Daniel J Allendorf1, Rodolfo E Bordoni2, Stefan C Grant3, Mansoor N Saleh4, Vishnu B Reddy5, Mary L Jerome6, Pamela M Dixon7, Deborah K Miley6, Karan P Singh8, Francisco Robert9. 1. Alabama Oncology, Shelby County, AL, USA. 2. Georgia Cancer Specialists/Northside Hospital Cancer Institute, Atlanta, GA, USA. 3. Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston-Salem, NC, 27157, USA. 4. Division of Hematology/Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, WTI 210B, Birmingham, AL, 35294-3300, USA. 5. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA. 6. Clinical Studies Unit, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. 7. Clinical Trials Network Office, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. 8. Department of Medicine, Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. 9. Division of Hematology/Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, WTI 210B, Birmingham, AL, 35294-3300, USA. pacorobertuab@cs.com.
Abstract
PURPOSE: The sequence bendamustine (B) + Irinotecan (I) followed by etoposide (E) + carboplatin (C) was hypothesized to increase progression-free survival (PFS) and overall survival (OS) in untreated extensive-disease small cell lung cancer (EDSCLC) patients compared to historical controls by exploiting mitotic catastrophe. Absent expression of ERCC-1 and expression of topoisomerases were hypothesized to be predictive for PFS and OS. METHODS: This was a phase I/IIa trial in 30 patients to determine the maximum tolerated dose (MTD) of B + I and the PFS of B + I E + C with secondary end points including overall response rate (ORR) and OS. Biomarkers measured by immunohistochemistry (IHC) obtained from diagnostic specimens were correlated with outcome. RESULTS: The MTD of B + I was not reached. During treatment with B + I, there were two grade 5 toxicities from neutropenic sepsis and metabolic encephalopathy. Other toxicities included fatigue, nausea/vomiting, diarrhea, and weight loss. For the sequence, the PFS and OS were 6.0 months and 10 months, respectively. The ORR for B + I and the sequence were 82% and 83%, respectively. Topoisomerase-2 expression was predictive for TTP and OS, but absent ERCC-1 expression was not, contrary to our hypothesis. CONCLUSIONS: B + I is an active regimen in EDSCLC. Toxicities included two grade 5 events but were otherwise manageable. The novel sequence B + I E + C increased PFS and OS compared to historical controls. Correlative studies are conflicting regarding the mechanism of action of this novel sequence.
PURPOSE: The sequence bendamustine (B) + Irinotecan (I) followed by etoposide (E) + carboplatin (C) was hypothesized to increase progression-free survival (PFS) and overall survival (OS) in untreated extensive-disease small cell lung cancer (EDSCLC) patients compared to historical controls by exploiting mitotic catastrophe. Absent expression of ERCC-1 and expression of topoisomerases were hypothesized to be predictive for PFS and OS. METHODS: This was a phase I/IIa trial in 30 patients to determine the maximum tolerated dose (MTD) of B + I and the PFS of B + I E + C with secondary end points including overall response rate (ORR) and OS. Biomarkers measured by immunohistochemistry (IHC) obtained from diagnostic specimens were correlated with outcome. RESULTS: The MTD of B + I was not reached. During treatment with B + I, there were two grade 5 toxicities from neutropenic sepsis and metabolic encephalopathy. Other toxicities included fatigue, nausea/vomiting, diarrhea, and weight loss. For the sequence, the PFS and OS were 6.0 months and 10 months, respectively. The ORR for B + I and the sequence were 82% and 83%, respectively. Topoisomerase-2 expression was predictive for TTP and OS, but absent ERCC-1 expression was not, contrary to our hypothesis. CONCLUSIONS: B + I is an active regimen in EDSCLC. Toxicities included two grade 5 events but were otherwise manageable. The novel sequence B + I E + C increased PFS and OS compared to historical controls. Correlative studies are conflicting regarding the mechanism of action of this novel sequence.
Entities:
Keywords:
Biomarkers; Chemotherapy; Extensive small cell lung cancer; Lung cancer