Comparison of power between randomized discontinuation design and upfront randomization design on progression-free survival.

Abstract

PURPOSE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Pingfu Fu, Afshin Dowlati, Mark Schluchter
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 27 Issue 25 Pg. 4135-41 (Sep 01 2009) ISSN: 1527-7755 [Electronic] United States
• PMID: 19636018 (Publication Type: Comparative Study, Evaluation Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents

Topics

• Antineoplastic Agents (therapeutic use)
• Cell Proliferation (drug effects)
• Clinical Trials, Phase II as Topic
• Disease-Free Survival
• Feasibility Studies
• Humans
• Models, Biological
• Neoplasms (drug therapy, pathology)
• Randomized Controlled Trials as Topic
• Research Design
• Time Factors
• Treatment Outcome