By: Scott Wadler M.D.
Richard T. Silver Distinguished Professorship of Hematology and Medical Oncology
Weill Cornell College of Cornell University

Most people have little idea how cancer drugs are developed. Recent press has reported that drug development from Petri dish to clinical approval by the FDA costs tens of millions of dollars, and is highly risky. Less than 10% of drugs that enter clinical development are approved. Other than those published data, it's unlikely that more than a handful of people are aware of the process of drug development.

The Beginning
New drugs are usually created at large pharmaceutical firms. Alternatively, "start up" or venture capital firms may have one to a handful of drugs in development. Academia is a source of new drugs. Novel drugs are also being developed at the National Institutes of Health in Bethesda. Preclinical screening involves testing drugs in a tumor model system in vitro (in a Petri dish). Often firms will submit new drugs to the NCI for screening in a 60-cell line model. Once a drug looks promising in the preclinical setting, it will then be tested in animal models for efficacy and toxicology, that is, how well it's likely to be tolerated in humans. Once it has passed these tests, drugs are ready for testing in humans.

Testing
The NCI has awarded contracts to institutions that perform "first in human" or Phase I testing of new drugs. These drugs are administered to patients in small to medium-sized trials (12-75 patients) to determine their tolerability in humans. Usually, additional testing such as pharmacokinetic tests are performed to learn more about the distribution and behavior of drugs in patients. Such tests can be extremely valuable in learning how to use a particular drug.

Once the drugs have passed Phase I, they go into "efficacy" or Phase II testing. This means testing a drug using 2-3 different schedules (i.e., continuous infusion, weekly bolus therapy, daily x 3 or daily x 5 every month, high dose 24 hour infusion, etc.) in all or most of the major tumor types. For drugs employed in combination therapy, the process is even more arduous.

The Consortium
In order to accomplish this complex task, the National Cancer Institute has established seven consortia among the major academic institutions. The New York consortium is composed of: Weill Medical College, New York University, Albert Einstein College of Medicine, Columbia University, North Shore University Medical Center, Mount Sinai School of Medicine, the University of Connecticut, and the University of Sydney in Australia. There are six other consortia with similar numbers of institutions. Obviously, the regulatory issues for conducting such trials are very complicated. These include protocol approval by the National Cancer Institute, approval by the Institutional Review Boards at each institution, creation of data/safety monitoring boards for each consortium to collect a toxicity database for each drug, creation of procedures for handling unexpected or unexpectedly severe complications of treatment within a consortium, procedures for rapid communication of life-threatening complications, creation of multi-institutional committees to write protocols, auditing committees, and creation of an electronic database to monitor accruals, toxicities and outcomes on any particular trial.

Clinical trials are complex to run. They require large numbers of regulatory personnel (who deal with the Institutional Review Boards and the NCI), data managers (who collect data from charts, collate the data, and send it to the NCI), research nurses and nurse practitioners (who assist the physicians in obtaining informed consent and monitoring patients throughout the course of the trial) and research pharmacists (who prepare the drugs and keep research records). In contrast, clinical investigators look forward to the implementation of the clinical portion of the trials, because this gives them opportunity to discover new, active agents against refractory diseases.

Some Current Trials
Several of these trials require some annotation. The AECOM trial, NCI 5850, run by Mark Einstein, is the first to test a novel heat shock protein vaccine against high grade premalignant lesions of the cervix. Standard of care for these lesions usually involves surgery, which can result in reduced fertility. Dr. Einstein has already enrolled over 35 patients in this trial with much higher than expected complete response rates. This trial has the potential to spare many women risky surgery with the same or better clinical outcomes. Immunologic studies to test the vaccine effects on immune function in patients receiving the vaccine are being performed by Anna Kadish at AECOM.

The Weill Medical College (WMC) trial, NCI 6490, will test the best chemotherapy (FOLFOX-folinic acid, 5FU + oxaliplatin) with bevacizumab (Avastin-an anti-angiogenesis monoclonal antibody) and with erbitux (cetuximab-an anti-epidermal growth factor monoclonal antibody) in the first line setting in patients with advanced colorectal cancer. This is an opportunity to combine our best agents in up front treatment, where we are likely to get our best results. Angiogenesis studies to test the effects of Avastin on blood vessel growth in patients receiving this regimen are being performed by Shahin Rafii at Weill.

The Zarnestra trials (NCI 1754, 6205, and 5598) in breast cancer and acute leukemia are designed to test the farnesyltransferase inhibitor (a drug that may inhibit ras-mediated signaling pathways) in patients with locally advanced and advanced breast cancer and leukemia. It is hoped that such an agent will increase the clinical benefits of treatment for such patients. Studies to test the effects of these drugs on ras-mediated cell pathways are being conducted by Said Sebti.

The trial of OSI-774 (Tarceva; NCI 5886) in combination with carboplatin and paclitaxel conducted by Stephanie Blank at NYU will test the effects of the novel epidermal growth factor inhibitor in combination with standard therapy in women with de novo ovarian cancer. Despite advances in the treatment of ovarian cancer, novel agents have not been adequately tested. The current trial offers an opportunity to dissect the role of the epidermal growth factor in the pathogenesis of these tumors.

Because of space limitations, we cannot fully discuss the benefits of all these treatments. The important point is to recognize the unique opportunity available at New York cancer research institutions, like the ones belonging to the New York Phase II consortium to benefit patients with advanced cancer using novel, targeted treatment strategies.

For additional information, please contact:
Keith Muhleman, CR&T.
Phone: 212-288-6604
Fax: 212-288-7704 or 212-746-8246
e-mail: kmuhleman@crt.org

TABLE 1. PATIENT ACCRUALS BY PROTOCOL AND INSTITUTION
NCI#	Protocol	Lead Institution
99	Evaluation of Chronic Thalidomide Adm. In Patients Undergoing Chemoembolization for Unresctable Hepatocellular Carcinoma	NYU/Mt. Sinai
4470	Phase II Study of Epothilone in Stage IV Malignant Melanoma	NYU
5598	Phase II Study of Zarnestra plus Doxorubicin/Cyclophosphamid and Zarnestra plus Docetaxel in Patients with Breast Cancer	AECOM
639	Randomized Phase II Trial of Thalidomide vs Thalidomide + Fludarabine in CLL	WMC
5611	Bevacizumab-Liver	Mt. Sinai
5941	PS341/Irinotecan-stomach cancer	WMC
5840	Oxaliplatin/Paclitaxel-Cervical CA	WMC
5886	OSI 774/Carbo/Taxol-Ovarian	NYU
5835	Genasense/Cisplat/Fluorouracil Advanced Esoph/Gastro Esoph Junction and Gastric Cancer	AECOM
5996	Phase II Study of Depsipeptide in Relapsed/Refractory Multiple Myeloma	WMC
6254	Phase II Study of Triapine in Combination with Gemcitabine in Tumors of the Biliary Ducts and and Gall Bladder	WMC
5850	HSPE7 Immunotherapy of CIN III	AECOM
5736	Phase II Study Oxaliplat/PS341	NYU
1754	Phase II Zarnestra-AML	WMC
6205	Zarnestra/Faslodex-Breast	AECOM
6490	Folfox-Avastin-Erbitux colon	WMC