Prognostic but not predictive role of platelet-derived growth factor receptors in patients with recurrent glioblastoma.

Platelet-derived growth factor receptor (PDGFR) signaling has been implicated in the pathogenesis of glioblastomas and represents a target for the tyrosine kinase inhibitor imatinib. To examine the prognostic or predictive role of PDGFRs in recurrent glioblastomas, expression was examined in tumor samples of 101 patients of CSTI571BDE40, a randomized trial comparing hydroxyurea monotherapy and a combination of hydroxyurea and imatinib. Furthermore, PDGFRα phosphorylation was investigated using in situ proximity ligation assay. PDGFRα protein was expressed in 33% of tumors and was associated with male sex, young age, presence of R132H mutated isocitrate dehydrogenase 1 protein and short median survival (142 vs. 187 days, p = 0.028). Tumor PDGFRα phosphorylation was also associated with short survival (p = 0.030). The subset of patients with PDGFRα positive glioblastoma did not have longer survival on treatment with hydroxyurea and imatinib compared with hydroxyurea monotherapy. In conclusion, both PDGFRα protein expression and phosphorylation status had a prognostic role in recurrent glioblastomas but did not define a group that showed benefit from the combination therapy consisting of hydroxyurea and imatinib.

Temozolomide in malignant glioma.

Glioblastoma multiforme WHO grade IV (GBM) is the most aggressive malignant glioma and the most frequent primary tumor of the central nervous system. The median survival of newly diagnosed GBM patients was between 9 to 12 months prior to treatment with temozolomide being introduced. Primary resection that is as complete as possible is recommended for malignant glioma. Conventional fractionated irradiation 55 to 60 gy with concomitant temozolomide followed by standard temozolomide 6 cycles (5/28) (EORTC/NCIC-regime published by R Stupp in 2005) is the standard of care for newly diagnosed GBM after surgery, independent of the methylation status of the MGM-T gene promoter. Age is no contraindication for treatment with temozolomide, although comorbidity and performance status have to be considered. For temozolomide naive GBM and astrocytoma grade III patients with disease progression, temozolomide is still the treatment of choice outside of clinical studies. A general consensus regarding the schedule of choice has not yet been achieved; so far the 5 out of 28 days regimen (5/28) is the standard of care in most countries. Patients with disease progression after standard temozolomide (5/28) are candidates for clinical studies. Outside of clinical studies, dose-dense (7/7), prolonged (21/28), or metronomic (28/28) temozolomide, or alternatively a nitrosourea-based regimen can be an option. The excellent toxicity profile of temozolomide allows for various combinations with antitumor agents. None of these combinations, however, have been demonstrated to be statistically significantly superior compared to temozolomide alone. The role of lower dosed, dose-dense, or continuous regimen with or without drug combination and the role of temozolomide for newly diagnosed astrocytoma grade III and low grade glioma still has to be determined.

Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide.

A randomized, multicenter, open-label, phase 3 study of patients with progressive, recurrent glioblastoma multiforme (GBM) for whom front-line therapy had failed was conducted. This study was designed to determine whether combination therapy with imatinib and hydroxyurea (HU) has superior antitumor activity compared with HU monotherapy in the treatment of recurrent GBM. The target population consisted of patients with confirmed recurrent GBM and an Eastern Cooperative Oncology Group performance status of 0-2 who had completed previous treatment comprising surgical resection, irradiation therapy, and first-line chemotherapy (preferably temozolomide (TMZ) containing regimen) and who have progressed despite treatment. If first-line chemotherapy did not contain TMZ, a second completed chemotherapy was acceptable. The primary efficacy parameter was progression-free survival (PFS). The primary comparison of combination therapy versus monotherapy for PFS was not significant (adjusted P = 0.56). The hazard ratio (HR) (adjusted HR = 0.93) was not clinically relevant. The median PFS for the combination arm was low at 6 weeks and similar to the median PFS in the monotherapy arm (6 weeks). The 6-month PFS for the two treatment groups was very similar (5% in the combination arm vs. 7% in the monotherapy arm). No clinically meaningful differences were found between the two treatment arms, and the primary study end point was not met. Among the patients receiving imatinib, no adverse events were reported that were either previously unknown or unexpected as a consequence of the disease.

Influence of enzyme-inducing antiepileptic drugs on trough level of imatinib in glioblastoma patients.

BACKGROUND: Imatinib mesylate is used in combination with hydroxyurea (HU) in ongoing clinical phase II studies in recurrent glioblastoma multiforme (GBM). CYP3A4 enzyme-inducing antiepileptic drugs (EIAEDs) like carbamazepine, phenytoin, and oxcarbazepine--as well as non-EIAEDs like valproic acid, levetiracetam, and lamotrigine--are frequently used in patients with GBM. Since CYP3A4 is the major isozyme involved in the metabolism of imatinib, we investigated the influence of EIAEDs on imatinib pharmacokinetics (pk). METHODS: GBM patients received 600 mg imatinib p.o./o.d. in combination with 1.0 g HU p.o./o.d..together with either EIAEDs, non-EIAEDs, or no antiepileptic drug (non-AEDs) comedication. Trough plasma levels of imatinib and its active main metabolite N-desmethyl-imatinib (CGP74588) were determined biweekly in these patients, total 543 samples being collected from 224 patients (up to 6 times / patient). All three groups were compared to each other and with historical pharmacokinetic data obtained from patients with chronic myeloid leukemia (CML). RESULTS: Mean imatinib trough levels in patients not receiving AEDs ( 1404 ng/ml, CV 64%) and on non-EIAEDs (1374 ng/ml, CV 46%) were comparable with mean imatinib trough levels of the historical control group of CML patients (1400 ng/ml, CV 50%). Mean trough levels of imatinib were reduced up to 2.9-fold (477 ng/ml, CV 70%) in patients treated with EIAEDs. Only slight, but although significant differences were observed in the mean trough level of the metabolite CGP74588 between EIAED-, non-EIAED and no-AED patients, 240 ng/ml (CV 57%), 351 ng/ml (CV 34%) and 356 ng/ml (CV 52%), respectively. The corresponding mean level for CML patients was 300 ng/ml (CV 50%). CONCLUSION: Significant decreases of imatinib and CGP74588 trough levels were observed for patients receiving EIAEDs. The EIAED-induced reduction in trough imatinib levels can be avoided by switching to non-EIAEDs comedication or compensated by administering higher imatinib doses. In addition these data demonstrate that there is no significant difference in the pharmacokinetics of imatinib between patients with glioblastoma and CML.

Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme.

PURPOSE: We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS: Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS). RESULTS: Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea. CONCLUSION: Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.