Dose-finding Studies Research Articles

OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models.

Bromodomain and extraterminal (BET) bromodomain (BRD) proteins are epigenetic readers that bind to acetylated lysine residues on chromatin, acting as co-activators or co-repressors of gene expression. BRD2 and BRD4, members of the BET family, are significantly increased in glioblastoma multiforme (GBM), the most common primary adult brain cancer. OTX015 (MK-8628), a novel BRD2/3/4 inhibitor, is under evaluation in dose-finding studies in solid tumors, including GBM. We investigated the pharmacologic characteristics of OTX015 as a single agent and combined with targeted therapy or conventional chemotherapies in glioblastoma cell lines. OTX015 displayed higher antiproliferative effects compared to its analog JQ1, with GI50 values of approximately 0.2 µM. In addition, C-MYC and CDKN1A mRNA levels increased transiently after 4 h-exposure to OTX015, while BRD2, SESN3, HEXIM-1, HIST2H2BE, and HIST1H2BK were rapidly upregulated and sustained after 24 h. Studies in three additional GBM cell lines supported the antiproliferative effects of OTX015. In U87MG cells, OTX015 showed synergistic to additive activity when administered concomitant to or before SN38, temozolomide or everolimus. Single agent oral OTX015 significantly increased survival in mice bearing orthotopic or heterotopic U87MG xenografts. OTX015 combined simultaneously with temozolomide improved mice survival over either single agent. The passage of OTX015 across the blood-brain barrier was demonstrated with OTX015 tumor levels 7 to 15-fold higher than in normal tissues, along with preferential binding of OTX015 to tumor tissue. The significant antitumor effects seen with OTX015 in GBM xenograft models highlight its therapeutic potential in GBM patients, alone or combined with conventional chemotherapies.

Integrating the escalation and dose expansion studies into a unified Phase I clinical trial

We focus on Phase I dose finding studies as they are currently undertaken. The design and analysis of these trials have changed over the last years and, in particular, it is now rare for a Phase I study to not include one or more dose-expansion cohorts (DEC). It is common to see DEC involving several hundred patients, building on an initial dose escalation study that may have no >20 to 30 patients. There has been recent focus by researchers on the design of DEC and the analysis of DEC data. It is reasonable to explicitly account for the uncertainty in the estimation of the MTD, the dose upon which the whole of the DEC is currently based. In this paper, we focus on the dose escalation phase prior to the DEC, with the purpose of adapting it to the needs of DEC. Specifically, before beginning the DEC phase, we need to identify those dose levels that will be taken into the DEC. We define a useful concept for this purpose, the co-MTD, and the results support that the estimated MTD and co-MTD contain the true MTD with high probability. We also provide stopping rules for when the data support that the dose escalation can end and the dose expansion can begin. Simulated trials support the use of the proposed approach and provide additional information on how this approach compares with current practice.

A Simulation Study to Decide the Timing of an Interim Analysis in a Bayesian Adaptive Dose-Finding Studies with Delayed Responses

A Simulation Study to Decide the Timing of an Interim Analysis in a Bayesian Adaptive Dose-Finding Studies with Delayed Responses

Novel dose-finding designs and considerations on practical implementations in oncology clinical trials

ABSTRACTOne of the main objectives in phase I oncology trials is to evaluate safety and tolerability of an experimental treatment by estimating the maximum tolerated dose (MTD) based on the rate of dose-limiting toxicities (DLT). To meet emerging challenges in dose-finding studies, over the past two decades, extensive research has been conducted by statistical and medical researchers to create innovative dose finding designs that perform better than the standard 3 + 3 design, which often exhibits undesirable statistical and operational properties. However, clinical implementation and practical usage of these new designs have been limited. This article begins with a review of the most recent literature and then provides some perspectives on implementing novel adaptive dose finding designs in oncology phase I trials from a pharmaceutical industry perspective. Statistical planning and logistical considerations on how to effectively execute such designs in multi-center clinical trials are discussed using two recent case studies.

Model selection versus model averaging in dose finding studies.

