Mdn280 1698.1705

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 [1]. 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 [2]. 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) [3].
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 [14]. 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 [15] or anthracyclines [16].
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 [24]. 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 [23].
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. [27]. 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 [25]. 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 [26].
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 [23]. 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 [8], 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 [33]. 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 [18]. 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 [3]. 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 [5].
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 1. Effects of chemotherapy and hormonal therapy for early breast cancer on studies of oblimersen and irinotecan where a higher number of recurrence and 15-year survival: an overview of the randomised trials. Lancet pyrexia could be demonstrated [33]. This phenomenon can 2. Kaufmann M, von Minckwitz G, Smith R et al. International expert panel on the be explained as a reaction to the tumorlysis and the cytokine use of primary (preoperative) systemic treatment of operable breast cancer: release [18, 34]. Furthermore, there was an increasing incidence review and recommendations. J Clin Oncol 2003; 21(13): 2600–2608.
of NCI-CTC grade 4 leucopoenia and neutropenia with 3. von Minckwitz G, Blohmer JU, Raab G et al. In vivo chemosensitivity-adapted increasing doses of oblimersen. This suggests an additional preoperative chemotherapy in patients with early-stage breast cancer: the cytotoxic effect of oblimersen against the white cell line, which GEPARTRIO pilot study. Ann Oncol 2005; 16(1): 56–63.
4. Chao DT, Korsmeyer SJ. BCL-2 family: regulators of cell death. Annu Rev 23. Marcucci G, Stock W, Dai G et al. Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: 5. Green DR, Evan GI. A matter of life and death. Cancer Cell 2002; 1(1): 19–30.
pharmacokinetics, pharmacodynamics, and clinical activity. J Clin Oncol 2005; 6. Reed JC. Apoptosis-targeted therapies for cancer. Cancer Cell 2003; 3(1): 17–22.
7. Buchele T. Proapoptotic therapy with oblimersen (bcl-2 antisense 24. Remmele W, Stegner HE. Recommendation for uniform definition of an oligonucleotide)—review of preclinical and clinical results. Onkologie 2003; 26 immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 1987; 8(3): 138–140.
8. Krajewski S, Thor AD, Edgerton SM et al. Analysis of Bax and Bcl-2 expression in 25. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the p53-immunopositive breast cancers. Clin Cancer Res 1997; 3(2): 199–208.
response to treatment in solid tumors. European Organization for Research and 9. Schmitt CA, Rosenthal CT, Lowe SW. Genetic analysis of chemoresistance in Treatment of Cancer, National Cancer Institute of the United States, National primary murine lymphomas. Nat Med 2000; 6(9): 1029–1035.
Cancer Institute of Canada. J Natl Cancer Inst 2000; 92(3): 205–216.
10. Tu SM, McConnell K, Marin MC et al. Combination adriamycin and suramin 26. Sinn HP, Schmid H, Junkermann H et al. Histologic regression of breast cancer induces apoptosis in bcl-2 expressing prostate carcinoma cells. Cancer Lett after primary (neoadjuvant) chemotherapy. Geburtshilfe Frauenheilkd 1994; 11. Koty PP, Zhang H, Levitt ML. Antisense bcl-2 treatment increases programmed 27. Miayake H, Tolcher A, Gleave ME. Chemosensitization and delayed androgen- cell death in non-small cell lung cancer cell lines. Lung Cancer 1999; 23(2): independent recurrence of prostate cancer with the use of antisense Bcl-2 oligodeoxynucleotides. J Natl Cancer Inst 2000; 92(1): 34–41.
12. Ziegler A, Luedke GH, Fabbro D et al. Induction of apoptosis in small-cell lung 28. Hopkins-Donaldson S, Cathomas R, Simoes-Wust AP et al. Induction of apoptosis cancer cells by an antisense oligodeoxynucleotide targeting the Bcl-2 coding and chemosensitization of mesothelioma cells by Bcl-2 and Bcl-xL antisense sequence. J Natl Cancer Inst 1997; 89(14): 1027–1036.
treatment. Int J Cancer 2003; 106(2): 160–166.
