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What Is the Right Dose? The Elusive Optimal Biologic Dose in Phase I Clinical Trials

Department of Oncology, Mayo Clinic, Rochester, MN

Phase I trials aim to determine the optimal dose of a new compound for subsequent testing in phase II trials. With cytotoxic agents, this dose typically corresponds to the highest dose associated with an acceptable level of toxicity, based on the underlying assumption stemming from the work of Skipper et al^1,2 that the higher the dose, the greater the likelihood of drug efficacy. In addition to the relationship between dose and antitumor response, cytotoxic agents also exhibit a dose-toxicity relationship. Thus, dose-related toxicity is regarded as a surrogate for efficacy.

Advances in molecular biology have led to a new generation of anticancer agents that inhibit aberrant and cancer-specific proliferative and antiapoptotic pathways. These agents may be cytostatic and may produce relatively minimal organ toxicity, compared with standard cytotoxics. This has fueled interest in alternatives to toxicity as a surrogate end point in phase I trials. The concept of an optimal biologic dose,³ defined as a dose that reliably inhibits a drug target or achieves a target plasma concentration, is seen as desirable and appropriate for the phase I study of mechanism-based, relatively nontoxic novel agents. This idea is appropriate if certain inherent problems can be resolved. In the case of a pharmacokinetic end point, it has to be shown that the target concentration chosen can inhibit the drug target in patient tumors. This requires accounting for plasma protein binding, which determines the amount of free drug available to interact with the target, as well as interindividual variations in drug absorption and metabolism. When target modulation is chosen as the end point, the drug target, as well as the magnitude of inhibition necessary for clinical benefit, has to be known. Finally, although target inhibition in normal tissue may provide important supplementary information, critical drug development decisions will need to be made with information gleaned from target suppression in tumor samples.⁴

In this issue of the Journal of Clinical Oncology, Carducci et al⁵ describe a multicenter phase I study of enzastaurin, a small-molecule inhibitor of the serine/threonine kinase protein kinase C beta (PKC-β). No classical toxicity-based maximum-tolerated dose (MTD) was defined up to a dose of 700 mg/d in this 47-patient study. Total enzastaurin exposure increased with increasing concentration up to 240 mg and appeared to reach a plateau at 525 and 700 mg. On the basis of plasma exposures, 525 mg was selected as the recommended phase II dose. This study illustrates the complexities of using a pharmacokinetically based end point in dose selection.

The investigators should be commended for selecting a target concentration based on the free fraction of drug which is the concentration that inhibits 90% (IC₉₀) of PKC-β activity, rather than the IC₅₀ values of total drug that typically are used in such studies. Thus a target mean steady-state total drug concentration of 1,400 nmol/L was chosen. The problems with this approach, however, are three-fold. First, the IC₉₀ values were defined from in vitro analysis. The IC₉₀ for inhibiting PKC in vivo is unknown. Data in normal tissue (peripheral-blood mononuclear cells) ex vivo are presented for only four patients. Therefore, the target drug concentration chosen may not be optimal. Second, there are no data indicating that the target dose of 1,400 nmol/L can inhibit the kinase activity of PKC-β in patient tumors. Third, substantial interpatient variability exist in the plasma profiles of enzastaurin. Thus, at the MTD, seven of the 12 patients had plasma levels at or above the target concentration, whereas five had levels below the target concentration.

It is known that genetic polymorphisms in drug-metabolizing enzymes (in this case, CYP3A4), as well as drug transporters, can lead to variations in plasma drug levels. These polymorphic enzyme variants are crucial with oral anticancer agents, which are usually dosed at a flat rate. Clearly, if enzastaurin were ineffective at a dose of 525 mg/d in phase II studies, an unanswered question would be whether this is the optimal dose. Although steady-state concentrations argued against escalating doses above 525 mg/d, an attempt could be made to define a classical MTD by administering the drug with food and exploring split dosing (such as twice daily dosing). Both approaches may overcome the plateau in drug absorption.⁶ An optimal biologic dose should inhibit the target in patient tumors. Most importantly, there should be absolute certainty of the drug target, and there should be evidence that modulating the target in tumors consistently leads to growth inhibition. The selected dose should incorporate the fact that there will be wide variations in steady-state drug levels in patients.

Having outlined these issues, how does one select a phase II dose of a drug with minimal dose-dependent organ toxicities? Apart from immunotherapeutic agents, the development of which has been reviewed recently,⁷ it is debatable if many such agents currently exist. Most small-molecule inhibitors of cellular proteins will demonstrate chronic low-grade toxicities at high doses that preclude continuous dosing. Thus, the concept of MTD will need to be redefined as a dose that can be safely administered chronically. With this definition, an MTD can be established for most drugs. In the rare case of truly minimally toxic agents, the optimal dose may be defined by saturation in absorption, quantity of tablets to be ingested, or volume of drug to be infused, and other practical issues that would preclude dose escalation.

Given these topics of discussion, it is not surprising that in a review of 60 phase I studies of targeted agents, Parulekar and Eisenhauer⁸ found that the optimal biologic dose rarely formed the basis of dose selection. Ultimately, until we are able to incorporate modulation of validated drug targets in tumors into studies and use information on allelic variants of polymorphic genes responsible for drug transport and metabolism to select doses for individual patients, efforts have to be made to define the MTD of phase I agents based on classical definitions of cycle I toxicity, as well as toxicities from, and the feasibility of chronic administration. In the meantime, the quest for the Holy Grail of optimal biologic dose continues.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

1. Skipper HE, Schabel FM Jr, Wilcox WS: Experimental evaluation of potential anti-cancer agents XIII: On criteria and kinetics associated with "curability" of experimental leukemia. Cancer Chemother Rep 35:1, 1964[Medline]

2. Skipper HE, Schabel FM, Mellett LB, et al: Implications of biochemical, cytokinetic, pharmacologic, and toxicologic relationships in the design of optimal therapeutic schedules. Cancer Chemother Rep 54:431-450, 1970[Medline]

3. Shaked Y, Emmenegger U, Man S, et al: Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood 106:3058-3061, 2005[Abstract/Free Full Text]

4. Adjei AA. Biologic endpoints for early trials of novel anticancer agents, in Adjei AA, Buolamwini J (eds): Novel Anticancer Agents: Strategies for Discovery and Clinical Testing. Boston, MS, Elsevier (Academic Press), 2006, pp 249-262

5. Carducci MA, Musib L, Kies MS, et al: Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer. J Clin Oncol 24:4092-4099, 2006[Abstract/Free Full Text]

6. Lorusso PM, Adjei AA, Varterasian M, et al: Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 23:5281-5293, 2005[Abstract/Free Full Text]

7. Simon R: Clinical trial designs for therapeutic cancer vaccines. Cancer Treat Res 123:339-350, 2005[Medline]

8. Parulekar WR, Eisenhauer EA: Phase I trial design for solid tumor studies of targeted, non-toxic agents: Theory and practice. J Natl Cancer Inst 96:990-997, 2004[Abstract/Free Full Text]

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