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Clinical Trials |
Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, and Center for Pediatric Pharmacokinetics and Therapeutics, Department of Clinical Pharmacy, University of Tennessee, Memphis, Tennessee 38163 [M. H. W., M. V. R., D. S. S., W. E. E.], and Department of Hematology-Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, and Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, Tennessee 38163 [G. K. R., C. B. P., C-H. P., A. S. P.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Our approach was to escalate systemic exposure, rather than dose, to determine the MTSE,3 rather than the MTD. Our group has advocated the MTSE approach (13) and has used it in several pediatric Phase I studies (14, 15, 16) . Pharmacokinetics in Phase I studies may be more variable than in Phase III studies because refractory disease and prior chemotherapy may alter renal or hepatic function. This was evident in pediatric patients with refractory solid tumors, in whom paclitaxel clearance ranged over 5-fold at a single dosage level (350 mg/m2) and 7-fold across dosage levels (200–420 mg/m2; Ref. 17 ). The variability illustrates the difficulty in defining an MTD in Phase I studies with relatively small numbers of patients. In contrast, the MTSE strategy accounts for interpatient variability in pharmacokinetics. This dosage individualization strategy provides a more rapid and precise determination of the maximum tolerated treatment intensity, avoids overlap in systemic exposure levels across dosages, and theoretically requires fewer patients than the MTD method.
We chose paclitaxel as an agent to test in the MTSE strategy because it possesses wide interpatient pharmacokinetic variability (17) , an accurate and precise analytical method to determine plasma concentrations (18) , and a ß half-life that allows estimation of pharmacokinetic parameters and dosage adjustment to reach steady-state concentrations before the end of a 24-h infusion (9) . In addition, paclitaxel exhibits measurable nonhematological toxicity (7, 8, 9) and an exposure-toxicity relationship (10 , 17) . In pediatric patients with refractory solid tumors, children with musculoskeletal or neurological toxicity had a higher median AUC (72 µM·h and 54 µM·h, respectively) than those without toxicity (30 µM·h; Ref. 17 ). Similarly, in adults with refractory solid tumors, neuropathy only appeared at AUCs greater than 29 µM·h (10) . These factors, combined with preclinical and adult clinical data demonstrating antileukemic activity of this agent (7) , provided the rationale for this MTSE Phase I trial.
This is the first published study of paclitaxel in pediatric patients with refractory acute leukemias. The major goals of this study were to escalate targeted systemic exposures of paclitaxel, to determine the exposure-limiting toxicity, to characterize its pharmacokinetics, to seek preliminary evidence of activity in this patient population, and to compare our findings with previously published data for adults and children.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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25% bone marrow blasts) refractory to conventional therapeutic modalities or for which no effective therapy was known were eligible for this study. Other eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0–2, adequate baseline nutritional status (defined as above the third percentile for weight, and normal total serum protein and albumin/globulin ratio), adequate baseline organ function (defined as a bilirubin level 
1.5 mg/dl, serum transaminase levels less than twice the upper limit of normal, and a creatinine level of 1.5 mg/dl), recovery from toxic effects of previous chemotherapy, ANC > 500/µl (unless disease related), a platelet count > 50,000/µl (with or without transfusion), and a life expectancy of at least 8 weeks. Patients with central nervous system leukemia (>5 mononuclear cells in noncentrifuged cerebrospinal fluid with unequivocal blasts) or uncontrolled infection were excluded from the study. The protocol was approved by the Institutional Review Board at St. Jude Children’s Research Hospital, and informed consent was obtained from patients, parents, or guardians according to institutional guidelines before study entry.
