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Randomized phase III trial investigating the survival benefit of adding thoracic radiotherapy to durvalumab (MEDI4736) immunotherapy plus chemotherapy in extensive stage small-cell lung cancer Clinical study protocol EudraCT no: 2021-001648-91 Sponsor NTNU, Norwegian University of Science and Technology Department of Clinical and Molecular Medicine Faculty of Medicine and Health Sciences 7491 Trondheim Norway Chief Investigator Bjørn H. Grønberg Professor, Department of Clinical and Molecular Medicine, NTNU
Consultant, Department of Oncology, St. Olavs Hospital, Trondheim University Hospital bjorn.h.gronberg@ntnu.no
+47 72 82 61 70 / +47 472 97 878 Sponsor Representative Magnus Steigedal Head of the Department of Clinical and Molecular Medicine, NTNU
magnus.steigedal@ntnu.no
+47 73 55 97 22 / +47 977 06 661
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signature page

I hereby declare that I will conduct the study in compliance with the protocol, ICH GCP and applicable regulatory requirements.  
| Name              | Title                     | Role               | Signature   | Date   |
|-------------------|---------------------------|--------------------|-------------|--------|
| Magnus Steigedal  | Head of                   | Sponsor            |             |        |
| Department        | Representative            |                    |             |        |
| Bjørn H. Grønberg | Professor and  Consultant | Chief Investigator |             |        |
|                   |                           |                    |             |        |  
Study Number TRIPLEX  
  
  
  
Protocol Version Number **1.1**
Date 05**-JAN-2022**
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1. protocol synopsis

Study title: **Randomized phase III trial investigating the survival benefit of adding thoracic radiotherapy** (TRT) to durvalumab immunotherapy plus chemotherapy in extensive stage small-cell lung cancer Protocol version number: **1.0**
Clinical phase: **Randomized phase III**
Study duration: **From 2021 until 2028** Investigational therapies and reference therapy:
**Reference therapy: Durvalumab plus carboplatin/etoposide**
**Investigational therapy: Durvalumab plus carboplatin/etoposide and TRT**
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research hypotheses

The main hypothesis is that adding TRT to durvalumab plus chemotherapy provides a survival benefit for patients with extensive stage (ES) small-cell lung cancer (SCLC). Specifically, we hypothesize that:
**combining TRT, durvalumab and chemotherapy is feasible and well tolerated** **adding TRT improves survival, response rates, and PFS** **the patients who benefit the most from the study treatment can be identified through analyses of**
tissue, blood and stool samples
**toxicity of prophylactic cranial irradiation (PCI) is acceptable in ES SCLC patients who receive**
durvalumab plus chemotherapy Objectives:
Primary Objective: To investigate whether adding TRT to durvalumab plus chemotherapy improves 1-year survival.  
Secondary Objectives: To investigate whether adding TRT improves 2-, 3-, 4- and 5-year overall survival. To investigate whether adding TRT improves overall response rates, response rates in non-irradiated lesions and PFS. To investigate whether TRT improves local control.  
To compare the frequency and severity of adverse events between the treatment arms.  
To compare health related quality of life between treatment arms. Exploratory Objectives:
To compare the duration of severe adverse events between the treatment arms.  
To compare the frequency and timing of brain metastases between treatment arms. To assess cognitive function in the whole study cohort and compare cognitive function between those who receive PCI and those who do not. To investigate associations between outcomes of study treatment and biomarkers in tissue, blood and stool (e.g. ctDNA in blood, miRNA, gut microbiome).  
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 Cognitive function in 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).  
Study population:
Patients with ES SCLC eligible for chemo-immunotherapy and TRT.  
Number of centers: **Approx. 25** Number of patients: **Approx. 302**
Study design: Open label randomized phase III trial  
  
Randomization:
Patients will be randomized 1:1 in blocks of various sizes to receive chemo-immunotherapy alone or chemo-immunotherapy plus TRT stratifying for presence of liver metastases (yes vs. no) and presence of brain metastases (yes vs. no). Inclusion criteria: 1. **Capable of giving signed informed consent which includes compliance with the requirements and**
restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent Study Number TRIPLEX
Protocol Version Number **1.1**
Date 05**-JAN-2022**  
and any locally required authorization (e.g. Health Insurance Portability and Accountability Act in the  
  
US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.  
2. **Age > 18 years at time of study entry.**
3. **ECOG performance status of 0 or 1.**
4. **Body weight >30 kg.**
5. **Adequate normal organ and marrow function as defined below:**
**Haemoglobin ≥10.0 g/dL.**
**Absolute neutrophil count (ANC) ≥1.5 × 10**9 **/L** **Platelet count ≥100 × 10**9/L
**Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This does not apply to patients**
with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology).  
**ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in**
which case it must be ≤5 x ULN.  
**Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the**
Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.  
6. **Patient is willing and able to comply with the protocol for the duration of the study including**
undergoing treatment and scheduled visits and examinations including follow-up.  
7. **Life expectancy of at least 3 months.** 8. **At least 1 lesion in the thorax, not previously irradiated, that qualifies as a RECIST 1.1 target lesion**
(TL) at baseline and is possible to irradiate to 30 Gy in 10 fractions. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to randomization.  
9. **Histologically or cytologically confirmed SCLC. Mixed histology may be acceptable as long as the SCLC**
component accounts for more than 90%.  
10. **Stage IV disease according to the TNM v8. Patients with stage III disease are eligible if the disease is**
too widespread to be treated as limited stage SCLC.  
11. **Pulmonary function: FEV1 >1 L or >30 % of predicted value and DLCO >30 % of predicted value.**
12. **Female patients of childbearing potential (postmenarcheal, not postmenopausal [>12 continuous**
months of amenorrhea with no identified cause other than menopause], and no surgical sterilization) should use highly effective contraception and take active measures to avoid pregnancy while undergoing systemic study therapy and for at least 5 months after the last dose.  
13. **Patients with brain metastases are eligible provided they are asymptomatic or treated and stable on**
steroids and/or anticonvulsants prior to the start of treatment.
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exclusion criteria

1. **Participation in another clinical study with an investigational product during the last 30 days.** 2. **Concurrent enrolment in another clinical study, unless it is an observational (non-interventional)**
clinical study or during the follow-up period of an interventional study.  
3. **Previous chemo- or radiotherapy for SCLC. Patients who have undergone surgery, but no adjuvant**
therapy are eligible.  
4. **Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of**
alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.  
5. **Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with**
the Chief Investigator.  
  
6. **Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with**  
  
durvalumab may be included only after consultation with the Chief Investigator.  
7. **Any concurrent chemotherapy, investigational product or biologic cancer therapy.**
8. **Any prior checkpoint inhibitor therapy, including durvalumab.**
9. **Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation**
within 4 weeks of the first dose of study drugs.  
10. **Immediate need for thoracic radiotherapy or bulky disease outside the thorax, or need for such**
radiotherapy before completion of chemo-immunotherapy 11. **Major surgical procedure within 28 days prior to the first dose of study drugs. Note: Local surgery of**
isolated lesions for palliative intent is acceptable.  
12. **History of allogenic organ transplantation.**
13. **Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel**
disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
a. **Patients with vitiligo or alopecia.** b. **Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone**
replacement.  
c. **Any chronic skin condition that does not require systemic therapy.** d. **Patients without active disease in the last 5 years may be included but only after consultation**
with the Chief Investigator.  
e. **Patients with celiac disease controlled by diet alone.**
14. **Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection,**
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia or QTcF value >470 ms on ECG, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring **AEs or compromise the**
ability of the patient to give written informed consent.  
15. **History of another primary malignancy except for:**
a. **Malignancy treated with curative intent and with no known active disease ≥5 years before the**
first dose of IP and of low potential risk for recurrence.  
b. **Localized breast or prostate cancer treated with hormonal therapy alone.**
c. **Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.** d. **Adequately treated carcinoma in situ without evidence of disease.**
16. **Leptomeningeal carcinomatosis.**
17. **Untreated, symptomatic central nervous system (CNS) metastases. Any neurologic symptoms that**
developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on steroids and/or anticonvulsants prior to the start of treatment.  
18. **History of active primary immunodeficiency.**
19. **Active infection including tuberculosis (clinical evaluation that includes clinical history, physical**
examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV
infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.  
  
20. **Current or prior use of immunosuppressive medication within 14 days before the first dose of**  
  
  
durvalumab. The following are exceptions to this criterion:
a. **Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection).**
b. **Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its**
equivalent.  
c. **Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).**
21. **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.  
22. **Female patients who are pregnant or breastfeeding or male or female patients of reproductive**
potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy.  
23. **Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.**
24. **Judgment by the investigator that the patient is unsuitable to participate in the study and the patient**
is unlikely to comply with study procedures, restrictions and requirements.
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investigational products dose and mode

**Four courses of durvalumab 1500 mg IV day 1, carboplatin (AUC=5, Calvert's formula) IV day 1 and**
etoposide 100 mg/m2 **BSA IV day 1. On days 2-4, etoposide is administered in a dose of 100 mg/m**2 BSA IV or 200 mg/m2 **BSA PO. Chemoimmunotherapy courses are administered every three weeks.**
After completing four courses, durvalumab 1500 mg IV is given every four weeks until intolerable toxicity, patient's wish, or disease progression and need for other treatment.  
**The dose of durvalumab will be adjusted to 20 mg/kg if a patient's body weight falls below 30 kg** **Patients randomized to the experimental arm will receive TRT of 30 Gy in 10 fractions, one fraction**
per day, 5 fractions per week, between the second and third chemo-immunotherapy course.  
**Patients who achieve a response when evaluated after completion of chemo-immunotherapy may**
be offered PCI of 25 Gy in 10 fractions or 30 Gy in 15 fractions, one fraction per day, 5 fractions per week according to local treatment policy.
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safety assessments

Toxicity will be classified according to CTCAE v5.0. Cognitive function will be assessed using the MoCA
test. Patients will report HRQoL on the EORTC QLQ C30+LC13.
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efficacy assessments

OS will be measured from the day of randomization until death by any cause, PFS from the day of randomization until RECIST 1.1 progression or death by any cause. Response to treatment and progression will be assessed according to RECIST 1.1. Response to treatment and progression will be assessed on CT and MRI scans at regular intervals. Sensitivity analyses including measurement of previously irradiated lesions (both thoracic lesions and brain metastases) will be performed.
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statistical methods and data analysis

Cox proportional hazard method will be used to compare survival. The primary survival analyses will be performed 14 months after the last patient entry (to ensure that 1-year survival data are captured).  
Pearson's Chi-Square test will be used to compare toxicity, overall response rates, and treatment completion rates. Mann-Whitney's test will be used to compare number of completed chemoimmunotherapy- and durvalumab-courses.  
Median OS will be estimated using the Kaplan-Meier method, and a Cox-model will be used for multivariable survival analysis adjusting for established prognostic factors in the target population (sex, PS, disease stage, presence brain metastases and liver metastases) and age. A separate analysis plan will be defined for the biomarker analyses.
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sample size determination

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 and 4 years after last patient entry. All patients will be followed for a maximum of 5 years when the final survival analysis will be performed.  
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 follow-up 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 chemoimmunotherapy courses (and TRT in the experimental arm) (per protocol population).  
An independent 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. The sample size calculation was performed using SPSS Sample Power v3.  
Study Number TRIPLEX  
  
