Making the Investigational Oncology Pipeline More Efficient and Effective: Are We Headed in the Right Direction?

Abstract

Advances in our knowledge of the molecular mechanisms involved in cancer biology have contributed to an increase in novel target-specific oncology therapeutics. Unfortunately, clinical development of new drugs is an expensive and slow process, and the patient and financial resources needed to study the vast number of potential therapies are limited, requiring novel approaches to clinical trial design and patient recruitment. In addition, traditional efficacy endpoints may not be adequate to fully determine the therapeutic worth of the new classes of targeted agents. In this new era of drug development, it has become increasingly clear that new clinical trial design paradigms that examine nontraditional endpoints have become necessary to assist in prioritizing the development of the most promising agents. It is also vital that individual patient management be considered, and the subpopulations of patients most likely to derive benefit or experience harm from a new therapy be identified as early as possible. Phase I and II clinical trials allow investigators doing clinical research the opportunity to define these critical endpoints and subpopulations early on, before conducting large-scale randomized phase III clinical trials, which require an abundance of financial and patient resources. Clin Cancer Res; 16(24); 5956-62. Ó2010 AACR.Principles driving oncology clinical trial design were primarily developed in the 1970s, during the introduction of many cytotoxic anticancer therapies. In the current era of molecularly targeted therapy, these traditional clinical trial design principles and trial endpoints are being reconsidered. At present, the most widely accepted metric for therapeutic utility remains improvement in the length of survival. However, alternate endpoints, such as time to disease progression, durable overall response rate, or improvement in disease-related symptoms, may be more appropriate endpoints for different classes of agents being evaluated. A major goal in clinical cancer drug development is to obtain regulatory approval for an efficacious agent and, to reach this goal, developers must often evaluate a novel therapy through a pivotal randomized control trial (RCT). As the proliferation of molecularly targeted agents has increased, it is important to refine the critical steps that lead to RCT design and execution. This article proposes innovative approaches to earlier phase I and II trials, which may ultimately yield change in how we design, conduct, and inform RCTs as we advance into the next generation of oncology clinical trials. Phase I Trials: Novel Designs and Impact on Patient Outcome(s)Currently, nearly 900 novel cancer agents are undergoing investigation in more than 6,000 clinical trials (1-3). Owing to this large number of investigational agents, a critical lack of financial and patient resources significantly reduces the chances for adequate development of many of these agents. As a result, clinical drug developers require continual innovation in their approaches to best dete...

Agents antiangiogéniques et association de TMC: attention danger

“…La plupart des TMC en développement sont des agents ciblant une ou plusieurs altérations moléculaires qui sont supposées être impliquées dans l'oncogenèse. Une voie de recherche possible pour essayer d'obtenir une réponse rapide à la question de l'efficacité du médica-ment consiste à enrichir la population en patients présentant une anomalie moléculaire spécifique : ainsi les patients ne sont traités qu'en connaissance de la biologie de leur propre cancer, et le but est d'essayer de trouver le bon médicament à un cancer donné [7]. Plusieurs équipes dans le monde, et en particulier en France, sont en train de développer des approches de ce type, et d'essayer de montrer que les phases I/II précoces de dévelop-pement puissent devenir de vérita-bles alternatives thérapeutiques pour des patients ayant un cancer avancé.…”

Clinical trials in the age of personalized medicine

“…While promising results for the compound emerged from phase I and phase II studies, the drug failed to show any advantage in a pivotal phase III trial with patients with refractory advanced non-small cell lung cancer. Subsequent analysis suggested that the drug might have had some success with a selected sub-population [49,50]. In light of this and other well-known phase III failures, the Task Force recommended that investigators consider stratified, adaptive designs that allow phase II trials to select a population in the course of a trial and continue study of the subpopulation in order to provide more precise indications for phase III trials [51,52].…”

Value and Cancer Care: Toward an Equitable Future

“…This consensus will not be achieved quickly or easily because these are not no-benefit treatments. Many of the articles in this issue of CCR Focus explore aspects of this problem in great depth (26)(27)(28)(29)(30). Even after health reform, our very heterogeneous and fragmented system will make it difficult to implement such limitations fairly and equitably.…”