Treatment
Paclitaxel was obtained initially from the National Cancer Institute and subsequently from Bristol Myers Squibb Company (Princeton, NJ) as a concentrated sterile solution in 50% polyoxyethylated castor oil (Cremophor EL) and 50% dehydrated alcohol. Paclitaxel was diluted to a final concentration of 0.3 mg/ml in 5% dextrose in water before administration by continuous i.v. infusion over 24 h. All patients were premedicated with 0.25 mg/kg dexamethasone 14 and 7 h before paclitaxel and 1.0 mg/kg diphenhydramine 30 min before treatment. The initial paclitaxel dosage rate was 315 mg/m2/24 h, the dose recommended for adult refractory leukemias (7)
. The paclitaxel targeted systemic exposure (AUC) level was initiated at 29 µM · h based on the AUC predicted if paclitaxel displayed linear pharmacokinetics and patients had the originally estimated average clearance of 221 ml/min/m2. After the first patient was enrolled, both the target systemic exposure and the pharmacokinetic model used for parameter estimation were revised based on results from the first patient and on discovery of nonlinear pharmacokinetics for paclitaxel (17)
. Because two patients (patients 2 and 4) exhibited exposure-limiting toxicity at the revised target of 45 µM · h, the protocol was amended to include the possibility for systemic exposure de-escalation to 33 µM · h. Patients who responded or whose disease stabilized were eligible to receive additional courses at 21-day intervals until there was evidence of disease progression, or until evidence of stable disease over two consecutive courses of therapy was documented. No intrapatient systemic exposure escalation was allowed in subsequent courses of therapy.
Pharmacokinetic Studies
Heparinized venous blood samples were obtained before paclitaxel administration and 2, 5, 8, 20, 23, 25, 26, 28, 36, and 48 h after the start of infusion. Plasma was obtained by centrifugation at 3000 rpm for 5 min. Plasma paclitaxel concentrations were measured by a high-performance liquid chromatography-UV method (18)
. The first four samples were assayed immediately for paclitaxel concentration, and the remaining plasma samples were frozen at -70°C for later analysis. The paclitaxel dose was adjusted in each patient based on pharmacokinetic parameters, which were estimated using the plasma concentrations at 2, 5, and 8 h and using a two-compartment model with saturable distribution and saturable elimination and a Bayesian algorithm (ADAPT II; Biomedical Simulations Resource, University of Southern California, Los Angeles, CA; Ref. 17
). To evaluate the validity of our sampling strategy and the "best case scenario" predictability of our pharmacokinetic model, we performed a simulation study. We estimated the plasma concentrations at 2, 5, and 8 h using the best-fit pharmacokinetic parameters from 30 patients we had studied previously (17)
. We then used only those three concentrations to re-estimate the pharmacokinetic parameters, using our saturable distribution and saturable elimination model. We simulated the AUC using parameters from that limited sampling and compared those AUCs with the observed AUCs, based on the full paclitaxel concentration-versus-time profile. The mean error was less than 23%, and 70% of the courses were within 25% of the calculated AUC. Thus, we proceeded with the MTSE strategy using the concentrations at 2, 5, and 8 h in the current trial. The prior parameter estimates (coefficients of variation) used for Bayesian analysis were as follows: Vm1–0 = 33 µmol · h-1 (30%); Km1–0 = 2 µmol/l (44%); Vm1–2 = 31 µmol · h-1 (90%); Km1–2 = 0.4 µmol/l (56%); K2–1 = 0.3 mol · h-1 (77%), and Vc = 9 l/m2 (37%). Parameters were used to simulate AUCs based on four to five infusion rates projected above or below the patients’ starting rates. A nonlinear model was fitted to the simulated AUC versus infusion rates, and the dosage was adjusted at 12 h after the start of infusion to achieve the target systemic exposure. The first patient was enrolled in the study prior to discovery that paclitaxel undergoes nonlinear disposition; consequently, the pharmacokinetic parameters and dosage adjustment were determined with a linear model for that patient. As a precaution, the maximum intrapatient intrainfusion rate increase was limited to 100%. Because of concentration dependence, paclitaxel clearance was estimated as the dividend of dose and AUC. We acknowledge that "clearance" is an "average" clearance applied to the entire concentration-versus-time curve (and thus is not a constant).
Toxicity and Response Evaluation
A complete history, physical examination, determination of performance status, bone marrow aspirate with or without biopsy, lumbar puncture, complete blood cell count with differential, serum chemistry, urinalysis, chest X-ray, and electrocardiogram were obtained before admission onto the study for each patient. Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria. Exposure-limiting toxicity was defined as reversible nonhematological toxicity of grade 3 or greater or the persistence of grade 4 hematological toxicity for 28 days in two or more patients treated at a given systemic exposure level. By protocol, a minimum of six patients should have been treated at the systemic exposure level just below the level associated with exposure-limiting toxicity, thus defining the MTSE. Serial monitoring of hematological function by complete blood cell counts with differential was performed three times weekly. Electrolyte values, liver and renal function, and nutritional status were obtained weekly, or more frequently as needed. Antileukemic activity was assessed before each paclitaxel course with appropriate clinical and laboratory studies. Patients were allowed to continue paclitaxel therapy if they had no evidence of progressive disease.
