EVALUATION OF A PEDIATRIC LIQUID FORMULATION TO IMPROVE 6-MERCAPTOPURINE THERAPY IN CHILDREN

2015 ◽  
Vol 101 (1) ◽  
pp. e1.60-e1
Author(s):  
Tiphanie Adam de Beaumanis ◽  
Lisa Lynqsie Hjalgrim ◽  
Jacob Nersting ◽  
Jörg Breitkreutz ◽  
Yves Bertrand ◽  
...  
Keyword(s):  
Clinical Study ◽  
Lymphoblastic Leukemia ◽  
Safety Data ◽  
Random Order ◽  
Relative Bioavailability ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Liquid Formulation ◽  
Open Label ◽  
Gold Hamsters

Background6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed and evaluated in the target population. Preclinical and clinical evaluation was performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization.MethodsThe pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal toxicity of 28 daily administrations in treated compared to controls gold hamsters. The multi-centre clinical study was single-dose, open-label, crossover trial, conducted in 15 ALL children during maintenance therapy. The bioavailability and palatability of a single 50 mg fixed dose of Loulla compared to 50 mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9 hours were obtained each day at to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0–9 and AUC0–∞. A questionnaire adapted to children testing Loulla palatability and preference for either Loulla or the usual 6-MP tablet was completed. Occurrence of adverse events was determined at study visits by vital sign measurements, patient's spontaneous reporting, investigator's questioning and clinical examination.ResultsThe preclinical study in gold hamsters showed that dosage-volume of 75 mg/kg/day was well tolerated. The relative bioavailability of liquid Loulla formulation compared to the reference presentation is 76% for AUC0-9 and AUC0-∞ and 80% for Cmax. The taste of Loulla and the mouth feeling after ingestion compare favorably to the tablet. No adverse event occurred.ConclusionPharmacokinetic, palatability and safety data support the use of Loulla in children.

Phase Ib trial of combining aldoxorubicin plus doxorubicin.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2550-2550
Author(s):  
Kamalesh Kumar Sankhala ◽  
Sant P. Chawla ◽  
Victoria S Chua ◽  
Doris Quon ◽  
Allison Bonk ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Safety Data ◽  
Tumor Xenograft ◽  
Fixed Dose ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Dose Escalation Study ◽  
Best Response ◽  
Grade 3

2550 Background: Aldoxorubicin is a novel drug that covalently binds to albumin in the circulation with release in low pH environments. Preclinical studies in pancreatic and ovarian tumor xenograft models demonstrated that aldoxorubicin plus doxorubicin administered at 50% of their MTD provided complete and prolonged tumor remission in these models with less toxicity than each drug administered at their MTD. We evaluated the toxicity profile of a fixed dose of doxorubicin and escalating doses of aldoxorubicin in subjects with advanced solid tumors. Methods: Phase 1b open label, dose-escalation study of aldoxorubicin administered at either 175, 240 or 320 mg/m2 (130, 180, or 240 mg/m2 doxorubicin equivalents) iv + 35 mg/m2doxorubicin iv, both on Day 1 of 21 day cycles, for up to 8 cycles. The MTD is the dose level immediately below where 2/6 subjects experience a dose limiting toxicity (DLT) , or the maximum dose of 320 mg/m2aldoxorubicin. Additional subjects may be enrolled at the MTD to provide more safety data. Results: 10 subjects have been treated as of January 21, 2013. No DLT was observed and the MTD was defined as 320 mg/m2 aldoxorubicin and 35 mg/m2 doxorubicin iv administered on Day 1 of 21 day cycles. A median of 4.5 cycles have been received. 3/10 subjects were terminated due to either progressive disease (2) or death (1). No subject was terminated due to an adverse event. Grade 3 or 4 neutropenia was seen at all dose levels (8/10 subjects). 4/10 subjects exhibited grade 3 or 4 thrombocytopenia and 3/10 subjects had grade 3 or 4 anemia. Neutropenic fever occurred in 3/10 subjects. Other grade 3/4 adverse events seen in 2 or fewer subjects included fatigue, increased liver enzymes and dehydration. No significant mucositis or cardiotoxicity was observed. At this time the best response has been stable disease in 6/10 subjects and a partial response in 1 subject (malignant fibrous histiocytoma). Conclusions: The combination of aldoxorubicin (320 mg/m2)) + doxorubicin (35 mg/m2) can be safely administered to subjects with solid tumors. Hematologic toxicity is common and can be controlled with growth factors. The dose of aldoxorubicin is 90% of the MTD of aldoxorubicin administered as a single agent. Thus, doxorubicin does not appear to add to the toxicity of this combination. Clinical trial information: NCT01673438.

