Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia.

The outcomes in children with refractory/relapsed (R/R) acute lymphoblastic leukemia (ALL) are dismal. The efficacy and safety of intravenous clofarabine 40 mg/m(2) per day, cyclophosphamide 440 mg/m(2) per day, and etoposide 100 mg/m(2) per day for 5 consecutive days in pediatric patients with R/R ALL was evaluated in this phase 2 study. The primary endpoint was overall response rate (complete remission [CR] plus CR without platelet recovery [CRp]). Among the 25 patients (median age, 14 years; pre-B cell ALL, 84%; ≥ 2 prior regimens: 84%; refractory to previous regimen: 60%), the overall response rate was 44% (7 CR, 4 CRp) with a 67.3-week median duration or remission censored at last follow-up. Most patients proceeded to alternative therapy, and 10 patients (40%) received hematopoietic stem cell transplantation. Six patients (24%) died because of treatment-related adverse events associated with infection, hepatotoxicity, and/or multiorgan failure. The study protocol was amended to exclude patients with prior hematopoietic stem cell transplantation after 4 of the first 8 patients developed severe hepatotoxicity suggestive of veno-occlusive disease. No additional cases of veno-occlusive disease occurred. The regimen offered encouraging response rates and sustained remission in R/R patients. Future investigation should include exploration of patient selection, dosing, and supportive care. This trial was registered at www.clinicaltrials.gov as #NCT00315705.

Phase I study of tandem high-dose chemotherapy with autologous peripheral blood stem cell rescue for children with recurrent brain tumors: a Pediatric Blood and MarrowTransplant Consortium study.

BACKGROUND: High-dose chemotherapy with autologous stem cell rescue (HDC/SCR) has produced responses and prolonged survival for some children with recurrent brain tumors, but is associated with considerable morbidity and mortality. A Phase I trial of two cycles of HDC/SCR for recurrent brain tumors in children was performed to determine the maximum tolerated doses for a novel regimen. PROCEDURES: Two cycles of HDC/SCR were given. Cycle 1 included thiotepa and carmustine given on days -5, -4, and -3. Four to six weeks later, patients received cycle 2 which included thiotepa and carboplatin given on days -5, -4, and -3. Autologous peripheral blood stem cells (PBSC) were infused on day 0 of each cycle. RESULTS: Thirty-two patients were treated and 25 patients received both cycles of HDC/SCR. Common toxicities included mucositis, emesis, diarrhea, anorexia, and pancytopenia. Eight of 32 (25%) assessable children died from regimen-related toxicity. Pulmonary failure occurred in seven patients. Seven patients had grade 3-4 neurotoxicity. The 3-year event-free survival (EFS) was 25%. CONCLUSIONS: We determined the maximum tolerated regimen to be thiotepa 600 mg/m(2) and carmustine 300 mg/m(2) followed by thiotepa 600 mg/m(2) and carboplatin 1,200 mg/m(2) . Pulmonary toxicity was considerable. The toxic death rate was similar to other trials of HDC/SCR for children with recurrent brain tumors performed during the same time period. The regimen resulted in prolonged time to progression for a significant number of patients and long-term survival for some patients with recurrent medulloblastoma and rhabdoid tumor.

Population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with cancer.

