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

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
(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 × 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 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, not previously irradiated, that qualifies as a RECIST 1.1
target lesion (TL) at baseline. Tumor assessment by computed tomography (CT)
scan or magnetic resonance imaging (MRI) must be performed within 28 days prior
to randomization.
9. At least 1 measurable lesion in the thorax which is possible to irradiate to
30 Gy in 10 fractions.
10. Histologically or cytologically confirmed SCLC.
11. 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.
12. Pulmonary function: FEV1 >1 L or >30 % of predicted value and DLCO
>30 % of predicted value.
13. 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.
14. 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.

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, 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.
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.