued study treatment or the study has completed.  
Any AEs that are unresolved at the patient's last visit in the study are followed up by the Investigator for as long as medically indicated, but without further recording in the CRF.  
AstraZeneca retains the right to request additional information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.  
The following variables will be collected for each AE:  Type of event/description of AE  **Maximum CTCAE grade**
The grading scales found in the NCI CTCAE version 5.0 will be utilized for all events with an assigned CTCAE
grading. For those events without assigned CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate, and severe events into CTCAE grades should be used. A copy of the CTCAE version 5.0 can be downloaded from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).  
13.6.1 Study recording period and follow-up for adverse events and serious adverse events If a patient discontinues from treatment for reasons other than disease progression, and therefore continues to have tumor assessments, SAEs related to study treatment of procedures must be captured until the patient is considered to have confirmed PD and will have no further tumor assessments.  
The investigator is responsible for following all SAEs until resolution, until the patient returns to baseline status, or until the condition has stabilized with the expectation that it will remain chronic, even if this extends beyond study participation.  
13.7 Relationship to protocol procedures The Investigator is also required to provide an assessment of the relationship of SAEs to protocol procedures on the SAE report form. This includes both non-treatment–emergent (i.e., SAEs that occur prior to the administration of IP) and treatment-emergent SAEs. A protocol-related SAE may occur as a result of a procedure or intervention required during the study (e.g., blood collection). The following guidelines should be used by Investigators to assess the relationship of SAEs to the protocol:  **Protocol related: The event occurred due to a procedure or intervention that was described in the**
protocol for which there is no alternative etiology according to the patient's medical record.  **Not protocol related: The event is related to an etiology other than the procedure or intervention that**
was described in the protocol. The alternative etiology must be documented in the study patient's medical record.  
In addition, the following variables will be collected for SAEs as applicable:  Description of SAE  Date the AE met criterion for SAE  Seriousness criteria fulfilled  Date of hospitalization  Date of discharge  The date when the AE started and stopped  The maximum CTCAE grade reported  Investigator causality rating against the study treatment or procedure, or concomitant medication  Action taken with regard to study treatment  Administration of treatment for the AE  Outcome  Probable cause of death  Date of death  **Whether an autopsy was performed**  
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13.8 Adverse events based on signs and symptoms All AEs spontaneously reported by the patient or reported in response to the open question from the study personnel: "Have you had any health problems since the previous visit/you were last asked?" or revealed by observation will be collected and recorded in the CRF.  
When collecting AEs, the recording of diagnoses is preferred, when possible, to recording a list of signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately.  
13.9 Adverse events based on examinations and tests The results from protocol-mandated laboratory tests and vital signs measurements will be recorded in the CRF. Deterioration as compared to baseline in protocol-mandated laboratory values and vital signs should therefore only be reported as AEs if they fulfill any of the SAE criteria or are the reason for discontinuation of study treatment. If deterioration in a laboratory value or vital sign is associated with clinical signs and symptoms, the sign or symptom will be reported as an AE and the associated laboratory result or vital sign will be considered as additional information. Whenever possible, the reporting Investigator should use the clinical rather than the laboratory term (e.g., anemia versus low hemoglobin value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated parameters should be reported as AEs.  
Deterioration of a laboratory value that is unequivocally due to disease progression should not be reported as an AE/SAE.  
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as compared with the baseline assessment will be reported as an AE.  
13.10 Disease progression Disease progression can be considered as a worsening of a patient's condition attributable to the disease which is being studied. It may be an increase in the severity of the disease under study and/or increase in the symptoms of the disease. The development of new or progression of existing metastasis to the primary cancer under study should be considered as disease progression and not an AE/SAE. Events that are unequivocally due to disease progression should not be reported as an AE/SAE during the study.  
13.11 New cancers The development of a new cancer should be regarded as an SAE. New primary cancers are other cancers than SCLC that have been identified after the patient's inclusion in this study.  
13.12 Deaths All deaths that occur during the study treatment period, or within the protocol-defined follow-up period after the administration of the last dose of study drug, must be reported as follows:  **Death clearly resulting from disease progression should be reported to the Study Monitor/Physician**
at the next monitoring visit and should be recorded in the CRF. It should not be reported as an SAE.  **Where death is not due (or not clearly due) to progression of the disease under study, the AE**
causing the death must be reported to the Study Monitor/Physician as an SAE within 24 hours. It should also be recorded in the CRF.  **The report should contain a comment regarding the co-involvement of PD, if appropriate, and**
should assign main and contributory causes of death.  **Deaths with an unknown cause should always be reported as an SAE. It should also be recorded in**
the CRF.  **A post-mortem may be helpful in the assessment of the cause of death, and if performed, a copy of**
the post-mortem results should be forwarded to the central trial office in Trondheim.  
