Pediatric Phase I Trials in Oncology: An Analysis of Study Conduct Efficiency
http://www.100md.com
《临床肿瘤学》
the Division of Clinical Pharmacology & Therapeutics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA
ABSTRACT
PURPOSE: To determine the efficacy and safety of pediatric phase I oncology trials in the era of dose-intensive chemotherapy and to analyze how efficiently these trials are conducted.
METHODS: Phase I pediatric oncology trials published from 1990 to 2004 and their corresponding adult phase I trials were reviewed. Dose escalation schemes using fixed 30% dose increments were studied to theoretically determine whether trials could be completed utilizing fewer patients and dose levels.
RESULTS: Sixty-nine pediatric phase I oncology trials enrolling 1,973 patients were identified. The pediatric maximum-tolerated dose (MTD) was strongly correlated with the adult MTD (r = 0.97). For three-fourths of the trials, the pediatric and adult MTD differed by no more than 30%, and for more than 85% of the trials, the pediatric MTD was less than or equal to 1.6 times the adult MTD. The median number of dose levels studied was four (range, two to 13). The overall objective response rate was 9.6%, the likelihood of experiencing a dose-limiting toxicity was 24%, and toxic death rate was 0.5%.
CONCLUSION: Despite the strong correlation between the adult and pediatric MTDs, more than four dose levels were studied in 40% of trials. There appeared to be little value in exploring dose levels greater than 1.6 times the adult MTD. Limiting pediatric phase I trials to a maximum of four doses levels would significantly shorten the timeline for study conduct without compromising safety.
INTRODUCTION
Phase I studies in oncology are the critical first step in the clinical evaluation of novel anticancer agents. The primary objectives of such studies include describing and defining the toxicities of the drug, determining the maximum-tolerated dose (MTD) or recommended phase II dose, and studying the pharmacokinetics of the drug. Pediatric phase I studies are almost always performed following adult phase I trials.1 Although this delays the timeline of pediatric drug development, it offers the distinct advantage of having data available from adult patients for the design of the pediatric trial. The greatest impact of this is in defining the starting dose for the phase I trial. Whereas the starting dose for adult phase I trials are based on animal toxicology and are often at least an order of magnitude lower than the ultimate recommended dose,2,3 pediatric trials historically begin at approximately 80% of the adult MTD,4 greatly diminishing the likelihood that a pediatric patient would be enrolled at a biologically ineffective dose.
One would anticipate that with a prior knowledge of the adult MTD, pediatric phase I trials would meet their primary objectives in an efficient manner. However, there are no published reports examining the efficiency of conducting pediatric phase I trials. Furthermore, the historical recommended starting dose of 80% was empirically derived during an era when children were less heavily pretreated and, in general, could tolerate higher doses of cytotoxic drugs than adult patients.5
We, therefore, reviewed the published experience with pediatric phase I trials from 1990 to 2004, a reporting period that encompasses an era when dose-intensive therapy was routinely administered as initial therapy in pediatric patients with high-risk tumors. Our objectives were not only to determine the safety and tolerability of pediatric phase I trials but also to examine how efficiently such trials are conducted. As a number of biologic agents are currently being developed, we also sought to get an initial indication of the pediatric phase I experience utilizing standard trial designs that were developed for the evaluation of cytotoxic drugs.
METHODS
Literature Review
Full length phase I pediatric clinical oncology trials published from 1990 to 2004 were identified by National Library of Medicine Gateway searches of English-language reports using the key words "pediatric," "phase," "cancer," and "trial." References of select articles were also reviewed for phase I studies. Lastly, the Children's Oncology Group database was used to identify completed and published phase I studies.
Studies included in the analysis were single-agent dose escalation trials; studies examining multiple agents were included only if a single drug was escalated. Phase I/II studies were included if there was a clear dose escalation scheme with a MTD and dose-limiting toxicities (DLTs) identified within the patient population. For the purposes of this study, we classified a drug as biologic if preclinical data suggested a primary mechanism of action that was immunologic, differentiating, or occurred via inhibition of a signal transduction pathway. Intrathecal agents, nondose escalation studies, pharmacokinetic only studies, and bone marrow transplant studies were excluded.
The following data were extracted from each publication: drug name, schedule, route of administration, concomitant cytotoxic or biologic drugs, concomitant hematopoietic growth factors, patient age (median and range), diagnoses, whether the study included patients with leukemia or solid tumors, starting dose, total number of patients entered, total number of patients assessable for toxicity, total number of patients assessable for response, number of dose levels studied, definition of DLT, DLTs, MTD, dose level at which the MTD occurred, less heavily pretreated MTD and dose level (if applicable), recommended phase II dose, steady-state plasma drug clearance, number of partial (PRs) and complete (CRs) responses, and number of deaths attributed to study drug.
Pediatric Versus Adult Tolerability to Phase I Agents
Corresponding adult phase I studies were identified by searching the references of the pediatric publications. If no publication were identified, the National Library of Medicine database was searched and, if necessary, the National Cancer Institute's Cancer Therapy Evaluation Program was then queried. Adult studies were included in the analysis if the route and schedule of administration were the same as the pediatric study. For studies that utilized a nonstandard definition of MTD, the data were reanalyzed using the standard definition of MTD defined as the dose level below that at which greater than or equal to two out of three to six patients experienced DLT.
Efficiency of Study Conduct
The correlation between the adult and pediatric MTDs for cytotoxic and biologic agents was determined by regression analysis. As pediatric phase trials often escalate dose in increments of approximately 30%, the lower and upper bounds spanning three, four, or five theoretical dose levels that would capture at least 80% of the pediatric to adult MTD ratios was determined. The number of dose levels studied and the number of patients entered were tabulated.
Safety
The types of DLTs observed on pediatric versus adult studies were recorded. The number of patients experiencing DLT and the number of patient deaths were tabulated. Toxic deaths were defined as a death of study participant in which the drug was possibly, probably, or definitely related to drug.
Efficacy
Response data from each pediatric study were tabulated. For solid tumor studies, PRs were typically defined as a reduction of at least 50% in the sums of the products of the largest diameters of measurable lesions without the appearance of new lesions for 4 weeks. CRs were typically defined as the disappearance of all known disease for at least 4 weeks. PR for leukemic patients was defined as a bone marrow leukemic blast percentage of 5% to 25% for children with acute lymphoblastic leukemia and 5% to 40% for children with acute myelogenous leukemia and recovery of peripheral blood counts to an absolute neutrophil count of 1,000/μL and platelet count of at least 100,000/μL. A complete leukemic response was defined as less than 5% leukemic blasts in a normocellular or slightly hypocellular bone marrow with recovery of peripheral blood counts at least an absolute neutrophil count of 1,000/μL and platelet count of at least 100,000/μL within 1 week of bone marrow response. Some individual study response definitions did not include time length requirements, and some did not define their criteria for response.
Pharmacokinetics
The coefficient of variation (CV) in plasma drug clearance or apparent clearance was determined for each pediatric study using data derived from patients studied at either all dose levels or at the MTD. When clearance data were not reported, it was calculated, when possible, by dividing the dose by the area under the concentration-time curve. Plasma drug clearance in adult patients was compared with that observed in children by regression analysis.
RESULTS
Literature Review
Sixty-nine (53 cytotoxic and 16 biologic studies) pediatric phase I oncology trials evaluating 46 different anticancer agents published between January 1990 and December 2004 met eligibility criteria. Of these 69 trials, 55 were single-agent studies and 14 were multiagent studies. Nine studies were in patients with leukemia only (two biologic, seven cytotoxic), and 14 studies (five biologic, nine cytotoxic) were performed in patients with either solid tumors or leukemia (Tables 1 and 2) . These 69 studies enrolled 1,973 patients (52% males) with a median of 25 patients per study. Of the 1,973 patients enrolled, 1,779 patients (90.2%) were fully assessable for toxicity, and 1,809 patients (91.7%) were assessable for response. The overall median age of children enrolled onto these phase I studies was 10.9 years. Neuroblastoma was the most common diagnosis (Fig 1).
Pediatric Versus Adult Tolerability to Phase I Agents
Of the 55 single-agent trials, 11 (eight cytotoxic) were excluded from the pediatric and adult comparison aspect of the study. Reasons for exclusion included: no corresponding adult study using the same schedule (n = 7), use of hematopoietic growth factors (n = 1), no defined pediatric MTD (n = 2), and only examining dose-intensity (n = 1).
The 44 single-agent trials available for comparison were divided according to cytotoxic versus biologic compounds studied. The MTDs of both adult and pediatric corresponding studies are shown in Tables 1, 2, and 3. Thirty-six single-agent cytotoxic studies (Fig 2A) and eight biologic studies (Fig 2B) were compared. For three-fourths of the trials, the pediatric and adult MTDs differed by no more than 30%, and for more than 85% of the trials, the pediatric MTD was less than or equal to 1.6 times the adult MTD.
Efficiency of Study Conduct
The pediatric MTD was strongly correlated with the adult MTD (r = 0.97). Defining boundaries one potential dose level below (0.7-fold) and two potential dose levels above (1.6-fold) the adult MTD allowed for determination of studies that fell outside of a theoretical four-dose level range (Fig 3). For cytotoxic agents, two studies had a MTD ratio less than 0.7 (topotecan given as a 24-hour infusion6 and piritrexim7), and three studies had a MTD ratio greater than 1.6 (fazarabine,8 irinotecan,9 and acivicin10). For biologic agents, one study (all-trans retinoic acid11) had a pediatric to adult MTD ratio less than 0.7, and three (fenretinide,12 recombinant tumor necrosis factor,13 and interleukin-214) had MTD ratios greater than 1.6.
The number of patients enrolled and the number of dose levels per study are shown in Figures 4A and 4B. Sixty-seven studies delineated the number of patients enrolled at each dose level. Two hundred ten out of the 317 dose levels studied (66%) enrolled more than three patients. The average number of dose levels studied was 4.6 (median, four; range, two to 13), the average number of patients enrolled per dose level was 5.1 (median, five; range, two to 23), and the average number of pediatric patients enrolled onto a study was 29 (median, 25; range, 11 to 81).
