Dose escalation methods in phase I cancer clinical trials

Christophe Le Tourneau, J Jack Lee, Lillian L Siu, Christophe Le Tourneau, J Jack Lee, Lillian L Siu

Abstract

Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Here we review dose escalation methods for phase I trials, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. However, with the emergence of molecularly targeted anticancer agents, potential alternative endpoints to delineate optimal biological activity, such as plasma drug concentration and target inhibition in tumor or surrogate tissues, have been proposed along with new trial designs. We also describe specific methods for drug combinations as well as methods that use a time-to-event endpoint or both toxicity and efficacy as endpoints. Finally, we present the advantages and drawbacks of the various dose escalation methods and discuss specific applications of the methods in developmental oncotherapeutics.

Figures

Figure 1
Figure 1
Typical dose–toxicity and dose–efficacy curves for cytotoxic agents. This example illustrates that at dose x, the probability of efficacy is 30% and the probability of toxicity is 10%; hence, the therapeutic index of the drug at dose x is 10% divided by 30% = 1/3.
Figure 2
Figure 2
Graphical depiction of dose escalation methods for phase I cancer clinical trials. Each box represents a cohort comprising the indicated number of patients treated at a given dose level. A) Simple up-and-down design. B) Traditional 3+3 design. C) Accelerated titration design. Dashed arrows represent intrapatient dose escalation. D) Pharmacologically guided dose escalation. E) Modified continual reassessment method. F) Escalation with overdose control. “Overdosing or excessive overdosing” refers to doses that exceed the MTD. DLT = dose-limiting toxicity; SD = starting dose; RD = recommended dose; DL = dose level; AUC = area under the curve for drug concentration as a function of time; p(DLT at next DL) = probability of dose-limiting toxicity at the next dose level.
Figure 3
Figure 3
Strategies for dose escalation in phase I trials testing combinations of two drugs. White bars represent drug 1, gray bars represent drug 2. A) Alternate dose escalation. B) Simultaneous dose escalation. C) Single-agent dose escalation. D) Compromised dose escalation with only one of the two agents achieving full dose escalation. DL = dose level.
Figure 4
Figure 4
Dose escalations methods used in phase I cancer clinical trials published between January 1, 2007, and December 1, 2008. Asterisk indicates that model fitting was not performed in any of the seven ATD trials to establish the recommended dose for phase II trials. ATD = accelerated titration design; mCRM = modified continual reassessment method; TITE-CRM = time-to-event continual reassessment method.

