Key Points NCI's Experimental Therapeutics program (NExT) is designed to safely shorten the timeline for new drug development. (Question 3) An early phase evaluation, also known as a phase 0 clinical trial, utilizes pharmacodynamics, the study of how the body responds to a drug, and pharmacokinetics, the study of how a drug behaves in the body, to gather vital information about a new drug. (Question 9) Phase 0 trials expose the patient to less toxicity, and can be performed in less time, with fewer patients, than traditional phase I trials. By conducting a phase 0 trial researchers can weed out the drugs that aren't producing the desired effects much more quickly, and can avoid moving those drugs onto Phase I, II and III trials. (Question 10)

Overview

1. What is a clinical trial?
Clinical trials are research studies that test how well new medical approaches work in people. Each study answers scientific questions and tries to find better ways to prevent, screen for, diagnose, or treat a disease. People who take part in cancer clinical trials have an opportunity to contribute to knowledge and accelerate research progress against this disease. They also receive up-to-date care from experts.

2. What is the standard process for conducting clinical trials?
Clinical trials are usually conducted in a series of steps, called phases. Treatment clinical trials are always assigned a phase. Before a new treatment can be available to the general public, it usually goes through all of the phases. This process may take many years. As each phase of testing is completed, the data are analyzed. Based on this analysis, researchers determine whether an agent of approach shows enough of a benefit to continue testing at the next phase.

• Phase I trials are the first step in testing a new approach in people. In these studies, researchers evaluate what dose is safe, how a new agent should be given (by mouth, injected into a vein, or injected into the muscle), and how often. Researchers watch closely for any harmful side effects. Phase 1 trials usually enroll a small number of patients (often two dozen or less) and take place at only a few locations. The dose of the new therapy is increased a little at a time. The highest dose with an acceptable level of side effects is determined to be appropriate for further testing.
• Phase II trials study the safety and effectiveness of an agent or intervention, and evaluate how it affects the human body. Phase II studies usually focus on a particular type of cancer, and include fewer than 100 patients.
• Phase III trials compare a new agent or intervention (or new use of a standard one) with the current standard therapy. Participants are randomly assigned to the standard group or the new group, usually by computer. This method, called randomization, helps to avoid bias and ensures that human choices or other factors do not affect the study's results. In most cases, studies move into Phase III testing only after they have shown promise in Phases I and II. Phase III trials often include large numbers of people across the country.

People who participate in a clinical trial work with a research team. Team members may include doctors, nurses, social workers, dietitians, and other health professionals. The health care team provides care, monitors participants' health, and offers specific instructions about the study. The research team may continue to contact participants after the trial ends.

NExT

3. What is NExT?
NExT stands for the NCI Experimental Therapeutics program. NExT is a collaboration between two divisions within the National Cancer Institute (NCI) -- the Division of Cancer Treatment and Diagnosis (DCTD) and the Center for Cancer Research (CCR). The aim of this program is to invigorate cancer drug development at NCI by combining the strength of DCTD's extensive expertise in anticancer drug development with CCR's dynamic in-house research and access to state-of-the-art facilities at the NIH Clinical Research Center in Bethesda, Md. This collaboration will also utilize recent guidance from the U.S. Food and Drug Administration (FDA) concerning exploratory studies of investigational new drugs (http://www.cancer.gov/newscenter/pressreleases/FDAGuidance).

In this new program, certain investigational drugs will go through an evaluation process earlier than usual and thus hopefully shorten the timeline for drug development.

4. Why is NExT important?

Only five percent of applications for new oncology drugs submitted to FDA under the Investigational New Drug (IND) application are actually successful. Some of the reasons for this low approval rate include a lack of preclinical systems to predict the efficacy and toxicity of new drugs, long timelines for drug development, high costs, and the increasing complexity of clinical trials involving molecularly-targeted agents and advanced technologies. Once oncology drugs make it to the second phase of clinical testing, approximately 70 percent do not advance to the third phase, often because of a lack of efficacy. NExT is designed to help address some of these problems.

5. How are different parts of NCI working together to move NExT forward?
DCTD and CCR have established NExT to enhance preclinical and clinical drug testing, including:

• A joint pipeline of new agents is now being actively managed by DCTD and CCR
• Decisions about what agents to develop are being made by a newly established joint development committee
• Joint drug development teams will be guided by a new DCTD Project Management Office, bringing a business-focused approach to tracking the progress of agents from discovery through early-phase clinical trial.

Together, DCTD and CCR investigators will facilitate testing of targeted therapies in patients earlier in the drug development process so that informed decisions to proceed with or stop development can be made before expensive bulk drug formulation occurs. These studies will also take advantage of new advances in molecular imaging, which can help detect whether an agent being tested is reaching its target and having the desired effect.

