Paediatric Strategy Forum for medicinal product development for acute myeloid leukaemia in children and adolescents: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

Purpose: The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives.

ACCELERATE and European Medicines Agency Paediatric Strategy Forum for medicinal product development of checkpoint inhibitors for use in combination therapy in paediatric patients.

The third multistakeholder Paediatric Strategy Forum organised by ACCELERATE and the European Medicines Agency focused on immune checkpoint inhibitors for use in combination therapy in children and adolescents. As immune checkpoint inhibitors, both as monotherapy and in combinations have shown impressive success in some adult malignancies and early phase trials in children of single agent checkpoint inhibitors have now been completed, it seemed an appropriate time to consider opportunities for paediatric studies of checkpoint inhibitors used in combination. Among paediatric patients, early clinical studies of checkpoint inhibitors used as monotherapy have demonstrated a high rate of activity, including complete responses, in Hodgkin lymphoma and hypermutant paediatric tumours.

Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis.

Midostaurin was a prototype kinase inhibitor, originally developed as a protein kinase C inhibitor and subsequently as an angiogenesis inhibitor, based on its inhibition of vascular endothelial growth factor receptor. Despite promising preclinical data, early clinical trials in multiple diseases showed only modest efficacy. In 1996, the relatively frequent occurrence of fms-like tyrosine kinase 3 () activating mutations in acute myeloid leukemia (AML) was first recognized.

Implementation of mechanism of action biology-driven early drug development for children with cancer.

An urgent need remains for new paediatric oncology drugs to cure children who die from cancer and to reduce drug-related sequelae in survivors. In 2007, the European Paediatric Regulation came into law requiring industry to create paediatric drug (all types of medicinal products) development programmes alongside those for adults. Unfortunately, paediatric drug development is still largely centred on adult conditions and not a mechanism of action (MoA)-based model, even though this would be more logical for childhood tumours as these have much fewer non-synonymous coding mutations than adult malignancies.

Population pharmacokinetics of intravenous and oral panobinostat in patients with hematologic and solid tumors.

Purpose: The study aimed to characterize the population pharmacokinetics of panobinostat, a pan-deacetylase inhibitor that has demonstrated efficacy in combination with bortezomib and dexamethasone in patients with multiple myeloma.

Methods: A nonlinear mixed-effect model was used to fit plasma panobinostat concentration-time data collected from patients across 14 phase 1 and phase 2 trials following either oral or intravenous (IV) administration. The model was used to estimate bioavailabilities of the two oral formulations and the effects of demographic and clinical covariates on the central volume of distribution and clearance of panobinostat.

Target-driven exploratory study of imatinib mesylate in children with solid malignancies by the Innovative Therapies for Children with Cancer (ITCC) European Consortium.

Aim: To explore imatinib efficacy and pharmacokinetics in children and adolescents with refractory/relapsing solid tumours, expressing imatinib-sensitive receptor tyrosine kinases.

Methods: Exploratory study on imatinib in tumours expressing, at least, one of the receptors KIT or platelet-derived growth factor receptor (PDGFR). Standard radiological response evaluation, pharmacokinetics, gene mutations and positron emission tomography imaging were assessed.

A phase I and pharmacokinetic study of LAF389 administered to patients with advanced cancer.

LAF389 is a synthetic analogue of bengamide B, a natural product isolated from Jaspidae sponges. LAF389 has both antiproliferative and antiangiogenetic properties, and preclinical investigations showed a broad antitumour activity. This clinical trial aimed to determine the safety and pharmacokinetic profile of LAF389 administered as a slow intravenous injection for 3 consecutive days every 3 weeks in patients with advanced solid tumours.

Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08.

Purpose: Phase I: To determine the maximum tolerated doses, toxicities, and pharmacokinetics of imatinib mesylate (Gleevec) in patients with malignant gliomas taking enzyme-inducing antiepileptic drugs (EIAED) or not taking EIAED. Phase II: To determine the therapeutic efficacy of imatinib.

Experimental Design: Phase I component used an interpatient dose escalation scheme.

Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children's Oncology Group phase 1 study.

