Diana Stempak

High-Dose Celecoxib and Metronomic “Low-dose” Cyclophosphamide Is an Effective and Safe Therapy in Patients with Relapsed and Refractory Aggressive Histology Non–Hodgkin's Lymphoma

Purpose: Angiogenesis is increased in aggressive histology non–Hodgkins lymphoma and may be a target with selective cyclooxygenase-2 inhibition and metronomic chemotherapy. Experimental Design: We assessed response, toxicity, and biomarkers of angiogenesis to low-dose cyclophosphamide (50 mg p.o. o.d.) and high-dose celecoxib (400 mg p.o. b.i.d.) in adult patients with relapsed or refractory aggressive non–Hodgkins lymphoma in a multicenter phase II prospective study. Results: Thirty-two of 35 patients (median age, 62 years) are evaluable for response. Patients had primarily relapsed diffuse large B-cell lymphoma (63%) were heavily pretreated (median of three regimens) and high risk (79% international prognostic index, ≥2) and 34% were relapsed after autologous stem cell transplant. With a median follow-up of 8.4 months, the overall best response rate is 37% (2 complete clinical response/complete clinical response unconfirmed and 9 partial response), with 22% achieving stable disease. Median overall and progression-free survivals are 14.4 and 4.7 months, respectively. The median response duration was 8.2 months. The most common toxicity was skin rash (40%); myelosuppression and gastrointestinal side effects were uncommon. Three patients developed deep vein thromboses and two heavily pretreated patients developed treatment-related acute myelogenous leukemia or myelodysplasia after 3.7 and 12 months of therapy. Circulating endothelial cells and their precursors declined and remained low in responders, whereas plasma vascular endothelial growth factor trended to decline in responding patients but increase in nonresponders. Trough celecoxib levels achieved targeted “antiangiogenic” levels. Conclusions: Low-dose cyclophosphamide and high-dose celecoxib is well tolerated and active in pretreated aggressive non–Hodgkins lymphoma. Close surveillance for arterial and venous thrombotic events is recommended. The decline in circulating endothelial cells and their precursors suggests that this combination may be working by inhibiting angiogenesis but should be validated in a larger patient sample.

A pilot pharmacokinetic and antiangiogenic biomarker study of celecoxib and low-dose metronomic vinblastine or cyclophosphamide in pediatric recurrent solid tumors.

Tumor vasculature is a reasonable target for cancer therapy and lower more frequent doses of traditional chemotherapeutics [low-dose metronomic (LDM) chemotherapy] has been shown to have antiangiogenic efficacy. This study evaluated the safety and pharmacokinetics of celecoxib and LDM vinblastine or cyclophosphamide in children with recurrent, refractory solid tumors. We also investigated whether a subset of circulating plasma proteins are surrogate markers of angiogenic activity. Thirty-three children were enrolled in this pilot study and received celecoxib (250 mg/m2 PO b.i.d.) and either vinblastine (1 mg/m2 IV 3×/wk) or cyclophosphamide (30 mg/m2 PO daily) continually. Celecoxib alone and with LDM chemotherapy was well tolerated and plasma concentrations were consistent with those shown to have antiangiogenic activity. Four patients (13%) had durable stable disease (28 to 78 wk) although no complete or partial responses were observed. The surrogate markers measured (vascular endothelial growth factor, basic fibroblast growth factor, soluble vascular cell adhesion molecule, soluble intercellular cell adhesion molecule, endostatin, and thrombospondin-1) were highly variable and no statistically significant relationship between them and disease progression or maintenance of stable disease was observed. We concluded that this regimen is well tolerated hence supporting the use of this form of therapy in pediatric patients. However, future studies should include more homogenous patient populations and focus on validating surrogate markers to monitor treatment activity.

A Phase I Trial and Pharmacokinetic Study of Sorafenib in Children with Refractory Solid Tumors or Leukemias: A Children's Oncology Group Phase I Consortium Report

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 q12h for consecutive 28 day cycles. Pharmacokinetics (day 1 and steady state) and pharmacodynamics were performed during cycle 1. Results Of sixty-five patients enrolled, 60 were eligible. In the solid tumor cohort (n=49), 4/6 patients experienced a DLT (hypertension, pain, rash/urticaria, thrombocytopenia, ALT/AST) at the starting dose (150 mg/m2/dose) which resulted in de-escalation to 105 mg/m2/dose. After eligibility criteria modification and dose re-escalation, the MTD was 200 mg/m2/dose for solid tumors and 150 mg/m2/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 cycles was observed in 14 solid tumor patients, and two patients with acute myeloid leukemia and FLT3 internal tandem duplication experienced a decrease in bone marrow blasts toPurpose: 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/m2/dose) which resulted in de-escalation to 105 mg/m2/dose. After eligibility criteria modification and dose re-escalation, the MTD was 200 mg/m2/dose for solid tumors and 150 mg/m2/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/m2/dose and 150 mg/m2/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); 6011–22. ©2012 AACR.

