A Phase II, Single Arm Study of CarbopLatin Plus Etoposide With Bevacizumab and Atezolizumab in Patients With exTEnded-disease Small-cell Lung Cancer (SCLC)
Small cell lung cancer (SCLC) is an aggressive type of neuroendocrine tumor with the majority of patients (about 60-70%) being diagnosed with metastatic disease and with a median survival ranging from 7 to 12 months. Combination chemotherapy (CT), namely a platinum and etoposide-based regimen, represents the cornerstone of treatment for extended disease (ED) SCLC. Despite this the duration of response is short and nearly all patients develop disease relapse or progression. The recent approval of atezolizumab in combination with carboplatin and etoposide as first line in patients with ED SCLC is surely a step forward in the understanding the molecular landscape and treatment of this complex tumor, but new therapeutic approaches need to be explored. This trial aims to assess the efficacy in terms of 1 year survival a new therapeutic strategy that combines to the standard CT (carboplatin and etoposide), two drugs indicated in the tratment of several types of tumors: bevacizumab and atezolizomab. The treatment will start with an induction phase during which eligible patients will receive, by intravenous way, a combination of the above mentioned drugs according to a specific administration regimen. This phase will last about 18 weeks. Therafter the treatment will proceed with a maintenence phase lasting for a maximum of 54 weeks during which the patients will receive only atezolizumab and bevacizumab, by intravenous way, according to a specific administration regimen. Treatment will be discontnued in case of disease progression, unacceptable toxicity, patient refusal or loss of clinical benefit (for atezolizumab). During the study period the patients will undergo to periodic visits and laboratory, radiologic assessments to monitor the efficacy and the safety of the ongoing treatment.
• Histologically or cytological documented small cell lung cancer (SCLC) or poorly differentiated (G3) neuroendocrine carcinoma of the lung
• Extensive stage disease (disease which cannot be encompassed in a single radiation portal including pleural dissemination and supraclavicular node metastasis)
• No prior chemotherapy or treatment with another systemic anti-cancer agent (Note: Patients who have received prior chemoradiotherapy for limited-stage SCLC must have been treated with curative intent and experienced a treatment-free interval of at least 6 months since last chemotherapy, radiotherapy or chemoradiotherapy cycle from diagnosis of extended-disease SCLC)
• No need for concomitant chest irradiation
• Males or females, age ≥18 years
• ECOG performance status 0-1
• Life expectancy \> 12 weeks
• Adequate hepatic and renal functions \[i.e. total bilirubin \< 1.5 times the ULN; - AST and ALT \< 3.0 times the ULN (AST and ALT \< 5.0 x ULN is acceptable if the liver has tumor involvement); Albumin≥ 25 g/L (2.5 g/dL); serum creatinine ≤1.5 times the ULN or creatinine clearance, calculated according to the formula of Cockcroft and Gault \> 60 ml/min; urine dipstick for proteinuria \<2+. If urine dipstick is \>2+, 24-hour urine must demonstrate ≤ 1 g of protein in 24 hours\]
• Adequate hematologic function, as evidenced by an absolute neutrophil count (ANC) ≥1500/µL, hemoglobin ≥9 g/dL (5.58 mmol/L), and platelets ≥100,000/µL.
• Adequate coagulation function as defined by International Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT) (PTT/aPTT) ≤ 1.5 x upper limits of normal \[ULN\]. Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant or low molecular weight heparin (LMWH). If receiving warfarin, the patient must have an INR ≤3.0. For heparin and LMWH there should be no active bleeding (that is, no bleeding within 14 days prior to first dose of protocol therapy) or pathological condition present that carries a high risk of bleeding (for example, tumor involving major vessels or known varices).
• Negative HIV test at screening with respect of any applicable law and the indication of Atezolizumab use.
• Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening. Please note: The HBV DNA test will be performed only for patients who have a positive total HBcAb test
• Negative hepatitis C virus (HCV) antibody test at screening.
• Female patients of childbearing potential must have a negative serum pregnancy test within 72 hours prior to first dose of protocol therapy.
• Male patients who are sexually active must use effective contraception during treatment with chemotherapy and for at least 6 months after the final dose of chemotherapy to avoid exposing the embryo. Men must refrain from donating sperm during this same period.
• For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception that results in a low failure rate (\< 1% per year) when used consistently and correctly, and to continue its use for 6 months after the last dose of atezolizumab or bevacizumab. Such methods include: combined (estrogen and progestogen containing) hormonal contraception, progestogen-only hormonal contraception associated with inhibition of ovulation together with another additional barrier method always containing a spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence.
• Ability to comply with the study protocol, in the investigator's judgment
• Written informed consent