A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors

被引:45
|
作者
Massard, Christophe [1 ]
Soria, Jean-Charles [1 ]
Anthoney, D. Alan [3 ,4 ]
Proctor, A. [3 ,4 ]
Scaburri, Angela [5 ]
Pacciarini, Maria Adele [5 ]
Laffranchi, Bernard [5 ]
Pellizzoni, Cinzia [6 ]
Kroemer, Guido [2 ,7 ,8 ,9 ]
Armand, Jean-Pierre [1 ]
Balheda, Rastilav [1 ]
Twelves, Christopher J. [3 ,4 ]
机构
[1] Univ Paris 11, Serv Innovat Therapeut Precoces SITEP, Dept Med, Inst Gustave Roussy, Villejuif, France
[2] INSERM, U848, Villejuif, France
[3] Univ Leeds, Leeds, W Yorkshire, England
[4] St Jamess Inst Oncol, Leeds, W Yorkshire, England
[5] Milan Int Oncol, Nerviano Med Sci NMS Grp, Nerviano, Italy
[6] Accelera SRL, Nerviano, Italy
[7] Ctr Rech Cordeliers, Paris, France
[8] Hop Europeen Georges Pompidou, AP HP, Paris, France
[9] Univ Paris 05, Paris, France
关键词
cell cycle; CDK; hepatic failure; cancer; FLAVOPIRIDOL;
D O I
10.4161/cc.10.6.15075
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Background: PHA-793887 is an inhibitor of multiple cyclin-dependent kinases (CDK) with activity against CDK2, CDK1 and CDK4. The primary objectives of this first in man study were to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase II dose of PHA-793887. Results: Although toxicity was acceptable at initial dose levels, PHA-793887 was poorly tolerated at doses >= 44 mg/m(2). The most frequent events across all dose levels were gastrointestinal or nervous system events. DLTs were experienced by two of three patients at the dose level of 66 mg/m(2), and by three of nine patients at the dose level of 44 mg/m(2). In all but one patient the DLT was hepatotoxicity; fatal hepatorenal failure was seen in one patient treated at the 44 mg/m(2) dose level. There were no objective responses, but disease stabilization was observed in five patients. Over the dose range investigated, pharmacokinetic studies showed that systemic exposure to PHA-793887 increased with the dose and was time-independent. The study terminated after the enrolment of 19 patients due to the severe hepatic toxicity. Patients and Methods: Cohorts of three to six patients were treated at doses of 11, 22, 44 and 66 mg/m(2) of PHA-793887 administered as 1-hour intravenous infusion on days 1, 8 and 15 in a 4-week cycle. Safety and pharmacokinetics were investigated. Conclusion: PHA-793887 induces severe, dose-related hepatic toxicity, which was not predicted by pre-clinical models and currently precludes its further clinical development.
引用
收藏
页码:963 / 970
页数:8
相关论文
共 50 条
  • [31] Phase I dose escalation study of the CDK4/6 inhibitor palbociclib in combination with the MEK inhibitor PD0325901 in patients with RAS mutant solid tumors
    Shapiro, Geoffrey I.
    Hilton, John
    Gandi, Leena
    Chau, Nicole
    Cleary, James
    Wolanski, Andrew
    Anderson, Adrienne
    Beardslee, Brian
    Hassinger, Faith
    Bhushan, Ketki
    Downey, Elizabeth
    Gibson, Joseph
    Pruitt-Thompson, Solida
    Muzikansky, Alona
    Barry, Suzanne
    Feeney, Nora
    Paweletz, Cloud
    Oxnard, Geoffrey
    Supko, Jeffrey
    Janne, Pasi
    Wong, Kwok-Kin
    Johnson, Bruce
    CANCER RESEARCH, 2017, 77
  • [32] A phase 1 dose-escalation study of BBI503, a first-in-class cancer stemness kinase inhibitor in adult patients with advanced solid tumors
    Laurie, Scott Andrew
    Jonker, Derek J.
    Edenfield, William Jeffery
    Stephenson, Joe
    Keller, Deborah
    Hitron, Matthew
    Li, Wei
    Li, Youzhi
    Gada, Keyur
    Gao, Yuan
    Li, Chiang
    JOURNAL OF CLINICAL ONCOLOGY, 2014, 32 (15)
  • [33] First-in-human phase I dose-escalation study of the oral selective C-met inhibitor EMD 1204831 in patients with advanced solid tumors.
    Amin, Hesham M.
    Falchook, Gerald Steven
    Fu, Siqing
    Hong, David S.
    Tsimberidou, Apostolia Maria
    Naing, Aung
    Wheler, Jennifer J.
    Piha-Paul, Sarina Anne
    Janku, Filip
    Klevesath, Manfred B.
    Jego, Virginie
    Johne, Andreas
    Kurzrock, Razelle
    JOURNAL OF CLINICAL ONCOLOGY, 2012, 30 (15)
  • [34] First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study
    Sullivan, Ryan J.
    Infante, Jeffrey R.
