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01.03.2008 | Original Article

Phase I and pharmacokinetic study of UCN-01 in combination with irinotecan in patients with solid tumors

verfasst von: Antonio Jimeno, Michelle A. Rudek, Thomas Purcell, Daniel A. Laheru, Wells A. Messersmith, Janet Dancey, Michael A. Carducci, Sharyn D. Baker, Manuel Hidalgo, Ross C. Donehower

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 3/2008

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Abstract

Purpose

7-Hydroxystaurosporine (UCN-01) is a protein kinase inhibitor that inhibits several serine–threonine kinases including PKC and PDK1. Due to the preclinical synergistic effects seen with topoisomerase I inhibitors and non-overlapping toxicity, UCN-01 and irinotecan were combined in a dose-finding study designed to determine the maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics (PK) of UCN-01 and irinotecan.

Methods

Patients with incurable solid malignancies received UCN-01 intravenously (IV) as a 3-h infusion on day 1 and irinotecan IV over 90 min on days 1 and 8 of a 21-day cycle. Doses of UCN-01 for subsequent cycles were half the starting dose. Dose level 1 (DL1) consisted of UCN-01 and irinotecan doses of 50 and 60 mg/m², respectively. Blood samples were collected in cycle 1 for UCN-01, irinotecan, and irinotecan metabolites.

Results

A total of 16 patients were enrolled on the trial at UCN-01/Irinotecan doses of 50/60 mg/m² (DL1; n = 1), 70/60 mg/m² (DL2; n = 6), 90/60 mg/m² (DL3; n = 4), and 70/90 mg/m² (DL4; n = 5). Two dose-limiting toxicities were observed each in DL3 and DL4 (2 grade 3 hypophosphatemia, 1 grade 4 hyperglycemia and grade 3 hypophosphatemia, 1 grade 4 febrile neutropenia). Fatigue, diarrhea, nausea, and anorexia were the most prevalent toxicities. No objective responses were documented, and four patients had stable disease for at least ten cycles. The long half-life (292.0 ± 135.7 h), low clearance (0.045 ± 0.038 l/h), and volume of distribution (14.3 ± 5.9 l) observed for UCN-01 are consistent with prior UCN-01 data. There was a significant decrease in C _max of APC, AUC of APC and SN-38, and AUC ratio of SN-38:irinotecan when comparing days 1 and 8 PK.

Conclusions

APC and SN-38 exposure decreased when administered in combination with UCN-01. The MTD of the combination based on protocol criteria was defined as 70 mg/m² of UCN-01 on day 1 and 60 mg/m² of irinotecan on days 1 and 8 in a 21-day cycle.

Akinaga S, Nomura K, Gomi K, Okabe M (1994) Effect of UCN-01, a selective inhibitor of protein kinase C, on the cell-cycle distribution of human epidermoid carcinoma, A431 cells. Cancer Chemother Pharmacol 33:273–280PubMedCrossRef

Bacic D, Schulz N, Biber J, Kaissling B, Murer H, Wagner CA (2003) Involvement of the MAPK-kinase pathway in the PTH-mediated regulation of the proximal tubule type IIa Na+/Pi cotransporter in mouse kidney. Pflugers Arch 446:52–60PubMedCrossRef

Bredel M, Pollack IF, Freund JM, Rusnak J, Lazo JS (1999) Protein kinase C inhibition by UCN-01 induces apoptosis in human glioma cells in a time-dependent fashion. J Neurooncol 41:9–20PubMedCrossRef

Carducci MA, Musib L, Kies MS, et al (2006) Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer. J Clin Oncol 24:4092–4099PubMedCrossRef

Courage C, Bradder SM, Jones T, Schultze-Mosgau MH, Gescher A (1997) Characterisation of novel human lung carcinoma cell lines selected for resistance to anti-neoplastic analogues of staurosporine. Int J Cancer 73:763–768PubMedCrossRef

D’Argenio DZ, Schumitzky A (1979) A program package for simulation and parameter estimation in pharmacokinetic systems. Comput Programs Biomed 9:115–134PubMedCrossRef

