Accelerated titration designs - Biometric Research Branch

More documents

Recommendations

Info

l~:r~ :f! "".," .~.; '0.1 ; ~ f "~~ ; ~.~ ; :.;;.Î '31 ! J.-r" ~~ I ~ ¡ '/11 108 ACCELERATED TITRATION DESIGNS fatal organ toxicity based on animal toxicology, paricularly if associated with a steep dose-response curve for toxicity, relatively small changes in dose/concentration may lead from minimal toxicity to severe toxicity, and thus smaller dose-escalation increments are preferable to ensure safety. Approaches to enhancing the proportion of patients in a phase I tral receiving 'therapeutic' dose levels includes not only limiting enrolment on lower dose levels but also allowing dose-escalation within individual patients. Intrapatient dose-escalation provides two advantages: it improves the lielihood of benefit from the agent for the, individual patient and it increases the experience at higher dose levels. Accelerated titration designs proposed by Simon et at. (7) allow intrapatient dose escalation if no toxicity :: grade 1 was seen in the first cycle at the assigned dose leveL. Whle it did not appreciably shorten the study duration, it did allow more patients to be treated at or near the recommended phase II dose and increased the number of cycles evaluated at the higher dose levels. Although the rationale supportng intrapatient dose-escalation is appealing, it does not seem to be widely applied. Thus, despite the appeal of escalating patients to higher doses than they were assigned initially, should safety criteria be met, some issues remain with its routine application in phase I protocols. Many phase I protocols continue to be written prohibiting intrapatient escalation since it is believed to have a minimal impact on tral effciency while bringing with it concerns about practical issues regarding the 'rules' for implementing dose-escalation and safety. Studies that have allowed intrapatient escalation withn their protocols have generally allowed dose-escalation to occur after the patient has been evaluated at the current dose level for the duration of the observation period and where the patient has had minimal/no toxicity. Less commonly used are rules that require not only that the patient has not had significant toxicity but also that the next higher dose level has been evaluated in one or more new patients - a more strngent and cumbersome criterion that may be favored to enhance safety and also to distinguish between acute versus cumulative toxic events. Although experience with intrapatient dose-escalation withn phase I studies is limited, to date its use within phase I studies using an accelerated titration design did not appear to compromise patient safety or complicate the interpretation of the study results. Of note, withn a given protocol, it is important to require a minimum number of newly recruited patients at each dose level and to base furter dose-escalation decisions upon the behavior of the drg in these individuals. 4.6 Conclusions Accelerated titration designs can dramatically reduce the number of patients accrued to a phase I tral, in comparson to the standard phase I design. They can also substantially shorten the duration of the phase I tral. With intrapatient dose-escalation and application of a dose-toxicity model, they provide much greater information than the stadard design and analysis with regard to cumulative toxicity, interpatient and ~ t... 1
-- ACCELERATED TITRATION DESIGNS 109 intrapatient varability, steepness of the dose-toxicity curve and separation of the dose-toxicity curves for the varing toxicity levels. They also provide all patients entered in the tral a maximum opportunity to be treated at a therapeutic dose. Despite this, we find that the designs are not widely used, which is likely to be due to the conservativeness of investigators. Even when they are used, they are often used with an initial dose set much more conservatively than would be done for the standard design and without use of intrapatient dose-escalation, thereby reducing their effectiveness. A recent comprehensive review of the risk-benefit rela- tionship for phase I trals conducted over the past decade reveals an overall toxicity death rate of only O.OOS (46). An accompanying editorial (47) argues that such a low toxicity death rate, in the context of treatment for an often rapidly fatal disease, suggests that phase I trals may be conducted in an overly cautious fashion. Appropriate utilization of designs such as the accelerated titration designs might increase the potential for benefit in phase I trals, with little increase in risk. References 1. S.G. Arbuck (1996) Workshop on phase I study design. Ninth NCIÆORTC New Drug Development Symposium, Amsterdam, March 12, 1996. Ann. Oncology, 7(6), 567- 73. 2. E.A. Eisenhauer, P.J. O'Dwyer, M. Christian and J.S. Humphrey (2000). Phase I clinical tral design in cancer drug development. J. Clin. Oncology, 18(3),684-92. 3. S.P. Dent and E.A Eisenhauer (1996) Phase I tral design: are new methodologies being put into practice? Ann. Oncology, 7(6), 561-6. 4. L.B. Sheiner (1990) Implications of an alternative approach to dose-response trals. J. Acquired Immune Deficiency Syndrome, 3(Suppl. 2), 20-. 5. L.B. Sheiner, S.L. Beal and N.e. Sambol (1989) Study designs for dose-ranging. Clin. Pharmacology Theory, 46(1), 63-77. 6. L.B. Sheiner, Y. Hashimoto and S.L. Beal (1991) A simulation study comparng designs for dose ranging. Statistics in Medicine, 10(3), 303-21 March. 7. R. Simon, B. Freidlin, L. Rubinstein, S.G. Arbuck, J. Collns and M.e. Chrstian (1997) Accelerated titration designs for phase I clinical trals in oncology. J. Natl Cancer Inst., 89(15),1138-47. 8. T.e. Chou and P. Talalay (1981) Generalized equations for the analysis of inhibitions of Michaelis-Menten and higher-order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors. Eur. J. Biochemistry, 115(1), 207-16. 9. T.e. Chou and P. Talalay (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drgs or enzyme inhbitors. Adv. Enzyme Regulation, 22, 27-55. 10. P.M. LoRusso, S. Prakash, A. Wozniak, L. Flaherty, M. Zalupski, A Shields, H. Sands, R. Parchment and B. Jasti (2002) Phase I clinical tral of 5-fluoropyrimidinone (5FP), an oral prodrg of 5-fluorouracil (5FU). Investigational New Drugs, 20(1), 63- 71. 11. M.P. Goetz, D. Toft, J. Reid, M. Ames, B. Stensgard, S. Safgren, AA. Adjei, J. Sloan, P. Atherton, V. Vasile, S. Salazaar, A Adjei, G. Croghan and e. Erlichman (2005) Phase I
Page 1 and 2: 4 Accelerated titration designs Jan
Page 3 and 4: - ACCELERATED TITRATION DESIGNS 93
Page 5 and 6: ACCELERATED TITRATION DESIGNS 40 35
Page 7 and 8: - ACCELERATED TITRATION DESIGNS 97
Page 9 and 10: ~ ACCELERATED TITRATION DESIGNS 1 0
Page 11 and 12: ~ ACCELERATED TITRATION DESIGNS To
Page 13 and 14: ~ Undevia CEP-2563, receptor 1 hour
Page 16 and 17: t ¡ 1 i I I r ! i l i I l 106 ACCE
Page 20 and 21: ~'Y 110 ACCELERATED TITRATION DESIG
Page 22 and 23: 112 ACCELERATED TITRATION DESIGNS 3

Accelerated titration designs - Biometric Research Branch

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?