6. Are there any new facilities associated with NExT?
DCTD has identified several resources to help achieve this goal. Chief among them is the establishment of two new laboratories by DCTD, the Pharmacodynamic Assay Development and Implementation Section in the SAIC Laboratory of Human Toxicology and Pharmacology and the National Clinical Target Validation Laboratory (NCTVL). These laboratories will develop and authenticate a variety of tests well in advance of human studies, so that they can be used in early phase trials to provide information about the safety and efficacy of the agents being tested.

DCTD has initiated a new molecular toxicology laboratory that will develop novel approaches to toxicologic prediction using normal human tissues. This is concurrent with the new commitment by DCTD and CCR to combine resources and focus on developing predictive, preclinical molecular tests. These tests will support the clinical development of agents for which NCI holds the IND.

These processes will be aided by the development of new imaging tools and agents that can track molecular events in tumors and normal tissues. Once completed, the portfolio of biomarkers and assays will be made available to all interested cancer researchers.

7. Will other institutions be involved in NExT?
As part of an intra-NCI collaboration, novel agents for high-priority targets originating from academic and other outside institutions will be eligible to take advantage of NCI's intramural, or in-house, resources.

8. Does NExT incorporate the concept of Phase 0 trials into its program?
Phase 0 trials are being conducted as part of the NExT program. Because the NExT program requires assets that are not readily available at most medical centers engaged in anticancer drug development, it takes the resources of the NCI to do this research. NExT has grown out of the stark reality that the number of new anticancer agents reaching human clinical trials has been decreasing. NExT not only allows phase 0 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.

Phase 0

9. What is a Phase 0 trial?
A Phase 0 trial is an important element of NExT. It promises to shorten -- by up to six to 12 months -- the timeline for taking anticancer drugs from the laboratory to the clinic. Specifically, a Phase 0 (Phase zero) clinical trial is designed to study the pharmacodynamic and pharmacokinetic properties of a drug. Pharmacodynamics (PD) describes the biochemical and physiological effects of a drug on the body, including how the drug is absorbed, moves throughout the body, binds to various structures, and interacts with certain molecules within target tissues. Pharmacokinetics (PK) describes the activity of a drug in the body over a long period of time. This includes the process by which drugs are absorbed, distributed in the body, localized in the tissues, and excreted. Considered together, data from pharmacodynamic and pharmacokinetic studies help researchers determine a rational dosage regimen for testing in clinical trials.

Unlike a Phase I trial, in a Phase 0 trial, a limited number of doses, and much lower doses of the drug are administered, therefore there is less risk to the participant. Also, fewer patients are needed (about 10-12 patients, on average in a Phase 0 study vs. about 20-25 patients in a Phase 1 trial). By studying PD and PK, researchers can weed out the drugs that aren't producing the desired effects much more quickly, and they can avoid moving those drugs onto Phase I, II, and III trials.

10. Why is NCI taking the lead on developing Phase 0 trials?
Despite increasing investment in new drugs, the rate of approval of such drugs by the U.S. Food and Drug Administration (FDA) to treat cancer remains low. Drugs continue to fail due to lack of efficacy or associated adverse events. Additionally, good screening tools that can accurately predict whether a new drug will be active or toxic are not available. Finally, timelines for development and testing of new drugs remain excessive. Seventy percent of oncology drugs that enter Phase II testing fail to enter Phase III, and for those that enter Phase III testing, 59 percent eventually fail. Moving from Phase I to Phase III often takes more than a decade.

11. What are the advantages of conducting a Phase 0 trial?
Due to their design, Phase 0 trials can be conducted in less time with fewer patients than Phase I trials. By conducting a Phase 0 trial on a particular drug, the process for Phase I and II trials on that drug is accelerated. Additionally, because Phase 0 trials study how the body reacts to the drug and how the drug acts in the body, if a drug is found to react poorly or to have serious side effects, the testing for that drug can be stopped sooner, without the additional expense of further trials. As a limited number of low doses of drug are given in a Phase 0 trial, the risk to the participant is minimal, if any.