References

    1. Korn EL, Arbuck SG, Pluda JM, Simon R, Kaplan RS, Christian MC. Clinical trial designs for cytostatic agents: are new approaches needed? J Clin Oncol. 2001;19(1):265–272.
    1. Parulekar WR, Eisenhauer EA. Phase I trial design for solid tumor studies of targeted, non-cytotoxic agents: theory and practice. J Natl Cancer Inst. 2004;96(13):990–997.
    1. Sleijfer S, Wiemer E. Dose selection in phase I studies: why we should always go for the top. J Clin Oncol. 2008;26(10):1576–1578.
    1. Cannistra SA. Challenges and pitfalls of combining targeted agents in phase I studies. J Clin Oncol. 2008;26(22):3665–3667.
    1. Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A. Translation of innovative designs into phase I trials. J Clin Oncol. 2007;25(31):4982–4986.
    1. Dixon WJ, Mood AM. A method for obtaining and analyzing sensitivity data. J Amer Stat Assoc. 1948;43:109–126.
    1. Storer BE. Design and analysis of phase I clinical trials. Biometrics. 1989;45(3):925–937.
    1. Derman C. Nonparametric up and down experimentation. Ann Math Stat. 1957;28:795–798.
    1. Durham SD, Flournoy N, Rosenberger WF. A random walk rule for phase I clinical trials. Biometrics. 1997;53(2):745–760.
    1. Storer BE. An evaluation of phase I clinical trial designs in the continuous dose-response setting. Stat Med. 2001;20:2399–2408.
    1. Tokuda Y, Watanabe T, Omuro Y, et al. Dose escalation and pharmacokinetic study of a humanized anti-HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. Br J Cancer. 1999;81(8):1419–1425.
    1. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031–1037.
    1. Ranson M, Hammond LA, Ferry D, et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol. 2002;20(9):2240–2250.
    1. Hidalgo M, Siu LL, Nemunaitis J, et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol. 2001;19(13):3267–3279.
    1. Baselga J, Pfister D, Cooper MR, et al. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol. 2000;18(4):904–914.
    1. Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001;19(3):843–850.
    1. Strumberg D, Richly H, Hilger RA, et al. Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol. 2005;23(5):965–972.
    1. Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol. 2006;24(1):25–35.
    1. Weiner LM, Belldegrun AS, Crawford J, et al. Dose and schedule study of panitumumab monotherapy in patients with advanced solid malignancies. Clin Cancer Res. 2008;14(2):502–508.
    1. Pandite L, Burris HA, Jones S, et al. A safety, tolerability, and pharmacokinetic (PK) study of GW572016 in patients with solid tumors. J Clin Oncol. 2004;22:14s, 238. Abstract 3179.
    1. Raymond E, Alexandre J, Faivre S, et al. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol. 2004;22(12):2336–2347.
    1. Wiernik PH, Schwartz EL, Strauman JJ, Dutcher JP, Lipton RB, Paietta E. Phase I clinical and pharmacokinetic study of taxol. Cancer Res. 1987;47(9):2486–2493.
    1. Mathé G, Reizenstein P. Phase I pharmacologic study of a new Vinca alkaloid: navelbine. Cancer Lett. 1985;27(2):285–293.
    1. Pazdur R, Newman RA, Newman BM, et al. Phase I trial of Taxotere: five-day schedule. J Natl Cancer Inst. 1992;84(23):1781–1788.
    1. Abbruzzese JL, Grunewald R, Weeks EA, et al. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol. 1991;9(3):491–498.
    1. Rowinsky EK, Grochow LB, Hendricks CB, et al. Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol. 1992;10(4):647–656.
    1. Negoro S, Fukuoka M, Masuda N, et al. Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer. J Natl Cancer Inst. 1991;83(16):1164–1168.
    1. Mackean M, Planting A, Twelves C, et al. Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer. J Clin Oncol. 1998;16(9):2977–2985.
    1. Hong RL, Tseng YL. Phase I and pharmacokinetic study of a stable, polyethylene-glycolated liposomal doxorubicin in patients with solid tumors: the relation between pharmacokinetic property and toxicity. Cancer. 2001;91(9):1826–1833.
    1. Newlands ES, Blackledge GR, Slack JA, et al. Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856) Br J Cancer. 1992;65(2):287–291.
    1. Mathé G, Kidani Y, Triana K, et al. A phase I trial of trans-1-diaminocyclohexane oxalato-platinum (l-OHP) Biomed Pharmacother. 1986;40(10):372–376.
    1. McDonald AC, Vasey PA, Adams L, et al. A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate. Clin Cancer Res. 1998;4(3):605–610.
    1. Ryan DP, Supko JG, Eder JP, et al. Phase I and pharmacokinetic study of ecteinascidin 743 administered as a 72-hour continuous intravenous infusion in patients with solid malignancies. Clin Cancer Res. 2001;7(2):231–242.
