Xi-Zhi Wen1,2, Qiu-Zhong Pan1,2, Bu-Shu Xu1,2, Wei Xiao2,3, De-Sheng Weng1,2, Jing-Jing Zhao1,2, Hai-Rong Xu4, Zhen Huang4, Xiao-Hui Niu5, Xing Zhang6,7. 1. Melanoma and Sarcoma Medical Oncology Unit, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China. 2. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People's Republic of China. 3. Department of Hematological Oncology, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China. 4. Department of Orthopaedic Oncology Surgery, Beijing Jishuitan Hospital, Beijing, 100000, China. 5. Department of Orthopaedic Oncology Surgery, Beijing Jishuitan Hospital, Beijing, 100000, China. niuxiaohui@263.net. 6. Melanoma and Sarcoma Medical Oncology Unit, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China. zhangxing@sysucc.org.cn. 7. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People's Republic of China. zhangxing@sysucc.org.cn.
Abstract
PURPOSE: The repeated use of doxorubicin is limited due to dose-limiting cardiac toxicity. Pegylated liposomal doxorubicin (PEG-LD, Duomeisu) has a reduced cardiac toxicity. This phase I study aimed to investigate the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of the PEG-LD and cisplatin combination in patients with metastatic and recurrent osteosarcoma. METHODS: Patients were given PEG-LD at a dose of 40, 50, or 60 mg/m2 on day 1 of each 21-day cycle, according to a 3 + 3 approach for dose escalation. Cisplatin was administered as a fixed dose of 100 mg/m2 for every cycle. Toxicities and tumor response were observed. RESULTS: A total of 15 patients were enrolled in this trial, and nine of the patients had received prior doxorubicin. The MTD of PEG-LD was reached at 50 mg/m2 in this regimen, with neutropenic fever and stomatitis as DTLs. The main adverse event (AE) was myelosuppression. The most common non-hematological AEs were vomiting, hypoproteinemia, stomatitis and transient sinus arrhythmia. Grade 3-4 toxicity was neutropenia, leukopenia, thrombocytopenia, anemia and stomatitis in the whole cohort. All the AEs were relieved after symptomatic and supportive treatment. Totally, the overall response rate was 13.3% and disease control rate was 66.7%. For the six patients who have not received prior doxorubicin, one partial response and five stable diseases were observed. CONCLUSION: We provide the data showing that PEG-LD 50 mg/m2 combined with cisplatin 100 mg/m2 demonstrated an acceptable safety profile and promising clinical activity in advanced osteosarcoma, which merits further evaluation in phase II studies. TRIAL REGISTRATION: ChiCTR1900021550.
PURPOSE: The repeated use of doxorubicin is limited due to dose-limiting cardiac toxicity. Pegylated liposomal doxorubicin (PEG-LD, Duomeisu) has a reduced cardiac toxicity. This phase I study aimed to investigate the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of the PEG-LD and cisplatin combination in patients with metastatic and recurrent osteosarcoma. METHODS: Patients were given PEG-LD at a dose of 40, 50, or 60 mg/m2 on day 1 of each 21-day cycle, according to a 3 + 3 approach for dose escalation. Cisplatin was administered as a fixed dose of 100 mg/m2 for every cycle. Toxicities and tumor response were observed. RESULTS: A total of 15 patients were enrolled in this trial, and nine of the patients had received prior doxorubicin. The MTD of PEG-LD was reached at 50 mg/m2 in this regimen, with neutropenic fever and stomatitis as DTLs. The main adverse event (AE) was myelosuppression. The most common non-hematological AEs were vomiting, hypoproteinemia, stomatitis and transient sinus arrhythmia. Grade 3-4 toxicity was neutropenia, leukopenia, thrombocytopenia, anemia and stomatitis in the whole cohort. All the AEs were relieved after symptomatic and supportive treatment. Totally, the overall response rate was 13.3% and disease control rate was 66.7%. For the six patients who have not received prior doxorubicin, one partial response and five stable diseases were observed. CONCLUSION: We provide the data showing that PEG-LD 50 mg/m2 combined with cisplatin 100 mg/m2 demonstrated an acceptable safety profile and promising clinical activity in advanced osteosarcoma, which merits further evaluation in phase II studies. TRIAL REGISTRATION: ChiCTR1900021550.
Authors: Joanne P Lagmay; Mark D Krailo; Ha Dang; AeRang Kim; Douglas S Hawkins; Orren Beaty; Brigitte C Widemann; Theodore Zwerdling; Lisa Bomgaars; Anne-Marie Langevin; Holcombe E Grier; Brenda Weigel; Susan M Blaney; Richard Gorlick; Katherine A Janeway Journal: J Clin Oncol Date: 2016-07-11 Impact factor: 44.544
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