Deaths occurring after the protocol defined safety follow-up period after the administration of the last dose of study drug should be recorded in the CRF. If the death occurred as a result of an event that started after  
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the defined safety follow-up period and the event is considered to be due to a late onset toxicity to study drug, then it should also be reported as an SAE.  
13.13 Reporting of serious adverse events and serious unexpected adverse reactions to the IRB and/or the Regulatory Authority All SAEs must be reported, whether or not considered causally related to the investigational product. The Sponsor is responsible for informing the IRB and/or the Regulatory Authority of SAEs and SUSARs as per local requirements. If any SAE occurs, investigators or other site personnel must inform appropriate Sponsor within one day i.e., immediately but no later than 24 hours of when he or she becomes aware of it.  
For fatal or life-threatening adverse events where important or relevant information is missing, active follow-up is undertaken immediately. Investigators or other site personnel inform Sponsor representatives of any follow-up information on a previously reported SAE within one calendar day i.e.,
immediately but no later than 24 hours **of when he or she becomes aware of it.** The reference document for definition of expectedness/listedness is the IB for durvalumab.  
13.14 Reporting of serious adverse events to AstraZeneca The central trial office in Trondheim is responsible for informing AstraZeneca (AZ) of SAEs. All SAEs have to be reported to AZ, whether or not considered causally related to durvalumab. SAEs related to durvalumab must be provided to AZ as individual case reports. SAEs unrelated to the durvalumab must be provided to AZ in quarterly reports.  
At the end of the study a final summary listing of all SAEs notified to the regulatory authority and/or AZ during the study, must be provided to AZ to enable reconciliation of safety information held by AZ for durvalumab. SAEs that do not require expedited reporting to the Regulatory Authority/IRB/IEC still need to be reported to AZ in quarterly reports.  
Suspected Unexpected Serious Adverse Reactions (SUSARs) must be reported to AZ at the same time these events are notified to regulatory authorities.  
13.14.1 Reporting of deaths to AstraZeneca The central trial office will report all SAEs resulting in death or death of unknown cause to AstraZeneca via AEMailboxClinicalTrialTCS@astrazeneca.com within 7 calendar days of awareness or sooner when required
(See Section 13.13).
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13.15 other events requiring reporting

An overdose is defined as a patient receiving a dose of durvalumab in excess of that specified in the Investigator's Brochure, unless otherwise specified in this protocol. Any overdose of a study patient with durvalumab, with or without associated AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to the sponsor. The sponsor must report these to AstraZeneca Patient Safety or designee using the designated Safety e-mailbox within 7 calendar days or sooner when required. If the overdose results in an AE, the AE must also be recorded as an AE. Overdose does not automatically make an AE serious, but if the consequences of the overdose are serious, for example death or hospitalization, the event is serious and must be recorded and reported as an SAE. There is currently no specific treatment in the event of an overdose of durvalumab. The investigator will use clinical judgment to treat any overdose.  
13.15.2 Hepatic function abnormality Hepatic function abnormality that fulfills the biochemical criteria of a potential Hy's Law case in a study patient, with or without associated clinical manifestations, is required to be reported as "hepatic function abnormal" within 24 hours of knowledge of the event to the sponsor. The Sponsor must report these  
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events to AstraZeneca Patient Safety using the designated Safety e-mailbox within 7 calendar days or sooner when required, unless a definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to durvalumab has been confirmed. The criteria for a potential Hy's Law case is Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3x Upper Limit of Normal
(ULN) together with total bilirubin ≥2xULN at any timepoint during the study following the start of study medication irrespective of an increase in Alkaline Phosphatase (ALP).  **If the definitive underlying diagnosis for the abnormality has been established and is unrelated to**
durvalumab, the decision to continue dosing of the study patient will be based on the clinical judgment of the investigator.  **If no definitive underlying diagnosis for the abnormality is established, dosing of the study patient**
must be interrupted immediately. Follow-up investigations and inquiries must be initiated by the investigational site without delay.  
