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Annual Meeting Proceedings Part 1 - American Society of Clinical ...

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2073 General Poster Session (Board #16D), Sat, 1:15 PM-5:15 PM<br />

Bevacizumab use and central nervous system (CNS) hemorrhage. Presenting<br />

Author: Nathalie LeTarte, Centre Hospitalier de l’université de Montreal<br />

(CHUM), Montreal, QC, Canada<br />

Background: Bevacizumab is widely used and may cause life-threatening<br />

bleeding, usually at sites <strong>of</strong> disease involvement such as the CNS. We<br />

attempted to identify clinical characteristics associated with CNS hemorrhage<br />

in a broad population. Methods: We did a retrospective review <strong>of</strong> the<br />

FDA Medwatch database <strong>of</strong> adverse events reported with bevacizumab from<br />

11/1997 to 5/2009. Results: We searched the database for keywords<br />

bleeding, hemorrhage, cerebral, intracranial, subarachnoid, cerebellar,<br />

hemorrhagic stroke, and brain. 17,466 reports were included in the<br />

database: 154 described CNS hemorrhage in 99 patients, and 1041<br />

reports described non-CNS bleeds. For CNS bleeds, cerebral hemorrhage<br />

was the most frequent event reported (n�39), followed by intracranial<br />

hemorrhage (n�20) and subarachnoid hemorrhage (n�18). Median age<br />

was 62 years; 54% <strong>of</strong> patients were female. Primary cancer was colorectal<br />

(42%), glioma (13%), and breast cancer (10%). Patients received a<br />

median <strong>of</strong> three (1-36) doses <strong>of</strong> bevacizumab prior to the bleed. 54% <strong>of</strong><br />

patients received myelosuppressive chemotherapy, and 30% had documented<br />

history <strong>of</strong> hypertension. Sixteen patients with CNS hemorrhage<br />

were reported to have CNS metastases. For 70 patients, information on<br />

CNS involvement was not reported. Death was reported as a complication <strong>of</strong><br />

hemorrhage in 48% <strong>of</strong> patients. Nine patients with brain metastases died<br />

and CNS hemorrhage was the cause <strong>of</strong> death in seven. Six patients with<br />

glioma died, and CNS hemorrhage was the cause in three. One patient with<br />

brain metastases, and one patient with glioma also experienced a non-CNS<br />

bleed. Five patients in each group had received heparin, warfarin or<br />

NSAIDs. Low platelet counts were reported in 3 patients with CNS<br />

metastases and 2 patients with glioma. The most common factor associated<br />

with CNS hemorrhage was medication predisposing to bleeding,<br />

followed by thrombocytopenia. Hypertension, a risk factor for CNS hemorrhage,<br />

was reported in 4 patients with brain metastases, and 2 patients with<br />

glioma. Conclusions: In this database, 154 <strong>of</strong> 1195 reports <strong>of</strong> bleeding<br />

associated with bevacizumab described a CNS bleed. Although CNS bleeds<br />

were not common, they were the reported cause <strong>of</strong> death in more than half<br />

<strong>of</strong> the cases.<br />

2075 General Poster Session (Board #16F), Sat, 1:15 PM-5:15 PM<br />

Phase II trial <strong>of</strong> bevacizumab and fotemustine in recurrent grade III<br />

gliomas. Presenting Author: Riccardo S<strong>of</strong>fietti, Division <strong>of</strong> Neuro-Oncology,<br />

University Hospital San Giovanni Battista, Turin, Italy<br />

Background: Bevacizumab (BV) has shown activity in recurrent grade III<br />

gliomas, and few data are available on the combination <strong>of</strong> BV and<br />

nitrosoureas. Fotemustine (FTM) is a nitrosourea with elevated lipophilic<br />

properties. Methods: In this phase II study patients with grade III gliomas<br />

recurrent after surgery, radiation therapy and concomitant/adjuvant temozolomide<br />

were eligible. The treatment consisted <strong>of</strong> an induction phase with<br />