Clofarabine for injection is a second-generation nucleoside analog approved in the United States (Clolar(®)) and Europe (Evoltra(®)) for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia. This report describes the population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with hematologic malignancies or solid tumors. Clofarabine pharmacokinetics were best described by a 2-compartment model with linear elimination and first-order absorption after oral administration. Clofarabine was rapidly absorbed following oral administration with a mean absorption time of less than 2 h and bioavailability of 57.5%. The important covariates affecting clofarabine pharmacokinetics were age, weight, and estimated creatinine clearance (eCrCL). No difference in pharmacokinetics was observed between sexes, races, or disease type. The elimination half-life was dependent on all the covariates but was generally less than 7 h in all cases. A difference in clofarabine pharmacokinetics was observed between adults and children. For a pediatric patient 3 years old weighing 16 kg with an eCrCL of 138 mL/min/1.73 m(2), the population estimates for total systemic clearance and volume of distribution at steady-state were 18.3 L/h (1.14 L/h/kg) and 92.9 L (5.81 L/kg), respectively. α- and ß-half-life were 0.9 and 4.4 h, respectively. For an elderly patient 82 years old weighing 96 kg with an eCrCL of 46 mL/min/1.73 m(2), the population estimates for CL and Vdss were 21.5 L/h (0.22 L/h/kg) and 257.4 L (268 L/kg), respectively. α- and ß-half-life were 0.5 and 10.6 h, respectively. Because of the difference in pharmacokinetics, adults have higher exposure than children given a similar dose standardized to body surface area. The exact mechanism of this difference is not understood. As eCrCL decreased, exposure increased due to reduced total systemic clearance. In the case of moderate (eCrCL 30 to 60 mL/min/1.73 m(2)) and severe (eCrCL <30 mL/min/1.73 m(2)) renal impairment, dose reduction may be needed to maintain similar exposure in an equivalent patient of the same age, weight, and normal renal function after both oral and intravenous administration. 6-Ketoclofarabine was a minor metabolite with peak plasma concentrations occurring about 1 h after the start of the infusion and having a metabolite ratio averaging less than 5% and not more than 8% for any particular individual. 6-Ketoclofarabine was rapidly cleared from plasma with an average apparent half-life of 4.9 h (range 3.9 to 6.2 h). No accumulation of 6-ketoclofarabine was observed with predose samples all below the limit of quantification on Days 8 and 15. Further monitoring of 6-ketoclofarabine is not required in future studies.

Biological modification strategies following marrow ablative, high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell rescue (AHSCR) for pediatric brain tumors.

Maintenance biology-based therapy following HDCT/AHSCR in pediatric brain tumors has not been tested as yet. Failure of the HDCT/AHSCR might be due to tumor-immunity dysregulation, reactivation of the angiogenic switch and other mechanisms. Angiogenesis has been shown to be reactivated following chemotherapy. The angiogenic factors engaged in this process in childhood brain tumors following HDCT/AHSCR have not been tested in the clinic. Metronomic chemotherapy has been found to be safe and angiogenesis inhibitors are currently tested in children. Other good possible candidates for clinical trials in this setting include retinoic acid and immunotherapy.

Advancement of pediatric blood and marrow transplantation research in North America: priorities of the Pediatric Blood and Marrow Transplant Consortium.

Advances in pediatric bone marrow transplantation (BMT) are slowed by the small number of patients with a given disease who undergo transplantation, a lack of sufficient infrastructure to run early-phase oncology protocols and studies of rare nonmalignant disorders, and challenges associated with funding multi-institutional trials. Leadership of the Pediatric Blood and Marrow Transplant Consortium (PBMTC), a large pediatric BMT clinical trials network representing 77 active and 45 affiliated centers worldwide, met in April 2009 to develop strategic plans to address these issues. Key barriers, including infrastructure development and funding, along with scientific initiatives in malignant and nonmalignant disorders, cellular therapeutics, graft-versus-host disease, and supportive care were discussed. The PBMTC's agenda for approaching these issues will result in infrastructure and trials specific to pediatrics that will run through the PBMTC or its partners, the Blood and Marrow Transplant Clinical Trials Network and the Children's Oncology Group.

Safety, efficacy, and pharmacokinetics of intravenous busulfan in children undergoing allogeneic hematopoietic stem cell transplantation.