Additional benefits of Phase 0 trials include the following:

• Because the toxicology testing required prior to initiating Phase 0 clinical trials is reduced due to the low doses of drug used, these trials can be initiated substantially sooner than the standard Phase 1 study.
• Phase 0 trials could facilitate rational drug selection, identify therapeutic failures early, and compress timelines for anticancer drug development.
• Phase 0 trials provide initial rationale and guiding principles for further drug development based on studies in humans (rather than xenografts, where tissues of one species are transplanted to another species).
• Phase 0 trials that focus on extensively characterizing how a drug works and whether it hits its intended target (including molecular imaging studies) in a limited number of patients could yield results that would optimally inform and expedite the subsequent development of molecularly-targeted agents.
• The results of Phase 0 trials can improve the efficiency and chance of success of subsequent trials.
• Phase 0 trials could help to evaluate the effects of an agent at the molecular level, select the lead agent from a group of compounds, and assist in optimizing the selection of the starting dose for subsequent studies. In addition, these studies can aid in developing reasonable dose escalation schedules, whereby doses of a drug are slowly increased over time in order to find the highest dose with an acceptable level of adverse side effects in the patient.
• Phase 0 trials can be conducted under the purview of an 'Exploratory Investigational New Drug (xIND) Application' as outlined in a FDA guidance issued early in January 2006. As a component of the FDA's Critical Pathway initiative, the xIND is intended to help sponsors identify and evaluate promising candidate drugs more quickly in patients.

12. What types of drugs are good candidates for a Phase 0 trial?
Phase 0 trials are useful for testing targeted therapeutic drugs with wide therapeutic indexes (i.e., have a desired effect on the target without significant side effects at certain doses), as well as drugs which require development of biomarkers which may be useful for future studies. Most conventional chemotherapy drugs currently on the market have a narrow range of efficacy, or therapeutic index (i.e., doses that are effective are close to the level of doses that cause side effects). Phase 0 trials are not appropriate for drugs that have very narrow therapeutic indexes.

13. What are some different types of Phase 0 trials?
There are several different types of phase 0 trials, ranging from those that examine new drugs to those that test new imaging agents. Some examples include:

• Testing to see if a new drug that was developed in the lab can bind to, and inhibit, its target in humans
• Provide PD and PK data prior to definitive testing in more people
• Refine what type of biomarker is most effective using tumor tissue
• Determine which of two agents is the most promising
• Using a variety of novel imaging technologies, determine the extent of drug that is distributed in the body and whether it effectively acts upon its target

14. What are the standards for a Phase 0 trial?
Some basic standards include:

• Validating targets or biomarkers in preclinical models and then in human tissue prior to initiating the clinical trial
• Reproducibility across labs and technicians of the assay used to measure the effect of the drug on the target
• Defining standard operating procedures for handling of tissues and biospecimens prior to initiating the clinical trial
• Demonstrating drug target or biomarker effect in preclinical models
• Determining the relationship between the pharmacodynamics and the pharmacokinetics.

15. Are there special considerations for Phase 0 clinical trials?
Because participants are being given very low doses of investigational new drugs, there is very little risk to the participant, but usually there is also no therapeutic benefit. Participants in Phase 0 trials will be helping to further the science and improve the speed at which new drugs are available to the general public, but will probably not "get better" as a result of their involvement in the trial. It would also be possible that, by participating in a Phase 0 trial, there may be a delay or obstruction of patient participation in another trial or therapy. This can be avoided, however, through proper planning on the part of the researchers and physicians involved in a patient's treatment. Patients may also have to provide pre-and post-treatment tissue biopsy samples.

Because of these issues, it may be harder to recruit patients to these types of trials than to conventional trials. During the informed consent process, researchers will clearly explain the rationale of the study, explicitly define the limited treatment and follow-up period required, and candidly state that there is absolutely no anticipated clinical benefit to the patient.

As a proof-of -principle, one of the first Phase 0 trials, using an agent called ABT-888, successfully recruited 6 patients, out of 17 screened, in about six months vs. the usual 12 to 18 months required for a phase 1 trial.

A request for the IND to conduct the study was filed with the FDA on May 12, 2006 and approval to begin the trial was received one month later, on June 15, 2006. Analyses of data from these first six patients were available in less than six months and provide a proof of concept.

16. What was NCI's first Phase 0 trial?
The results from NCI's first Phase 0 trial were presented at the 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO) on Sunday, June 3, 2007 in Chicago, Ill. The abstract, #3518, is titled "Inhibition of Poly (ADP-ribose) polymerase (PARP) by ABT-888 in patients with advanced malignancies: results of a phase 0 trial."

For more information about cancer, visit http://www.cancer.gov, or call NCI's Cancer Information Service at 1-800-4 CANCER.

For more information on NExT, go to http://dctd.cancer.gov/MajorInitiatives/02NExT.htm

For more information on NCI's Division of Cancer Treatment and Diagnosis, go to http://dctd.cancer.gov/

For more information on NCI's Center for Cancer Research, go to http://ccr.cancer.gov

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