scholarly journals Population Pharmacokinetics of Atazanavir in Patients with Human Immunodeficiency Virus Infection

2006 ◽  
Vol 50 (11) ◽  
pp. 3801-3808 ◽  
Author(s):  
Sara Colombo ◽  
Thierry Buclin ◽  
Matthias Cavassini ◽  
Laurent A. Décosterd ◽  
Amalio Telenti ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Population Analysis ◽  
Pharmacokinetic Profile ◽  
Relative Bioavailability ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Genetic Traits

ABSTRACT Atazanavir (ATV) is a new azapeptide protease inhibitor recently approved and currently used at a fixed dose of either 300 mg once per day (q.d.) in combination with 100 mg ritonavir (RTV) or 400 mg q.d. without boosting. ATV is highly bound to plasma proteins and extensively metabolized by CYP3A4. Since ATV plasma levels are highly variable and seem to be correlated with both viral response and toxicity, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the ATV pharmacokinetic profile in a target population of HIV patients, to characterize interpatient and intrapatient variability, and to identify covariates that might influence ATV disposition. A population analysis was performed with NONMEM with 574 plasma samples from a cohort of 214 randomly selected patients receiving ATV. A total of 346 randomly collected ATV plasma levels and 19 full concentration-time profiles at steady state were available. The pharmacokinetic parameter estimates were an oral clearance (CL) of 12.9 liters/h (coefficient of variation [CV], 26%), a volume of distribution of 88.3 liters (CV, 29%), an absorption rate constant of 0.405 h−1 (CV, 122%), and a lag time of 0.88 h. A relative bioavailability value was introduced to account for undercompliance due to infrequent follow-ups (0.81; CV, 45%). Among the covariates tested, only RTV significantly reduced CL by 46%, thereby increasing the ATV elimination half-life from 4.6 h to 8.8 h. The pharmacokinetic parameters of ATV were adequately described by a one-compartment population model. The concomitant use of RTV improved the pharmacokinetic profile. However, the remaining high interpatient variability suggests the possibility of an impact of unmeasured covariates, such as genetic traits or environmental influences. This population pharmacokinetic model, together with therapeutic drug monitoring and Bayesian dosage adaptation, can be helpful in the selection and adaptation of ATV doses.

BIOV-111 a European Phase II Trial of Clofarabine (Evoltra®) in Refractory and Relapsed Childhood Acute Lymphoblastic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1859-1859 ◽  
Author(s):  
Pamela Kearns ◽  
Gerard Michel ◽  
Brigitte Nelken ◽  
Simon Joel ◽  
Essam Al-Ghazaly ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Cardiac Failure ◽  
Response Rate ◽  
Treated Patient ◽  
Lymphoblastic Leukemia ◽  
Safety Data ◽  
Open Label ◽  
Serious Adverse Events ◽  
Platelet Recovery