A key objective of Phase II dose finding studies in clinical drug development is to adequately characterize the dose response relationship of a new drug. An important decision is then on the choice of a suitable dose response function to support dose selection for the subsequent Phase III studies. In this paper, we compare different approaches for model selection and model averaging using mathematical properties as well as simulations. We review and illustrate asymptotic properties of model selection criteria and investigate their behavior when changing the sample size but keeping the effect size constant. In a simulation study, we investigate how the various approaches perform in realistically chosen settings. Finally, the different methods are illustrated with a recently conducted Phase II dose finding study in patients with chronic obstructive pulmonary disease. Copyright © 2016 John Wiley & Sons, Ltd.

Dimension of model parameter space and operating characteristics in adaptive dose-finding studies.

Adaptive, model-based, dose-finding methods, such as the continual reassessment method, have been shown to have good operating characteristics. One school of thought argues in favor of the use of parsimonious models, not modeling all aspects of the problem, and using a strict minimum number of parameters. In particular, for the standard situation of a single homogeneous group, it is common to appeal to a one-parameter model. Other authors argue for a more classical approach that models all aspects of the problem. Here, we show that increasing the dimension of the parameter space, in the context of adaptive dose-finding studies, is usually counter productive and, rather than leading to improvements in operating characteristics, the added dimensionality is likely to result in difficulties. Among these are inconsistency of parameter estimates, lack of coherence in escalation or de-escalation, erratic behavior, getting stuck at the wrong level, and, in almost all cases, poorer performance in terms of correct identification of the targeted dose. Our conclusions are based on both theoretical results and simulations. Copyright © 2016 John Wiley & Sons, Ltd.

Dose Expansion Cohorts in Phase I Trials

ABSTRACTA rapidly increasing number of Phase I dose-finding studies, those based on the standard 3+3 design in particular, are being prolonged with the inclusion of dose expansion cohorts (DEC) to better characterize the toxicity profiles of experimental agents and to study disease-specific cohorts. These trials consist of two phases: the usual dose escalation phase that aims to establish the maximum tolerated dose (MTD), and the dose expansion phase that accrues additional patients, often with different eligibility criteria, and where additional information is collected. Currently, not all protocols specify whether and how the MTD will be updated in the light of new data accumulated from the DEC. Here, we propose methods that allow monitoring of safety in the DEC by reevaluating the MTD in light of additional information. Our working assumption is that, regardless of the design being used for dose escalation, during the DEC we are experimenting in the neighborhood of a target dose with an acceptable rate of toxicity. We refine our initial estimate of the MTD by continuing experimentation in the immediate vicinity of the initial estimate of the MTD. The auxiliary information provided by such an evaluation will include toxicity, pharmacokinetic, efficacy, and other endpoints. We consider approaches specifically focused on the aims of DEC that examine efficacy alone or simultaneously with safety. Simulations provide further insight into the behavior of the proposed tests. Supplementary materials for this article are available online.

Between Scylla and Charybdis: Where does the treatment of Addison's disease in late-life depression go first?

IntroductionOlder adults with adrenocortical insufficiency, including Addison's disease (AD), are at an increased risk for developing late-life depression. Treatment of AD with glucocorticoid replacement therapy may exacerbate depressive symptoms and may complicate treatment of late-life depression.ObjectivesTo present a case with algorithm of decision-making in a particular case of glucocorticoid induced depression in patient with syndrome of Addison.AimsTo report a case-study, describing treatment of Addison's disease in LLD.MethodsA case report is presented and discussed, followed by a literature review.ResultsA 77-year-old female, diagnosed with Addison's disease, was referred with persistent fatigue, weakness, weight loss, sleep disturbances, and depressive symptoms over the previous 6 months. She was taken losartan 100 mg/day, zolpidem 10 mg/day, fludrocortisone 100 μg/day, and hydrocortisone 35 mg/day. There was no personal or family history of psychiatric problems. Clinical examination was normal aside from skin hyperpigmentation. After initial minimal dose reduction of glucocorticoids, Addison's disease remained under control. One week later, her depressive symptoms disappeared without administration of antidepressants.ConclusionThe association between glucocorticoid replacement therapy and late-life depression is not well understood. The current case shows that treatment of glucocorticoid-induced depression in subjects with Addison's disease is achievable by minimal adjustments in glucocorticoid regiment. However, collaboration with endocrinology is of vital importance to prevent an Addison's crisis. Pharmacokinetic dose-finding studies are required to find optimal glucocorticoid adjustment strategy.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials.

