As trends shift in cancer pharmacology, yesterdays clinical trial designs for drugs with broad cytotoxic properties may not be appropriate for todays targeted inhibitors of neoplastic growth.
Relatively new drug design projects include cytostatic agents, immune system modulators, and angiogenesis inhibitors. To the extent that these targeted strategies succeed, the older strategy of developing drugs with broad-spectrum cytotoxic activity may fade.
A clinical test of one of these new drugs means proving that the target is inhibited in humans and showing that cancer comes under control as a result. The Molecular Targets Faculty at the National Cancer Institute recently held a workshop to discuss how clinical trials need to be redesigned so that the results yield this information.
Pinpointing proteins in essential cancer pathways enables drug designers to tackle cancers based on their understanding of the cancers mechanisms of transformation, cell growth, and metastasis. Herceptin (trastuzumab), a monoclonal antibody against the overexpressed Her-2/neu protein in inflammatory breast cancer, is a crowning example of this approach.
These new drugs will change clinical trial eligibility requirements, noted Louise Grochow, M.D., chief of NCIs Investigational Drug Branch. Previously, any patient with a solid tumor was admissible in a trial, and patient selection was based on straightforward histology. "Now, when were confident we understand how an agent works, we may be defining eligibility based on the presence of the target in a patients tumor," Grochow said. It makes no sense to expose patients to even low toxicity if they have no chance of benefiting."
When trials begin, clinicians will have to show that the targeted drugs work in vivo. "You really dont know what youre doing unless you can show your drug inhibits the target in your patient," said Garth Powis, D.Phil., director of basic science at the Arizona Cancer Center, Tucson, who develops thioredoxin inhibitors that induce tumor apoptosis. Meeting this challenge requires a clinical assay for target inhibition.
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Now, clinicians must keep in mind that targeted drugs could have very mild side effects, making phase I studies more complicated in the search for the correct drug dose. The idea that "more is better" will no longer be true, said Grochow. With targeted drugs, dose and toxicity studies will often aim for the maximal molecular effect rather than for the maximum tolerated dose.
Testing cancer drugs in combination must also change, she said. Until now, combining drugs has been empirical. Doctors commonly choose drugs with non-overlapping toxic effects and combine them at maximum doses. In the new era, combinations favored for clinical testing will either attack different cancer pathways or work against the same pathway at different steps.
Showing a drug works against its target in patients in clinical trials implies having access to tumor samples. Unfortunately, this is not guaranteed. "The biggest problem in these trials," Powis said, "is getting hold of patients target tissue." Clinicians must balance the need for samples and when to take them with the knowledge that patients may limit consent to biopsies. Biopsy specimens, moreover, are not perfect; they do not always contain tumor cells. And of course, sometimes they will simply be out of reach.
This is why Powis has suggested alternatives to tumor biopsies. He has explored taking tumor cells from other sites, particularly from blood and bone marrow. According to Powis, it is well known that cells from tumors circulate in the blood.
Powis also tests DNA microarrays for examining drug effects. The goal is to predict gene expression patterns that change in response to medication. This requires study of drug-induced gene expression in human tumor cells in vivo and in vitro and in animal models of human tumors.
Researchers predict a big future for noninvasive imaging as a tool to study cancer drug effects in vivo. "The hope is that we can validate imaging techniques to the point that they can replace the need for live tissue," said Peter Choyke, M.D., of NCIs Functional Tumor Imaging Group.
Tumor imaging in clinical trials will use nonspecific imaging compounds like fluorodeoxyglucose (FDG) for positron emission tomography and gadolinium chelates for magnetic resonance imaging. These techniques are quantitative, pick up cancers that computed tomography scans miss, and reveal tumors that escape chemotherapy.
As an example, Choyke explains how PET and FDG can show a tumor reacting to a drug. If a drug attacks a tumor, the effect will show up as a change in the tumors FDG radiation over time. MRI similarly can reveal temporal tumor changes. Choyke uses dynamic enhanced MRI to study antiangiogenesis drugs. Powis uses diffusional MRI to detect drug-induced apoptosis.
These imaging techniques still must be validated in animal models of human tumors. This requires finding the link between drug-induced molecular tumor events and functional tumor images. PET and MRI scanning of laboratory animals have advanced to the point that this is technically possible, said Choyke. (See related story, p. 1773.)
Choyke is confident imaging technology in cancer trials will go far. "Ultimately, you can think about an imaging agent tailored to the specific biology of a patients tumor, where we can tell how the patient is doing without guesswork. Thats the dream."
Moving towards that dream, as Grochow pointed out, means that clinical trials for targeted cancer drugs will enlist experts unaccustomed to working togetherimaging specialists and radiologists will often be new to such clinical trials. Assembling these teams well before phase I will be key to succeeding with these new style clinical experiments, she said.
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