Abstract BIOV-111 is a European phase II non-randomised, open-label study of a next generation purine nucleoside analogue, clofarabine (Evoltra®), in pediatric patients with relapsed/refractory ALL. We report on the efficacy and safety data. Eligible patients (pts) had either primary refractory (2 pts) or relapsed/refractory (51 pts with ≥ 2 prior lines of treatment) ALL. Clofarabine 52mg/m2 daily × 5 days was given every 28–42 days (1 course). The primary endpoint is overall response rate (ORR) defined as either a complete response (CR) or CR without platelet recovery (CRp) after 2 courses. Adverse events (AEs) were graded according to NCI CTC (v3). Plasma, urine and intracellular clofarabine pharmacokinetics were also investigated. To date, 96 courses have been administered to 53 pts from 25 centres. The median number of prior treatments was 2 (range 1–5) and 20 pts (38%) had been previously transplanted. 8/29 pts receiving ≥2 courses responded (1CR, 7CRp) giving an ORR of 28%. Responses were observed in 14/53 (26%) pts receiving at least one course of clofarabine (6CR, 7CRp, 1 PR ). Eight (57%) responders had a prior transplant and 1 of these patients was transplanted post clofarabine. One pt with a prior transplant remains in remission at 20+ months. Four pts (1CR, 3CRp) have proceeded to transplantation. Serious adverse events (n=103) included febrile neutropenia (51/103), seizures (4/103), streptococcal septicaemia (3/103), palmo-plantar erythrodysaesthesia (2/103) and bone pain (2/103). Three hepatic events occurred (raised bilirubin, raised ALT/AST), 1 renal failure and 1 cardiac failure. AEs occurred in 4 pts. The renal and cardiac failure AE occurred in a pt with known anthracycline cardiac myopathy and renal impairment at study entry. Median end of infusion plasma clofarabine concentration (n=25) on days 1 and 2 were 1.5 (0.5–3.2) uM vs 2.0 (0.1–5.1) uM respectively (p=0.01) and were not different in pts achieving a response. Urinary clofarabine recovery on days 1, 5 and 6 (drug -free) was 48±18 %, 46±12 % and 5±3 %. Clofarabine TP analyses are ongoing. Response rates in this ongoing BIOV-111 study are consistent with the pivotal clofarabine study (CLO-212) in relapsed/refractory pediatric ALL. Notably, BIOV-111 has a lower incidence of AEs, including hepatic and renal AEs; (4% and 1% respectively vs 10% and 8% in CLO-212), possibly attributable to fewer prior treatments compared to CLO-212 (median 2 vs 3 respectively). Clofarabine achieves a significant response rate in this heavily pre-treated patient population and durable responses have been observed which may confer a survival advantage with longer follow-up.

scholarly journals Pharmacokinetics of Single-Dose and Multi-Dose of Lovastatin/Niacin ER Tablet in Healthy Volunteers

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Yan-yan Jia ◽  
Song Ying ◽  
Chen-tao Lu ◽  
Jing Yang ◽  
Li-kun Ding ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Healthy Volunteers ◽  
Least Square ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Mixed Dyslipidemia ◽  
Dose Oral ◽  
Dose Combination ◽  
Healthy Chinese

An extended-release (ER) niacin and lovastatin fixed-dose combination has been developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The purpose of the present study was to examine the drug interaction between niacin and lovastatin after multi-dose oral administration of lovastatin/niacin ER combination in healthy Chinese volunteers. A single-center, randomized, open-label, 5-period crossover study was conducted in thirty healthy volunteers aged 18 to 45 years with a washout period of 8 days. Subjects were randomized to receive multiple doses of treatment A (1 500 mg niacin ER tablet), B (1 20 mg lovastatin tablet), C (1 20 mg lovastatin and 500 mg niacin-ER tablet), D (2 10 mg lovastatin and 350 mg niacin-ER tablets) or E (2 10 mg lovastatin and 500 mg niacin-ER tablets) in 1 of 5 sequences (ABCDE, BCDEA, CDEAB, DEABC, EABCD) per period. Lovastatin, niacin and its metabolites (nicotinuric acid and nicotinamide) were determined in plasma by LC/MS method. Pharmacokinetic parameters were calculated, and least square mean ratios and 90% confidence intervals for Cmax⁡ and AUC (0–24) were determined for lovastatin/niacin ER versus niacin ER or lovastatin. It revealed that the formulation had no potential drug interaction in healthy Chinese volunteers when the dosage was increased from 500 mg to 1000 mg.

scholarly journals Valganciclovir Results in Improved Oral Absorption of Ganciclovir in Liver Transplant Recipients

2000 ◽  
Vol 44 (10) ◽  
pp. 2811-2815 ◽  
Author(s):  
Mark D. Pescovitz ◽  
John Rabkin ◽  
Robert M. Merion ◽  
Carlos V. Paya ◽  
John Pirsch ◽  
...  
Keyword(s):  
Liver Transplant ◽  
Oral Absorption ◽  
Random Order ◽  
Relative Bioavailability ◽  
Equivalence Testing ◽  
Transplant Recipients ◽  
Open Label ◽  
Once Daily ◽  
Liver Transplant Recipients ◽  
Cmv Prophylaxis