The purpose of this study was to determine dose-limiting toxicities and pharmacokinetics of imatinib in children with refractory or recurrent Philadelphia chromosome-positive (Ph(+)) leukemias. Oral imatinib was administered daily at dose levels ranging from 260 to 570 mg/m(2). Plasma pharmacokinetic studies were performed on days 1 and 8 of course 1.

Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects.

The study under discussion was a drug-drug interaction study in which the effect of ketoconazole, a potent CYP450 3A4 inhibitor, on the pharmacokinetics of Glivec (imatinib) was investigated. A total of 14 healthy subjects (13 male, 1 female) were enrolled in this study. Each subject received a single oral dose of imatinib 200 mg alone, and a single oral dose of imatinib 200 mg coadministered with a single oral dose of ketoconazole 400 mg according to a two-period crossover design.

Bioequivalence, safety, and tolerability of imatinib tablets compared with capsules.

Purpose: Imatinib (Glivec) has been established as a highly effective therapy for chronic myeloid leukemia and gastrointestinal tumors. The recommended daily dosage of 400-600 mg requires simultaneous intake of up to six of the current 100-mg capsules. Due to the need to swallow multiple capsules per dose, there is a potential negative impact on treatment adherence; therefore, a new imatinib 400-mg film-coated tablet has been developed.

Correlation of major cytogenetic response with a pharmacogenetic marker in chronic myeloid leukemia patients treated with imatinib (STI571).

Purpose: Imatinib, an inhibitor of the Bcr-Abl tyrosine kinase, is indicated for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia. We examined genotypes from patients enrolled in the International Randomized Study of IFN-alpha versus STI571 in an attempt to identify factors that associate with cytogenetic response.

Experimental Design: Sixty-eight polymorphic loci in 26 genes were examined in a subset of 187 patients (imatinib-treated patients, n = 113; IFN + 1-beta-D-arabinofuranosylcytosine-treated patients, n = 74).

Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients.

Purpose: To evaluate the basic pharmacokinetic (PK) characteristics of imatinib mesylate and assess the relationship between the PK and pharmacodynamic (PD) properties of the drug.

Patients And Methods: The PK and PD properties of imatinib were investigated during a phase I trial that included 64 adult patients with Philadelphia chromosome-positive leukemias. Patients received imatinib orally once or twice daily.

Clinical efficacy, tolerability, and safety of SAM486A, a novel polyamine biosynthesis inhibitor, in patients with relapsed or refractory non-Hodgkin's lymphoma: results from a phase II multicenter study.

Purpose: SAM486A is a new inhibitor of S-adenosyl-methionine-decarboxylase, a key enzyme for polyamine biosynthesis. It is more potent than the first generation S-adenosyl-methionine-decarboxylase inhibitor methylglyoxal bis-guanylhydrazone. This Phase IIa study reports the findings of SAM486A monotherapy in patients with refractory or relapsed non-Hodgkin's lymphoma (NHL).

Absolute bioavailability of imatinib (Glivec) orally versus intravenous infusion.

The purpose of this study was to investigate the absolute bioavailability of a single oral dose of imatinib (Glivec), 400 mg (capsules vs. oral solution), compared with imatinib, 100 mg (intravenous [i.v.

Pharmacogenomic analysis of cytogenetic response in chronic myeloid leukemia patients treated with imatinib.

Purpose: To better understand the molecular basis of cytogenetic response in chronic myeloid leukemia patients treated with imatinib, we studied gene expression profiles from a total of 100 patients from a large, multinational Phase III clinical trial (International Randomized Study of IFN-alpha versus STI571).

Experimental Design: Gene expression data for >12,000 genes were generated from whole blood samples collected at baseline (before imatinib treatment) using Affymetrix oligonucleotide microarrays. Cytogenetic response was determined based on the percentage of Ph(+) cells from bone marrow following a median of 13 months of treatment.

Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec, STI571) in healthy subjects.

Objective: This study was carried out to investigate the influence of CYP3A induction with rifampicin on imatinib (Gleevec) exposure.

