gms | German Medical Science

66. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e. V. (GMDS), 12. Jahreskongress der Technologie- und Methodenplattform für die vernetzte medizinische Forschung e. V. (TMF)

26. - 30.09.2021, online

Comparing intrapatient dose escalation to other dose-finding designs

Meeting Abstract

  • Jannik Labrenz - NCT Trial Center, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany; Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany
  • Jonas S. Heitmann - Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
  • Annette Kopp-Schneider - Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany
  • Lisa-Marie Lanz - NCT Trial Center, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany
  • Helmut R. Salih - Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
  • Richard F. Schlenk - NCT Trial Center, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany; Department of Internal Medicine V and Internal Medicine VI, University Hospital Heidelberg, Heidelberg, Germany

Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie. 66. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e. V. (GMDS), 12. Jahreskongress der Technologie- und Methodenplattform für die vernetzte medizinische Forschung e.V. (TMF). sine loco [digital], 26.-30.09.2021. Düsseldorf: German Medical Science GMS Publishing House; 2021. DocAbstr. 112

doi: 10.3205/21gmds081, urn:nbn:de:0183-21gmds0817

Veröffentlicht: 24. September 2021

© 2021 Labrenz et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Introduction: Dose-finding phase I trials aim to determine the recommended phase II dose (RP2D) for further phase II drug development. One way to define the RP2D is to determine the maximum tolerated dose (MTD) which is based on dose-limiting toxicities (DLT). Rule-based approaches, in particular the 3+3 design, are more frequent than model-based approaches in clinical practice [1], [2].

One disadvantage of the 3+3 design is that dose escalation is rather slow and many patients are treated at subtherapeutic doses [3]. A rule-based alternative addressing this problem is to escalate more quickly by employing intrapatient dose escalation before returning to the 3+3 design. Simon et al. [4] suggest intrapatient dose escalation already as a component of their accelerated titration designs. However, the review of van Brummelen et al. [2] shows that only 12 out of 161 rule-based phase I trials between 2012 and 2014 employed an accelerated titration design. An intrapatient dose escalation design might be particularly useful for trials with molecularly targeted agents because toxicity does not necessarily increase with dose and efficacy (target inhibition) may be seen already at dose levels at which no DLTs occur not necessitating dose escalation until the MTD is reached.

Methods: We conduct simulations to compare intrapatient dose escalation designs to the 3+3 design and the Continual Reassessment Method (CRM) introduced by O’Quigley et al. [5]. The considered designs are 3+3, CRM, Intrapatient Escalation followed by 3+3 and Intrapatient Escalation followed by CRM. The endpoints are accuracy (percentage of trials which recommend the true MTD), sample size, safety (median number of DLTs) and therapeutic efficiency (percentage of doses given at the true MTD). We compare the designs for different scenarios regarding the number of doses and the assumed true toxicity.

Results: For the scenarios where the true MTD is the highest dose and the toxicity is low, Intrapatient Escalation followed by 3+3 has a higher accuracy, a lower sample size and a higher therapeutic efficiency than the other designs. However, in the scenarios where the true MTD is not the highest dose the Intrapatient Escalation followed by 3+3 design leads to more doses given above the true MTD and more RP2D above the true MTD than other designs. Employing a subsequent CRM instead of a subsequent 3+3 improves the results in this scenario by allowing a faster de-escalation.

Discussion: No dose-finding design outperforms the other designs in all scenarios. If there is evidence of low toxicity at doses necessary for target inhibition and avoiding subtherapeutic doses is a priority, intrapatient dose escalation is an appropriate dose-finding design to consider. The decision on which design to use should be made case-by-case, aided by expert knowledge and (possibly) simulations.

Conclusions: Our simulations show that including an intrapatient dose escalation stage in dose-finding phase I trials decreases the number of subtherapeutic doses given without i) decreasing safety, ii) decreasing accuracy, iii) increasing sample size when the true MTD is either the highest dose or the true MTD is above the highest dose.

The authors declare that they have no competing interests.

The authors declare that an ethics committee vote is not required.


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