ABSTRACT The pharmacokinetics of an orally administered valine ester of ganciclovir (GCV), valganciclovir (VGC), were studied. These were compared to the pharmacokinetics of oral and intravenous GCV. Twenty-eight liver transplant recipients received, in an open-label random order with a 3- to 7-day washout, each of the following: 1 g of oral GCV three times a day; 450 mg of VGC per os (p.o.) once a day (q.d.); 900 mg of VGC p.o. q.d.; and 5 mg of intravenous (i.v.) GCV per kg of body weight q.d., given over 1 h. GCV and VGC concentrations were measured in blood over 24 h. One-sided equivalence testing was performed to test for noninferiority of 450 mg of VGC relative to oral GCV (two-sided 90% confidence interval [CI] > 80%) and nonsuperiority of 900 mg of VGC relative to i.v. GCV (two-sided 90% CI < 125%). The exposure of 450 mg of VGC (20.56 μg · h/ml) was found to be noninferior to that of oral GCV (20.15 μg · h/ml; 90% CI for relative bioavailability of 95 to 109%), and the exposure of 900 mg of VGC (42.69 μg · h/ml) was found to be nonsuperior to that of i.v. GCV (47.61 μg · h/ml; 90% CI = 83 to 97%). Oral VGC delivers systemic GCV exposure equivalent to that of standard oral GCV (at 450 mg) or i.v. GCV (at 900 mg of VGC). VGC has promise for effective CMV prophylaxis or treatment with once-daily oral dosing in transplant recipients.

scholarly journals Randomized, Open-Label, Two-Way Crossover Study To Compare The Bioequivalence Of Two Formulations Of Esomeprazole In Healthy Male Volunteers

KYAMC Journal ◽  
2017 ◽  
Vol 4 (1) ◽  
pp. 326-330
Author(s):  
Uttam Kumar Sarker ◽  
Mir Misbahuddin ◽  
Md Shariful Hasan Ripon ◽  
Md Rabiul Islam
Keyword(s):  
Half Life ◽  
Plasma Concentrations ◽  
Bioequivalence Study ◽  
Relative Bioavailability ◽  
Hplc Method ◽  
Pharmacokinetic Parameters ◽  
Test Drug ◽  
Healthy Male ◽  
Open Label ◽  
Reference Drug

A crossover-randomized bioequivalence study of two oral formulations of esomeprazole (40 mg) capsules were carried out in 16 healthy male Bangladeshi volunteers. The test and reference formulations were PRONEX™ (Drug International Ltd, Bangladesh) and NEXIUM™ (AstraZeneca AB, Sweden), respectively. Each tablet was administered with 150 mL of water to subjects after overnight fasting on 2 treatment days separated by 1 week washout period. After dosing, serial blood samples were collected for a period of 24 hours. The plasma concentrations of esomeprazole were estimated using a validated HPLC method. The pharmacokinetic parameters Cmax, Tmax, AUC0g24h, t1/2, and Kel were determined. The mean (± SD) AUC0g24h for esomeprazole of test drug PRONEXTM for 16 volunteers was 1509 (± 546) ng.hr/mL whereas it was 1622 (± 589) ng.hr/mL for esomeprazole of NEXIUMTM. The relative bioavailability (PRONEXTM/NEXIUMTM ratio) was 93%. The Cmax, tmax, half-life of elimination (t1/2) and the rate of elimination (Kel) of esomeprazole of test drug were 1653 (± 706) ng/mL, 2.13 (± 0.81) hours, 2.00 (± 0.61) hour and 0.3465 respectively. The Cmax, tmax, half-life of elimination (t1/2) and the rate of elimination (Kel) of esomeprazole of reference drug were 1820 (± 877) ng/mL, 2.80 (± 0.67) hours, 2.14 (± 0.55) hour and 0.3238 respectively. The 90% CI for the test and reference drugs were found within the acceptance range of 80-125%. In conclusion, PRONEX™ is bioequivalent to NEXIUM ™ in terms of absorption.KYAMC Journal Vol. 4, No.-1, July 2013, Page 326-330

scholarly journals Randomized Trial of Food Effect on Pharmacokinetic Parameters of ABX464 Administered Orally to Healthy Male Subjects

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Didier Scherrer ◽  
Regine Rouzier ◽  
Marine Cardona ◽  
P. Noel Barrett ◽  
Jean-Marc Steens ◽  
...  
Keyword(s):  
Maximum Concentration ◽  
Food Effect ◽  
Randomized Study ◽  
Relative Bioavailability ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Time Curve ◽  
Novel Approach ◽  
Elimination Half ◽  
Group 2