    1. Ibrahim NK, Desai N, Legha S, et al. Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res. 2002;8(5):1038–1044.
    1. Abraham J, Agrawal M, Bakke S, et al. Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days. J Clin Oncol. 2003;21(9):1866–1873.
    1. Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC. Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst. 1997;89(15):1138–1147.
    1. Collins JM, Grieshaber CK, Chabner BA. Pharmacologically guided phase I clinical trials based upon preclinical drug development. J Natl Cancer Inst. 1990;82(16):1321–1326.
    1. Graham MA, Workman P. The impact of pharmacokinetically guided dose escalation strategies in phase I clinical trials: critical evaluation and recommendations for future studies. Ann Oncol. 1992;3(5):339–347.
    1. Leung DH, Wang Y. Isotonic designs for phase I trials. Control Clin Trials. 2001;22(2):126–138.
    1. Ivanova A, Montazer-Haghighi A, Mohanty SG, Durham SD. Improved up-and-down designs for phase I trials. Stat Med. 2003;22(1):69–82.
    1. Stylianou M, Follmann DA. The accelerated biased coin up-and-down design in phase I trials. J Biopharm Stat. 2004;14(1):249–260.
    1. Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC. Shortening the timeline of pediatric phase I trials: the rolling six design. J Clin Oncol. 2008;26(2):190–195.
    1. Ji Y, Li Y, Bekele BN. Dose-finding in phase I clinical trials based on toxicity probability intervals. Clin Trials. 2007;4(3):235–244.
    1. O’Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics. 1990;46(1):33–48.
    1. Korn EL, Midthune D, Chen TT, Rubinstein LV, Christian MC, Simon RM. A comparison of two phase I trial designs. Stat Med. 1994;13(18):1799–1806.
    1. O’Quigley J, Chevret S. Methods for dose finding studies in cancer clinical trials: a review and results of a Monte Carlo study. Stat Med. 1991;10(11):1647–1664.
    1. Goodman SN, Zahurak ML, Piantadosi S. Some practical improvements in the continual reassessment method for phase I studies. Stat Med. 1995;14(11):1149–1161.
    1. Moller S. An extension of the continual reassessment methods using a preliminary up-and-down design in a dose finding study in cancer patients, in order to investigate a greater range of doses. Stat Med. 1995;14(9-10):911–922.
    1. Faries D. Practical modifications of the continual reassessment method for phase I cancer clinical trials. J Biopharm Stat. 1994;4(2):147–164.
    1. Piantadosi S, Fisher JD, Grossman S. Practical implementation of a modified continual reassessment method for dose-finding trials. Cancer Chemother Pharmacol. 1998;41(6):429–436.
    1. Heyd JM, Carlin BP. Adaptive design improvements in the continual reassessment method for phase I studies. Stat Med. 1999;18(11):1307–1321.
    1. Siu LL, Rowinsky EK, Hammond LA, et al. A phase I and pharmacokinetic study of SAM486A, a novel polyamine biosynthesis inhibitor, administered on a daily-times-five every-three-week schedule in patients with advanced solid malignancies. Clin Cancer Res. 2002;8(7):2157–2166.
    1. Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with overdose control. Stat Med. 1998;17(10):1103–1120.
    1. Rogatko A, Babb JS, Tighiouart M, Khuri FR, Hudes G. New paradigm in dose-finding trials: patient-specific dosing and beyond phase I. Clin Cancer Res. 2005;11(15):5342–5346.
    1. Chu PL, Lin Y, Shih WJ, Unifying CRM. EWOC designs for phase I cancer clinical trials. J Stat Plan Inference. 2009;139:1146–1163.
    1. Cheung YK, Chappell R. Sequential designs for phase I clinical trials with late-onset toxicities. Biometrics. 2000;56(4):1177–1182.
    1. Normolle D, Lawrence T. Designing dose-escalation trials with late-onset toxicities using the time-to-event continual reassessment method. J Clin Oncol. 2006;24(27):4426–4433.
    1. Muler JH, McGinn CJ, Normolle D, et al. Phase I trial using a time-to-event continual reassessment strategy for dose escalation of cisplatin combined with gemcitabine and radiation therapy in pancreatic cancer. J Clin Oncol. 2004;22(2):238–243.
    1. Desai SP, Ben-Josef E, Normolle DP, et al. Phase I study of oxaliplatin, full-dose gemcitabine, and concurrent radiation therapy in pancreatic cancer. J Clin Oncol. 2007;25(29):4587–4592.
    1. Bekele BN, Ji Y, Shen Y, Thall PF. Monitoring late-onset toxicities in phase I trials using predicted risks. Biostatistics. 2008;9(3):442–457.
    1. Thall PF, Cook JD. Dose-finding based on efficacy-toxicity trade-offs. Biometrics. 2004;60(3):684–693.
