A phase I trial of lenalidomide in patients with recurrent primary central nervous system tumors.
ABSTRACT Inhibition of angiogenesis represents a promising new therapeutic strategy for treating primary malignant brain tumors. Lenalidomide, a potent analogue of the antiangiogenic agent thalidomide, has shown significant activity in several hematologic malignancies, and therefore we chose to explore its tolerability and activity in patients with primary central nervous system tumors.
A phase I interpatient dose escalation trial of lenalidomide in patients with recurrent primary central nervous system tumors was conducted.
Thirty-six patients were accrued to the study, of which 28 were evaluable for toxicity, the primary end point of the trial. We show that lenalidomide can be given safely up to doses of 20 mg/m(2), with the only toxicity being a probable increased risk of thromboembolic disease. Pharmacokinetic studies reveal good bioavailability, linear kinetics, and no effects of enzyme-inducing antiepileptic drugs on the metabolism of lenalidomide. No objective radiographic responses were seen in any of the treated patients. In the group of 24 patients with recurrent glioblastoma, the median time to tumor progression was <2 months and only 12.5% of patients were progression-free at 6 months.
Lenalidomide is well tolerated in patients with recurrent glioma in doses up to 20 mg/m(2). Treatment may be associated with an increased risk of thromboembolic disease. Preliminary data suggest that single agent activity may be limited in patients with recurrent glioblastoma at the doses evaluated although larger studies will be needed to confirm these observations.
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ABSTRACT: Glioblastomas are amongst the most highly vascularised tumours, and the pursuit of anti-angiogenic approaches such as bevacizumab has provided short-term benefits. The purpose of this study was to determine whether the vascular-disrupting agent, dimethylxanthenone-4-acetic acid (DMXAA), could provide longer-lasting therapeutic benefits in a murine model of glioblastoma. Luciferase-expressing murine GL261 glioma cells were inoculated subcutaneously or intracranially into C57Bl/6 mice. Mice with tumours were administered DMXAA, and tumours measured using callipers or by optical imager. Concentrations of DMXAA in plasma and brain were measured by LC-MS/MS. DMXAA (25 mg/kg) caused widespread necrosis at 24 h, a 9-day growth delay and complete regressions in 50 % of the mice with subcutaneous GL261 tumours. Co-administered lenalidomide (100 mg/kg) increased the growth delay to 20 days and the percentage of cures to 83 %. The same dose of DMXAA with or without lenalidomide had minimal effects on intracranial GL261 tumours. Concentrations of DMXAA extracted from brain tissue were approximately 25-fold lower than those measured in plasma 15 min to 4 h after DMXAA administration. The presence of intracranial GL261 tumours did not alter the concentrations of DMXAA entering the brain. DMXAA does not appear to cross the blood-brain barrier efficiently. Thus, whilst excellent activity was obtained against subcutaneous GL261 gliomas, minimal effects were observed against intracranial GL261 tumours. These results emphasise the need to use appropriate orthotopic models for the evaluation of new approaches for the treatment of brain cancers.Cancer Chemotherapy and Pharmacology 01/2014; · 2.80 Impact Factor
Article: Targeted therapy in gliomas.[Show abstract] [Hide abstract]
ABSTRACT: The survival outcome of patients with malignant gliomas is still poor, despite advances in surgical techniques, radiation therapy and the development of novel chemotherapeutic agents. The heterogeneity of molecular alterations in signaling pathways involved in the pathogenesis of these tumors contributes significantly to their resistance to treatment. Several molecular targets for therapy have been discovered over the last several years. Therapeutic agents targeting these signaling pathways may provide more effective treatments and may improve survival. This review summarizes the important molecular therapeutic targets and the outcome of published clinical trials involving targeted therapeutic agents in glioma patients.Current Oncology Reports 04/2014; 16(4):379. · 3.33 Impact Factor
Article: Primary testicular lymphoma.[Show abstract] [Hide abstract]
ABSTRACT: Primary testicular lymphoma (PTL) is a rare, clinically aggressive form of extranodal lymphoma. The vast majority of cases are histologically diffuse large B-cell lymphoma, but rarer subtypes are clinically important and must be recognised. In this review we discuss the incidence, clinical presentation and prognostic factors of PTL and present a summary of the recent advances in our understanding of the pathophysiology which may account for the characteristic clinical features. Although outcomes for patients with PTL have historically been poor, significant gains have been made with the successive addition of radiotherapy, full-course anthracycline-based chemotherapy, rituximab and CNS-directed prophylaxis. We describe the larger retrospective series, prospective clinical trials and critically examine the role of radiotherapy. Although 3-weekly RCHOP with intrathecal methotrexate and locoregional RT is the current international standard of care, a substantial minority of patients progress, representing an unmet medical need. Finally, we discuss new treatment approaches and recent discoveries which may translate into improved outcomes for patients with PTL.Blood 11/2013; · 9.06 Impact Factor