Oblimersen combined with docetaxel, adriamycinand cyclophosphamide as neo-adjuvant systemictreatment in primary breast cancer: final results ofa multicentric phase I study
J. Rom1*, G. von Minckwitz2,5, W. Eiermann3, M. Sievert4, B. Schlehe1, F. Marme´1, F. Schuetz1,A. Scharf1, M. Eichbaum1, H.-P. Sinn5, M. Kaufmann6, C. Sohn1 & A. Schneeweiss11Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg; 2German Breast Group, Neu Isenburg; 3Frauenklinik vom RotenKreuz, Mu¨nchen; 4Sanofi-Aventis GmbH, Berlin; 5Department of Pathology, University of Heidelberg, Heidelberg; 6University of Frankfurt,
Department of Gynecology and Obstetrics, Frankfurt, Germany
Received 23 January 2008; revised 6 April 2008; accepted 7 April 2008
Background: Combining the Bcl-2 down-regulator oblimersen with cytotoxic treatment leads to synergistic
antitumor effects in preclinical trials. This multicentric phase I study was carried out to evaluate maximum tolerated
dose (MTD), safety and preliminary efficacy of oblimersen in combination with docetaxel, adriamycin and
cyclophosphamide as neo-adjuvant systemic treatment (NST) in primary breast cancer (PBC). Methods: Previously untreated patients with PBC T2–4a–c N0–3 M0 received one cycle of docetaxel 75 mg/m2,
adriamycin 50 mg/m2 and cyclophosphamide 500 mg/m2 administered on day 5 combined with escalating doses of
oblimersen as a 24-h continuous infusion on days 1–7 followed by five cycles of combination of docetaxel, adriamycin
and cyclophosphamide (TAC) without oblimersen every 3 weeks. Prophylactic antibiotic therapy and granulocyte
colony-stimulating factor administration were used in all six cycles. Blood serum samples were taken throughout the
treatment period for pharmacokinetic analysis. Results: Twenty-eight patients were enrolled (median age, 50 years; ductal-invasive histology, 68%; tumorsize 2–5
cm, 61%; grade 3, 43%; hormone receptor negative, 36%; Her2 positive 18%) and received oblimersen in a dose of 3
mg/kg/day (cohort I, nine patients), 5 mg/kg/day (cohort II, nine patients) and 7 mg/kg/day (cohort III, 10 patients)
respectively. No dose-limiting toxicity occurred. Following oblimersen combined with TAC, the most severe toxicity
was neutropenia [National Cancer Institute—Common Toxicity Criteria (NCI-CTC) grades 1–2/3/4] which developed in
0/0/56% of patients (cohort I), 11/0/56% of patients (cohort II) and 20/20/50% of patients (cohort III). No febrile
neutropenia occurred. Most common adverse events (all NCI-CTC grade £ 2) were fatigue, nausea, alopecia,
headache and flue-like symptoms observed in 78% (cohort I), 89% (cohort II) and 90% (cohort III) of patients. With
increasing dose of oblimersen, a higher incidence of grade IV leukopenia and neutropenia was noted. At the MTD of 7
mg/kg/day of oblimersen, serious adverse events occurred in 40% of the patients. Conclusion: Oblimersen up to a dose of 7 mg/kg/day administered as a 24-h infusion on days 1–7 can be safely
administered in combination with standard TAC on day 5 as NST in patients with PBC. The safety and preliminary
efficacy warrants further evaluation of oblimersen in combination with every cycle of the TAC regimen in a randomized
trial. Key words: breast cancer, neo-adjuvant systemic treatment, oblimersen
ultimately die due to widespread disease. In the past 10 years,adjuvant hormonal or chemotherapy treatment has been
Surgery is the main modality of treatment in patients with
increasingly used on the basis of the studies showing that
breast cancer. Surgery and/or radiotherapy can control local-
adjuvant treatment can prolong time to recurrence and survival
regional disease in the majority of patients. However, >60% will
in some subsets of patients . Neo-adjuvant (preoperative)systemic treatment (NST) and adjuvant chemotherapy offer
*Correspondence to: Dr J. Rom, Department of Gynecology and Obstetrics, University
patients a similar gain of survival . Preoperative
of Heidelberg, Vossstrasse 9, D-69115 Heidelberg, Germany. Tel: +49-6221-56 37987;Fax: +49-6221-56-7066; E-mail: [email protected]
chemotherapy is the standard of care in advanced breast cancer.
ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
The combination of docetaxel, adriamycin and
regulatory requirements. Written informed consent was obtained from each
cyclophosphamide (TAC regimen) represents one of the
participating patient before enrollment.
standard chemotherapies applied before surgery leading toa pathologic complete response (pCR) rate of 25% in
chemosensitive primary breast cancers (PBCs) .
Patient eligibility criteria included histologically confirmed previously
To improve the antitumor efficacy of chemotherapy,
untreated PBC T2–4a–c N0–3 M0, age ‡ 18 years, Karnofsky performance
a combination with apoptosis-modulating drugs would be
status ‡ 80%, adequate hematologic (absolute neutrophil count ‡1.5 · 109/
interesting to evaluate. Key proteins involved in the regulation
l, platelet count >100 · 109/l), hepatic, renal and cardiac function. Patients were excluded if they had inflammatory breast cancer, any prior
of apoptosis are Bax (promoter of apoptosis) or Bcl-2
treatment for breast cancer or simultaneous concurrence of all of the
(apoptosis antagonistic) [4–6]. The antiapoptotic regulatory
following factors: age > 35 years, tumor size < 5 cm, estrogen receptor
protein Bcl-2 demonstrates an attractive and new molecular
(ER) and progesterone receptor (PgR) positivity, no suggestion of axillary
target in the therapy of PBC [7, 8]. A significant correlation
lymph node involvement by palpation or ultrasound and grading 1–2
between an overexpression of Bcl-2 and a multidrug resistance
because patients with a concomitance of these factors may not require
to chemotherapy [9, 10] and an increased apoptosis by
down-regulation of Bcl-2 through antisense oligonucleotides[9, 11–13] has been shown.
The 18-mer phosphorothiate oligonucleotide (5#-
Histological diagnosis was confirmed by initial core cut biopsy. Paraffin-
TCTCCCAGCGTGCGCCAT-3#) oblimersen (Genasense,
embedded tumor tissue from this biopsy was stained using an automated
G3139) is complementary to the first six codons of the Bcl-2
immunohistochemical technique (BioTek TechMateä, BioTek Solutions,
messenger RNA and depending on the dose it can down-
Newport Beach, CA) with strict adherence to the staining protocol. The
regulate the Bcl-2 protein . The antitumor effect of
following primary antibodies were used (clones in brackets): Her2 (A0485),
oblimersen was significantly improved in combination with
ER (1D5) and PgR (PR88) (all reagents from DakoCytomation Ltd, Ely,
chemotherapeutics like docetaxel  or anthracyclines .
UK). Hormone receptor positivity was assumed when the semiquantitative
Since it is known that the combination of oblimersen/docetaxel
score was at least 3 points out of a maximum of 12 points . Her2
and oblimersen/adriamycin leads to synergistic antitumor
immunoreaction was scored from 0 to 3 with respect to cell membrane
effects in preclinical trials, a combination of TAC with
staining. In the case of a Her2 score 2, FISH was carried out.
oblimersen looks very promising to further increase theefficacy of TAC [17, 18]. Furthermore, oblimersen has only
a moderate toxicity and could easily be combined with other
Oblimersen in combination with TAC was given as continuous i.v.
chemotherapy regimens without compromising their safety
infusion on days 1–7 for one cycle in combination with a fixed dose of75 mg/m2 i.v. docetaxel, a fixed dose of 50 mg/m2 i.v. adriamycin and
[19–22]. Oblimersen can be given safely in combination with
a fixed dose of 500 mg/m2 i.v. cyclophosphamide (TAC regimen) on day 5.
intense chemotherapy and the down-regulation of Bcl-2 may
Following one cycle of oblimersen combined with TAC, the TAC
correlate with response to chemotherapy .
