National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
October 20, 2009 • Volume 6 / Number 20

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Guest Director's Update

The NExT Steps in Drug Development at NCI

Dr. James H. Doroshow

The FDA’s recent approval of the new agent pralatrexate (Folotyn) for the treatment of peripheral T-cell lymphoma (PTCL) was especially satisfying news for those of us at NCI who have been involved with this drug. Of course, we are always pleased to see a new, effective cancer treatment reach the clinic, especially one for patients with this rare form of lymphoma who have relapsed after or failed to respond to their initial treatment.

NCI has a particular interest in this drug because it is the first agent from NCI’s Rapid Access to Intervention Development (RAID) program to receive FDA approval for a cancer indication. For a program that was in existence for a decade, the fact that this is the first approval demonstrates how difficult it can be to bring a new treatment to patients. Now that RAID has been incorporated into NCI’s Experimental Therapeutics (NExT) program, we believe that efficiencies and improvements in NCI’s drug development efforts are achievable and real.

There is a great deal of excitement about NExT, which is a collaboration between NCI’s Division of Cancer Treatment and Diagnosis and Center for Cancer Research (CCR). The program’s goal is to speed up the drug development process by getting promising drugs—particularly those for pediatric and rare cancers—into human trials more quickly and to prune agents from the development pipeline that are unlikely to be effective, saving valuable resources.

NExT was designed to bring NCI’s diverse drug development efforts into a single pipeline and to follow a formalized, business-like approach to the development of potentially promising therapeutics. At the same time, the broad array of services and resources such as toxicology testing and drug manufacturing that was available to researchers via RAID is still available with NExT.

Where RAID was more focused on aiding researchers with highly specific tasks, drugs accepted into NExT can provide a more comprehensive approach to advancing agents through the development pipeline, including established milestones that drive “go/no-go” decisions about whether to continue NCI’s role in the development of a given agent. The objective is to move drug candidates through preclinical work into first-in-human studies, including phase 0 trials in which nontoxic doses of the agent are tested in a small number of patients. Using advanced imaging and other techniques, in these trials we can determine in a matter of months whether the drug is reaching its intended target and having the intended biologic effects. This will give us more confidence in the decision to move the agent further along in human trials and help to shave at least a year off of the time it typically takes to develop a drug, while also limiting the resources spent developing treatments that will likely never benefit patients.

A number of agents are already in the NExT pipeline, including agents being investigated by researchers from CCR, large academic medical centers, and private industry. (See the box below.) And we’ve already seen an example of how NExT will function. NCI worked with Abbott Laboratories in the early clinical development of its PARP inhibitor, ABT-888, and in testing it in the first-ever phase 0 trial of only 13 patients. The trial demonstrated that the drug, which interferes with a cell’s ability to repair DNA damage, was in fact hitting its biologic target. Now we are working with Abbott to test this agent in phase I and II clinical trials in patients with a variety of tumors.

Although many of the agents in NExT will be supported from preclinical testing through first-in-human studies, the program is open for applicants to enter and exit at any stage in the process. There may be cases, for example, where a research team or private company is already testing an agent in early stage trials in adults, but they may be interested in using NExT to develop the agent for use in a pediatric population, an area in which NCI has unique expertise and resources.

So whether it is serving as a bridge at critical points in the development path, as was the case for pralatrexate, or as a more comprehensive driver of an agent’s development from the earliest stages of preclinical research, we are confident that with NExT we can have many more successes in the coming decade.

Dr. James H. Doroshow
Director, NCI Division of Cancer Treatment and Diagnosis

In the NExT Pipeline

Dr. Yves Pommier, chief of CCR’s Laboratory of Molecular Pharmacology, has two compounds in the NExT program on the verge of being tested in phase I trials. In both laboratory tests and animal model studies, the two compounds, known as indenoisoquinolines, or indenos, have demonstrated an impressive ability to kill cancer cells with little evidence of toxicity.

Like a class of compounds known as camptothecins, the indenos target topoisomerase 1, which plays a critical role in DNA replication during cell division. But the indenos have some advantages over camptothecins, Dr. Pommier said, including more chemical stability and the ability to remain active in the blood for longer periods.

“It takes time to realize that you have something worthy of pursuing in human trials,” Dr. Pommier stressed. The compounds have been under development for more than a decade, he noted, so the researchers involvement in NExT is a bridging step before likely working with industry to conduct large-scale human trials.

At Ohio State University (OSU) Medical Center, Dr. Michael Grever and his colleagues, Drs. Doug Kinghorn and David Lucas, are pursuing the development of an agent called silvestrol, a natural product derived from a plant found in Sarawak, on the island of Borneo. Their research is focused on developing new treatments for chronic lymphocytic leukemia and acute lymphoblastic leukemia, both of which involve the overproduction of malignant B cells.

In very low concentrations, silvestrol induced selective killing of leukemic cells taken from patients. And in an animal model of a highly aggressive leukemia, treatment with silvestrol appeared to completely eradicate the disease in some cases. The compound causes little if any apparent damage to normal immune system cells, Dr. Grever said—a common problem with current treatments for these cancers.

As part of its involvement in NExT, silvestrol is undergoing intensive safety analyses at NCI, and the OSU researchers are working in close collaboration with scientists in Sarawak. His goal with NExT, Dr. Grever said, is to help move silvestrol into phase I clinical trials.