Each reported event of hepatic function abnormality will be followed by the investigator and evaluated by the sponsor and AstraZeneca. 13.15.3 Pregnancy Maternal exposure If a patient becomes pregnant during study participation, study treatment should be discontinued immediately.  
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study may have interfered with the effectiveness of a contraceptive medication. Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and handled as SAEs. Elective abortions without complications should not be handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up and documented even if the patient was discontinued from the study. If any pregnancy occurs during the study, the investigator or other site personnel should inform the sponsor within 1 day, i.e., immediately, but no later than 24 hours of when he or she becomes aware of it.  
The sponsor will work with the Investigator to ensure that all relevant information is provided within 1 to 5 calendar days. Sponsor must report to AstraZeneca Patient Safety using the designated Safety e-mailbox within 7 calendar days or sooner when required, for pregnancies with SAEs and within 30 days for all other pregnancies. The same timelines apply when outcome information is available.  
Paternal exposure Male patients should refrain from fathering a child or donating sperm during the study and for 180 days after the last dose of durvalumab + any drug combination therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period. Pregnancy of the patient's partner is not considered to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose until 180 days after the last dose of durvalumab + any drug combination therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period should, if possible, be followed up and documented.  
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, the investigator must obtain consent from the patient's partner. The local study team should adopt the generic ICF template in line with local procedures and submit it to the relevant IRB/REB/IEC prior to use.  
13.16 Medication error For the purposes of this clinical study a medication error is an unintended failure or mistake in the treatment process for an AstraZeneca study drug that either causes harm to the patient or has the potential to cause harm to the patient. A medication error is not lack of efficacy of the drug, but rather a human or process related failure while the drug is in control of the study site staff or patient.  
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Medication error includes situations where an error  Occurred  Was identified and intercepted before the patient received the drug  **Did not occur, but circumstances were recognized that could have led to an error**
Examples of events to be reported in clinical studies as medication errors:  Drug name confusion  **Dispensing error e.g. medication prepared incorrectly, even if it was not actually given to the**
patient  Drug not administered as indicated, for example, wrong route or wrong site of administration  Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as a solid tablet  Drug not stored as instructed e.g. kept in the fridge when it should be at room temperature  Wrong patient received the medication  **Wrong drug administered to patient**
Examples of events that do not require reporting as medication errors in clinical studies:  **Errors related to or resulting from IVRS/IWRS - including those that lead to one of the above listed**
events that would otherwise have been a medication error  Patient accidentally missed drug dose(s) e.g. forgot to take medication  Accidental overdose (will be captured as an overdose)  **Errors related to background and rescue medication, or standard of care medication in open label**
studies, even if an AZ product Medication errors are not regarded as AEs, but AEs may occur as a consequence of the medication error.  
If a medication error occurs during the study, the Investigator or other site personnel must inform Sponsor within 1 day i.e., immediately but no later than 24 hours **of when he or she becomes aware of it.**
The Sponsor works with the **Investigator to ensure that all relevant information is completed within 1 or 5**
calendar days. The Sponsor must report to AstraZeneca Patient Safety using the designated Safety emailbox within 7 calendar days or sooner when required if there is an SAE associated with the medication error and within 30 days for all other medication errors.  
14. **Endpoints, statistical methods and sample size determination**
14.1 Endpoints Primary endpoint  **1-year overall survival**
Secondary endpoints  2-year, 3-year, 4-year and 5-year overall survival.  Overall response rates  Response rates in non-irradiated lesions  Progression free survival  Progression free survival in non-irradiated lesions  Local control rates in the thorax  Frequency and severity of adverse events  **Health-related quality of life**
Exploratory endpoints  Duration of severe adverse events  Frequency and timing of brain metastases  **Assess cognitive function in the whole study cohort and compare cognitive function between**
patients who receive PCI and those who do not.  **Associations between outcomes of study treatment and biomarkers in tissue, blood and stool (e.g.**
ctDNA in blood, miRNA and gut microbiome).  
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14.2 Description of analysis sets 14.2.1 Safety analysis set All patients who commence chemoimmunotherapy 14.2.2 Efficacy analysis set The primary analyses will be performed on the intention to treat population, i.e. all eligible patients who are randomized. Secondarily, we will analyze patients who have received a minimum of three courses of chemoimmunotherapy (both arms) plus TRT (experimental arm) (per protocol population).
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14.3 methods of statistical analyses

The frequency and severity of AEs will be compared between the treatment arms using the Pearson's Chisquare and Fisher's exact test as appropriate.  