    1. Zhang W, Sargent DJ, Mandrekar S. An adaptive dose-finding design incorporating both toxicity and efficacy. Stat Med. 2006;25(14):2365–2383.
    1. Yin G, Li Y, Ji Y. Bayesian dose-finding in phase I/II clinical trials using toxicity and efficacy odds ratios. Biometrics. 2006;62(3):777–787.
    1. Paoletti X, Baron B, Schöffski P, et al. Using the continual reassessment method: lessons learned from an EORTC phase I dose finding study. Eur J Cancer. 2006;42(10):1362–1368.
    1. Korn EL, Simon R. Using the tolerable-dose diagram in the design of phase I combination chemotherapy trials. J Clin Oncol. 1993;11(4):794–801.
    1. Thall PF, Millikan RE, Mueller P, Lee SJ. Dose-finding with two agents in Phase I oncology trials. Biometrics. 2003;59(3):487–496.
    1. Huang X, Biswas S, Oki Y, Issa JP, Berry DA. A parallel phase I/II clinical trial design for combination therapies. Biometrics. 2007;63(2):429–436.
    1. Yuan Y, Yin G. Sequential continual reassessment method for two-dimensional dose finding. Stat Med. 2008;27(27):5664–5678.
    1. Yin G, Yuan YA. Latent contingency table approach to dose finding for combinations of two agents [published online ahead of print August 28, 2008] Biometrics. 2008 doi: 10.1111/j.1541-0420.2008.01119.x.
    1. Von Hoff DD, Nieves JA, Vocila LK, Weitman SD, Cvitkovic E. The complete phase Ib clinical trial: a method to accelerate new agent development. J Clin Oncol. 2007;25(18s):112. Abstract 2562.
    1. Schilsky RL. Phase I and II clinical trial design for targeted agents. Targ Oncol. 2006;1(4):220–227.
    1. Friedman HS, Kokkinakis DM, Pluda J, et al. Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma. J Clin Oncol. 1998;16(11):3570–3575.
    1. Hunsberger S, Rubinstein LV, Dancey J, Korn EL. Dose escalation trial designs based on a molecularly targeted endpoint. Stat Med. 2005;24(14):2171–2181.
    1. Mandrekar SJ, Cui Y, Sargent DJ. An adaptive phase I design for identifying a biologically optimal dose for dual agent drug combinations. Stat Med. 2007;26(11):2317–2330.
    1. Polley MY, Cheung YK. Two-stage designs for dose-finding trials with a biologic endpoint using stepwise tests. Biometrics. 2008;64(1):232–241.
    1. Booth CM, Calvert AH, Giaccone G, Lobbezoo MW, Seymour LK, Eisenhauer EA. Endpoints and other considerations in phase I studies of targeted anticancer therapy: recommendations from the Task Force on Methodology for the Development of Innovative Cancer Therapies (MDICT) Eur J Cancer. 2008;44(1):19–24.
    1. Horstmann E, McCabe MS, Grochow L, et al. Risks and benefits of phase 1 oncology trials, 1991 through 2002. N Engl J Med. 2005;352:895–904.
    1. Dent SF, Eisenhauer EA. Phase I trial design: are new methodologies being put into practice? Ann Oncol. 1996;7(6):561–566.
    1. Eisenhauer EA, O’Dwyer PJ, Christian M, Humphrey JS. Phase I clinical trial design in cancer drug development. J Clin Oncol. 2000;18(3):684–692.
    1. Eckhardt SG, Siu LL, Clark G, DeMoor C, Von Hoff DD, Rowinsky EK. The continual reassessment method (CRM) for dose escalation in phase I trials in San Antonio does not result in more rapid study completion. Proc Am Soc Clin Oncol. 1999;18:163. Abstract 627.
    1. Walling J, Zervos PH, McCarthy S, et al. Dose escalation methodology in phase I clinical trials: a comparison of the modified continual reassessment method (MCRM) and a traditional method. Experience with the multitargeted antifolate (MTA) Proc Am Soc Clin Oncol. 1997;16:209. Abstract 733.
    1. Koyfman SA, Agrawal M, Garrett-Mayer E, et al. Risks and benefits associated with novel phase 1 oncology trial designs. Cancer. 2007;110(5):1115–1124.
    1. Roberts TG, Jr, Goulart BH, Squitieri L, et al. Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. JAMA. 2004;292(17):2130–2140.
    1. Estey E, Hoth D, Simon R, Marsoni S, Leyland-Jones B, Wittes R. Therapeutic response in phase 1 trials of antineoplastic agents. Cancer Treat Rep. 1986;70(9):1105–1115.
    1. Von Hoff DD, Turner J. Response rates, duration of response, and dose response effects in phase 1 studies of antineoplastics. Invest New Drugs. 1991;9(1):115–122.
    1. Arkenau HT, Olmos D, Ang JE, de Bono J, Judson I, Kaye S. Clinical outcome and prognostic factors for patients treated within the context of a phase-1 study: the Royal Marsden Hospital experience. Br J Cancer. 2008;98(6):1029–1033.
    1. Adjei AA. What is the right dose? The elusive optimal biologic dose in phase I clinical trials. J Clin Oncol. 2006;24(25):4054–4055.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir