Journal of Clinical Oncology, Vol 26, No 2 (January 10), 2008: pp. 170-171
© 2008 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2007.14.5052
3 + 3  (Rolling) 6
Christine Hartford,
Samuel L. Volchenboum,
Susan L. Cohn
Department of Pediatrics, The University of Chicago, Chicago, IL
Despite significant outcome improvements that have been made over the last few decades in the field of pediatric oncology, cancer remains the most common fatal disease of childhood.1 New, more effective treatment strategies with the potential for a wider therapeutic index are desperately needed for children who fail to respond to current approaches. However, the process of developing new anticancer drugs for childhood malignancies is particularly challenging because of the relative rarity of these cancers and the resulting limited number of pediatric patients eligible for pharmaceutical trials. In addition, compared with adult malignancies, the current paradigm for early-phase clinical trials results in an inherently longer timeline for the development of new agents for children with cancer. New initiatives are necessary to stimulate the development of novel therapeutics for pediatric indications and to facilitate efficient drug testing in a manner that does not compromise safety.
The existing model of anticancer drug development requires that an agent first undergo testing in the adult population. Once the adult maximum-tolerated dose (MTD) is determined, the agent is tested in children, with the starting dose at 80% of the adult MTD. This is, of course, dependent on sufficient interest on the part of drug companies to test the agent in the pediatric population. If this is the case, then the traditional 3 + 3 trial design is most commonly followed. With this design, cohorts of three patients are enrolled onto a particular dose level and, depending on the rate and severity of toxicities demonstrated in these three patients, the dose may or may not be escalated further to determine the MTD. While the toxicity data are being evaluated in the cohort of three patients, accrual to the study is suspended. The benefit of this model is that substantial toxicity information is known before a child is exposed to a new agent. In addition, because the dose at which pediatric patients are first treated is relatively high, there is a greater likelihood that the dose will be efficacious. However, this model also increases the development timeline of new agents for childhood cancers, and many drugs that may be effective and safe in pediatric patients are never tested in this cohort.
In this issue, Skolnik et al2 introduce a novel phase I trial design that may decrease the duration of pediatric phase I studies without increasing the risk of toxicity. The model is based on an extensive analysis of prior pediatric phase I studies by Lee et al,3 which revealed that the average number of patients treated at each dose level was 5.1, the average number of dose levels studied was 4.6, and the eventual pediatric MTD ranged from 0.7 to 1.6 times the adult MTD. The analysis also demonstrated a toxic death rate of 0.5% for single-agent phase I trials.3 This result differed from the toxic death rates as high as 2.5% in a meta-analysis of pediatric drug studies by Furman et al.4 Thus, the precise toxic rate remains unclear. In the proposed pediatric phase I schema, called rolling six, patients are continually accrued based on the data available at the time of enrollment, allowing up to six patients to be enrolled at a time, increasing the dose level in accordance with patient data at the time of accrual. The authors hypothesize that this design would shorten the time to determine MTD while minimizing toxic deaths.
To validate their hypothesis, Skolnik et al2 used discrete event simulation, a technique for modeling complex systems where individual events can occur at specific times. Although this method has been used to model many facets from medicine, including vaccination programs, patient tracking and scheduling systems, and public health initiatives, there are no published reports of this method used to model an algorithm for phase I clinical drug trials. Using data from 12 completed phase I Children's Oncology Group studies, the authors simulated 1,000 clinical trials using the 3 + 3 and rolling six designs. They assigned a sliding scale of dose-limiting toxicity (DLT) risk according to the dose level. In addition, each patient was assigned several time variables, including interpatient arrival time, study start time, time to DLT, time to inassessability, and study evaluation period time. To model different clinical scenarios, they modulated these times as well as the risk of DLT. In all scenarios, the rolling six design outperformed the 3 + 3 method in key metrics such as the time to complete the study. On average, three more patients were enrolled onto the rolling six trials, and there were no differences in the rates of DLTs. It should be noted, however, that the statistical significance of the findings is not clear, and either larger simulated analyses or actual clinical studies will be needed to determine whether the rolling six method indeed shortens the study time.
Of course, any new method must be shown to be as safe as prior designs. In general, pediatric MTDs are found to be similar to (and often greater than) adult MTDs.3 Nevertheless, there have been cases in which children have differed significantly from adults in their susceptibility to toxic adverse effects. For instance, children were especially vulnerable to the CNS toxicities of all-trans-retinoic acid, which was not predictable from the adult phase I data.5 Thus, it is possible that, in the proposed trial design, more children would experience adverse effects than in a traditional 3 + 3 study format. Nevertheless, the proposed new paradigm for pediatric phase I drug evaluation is intriguing and merits further study to confirm its efficacy and safety.
Pediatric oncologists are confronted with the challenge of testing new agents in as few patients as possible, in a way that is as safe as possible, and over a timeline that is as short as possible. Novel strategies will be needed to successfully meet this challenge, especially in a time when new classes of targeted agents require new definitions of study end points and response criteria. At the University of Chicago, we are collaborating closely with our medical colleagues in the phase I program for adult cancer to expedite the access of promising new agents to children. The eligibility criteria of several adult phase I studies have been amended to include minors, aged 14 to 18 years, once the MTD has been determined. If a drug is proven to be safe in the adolescent cohort, we plan to expand the eligibility criteria further to allow younger children to enroll. Pediatric investigators have a long history of developing new paradigms for clinical cancer research, and the significant improvement in survival for common childhood cancers has resulted from the clinical trials conducted in the Children's Oncology Group and other pediatric cooperative group consortiums. To ensure further progress in the care of children with cancer, new paradigms that will evaluate the efficacy of novel anticancer agents in a safe and timely manner must be developed and implemented.
Authors' Disclosures of Potential Conflicts of Interest
The author(s) indicated no potential conflicts of interest.
Author Contributions
Conception and design: Susan L. Cohn
Data analysis and interpretation: Christine Hartford, Samuel L. Volchenboum, Susan L. Cohn
Manuscript writing: Christine Hartford, Samuel L. Volchenboum, Susan L. Cohn
Final approval of manuscript: Christine Hartford, Samuel L. Volchenboum, Susan L. Cohn
REFERENCES
1. Ries LAG, Melbert D, Krapcho M, et al: SEER cancer statistics review, 1975-2004. http://seer.cancer.gov/csr/1975_2004/ 2. Skolnik JM, Barrett JS, Jayaraman B, et al: Shortening the timeline of pediatric phase I trials: The rolling six design. J Clin Oncol 26:190-195, 2008[Abstract/Free Full Text] 3. Lee DP, Skolnik JM, Adamson PC: Pediatric phase I trials in oncology: An analysis of study conduct efficiency. J Clin Oncol 23:8431-8441, 2005[Abstract/Free Full Text] 4. Furman WL, Pratt CB, Rivera GK, et al: Mortality in pediatric phase I clinical trials. J Natl Cancer Inst 81:1193-1194, 1989[Free Full Text] 5. Mahmoud HH, Hurwitz CA, Roberts WM, et al: Tretinoin toxicity in children with acute promyelocytic leukaemia. Lancet 342:1394-1395, 1993[CrossRef][Medline]
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