Vinay M. Daryani

Phase II evaluation of sunitinib in the treatment of recurrent or refractory high-grade glioma or ependymoma in children: a children's Oncology Group Study ACNS1021.

Sunitinib malate is a small multi‐targeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet‐derived growth factor receptor (PDGFR) and stem cell factor receptor (KIT), which are highly expressed by some high‐grade brain tumors. We conducted a phase II study to estimate the efficacy and further characterize the pharmacokinetics of sunitinib in pediatric patients with recurrent or refractory high‐grade glioma (Stratum A) or ependymoma (Stratum B). This was a prospective, multicenter Phase II trial conducted through the Childrens Oncology Group (ClinicalTrials.gov Identifier NCT01462695). Sunitinib, 15 mg/m2, was orally administered once daily for 4 weeks every 6 weeks. The safety and tolerability of sunitinib, an estimate of progression‐free survival (PFS), analyses of sunitinib pharmacokinetics (PK) and pharmacodynamics modulation of plasma VEGF and VEGFR2 were also assessed. Thirty eligible patients (17 patients on Stratum A, 13 patients on Stratum B) were enrolled and 29 patients were evaluable for response. Sunitinib was reasonably well tolerated in children with recurrent ependymoma or high‐grade glioma. Most adverse events were of mild‐to‐moderate severity and manageable with supportive treatment. While there was a statistically significant modulation of plasma VEGFR2 with sunitinib exposure, there were no sustained tumor responses. Both strata were closed at time of planned interim analysis as there was not sufficient efficacy associated with sunitinib in children with recurrent brain tumors. Sunitinib was well tolerated in children and young adults with recurrent high‐grade glioma or ependymoma but had no single agent objective antitumor activity in these patients.

Neurocognitive and Patient-Reported Outcomes in Adult Survivors of Childhood Osteosarcoma

IMPORTANCE This study provides the first objective data documenting neurocognitive impairment in long-term survivors of childhood osteosarcoma. OBJECTIVE To examine neurocognitive, neurobehavioral, emotional, and quality-of-life outcomes in long-term survivors of childhood osteosarcoma. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional cohort study at an academic research hospital, with prospective treatment and chronic health predictors. Outcome data were collected from June 2008 to August 2014. Data analysis was completed in April 2015. Survivors of osteosarcoma recruited from the St Jude Lifetime Cohort Study were compared with community controls. MAIN OUTCOMES AND MEASURES Neurocognitive function, neurobehavioral symptoms, emotional distress, and quality of life. Outcomes were examined in relation to pharmacokinetic indices of methotrexate exposure and current chronic health conditions, which were assessed through medical examination and coded according to Common Terminology Criteria for Adverse Events, Version 4.03. RESULTS Eighty survivors of osteosarcoma (mean [SD] age, 38.9 [7.6] years; time since diagnosis, 24.7 [6.6] years; 42% female) were compared with 39 community controls (age, 39.0 [11.7] years; 56% female). Survivors demonstrated lower mean scores in reading skills (-0.21 [95% CI, -0.32 to -0.10] vs 0.05 [95% CI, -0.13 to 0.23]; P = .01), attention (-0.78 [95% CI, -1.32 to -0.24] vs 0.24 [95% CI, -0.07 to 0.55]; P = .002), memory (-0.24 [95% CI, -0.48 to 0] vs 0.27 [95% CI, -0.08 to 0.62]; P = .01), and processing speed (-0.15 [95% CI, -0.35 to 0.05] vs 0.74 [95% CI, 0.44 to 1.03]; P < .001). Results of pharmacokinetic analysis showed that high-dose methotrexate maximum plasma concentration (estimate = 0; P = .48), median clearance (estimate = -0.11; P = .76), and median/cumulative exposure (estimate = 0; P = .45) were not associated with neurocognitive outcomes. Any grade 3 or 4 Common Terminology Criteria for Adverse Events cardiac, pulmonary, or endocrine condition was associated with poorer memory (t = 2.93; P = .006) and slower processing speed (t = 3.03; P = .002). Survivor-reported poor general health was associated with decreased sustained attention (estimate = 0.24; P = .05) and processing speed (estimate = 0.34; P = .005). CONCLUSIONS AND RELEVANCE Long-term survivors of osteosarcoma are at risk for neurocognitive impairment, which is related to current chronic health conditions and not to original treatment with high-dose methotrexate. Prospective longitudinal studies are needed to identify onset and progression of impairment to inform optimal interventions.

