Lyndon Kim

Phase II Trial of Single-Agent Bevacizumab Followed by Bevacizumab Plus Irinotecan at Tumor Progression in Recurrent Glioblastoma

PURPOSE To evaluate single-agent activity of bevacizumab in patients with recurrent glioblastoma. PATIENTS AND METHODS Patients with recurrent glioblastoma were treated with bevacizumab 10 mg/kg every 2 weeks. After tumor progression, patients were immediately treated with bevacizumab in combination with irinotecan 340 mg/m(2) or 125 mg/m(2) every 2 weeks, depending on use of enzyme-inducing antiepileptic drugs. Complete patient evaluations were repeated every 4 weeks. RESULTS Forty-eight heavily pretreated patients were accrued to this study. Thromboembolic events (12.5%), hypertension (12.5%), hypophosphatemia (6%), and thrombocytopenia (6%) were the most common drug-associated adverse events. Six patients (12.5%) were removed from study for drug-associated toxicity (five thromboembolic events, one bowel perforation). Thirty-four patients (71%) and 17 patients (35%) achieved radiographic response based on Levin and Macdonald criteria, respectively. Median progression-free survival (PFS) was 16 weeks (95% CI, 12 to 26 weeks). The 6-month PFS was 29% (95% CI, 18% to 48%). The 6-month overall survival was 57% (95% CI, 44% to 75%). Median overall survival was 31 weeks (95% CI, 21 to 54 weeks). Early magnetic resonance imaging response (first 96 hours and 4 weeks) was predictive of long-term PFS, with the Levin criteria being more predictive than Macdonald criteria. Of 19 patients treated with bevacizumab plus irinotecan at progression, there were no objective radiographic responses. Eighteen patients (95%) experienced disease progression by the second cycle, and the median PFS was 30 days. CONCLUSION We conclude that single-agent bevacizumab has significant biologic and antiglioma activity in patients with recurrent glioblastoma.

A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas.

Enzastaurin, a potent inhibitor of protein kinase C-beta, inhibits angiogenesis and has direct cytotoxic activity against glioma cells in preclinical studies. Patients with recurrent high-grade gliomas were stratified by histology and use of enzyme-inducing antiepileptic drugs (EIAEDs). Patients on EIAED were treated on the phase I dose-escalation portion of the trial with evaluation of serum pharmacokinetics as the primary endpoint. Patients not on EIAED were treated on the phase II portion of the trial with radiographic response and progression-free survival (PFS) as primary objectives. Patients in phase I received enzastaurin 525-900 mg/d. Phase II patients received 500 or 525 mg/d. One hundred and eighteen patients were accrued to this trial. Therapy was well tolerated with thrombosis, thrombocytopenia, hemorrhage, and elevated alanine aminotransferase as the most commonly observed drug-associated grade 3 or higher toxicities. Patients on EIAED had serum enzastaurin exposure levels approximately 80% lower than those not on EIAED. Dose escalations up to 900 mg/d did not substantially increase serum exposure levels and a maximally tolerated dose was never reached. Twenty-one of 84 evaluable patients (25%) experienced an objective radiographic response. The 6-month PFS was 7% for patients with glioblastoma and 16% for patients with anaplastic glioma. Phosphorylation of glycogen synthase kinase-3 in peripheral blood mononuclear cells was identified as a potential biomarker of drug activity. Enzastaurin has anti-glioma activity in patients with recurrent high-grade glioma, but does not appear to have enough single-agent activity to be useful as monotherapy.

Phase 2 Trial of Talampanel, a Glutamate Receptor Inhibitor, for Adults With Recurrent Malignant Gliomas

Glioma cells secrete glutamate and also express α‐amino‐3‐hydroxy‐5 methyl‐4‐isoxazolepropionate (AMPA) glutamate receptors, which contribute to the proliferation, migration, and neurotoxicity of malignant gliomas. Talampanel is an oral AMPA receptor inhibitor with excellent central nervous system penetration and good tolerability in clinical trials for epilepsy and other neurologic disorders.

A phase I trial of enzastaurin in patients with recurrent gliomas.

