The first phase 0 clinical trial of a drug in cancer treatment, involving 13 patients with advanced cancers, showed that the drug, ABT-888, affected its target and was well tolerated. Most importantly, this trial showed that it is possible to enroll a small number of patients, treat them with a low dose of a new drug, identify whether the desired target of the drug was affected, and obtain all of this critical information relatively quickly. The study was conducted by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health, and appeared online April 13, 2009, in the Journal of Clinical Oncology.

ABT-888 inhibits an enzyme that plays a critical role in the repair of damaged DNA, and giving it along with chemotherapy drugs that damage DNA could improve the effectiveness of those drugs. Instead of being tested in a traditional phase I clinical trial, which explores both drug safety and tolerance, this drug was tested in a newer, earlier type of clinical trial, part of the pioneering NCI Experimental Therapeutics (NExT) program, called a Phase 0 trial that focuses primarily on tolerance and the ability of the drug to hit a target.

The drug, ABT-888, provided by Abbott Laboratories, Abbott Park, Ill., was administered in a single oral dose of 10, 25, or 50 milligrams. The goals of the trial were to determine the range and time course for the target enzyme inhibition in tumor samples and blood cells collected after the drug was administered and to evaluate how the body handles ABT-888. Within five months of beginning the study, the investigators obtained essential biochemical and pharmacologic data that are now guiding the design of subsequent phase I trials of ABT-888 in combination with other drugs.

"For the past several decades there has been a low success rate of new therapies for the treatment of cancer. This has necessitated reevaluation of the standard anticancer drug development paradigm, of which phase 0 trials will be a key part of a new approach," said Shivaani Kummar, M.D., NCI Center for Cancer Research (CCR), who led the trial.

The lack of preclinical models that can predict outcomes for a majority of human cancers, lengthy timelines for the clinical evaluation of new therapies, and high costs have hampered drug discovery. This ultimately led the U.S. Food and Drug Administration to develop the Exploratory Investigational New Drug (IND) Guidance in January 2006 to help identify and evaluate promising candidate drugs in patients more quickly. Because phase 0 trials conducted under an exploratory IND involve nontoxic drug doses that are administered for short periods of time to small numbers of patients, the preclinical toxicology data required to support a phase 0 trials are less than those required to support a phase I trial; thus, these first-in-human trials can be initiated earlier in the drug development process than traditional phase I studies.

The trial also employed a novel statistical evaluation scheme developed specifically for phase 0 trials, in which the end points are pharmacodynamic measurements rather than toxicity (the end point in phase I trials). Pharmacodynamics is the study of mechanisms of drug action and of the relationship between drug concentration and effectiveness.

Using the novel statistical evaluation method, the researchers demonstrated statistically significant inhibition of enzyme activity in the patient tumor samples and blood cells after a single dose of ABT-888. The statistical correlation observed between the effects of ABT-888 in blood samples versus tumor samples raises the possibility of using blood cells as tumor surrogates, potentially obviating the need for biopsies.

"The successful and expeditious conduct of this trial, and the impact it has had on the development timeline of ABT-888 at Abbott, provide an initial example of a new paradigm for early therapeutics development in oncology," said James H. Doroshow, M.D., Director of NCI's Division of Cancer Treatment and Diagnosis, who spearheads the NExT program.

More phase 0 trials will need to be completed and their long-term impact on improving drug development timelines and success rates assessed before such trials will be considered to have an established role in the anticancer drug development process.

The study was conducted by a team of scientists from NCI's Division of Cancer Treatment and Diagnosis and Center for Cancer Research, and SAIC-NCI-Frederick, Md.

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

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

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. 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).

Reference: Kummar S, Kinder R, Gutierrez ME, Rubinstein L, Parchment RE, Phillips LR, Ji J, Monks A, Low JA, Murgo AJ, Collins C, Steinberg SM, Eliopoulos H, Giranda VL, Gordon G, Helman, L, Wiltrout R, Tomaszewski JE, and Doroshow JH. Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients with Advanced Malignancies. J Clin Oncology. Online April 13, 2009

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