Safety
There were sufficiently detailed DLT data available from 1,066 patients (47 studies) to estimate that the likelihood of a patient developing a DLT once enrolled onto a study was 24%. There were 10 toxic deaths (0.5% toxic death rate) across all studies. Further analysis of deaths attributed to drug show a mean of 0.14 deaths per study (median, zero; range, zero to three). All but two of the toxic deaths were at dose levels above the MTD, and of the remaining two, one was at the highest dose given in a study that did not reach an MTD and the other was at the MTD. Toxic deaths included one patient who died from intractable seizures and aspiration pneumonia, two from respiratory distress and hepatobiliary dysfunction, one from progressive midbrain dysfunction in which drug causality could not be ruled out, one from hepatic necrosis and encephalopathy, two from profound aplasia, and three patients with fulminant hepatic failure.
Efficacy
Objective responses were recorded in 67 trials. Forty out of the 67 studies representing 26 different drugs had at least one objective response. In total, there were 50 CRs and 123 PRs in the 1,809 patients assessable for response, for an overall objective response rate of 9.6%. The average number of responses observed on a study was 2.6 (median, one; range, zero to 15). When analyzed separately, the response rate for single-agent phase I studies was 6.8% and for multiagent phase I studies 20.1%. The dose levels at which responses were observed, however, were not routinely reported, and thus, no correlation could be made between response observed and dose level treated.
Pharmacokinetics
Twenty-one studies reported the necessary pharmacokinetic data to allow for calculation of CV in drug clearance (Table 3). The median CV in drug clearance was 42% (range, 11% to 69%). Plasma drug clearance in children was highly correlated with that observed in adults (r = 0.97), with a median ratio of pediatric to adult clearance (or apparent clearance) of 0.95. Despite the strong correlation, there was a wide range of ratios observed across studies (0.06 to 2.2).
DISCUSSION
With the exception of childhood leukemias, the proportion of diagnoses of children enrolling on pediatric phase I trials generally reflects the number of patients who experience a relapse of their disease (Fig 1). Patients with neuroblastoma, brain tumors, or sarcomas represented approximately two-thirds of patients enrolled on phase I trials. Multiple factors may contribute to the under-representation of children with leukemia on phase I trials, including the availability of varied salvage regimens, including stem-cell transplants, the rapidity of disease progression in recurrent leukemia, and phase I trial design limitations.
In an era when children with newly-diagnosed, high-risk malignancies are routinely treated with dose intensive regimens, the conduct of phase I trials in relapsed or refractory patients continues to be safe and relatively well-tolerated. Approximately one in four children enrolled onto a phase I trial experienced a DLT. Because the design of phase I trials in most circumstances necessitates the determination of a MTD, this degree of toxicity is anticipated and is significantly less than the 80% frequency of grade 3 or greater toxicity observed on many front-line multiagent regimens.16 Importantly, treatment-related mortality was less than 0.5%.
The likelihood of achieving an objective response when participating in a pediatric phase I trial was 9.6%. This is similar to the 7.9% objective response rate reported in pediatric phase I trials conducted in earlier eras17 but higher than the 3% to 6% objective response rate observed on phase I trials conducted in adult patients.18-22 Not surprisingly, and similar to phase I trials in adults,21 the response rate was higher in trials that combined an investigational drug with drugs with known anticancer activity (20.1%) versus an investigational drug alone (6.8%). It should be emphasized that the definition of direct patient benefit may extend beyond objective response, in the form of disease stabilization or symptom relief, and thus, the proportion of patients who derived direct benefit from participation on a phase I trial should not be equated to the observed response rate. However, data on symptom relief and disease stabilization have not historically been captured during the conduct of phase I trials, and thus, estimates of the fraction of patients who derive direct benefit, although greater than the response rate, cannot be made.
In general, the definition of nonhematologic DLTs was identical in adult and pediatric trials (data not shown). For the hematologic toxicity, however, often either a greater degree or a longer duration of myelosuppression was required in pediatric studies than in adult studies to qualify as a DLT. This may, in part, account for the higher MTDs occasionally observed in pediatric studies in which myelosuppression was dose-limiting.
The types of toxicities experienced by children enrolled onto phase I trials were, with few exceptions, the same as those experienced by adult patients (Tables 1 and 2). Not surprisingly, we also found a strong correlation between the MTD observed in adult patients and the MTD defined in pediatric patients (Fig 3). The correlation was stronger for cytotoxic drugs (r = 0.97) than for biologic agents (r = 0.3). However, one cannot conclude that differences in MTD, when observed, were the result of true differences in tolerability. For certain drugs, such as the retinoids,11,23,24 a difference in tolerability between adult and pediatric patients indeed appears to underlie the differences in MTD. Of the six drugs in which the pediatric MTD exceeded the adult MTD by a factor greater than 1.6, two (fazarabine,8 irinotecan6) had a ratio of only 1.7, and for the three biologic agents (fenretinide,12 rTNF,13 and IL-214), a difference in the definition of DLT was the major factor underlying the discordant MTDs. Of note, following completion of the fenretinide phase I pediatric trial, subsequent studies of fenretinide found that higher doses could also be tolerated in adult patients.25
Despite the strong correlation between the adult and pediatric MTD, 40% of studies enrolled patients onto more than four dose levels (Fig 4A), and 46% of studies required more than 25 assessable patients to reach their conclusion (Fig 4B). One would anticipate that for studies requiring more than four dose levels, the pediatric MTD would greatly exceed the adult MTD. However, we did not find this to be the case, as the pediatric MTD was less than two-fold the adult MTD for all of the cytotoxic drugs and all but two of the biologic drugs studied.
The primary reasons that such a high fraction of studies were not efficient in reaching their conclusion appears to be two-fold. First, the likelihood that the pediatric MTD would exceed the adult MTD by more than 1.6-fold is small (Figs 1A and 1B), making exploration of levels beyond this of little value. Secondly, many studies, either by initial design or by later modification, explored dose levels that differed from a previously studied dose level by increments significantly smaller than 30%.
On the basis of this analysis, we propose that changes in study design could increase the efficiency in which pediatric phase I trials are conducted. Unless it is anticipated that pediatric oncologists, patients, and families would be willing to have children tolerate significantly worse toxicities than those experienced on the corresponding adult phase I trial, there appears little value in exploring dose levels more than 1.6 times the adult MTD. Caveats to this recommendation are two-fold: if drug disposition (pharmacokinetics) differs significantly from adults, or if the toxicity profile in children is found to differ significantly from adults, higher (or potentially lower) dose levels might need to be explored. Secondly, attempts to fine-tune the recommendation for phase II dosing by examining increments of less than 30% should, in general, not be made during the conduct of the phase I study. Limiting pediatric phase I trials to the study of no more than four doses levels (0.7, 1.0, 1.3, and 1.6 times the adult MTD), would significantly shorten the timeline for the conduct of these studies and would be unlikely to result in a conclusion that differs substantively from trials that examine a greater number of dose levels.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Smith M, Bernstein M, Bleyer WA, et al: Conduct of phase I trials in children with cancer. J Clin Oncol 16:966-978, 1998
Goldsmith MA, Slavik M, Carter SK: Quantitative prediction of drug toxicity in humans from toxicology in small and large animals. Cancer Res 35:1354-1364, 1975
Grieshaber CK, Marsoni S: Relation of preclinical toxicology to findings in early clinical trials. Cancer Treat Rep 70:65-72, 1986
Marsoni S, Ungerleider RS, Hurson SB, et al: Tolerance to antineoplastic agents in children and adults. Cancer Treat Rep 69:1263-1269, 1985
Carlson L, Ho P, Smith M, et al: Pediatric phase I drug tolerance: A review and comparison of recent adult and pediatric phase I trials. J Pediatr Hematol Oncol 18:250-256, 1996
Blaney SM, Balis FM, Cole DE, et al: Pediatric phase I trial and pharmacokinetic study of topotecan administered as a 24-hour continuous infusion. Cancer Res 53:1032-1036, 1993
Adamson PC, Balis FM, Miser J, et al: Pediatric phase I trial and pharmacokinetic study of piritrexim administered orally on a five-day schedule. Cancer Res 50:4464-4467, 1990
Bernstein ML, Whitehead VM, Grier H, et al: A phase I trial of fazarabine in refractory pediatric solid tumors. A Pediatric Oncology Group study. Invest New Drugs 11:309-312, 1993
Mugishima H, Matsunaga T, Yagi K, et al: Phase I study of irinotecan in pediatric patients with malignant solid tumors. J Pediatr Hematol Oncol 24:94-100, 2002
Baruchel S, Bernstein M, Whitehead VM, et al: A phase I study of acivicin in refractory pediatric solid tumors. A Pediatric Oncology Group study. Invest New Drugs 13:211-216, 1995
