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Originally published as JCO Early Release 10.1200/JCO.2007.15.5192 on March 10 2008 © 2008 American Society of Clinical Oncology.
Dose Selection in Phase I Studies: Why We Should Always Go for the TopDepartment of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands The primary objective of phase I studies is the selection of a drug dose to be further explored in subsequent trials. For traditional cytotoxic agents, increased exposure to a drug augments tumor-cell kill in preclinical models. This dose-response relationship in preclinical models was extrapolated to humans as a consequence of which "the more the better" approach became one of the most popular in oncology. In phase I studies, the maximum tolerated dose (MTD) of a drug is established through carefully escalating drug doses and it is this dose that is used in subsequent studies. In recent years, we have witnessed a major shift from conventional cytotoxic agents to molecular targeted drugs. Through tremendous expansion of our understanding of cellular processes, notably signal transduction pathways, factors underlying the pathogenesis of various tumor types have been gleaned. This progress also enabled drugs to be designed inhibiting specific tumor driven factors, thereby aiming for tumor specificity and avoidance of toxicity. At the same time, molecular biomarkers were introduced that may act as sensitive molecular indicators revealing target inhibitions or downstream effects. Mainly driven by a wave of pessimism because of the failure of high-dose chemotherapeutic regimens and, simultaneously, a wave of optimism because of the advent of molecularly targeted drugs, it was suggested that biomarkers should guide us in selecting the proper doses from phase I trials. After all, why should we treat patients with molecularly targeted drugs at the MTD, thereby exposing them to more adverse effects, while at lower doses the target has been inhibited to the maximum? As a result, new terms such as optimal biologic dose or biologically active dose were introduced.
The serine/threonine kinase mammalian target of rapamycin (mTOR) is part of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mTOR pathway. mTOR plays a pivotal role in integrating a variety of cellular signals such as the presence of growth factors or nutrient levels to control various cellular processes including cell proliferation, cell survival, and angiogenesis.1 Cellular effects of mTOR activation are mediated by phosphorylation of several downstream pathways and substrates including ribosomal S6 kinase 1 (S6K1) and the complex of eukaryotic initiation factor 4E (eIF-4E) and its binding protein (4E-BP1) that both govern protein translation. Through phosphorylation of 4E-BP1, this protein dissociates from eIF-4E thereby enabling the formation of a new complex consisting of eIF-4E with eIF-4F and eIF-4G which in its turn results in protein translation. Likewise, phosphorylation by mTOR activates S6K1 which then phosphorylates the S6 protein of the small ribosomal subunit enabling the subunit to participate in ribosome formation and hence protein synthesis.1 Since several of these factors can be measured in multiple tissues, while in a rat model suppression of tumor growth by an mTOR-inhibitor was correlated with reduced phosphorylation of 4E-BP1 and S6K1 in tumors and peripheral blood mononuclear cells (PBMCs),2 these factors were thought to serve as biomarkers for monitoring mTOR inhibition. In addition to these factors, mTOR acts via hypoxia inducible factor-1 In this issue of the Journal of Clinical Oncology, three articles addressing the mTOR inhibitor everolimus (RAD001) appear. Tanaka et al3 describe the development and use of a pharmacokinetic (PK)/pharmacodynamic (PD) model enabling the prediction of relationships among drug doses, concentrations, and effects. The model was computed using PK data and S6K1 activity measurement in PBMCs from patients with cancer and rats together with S6K1 activity in tumors from rats.3 The second study is a phase I study from O'Donnell et al4 in which everolimus was explored at weekly doses up to 70 mg. S6K1 activity, serving as a biomarker, was measured in PBMCs. All tested weekly doses were tolerated and no MTD was revealed. Because S6K1 activity in PBMCs was found to be sufficiently inhibited for at least 7 days at 20 mg weekly, this dose was considered an appropriate starting dose for subsequent studies. As the PK/PD model of Tanaka et al3 suggested that daily doses of everolimus are more potent than weekly doses, daily administered everolimus was assessed as well. Both 5- and 10-mg daily were well tolerated. According to the PK/PD model, both doses would completely inhibit S6K1 activity, rendering 5-mg daily as the recommended starting dose for further exploration.4 The third study is from Tabernero and collaborators5 who also performed a phase I study assessing weekly and daily everolimus. Pre- and on-treatment skin and tumor biopsies were taken to determine biomarker expression including phosphorylated S6, eIF-4G, and 4E-BP1. In contrast to O'Donnell et al,4 weekly everolimus at 70 mg appeared to be too toxic as the number of dose-limiting toxicities that was encountered exceeded the number allowed for MTD. The lower weekly and the daily doses explored were well tolerated. Importantly, findings between skin and corresponding tumor samples were consistent for the assessed biomarkers. A near complete inhibition of S6 and eIF-4G activity in both skin and tumor samples at doses of 10 mg/d and 50 mg/wk led to the recommendation that these doses should be explored further.5 The authors of these three articles have to be applauded for these studies incorporating extensive translational research. Remarkably, instead of the MTD, the observed effects on biomarkers played a major, if not crucial, role in the dose recommendation for further studies. In clear contrast to phase I studies with traditional cytotoxic agents, identification of the MTD was not even an objective in these studies. This raises the important question: in this era of molecularly targeted drugs, does dose selection based on outcomes from biomarker studies alone suffice or do we still need to establish the MTD?
