Translation of Innovative Designs Into Phase I Trials

Abstract

A consequence of using less effective designs is that more patients are treated with doses outside the therapeutic window. Simulation studies have shown that up-and-down designs treated only 35% of patients at optimal dose levels versus 55% for Bayesian adaptive designs. This implies needless loss of treatment efficacy and, possibly, lives. We suggest that regulatory agencies (eg, US Food and Drug Administration) should proactively encourage the adoption of statistical designs that would allow more patients to be treated at near-optimal doses while controlling for excessive toxicity.

Threshold Effect of Free Radical Quenching in a Progressive Breast Cancer Cell Line Model

“…The practice of metronomic chemotherapy which entails chronic low dose chemotherapy exposure has proven to be a valuable tool in the fight against cancer and has quickly moved from clinical trials to a mainstream therapeutic option. To date several articles have been published using various chemotherapeutic agents for several types of cancer with encouraging results in both pediatric and adult settings [25], [26], [27], [28]. Furthermore, our results support the idea of administering low doses in equally spaced administration cycles, over the traditional high dose protocols with imposition of rest periods due to overt toxicity.…”

“…The traditional "maximum tolerated dose" has been accompanied with overt toxicity demanding rest periods between cycles of therapy. This practice has resulted in re-growth of tumor cells and selection of clones resistant to chemotherapy [25], [26], [27], [28], [29]. To avoid this pitfall in conventional chemotherapeutic regimens, a new modality of drug administration called "metronomic chemotherapy" has been suggested [30].…”

Clinical Trial Phases

“…The starting dose is based on extrapolation from animal toxicological data. Increasing dose levels have been fixed in advance and usually follow a modified Fibonacci sequence in which the dosing increments become smaller as the dose increases [30]. If none of the patients experience a dose-limiting toxicity, 3 more patients will be treated at the next higher dose.…”

Novel Oncology Drug Development Strategies in the Era of Personalised Medicine

“…In a standard dose escalation phase I trial, cohorts of three to six patients are treated at predefined dose levels, dose-limiting toxicity (DLT) is observed and the maximum tolerated dose (MTD) is defined as the dose level where >33% of patients treated have experienced a DLT. Dose levels are commonly defined using modification of the original Fibonacci design (increasing dose by fixed increments of 100%, 67%, 50%, 40% followed by 33% for all subsequent levels) but slow attainment of the MTD and exposure of significant numbers of patients to low doses have been criticisms of this approach (Rogatko et al, 2007). An accelerated trial design (Simon et al, 1997) is now a widely accepted alternative to the Fibonacci dose-definition model and many trials now allow individual patients to be doseescalated within a study if safe to do so, aiming to minimise those being exposed to ineffective doses.…”