F M Balis

The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

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Publications (267)2085.85 Total impact

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    ABSTRACT: Background Juvenile myelomonocytic leukemia (JMML) is not durably responsive to chemotherapy, and approximately 50% of patients relapse after hematopoietic stem cell transplant (HSCT). Here we report the activity and acute toxicity of the farnesyl transferase inhibitor tipifarnib, the response rate to 13-cis retinoic acid (CRA) in combination with cytoreductive chemotherapy, and survival following HSCT in children with JMML.ProcedureEighty-five patients with newly diagnosed JMML were enrolled on AAML0122 between 2001 and 2006. Forty-seven consented to receive tipifarnib in a phase II window before proceeding to a phase III trial of CRA in combination with fludarabine and cytarabine followed by HSCT and maintenance CRA. Thirty-eight patients enrolled only in the phase III trial.ResultsOverall response rate was 51% after tipifarnib and 68% after fludarabine/cytarabine/CRA. Tipifarnib did not increase pre-transplant toxicities. Forty-six percent of the 44 patients who received protocol compliant HSCT relapsed. Five-year overall survival was 55 ± 11% and event-free survival was 41 ± 11%, with no significant difference between patients who did or did not receive tipifarnib.Conclusions Administration of tipifarnib in the window setting followed by HSCT in patients with newly diagnosed JMML was safe and yielded a 51% initial response rate as a single agent, but failed to reduce relapse rates or improve long-term overall survival. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 12/2014; · 2.35 Impact Factor
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    ABSTRACT: Ch14.18 improves survival in children with high-risk neuroblastoma but is associated with substantial toxicity. Ch14.18 pharmacokinetics were previously reported to be highly variable and characterized by a higher clearance in children than in adults, and a large volume of distribution. Identifying factors responsible for its variability could lead to alternative dosing strategies that reduce toxicity.
    Cancer Chemotherapy and Pharmacology 09/2014; · 2.80 Impact Factor
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    ABSTRACT: Background Pirfenidone, an oral anti-inflammatory, antifibrotic agent with activity in idiopathic pulmonary fibrosis, may mediate anti-tumor activity in neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PN) by inhibition of fibroblast proliferation and collagen synthesis. The primary objective of this open label, single arm phase II trial was to evaluate the activity of pirfenidone in children and young adults with inoperable PN.ProcedurePatients (3–21 years) with NF1-related progressive PN received pirfenidone at the previously determined optimal dose (500 mg/m2 orally, q8h) on a continuous dosing schedule (one cycle = 28 days). Volumetric MRI analysis was used to assess response. Progression was defined as ≥20% PN volume increase compared to baseline. Pirfenidone would be considered active if it doubled the median time to progression (TTP) compared to the TTP on the placebo arm of a phase II trial with the farnesyltransferase inhibitor tipifarnib, which used near identical eligibility criteria. Toxicities, objective response rate, and quality of life (QOL) also were evaluated.ResultsThirty-six patients were enrolled and tolerated pirfenidone well with intermittent nausea and vomiting as the most frequent toxicities. A dose reduction was required in only three patients. The median TTP for pirfenidone was 13.2 months compared to 10.6 months for the placebo control group from the tipifarnib trial (two-tailed P = 0.92; one-tailed P = 0.46). No objective responses were observed.Conclusions Pirfenidone was well tolerated, but did not demonstrate activity as defined in this trial and does not warrant further evaluation in children with NF1 and progressive PN. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 04/2014; · 2.35 Impact Factor
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    ABSTRACT: BackgroundRAS is dysregulated in neurofibromatosis type 1 (NF1) related plexiform neurofibromas (PNs). The activity of tipifarnib, which blocks RAS signaling by inhibiting its farnesylation, was tested in children and young adults with NF1 and progressive PNs.Methods Patients aged 3-25 years with NF1-related PNs and imaging evidence of tumor progression were randomized in a double-blinded fashion to receive tipifarnib (200 mg/m(2) orally every 12 h) or placebo (phase A) and crossed over to the opposite treatment arm at the time of tumor progression (phase B). PN volumes were measured with MRI, and progression was defined as ≥20% volume increase. Time to progression (TTP) in phase A was the primary endpoint, and the trial was powered to detect whether tipifarnib doubled TTP compared with placebo. Toxicity, response, and quality of life were also monitored.ResultsSixty-two patients were enrolled. Tipifarnib and placebo were well tolerated. On phase A, the median TTP was 10.6 months on the placebo arm and 19.2 months on the tipifarnib arm (P = .12; 1-sided). Quality of life improved significantly compared with baseline on the tipifarnib arm but not on the placebo arm. Volumetric tumor measurement detected tumor progression earlier than conventional 2-dimensional (WHO) and 1-dimensional (RECIST) methods.Conclusions Tipifarnib was well tolerated but did not significantly prolong TTP of PNs compared with placebo. The randomized, flexible crossover design and volumetric PN assessment provided a feasible and efficient means of assessing the efficacy of tipifarnib. The placebo arm serves as an historical control group for phase 2 single-arm trials directed at progressive PNs.