The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. A total of 13,008 toxicities were captured: 46% of patients' first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m(2), the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials.

Implementation of adaptive methods in early-phase clinical trials.

There has been constant development of novel statistical methods in the design of early-phase clinical trials since the introduction of model-based designs, yet the traditional or modified 3+3 algorithmic design remains the most widely used approach in dose-finding studies. Research has shown the limitations of this traditional design compared with more innovative approaches yet the use of these model-based designs remains infrequent. This can be attributed to several causes including a poor understanding from clinicians and reviewers into how the designs work, and how best to evaluate the appropriateness of a proposed design. These barriers are likely to be enhanced in the coming years as the recent paradigm of drug development involves a shift to more complex dose-finding problems. This article reviews relevant information that should be included in clinical trial protocols to aid in the acceptance and approval of novel methods. We provide practical guidance for implementing these efficient designs with the aim of augmenting a broader transition from algorithmic to adaptive model-guided designs. In addition we highlight issues to consider in the actual implementation of a trial once approval is obtained. Copyright © 2016 John Wiley & Sons, Ltd.

Digitally Analyzed Conjunctival Redness: Does Repeated Conjunctival Provocation Intrinsically Cause Local Desensitization of the Eye?

Background: Allergic reactions in patients with seasonal or perennial rhinoconjunctivitis mediated by airborne allergens can be effectively assessed with the conjunctival provocation test (CPT). The CPT is a fast and easy diagnostic procedure that challenges the ocular mucosa with instillations of allergen solutions into the conjunctival region. This paper aimed to investigate the possible influence of repeated diagnostic CPT procedures on the patient's clinical presentation, i.e. to analyze desensitization effects caused by diagnostic solutions and to show the reproducibility of CPT results. Methods: Treatment progress in 120 placebo-treated patients from 2 immunotherapeutic dose-finding studies was estimated and documented, as based on the CPT which was applied at 4 visits with intervals of 4, 8 and 16 weeks. High-resolution digital photos collected as part of the CPT documentation were analyzed by an external observer and by digital analysis software to determine conjunctival redness, completely independent of the subjectivity of investigators and patients. Results: Two extremal scenarios of the redness changes were considered after provocation with 10,000 standard quality units/ml. A maximal decrease of about 3% (t test: p = 0.0002; U test: p = 0.001) and a minimal decrease of about 1% (t test: p = 0.254; U test: p = 0.431) were found. Conclusions: The observed decrease in conjunctival hyperemia can be explained by local desensitization or by placebo effect. Due to the setup of both studies considered, we could not ascertain how these factors influence the decrease in redness. In order to attribute the observed effects to local conjunctival desensitization with certainty, further pilot studies are needed.

Abstract P4-13-19: Poziotinib, an oral, irreversible pan-HER inhibitor, demonstrates promising clinical activity in metastatic HER2 positive breast cancer patients

