Comparison of power between randomized discontinuation design and upfront randomization design on progression-free survival.
ABSTRACT Enrichment based on molecular characteristics has emerged as an important inclusion criterion in phase II trials of targeted anticancer agents. In this study, we evaluate a well-described method of population enrichment by tumor growth characteristics in the early development stage of targeted cytostatic agents.
For some solid tumors, such as pancreatic carcinoma, using a time-to-event end point (eg, time to disease progression) to evaluate the efficacy of a cytostatic agent in a phase II trial is more relevant than clinical response by Response Evaluation Criteria in Solid Tumors. In this setting, we compared the power of the randomized discontinuation and upfront randomization designs under two previously proposed tumor growth models for treatment effect when the end point is time-to-event.
By selecting patients with more homogeneous tumor growth characteristics, the randomized discontinuation design is more efficient than the upfront randomization design when treatment benefit is restricted to slow-growing tumors. Under a model where only a subset of patients expressing the molecular target are sensitive to the agent, the randomized discontinuation design is more powerful than the upfront randomization design when the treatment effect is small; and vice versa when the treatment effect is moderate to large.
For selected targeted agents where a bioassay to select patients expressing the specific molecular target is not available, the randomized discontinuation design is a feasible alternative patient enrichment strategy in certain disease settings and provides a reasonable platform to evaluate drugs before phase III testing.
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ABSTRACT: These studies were designed to determine whether the synthetic steroid mifepristone inhibits ovarian cancer growth in vitro and in vivo and the molecular mechanisms involved. The effect of mifepristone on ovarian cancer cell growth in vitro was studied in ovarian cancer cell lines of different genetic backgrounds (SK-OV-3, Caov-3, OV2008, and IGROV-1). In addition, the growth inhibition capacity of mifepristone on ovarian carcinoma xenografts was tested in nude mice. Mifepristone inhibited ovarian cancer cell proliferation in a dose- and time-dependent manner. The cytostatic effect of mifepristone was confirmed in a clonogenic survival assay and was not linked to loss of viability. Mifepristone blocked DNA synthesis, arrested the cell cycle at the G(1)-S transition, up-regulated cyclin-dependent kinase (cdk) inhibitors p21(cip1)and p27(kip1), down-regulated transcription factor E2F1, decreased expression of the E2F1-regulated genes cdk1 (cdc2) and cyclin A, and modestly decreased cdk2 and cyclin E levels. The abrupt arrest in cell growth induced by mifepristone correlated with reduced cdk2 activity, increased association of cdk2 with p21(cip1) and p27(kip1), increased nuclear localization of the cdk inhibitors, and reduced nuclear abundance of cdk2 and cyclin E. In vivo, mifepristone significantly delayed the growth of ovarian carcinoma xenografts in a dose-dependent manner and without apparent toxic effects for the animals. These preclinical studies show that mifepristone is effective as a single agent in vitro and in vivo, inhibiting the growth of human epithelial ovarian cancer cells. Mifepristone markedly reduces cdk2 activity likely due to increased association of cdk2 with the cdk inhibitors p21(cip1) and p27(kip1) and reduced nuclear cdk2/cyclin E complex availability. Acting as a cytostatic agent, mifepristone promises to be of translational significance in ovarian cancer therapeutics.Clinical Cancer Research 07/2007; 13(11):3370-9. · 7.74 Impact Factor
Article: Design of phase II cancer trials using a continuous endpoint of change in tumor size: application to a study of sorafenib and erlotinib in non small-cell lung cancer.[show abstract] [hide abstract]
ABSTRACT: The primary objective of phase II cancer clinical trials is to determine whether a new regimen has sufficient activity to warrant further study, with activity generally defined as tumor shrinkage. However, oncology drug development has been limited by high rates of failure (lack of efficacy) in subsequent phase III testing. This high failure rate may reflect the process by which antineoplastic agents are usually evaluated in phase II trials, i.e., via single-arm studies in which the primary efficacy measure is the proportion of patients who achieve a complete or partial response to the treatment. This design may efficiently eliminate truly ineffective therapy but may not reliably indicate whether subsequent phase III testing is warranted. We describe the design of a randomized phase II clinical trial of sorafenib in combination with erlotinib for the treatment of patients with non-small-cell lung cancer using change in tumor size, measured on a continuous scale, as the primary outcome variable. For the purpose of determining the sample size of the trial, we made assumptions as to the likely magnitude of treatment effect and the variability in tumor size changes based on data from four previous trials using these agents. The study design includes two different dosage arms and a placebo group with a total sample size of 150 patients and is powered to detect a modest reduction in the mean tumor size burden in the high-dose sorafenib arm compared with a slight increase in the placebo group. Clinical trial designs that treat change in tumor size as a continuous variable rather than categorizing the changes are feasible, and by inclusion of a prospective control group they offer advantages over conventional single-arm trials.CancerSpectrum Knowledge Environment 11/2007; 99(19):1455-61. · 14.07 Impact Factor
Article: Threats to the validity of clinical trials employing enrichment strategies for sample selection.[show abstract] [hide abstract]
ABSTRACT: Subject selection and exclusion criteria employed in typical clinical effectiveness trials of investigational new drugs have two fundamental aims: (1) to ensure that patients entering a study are truly suffering from the condition the drug is intended to treat and (2) to maximize the likelihood that the study will detect an effect of the drug if, in fact, one exists. Typical protocol selection criteria not only specify exacting procedures for establishing and documenting the diagnosis of those recruited for a study but also seek to increase, relative to the prevalence in the general population, the proportion of individuals in the sample likely to respond to pharmacological treatment. Because it is ordinarily impossible to learn prior to extensive clinical experience with a new drug which, if any, patient characteristics reliably predict a consistent treatment response, strategies for sample "enrichment" typically operate by excluding patients (for example, those with very advanced and/or complicated illness, those with serious concomitant illness, those at the extremes of age, those with very mild illness, and so forth) in whom a dependable response to treatment seems unlikely on logical and/or generic grounds. Some studies use positive strategies for sample "enrichment." In studies evaluating drugs intended to treat recurrent episodes of psychiatric illnesses, many protocols recommend selective recruitment of patients with a history of meaningful positive responses to antipsychotic treatment during prior episodes. Sample selection procedures of these kinds impose limits on the generalizability of a study's results (i.e., external validity), but the use of nonrandom patient samples is ordinarily held to have no effect on the internal validity of the results. In short, studies employing highly selected patient samples are, despite their limited external validity, regularly accepted as valid sources of evidence bearing on a drug's effectiveness. There are exceptions, however; this paper describes one in which the use of a seemingly innocuous sample enrichment maneuver proved highly damaging to the ultimate credibility of an important multicenter trial. In particular, exposure to an experimental treatment during an open qualification phase may invalidate drug-placebo comparisons made during a later randomized, blinded, controlled phase. Our review of the trial also reveals that the enrichment maneuver employed probably failed to accomplish its intended aims, selecting patients whose improvements on the outcome variable may be as reasonably ascribed to chance as to drug effect. This is all the more surprising because the method of sample enrichment employed has much in common with those long recommended in the clinical trial literature.Controlled Clinical Trials 04/1998; 19(2):178-87.