regimen alone was administered every 3 weeks for five cycles. The dose
Preoperative chemotherapy in breast cancer is an ideal
of oblimersen was planned to be escalated according to the scheme
model to evaluate the effects (safety and activity) of new
outlined in Table 1 until dose-limiting toxicity (DLT) would occur in
compounds in this type of tumor. The possibility to have an
more than one of three, two of six or three of nine patients. To increase
easy access to untreated tumor cells before treatment, to
the probability to have patients with adequate tumor biopsies at all biopsy
compare this with the surgical specimen after treatment and
time points available in all oblimersen dose levels, nine patients were
to have additional tumor material from a biopsy during
included in each cohort. An intrapatient dose escalation was not allowed.
treatment, enables to give an insight into biologic effects of
DLT included febrile neutropenia (grade 4 neutropenia with a body
the used treatment on the tumor cells.
temperature >38.5°C), grade 4 thrombocytopenia and any grade 3 or 4
The objectives of this dose-finding phase I study were to
non-hematologic toxicity except for grade 3 alopecia, nausea or
define the maximum tolerated dose (MTD), the safety profile
vomiting. MTD would be defined as the dose at which not more than
and the preliminary clinical and pathological efficacy of one
one of three, two of six or three of nine patients experience DLT.
cycle oblimersen in combination with TAC followed by five
Dexamethason 8 mg was administered orally (p. o.) every 12 h for a total
cycles TAC as NST in patients with PBC.
of six doses starting 12 h before TAC administration. As commonlyrecommended, prophylactic pegfilgrastim (6 mg s.c. fixed dose) the day
Table 1. Dose escalation scheme of oblimersen
This phase I study was carried out to define the MTD for phase IIstudies, safety profile and efficacy of escalating doses of oblimersen in
combination with standard dose of TAC in cycle 1 followed by five cycles of
standard TAC as NST in PBC patients. This trial was stopped due to
premature end of the project after three dose groups were completed. The
study protocol was reviewed and approved by the ethics committee of
the University of Heidelberg, Germany. The study was conducted following
the Declaration of Helsinki in accordance with the Harmonized Tripartite
Guideline for Good Clinical Practice and in accordance with applicable
after TAC and prophylactic antibiotic therapy with ciprofloxacin 500 mg
chemotherapy. If the final tumor size allowed breast-conserving surgery, the
p. o. twice daily were administered for 10 days starting 5 days after TAC
following guidelines were observed: (i) surgical margins were free of
infusion. Adjuvant endocrine treatment in case of positive ER or PgR
invasive or noninvasive breast cancer and, if required, repeat excision was
was applied according to current national guidelines. No trastuzumab
carried out; (ii) an adequate cosmetic result was anticipated and (iii) if
cosmetically acceptable, the whole previously involved area was excised. Inpatients without tumor in diagnostic imaging or palpation or an
blood serum sample collection and analysis
unfavorable ratio of tumor to breast size, a biopsy specimen of adequatesize was taken from a representative area. All patients undergoing
Each blood sample was identified by study code, subject number, date and
a breast-conserving procedure received standard radiotherapy to the
time of sampling and sample number. Approximately 5 ml of blood was
remaining breast. Radiotherapy to the chest wall or regional lymph nodes
collected at the following time points: PK1 (before oblimersen infusion
was carried out according to the national standards. Pathological tumor
on day 1), PK2 (24 h after start of oblimersen infusion on day 2), PK3
response was assessed on all specimens removed at surgery according to
(before start of TAC infusion on day 5), PK4 (1 h after TAC infusion on
Sinn et al. . pCR was defined as no microscopic evidence of
day 5), PK5 (2 h after TAC infusion on day 5) and PK6 (end of
residual viable tumor cells (invasive or noninvasive) in any resected
oblimersen infusion on day 7). Blood samples were drawn into EDTA
specimen of the breast and axillary nodes.