14.3.2 Efficacy analyses For the primary endpoint, the Cox proportional hazards method will be used to compare survival between the treatment groups. Considering that median overall survival was 12-13 months in the two trials that established chemo-immunotherapy as treatment of ES SCLC, the study is designed to perform the primary survival analyses 14 months after last patient entry (to ensure that all survival data at 1 year are captured),
which is a timepoint when we believe that the first signal of an effect of the experimental treatment can be seen. Additional survival analyses will be performed 2-, 3-, 4- and 5-year after last patient entry.  
Median OS, PFS and time to progression in the brain will be estimated using the Kaplan-Meier method, and a Cox-model will be used for multivariable analyses adjusting for established prognostic factors in the target population (sex, PS, disease stage, presence of brain metastases and liver metastases)
and age. Pearson's Chi-square test will be used to compare response rates (overall and in non-irradiated lesions), frequency of brain metastases, and location of metastases.  
All HRQoL scores will be transformed to a scale of 0-100 according to the EORTC QLQ scoring manual. Mean scores will be compared at each assessment timepoint. A difference of 10 points is considered clinically relevant. Primary HRQoL-endpoints are dyspnea, global quality of life and physical function. All other HRQoL-scales will be included in complementary analyses.  
14.3.3 Exploratory analyses Cognitive function (MoCA-scores) will be compared using the Mann-Whitney test, and time until decline of MoCA-scores will be compared. Associations between biomarkers in tissue, blood and stool samples, and treatment outcomes, baseline characteristics, and survival will be investigated. A detailed project plan including biomarker and data analysis plan will be defined when sufficient biological material and clinical data to start the translational research have been collected. 14.3.4 Interim analyses The Safety and data monitoring committee will perform an interim analysis when 2/3 of the target number of patients (n≥85 in both arms) have completed a minimum of three chemotherapy courses (and TRT in the experimental arm). According to the O'Brien-Fleming approach, an alpha of 0.0054 will be allocated to the interim analyses. Consequently, enrolment will be stopped if the survival difference is statistically significant with a 2-sided p≤0.0054. If enrolment continues beyond the interim analysis, the significance level for the primary survival analysis is p≤0.0492.  
14.4 Determination of sample size The sample size calculation assumes an accrual period of 30 months and that the primary survival analysis is performed 14 months after last patient entry. Additional survival analyses will be performed 2, 3, 4 and 5 years after last patient entry. All patients will be followed for a maximum of 5 years when the final survival Page 53 of 59  
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analysis will be performed.  
Furthermore, the calculation is based on a constant hazard ratio of  
  
0.65, corresponding to median survival times of 13.10 months for the control group and 20.02 months for the experimental group, and 1-year survival rates of 53% in the control group and 66% in the experimental group. This effect was selected as an effect of clinical relevance and an effect of this magnitude might be anticipated if there is a synergistic effect of combining radiotherapy with durvalumab.  
The criterion for significance (alpha) has been set at 5%. The test is 2-tailed, which means that an effect in either direction will be interpreted. For this study design, alpha and tails, the population effect size described above, and to have power of 80% to yield a statistically significant result, 128 patients are required in each treatment group. Enrolment will continue until 128 or more patients in the control arm have completed minimum three chemo-immunotherapy courses, and minimum 128 patients in the experimental group have completed minimum three chemo-immunotherapy courses plus TRT of 30 Gy. We expect a loss to followup and inability to complete three courses (plus TRT in the experimental group) of maximum 15% and estimate that we need to enroll a total of 302 patients.  
All eligible patients who are randomized will be included in the primary efficacy analyses (ITTpopulation). All patients who commence chemo-immunotherapy will be included in the toxicity analyses. In addition, we will perform analyses of the patients who complete minimum three chemo-immunotherapy courses (and TRT in the experimental arm) (per protocol population). The sample size calculation was performed using SPSS Sample Power v3.
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15. ethical and regulatory requirements

15.1 Ethical conduct of the study The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH GCP, and applicable regulatory requirements Patient data protection.  
15.2 Ethics and regulatory review Approval from all relevant national and local regulatory authorities will be collected before enrolment starts.  
15.3 Informed consent Informed consent of each subject will be obtained through a written and verbal explanation process that addresses all elements required by ICH GCP. Sponsor will develop a core ICF for use by all investigators in the clinical study. The National Coordinating Investigator in each country will, based on this core ICF, be responsible for developing an ICF in all official languages in their country which complies with local and national laws and regulations.  
