uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Two-stage model-based clinical trial design to optimize phase I development of novel anticancer agents
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
Show others and affiliations
2010 (English)In: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 28, no 1, 61-75 p.Article in journal (Refereed) Published
Abstract [en]


The phase I program of anticancer agents usually consists of multiple dose escalation studies to select a safe dose for various administration schedules. We hypothesized that pharmacokinetic and pharmacodynamic (PK-PD) modeling of an initial phase I study (stage 1) can be used for selection of an optimal starting dose for subsequent studies (stage 2) and that a post-hoc PK-PD analysis enhances the selection of a recommended dose for phase II evaluation. The aim of this analysis was to demonstrate that this two-stage model-based design, which does not interfere in the conduct of trials, is safe, efficient and effective.


PK and PD data of dose escalation studies were simulated for nine compounds and for five administration regimens (stage 1) for drugs with neutropenia as dose-limiting toxicity. PK-PD models were developed for each simulated study and were used to determine a starting dose for additional phase I studies (stage 2). The model-based design was compared to a conventional study design regarding safety (number of dose-limiting toxicities (DLTs)), efficiency (number of patients treated with a dose below the recommended dose) and effectiveness (precision of dose selection). Retrospective data of the investigational anticancer drug indisulam were used to show the applicability of the model-based design.


The model-based design was as safe as the conventional design (median number of DLTs = 3) and resulted in a reduction of the number of patients who were treated with a dose below the recommended dose (-27%, power 89%). A post-hoc model-based determination of the recommended dose for future phase II studies was more precise than the conventional selection of the recommended dose (root mean squared error 8.3% versus 30%).


A two-stage model-based phase I design is safe for anticancer agents with dose-limiting myelosuppression and may enhance the efficiency of dose escalation studies by reducing the number of patients treated with a dose below the recommended dose and by increasing the precision of dose selection for phase II evaluation.

Place, publisher, year, edition, pages
2010. Vol. 28, no 1, 61-75 p.
Keyword [en]
Oncology, Phase I trial design, Optimal design, Dose escalation, Dose finding, Pharmacokinetics, Pharmacodynamics, Modeling and simulation
National Category
Medical and Health Sciences Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-137961DOI: 10.1007/s10637-008-9216-2ISI: 000273317700007OAI: oai:DiVA.org:uu-137961DiVA: diva2:378971
Available from: 2010-12-16 Created: 2010-12-16 Last updated: 2011-11-30Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Karlsson, Mats O.
By organisation
Department of Pharmaceutical Biosciences
In the same journal
Investigational new drugs
Medical and Health SciencesPharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar

Altmetric score

Total: 157 hits
ReferencesLink to record
Permanent link

Direct link