Renaud Capdeville

Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia

BACKGROUND BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML. METHODS We conducted a phase 1, dose-escalating trial of STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase. STI571 was administered orally to 83 patients with CML in the chronic phase in whom treatment with interferon alfa had failed. Patients were successively assigned to 1 of 14 doses ranging from 25 to 1000 mg per day. RESULTS Adverse effects of STI571 were minimal; the most common were nausea, myalgias, edema, and diarrhea. A maximal tolerated dose was not identified. Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy. Of the 54 patients treated with doses of 300 mg or more, cytogenetic responses occurred in 29, including 17 (31 percent of the 54 patients who received this dose) with major responses (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome); 7 of these patients had complete cytogenetic remissions. CONCLUSIONS STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed. Our results provide evidence of the essential role of BCR-ABL tyrosine kinase activity in CML and demonstrate the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer.

Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome

BACKGROUND BCR-ABL, a constitutively activated tyrosine kinase, is the product of the Philadelphia chromosome. This enzyme is present in virtually all cases of chronic myeloid leukemia (CML) throughout the course of the disease, and in 20 percent of cases of acute lymphoblastic leukemia (ALL). On the basis of the substantial activity of the inhibitor in patients in the chronic phase, we evaluated STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase, in patients who had CML in blast crisis and in patients with ALL who had the Ph chromosome. METHODS In this dose-escalating pilot study, 58 patients were treated with STI571; 38 patients had a myeloid blast crisis and 20 had ALL or a lymphoid blast crisis. Treatment was given orally at daily doses ranging from 300 to 1000 mg. RESULTS Responses occurred in 21 of 38 patients (55 percent) with a myeloid-blast-crisis phenotype; 4 of these 21 patients had a complete hematologic response. Of 20 patients with a lymphoid blast crisis or ALL, 14 (70 percent) had a response, including 4 who had complete responses. Seven patients with a myeloid blast crisis continue to receive treatment and remain in remission from 101 to 349 days after starting the treatment. All but one patient with a lymphoid blast crisis or ALL has relapsed. The most frequent adverse effects were nausea, vomiting, edema, thrombocytopenia, and neutropenia. CONCLUSIONS The BCR-ABL tyrosine kinase inhibitor STI571 is well tolerated and has substantial activity in the blast crises of CML and in Ph-positive ALL.

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.

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. PK parameters of imatinib, derived from the plasma concentration-time curves, were determined. PD response, defined as the WBC after 1 month of treatment with imatinib, was used to develop an efficacy model. A maximum inhibition-effect model was used to describe the relationship between reduction in WBC and drug exposure parameters. RESULTS Imatinib exposure was dose proportional after oral administration for the dose range of 25 to 1,000 mg. There was a 1.5- to three-fold drug accumulation after repeated once-daily dosing. Mean plasma trough concentration was 0.57 microg/mL (approximately 1 micromol/L) 24 hours after administration of 350 mg of imatinib at steady-state, which exceeds the 50% inhibitory concentration required to inhibit proliferation of Bcr-Abl-positive leukemic cells. Analysis of PK/PD relationships indicates that the initial hematologic response depends on the administered dose for patients with chronic myeloid leukemia. CONCLUSION Drug exposure (area under the concentration-time curve) is dose proportional for the dose range of 25 to 1,000 mg, and there is a 1.5- to three-fold drug accumulation at steady-state after once-daily dosing. Analysis of the relationship between PD (WBC reduction) and PK parameters at steady-state indicates that a dose of 400 mg or greater is required for maximal PD effect.

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. End points of the phase II component were 6-month progression-free survival and response. Results: Fifty patients enrolled in the phase I component (27 EIAED and 23 non-EIAED). The maximum tolerated dose for non-EIAED patients was 800 mg/d. Dose-limiting toxicities were neutropenia, rash, and elevated alanine aminotransferase. EIAED patients received up to 1,200 mg/d imatinib without developing dose-limiting toxicity. Plasma exposure of imatinib was reduced by ∼68% in EIAED patients compared with non-EIAED patients. Fifty-five non-EIAED patients (34 glioblastoma multiforme and 21 anaplastic glioma) enrolled in the phase II component. Patients initially received 800 mg/d imatinib; 15 anaplastic glioma patients received 600 mg/d after hemorrhages were observed. There were 2 partial response and 6 stable disease among glioblastoma multiforme patients and 0 partial response and 5 stable disease among anaplastic glioma patients. Six-month progression-free survival was 3% for glioblastoma multiforme and 10% for anaplastic glioma patients. Five phase II patients developed intratumoral hemorrhages. Conclusions: Single-agent imatinib has minimal activity in malignant gliomas. CYP3A4 inducers, such as EIAEDs, substantially decreased plasma exposure of imatinib and should be avoided in patients receiving imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. The evaluation of the activity of combination regimens incorporating imatinib is under way in phase II trials.

Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia.

The inhibition by imatinib of the cytochrome P450 3A4 isoenzyme may reduce the CYP3A4-mediated metabolic clearance of clinically important coadministered drugs. The main purpose of this study was to evaluate the effect of the coadministration of imatinib on the pharmacokinetics of simvastatin, a probe CYP3A4 substrate. In total, 20 patients with chronic myeloid leukaemia received an oral dose of 40 mg of simvastatin on study day 1. On study days 2–7, each patient received 400 mg of imatinib once daily orally and on study day 8, 400 mg imatinib together with 40 mg of simvastatin was given. Blood levels of simvastatin were measured predose and for 24 h postdose on study days 1 and 8. Two additional blood samples were taken for imatinib pharmacokinetic (PK) assessment on day 8 before, and 24 h after, imatinib administration. Imatinib increased the mean maximum concentration (Cmax) value of simvastatin two-fold and the area under concentration–time curve (AUC (0–inf)) value 3.5-fold (P<0.001) compared with simvastatin alone. There was a statistically significant decrease in total-body clearance of drug from the plasma (CL/F) with a mean reduction of 70% for simvastatin (P<0.001): the mean half-life of simvastatin was prolonged from 1.4–2.7 h when given together with imatinib. No changes in imatinib PK parameters were found when given concomitantly with simvastatin. In conclusion, the coadministration of imatinib at steady state with 40 mg simvastatin increases the exposure (Cmax and AUCs) of simvastatin significantly (P<0.001) by two-three-fold. Caution is therefore required when administering imatinib with CYP3A4 substrates with a narrow therapeutic window. The coadministration of simvastatin with imatinib (400 mg) was well tolerated and no major safety findings were reported in this study.

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.] infusion), in healthy subjects. Twelve subjects received a single treatment in each treatment period: a 400‐mg oral dose of imatinib in capsule form or as a solution or a 100‐mg i.v. infusion of imatinib. Plasma imatinib concentrations were measured following each treatment; pharmacokinetic parameters and absolute bioavailability were determined. Absolute bioavailability values (compared with i.v. infusion) for the imatinib capsule and oral solution were 98.3% and 97.2%, respectively. Both the rate and extent of imatinib absorption, as measured by Cmax, partial AUC, and total AUC, were similar for the oral solution and the imatinib capsule intended for the market. The 400‐mg oral dose of imatinib, as a capsule or a solution, was completely absorbed and was almost completely bioavailable (> 97%).

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-α 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. Results: A genomic profile of response was developed using a subset of individuals that exhibited the greatest divergence in cytogenetic response; those with complete response (0% Ph+ cells; n = 53) and those with minimal or no response (>65% Ph+ cells; n = 13). A total of 55 genes was identified that were differentially expressed between these two groups. Using a “leave-one-out” strategy, we identified the optimum 31 genes from this list to use as our genomic profile of response. Using this genomic profile, we were able to distinguish between individuals that achieved major cytogenetic response (0–35% Ph+ cells) and those that did not, with a sensitivity of 93.4% (71 of 76 patients), specificity of 58.3% (14 of 24 patients), positive predictive value of 87.7%, and negative predictive value of 73.7%. Conclusions: Interestingly, many of the genes identified appear to be strongly related to reported mechanisms of BCR-ABL transformation and warrant additional research as potential drug targets. The validity and clinical implications of these results should be explored in future studies.

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. Ongoing and planned studies are focused on optimizing CML treatment with imatinib, evaluating imatinib-based combination therapy, defining additional therapeutic targets and exploring the use of imatinib in children. In particular, results from several combination phase I studies are expected shortly, including an evaluation of combination imatinib-interferon-alpha therapy and imatinib-cytarabine in chronic phase CML, and a phase I study of single-agent imatinib in children with Philadelphia chromosome-positive leukemia is ongoing. A large phase III trial comparing imatinib with standard inferferon alfa plus cytarabine in first-line CML treatment is also ongoing.

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. RESULTS Thirty-six patients (median age: 13.7 years) with brain (12), mesenchymal/bone (14) or other solid tumours, received imatinib 340 mg/m(2)/d over a total of 255 months. Fifteen tumours expressed KIT in 30% cells, 19 expressed PDGFRA and 25 expressed PDGFRB. Twenty patients experienced grades 1-2 treatment-related toxicities. Ten patients achieved stable disease; one chordoma had metabolic response. Pharmacokinetic data showed high inter-patient variability (variation coefficient: 44% and 53% for plasma imatinib and CGP 74588 AUCs, respectively). CONCLUSIONS Imatinib was tolerated well, but failed to show efficacy according to standard criteria in paediatric malignancies expressing KIT or PDGFR.