    Neuro-Oncology 02/2014; · 6.18 Impact Factor
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    ABSTRACT: ABT-751, an orally bioavailable sulfonamide binds the colchicine site of beta-tubulin and inhibits microtubule polymerizaton. Prior phase I studies established the recommended dose in children with solid tumors as 200 mg/m(2) PO daily × 7 days every 21 days and subjects with neuroblastoma experienced prolonged stable disease. We conducted a phase 2 study (NCT00436852) in children and adolescents with progressive neuroblastoma to determine if ABT-751 prolonged the time to progression (TTP) compared to a hypothesized standard based on a historical control population. Children and adolescents (n = 91) with a median (range) age 7.7 (2.3-21.5) years and progressive neuroblastoma were enrolled and stratified by disease status into disease measureable by CT/MRI (n = 47) or disease assessable by (123) I-metaiodobenzylguanine scintigraphy (MIBG, n = 44). Response was evaluated using RECIST for measureable disease and the Curie score for MIBG-avid disease. ABT-751 was well tolerated. The objective response rate was 7%. The median TTP was 42 days (95% CI: 36, 56) in the measureable disease stratum and 45 days (95% CI: 42, 85) in the MIBG-avid disease stratum. TTP was similar to the historical control group (n = 136, median TTP 42 days). For the combined strata (n = 91), 1-year progression free survival (PFS) was 13 ± 4% and overall survival (OS) was 48 ± 5%. The low objective response rate and failure to prolong TTP indicate that ABT-751 is not sufficiently active to warrant further development for neuroblastoma. However, this trial demonstrates the utility of TTP as the primary endpoint in phase 2 trials in children and adolescents with neuroblastoma. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 12/2013; · 2.35 Impact Factor
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    ABSTRACT: PURPOSE: Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC. EXPERIMENTAL DESIGN: We conducted a phase I/II trial of vandetanib for children (5-12 years) and adolescents (13-18 years) with MTC to define a recommended dose and assess anti-tumor activity. The starting dose was 100 mg/m2 administered orally, once daily, continuously for 28 day treatment cycles. The dose could be escalated to 150 mg/m2/d after 2 cycles. Radiographic response to vandetanib was quantified using RECIST(v1.0), biomarker response was measured by comparing post-treatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient reported outcome was used to assess clinical benefit. RESULTS: Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2-52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n=15) the confirmed objective partial response rate was 47% (exact 95%CI, 21%, 75%). Biomarker partial response was confirmed for calcitonin in twelve subjects and for CEA in eight subjects. CONCLUSIONS: Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m2/d is a well tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC.