tubes which were placed in a wet ice bath and centrifuged for 20 min with2200 g at 4°C. The resulting plasma was transferred into polypropylene
tubes and frozen at 220°C until shipment. For analysis, frozen plasma
Descriptive statistical methods were used for the analysis of all parameters.
samples were shipped on dry ice to the Department of Drug Metabolism
All results were presented by dose level. The bioanalytical data were
Pharmacokinetics at Aventis, Bridgewater, NJ. Before sample analysis,
acquired and integrated using the Millennium 32 version 4.0 software
a one-day prestudy qualification was carried out. The human plasma
(Waters, Milford, MA). Corrected peak area results were exported from
concentrations for oblimersen (analyte structure, 5#-TCT CCC AGC
Millennium 32 software into Watson version 7.0 (PSS Inc., Wayne, PA) in
GTG CGC CAT-3#) and its N-1 (analyte structure, 5#-TCT CCC AGC
an in tab-delimited text file format. Watson was used to calculate standard
GTG CGC CA-3#) and N-2 (analyte structure, 5#-TCT CCC AGC GTG
curve parameters and concentration data for oblimersen and its N-1 and
CGC C-3#) metabolites were analyzed using a capillary gel electrophoresis
N-2 metabolites. The normalized areas for each analyte (corrected area of
with ultraviolet absorbance detection (CGE/UV) method . Using 0.5 ml
analyte divided by corrected area of internal standard; where corrected area
of EDTA plasma, the calibration range extended from a lower limit of
equals peak area divided by migration time) were plotted against nominal
quantification of 30 up to 4480 ng/ml. The quantitation range extended
standard concentrations to construct calibration curves. The equation of
up to 35 000 ng/ml with 10-fold dilution for oblimersen and its N-1 and
best fit was obtained by fitting the data to a quadratic equation using
N-2 metabolite. The coefficients of determination (r2) for the standard
nonlinear least-squares regression analysis with 1/x2 weighting and used to
curves were ‡0.9739 over seven analysis runs. Accuracy, defined as the
calculate concentrations of the unknown samples and quality controls.
percentage bias between the nominal and the mean measured
Concentration data were reported in three significant figures as the free acid
concentrations of quality controls, ranged from 21.6% to 2.7% (n = 41)
for oblimersen and its N-1 and N-2 metabolites. Calculations of summary
for oblimersen, from 20.5% to 20.2% (n = 41) for its N-1 and from
statistics were carried out in Watson using the rounded concentration data.
22.5% to 11.1% (n = 41) for its N-2 metabolite in plasma over the analysis
The pharmacokinetic parameters of oblimersen and its N1- and N2-
period. The mean accuracy of the dilution controls (1 : 10) was 23.8% for
metabolite were calculated using the SAS/Stat Software (SAS Institute
oblimersen, 26.3% for its N-1 and 26.3% for its N-2 metabolite. The
Inc., Heidelberg, Germany). Actual sampling times were used for the
precision of the assays, established by the coefficient of variation of the
pharmacokinetic analysis. For predose samples, the actual sampling time
quality controls, was better than or equal to 9.4% in plasma.
was set to zero. The pharmacokinetic parameter determined for oblimersenwas area under the serum concentration versus time curve (AUC) from
evaluation of toxicity and clinical response
time point zero to 96 h after the beginning of drug administration (AUC0–
For all safety data, the observation period was divided into two segments:
96). Due to large indefinable variations of the serum concentration curves, it
adverse events at cycle 1 and adverse events after cycle 1, i.e. during cycles
was not possible to analyze the time point 96–168 h after begin of infusion.
2–6. The terminus ‘at cycle 1’ encompassed the time period from startof oblimersen infusion until 21 days after the first administration ofTAC. ‘After cycle 1’ denotes the time period from the second
administration until 21 days after the sixth administration of TAC.