Smith MA, Adamson PC, Balis FM, et al: Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer. J Clin Oncol 10:1666-1673, 1992
Garaventa A, Luksch R, Lo Piccolo MS, et al: Phase I trial and pharmacokinetics of fenretinide in children with neuroblastoma. Clin Cancer Res 9:2032-2039, 2003
Furman WL, Strother D, McClain K, et al: Phase I clinical trial of recombinant human tumor necrosis factor in children with refractory solid tumors: A Pediatric Oncology Group study. J Clin Oncol 11:2205-2210, 1993
Roper M, Smith MA, Sondel PM, et al: A phase I study of interleukin-2 in children with cancer. Am J Pediatr Hematol Oncol 14:305-311, 1992
Matthay KK, DeSantes K, Hasegawa B, et al: Phase I dose escalation of 131I-metaiodobenzylguanidine with autologous bone marrow support in refractory neuroblastoma. J Clin Oncol 16:229-236, 1998
Crist WM, Anderson JR, Meza JL, et al: Intergroup rhabdomyosarcoma study-IV: Results for patients with nonmetastatic disease. J Clin Oncol 19:3091-3102, 2001
Shah S, Weitman S, Langevin AM, et al: Phase I therapy trials in children with cancer. J Pediatr Hematol Oncol 20:431-438, 1998
Decoster G, Stein G, Holdener EE: Responses and toxic deaths in phase I clinical trials. Ann Oncol 1:175-181, 1990
Sekine I, Yamamoto N, Kunitoh H, et al: Relationship between objective responses in phase I trials and potential efficacy of non-specific cytotoxic investigational new drugs. Ann Oncol 13:1300-1306, 2002
Von Hoff DD, Turner J: Response rates, duration of response, and dose response effects in phase I studies of antineoplastics. Invest New Drugs 9:115-122, 1991
Horstmann E, McCabe MS, Grochow L, et al: Risks and benefits of phase I oncology trials, 1991 through 2002. N Engl J Med 352:895-904, 2005
Roberts TG Jr., Goulart BH, Squitieri L, et al: Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. JAMA 292:2130-2140, 2004
Adamson PC, Reaman G, Finklestein JZ, et al: Phase I trial and pharmacokinetic study of all-trans-retinoic acid administered on an intermittent schedule in combination with interferon-alpha2a in pediatric patients with refractory cancer. J Clin Oncol 15:3330-3337, 1997
Adamson PC, Widemann BC, Reaman GH, et al: A phase I trial and pharmacokinetic study of 9-cis-retinoic acid (ALRT1057) in pediatric patients with refractory cancer: A joint Pediatric Oncology Branch, National Cancer Institute, and Children's Cancer Group study. Clin Cancer Res 7:3034-3039, 2001
Puduvalli VK, Yung WK, Hess KR, et al: Phase II study of fenretinide (NSC 374551) in adults with recurrent malignant gliomas: A North American Brain Tumor Consortium study. J Clin Oncol 22:4282-4289, 2004
Sisson J, Shapiro B, Beierwaltes WH, et al: Treatment of malignant pheochromocytoma with a new radiopharmaceutical. Trans Assoc Am Physicians 96:209-217, 1983
Cunningham J, Bukowski RM, Budd GT, et al: 5-Fluorouracil and folinic acid: A Phase I-II trial in gastrointestinal malignancy. Invest New Drugs 2:391-395, 1984
Patel R, Newman EM, Villacorte DG, et al: Pharmacology and phase I trial of high-dose oral leucovorin plus 5-fluorouracil in children with refractory cancer: A report from the Children's Cancer Study Group. Cancer Res 51:4871-4875, 1991
Seifert P, Baker LH, Reed ML, et al: Comparison of continuously infused 5-fluorouracil with bolus injection in treatment of patients with colorectal adenocarcinoma. Cancer 36:123-128, 1975
Green DM, Krischer JP, Bell B, et al: Phase I study of a 120-hour continuous intravenous infusion of 5-fluorouracil in pediatric patients with recurrent solid tumors: A Pediatric Oncology Group study. Med Pediatr Oncol 18:321-324, 1990
Rubin E, Wood V, Bharti A, et al: A phase I and pharmacokinetic study of a new camptothecin derivative, 9-aminocamptothecin. Clin Cancer Res 1:269-276, 1995
Langevin AM, Casto DT, Thomas PJ, et al: Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: A Pediatric Oncology Group study. J Clin Oncol 16:2494-2499, 1998
Sridhar KS, Ohnuma T, Chahinian AP, et al: Phase I study of acivicin in patients with advanced cancer. Cancer Treat Rep 67:701-703, 1983
Prendiville J, Crowther D, Thatcher N, et al: A phase I study of intravenous bryostatin 1 in patients with advanced cancer. Br J Cancer 68:418-424, 1993
Weitman S, Langevin AM, Berkow RL, et al: A Phase I trial of bryostatin-1 in children with refractory solid tumors: A Pediatric Oncology Group study. Clin Cancer Res 5:2344-2348, 1999
Murgo A: Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, 2004
Falletta JM, Cushing B, Lauer S, et al: Phase I evaluation of diaziquone in childhood cancer. A Pediatric Oncology Group study. Invest New Drugs 8:167-170, 1990
Extra JM, Rousseau F, Bruno R, et al: Phase I and pharmacokinetic study of Taxotere (RP 56976; NSC 628503) given as a short intravenous infusion. Cancer Res 53:1037-1042, 1993
Blaney SM, Seibel NL, O'Brien M, et al: Phase I trial of docetaxel administered as a 1-hour infusion in children with refractory solid tumors: A collaborative pediatric branch, National Cancer Institute and Children's Cancer Group trial. J Clin Oncol 15:1538-1543, 1997
Hainsworth JD, Johnson DH, Frazier SR, et al: Chronic daily administration of oral etoposide–a phase I trial. J Clin Oncol 7:396-401, 1989
Mathew P, Ribeiro RC, Sonnichsen D, et al: Phase I study of oral etoposide in children with refractory solid tumors. J Clin Oncol 12:1452-1457, 1994
Pratt CB, Relling MV, Meyer WH, et al: Phase I study of flavone acetic acid (NSC 347512, LM975) in patients with pediatric malignant solid tumors. Am J Clin Oncol 14:483-486, 1991
Casper ES, Mittelman A, Kelson D, et al: Phase I clinical trial of fludarabine phosphate (F-ara-AMP). Cancer Chemother Pharmacol 15:233-235, 1985
Avramis VI, Champagne J, Sato J, et al: Pharmacology of fludarabine phosphate after a phase I/II trial by a loading bolus and continuous infusion in pediatric patients. Cancer Res 50:7226-7231, 1990
Abbruzzese JL, Grunewald R, Weeks EA, et al: A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491-498, 1991
Reid JM, Qu W, Safgren SL, et al: Phase I trial and pharmacokinetics of gemcitabine in children with advanced solid tumors. J Clin Oncol 22:2445-2451, 2004
Elliott TE, Buckner JC, Cascino TL, et al: Phase II study of ifosfamide with mesna in adult patients with recurrent diffuse astrocytoma. J Neurooncol 10:27-30, 1991
Pratt CB, Douglass EC, Kovnar EH, et al: A phase I study of ifosfamide given on alternate days to treat children with brain tumors. Cancer 71:3666-3669, 1993
Pratt CB, Meyer WH, Douglass EC, et al: A phase I study of ifosfamide with Mesna given daily for 3 consecutive days to children with malignant solid tumors. Cancer 71:3661-3665, 1993
Taylor S, Belt RJ, Haas CD, et al: Phase I trial of Indicine-N-Oxide on two dose schedules. Cancer 51:1988-1991, 1983
Ohnuma T, Sridhar KS, Ratner LH, et al: Phase I study of indicine N-oxide in patients with advanced cancer. Cancer Treat Rep 66:1509-1515, 1982
Whitehead VM, Bernstein ML, Vega R, et al: Phase I trial of indicine-N-oxide in children with leukemia and solid tumors: A Pediatric Oncology Group study. Cancer Chemother Pharmacol 26:377-379, 1990
Catimel G, Chabot GG, Guastalla JP, et al: Phase I and pharmacokinetic study of irinotecan (CPT-11) administered daily for three consecutive days every three weeks in patients with advanced solid tumors. Ann Oncol 6:133-140, 1995
Abigerges D, Chabot GG, Armand JP, et al: Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 13:210-221, 1995
Vassal G, Doz F, Frappaz D, et al: A phase I study of irinotecan as a 3-week schedule in children with refractory or recurrent solid tumors. J Clin Oncol 21:3844-3852, 2003
Rafi I, Boddy AV, Calvete JA, et al: Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors. J Clin Oncol 16:1131-1141, 1998
Estlin EJ, Pinkerton CR, Lewis IJ, et al: A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation. Br J Cancer 84:11-18, 2001
Wiernik PH, Schwartz EL, Einzig A, et al: Phase I trial of taxol given as a 24-hour infusion every 21 days: Responses observed in metastatic melanoma. J Clin Oncol 5:1232-1239, 1987
Hurwitz CA, Relling MV, Weitman SD, et al: Phase I trial of paclitaxel in children with refractory solid tumors: A Pediatric Oncology Group Study. J Clin Oncol 11:2324-2329, 1993
Uziely B, Jeffers S, Isacson R, et al: Liposomal doxorubicin: Antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 13:1777-1785, 1995
Marina NM, Cochrane D, Harney E, et al: Dose escalation and pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in children with solid tumors: A pediatric oncology group study. Clin Cancer Res 8:413-418, 2002
Laszlo J, Brenckman WD Jr, Morgan E, et al: Initial clinical studies of piritrexim. NCI Monogr 121-125, 1987
Feun LG, Savaraj N, Benedetto P, et al: Phase I trial of piritrexim capsules using prolonged, low-dose oral administration for the treatment of advanced malignancies. J Natl Cancer Inst 83:51-55, 1991
Adamson PC, Balis FM, Miser J, et al: Pediatric phase I trial, pharmacokinetic study, and limited sampling strategy for piritrexim administered on a low-dose, intermittent schedule. Cancer Res 52:521-524, 1992
LoRusso P, Foster BJ, Poplin E, et al: Phase I clinical trial of pyrazoloacridine NSC366140 (PD115934). Clin Cancer Res 1:1487-1493, 1995
Berg SL, Blaney SM, Adamson PC, et al: Phase I trial and pharmacokinetic study of pyrazoloacridine in children and young adults with refractory cancers. J Clin Oncol 16:181-186, 1998
Merchant J, Tutsch K, Dresen A, et al: Phase I clinical and pharmacokinetic study of NSC 655649, a rebeccamycin analogue, given in both single-dose and multiple-dose formats. Clin Cancer Res 8:2193-2201, 2002
Tolcher AW, Eckhardt SG, Kuhn J, et al: Phase I and pharmacokinetic study of NSC 655649, a rebeccamycin analog with topoisomerase inhibitory properties. J Clin Oncol 19:2937-2947, 2001
Langevin AM, Weitman SD, Kuhn JG, et al: Phase I trial of rebeccamycin analog (NSC #655649) in children with refractory solid tumors: A pediatric oncology group study. J Pediatr Hematol Oncol 25:526-533, 2003