The Principal Investigator(s) at each center will:  **Ensure each subject is given full and adequate oral and written information about the nature, purpose,**
possible risk and benefit of the study.  Ensure each subject is notified that they are free to discontinue from the study at any time.  **Ensure that each subject is given the opportunity to ask questions and allowed time to consider the**
information provided.  **Ensure each subject provides signed and dated ICF before conducting any procedure specifically for the**
study.  Ensure the original, signed ICFs are stored in the Investigator's Site File.  Ensure a copy of the signed ICF is given to the subject.  
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**Ensure that any incentives for subjects who participate in the study as well as any provisions for**
subjects harmed due to study participation are described in the ICF.  
15.4 Changes to the protocol and ICF
Study procedures will not be changed without the mutual agreement of the Principal Investigator and sponsor. Any changes will be documented in a study protocol amendment. For a substantial change to the protocol, the sponsor will distribute amended versions of the protocol to all investigator(s). Before implementation, amended protocols, including revised ICD, must be approved by the relevant local and national regulatory authorities. Any non-substantial changes will be communicated to all relevant regulatory authorities.  
15.5 Audits and inspections Authorized representatives of a Competent Authority and IRB/REB/IEC may visit the centers to perform inspections, including source data verification. Likewise, the representatives from sponsor may visit the centers to perform an audit. The purpose of an audit or inspection is to systematically and independently examine all study-related activities and documents to determine whether these activities were conducted, and data were recorded, analyzed, and accurately reported according to the protocol, Good Clinical Practice (ICH GCP), and any applicable regulatory requirements. The principal investigator at each study site will ensure that the inspectors and auditors will be provided with access to source data/documents.
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16. study management

16.1 Training of study site personnel A site initiation visit will be performed at all sites before study start. Training will include walkthrough of the protocol, study procedures, CRF, study drug management, and reporting of AEs. Furthermore, all personnel who will perform the MoCA test will need to complete the online training. All study procedures will be described in a study procedure manual.  
16.2 Monitoring of the study 16.2.1 Source data The study will be monitored according to a separate monitoring plan.  
16.3 Study timetable and end of study We expect to enroll the first patient in Q1 2022, and to complete enrolment in Q2 2024. According to this schedule, the analyses for the primary endpoint will be performed in Q3 2025. All patients will be followed for a maximum of 5 years, and we expect to complete follow-up in Q2 2029.  
17. **Data management**
The trial will be conducted in compliance with the protocol, ICH GCP and the applicable regulatory requirements. The staff at the central trial office at NTNU in Trondheim will oversee that data are collected and stored appropriately. The investigators must maintain adequate and accurate records to enable the study to be conducted according to protocol and fully documented, including but not limited to the protocol, protocol amendments, ICFs, and documentation of EC and governmental approval.  
All patients will provide a written informed consent before any data are collected. The study personnel will enter data required by the protocol into the electronic, web-based Case report forms (WebCRF). Participants will be assigned a unique study ID at each site. All data recorded and transferred will be linked to this ID, no personal data will be stored in the CRF or transferred to the central trial office.  
The web-based CRF has been developed in close collaboration between the Central Study Management, the protocol committee and the Unit for Applied Clinical Research, NTNU. During study conduct, the data are stored on a secure server at the St. Olavs hospital with  
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restricted access. According to current regulations for clinical medical research, all data will be transferred to the Norwegian Centre for Research Data and stored for 15 years after study completion. All personally identifiable data will then be deleted. The investigators are responsible for assuring that data entered in the CRF is complete, accurate, and that entry is performed in a timely manner, and no later than 2 weeks after each visit, procedure or AE.  
The CRF enables the central study management in Trondheim, in collaboration with monitors, to monitor data entry and send reminders if data are not entered within a reasonable timeframe. The protocol specifies how SAEs, SUSARs and AESIs should be defined and reported. All SAE, SUSAR and AESI reports will immediately be reviewed by the medical personnel at the central trial office and complementary information will be requested when needed.  
All sites will be monitored on a regular basis and minimum once per year during the study treatment period. The purpose is to verify that the patients' interests are secured, that the reported data are correct and complete, and that the trial is conducted in compliance with the trial protocol, general principles of Good Clinical Practice, and regulations by authorities. Any issues will be discussed with the site's Principal Investigator and the National Principal Investigator and may lead to closure of sites if not resolved.  
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