Abstract Background: Poziotinib is a novel, oral, irreversible pan-HER inhibitor that has been studied in two completed Phase 1 clinical trials in patients with advanced solid tumors (HM-PHI-101; HM-PHI-102) and is currently being studied in several Phase 2 clinical trials. Preclinical studies have shown poziotinib to be more potent in vitro than other EGFR- and HER2-directed tyrosine kinase inhibitors. This study collates the clinical experience of poziotinib in patients with advanced HER2 positive breast cancer from the two completed Phase 1 trials. Results: The maximum tolerated dose (MTD) and safety of poziotinib were evaluated in HM-PHI-101 (once daily, Day 1-14 q3 weeks) and in HM-PHI-102 (continuous dosing). The Dose Limiting Toxicity (DLT) was diarrhea in both studies. Anti-diarrheal medicine was allowed, but prophylactic anti-diarrheal therapy was not used. The most frequently reported Grade 3 AE was diarrhea (40%). The MTD for intermittent dosing of poziotinib was 24 mg and the MTD for continuous dosing was 16 mg. The Dose Limiting Toxicity (DLT) was diarrhea in both studies. Anti-diarrheal medicine was allowed, but prophylactic anti-diarrheal therapy was not used. In total, 10 patients with HER2 positive metastatic breast cancer were treated in the two trials (median age 56.5, range 30-69). These patients were heavily pretreated (median number of previous treatment regimens 5, range 3-9), and all patients had failed treatment with both trastuzumab and lapatinib. The Overall Response Rate (ORR) in these breast cancer patients was 60% and Clinical Benefit Rate (CBR) was 80%. The median duration of response was 32.5 weeks (range 18 - 56 weeks). Two patients in the early dose cohorts of 1 or 2mg had progressive disease. The median progression free survival (PFS) was 28 weeks (6, 6, 12, 17, 25, 31, 37, 49, 57, and 98 weeks). Conclusions: Poziotinib showed very promising clinical activity in Phase 1 patients with metastatic HER2 positive breast cancer, who had been heavily pretreated and failed two prior HER2-directed therapies. The ORR in this patient population was 60% and the CBR was 80% in these two early dose finding studies. The AEs observed in these studies was consistent with other pan-HER and EGFR inhibitors. While the majority of DLT cases involves diarrhea, toxicity of other adverse events was relatively tolerable. An intermittent dosing schedule seemed appropriate for poziotinib. Multiple Phase 2 studies with poziotinib are ongoing in patients with breast cancer and other solid tumors. Citation Format: Im S-A, Kim J-H, Lee K-H, Kim SH, Oh D-Y, Kim Y-J, Han S-W, Kim T-Y, Kim T-Y, Jung J, Bang Y-J. Poziotinib, an oral, irreversible pan-HER inhibitor, demonstrates promising clinical activity in metastatic HER2 positive breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-19.

Sequential monitoring of Phase I dose expansion cohorts.

A relatively recent development in the design of Phase I dose-finding studies is the inclusion of expansion cohort(s), that is, the inclusion of several more patients at a level considered to be the maximum tolerated dose established at the conclusion of the 'pure' Phase I part. Little attention has been given to the additional statistical analysis, including design considerations, that we might wish to consider for this more involved design. For instance, how can we best make use of new information that may confirm or may tend to contradict the estimate of the maximum tolerated dose based on the dose escalation phase. Those patients included during the dose expansion phase may possess different eligibility criteria. During the expansion phase, we will also wish to have an eye on any evidence of efficacy, an aspect that clearly distinguishes such studies from the classical Phase I study. Here, we present a methodology that enables us to continue the monitoring of safety in the dose expansion cohort while simultaneously trying to assess efficacy and, in particular, which disease types may be the most promising to take forward for further study. The most elementary problem is where we only wish to take account of further toxicity information obtained during the dose expansion cohort, and where the initial design was model based or the standard 3+3. More complex set-ups also involve efficacy and the presence of subgroups. Copyright © 2016 John Wiley & Sons, Ltd.

Agents with vasodilator properties in acute heart failure.