  
Protocol Version Number **1.1**
Date 05**-JAN-2022**
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2. schedule of study assessments

| Year                                                                                                                                                                                                                                                                                                        | 1 ab                   | 0                                     | 3                                     | 3-4      | 3-4        | 6     | 9   | 11-12   | 13   | 13-15   | 17   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------|---------------------------------------|---------------------------------------|----------|------------|-------|-----|---------|------|---------|------|
| Week                                                                                                                                                                                                                                                                                                        | -4 to -1 Screening     | Durvalumab/ carboplatin/  etoposide 1 | Durvalumab/ carboplatin/  etoposide 2 | Response | Start of   |       |     |         |      |         |      |
| evaluation                                                                                                                                                                                                                                                                                                  | thoracic  radiotherapy | Durvalumab/ carboplatin/  etoposide 3 | Durvalumab/ carboplatin/  etoposide 4 | Response | Durvalumab | Start |     |         |      |         |      |
| evaluation                                                                                                                                                                                                                                                                                                  | 5                      | of  PCI                               | Durvalumab 6                          |          |            |       |     |         |      |         |      |
| Informed consent                                                                                                                                                                                                                                                                                            | X                      |                                       |                                       |          |            |       |     |         |      |         |      |
| Eligibility criteria                                                                                                                                                                                                                                                                                        | X                      |                                       |                                       |          |            |       |     |         |      |         |      |
| Medical history, demography, height,                                                                                                                                                                                                                                                                        | X                      |                                       |                                       |          |            |       |     |         |      |         |      |
| tobacco use  Clinical examination/                                                                                                                                                                                                                                                                          | X                      | X                                     | X                                     | X        | X          | X     | X   | X       |      |         |      |
| performance status/weight  ECGc                                                                                                                                                                                                                                                                             | X                      |                                       |                                       |          |            |       |     |         |      |         |      |
| Concomitant medication                                                                                                                                                                                                                                                                                      | X                      | X                                     | X                                     | X        |            |       |     |         |      |         |      |
| HRQoL (QLQ C30 + LC13)                                                                                                                                                                                                                                                                                      | X                      | X                                     |                                       |          |            |       |     |         |      |         |      |
| Cognitive function (MoCA)                                                                                                                                                                                                                                                                                   | X                      | X                                     |                                       |          |            |       |     |         |      |         |      |
| Clinical chemistryde                                                                                                                                                                                                                                                                                        | X                      | X                                     | X                                     | X        | X          | X     | X   |         |      |         |      |
| Hematologyf                                                                                                                                                                                                                                                                                                 | X                      | X g                                   | X g                                   | X g      | X g        |       |     |         |      |         |      |
| Pregnancy test in women                                                                                                                                                                                                                                                                                     | X                      | X                                     | X                                     | X        | X          | X     | X   |         |      |         |      |
| of childbearing potentialh Hepatitis B&C, HIV if suspectedi                                                                                                                                                                                                                                                 | X                      |                                       |                                       |          |            |       |     |         |      |         |      |
| Pulmonary functionj                                                                                                                                                                                                                                                                                         | X                      | X                                     |                                       |          |            |       |     |         |      |         |      |
| Assessment of adverse events                                                                                                                                                                                                                                                                                | X                      | X                                     | X                                     | X        | X          | X     | X   | X       | X    |         |      |
| CT thorax/upper abdomenk                                                                                                                                                                                                                                                                                    | X                      | X l                                   | X                                     |          |            |       |     |         |      |         |      |
| MRI of the braink,m                                                                                                                                                                                                                                                                                         | X                      | X                                     |                                       |          |            |       |     |         |      |         |      |
| Collection of tumor tissuen                                                                                                                                                                                                                                                                                 | X                      |                                       |                                       |          |            |       |     |         |      |         |      |
| Blood biomarker analyses                                                                                                                                                                                                                                                                                    | X                      | X                                     | X                                     | X        |            |       |     |         |      |         |      |
| Stool for biomarker analyseso                                                                                                                                                                                                                                                                               | X                      | X                                     | X                                     | X        |            |       |     |         |      |         |      |
| Randomization                                                                                                                                                                                                                                                                                               | X                      |                                       |                                       |          |            |       |     |         |      |         |      |
| aEvery effort should be made to minimize the time between start of screening and starting treatment.  b If laboratory or imaging procedures were performed for alternate reasons prior to signing consent, these can be used for screening purposes with consent of the patient provided they were obtained |                        |                                       |                                       |          |            |       |     |         |      |         |      |  
Pulmonary functionj X X  
Assessment of adverse events X X X X X X X X X  
CT thorax/upper abdomenk X X  
l X  
MRI of the braink,m X X Collection of tumor tissuen X  
Blood biomarker analyses X X X X Stool for biomarker analyseso **X X X X**  
Randomization X  
a**Every effort should be made to minimize the time between start of screening and starting treatment.** b**If laboratory or imaging procedures were performed for alternate reasons prior to signing consent, these can be used for screening purposes with consent of the patient provided they were obtained**  
within 28 days of randomization.  
c**Any clinically significant abnormalities detected require triplicate ECG results.**  
d**If screening clinical chemistry and hematology assessments are performed within 5 days prior to Day 1 (first infusion day of each course), they do not need to be repeated at Day 1.**  
e**Bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, creatinine, sodium (Na), potassium (K), thyroid stimulating hormone (TSH), free thyroxine (FT4),**  
erythrocyte sedimentation rate (ESR), glucose, lactate dehydrogenase (LDH). Tri-iodothyronine (T3) or FT4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to  
the endocrine system.  
f**HgB, leukocytes, neutrophil granulocytes, and platelets**  
gOn day 1 and 10 of each chemotherapy course.  
  
  
Date 05**-JAN-2022**
h**For women of childbearing potential only. A urine or serum pregnancy test is acceptable. Women of childbearing potential are required to have a pregnancy test within 7 days prior to the first dose**
of study drugs and then before every durvalumab course. Pregnancy test may occur on Day 1, but results must be available and reviewed by the treating physician or Investigator prior to commencing an infusion.  
i**Hepatitis B surface antigene (HBsAg), Hepatitis B core antibody (HBcAb), and Hepatitis C antibody (HCV Ab) tests are mandatory. If a patient has a negative HBsAg test and a positive HBcAb test, an**
HBV DNA test must be performed to determine if the patient has an HBV infection. If a patient has a positive HCV Ab test, an HCV RNA test must be performed to determine if the patient has an HCV infection. j**FEV1, FEV1%, FVC, FVC%, and DLCO%**
k**RECIST assessments will be performed on images from CT of the chest and upper abdomen and MRI of the brain, each preferably with IV contrast. Additional anatomy should be imaged based on**
signs and symptoms of individual patients at baseline and follow-up. Confirmation of response is not mandatory. If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the subsequent assessments at their next scheduled visit.  
l**CT scan for radiotherapy planning may be used for patients in the experimental arm. A regular CT scan should be performed for patients in the control arm at the same time as CT scans for**
radiotherapy planning would be performed, usually 3-4 weeks after the first day of the first chemo-immunotherapy course.  
m**May be replaced with CT if MRI is unavailable.**
n**Archival diagnostic material or re-biopsy for confirmation of suspected relapse.**
o**Not mandatory.**  
| Year                                                | 1                                                                                                                                      | 2   |      |    |      |    |      |    |      |    |
|-----------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|-----|------|----|------|----|------|----|------|----|
| Week                                                | 21                                                                                                                                     | 29  | 37   | 45 | 1    | 9  | 17   | 25 | 33   | 41 |
| Durvalumab                                          | Durvalumab every 4 weeks until progressive disease and need for other treatment, unacceptable toxicity or patients wish to discontinue |     |      |    |      |    |      |    |      |    |
| Clinical examination/  performance status/weight    | X                                                                                                                                      | X   | X    | X  | X    | X  | X    | X  | X    | X  |
| Concomitant medication                              | X                                                                                                                                      | X   | X    | X  | X    | X  | X    | X  | X    | X  |
| HRQoL (QLQ C30 + LC13)                              | X                                                                                                                                      | X   | X    | X  | X    | X  | X    |    |      |    |
| Cognitive function (MoCA)                           | X                                                                                                                                      | X   | X    |    |      |    |      |    |      |    |
| Clinical chemistrye                                 | X                                                                                                                                      | X   | X    | X  | X    | X  | X    | X  | X    | X  |
| Hematology                                          | X                                                                                                                                      | X   | X    | X  | X    | X  | X    | X  | X    | X  |
| Pregnancy test in women  of childbearing potentialh | Before every durvalumab course                                                                                                         |     |      |    |      |    |      |    |      |    |
| Assessment of adverse events                        | X                                                                                                                                      | X   | X    | X  | X    | X  | X    | X  | X    | X  |
| CT thorax/upper abdomenk                            | X                                                                                                                                      | X   | X    | X  | X    | X  | X    | X  | X    | X  |
| MRI of the braink,m                                 | (X)o                                                                                                                                   | X   | (X)o | X  | (X)o | X  | (X)o | X  | (X)o | X  |
| Blood for biomarker analyses                        | X                                                                                                                                      | X   |      |    |      |    |      |    |      |    |
| Stool for biomarker analyseso                       | X                                                                                                                                      | X   |      |    |      |    |      |    |      |    |  
Study Number TRIPLEX  
  
Protocol Version Number **1.1**
Date 05**-JAN-2022**  
| Progressive  disease or  patient lost to  follow-up   |      |    |      |    |      |    |      |    |      |    |      |    |       |    |
|-------------------------------------------------------|------|----|------|----|------|----|------|----|------|----|------|----|-------|----|
| Week                                                  | 49   | 10 | 23   | 36 | 49   | 10 | 23   | 36 | 49   | 10 | 23   | 36 | 52    |    |
| Clinical examination/ performance status/weight       | X    | X  | X    | X  | X    | X  | X    | X  | X    | X  | X    | X  | X     | X  |
| HRQoL (QLQ C30 + LC13)                                | X    | X  |      |    |      |    |      |    |      |    |      |    |       |    |
| Cognitive function (MoCA)                             | X    | X  | X    | X  |      |    |      |    |      |    |      |    |       |    |
| Clinical chemistrye                                   | X    | X  |      |    |      |    |      |    |      |    |      |    |       |    |
| Hematologyf                                           | X    | X  |      |    |      |    |      |    |      |    |      |    |       |    |
| Assessment of adverse events                          | X    | X  | X    | X  | X    | X  | X    | X  | X    | X  | X    | X  | X     | X  |
| CT thorax/upper abdomenk                              | X    | X  | X    | X  | X    | X  | X    | X  | X    | X  | X    | X  | X     | X  |
| MRI of the braink,m                                   | (X)o | X  | (X)o | X  | (X)o | X  | (X)o | X  | (X)o | X  | (X)o | X  | (X) o | X  |
| Blood for biomarker analyses                          | X    | X  | X    | X  |      |    |      |    |      |    |      |    |       |    |
| Stool for biomarker analyseso                         | X    | X  | X    | X  |      |    |      |    |      |    |      |    |       |    |
| Biopsy of progressing lesiono                         | X    |    |      |    |      |    |      |    |      |    |      |    |       |    |
| Year                                                  | 3    | 4  | 5    |    |      |    |      |    |      |    |      |    |       |    |  
Follow-up for patients who have completed study treatment: **According to the study schedule.**
Follow-up of patients who have discontinued study treatment due to other reasons than RECIST 1.1 progressive disease (PD) and need for other treatment: Should be followed according to the study schedule until RECIST 1.1 PD and need for other treatment. Assessments at RECIST 1.1 PD: **All evaluations and assessments listed in the last column of the study schedule ("PD") should be performed when disease** progression occurs. If any assessment has been performed within the last 7 days, they do not need to be repeated, but it is essential that all assessments are performed (stool sampling and re-biopsy are not mandatory). Follow-up for patients beyond RECIST 1.1 PD: **As long as patients are considered to benefit clinically from continuing study treatment and are not in need for** other systemic treatment, they can continue study treatment. This usually applies for patients who have completed chemoimmunotherapy and receive durvalumab monotherapy. A confirmatory CT evaluation should be performed within 4-6 weeks to ensure that they do not experience rapid disease progression requiring other therapy. At a minimum, subsequent intervals between CT evaluations should be according to the study schedule.  
Follow-up for patients who discontinue study treatment due to RECIST 1.1 PD: **Post-study AEs/SAEs should be reported according to protocol. Post-study**
treatment and survival must be recorded. Patients will be followed and treated according to local routines.  
  
  
  
Date 05**-JAN-2022**
Table of contents Page  
| 1.                                                                               | PROTOCOL SYNOPSIS                                                | 3   |
|----------------------------------------------------------------------------------|------------------------------------------------------------------|-----|
| 2.                                                                               | SCHEDULE OF STUDY ASSESSMENTS, PROCEDURES AND TREATMENT          | 9   |
| 3.                                                                               | ABBREVIATIONS AND DEFINITION OF TERMS                            | 17  |
| 4.                                                                               | INTRODUCTION                                                     | 19  |
| 4.1 Disease background                                                           | 19                                                               |     |
| 4.1.1 Lung cancer                                                                | 19                                                               |     |
| 4.1.2 Treatment of SCLC                                                          | 19                                                               |     |
| 4.2 Immunotherapies                                                              | 19                                                               |     |
| 4.2.1 Durvalumab                                                                 | 20                                                               |     |
| 4.2.2 Immunotherapies in lung cancer                                             | 20                                                               |     |
| 4.2.3 Immunotherapy in SCLC                                                      | 20                                                               |     |
| 4.2.4 Combined chemotherapy and immunotherapy as first-line treatment of ES SCLC | 20                                                               |     |
| 4.2.5 Predictive biomarkers                                                      | 21                                                               |     |
| 4.2.6 Paraneoplastic neurological syndrome (PNS) in SCLC                         | 21                                                               |     |
| 4.2.7 TRT in ES SCLC                                                             | 22                                                               |     |
| 4.2.8 Synergistic effect of combining RT and immunotherapy                       | 22                                                               |     |
| 4.2.9 Prophylactic cranial irradiation in ES SCLC                                | 23                                                               |     |
| 4.3 Research hypotheses                                                          | 23                                                               |     |
| 4.4 Rationale for conducting this study                                          | 23                                                               |     |
| 4.5 Benefit/risk and ethical assessment                                          | 24                                                               |     |
| 4.5.1 Potential benefits                                                         | 24                                                               |     |
| 4.5.2 Overall risks of durvalumab                                                | 24                                                               |     |
| 4.5.3 Overall benefit-risk                                                       | 25                                                               |     |
| 5.                                                                               | PROVIDE SUMMARY OF OVERALL BENEFIT-RISK FOR THE STUDY OBJECTIVES | 25  |
| 5.1 Primary objective(s)                                                         | 25                                                               |     |
| 5.1.1 Secondary objective(s)                                                     | 25                                                               |     |
| 5.2 Exploratory objective(s)                                                     | 26                                                               |     |
| 6.                                                                               | STUDY DESIGN                                                     | 26  |
| 6.1 Overview of study design                                                     | 26                                                               |     |
| 6.2 Study oversight for safety evaluation                                        | 26                                                               |     |
| 7.                                                                               | PATIENT SELECTION                                                | 26  |  
Study Number TRIPLEX  
  