BV at 10mg/kg intravenously on day 1 and 15 and FTM at 75mg/m2<br />

intravenously on day 1 and 8, followed after a 3 week interval by a<br />

maintenance phase with BV 10mg/kg and FTM 75mg/m2 every 3 weeks<br />

until tumor progression or unacceptable toxicity. Patients had undergone<br />

clinical and MRI assessment 1 month after the start <strong>of</strong> treatment and<br />

thereafter every 2 months. The primary endpoint was progression-free<br />

survival at 6 months (PFS-6), whereas secondary end-points were response<br />

rate (RR), based on RANO criteria, progression-free survival (PFS), overall<br />

survival (OS), and safety. Results: From May 2008 to September 2011, 32<br />

patients (males 23, females 9, median age 46) were enrolled. PFS-6, PFS<br />

-12 and median PFS were 31%, 7% and 5 months (range: 1-43�),<br />

respectively. OS-6, OS-12 and median OS were 78%, 37.8% and 8.6<br />

months (3.5-43�), respectively. Response rates were as follows: 4 CR<br />

(12.5%), 12 PR (37.5%), 14 SD (44%) and 2 PD (6%). A significant<br />

neurological improvement was observed in 48% <strong>of</strong> symptomatic patients,<br />

being steroids reduced or withdrawn in 83% <strong>of</strong> patients. 29/32 (91%)<br />

patients have progressed and patterns <strong>of</strong> tumor progression were local in 20<br />

(69%), multicentric in previous multicentrinc tumors in 5 (17%), gliomatosis-like<br />

in 3 (10%) and local plus leptomeningeal seeding in 1 (4%). 23/29<br />

patients had salvage treatment after failure. Toxicities after BV were as<br />

expected; 5 patients interrupted FTM for grade III-IV myelotoxicity. We did<br />

not observe any additional toxicity from the combination. Conclusions: The<br />

combination <strong>of</strong> bevacizumab and fotemustine in grade III gliomas recurrent<br />

after standard treatment seems to have some activity.<br />

Central Nervous System Tumors<br />

133s<br />

2074^ General Poster Session (Board #16E), Sat, 1:15 PM-5:15 PM<br />

Phase II study to evaluate the efficacy and safety <strong>of</strong> rilotumumab and<br />

bevacizumab (BEV) in subjects with recurrent malignant glioma (MG).<br />

Presenting Author: Mary Lou Affronti, Duke University Medical Center,<br />

Durham, NC<br />

Background: Prognosis <strong>of</strong> recurrent MG remains poor with a median survival<br />

<strong>of</strong> 3-9 months. Few evidence based treatments are available and response<br />

rates have been � 20% with 6 month progression–free survival (PFS) <strong>of</strong> �<br />

9-16%. Poor prognosis is linked to the MG’s ability to induce vascular<br />

proliferation and invasion. MG’s have an abundance <strong>of</strong> neo-vascularization<br />

and high levels <strong>of</strong> vascular endothelial growth factor (VEGF). BEV, an<br />

antibody to VEGF, is the most active agent tested for recurrent MG with an<br />

overall response rate <strong>of</strong> 21.2%. Rilotumumab is a human monoclonal<br />

antibody that blocks human hepatocyte growth factor (HGF) and its<br />

receptor c-Met. HGF/c-Met signaling plays a role in MG tumorigenicity<br />

inducing angiogenesis and expression <strong>of</strong> additional angiogenic autocrine<br />

factors such as VEGF. The novel combination <strong>of</strong> rilotumumab (C-Met<br />

inhibitor) with an anti-VEGF drug (BEV) to block vascular invasion and<br />

tumor proliferation may demonstrate synergistic tumor growth inhibition.<br />

Methods: A two-stage design is used to assess radiographic response rate<br />

with � 3 responses required for the first stage. Secondary endpoints were<br />

PFS, overall survival (OS) and toxicity. Subjects with recurrent BEV-naïve<br />

MGs received rilotumumab at 20 mg/kg in combination with BEV at 10<br />

mg/kg every two weeks � 28 days after the last surgical procedure. A brain<br />

MRI was obtained after each 6-week cycle. Results: 15 <strong>of</strong> the 19 patients<br />

