Patients With ES-SCLC and ECOG PS=2 Receiving Atezolizumab-Carboplatin-Etoposide
Patients With ES-SCLC and ECOG PS=2 Receiving Atezolizumab-Carboplatin-Etoposide
Small cell lung cancer (SCLC) is a rapidly proliferating, neuroendocrine tumor that accounts
 for about 15% of all lung cancers. Most patients have metastases at primary diagnosis
 involving sites like bone, adrenal glands, liver and brain.

 Compared with non-small-cell lung cancer (NSCLC) SCLC has a unique natural history with a
 shorter doubling time, higher growth fraction, earlier development of widespread metastases,
 and uniform initial response to chemo- or radiotherapy.

 The combination of cis- or carboplatin and etoposide is the standard of care in the
 first-line treatment of stage IV (extensive-disease) SCLC (ED-SCLC). Despite response rates
 of 50-80%, most patients relapse within six months and the median survival time is less than
 10 months. Between 14 and 23% of SCLC patients develop brain metastases.

 New cytotoxic agents as well as targeted therapies have not been able to show any improvement
 of survival in this group of patients.

 Early phase trials of PD 1/PD L1-blocking immunotherapeutic agents in patients with recurrent
 or ED SCLC have shown promising response rates and good tolerability. Immunotherapy may also
 contribute to the efficacy of systemic treatment by maintaining initial responses to
 chemotherapy. A double-blind, placebo-controlled phase 3 trial indicates that the addition of
 atezolizumab to standard chemotherapy significantly improves overall survival and
 progression-free survival compared with chemotherapy alone in treatment-naïve patients with
 ED-SCLC who are in good general condition (ECOG 0 or 1). However, about one in three SCLC
 patients has a poor performance status (ECOG≥2), which is associated with even shorter
 survival times of under eight months. At present, there is little information regarding the
 feasibility, safety and efficacy of adding atezolizumab to standard chemotherapy for this
 considerable fraction of patients.

 The investigators expect, that atezolizumab in addition to chemotherapy is feasible in
 patients with stage IV SCLC and reduced performance status and therefore crucial efficacy
 data can be acquired in this trial to evaluate a putative Phase III transition in this
 particular patient population.
Inclusion Criteria:

 -  Written informed consent including participation in translational research obtained
 from the subject prior to performing any protocol-related procedures, including
 screening evaluations that are not SOC.

 -  ECOG 2

 -  At least one measurable tumor lesion (according to RECIST1.1)

 -  Histologically confirmed small cell lung cancer (SCLC)

 -  Stage IV disease (according to UICC8)

 -  No active autoimmune disease

 -  Adequate organ function defined as:

 -  neutrophil count > 1.5 x 109/L

 -  thrombocytes ≥ 100 x 109/L

 -  hemoglobin ≥ 9 g/dL

 -  INR ≤ 1.4 or aPTT ≤ 40 sec during the last 7 days before therapy [Subjects under
 therapeutic anticoagulation are permitted.]

 -  bilirubin < 1.5 x ULN

 -  AST (SGOT)/ALT (SGPT) < 3 x institutional ULN (< 5 x ULN in case of liver
 metastases)

 -  creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 45 mL/min

 -  Availability of tumor tissue/block

 -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
 test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to
 the first dose of IMP.

 -  Women of childbearing potential (WOCBP) must use appropriate method(s) of
 contraception. [WOCBP should use an adequate method to avoid pregnancy for 6 months
 after the last dose of IMP.]

 -  Men who are sexually active with WOCBP must use any contraceptive method with a
 failure rate of less than 1% per year. Men receiving IMP and who are sexually active
 with WOCBP will be instructed to adhere to contraception for a period of 6 months
 after the last dose of IMP. Women who are not of childbearing potential (ie, who are
 postmenopausal or surgically sterile) and men who are azoospermic do not require
 contraception.

 -  Subject 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.

 Exclusion Criteria:

 -  Any preceding systemic anticancer therapy for stage IV SCLC. [Up to one
 full-cycle-dosing of carboplatin+etoposide chemotherapy within the context of SOC is
 permitted prior to study treatment.] (Note: Prior treatment for limited stage disease
 allowed).

 -  Participation in another clinical study with an investigational product during the
 last 30 days before inclusion or 7 half-lives of previously used trial medication,
 whichever is longer

 -  Prior therapy with an anti-Programmed cell death protein 1 (anti-PD-1),
 anti-Programmed cell death-ligand 1 (anti-PD-L1), anti-Programmed cell death-ligand 2
 (anti-PD-L2), anti-CD137 (4-1BB ligand, a member of the Tumor Necrosis Factor Receptor
 [TNFR] family), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4)
 antibody (including ipilimumab or any other antibody or drug specifically targeting
 T-cell co-stimulation or checkpoint pathways).

 -  Previous treatment in the present study (does not include screening failure).

 -  Symptomatic CNS metastases. [Patients with asymptomatic brain metastases may be
 included.]

 -  Major surgery ≤ 28 days before first dose of study treatment

 -  Any uncontrolled systemic disease, condition or comorbidity that, in the opinion of
 the investigator, would interfere with evaluation of study treatment or interpretation
 of patient safety or study results, including but not limited to:

 1. known active HBV, HCV or HIV infection [Patients who are HIV-positive are allowed
 in the trial, so long as they are stable on anti-retroviral therapy, have a CD4
 count ≥ 200 cells/μL, and have an undetectable viral load at the time of
 screening.]

 2. active tuberculosis

 3. any other active infection requiring systemic therapy

 4. history of allogeneic tissue/solid organ transplant

 5. diagnosis of immunodeficiency or patient is receiving chronic systemic steroid
 therapy or any other form of immunosuppressive therapy within 7 days prior to the
 first dose of IMP

 6. other active malignancy requiring treatment

 7. clinically significant or symptomatic cardiovascular/cerebrovascular disease
 (incl. myocardial infarction, unstable angina, symptomatic congestive heart
 failure, serious uncontrolled cardiac arrhythmia) within 6 months before
 enrolment

 -  Female subjects who are pregnant, breast-feeding or male/female patients of
 reproductive potential who are not employing an effective method of birth control
 (failure rate of less than 1% per year).

 -  Known hypersensitivity to carboplatin, etoposide or atezolizumab or any of the
 constituents of the product.

 -  Medication that is known to interfere with any of the agents applied in the trial.

 -  Any condition or disease which might interfere with the subject's ability to comply
 with the study procedures (e.g., dementia).

 -  Patient who has been incarcerated or involuntarily institutionalized by court order or
 by the authorities [§ 40 Abs. 1 S. 3 Nr. 4 AMG].

 -  Patients who are unable to consent because they do not understand the nature,
 significance and implications of the clinical trial and therefore cannot form a
 rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].