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Journal of Clinical Oncology, Vol 24, No 21 (July 20), 2006: pp. 3510-3511 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.7199
In ReplyUS Food and Drug Administration, Silver Spring, MD We appreciate Drs Takimoto and Mita for continuing the dialogue on organ impairment studies in oncology patients.1 From their letter, we share common views but also have issues that require continued dialogue. Although we agree with Takimoto and Mita's concern about the difficulty in accruing renally impaired cancer patients in a timely manner to complete a study, it is more important to achieve one of the objectives of the study—dosing recommendations in renally impaired patients—which, from our perspective, did not occur for a number of reasons as described in our editorial.2 To reiterate,2 a major hurdle confounding the study3 was the addition of folate plus vitamin B12 supplementation in the middle of the study. In the preapproval decision making in the drug development process, it appeared that there was no accounting for the potential antagonism of the addition of folates to an antifolate (ie, at least without further dose escalation of the antifolate). In their renal impairment study, the ceiling dose of 600 mg/m2 pemetrexed was problematic with the addition of the vitamin supplementation. Before the mandated supplementation, in the patients who did not receive supplements, the target drug exposure should be equivalent to the exposure in patients with normal organ function. However, in the patients who received supplements, the same principle should hold—drug exposure equivalent to the exposure in patients with normal organ function—but in this case, the new ceiling dose was unknown or at least not indicated in their article, as well as, the new drug exposure parameters. Clearly, adding folate plus B12 supplementation to an antifolate (ie, pemetrexed) may shift the dose response of toxicity and efficacy, and in general, result in toleration of higher drug exposure by both healthy and neoplastic cells. This was, in part, supported, by in vitro4,5 and in vivo models and recent clinical data (ie, with vitamin supplementation, the dose of pemetrexed in heavily pretreated patients can be increased to 925 mg/m2; dose-limiting toxicity in cycle one in two of six patients).6 In the approved label, the recommendation of 500 mg/m2 of pemetrexed with folate plus B12 supplementation was not based on the benefit of information from additional pemetrexed dose escalation in the presence of folate plus B12 supplementation. In our view, Takimoto and Mita's study1 presented an opportunity to provide this information at least in patients with normal renal function if not also in patients with impaired renal function. Another point made in our editorial was that there are challenges in conducting renal impairment study of a cytotoxic agent with a narrow therapeutic window.2 With this in mind, we were not convinced with the recommendation for dosing in the 40 mL/minute to 45 mL/minute glomerular filtration (GFR) range based on results from Takimoto and Mita's article.3 No specific information has been provided on the three patients discussed who had a GFR of 40 mL/minute to 45 mL/minute (ie, GFRs, nonsupplemented or supplemented status, pharmacokinetics, or toxicities). We agree with Takimoto and Mita that "dosing recommendations extrapolated from small numbers of patients may be flawed."2 All six of the patients entered in the 400 mg/m2 GFR cohort of 40 mL/minute to 59 mL/minute were nonsupplemented patients; one patient had dose-limiting toxicities. Eight of nine patients entered in the 500 mg/m2 GFR cohort of 40 mL/minute to 59 mL/minute were patients who received supplements; none of these patients had dose-limiting toxicities. In addition, the steep slope in the relationship between pemetrexed plasma clearance and GFR rate in Takimoto and Mita's article (Fig 2)3 warranted a careful dose selection for patients with low GFR. Thus, Takimoto and Mita's proposed recommendation would be based on an unplanned analysis of a limited and incomplete database derived from a study with limitations described above. The only clinical and pharmacokinetic information available below this GFR level was from one patient with a GFR of less than 20 mL/minute who died. The other safety concern was the possible negation of any efficacy because of supplementation and nondose escalation of the drug to achieve drug exposure with efficacy in the presence of supplementation. Finally, in general, we believe that in the case of organ dysfunction studies, pharmacokinetics should be the primary end point with toxicity the secondary end point. The variability in the clearance of a drug is likely to be less than the variability in toxicity. Nevertheless, in agreement with Takimoto and Mita, both data sets should be analyzed together. However, the first measurable event in the patient with organ dysfunction is pharmacokinetics. The change in pharmacokinetics may herald events to come in toxicity. For example, the pharmacokinetics from the patient who died (Fig 1A of Takimoto and Mita's article) gave an early signal (if available before the death of the patient) that the pemetrexed elimination was markedly delayed. Had this profile been obtained from a patient receiving methotrexate, another antifolate, leucovorin rescue would have been administered. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. ACKNOWLEDGMENTS The views expressed in this article are those of the authors and do not necessarily reflect the official views of the US Food and Drug Administration. REFERENCES
1. Takimoto CH, Mita AC: Design, conduct, and interpretation of organ impairment studies in oncology patients. J Clin Oncol 24:3509-3510, 2006 2. Rahman A, White RM: Cytoxic anticancer agents and renal impairment study: The challenge remains. J Clin Oncol 24:533-536, 2006 3. Mita AC, Sweeney CJ, Baker SD, et al: A phase I and pharmacokinetic study of pemetrexed administered every 3 weeks to advanced cancer patients with normal and impaired renal function. J Clin Oncol 24:552-562, 2006 4. Backus HHJ, Pinedo HM, Wouters D, et al: Folate depletion increases sensitivity of solid tumor cell lines to 5-fluorouracil and antifolates. Int J Cancer 87:771-778, 2000[CrossRef][Medline] 5. Worzalla JF, Shih C, Schultz RM, et al: Role of folic acid in modulating the toxicity and efficacy of the multitargeted antifolate, LY231514. Anticancer Res 18:3235-3240, 1998[Medline] 6. Hammond LA, Forero L, Beeram M, et al: Phase I study of pemetrexed (LY231514) with vitamin supplementation in patients with locally advanced or metastatic cancer. Proc Amer Soc Clin Oncol 22:133, 2003 (abstr 532)
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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