Newlands ES, Blackledge GR, Slack JA, et al: Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer 65:287-291, 1992
Nicholson HS, Krailo M, Ames MM, et al: Phase I study of temozolomide in children and adolescents with recurrent solid tumors: A report from the Children's Cancer Group. J Clin Oncol 16:3037-3043, 1998
Estlin EJ, Lashford L, Ablett S, et al: Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children's Cancer Study Group. Br J Cancer 78:652-661, 1998
van Warmerdam LJ, ten Bokkel Huinink WW, Rodenhuis S, et al: Phase I clinical and pharmacokinetic study of topotecan administered by a 24-hour continuous infusion. J Clin Oncol 13:1768-1776, 1995
Burris HA 3rd, Awada A, Kuhn JG, et al: Phase I and pharmacokinetic studies of topotecan administered as a 72 or 120 h continuous infusion. Anticancer Drugs 5:394-402, 1994
Pratt CB, Stewart C, Santana VM, et al: Phase I study of topotecan for pediatric patients with malignant solid tumors. J Clin Oncol 12:539-543, 1994
Rowinsky EK, Grochow LB, Hendricks CB, et al: Phase I and pharmacologic study of topotecan: A novel topoisomerase I inhibitor. J Clin Oncol 10:647-656, 1992
Saltz L, Sirott M, Young C, et al: Phase I clinical and pharmacology study of topotecan given daily for 5 consecutive days to patients with advanced solid tumors, with attempt at dose intensification using recombinant granulocyte colony-stimulating factor. J Natl Cancer Inst 85:1499-1507, 1993
Tubergen DG, Stewart CF, Pratt CB, et al: Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: A pediatric oncology group study. J Pediatr Hematol Oncol 18:352-361, 1996
Gerrits CJ, Burris H, Schellens JH, et al: Oral topotecan given once or twice daily for ten days: A phase I pharmacology study in adult patients with solid tumors. Clin Cancer Res 4:1153-1158, 1998
Daw NC, Santana VM, Iacono LC, et al: Phase I and pharmacokinetic study of topotecan administered orally once daily for 5 days for 2 consecutive weeks to pediatric patients with refractory solid tumors. J Clin Oncol 22:829-837, 2004
Stewart JA, McCormack JJ, Tong W, et al: Phase I clinical and pharmacokinetic study of trimetrexate using a daily x5 schedule. Cancer Res 48:5029-5035, 1988
Pappo AS, Vats T, Williams TE, et al: Phase I trial of trimetrexate in pediatric solid tumors: A Pediatric Oncology Group study. Med Pediatr Oncol 21:280-282, 1993
Lashford LS, Lewis IJ, Fielding SL, et al: Phase I/II study of iodine 131 metaiodobenzylguanidine in chemoresistant neuroblastoma: A United Kingdom Children's Cancer Study Group investigation. J Clin Oncol 10:1889-1896, 1992
Lichtman SM, Ratain MJ, Van Echo DA, et al: Phase I trial of granulocyte-macrophage colony-stimulating factor plus high-dose cyclophosphamide given every 2 weeks: A Cancer and Leukemia Group B study. J Natl Cancer Inst 85:1319-1326, 1993
Abrahamsen TG, Lange BJ, Packer RJ, et al: A phase I and II trial of dose-intensified cyclophosphamide and GM-CSF in pediatric malignant brain tumors. J Pediatr Hematol Oncol 17:134-139, 1995
Seibel NL, Blaney SM, O'Brien M, et al: Phase I trial of docetaxel with filgrastim support in pediatric patients with refractory solid tumors: A collaborative Pediatric Oncology Branch, National Cancer Institute and Children's Cancer Group trial. Clin Cancer Res 5:733-737, 1999
Blaney S, Berg SL, Pratt C, et al: A phase I study of irinotecan in pediatric patients: A pediatric oncology group study. Clin Cancer Res 7:32-37, 2001
Hayashi RJ, Blaney S, Sullivan J, et al: Phase 1 study of Paclitaxel administered twice weekly to children with refractory solid tumors: A pediatric oncology group study. J Pediatr Hematol Oncol 25:539-542, 2003
Brown TD, O'Rourke TJ, Kuhn JG, et al: Phase I trial of sulofenur (LY186641) given orally on a daily x 21 schedule. Anticancer Drugs 5:151-159, 1994
Pratt CB, Bowman LC, Marina N, et al: A phase I study of sulofenur in refractory pediatric malignant solid tumors. Invest New Drugs 13:63-66, 1995
Kitchen BJ, Balis FM, Poplack DG, et al: A pediatric phase I trial and pharmacokinetic study of thioguanine administered by continuous i.v. infusion. Clin Cancer Res 3:713-717, 1997
Meyers FJ, Welborn J, Lewis JP, et al: Infusion carboplatin treatment of relapsed and refractory acute leukemia: Evidence of efficacy with minimal extramedullary toxicity at intermediate doses. J Clin Oncol 7:173-178, 1989
Ettinger LJ, Krailo MD, Gaynon PS, et al: A phase I study of carboplatin in children with acute leukemia in bone marrow relapse. A report from the Childrens Cancer Group. Cancer 72:917-922, 1993
Grunewald R, Kantarjian H, Du M, et al: Gemcitabine in leukemia: A phase I clinical, plasma, and cellular pharmacology study. J Clin Oncol 10:406-413, 1992
Steinherz PG, Seibel NL, Ames MM, et al: Phase I study of gemcitabine (difluorodeoxycytidine) in children with relapsed or refractory leukemia (CCG-0955): a report from the Children's Cancer Group. Leuk Lymphoma 43:1945-1950, 2002
Kantarjian HM, Beran M, Ellis A, et al: Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia. Blood 81:1146-1151, 1993
Rowinsky EK, Adjei A, Donehower RC, et al: Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia. J Clin Oncol 12:2193-2203, 1994
Furman WL, Baker SD, Pratt CB, et al: Escalating systemic exposure of continuous infusion topotecan in children with recurrent acute leukemia. J Clin Oncol 14:1504-1511, 1996
Rowinsky EK, Kaufmann SH, Baker SD, et al: A phase I and pharmacological study of topotecan infused over 30 minutes for five days in patients with refractory acute leukemia. Clin Cancer Res 2:1921-1930, 1996
Furman WL, Stewart CF, Kirstein M, et al: Protracted intermittent schedule of topotecan in children with refractory acute leukemia: A pediatric oncology group study. J Clin Oncol 20:1617-1624, 2002
Carson DA, Wasson DB, Beutler E: Antileukemic and immunosuppressive activity of 2-chloro-2'-deoxyadenosine. Proc Natl Acad Sci U S A 81:2232-2236, 1984
Santana VM, Mirro J Jr., Harwood FC, et al: A phase I clinical trial of 2-chlorodeoxyadenosine in pediatric patients with acute leukemia. J Clin Oncol 9:416-422, 1991
Kurie JM, Lee JS, Griffin T, et al: Phase I trial of 9-cis retinoic acid in adults with solid tumors. Clin Cancer Res 2:287-293, 1996
Rizvi NA, Marshall JL, Ness E, et al: Phase I study of 9-cis-retinoic acid (ALRT1057 capsules) in adults with advanced cancer. Clin Cancer Res 4:1437-1442, 1998
Conley BA, Egorin MJ, Sridhara R, et al: Phase I clinical trial of all-trans-retinoic acid with correlation of its pharmacokinetics and pharmacodynamics. Cancer Chemother Pharmacol 39:291-299, 1997
Camerini T, Mariani L, De Palo G, et al: Safety of the synthetic retinoid fenretinide: Long-term results from a controlled clinical trial for the prevention of contralateral breast cancer. J Clin Oncol 19:1664-1670, 2001
Sarna G, Pertcheck M, Figlin R, et al: Phase I study of recombinant beta ser 17 interferon in the treatment of cancer. Cancer Treat Rep 70:1365-1372, 1986
Allen J, Packer R, Bleyer A, et al: Recombinant interferon beta: A phase I-II trial in children with recurrent brain tumors. J Clin Oncol 9:783-788, 1991
Kohler PC, Hank JA, Moore KH, et al: Phase 1 clinical trial of recombinant interleukin-2: a comparison of bolus and continuous intravenous infusion. Cancer Invest 7:213-223, 1989
Creagan ET, Kovach JS, Moertel CG, et al: A phase I clinical trial of recombinant human tumor necrosis factor. Cancer 62:2467-2471, 1988
Villablanca JG, Khan AA, Avramis VI, et al: Phase I trial of 13-cis-retinoic acid in children with neuroblastoma following bone marrow transplantation. J Clin Oncol 13:894-901, 1995
Pais RC, Abdel-Mageed A, Ghim TT, et al: Phase I study of recombinant human interleukin-2 for pediatric malignancies: Feasibility of outpatient therapy. A Pediatric Oncology Group Study. J Immunother 12:138-146, 1992
Eckhardt SG, Rizzo J, Sweeney KR, et al: Phase I and pharmacologic study of the tyrosine kinase inhibitor SU101 in patients with advanced solid tumors. J Clin Oncol 17:1095-1104, 1999
Adamson PC, Blaney SM, Widemann BC, et al: Pediatric phase I trial and pharmacokinetic study of the platelet-derived growth factor (PDGF) receptor pathway inhibitor SU101. Cancer Chemother Pharmacol 53:482-488, 2004
Grossbard ML, Lambert JM, Goldmacher VS, et al: Anti-B4-blocked ricin: A phase I trial of 7-day continuous infusion in patients with B-cell neoplasms. J Clin Oncol 11:726-737, 1993
Dinndorf P, Krailo M, Liu-Mares W, et al: Phase I trial of anti-B4-blocked ricin in pediatric patients with leukemia and lymphoma. J Immunother 24:511-516, 2001
Kurzrock R, Quesada JR, Talpaz M, et al: Phase I study of multiple dose intramuscularly administered recombinant gamma interferon. J Clin Oncol 4:1101-1109, 1986
Mahmoud HH, Pui CH, Kennedy W, et al: Phase I study of recombinant human interferon gamma in children with relapsed acute leukemia. Leukemia 6:1181-1184, 1992
Gabizon A, Isacson R, Libson E, et al: Clinical studies of liposome-encapsulated doxorubicin. Acta Oncol 33:779-786, 1994
Peng YM, Dalton WS, Alberts DS, et al: Pharmacokinetics of N-4-hydroxyphenyl-retinamide and the effect of its oral administration on plasma retinol concentrations in cancer patients. Int J Cancer 43:22-26, 1989
Kerr DJ, Kaye SB, Cassidy J, et al: Phase I and pharmacokinetic study of flavone acetic acid. Cancer Res 47:6776-6781, 1987
Johnson SA: Clinical pharmacokinetics of nucleoside analogues: Focus on haematological malignancies. Clin Pharmacokinet 39:5-26, 2000
Riccardi A, Mazzarella G, Cefalo G, et al: Pharmacokinetics of temozolomide given three times a day in pediatric and adult patients. Cancer Chemother Pharmacol 52:459-464, 2003
Kovach JS, Rubin J, Creagan ET, et al: Phase I trial of parenteral 6-thioguanine given on 5 consecutive days. Cancer Res 46:5959-5962, 1986(Debra P. Lee, Jeffrey M. )
ABSTRACT
PURPOSE: To determine the efficacy and safety of pediatric phase I oncology trials in the era of dose-intensive chemotherapy and to analyze how efficiently these trials are conducted.