    Clinical Cancer Research 06/2013; · 7.84 Impact Factor
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    ABSTRACT: BACKGROUND: Various human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma. METHODS: In this open-label, phase 1 dose-escalation trial, patients older than 12 months and younger than 22 years with measurable or evaluable solid or CNS tumours, or anaplastic large-cell lymphoma, refractory to therapy and for whom there was no known curative treatment were eligible. Crizotinib was given twice daily without interruption. Six dose levels (100, 130, 165, 215, 280, 365 mg/m(2) per dose) were assessed in the dose-finding phase of the study (part A1), which is now completed. The primary endpoint was to estimate the maximum tolerated dose, to define the toxic effects of crizotinib, and to characterise the pharmacokinetics of crizotinib in children with refractory cancer. Additionally, patients with confirmed ALK translocations, mutations, or amplification (part A2 of the study) or neuroblastoma (part A3) could enrol at one dose level lower than was currently given in part A1. We assessed ALK genomic status in tumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with anaplastic large-cell lymphoma. All patients who received at least one dose of crizotinib were evaluable for response; patients completing at least one cycle of therapy or experiencing dose limiting toxicity before that were considered fully evaluable for toxicity. This study is registered with ClinicalTrials.gov, NCT00939770. FINDINGS: 79 patients were enrolled in the study from Oct 2, 2009, to May 31, 2012. The median age was 10·1 years (range 1·1-21·4); 43 patients were included in the dose escalation phase (A1), 25 patients in part A2, and 11 patients in part A3. Crizotinib was well tolerated with a recommended phase 2 dose of 280 mg/m(2) twice daily. Grade 4 adverse events in cycle 1 were neutropenia (two) and liver enzyme elevation (one). Grade 3 adverse events that occurred in more than one patient in cycle 1 were lymphopenia (two), and neutropenia (eight). The mean steady state peak concentration of crizotinib was 630 ng/mL and the time to reach this peak was 4 h (range 1-6). Objective tumour responses were documented in 14 of 79 patients (nine complete responses, five partial responses); and the anti-tumour activity was enriched in patients with known activating ALK aberrations (eight of nine with anaplastic large-cell lymphoma, one of 11 with neuroblastoma, three of seven with inflammatory myofibroblastic tumour, and one of two with NSCLC). INTERPRETATION: The findings suggest that a targeted inhibitor of ALK has antitumour activity in childhood malignancies harbouring ALK translocations, particularly anaplastic large-cell lymphoma and inflammatory myofibroblastic tumours, and that further investigation in the subset of neuroblastoma harbouring known ALK oncogenic mutations is warranted. FUNDING: Pfizer and National Cancer Institute grant to the Children's Oncology Group.
    The Lancet Oncology 04/2013; · 25.12 Impact Factor
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    ABSTRACT: BACKGROUND: Sorafenib targets multiple pathways thought to be crucial in growth of plexiform neurofibroma (PN) in children with neurofibromatosis type 1 (NF1). Sorafenib has been tolerated with manageable toxicities in adults and children with refractory cancer. We conducted a separate study in this population. Monitoring long-term toxicities such as effects on growth and obtaining additional pharmacokinetic data were of importance due to the young age and long duration of therapy seen in previous phase I trials in children with NF1. PROCEDURE: Children ≥3 and ≤18-year-old with NF1 and inoperable PN were eligible. Sorafenib was administered orally twice daily for consecutive 28-day cycles. Maximum tolerated dose (MTD) was determined from toxicities observed during the first three cycles. RESULTS: Nine children enrolled, median age 8 (6-12) years. At the starting 115 mg/m(2) /dose (n = 5), two experienced dose-limiting grade 3 pain in their PN. At the de-escalated 80 mg/m(2) /dose (n = 4), approximately 40% of the pediatric solid tumor MTD, two had dose-limiting toxicity (grade 3 rash and grade 4 mood alteration), exceeding the MTD. At 80 mg/m(2) /dose, the median AUC(0-12 hours) at steady-state was 39.5 µg hours/ml. Toxicities appeared to correspond with decreases in quality of life (QOL). No tumor shrinkage was observed. CONCLUSIONS: Children with NF1 and PN did not tolerate sorafenib at doses substantially lower than the MTD in children and adults with malignant solid tumors. Future trials with targeted agents for children with NF1 may require a more conservative starting dose and separate definitions of dose limiting toxicities (DLT) than children with cancer. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 09/2012; · 2.35 Impact Factor
