SLIDES & TRANSCRIPTS
Tuesday, February 15, 2000

What Model in Clinical Design Should We Use to Examine New Cytostatic Compounds?
Neal Meropol, MD

DR. MAYER: So this afternoon our first session will be a panel to discuss the question, what model in clinical design should we use to examine new cytostatic compounds, picking up on what we heard from before lunch and chairing the first session this afternoon is Neal Meropol from Fox Chase Cancer Center in Philadelphia.

DR. MEROPOL: I would like to thank Dr. Mayer and Dr. O'Connell for inviting me to participate in this. Our charge over the next hour and one-half is to initiate discussion with regard to clinical trial models for use in examining new cytostatic compounds as were introduced in the previous session. I will be joined today by two panelists. The first will be Elizabeth Eisenhauer from the National Cancer Institute of Canada Clinical Trials Group in Queen's University, and following that we will have Ed Korn from the NCI Cancer Therapy Evaluation Program.

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I will just present a couple of introductory comments. As I was thinking about how to frame the next 45 minutes of didactics if you will, I came up with what we typically view as ten tenets that have been characteristically followed over the past decade or two decades in the design of cancer clinical trials, and as I hope we will demonstrate over the next 45 minutes to hour and one-half, at least nine of these tenets that have ruled our lives may no longer be entirely valid.

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So commandment number one, the primary end point of a Phase I study is toxicity. Two, more is better. Three, the primary end point of a phase II study is response rate. Four, response rate is the best surrogate for clinical activity. We must move sequentially from Phase I to Phase II to Phase III.

Commandment number six, we have to show single agent activity before conducting combination studies.

Number seven is that pharmacodynamic effects in normal tissue always correlate directly with the effects in tumor tissue.

Don't ever publicly support a randomized Phase II study design. We have already heard someone earlier today suggest this possibility. Don't talk to your statistician and lab collaborators until after you design the study. That may no longer be valid as well, and finally, survival is the ultimate end point, and perhaps of the ten on the list that I have lived by perhaps this is the only remaining valid instruction.

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There are two ways to kind of conceptualize what we heard in the last session about new drugs being developed against colorectal and other types of cancer. The first one is to categorize the drugs based on the identification of new targets, and as we heard earlier we can think of drugs that target cancer cell growth regulation and examples here are inhibitors of growth factor receptors, ras signal transduction pathways or p53.

Another way to look at targeting colorectal cancer is targeting the host response to cancer and immunotherapy is what would fit in here, and finally to look at the tumor microenvironment interactions, and examples here are the vascular endothelial growth factor pathway and the action of matrix metalloproteinases.

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Another way to conceptualize what we heard earlier is to think of this in terms of new modalities that are now available as opposed to new targets that have been identified, and we have heard about all of these earlier today as well.

The first modality is advances in immunotherapy, and this could include monoclonal antibodies, vaccines such as the anti-idiotype vaccine that we heard earlier today, cytokines, angiogenesis inhibitors, which can come in the form of antibodies or small molecules, signal transduction inhibitors, such as receptor tyrosine-kinase inhibitors or farnesyltransferase inhibitors and, finally, gene therapy which can take the form of genes inserted into genetically engineered viruses that serve as vaccines or gene replacement therapy, both of which we heard about in this morning's session.

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What are the clinical contexts we should be thinking about as we move forward in designing clinical trials with these novel agents? First, context is adjuvant therapy which is the ultimate setting of micrometastatic disease. We have the setting of resected metastatic disease which is also micrometastatic disease but with a higher tumor burden in general, the setting of measurable metastasis which has been the typical setting for testing new agents in the past. But we could look at either initial therapy in patients who have not been previously treated or patients that have been treated to maximal response and then look at newer end points such as time to progression, and finally we could look at the pre-operative setting which has the advantage of being able to look at the effect of the new treatment on either primary or metastatic tumor that is subsequently resected.

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So I would like to leave with one final slide before Dr. Eisenhauer speaks and that is to present a hypothetical drug scenario which should smell like many of the drugs that we have heard about today and that many of us are developing in our own practices at home.

There is a mutation in the colorectal cancer gene, the CRC gene which, of course, is an imaginary gene that is consistently associated with colorectal cancer. A therapeutic agent is developed that inhibits the function of the protein product of this gene, P99CRC or that targets cell expressing P99 or that introduces native CRC protein into cells, and in animal models this new agent causes stabilization of established tumors with prolonged survival and no toxicity.

So I will leave there and introduce Elizabeth Eisenhauer who will walk us through many of the issues that we face in drug development as it relates to new cytostatic agents.

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