Single-dose and steady-state pharmacokinetics of celecoxib in children

Celecoxib is a member of a novel group of agents that selectively inhibit cyclooxygenase 2 (COX‐2). COX‐2 inhibitors have emerged as an important class of drugs because of the lower incidence of side effects when compared with traditional nonsteroidal anti‐inflammatory drugs, which inhibit both cyclooxygenase 1 and COX‐2. Because children often differ from adults with respect to drug disposition, the objective of this study was to determine the single‐dose and steady‐state pharmacokinetics of celecoxib in pediatric patients.

A Phase I Trial and Pharmacokinetic Study of the Raf Kinase and Receptor Tyrosine Kinase Inhibitor Sorafenib in Children with Refractory Solid Tumors or Refractory Leukemias

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 q12h for consecutive 28 day cycles. Pharmacokinetics (day 1 and steady state) and pharmacodynamics were performed during cycle 1. Results Of sixty-five patients enrolled, 60 were eligible. In the solid tumor cohort (n=49), 4/6 patients experienced a DLT (hypertension, pain, rash/urticaria, thrombocytopenia, ALT/AST) at the starting dose (150 mg/m2/dose) which resulted in de-escalation to 105 mg/m2/dose. After eligibility criteria modification and dose re-escalation, the MTD was 200 mg/m2/dose for solid tumors and 150 mg/m2/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 cycles was observed in 14 solid tumor patients, and two patients with acute myeloid leukemia and FLT3 internal tandem duplication experienced a decrease in bone marrow blasts toPurpose: 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/m2/dose) which resulted in de-escalation to 105 mg/m2/dose. After eligibility criteria modification and dose re-escalation, the MTD was 200 mg/m2/dose for solid tumors and 150 mg/m2/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/m2/dose and 150 mg/m2/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); 6011–22. ©2012 AACR.

Glutathione stability in whole blood: effects of various deproteinizing acids.

High-performance liquid chromatography separation of reduced and oxidized glutathione (GSH and GSSG) in biologic samples using electrochemical detection offers the convenience of both simultaneous quantitation and simple sample preparation. Rapid acidification is required to prevent GSH autooxidation, GSH and GSSG degradation, and precipitate proteins that interfere with analysis. Currently, little consistency exists in the literature regarding acid selection or the feasibility of sample storage before analysis. The purpose of this work was to examine the effects of perchloric (PCA), trichloroacetic (TCA), metaphosphoric (MPA), and 5-sulfosalicylic (SSA) acids on the short-term stability of GSH and GSSG measurements in whole blood. Samples were collected from adult volunteers and treated with multiple concentrations of each acid. The samples were analyzed immediately and aliquots were stored at −80°C for up to 28 days. The suitability of each acid was assessed by percentage change of GSH and GSSG from baseline, efficiency of protein removal, and alteration of chromatogram characteristics. In general, increasing the acid concentration improved sample stability. Nevertheless, SSA did not achieve acceptable sample stability at any concentration tested. MPA was found to leave substantial amounts of protein in the samples, and TCA may interfere with the peaks of interest. Based on these results, a final concentration of 15% PCA is suggested for analysis of glutathione in whole blood. Although immediate sample preparation is preferred, 15% PCA can maintain sample integrity for 4 weeks after storage at −80°C.

A multi-centre Canadian pilot study of metronomic temozolomide combined with radiotherapy for newly diagnosed paediatric brainstem glioma.

PURPOSE Survival rates for paediatric diffuse intrinsic brainstem glioma (DIBSG) are dismal. Metronomic dosing of temozolomide (TMZ) combined with standard radiotherapy may improve survival by increasing the therapeutic index and anti-angiogenic effect of TMZ. This study aimed to evaluate the safety and efficacy of this regimen in paediatric DIBSG patients. METHODS Children aged 18 years or younger with newly diagnosed DIBSG were treated with standard radiotherapy and concomitant metronomic TMZ at 85 mg/m(2)/day for 6 weeks, followed by metronomic TMZ monotherapy at the same dose. Treatment was continued until tumour progression or unacceptable toxicity occurred. Primary endpoints included overall survival and toxicities. For patients who consented, plasma and urine samples were collected at diagnosis, post-induction and prior to each course of maintenance therapy for the quantification of angiogenesis markers. RESULTS Fifteen eligible patients were enrolled, with a median age of 6.4 years. The most common toxicities were myelosuppression, most notably prolonged lymphopaenia and thrombocytopaenia. The only dose-limiting toxicity was thrombocytopaenia. Intratumoural haemorrhage was confirmed in one patient. Median time to progression was 5.13 months (95% CI = 6.4, 10.8) and median overall survival (OS) was 9.8 months (95% CI = 6.4, 10.8). Six-months OS was 80% ± 10.3%, with a 1-year OS of 20% ± 10.3%. Serum levels of both VEGF and endoglin tended to decrease during the first two cycles of therapy. CONCLUSION Chemoradiotherapy with metronomic dosing of TMZ showed similar toxicity to previous TMZ regimens, and does not appear to improve survival in paediatric DIBSG.