METHODS: Phase I pediatric oncology trials published from 1990 to 2004 and their corresponding adult phase I trials were reviewed. Dose escalation schemes using fixed 30% dose increments were studied to theoretically determine whether trials could be completed utilizing fewer patients and dose levels.
RESULTS: Sixty-nine pediatric phase I oncology trials enrolling 1,973 patients were identified. The pediatric maximum-tolerated dose (MTD) was strongly correlated with the adult MTD (r = 0.97). For three-fourths of the trials, the pediatric and adult MTD differed by no more than 30%, and for more than 85% of the trials, the pediatric MTD was less than or equal to 1.6 times the adult MTD. The median number of dose levels studied was four (range, two to 13). The overall objective response rate was 9.6%, the likelihood of experiencing a dose-limiting toxicity was 24%, and toxic death rate was 0.5%.
CONCLUSION: Despite the strong correlation between the adult and pediatric MTDs, more than four dose levels were studied in 40% of trials. There appeared to be little value in exploring dose levels greater than 1.6 times the adult MTD. Limiting pediatric phase I trials to a maximum of four doses levels would significantly shorten the timeline for study conduct without compromising safety.
INTRODUCTION
Phase I studies in oncology are the critical first step in the clinical evaluation of novel anticancer agents. The primary objectives of such studies include describing and defining the toxicities of the drug, determining the maximum-tolerated dose (MTD) or recommended phase II dose, and studying the pharmacokinetics of the drug. Pediatric phase I studies are almost always performed following adult phase I trials.1 Although this delays the timeline of pediatric drug development, it offers the distinct advantage of having data available from adult patients for the design of the pediatric trial. The greatest impact of this is in defining the starting dose for the phase I trial. Whereas the starting dose for adult phase I trials are based on animal toxicology and are often at least an order of magnitude lower than the ultimate recommended dose,2,3 pediatric trials historically begin at approximately 80% of the adult MTD,4 greatly diminishing the likelihood that a pediatric patient would be enrolled at a biologically ineffective dose.
One would anticipate that with a prior knowledge of the adult MTD, pediatric phase I trials would meet their primary objectives in an efficient manner. However, there are no published reports examining the efficiency of conducting pediatric phase I trials. Furthermore, the historical recommended starting dose of 80% was empirically derived during an era when children were less heavily pretreated and, in general, could tolerate higher doses of cytotoxic drugs than adult patients.5
We, therefore, reviewed the published experience with pediatric phase I trials from 1990 to 2004, a reporting period that encompasses an era when dose-intensive therapy was routinely administered as initial therapy in pediatric patients with high-risk tumors. Our objectives were not only to determine the safety and tolerability of pediatric phase I trials but also to examine how efficiently such trials are conducted. As a number of biologic agents are currently being developed, we also sought to get an initial indication of the pediatric phase I experience utilizing standard trial designs that were developed for the evaluation of cytotoxic drugs.
METHODS
Literature Review
Full length phase I pediatric clinical oncology trials published from 1990 to 2004 were identified by National Library of Medicine Gateway searches of English-language reports using the key words "pediatric," "phase," "cancer," and "trial." References of select articles were also reviewed for phase I studies. Lastly, the Children's Oncology Group database was used to identify completed and published phase I studies.
Studies included in the analysis were single-agent dose escalation trials; studies examining multiple agents were included only if a single drug was escalated. Phase I/II studies were included if there was a clear dose escalation scheme with a MTD and dose-limiting toxicities (DLTs) identified within the patient population. For the purposes of this study, we classified a drug as biologic if preclinical data suggested a primary mechanism of action that was immunologic, differentiating, or occurred via inhibition of a signal transduction pathway. Intrathecal agents, nondose escalation studies, pharmacokinetic only studies, and bone marrow transplant studies were excluded.
The following data were extracted from each publication: drug name, schedule, route of administration, concomitant cytotoxic or biologic drugs, concomitant hematopoietic growth factors, patient age (median and range), diagnoses, whether the study included patients with leukemia or solid tumors, starting dose, total number of patients entered, total number of patients assessable for toxicity, total number of patients assessable for response, number of dose levels studied, definition of DLT, DLTs, MTD, dose level at which the MTD occurred, less heavily pretreated MTD and dose level (if applicable), recommended phase II dose, steady-state plasma drug clearance, number of partial (PRs) and complete (CRs) responses, and number of deaths attributed to study drug.
Pediatric Versus Adult Tolerability to Phase I Agents
Corresponding adult phase I studies were identified by searching the references of the pediatric publications. If no publication were identified, the National Library of Medicine database was searched and, if necessary, the National Cancer Institute's Cancer Therapy Evaluation Program was then queried. Adult studies were included in the analysis if the route and schedule of administration were the same as the pediatric study. For studies that utilized a nonstandard definition of MTD, the data were reanalyzed using the standard definition of MTD defined as the dose level below that at which greater than or equal to two out of three to six patients experienced DLT.
Efficiency of Study Conduct
The correlation between the adult and pediatric MTDs for cytotoxic and biologic agents was determined by regression analysis. As pediatric phase trials often escalate dose in increments of approximately 30%, the lower and upper bounds spanning three, four, or five theoretical dose levels that would capture at least 80% of the pediatric to adult MTD ratios was determined. The number of dose levels studied and the number of patients entered were tabulated.
Safety
The types of DLTs observed on pediatric versus adult studies were recorded. The number of patients experiencing DLT and the number of patient deaths were tabulated. Toxic deaths were defined as a death of study participant in which the drug was possibly, probably, or definitely related to drug.
Efficacy
Response data from each pediatric study were tabulated. For solid tumor studies, PRs were typically defined as a reduction of at least 50% in the sums of the products of the largest diameters of measurable lesions without the appearance of new lesions for 4 weeks. CRs were typically defined as the disappearance of all known disease for at least 4 weeks. PR for leukemic patients was defined as a bone marrow leukemic blast percentage of 5% to 25% for children with acute lymphoblastic leukemia and 5% to 40% for children with acute myelogenous leukemia and recovery of peripheral blood counts to an absolute neutrophil count of 1,000/μL and platelet count of at least 100,000/μL. A complete leukemic response was defined as less than 5% leukemic blasts in a normocellular or slightly hypocellular bone marrow with recovery of peripheral blood counts at least an absolute neutrophil count of 1,000/μL and platelet count of at least 100,000/μL within 1 week of bone marrow response. Some individual study response definitions did not include time length requirements, and some did not define their criteria for response.
Pharmacokinetics
The coefficient of variation (CV) in plasma drug clearance or apparent clearance was determined for each pediatric study using data derived from patients studied at either all dose levels or at the MTD. When clearance data were not reported, it was calculated, when possible, by dividing the dose by the area under the concentration-time curve. Plasma drug clearance in adult patients was compared with that observed in children by regression analysis.
RESULTS
Literature Review
Sixty-nine (53 cytotoxic and 16 biologic studies) pediatric phase I oncology trials evaluating 46 different anticancer agents published between January 1990 and December 2004 met eligibility criteria. Of these 69 trials, 55 were single-agent studies and 14 were multiagent studies. Nine studies were in patients with leukemia only (two biologic, seven cytotoxic), and 14 studies (five biologic, nine cytotoxic) were performed in patients with either solid tumors or leukemia (Tables 1 and 2) . These 69 studies enrolled 1,973 patients (52% males) with a median of 25 patients per study. Of the 1,973 patients enrolled, 1,779 patients (90.2%) were fully assessable for toxicity, and 1,809 patients (91.7%) were assessable for response. The overall median age of children enrolled onto these phase I studies was 10.9 years. Neuroblastoma was the most common diagnosis (Fig 1).
Pediatric Versus Adult Tolerability to Phase I Agents
Of the 55 single-agent trials, 11 (eight cytotoxic) were excluded from the pediatric and adult comparison aspect of the study. Reasons for exclusion included: no corresponding adult study using the same schedule (n = 7), use of hematopoietic growth factors (n = 1), no defined pediatric MTD (n = 2), and only examining dose-intensity (n = 1).
The 44 single-agent trials available for comparison were divided according to cytotoxic versus biologic compounds studied. The MTDs of both adult and pediatric corresponding studies are shown in Tables 1, 2, and 3. Thirty-six single-agent cytotoxic studies (Fig 2A) and eight biologic studies (Fig 2B) were compared. For three-fourths of the trials, the pediatric and adult MTDs differed by no more than 30%, and for more than 85% of the trials, the pediatric MTD was less than or equal to 1.6 times the adult MTD.
Efficiency of Study Conduct
The pediatric MTD was strongly correlated with the adult MTD (r = 0.97). Defining boundaries one potential dose level below (0.7-fold) and two potential dose levels above (1.6-fold) the adult MTD allowed for determination of studies that fell outside of a theoretical four-dose level range (Fig 3). For cytotoxic agents, two studies had a MTD ratio less than 0.7 (topotecan given as a 24-hour infusion6 and piritrexim7), and three studies had a MTD ratio greater than 1.6 (fazarabine,8 irinotecan,9 and acivicin10). For biologic agents, one study (all-trans retinoic acid11) had a pediatric to adult MTD ratio less than 0.7, and three (fenretinide,12 recombinant tumor necrosis factor,13 and interleukin-214) had MTD ratios greater than 1.6.
The number of patients enrolled and the number of dose levels per study are shown in Figures 4A and 4B. Sixty-seven studies delineated the number of patients enrolled at each dose level. Two hundred ten out of the 317 dose levels studied (66%) enrolled more than three patients. The average number of dose levels studied was 4.6 (median, four; range, two to 13), the average number of patients enrolled per dose level was 5.1 (median, five; range, two to 23), and the average number of pediatric patients enrolled onto a study was 29 (median, 25; range, 11 to 81).