  
  
Protocol Version Number **1.1**
Date 05**-JAN-2022**  
| 7.1 Inclusion criteria                                                                         | 26                           |    |
|------------------------------------------------------------------------------------------------|------------------------------|----|
| 7.2 Exclusion criteria                                                                         | 27                           |    |
| 7.3 Withdrawal of patients from study treatment and/or study                                   | 29                           |    |
| 7.3.1 Permanent discontinuation of chemotherapy and durvalumab                                 | 29                           |    |
| 7.3.2 Lost to follow-up                                                                        | 29                           |    |
| 7.3.3 Withdrawal of consent                                                                    | 29                           |    |
| 7.4 End of trial                                                                               | 30                           |    |
| 8.                                                                                             | STUDY THERAPY                | 30 |
| 8.1 Durvalumab                                                                                 | 30                           |    |
| 8.1.1 Durvalumab schedule                                                                      | 30                           |    |
| 8.1.2 Formulation/packaging/storage                                                            | 30                           |    |
| 8.1.3 Preparation of durvalumab doses for administration with an IV bag                        | 30                           |    |
| 8.1.4 Monitoring of dose administration                                                        | 31                           |    |
| 8.2 Carboplatin and etoposide chemotherapy                                                     | 31                           |    |
| 8.2.1 Formulation/packaging/storage                                                            | 31                           |    |
| 8.2.2 Product preparation and administration                                                   | 31                           |    |
| 8.2.3 Suggested antiemetic medication (carboplatin)                                            | 32                           |    |
| 8.2.4 Recommendations before a new course of chemotherapy:                                     | 32                           |    |
| 8.2.5 Suggestions for dose adjustments:                                                        | 32                           |    |
| 8.2.6 Duration of treatment and criteria for treatment through progression and for retreatment | 32                           |    |
| 8.2.7 Accountability and dispensation                                                          | 33                           |    |
| 8.2.8 Disposition of unused investigational study drug                                         | 33                           |    |
| 8.2.9 Monitoring of dose administration                                                        | 33                           |    |
| 8.3 Thoracic radiotherapy                                                                      | 33                           |    |
| 8.3.1 Timing                                                                                   | 33                           |    |
| 8.3.2 TRT fractionation schedule                                                               | 33                           |    |
| 8.3.3 Treatment planning CT-scan                                                               | 34                           |    |
| 8.3.4 TRT guidelines in the CREST trial                                                        | 34                           |    |
| 8.3.5 Targets for TRT in the present trial                                                     | 34                           |    |
| 8.3.6 Delineation of target volumes                                                            | 34                           |    |
| 8.3.7 Delineation of organs at risk (OARs) and corresponding normal tissue dose constraints    | 34                           |    |
| 8.3.8 Treatment planning                                                                       | 35                           |    |
| 8.3.9 Treatment                                                                                | 35                           |    |
| 8.3.10 Quality assurance of the thoracic radiotherapy                                          | 35                           |    |
| 8.3.11 TRT in the control arm                                                                  | 35                           |    |
| 8.4 Prophylactic cranial irradiation (PCI)                                                     | 35                           |    |
| 8.4.1 Treatment of brain metastases                                                            | 35                           |    |
| 8.4.1                                                                                          | Irradiation of other lesions | 35 |
| 8.5 Post-study therapy                                                                         | 36                           |    |
| 9.                                                                                             | TREATMENT PLAN               | 36 |  
Study Number TRIPLEX  
  
Protocol Version Number **1.1**  
Date 05**-JAN-2022**  
| Date                                                                 | 05-JAN-2022                                                |    |
|----------------------------------------------------------------------|------------------------------------------------------------|----|
| 9.1 Patient enrollment and randomization                             | 36                                                         |    |
| 9.1.1 Procedures for randomization                                   | 36                                                         |    |
| 9.1.2 Procedures for handling patients incorrectly enrolled          | 36                                                         |    |
| 10.                                                                  | RESTRICTIONS DURING THE STUDY AND CONCOMITANT TREATMENT(S) | 36 |
| 10.1 Restrictions during the study                                   | 36                                                         |    |
| 10.1.1 Blood donation                                                | 37                                                         |    |
| 10.2 Concomitant treatment(s)                                        | 37                                                         |    |
| 10.2.1 Permitted concomitant medications                             | 37                                                         |    |
| 10.2.2 Excluded concomitant medications                              | 37                                                         |    |
| 11.                                                                  | STUDY PROCEDURES                                           | 38 |
| 11.1 Schedule of study procedures                                    | 38                                                         |    |
| 11.1.1 For both treatment arms                                       | 38                                                         |    |
| 11.1.2 For durvalumab maintenance therapy                            | 39                                                         |    |
| 11.1.3 Screening phase                                               | 39                                                         |    |
| 11.1.4 Treatment phase                                               | 40                                                         |    |
| 11.1.5 End of treatment                                              | 40                                                         |    |
| 11.2 Patient reported outcomes (PRO)                                 | 40                                                         |    |
| 11.2.1 Assessment of health-related quality of life (HRQoL)          | 40                                                         |    |
| 11.3 Assessment of cognitive function                                | 40                                                         |    |
| 11.4 Biological sampling procedures                                  | 40                                                         |    |
| 11.4.1 Collection of biological material for translational research  | 40                                                         |    |
| 11.4.2 Tissue samples                                                | 40                                                         |    |
| 11.4.3 Blood samples                                                 | 41                                                         |    |
| 11.4.4 Stool samples                                                 | 41                                                         |    |
| 11.4.5 Proposed biomarker analyses                                   | 42                                                         |    |
| 11.4.6 Withdrawal of informed consent for donated biological samples | 42                                                         |    |
| 12.                                                                  | DISEASE EVALUATION AND METHODS                             | 42 |
| 12.1 Sensitivity analyses                                            | 43                                                         |    |
| 13.                                                                  | ASSESSMENT OF SAFETY                                       | 43 |
| 13.1 Clinical laboratory tests                                       | 43                                                         |    |
| 13.1.1 Physical examinations                                         | 44                                                         |    |
| 13.2 WHO/ECOG performance status                                     | 44                                                         |    |
| 13.3 Other safety assessments                                        | 45                                                         |    |
| 13.4 Safety parameters                                               | 45                                                         |    |
| 13.4.1 Definition of adverse events (AEs)                            | 45                                                         |    |
| Page 14 of 59                                                        |                                                            |    |  
Study Number TRIPLEX  
  
Protocol Version Number **1.1**
Date 05**-JAN-2022**  
| 13.4.2 Definition of serious adverse events (SAEs)                                                                             | 45                                                           |    |
|--------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|----|
| 13.4.3 Definition of adverse events of special interest (AESI)                                                                 | 46                                                           |    |
| 13.4.4 Pneumonitis/ILD investigation                                                                                           | 47                                                           |    |
| 13.5 Assessment of safety parameters                                                                                           | 47                                                           |    |
| 13.5.1 Assessment of severity                                                                                                  | 47                                                           |    |
| 13.6 Recording of adverse events and serious adverse events                                                                    | 47                                                           |    |
| 13.6.1 Study recording period and follow-up for adverse events and serious adverse events                                      | 48                                                           |    |
| 13.7 Relationship to protocol procedures                                                                                       | 48                                                           |    |
| 13.8 Adverse events based on signs and symptoms                                                                                | 49                                                           |    |
| 13.9 Adverse events based on examinations and tests                                                                            | 49                                                           |    |
| 13.10 Disease progression                                                                                                      | 49                                                           |    |
| 13.11 New cancers                                                                                                              | 49                                                           |    |
| 13.12 Deaths                                                                                                                   | 49                                                           |    |
| 13.13 Reporting of serious adverse events and serious unexpected adverse reactions to the IRB and/or the  Regulatory Authority | 50                                                           |    |
| 13.14 Reporting of serious adverse events to AstraZeneca                                                                       | 50                                                           |    |
| 13.14.1 Reporting of deaths to AstraZeneca                                                                                     | 50                                                           |    |
| 13.15 Other events requiring reporting                                                                                         | 50                                                           |    |
| 13.15.1 Overdose                                                                                                               | 50                                                           |    |
| 13.15.2 Hepatic function abnormality                                                                                           | 50                                                           |    |
| 13.15.3 Pregnancy                                                                                                              | 51                                                           |    |
| 13.16 Medication error                                                                                                         | 51                                                           |    |
| 14.                                                                                                                            | ENDPOINTS, STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION | 52 |
| 14.1 Endpoints                                                                                                                 | 52                                                           |    |
| Primary endpoint                                                                                                               | 52                                                           |    |
| Secondary endpoints                                                                                                            | 52                                                           |    |
| Exploratory endpoints                                                                                                          | 52                                                           |    |
| 14.2 Description of analysis sets                                                                                              | 53                                                           |    |
| 14.2.1 Safety analysis set                                                                                                     | 53                                                           |    |
| 14.2.2 Efficacy analysis set                                                                                                   | 53                                                           |    |
| 14.3 Methods of statistical analyses                                                                                           | 53                                                           |    |
| 14.3.1 Safety analyses                                                                                                         | 53                                                           |    |
| 14.3.2 Efficacy analyses                                                                                                       | 53                                                           |    |
| 14.3.3 Exploratory analyses                                                                                                    | 53                                                           |    |
| 14.3.4 Interim analyses                                                                                                        | 53                                                           |    |
| Page 15 of 59                                                                                                                  |                                                              |    |  
  
| 14.4 Determination of sample size     | 53                                  |    |
|---------------------------------------|-------------------------------------|----|
| 15.                                   | ETHICAL AND REGULATORY REQUIREMENTS | 54 |
| 15.1 Ethical conduct of the study     | 54                                  |    |
| 15.2 Ethics and regulatory review     | 54                                  |    |
| 15.3 Informed consent                 | 54                                  |    |
| 15.4 Changes to the protocol and ICF  | 55                                  |    |
| 15.5 Audits and inspections           | 55                                  |    |
| 16.                                   | STUDY MANAGEMENT                    | 55 |
| 16.1 Training of study site personnel | 55                                  |    |
| 16.2 Monitoring of the study          | 55                                  |    |
| 16.2.1 Source data                    | 55                                  |    |
| 16.3 Study timetable and end of study | 55                                  |    |
| 17.                                   | DATA MANAGEMENT                     | 55 |
| 18.                                   | LIST OF REFERENCES                  | 56 |  
05
untitled h1
3. abbreviations and definition of

