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

2073 General Poster Session (Board #16D), Sat, 1:15 PM-5:15 PM
Bevacizumab use and central nervous system (CNS) hemorrhage. Presenting
Author: Nathalie LeTarte, Centre Hospitalier de l’université de Montreal
(CHUM), Montreal, QC, Canada
Background: Bevacizumab is widely used and may cause life-threatening
bleeding, usually at sites of disease involvement such as the CNS. We
attempted to identify clinical characteristics associated with CNS hemorrhage
in a broad population. Methods: We did a retrospective review of the
FDA Medwatch database of adverse events reported with bevacizumab from
11/1997 to 5/2009. Results: We searched the database for keywords
bleeding, hemorrhage, cerebral, intracranial, subarachnoid, cerebellar,
hemorrhagic stroke, and brain. 17,466 reports were included in the
database: 154 described CNS hemorrhage in 99 patients, and 1041
reports described non-CNS bleeds. For CNS bleeds, cerebral hemorrhage
was the most frequent event reported (n�39), followed by intracranial
hemorrhage (n�20) and subarachnoid hemorrhage (n�18). Median age
was 62 years; 54% of patients were female. Primary cancer was colorectal
(42%), glioma (13%), and breast cancer (10%). Patients received a
median of three (1-36) doses of bevacizumab prior to the bleed. 54% of
patients received myelosuppressive chemotherapy, and 30% had documented
history of hypertension. Sixteen patients with CNS hemorrhage
were reported to have CNS metastases. For 70 patients, information on
CNS involvement was not reported. Death was reported as a complication of
hemorrhage in 48% of patients. Nine patients with brain metastases died
and CNS hemorrhage was the cause of death in seven. Six patients with
glioma died, and CNS hemorrhage was the cause in three. One patient with
brain metastases, and one patient with glioma also experienced a non-CNS
bleed. Five patients in each group had received heparin, warfarin or
NSAIDs. Low platelet counts were reported in 3 patients with CNS
metastases and 2 patients with glioma. The most common factor associated
with CNS hemorrhage was medication predisposing to bleeding,
followed by thrombocytopenia. Hypertension, a risk factor for CNS hemorrhage,
was reported in 4 patients with brain metastases, and 2 patients with
glioma. Conclusions: In this database, 154 of 1195 reports of bleeding
associated with bevacizumab described a CNS bleed. Although CNS bleeds
were not common, they were the reported cause of death in more than half
of the cases.
2075 General Poster Session (Board #16F), Sat, 1:15 PM-5:15 PM
Phase II trial of bevacizumab and fotemustine in recurrent grade III
gliomas. Presenting Author: Riccardo Soffietti, Division of Neuro-Oncology,
University Hospital San Giovanni Battista, Turin, Italy
Background: Bevacizumab (BV) has shown activity in recurrent grade III
gliomas, and few data are available on the combination of BV and
nitrosoureas. Fotemustine (FTM) is a nitrosourea with elevated lipophilic
properties. Methods: In this phase II study patients with grade III gliomas
recurrent after surgery, radiation therapy and concomitant/adjuvant temozolomide
were eligible. The treatment consisted of an induction phase with
BV at 10mg/kg intravenously on day 1 and 15 and FTM at 75mg/m2
intravenously on day 1 and 8, followed after a 3 week interval by a
maintenance phase with BV 10mg/kg and FTM 75mg/m2 every 3 weeks
until tumor progression or unacceptable toxicity. Patients had undergone
clinical and MRI assessment 1 month after the start of treatment and
thereafter every 2 months. The primary endpoint was progression-free
survival at 6 months (PFS-6), whereas secondary end-points were response
rate (RR), based on RANO criteria, progression-free survival (PFS), overall
survival (OS), and safety. Results: From May 2008 to September 2011, 32
patients (males 23, females 9, median age 46) were enrolled. PFS-6, PFS
-12 and median PFS were 31%, 7% and 5 months (range: 1-43�),
respectively. OS-6, OS-12 and median OS were 78%, 37.8% and 8.6
months (3.5-43�), respectively. Response rates were as follows: 4 CR
(12.5%), 12 PR (37.5%), 14 SD (44%) and 2 PD (6%). A significant
neurological improvement was observed in 48% of symptomatic patients,
being steroids reduced or withdrawn in 83% of patients. 29/32 (91%)
patients have progressed and patterns of tumor progression were local in 20
(69%), multicentric in previous multicentrinc tumors in 5 (17%), gliomatosis-like
in 3 (10%) and local plus leptomeningeal seeding in 1 (4%). 23/29
patients had salvage treatment after failure. Toxicities after BV were as
expected; 5 patients interrupted FTM for grade III-IV myelotoxicity. We did
not observe any additional toxicity from the combination. Conclusions: The
combination of bevacizumab and fotemustine in grade III gliomas recurrent
after standard treatment seems to have some activity.
