Does a higher radiation dose prolong survival of patients with limited-stage small cell lung cancer receiving immunotherapy after chemotherapy and radiation therapy (DAHRTS trial)?

Prior treatment

• Participation in another clinical study with an investigational product the last 30 days.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab. Note: Patients, if enrolled, should not receive live vaccine whilst receiving and up to 30 days after the last dose of durvalumab
• Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study. However, concurrent participation in the PRIMALung and MAVERICK studies is acceptable.
• Previous chemo- or radiotherapy for SCLC
• Previous checkpoint inhibitor therapy including durvalumab.
• Major surgical procedure within 28 days prior to initiation of study treatment. Local surgery for diagnostics or symptom relief is acceptable.
• 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 f) Patients who per local clinical practice (outside trials) are considered fit for durvalumab therapy may be included but only after consultation with the Chief Investigator
• Other primary malignancy (including hematologic) except for: a) Malignancy treated with curative intent and with no active disease ≥5 years. b) Localized breast or prostate cancer treated with hormonal therapy alone. c) Adequately treated non-melanoma skin cancer or lentigo maligna, superficial cancer or carcinoma in situ without evidence of disease. d) Other malignancy with low risk of metastases which is unlikely to require systemic cancer therapy or reduce the patient’s survival time (e.g. 5-years OS rate of >90%)
• Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment (except for hormonal therapy alone for localized breast or prostate cancer, see exclusion criterion 11b). Concurrent use of hormonal therapy for non–cancer-related conditions (e.g. hormone replacement therapy) is acceptable.
• Current or prior use of immunosuppressive medication. The following exceptions apply: a) Intranasal, inhaled, topical steroids, or local steroid injections. b) Systemic corticosteroids at 10 mg/day of prednisone or its equivalent. c) Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication). d) Steroids given to alleviate SCLC tumor induced edema or compression. e) Prophylactic medication in relation to chemotherapy.

Other illness

• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
• History of allogenic stem cell organ transplantation.
• History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on diagnostic CT scan (i.e. before chemotherapy).
• 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, 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.
• History of active primary immunodeficiency
• Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies).
• Active infection including tuberculosis (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result) or 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

Lab values

• 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. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Chief Investigator. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Chief Investigator.

Other

• Pathological pericardial effusion.
• Pregnant and breastfeeding women.

• No malignant cells in pleural fluid. At least 1 sample should be collected for cytological examination if pleural fluid is present. If the collectable volume is too small for such an examination, the patient is eligible
• Considered eligible for BID TRT of 60 Gy to all lesions (i.e. patients with previous radiotherapy to the thorax might be eligible).
• ECOG performance status 0-2.
• Measurable disease according to the RECIST 1.1. on diagnostic images obtained before chemotherapy commences
• Adequate organ function before chemotherapy commences: a) Serum alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN) b) Total serum bilirubin ≤ 1.5 x ULN c) Haemoglobin ≥9.0 g/dL d) Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L e) Platelets ≥ 100 x 109 /L f) Creatinine < 125 µmol/L and GFR > 50 ml/min measured using an appropriate method according to local practice (e.g. Iohexol plasma clearance or CrEDTA clearance) or calculated by the Cockcroft-Gault formula using actual body weight
• Conscious and capable of giving signed informed consent themselves.
• Pulmonary function: FEV1 >1 L or >30 % of predicted value and DLCO >30 % of predicted value. If lower values are considered to be due to tumor compression of central airways, the patient is eligible.
• 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 chemotherapy and durvalumab treatment and for at least 5 months after the last dose (sexual abstinence, vasectomy, tubular occlusion, intrauterine device or hormonal implants/-intravaginal device/-combine pill/-mini pill/-patch). Details about birth control methods considered to be highly effective are listed in Section 11.1.
• Must have a life expectancy of at least 12 weeks.
• 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
• Age ≥ 18 years(if applicable: ≥ 20 years for Japanese patients).
• Body weight >30 kg.
• Histologically or cytologically confirmed small-cell lung cancer. Mixed histology is acceptable provided the SCLC component accounts for ≥90% of tumor cells
• Stage I-III according to TNM v9 ineligible for surgery.