What your obsolete dose-finding study <i>r</i><i>eally</i> costs: money, innovation and lives
Creators: name: Norris, David C.
Publisher: name: F1000Research
Year: 2017

description: BACKGROUND<br>Even after a decade of great advances for Bayesian adaptive design and model-based dose-finding, oncology dose-finding studies continue to pursue the mirage of ‘the’ maximum tolerated dose (MTD). This fallacious, anti-precision concept maintains a pretext for one-size-fits-all dosing that ignores the long-recognized heterogeneity of cancer patients’ pharmacokinetics and pharmacodynamics (PK/PD), as well as the equally important diversity of their individual <i>values</i> and <i>goals of care</i>. Under this conceptual yoke, these dose-finding studies constitute a significant choke-point in drug development, where a severe discount may be applied to the potential value in new molecules through the hobbling of subsequent efficacy trials by inadequate individual-level dosing.<br><br>DOSE TITRATION ALGORITHM TUNING<br>Dose Titration Algorithm Tuning (DTAT), a new methodologic advance [1], shows we can reconceive the aim of early-phase drug studies, not as ‘dose-finding’, but now as <i>dose titration algorithm (DTA)</i>-finding. This new conception lets us see through the mirage of <i>‘the’ MTD</i>, to a properly individualized notion of <i>MTD<sub>i</sub></i>.<br><br>IMPACT ON PATIENTS &amp; INNOVATION<br>A large body of literature stretching back 2 decades ([2-4], <i>inter alia</i>) shows that patients who have adverse effects (such as neutropenia) from their chemotherapy also have better outcomes from treatment. DTAT allows safe titration to <i>each individual patient’s</i> maximum tolerated dose, so that each patient gets his or her best chance of achieving a remission. This, in turn, gives each investigational new drug (IND) the best chance to succeed in Phase 2 and 3 efficacy trials.<br><br>BEYOND THE CYTOTOXICS<br>In the important area of immuno-oncology, common dose-limiting toxicities (DLTs) admit monitoring on time-scales comparable to the chemotherapy induced neutropenia (CIN) simulated in [1]. The <i>cytokine release syndrome</i> (CRS) that accompanies CAR-T therapies, for example, typically arises within 1 week of administration (even earlier with concomitant high-dose IL-2) and constitutes a clinical <i>syndrome</i> that admits multivariate monitoring on numerous quantitative clinical and laboratory measures. Even molecularly targeted agents (MTAs), for which <i>late</i> toxicities have attracted the lion’s share of attention, remain accessible to the DTAT principle—with DTA learning simply occurring on a longer time scale.<br><br>WHAT DTAT MEANS TO YOU<br>DTAT presents a <i>prima facie</i> case for discarding the outmoded concept of ‘the’ maximum tolerated dose (MTD) of cancer therapeutics. The DTAT principle should be of interest to a wide range of stakeholders, from cancer patients with a stake in receiving optimal individualized ‘MTD<sub>i</sub>’ dosing, to shareholders in pharmaceutical innovation with a stake in efficient dosefinding before Phase III trials.<br><br>REFERENCES

	Norris DC. Dose Titration Algorithm Tuning (DTAT) should supersede ‘the’ Maximum Tolerated Dose (MTD) in oncology dose-finding trials. <i>F1000Research</i>. 2017;6:112. doi:10.12688/f1000research.10624.2.
	Saarto T, Blomqvist C, Rissanen P, Auvinen A, Elomaa I. Haematological toxicity: a marker of adjuvant chemotherapy efficacy in stage II and III breast cancer. <i>Br J Cancer</i>. 1997;75(2):301-305.
	Yamanaka T, Matsumoto S, Teramukai S, Ishiwata R, Nagai Y, Fukushima M. Predictive value of chemotherapy-induced neutropenia for the efficacy of oral fluoropyrimidine S-1 in advanced gastric carcinoma. <i>Br J Cancer</i>. 2007;97(1):37-42. doi:10.1038/sj.bjc.6603831.
	Su Z, Mao Y-P, OuYang P-Y, Tang J, Lan X-W, Xie F-Y. Leucopenia and treatment efficacy in advanced nasopharyngeal carcinoma. BMC Cancer. 2015;15:429. doi:10.1186/s12885-015-1442-3
	Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. <i>J Clin Oncol</i>. 2002;20(24):4713-4721. doi:10.1200/JCO.2002.02.140.