A new compound, called ABT-888, has passed the first stage of clinical examination using a new model for drug development that promises to shorten — by up to six to 12 months — the timeline for taking anticancer drugs from the laboratory to the clinic, according to a team of researchers at the National Cancer Institute (NCI), part of the National Institutes of Health. This result (abstract #3518) was presented June 3, 2007, at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Ill.

Instead of being tested in the traditional phase I clinical trial, which explores drug safety and tolerance, ABT-888 was tested in a new type of study called an early Phase I trial (also sometimes called a Phase 0 trial). Conducted as part of the pioneering NCI Experimental Therapeutics (NExT) program, this early phase I trial shows that using an approach that adds a focus on the mechanism of action (the specific target in a cell that the drug attacks) can reduce the number of patients required for an early clinical study, and the time necessary to gather critical information for development of the drug.

“With this trial, NCI is doing much more than studying a new intervention; it is blazing a trail for early phase trials, which will hasten our progress across cancer research and drug discovery,” said NCI Director John E. Niederhuber, M.D. “Conducting the ABT-888 trial also required close collaboration and consultation with the FDA, in order to negotiate the prototype for a new regulatory process.”

“The time from initiation of the trial to the analyses of the data that provided proof-of-concept was less than six months,” said Shivaani Kummar, M.D., NCI Center for Cancer Research (CCR), who led the trial.

The study was conducted by a team of scientists from NCI-Frederick, Md., CCR, and the Division of Cancer Treatment and Diagnosis (DCTD). “Early Phase I trials allow new cancer therapies to be evaluated in clinical trials sooner than what is done currently,” Kummar said. The first six patients enrolled in the trial had a variety of cancers and provided the information needed to signal that ABT-888 should proceed to a more comprehensive series of NCI-sponsored Phase I trials, which are expected to start in the next few months.

ABT-888 inhibits an enzyme critical for repairing damage to DNA. In the absence of an active enzyme, tumor cells are more sensitive to the effects of several cancer drugs. Abbott Laboratories, Abbott Park, Ill., developed ABT-888 as part of a clinical trial agreement with NCI to study whether performing an early phase I trial would hasten the overall drug development plan for this agent.

A unique aspect of this trial was the development of a rigorous assay to measure a biomarker affected by ABT-888. The study showed that the compound inhibited its targeted enzyme in tumor cells as well as in circulating white blood cells. This latter finding suggests that white blood cells, which are easily accessible, can be used in subsequent trials as an easy way to measure whether the agent is altering its presumed target.

This early phase I trial was a proof-of-principle study aimed to determine whether this new approach to early drug testing could work and that fits in well with the goals of NExT. “The NExT program requires research resources that are not readily available at most medical centers engaged in anticancer drug development,” said James H. Doroshow, M.D., DCTD director, who spearheads the program. “It requires the scientific and clinical infrastructure of the NCI to do this research.”

“The NExT program has grown out of the reality that the number of new anticancer agents reaching human clinical trials has been modest,” said Doroshow. Even when compounds do proceed to clinical testing, they often fail because of unexpected toxicities or are not effective. NExT not only allows early phase I trials to be conducted in humans, it brings together the teams of scientists necessary to develop and perform assays that can measure the biological effects of potential new anticancer agents. The assays provide a tool for the systematic removal of investigational agents from NCI’s drug development pipeline that do not show expected biological effects and inform and expedite decisions about further clinical development.

“The goal of the NExT program is to shave up to one year off the typical 10- to 12-year drug-development cycle,” said Doroshow.

The underlying rationale for the NExT program is a guidance issued in 2006 by the U.S. Food and Drug Administration (http://www.cancer.gov/newscenter/pressreleases/FDAGuidance). The guidance allows human trials to proceed before certain time-consuming and expensive drug development steps, such as extensive preclinical toxicology and bulk production of an agent, occur. Limited toxicity studies are allowed because only restricted doses or shortened courses of drug therapy are permitted in early phase I trials. If an agent succeeds in an early Phase I trial, more comprehensive toxicological studies are performed before the agent undergoes more extensive clinical testing. Early phase I data are anticipated to be useful in improving the efficiency and success of subsequent clinical trials, thereby shortening the overall drug development timeline.

For more information about cancer, please visit the NCI Web site at http://www.cancer.gov, or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

For a Q&A on phase 0 and NExT, go to http://www.cancer.gov/newscenter/pressreleases/PhaseZeroNExT.

For more information on NExT, go to http://dctd.cancer.gov/DirectorsMessage/next.htm.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.