Purpose: Enzastaurin is a selective inhibitor of protein kinase C β. Prior phase I studies did not show increased drug exposures with escalating once daily administration. Limits from gastrointestinal absorption may be overcome by twice daily dosing, potentially improving antitumor effects. Experimental Design: We conducted a phase I dose escalation study in 26 patients with recurrent malignant glioma, stratified by use of enzyme-inducing antiepileptic drugs, to investigate whether divided twice daily dosing results in higher exposures compared with once daily dosing. Phosphorylated glycogen synthase 3 β was analyzed as a potential biomarker of enzastaurin activity. Results: Enzastaurin was poorly tolerated at all dose levels evaluated (500, 800, and 1,000 mg total daily), with thrombocytopenia and prolonged QTc as dose-limiting toxicities. The average drug concentration of enzastaurin under steady-state conditions was doubled by twice daily dosing compared with daily dosing [1.990; 90% confidence interval (CI), 1.450-2.730]. Additionally, geometric mean ratios doubled with 800 versus 500 mg dosing for both daily (2.687; 90% CI, 1.232-5.860) and twice daily regimens (1.852; 90% CI, 0.799-4.292). Two patients achieved long-term benefit (over 150 weeks progression free). Conclusions: Higher and more frequent dosing of enzastaurin resulted in improved drug exposure but with unacceptable toxicity at the doses tested. Phosphorylated glycogen synthase 3 β may be a useful biomarker of the biological activity of enzastaurin. Enzastaurin has activity in a subset of malignant glioma patients and warrants continued study in combination with other agents using a maximal once daily dose of 500 mg.

Cytotoxic chemotherapeutic management of newly diagnosed glioblastoma multiforme

The addition of temozolomide to radiation therapy is an option for patients with newly diagnosed glioblastoma (GBM) who are older than 70 years with a Karnofsky performance status (KPS) above 50. For patients 70 years or older with newly diagnosed GBM, temozolomide alone is a well tolerated alternative to radiation therapy and its benefit might be comparable to that obtained with radiation therapy alone. Radiation therapy followed by one of the nitrosoureas is recommended for those patients who cannot receive temozolomide.

A phase II trial of LY317615 in patients with recurrent high grade gliomas

1511 Background: Gliomas are amongst the most angiogenic of all solid tumors and experimental evidence suggests that angiogenesis inhibition can be an effective approach for inhibiting glioma growth in vivo. PKC-β2 is an important signaling molecule in the induction of, and signaling through the VEGF pathway, thus making PKC-β2 an attractive therapeutic target. LY317615 is a macrocytic bisindolylmaleimide which disrupts the intrinsic phosphotransferase activity of conventional and novel PKC isoforms via an interaction at the ATP binding site and displays selectivity in inhibiting the beta isoform. Preclinical studies demonstrate potent antiangiogenic activity of LY317615. A normal volunteer and a phase I trial in solid tumor patients (pts) demonstrate the drug is very well tolerated at doses that achieve a biologically active serum concentration. Based on the dependence of glioma growth on VEGF-mediated angiogenesis, and the promising preclinical and clinical data, we have initiated a phase II trial of LY317615 in pts with recurrent and progressive high grade gliomas following standard therapy. METHODS Treatment consists of oral LY317615 administered daily on an every 6 week cycle after which pts undergo a complete physical/neurological, biochemical and radiographic reevaluation. We stratified pts based on those taking enzyme inducing antiepileptic drugs (EIAED; Group B) and those not taking EIAED (Group A) and conducted pharmacokinetic studies. RESULTS To date 32 pts (17 pts in Group A and 15 pts in Group B) have been accrued to the trial and 28 pts were evaluable for response. Treatment has been well tolerated with only one possible case of drug-related toxicity > grade 1 (Grade 2 thrombocytopenia). 11 pts have received more than 1 cycle of treatment (6 pts in Group A and 5 pts in Group B) and several pts have been stable on treatment for greater then 3 months and a number of other pts continue treatment with LY317615. Objective radiographic responses have been seen in 5 pts. CONCLUSION LY317615 appears to have antitumoral activity against recurrent malignant gliomas. The trial continues to accrue additional pts and mature clinical and pharmacokinetic data will be presented at the meeting. [Table: see text].