Methods: The study employed a single center, single-sequence design. A group of 14 healthy male and female subjects received imatinib as a single 400 mg oral dose on two occasions: on study day 1 and on study day 15.

Imatinib: a targeted clinical drug development.

Imatinib (Gleevec) (formerly STI571) is an orally bioavailable rationally developed inhibitor of the tyrosine kinases Bcr-Abl, Kit, and platelet-derived growth factor receptor (PDGFR). In 4 years of clinical development, more than 12,000 patients have been treated in the clinical development program. Imatinib was first shown to be highly effective in the treatment of all stages of chronic myelogenous leukemia (CML).

Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia.

Background: Imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase, produces high response rates in patients with chronic-phase chronic myeloid leukemia (CML) who have had no response to interferon alfa. We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML.

Methods: We randomly assigned 1106 patients to receive imatinib (553 patients) or interferon alfa plus low-dose cytarabine (553 patients).

Quantitative monitoring of BCR/ABL transcript during STI-571 therapy.

PCR for the BCR/ABL fusion transcript provides a highly sensitive and specific method for detecting minimal residual disease in patients with chronic myeloid leukemia (CML). We sought to determine if quantitative PCR measurement of peripheral blood BCR/ABL transcript can be used to monitor response in CML patients with clinically evident disease while receiving the protein tyrosine kinase inhibitor STI-571. Serial bone marrow cytogenetics and peripheral blood BCR/ABL mRNA levels were measured in 17 patients [9 with chronic phase (CP) and 8 with accelerated phase or blast crisis (AP/BC)] during 1 year of treatment.

Imatinib: the first 3 years.

Imatinib (Glivec, formerly STI571, Novartis Pharma AG, Basel, Switzerland) potently inhibits several protein tyrosine kinases, including Bcr-Abl, Kit, and the platelet-derived growth factor receptor. Phase I and II studies demonstrated that orally administered imatinib is highly effective and well tolerated in all phases of chronic myeloid leukemia (CML) at doses ranging from 400 to 600 mg. Importantly, preliminary evidence suggests that patients with advanced CML achieving hematologic or major cytogenetic responses to imatinib may have longer survival than those without such responses, whereas chronic phase patients who respond to treatment may have longer times to disease progression.

A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias.

The translocation (9;22) gives rise to the p190(Bcr-Abl) and p210(Bcr-Abl) tyrosine kinase proteins, considered sufficient for leukemic transformation. Philadelphia-positive (Ph(+)) acute leukemia patients failing to respond to initial induction therapy have a poor prognosis with few effective treatment options. Imatinib is an orally administered, potent inhibitor of the Bcr-Abl tyrosine kinase.

Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.

Background: Constitutive activation of KIT receptor tyrosine kinase is critical in the pathogenesis of gastrointestinal stromal tumors. Imatinib mesylate, a selective tyrosine kinase inhibitor, has been shown in preclinical models and preliminary clinical studies to have activity against such tumors.

Methods: We conducted an open-label, randomized, multicenter trial to evaluate the activity of imatinib in patients with advanced gastrointestinal stromal tumor.

The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML.

In chronic myelogenous leukemia (CML), the development of chromosomal abnormalities in addition to the Philadelphia chromosome (clonal evolution) is considered by many to be a feature of accelerated phase (AP). Imatinib mesylate (STI571), a selective inhibitor of the Bcr-Abl tyrosine kinase, has significant activity in AP CML. As clonal evolution could allow Bcr-Abl independent proliferation, we analyzed its impact on the outcome of 71 AP patients treated with 600 mg of imatinib mesylate.

Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug.

In the early 1980s, it became apparent that the work of pioneers such as Robert Weinberg, Mariano Barbacid and many others in identifying cancer-causing genes in humans was opening the door to a new era in anticancer research. Motivated by this, and by dissatisfaction with the limited efficacy and tolerability of available anticancer modalities, a drug discovery programme was initiated with the aim of rationally developing targeted anticancer therapies. Here, we describe how this programme led to the discovery and continuing development of Glivec (Gleevec in the United States), the first selective tyrosine-kinase inhibitor to be approved for the treatment of a cancer.