Central Nervous System Tumors
133s
2074^ General Poster Session (Board #16E), Sat, 1:15 PM-5:15 PM
Phase II study to evaluate the efficacy and safety of rilotumumab and
bevacizumab (BEV) in subjects with recurrent malignant glioma (MG).
Presenting Author: Mary Lou Affronti, Duke University Medical Center,
Durham, NC
Background: Prognosis of recurrent MG remains poor with a median survival
of 3-9 months. Few evidence based treatments are available and response
rates have been � 20% with 6 month progression–free survival (PFS) of �
9-16%. Poor prognosis is linked to the MG’s ability to induce vascular
proliferation and invasion. MG’s have an abundance of neo-vascularization
and high levels of vascular endothelial growth factor (VEGF). BEV, an
antibody to VEGF, is the most active agent tested for recurrent MG with an
overall response rate of 21.2%. Rilotumumab is a human monoclonal
antibody that blocks human hepatocyte growth factor (HGF) and its
receptor c-Met. HGF/c-Met signaling plays a role in MG tumorigenicity
inducing angiogenesis and expression of additional angiogenic autocrine
factors such as VEGF. The novel combination of rilotumumab (C-Met
inhibitor) with an anti-VEGF drug (BEV) to block vascular invasion and
tumor proliferation may demonstrate synergistic tumor growth inhibition.
Methods: A two-stage design is used to assess radiographic response rate
with � 3 responses required for the first stage. Secondary endpoints were
PFS, overall survival (OS) and toxicity. Subjects with recurrent BEV-naïve
MGs received rilotumumab at 20 mg/kg in combination with BEV at 10
mg/kg every two weeks � 28 days after the last surgical procedure. A brain
MRI was obtained after each 6-week cycle. Results: 15 of the 19 patients
required for the first stage have been accrued. 10(67%) were male and �
50 years. 73% received � 2 prior regimens and 46% had � 2 prior
progressions. Best tumor response included 1(7%) complete response, 2
(13%) partial responses, 8 (53%) stable disease, 1 (7%) progressive
disease with 20% (3/15) non-evaluable due to early termination secondary
to toxicity. Median PFS was 3.9 months (95% CI: 1, 7.1) with a 6-month
PFS of 25.4% (95% CI: 6.4, 50.5) and 6-month OS of 68.3% (95% CI:
34, 87.1). Toxicities are listed below. Maximum average weight increase
over all cycles was 6.3 % (SD � 6.09). Conclusions: Rilotumumab in
combination with BEV is an active regimen in MG. Toxicity will need to be
closely monitored.
Toxicity Grade 3 Grade 4 Grade 5
Prolonged QTc interval 1 (7%)
Hypotension 1 (7%)
Hypokalemia 1 (7%)
DVT/PE 1 (7%) 2 (13%) 1 (7%)
2076 General Poster Session (Board #16G), Sat, 1:15 PM-5:15 PM
Adult low-grade gliomas: The Cleveland Clinic experience. Presenting
Author: Lizbeth Robles Irizarry, Cleveland Clinic, Cleveland, OH
Background: Low-grade gliomas account for 10-20% of all primary brain
tumors. There is limited data on specific prognostic factors for patients with
low-grade gliomas. Methods: After obtaining IRB approval, the Cleveland
Clinic Brain Tumor and Neuro-Oncology Center’s database was used to
identify patients with histologically confirmed grade 2 glioma at the time of
diagnosis. Multivariable analysis was conducted with use of a Cox proportional
hazards model and a stepwise selection algorithm that used p�0.10
as the criteria for entry and p�0.05 as retention in the model to identify
independent predictors of survival. Results: Chart records of 478 patients
(54% of whom were men) diagnosed between 1991 and 2010 were
included for analysis. The median age at presentation was 41 years (range,
18-83 years). 42% of patients had biopsy only, 27% had gross total
resection, 6% had near total resection, and 25% had subtotal resection.
22% of patients were initially treated with radiation, 30% with adjuvant
chemotherapy, and 7% with concurrent chemotherapy. Median progression
free survival and median overall survival (OS) were 5.1 years and 12.8
years, respectively. On multivariate analysis, independent of additional
therapy, five factors were identified as independent predictors of OS: age at
diagnosis (p�0.002), Karnofsky performance status (KPS, p�0.0001),
histology (astrocytoma vs. other, p�0.001), hemispheric location (left or
bilateral involvement vs. right, p�0.02) and gender (male vs. female,
p�0.0003). Conclusions: Older age, male gender, poor performance
status, astrocytic histology, and left hemispheric or bilateral involvement
are associated with higher mortality.
Risk factors for mortality: Multivariable Cox proportional hazards analysis.
Factor1 Hazard ratio (95% C.I.) p2 KPS (55 vs. 50-55 vs.