PURPOSE: To determine the safety, efficacy, and PK profile of intravenous busulfan (Bu) in the context of a Bu and cyclophosphamide (IVBuCy) preparative regimen in children undergoing allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: Twenty-four children were enrolled in an open-label, multicenter trial of IVBuCy as the preparative regimen for HLA-matched sibling allogeneic HSCT. IVBu was administered q6 hr for 16 doses with a targeted area under the curve (AUC) of 900-1,350 microMol-min. The initial dose was 0.8 mg/kg for children >4 years of age and 1 mg/kg for those <4 years of age. PK of the first dose IVBu was determined to calculate a single dosage adjustment, and with the 9th and 13th doses to confirm steady-state PK. RESULTS: The targeted AUC was achieved with the first dose in 17/24 (71%) of the children using the age-adjusted dosing approach. Dosing was increased in five patients, and reduced in two patients to achieve target values. After dose adjustment based on PK, 91% of the children had an AUC within the target range at steady state (AUCss). Median final dosing and clearance (CL) of IVBu were 1.1 mg/kg and 4.1 ml/min/kg in patients < or =4 years, and 0.9 mg/kg and 2.9 ml/min/kg in patients >4 years. All children were engrafted with documented donor chimerism. No late rejections or graft failures occurred. Four patients had veno-occlusive disease, three of which resolved within 2 weeks of onset. Two children died from transplant-related causes unrelated to Bu. CONCLUSION: IVBu is a safe and effective and offers the benefit of predictable and consistent systemic exposure.

Phase II study of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia.

PURPOSE: To determine the efficacy and safety of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia (AML). PATIENTS AND METHODS: A phase II, open-label, multicenter study was conducted with single-agent clofarabine in pediatric patients with refractory or relapsed AML. Clofarabine was administered intravenously over 2 hours at the pediatric maximum-tolerated dose (MTD) of 52 mg/m(2) daily for 5 consecutive days. Cycles were repeated every 2 to 6 weeks. Responses determined by an independent response review panel. RESULTS: The 42 patients treated on the study had a median age of 13 years (range, 2 to 22 years) and had received a median number of two (range, one to five) prior regimens. The response rate was 26% and included one complete response without platelet recovery and 10 partial responses. The median duration of response was 20 weeks (range, 2 to >or= 156 weeks). Six of 28 patients who were refractory to the immediately preceding therapy achieved response. Thirteen patients (31%), including seven responders, proceeded to hematopoietic stem-cell transplantation (HSCT) after treatment with clofarabine and survived between 24 to >or= 160 weeks. Five patients (12%) remain alive post-transplantation at >or= 63, >or= 71, >or= 86, >or= 114, and >or= 130 weeks. The most common grade 3 or greater adverse events without regard to causality were febrile neutropenia, catheter-related infection, epistaxis, hypotension, nausea, and fever. Transient elevation of liver enzymes and hypokalemia occurred frequently. Five patients died within 30 days of clofarabine administration secondary to progressive disease, and another five died as a result of an adverse event. CONCLUSION: Clofarabine is active in pediatric patients with multiply relapsed or refractory AML. Responses allowed several refractory patients to proceed to HSCT. The toxicity profile was expected in this patient population.

The treatment of pediatric Philadelphia positive (Ph+) leukemias in the imatinib era.

BACKGROUND: As the treatment of Philadelphia positive (Ph+) leukemias in the era of imatinib continues to evolve, the role of allogeneic hematopoietic cell transplantation (allogeneic-HCT) in first remission is becoming more unclear. PROCEDURE: Thirty-two pediatric centers across the United States and Canada were surveyed regarding current treatment practices for Ph+ acute lymphoblastic leukemia (ALL) and chronic myelogenous leukemia (CML). The survey addressed treatment approaches for Ph+ ALL and CML in terms of imatinib therapy and use of allogeneic-HCT. RESULTS: Twenty-three of the 32 centers returned the survey to provide a 72% response rate. Of the 27 physicians responding to the survey, 22 (81%) recommended a matched sibling donor (MSD) allogeneic-HCT, when available, in first remission for Ph+ ALL compared to 17/27 (63%) for patients with first chronic phase CML. There was universal agreement among survey responders regarding the use of imatinib upfront in Ph+ ALL and CML patients while 13 of 27 (48%) physicians reported using imatinib as maintenance therapy post-HCT for Ph+ ALL compared to 9 of 27 (33%) for CML. CONCLUSIONS: Although a treatment consensus did not exist based on the results of this small survey, current treatment practices for pediatric Ph+ ALL and CML appear to favor allogeneic-HCT when a MSD is available. The use of post-HCT imatinib as maintenance therapy to avoid relapse for either Ph+ ALL or CML remains uncertain and awaits future prospective studies.

Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313.

The role of reduced-intensity conditioning (RIC) regimens in pediatric cancer treatment is unclear. To define the efficacy of a busulfan/fludarabine/antithymocyte globulin RIC regimen in pediatric patients ineligible for myeloablative transplantation, we completed a trial at 23 institutions in the Pediatric Blood and Marrow Transplant Consortium. Forty-seven patients with hematologic malignancies were enrolled. Sustained engraftment occurred in 98%, 89%, and 90%, and full donor chimerism was achieved in 88%, 76%, and 78% of evaluable related bone marrow/peripheral blood stem cells (BM/PBSCs), unrelated BM/PBSCs, and unrelated cord blood recipients. With a median follow-up of 24 months (range, 11-53 months), 2-year event-free survival, overall survival (OS), transplantation-related mortality, and relapse were 40%, 45%, 11%, and 43%, respectively. Univariate analysis revealed an inferior outcome when patients had undergone previous total body irradiation (TBI)-containing myeloablative transplantation (2-year OS, 23% vs 63% vs 52%, previous TBI transplantation vs no TBI transplantation vs no transplantation, P = .02) and when patients not previously treated with TBI had detectable disease at the time of the RIC procedure (2-year OS, 0% vs 63%, detectable vs nondetectable disease, P = .01). Favorable outcomes can be achieved with RIC approaches in pediatric patients in remission who are ineligible for myeloablative transplantation. This study was registered at www.clinicaltrials.gov as #NCT00795132.

(123)I-mIBG scintigraphy in patients with known or suspected neuroblastoma: Results from a prospective multicenter trial.

BACKGROUND: A prospective trial was conducted to confirm the diagnostic performance of (123)I-mIBG scintigraphy in patients with known or suspected neuroblastoma. PROCEDURE: One hundred patients (mean age 4.7 years) were enrolled, 86 with a previous diagnosis of neuroblastoma, 13 with suspected disease based upon symptoms, imaging findings, and elevated catecholamines, and one adult with an abdominal tumor thought to be of neuroendocrine origin. All patients underwent whole-body planar imaging 24 hr following IV administration of 1-10 mCi (37-370 MBq) (123)I-mIBG. SPECT imaging of the thorax/abdomen/pelvis was performed in 51 patients. Images were interpreted by three blinded readers, with consensus requiring agreement of at least two readers. Disease status was confirmed by histopathology, imaging results, catecholamine measurements, and follow-up. RESULTS: Sixty-four patients had active disease, 30 were without disease, and 6 were judged indeterminate because of insufficient confirmatory data. (123)I-mIBG scintigraphy had a sensitivity of 88% (56/64) and specificity of 83% (25/30). Sensitivity was 91% (30/33) among the subset of subjects who had both planar and SPECT imaging. Among 53 patients with recent histopathology, sensitivity and specificity were 93% and 92%, respectively. Most false-negative interpretations were in patients with minimal residual disease (n = 4), while false-positive interpretations generally involved atypical adrenal or other physiological uptake (n = 4). CONCLUSIONS: This prospective multicenter trial of (123)I-mIBG scintigraphy documents high sensitivity and specificity of this imaging technique in patients with both newly diagnosed and previously treated neuroblastoma.

Dose intensive melphalan and cyclophosphamide with autologous hematopoietic stem cells for recurrent medulloblastoma or germinoma.