The following abbreviations and special terms are used in this clinical study protocol.  
| Abbreviation or term   | Explanation                                                 |
|------------------------|-------------------------------------------------------------|
| AE                     | Adverse event                                               |
| AESI                   | Adverse event of special interest                           |
| ALP                    | Alkaline phosphatase                                        |
| ALT                    | Alanine aminotransferase                                    |
| AST                    | Aspartate aminotransferase                                  |
| AUC                    | Area under the concentration-time curve                     |
| BSA                    | Body surface area                                           |
| CI                     | Confidence interval                                         |
| CL                     | Clearance                                                   |
| CNS                    | Central nervous system                                      |
| CR                     | Complete response                                           |
| CT                     | Computed tomography                                         |
| CTLA-4                 | Cytotoxic T-lymphocyte-associated antigen-4                 |
| DNA                    | Deoxyribonucleic acid                                       |
| ECG                    | Electrocardiogram                                           |
| ECOG                   | Eastern Cooperative Oncology Group                          |
| EDTA                   | Disodium edetate dihydrate                                  |
| ES                     | Extensive stage                                             |
| FFPE                   | Formalin fixed paraffin embedded                            |
| FSH                    | Follicle-stimulating hormone                                |
| GCP                    | Good Clinical Practice                                      |
| HIV                    | Human immunodeficiency virus                                |
| ICF                    | Informed consent form                                       |
| ICH                    | International Conference on Harmonization                   |
| ICI                    | Immune checkpoint inhibitor                                 |
| ICRU                   | International Commission on Radiation Unit and Measurements |
| IEC                    | Independent Ethics Committee                                |
| IgG                    | Immunoglobulin                                              |
| ILD                    | Interstitial lung disease                                   |
| imAE                   | Immune-mediated adverse event                               |
| IRB                    | Institutional Review Board                                  |
| IV                     | Intravenous(ly)                                             |
| LS                     | Limited stage                                               |
| mAb                    | Monoclonal antibody                                         |
| MoCA                   | Montreal Cognitive Assessment                               |
| miRNA                  | Micro ribonucleic acid                                      |
| MRI                    | Magnetic resonance imaging                                  |
| mRNA                   | Messenger ribonucleic acid                                  |  
Page 17 of 59  
05  
| Abbreviation or term   | Explanation                                                              |
|------------------------|--------------------------------------------------------------------------|
| MTD                    | Maximum tolerated dose                                                   |
| NCI CTCAE              | National Cancer Institute Common Terminology Criteria for Adverse        |
| Events                 |                                                                          |
| NSCLC                  | Non-small cell lung cancer                                               |
| OR                     | Objective response                                                       |
| ORR                    | Objective response rate                                                  |
| OS                     | Overall survival                                                         |
| PBMC                   | Peripheral blood mononuclear cell                                        |
| PCI                    | Prophylactic cranial irradiation                                         |
| PD                     | Progressive disease                                                      |
| PD-1                   | Programmed cell death 1                                                  |
| PD-L1                  | Programmed cell death ligand 1                                           |
| PFS                    | Progression-free survival                                                |
| PR                     | Partial response                                                         |
| PRO                    | Patient reported outcome                                                 |
| QTc                    | Time between the start of the Q wave and the end of the T wave corrected |
| for heart rate         |                                                                          |
| QTcF                   | QT interval on ECG corrected using the Frederica's formula               |
| REB                    | Research Ethics Board                                                    |
| RECIST                 | Response Evaluation Criteria in Solid Tumors                             |
| RNA                    | Ribonucleic acid                                                         |
| RT                     | Radiotherapy                                                             |
| SAE                    | Serious adverse event                                                    |
| SCLC                   | Small-cell lung cancer                                                   |
| SD                     | Stable disease                                                           |
| SoA                    | Schedule of assessments                                                  |
| SUSAR                  | Suspected unexpected serious adverse reaction                            |
| TEAE                   | Treatment-emergent adverse event                                         |
| TIL                    | Tumor infiltrating lymphocyte                                            |
| TRT                    | Thoracic radiotherapy                                                    |
| TSH                    | Thyroid stimulating hormone                                              |
| ULN                    | Upper limit of normal                                                    |
| WBRT                   | Whole brain radiotherapy                                                 |
| WHO                    | World Health Organization                                                |  
05
untitled h1
4. introduction

4.1 Disease background 4.1.1 Lung cancer Lung cancer is the deadliest cancer, causing more years of life lost than the other three most common cancers altogether (breast, prostate and colon cancer).1,2 More than 3300 are diagnosed with lung cancer every year in Norway, and 2200 die from the disease, accounting for more than 5% of all deaths.3 Small-cell lung cancer (SCLC) accounts for 13-15% of lung cancer cases.3,4 Untreated, the prognosis is poor (2-4 months) since SCLC grows more rapidly and metastasizes more frequently than other types of lung cancer. Due to the aggressive biology, it has been estimated that SCLC causes 4% of all cancer related deaths.5 4.1.2 Treatment of SCLC
Patients with localized disease (T1-2N0) are offered surgery followed by adjuvant chemotherapy and/or radiotherapy and prophylactic cranial irradiation, but very few (approx. 5 per year in Norway) are operable since most have regional or metastatic disease at the time of diagnosis.6-8 For inoperable patients, chemotherapy is the main treatment, and platinum/etoposide remains the standard regimen, at least in the western world.9 A Japanese trial showed that platinum/irinotecan was superior to platinum/etoposide in ES SCLC, but the relatively large survival benefit was not confirmed in trials performed in other countries.10-12 A possible explanation is differences in pharmacogenomics.13 A meta-analysis showed a small benefit of platinum/irinotecan over platinum/etoposide in terms of survival but was mainly driven by Asian studies.14 Thus, platinum/etoposide remains the standard regimen in the Western world.9 **Concurrent chemotherapy and TRT is superior to chemotherapy alone when all lesions can be**
included in a RT field (limited stage, "LS SCLC").15 Chemotherapy alone has until recently been the standard treatment for patients with more widespread disease (extended stage, "ES SCLC").9 Prophylactic cranial irradiation (PCI) reduces the frequency of brain metastases and prolongs survival in LS patients who respond to the primary treatment.16 The role of PCI is more debated in patients with ES. One European study showed that PCI reduces the risk of brain metastases and prolongs survival in this setting,17 while a Japanese study did not confirm the survival benefit, suggesting that active surveillance is a better approach than PCI.18 **Up to 90% of LS patients respond and 25-30% are cured by chemoradiotherapy and are alive after 5**
years.19,20 The response rate is lower for ES SCLC (approx. 65%), almost all patients relapse within 1-2 years, and the 5-year survival is around 3%.5 There have been major improvements in treatment outcomes for NSCLC, but the survival rates for SCLC have remained more or less unchanged the last 20 years.2,21 One reason for the lack of progress is that most lung cancer research focuses on NSCLC. At the ASCO annual meeting 2020, 6300 abstracts were submitted. Of these, 512 reported lung cancer research, but only 22 (4.3%) concerned SCLC. The poor survival, the low 5-year survival, the lack of progress, research and new therapies for SCLC underscores the need for research on this orphaned disease.  
4.2 Immunotherapies It is increasingly understood that cancers are recognized by the immune system, and, under some circumstances, the immune system may control or even eliminate tumors.22 PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T-cell activation.23 When PD-L1 binds to PD-1, an inhibitory signal is transmitted into the T-cell, which reduces cytokine production and suppresses T-cell proliferation. Tumor cells exploit this immune checkpoint pathway as a mechanism to evade detection and inhibit immune response. PD-L1 is expressed in a broad range of cancers, and it is well established that anti–PD-L1 and anti PD-1 antibodies have clinical activity and a manageable safety profile in a wide range of cancers, including lung cancer.24-26  
05  
  
  
4.2.1 Durvalumab Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass that inhibits binding of PD-L1 and was developed by AstraZeneca/MedImmune for use in the treatment of cancer. The proposed mechanism of action is interference in the interaction of PD-L1 with PD-1 and CD80 which releases the inhibition of immune responses to tumor cells. To date durvalumab has been given to more than 8000 patients as part of ongoing studies either as monotherapy or in combination with other anti-cancer agents. Details on the safety profile of durvalumab monotherapy are summarized in 4.5.2. The current durvalumab Investigator's Brochure (IB) contains a complete summary of non-clinical and clinical information including safety, efficacy and pharmacokinetics.  
4.2.2 Immunotherapies in lung cancer For lung cancer patients, immune checkpoint inhibitor (ICI) therapy was first established for NSCLC and is now standard therapy as monotherapy and combined with cytotoxic chemotherapy - as first line and relapse treatment in metastatic disease, and as consolidation therapy after concurrent chemoradiotherapy for stage III disease.24-27 4.2.3 Immunotherapy in SCLC
The first signals of an effect of immune checkpoint inhibitors (ICIs) in SCLC came from phase I/II studies.  
One third of patients with pre-treated SCLC (n=24) had an objective response from pembrolizumab.28 In a randomized phase II trial, pre-treated SCLC patients achieved an objective response rate of 23% and a median survival of 7.7 months after receiving nivolumab plus ipilimumab.29 Later, a phase II study showed antitumor activity of durvalumab in pre-treated ES SCLC patients,30 and two phase II studies showed activity of durvalumab plus tremelimumab in pre-treated ES SCLC.31,32 Promising results from early phase studies led to the initiation of several larger studies of checkpoint inhibitors in ES SCLC (monotherapy, combinations with other checkpoint inhibitors or chemotherapy), both in the first line setting, as maintenance therapy after primary chemotherapy and in previously treated patients. Furthermore, several studies of immunotherapy concurrently or after chemoradiotherapy in LS SCLC are ongoing.  
Most studies of ICIs in NSCLC are positive, but several studies of ICIs in SCLC have been negative. In a phase II trial of patients who had progressed after first-line platinum-doublet chemotherapy, patients were randomized to receive atezolizumab monotherapy or chemotherapy. Atezolizumab resulted in significantly inferior response rate and median PFS.33 In a phase III trial, ES SCLC patients with non-progression after first-line platinum-chemotherapy were randomized to placebo, nivolumab monotherapy or nivolumab plus ipilimumab. There was no significant benefit in OS of neither nivolumab monotherapy (median OS 10.4 vs. 9.6 months; HR 0.84, 95%
CI 0.7-1.0), or nivolumab plus ipilimumab (9.2 vs. 9.6 months; HR 0.92, 95% CI 0.8-1.1; p=0.37).34 Another phase III trial randomized patients with recurrent SCLC to receive nivolumab monotherapy or chemotherapy (topotecan or amrubicin). There was no significant benefit in OS (7.5 vs. 8.4 months; HR
0.86, 95% CI 0.71-1.04; p=0.11).35 4.2.4 Combined chemotherapy and immunotherapy as first-line treatment of ES SCLC
Two recent studies have established ICIs in the treatment of ES SCLC. Both compared chemotherapy plus a PD-L1 inhibitor with chemotherapy alone. In the Impower 133 trial, patients were randomized to four courses of carboplatin/etoposide with atezolizumab or placebo. There was a significant benefit in terms of median OS (12.3 vs. 10.3 months; p=0.007) and median PFS (5.2 vs. 4.3 months; p=0.02).36 In the CASPIAN trial, patients were randomized to receive four courses of platinum plus etoposide plus durvalumab or durvalumab plus tremelimumab, or up to six courses of platinum plus etoposide. The durvalumab-combination provided a significant benefit in terms of survival compared with platinum plus etoposide alone (13.0 vs. 10.3 months; p=0.0047), which numerically was similar to what was observed in Impower 133. The addition of tremelimumab did not significantly improve the efficacy of durvalumab.37 A third trial combining chemotherapy with an ICI was published this summer. In the KEYNOTE-604, patients were randomized to receive platinum/etoposide plus pembrolizumab or placebo. There was a  
 significant prolongation of PFS (HR 0.75; p=0.0023) and a prolongation of OS (HR 0.80; p=0.0164). The difference in survival did, however, not reach the pre-specified threshold of p=0.0128. Numerically, the median OS was lower than in the CASPIAN and Impower 133; 10.8 months in the pembrolizumab arm, and 9.7 months in the placebo arm.38 In all these trials, adding an ICI was well tolerated.  
These three studies show that combining chemotherapy with an ICI is the new standard first-line regimen for ES SCLC, and that durvalumab and atezolizumab are the ICIs of choice. The benefit in terms of median OS is, however, limited (2.0 and 2.7 months), The survival curves do not split until after 6 months after start of treatment. Whether adding an ICI provides a long-term survival, similar to what have been observed in studies of advanced NSCLC, is unknown due to the short follow-up time.  
  
4.2.5 Predictive biomarkers The most relevant biomarkers for predicting response to ICIs are PD-L1 expression and TMB. However, the predictive role of these markers appears to be insignificant in SCLC.  
PD-L1 expression was assessed in KEYNOTE 604. The proportion of PD-L1 positive was lower than in NSCLC (approx. 40% vs. 65%), and PD-L1 expression was not associated with response to pembrolizumab.38 TMB was assessed in Impower 133, and the efficacy was similar regardless of TMB.36 Thus, there are no established predictive factors for ICIs in SCLC.  
4.2.6 Paraneoplastic neurological syndrome (PNS) in SCLC
3-5% of patients with SCLC have a paraneoplastic neurological syndrome (PNS) syndrome,39 which is more frequent than in most other solid tumors. Due to the neuroectodermal origin of the cells that form SCLC, they share expression of many peptides only found in the brain. As the blood-brain barrier diminishes the extent and efficacy of the patrolling qualities of our own immune system, antigens expressed by SCLC and the brain alone are less vigorously recognized as body-self. Normally, cells producing antibodies aimed at body-self antigens would directly go into apoptosis, without ever entering the blood stream. The combination of an aggressive anti-tumor response in combination with the limited recognition of brain antigens can therefore easily lead to auto-antibody formation. These auto-antibodies can then try to control the SCLC, while at the same time inducing a PNS as a side-effect.40 SCLC-patients with PNS have consistently shown an improved overall survival, probably due to a better tumor control.41-43 These patients are thought to have an inflamed anti-tumor micro-environment with an increase of CD3-, CD4- and CD8- T-cell infiltrates. An improvement in median overall survival of up to 6 months, and an increased tail of long-term survivors have been observed (up to 30% alive after 2 years).41 A far larger proportion of asymptomatic SCLC patients has one or several auto-antibodies aimed against neuronal proteins, and approximately 40% of SCLC patients have low titer antibodies against SOX1 or HuD,41 and when including combinations of other auto-antibodies (e.g. anti-CV2, anti-recoverine, antiZic4,44 anti-VGCC,45 Trim4646 or anti-KCTD1647) this proportion increases to >50%.  
Whether subclinical autoantibodies are associated with survival in SCLC patients is unclear. Some studies show that they are associated with improved survival, while others have not found such associations. As the effects of anti-PD-L1 therapy vary considerably among SCLC patients, it seems reasonable to investigate whether the immune system is linked to response to such treatment, especially whether a propensity to develop auto-antibodies increases the chance of responding to immune checkpoint inhibitor therapy. One clue supporting this possibility is our observation that patients who developed an antibody-mediated paraneoplastic neurological syndrome, like anti-GABAbR encephalitis, during PD-(l)1 treatment had a prolonged good anti-tumor response at the same time.  
4.2.7 TRT in ES SCLC
A randomized phase III trial showed that TRT improves PFS in ES SCLC (HR 0.73, p=0.001), and the PFS
curves split immediately after administering TRT. The study did not, however, meet the primary endpoint of improved 1-year survival in the overall population (33% vs. 28%, p=.066), but there was a significant benefit in terms of 18-months (16% vs 9%, p=0.03) and 24-months survival (13% vs. 3%, p=0.004). Among patients with residual thoracic disease after chemotherapy, there was a significant improvement in OS (HR
.81, p=0.044). Thus, the role of TRT has been debated, and is not routinely offered in Scandinavia, and was not allowed in the CASPIAN or Impower 133.48  
  
