Clinical Study Received: September 3, 2014 Accepted: January 5, 2015 Published online: March 25, 2015
Chemotherapy 2014;60:180–184 DOI: 10.1159/000371870
Phase I/II Study of Amrubicin and Nedaplatin in Patients with Untreated, Advanced, Non-Small Cell Lung Cancer Daiki Ogawara a Yoichi Nakamura a Minoru Fukuda a Katsumi Nakatomi a Hiroyuki Yamaguchi a Kohei Motoshima a Kosuke Mizoguchi a Hirofumi Nakano b Shinnosuke Takemoto a Hiroshi Gyotoku a Seiji Nagashima c Shigeru Kohno a
a
Second Department of Internal Medicine, Nagasaki University Hospital, Nagasaki, b Department of Respiratory Medicine, Ureshino Medical Center, Ureshino, and c Department of Respiratory Medicine, Nagasaki Medical Center, Ohmura, Japan
Abstract A phase I/II study of combination chemotherapy with amrubicin and nedaplatin for patients with untreated, advanced, non-small cell lung cancer (NSCLC) was conducted. Amrubicin was given on days 1–3, with nedaplatin given on day 1. The treatment was repeated every 3 weeks. In the phase I trial, the initial amrubicin dose of 25 mg/m2 was escalated in 5-mg/m2 increments until the maximum tolerated dose was reached, with the dose of nedaplatin fixed at 100 mg/m2. In the phase II trial, the primary endpoint was the overall response rate (ORR), assuming 20% for a standard therapy and 40% for a target therapy (α = 0.05 and β = 0.20), and the estimated required total number of patients was 35. In the phase I study, nedaplatin 100 mg/m2 and amrubicin 25 mg/m2 was recommended. In the phase II study, 17 out of 35 patients achieved a partial response, and the ORR was 48.6%. Grade 3/4 neutropenia, grade 3 anemia and grade 3/4 thrombocytopenia occurred in 62.9, 11.4 and 11.4% of
© 2015 S. Karger AG, Basel 0009–3157/15/0603–0180$39.50/0 E-Mail [email protected] www.karger.com/che
cycles, respectively. Febrile neutropenia occurred in 5 cycles (3.9%) and all cases were manageable. The recommended dose of this combination is well tolerated and effective in patients with advanced NSCLC. © 2015 S. Karger AG, Basel
Introduction
Lung cancer is the leading cause of cancer-related deaths worldwide [1]. Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers, and most of them are in advanced stages, such as stage III or IV, at the time of diagnosis. The median survival time (MST) had previously been shown to be approximately 10 months in several phase III trials for advanced NSCLC [2–6]. This is still intractable, and there is no satisfactory treatment despite therapeutic advances. Recently, molecular-targeted agents such as gefitinib, erlotinib and crizotinib have been shown to have high efficacy in patients who have epidermal growth factor receptor-positive or chromosomal rearrangement of the anaplastic lymphoma kinase gene-positive advanced Yoichi Nakamura, MD, PhD Second Department of Internal Medicine Nagasaki University Hospital 1-7-1 Sakamoto, Nagasaki 852-8501 (Japan) E-Mail yi-nakamu @ umin.ac.jp
Downloaded by: University of Exeter 149.126.76.97 - 8/14/2015 10:17:01 AM
Key Words Non-small cell lung cancer · Phase I/II trials · Nedaplatin · Amrubicin · First-line therapy
cancer and in accordance with the 7th edition, and all classified as stage IV); age 20–75 years; no prior chemotherapy or radiation therapy for the primary tumor; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; measurable disease; life expectancy of 12 weeks or more; adequate bone marrow function (white blood cell count ≥4,000/μl, platelet count ≥100,000/μl and hemoglobin ≥9.0 g/dl); renal function (serum creatinine levels equal to or below the upper limit of the normal range), and hepatic function (total serum bilirubin level
Chemotherapy 2014;60:180–184 DOI: 10.1159/000371870
Phase I/II Study of Amrubicin and Nedaplatin in Patients with Untreated, Advanced, Non-Small Cell Lung Cancer Daiki Ogawara a Yoichi Nakamura a Minoru Fukuda a Katsumi Nakatomi a Hiroyuki Yamaguchi a Kohei Motoshima a Kosuke Mizoguchi a Hirofumi Nakano b Shinnosuke Takemoto a Hiroshi Gyotoku a Seiji Nagashima c Shigeru Kohno a
a
Second Department of Internal Medicine, Nagasaki University Hospital, Nagasaki, b Department of Respiratory Medicine, Ureshino Medical Center, Ureshino, and c Department of Respiratory Medicine, Nagasaki Medical Center, Ohmura, Japan
Abstract A phase I/II study of combination chemotherapy with amrubicin and nedaplatin for patients with untreated, advanced, non-small cell lung cancer (NSCLC) was conducted. Amrubicin was given on days 1–3, with nedaplatin given on day 1. The treatment was repeated every 3 weeks. In the phase I trial, the initial amrubicin dose of 25 mg/m2 was escalated in 5-mg/m2 increments until the maximum tolerated dose was reached, with the dose of nedaplatin fixed at 100 mg/m2. In the phase II trial, the primary endpoint was the overall response rate (ORR), assuming 20% for a standard therapy and 40% for a target therapy (α = 0.05 and β = 0.20), and the estimated required total number of patients was 35. In the phase I study, nedaplatin 100 mg/m2 and amrubicin 25 mg/m2 was recommended. In the phase II study, 17 out of 35 patients achieved a partial response, and the ORR was 48.6%. Grade 3/4 neutropenia, grade 3 anemia and grade 3/4 thrombocytopenia occurred in 62.9, 11.4 and 11.4% of
© 2015 S. Karger AG, Basel 0009–3157/15/0603–0180$39.50/0 E-Mail [email protected] www.karger.com/che
cycles, respectively. Febrile neutropenia occurred in 5 cycles (3.9%) and all cases were manageable. The recommended dose of this combination is well tolerated and effective in patients with advanced NSCLC. © 2015 S. Karger AG, Basel
Introduction
Lung cancer is the leading cause of cancer-related deaths worldwide [1]. Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers, and most of them are in advanced stages, such as stage III or IV, at the time of diagnosis. The median survival time (MST) had previously been shown to be approximately 10 months in several phase III trials for advanced NSCLC [2–6]. This is still intractable, and there is no satisfactory treatment despite therapeutic advances. Recently, molecular-targeted agents such as gefitinib, erlotinib and crizotinib have been shown to have high efficacy in patients who have epidermal growth factor receptor-positive or chromosomal rearrangement of the anaplastic lymphoma kinase gene-positive advanced Yoichi Nakamura, MD, PhD Second Department of Internal Medicine Nagasaki University Hospital 1-7-1 Sakamoto, Nagasaki 852-8501 (Japan) E-Mail yi-nakamu @ umin.ac.jp
Downloaded by: University of Exeter 149.126.76.97 - 8/14/2015 10:17:01 AM
Key Words Non-small cell lung cancer · Phase I/II trials · Nedaplatin · Amrubicin · First-line therapy
cancer and in accordance with the 7th edition, and all classified as stage IV); age 20–75 years; no prior chemotherapy or radiation therapy for the primary tumor; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; measurable disease; life expectancy of 12 weeks or more; adequate bone marrow function (white blood cell count ≥4,000/μl, platelet count ≥100,000/μl and hemoglobin ≥9.0 g/dl); renal function (serum creatinine levels equal to or below the upper limit of the normal range), and hepatic function (total serum bilirubin level