Millions of patients worldwide are admitted for acute heart failure (AHF) each year and physicians caring for these patients are confronted with the short-term challenges of reducing symptoms while preventing end organ dysfunction without causing additional harm, and the intermediate-term challenges of improving clinical outcomes such as hospital readmission and survival. There are limited data demonstrating the efficacy of any currently available therapies for AHF to meet these goals. After diuretics, vasodilators are the most common intravenous therapy for AHF, but neither nitrates, nitroprusside, nor nesiritide have robust evidence supporting their ability to provide meaningful effects on clinical outcomes, except perhaps early symptom improvement. Recently, a number of novel agents with vasodilating properties have been developed for the treatment of AHF. These agents include serelaxin, natriuretic peptides (ularitide, cenderitide), β-arrestin-biased angiotensin II type 1 receptor ligands (TRV120027), nitroxyl donors (CXL-1020, CXL-1427), soluble guanylate cyclase modulators (cinaciguat, vericiguat), short-acting calcium channel blockers (clevidipine), and potassium channel activators (nicorandil). These development programmes range from the stage of early dose-finding studies (e.g. TRV120027, CXL-1427) to large, multicentre mortality trials (e.g. serelaxin, ularitide). There is an urgent need for agents with vasodilating properties that will improve both in-hospital and post-discharge clinical outcomes, and these novel approaches may provide opportunities to address this need.

Efficacy of α2-Agonists for Sedation in Pediatric Critical Care: A Systematic Review.

Children in PICUs normally require analgesics and sedatives to maintain comfort, safety, and cooperation with interventions. α2-agonists (clonidine and dexmedetomidine) have been described as adjunctive (or alternative) sedative agents alongside opioids and benzodiazepines. This systematic review aimed to determine whether α2-agonists were effective in maintaining patients at a target sedation score over time compared with a comparator group. We also aimed to determine whether concurrent use of α2-agonists provided opioid-sparing effects. A systematic search was performed using the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, CINAHL, and LILACS. We included randomized controlled trials of children in PICU treated with clonidine or dexmedetomidine for the indication of sedation. Two authors independently screened articles for inclusion. Six randomized controlled trials with sufficient data were identified and critically appraised. Three clonidine trials (two vs placebo and one vs midazolam) and three dexmedetomidine trials (two vs fentanyl, one vs midazolam) were included. Due to study heterogeneity it was not possible to pool studies. A narrative synthesis is provided. Reporting of study results using the outcome "time maintained at target sedation score' for clonidine or dexmedetomidine was poor. Only one trial compared clonidine with midazolam using a sedation score outcome. This study was underpowered to demonstrate equivalence to midazolam as a sedative. The adjunctive use of clonidine demonstrated significant decreases in opioid use in neonates but not in older groups. Clonidine dose was inconsistent between studies. Dexmedetomidine demonstrated an opioid-sparing effect in two small trials. Further studies, including dose-finding studies and studies with sedation score-based outcomes, are needed.

Variation of topical application to skin under good clinical practice (GCP): A “best performance” scenario

Introduction: Application of topical products by individuals is inherently variable and accurate dosing can be difficult to control. Variation of the dose used under optimal conditions in drug trials is unknown. Methods: This trial was part of a double-blind, randomized, placebo-controlled good clinical practice (GCP) study designed to investigate the local tolerability and safety on healthy skin of captopril 1% ointment versus a placebo ointment. Volunteers were instructed to apply an even layer of test ointment on a 51 cm2 test area on the arm twice daily over a 3-week period. At weekly follow-up visits, tubes were weighed and adherence to treatment checked. Results: Of the 37 recruited volunteers, 36 (17 women, 19 men) completed the study. Their mean age was 24 (18–35) years. A 13.6-fold difference in the applied amount was found ranging from 1.26 mg/cm2 to 17.19 mg/cm2 per application at week 4, with median 5.60 mg/cm2 applied versus 2 mg/cm2 (standard for good application) resulting in a 2.8-fold over-dosage. Conclusion: There was a major variation of test ointment application studied under GCP conditions with adherent participants. In dermatological practice, the variation is assumed to be even higher. This should be taken into account in clinical trials, especially dose-finding studies typically operating with 3–5-fold increments.