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    ABSTRACT: PURPOSE: To determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of sorafenib in children with refractory extracranial solid tumors and evaluate the tolerability of the solid tumor MTD in children with refractory leukemias.EXPERIMENTAL DESIGN: Sorafenib was administered orally every 12 hours for consecutive 28-day cycles. Pharmacokinetics (day 1 and steady-state) and pharmacodynamics were conducted during cycle 1.RESULTS: Of 65 patients enrolled, 60 were eligible. In the solid tumor cohort (n = 49), 4 of 6 patients experienced a DLT [hypertension, pain, rash/urticaria, thrombocytopenia, alanine aminotransferase (ALT)/aspartate aminotransferase (AST)] at the starting dose (150 mg/m(2)/dose) which resulted in de-escalation to 105 mg/m(2)/dose. After eligibility criteria modification and dose re-escalation, the MTD was 200 mg/m(2)/dose for solid tumors and 150 mg/m(2)/dose for leukemias. Sorafenib exposure was highly variable between patients but was within the ranges reported in adults. The apparent sorafenib clearance increased with patient age. Diarrhea, rash, fatigue, and increased ALT/AST were the most common sorafenib-related toxicities. Stable disease for 4 or more cycles was observed in 14 solid tumor patients, and 2 patients with acute myeloid leukemia (AML) and FLT3 internal tandem duplication (FLT3ITD) experienced a decrease in bone marrow blasts to less than 5%.CONCLUSIONS: The recommended phase II dose of sorafenib administered every 12 hours continuously for children with solid tumors is 200 mg/m(2)/dose and 150 mg/m(2)/dose for children with leukemias. Sorafenib toxicities and distribution in children are similar to adults. The activity of sorafenib in children with AML and FLT3ITD is currently being evaluated, and a phase II study for select solid tumors is ongoing. Clin Cancer Res; 18(21); 1-12. ©2012 AACR.
    Clinical Cancer Research 09/2012; · 7.84 Impact Factor
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    ABSTRACT: The objectives of this phase I study were to determine the maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of a 24-hour continuous intravenous infusion of trabectedin administered to children and adolescents with refractory or relapsed solid tumors. Patients between the ages of 4 and 16 years old with refractory solid tumors received trabectedin as a 24-hour infusion every 21 days. Dexamethasone and prophylactic growth factor support were administered with each cycle. Pharmacokinetic studies were conducted during cycle 1. Patients (n = 12) median (range) age 14.5 (8-16) years received trabectedin at 1.1 (n = 3), 1.5 (n = 6), or 1.7 (n = 3) mg/m(2) . At the 1.5 mg/m(2) dose level, one patient had dose limiting anorexia and fatigue. At 1.7 mg/m(2) , two patients experienced dose limiting toxicity, dehydration, and gamma-glutamyl transpeptidase elevation. Non-dose limiting toxicities included elevated serum transaminases, myelosuppression, nausea, emesis, and fatigue. Plasma pharmacokinetic parameters were similar to historical data in adults. One partial response was observed in a patient with neuroendocrine carcinoma. Stable disease (≥6 cycles) was achieved in three patients (osteosarcoma n = 2, desmoplastic small round cell tumor n = 1). The MTD of trabectedin in pediatric patients with refractory solid tumors is 1.5 mg/m(2) IV over 24 hours every 21 days. Dexamethasone to ameliorate hepatic toxicity and prophylactic growth factor support are required. Pediatr Blood Cancer 2012; 59: 865-869. © 2012 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 07/2012; 59(5):865-9. · 2.35 Impact Factor
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    ABSTRACT: Despite the clinical success of platinum-containing drugs in the treatment of solid tumors, acquired resistance remains a major obstacle. We previously identified a group of novel transplanaramine or transplatinum compounds based on distinct activity profiles in the NCI-60 panel. In the present study, parental KB-3.1 cells with wild-type p53 and its cisplatin- and oxaliplatin-resistant sublines harboring mutant p53 proteins were used to contrast several transplatinum compounds with cisplatin and oxaliplatin. The transplatinum compounds retained cytotoxic activity in the resistant cell lines. While intracellular accumulation and DNA platination of cisplatin and oxaliplatin was decreased in the resistant cells, the transplatinum compounds both accumulated intracellularly and platinated DNA at comparable levels in all cell lines. Cytoflow analysis confirmed that cisplatin and oxaliplatin alter the cell cycle distribution and result in apoptosis; however, at comparably toxic concentrations, the transplatinum compounds did not alter the cell cycle distribution. Analysis of the cytoplasmic fraction treated with acetone showed that cisplatin and oxaliplatin readily bound to macromolecules in the pellet, whereas a larger percentage of the transplatinum compounds remained in the supernatant. We concluded that, distinct from platinum compounds currently in use, transplatinum compounds accumulate intracellularly in resistant cells at levels comparable to those in drug-sensitive cells, do not affect the cell cycle and thus retain cytotoxicity independent of p53 status and likely have cytoplasmic targets that are important in their activity.