4.2.8 Synergistic effect of combining RT and immunotherapy RT has traditionally been considered to be a local treatment, mainly affecting the targeted tumor cells.  
There are reports of an abscopal effect, i.e. treatment response on lesions outside the RT fields, but these reports are few in numbers.49 There are, however, reasons to believe that there is a synergistic effect of concurrent RT and immune checkpoint inhibitor therapy that are of more clinical relevance. In addition to the direct cytotoxic effect on tumor cells, RT may also change the tumor microenvironment in a way that may promote an improved systemic effect of checkpoint inhibitors. It has been shown that RT induce upregulation of tumor surface MHC-I and PD-L1 expression, increase the proportion of beneficial TILs and their effector activity, drive polyclonal T-cell responses, which may create a suitable neoantigen repertoire. On the other hand, RT
may also attract immunosuppressive cells.50-54 Though there are reasons to believe that combining RT and immunotherapy improves efficacy of the systemic treatment, it is not yet established how to optimally combine these therapies. It appears that concurrent administration or administration of immunotherapy immediately after RT is the most effective approach.27,52 Combining immunotherapy and RT in lung cancer, including ES SCLC, appears to be safe,55,56 but even if there is a lot of interest in investigating the potential synergistic effect, there is hitherto no results from randomized trials confirming that the combination results in a clinically relevant improved effect. In a recent publication, patients with head and neck squamous cell carcinomas randomized to receive stereotactic body RT to one lesion, did not experience a higher effect of concurrent nivolumab treatment.  
However, the study was small (n=62), and the results are not necessarily applicable to ES SCLC.57  
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4.2.9 Prophylactic cranial irradiation in ES SCLC
Whether PCI is beneficial for patients who receive combined immunotherapy and chemotherapy is unknown. It is unknown whether receiving checkpoint inhibitor therapy increases the potential detrimental cognitive effect of PCI, and the benefit of PCI may be reduced due to improved disease control due to the improved efficacy of the triple combination. The only available data on PCI in patients receiving ICI, are from a subgroup analysis of the 44 patients who received PCI as part of the Impower 133 trial. There were no indications of more side effects among those who received PD-L1 inhibitor therapy, but the cohort was small and follow-up did not include assessment of long-term neurocognitive decline.58 4.3 Research hypotheses The main hypothesis is that adding TRT to chemotherapy plus durvalumab provides a survival benefit for patients with extensive stage (ES) small-cell lung cancer (SCLC). Specifically, we hypothesize that:  combining TRT, chemotherapy and durvalumab is feasible and well tolerated  adding TRT improves 1- and 2-year survival, median OS, response rates, and PFS  **the patients who benefit the most from the study treatment can be identified through analyses of**
tissue, blood and stool samples  **PCI is well tolerated, reduces the risk of brain metastases and prolongs survival in ES SCLC patients who**
receive chemotherapy plus durvalumab compared with patients who do not receive PCI
4.4 Rationale for conducting this study  **Chemotherapy plus an PD-L1 inhibitor is considered a new standard of care for first-line treatment of**
ES SCLC but is not yet available/reimbursed in all countries. Durvalumab plus platinum/etoposide is one of these new standard regimens. However, the survival benefit is limited, especially for the first 6 months, and a more effective treatment is needed.  A more effective initial therapy might improve survival the first 6 months and long-term survival.  **It has been demonstrated that TRT improves survival in ES SCLC, and the effect in terms of PFS is**
immediate.  **Several studies suggest a synergistic effect of combining RT and ICI. Concurrent administration appears**
to be the most effective approach, and we will administer the TRT between the second and third chemoimmunotherapy courses. This is deemed to be the earliest time point that TRT may be administered at all sites. We know that SCLC patients may achieve a substantial response to one chemotherapy course (Halvorsen, 2016) **and believe that administering TRT earlier than in the CREST**
trial will make it easier to locate the target lesions, increases the likelihood of irradiating viable tumor cells, and consequently increase the chance for achieving a synergistic effect of the TRT and the immunotherapy - and not merely an additive effect.  **Combining high-dose TRT, platinum doublet chemotherapy and ICI appears to be well tolerated. Thus,**
combining medium dose TRT with durvalumab and carboplatin/etoposide should be feasible and well tolerated. However, since there is no data on this combination, investigating whether ading TRT
increases the frequency or severity of side effects is an essential part of this trial.  **The benefits and tolerability of PCI in ES SCLC patients receiving chemotherapy plus ICI are unknown.**
We will compare the timing and frequency of brain metastases between patients who receive PCI and those who do not. Furthermore, we will measure and compare cognitive function before and after PCI.  **The survival benefit from adding ICI does not appear before after 6 months. Thus, we restrict the**
protocol for patients in performance status 0-1. In a previous trial on chemotherapy in ES SCLC, median OS was below 6 months among patients with a PS of 2 or more.  **The optimal length of durvalumab treatment remains to be defined since there is limited data on the**
long-term benefit of checkpoint inhibitors in ES SCLC. Thus, durvalumab treatment will continue until PD and need for other treatment, unacceptable toxicity or patients wish to discontinue.  **There is very limited knowledge of prognostic and predictive biomarkers in SCLC in general and for ICI**
therapy specifically since few have conducted such research and the markers established for other  
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types of cancer appears to be of little relevance in SCLC. We will collect tumor, blood and stool for translational research aiming at characterizing patients who benefit the most from the study therapy.  **SCLC patients with paraneoplastic neurological syndrome (PNS) syndrome and asymptomatic patients**
with autoantibodies against neuronal proteins may have a better and more prolonged response to ICIs. We will investigate whether there are associations between the presence and type of autoantibodies and long-term benefit of the study therapy.  
4.5 Benefit/risk and ethical assessment 4.5.1 Potential benefits The potentially improved disease control from adding TRT to the systemic treatment is the most important potential benefit for the participants. For patients with such an aggressive disease as SCLC, prolonged disease control is of outmost importance, as this improves quality of life, maintains functional level, and prolongs survival time. For the health care system, better disease control will reduce the need for resources required to provide optimal care and support.  
Hitherto, all SCLC patients are treated equally, though we know from experience that there is a large heterogeneity with respect to treatment response, response duration, symptom development and survival time.19,59 Our knowledge of prognostic and predictive biomarkers in SCLC is in general very limited.  
The planned translational research may lead to a novel classification system based on molecular markers, with potentially large impacts for both patients and the health care systems.  
A classification system will enable us to avoid ineffective, unnecessary, potentially toxic therapy, and patients will avoid spending time for futile therapy. Scientifically, the impact of an improved classification is huge, as it allows for more targeted enrolment in trials that will improve the relevance, feasibility and quality of future research. Targeted enrolment allows for reduced sample sizes, shorter readout time, reduced costs, and increased number of trials that can be conducted. 4.5.2 Overall risks of durvalumab Monoclonal antibodies directed against immune checkpoint proteins aim to boost endogenous immune responses directed against tumor cells. By stimulating the immune system however, there is the potential for adverse effects (AEs) on other tissues.  
Most adverse drug reactions seen with ICIs are due to the effects of inflammatory cells on specific tissues. These immune mediated effects can occur in nearly any organ system and are most commonly seen as gastrointestinal AEs such as colitis and diarrhea, pneumonitis/interstitial lung disease (ILD), hepatic AEs such as hepatitis and liver enzyme elevations, skin events such as rash and dermatitis and endocrinopathies including hypo- and hyper-thyroidism.  
Risks with durvalumab include, but are not limited to, diarrhea/colitis pneumonitis/ILD,
endocrinopathies (hypo- and hyper-thyroidism, type I diabetes mellitus, hypophysitis and adrenal insufficiency) hepatitis/increases in transaminases, nephritis/increases in creatinine, pancreatitis/increases in amylase and lipase, rash/pruritus/dermatitis, myocarditis, myositis/polymyositis, thyroiditis, pemphigoid, myasthenia gravis, immune thrombocytopenia, and other rare or less frequent inflammatory events including neurotoxicities, infusion-related reactions, hypersensitivity reactions, and infections/serious infections. In monotherapy clinical studies, most common AEs (all grades) (≥ 15% of patients) are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back pain, pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, rash, and pruritus. Approximately 9.4% of patients experienced an AE that resulted in permanent discontinuation of durvalumab and approximately 6.5 % of patients experienced a serious adverse event (SAE) that was considered to be related to durvalumab. For information on all identified and potential risks with durvalumab, please refer to the current version of the durvalumab IB.  
Most of the treatment-related AEs were manageable with dose delays, symptomatic treatment, and in the case of events suspected to have an immune basis, the use of established treatment guidelines for immune-mediated side-effect.  
Overall, adding durvalumab to platinum/etoposide chemotherapy in the CASPIAN trial did not Page 24 of 59  
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increase the frequency or severity of AEs. The proportion who experiences grade 3-4 toxicity was 62% both among patients who received chemoimmunotherapy and in the control arm. Immune-related AEs occurred in 20% of patients in the durvalumab-arm. Of these, 12/265 (5%) experienced grade 3 or 4 AEs, and one patient died from immune related hepatotoxicity.37 In a small phase I/II study, 10 patients on durvalumab received palliative RT. There were no severe RT-related AEs.60 A phase II trial (n=40) of concurrent chemoradiotherapy to 60-66 Gy and the PD-L1 inhibitor atezolizumab in unresectable NSCLC, did not reveal any indications of increased RT toxicity compared with historical data.56 In the PACIFIC trial, consolidation durvalumab therapy was well tolerated in patients who did not progress after chemoradiotherapy in locally advanced NSCLC.27 Overall, there are currently no clinical data suggesting that combining chemoimmunotherapy with low-dose TRT causes severe radiotoxicity.  
4.5.3 Overall benefit-risk Results from the CASPIAN trial shows that durvalumab plus platinum/etoposide chemotherapy is well tolerated and prolongs survival. TRT is well tolerated in ES SCLC patients, and studies suggest that concurrent chemo-immunotherapy and TRT is well tolerated in NSCLC. On this basis, we believe that the overall risk is low, and that the experimental therapy may provide a clinically relevant survival benefit for an important group of patients in desperate need for better therapies.
untitled h1
5. provide summary of overall

5.1 Primary objective(s)
We consider survival the most relevant endpoint for ES SCLC patients. Since we will irradiate lesions in the experimental arm, there are potential methodological issues with using PFS as the primary outcome, since the RECIST criteria consider irradiated lesions non-measurable. Survival may be influenced by post-study therapy, but there is little variation in relapse therapy for ES SCLC. All post-study therapy will be registered. There is currently no data suggesting whether the combination therapy may provide a synergistic effect or an additive effect. Thus, it is difficult to predict how the PFS-curves may be influenced by adding TRT, and it is consequently difficult to select the most appropriate PFS-endpoint.  
In conclusion, we consider 1-year overall survival to be the most appropriate endpoint, it is easily measured, and provides a strong and clinically relevant measure of the potential effect of the experimental therapy. There is no risk associated with this measure.  
5.1.1 Secondary objective(s)
In general, the major benefit of ICIs in cancer treatment is that some patients achieve long term survival.  
Thus, we plan a follow-up of 5 year after last patient entry to accurately assess whether some patients achieve a long term survival. Follow-up time in completed trials of chemo-immunotherapy in ES SCLC was designed with a too short follow-up time to assess survival beyond 2 years. Current data shows that high-dose TRT can safely be administered concurrently with chemotherapy and checkpoint inhibitors, but we cannot rule out that TRT adds significant toxicity in patients with ES-SCLC.  
Thus, we will compare frequency and severity of adverse events, as well as patient-reported health-related quality of life, between treatment arms. PFS may be difficult to accurately assess (see above), but is still of interest, especially when it comes to local control. We assume that adding TRT improves local control, but if there is a synergistic effect of combining RT and durvalumab, the course of disease may also be altered. Thus, assessing the location and timing of metastases is of great interest. Furthermore, a synergistic effect should improve response rates, and to further investigate whether such an effect occurs, we will compare response rates in non-irradiated lesions (i.e. all non-irradiated lesions in the experimental arm compared with overall response rate in the control arm). The role of PCI in ES SCLC is debated. If adding TRT improves efficacy of chemoimmunotherapy, the value of PCI may be small. On the other hand, one can also imagine that TRT plus chemoimmunotherapy improves systemic disease control, and that brain metastases represent a major site for treatment failure.  
5.2 Exploratory objective(s)
If there is a synergistic effect of TRT and chemoimmunotherapy, the frequency of brain metastases may decrease in the experimental arm, or the time until brain metastases occur may be prolonged. Thus, we will compare the frequency and timing of brain metastases. To explore potential benefits or disadvantages of PCI, we will measure cognitive function before and after chemoimmunotherapy and PCI. It is evident that not all ES SCLC patients benefit from durvalumab. Costs of new therapies has become an increasingly important issue. Identifying those who benefit the most from each therapy, will enable us to better individualize therapy for each patient. There are several benefits for both patients and society. Patients will avoid spending time for futile therapy, avoid unnecessary toxicity, and may be offered other, more effective treatments. More targeted therapy will reduce costs, but also better use of our health services' resources. Thus, the biomarker analyses may have significant implications for future clinical practice and research.  
6. **Study design**
6.1 Overview of study design International, randomized phase III trial. Patients will be randomized 1:1 stratified for established prognostic factors (presence of brain metastases, and presence of liver metastases) to receive chemoimmunotherapy plus TRT or chemoimmunotherapy alone.  
  