Phase I study of 5-fluorouracil in children and young adults with recurrent ependymoma

BACKGROUND We report a phase I study to examine the pharmacokinetics, safety, and recommended dosage of weekly intravenous bolus 5-fluorouracil (5-FU) in children and young adults with recurrent ependymoma. METHODS Patients 22 years of age or less with recurrent ependymoma were treated with bolus dosage 5-FU weekly for 4 weeks followed by a 2-week rest period, defining one cycle. Patients could continue on therapy for 16 cycles. The starting 5-FU dosage was 500 mg/m(2). Dose-limiting toxicity was determined after one cycle. Patients were initially enrolled according to a rolling-6 design; subsequent dose re-escalation phase was based on a 3 + 3 design. RESULTS We treated patients at 400 (n = 6), 500 (n = 15), and 650 (n = 5) mg/m(2), with de-escalation due to toxicity. Twenty-three of twenty-six patients enrolled were evaluable. Five patients experienced grade 4 neutropenia (n = 2: 650 mg/m(2); n = 3: 500 mg/m(2)). One patient experienced grade 3 diarrhea. At 500 mg/m(2), the median 5-FU maximal concentration, AUC0-∞, and alpha half-life were 825 µM, 205 µM × h, and 9.9 min, respectively. Interim analysis revealed an association between hematologic toxicity and prior number of chemotherapeutic regimens (P = .03). The study was amended to re-escalate the dosage in a less heavily pretreated cohort of patients. CONCLUSIONS These phase I clinical data provide initial pharmacokinetic parameters to describe i.v. bolus 5-FU disposition in children with recurrent ependymoma. Tumor exposures effective in preclinical testing can be achieved with tolerable bolus dosages in patients. Bolus 5-FU is well tolerated and possesses antitumor activity.

Feasibility of Pegylated Interferon in Children and Young Adults With Resected High-Risk Melanoma.

Pegylated interferon α‐2b (IFN α‐2b) improves disease‐free survival in adults with resected stage III melanoma. We conducted a study to determine the feasibility and safety of incorporating pegylated IFN α‐2b as adjuvant therapy in the treatment of children and adolescents with high‐risk melanoma. Pharmacokinetic studies of IFN α‐2b and neuropsychological and quality of life (OL) assessments were performed.

Population Pharmacokinetics of Oral Topotecan in Infants and Very Young Children with Brain Tumors Demonstrates a Role of ABCG2 rs4148157 on the Absorption Rate Constant

For infants and very young children with brain tumors, chemotherapy after surgical resection is the main treatment due to neurologic and neuroendocrine adverse effects from whole brain irradiation. Topotecan, an anticancer drug with antitumor activity against pediatric brain tumors, can be given intravenous or orally. However, high interpatient variability in oral drug bioavailability is common in children less than 3 years old. Therefore, this study aimed to determine the population pharmacokinetics of oral topotecan in infants and very young children, specifically evaluating the effects of age and ABCG2 and ABCB1 on the absorption rate constant (Ka), as well as other covariate effects on all pharmacokinetic parameters. A nonlinear mixed effects model was implemented in Monolix 4.3.2 (Lixoft, Orsay, France). A one-compartment model with first-order input and first-order elimination was found to adequately characterize topotecan lactone concentrations with population estimates as [mean (S.E.)]; Ka = 0.61 (0.11) h−1, apparent volume of distribution (V/F) = 40.2 (7.0) l, and apparent clearance (CL/F) = 40.0 (2.9) l/h. After including the body surface area in the V/F and CL/F as a power model centered on the population median, the ABCG2 rs4148157 allele was found to play a significant role in the value of Ka. Patients homozygous or heterozygous for G>A demonstrated a Ka value 2-fold higher than their GG counterparts, complemented with a 2-fold higher maximal concentration as well. These results demonstrate a possible role for the ABCG2 rs4148157 allele in the pharmacokinetics of oral topotecan in infants and very young children, and warrants further investigation.