    Cell cycle (Georgetown, Tex.) 03/2012; 11(5):963-73. · 5.24 Impact Factor
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    ABSTRACT: To estimate the sustained (≥8 weeks) objective response rate in pediatric patients with recurrent or progressive high-grade gliomas (HGG, Stratum A) or brainstem gliomas (BSG, Stratum B) treated with the combination of O6-benzylguanine (O6BG) and temozolomide(®) (TMZ). Patients received O6BG 120 mg/m(2)/d IV followed by TMZ 75 mg/m(2)/d orally daily for 5 consecutive days of each 28-day course. The target objective response rate to consider the combination active was 17%. A two-stage design was employed. Forty-three patients were enrolled; 41 were evaluable for response, including 25 patients with HGG and 16 patients with BSG. The combination of O6BG and TMZ was tolerable, and the primary toxicities were myelosuppression and gastrointestinal symptoms. One sustained (≥8 weeks) partial response was observed in the HGG cohort; no sustained objective responses were observed in the BSG cohort. Long-term (≥6 courses) stable disease (SD) was observed in 4 patients in Stratum A and 1 patient in Stratum B. Of the 5 patients with objective response or long-term SD, 3 underwent central review with 2 reclassified as low-grade gliomas. The combination of O6BG and TMZ did not achieve the target response rate for activity in pediatric patients with recurrent or progressive HGG and BSG.
    Journal of Neuro-Oncology 02/2012; 106(3):643-9. · 3.12 Impact Factor
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    ABSTRACT: Most medullary thyroid cancers (MTC) express somatostatin receptors; therefore, (111)In-octreotide somatostatin receptor scintigraphy (SRS) may be useful in detecting sites of metastases in children with MTC. The aim of the study was to evaluate tumor metastases in children and adolescents with MTC using SRS in comparison to conventional imaging. A case series was conducted as part of baseline evaluation for cancer treatment protocol at the National Institutes of Health Clinical Center. Eleven patients with a median age of 15 (range, 9-17) yr participated in the study, 10 with histologically proven, metastatic MTC due to the M918T mutation of the RET protooncogene, and one with a known RET polymorphism. After receiving 0.086 mCi/kg (111)Indium-pentreotide, patients were examined with a single photon emission computed tomography scan 4 and 24 h after injection. Baseline conventional imaging, including computed tomography (neck, chest, abdomen, ± pelvis, adrenals), magnetic resonance imaging (neck), and bone scan, was performed on all patients. SRS results were compared with conventional imaging. Five of the 11 patients had abnormal findings on SRS. Of the 53 total target lesions present in the patients, only 24.5% were accurately identified through SRS. SRS appears to be less sensitive than conventional imaging at detecting the full extent of metastatic disease in children and adolescents with hereditary MTC. SRS incompletely identified sites of tumor and failed to visualize small sites of tumor or liver and lung metastases, and it has a limited role in the evaluation of metastatic disease in pediatric MTC patients.
