Biomaterial Database

Model-guided determination of maximum tolerated dose in phase I clinical trials: evidence for increased precision. 1993

R Mick, and M J Ratain

Department of Medicine, University of Chicago, Pritzker School of Medicine, Ill.

BACKGROUND A widely used phase I design in clinical trials of chemotherapy for cancer and for AIDS (acquired immunodeficiency syndrome) allows for dose escalation in cohorts of three to six patients. Escalation continues until a predefined percentage of patients experience unacceptable toxic effects at a given dose level. A safe and maximum tolerated dose (MTD) for phase II study is then determined. This standard phase I study design has serious inadequacies. MTD is not a model-based estimate of the true dose that would yield the targeted dose-limiting toxicity rate. Moreover, this simplistic study design allows some patients in the phase I study to be treated at doses unlikely to have therapeutic efficacy. OBJECTIVE We constructed a novel quantitative assessment design that repetitively evaluates accumulating dose-toxicity data by repeatedly fitting and updating a pharmacodynamic model after small cohorts of patients are treated. The goal was to more accurately estimate the MTD. METHODS One hundred phase I studies were simulated by both the standard and quantitative assessment phase I designs. We compared determination of MTD, frequency of grade 0 leukopenia (no toxicity), and study size in the studies simulated using the standard design with those in the studies simulated using the quantitative assessment design. RESULTS The median MTD determined from the 100 studies was nearly identical for the two designs: 100 and 95 mg/m2 per day for standard and quantitative assessment designs, respectively. However, the interstudy variation in the MTD was decreased in the quantitative assessment design. Moreover, the study size was significantly reduced (P < .0001), and the median percentage of patients treated at subtoxic doses (no leukopenia) was significantly lower for the quantitative assessment design (44% versus 48%; P < .0001). CONCLUSIONS Our results show clear evidence that a phase I study design using dose and toxicity data in a repetitive and quantitative manner can identify the MTD with more accuracy than the standard design. CONCLUSIONS New approaches must be explored to improve our ability to identify the optimal dose for phase II studies of chemotherapy for cancer and for AIDS. There is evidence that the quantitative assessment design will identify the MTD with fewer patients, more precision, and fewer patients exposed to suboptimal doses.

UI	MeSH Term	Description	Entries
D009369	Neoplasms	New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.	Benign Neoplasm,Cancer,Malignant Neoplasm,Tumor,Tumors,Benign Neoplasms,Malignancy,Malignant Neoplasms,Neoplasia,Neoplasm,Neoplasms, Benign,Cancers,Malignancies,Neoplasias,Neoplasm, Benign,Neoplasm, Malignant,Neoplasms, Malignant
D004305	Dose-Response Relationship, Drug	The relationship between the dose of an administered drug and the response of the organism to the drug.	Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D005047	Etoposide	A semisynthetic derivative of PODOPHYLLOTOXIN that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle.	Demethyl Epipodophyllotoxin Ethylidine Glucoside,Celltop,Eposide,Eposin,Eto-GRY,Etomedac,Etopos,Etoposide Pierre Fabre,Etoposide Teva,Etoposide, (5S)-Isomer,Etoposide, (5a alpha)-Isomer,Etoposide, (5a alpha,9 alpha)-Isomer,Etoposide, alpha-D-Glucopyranosyl Isomer,Etoposido Ferrer Farma,Exitop,Lastet,NSC-141540,Onkoposid,Riboposid,Toposar,VP 16-213,VP-16,Vepesid,Vépéside-Sandoz,Eto GRY,Etoposide, alpha D Glucopyranosyl Isomer,NSC 141540,NSC141540,Teva, Etoposide,VP 16,VP 16 213,VP 16213,VP16,Vépéside Sandoz,alpha-D-Glucopyranosyl Isomer Etoposide
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D015233	Models, Statistical	Statistical formulations or analyses which, when applied to data and found to fit the data, are then used to verify the assumptions and parameters used in the analysis. Examples of statistical models are the linear model, binomial model, polynomial model, two-parameter model, etc.	Probabilistic Models,Statistical Models,Two-Parameter Models,Model, Statistical,Models, Binomial,Models, Polynomial,Statistical Model,Binomial Model,Binomial Models,Model, Binomial,Model, Polynomial,Model, Probabilistic,Model, Two-Parameter,Models, Probabilistic,Models, Two-Parameter,Polynomial Model,Polynomial Models,Probabilistic Model,Two Parameter Models,Two-Parameter Model
D017321	Clinical Trials, Phase I as Topic	Works about studies performed to evaluate the safety of diagnostic, therapeutic, or prophylactic drugs, devices, or techniques in healthy subjects and to determine the safe dosage range (if appropriate). These tests also are used to determine pharmacologic and pharmacokinetic properties (toxicity, metabolism, absorption, elimination, and preferred route of administration). They involve a small number of persons and usually last about 1 year. This concept includes phase I studies conducted both in the U.S. and in other countries.	Clinical Trials, Phase I,Drug Evaluation, FDA Phase I,Evaluation Studies, FDA Phase I,Human Microdosing Trial,Phase 1 Clinical Trial,Phase I Clinical Trial,Phase I Clinical Trials,Clinical Trials, Phase 1,Drug Evaluation, FDA Phase 1,Drug Evaluation, FDA Phase I as Topic,Evaluation Studies, FDA Phase 1,Human Microdosing Trials,Microdosing Trials, Human,Phase 1 Clinical Trials,Microdosing Trial, Human,Trial, Human Microdosing,Trials, Human Microdosing