Dasmahapatra GP, Didolkar P, Alley MC, Ghosh S, Sausville EA, Roy KK (2004) In vitro combination treatment with perifosine and UCN-01 demonstrates synergism against prostate (PC-3) and lung (A549) epithelial adenocarcinoma cell lines. Clin Cancer Res 10:5242–5252PubMedCrossRef

de Bruijn P, Willems EW, Loos WJ, Verweij J, Sparreboom A (2004) determination of the irinotecan metabolite 7-ethyl-10-O-glucuronyl-camptothecin in human samples. Anal Biochem 328:84–86PubMedCrossRef

Dees EC, Baker SD, O’Reilly S, et al (2005) A phase I and pharmacokinetic study of short infusions of UCN-01 in patients with refractory solid tumors. Clin Cancer Res 11:664–671PubMed

10.

Fuse E, Tanii H, Kurata N, et al (1998) Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human alpha1-acid glycoprotein. Cancer Res 58:3248–3253PubMed

11.

Graves PR, Yu L, Schwarz JK, et al (2000) The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. J Biol Chem 275:5600–5605PubMedCrossRef

12.

Green LJ, Marder P, Ray C, et al (2006) Development and validation of a drug activity biomarker that shows target inhibition in cancer patients receiving enzastaurin, a novel protein kinase C-beta inhibitor. Clin Cancer Res 12:3408–3415PubMedCrossRef

13.

Helliwell PA, Rumsby MG, Kellett GL (2003) Intestinal sugar absorption is regulated by phosphorylation and turnover of protein kinase C betaII mediated by phosphatidylinositol 3-kinase- and mammalian target of rapamycin-dependent pathways. J Biol Chem 278:28644–28650PubMedCrossRef

14.

Hotte SJ, Oza A, Winquist EW, et al (2006) Phase I trial of UCN-01 in combination with topotecan in patients with advanced solid cancers: a Princess Margaret Hospital Phase II Consortium study. Ann Oncol 17:334–340PubMedCrossRef

15.

Idris I, Gray S, Donnelly R (2004) Protein kinase C-beta inhibition and diabetic microangiopathy: effects on endothelial permeability responses in vitro. Eur J Pharmacol 485:141–144PubMedCrossRef

16.

Kawakami K, Futami H, Takahara J, Yamaguchi K (1996) UCN-01, 7-hydroxyl-staurosporine, inhibits kinase activity of cyclin-dependent kinases and reduces the phosphorylation of the retinoblastoma susceptibility gene product in A549 human lung cancer cell line. Biochem Biophys Res Commun 219:778–783PubMedCrossRef

17.

Kehrer DF, Mathijssen RH, Verweij J, de Bruijn P, Sparreboom A (2002) Modulation of irinotecan metabolism by ketoconazole. J Clin Oncol 20:3122–3129PubMedCrossRef

18.

Kellett GL (2001) The facilitated component of intestinal glucose absorption. J Physiol 531:585–595PubMedCrossRef

19.

Komander D, Kular GS, Bain J, Elliott M, Alessi DR, Van Aalten DM (2003) Structural basis for UCN-01 (7-hydroxystaurosporine) specificity and PDK1 (3-phosphoinositide-dependent protein kinase-1) inhibition. Biochem J 375:255–262PubMedCrossRef

20.

Kortmansky J, Sauter N, O’Reilly E (2004) Management of hyperglycemia in patients with metastatic pancreatic cancer receiving UCN-01 and fluorouracil (2004 ASCO annual meeting proceedings (post-meeting edn)). J Clin Oncol 22:14S (July 15 Suppl):2140

21.

Luiken JJ, Coort SL, Koonen DP, Bonen A, Glatz JF (2004) Signalling components involved in contraction-inducible substrate uptake into cardiac myocytes. Proc Nutr Soc 63:251–258PubMedCrossRef

22.

Mathijssen RH, Verweij J, de Bruijn P, Loos WJ, Sparreboom A (2002) Effects of St John’s wort on irinotecan metabolism. J Natl Cancer Inst 94:1247–1249PubMed

23.

