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Design, Conduct, and Interpretation of Organ Impairment Studies in Oncology Patients

Institute for Drug Development at the Cancer Therapy and Research Center, San Antonio, TX

Alain C. Mita

University of Texas Health Science Center, San Antonio, TX

To the Editor:

The recent editorial by Drs Rahman and White¹ raises some important issues and provides a valuable perspective on the design and conduct of organ dysfunction studies in oncology patients. Because the basis for their comments is our study of pemetrexed in patients with renal impairment,² we would like to elaborate on the issues raised in their thoughtful editorial.

As noted by Drs Rahman and White, our study had two major limitations inherent to this type of trial. First, it was difficult to accrue full cohorts of renally impaired cancer patients in a two center trial conducted over a 2-year time period. The number of protocol eligible cancer patients with impaired organ function is limited, making timely completion of these types of studies a challenge. Currently, we strongly support the conduct of these trials in well-coordinated, multicenter groups comprised of experienced phase I investigators. For example, the National Cancer Institute's Organ Dysfunction Working Group³ and the Southwest Oncology Group Early Therapeutics Committee have established records of accomplishment for conducting these studies efficiently at up to 12 centers over a 15-month period. A second limitation is the difficulty in assessing dose-related toxicity end points in this population. Unlike standard phase I trials, where the recommended doses are examined in additional phase II and III clinical studies, dosing recommendations in organ impaired cancer patients are seldom confirmed in subsequent clinical trials because of the obvious logistical issues. Thus, organ dysfunction trials represent a limited window of opportunity to get the dose correct for this select population. Furthermore, we agree that dosing recommendations extrapolated from small numbers of patients may be flawed, even when using accepted phase I study designs. However, clinical dosing recommendations are strengthened considerably when augmented by supporting pharmacokinetic data demonstrating uniform systemic drug exposures across cohorts of organ dysfunction patients. In our study, toxicity assessments were further complicated by the implementation of folic acid supplementation during the middle of this trial. This alteration was mandated for all ongoing pemetrexed studies after the recognition that folic acid supplementation ameliorates some drug related toxicities.⁴

Despite these acknowledged shortcomings, we feel the final recommendations of our trial are both warranted and based on a sound rationale. As stated in the report, we successfully accrued 15 patients to the cohort defined by a glomerular filtration rate (GFR) between 40 mL/minute and 59 mL/minute. These patients were evenly distributed throughout this GFR range and three patients fell into the relatively narrow window of a GFR from 40 mL/minute to 45 mL/minute. Our clinical toxicity assessment and pharmacokinetic analyses indicate that differences in pemetrexed clearance in patients with GFRs greater than 40 mL/minute are insufficient to warrant dose adjustments. As a consequence, these patients can be safely treated with the recommended dose of 500 mg/m². In addition, because of the difficulties in patient accrual, we did not completely fill all the patient cohorts. Only five patients instead of six were treated at 600 mg/m² in the GFR 60 mL/minute to 79 mL/minute cohort and one patient experienced dose-limiting toxicity. Thus, in the absence of a complete cohort, it is not prudent to recommend the higher dose level. Furthermore, the recommendation of a higher dose would directly contradict the US Food and Drug Administration-approved dose of 500 gm/m² of pemetrexed administered with vitamin supplementation to patients with healthy renal function. The important issue of whether the dose of pemetrexed with folic acid can be escalated further in this patient population must be addressed in additional clinical studies. A phase I trial specifically addressing this question has been recently completed and these data are being analyzed.⁵

We are in general agreement with some of the final recommendations made by Drs Rahman and White. Ultimately, organ dysfunction studies are clinical pharmacokinetic and pharmacodynamic experiments. They represent the rational prospective attempts to collect clinically useful dosing information from a difficult to study patient population and to formulate dosing recommendations based on these data. Given such limitations, the following recommendations are prudent. The design of these trials should be based on all the pharmacokinetic and clinical information available at the time of the study design. Starting doses and planned dose adjustments should be based on expected changes in drug clearance that are considered to be clinically relevant, and the overall study design should attempt to achieve uniform systemic drug exposures in all organ dysfunction cohorts. The targeted range systemic exposures should correspond to those achieved in previously studied control patients with healthy organ function. If the margin of safety is expected to be narrow, then accrual to the most severe cohort can be deferred until adequate safety and pharmacokinetic information is obtained in the less impaired groups. However, this restriction will extend the study duration by limiting the time available to accrue the most difficult to enroll patients.

Where we differ slightly from Drs Rahman and White is in their conclusion that the pharmacokinetic profile be the primary end point and toxicity be considered secondary in organ dysfunction studies. We recommend that both pharmacokinetic and clinical toxicity data be carefully analyzed together to define the relationship between drug clearance and organ function, and the relationship between systemic exposure and drug toxicity and/or efficacy. Thus, both pharmacokinetic and toxicity assessments are equally important in the conduct of these trials. Furthermore, these organ dysfunction studies are invaluable as a bridge to the larger body of pharmacokinetic and pharmacodynamic information collected in phase I through III studies. Finally, we agree with Drs Rahman and White that we need to do these studies during drug development for all oncologic agents with relevant clinical toxicities so that this critical information is available at the time of product approval and labeling, and most importantly, we need to do them in the most optimal way possible.

Authors' Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Chris H. Takimoto Eli Lilly and Company (B)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

REFERENCES

1. Rahman A, White RM: Cytotoxic anticancer agents and renal impairment study: The challenge remains. J Clin Oncol 24:533-536, 2006[Free Full Text]

2. Mita AC, Sweeney CJ, Baker SD, et al: 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[Abstract/Free Full Text]

3. Takimoto CH, Remick SC, Sharma S, et al: Administration of oxaliplatin to patients with renal dysfunction: A preliminary report of the national cancer institute organ dysfunction working group. Semin Oncol 30:20-25, 2003[Medline]

4. Niyikiza C, Baker SD, Seitz DE, et al: Homocysteine and methylmalonic acid: Markers to predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther 1:545-552, 2002[Abstract/Free Full Text]

5. 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 Am Soc Clin Oncol 22:133, 2003 (abstr 532)

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