Phase I trial of volasertib, a Polo-like kinase inhibitor, plus platinum agents in solid tumors: safety, pharmacokinetics and activity

Ahmad Awada, Herlinde Dumez, Philippe G Aftimos, Jo Costermans, Sylvie Bartholomeus, Kathleen Forceville, Thierry Berghmans, Marie-Anne Meeus, Jessica Cescutti, Gerd Munzert, Korinna Pilz, Dan Liu, Patrick Schöffski, Ahmad Awada, Herlinde Dumez, Philippe G Aftimos, Jo Costermans, Sylvie Bartholomeus, Kathleen Forceville, Thierry Berghmans, Marie-Anne Meeus, Jessica Cescutti, Gerd Munzert, Korinna Pilz, Dan Liu, Patrick Schöffski

Abstract

Background: This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and activity of volasertib, a selective Polo-like kinase 1 inhibitor that induces mitotic arrest and apoptosis, combined with cisplatin or carboplatin in patients with advanced/metastatic solid tumors (NCT00969761; 1230.6).

Methods: Sequential patient cohorts (3 + 3 dose-escalation design) received a single infusion of volasertib (100-350 mg) with cisplatin (60-100 mg/m(2)) or carboplatin (area under the concentration versus time curve [AUC]4-AUC6) on day 1 every 3 weeks for up to six cycles. Sixty-one patients received volasertib/cisplatin (n = 30) or volasertib/carboplatin (n = 31) for a median of 3.5 (range, 1-6) and 2.0 (range, 1-6) treatment cycles, respectively.

Results: The most common cycle 1 dose-limiting toxicities (DLTs) were thrombocytopenia, neutropenia and fatigue. MTDs (based on cycle 1 DLTs) were determined to be volasertib 300 mg plus cisplatin 100 mg/m(2) and volasertib 300 mg plus carboplatin AUC6. Co-administration did not affect the pharmacokinetics of each drug. Partial responses were observed in two patients in each arm. Stable disease was achieved in 11 and six patients treated with volasertib/cisplatin and volasertib/carboplatin, respectively.

Conclusions: Volasertib plus cisplatin or carboplatin at full single-agent doses was generally manageable and demonstrated activity in heavily pretreated patients with advanced solid tumors.

Figures

Fig. 1
Fig. 1
gMean plasma concentration-time profiles of total volasertib after intravenous infusion of volasertib in combination with (a) cisplatin or (b) carboplatin (semi-log scale). Abbreviations: AUC area under the concentration versus time curve, gMean geometric mean

