Carboplatin or Cisplatin, Etoposide, and Durvalumab with Hypofractionated Ablative Radiation Therapy for the Treatment of Extensive-Stage Small Cell Lung Cancer, DARES Study

Inclusion Criteria

• 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 United States [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
• Age >= 18 years at time of study entry
• Have a histologic diagnosis of small cell lung cancer with known metastatic disease
• Patient is suitable to receive a platinum-based chemotherapy regimen as first line treatment for extensive stage small cell lung cancer (SCLC)
• Brain metastases must be asymptomatic or treated and stable off steroids and anticonvulsant for at least 2 weeks prior to study treatment
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Life expectancy of at least 12 weeks
• Body weight > 30 kg
• Hemoglobin >= 9.0 g/dL
• Absolute neutrophil count (ANC) >= 1.5 x 10^9 /L
• Platelet count >= 100 x 10^9/L
• Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN). This will 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), who will be allowed only in consultation with their physician
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [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
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled visits, examinations and follow up
• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 including at least ONE lesion that meets criteria for ablative radiation, including 0.25 cc to 65 cc of viable tumor (i.e. primary disease or metastases) approximately 5 cm in maximal dimension. Tumors larger than 65 cc can be partially treated
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 24 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

Exclusion Criteria

• Participation in another clinical study with an investigational product during the last 2 weeks
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
• Any unresolved toxicity National Cancer Institute (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 study physician * Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the study physician
• Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment, outside of those specified as part of this clinical trial. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable
• 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 drug
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable
• History of allogenic organ transplantation
• 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: * Patients with vitiligo or alopecia * Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Patients without active disease in the last 5 years may be included but only after consultation with the study physician * Patients with celiac disease controlled by diet alone
• 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 adverse events (AEs) or compromise the ability of the patient to give written informed consent
• 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 * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease
• History of leptomeningeal carcinomatosis
• Has a paraneoplastic syndrome (PNS) of autoimmune nature, requiring systemic treatment (systemic steroids or immunosuppressive agents) or has a clinical symptomatology suggesting worsening of PNS
• Patients with uncontrolled brain metastases. Patients with controlled brain metastases will be allowed on protocol. Controlled brain metastases will be defined as treated AND radiologically/clinically stable). Based on inclusion criterion #5 brain mets should be asymptomatic or treated and stable off steroids and anticonvulsant therapy for at least 2 weeks prior to study treatment
• History of active primary immunodeficiency
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (HIV). 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 ribonucleic acid (RNA)
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: * 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)
• 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
• 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
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
• Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment
• Has received prior chemotherapy, immunotherapy or thoracic radiation for small cell lung cancer
• Has prior exposure to anti-PD1/PD-L1 or anti-CTLA4 therapy
• Has had prior radiation therapy (defined as > 10% of prior prescription dose) to the area planning to be treated with trial RT