ABSTRACT ABX464 is an antiviral that provides a novel approach to the reduction and control of HIV infection. Investigation of food influence is important in the optimization of treatment. An open-label, food effect, randomized study which included 2 groups of 24 subjects each was carried out to assess the bioavailability and safety of single (group 1) and repeated (group 2) oral doses of ABX464 (50 mg) under fed or fasted conditions. The maximum concentration (C max) and the area under the concentration-time curve from time zero to infinity (AUC0–∞) of ABX464 were demonstrated to increase with food after a single dose of ABX464 (219% and 188%, respectively). The apparent terminal elimination half-lives (t 1/2s) under fed and fasted conditions were comparable, at about 0.80 h. The median time to maximum concentration (T max) was delayed from 1.5 to 2.8 h, and the ratio of the AUC0–∞ obtained under fed conditions to the AUC0–∞ obtained under fasted conditions (F rel) was 2.69. Comparable results were obtained on day 1 and day 10 in group 2. The increases in C max and AUC0–∞ of the metabolite ABX464–N-glucuronide (ABX464-NGlc) were, however, much more limited when ABX464 was given with food. The t 1/2s were also comparable under the two conditions (around 100 h). Between day 1 and day 10, the C max increased by 5% under the fasted condition and by 25% under the fed condition. The most common related treatment-emergent adverse events were headaches, vomiting, and nausea. It was concluded that food has a significant impact on the levels of ABX464 in plasma with a delay in absorption and increased relative bioavailability, with a lesser impact on its biotransformation into ABX464-NGlc. ABX464 was well tolerated under both fasted and fed conditions. (This study has been registered at ClinicalTrials.gov under registration no. NCT02731885.)

scholarly journals Relative Oral Bioequivalence of Two 6-Mercaptopurine (6-MP) Liquid Formulations in Children with Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2242-2242
Author(s):  
Jaszianne A. Tolbert ◽  
Keith J. August ◽  
Susan M Abdel-Rahman ◽  
Scott J Weir ◽  
J Steven Leeder ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Preliminary Investigation ◽  
Systemic Exposure ◽  
Fixed Dose ◽  
Liquid Formulation ◽  
Post Dose ◽  
Small Children ◽  
Oral Liquid ◽  
Suspending Agents

Abstract Introduction: Oral 6-MP remains a key drug for acute and maintenance treatment of ALL. Maintaining adequate systemic exposure so as to prevent disease relapse is challenging given variability in the pharmacokinetics (PK). Historically, pharmacies have prepared extemporaneous formulations of 6-MP to permit more individualized (i.e. mg/kg) and accurate dosing in small children which is difficult when using fixed dose tablets. We performed a preliminary investigation of the relative bioequivalence (rBE) of two extemporaneous oral liquid formulations of 6-MP. Methods: Children with ALL participated in a randomized, 2-sequence, 2-period crossover study conducted at a single site. In study arm A, patients received a 5 mg/ml oral, liquid formulation of 6-MP prepared in 1:1 Ora-Plus®:Ora-Sweet and a marketed 50 mg tablet (Roxane Laboratories). Study arm B evaluated a 50 mg/ml liquid formulation prepared in methylcellulose and simple syrup against the 50 mg tablet. Participants were administered their prescribed 6-MP dose following an overnight fast. Serial blood samples (n=14) were collected prior to and over 8 hours post-dose. Plasma 6-MP concentrations were quantitated under GLP conditions using a validated, LC-MS/MS method. 6-MP PK was determined using a standard noncompartmental approach. The relative oral bioavailability of 6-MP was determined by generating 90% confidence intervals for log transformed ratios (test/reference) of Cmax, AUC0-n, and AUC0-inf. Results: Twenty four participants (6-17 yrs) enrolled in this study. Eleven subjects (6 female) were in the 5 mg/ml study arm and 13 (8 female) were in the 50 mg/ml study arm.The inverse log of the 90% confidence interval generated by the ratio of thedifferences in exposures between the respective oral liquid formulations versus the tablet were as follows:Table 1Parameter Test Formulations5 mg/ml liquid50 mg/ml liquidCmax (ng/ml)1.64-2.721.07-1.72AUC0-n (ng/ml*hr)1.10-1.650.85-1.17AUC0-inf (ng/ml*hr)1.10-1.650.84-1.13 All estimates of exposure for the 5 mg/ml liquid exceeded the accepted range of bioequivalence (i.e. 0.80-1.25) per FDA criteria. Cmax for the 50 mg/ml liquid similarly exceeded theaccepted range. In contrast, AUC0-n and AUC0-inf for this particular formulation were within the accepted range based on FDA criteria. Conclusions: While both liquid formulations exhibited comparable bioavailability, neither formulation was bioequivalent to the tablet formulation for both Cmax and AUC. The systemic exposure to 6-MP (as reflected by AUC) from the 50 mg/ml oral liquid was bioequivalent to the tablet. Our data demonstrate that not all liquid formulations of 6-MP are equivalent with respect to bioavailability of the active ingredient. Differences in formulation constituents (e.g., suspending agents, vehicles), viscosity and potentially, 6-MP concentration likely contribute to the variability observed in systemic drug availability from liquid formulations and must be considered. Disclosures No relevant conflicts of interest to declare.

