Abstract
The ideal starting dose for an oncology first-in-patient (FIP) trial should be low enough to be safe but not too far removed from therapeutically relevant doses. A low starting dose combined with small dose increments could lead to a lengthy dose escalation and could expose patients unnecessarily to sub-therapeutic dosing. In the current analyses, we reviewed 59 approved small molecule oncology drugs (SMOD) with the overarching goals to assess the current approaches of FIP starting dose selection and dose escalation, and to identify potential opportunities for improving trial efficiency and minimizing number of patients receiving sub-therapeutic dose levels. Of 59 SMODs, the majority (~ 66%) were kinase inhibitors and ~ 73% were approved for solid tumor indications. Most of the trials used a 3 + 3 design for dose escalation and had a median (range) of 4 cohorts (0–11) to reach MTD from the starting dose. The maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) to starting dose ratio was highly variable with a median (range) of 8 (0.25–125). About 71% of the FIP trials had < 6 dose escalation steps to reach MTD or RP2D (with 15% ≤ 2 dose escalations), but the remaining 29% of trials had ≥ 6 dose escalation steps to reach MTD or RP2D suggesting that there is still room for increasing efficiency by reducing the number of dose escalation steps, reducing the variability in MTD to starting dose ratio, and consequently reducing significant number of patients exposed at sub-therapeutic doses in the dose escalation phase of FIP study.
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References
Adashek JJ, LoRusso PM, Hong DS, Kurzrock R (2019) Phase I trials as valid therapeutic options for patients with cancer. Nat Rev Clin Oncol 16(12):773–778. https://doi.org/10.1038/s41571-019-0262-9
EMEA/CHMP (2007) Guideline on strategies to identify and mitigate risks for fist-in-human clinical trials with investigational medicinal products
EMEA/CHMP (2018) Guideline on strategies to identify and mitigate risks for fist-in-human clinical trials with investigational medicinal products
FDA (2005) Guidance for industry. Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers
ICH (2010) ICH guideline S9 on nonclinical evaluation for anticancer pharmaceuticals
Kummar S, Gutierrez M, Doroshow JH, Murgo AJ (2006) Drug development in oncology: classical cytotoxics and molecularly targeted agents. Br J Clin Pharmacol 62(1):15–26. https://doi.org/10.1111/j.1365-2125.2006.02713.x
FDA (2019) Severely debilitating or life-threatening hematologic disorders: nonclinical development of pharmaceuticals guidance for industry
Zou PLS, Li M, Yu L, Sun D (2016) A global perspective on first-in-mand dose selection: oncology and beyond. In: Bonate PL, Howrad DR (eds) Pharmacokinetics in drug development. Springer International, Cham, pp 39–58
Reigner BG, Blesch KS (2002) Estimating the starting dose for entry into humans: principles and practice. Eur J Clin Pharmacol 57(12):835–845. https://doi.org/10.1007/s00228-001-0405-6
Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, Pithavala YK, Reich SD, Freddo JL, Wilding G (2005) Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 23(24):5474–5483. https://doi.org/10.1200/JCO.2005.04.192
Le Tourneau C, Lee JJ, Siu LL (2009) Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst 101(10):708–720. https://doi.org/10.1093/jnci/djp079
Tam K (2013) Estimating the “First in human” dose—a revisit with particular emphasis on oncology drugs. ADMET DMPK 4(1):63–75. https://doi.org/10.5599/admet.1.4.10
Penta JS, Rosner GL, Trump DL (1992) Choice of starting dose and escalation for phase I studies of antitumor agents. Cancer Chemother Pharmacol 31(3):247–250. https://doi.org/10.1007/bf00685555
Le Tourneau C, Stathis A, Vidal L, Moore MJ, Siu LL (2010) Choice of starting dose for molecularly targeted agents evaluated in first-in-human phase I cancer clinical trials. J Clin Oncol 28(8):1401–1407. https://doi.org/10.1200/JCO.2009.25.9606
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RKM, DY, DB, and RP are employees of Pfizer and hold Pfizer stock or stock options.
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Mittapalli, R.K., Yin, D., Beaupre, D. et al. Starting dose selection and dose escalation for oncology small molecule first-in-patient trials: learnings from a survey of FDA-approved drugs. Cancer Chemother Pharmacol 87, 23–30 (2021). https://doi.org/10.1007/s00280-020-04202-0
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DOI: https://doi.org/10.1007/s00280-020-04202-0