Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy.

Targeting the stromal cell-derived factor 1α (SDF-1α)/C-X-C chemokine receptor type 4 (CXCR4) axis has been shown to be a promising therapeutic approach to overcome chemoresistance in acute myeloid leukemia (AML). We investigated the antileukemia efficacy of a novel peptidic CXCR4 antagonist, LY2510924, in preclinical models of AML. LY2510924 rapidly and durably blocked surface CXCR4 and inhibited stromal cell-derived factor 1 (SDF-1)α-induced chemotaxis and prosurvival signals of AML cells at nanomolar concentrations more effectively than the small-molecule CXCR4 antagonist AMD3100. In vitro, LY2510924 chiefly inhibited the proliferation of AML cells with little induction of cell death and reduced protection against chemotherapy by stromal cells. In mice with established AML, LY2510924 caused initial mobilization of leukemic cells into the circulation followed by reduction in total tumor burden. LY2510924 had antileukemia effects as monotherapy as well as in combination with chemotherapy. Gene expression profiling of AML cells isolated from LY2510924-treated mice demonstrated changes consistent with loss of SDF-1α/CXCR4 signaling and suggested reduced proliferation and induction of differentiation, which was proved by showing the attenuation of multiple prosurvival pathways such as PI3K/AKT, MAPK, and ß-catenin and myeloid differentiation in vivo. Effective disruption of the SDF-1α/CXCR4 axis by LY2510924 may translate into effective antileukemia therapy in future clinical applications.

Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma.

This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.

Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma.

PURPOSE: This phase III open-label study compared the efficacy and safety of enzastaurin versus lomustine in patients with recurrent glioblastoma (WHO grade 4). PATIENTS AND METHODS: Patients were randomly assigned 2:1 to receive 6-week cycles of enzastaurin 500 mg/d (1,125-mg loading dose, day 1) or lomustine (100 to 130 mg/m(2), day 1). Assuming a 45% improvement in progression-free survival (PFS), 397 patients were required to provide 80% power to achieve statistical significance at a one-sided level of .025. RESULTS: Enrollment was terminated at 266 patients (enzastaurin, n = 174; lomustine, n = 92) after a planned interim analysis for futility. Patient characteristics were balanced between arms. Median PFS (1.5 v 1.6 months; hazard ratio [HR] = 1.28; 95% CI, 0.97 to 1.70), overall survival (6.6 v 7.1 months; HR = 1.20; 95% CI, 0.88 to 1.65), and 6-month PFS rate (P = .13) did not differ significantly between enzastaurin and lomustine, respectively. Stable disease occurred in 38.5% and 35.9% of patients and objective response occurred in 2.9% and 4.3% of patients, respectively. Time to deterioration of physical and functional well-being and symptoms did not differ between arms (HR = 1.12; P = .54). Four patients discontinued enzastaurin because of drug-related serious adverse events (AEs). Eleven patients treated with enzastaurin died on study (four because of AEs; one was drug-related). All four deaths that occurred in patients receiving lomustine were disease-related. Grade 3 to 4 hematologic toxicities were significantly higher with lomustine (46 events) than with enzastaurin (one event; P < or = .001). CONCLUSION: Enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma.

Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: a phase I study.

We conducted a phase I study to determine the safety and recommended phase II dose of enzastaurin (oral inhibitor of the protein kinase C-beta [PKCbeta] and the PI3K/AKT pathways) when given in combination with radiation therapy (RT) plus temozolomide to patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Patients with Karnofsky performance status > or =60 and no enzyme-inducing anti-epileptic drugs received RT (60 Gy) over 6 weeks, concurrently with temozolomide (75 mg/m(2) daily) followed by adjuvant temozolomide (200 mg/m(2)) for 5 days/28-d cycle. Enzastaurin was given once daily during RT and adjuvantly with temozolomide; the starting dose of 250 mg/d was escalated to 500 mg/d if < or =1/6 patients had dose-limiting toxicity (DLT) during RT and the first adjuvant cycle. Patients continued treatment for 12 adjuvant cycles unless disease progression or unacceptable toxicity occurred. Twelve patients enrolled. There was no DLT in the first 6 patients treated with 250 mg enzastaurin. At 500 mg, 2 of 6 patients experienced a DLT (1 Grade 4 and 1 Grade 3 thrombocytopenia). The patient with Grade 3 DLT recovered to Grade <1 within 28 days and adjuvant temozolomide and enzastaurin was reinitiated with dose reductions. The other patient recovered to Grade <1 toxicity after 28 days and did not restart treatment. Enzastaurin 250 mg/d given concomitantly with RT and temozolomide and adjuvantly with temozolomide was well tolerated and is the recommended phase II dose. The proceeding phase II trial has finished accrual and results will be reported in 2009.