A European Phase II Study (BIOV-111) of Clofarabine (Evoltra®) in Refractory and Relapsed Childhood Acute Lymphoblastic Leukemia: Final Results.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 11-11 ◽  
Author(s):  
Pamela Kearns ◽  
Gerard Michel ◽  
Brigitte Nelken ◽  
Simon Joel ◽  
Essam Al-Ghazaly ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
Phase Ii ◽  
Cardiac Failure ◽  
Lymphoblastic Leukemia ◽  
Safety Data ◽  
Response Rates ◽  
Pharmacokinetic Parameters ◽  
Durable Response ◽  
Platelet Recovery

Abstract The BIOV-111 study was a European multicentre phase II non-randomised, open-label study of the novel purine nucleoside analogue, clofarabine (Evoltra ®). The study recruited patients ≤ 21 years old at initial diagnosis with primary refractory or relapsed/refractory acute lymphoblastic leukemia (ALL). The dose of clofarabine was 52mg/m2 daily x 5 days, every 28–42 days. Patients were evaluable after one complete course. The primary endpoint was overall response rate (OR) defined as either a complete response (CR) or CR without platelet recovery (CRp). Pharmacokinetic parameters and molecular responses were assessed in a sub-group of cases. The study enrolled a total of 74 patients. 65 were evaluable for response. We report the final efficacy and safety data on these evaluable patients. In total 120 courses of clofarabine were administered to 65 patients from 25 centres. The median age was 10 yrs (range 0.5–23 yrs). The median number of prior treatments was 2 (range 1–5) and 22 patients (34%) had been previously transplanted. The OR was 26% (6 CR, 11 CRp). In addition 1 PR was observed. 11/18 (61%) responders had a prior transplant and 3 of these patients received a further transplant post clofarabine. Of the 7 patients proceeding to transplant post-clofarabine; 3 patients had achieved a CR and 4 achieved a CRp. The updated median duration of response and survival will be presented. The pharamockinetic analyses showed plasma clofarabine concentration did not correlate with treatment outcome, however the ratio of day2/day 1 end of infusion intracellular clofarabine triphosphate (cloTP) levels were higher in responding pts. Serious adverse events included febrile neutropenia 50.8%, hepatic events (raised bilirubin, raised ALT/AST) 6.2%, renal failure 6.2%, palmar-plantar erythrodysaesthesia 4.6% and bone pain 4.6%, seizures 7.7% and cardiac failure 1%. In conclusion, this study demonstrated that clofarabine can achieve significant, durable response rates in heavily pre-treated paediatric patients with relapsed/refractory ALL and intracellular cloTP accumulation may be predictive of response. The response rates in this study are consistent with a previous clofarabine study (CLO-212) in relapsed/refractory pediatric ALL, however in BIOV-111 a lower incidence of adverse events was observed, including hepatic and renal adverse events, possibly attributable to fewer prior treatments compared to CLO-212 (median 2 vs 3 respectively). The reported episodes of seizure and cardiac failure were associated with pre-existing co-morbidities and/or sepsis in the majority of cases. The safety profile of clofarabine was manageable and acceptable and does not preclude subsequent HSCT.

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