Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients with prior antiangiogenic therapy.

Background: Cabozantinib is a potent, multitarget inhibitor of MET and vascular endothelial growth factor receptor 2 (VEGFR2). This open-label, phase II trial evaluated cabozantinib in patients with recurrent or progressive glioblastoma (GBM). Methods: Patients were initially enrolled to a starting cabozantinib dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of safety concerns. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate, assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, glucocorticoid use, and safety. Results: Among 222 patients enrolled, 70 had received prior antiangiogenic therapy. Herein, we report results in this subset of 70 patients. The objective response rate was 4.3%, and the median duration of response was 4.2 months. The proportion of patients alive and progression free at 6 months was 8.5%. Median progression-free survival was 2.3 months, and median overall survival was 4.6 months. The most common adverse events reported in all patients, regardless of dose group, included fatigue (74.3%), diarrhea (47.1%), increased alanine aminotransferase (37.1%), headache (35.7%), hypertension (35.7%), and nausea (35.7%); overall, 34 (48.6%) patients experienced adverse events that resulted in dose reductions. Conclusions: Cabozantinib treatment appeared to have modest clinical activity with a 4.3% response rate in patients who had received prior antiangiogenic therapy for GBM. Clinical Trials Registration Number: NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288).

Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients naive to antiangiogenic therapy.

Background: Cabozantinib is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET that has demonstrated clinical activity in advanced solid tumors. This open-label, phase II trial evaluated cabozantinib in patients with recurrent or refractory glioblastoma (GBM). Methods: Patients were initially enrolled at a starting dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of toxicity. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, and safety. Results: Among 152 patients naive to prior antiangiogenic therapy, the objective response rate was 17.6% and 14.5% in the 140 mg/day and 100 mg/day groups, respectively, which did not meet the predefined statistical target for success. The proportions of patients alive and progression free at 6 months were 22.3% and 27.8%, respectively. Median progression-free survival was 3.7 months in both groups, and median overall survival was 7.7 months and 10.4 months, respectively. The incidence of grade 3/4 adverse events (AEs) was 79.4% and 84.7% in the 140 mg/day and 100 mg/day groups, respectively, and dose reductions due to AEs were experienced by 61.8% and 72.0%, respectively. Common grade 3/4 AEs included fatigue, diarrhea, and palmar-plantar erythrodysesthesia syndrome. Conclusions: Cabozantinib showed evidence of clinical activity in patients with recurrent GBM naive to antiangiogenic therapy, although the predefined statistical target for success was not met. At the starting doses assessed, AEs were frequently managed with dose reductions. Clinical Trials Registration Number: NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288).

Volumetric response quantified using T1 subtraction predicts long-term survival benefit from cabozantinib monotherapy in recurrent glioblastoma.

Background: To overcome challenges with traditional response assessment in anti-angiogenic agents, the current study uses T1 subtraction maps to quantify volumetric radiographic response in monotherapy with cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and AXL, in an open-label, phase II trial in patients with recurrent glioblastoma (GBM) (NCT00704288). Methods: A total of 108 patients with adequate imaging data and confirmed recurrent GBM were included in this retrospective study from a phase II multicenter trial of cabozantinib monotherapy (XL184-201) at either 100 mg (N = 87) or 140 mg (N = 21) per day. Contrast enhanced T1-weighted digital subtraction maps were used to define volume of contrast-enhancing tumor at baseline and subsequent follow-up time points. Volumetric radiographic response (>65% reduction in contrast-enhancing tumor volume from pretreatment baseline tumor volume sustained for more than 4 wk) was tested as an independent predictor of overall survival (OS). Results: Volumetric response rate for all therapeutic doses was 38.9% (41.4% and 28.6% for 100 mg and 140 mg doses, respectively). A log-linear association between baseline tumor volume and OS (P = 0.0006) and a linear correlation between initial change in tumor volume and OS (P = 0.0256) were observed. A significant difference in OS was observed between responders (median OS = 20.6 mo) and nonresponders (median OS = 8.0 mo) (hazard ratio [HR] = 0.3050, P < 0.0001). Multivariable analyses showed that continuous measures of baseline tumor volume (HR = 1.0233, P < 0.0001) and volumetric response (HR = 0.2240, P < 0.0001) were independent predictors of OS. Conclusions: T1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit.

A phase 2 randomised discontinuation trial of cabozantinib in patients with ovarian carcinoma.

BACKGROUND: Cabozantinib (XL184), an orally bioavailable inhibitor of vascular endothelial growth factor receptor 2 and MET, was assessed in a cohort of ovarian carcinoma patients as part of a phase 2 randomised discontinuation trial (RDT) with cohorts from nine different tumour types. PATIENTS AND METHODS: Patients received 100-mg cabozantinib daily. Those with stable disease (SD) per Response Evaluation Criteria in Solid Tumors at week 12 were randomised to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) after random assignment. RESULTS: Seventy patients with ovarian carcinoma, 50% of whom were platinum refractory/resistant, were enrolled in this RDT. Median PFS from day 1 was 5.5 months for all patients. The ORR at week 12 was 21%; one patient achieved a complete response (CR), and 14 patients (20%) achieved a confirmed partial response (PR). The overall disease control rate (CR + PR + SD) at week 12 was 50%. Throughout the study, 70% of the patients with ≥1 postbaseline scan had tumour regression, and randomisation was discontinued early. For patients with SD randomised to cabozantinib, PFS was 5.9 months after randomisation. The most common grade 3/4 adverse events were diarrhoea (14%), palmar-plantar erythrodysesthesia syndrome (6%), asthenia (6%), hypertension (6%) and neutropenia (6%). Dose reductions were required in 37% of the patients during the first 12 weeks. CONCLUSION: Cabozantinib demonstrates clinical activity, with acceptable toxicities, in patients with ovarian carcinoma based on ORR and regression of tumour target lesions. REGISTRATION: This trial is registered at ClinicalTrial.gov (NCT00940225).

