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

2031 Poster Discussion Session (Board #19), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
NCCTG N057K phase II trial of everolimus, temozolomide, and radiotherapy
in patients with newly diagnosed glioblastoma: A North Central
Cancer Treatment Group trial. Presenting Author: Daniel Ma, Mayo Clinic,
Rochester, MN
Background: The mammalian target of rapamycin (mTOR) functions within
the PI3K/Akt pathway as a critical modulator of cell survival. Preclinical
studies in GBM indicate that the combination of mTOR inhibitors, such as
everolimus (RAD001), with either radiation therapy (RT) or temozolomide
(TMZ) provide increased tumor cell killing. Methods: Newly diagnosed GBM
pts were eligible for the study. RAD001 was dosed orally at 70 mg/week
weekly, starting 1 week prior to RT/TMZ, and continued throughout
RT/TMZ, adjuvant TMZ and then until progression. This was a single arm
phase II design powered to detect a true overall survival at 12 months
(OS12) of 73% (vs 58% in historical controls). Secondary endpoints were
toxicity, response rate, and time to progression (TTP). A subgroup of
patients with measurable residual disease were eligible for the PET imaging
component of the study, consisting of an 18FLT-PET/CT scan performed
before and after the initial two doses of RAD001 but before the first dose of
RT or TMZ. Results: 103 patients were accrued to phase II of which 100
were evaluable. The median age was 60.5 years (23-81), median ECOG PS
was 1, 46 patients had GTR, 33 STR, and the remainder had biopsy at
diagnosis. Treatment tolerance was acceptable: 17% patient had at least
one grade 3 hematologic toxicity; 14% had at least one grade 4 hematologic
toxicity, 42% had at least one grade 3 non-heme toxicity, while 12%
had at least one grade 4 non-heme toxicity. No increased incidence of
infectious complications was observed and there were no treatment related
deaths. Median PFS was 5.3 months (1.3-21.4), with 22 patients
progression free. Mature OS data will be available at the meeting. MGMT
methylation status analysis is ongoing. Of the pts who had evaluable
FLT-PET data, three of eight (37.5%) had a drop in SUVmax �25% after
two treatments of RAD001. Conclusions: RAD001 with standard of care
chemoradiation had moderate toxicity. Serial 18FLT-PET was feasible for
evaluating drug-induced changes in tumor proliferation following RAD001.
Final outcome data and association of MGMT status with outcome will be
reported at the meeting.
2033 Poster Discussion Session (Board #21), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Final results of a randomized phase III trial of nimotuzumab for the
treatment of newly diagnosed glioblastoma in addition to standard radiation
and chemotherapy with temozolomide versus standard radiation and
temoziolamide. Presenting Author: Manfred Westphal, Department of
Neurosurgery, UKE Hamburg, Hamburg, Germany
Background: The receptor for epidermal growth factor (EGF-R) has consistently
been found expressed or overexpressed in human malignant glioma
disease. Therapeutic targeting of the EGF-R has shown mixed responses
which appear to be restricted by specific features of the tumor cells.Nimotuzumab
binds preferentially to highly over expressing cells, a phase III trial
was initiated to test efficacy in glioma. Methods: Nimotuzumab was tested
in an open label, randomized, multicenter Phase III trial in patients with
histologically confirmed, newly diagnosed glioblastoma. 12 consecutive
weekly infusions of 400mg during standard radiotherapy with Temozolomide
followed by biweekly infusions of 400mg arm A was randomized
against standard radio chemotherapy alone arm B. Primary endpoint was
PFS as determined by centralized neuro-imaging review. OS as secondary
endpoint with quality of life, safety as additional parameters.MGMT and
EGF-R were assessed where sufficient materials could be retrieved as well
as tumor hypoxia. Results: Between 2007 and 2010, 149 patients were
randomized and 142 were available for analysis. Stratification according to
resection status resulted in 40 pts in the treatment arm and 41 in the
control arm with residual tumor and 31 vs 30 pts without residual tumor.
PFS: 12 month was 25.5% arm A vs 20.3% in arm B (p � 0.78) and OS:
679 days vs 596 days. For non - methylated MGMT the difference was most
notable: OS arm A 28 pats: 19.6 months vs arm B 28 pats 15.0 months
EGF-R amplification, gave no clear signal, neither was there a statistically
significant treatment effect between with or without residual tumor. Tumor
hypoxia does not appear to have predictive value in the overall group but
possibly in subgroups.AEs and SAEs did not reveal a new specific toxicity
profile beyond the known side effects from glioma treatment with current
standard. Conclusions: Nimotuzumab shows a clear trend towards efficacy
in MGMT non-methylated glioblastoma patients. Safety profile and indications
for subgroup efficacy potentially justify focused evaluation of antibody
therapy against glioblastoma.