Safety
There were sufficiently detailed DLT data available from 1,066 patients (47 studies) to estimate that the likelihood of a patient developing a DLT once enrolled onto a study was 24%. There were 10 toxic deaths (0.5% toxic death rate) across all studies. Further analysis of deaths attributed to drug show a mean of 0.14 deaths per study (median, zero; range, zero to three). All but two of the toxic deaths were at dose levels above the MTD, and of the remaining two, one was at the highest dose given in a study that did not reach an MTD and the other was at the MTD. Toxic deaths included one patient who died from intractable seizures and aspiration pneumonia, two from respiratory distress and hepatobiliary dysfunction, one from progressive midbrain dysfunction in which drug causality could not be ruled out, one from hepatic necrosis and encephalopathy, two from profound aplasia, and three patients with fulminant hepatic failure.
Efficacy
Objective responses were recorded in 67 trials. Forty out of the 67 studies representing 26 different drugs had at least one objective response. In total, there were 50 CRs and 123 PRs in the 1,809 patients assessable for response, for an overall objective response rate of 9.6%. The average number of responses observed on a study was 2.6 (median, one; range, zero to 15). When analyzed separately, the response rate for single-agent phase I studies was 6.8% and for multiagent phase I studies 20.1%. The dose levels at which responses were observed, however, were not routinely reported, and thus, no correlation could be made between response observed and dose level treated.
Pharmacokinetics
Twenty-one studies reported the necessary pharmacokinetic data to allow for calculation of CV in drug clearance (Table 3). The median CV in drug clearance was 42% (range, 11% to 69%). Plasma drug clearance in children was highly correlated with that observed in adults (r = 0.97), with a median ratio of pediatric to adult clearance (or apparent clearance) of 0.95. Despite the strong correlation, there was a wide range of ratios observed across studies (0.06 to 2.2).
DISCUSSION
With the exception of childhood leukemias, the proportion of diagnoses of children enrolling on pediatric phase I trials generally reflects the number of patients who experience a relapse of their disease (Fig 1). Patients with neuroblastoma, brain tumors, or sarcomas represented approximately two-thirds of patients enrolled on phase I trials. Multiple factors may contribute to the under-representation of children with leukemia on phase I trials, including the availability of varied salvage regimens, including stem-cell transplants, the rapidity of disease progression in recurrent leukemia, and phase I trial design limitations.
In an era when children with newly-diagnosed, high-risk malignancies are routinely treated with dose intensive regimens, the conduct of phase I trials in relapsed or refractory patients continues to be safe and relatively well-tolerated. Approximately one in four children enrolled onto a phase I trial experienced a DLT. Because the design of phase I trials in most circumstances necessitates the determination of a MTD, this degree of toxicity is anticipated and is significantly less than the 80% frequency of grade 3 or greater toxicity observed on many front-line multiagent regimens.16 Importantly, treatment-related mortality was less than 0.5%.
The likelihood of achieving an objective response when participating in a pediatric phase I trial was 9.6%. This is similar to the 7.9% objective response rate reported in pediatric phase I trials conducted in earlier eras17 but higher than the 3% to 6% objective response rate observed on phase I trials conducted in adult patients.18-22 Not surprisingly, and similar to phase I trials in adults,21 the response rate was higher in trials that combined an investigational drug with drugs with known anticancer activity (20.1%) versus an investigational drug alone (6.8%). It should be emphasized that the definition of direct patient benefit may extend beyond objective response, in the form of disease stabilization or symptom relief, and thus, the proportion of patients who derived direct benefit from participation on a phase I trial should not be equated to the observed response rate. However, data on symptom relief and disease stabilization have not historically been captured during the conduct of phase I trials, and thus, estimates of the fraction of patients who derive direct benefit, although greater than the response rate, cannot be made.
In general, the definition of nonhematologic DLTs was identical in adult and pediatric trials (data not shown). For the hematologic toxicity, however, often either a greater degree or a longer duration of myelosuppression was required in pediatric studies than in adult studies to qualify as a DLT. This may, in part, account for the higher MTDs occasionally observed in pediatric studies in which myelosuppression was dose-limiting.
The types of toxicities experienced by children enrolled onto phase I trials were, with few exceptions, the same as those experienced by adult patients (Tables 1 and 2). Not surprisingly, we also found a strong correlation between the MTD observed in adult patients and the MTD defined in pediatric patients (Fig 3). The correlation was stronger for cytotoxic drugs (r = 0.97) than for biologic agents (r = 0.3). However, one cannot conclude that differences in MTD, when observed, were the result of true differences in tolerability. For certain drugs, such as the retinoids,11,23,24 a difference in tolerability between adult and pediatric patients indeed appears to underlie the differences in MTD. Of the six drugs in which the pediatric MTD exceeded the adult MTD by a factor greater than 1.6, two (fazarabine,8 irinotecan6) had a ratio of only 1.7, and for the three biologic agents (fenretinide,12 rTNF,13 and IL-214), a difference in the definition of DLT was the major factor underlying the discordant MTDs. Of note, following completion of the fenretinide phase I pediatric trial, subsequent studies of fenretinide found that higher doses could also be tolerated in adult patients.25
Despite the strong correlation between the adult and pediatric MTD, 40% of studies enrolled patients onto more than four dose levels (Fig 4A), and 46% of studies required more than 25 assessable patients to reach their conclusion (Fig 4B). One would anticipate that for studies requiring more than four dose levels, the pediatric MTD would greatly exceed the adult MTD. However, we did not find this to be the case, as the pediatric MTD was less than two-fold the adult MTD for all of the cytotoxic drugs and all but two of the biologic drugs studied.
The primary reasons that such a high fraction of studies were not efficient in reaching their conclusion appears to be two-fold. First, the likelihood that the pediatric MTD would exceed the adult MTD by more than 1.6-fold is small (Figs 1A and 1B), making exploration of levels beyond this of little value. Secondly, many studies, either by initial design or by later modification, explored dose levels that differed from a previously studied dose level by increments significantly smaller than 30%.
On the basis of this analysis, we propose that changes in study design could increase the efficiency in which pediatric phase I trials are conducted. Unless it is anticipated that pediatric oncologists, patients, and families would be willing to have children tolerate significantly worse toxicities than those experienced on the corresponding adult phase I trial, there appears little value in exploring dose levels more than 1.6 times the adult MTD. Caveats to this recommendation are two-fold: if drug disposition (pharmacokinetics) differs significantly from adults, or if the toxicity profile in children is found to differ significantly from adults, higher (or potentially lower) dose levels might need to be explored. Secondly, attempts to fine-tune the recommendation for phase II dosing by examining increments of less than 30% should, in general, not be made during the conduct of the phase I study. Limiting pediatric phase I trials to the study of no more than four doses levels (0.7, 1.0, 1.3, and 1.6 times the adult MTD), would significantly shorten the timeline for the conduct of these studies and would be unlikely to result in a conclusion that differs substantively from trials that examine a greater number of dose levels.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Smith M, Bernstein M, Bleyer WA, et al: Conduct of phase I trials in children with cancer. J Clin Oncol 16:966-978, 1998
Goldsmith MA, Slavik M, Carter SK: Quantitative prediction of drug toxicity in humans from toxicology in small and large animals. Cancer Res 35:1354-1364, 1975
Grieshaber CK, Marsoni S: Relation of preclinical toxicology to findings in early clinical trials. Cancer Treat Rep 70:65-72, 1986
Marsoni S, Ungerleider RS, Hurson SB, et al: Tolerance to antineoplastic agents in children and adults. Cancer Treat Rep 69:1263-1269, 1985
Carlson L, Ho P, Smith M, et al: Pediatric phase I drug tolerance: A review and comparison of recent adult and pediatric phase I trials. J Pediatr Hematol Oncol 18:250-256, 1996
Blaney SM, Balis FM, Cole DE, et al: Pediatric phase I trial and pharmacokinetic study of topotecan administered as a 24-hour continuous infusion. Cancer Res 53:1032-1036, 1993
Adamson PC, Balis FM, Miser J, et al: Pediatric phase I trial and pharmacokinetic study of piritrexim administered orally on a five-day schedule. Cancer Res 50:4464-4467, 1990
Bernstein ML, Whitehead VM, Grier H, et al: A phase I trial of fazarabine in refractory pediatric solid tumors. A Pediatric Oncology Group study. Invest New Drugs 11:309-312, 1993
Mugishima H, Matsunaga T, Yagi K, et al: Phase I study of irinotecan in pediatric patients with malignant solid tumors. J Pediatr Hematol Oncol 24:94-100, 2002