6.2 Study oversight for safety evaluation A Data and safety monitoring committee (DSMC) will monitor the incidence and nature of all SAEs when 5, 15 and 30 patients have received 3 or more courses of chemoimmunotherapy and TRT and then every 6 months until all patients have completed study treatment to ensure patient safety. The members of the DSMC will be experienced clinicians and a statistician. Following each data review, the DSMC will provide recommendations to the Chief Investigator as to whether the study should continue or be amended, or whether the study should be stopped due to safety concerns (i.e., evidence of harm). The Chief Investigator will, together with the National Coordinating Investigators, make decisions on the basis of the DSMC
recommendations. Any outcomes of these safety reviews that affect study conduct will be communicated in a timely manner to the investigators for notification of the IRB/REB/IECs.  
7. **Patient selection**
7.1 Inclusion criteria For inclusion in the study patients must fulfill all the following criteria: 1. **Capable of giving signed informed consent which includes compliance with the requirements and**
restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.  
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2. **Age > 18 years at time of study entry.**
3. **ECOG performance status of 0 or 1.** 4. **Body weight >30 kg.**
5. **Adequate normal organ and marrow function as defined below:**
Haemoglobin ≥10.0 g/dL.  **Absolute neutrophil count (ANC) ≥1.5 × 109**  
  
/L.  **Platelet count ≥100 × 109** /L.  **Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This does not apply to patients with**
confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology).  ALT (SGPT) ≤2.5 x ULN unless liver metastases are present, in which case it must be ≤5 x ULN.  **Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the**
Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
Males Creatinin-clearance (mL/min) = Weight (kg) x (140 - **age) 72 x serum creatinine (mg/dL)**
Females Creatinin-clearance (mL/min) = Weight (kg) x (140 - age) x 0.85 72 x serum creatinine (mg/dL)
6. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up. 7. Life expectancy of at least 3 months.  
8. At least 1 lesion in the thorax, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL)
at baseline and is possible to irradiate to 30 Gy in 10 fractions. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to randomization.  
9. Histologically or cytologically confirmed SCLC. Mixed histology may be acceptable as long as the SCLC
component accounts for more than 90%.  
10. Stage IV disease according to the TNM v8. Patients with stage III disease are eligible if the disease is too widespread to be treated as LS SCLC. 11. Pulmonary function: FEV1 >1 L or >30 % of predicted value and DLCO >30 % of predicted value.  
12. Female patients of childbearing potential (postmenarcheal, not postmenopausal [>12 continuous months of amenorrhea with no identified cause other than menopause], and no surgical sterilization) should use highly effective contraception and take active measures to avoid pregnancy while undergoing systemic study therapy and for at least 5 months after the last dose.  
13. Patients with brain metastases are eligible provided they are asymptomatic or treated and stable on steroids and/or anticonvulsants prior to start of treatment.  
7.2 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 the last 30 days.** 2. **Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical**
study or during the follow-up period of an interventional study.  
3. **Previous chemo- or radiotherapy for SCLC. Patients who have undergone surgery, but no adjuvant**
therapy are eligible.  
4. **Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of**
alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.  
5. **Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the**
Chief Investigator.  
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6. **Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with**
durvalumab may be included only after consultation with the Chief Investigator.  
7. **Any concurrent chemotherapy, investigational product or biologic cancer therapy.** 8. **Any prior checkpoint inhibitor therapy, including durvalumab.**
9. **Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within**
4 weeks of the first dose of study drugs.  
10. **Immediate need for thoracic radiotherapy or bulky disease outside the thorax, or need for such**
radiotherapy before completion of chemo-immunotherapy 11. **Major surgical procedure within 28 days prior to the first dose of study drugs. Note: Local surgery of**
isolated lesions for palliative intent is acceptable.  
12. **History of allogenic organ transplantation.**
13. **Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel**
disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
a. **Patients with vitiligo or alopecia.**
b. **Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone**
replacement.  
c. **Any chronic skin condition that does not require systemic therapy.**
d. **Patients without active disease in the last 5 years may be included but only after consultation**
with the Chief Investigator.  
e. **Patients with celiac disease controlled by diet alone.**
13. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia QTcF value >470 ms on ECG, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring **AEs or compromise the ability of the**
patient to give written informed consent.  
14. History of another primary malignancy except for:  **Malignancy treated with curative intent and with no known active disease ≥5 years before the**
first dose of IP and of low potential risk for recurrence.  Localized breast or prostate cancer treated with hormonal therapy alone.  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease  **Adequately treated carcinoma in situ without evidence of disease.**
15. Leptomeningeal carcinomatosis.  
16. Untreated, symptomatic central nervous system (CNS) metastases. Any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on steroids and/or anticonvulsants prior to the start of treatment.  
17. History of active primary immunodeficiency. 18. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV
infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 19. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:  
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Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection).  **Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its**
equivalent.  **Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).**
20. 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.  
21. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy. 22. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.  
23. Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements. Procedures for withdrawal of incorrectly enrolled patients are presented in 9.1.2.  
7.3 Withdrawal of patients from study treatment and/or study 7.3.1 Permanent discontinuation of chemotherapy and durvalumab Discontinuation of study treatment, for any reason, does not impact the patient's participation in the study.  
A patient who decides to discontinue IP should be asked about the reason(s) for discontinuation and the presence of any AE. The patient should continue attending subsequent study visits, and data collection should continue according to the study protocol. If the patient does not agree to continue in-person study visits, a modified follow-up must be arranged to ensure the collection of endpoints and safety information.  
This follow-up could be a telephone contact with the patient, a contact with a relative or treating physician, or information from medical records. The approach taken should be recorded in the medical records. A patient who agrees to modified follow-up is not considered to have withdrawn consent or to have withdrawn from the study. Patients who permanently discontinue study treatment for other reasons than objective RECIST disease progression should be followed according to the study schedule similar to patients who are on study treatment.  
All patients will be followed for survival until the end of the study. Patients who decline to return to the site for evaluations should be contacted by telephone if they agree.  
7.3.2 Lost to follow-up Patients will be considered lost to follow-up only if no contact has been established by the time the study is completed, such that there is insufficient information to determine the patient's status at that time. Investigators should document attempts to re-establish contact with patients.  
In order to support key end points of PFS and OS analyses, the survival status of all patients in the full analysis and the safety analysis sets should be re-checked, this includes those patients who withdrew consent or are classified as "lost to follow-up". For patients lost to follow-up, site personnel should check hospital records, the patients' current physician, and a publicly available death registry (if available) to obtain survival status.  
If a patient has actively withdrawn consent to the processing of their personal data, the survival status of the patient can be obtained by site personnel from publicly available death registries (if available)
where it is possible to do so under applicable local laws to obtain a current survival status.  
7.3.3 Withdrawal of consent Patients are free to withdraw from the study at any time without prejudice to further treatment. Patients who withdraw consent for further participation in the study will not receive any further study treatment or further study observation, with the exception of follow-up for survival, which will continue until the end of the study unless the patient has expressly withdrawn their consent to survival follow-up. Note that the patient may be offered additional tests or tapering of treatment to withdraw safely.  
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A patient who withdraws consent may be asked about the reason(s) for withdrawal and the presence of any AE but does not have to give reasons for withdrawing. The Investigator will follow up AEs outside of the clinical study. If a patient withdraws consent, they will be specifically asked if they also withdraw consent to all further follow-up (e.g. survival contact phone calls).  
7.4 End of trial Patients will be enrolled until the target number of patients who have received three or more courses of chemoimmunotherapy in the control arm and the target number of patients who have received three or more courses of chemoimmunotherapy plus TRT in the experimental arm have been reached. Recruitment will stop earlier if:  recommended by the Data and Safety Monitoring Committee  **recruitment of patients is so slow that it is not possible to answer the research questions within a**
reasonable timeframe. This will be decided by Sponsor after discussion with National Coordinating Investigators.  new data show that eligible patients should be offered other and better treatment.  **new data show that participation puts patients at unreasonable risk and/or there are no reasons to**
believe that the patients benefit from participating in the trial.
8. **Study therapy**
8.1 Durvalumab 8.1.1 Durvalumab schedule All patients will receive 1500 mg durvalumab IV on day 1 of each chemotherapy course regardless of delays of chemotherapy courses. Durvalumab is administered before carboplatin/etoposide.  
After completion of chemotherapy, they will then receive durvalumab 1500 mg IV every 4 weeks until PD and need for other treatment, unacceptable toxicity or patients wish to discontinue.  
If a patient's weight falls to 30 kg or below (≤30 kg) the patient should receive weight-based dosing equivalent to 20 mg/kg of durvalumab until the weight improves to >30 kg, at which point the patient should start receiving the fixed dosing of durvalumab 1500 mg. 8.1.2 Formulation/packaging/storage Durvalumab will be supplied by AstraZeneca as a 500-mg vial concentrate for solution for infusion. The solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume (w/v) polysorbate 80; it has a pH of 6.0 and density of 1.054 g/mL. The label-claim volume is 10.0 mL. Durvalumab is a sterile, clear to opalescent, colorless to slightly yellow solution free from visible particles. Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Investigational product should be kept in original packaging until use to prevent prolonged light exposure.  
8.1.3 Preparation of durvalumab doses for administration with an IV bag The dose of durvalumab for administration must be prepared by the Investigator's or site's designated IP
manager using aseptic technique. Please refer to local prescribing information for in-use storage conditions and times.  
A dose of 1500 mg (for patients >30 kg in weight) will be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab concentration ranging from 1 to 15 mg/ml and delivered through an IV administration set with a 0.2- or 0.22-μm filter. Add 30 mL (i.e. 1500 mg) of durvalumab to the IV bag. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag.  
If a patient's weight falls to ≤ 30 kg weight-based dosing at 20 mg/kg will be administered using an IV bag size selected such that the final concentration is between 1 and 15 mg/mL. Standard infusion time is 1 hour, however, if there are interruptions, the total infusion time must not exceed 8 hours at room temperature. Do not co-administer other drugs through the same infusion line.  
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The IV line will be flushed according to local practice to ensure that the full dose is administered. Infusion time does not include the final flush time.  
If either preparation time or infusion time exceeds the time limits a new dose must be prepared from new vials. Durvalumab does not contain preservatives, and any unused portion must be discarded.  
8.1.4 Monitoring of dose administration Patients will be monitored before, during and after the infusion of durvalumab. Patients are monitored (pulse rate, blood pressure) every 30 minutes during the infusion period (including times where infusion rate is slowed or temporarily stopped).  
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial rate until completion of the infusion. For patients with a ≤Grade 2 infusion-related reaction, subsequent infusions may be administered at 50% of the initial rate. Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent medications per institutional standard may be administered at the discretion of the investigator. If the infusion-related reaction is Grade 3 or higher in severity, study drug will be discontinued. The standard infusion time is one hour. If there are interruptions during infusion, the total allowed time from infusion start to completion of infusion should not exceed 8 hours at room temperature (otherwise a new infusion preparation is required). For management of patients who experience an infusion reaction, please refer to the toxicity and management guidelines in Appendix 1.  
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs and medical equipment to treat acute anaphylactic reactions must be immediately available, and study personnel must be trained to recognize and treat anaphylaxis. The study site must have immediate access to emergency resuscitation teams and equipment in addition to the ability to admit patients to an intensive care unit if necessary.  
8.2 Carboplatin and etoposide chemotherapy 8.2.1 Formulation/packaging/storage Commercially available drugs will be used. The drugs will be stored according to label. All patients are to receive four courses of carboplatin (area under the curve (AUC) 5 mg/ml per min, Calvert's formula) iv on day 1 plus etoposide 100 mg/m2 BSA iv day 1 followed by etoposide 200 mg/m2 po or etoposide 100 mg/m2 BSA IV days 2-4. Courses are administered every 3 weeks until a maximum of four courses.  
BSA is calculated according to the formula by Dubois and Dubois: BSA=0.007184 x weight0.425 x height0.725. It is recommended to consider capping the dose at a BSA of 2.2 m2
.  
Calvert's formula: carboplatin dose (mg) = AUC (mg ml-1 min) x [GFR (ml/min) + 25 (ml/min)
For most patients, GFR/creatinine-clearance will be calculated according to the Cockroft-Gault formula. For patients with a body weight falling below 30 kg or a serum-creatinine below the lower normal value, creatinine-clearance should be measured by 24-hour urine collection. It is recommended to reduce the etoposide-dose by 25% if creatinine-clearance is below 50 mg/minute. The use of G-CSF is allowed.  
8.2.2 Product preparation and administration According to local routines. Suggested preparation and administration of carboplatin plus etoposide:  
Day 1:  Carboplatin is diluted in 500 ml 5% glucose and infused over 30 minutes  **Etoposide is diluted in 500 ml 0.9% NaCl and infused over 30 minutes**
Day 2-4:  Half the etoposide-dose is taken orally in the morning, half the dose in the evening. The tablets are  
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taken with a glass of water. If etoposide is given IV, it will be administered as on Day 1.  
  