13. Zangemeister-Wittke U, Schenker T, Luedke GH et al. Synergistic cytotoxicity 29. Frankel SR. Oblimersen sodium (G3139 Bcl-2 antisense oligonucleotide) therapy of bcl-2 antisense oligodeoxynucleotides and etoposide, doxorubicin and in Waldenstrom’s macroglobulinemia: a targeted approach to enhance cisplatin on small-cell lung cancer cell lines. Br J Cancer 1998; 78(8): apoptosis. Semin Oncol 2003; 30(2): 300–304.
30. Waters JS, Webb A, Cunningham D et al. Phase I clinical and pharmacokinetic 14. Cotter FE, Johnson P, Hall P et al. Antisense oligonucleotides suppress B-cell study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin’s lymphoma growth in a SCID-hu mouse model. Oncogene 1994; 9(10): lymphoma. J Clin Oncol 2000; 18(9): 1812–1823.
31. Morris MJ, Tong WP, Cordon-Cardo C et al. Phase I trial of BCL-2 antisense 15. Yang D, Ling Y, Amazan M et al. Tumor regression of human breast carcinomas oligonucleotide (G3139) administered by continuous intravenous infusion in by combination therapy of anti-bcl-2 antisense oligonucleotide and patients with advanced cancer. Clin Cancer Res 2002; 8(3): 679–683.
chemotherapeutic drugs. Proc Am Assoc Cancer Res 1999; 40: 729 (Abstr 4814).
32. Mita MM, Ochoa L, Rowinsky EK et al. A phase I, pharmacokinetic and 16. Kitada S, Takayama S, De Riel K et al. Reversal of chemoresistance of lymphoma biologic correlative study of oblimersen sodium (Genasense, G3139) and cells by antisense-mediated reduction of bcl-2 gene expression. Antisense Res irinotecan in patients with metastatic colorectal cancer. Ann Oncol 2006; 17(2): 17. Tolcher AW, Chi K, Kuhn J et al. A phase II, pharmacokinetic, and biological 33. O’Brien SM, Cunningham CC, Golenkov AK et al. Phase I to II multicenter study correlative study of oblimersen sodium and docetaxel in patients with hormone- of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in patients with refractory prostate cancer. Clin Cancer Res 2005; 11(10): 3854–3861.
advanced chronic lymphocytic leukemia. J Clin Oncol 2005; 23(30): 18. O’Brien S, Moore JO, Boyd TE et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in 34. de Bono JS, REK, Kuhn J et al. Phase I pharmacokinetic (PK) and patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol pharmacodynamic (PD) trial of bcl-2 antisense (Genasense) and docetaxel (D) in hormone refractory prostate cancer. Proc Am Soc Clin Oncol 2001; 20: 81.
19. Herbst RS, Frankel SR. Oblimersen sodium (Genasense bcl-2 antisense 35. Jansen B, WV, Heere-Ress E, Hoeller C et al. Clinical, pharmocologic, and oligonucleotide): a rational therapeutic to enhance apoptosis in therapy of lung pharmacodynomic study of genasense (G3139, Bcl-2 antisense oligonucleotide) cancer. Clin Cancer Res 2004; 10(12 Pt 2): 4245s–4248s.
and dacarbazine (DTIC) in patients with malignant melanoma. Proc Am Soc Clin 20. Bedikian AY, Millward M, Pehamberger H et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen 36. Moore J, Seiter K, Kolitz J et al. A phase II study of Bcl-2 antisense (oblimersen Melanoma Study Group. J Clin Oncol 2006; 24(29): 4738–4745.
sodium) combined with gemtuzumab ozogamicin in older patients with acute 21. Gertz MA, Geyer SM, Badros A et al. Early results of a phase I trial of oblimersen myeloid leukemia in first relapse. Leuk Res 2006; 30(7): 777–783.
sodium for relapsed or refractory Waldenstrom’s macroglobulinemia. Clin 37. Tolcher AW, Kuhn J, Schwartz G et al. A Phase I pharmacokinetic and biological correlative study of oblimersen sodium (genasense, g3139), an antisense 22. Klasa RJ, Gillum AM, Klem RE et al. Oblimersen Bcl-2 antisense: facilitating oligonucleotide to the bcl-2 mRNA, and of docetaxel in patients with apoptosis in anticancer treatment. Antisense Nucleic Acid Drug Dev 2002; 12(3): hormone-refractory prostate cancer. Clin Cancer Res 2004; 10(15):


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