PURPOSE: To determine the response, toxicity, and survival for children with progressive or recurrent medulloblastoma and germinoma using a single myeloablative course of chemotherapy supported by autologous hematopoietic stem cells. PATIENTS AND METHODS: Subjects were in second remission or had minimal residual disease at the time of study entry. The conditioning regimen consisted of cyclophosphamide 6,000 mg/m(2) plus melphalan 180 mg/m(2). RESULTS: Twenty-nine evaluable pediatric patients were accrued. The most frequent major toxicities were myelosuppression, infections, and stomatitis, but no toxic deaths were recorded. Best responses were: CR = 6, CCR = 13, PR = 6, SD = 2, and PD = 2. There were 6 medulloblastoma and 3 germinoma survivors with a median follow-up of 7.5 years (range = 2.8-10). Two germinoma survivors received radiotherapy after autografting for presumptive progressive disease. CONCLUSION: Myeloablative chemotherapy consisting of cyclophosphamide and melphalan was tolerable in the relapsed brain tumor setting with 19/29 cases achieving CR or CCR status and 9/29 becoming long-term survivors.

A pilot study of addition of amifostine to melphalan, carboplatin, etoposide, and cyclophosphamide with autologous hematopoietic stem cell transplantation in pediatric solid tumors-A pediatric blood and marrow transplant consortium study.

Limited information is available regarding the use of amifostine in pediatric hematopoietic stem cell transplant (HSCT) patients. Melphalan, carboplatin, etoposide +/- cyclophosphamide is a commonly used preparatory regimen in pediatric solid tumor HSCT. Therefore, we decided to determine the feasibility of the addition of amifostine (750 mg/m b.i.d. x 4 d) to melphalan (200 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) (level 1) and escalating doses of cyclophosphamide (3000 mg/m and 3800 mg/m, levels 2 and 3, respectively) followed by autologous HSCT. Thirty-two patients with a variety of pediatric solid tumors were studied. Seventeen patients were accrued at level 1, 9 at level 2, and 6 at level 3. Major toxicities during the administration of the preparatory regimen were hypocalcemia, emesis, and hypotension. Hypocalcemia required aggressive calcium supplementation during the conditioning phase. No dose limiting toxicities were encountered at level 3. Amifostine at 750 mg/m b.i.d. for 4 days can be administered with a double alkylator regimen consisting of melphalan (200 mg/m), cyclophosphamide (up to 3800 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) with manageable toxicities.

Phase II trial of irinotecan in children with refractory solid tumors: a Children's Oncology Group Study.

PURPOSE: A phase II study was performed to determine the efficacy of irinotecan (IRN) in children with refractory solid tumors. Secondary objectives were to evaluate toxicity, pharmacokinetics, pharmacodynamics, and UGT1A1 genotype. PATIENTS AND METHODS: A total of 181 patients were enrolled, of whom 171 were eligible. Patients received IRN 50 mg/m2/d for 5 days repeated every 3 weeks. Pharmacokinetic studies and UGT1A1 genotyping were performed. RESULTS: Of 161 patients assessable for response, one patient with hepatoblastoma had a complete response, with partial responses observed in patients with medulloblastoma (n = 4), rhabdomyosarcoma (n = 1), neuroblastoma (n = 1), and germinoma (n = 1), for an overall response rate of 5%. Grade 4 neutropenia and grade 3 to 4 diarrhea occurred in less than 7% of the courses administered. Pharmacokinetic studies were available for 79 patients. The mean +/- standard deviation IRN plasma clearance was 374 +/- 148 mL/min/m2, with median relative extent of conversion and relative extent of glucuronidation of 0.05 (range, 0.01 to 0.25) and 2.24 (range, 0.39 to 9.6), respectively. No association between UGT1A1 genotype (n = 61) and toxicity or pharmacokinetic parameters was observed. CONCLUSION: IRN 50 mg/m2/d for 5 days every 21 days is well tolerated, but was not effective as a single agent in a spectrum of solid tumors, with the possible exception of patients with medulloblastoma (16% response rate). There was no association between UGT1A1*28 genotype and toxicity or pharmacokinetic parameters.

Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children's Oncology Group.