Central Nervous System Tumors
123s
2032 Poster Discussion Session (Board #20), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Phase I/randomized phase II trial of either dasatinib or placebo combined
with standard chemoradiotherapy for newly diagnosed glioblastoma multiforme
(GBM): Final results of phase I study. Presenting Author: Nadia N.
Laack, Mayo Clinic, Rochester, MN
Background: Dasatinib is a potent oral ATP competitive multi-targeted
kinase inhibitor of multiple members of the Src kinase family, known to be
involved in gliomagenesis and invasion. N0877 is a phase I/randomized
phase II trial evaluating the combination of dasatinib, radiation (RT) and
temozolomide (TMZ) in newly diagnosed GBM. The phase I portion has
been completed and is the focus of this report. Methods: A cohorts-of-3
design was used to assess the safety of dasatinib in combination with RT
and concomitant TMZ, and establish the phase II dose of the combination.
Dasatinib was given orally for 42 days, beginning with the first day of RT
(total dose 60 Gy) and first dose of TMZ (75 mg/m2/d). A 24 - 42 day rest
(cycle 2) followed the RT/TMZ/dasatinib. Patients (pts) were observed for
DLT to the end of cycle 2. Patients then received 6 cycles (28 day cycles) of
dasatinib (once daily) and TMZ (days 1-5). At the completion of 6 cycles of
TMZ � dasatinib, pts stay on dasatinib only (28 day cycles) until
progressive disease. Results: Phase I component is complete with 13
patients (3 at dose level 0, 3 at dose level 0-A, 7 at dose level 1). One
patient in dose level 1 had to be replaced due to the development of
unrelated medical issues. One DLT (grade 4 pancytopenia) was observed in
1 patient at dose level 0 (50mg bid) and one DLT (grade 3 rash) was
observed in 1 patient at dose level 1 (150mg qd). MTD of dasatinib was
determined to be 150mg daily. Most common adverse events throughout
the entire study period were hematologic with the most common toxicity
being lymphopenia (grade 3 in 69% of patients, grade 4 in 8%). Other
toxicities attributed to treatment and occurring in � 10% of patients
included anemia (31%), neutropenia (15%), and fatigue(15%). Best
response was stable disease in 10 patients, progressive disease in 1
patient, and not evaluable in 2. Conclusions: MTD for dasatinib in
combination with TMZ and RT in newly diagnosed GBM patients is 150mg
daily. Toxicity was primarily hematologic with minimal non-hematologic
events. This dose is currently being used in the ongoing placebo-controlled,
randomized phase II trial.
2034 Poster Discussion Session (Board #22), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
APG101_CD_002: A phase II, randomized, open-label, multicenter study
of weekly APG101 plus reirradiation versus reirradiation in the treatment of
patients with recurrent glioblastoma. Presenting Author: Martin Bendszus,
Department of Neuroradiology, University Hospital Heidelberg, Heidelberg,
Germany
Background: Preclinical data indicate antiinvasive activity of APG101, an
intravenous CD95 ligand-binding fusion protein, as well as synergistic
activity together with radiotherapy in glioblastoma. Methods: Patients with
recurrent glioblastoma after prior standard radiochemotherapy with temozolomide
(� 1 second-line chemotherapy) were considered for re-irradiation
provided a tumor diameter 1-4 cm and time since the end radiotherapy � 8
months. Patients were randomized 1:2 between radiotherapy (36 Gy; 5
times 2 Gy per week) or radiotherapy plus APG101 at 400 mg weekly flat
dose to be continued until progression. Radiotherapy plans were centrally
evaluated. Primary endpoint was 6-months progression free survival (PFS-
6). MRIs were performed every 6-weeks and centrally read. Sample size of
the investigational treatment arm according to a two-stage design of Simon
required 55 patients. A control arm of 28 patients was implemented to
validate the assumptions on PFS-6 in a cohort of patients treated with
reirradiation alone. Results: Between 12/09 and 09/11, 84 pts in 25
centers were randomized and treated, preliminary data of the current report
are available on 71 patients (49 APG01 � irradiation, 22 irradiation
alone). Median age was 57 years, median KPS 90%. The maximal tumor
diameter was � 2-5 cm in 34 patients and � 2.5 cm in 37 patients. No
SUSARs have to be reported. Nine patients achieved PFS-6 in the APG101
arm and none in the radiotherapy arm. Conclusions: APG101_CD_002 is
the first trial evaluating CD95-mediated pathway inhibition as a therapeutic
strategy. This trial is also the prospective trial on reirradiation in
glioblastoma. Side effects of the combination were minimal, and treatment
could be delivered as planned. The experimental arm met the primary
endpoint. The approach to block rather than stimulate the CD95 system is
breaking a paradigm. Our data suggest that CD95 inhibition by APG101
should be evaluated in the management of newly diagnosed glioblastoma in
combination with standard radiochemotherapy. Further molecular data and
updated results will be presented.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.