|New Study Heralds Shortened Timeline for Anticancer
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
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
“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
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.
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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.