Phase 0 clinical trials: Recommendations from the task force on methodology for the development of innovative cancer therapies

Abstract

The Methodology for the Development of Innovative Cancer Therapies (MDICT) task force has been established as an expert forum to develop practical guidance on the development of innovative anticancer agents, in particular targeted agents. The task force recently addressed the utility, design, and application of Phase 0 clinical trials in anticancer drug development. It was concluded that the role of nontherapeutic Phase 0 trials is controversial for several reasons, including the lack of clinical benefit for participating patients. However, it was recognized that Phase 0 trials provide an opportunity to generate essential human pharmacokinetic and pharmacodynamic data earlier in the drug development process, which could be a major advantage in the design and decision making concerning further clinical development of an agent. Construction of a "decision chart" was highly recommended to assist investigators and sponsors in determining whether an agent is suitable for evaluation in a Phase 0 trial.

Tumor-Specific Uptake of Fluorescent Bevacizumab–IRDye800CW Microdosing in Patients with Primary Breast Cancer: A Phase I Feasibility Study

“…With an average conjugation ratio of 1:4 protein:IRDye800CW, the total molecular weight is 1.537 kDa. This means for our 4.5 mg tracer dose bevacizumabIRDye800CW, which translates into 26 nmol of bevacizumabIRDye800CW, adhering to the FDA/EMA regulations of microdosing for proteins and according to the Task Force on Methodology for the Development of Innovative Cancer Therapies (20,21). Additional information is provided in the Supplementary Materials and Methods, section "bevacizumab-IRDye800CW preparation and injection.…”

“…Successful and specific imaging has been performed in patients with melanoma, renal cell cancer, neuroendocrine tumors, and breast cancer using 111 In-and 89 Zr-radiolabeled bevacizumab (11,(15)(16)(17)(18)(19). In these studies, a systemic total microdose of 4.5 mg labeled bevacizumab, that is, 30 nmol adhering to the definition of microdosing for proteins according to FDA/EMEA guidelines (20) and as described separately for proteins by Kummar and colleagues (21), was used, which is subtherapeutic compared with the therapeutic dose of 5 to 15 mg/kg bodyweight (22)(23)(24). In a recent PET imaging study with 89 Zr-bevacizumab in 23 patients with primary breast cancer, 25 of 26 tumors (96%) were visualized by PET 4 days after 89 Zr-bevacizumab tracer injection with tumor-to-normal tissue ratios of 1.4:10.3 (19).…”

A Review on: Phase ‘0’ Clinical Trials or Exploratory Investigational New Drug

“…James 12 , Anthony 10 , Murgo et al 21 , Takimoto 22 and Kummar et al 23 have explained the differences of phase trials described in Table 1 for oncology study. Anthony 10 , Lorusso 16 , and Lappin and Garner 24 had discussed the goals of phase '0' clinical trials as fallows.…”

Drug Experimentation in Healthy Volunteers

“…In this respect, phase 0 trials can provide critical human PK/PD data to support the design of future studies (Kummar et al, 2009). Healthy volunteers, as indicated by international guidelines (EMEA, 2004), can be enrolled to perform phase 0 and early phase I trials to study new anticancer drugs, evaluating specific surrogate biomarkers of antitumor activity and preliminary pharmacokinetics.…”