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Phase II Stopping Rules That Employ Response Rates and Early Progression

John R. Goffin, Dongsheng Tu

From the Juravinski Cancer Centre, McMaster University, Hamilton; and the National Cancer Institute of Canada Clinical Trials Group and Department of Mathematics and Statistics, Queen's University, Kingston, Ontario, Canada

Corresponding author: John R. Goffin, Juravinski Cancer Centre, 699 Concession St, Hamilton, Ontario L8V 5C2; e-mail: john.goffin{at}hrcc.on.ca

Purpose Phase II oncology trials traditionally have used response rate (RR) as the primary end point, but newer targeted agents require the consideration of alternative end points. High rates of early progressive disease (EPD) suggest inadequate drug activity and may be useful in the early stopping of trials. This study used a simulation to define a set of rules to assess a combined end point of RR and EPD.

Methods The simulation assumed a two-stage trial with a specified error and power. It randomly generated the true response rate, r, of the agent under study and its true rate of early progressive disease, epd, for each run of the simulation. Two pairs of parameters were specified: (r_nul, epd_nul) and (r_alt, epd_alt). A drug was considered uninteresting for further development if r was less than or equal to r_nul and epd was greater than or equal to epd_nul (ie, the null hypothesis) and interesting for further development if r was greater than or equal to r_alt or epd was less than or equal to epd_alt (ie, the alternate hypotheses). Thresholds for the required number of patients with responses, n_r and EPD, n_p, were generated for each set of parameters.

Results Thresholds for n_r and n_p that satisfied the specified error rates were generated. There was at least an 89% likelihood that a study would be stopped at the first stage of accrual if r and epd were uninteresting.

Conclusion The simulation was able to establish stopping rules by combining the RR and the EPD that achieved the desired error rates. High rates of early stopping suggest that this design could shorten phase II trials of inactive agents.

Supported by a grant from the Amgen Career Development Award (J.R.G.).

Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Related Correspondence

• Problems Identified With Phase II Stopping Rules That Employ Response and Early-Progression Rates
  James R. Anderson and Mark D. Krailo
  JCO 2009 27: 646-647 [Full Text]

This article has been cited by other articles:

				J. R. Anderson and M. D. Krailo Problems Identified With Phase II Stopping Rules That Employ Response and Early-Progression Rates J. Clin. Oncol., February 1, 2009; 27(4): 646 - 647. [Full Text] [PDF]

				J. R. Goffin In Reply J. Clin. Oncol., February 1, 2009; 27(4): 647 - 647. [Full Text] [PDF]