Pulmonary metastases in patients with recurrent, treatment‐resistant meningioma

Meningioma is the most common extra‐axial primary intracranial tumor in adults that rarely metastasizes outside of the central nervous system (CNS). Among recognized sites of metastases, the lung is the most common, but the importance of lung metastases relative to prognosis is unknown. 111Indium (111In)‐octreotide scintigraphy (octreotide scanning) is a valuable imaging modality with which to evaluate intracranial meningiomas and their response to treatment with somatostatin analogues and has the potential to identify extracranial metastatic disease.

The potential role of magnetic resonance spectroscopy in image-guided radiotherapy.

Magnetic resonance spectroscopy (MRS) is a non-invasive technique to detect metabolites within the normal and tumoral tissues. The ability of MRS to diagnose areas of high metabolic activity linked to tumor cell proliferation is particularly useful for radiotherapy treatment planning because of better gross tumor volume (GTV) delineation. The GTV may be targeted with higher radiation dose, potentially improving local control without excessive irradiation to the normal adjacent tissues. Prostate cancer and glioblastoma multiforme (GBM) are two tumor models that are associated with a heterogeneous tumor distribution. Preliminary studies suggest that the integration of MRS into radiotherapy planning for these tumors is feasible and safe. Image-guided radiotherapy (IGRT) by virtue of daily tumor imaging and steep dose gradient may allow for tumor dose escalation with the simultaneous integrated boost technique (SIB) and potentially decrease the complications rates in patients with GBM and prostate cancers.

Chemoirradiation for Glioblastoma Multiforme: The National Cancer Institute Experience

Purpose Standard treatment for glioblastoma (GBM) is surgery followed by radiation (RT) and temozolomide (TMZ). While there is variability in survival based on several established prognostic factors, the prognostic utility of other factors such as tumor size and location are not well established. Experimental Design The charts of ninety two patients with GBM treated with RT at the National Cancer Institute (NCI) between 1998 and 2012 were retrospectively reviewed. Most patients received RT with concurrent and adjuvant TMZ. Topographic locations were classified using preoperative imaging. Gross tumor volumes were contoured using treatment planning systems utilizing both pre-operative and post-operative MR imaging. Results At a median follow-up of 18.7 months, the median overall survival (OS) and progression-free survival (PFS) for all patients was 17.9 and 7.6 months. Patients with the smallest tumors had a median OS of 52.3 months compared to 16.3 months among patients with the largest tumors, P = 0.006. The patients who received bevacizumab after recurrence had a median OS of 23.3 months, compared to 16.3 months in patients who did not receive it, P = 0.0284. The median PFS and OS in patients with periventricular tumors was 5.7 and 17.5 months, versus 8.9 and 23.3 months in patients with non-periventricular tumors, P = 0.005. Conclusions Survival in our cohort was comparable to the outcome of the defining EORTC-NCIC trial establishing the use of RT+TMZ. This study also identifies several potential prognostic factors that may be useful in stratifying patients.

Primary Brain Tumors: Characteristics, Practical Diagnostic and Treatment Approaches

Primary brain tumors are classified according to the tissue of phylogenic origin. Tumors arising from the neuroepithelium encompass a subgroup of neoplasms collectively referred to as “Gliomas”. Of this subgroup; astrocytomas are by far the most common. Astrocytomas are further subdivided by a four tier grading system based on The World Health Organization (WHO) classification where Grade I tumors represent the most benign and am enable to cure by surgical resection. Grade II astrocytomas are more infiltrative, but less aggressive than their more malignant counterpart Grades III and IV. However, due to their infiltrative nature grades II-IV are not cured by surgical extirpation. The most frequently used treatment regimen for malignant primary brain tumors include surgery for debulking or biopsy followed by postoperative radiation that is often combined with chemotherapy followed by 6 months of adjuvant chemotherapy. When paired with improved imaging and diagnostic modalities as well as new anti-angiogenic and molecular targeted therapies, the outcome for patients newly diagnosed with a malignant glioma has improved considerably. In addition, cancer stem cell research offers insight into the biology and pathogenesis of primary brain tumors. Currently, many studies implementing angiogenesis inhibitors and biologic modifiers offer encouragement for more patient participation in well-designed clinical trials for those patients who are eligible.