Dose Finding for Drug Combinations

Mourad Tighiouart ()
Additional contact information
Mourad Tighiouart: Cedars-Sinai Medical Center

Chapter 55 in Principles and Practice of Clinical Trials, 2022, pp 1003-1030 from Springer

Abstract: Abstract We present early phase cancer clinical trial designs for drug combinations focusing on continuous dose levels. For phase I trials, the goal is to estimate the maximum tolerated dose (MTD) curve in the two-dimensional Cartesian plane. Parametric models are used to describe the relationship between the doses of the two agents and the probability of dose limiting toxicity (DLT). Trial design proceeds using cohorts of two patients receiving doses according to univariate escalation with overdose control (EWOC) or continual reassessment method (CRM). The maximum tolerated dose curve is estimated as a function of Bayes estimates of the model parameters. In the case where some DLTs can be attributed to one agent but not the other, we describe how these parametric designs can be extended to account for an unknown fraction of attributable DLTs. For treatments where efficacy is resolved after few cycles of therapy, it is standard practice to perform single or randomized phase II trials using the MTD(s) obtained from a phase I trial. In our setting, we show how the MTD curve is carried out into a phase II trial where patients are allocated to doses likely to have high probability of treatment efficacy using a Bayesian adaptive design. The methodology is illustrated with an application to an early phase trial of cisplatin and cabazitaxel in advanced stage prostate cancer patients with visceral metastasis. Finally, we describe how these methods are adapted to the case of a pre-specified set of discrete dose combinations.

Keywords: Dose fiinding; Drug combinations; MTD; DLT; EWOC; CRM; Adaptive designs; Attributable toxicity; Efficacy; Cubic splines (search for similar items in EconPapers)
Date: 2022
References: Add references at CitEc
Citations:

There are no downloads for this item, see the EconPapers FAQ for hints about obtaining it.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:spr:sprchp:978-3-319-52636-2_80

Ordering information: This item can be ordered from
http://www.springer.com/9783319526362

DOI: 10.1007/978-3-319-52636-2_80

Access Statistics for this chapter

More chapters in Springer Books from Springer
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().