BACKGROUND: Effective chemotherapy is lacking for most types of central nervous system (CNS) tumors in children. Temozolomide, an agent with activity against adult brain tumors, was investigated in children and adolescents with recurrent CNS tumors. METHODS: Temozolomide was administered orally as monthly 5-day courses at doses of 200 mg/m(2)/d (patients with no prior craniospinal irradiation [CSI]) or 180 mg/m(2)/d (prior CSI). Patients with a complete (CR) or partial (PR) response or stable disease (SD) could continue temozolomide for up to 12 cycles. RESULTS: The cohort comprised 122 patients, including 113 with CNS tumors. Median age was 11 years (range, 1-23 years). Among 104 evaluable patients with CNS tumors, 5 PRs and 1 CR were observed. PRs occurred in 1 of 23 evaluable patients with high-grade astrocytoma, 1 of 21 with low-grade astrocytoma, and 3 of 25 with medulloblastoma/primitive neuroectodermal tumor (PNET). The CR occurred in an additional patient with medulloblastoma/PNET. No responses were observed in patients with ependymoma, brain-stem glioma, or other CNS tumors. Notably, 41% of patients with low-grade astrocytoma had SD through 12 courses. The most frequent toxicities were grade 3 or 4 neutropenia (19%) and thrombocytopenia (25%); nonhematologic toxicity was infrequent. CONCLUSIONS: Although overall objective responses were limited, further exploration of temozolomide may be warranted in children with medulloblastoma and other PNETs, or in patients with low-grade astrocytoma, perhaps in a setting of less pretreatment than the patients in the current study, or in the context of multiagent therapy.

Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia.

PURPOSE: To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: In a phase II, open-label, multicenter study, 61 pediatric patients with refractory or relapsed ALL received clofarabine 52 mg/m2 intravenously over 2 hours daily for 5 days, every 2 to 6 weeks. The median age was 12 years (range, 1 to 20 years), and the median number of prior regimens was three (range, two to six regimens). RESULTS: The response rate was 30%, consisting of seven complete remissions (CR), five CRs without platelet recovery (CRp), and six partial remissions. Remissions were durable enough to allow patients to proceed to hematopoietic stem-cell transplantation (HSCT) after clofarabine. Median CR duration in patients who did not receive HSCT was 6 weeks, with four patients maintaining CR or CRp for 8 weeks or more (8+, 12, 37+, and 48 weeks) on clofarabine therapy alone. The most common adverse events of grade > or = 3 were febrile neutropenia, anorexia, hypotension, and nausea. CONCLUSION: Clofarabine is active as a single agent in pediatric patients with multiple relapsed or refractory ALL. The toxicity profile is as expected in this heavily pretreated patient population. Studies exploring rational combinations of clofarabine with other agents are ongoing in an effort to maximize clinical benefit.

Temozolomide and radiation for aggressive pediatric central nervous system malignancies.

This study describes the outcomes of children treated with combinations of temozolomide and radiation therapy for various aggressive central nervous system malignancies. Their age at diagnosis ranged from 1 to 15 years. Patients with focal disease were treated with concomitant temozolomide (daily 75 mg/m) and three-dimensional conformal radiotherapy in a dose that ranged from 50 to 54 Gy, followed by temozolomide (200 mg/m/d x 5 days/month in three patients, 150 mg/m x 5 days/ month in one patient). Patients with disseminated disease were treated with craniospinal radiation (39.6 Gy) before conformal boost. One patient received temozolomide (200 mg/m x 5 days/month) before craniospinal radiation, and one patient received temozolomide (daily 95 mg/m) concomitant with craniospinal radiation and a radiosurgical boost, followed by temozolomide (200 mg/m x 5 days/month). Three patients achieved a partial response during treatment, with two of these patients dying of progressive disease after treatment. One patient has no evidence of disease. Three patients achieved stable disease, with one of these patients dying of progressive disease after treatment. Toxicities observed included low-grade neutropenia, thrombocytopenia, and lymphopenia. The combination of temozolomide and radiotherapy appears to be well tolerated in a variety of treatment schemas for aggressive pediatric central nervous system malignancies. This information is of particular use in designing future studies, given the recent positive results in a randomized study examining the use of temozolomide concomitant with radiation in the treatment of adult glioblastoma.