    The Journal of Clinical Endocrinology and Metabolism 12/2011; 97(2):E207-12. · 6.31 Impact Factor
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    ABSTRACT: Targeted anticancer agents have been reported to have side effects on the skeletal system such as thickening of the epiphyseal growth plate in preclinical models of juvenile, but not mature, animals. Careful evaluation of skeletal toxicity in the clinical development of targeted therapies for children is required. We validated a novel method to measure the growth plate volume using MRI. A semiautomated method of volumetric growth plate measurement was developed on the basis of the differences of pixel intensity of the growth plate from surrounding bone on T(1) sagittal MRI. Two observers measured the femoral growth plate volume and thickness on three different days using 20 pediatric knee MRIs obtained at the NIH. Five subjects had two knee MRIs obtained on the same day to evaluate intrasubject reproducibility. Volumetric analysis showed low intraobserver variability, with the coefficient of variation for the two observers ranging from 0.2% to 6.1%. Interobserver correlation was 0.99, and good concordance was shown with a mean volume difference of -1.8 mm(3). One-dimensional measurements had poorer intra and interobserver consistency. No statistically significant differences in volumetric measurements were observed between the two scans done on the same day in five subjects (P = 0.5). MRI volumetric growth plate measurement is a reproducible and sensitive method to evaluate meaningful growth plate volume changes over time. This tool, along with close monitoring of height and laboratory evaluations for bone metabolism, may be used to evaluate potential bone and growth toxicities of children enrolled in trials of investigational drugs.
    Clinical Cancer Research 08/2011; 17(18):5982-90. · 7.84 Impact Factor
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    ABSTRACT: Satraplatin is an orally bioavailable platinum analog with preclinical activity in cisplatin resistant models and clinical activity in adults with refractory cancers. The cerebrospinal fluid (CSF) penetration of cisplatin and carboplatin in non-human primates (NHP) is limited (3.7 and 2.6%, respectively). We evaluated the plasma and CSF pharmacokinetics (PK) of satraplatin after an intravenous (IV) dose in NHP. Satraplatin (120 mg/m(2)) was administered as 1 h IV infusion in DMSO (5%) and normal saline to 5 NHP. Serial blood and CSF samples were obtained over 48 h. Plasma ultrafiltrate (UF) was immediately prepared by centrifugation. Platinum was quantified in plasma UF and CSF using a validated atomic absorption spectroscopy assay with lower limit of quantification (LLQ) of 0.025 μM in UF and 0.006 μM after concentration in CSF. Pharmacokinetic parameters were estimated using non-compartmental analyses. CSF penetration was calculated from the CSF AUC(0-48h) : plasma UF AUC(0-48h). Satraplatin was well tolerated. Median (range) PK parameters in plasma UF were: maximum concentration (C (max)) 8.3 μM (5.7-10.6), area under the curve (AUC(0-48h)) 29.2 μM h (22.6-33.2), clearance 0.36 l/h/kg (0.31-0.37), and t (1/2) 18.8 h (13.4-25). Satraplatin was detected in the CSF of all NHP. Median (range) PK parameters in CSF were: C (max) 0.07 μM (0.02-0.12), AUC(0-48h) 1.2 μM h (0.49-2.43). The median (range) CSF penetration of satraplatin was 4.3% (2.2-7.4). Satraplatin penetration into CSF is similar to that of carboplatin and cisplatin, despite its greater lipophilicity. The development of a phase I trial of satraplatin for refractory childhood solid tumors including brain tumors is in progress.
