A phase 1 study of combined guadecitabine and cisplatin in platinum refractory germ cell cancer

被引:25
作者
Albany, Costantine [1 ]
Fazal, Zeeshan [2 ,3 ]
Singh, Ratnakar [2 ,3 ]
Bikorimana, Emmanuel [2 ,3 ]
Adra, Nabil [1 ]
Hanna, Nasser H. [1 ]
Einhorn, Lawrence H. [1 ]
Perkins, Susan M. [4 ]
Sandusky, George E. [1 ]
Christensen, Brock C. [5 ]
Keer, Harold [6 ]
Fang, Fang [7 ]
Nephew, Kenneth P. [7 ]
Spinella, Michael J. [2 ,3 ]
机构
[1] Indiana Univ Sch Med, Indiana Univ, Melvin & Bren Simon Comprehens Canc Ctr, Div Hematol Oncol, Indianapolis, IN 46202 USA
[2] Univ Illinois, Dept Comparat Biosci, 2001 South Lincoln St, Urbana, IL 61802 USA
[3] Univ Illinois, Canc Ctr Illinois, Urbana, IL USA
[4] Indiana Univ Sch Med, Dept Biostat, Indianapolis, IN 46202 USA
[5] Geisel Sch Med Dartmouth, Dept Epidemiol, Hanover, NH USA
[6] Astex Pharmaceut Inc, Pleasanton, CA USA
[7] Indiana Univ Sch Med, Med Sci Program, Bloomington, IN USA
来源
CANCER MEDICINE | 2021年 / 10卷 / 01期
基金
美国国家卫生研究院;
关键词
cisplatin; DNA methylation; DNA methyltransferase; epigenetics; guadecitabine; SGI‐ 110; testicular cancer; TUMORS; DIFFERENTIATION; METHYLATION; CHEMOTHERAPY; ASSOCIATION; CARBOPLATIN; RESISTANT; RECURRENT; RELAPSE; TRIAL;
D O I
10.1002/cam4.3583
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose Germ cell tumors (GCTs) are cured with therapy based on cisplatin, although a clinically significant number of patients are refractory and die of progressive disease. Based on preclinical studies indicating that refractory testicular GCTs are hypersensitive to hypomethylating agents (HMAs), we conducted a phase I trial combining the next-generation HMA guadecitabine (SGI-110) with cisplatin in recurrent, cisplatin-resistant GCT patients. Methods Patients with metastatic GCTs were treated for five consecutive days with guadecitabine followed by cisplatin on day 8, for a 28-day cycle for up to six cycles. The primary endpoint was safety and toxicity including dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). Results The number of patients enrolled was 14. The majority of patients were heavily pretreated. MTD was determined to be 30 mg/m(2) guadecitabine followed by 100 mg/m(2) cisplatin. The major DLTs were neutropenia and thrombocytopenia. Three patients had partial responses by RECIST criteria, two of these patients, including one with primary mediastinal disease, completed the study and qualified as complete responses by serum tumor marker criteria with sustained remissions of 5 and 13 months and survival of 16 and 26 months, respectively. The overall response rate was 23%. Three patients also had stable disease indicating a clinical benefit rate of 46%. Conclusions The combination of guadecitabine and cisplatin was tolerable and demonstrated activity in patients with platinum refractory germ cell cancer.
引用
收藏
页码:156 / 163
页数:8
相关论文
共 43 条
  • [1] Adra N, 2017, CLIN ADV HEMATOL ONC, V15, P386
  • [2] Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine
    Albany, Costantine
    Hever-Jardine, Mary P.
    von Herrmann, Katherine M.
    Yim, Christina Y.
    Tam, Janice
    Warzecha, Joshua M.
    Shin, Leah
    Bock, Sarah E.
    Curran, Brian S.
    Chaudhry, Aneeq S.
    Kim, Fred
    Sandusky, George E.
    Taverna, Pietro
    Freemantle, Sarah J.
    Christensen, Brock C.
    Einhorn, Lawrence H.
    Spinella, Michael J.
    [J]. ONCOTARGET, 2017, 8 (02) : 2949 - 2959
  • [3] Current Management of Refractory Germ Cell Tumors and Future Directions
    Allen, J. Clayton
    Kirschner, Austin
    Scarpato, Kristen R.
    Morgans, Alicia K.
    [J]. CURRENT ONCOLOGY REPORTS, 2017, 19 (02)
  • [4] The association between clinician-based common terminology criteria for adverse events (CTCAE) and patient-reported outcomes (PRO): a systematic review
    Atkinson, Thomas M.
    Ryan, Sean J.
    Bennett, Antonia V.
    Stover, Angela M.
    Saracino, Rebecca M.
    Rogak, Lauren J.
    Jewell, Sarah T.
    Matsoukas, Konstantina
    Li, Yuelin
    Basch, Ethan
    [J]. SUPPORTIVE CARE IN CANCER, 2016, 24 (08) : 3669 - 3676
  • [5] High DNA Methyltransferase 3B Expression Mediates 5-Aza-Deoxycytidine Hypersensitivity in Testicular Germ Cell Tumors
    Beyrouthy, Maroun J.
    Garner, Kristen M.
    Hever, Mary P.
    Freemantle, Sarah J.
    Eastman, Alan
    Dmitrovsky, Ethan
    Spinella, Michael J.
    [J]. CANCER RESEARCH, 2009, 69 (24) : 9360 - 9366
  • [6] Acute Hypersensitivity of Pluripotent Testicular Cancer-Derived Embryonal Carcinoma to Low-Dose 5-Aza Deoxycytidine Is Associated with Global DNA Damage-Associated p53 Activation, Anti-Pluripotency and DNA Demethylation
    Biswal, Bijesh K.
    Beyrouthy, Maroun J.
    Hever-Jardine, Mary P.
    Armstrong, David
    Tomlinson, Craig R.
    Christensen, Brock C.
    Marsit, Carmen J.
    Spinella, Michael J.
    [J]. PLOS ONE, 2012, 7 (12):
  • [7] Epigenetics and testicular germ cell tumors
    Buljubasic, Robert
    Buljubasic, Maja
    Bojanac, Ana Katusic
    Ulamec, Monika
    Vlahovic, Maja
    Jezek, Davor
    Bulic-Jakus, Floriana
    Sincic, Nino
    [J]. GENE, 2018, 661 : 22 - 33
  • [8] Epigenetic alterations as therapeutic targets in Testicular Germ Cell Tumours : current and future application of 'epidrugs'
    Cardoso, Ana Rita
    Lobo, Joao
    Miranda-Goncalves, Vera
    Henrique, Rui
    Jeronimo, Carmen
    [J]. EPIGENETICS, 2021, 16 (04) : 353 - 372
  • [9] Managing seminomatous and nonseminomatous germ cell tumors
    Chahoud, Jad
    Zhang, Miao
    Shah, Amishi
    Lin, Sue-Hwa
    Pisters, Louis L.
    Tu, Shi-Ming
    [J]. CURRENT OPINION IN ONCOLOGY, 2018, 30 (03) : 181 - 188
  • [10] MGMT and CALCA promoter methylation are associated with poor prognosis in testicular germ cell tumor patients
    da Silva Martinelli, Camila Maria
    Lengert, Andre van Helvoort
    Carcano, Flavio Mavignier
    Albino Silva, Eduardo Caetano
    Brait, Mariana
    Lopes, Luiz Fernando
    Vidal, Daniel Onofre
    [J]. ONCOTARGET, 2017, 8 (31) : 50608 - 50617