8.2.3 Suggested antiemetic medication (carboplatin)
Day 1:  **Ondansetron 16 mg PO or IV plus dexamethason 8 mg PO or IV (or equipotent dose of other**
corticosteroid) 1 hour before infusion of chemotherapy commences Day 2-3:  **Dexamethason 8 mg PO (or equipotent dose of another corticosteroid)**
Other antiemetic therapy may be administered according to local routines.  
8.2.4 Recommendations before a new course of chemotherapy:  **All grade 3-4 adverse events should have resolved to grade 0-2 or to the same level as before the**
preceding course of chemotherapy  **ANC ≥ 1.5 x 109**
/L and platelets ≥ 100 x 109
/L. Lower values might be acceptable if the nadir-phase has passed.  **Creatinine < 125 μmol/litre (if creatinine ≥ 125 μmol/litre, cisplatin should be replaced with**
carboplatin)
8.2.5 Suggestions for dose adjustments:  **In case of grade 4 neutropenia (< 0.5 x 109**
/L), grade 4 thrombocytopenia (< 50 x 109
/L) or febrile neutropenia (< 1.0 x 109
/L, fever and treatment with antibiotics) after the preceding course, it is suggested to reduce the doses for the next course to 80% of the preceding course.  **If ANC < 1.5 x 109**
/L or platelets < 100 x 109
/L on day 22 (day for the next course), it is suggested to delay the next course until resolution of the cytopenia. A dose reduction of 20% is suggested if a course is postponed more than a week.  **If a course is postponed more than three weeks, the chemotherapy should be discontinued.**
8.2.6 Duration of treatment and criteria for treatment through progression and for retreatment Maximum 4 courses of chemoimmunotherapy will be administered. Durvalumab treatment will then continue until PD and need for other treatment, unacceptable toxicity or patients wish to discontinue.  
Chemotherapy should be discontinued if a course is postponed more than three weeks, and may be discontinued earlier if severe, unacceptable, toxicity considered to be due to the chemotherapy occurs.  
Patients may continue durvalumab regardless of the number of chemotherapy courses completed provided the criteria for discontinuation of durvalumab are not met.  
Chemo- and/or immunotherapy will be discontinued if RECIST 1.1-defined radiological progression and need for other treatment occur. Other reasons for discontinuation include unacceptable toxicity, withdrawal of consent, or patient's wish.  
During the treatment period, patients who are clinically stable at an initial RECIST 1.1-defined PD
may continue to receive study treatment at the discretion of the Investigator and patient as long as they are deemed to be receiving clinical benefit. In case, a follow-up scan is to be collected after the initial RECIST 1.1-defined PD, 4-6 weeks after the prior assessment of PD for confirmation of PD and to ensure that potentially rapid progression of relapsing SCLC is revealed within a reasonable timeframe to ensure that patients may be offered other treatment for PD.  
Patients with PD who continue to receive IP at the discretion of the Investigator should undergo image acquisitions and tumor assessments according to the regular schedule for the duration of treatment. Patients with rapid tumor progression or with symptomatic progression that requires urgent medical intervention (e.g. CNS-metastasis, respiratory failure due to tumor compression, or spinal cord compression) will usually not be eligible for continuing durvalumab treatment. If a general disease control has been achieved, and oligometastatic progression occurs, exceptions may be considered after discussing with the Chief Investigator.  
For all patients who are treated through progression and for patients who are restarting  
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durvalumab (alone or in combination with chemotherapy), the Investigator should ensure that:  **The patient does not have any significant, unacceptable, or irreversible toxicities that indicate**
continuing treatment will not further benefit the patient. The patient may not have experienced a toxicity that required permanent discontinuation of study treatment.  **There is absence of clinical symptoms or signs indicating clinically significant disease progression**
accompanied by a decline in WHO/ECOG performance status to >1  **There is absence of rapid disease progression or threat to vital organs or critical anatomical sites**
(e.g. CNS-metastasis, respiratory failure due to tumor compression, or spinal cord compression)
requiring urgent alternative medical intervention  **The patient still fulfills the eligibility criteria for this study (see 7.1) with the exception of**
inclusion criteria 8, 9, 11 and 12 and exclusion criteria 3 and 8. **Patients must agree to restart**
durvalumab therapy.  **The patient has not received an intervening systemic anticancer therapy after their assigned**
treatment discontinuation.  **The patient has had a retreatment baseline tumor assessment within a maximum of 28 days**
prior to restarting their assigned treatment; all further scans should occur with the same frequency as during the initial 12 months of treatment (relative to the date of restarting treatment) until study treatment is stopped (maximum of 12 months of further treatment).  
Patients who the Investigator determine may not continue treatment after RECIST 1.1-defined PD will be followed for survival. Patients who have discontinued treatment due to toxicity or symptomatic deterioration, or who have commenced subsequent anticancer therapy, will be followed up with tumor assessments until RECIST 1.1-defined PD plus an additional follow-up scan or until death (whichever comes first) and followed for survival.  
8.2.7 Accountability and dispensation All sites will keep drug accountability records during the study. At most sites, these records will be maintained and kept at the local pharmacy.  
8.2.8 Disposition of unused investigational study drug The site will account for all investigational study drug dispensed and appropriately destroyed. Certificates of delivery and destruction must be signed and reported to sponsor.  
8.2.9 Monitoring of dose administration According to local routines.  
8.3 Thoracic radiotherapy 8.3.1 Timing Ideally, patients randomized to the experimental arm are to receive TRT between the second and third chemo-immunotherapy course. TRT may start concurrently with the second course, and TRT should be completed before the third chemo-immunotherapy course commences.  
However, there might be logistical challenges if chemo-immunotherapy courses are delayed due to toxicity from chemo-immunotherapy. In case, TRT may start after the second course even if the second course is delayed, but TRT may also start as scheduled regardless of the delay of the second chemoimmunotherapy course (i.e. 21-28 days after the first day of the first chemo-immunotherapy).  
If TRT is delayed due to intercurrent disease prohibiting TRT starting as planned, TRT should be administered as soon as possible. If TRT is not administered, patients should still receive chemoimmunotherapy as scheduled.  
8.3.2 TRT fractionation schedule Patients should receive 30 Gy in 10 fractions, 5 fractions per week. The optimal treatment time is 12 days,  
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but up to 15 days is allowed in case of holidays or unplanned delays.  
8.3.3 Treatment planning CT-scan The treatment planning CT scan (or PET CT scan if that is the local routine) should be done with the patient immobilized in supine position according to local standard procedures for radiotherapy of the thorax. The whole thorax should be included in the CT scan and IV contrast should be used. Slice thickness should be ≤
3 mm. The use of 4DCT is recommended and breath-hold technique or gating is allowed, but not mandatory.  
8.3.4 TRT guidelines in the CREST trial The planning target volume (PTV) was defined as the post-chemotherapy volume with a margin of 15 mm.  
The initially positive hilar and mediastinal nodal stations were included, also in case of a complete response. The V20 should be <35% of the total lung volume. A lung correction was required for all treatment plans. All modern RT techniques (including IMRT and VMAT) were allowed. The definition of volumes and calculation of doses should be performed according to the ICRU.48 8.3.5 Targets for TRT in the present trial Preferably, the target volume should include the primary lung tumor and regional lymph node metastases identified before chemoimmunotherapy commenced, also in case of a complete response. Extensive, elective nodal irradiation is not allowed.  
If possible, all thoracic lesions should be included in the radiotherapy field. If this is not possible, lesions compressing central airways or mediastinal structures (e.g. large vessels and nerves) should be prioritized. A minimum of one lesion should be irradiated. If a complete response is achieved by the time of the CT planning scan, this lesion may be a previously enlarged lymph node.  
8.3.6 Delineation of target volumes The gross tumor volume (GTV) will include the residual volume after the first (or second) chemoimmunotherapy course. The clinical target volume (CTV) will account for microscopic spread and is generated by expanding the GTV with 5 mm in all directions, but not across anatomic barriers such as trachea, heart, esophagus, bones, except when there is radiological invasion into these structures. The planning target volume (PTV) is defined by expanding the CTV with a margin defined according to local routines.  
8.3.7 Delineation of organs at risk (OARs) and corresponding normal tissue dose constraints In thoracic radiation the critical normal structures (organs at risk) that are likely to receive a significant radiation dose are: spinal cord; lungs; heart and pericardium; oesophagus. It is important to know the dose delivered to these structures, as this must be kept within normal tissue 'tolerance'. The following OARs should be contoured:  
| Organ at risk                                | Physical dose                     | Delineation                 |                           |
|----------------------------------------------|-----------------------------------|-----------------------------|---------------------------|
| Lungs                                        | Mean lung dose ≤12 Gy             |                             |                           |
| V20 Gy <30%                                  |                                   |                             |                           |
| V5 Gy preferably <55%                        |                                   | Both lungs minus GTV (IGTV) |                           |
| Spinal                                       |                                   |                             |                           |
| canal                                        |                                   |                             |                           |
| D0.03 cm3                                    |                                   |                             |                           |
| ≤                                            |                                   |                             |                           |
| 30 Gy                                        | Contoured as the bony edge of     |                             |                           |
| the vertebral foramens from 2 cm             |                                   |                             |                           |
| above and below the PTV                      |                                   |                             |                           |
| Heart                                        | V10 Gy <10%                       |                             | The whole heart below the |
| Mean heart dose should be as low as possible |                                   |                             |                           |
| division of the truncus pulmonalis           |                                   |                             |                           |
| Esophagus                                    |                                   |                             |                           |
| D0.03 cm3 ≤ 30 Gy                            | From just below the larynx to the |                             |                           |
| Mean esophageal dose should be as low as     |                                   |                             |                           |
| gastric-esophageal junction                  |                                   |                             |                           |  
8.3.8 Treatment planning Megavoltage equipment with a nominal photon energy of 6 MV is recommended. Inverse planning techniques like intensity modulated RT (IMRT) and rotational techniques such as volumetric modulated arc therapy (VMAT) and modern dose calculation algorithms (Monte Carlo, AAA, Collapsed Cone etc) should be used. A dose calculation grid of 2 mm3 is recommended. A median dose of 30 Gy should be delivered to the CTV. 98% of the PTV should be covered by the 95 % isodose. In those parts of the PTV consisting of normal lung tissue, a coverage of the 90% isodose is sufficient. A near maximum dose (D2%) of 107% is accepted.  
8.3.9 Treatment Daily cone beam CT (CBCT) with soft tissue match according to the target volume is mandatory.  
8.3.10 Quality assurance of the thoracic radiotherapy The first radiotherapy plan at each site should be sent to the central trial office in Trondheim as soon as possible. All radiotherapy plans will be reviewed by a study physician and a medical physicist, and feedback provided within 5 working days. When all patients have completed TRT, all radiotherapy plans should be sent to the central trial office for review.  
8.3.11 TRT in the control arm TRT may be offered patients in the control arm upon progression if this is considered the best alternative. Routine consolidation TRT after completion of chemoimmunotherapy is not allowed.  
8.4 Prophylactic cranial irradiation (PCI)
PCI is not mandatory, but patients who respond to chemoimmunotherapy and have not previously received brain irradiation, should be offered PCI at the hospitals where this is established treatment of ES SCLC. PCI should start between 4 to 6 weeks after the last chemoimmunotherapy course. PCI should be administered according to local routines. Hippocampus-sparing PCI is allowed. Recommended schedules are 25 Gy in 10 fractions or 30 Gy in 15 fractions. One schedule should be used for all patients at each site. PCI may be administered concurrently with durvalumab infusions.  
8.4.1 Treatment of brain metastases The treatment of brain metastases varies between hospitals. Patients with brain metastases may receive whole brain radiotherapy (WBRT) before or after chemoimmunotherapy. Recommended schedules are 30 Gy in 10 fractions (preferred) or 20 Gy in 4-5 fractions. WBRT should be administered according to local routines. WBRT may be offered patients who have received PCI if this is the local treatment policy. An alternative to WBRT is stereotactic radiosurgery (SRS) provided the number, size and location of the brain metastases allows for SRS. The role of SRS in brain metastases from SCLC is less defined than for NSCLC, but especially for patients who have received PCI, have good and long extracranial disease control, and limited number of brain metastases, SRS may be a better alternative than WBRT. Surgery may be an alternative but is seldom offered SCLC patients. Isolated progression in the brain does not necessarily warrant a change in systemic treatment provided local control is achieved by SRS, WBRT or surgery.  
8.4.2 Irradiation of other lesions Irradiation of other lesions is allowed according to each hospital's routines. This applies for both trial arms.  
If possible, it is preferred that any additional RT in the control arm is delivered after completion of chemoimmunotherapy.  
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8.5 Post study therapy Upon progression, patients should be treated according to each hospital's routines. All post-study treatment, including all RT, should be recorded.  
9. **Treatment plan**
9.1 Patient enrollment and randomization 9.1.1 Procedures for randomization After patients are assigned a study ID and registered in the CRF, investigators randomize patients using the randomization module in the CRF. Patients will be randomized 1:1 in blocks of various sizes to receive chemo-immunotherapy alone or chemo-immunotherapy plus TRT stratifying for presence of liver metastases (yes vs. no), and presence of brain metastases (yes vs. no). The study is open label, and patients and investigators will know the results of the randomization. They will not, however, know the results of previous randomizations or the block sizes.  
9.1.2 Procedures for handling patients incorrectly enrolled Patients who are incorrectly enrolled and/or randomized will be discussed with the Chief Investigator before deciding whether the patient should be withdrawn. If there has been a major protocol violation, the patient will be withdrawn from the study.
untitled h1
10. restrictions during the study