Baruchel S, Bernstein M, Whitehead VM, et al: A phase I study of acivicin in refractory pediatric solid tumors. A Pediatric Oncology Group study. Invest New Drugs 13:211-216, 1995
Smith MA, Adamson PC, Balis FM, et al: Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer. J Clin Oncol 10:1666-1673, 1992
Garaventa A, Luksch R, Lo Piccolo MS, et al: Phase I trial and pharmacokinetics of fenretinide in children with neuroblastoma. Clin Cancer Res 9:2032-2039, 2003
Furman WL, Strother D, McClain K, et al: Phase I clinical trial of recombinant human tumor necrosis factor in children with refractory solid tumors: A Pediatric Oncology Group study. J Clin Oncol 11:2205-2210, 1993
Roper M, Smith MA, Sondel PM, et al: A phase I study of interleukin-2 in children with cancer. Am J Pediatr Hematol Oncol 14:305-311, 1992
Matthay KK, DeSantes K, Hasegawa B, et al: Phase I dose escalation of 131I-metaiodobenzylguanidine with autologous bone marrow support in refractory neuroblastoma. J Clin Oncol 16:229-236, 1998
Crist WM, Anderson JR, Meza JL, et al: Intergroup rhabdomyosarcoma study-IV: Results for patients with nonmetastatic disease. J Clin Oncol 19:3091-3102, 2001
Shah S, Weitman S, Langevin AM, et al: Phase I therapy trials in children with cancer. J Pediatr Hematol Oncol 20:431-438, 1998
Decoster G, Stein G, Holdener EE: Responses and toxic deaths in phase I clinical trials. Ann Oncol 1:175-181, 1990
Sekine I, Yamamoto N, Kunitoh H, et al: Relationship between objective responses in phase I trials and potential efficacy of non-specific cytotoxic investigational new drugs. Ann Oncol 13:1300-1306, 2002
Von Hoff DD, Turner J: Response rates, duration of response, and dose response effects in phase I studies of antineoplastics. Invest New Drugs 9:115-122, 1991
Horstmann E, McCabe MS, Grochow L, et al: Risks and benefits of phase I oncology trials, 1991 through 2002. N Engl J Med 352:895-904, 2005
Roberts TG Jr., Goulart BH, Squitieri L, et al: Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. JAMA 292:2130-2140, 2004
Adamson PC, Reaman G, Finklestein JZ, et al: Phase I trial and pharmacokinetic study of all-trans-retinoic acid administered on an intermittent schedule in combination with interferon-alpha2a in pediatric patients with refractory cancer. J Clin Oncol 15:3330-3337, 1997
Adamson PC, Widemann BC, Reaman GH, et al: A phase I trial and pharmacokinetic study of 9-cis-retinoic acid (ALRT1057) in pediatric patients with refractory cancer: A joint Pediatric Oncology Branch, National Cancer Institute, and Children's Cancer Group study. Clin Cancer Res 7:3034-3039, 2001
Puduvalli VK, Yung WK, Hess KR, et al: Phase II study of fenretinide (NSC 374551) in adults with recurrent malignant gliomas: A North American Brain Tumor Consortium study. J Clin Oncol 22:4282-4289, 2004
Sisson J, Shapiro B, Beierwaltes WH, et al: Treatment of malignant pheochromocytoma with a new radiopharmaceutical. Trans Assoc Am Physicians 96:209-217, 1983
Cunningham J, Bukowski RM, Budd GT, et al: 5-Fluorouracil and folinic acid: A Phase I-II trial in gastrointestinal malignancy. Invest New Drugs 2:391-395, 1984
Patel R, Newman EM, Villacorte DG, et al: Pharmacology and phase I trial of high-dose oral leucovorin plus 5-fluorouracil in children with refractory cancer: A report from the Children's Cancer Study Group. Cancer Res 51:4871-4875, 1991
Seifert P, Baker LH, Reed ML, et al: Comparison of continuously infused 5-fluorouracil with bolus injection in treatment of patients with colorectal adenocarcinoma. Cancer 36:123-128, 1975
Green DM, Krischer JP, Bell B, et al: Phase I study of a 120-hour continuous intravenous infusion of 5-fluorouracil in pediatric patients with recurrent solid tumors: A Pediatric Oncology Group study. Med Pediatr Oncol 18:321-324, 1990
Rubin E, Wood V, Bharti A, et al: A phase I and pharmacokinetic study of a new camptothecin derivative, 9-aminocamptothecin. Clin Cancer Res 1:269-276, 1995
Langevin AM, Casto DT, Thomas PJ, et al: Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: A Pediatric Oncology Group study. J Clin Oncol 16:2494-2499, 1998
Sridhar KS, Ohnuma T, Chahinian AP, et al: Phase I study of acivicin in patients with advanced cancer. Cancer Treat Rep 67:701-703, 1983
Prendiville J, Crowther D, Thatcher N, et al: A phase I study of intravenous bryostatin 1 in patients with advanced cancer. Br J Cancer 68:418-424, 1993
Weitman S, Langevin AM, Berkow RL, et al: A Phase I trial of bryostatin-1 in children with refractory solid tumors: A Pediatric Oncology Group study. Clin Cancer Res 5:2344-2348, 1999
Murgo A: Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, 2004
Falletta JM, Cushing B, Lauer S, et al: Phase I evaluation of diaziquone in childhood cancer. A Pediatric Oncology Group study. Invest New Drugs 8:167-170, 1990
Extra JM, Rousseau F, Bruno R, et al: Phase I and pharmacokinetic study of Taxotere (RP 56976; NSC 628503) given as a short intravenous infusion. Cancer Res 53:1037-1042, 1993
Blaney SM, Seibel NL, O'Brien M, et al: Phase I trial of docetaxel administered as a 1-hour infusion in children with refractory solid tumors: A collaborative pediatric branch, National Cancer Institute and Children's Cancer Group trial. J Clin Oncol 15:1538-1543, 1997
Hainsworth JD, Johnson DH, Frazier SR, et al: Chronic daily administration of oral etoposide–a phase I trial. J Clin Oncol 7:396-401, 1989
Mathew P, Ribeiro RC, Sonnichsen D, et al: Phase I study of oral etoposide in children with refractory solid tumors. J Clin Oncol 12:1452-1457, 1994
Pratt CB, Relling MV, Meyer WH, et al: Phase I study of flavone acetic acid (NSC 347512, LM975) in patients with pediatric malignant solid tumors. Am J Clin Oncol 14:483-486, 1991
Casper ES, Mittelman A, Kelson D, et al: Phase I clinical trial of fludarabine phosphate (F-ara-AMP). Cancer Chemother Pharmacol 15:233-235, 1985
Avramis VI, Champagne J, Sato J, et al: Pharmacology of fludarabine phosphate after a phase I/II trial by a loading bolus and continuous infusion in pediatric patients. Cancer Res 50:7226-7231, 1990
Abbruzzese JL, Grunewald R, Weeks EA, et al: A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491-498, 1991
Reid JM, Qu W, Safgren SL, et al: Phase I trial and pharmacokinetics of gemcitabine in children with advanced solid tumors. J Clin Oncol 22:2445-2451, 2004
Elliott TE, Buckner JC, Cascino TL, et al: Phase II study of ifosfamide with mesna in adult patients with recurrent diffuse astrocytoma. J Neurooncol 10:27-30, 1991
Pratt CB, Douglass EC, Kovnar EH, et al: A phase I study of ifosfamide given on alternate days to treat children with brain tumors. Cancer 71:3666-3669, 1993
Pratt CB, Meyer WH, Douglass EC, et al: A phase I study of ifosfamide with Mesna given daily for 3 consecutive days to children with malignant solid tumors. Cancer 71:3661-3665, 1993
Taylor S, Belt RJ, Haas CD, et al: Phase I trial of Indicine-N-Oxide on two dose schedules. Cancer 51:1988-1991, 1983
Ohnuma T, Sridhar KS, Ratner LH, et al: Phase I study of indicine N-oxide in patients with advanced cancer. Cancer Treat Rep 66:1509-1515, 1982
Whitehead VM, Bernstein ML, Vega R, et al: Phase I trial of indicine-N-oxide in children with leukemia and solid tumors: A Pediatric Oncology Group study. Cancer Chemother Pharmacol 26:377-379, 1990
Catimel G, Chabot GG, Guastalla JP, et al: Phase I and pharmacokinetic study of irinotecan (CPT-11) administered daily for three consecutive days every three weeks in patients with advanced solid tumors. Ann Oncol 6:133-140, 1995
Abigerges D, Chabot GG, Armand JP, et al: Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 13:210-221, 1995
Vassal G, Doz F, Frappaz D, et al: A phase I study of irinotecan as a 3-week schedule in children with refractory or recurrent solid tumors. J Clin Oncol 21:3844-3852, 2003
Rafi I, Boddy AV, Calvete JA, et al: Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors. J Clin Oncol 16:1131-1141, 1998
Estlin EJ, Pinkerton CR, Lewis IJ, et al: A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation. Br J Cancer 84:11-18, 2001
Wiernik PH, Schwartz EL, Einzig A, et al: Phase I trial of taxol given as a 24-hour infusion every 21 days: Responses observed in metastatic melanoma. J Clin Oncol 5:1232-1239, 1987
Hurwitz CA, Relling MV, Weitman SD, et al: Phase I trial of paclitaxel in children with refractory solid tumors: A Pediatric Oncology Group Study. J Clin Oncol 11:2324-2329, 1993
Uziely B, Jeffers S, Isacson R, et al: Liposomal doxorubicin: Antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 13:1777-1785, 1995
Marina NM, Cochrane D, Harney E, et al: Dose escalation and pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in children with solid tumors: A pediatric oncology group study. Clin Cancer Res 8:413-418, 2002
Laszlo J, Brenckman WD Jr, Morgan E, et al: Initial clinical studies of piritrexim. NCI Monogr 121-125, 1987
Feun LG, Savaraj N, Benedetto P, et al: Phase I trial of piritrexim capsules using prolonged, low-dose oral administration for the treatment of advanced malignancies. J Natl Cancer Inst 83:51-55, 1991
Adamson PC, Balis FM, Miser J, et al: Pediatric phase I trial, pharmacokinetic study, and limited sampling strategy for piritrexim administered on a low-dose, intermittent schedule. Cancer Res 52:521-524, 1992
LoRusso P, Foster BJ, Poplin E, et al: Phase I clinical trial of pyrazoloacridine NSC366140 (PD115934). Clin Cancer Res 1:1487-1493, 1995
Berg SL, Blaney SM, Adamson PC, et al: Phase I trial and pharmacokinetic study of pyrazoloacridine in children and young adults with refractory cancers. J Clin Oncol 16:181-186, 1998
Merchant J, Tutsch K, Dresen A, et al: Phase I clinical and pharmacokinetic study of NSC 655649, a rebeccamycin analogue, given in both single-dose and multiple-dose formats. Clin Cancer Res 8:2193-2201, 2002
Tolcher AW, Eckhardt SG, Kuhn J, et al: Phase I and pharmacokinetic study of NSC 655649, a rebeccamycin analog with topoisomerase inhibitory properties. J Clin Oncol 19:2937-2947, 2001