Estimation of mortality savings due to a national program for diabetes care.

BACKGROUND: Diabetes-related complications can be reduced by better control of glycemia, lipid abnormalities and blood pressure. In recent years, efforts at improving diabetes care in Israel have been made. This study aims to estimate mortality savings related to a national program for diabetes care in Israel. METHODS: Total population data for Israel was projected to 2020. Current diabetes prevalence and disease management data were obtained from a national program of diabetes care. Projections of the program's effect were based on two models: improvement in glycemic control, reflected in Hb A1c levels, and improvement in overall diabetes care, reflected in the percentage with LDL<100 mg/dl, a proxy for multi-factorial control. Potential years of life lost (PYLL) and quality-adjusted life years (QALYs) saved were calculated. RESULTS: A drop in average Hb A1c values from 8.13% at baseline to 7.36% in 2020 is expected, and as a result 4216 deaths from diabetes will be prevented over the period 2001-2020, saving around 47,773 life years or 34,342 QALYs. Overall diabetes care, reflected in improving the control rate of LDL levels to <100 mg/dl from 36% in 2000 to 58% in 2020, is estimated to prevent around 4803 deaths from diabetes over the period 2001-2020., so the program will save around 47,127 PYLL or 32,862 QALYs. CONCLUSIONS: A nationwide program of diabetes care is estimated to result in significant reductions of overall, as well as CHD-related, mortality.

A national study on lipid management.

BACKGROUND: Hyperlipidemia remains a major cause of morbidity in Western countries. The objective of this study was to document the percentage of adults who underwent periodical LDL measurement, and the percentage of patients with diabetes and post-angioplasty who were treated to goal. METHODS: Using a national database, data were obtained on the percentage of adults who had an LDL performed and the percentage of adults with an LDL at pre-specified levels. We also assessed the attainment of target LDL levels in diabetic and post-angioplasty patients. Data were also collected from patients with an acute coronary syndrome (ACS) admitted to seven hospitals within a 5 year period (2000-2004). RESULTS: Primary prevention: In 2005, 64.6% of the total population of 754,910 aged 35-44 had at least one record of LDL cholesterol measurement documented. This figure was 79.6% in the 717,617 adults aged 45-54. Secondary prevention: Of 253,233 diabetics in 2005, 220,023 (86.9%) have undergone at least one annual LDL measurement. The percentage of patients on statin therapy 3 and 12 months after an ACS admission increased significantly during the years 2000-2004 and reached 87%. Of the 42,292 patients who underwent PTCA during 2005, 34,346 (81.2%) have purchased at least 3 prescriptions of statins during 2005, 35,261 (83.4%) have performed at least one LDL measurement and 57.8% attained an LDL level of <100 mg/dl. CONCLUSIONS: We have shown an improvement in primary and secondary preventions of CV disease as documented by LDL measured and attainment of treatment goals, but further efforts are needed.

Do patients with diabetes and low socioeconomic status receive less care and have worse outcomes? A national study.

PURPOSE: The objective of the study was to assess the influence of socioeconomic status (SES) on the care of patients with diabetes. METHODS: Quality indicators for patients who were taking medication for diabetes were established. Overall compliance with the quality indicators, as well as prevalence of diabetes by age, were obtained from a national database. Patients with national tax exemptions (used as a marker for low SES) were compared to those without. RESULTS: Of 4,110,852 citizens aged 18-74, 210,988 (5.1%) were receiving medication for diabetes. The prevalence of diabetes reached 19.9% in people aged 65-74. 495,392 citizens had an exemption, and they had a higher prevalence of diabetes that those who did not (15.4% vs. 3.7%). Patients with an exemption had a higher rate of having a yearly HbA1c done, a yearly LDL level done, a yearly eye exam, a yearly urinary protein exam, of being treated with insulin for an elevated HbA1c than those without an exemption. In patients with an exemption there was a lower percentage with an HbA1c less than 7%, a higher percentage with an HbA1c greater than 9%, and a lower percentage with an LDL less than 130. Multivariate analysis showed that exemption status was a predictor of better performance on process measures (LDL test done, OR-1.03, 95% CI 1.01-1.06, HbA1c test done, OR 1.03, 95% CI- 1.01-1.05) and of worse outcomes (high LDL, OR 0.92, 95% CI, 0.90-0.95 and high HbA1c, OR, 0.85, 95% CI, 0.83-0.87). CONCLUSIONS: In a country with universal healthcare, patients from a lower SES had an increased prevalence of diabetes and had greater adherence to preventive healthcare measures However, they were less successful in meeting target treatment goals.