Utilization and cost of health care services associated with primary malignant brain tumors in the United States.

OBJECTIVES: To evaluate the economic burden of primary malignant brain tumors in a commercially insured population in the United States, and to identify the primary drivers of health care resource use and cost. PATIENTS AND METHODS: A retrospective cohort analysis was performed using a 1998-2000 database containing inpatient, outpatient, and pharmacy claims for employees, their dependents, and early retirees of over 50 large US employers with wide geographic distribution. Patients were followed from first brain tumor diagnosis until death, termination of health benefits coverage, or study end. Controls without any cancer diagnosis were matched at a 3:1 ratio by demographic characteristics and length of follow-up. RESULTS: Patients with malignant brain tumors (n = 653) had significantly greater health service utilization and costs for hospitalizations, emergency room visits, outpatient office visits, laboratory tests, radiology services, and pharmacy-dispensed drugs (all P < 0.05) than did controls (n = 1959). Regression-adjusted mean monthly costs were $6364 for brain tumor patients, compared with $277 for controls (P < 0.0001). The primary cost driver was inpatient care ($4502 per month). Total costs during the study period were $49,242 for those with brain tumors and $2790 for controls (P < 0.0001). CONCLUSION: Patients with malignant brain tumors accrued health care costs that were 20 times greater than demographically matched control subjects without cancer. The costs for inpatient services were the primary drivers of total health resource use. Despite their low incidence, primary malignant brain tumors produce a substantial burden on the US health care system. There is a marked need for improved and new approaches to treatment to reduce the resource use and to offset health care costs associated with this disease.

Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer.

PURPOSE: This phase I study was conducted to determine the recommended dose of enzastaurin, an oral protein kinase C beta (PKCbeta) inhibitor, for phase II trials. Secondary objectives were maximum-tolerated dose (MTD), pharmacokinetics (PK), toxicity, and response. PATIENTS AND METHODS: Patients at least 18 years of age with advanced cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1 lower received enzastaurin orally once daily at a starting dose of 20 mg. Dose escalation proceeded using a modified Simon design. RESULTS: All 47 patients enrolled (mean age, 58 years) received at least one dose of enzastaurin, with a median of two cycles (range, one to 17 cycles). Prevalent malignancies were lung (n = 10) and head and neck cancers (n = 9). Although no MTD was identified up to 700 mg/d, 525 mg was chosen as the recommended dose, and 12 additional patients were accrued at that level. Three dose-limiting toxicities (QTc changes) occurred: one at the 700-mg dose (patient discontinued), and two in the expansion cohort at the 525-mg dose. Total analytes (enzastaurin and its metabolites) exposure increased with increasing doses up to 240 mg, and appeared to plateau at 525 and 700 mg. Grade 1 chromaturia, fatigue, and other GI toxicities were the most common, while no clinically significant grade 3/4 toxicities occurred. Two deaths, unrelated to enzastaurin, occurred. Twenty-one patients (45%) achieved stable disease (SD) for two to 16 cycles. CONCLUSION: On the basis of plasma exposures and safety data, enzastaurin 525 mg once daily is the recommended phase II dose. Enzastaurin is well tolerated up to 700 mg/d. Evidence of early activity was seen with significant stable disease.