Statistical Analysis
Spearman correlation was computed to assess the relationship between the ratio of the achieved-to-target AUC and average "clearance." To determine an estimate of the AUC that patients would have achieved had dosage not been individualized, the AUC was estimated using each patient’s pharmacokinetic parameters and the fixed starting dosage for each patient. A Fisher’s exact test was used to compare the frequency that the achieved AUC versus the projected AUC (with no dose adjustment) was within 25% of the target AUC. A Wilcoxon matched pairs test was used to compare the estimated clearances based on data from the first 8 h and that based on sampling for the entire 48 h. Bias and precision of the achieved AUC (with dose adjustment) and the projected AUC (with no dose adjustment) relative to the target AUC were evaluated by comparing the mean prediction error and mean squared prediction error (19)
using a Wilcoxon matched pairs test (Statistica for Windows; Statsoft, Inc., Tulsa, OK).
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RESULTS |
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. Three patients had B-lineage ALL, three had T-lineage ALL, and one had leukemic conversion from an anaplastic large cell lymphoma. All patients had failed extensive prior chemotherapy, including two who had received allogeneic bone marrow transplantation (one matched related and one matched unrelated). In addition, one patient previously had received cranial irradiation. Only one patient had a WBC > 25,000/µl at the time of study entry.
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. Pharmacokinetic parameter values, as estimated using the saturable distribution plus saturable elimination model, are listed in Table 3
. Median "clearance" was 160 ml/min/m2 (range, 113–311 ml/min/m2). Estimated clearance for each patient determined using the paclitaxel concentrations at 0, 2, 5, and 8 h was predictive of that individual’s clearance for the entire 48 h (r = 0.8; P = 0.03) and was not significantly different (P = 0.18). Although the ratio of the achieved AUC to the target AUC varied from 0.509 to 1.509, the median ratio was 1.002 (Fig. 2)
. Five of the seven courses were within 25% of the targeted systemic exposure after dosage adjustment, whereas none of the seven courses was projected to have been within 25% of the target had no dose adjustment been made (P = 0.021). Although there was no difference in bias when the achieved-versus-projected AUC was compared with the target AUC (mean prediction error, -1.73 versus -2.06 µM · h; P = 0.87), precision was better with the targeted approach (mean squared prediction error, 140 versus 422 µM2 · h2; P = 0.028). The achieved AUC tended to be lower than the target in those with high "clearance" and higher than the target in those with low "clearance" (r = -0.857; P = 0.14; Fig. 2
), in spite of dosage adjustments. The two patients who had bone marrow transplantations also had the largest error in targeted-versus-achieved AUC.
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. Toxicity at the 45 µM · h level was considered unacceptable. Two of the three patients treated at the 45 µM · h systemic exposure level had grade 3 mucositis with achieved AUCs of 45 and 23 µM · h, respectively. Symptoms resolved within 14 days. The one patient who received a second course of paclitaxel also experienced grade 3 mucositis at the lower systemic exposure level (31.5 µM · h). At the 33 µM · h systemic exposure level, two of the three patients had moderate (grade 2) mucositis 2 and 4 days after paclitaxel infusion with achieved AUCs of 39 and 37 µM · h, respectively. The one patient at the 29 µM · h systemic exposure level had grade 2 mucositis 4 days after paclitaxel infusion, which resolved after 14 days. The median paclitaxel AUC and the interval during which concentrations were > 0.1 µM in the five children experiencing mucositis were not significantly different from those in the two children with no toxicity (AUC 38.0 µM · h versus 41.9 µM · h, respectively; P = 0.739; time > 0.1 µM, 46.5 h versus 52.5 h, respectively; P = 0.739). No instances of hypersensitivity or neurotoxic reactions were observed. Significant myelosuppression (ANC < 500/µl) was documented at all systemic exposure levels; however in three of the eight treatment courses, patients already had an ANC < 500/µl before paclitaxel administration. In the other patients, ANC nadirs and time to nadir did not vary substantially between the systemic exposure levels studied. The leukocyte nadir occurred at a median of 11 days after completion of paclitaxel (range, 5–13 days). Neutropenia persisted in five of the seven patients until the end of follow-up (up to 21 days), including two patients who were removed from the study because of persistent disease after 6 and 11 days, respectively. Neutropenia persisted for 7 and 12 days, respectively, in the other two patients.