required for the first stage have been accrued. 10(67%) were male and �<br />

50 years. 73% received � 2 prior regimens and 46% had � 2 prior<br />

progressions. Best tumor response included 1(7%) complete response, 2<br />

(13%) partial responses, 8 (53%) stable disease, 1 (7%) progressive<br />

disease with 20% (3/15) non-evaluable due to early termination secondary<br />

to toxicity. Median PFS was 3.9 months (95% CI: 1, 7.1) with a 6-month<br />

PFS <strong>of</strong> 25.4% (95% CI: 6.4, 50.5) and 6-month OS <strong>of</strong> 68.3% (95% CI:<br />

34, 87.1). Toxicities are listed below. Maximum average weight increase<br />

over all cycles was 6.3 % (SD � 6.09). Conclusions: Rilotumumab in<br />

combination with BEV is an active regimen in MG. Toxicity will need to be<br />

closely monitored.<br />

Toxicity Grade 3 Grade 4 Grade 5<br />

Prolonged QTc interval 1 (7%)<br />

Hypotension 1 (7%)<br />

Hypokalemia 1 (7%)<br />

DVT/PE 1 (7%) 2 (13%) 1 (7%)<br />

2076 General Poster Session (Board #16G), Sat, 1:15 PM-5:15 PM<br />

Adult low-grade gliomas: The Cleveland Clinic experience. Presenting<br />

Author: Lizbeth Robles Irizarry, Cleveland Clinic, Cleveland, OH<br />

Background: Low-grade gliomas account for 10-20% <strong>of</strong> all primary brain<br />

tumors. There is limited data on specific prognostic factors for patients with<br />

low-grade gliomas. Methods: After obtaining IRB approval, the Cleveland<br />

Clinic Brain Tumor and Neuro-Oncology Center’s database was used to<br />

identify patients with histologically confirmed grade 2 glioma at the time <strong>of</strong><br />

diagnosis. Multivariable analysis was conducted with use <strong>of</strong> a Cox proportional<br />

hazards model and a stepwise selection algorithm that used p�0.10<br />

as the criteria for entry and p�0.05 as retention in the model to identify<br />

independent predictors <strong>of</strong> survival. Results: Chart records <strong>of</strong> 478 patients<br />

(54% <strong>of</strong> whom were men) diagnosed between 1991 and 2010 were<br />

included for analysis. The median age at presentation was 41 years (range,<br />

18-83 years). 42% <strong>of</strong> patients had biopsy only, 27% had gross total<br />

resection, 6% had near total resection, and 25% had subtotal resection.<br />

22% <strong>of</strong> patients were initially treated with radiation, 30% with adjuvant<br />

chemotherapy, and 7% with concurrent chemotherapy. Median progression<br />

free survival and median overall survival (OS) were 5.1 years and 12.8<br />

years, respectively. On multivariate analysis, independent <strong>of</strong> additional<br />

therapy, five factors were identified as independent predictors <strong>of</strong> OS: age at<br />

diagnosis (p�0.002), Karn<strong>of</strong>sky performance status (KPS, p�0.0001),<br />

histology (astrocytoma vs. other, p�0.001), hemispheric location (left or<br />

bilateral involvement vs. right, p�0.02) and gender (male vs. female,<br />

p�0.0003). Conclusions: Older age, male gender, poor performance<br />

status, astrocytic histology, and left hemispheric or bilateral involvement<br />

are associated with higher mortality.<br />

Risk factors for mortality: Multivariable Cox proportional hazards analysis.<br />

Factor1 Hazard ratio (95% C.I.) p2 KPS (55 vs. 50-55 vs.

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