A phase II trial evaluating the feasibility of adding bevacizumab to standard osteosarcoma therapy

Increased vascular endothelial growth factor (VEGF) expression in osteosarcoma correlates with a poor outcome. We conducted a phase II trial to evaluate the feasibility and efficacy of combining bevacizumab, a monoclonal antibody against VEGF, with methotrexate, doxorubicin and cisplatin (MAP) in patients with localized osteosarcoma. Eligible patients received two courses of MAP chemotherapy before definitive surgery at week 10. Bevacizumab (15 mg/kg) was administered 3 days before starting chemotherapy then on day 1 of weeks 3 and 5 of chemotherapy. After surgery, patients received MAP for a total of 29 weeks; bevacizumab was added every 2 or 3 weeks on day 1 of chemotherapy at least 5 weeks after surgery. Group sequential monitoring rules were used to monitor for unacceptable bevacizumab‐related targeted toxicity (grade 4 hypertension, proteinuria or bleeding, grade 3 or 4 thrombosis/embolism, and grade 2–4 major wound complications). Thirty‐one patients (median age 12.8 years) with localized osteosarcoma were enrolled. No unacceptable targeted toxicities were observed except for wound complications (9 minor and 6 major), which occurred in 15 patients; none required removal of prosthetic hardware or amputation. The estimated 4‐year event‐free survival (EFS) rate and overall survival rate were 57.5 ± 10.0% and 83.4 ± 7.8%, respectively. Eight (28%) of 29 evaluable patients had good histologic response (<5% viable tumor) to preoperative chemotherapy. The addition of bevacizumab to MAP for localized osteosarcoma is feasible but frequent wound complications are encountered. The observed histologic response and EFS do not support further evaluation of bevacizumab in osteosarcoma.

Determination of methotrexate, 7-hydroxymethotrexate, and 2,4-diamino-N10-methylpteroic acid by LC–MS/MS in plasma and cerebrospinal fluid and application in a pharmacokinetic analysis of high-dose methotrexate

ABSTRACT A rapid and robust method for measuring methotrexate (MTX) and its two primary metabolites, 7-hydroxymethotrexate (7-OHMTX) and 2,4-diamino-N10-methylpteroic acid (DAMPA), was developed for use in pharmacokinetic studies of plasma and cerebrospinal fluid samples collected from infants with malignant brain tumors. Sample aliquots (100 µL) were prepared for bioanalysis of MTX and metabolites using a Waters Oasis HLB microelution solid-phase extraction (SPE) plate. Chromatography was performed using a Phenomenex Synergi Polar-RP 4 µ 75 × 2.0 mm ID column heated to 40°C. A rapid gradient elution on a Shimadzu HPLC system was used, with mobile phase A consisting of water/formic acid (100/0.1 v/v) and mobile phase B consisting of acetonitrile/formic acid (100/0.1 v/v). Column eluent was analyzed using AB Sciex QTRAP 5500 instrumentation in electrospray ionization mode. The ion transitions (m/z) monitored were 455.2 → 308.1, 471.1 → 324.1, and 326.2 → 175.1 for MTX, 7-OHMTX, and DAMPA, respectively. The method was linear over 0.0022–5.5 µM for MTX, 0.0085–21 µM for 7-OHMTX, and 0.0031–7.7 µM for DAMPA. The method was applied to the analysis of serial plasma samples obtained from infants diagnosed with malignant brain tumors receiving high-dose methotrexate and results were compared to MTX concentrations from an immunoassay based on fluorescence polarization. GRAPHICAL ABSTRACT

Translational Pharmacokinetic-Pharmacodynamic Modeling and Simulation: Optimizing 5-Fluorouracil Dosing in Children With Pediatric Ependymoma

We previously investigated novel therapies for pediatric ependymoma and found 5‐fluorouracil (5‐FU) i.v. bolus increased survival in a representative mouse model. However, without a quantitative framework to derive clinical dosing recommendations, we devised a translational pharmacokinetic‐pharmacodynamic (PK‐PD) modeling and simulation approach. Results from our preclinical PK‐PD model suggested tumor concentrations exceeded the 1‐hour target exposure (in vitro IC90), leading to tumor growth delay and increased survival. Using an adult population PK model, we scaled our preclinical PK‐PD model to children. To select a 5‐FU dosage for our clinical trial in children with ependymoma, we simulated various 5‐FU dosages for tumor exposures and tumor growth inhibition, as well as considering tolerability to bolus 5‐FU administration. We developed a pediatric population PK model of bolus 5‐FU and simulated tumor exposures for our patients. Simulations for tumor concentrations indicated that all patients would be above the 1‐hour target exposure for antitumor effect.

