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

122s Central Nervous System Tumors
2027 Poster Discussion Session (Board #15), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Vorinostat, temozolomide, and bevacizumab for patients with recurrent
glioblastoma: A phase I/II trial. Presenting Author: Katherine B. Peters,
Duke University Medical Center, Durham, NC
Background: Prognosis for recurrent glioblastoma (GBM) remains poor with
median survival between 3 to 6 months. Use of anti-vascular endothelial
growth factor inhibitor, bevacizumab (BEV), has advanced this area of
research, but continued studies have focused on whether the addition of
other chemotherapies can improve efficacy in recurrent GBM. Vorinostat, a
small molecule inhibitor of histone deactylase (HDAC), has anti-tumor
activity directly through HDAC inhibition and indirectly by promoting
anti-angiogenesis. Its good oral bioavailability and favorable toxicity profile
make it a promising additive agent to standard therapy. Thus, we evaluated
the efficacy of vorinostat in combination with BEV and daily temozolomide
(TMZ) in recurrent GBM. Methods: This was a phase I/II open-label, single
arm study in recurrent GBM patients. Primary endpoint was 6-month
progression free survival (PFS). Secondary endpoints were safety/
tolerability, radiographic response, PFS, and overall survival of recurrent
GBM patients treated with BEV plus daily TMZ and vorinostat. Chief
eligibility criteria included age � 18 years, KPS � 70, time interval � four
weeks from previous treatment, and maximum of 2 prior progressions.
Dosing regimen was as follows: BEV 10 mg/kg IV every two weeks, TMZ 50
mg/m2 po daily, and vorinostat 400 mg po for 7 days on then 7 days off in a
28 day cycle. Results: 46 recurrent GBM patients were enrolled with 42 of
those patients receiving a vorinostat dose of 400 mg. Most common grade 2
and above toxicities were leukopenia (36%), neutropenia (29%), fatigue
(24%), and thrombocytopenia (19%). Serious toxicities included 4 grade 4
toxicities (grade 4 hyperglycemia, pulmonary embolism, bowel perforation
and intracranial hematoma) and 1 patient expired on day of informed
consent due to pulmonary embolism (grade 5). With a median follow-up of
11.3 months (95% CI: 10.1, 13.1 months), the 6-month PFS was 52.4%
(95% CI: 36.4%, 66.1%). Best radiographic responses were 2 complete
responses, 17 partial responses, 20 stable responses, and 1 radiographic
progression. Conclusions: In summary, combination of BEV, daily TMZ, and
vorinostat has promising efficacy on recurrent GBM with reasonable
toxicity/safety.
2029^ Poster Discussion Session (Board #17), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Bevacizumab versus bevacizumab plus vorinostat in adults with recurrent
malignant glioma: Results of a phase I part of a phase I/II trial. Presenting
Author: Jing Wu, University of North Carolina at Chapel Hill, Lineberger
Comprehensive Cancer Center, Department of Neurosurgery, Chapel Hill,
NC
Background: Antiangiogenic therapy using bevacizumab (Bev) has shown
promising activity against recurrent glioblastoma (GBM). However, most
patients have disease progression after striking but transient responses.
Salvage therapies have been uniformly ineffective, suggesting development
of resistance mechanisms including upregulation of other proangiogenic
factors and increased activity of hypoxia inducible factors (HIF)-1a.
Vorinostat, a histone deacetylase (HDAC) inhibitor has single agent activity
against recurrent GBM and downregulates HIF-1a and other proangiogenic
and invasive factors. We hypothesized that HDAC inhibition combined with
Bev would result in improved clinical outcome. We report the results of the
Phase I portion of the study preceding the initiation of the 2-arm adaptive
randomized Phase II study. Methods: Adults with recurrent malignant
glioma, KPS � 60, normal hepatic, renal and marrow organ function and no
prior exposure to Bev or Vorinostat were enrolled to the combination therapy
after the confirmation of recurrent GBM. A conventional 3�3 Phase I
design was used to determine the maximum tolerated dose (MTD) and the
toxicity profile of the combination of Bev and Vorinostat. The starting dose
was Bev at 10mg/kg administered on days 1 and 15 intravenously and
Vorinostat 400 mg/day orally on days 1 to 7, and days 15 to 21 with each
cycle being 28 days. Results: A total of 6 patients were enrolled and all 6
patients were evaluable. Three patients were enrolled in the first cohort at
the starting dose of the combination and completed the first cycle. One
patient experienced a grade 3 ALT elevation and grade 3 hyperglycemia,
which were designated as possibly related to vorinostat and constituting a
dose-limiting toxicity (DLT). No grade 4 toxicities were noted. The cohort
was expanded by 3 more patients with none of these patients experienced a
DLT in the first cycle. The starting dose level of Bev and vorinostat was
declared the Phase II dose. Conclusions: Combination of Bev (10 mg/kg q 2
weeks) and of vorinostat (400 mg on days 1 to 7 and 15 to 21) has tolerable
toxicity profile. This will be followed by a multicenter Bayesian adaptive
randomized Phase II study.