Lixisenatide: a once-daily glucagon-like peptide-1 receptor agonist

Lixisenatide (AVE0010) is a once-daily glucagon-like peptide-1 (GLP-1) receptor agonist used in the treatment of type 2 diabetes. Phase II dose-finding and pharmacodynamic studies identified the 20 µg once-daily dose as having the optimum combination of efficacy, convenience and tolerability. Lixisenatide was prospectively investigated in a series of 11 multinational, randomised, controlled phase III trials (GLP-1 agonist AVE0010 in patients with type 2 diabetes mellitus for Glycemic control and safety evaluation [Getgoal] programme) that included a direct head-to-head study with exenatide. The Getgoal programme established the efficacy and safety profile of lixisenatide 20 µg once daily across the spectrum of patients with type 2 diabetes, including patients not treated with anti-diabetic agents, those failing on oral agents and as an adjunct to basal insulin therapy. The main efficacy endpoints were met in all studies, with the baseline to endpoint reductions in HbA1c consistently ranging from 0.7% to 1.0%. In a head-to-head comparison with exenatide 10 µg twice daily, lixisenatide 20 µg once daily was non-inferior for HbA1c reduction, achieved with threefold fewer patients with symptomatic hypoglycemia events and better gastrointestinal tolerability. Three randomised trials of lixisenatide treatment added to basal insulin showed significantly improved glycemic control over placebo, with pronounced postprandial glucose reductions and good tolerability. Discontinuations for adverse events were consistently low, ranging from 2.5% to 10.4%. As the provision of individualized care moves center stage in diabetes management, lixisenatide with once-daily dosing, a single maintenance dose and fixed-dose pens offers an important treatment option for type 2 diabetes.

A New Approach to Dose Estimation in Drug Development Based on Maximization of Likelihood of Grouped Data

Identifying the ‘right’ dose is one of the most critical and difficult steps in the clinical development process of any medicinal drug. Its importance cannot be understated: selecting too high a dose can result in unacceptable toxicity and associated safety problems, while choosing too low a dose leads to smaller chances of showing sufficient efficacy in confirmatory trials, thus reducing the chance of approval for the drug. The optimal dose is the dose that gives the desired effect with minimum side effects. The dose of a drug is of course ‘optimal’ only for a given subject, but not necessarily for any other. In view of this the objective of a dose-finding trials is not to determine a single fixed dose for use in the early phases of clinical trials or in medical practice, but to determine an interval of doses within which there is a stated degree of confidence that the defined, acceptable therapeutic response and the frequency of adverse reactions will lie above and below, respectively, certain acceptable predetermined levels. If the subject samples used in the dose finding studies adequately represent the subject population for which the drug is intended, the interval of doses so defined can be applied to the subject population as a whole. In this paper, we propose the technique based on maximization of likelihood function in order to estimate the maximal tolerated dose (MTD) and minimal effective dose (MED) on the basis of l samples of subjects, which are grouped in a simplest way. The necessary and sufficient conditions for the existence and uniqueness of the maximum likelihood estimates are derived. The proposed approach to dose estimation in drug development is simple and suitable for medical practice. The numerical examples are given.

Topical Analgesics: Critical Issues Related to Formulation and Concentration

Topical analgesics are in need to be differentiated from transdermal formulations of analgesics. Topical analgesics are characterized by local analgesic effects in the absence of systemic effects, and do not require a transdermal delivery formulation. There are two key issues in the development of topical analgesics. 1. For optimal clinical effects specific characteristics for the vehicle (a cream base or gel base) are required, depending on the physicochemical characteristics of the pharmaceutical active ingredient in the carrier. 2. One cannot and should not skip well designed phase II dose-finding studies, and this unfortunately happens often, as we will discuss in this paper. In fact, we will demonstrate underdosing is one of the major hurdles to detect meaningful and statistically relevant clinical effects of topical analgesics. In the case of gels or creams containing ketamine, amitriptyline and baclofen, the dose-finding most probably needs to start at 10% for ketamine and amitriptyline and 2.5% for baclofen, while the doses tested were much lower: 4%, 2% and 1% respectively. Topical analgesics are promising inroads for the treatment of neuropathic pain, once sufficient attention is given to aspects such as formulation and concentration.

IV Administration of Erwinia-Derived Asparaginase in Pediatric Patients with Acute Lymphoblastic Leukemia: Single-Centre Case Series.

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