Derivation of new equations to estimate glomerular filtration rate in pediatric oncology patients

Background and objectiveMonitoring renal function is critical in treating pediatric patients, especially when dosing nephrotoxic agents. We evaluated the validity of the bedside Schwartz and Brandt equations in pediatric oncology patients and developed new equations for estimated glomerular filtration rate (eGFR) in these patients.MethodsA retrospective analysis was conducted comparing eGFR using the bedside Schwartz and Brandt equations to measured GFR (mGFR) from technetium-99m diethylenetriamine pentaacetic acid (99mTc-DTPA) between January 2007 and August 2013. An improved equation to estimate GFR was developed, simplified, and externally validated in a cohort of patients studied from September 2013 to June 2015. Carboplatin doses calculated from 99mTc-DTPA were compared with doses calculated by GFR-estimating equations.ResultsOverall, the bedside Schwartz and Brandt equations did not precisely or accurately predict measured GFR (mGFR). Using a data subset, we developed a five-covariate equation, which included height, serum creatinine, age, blood urea nitrogen (BUN), and gender, and a simplified version (two-covariates), which contained height and serum creatinine. These equations were used to estimate GFR in 2036 studies, resulting in precise and accurate predictors of mGFR values. Equations were validated in an external cohort of 570 studies; both new equations were more accurate in calculating carboplatin doses than either the bedside Schwartz or Brandt equation.ConclusionsTwo new equations were developed to estimate GFR in pediatric oncology patients, both of which did a better job at estimating mGFR than published equations.

Abstract 2708: Development of an individualized 3D transport model of topotecan for a patient-derived orthotopic xenograft model of pediatric neuroblastoma

Resistance to chemotherapeutics and targeted therapies in pediatric solid tumors including neuroblastoma is a common cause of poor clinical outcome. These failures in part stem from shortcomings in understanding inter- and intra-tumor heterogeneities of drug penetration due to heterogeneities in blood perfusion. Herein we propose to develop an individualized 3D transport model of topotecan (TPT) for a patient-derived orthotopic xenograft model of pediatric NB5 neuroblastoma to account for inter- and intra-tumor heterogeneities in blood perfusion. The transport model uses a 3D reaction-diffusion equation to simulate diffusion of TPT from blood vessels into the tumor tissue and its flux in and out of intracellular space. Our transport model takes three types of inputs to predict TPT exposure maps defined over the volume of an individual tumor: a) plasma concentration-time profiles from an individualized physiologically-based pharmacokinetic (PBPK) model of TPT (separate cohort), b) 3D blood perfusion map of the individual tumor from contrast enhanced ultrasound (CEUS) using VisualSonics VEVO 2100 imaging system, and c) in vitro TPT cellular uptake and efflux kinetics from two-photon imaging. We use in vitro pharmacodynamics (PD) experiments with NB5 cells exposed to TPT to derive probabilistic PD-rules for drug effects (e.g., γ-H2AX response). Based on these rules and the exposure maps, we then compute probabilities of effects for the entire tumor volume. We will validate the predicted drug effect maps by comparing them to the observed effects measured by immunohistochemistry marker for γ-H2AX from the same tumor (location matched) using spatial correlation techniques. Citation Format: Abbas Shirinifard, Suresh Thiagarajan, Yogesh T. Patel, Abigail D. Davis, Megan O. Jacus, Stacy L. Throm, Jessica Roberts, Vinay Daryani, Clinton F. Stewart, Andras Sablauer. Development of an individualized 3D transport model of topotecan for a patient-derived orthotopic xenograft model of pediatric neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2708.