    Cancer Chemotherapy and Pharmacology 06/2011; 69(1):247-52. · 2.80 Impact Factor
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    ABSTRACT: O(6)-alkylguanine-DNA alkyltransferase (AGT) repairs DNA damage from alkylating agents by transferring the alkyl adducts from the O(6)-position of guanine in DNA to AGT. The folate analog O(4)-benzylfolic acid (O(4)BF) is an inhibitor of AGT with reported selectivity of the alpha-folate receptor in tumors. We studied plasma and cerebrospinal fluid (CSF) pharmacokinetics and CSF penetration of O(4)BF in a non-human primate model. Rhesus monkeys (Macaca mulatta) received O(4)BF (10-50 mg/kg) intravenously, and serial blood and CSF samples were obtained. Analyte concentrations in plasma were measured by HPLC/photo diode array, and an HPLC/MS/MS assay was used for CSF samples. A putative metabolite of O(4)BF was detected in plasma and CSF. O(4)BF and the metabolite inactivated purified AGT with ED(50) of 0.04 mcM. The median clearance of O(4)BF was 8 ml/min/kg and half-life was 1.1 h. The metabolite had a substantially longer half-life (>20 h) and greater AUC than O(4)BF. The AUC of the metabolite increased disproportionately to the dose of O(4)BF, suggesting saturable elimination. CSF penetration of O(4)BF and its metabolite was < 1%. At the 50 mg/kg dose level, the C(max) in CSF for O(4)BF was less than 0.09 mcM and for the metabolite the C(max) ranged from 0.02 to 0.04 mcM (O(4)BF equivalents). Concentrations of O(4)BF and the metabolite in CSF exceeded the ED(50) of AGT; however, recently reported lack of receptor specificity and pharmacokinetic data suggesting saturable elimination of both O(4)BF and its metabolite may limit dose-escalation and future clinical development of this agent.
    Cancer Chemotherapy and Pharmacology 06/2011; 67(6):1291-7. · 2.80 Impact Factor
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    ABSTRACT: The objectives of this trial were to define the toxicity profile, dose, pharmacokinetics, and pharmacodynamics of the farnesyl transferase (FTase) inhibitor, tipifarnib, in children and adolescents with hematological malignancies. Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at a dose of 300 mg/m(2) /dose. Pharmacokinetic sampling was performed for 36 hr after the first dose and leukemic blasts were collected pre-treatment and at steady state for determination of FTase activity. Of 29 patients enrolled, 18 were fully evaluable for toxicity, and 23 for response; 26 had pharmacokinetic and pharmacodynamic sampling. The recommended dose is 300 mg/m(2) /dose and toxicities included skin rash, mucositis, nausea, vomiting, and diarrhea. Neurotoxicity, which was dose-limiting in adults at doses exceeding 600 mg/dose, was infrequent and mild. The plasma pharmacokinetics of tipifarnib were highly variable but comparable to adults with acute leukemia and children with solid tumors. The median apparent clearance of tipifarnib was 630 ml/min/m(2) and the median half-life was 4.7 hr. At steady state on 300 mg/m(2) /dose, FTase activity was inhibited by 82% in leukemic blasts. No objective responses were observed. Oral tipifarnib is well tolerated in children with leukemia on a twice daily for 2 days schedule at 300 mg/m(2) /dose.
    Pediatric Blood & Cancer 02/2011; 56(2):226-33. · 2.35 Impact Factor
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    ABSTRACT: This pediatric phase I study was designed to identify the doses of RG1507, a monoclonal antibody against the Type 1 Insulin-like Growth Factor Receptor (IGF1R), that achieves exposures equivalent to those achieved in adults at recommended doses. Children with relapsed or refractory solid tumors were treated using the same doses and administration schedules of RG1507 (3 and 9 mg/kg/wk, and 16 mg/kg every 3 weeks [q3W]) as those studied in adults. Detailed pharmacokinetic (PK) sampling was performed after the first dose; selected peak and trough levels were subsequently obtained. Target exposures were ≥85% of mean areas under concentration x time curves (AUCs) in adults at doses of 9 mg/kg/wk and 16 mg/kg q3W. A maximum tolerated dose could be identified if dose-limiting toxicities (DLT) occurred. Thirty-one evaluable patients aged 3-17 years were enrolled at 3 mg/kg/wk (n = 3), 9 mg/kg/wk (n = 18), or 16 mg/kg q3W (n = 10). There were no DLTs. At 9 mg/kg/wk the mean AUC(0-7d) (21,000 μg h/mL) exceeded the target (16,000 μg h/mL). At 16 mg/kg q3W, the mean AUC(021d) (70,000 μg h/mL) exceeded the target (59,400 μg h/mL). Clearance normalized to body weight was age dependent. There were no objective responses. Seven patients had stable disease for >12 weeks, including two patients with osteosarcoma with stable disease for 52+ and 78+ weeks. The recommended doses of RG1507 in children with solid tumors are 9 mg/kg/wk and 16 mg/kg q3W. This flexible design is well suited for trials of agents associated with limited toxicity.