Grade 3 thrombocytopenia (platelet count, 25,000–50,000/µl) occurred in one patient, and grade 4 thrombocytopenia (platelet count < 25,000/µl) developed in all other patients and occurred a median of 9 days (range, 4–16 days) after completion of paclitaxel infusion. One patient had a platelet count < 25,000/µl at the time of diagnosis. There were no patient characteristics or pharmacokinetic parameters that significantly correlated with hematological toxicity.
Response
All patients had lymphoblasts in the bone marrow (median, 89%; range, 51–100%), and all but one patient had peripheral blasts (median 0.8 x 103/µl; range, 0 x 103/µl to 62.5 x 103/µl) at enrollment. Peripheral blast count did not decrease in two patients, but declined in five patients to a median of 0.6 x 103/µl (range, 0 x 103/µl to 22.2 x 103/µl) 3 days (median; range, 2–17 days) after paclitaxel therapy. Six of the seven patients had worsening of their leukemia soon after treatment (within 20 days). Three had bone marrow biopsies 21 days after paclitaxel, which revealed blast percentages that were similar or higher than at diagnosis. The other three patients had increases in peripheral blast counts. Only one 18-year-old patient with T-lineage ALL, at the 45 µM · h systemic exposure level, was eligible for a second course. Following the second course, however, the disease progressed rapidly.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Pharmacokinetic parameters of paclitaxel administered over 24 h in children with refractory leukemias were similar to those achieved in pediatric patients with refractory solid tumors receiving the same dosing schedule (17) . Systemic clearance in our patients with leukemia ranged from 113 to 311 ml/min/m2, comparable with that observed in both children (72–518 ml/min/m2; Ref. 17 ) and adults (280–458 ml/min/m2; Refs. 7 , 9 , 20 , 21 ) given 24-h infusions. It should be noted that paclitaxel clearance is dose-dependent, and thus will change within the same patient at different dosage levels.
In the current study, the MTSE strategy reduced the variability in systemic exposure attributable to interindividual differences in drug disposition. This approach achieved similar bias, but better precision, than conventional dosing, as determined by comparing the achieved AUC with the projected AUC had the dose remained constant over the 24 h. Inaccuracy in achieving the target AUC could have been due to a high ratio of the number of parameters relative to the number of plasma concentrations (resulting in inaccuracy in the initial parameter estimates) or to true intrainfusion changes in clearance (for example, because of interacting or concurrent drugs). CYP3A4 may play a primary role in the metabolism of paclitaxel, and coadministration of CYP3A4 substrates and inducers may cause substantial variability in its clearance (18 , 22 , 23) . In six of the eight courses, CYP3A4 substrates (e.g., fluconazole, nifedipine, or acetaminophen; Refs. 18 , 24 , 25 ) were administered to our patients during paclitaxel infusion. The mean difference between patients’ final clearance and that estimated using the concentrations at 0, 2, 5, and 8 h was 26.3% in patients who received a CYP3A4 substrate, whereas it was 5.3% in those who did not receive a CYP3A4 substrate. In addition, the achieved AUC in the two patients who had bone marrow transplantations had the greatest deviation from the target. These patients, both having received CYP3A4 substrates during paclitaxel infusion, had the largest differences in estimated clearance based on initial pharmacokinetic parameters and those based on final parameter estimates (patient 4 had a 41% increase in clearance, and patient 6 had a 42% decrease). Interestingly, patients with paclitaxel clearances above 160 ml/min/m2 typically achieved an AUC below the target, whereas those with clearances below 160 ml/min/m2 achieved AUCs above the target, despite upward and downward dosage adjustment, respectively.