Despite all major leaps in cellular and molecular biology, there is currently no agent for which a biomarker has been identified that is known to adequately reflect antitumor activity of that particular agent in humans. This includes mTOR inhibitors such as everolimus. Although in experimental rat models with everolimus-sensitive tumors, antitumor activity paralleled effects on S6K1 and 4E-BP1 phosphorylation in PBMCs and tumors,2,3 we do not yet know whether this is applicable to humans. It is likely that inhibition of other downstream pathways of mTOR, such as through hypoxia inducible factor-1 However, even if all issues surrounding biomarkers can be solved, we still should not discard the MTD. To determine whether the optimal dose of a drug is the MTD or a lower, biologically active dose, obviously requires randomized studies. Such studies are very scarce at present. With respect to mTOR inhibitors, three different doses of temsirolimus (CCI-779) were assessed in a randomized phase II in patients with refractory advanced renal cell carcinoma.7 Differences between the doses in terms of toxicity or efficacy were not seen, but this is not unexpected because this study was not adequately powered to assess differences. Robust data are available for the molecularly targeted drug imatinib, which compares the MTD to a lower dose. In a phase I study in patients with advanced gastrointestinal stromal tumors (GISTs), the MTD of imatinib was identified as 800 mg.8 Because in single-arm studies imatinib at a lower dose of 400 mg clearly exhibited antitumor activity against GISTs, two randomized trial phase III studies compared 400 mg with 800 mg imatinib. A meta-analysis from these studies revealed only a small difference in median progression-free survival (PFS) favoring the MTD (800 mg) over 400 mg imatinib. Overall survival was equivalent for both doses.9 Thus, at first glance, it seems like a lower dose of imatinib is not much worse than imatinib at the MTD, while the MTD is characterized by more profound toxicities. However, the same meta-analysis demonstrated that, in contrast to other patients, patients with c-KIT exon-9 mutated GISTs benefit considerably more from imatinib at 800 mg than at 400 mg.9 In addition, escalation to 800 mg imatinib in patients progressing during treatment with imatinib at 400 mg yields a substantial number of the patients to reach durable progression-free periods.10 Consequently, although many patients with GISTs fare well on imatinib at a lower dose than the MTD, treatment with imatinib at the MTD is highly relevant for particular subgroups. Without previously identifying the MTD of imatinib in phase I studies, our insights into managing GISTs would not have reached the level of knowledge it is today. It is unlikely that this holds true for imatinib only; for other molecularly targeted drugs, such as sunitinib and sorafenib, evidence is accumulating that the higher the dose, the better the outcome.11,12 Also with respect to mTOR inhibitors, it may be possible that doses higher than those established in phase I studies as optimal biologic ones yield a better outcome for particular subgroups. In summary, there are currently too many uncertainties to solely rely on biomarkers for dose selection. But even if biomarkers allow us to properly select biologically active doses, information on the highest achievable doses of a drug is still pivotal for the optimal use and further exploration of that drug. Each phase I study, including those with molecularly targeted drugs, should aim to identify the MTD of the examined drug. That is why we always should go for the top. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Stefan Sleijfer, Wyeth Pharmaceuticals (U) Stock Ownership: None Honoraria: None Research Funding: Stefan Sleijfer, Novartis Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Stefan Sleijfer, Erik Wiemer Collection and assembly of data: Stefan Sleijfer, Erik Wiemer Data analysis and interpretation: Stefan Sleijfer, Erik Wiemer Manuscript writing: Stefan Sleijfer, Erik Wiemer Final approval of manuscript: Stefan Sleijfer, Erik Wiemer REFERENCES
1. Abraham RT, Gibbons JJ: The mammalian target of rapamycin signaling pathway: Twists and turns in the road to cancer therapy. Clin Cancer Res 13:3109-3114, 2007 2. Boulay A, Zumstein-Mecker S, Stephan C, et al: Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 64:252-261, 2004 3. Tanaka C, O'Reilly T, Kovarik JM, et al: Identifying optimal biologic doses of everolimus (RAD001) in cancer patients based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 26:1596-1602, 2008 4. O'Donnell A, Faivre S, Burris III HA, et al: A phase I pharmacokinetic and pharmacodynamic study of the oral mTOR inhibitor everolimus (RAD001) in patients with advanced solid tumors. J Clin Oncol 26:1588-1595, 2008 5. Tabernero J, Rojo F, Calvo E, et al: Dose- and schedule-dependent inhibition of the mTOR pathway with everolimus: A phase I tumor pharmacodynamic study in patients with solid tumors. J Clin Oncol 26:1603-1610, 2008 6. Mabuchi S, Altomare DA, Cheung M, et al: RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin Cancer Res 13:4261-4270, 2007 7. Atkins MB, Hidalgo M, Stadler WM, et al: Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22:909-918, 2004 8. Van Oosterom AT, Judson I, Verweij J, et al: Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: A phase I study. Lancet358:1421-1423, 2001[CrossRef][Medline] 9. Van Glabbeke M, Owzar K, Rankin C, et al: Comparison of two doses of imatinib for the treatment of gastrointestinal stromal tumors (GIST): A meta-analysis based on 1640 patients. J Clin Oncol 25:546s, 2007 (suppl; abstr 10004) 10. Zalcberg JR, Verweij J, Casali PG, et al: Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 41:1751-1757, 2005[CrossRef][Medline] 11. Houk BE, Bello CL, Michaelson MD, et al: Exposure-response of sunitinib in metastatic renal cell carcinoma (mRCC): A population pharmacokinetic/ pharmacodynamic (PKPD) approach. J Clin Oncol 25:5027, 2007 12. Amato RJ, Harris P, Dalton M, et al: A phase II trial of intra-patient dose-escalated sorafenib in patients (pts) with metastatic renal cell cancer (MRCC). J Clin Oncol 25:241s, 2007 (suppl; abstr 5027)[CrossRef]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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, which stimulates the production of oncogenic proteins such as vascular endothelial growth factor and transforming growth factor 
