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When, Why, and How

By Allison Proffitt
Dec. 17, 2007 | Phase 0 is "not just another clinical trial," says James Doroshow, director of cancer treatment and diagnosis, National Cancer Institute. "It's really the end of pre-clinical" research where the "intent is biomarker development."

Speaking at a recent American Association of Cancer Research conference in Singapore, Doroshow discussed the challenges and promise of Phase 0 trials culled from the "first Phase 0 oncology trial." His goals were to determine a non-toxic dose range at which a candidate inhibited PARP (poly (ADP-ribose) polymerase) in tumors and in peripheral blood cells.

"We knew in three to four weeks that we had results," he said. The Phase 0 study established that the drug inhibited the target at clinically achievable concentrations. Researchers were able to perform real-time pharmacokinetic (PK) and dynamic (PD) analyses, netting results within 72 hours, and develop standard procedures for processing tissue samples and gathering PK/PD data.
"Why would you not do it?" Doroshow asked rhetorically. He concedes that Phase 0 studies require "significant investments of resources... a multidisciplinary team is crucial." But Doroshow considers the expenditure worthwhile. Phase 0 "helps point the way to data needed for phase 1." It saves time and offers toxicity data early in the process. As more money flows into biomarker assays, researchers will be designing "smaller but smarter trials," he said.

There are challenges, both statistical and ethical. Barriers to enrollment include studies with no therapeutic intent, and sometimes the need for pre- and post- study tissue biopsies. But these drawbacks can be overcome with a well-run informed consent process and a clearly expressed rationale. Statistically, limited sample sizes can cause problems, but Doroshow believes those can be managed by obtaining a measure of intra-patient variability for the pre-treatment endpoint value.

Phase 0 trials are not always appropriate, but Doroshow believes they should be considered for a targeted drug with a wide therapeutic index under development for chronic or multi-dose oral administration. He cautions that Phase 0 will not generally be appropriate for cytotoxic agents with very narrow therapeutic indices delivered intravenously.

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