Dose Escalation Designs in Universal Context of Titration for Oncology Drug Development
The category-theoretic perspective can function as a simplifying abstraction, isolating propositions that hold for formal reasons from those whose proofs require techniques particular to a given mathematical discipline.
— Emily Riehl, Preface to 'Category Theory in Context' (2016)
This project aims to formulate dose-escalation trial protocols using ideas from Applied Category Theory (ACT), carrying out the attendant computations on a 'workbench' developed using the monotonic subset of Prolog, including CLP(ℤ). In accordance with the quotation above, this categorial formulation serves to exhibit certain properties of dose-escalation designs as deducible from more basic premises than we may otherwise appreciate. Working in Prolog promotes a clarification of thought and elegance of expression that harmonize perfectly with the intellectual spirit of categorial investigations such as these. (For an extensive discussion of the advantages of Prolog in medical and other such safety-critical applications, and our rationale for selecting Scryer Prolog in particular, please see Section 2 of [1].)
DEDUCTION represents the latest—and possibly conclusive—development within the Dose Titration Algorithm Tuning (DTAT) research programme, which has been ongoing now for the better part of a decade. The full bibliography found here links to 'lay explainers', short videos or online apps accompanying most of the scholarly outputs, reflecting the DTAT programme's long commitment to lay outreach. Although this outreach has been pursued with cancer patient advocates most especially in mind, these resources may prove useful even to experts in adjacent fields, since DTAT draws upon ideas from several disciplines not often brought under one roof.
We are carrying out the DEDUCTION effort in this public repository.
Presently, the core output is an evolving monograph catform.pdf,
built from catform.tex and subject to occasional tagged releases.
Our Prolog workbench is being developed mainly in catform.pl, using
Markus Triska's ediprolog.
DEDUCTION is presently (as of Christmas Day, 2024) on the cusp of solving — within weeks, not months — two crucial problems in dose-escalation protocol design:
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Starting with a given dose-escalation design, possibly defined in terms depending on enrollment of non-singular cohorts to be dosed simultaneously, extend this design faithfully to achieve what has been termed rolling enrollment [2] while accounting for the possibility of pending toxicity assessments [3].
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Given any dose-escalation design, in which by definition "intra-patient dose escalation is not allowed" [4], extend this faithfully to a dose-titration design eliminating this constraint.
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Norris DC, Triska M. An Executable Specification of Oncology Dose-Escalation Protocols with Prolog. February 13, 2024. http://arxiv.org/abs/2402.08334
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Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC. Shortening the Timeline of Pediatric Phase I Trials: The Rolling Six Design. Journal of Clinical Oncology. 2008;26(2):190-195. doi:10.1200/JCO.2007.12.7712
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Frankel PH, Chung V, Tuscano J, et al. Model of a Queuing Approach for Patient Accrual in Phase 1 Oncology Studies. JAMA Network Open. 2020;3(5):e204787-e204787. doi:10.1001/jamanetworkopen.2020.4787
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Norris DC. Ethical Review and Methodologic Innovation in Phase 1 Cancer Trials. JAMA Pediatrics. 2019;173(6):609. doi:10.1001/jamapediatrics.2019.0811