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Phase I trials of single agents in adult solid tumours: preclinical and clinical aspects
Abstract:
Considerable progress has been made in the treatment of cancer. However, there is still a need for new drug development. The preclinical antitumour activity of new anticancer agents is evaluated by sequential testing in murine tumours and human xenografts in mice. More recently, the human tumour stem cell assay has been introduced into the preclinical screen. Toxicology studies are done in animals in order to characterize qualitatively and quantitatively the side effects of the new compounds. These toxicology studies allow an appropriate starting dose to be selected for clinical trials. Most commonly, the starting dose for clinical trials corresponds to 1/10 of the dose that will induce a 10% lethality in the mouse (LD10), if that dose is tolerated by the dog. The escalation scheme for clinical trials must be a compromise between the safety of the patient and quickly reaching biologically active doses. This may be achieved by using the so-called modified Fibonacci scheme. A slightly more rapid alternative is to increase the dose by 100% until the equivalent of the LD10 in the mouse is reached, and then by 50% until toxic effects are observed. Further dose increases depend on the type and severity of these toxic side-effects. Patients included in phase I clinical trials of anticancer agents must have histologically proven malignant disease that cannot be treated by conventional therapeutic modalities. They should have normal haematological, renal and hepatic functions and should be expected to live long enough to evaluate properly the toxic effects of the new compounds.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Developing new anticancer drugs requires rigorous preclinical testing and careful dose escalation in clinical trials. This ensures patient safety while efficiently identifying effective treatments for cancer.
Area of Science:
- Oncology
- Pharmacology
- Toxicology
Background:
- Cancer treatment has advanced, yet novel drug development remains crucial.
- Preclinical evaluation of anticancer agents involves murine tumor models, human xenografts, and human tumor stem cell assays.
- Animal toxicology studies are essential for characterizing side effects and determining safe starting doses for human trials.
Purpose of the Study:
- To outline the established preclinical and clinical trial methodologies for new anticancer drug development.
- To describe the process of selecting starting doses and dose escalation schemes for phase I clinical trials.
- To define the eligibility criteria for patients participating in phase I anticancer drug trials.
Main Methods:
- Preclinical efficacy assessment using murine tumors and human xenografts.
- Inclusion of the human tumor stem cell assay in preclinical screening.
- Animal toxicology studies to identify dose-limiting toxicities and establish the 10% lethal dose (LD10).
Main Results:
- The 1/10th LD10 in mice, if tolerated by dogs, commonly serves as the starting dose for clinical trials.
- Dose escalation strategies, such as the modified Fibonacci scheme or a 100%/50% increase, aim to balance patient safety with rapid identification of active doses.
- Patient selection for phase I trials prioritizes those with advanced, treatment-refractory malignancies and adequate organ function.
Conclusions:
- A systematic approach combining preclinical efficacy, toxicology, and carefully designed clinical trial dose escalation is vital for advancing new cancer therapies.
- Optimized dose escalation schemes are necessary to efficiently reach therapeutic levels while minimizing patient risk.
- Strict patient eligibility criteria ensure the reliable evaluation of safety and preliminary efficacy of novel anticancer agents.