References

    1. Schöffski P. Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist. 2009;14:559–570. doi: 10.1634/theoncologist.2009-0010.
    1. Strebhardt K. Multifaceted polo-like kinases: drug targets and antitargets for cancer therapy. Nat Rev Drug Discov. 2010;9:643–660. doi: 10.1038/nrd3184.
    1. Liu X, Erikson RL. Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells. Proc Natl Acad Sci U S A. 2003;100:5789–5794. doi: 10.1073/pnas.1031523100.
    1. Spänkuch-Schmitt B, Bereiter-Hahn J, Kaufmann M, Strebhardt K. Effect of RNA silencing of polo-like kinase-1 (PLK1) on apoptosis and spindle formation in human cancer cells. J Natl Cancer Inst. 2002;94:1863–1877. doi: 10.1093/jnci/94.24.1863.
    1. Xu WJ, Zhang S, Yang Y, Zhang N, Wang W, Liu SY, Tian HW, Dai L, Xie Q, Zhao X, Wei YQ, Deng HX. Efficient inhibition of human colorectal carcinoma growth by RNA interference targeting polo-like kinase 1 in vitro and in vivo. Cancer Biother Radiopharm. 2011;26:427–436. doi: 10.1089/cbr.2010.0922.
    1. Cheng MW, Wang BC, Weng ZQ, Zhu XW. Clinicopathological significance of Polo-like kinase 1 (PLK1) expression in human malignant glioma. Acta Histochem. 2012;114:503–509. doi: 10.1016/j.acthis.2011.09.004.
    1. Wolf G, Elez R, Doermer A, Holtrich U, Ackermann H, Stutte HJ, Altmannsberger HM, Rübsamen-Waigmann H, Strebhardt K. Prognostic significance of polo-like kinase (PLK) expression in non-small cell lung cancer. Oncogene. 1997;14:543–549. doi: 10.1038/sj.onc.1200862.
    1. Takahashi T, Sano B, Nagata T, Kato H, Sugiyama Y, Kunieda K, Kimura M, Okano Y, Saji S. Polo-like kinase 1 (PLK1) is overexpressed in primary colorectal cancers. Cancer Sci. 2003;94:148–152. doi: 10.1111/j.1349-7006.2003.tb01411.x.
    1. Wang ZX, Xue D, Liu ZL, Lu BB, Bian HB, Pan X, Yin YM. Overexpression of polo-like kinase 1 and its clinical significance in human non-small cell lung cancer. Int J Biochem Cell Biol. 2012;44:200–210. doi: 10.1016/j.biocel.2011.10.017.
    1. Han DP, Zhu QL, Cui JT, Wang PX, Qu S, Cao QF, Zong YP, Feng B, Zheng MH, Lu AG. Polo-like kinase 1 is overexpressed in colorectal cancer and participates in the migration and invasion of colorectal cancer cells. Med Sci Monit. 2012;18:BR237–BR246.
    1. Strebhardt K, Ullrich A. Targeting polo-like kinase 1 for cancer therapy. Nat Rev Cancer. 2006;6:321–330. doi: 10.1038/nrc1841.
    1. Rudolph D, Steegmaier M, Hoffmann M, Grauert M, Baum A, Quant J, Haslinger C, Garin-Chesa P, Adolf GR. BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res. 2009;15:3094–3102. doi: 10.1158/1078-0432.CCR-08-2445.
    1. Schöffski P, Awada A, Dumez H, Gil T, Bartholomeus S, Wolter P, Taton M, Fritsch H, Glomb P, Munzert G. A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours. Eur J Cancer. 2012;48:179–186. doi: 10.1016/j.ejca.2011.11.001.
    1. Baum A, Gurtler U, Munzert G, Steegmaier M. In vivo efficacy of BI 2536, a potent and selective inhibitor of the mitotic kinase PIK1, in combination with various cytotoxic agents. Eur J Cancer Suppl. 2006;4:110–111. doi: 10.1016/S1359-6349(06)70361-5.
    1. Kreis NN, Sommer K, Sanhaji M, Kramer A, Matthess Y, Kaufmann M, Strebhardt K, Yuan J. Long-term downregulation of Polo-like kinase 1 increases the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) Cell Cycle. 2009;8:460–472. doi: 10.4161/cc.8.3.7651.
    1. Baum A, Garin-Chesa P, Gurtler U, Munzert G, Rudolph DI (2007) Efficacy of BI 2536, a potent and selective inhibitor of the mitotic kinase Plk1, in models of human non-small cell lung carcinoma. J Thorac Oncol(Supplement 2):S435, abstr
    1. Spänkuch B, Heim S, Kurunci-Csacsko E, Lindenau C, Yuan J, Kaufmann M, Strebhardt K. Down-regulation of Polo-like kinase 1 elevates drug sensitivity of breast cancer cells in vitro and in vivo. Cancer Res. 2006;66:5836–5846. doi: 10.1158/0008-5472.CAN-06-0343.
    1. Calvert AH, Newell DR, Gumbrell LA, O’Reilly S, Burnell M, Boxall FE, Siddik ZH, Judson IR, Gore ME, Wiltshaw E. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989;7:1748–1756.
    1. US Food and Drug Administration (2013) Recommendations on Carboplatin Dosing. . Accessed 24 September 2014
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Accord Healthcare Limited (2012) Carboplatin 10 mg/ml concentrate for solution for infusion. Summary of Product Characteristics
    1. Accord Healthcare Limited (2012) Cisplatin 1 mg/ml concentrate for solution for infusion. Summary of Product Characteristics
    1. Duffull SB, Robinson BA. Clinical pharmacokinetics and dose optimisation of carboplatin. Clin Pharmacokinet. 1997;33:161–183. doi: 10.2165/00003088-199733030-00002.
    1. van der Vijgh WJ. Clinical pharmacokinetics of carboplatin. Clin Pharmacokinet. 1991;21:242–261. doi: 10.2165/00003088-199121040-00002.
    1. Vermorken JB, Rottey S, Ehrnrooth E, Pelling K, Lahogue A, Wind S, Machiels JP. A phase Ib, open-label study to assess the safety of continuous oral treatment with afatinib in combination with two chemotherapy regimens: cisplatin plus paclitaxel and cisplatin plus 5-fluorouracil, in patients with advanced solid tumors. Ann Oncol. 2013;24:1392–1400. doi: 10.1093/annonc/mds633.

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