10.1 Restrictions during the study The following restrictions apply while the patient is receiving study treatment and for the specified times before and after:
Female patient of child-bearing potential:  **Female patients of childbearing potential who are not abstinent and intend to be sexually active with a**
non-sterilized male partner must use at least 1 highly effective method of contraception (Table 1) from the time of screening throughout the total duration of the drug treatment and the drug washout period (90 days after the last dose of durvalumab monotherapy). Non-sterilized male partners of a female patient of childbearing potential must use male condom plus spermicide throughout this period.  
Cessation of birth control after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Female patients should also refrain from breastfeeding throughout this period.  
Male patients with a female partner of childbearing potential:  **Non-sterilized male patients who are not abstinent and intend to be sexually active with a female**
partner of childbearing potential must use a male condom plus spermicide from the time of screening throughout the total duration of the drug treatment and the drug washout period (90 days after the last dose of durvalumab monotherapy). Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Male patients should refrain from sperm donation throughout this period.  **Female partners (of childbearing potential) of male patients must also use a highly effective method of**
contraception throughout this period (Table 1).
N.B Females of childbearing potential are defined as those who are not surgically sterile (i.e. bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.  
Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:  **Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12**
months or more following cessation of exogenous hormonal treatments and if they have luteinizing  
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hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution.  **Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12**
months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago.
Highly effective methods of contraception, defined as one that results in a low failure rate (i.e. less than 1%
per year) when used consistently and correctly are described in Table 1. Note that some contraception methods are not considered highly effective (e.g. male or female condom with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral contraceptive pills).  
| Table 1 Highly Effective Methods of Contraception (<1% Failure Rate)  Barrier/Intrauterine  methods    |                                           |
|----------------------------------------------------------------------------------------------------------|-------------------------------------------|
| Hormonal Methods                                                                                         |                                           |
|                                                                                                         |                                           |
| Copper T intrauterine device                                                                             |                                           |
|                                                                                                         |                                           |
| Levonorgestrel-releasing                                                                                 |                                           |
| intrauterine system (e.g.,                                                                               |                                           |
| Mirena®)a                                                                                                |                                           |
|                                                                                                         |                                           |
| Implants: Etonogestrel-releasing implants: e.g.                                                          |                                           |
| Implanon® or Norplant®                                                                                   |                                           |
|                                                                                                         |                                           |
| Intravaginal: Ethinylestradiol/etonogestrel-releasing                                                    |                                           |
| intravaginal devices: e.g. NuvaRing®                                                                     |                                           |
|                                                                                                         |                                           |
| Injection: Medroxyprogesterone injection: e.g. DepoProvera®                                                                                                          |                                           |
|                                                                                                         |                                           |
| Combined Pill: Normal and low dose combined oral                                                         |                                           |
| contraceptive pill                                                                                       |                                           |
|                                                                                                         |                                           |
| Patch: Norelgestromin/ethinylestradiol-releasing                                                         |                                           |
| transdermal system: e.g. Ortho Evra®                                                                     |                                           |
|                                                                                                         |                                           |
| Minipill: Progesterone based oral contraceptive pill using                                               |                                           |
| desogestrel: Cerazette® is currently the only highly                                                     |                                           |
| effective progesterone-based                                                                             |                                           |
| a                                                                                                        |                                           |
|                                                                                                          | This is also considered a hormonal method |  
10.1.1 Blood donation Patients should not donate blood while participating in this study, or for at least 90 days following the last infusion of durvalumab or 90 days after receipt of the final dose of durvalumab.  
| Table 2 Supportive Medications                                       |        |                       |
|----------------------------------------------------------------------|--------|-----------------------|
| Supportive medication/class of drug:                                 | Usage: |                       |
| Concomitant medications or treatments (e.g.,                         |        |                       |
| acetaminophen or                                                     |        |                       |
| diphenhydramine) deemed necessary to provide adequate prophylactic   |        |                       |
| or supportive care, except for those medications identified as       |        |                       |
| "prohibited," as listed above                                        |        | To be administered as |
| prescribed by the Investigator                                       |        |                       |
| Best supportive care (including antibiotics, nutritional support,    |        |                       |
| Should be used, when                                                 |        |                       |
| correction of metabolic disorders, optimal symptom control, and pain |        |                       |
| necessary, for all patients                                          |        |                       |
| management [including palliative RT to non-target lesions])          |        |                       |
| Inactivated viruses, such as those in the influenza vaccine          |        |                       |
| Permitted                                                            |        |                       |  
10.2.2 Excluded concomitant medications  
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| Table 3 Prohibited Concomitant Medications             |                                                    |                                               |
|--------------------------------------------------------|----------------------------------------------------|-----------------------------------------------|
| Prohibited medication/class of drug:                   | Usage:                                             |                                               |
| Any investigational anticancer therapy other than      |                                                    |                                               |
| Should not be given concomitantly whilst the           |                                                    |                                               |
| those under investigation in this study                |                                                    |                                               |
| patient is on study treatment                          |                                                    |                                               |
| mAbs against CTLA-4, PD-1, or PD-L1 other than         |                                                    |                                               |
| Should not be given concomitantly whilst the           |                                                    |                                               |
| those under investigation in this study                |                                                    |                                               |
| patient is on study treatment                          |                                                    |                                               |
| Any concurrent chemotherapy, immunotherapy, or         |                                                    |                                               |
| Should not be given concomitantly whilst the           |                                                    |                                               |
| biologic or hormonal therapy for cancer treatment      |                                                    |                                               |
| patient is on study treatment. (Concurrent use of      |                                                    |                                               |
| other than those under investigation in this study     |                                                    |                                               |
| hormones for non-cancer-related conditions             |                                                    |                                               |
| [e.g., insulin for diabetes and hormone                |                                                    |                                               |
| replacement therapy] is acceptable. Local              |                                                    |                                               |
| treatment of isolated lesions, excluding target        |                                                    |                                               |
| lesions, for palliative intent is acceptable [e.g., by |                                                    |                                               |
| local surgery or RT])                                  |                                                    |                                               |
| Immunosuppressive medications including, but not       |                                                    |                                               |
| limited to, systemic corticosteroids at doses          |                                                    |                                               |
| exceeding 10 mg/day of prednisone or equivalent,       |                                                    |                                               |
| methotrexate, azathioprine, and tumor necrosis         |                                                    |                                               |
| factor-α blockers                                      |                                                    | Should not be given concomitantly or used for |
| premedication prior to the I-O infusions. The          |                                                    |                                               |
| following are allowed exceptions:                     |                                                    |                                               |
| Use of immunosuppressive medications for the           |                                                    |                                               |
| management of IP-related AEs                           |                                                    |                                               |
|                                                       |                                                    |                                               |
| Short-term antiemetic therapy in relation with         |                                                    |                                               |
| chemotherapy-courses                                   |                                                    |                                               |
|                                                       |                                                    |                                               |
| For the treatment of hypersensitivity reactions        |                                                    |                                               |
| caused by the study treatment                          |                                                    |                                               |
|                                                       |                                                    |                                               |
| Use in patients with contrast allergy                  |                                                    |                                               |
|                                                       |                                                    |                                               |
| Use of inhaled, topical and intranasal                 |                                                    |                                               |
| corticosteroids is permitted                           |                                                    |                                               |
| A temporary period of steroids will be allowed if      |                                                    |                                               |
| clinically indicated and considered to be essential    |                                                    |                                               |
| for the management of non-immunotherapy                |                                                    |                                               |
| related events experienced by the patient (e.g.,       |                                                    |                                               |
| chronic obstructive pulmonary disease, radiation,      |                                                    |                                               |
| nausea, etc.).                                         |                                                    |                                               |
| Live attenuated vaccines                               | Should not be given through 30 days after the last |                                               |
| dose of IP (including SoC)                             |                                                    |                                               |
| Herbal and natural remedies which may have             |                                                    |                                               |
| Should not be given concomitantly unless agreed        |                                                    |                                               |
| immune-modulating effects                              |                                                    | by the sponsor                                |  
11. **Study procedures**
11.1 Schedule of study procedures Before study entry, throughout the study, and following study drug discontinuation, various clinical and diagnostic laboratory evaluations are outlined. The purpose of obtaining these detailed measurements is to ensure adequate safety and tolerability assessments. Clinical evaluations and laboratory studies may be repeated more frequently if clinically indicated.  
11.1.1 For both treatment arms  **An early response evaluation will be performed 3-4 weeks after the first chemo-immunotherapy course**
(at the time of TRT start in the experimental arm). For patients randomized to the experimental arm, the CT planning scan might be used for response evaluation. For patients on the control arm, a regular CT scan must be performed.  Response evaluation and measurement of HRQoL after completion of chemo-immunotherapy will be Page 38 of 59
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performed 2-3 weeks after the fourth course  **If chemotherapy is discontinued before the fourth course, response evaluation and HRQoL**
measurement will be performed according to schedule (week 11-12).  **Subsequent tumor efficacy (RECIST) and other assessment dates are not affected by dose delays and**
remain as originally scheduled, as they are based on the date of inclusion and not the date of therapy.  
11.1.2 For durvalumab maintenance therapy  **Patients may delay dosing under certain circumstances such as e.g. intercurrent disease and holidays if**
this is considered appropriate by their physician.  Dosing may be delayed per Toxicity Management Guidelines, due to either an immune or a nonimmune-related AE.  **If dosing must be delayed for reasons other than treatment-related toxicity, dosing will resume as soon**
as feasible  **Dosing intervals of subsequent cycles may be shortened as clinically feasible in order to gradually align**
treatment cycles with the schedule of tumor efficacy (RECIST) and patient reported outcomes (PRO)
assessments. Subsequent time between 2 consecutive doses cannot be less than 22 days, based on the half-lives of durvalumab (see current Investigator Brochure for durvalumab).  
11.1.3 Screening phase Screening procedures will be performed up to 28 days before Day 1 of the first chemo-immunotherapy course, unless otherwise specified. All patients must first read, understand, and sign the IRB/REB/IECapproved ICF before any study-specific screening procedures are performed. After signing the ICF,
completing all screening procedures, and being deemed eligible for entry, patients will be enrolled in the study. Procedures that are performed prior to the signing of the ICF and are considered standard of care may be used as screening assessments if they fall within the 28-day screening window.  
The following procedures will be performed during the screening visit:  Informed Consent  Review of eligibility criteria  Medical history, demographics, and smoking history  Complete physical exam  ECOG Performance Status  Weight and height  **12-lead ECG (in triplicate if there are any significant abnormalities on the first ECG, each recording**
should be made 2-5 minutes apart)  Review of prior/concomitant medications  CT of the thorax and upper abdomen  MRI of the brain  Pulmonary function  Cognitive function (MoCA test)  HRQoL-questionnaire  Pregnancy test in women of childbearing potential  Collection of blood and stool samples for biomarker analyses including neuronal auto-antibodies  **Clinical laboratory tests for:**
o **Hematology (see Table 4)**
o **Clinical chemistry (see Table 5)** o **Creatinine Clearance** o Serum pregnancy test (for women of childbearing potential only)  
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