Abstract
The principles of phase I studies in oncology have been extensively outlined in Chap. 5. The systemic treatment of cancer has long been based on cytotoxic drugs, and, more recently, it has been extended with the use of drugs aiming at a molecular aberration in the cancer cell. The principles of cytotoxic drug treatment itself are outlined elsewhere. But as a consequence of these principles, cytotoxic drugs are commonly given in so-called cycles. This, in turn, is due to the fact that the effect of cytotoxic drugs is limited not only to the cancer cell itself, but also affects normal cells in the body. The cytotoxic drug effect mainly has a differential between these normal cells and the cancer cell in the capability of these cells to recover. This means that we have to allow the normal cells to first recover from the drug effects, before a new dose can be given. This recovery phase thus dictates intervals between drug administrations.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- PD:
-
Pharmacodynamics
- PK:
-
Pharmacokinetics
References
Arbuck SG: Workshop on phase I study design. Ninth NCI/EORTC New Drug Development Symposium, Amsterdam, March 12, 1996. Ann Oncol 1996; 7: 567–573.
Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J: Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1999; 17: 2341–2354.
Anderson H, Lund B, Bach F, Thatcher N, Walling J, Hansen HH: Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 1994; 12: 1821–1826.
Burstein HJ, Manola J, Younger J, Parker LM, Bunnell CA, Scheib R, Matulonis UA, Garber JE, Clarke KD, Shulman LN, Winer E: Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 2000; 18: 1212–1219.
Gore M, ten Bokkel Huinink W, Carmichael J, Gordon A, Davidson N, Coleman R, Spaczynski M, Héron JF, Bolis G, Malmström H, Malfetano J, Scarabelli C, Vennin P, Ross G, Fields SZ: Clinical evidence for topotecan-paclitaxel non-cross-resistance in ovarian cancer. J Clin Oncol 2001; 19: 1893–1900.
Verweij J: “No risk, no fun”: challenges for the oncology phase I clinical trial time-performance. Eur J Cancer 2008; 44(17): 2600–2607.
LoRusso PM, Rudin CM, Borad MJ, Vernillet L, Darbonne WC, Mackey H, DiMartino JF, de Sauvage F, Low JA, Von Hoff DD: A first-in-human, first-in-class, phase (ph) I study of systemic Hedgehog (Hh) pathway antagonist, GDC-0449, in patients (pts) with advanced solid tumors. J Clin Oncol 2008; 26(suppl): 3516.
Soepenberg O, Sparreboom A, de Jonge MJ, Planting AS, de Heus G, Loos WJ, Hartman CM, Bowden C, Verweij J: Real-time pharmacokinetics guiding clinical decisions: phase I study of a weekly schedule of liposome encapsulated paclitaxel in patients with solid tumours. Eur J Cancer 2004; 40: 681–688.
El-Maraghi LH, Eisenhauer EA: Review of phase II trial designs used in studies of molecular targeted agents: outcomes and predictors of success in phase III. J Clin Oncol 2008; 26: 1346–1354.
Goulart BH, Clark JW, Pien HH, Roberts TG, Finkelstein SN, Chabner BA: Trends in the use and role of biomarkers phase I oncology trials. Clin Cancer Res 2007; 13: 6719–6726.
Rowinsky EK, Kaufmann SH, Baker SD, Grochow LB, Chen TL, Peereboom D, Bowling MK, Sartorius SE, Ettinger DS, Forastiere AA, Donehower RC: Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence. J Clin Oncol 1996; 14: 3074–3084.
De Jonge MJA, Sparreboom A, Gelderblom H, Planting AS, van der Burg MEL, Loos WJ, Brouwer E, van Beurden V, Mantel MA, Doyle E, Hearn S, Verweij J: Phase I and pharmacological study of oral topotecan and intravenous cisplatin: sequence dependent hematologic side effects. J Clin Oncol 2000; 18: 2104–2115.
De Jonge MJA, Sparrreboom A, Planting AS, van der Burg MEL, de Boer-Dennert MM, ter Steeg J, Jacques C, Verweij J: Phase I study of 3-weekly schedule of irinotecan combined with cisplatin in patients with advanced solid tumors. J Clin Oncol 2000; 18: 187–194.
Smorenburg CH, Sparreboom A, Bontenbal M, Verweij J: Combination chemotherapy of taxanes and antimetabolites: its use and limitations. Eur J Cancer 2001; 37(18): 2310–2323.
Van Cutsum E, Findlay M, Osterwalder B, Kocha W, Dalley D, Pazdur R, Cassidy J, Dirix L, Twelves C, Allman D, Seitz J-F, Scholmerich J, Burger HU, Verweij J: Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study. J Clin Oncol 2000; 18(6): 1337–1345.
Engels FK, Verweij J: Docetaxel administration schedule: from fever to tears? A review of randomised studies. Eur J Cancer 2005; 41: 1117–1126.
Therasse P, Arbuck SG, Eisenhauer EA et al.: New guidelines to evaluate the response to treatment in solid tumours. J Natl Cancer Inst 2000; 92: 205–216.
Therasse P, Eisenhauer EA, Verweij J: RECIST revisited: a review of validation studies on tumour assessment. Eur J Cancer 2006; 42: 1031–1039.
Byrne MJ, Nowak AK: Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol 2004; 15: 257–260.
MacDonald DR, Cascino TL, Schold SC, Cairncross JG: Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990; 8: 1277–1280.
Scher HI, Michael JM, Kelly WK et al.: Prostate cancer clinical trails endpoints: “RECIST”ïng a step backwards. Clin Cancer Res 2005; 11: 5223–5232.
Bajetta E, Di Leo A, Zampino MG et al.: Multicenter randomized trial of dacarbazine alone or in combination with two different doses and schedules of interferon alfa-2a in the treatment of advanced melanoma. J Clin Oncol 1994; 12: 806–811.
Mick R, Crowley J, Caroll R et al.: Phase II clinical trial design for noncytotoxic anticancer agents for which time to disease progression is the primary endpoint. Control Clin Trials 2000; 21: 343–359.
Korn E, Arbuck S, Pluda J et al.: Clinical trial designs for cytostatic agents: are new approaches needed? J Clin Oncol 2001; 19: 265–272.
Van Glabbeke M, Verweij J, Judson I et al.: Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas. Eur J Cancer 2002; 38: 543–549.
Van Oosterom AT: Progression arrest. In: Pinedo H, Verweij J (eds) Clinical Management of Soft Tissue Sarcomas. Martinus Nijhoff Publishers, Boston, MA, 1986; pp. 131–138.
Zee B, Melnychuk D, Dancey J et al.: Multinomial phase II cancer trials incorporating response and early progression. J Bioph Stat 1999; 9: 351–363.
Dent S, Zee B, Dancey J et al.: Application of a new multinomial phase II stopping rule using response and early progression. J Clin Oncol 2001; 19: 785–791.
The Protocol Review Committee, the Data Center, the Research and Treatment Division, the New Drug Development Office: European Organization for Research and Treatment of Cancer: phase II trials in the EORTC. Eur J Cancer 1997; 33: 1361–1363.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
de Jonge, M.J.A., Verweij, J. (2011). Early Clinical Trials with Cytotoxic Agents. In: Garrett-Mayer, E. (eds) Principles of Anticancer Drug Development. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7358-0_13
Download citation
DOI: https://doi.org/10.1007/978-1-4419-7358-0_13
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-7357-3
Online ISBN: 978-1-4419-7358-0
eBook Packages: MedicineMedicine (R0)