The exposure-limiting toxicity in this study was mucositis, the same as that observed in adults with refractory acute leukemias treated with the same schedule, in whom dose escalation was precluded above 390 mg/m2 (7)
. Two of our three patients at the 45 µM · h systemic exposure level had grade 3 mucositis. The three patients with grade 3 mucositis received a median dose of 374 mg/m2 (range, 366–378 mg/m2). There was considerable overlap in systemic exposure and dose in patients who did and who did not experience mucositis. The systemic exposure in patients with moderate to severe (grades 2 and 3) mucositis was not significantly different from those without mucositis (38.0 versus 41.9 µM · h, respectively; P = 0.739). In contrast, mucositis was rarely observed in children with refractory solid tumors (8
, 17)
and in adult studies that evaluated lower doses of paclitaxel. Neurotoxicity, in particular sensory neuropathies, was dose-limiting in patients with refractory solid tumors receiving 24-h infusions (8
, 9)
, but was not seen in any of the patients in our study. Myelosuppression was dose-limiting in a number of Phase I studies in adults with solid tumors receiving lower doses of paclitaxel over shorter infusion times (10, 11, 12)
, although the frequency of neutropenia was greater when paclitaxel was given over 24 h rather than 3 h (20)
. We observed significant neutropenia (ANC 500/µl) at all systemic exposure levels, an observation that could have been due to refractory leukemia or to paclitaxel exposure.
Exposure-limiting toxicity occurred at much lower AUCs than occurred with the same schedule of paclitaxel given to children with refractory solid tumors. The MTSE was exceeded at the very first systemic exposure level (45 µM · h), a level exceeded by about 50% of the patients treated in the Phase I study of patients with solid tumors (8)
. Extensive previous chemotherapy, including other mucosal toxins (e.g., etoposide, busulfan, and cytarabine), may have increased susceptibility to gastrointestinal toxicity. As a result, mucositis was elicited at low AUCs, which limited escalation of paclitaxel treatment intensity. Simply comparing the "number of prior courses" of chemotherapy does not help to differentiate this poorly tolerant leukemic population because 
50% of children with solid tumors received more than three courses of chemotherapy prior to paclitaxel (8)
and five of seven children in our study had failed three or more prior chemotherapy protocols. Similar to findings in adults with refractory acute leukemias (7)
, treatment intensity causing exposure-limiting nonhematological toxicity may not have been significantly different from that causing moderate-to-severe hematological toxicity. This narrow therapeutic range may have limited our ability to escalate paclitaxel treatment intensity and limited its effectiveness as an antileukemic agent. Thus, the trial was discontinued before the MTSE was defined formally. It is not known whether less heavily pretreated patients, such as those eligible for Phase II studies, are able to tolerate higher paclitaxel systemic exposures.
In this study, we individualized paclitaxel treatment by adjusting doses to achieve a targeted systemic exposure in each patient. The MTSE strategy resulted in reduced interpatient variability in AUC compared with conventional dosing. However, because the effectiveness of frontline therapy for acute leukemias has improved and treatment has intensified, the number of patients available for Phase I trials has declined and their clinical condition is usually such that they may have reduced tolerance to subsequent chemotherapy. Despite a similar pharmacokinetic profile in children with acute leukemias and solid tumors, exposure-limiting toxicity occurred at lower AUCs in our refractory leukemia patients, which may not forecast paclitaxel tolerance in the Phase II or III setting accurately. It may be necessary to develop alternatives to traditional Phase I studies as the mechanism for future evaluations of new drugs for childhood leukemias.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by the National Institutes of Health, Bethesda, MD, Cancer Center CORE Grants CA-21765 and CA-78224, a Center of Excellence Grant from the State of Tennessee, and American Lebanese Syrian Associated Charities, Memphis, TN. 
2 To whom requests for reprints should be addressed, at Pharmaceutical Department, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105. Phone: (901) 495-3663.
3 The abbreviations used are: MTSE, maximum tolerated systemic exposure; MTD, maximum tolerated dose; AUC, area under the concentration-versus-time curve; ANC, absolute neutrophil count; ALL, acute lymphoblastic leukemia.
Received 10/ 8/98; revised 11/24/98; accepted 11/30/98.
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) and (B) another (patient 7) with dose de-escalation 12 h after the start of infusion (dose, 241 mg/m2; AUC, 36.9 µM · h; 
). Symbols represent measured paclitaxel plasma concentrations and lines represent the best-fit curves using Bayesian estimation algorithms for a two-compartment model with saturable distribution and saturable elimination. Thick gray lines are simulated concentrations based on initial pharmacokinetic parameters estimated from the plasma concentrations at 2, 5, and 8 h and assuming a constant dose of 315 mg/m2 over 24 h.