    Janku, Filip
    Wong, Deborah Jean Lee
    Sosman, Jeffrey A.
    Keedy, Vicki
    Patel, Manish R.
    Shapiro, Geoffrey I.
    Mier, James W.
    Tolcher, Anthony W.
    Wang-Gillam, Andrea
    Sznol, Mario
    Flaherty, Keith
    Buchbinder, Elizabeth
    Carvajal, Richard D.
    Varghese, Anna M.
    Lacouture, Mario E.
    Ribas, Antoni
    Patel, Sapna P.
    DeCrescenzo, Gary A.
    Emery, Caroline M.
    Groover, Anna L.
    Saha, Saurabh
    Varterasian, Mary
    Welsch, Dean J.
    Hyman, David M.
    Li, Bob T.
    CANCER DISCOVERY, 2018, 8 (02) : 184 - 195
  • [35] Phase I Dose-Escalation Study of the Dual PI3K-mTORC1/2 Inhibitor Gedatolisib in Combination with Paclitaxel and Carboplatin in Patients with Advanced Solid Tumors
    Colombo, Ilaria
    Genta, Sofia
    Martorana, Federica
    Guidi, Monia
    Frattini, Milo
    Samartzis, Eleftherios Pierre
    Brandt, Simone
    Gaggetta, Sheila
    Moser, Laura
    Pascale, Mariarosa
    Terrot, Tatiana
    Sessa, Cristiana
    Stathis, Anastasios
    CLINICAL CANCER RESEARCH, 2021, 27 (18) : 5012 - 5019
  • [36] Phase I, multi-center, dose-escalation and dose-expansion study of IMP7068, a WEE1 inhibitor, in patients with advanced solid tumors
    Lin, C-C.
    Grewal, J.
    Baranda, J. C.
    Schneider, R. E.
    Zhang, J.
    Bai, L-Y.
    Yeh, Y-M.
    Sommerhalder, D.
    Li, G.
    Shen, L.
    Hsu, H-C.
    Alese, O.
    Yin, R.
    Hsieh, C-Y.
    Cai, S. X.
    Tian, Y. E.
    Xia, H.
    Li, B.
    Zhang, M.
    Zhang, C.
    ANNALS OF ONCOLOGY, 2023, 34 : S466 - S466
  • [37] Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors
    Anthony W. Tolcher
    Razelle Kurzrock
    Vincente Valero
    Rene Gonzalez
    Rebecca S. Heist
    Antoinette R. Tan
    Julie Means-Powell
    Theresa L. Werner
    Carlos Becerra
    Chenxi Wang
    Cathrine Leonowens
    Shanker Kalyana-Sundaram
    Joseph F. Kleha
    Jennifer Gauvin
    Anthony M. D’Amelio
    Catherine Ellis
    Nageatte Ibrahim
    Li Yan
    Cancer Chemotherapy and Pharmacology, 2020, 85 : 673 - 683
  • [38] Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors
    Tolcher, Anthony W.
    Kurzrock, Razelle
    Valero, Vincente
    Gonzalez, Rene
    Heist, Rebecca S.
    Tan, Antoinette R.
    Means-Powell, Julie
    Werner, Theresa L.
    Becerra, Carlos
    Wang, Chenxi
    Leonowens, Cathrine
    Kalyana-Sundaram, Shanker
    Kleha, Joseph F.
    Gauvin, Jennifer
    D'Amelio, Anthony M.
    Ellis, Catherine
    Ibrahim, Nageatte
    Yan, Li
    CANCER CHEMOTHERAPY AND PHARMACOLOGY, 2020, 85 (04) : 673 - 683
  • [39] Phase I Dose-escalation and Pharmacokinetic Trial of Lapatinib (GW572016), a Selective Oral Dual Inhibitor of ErbB-1 and-2 Tyrosine Kinases, in Japanese Patients with Solid Tumors
    Nakagawa, Kazuhiko
    Minami, Hironobu
    Kanezaki, Masayuki
    Mukaiyama, Akihira
    Minamide, Yoshiyuki
    Uejima, Hisao
    Kurata, Takayasu
    Nogami, Toshiji
    Kawada, Kenji
    Mukai, Hirofumi
    Sasaki, Yasutsuna
    Fukuoka, Masahiro
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY, 2009, 39 (02) : 116 - 123
  • [40] First-in-human study of HMPL-295, an ERK1/2 inhibitor, in patients with advanced solid tumors: Dose-escalation results of monotherapy
    Yu, Xianjun
    Zhang, Jian
    Sun, Yuping
    Deng, Yanhong
    Guo, Shuangshuang
    Hong, Wei
    Shi, Si
    Liu, Rujiao
    Gao, Shuiping
    Dang, Qi
    Zhang, Jianwei
    Su, Weiguo
    Shi, Michael
    Fan, Songhua
    Zhang, Bo
    Pan, Beiqing
    Jia, Xiaoyun
    Wang, Jian
    Zhong, Chen
    Ma, Luguang
    JOURNAL OF CLINICAL ONCOLOGY, 2024, 42 (16)