From June 2004 to September 2005, 28 patients were enrolled
Adverse events, i.e. any unfavorable and unintended sign, symptom,
into this phase I study (University of Heidelberg 20 patients,
syndrome or illness that developed or worsened during the observation
University of Munich five patients, University of Frankfurt
period, were reported according to the National Cancer
three patients). Median age was 50 years (range 35–64), median
Institute—Common Toxicity Criteria (NCI-CTC) version 3.0 regardless
Karnofsky performance status 90% (range 90%–100%), 61% of
of the relationship to treatment. Clinically relevant abnormal results of
patients had clinically T2 tumors, 68% had a ductal-invasive
diagnostic procedures including abnormal laboratory findings requiring
histology and 86% were node positive. In all, 43% of tumors
unscheduled diagnostic procedures or treatment measures or resulting in
were poorly differentiated, 36% hormone receptor negative and
withdrawal from the study were considered to be adverse events.
Before treatment, after two and four cycles of TAC and before surgery,
18% overexpressed Her2. Patient and tumor characteristics in
the greatest tumor diameter was measured by palpation and breast
ultrasound. Furthermore, before treatment and before surgery, clinical
Oblimersen was given i.v. on days 1–7 in cycle 1 at three
tumor response was assessed according to Revised Evaluation Criteria in
different dose levels. Nine patients received 3 mg/kg/day
Solid Tumors by mammography and, if indicated, by magnetic resonance
(cohort I), nine patients 5 mg/kg/day (cohort II) and
imaging with the size of the tumor at baseline serving as reference .
10 patients 7 mg/kg/day (cohort III). No deaths occurred. Five
Patients proceeded to surgery within 4 weeks after receiving the last dose of
patients discontinued the study treatment prematurely. Three
Table 2. Patient and tumor characteristics
Table 3. Number (%) of patients with at least one non-hematologicaladverse event at cycle one (OTAC)
nausea, stomatitis, fatigue and alopecia (for details see Table 5).
Sporadic asymptomatic abnormal electrocardiograms were
recorded without apparent association to study treatment
which completely resolved without specific therapy. Four
serious adverse events occurred. One patient in cohort I
developed an NCI-CTC grade 4 hyperemesis following cycle
3. In cohort II, one patient had an NCI-CTC grade 3
pancytopenia and one patient a life-threatening sepsis following
cycle 4. In cohort III, one patient developed an NCI-CTCgrade 4 leucopoenia after cycle 6. There was a trend to less
ER, estrogen receptor; PgR, progesterone receptor; Her2, human epidermal
severe neutropenia with higher pretreatment of oblimersen
(63% of patients in cohort I, 44% of patients in cohort II and25% of patients in cohort III). Only one patient developed
patients went off study following cycle 1. In one patient, the
NCI-CTC grade 3 anemia and thrombocytopenia, no NCI-CTC
diagnosis was corrected to noninvasive ductal carcinoma and
grade 4 anemia or thrombocytopenia was observed.
two patients did not wish to continue. Two patients left the
The bioanalytical data of 153 samples from 27 patients at
study following cycle 4 due to grade 4 pancytopenia with sepsis
six different time points were assessable for analysis (PK1: 27,
and accidental intervertebral disc protrusion, respectively,
PK2: 26, PK3–PK6: 25). The samples of one patient could
which delayed the following treatment for >2 weeks. All five
not be analyzed because of technical problems during analysis
patients gave their agreement to follow further medical history.
preparation. Due to a large indefinable variation of the
A total of 24 patients (86%) experienced an adverse event, 78%,
serum concentration time curves beginning with the first
89% and 90% in cohort I, II and III, respectively.
blood sample following chemotherapy, only the first three
At cycle 1, the most frequent adverse events were fatigue,
blood samples (hours 0–96) were analyzed. Median serum
nausea, anorexia, dysgeusia, headache and alopecia (for details
concentration time curve profile hours 0–96 for all dose
see Table 3). Most adverse events were mild to moderate (NCI-
levels of oblimersen are shown in Figure 1A–C. An example of
CTC grade £ 2), one alert term event occurred. Only four
the large variation in the serum concentration time curve of
serious adverse events occurred, all in cohort III, in relation to
oblimersen at all six different time points is shown in Figure
the study drug, requiring prolonged hospitalization. Two
1D. Maximum serum concentrations were reached within
patients developed an NCI-CTC grade 3 influenza-like illness,
24 h after start of the infusion of oblimersen. The mean area
one patient a NCI-CTC grade 3 pyrexia and one patient an
under the serum concentration time curves from time point
NCI-CTC grade 4 life-threatening leucopoenia. There was an
0 to 96 were 113.13 lg/ml · h, 184.03 lg/ml · h and 323.87
increasing percentage of neutropenia NCI-CTC grade 4 with
lg/ml · h in cohort I, II and III, respectively (Table 6).
