Oncologic Phase 0 Trials Incorporating Clinical Pharmacodynamics: from Concept to Patient

Abstract

The U.S. Food and Drug Administration recently issued an Exploratory Investigational New Drug (IND) guidance that provides a platform for the evaluation of targeted anticancer agents in small, early-phase human clinical trials that can be used to establish the feasibility of proof-of-principle target modulation assays, as well as the preliminary pharmacokinetics and molecular imaging potential of new anticancer molecules. The exploratory IND allows for reduced requirements for manufacturing and toxicologic assessment. Early clinical trials done in this fashion have no therapeutic intent. In this series of articles in CCR Focus, the development of this new IND mechanism, its effect on clinical trial design and clinical pharmacodynamics, the ethical implications of nontherapeutic clinical investigations, and the perspective of the pharmaceutical industry on this approach are examined.The focus of oncologic drug discovery has changed markedly over the past 5 years, based on the initial success of the first generation of molecularly targeted therapeutic agents and the dramatic increase in our knowledge of the potential signal transduction sites available for therapeutic interference. Despite this remarkable increase in the breadth of our insights into basic tumor cell biology, however, the increase in the number of new therapeutic molecules expected to follow from those insights has not fully materialized. Attention, therefore, has been focused recently on the serious challenges facing oncologic drug development. The leading cause of attrition in clinical trials of novel oncologic therapeutics is now a lack of clinical activity (rather than toxicity), and unfortunately, only 5% to 10% of the molecules that are subjects of Investigational New Drug (IND) applications progress beyond early phases of development (1). Furthermore, an increase in development timelines, as well as the lack of predictability of toxicity and effectiveness testing when traditional animal models are used, have led to increased costs, and risk aversion by a pharmaceutical industry that is undergoing major consolidation (2, 3). Oncologic drug development has also been challenged by a paucity of biomarkers that could permit regulatory approvals to advance more rapidly based on validated molecular signals that predict early clinical end points (4).It is remarkable to consider that the basic clinical trial structure for oncologic new drug development, progressing from studies of safety, to efficacy, to comparative therapeutic benefit has been largely unchanged for >35 years (5). Furthermore, despite numerous advances in the biostatistical design of phase I clinical trials over this time frame (6, 7), most early-phase clinical investigations still do not effectively take advantage of the tools of modern molecular biology to confirm the mechanism(s) of action of the agents under study (8,9).Despite, or perhaps because of, this broad range of obstacles, there is a pressing need to shorten cancer drug development timelines, to enhance molecula...

Exploratory Clinical Trials: Implementation Modes & Guidelines, Scope and Regulatory Framework

“…In general, the analytical methods used for evaluation should be relevant and should use validated criteria (in terms of repeatability, sensitivity, variability and robustness). Several authors at the National Cancer Institute [3,14,15] thus recommend the use of two different tests for evaluating a substance's mechanism of action on a target. This recommendation appears reasonable, notably when the relation PK/PD has not yet been explored or in the absence of an established relationship.…”

“…The main steps in the lengthy clinical development process (safety, tolerability, efficacy and therapeutic benefit) have hardly changed over the last 35 years, despite the availability of new tools. [3] It has been suggested that the ability to answer a certain number of critical questions concerning a molecule (mechanism of action, targets, etc.) very early in the development process would mitigate the risk of project discontinuation in Phase III.…”

Combining Targeted Therapies: Practical Issues to Consider at the Bench and Bedside

“…For example, an EGFR inhibitor plus dasatinib versus an EGFR inhibitor plus a MET inhibitor, with the endpoint being overcoming resistance to EGFR inhibitors. A similar objective could be achieved with a phase 0 trial combining targeted therapies for biomarker testing (for this, the doses of both drugs of the combination must be well known, there must be no expectation of interaction between the drugs, and the biomarker must already have been validated) [63,64].…”

Essais cliniques exploratoires : quelles modalités de mise en œuvre, recommandations de mise en œuvre, champ d’application, cadre réglementaire ?

“…D'une manière gé-nérale, les méthodes analytiques du critère de jugement doivent être pertinentes, avec utilisation de critères validés (en termes de répétabilité, sensibilité, variabilité, robustesse). Plusieurs auteurs du National Cancer Institute [3,14,15] recommandent ainsi l'utilisation de deux tests différents pour évaluer le mécanisme d'action d'un produit sur une cible. Cette recommandation semblent raisonnables, notamment lorsque la relation PK/PD n'a pas encore été recherchée ou en l'absence de relation établie.…”

“…Les grandes étapes du long processus de développement clinique (tolérance et sécurité d'emploi, efficacité, bénéfice thérapeutique) ont relativement peu changé au cours des 35 dernières années alors que de nouveaux outils sont accessibles. [3] Il a été suggéré que le fait de pouvoir répondre très précocement à un certain nombre de questions critiques concernant une molécule (mécanisme d'action, cibles. .…”