Langevin AM, Weitman SD, Kuhn JG, et al: Phase I trial of rebeccamycin analog (NSC #655649) in children with refractory solid tumors: A pediatric oncology group study. J Pediatr Hematol Oncol 25:526-533, 2003
Newlands ES, Blackledge GR, Slack JA, et al: Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer 65:287-291, 1992
Nicholson HS, Krailo M, Ames MM, et al: Phase I study of temozolomide in children and adolescents with recurrent solid tumors: A report from the Children's Cancer Group. J Clin Oncol 16:3037-3043, 1998
Estlin EJ, Lashford L, Ablett S, et al: Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children's Cancer Study Group. Br J Cancer 78:652-661, 1998
van Warmerdam LJ, ten Bokkel Huinink WW, Rodenhuis S, et al: Phase I clinical and pharmacokinetic study of topotecan administered by a 24-hour continuous infusion. J Clin Oncol 13:1768-1776, 1995
Burris HA 3rd, Awada A, Kuhn JG, et al: Phase I and pharmacokinetic studies of topotecan administered as a 72 or 120 h continuous infusion. Anticancer Drugs 5:394-402, 1994
Pratt CB, Stewart C, Santana VM, et al: Phase I study of topotecan for pediatric patients with malignant solid tumors. J Clin Oncol 12:539-543, 1994
Rowinsky EK, Grochow LB, Hendricks CB, et al: Phase I and pharmacologic study of topotecan: A novel topoisomerase I inhibitor. J Clin Oncol 10:647-656, 1992
Saltz L, Sirott M, Young C, et al: Phase I clinical and pharmacology study of topotecan given daily for 5 consecutive days to patients with advanced solid tumors, with attempt at dose intensification using recombinant granulocyte colony-stimulating factor. J Natl Cancer Inst 85:1499-1507, 1993
Tubergen DG, Stewart CF, Pratt CB, et al: Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: A pediatric oncology group study. J Pediatr Hematol Oncol 18:352-361, 1996
Gerrits CJ, Burris H, Schellens JH, et al: Oral topotecan given once or twice daily for ten days: A phase I pharmacology study in adult patients with solid tumors. Clin Cancer Res 4:1153-1158, 1998
Daw NC, Santana VM, Iacono LC, et al: Phase I and pharmacokinetic study of topotecan administered orally once daily for 5 days for 2 consecutive weeks to pediatric patients with refractory solid tumors. J Clin Oncol 22:829-837, 2004
Stewart JA, McCormack JJ, Tong W, et al: Phase I clinical and pharmacokinetic study of trimetrexate using a daily x5 schedule. Cancer Res 48:5029-5035, 1988
Pappo AS, Vats T, Williams TE, et al: Phase I trial of trimetrexate in pediatric solid tumors: A Pediatric Oncology Group study. Med Pediatr Oncol 21:280-282, 1993
Lashford LS, Lewis IJ, Fielding SL, et al: Phase I/II study of iodine 131 metaiodobenzylguanidine in chemoresistant neuroblastoma: A United Kingdom Children's Cancer Study Group investigation. J Clin Oncol 10:1889-1896, 1992
Lichtman SM, Ratain MJ, Van Echo DA, et al: Phase I trial of granulocyte-macrophage colony-stimulating factor plus high-dose cyclophosphamide given every 2 weeks: A Cancer and Leukemia Group B study. J Natl Cancer Inst 85:1319-1326, 1993
Abrahamsen TG, Lange BJ, Packer RJ, et al: A phase I and II trial of dose-intensified cyclophosphamide and GM-CSF in pediatric malignant brain tumors. J Pediatr Hematol Oncol 17:134-139, 1995
Seibel NL, Blaney SM, O'Brien M, et al: Phase I trial of docetaxel with filgrastim support in pediatric patients with refractory solid tumors: A collaborative Pediatric Oncology Branch, National Cancer Institute and Children's Cancer Group trial. Clin Cancer Res 5:733-737, 1999
Blaney S, Berg SL, Pratt C, et al: A phase I study of irinotecan in pediatric patients: A pediatric oncology group study. Clin Cancer Res 7:32-37, 2001
Hayashi RJ, Blaney S, Sullivan J, et al: Phase 1 study of Paclitaxel administered twice weekly to children with refractory solid tumors: A pediatric oncology group study. J Pediatr Hematol Oncol 25:539-542, 2003
Brown TD, O'Rourke TJ, Kuhn JG, et al: Phase I trial of sulofenur (LY186641) given orally on a daily x 21 schedule. Anticancer Drugs 5:151-159, 1994
Pratt CB, Bowman LC, Marina N, et al: A phase I study of sulofenur in refractory pediatric malignant solid tumors. Invest New Drugs 13:63-66, 1995
Kitchen BJ, Balis FM, Poplack DG, et al: A pediatric phase I trial and pharmacokinetic study of thioguanine administered by continuous i.v. infusion. Clin Cancer Res 3:713-717, 1997
Meyers FJ, Welborn J, Lewis JP, et al: Infusion carboplatin treatment of relapsed and refractory acute leukemia: Evidence of efficacy with minimal extramedullary toxicity at intermediate doses. J Clin Oncol 7:173-178, 1989
Ettinger LJ, Krailo MD, Gaynon PS, et al: A phase I study of carboplatin in children with acute leukemia in bone marrow relapse. A report from the Childrens Cancer Group. Cancer 72:917-922, 1993
Grunewald R, Kantarjian H, Du M, et al: Gemcitabine in leukemia: A phase I clinical, plasma, and cellular pharmacology study. J Clin Oncol 10:406-413, 1992
Steinherz PG, Seibel NL, Ames MM, et al: Phase I study of gemcitabine (difluorodeoxycytidine) in children with relapsed or refractory leukemia (CCG-0955): a report from the Children's Cancer Group. Leuk Lymphoma 43:1945-1950, 2002
Kantarjian HM, Beran M, Ellis A, et al: Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia. Blood 81:1146-1151, 1993
Rowinsky EK, Adjei A, Donehower RC, et al: Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia. J Clin Oncol 12:2193-2203, 1994
Furman WL, Baker SD, Pratt CB, et al: Escalating systemic exposure of continuous infusion topotecan in children with recurrent acute leukemia. J Clin Oncol 14:1504-1511, 1996
Rowinsky EK, Kaufmann SH, Baker SD, et al: A phase I and pharmacological study of topotecan infused over 30 minutes for five days in patients with refractory acute leukemia. Clin Cancer Res 2:1921-1930, 1996
Furman WL, Stewart CF, Kirstein M, et al: Protracted intermittent schedule of topotecan in children with refractory acute leukemia: A pediatric oncology group study. J Clin Oncol 20:1617-1624, 2002
Carson DA, Wasson DB, Beutler E: Antileukemic and immunosuppressive activity of 2-chloro-2'-deoxyadenosine. Proc Natl Acad Sci U S A 81:2232-2236, 1984
Santana VM, Mirro J Jr., Harwood FC, et al: A phase I clinical trial of 2-chlorodeoxyadenosine in pediatric patients with acute leukemia. J Clin Oncol 9:416-422, 1991
Kurie JM, Lee JS, Griffin T, et al: Phase I trial of 9-cis retinoic acid in adults with solid tumors. Clin Cancer Res 2:287-293, 1996
Rizvi NA, Marshall JL, Ness E, et al: Phase I study of 9-cis-retinoic acid (ALRT1057 capsules) in adults with advanced cancer. Clin Cancer Res 4:1437-1442, 1998
Conley BA, Egorin MJ, Sridhara R, et al: Phase I clinical trial of all-trans-retinoic acid with correlation of its pharmacokinetics and pharmacodynamics. Cancer Chemother Pharmacol 39:291-299, 1997
Camerini T, Mariani L, De Palo G, et al: Safety of the synthetic retinoid fenretinide: Long-term results from a controlled clinical trial for the prevention of contralateral breast cancer. J Clin Oncol 19:1664-1670, 2001
Sarna G, Pertcheck M, Figlin R, et al: Phase I study of recombinant beta ser 17 interferon in the treatment of cancer. Cancer Treat Rep 70:1365-1372, 1986
Allen J, Packer R, Bleyer A, et al: Recombinant interferon beta: A phase I-II trial in children with recurrent brain tumors. J Clin Oncol 9:783-788, 1991
Kohler PC, Hank JA, Moore KH, et al: Phase 1 clinical trial of recombinant interleukin-2: a comparison of bolus and continuous intravenous infusion. Cancer Invest 7:213-223, 1989
Creagan ET, Kovach JS, Moertel CG, et al: A phase I clinical trial of recombinant human tumor necrosis factor. Cancer 62:2467-2471, 1988
Villablanca JG, Khan AA, Avramis VI, et al: Phase I trial of 13-cis-retinoic acid in children with neuroblastoma following bone marrow transplantation. J Clin Oncol 13:894-901, 1995
Pais RC, Abdel-Mageed A, Ghim TT, et al: Phase I study of recombinant human interleukin-2 for pediatric malignancies: Feasibility of outpatient therapy. A Pediatric Oncology Group Study. J Immunother 12:138-146, 1992
Eckhardt SG, Rizzo J, Sweeney KR, et al: Phase I and pharmacologic study of the tyrosine kinase inhibitor SU101 in patients with advanced solid tumors. J Clin Oncol 17:1095-1104, 1999
Adamson PC, Blaney SM, Widemann BC, et al: Pediatric phase I trial and pharmacokinetic study of the platelet-derived growth factor (PDGF) receptor pathway inhibitor SU101. Cancer Chemother Pharmacol 53:482-488, 2004
Grossbard ML, Lambert JM, Goldmacher VS, et al: Anti-B4-blocked ricin: A phase I trial of 7-day continuous infusion in patients with B-cell neoplasms. J Clin Oncol 11:726-737, 1993
Dinndorf P, Krailo M, Liu-Mares W, et al: Phase I trial of anti-B4-blocked ricin in pediatric patients with leukemia and lymphoma. J Immunother 24:511-516, 2001
Kurzrock R, Quesada JR, Talpaz M, et al: Phase I study of multiple dose intramuscularly administered recombinant gamma interferon. J Clin Oncol 4:1101-1109, 1986
Mahmoud HH, Pui CH, Kennedy W, et al: Phase I study of recombinant human interferon gamma in children with relapsed acute leukemia. Leukemia 6:1181-1184, 1992
Gabizon A, Isacson R, Libson E, et al: Clinical studies of liposome-encapsulated doxorubicin. Acta Oncol 33:779-786, 1994
Peng YM, Dalton WS, Alberts DS, et al: Pharmacokinetics of N-4-hydroxyphenyl-retinamide and the effect of its oral administration on plasma retinol concentrations in cancer patients. Int J Cancer 43:22-26, 1989
Kerr DJ, Kaye SB, Cassidy J, et al: Phase I and pharmacokinetic study of flavone acetic acid. Cancer Res 47:6776-6781, 1987
Johnson SA: Clinical pharmacokinetics of nucleoside analogues: Focus on haematological malignancies. Clin Pharmacokinet 39:5-26, 2000
Riccardi A, Mazzarella G, Cefalo G, et al: Pharmacokinetics of temozolomide given three times a day in pediatric and adult patients. Cancer Chemother Pharmacol 52:459-464, 2003
Kovach JS, Rubin J, Creagan ET, et al: Phase I trial of parenteral 6-thioguanine given on 5 consecutive days. Cancer Res 46:5959-5962, 1986(Debra P. Lee, Jeffrey M. )