A Canadian paediatric brain tumour consortium (CPBTC) phase II molecularly targeted study of imatinib in recurrent and refractory paediatric central nervous system tumours

PURPOSE To evaluate the safety, efficacy and pharmacokinetics of imatinib in children with recurrent or refractory central nervous system (CNS) tumours expressing KIT and/or PDGFRA. METHODS Nineteen patients aged 2-18 years, with recurrent or refractory CNS tumours expressing either of the target receptors KIT and/or PDGFRA (by immunohistochemistry) were eligible. Participants received imatinib orally at a dose of 440 mg/m(2)/day and toxicities and tumour responses were monitored. Serial blood and cerebrospinal fluid samples for pharmacokinetics were obtained in a subset of consenting patients. Frozen tumour samples were analysed retrospectively for KIT and PDGFRA gene amplification in a subset of patients for whom samples were available. RESULTS Common toxicities were lymphopaenia, neutropaenia, leucopaenia, elevated serum transaminases and vomiting. No intratumoural haemorrhages were observed. Although there were no objective responses to imatinib, four patients had long-term stable disease (SD) (38-104 weeks). Our results suggest a possible relationship between KIT expression and maintenance of SD with imatinib treatment; KIT immunopositivity was seen in only 58% (11/19) of study participants overall, but in 100% of patients with SD at 38 weeks. All patient tumours showed PDGFRA expression. Pharmacokinetic data showed a high interpatient variability, but corresponded with previously reported values. CONCLUSIONS Imatinib at 440 mg/m(2)/day is relatively safe in children with recurrent CNS tumours, but induced no objective responses. Demonstration of SD in previously progressing patients (KIT-expressing) suggests cytostatic activity of imatinib.

Metronomic Dosing of Chemotherapy: Applications in Pediatric Oncology

Pediatric cancer has a better outcome profile than adult cancers. However, refractory disease and the potential for long-term morbidity resulting from the use of conventional therapies necessitate the development of novel treatments for this population. Recent advances in oncology include the use of low dose metronomic (LDM) chemotherapy. The promise of this novel therapeutic approach includes reduced toxicity and the potential for efficacy predominantly through an antiangiogenic effect. The clinical benefit may be realized especially when combined with other antiangiogenic agents and/or conventional maximally tolerated doses of chemotherapy. In this article, we review the evidence for the use of LDM chemotherapy with a focus on pediatric cancer. Included are some of the possible risks attributable to this therapy in a pediatric setting and some of the hurdles to overcome in order to conduct good clinical research. Emphasis is placed on the development of proper surrogate markers to monitor antiangiogenic therapy in order to both optimize the dosing schedule for LDM chemotherapy and to provide a way of tracking therapeutic efficacy.

Cytochrome P450 2C9 genotype: Impact on celecoxib safety and pharmacokinetics in a pediatric patient

o the Editor: In the November 2002 and March 2005 issues of the ournal, we presented pharmacokinetic results of a clinical rial evaluating celecoxib and low-dose metronomic chemoherapy as antiangiogenic treatment in children with recurrent olid tumors. We identified a patient who was exposed to a ignificantly higher concentration of celecoxib. This letter resents the correlation between celecoxib pharmacokinetics nd cytochrome P450 (CYP) 2C9 genotype in children for the rst time. Four children were studied (Table I). The first step in celecoxib metabolism is methylydroxylation primarily mediated by the polymorphic YP2C9. Two genetic polymorphisms have a functional ffect on CYP2C9 activity—alleles CYP2C9*2 and YP2C9*3. The enzyme coded by the *2 allele, CYP2C9.2, hows only a moderate decrease in activity, whereas the nzyme coded by the *3 allele, CYP2C9.3 (especially in the omozygous state), shows a marked decrease in activity when ompared with the wild-type CYP2C9.1. The patient of interest was homozygous for CYP2C9*3, an xtremely rare genotype. Two patients were homozygous for he *1 allele, and one was a CYP2C9*1/*2 carrier. The *2 llele did not have a noticeable impact on celecoxib pharmaokinetics compared with the wild-type patients, which is onsistent with previous observations. However, the *3 al-