Population pharmacokinetics of clofarabine, a second-generation nucleoside analog, in pediatric patients with acute leukemia.

The population pharmacokinetics of plasma clofarabine and intracellular clofarabine triphosphate were characterized in pediatric patients with acute leukemias. Traditional model-building techniques with NONMEM were used. Covariates were entered into the base model using a forward selection significance level of .05 and a backwards deletion criterion of .005. Model performance, stability, and influence analysis were assessed using the nonparametric bootstrap and n-1 jackknife. Simulations were used to understand the relationship between important covariates and exposure. A 2-compartment model with weight (scaled to a 40-kg reference patient) modeled as a power function on all pharmacokinetic parameters (0.75 on clearance-related terms and 1.0 on volume-related terms) was fit to plasma clofarabine concentrations (n = 32). White blood cell (WBC) count, modeled as a power function (scaled to a WBC count of 10 x 10(3)/microL), was a significant predictor of central volume with power term 0.128 +/- 0.0314. A reference patient had a systemic clearance of 32.8 L/h (27% between-subject variability [BSV]), a central volume of 115 L (56% BSV), an intercompartmental clearance of 20.5 L/h (27% BSV), and a peripheral volume of 94.5 L (39% BSV). Intracellular clofarabine triphosphate concentrations were modeled using a random intercept model without any covariates. The average predicted concentration was 11.6 +/- 2.62 microM (80% BSV), and although clofarabine triphosphate half-life could not be definitively estimated, its value was taken to be longer than 24 hours. The results confirm that clofarabine should continue being dosed on a per-squaremeter or per-body-weight basis.

Phase 2 study of idarubicin in pediatric brain tumors: Pediatric Oncology Group study POG 9237.

Idarubicin (IDA), the 4-demethoxy analog of daunomycin, has had significant cytotoxicity in many malignancies. In previous reports, the alcohol metabolite of IDA, 4-demethoxydaunorubicinol (idarubicinol, or IDOL), had cytotoxic activity and the ability to penetrate the blood-brain barrier. For this reason, the Pediatric Oncology Group conducted a Phase 2 trial of IDA for children with recurrent or progressive brain tumors. Ninety-one eligible children were entered on this study, with ages ranging from 3 months to 19 years. Patients were stratified by tumor types into 6 categories: stratum 1, low-grade astrocytoma; stratum 2, malignant glioma (glioblastoma multiforme and anaplastic astrocytoma); stratum 3, medulloblastoma; stratum 4, brainstem glioma; stratum 5, ependymoma; and stratum 6, miscellaneous malignant tumors not included in the previous diagnoses. IDA(18 mg/m2) was infused over 4 h and followed by granulocyte colony-stimulating factor (G-CSF) beginning day 5 after infusion of IDA. G-CSF was continued until blood cell count recovery. Cycles were repeated at approximately 21-day intervals until patients developed progressive disease or had completed 6 cycles with stable or improved disease. Pharmacokinetic plasma and cerebrospinal fluid (CSF) samples were collected from a subset of these patients. Response was poor in all strata. Most patients developed progressive disease; however, in 21 patients with medulloblastoma there was 1 partial response, and 6 patients had stable disease (SD) that in 4 patients lasted more than 20 weeks. Grades 3/4 hematopoietic toxicities were the most common toxic events, and 14 infection-related events resulted in hospitalization of patients. Only 1 patient developed reduced cardiac function. The systemic clearance data for IDA and IDOL were nearly identical to those published on patients with leukemia, and the plasma elimination of the IDOL metabolite was substantially longer than that of the parent drug IDA. The peak CSF:plasma ratios of IDA and IDOL were very low. The overall response rates to IDA were disappointing despite periods of prolonged SD in nearly a fourth of the patients. We conclude from this data and from that in nonhuman primates that it is unlikely that IDA, daunomycin, or other related anthracyclines will be useful for treating primary CNS tumors.