increasing dose of study drug at cycle 1 (0% of patients in
Interindividual variability in all pharmacokinetic parameters of
cohort I, 25% of patients in cohort II and 55% of patients in
oblimersen and its N1- and N2-meabolite was relatively low.
Six patients were not assessable for response due to missing
After cycle 1, during the following treatment with five cycles
tumor lesion measurement before surgery. Among the
of TAC, the most frequent adverse events were constipation,
19 patients assessable for clinical response, seven patients (28%)
Table 4. Number of hematological adverse events during at cycle one (OTAC) and after cycle one (TAC · 5) treatment
NTC—CTI, National Cancer Institute—Common Toxicity Criteria.
Table 5. Number (%) of patients with at least one non-hematological adverse event during TAC treatment
achieved a complete (three patients in cohort I, two patients in
chemotherapy, in 10 patients (40%) a mastectomy and in
cohort II and two patients in cohort III) and also seven patients
14 patients (56%) a breast-conserving surgery was carried out;
(28%) a partial remission for an overall clinical response rate of
data from one patient were not available. In all patients,
56%. Among 25 patients who received at least two cycles of
a conventional resection of the axilla was done with a median
Concentration time curve of oblimersen (3mg/kg/d) Concentration time curve of oblimersen (5mg/kg/d) Concentration (ng/ml) Concentration (ng/ml) Time (hours) Time (hours) Concentration time curve of oblimersen (7mg/kg/d) Concentration time curve of oblimersen (3mg/kg/d) Concentration (ng/ml) Concentration (ng/ml) Time (hours) Time (hours)
Figure 1. Concentration time curve 96 h following start of oblimersen infusion in the three different dose groups (A–C) and 168 h following start ofoblimersen infusion in the 3 mg dose group (D).
Table 6. AUC0–96 of oblimersen, its N1 metabolite and N2 metabolite
number of 16 axillary lymph nodes excised (range 2–29 axillary
important targets which regulate the apoptosis. Down-
lymph nodes). None of the patients received a sentinel lymph
regulating Bcl-2 by using a Bcl-2-directed antisense
node biopsy. It was necessary to reoperate five patients as
oligonucleotide can increase chemotherapy-induced apoptosis
resection margins were not free of tumor following the first
and the overall effectiveness of the chemotherapy can be
surgery. Tumors showed no pathologically documented
improved [28–30]. Combining different chemotherapeutics
response (pathological response) in three patients. In
with oblimersen has been shown to be feasible and promising
19 patients, regressive changes of tumor were found, five of
showing e.g. significantly better response rates and progression-
them (20%) showed a histologic complete remission and 14
free survival in advanced melanoma patients [19–22].
patients a partial remission (Table 7).
Oblimersen can also be given safely in combination withintense chemotherapy and the down-regulation of Bcl-2 may
correlate with response to chemotherapy . The schedule ofadministration for the used combination of oblimersen and
Several agents to control regulatory proteins that lead to
TAC is on the basis of a maximal down-regulation of Bcl-2
apoptosis are currently undergoing clinical and preclinical
and apoptosis by the prolonged infusion of oblimersen before
evaluations. The Bcl-2-family, also overexpressed in patients
and during exposure to the chemotherapy [31, 32]. The
with malignant tumors of the breast , is one of those
maximum reduction of bcl-2 can be noted after 72–120 h
Table 7. Tumor response in the three different dose groups after one
was shown in a study with the combination of irinotecan and
cycle of OTAC and at least one cycle of TAC
oblimersen . In contrast to the combination of oblimersen,fludarabine and cyclophosphamide compared with the control
arm without oblimersen, the incidence of severe neutropenia
was slightly higher in the control arm . Anemia and
thrombocytopenia were not pronounced following oblimersen
as compared with TAC alone. However, numbers are rathersmall and interpretation should be made with caution. The
mean serum concentrations in all dose groups were reached
24 h after starting the infusion. Stable plasma levels of
oblimersen could also be achieved after 10–24 h in trials of
oblimersen in combination with dacarbazin or docetaxel [32,
35, 36]. In this study, a large variation at the time of the
chemotherapy in the serum concentrations could be seen.