    Clinical Cancer Research 02/2011; 17(3):611-9. · 7.84 Impact Factor
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    ABSTRACT: PURPOSE Dasatinib is an orally available tyrosine kinase inhibitor with low nanomolar activity against SRC family kinases, BCR-ABL, c-KIT, EPHA2, and the PDGF-β receptor. Dasatinib was found to have selective activity in several tumor models in the Pediatric Preclinical Testing Program. PATIENTS AND METHODS A phase I study of dasatinib in pediatric patients with refractory solid tumors or imatinib-refractory, Philadelphia chromosome-positive leukemia was performed. Dose levels of 50, 65, 85, and 110 mg/m²/dose, administered orally twice daily for 28 days, with courses repeated without interruption, were studied. Pharmacokinetic studies were performed with the initial dose. RESULTS: A total of 39 patients (solid tumors, n = 28; chronic myeloid leukemia [CML], n = 9; acute lymphoblastic leukemia, n = 2) were enrolled. No dose-limiting toxicities (DLTs) were observed at the 50, 65, and 85 mg/m² dose levels. At 110 mg/m², two of six patients experienced DLT including grade 2 diarrhea and headache. In children with leukemia, grade 4 hypokalemia (50 mg/m²), grade 3 diarrhea (85 mg/m²), and grade 2 creatinine elevation (50 mg/m²) were observed. DLT in later courses included pleural effusions, hemangiomatosis, and GI hemorrhage. There were three complete cytogenetic responses, three partial cytogenetic responses, and two partial/minimal cytogenetic responses observed in evaluable patients with CML. CONCLUSION Overall, drug disposition and tolerability of dasatinib were similar to those observed in adult patients.
    Journal of Clinical Oncology 01/2011; 29(7):839-44. · 18.04 Impact Factor
  • Article: Commentary.
    Elizabeth Fox, Frank M Balis
    Clinical Chemistry 12/2010; 56(12):1795. · 7.15 Impact Factor

Publication Stats

5k Citations
2,085.85 Total Impact Points

Institutions

  • 2007–2014
    • The Children's Hospital of Philadelphia
      • • Department of Pediatrics
      • • Division of Oncology
      Philadelphia, Pennsylvania, United States
  • 2012
    • Childrens Hospital of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 2007–2012
    • NCI-Frederick
      Maryland, United States
  • 1986–2011
    • National Cancer Institute (USA)
      • • Pediatric Oncology Branch
      • • Center for Cancer Research
      Maryland, United States
  • 2007–2010
    • Children's National Medical Center
      Washington, Washington, D.C., United States
  • 2008–2009
    • National Cancer Institute
      Μπογκοτά, Bogota D.C., Colombia
  • 2003–2009
    • West Virginia University
      Morgantown, West Virginia, United States
  • 1986–2009
    • National Institutes of Health
      • • Branch of Pediatric Oncology
      • • Branch of Medical Oncology Branch and Affiliates
      Bethesda, MD, United States
  • 1998–2008
    • Baylor College of Medicine
      • Department of Pediatrics
      Houston, Texas, United States
  • 2004
    • Texas Children's Cancer and Hematology Centers
      Houston, Texas, United States
  • 2002
    • University of Pittsburgh
      • Department of Medicine
      Pittsburgh, PA, United States
  • 2001
    • Universität Konstanz
      Constance, Baden-Württemberg, Germany
  • 1996
    • University of Washington Seattle
      Seattle, Washington, United States
  • 1991–1995
    • Walter Reed National Military Medical Center
      Washington, Washington, D.C., United States
  • 1983–1987
    • George Washington University
      • Department of Pharmacology and Physiology
      Washington, D. C., DC, United States