Monks A, Harris ED, Vaigro-Wolff A, Hose CD, Connelly JW, Sausville EA (2000) UCN-01 enhances the in vitro toxicity of clinical agents in human tumor cell lines. Invest New Drugs 18:95–107PubMedCrossRef

24.

Oriente F, Andreozzi F, Romano C, et al (2005) Protein kinase C-alpha regulates insulin action and degradation by interacting with insulin receptor substrate-1 and 14-3-3 epsilon. J Biol Chem 280:40642–40649PubMedCrossRef

25.

Sausville EA, Lush RD, Headlee D, et al (1998) Clinical pharmacology of UCN-01: initial observations and comparison to preclinical models. Cancer Chemother Pharmacol 42(Suppl):S54–S59PubMedCrossRef

26.

Sausville EA, Arbuck SG, Messmann R, et al (2001) Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms. J Clin Oncol 19:2319–2333PubMed

27.

Seynaeve CM, Stetler-Stevenson M, Sebers S, Kaur G, Sausville EA, Worland PJ (1993) Cell cycle arrest and growth inhibition by the protein kinase antagonist UCN-01 in human breast carcinoma cells. Cancer Res 53:2081–2086PubMed

28.

Sparreboom A, Chen H, Acharya MR, et al (2004) Effects of alpha1-acid glycoprotein on the clinical pharmacokinetics of 7-hydroxystaurosporine. Clin Cancer Res 10:6840–6846PubMedCrossRef

29.

Takahashi I, Kobayashi E, Asano K, Yoshida M, Nakano H (1987) UCN-01, a selective inhibitor of protein kinase C from Streptomyces. J Antibiot (Tokyo) 40:1782–1784

30.

Takahashi I, Saitoh Y, Yoshida M, et al (1989) UCN-01 and UCN-02, new selective inhibitors of protein kinase C. II. Purification, physico-chemical properties, structural determination and biological activities. J Antibiot (Tokyo) 42:571–576

31.

Therasse P, Arbuck SG, Eisenhauer EA, et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRef

32.

Traebert M, Volkl H, Biber J, Murer H, Kaissling B (2000) Luminal and contraluminal action of 1-34 and 3-34 PTH peptides on renal type IIa Na-P(i) cotransporter. Am J Physiol Renal Physiol 278:F792–F798PubMed

33.

Tse AN, Schwartz GK (2004) Potentiation of cytotoxicity of topoisomerase i poison by concurrent and sequential treatment with the checkpoint inhibitor UCN-01 involves disparate mechanisms resulting in either p53-independent clonogenic suppression or p53-dependent mitotic catastrophe. Cancer Res 64:6635–6644PubMedCrossRef

34.

Usuda J, Saijo N, Fukuoka K, et al (2000) Molecular determinants of UCN-01-induced growth inhibition in human lung cancer cells. Int J Cancer 85:275–280PubMed

35.

van Erp NP, Baker SD, Zhao M, et al (2005) Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan. Clin Cancer Res 11:7800–7806PubMedCrossRef

36.

Yu Q, La Rose J, Zhang H, Takemura H, Kohn KW, Pommier Y (2002) UCN-01 inhibits p53 up-regulation and abrogates gamma-radiation-induced G(2)-M checkpoint independently of p53 by targeting both of the checkpoint kinases, Chk2 and Chk1. Cancer Res 62:5743–5748PubMed

Titel: Phase I and pharmacokinetic study of UCN-01 in combination with irinotecan in patients with solid tumors
verfasst von: Antonio Jimeno
Michelle A. Rudek
Thomas Purcell
Daniel A. Laheru
Wells A. Messersmith
Janet Dancey
Michael A. Carducci
Sharyn D. Baker
Manuel Hidalgo
Ross C. Donehower
Publikationsdatum: 01.03.2008
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 3/2008
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-007-0485-9

Springer Medizin

Phase I and pharmacokinetic study of UCN-01 in combination with irinotecan in patients with solid tumors