2028 Poster Discussion Session (Board #16), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Bevacizumab for recurrent WHO grade III anaplastic glioma (AG). Presenting
Author: Anna Maria Delios, Memorial Sloan-Kettering Cancer Center,
New York, NY
Background: Salvage treatment with bevacizumab (BEV) has been increasingly
used in grade III AG, but limited data are available, with conflicting
results reported. Because of differences in molecular characteristics,
angiogenesis mechanisms, growth rate and chemosensitivity, results observed
in glioblastoma (GBM) treated with BEV may not apply to AG, and
may differ between anaplastic astrocytomas (AA) and oligodendrogliomas
(AO). Methods: IRB approved retrospective review of all pts with recurrent
WHO grade III AG treated with BEV at MSKCC. Response and progression
were determined by RANO criteria. Results: BEV was given to 39 pts with
recurrent grade III AG (AA: 26; AO: 10; anaplastic oligoastrocytoma [AOA]:
3); median (med) age: 49 (range 20-75); med KPS: 80 (60-100). MGMT
promoter methylation was determined in 17 pts (methylated 8, unmethylated
9). Amongst AO/AOA, 1p/19q co-deletion was present in 6 and absent
in 5. IDH1/ IDH2 mutations were present in 3/5 tested tumors. Med time
from diagnosis of AG to BEV treatment was 11.5m (3 – 112.5). The med
number of previous recurrences was 1 (range 1-4). BEV was given as single
agent to 16 pts and combined with a cytotoxic agent in 23. Objective
response rate (ORR) was 41% (complete response: 5; partial: 11). The med
progression-free survival (PFS) was 4.8m (6-m PFS: 35% [95% CI
20-50]). The med overall survival (OS) was 11.5 m (1y-OS: 45% [95% CI
29-61]). In pts achieving ORR, med OS was 13 m vs 4minptswith
stable/progressive disease (P�0.02). Pts at first recurrence fared better
than pts with more than one recurrence (med PFS: 6 vs 3.4 months,
P�0.04). AO/AOA tended to fare worse than AA (med PFS 3 vs 5.5 m,
P�0.07). There were no differences in PFS (P�0.8) or OS (P�0.4)
between single agent vs BEV � cytotoxic agent. Toxicity included one grade
4 brain hemorrhage. Conclusions: In this relatively large series, BEV was
associated with higher ORR and PFS as compared to historical controls,
although improvements in those endpoints were of a lower magnitude than
in GBM. While ORR predicted OS, improvements in OS were not apparent;
results in AO were particularly disappointing. The use of BEV in this
population requires reappraisal in a randomized study with adequate
stratification for histology and number of previous recurrences.
2030 Poster Discussion Session (Board #18), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Differences in outcome due to bevacizumab (BEV) discontinuation versus
BEV failure in adults with glioblastoma. Presenting Author: Mark Daniel
Anderson, University of Texas M. D. Anderson Cancer Center, Houston, TX
Background: BEV is approved for use in recurrent glioblastoma. Patients
(pts) who benefit from BEV therapy are often treated until tumor progression
but fail to respond to salvage therapy suggesting that BEV may alter
tumor biology. In a subset of pts who benefit from BEV, treatment is
discontinued for reasons other than disease progression; the characteristics
and outcomes of this subset are poorly defined. Methods: In this IRB
approved retrospective study, our neuro-oncology longitudinal database
was screened for pts treated with BEV for � 6 months (mo) between
2005-2010 and 18 pts were identified in whom BEV was discontinued for
reasons other than disease progression (BEV-D group). A cohort of 72 pts
who received BEV until treatment failure due to progression was used as
comparator (BEV-F group). Results: In the BEV-D group, 5 pts completed a
planned treatment course and 13 stopped BEV due to toxicity; in this
group, progression free survival at 12 mo (PFS12) was 83.3% (95% CI,
56.8-94.3) and median time to progression (TTP) 27.6 mo. Median TTP
after BEV discontinuation was 7.0 mo. In contrast, in the BEV-F group,
PFS12 was 24.6% (95% CI, 13.9-36.2) and median PFS 9.7 mo. Length
of BEV therapy was not significantly different between the groups with a
median time to discontinuation of 10.2 and 12 mo. In 12/18 pts in the
BEV-D group who subsequently had tumor recurrence a predominantly
local pattern of progression was seen unlike those in the BEV-F group who
had more infiltrative or distant failures. Salvage therapy yielded a PFS-6 of
28.6% (95% CI, 4.1-61.2) with a median PFS of 17.1 wk compared with
6.8% (95% CI, 1.2-19.8) and 9 wk in the comparator group. Conclusions:
Among pts who benefit from BEV therapy, the BEV-D group did not
experience an immediate progression suggesting continued benefit after
BEV cessation. This cohort also had a less invasive pattern of recurrence
and a possibly improved response to salvage therapy compared with BEV-F
group. Our results suggest that planned cessation of BEV therapy could
potentially change patterns of progression and response to subsequent
therapy. This strategy warrants further evaluation in prospective studies
given the absence of effective salvage therapy after BEV failure.
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