5. Drug Development: Preclinical Evaluation of Cytotoxic Agents Preclinical evaluation of potentially useful cytotoxic agents comprises in vitro and in vivo analyses. In vitro analysis may include assays designed to evaluate the mechanism of action of compounds against specific mechanistic or molecular targets or activity at the cellular level in terms of cytotoxicity, growth inhibition, or differentiation. Thereafter, Stage I in vivo testing is designed to identify the maximum tolerated dose and dose-limiting toxicities of the compound, in addition to preliminary efficacy findings. Stage II in vivo testing is designed to define the spectrum of activity, schedule dependency, optimal route of administration, potential for cross resistance with other agents, and potential usefulness in combination therapies.
9. Drug Development: Clinical Endpoints: Complete Remission One criterion for evaluating response to chemotherapy involves degrees of remission from the signs of disease. A complete remission is a response to treatment in which all clinical, radiologic, and biologic signs of a tumor have been observed to disappear. All fields demonstrating the primary tumor, node-positive disease, and metastatic disease must be confirmed to be disease-free for designation as a complete remission.
10. Drug Development: Clinical Endpoints: Partial Remission Remission that is less than complete may be designated as partial remission if the tumor bulk has been reduced by at least 50%.
11. Drug Development: Clinical Endpoints: Disease Progression A response designation of disease progression indicates failure of therapy to arrest tumor growth. Specifically, tumor growth must exceed the multiple of two tumor diameters by at least 25%.
The ultimate test of any agent is the phase III trial. These are large and seek to address differences in treatments using outcomes such as overall survival, cure rate and quality of life. Issues of bias are minimized by the randomized design. The sample size determines the power with which one can detect differences of interest between treatment arms.
Introduction to Clinical Trials Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium ESO student course, Ioannina, 2011
Measurable lesions defined by unidimensional measurement
Tumor burden based on sum of diameters
Categories of response:
PR (30% decrease in sum from baseline)
PD (20% increase in sum from nadir)
Courtesy of E.A. Eisenhauer
For example: Response classification same… Time point Response: Patients with Target (+/- non-target) Disease: Target lesions Non-Target lesions New Lesions Overall response CR CR No CR CR Non-CR/Non-PD No PR CR Not evaluated No PR PR Non-PD or not all evaluated No PR SD Non-PD or not all evaluated No SD Not all evaluated Non-PD No NE PD Any Any PD Any PD Any PD Any Any Yes PD
Summary: What HAS changed in RECIST 1.1 RECIST 1.0 RECIST 1.1 Measuring tumor burden 10 targets 5 per organ For response: 5 targets (2 per organ) Lymph node Measure long axis as for other lesions. Silent on normal size Measure short axis. Define normal size. Progression definition 20% increase in sum 20% increase and at least 5 mm absolute increase Non-measurable disease PD “ must be unequivocal” Expanded definition to convey impact on overall burden of disease. Examples. Confirmation required Required when response primary endpoint—but not PFS New lesions -- New section which includes comment on FDG PET interpretation