The recommended dose of 7 mg/kg/day of oblimersen was
shown to be feasible in different phase II and III studies and
could safely be combined with chemotherapy [33, 37, 38].
Following only one cycle of oblimersen in combination with
TAC and five cycles of TAC alone, we observed a pCR defined
as no tumor reside in breast and axilla in five of 22 patients
(18%) assessable for pathological response. Only three of 22
patients did not show any pathological signs of chemotherapy
response. This is in the range of pCR rates reported from NST
trials with TAC alone . However, oblimersen was only
administered for 7 days concurrent with cycle 1. Furthermore,
CR, complete response; PR, partial response; NC, no change; na, not
the primary objectives of this phase I trial were to determine
available; BCS, breast-conserving surgery.
MTD and safety rather than clinical and pathological efficacy. The numbers of patients are too small to draw firm conclusionsregarding efficacy of oblimersen in breast cancer and furtherstudies are needed. Additional parameters are currently
after start of oblimersen infusion. It is recommended to start
evaluated (e.g. Bax, Bcl-2) to identify any pretreatment
the infusion of oblimersen at least 96 h before chemotherapy
tumor or patient characteristics or posttreatment changes
with a minimum dose above 2 mg/kg/day. Due to unclear
induced by oblimersen which are predictive of response.
time point of induction of apoptosis after chemotherapy, the
In conclusion, oblimersen up to a dose of 7 mg/kg/day
oblimersen infusion should be continued 24–48 h after
given as a 24-h infusion on days 1–7 is feasible and can be safely
application of cytostatic treatment.
administered in combination with standard TAC regimen on
Bcl-2 which is overexpressed in patients with breast cancer is
day 5 as NST in patients with PBC. The preliminary efficacy
one of the most important targets that regulate apoptosis .
warrants further evaluation of oblimersen in combination
We carried out a multicentric phase I study of continuous
with every cycle of the TAC regimen in a randomized trial.
infusion of oblimersen administered in combination withTAC as NST in patients with PBC. We found an MTD of
oblimersen of 7 mg/kg/day administered on days 1–7 incombination with standard-dosed TAC administered on day 5.
At that dose level, serious adverse events like leucopenia,pyrexia and influenza-like symptoms occurred in four of 10
patients. As we sought to identify a dose of oblimersen thatwould not compromise the ability to administer TAC at full
We would like to thank Thomas Buechele, Bettina Kammer,
dose and schedule, we stopped further dose escalation. The
Christine Einig and Christian Kieslich for their work.
safety profile of oblimersen in combination with TAC is wellconsistent with the adverse events observed with TAC alone,
although the addition of oblimersen might increase influenza-like symptoms, in particular pyrexia. This is in line with other
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Financial Incentive–Based Approaches for Weight Loss A Randomized Trial Context Identifying effective obesity treatment is both a clinical challenge and a pub- lic health priority due to the health consequences of obesity. Objective To determine whether common decision errors identified by behavioral economists such as prospect theory, loss aversion, and regret could be used to designa
AN INFORMATION THEORETIC APPROACH TO JOINT PROBABILISTIC FACE DETECTION AND TRACKING Department of InformaticsUniversity of ThessalonikiE-mail: eloutas,nikou,pitas @zeus.csd.auth.gr ABSTRACT Head orientation is calculated by using either feature basedmethods [6, 7] or appearance based methods [8, 9]. The latter rely A joint probabilistic face detection and tracking algorithm for com-