Showing papers in "Ejc Supplements in 2006"

Electrochemotherapy – An easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: Results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study

Abstract: Purpose: To evaluate and confirm efficacy and safety of electrochemotherapy with bleomycin or cisplatin on cutaneous and subcutaneous tumour nodules of patients with malignant melanoma and other malignancies in a multicenter study. Patients and methods: This was a two year long prospective non-randomised study on 41 patients evaluable for response to treatment and 61 evaluable for toxicity. Four cancer centers enrolled patients with progressive cutaneous and subcutaneous metastases of any histologically proven cancer. The skin lesions were treated by electrochemotherapy, using application of electric pulses to the tumours for increased bleomycin or cisplatin delivery into tumour cells. The treatment was performed using intravenous or intratumoural drug injection, followed by application of electric pulses generated by a Cliniporator TM using plate or needle electrodes. Tumour response to electrochemotherapy as well as possible sideeffects with respect to the treatment approach, tumour histology and location of the tumour nodules and electrode type were evaluated. Results: An objective response rate of 85% (73.7% complete response rate) was achieved on the electrochemotherapy treated tumour nodules, regardless of tumour histology, and drug used or route of its administration. At 150 days after the treatment (median follow up was 133 days and range 60‐380 days) local tumour control rate for electrochemotherapy was 88% with bleomycin given intravenously, 73% with bleomycin given intratumourally and 75% with cisplatin given intratumourally, demonstrating that all three approaches were

Standard operating procedures of the electrochemotherapy: Instructions for the use of bleomycin or cisplatin administered either systemically or locally and electric pulses delivered by the CliniporatorTM by means of invasive or non-invasive electrodes

Abstract: Lluis M. Mir*, Julie Gehl, Gregor Sersa, Christopher G. Collins , Jean-Remi Garbay, Valerie Billard, Poul F. Geertsen, Z. Rudolf , Gerald C. O’Sullivan, Michel Marty Institut Gustave-Roussy, 39 Rue Camille Desmoulins, F-94805 Villejuif Cedex, France CNRS UMR 8121, Institut Gustave-Roussy, F-94805 Villejuif Cedex, France Univ Paris-Sud, UMR 8121, France Department of Oncology, 54B1, University of Copenhagen at Herlev Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia Cork Cancer Research Centre, Mercy Hospital, Greenville Place, Cork, Ireland

Bases and rationale of the electrochemotherapy

Abstract: Electrochemotherapy (ECT) is a non-thermal tumour ablation modality. ECT is safe and effective on any type of solid tumour. ECT is based on the achievement of in vivo tumor cell electropermeabilization by means of electric pulses locally delivered to the tumors. ECT is also based on the use of non-permeant drugs possessing high intrinsic cytotoxicity (such as bleomycin), or low-permeant drugs with known efficacy (such as cisplatin), which act directly on the cellular DNA. These drugs have to be injected before the electric pulses delivery. Cell electropermeabilisation, a physical procedure that affects all tumor cell types, allows these anticancer drugs to enter the cells, thus magnifying their cytotoxicity by orders of magnitude. However, there are other reasons explaining why this treatment is simple, safe and efficient. Selectivity towards the dividing tumour cells and safety of the procedure are due to the fact that, at least for the bleomycin injected intravenously, treatment causes a mitotic cell death that rapidly kills the dividing tumor cells and spares the neighboring non-dividing normal cells.

Importance of tumour coverage by sufficiently high local electric field for effective electrochemotherapy

Abstract: Electrochemotherapy is an effective local treatment of solid tumours which combines delivery of chemotherapeutic drug and electric pulses. Electric pulses increase permeability of plasma membrane transiently and reversibly, leading to increased transport of the drug into the cell. As all clonogenic cells in the tumour need to be eradicated for effective treatment, all cells have to be permeabilised, i.e. all cells in the tumour have to be exposed to appropriate electric pulses. Electric pulses are delivered to tissue by electric pulses generator via electrodes. In general there are two types of electrodes, plate electrodes and needle electrodes. The target tissue, i.e. tumour, is to be positioned well in-between the electrodes. The electrodes should thus fit the size of the tumour for good electric field distribution. Plate electrodes which are noninvasive are better suited for tumours on the surface on the skin, whereas needle electrodes which are used invasively with appropriate and sufficient depth of their insertion are more appropriate for treating tumours seeded deeper in the skin.

The state-of-the-art of electrochemotherapy before the ESOPE study; advantages and clinical uses

Abstract: Electrochemotherapy provides effective local control of cutaneous and subcutaneous tumour nodules of different malignancies. High objective response rate of ∼80% treated nodules was reported in the majority of clinical studies, with 30–100% long lasting complete responses. This high level of local tumour control was obtained with either systemic drug injection (bleomycin) or local drug injection (cisplatin or bleomycin) with subsequent application of electric pulses to the tumour nodules. The treatment is mostly used for palliation and has in case of in transit metastases of melanoma significant clinical benefit and impact on the quality of life. Furthermore, other clinical uses of electrochemotherapy are: neoadjuvant treatment in form of cytoreductive treatment before conventional treatments, organ and function sparing treatment and treatment of choice of painful and haemorrhagic nodules. Intraoperative treatment of tumours and development of endoluminal electrodes will bring new indications for electrochemotherapy.

200 POSTER Strictly target cell-dependent activation of T cells by bispecific single-chain antibody constructs of the BITE class

Abstract: Bispecific antibodies have been extensively studied in vitro and in vivo for their use in redirected tumor cell lysis. A particular challenge of bispecific antibody constructs that recognize the invariant CD3 signaling complex is a controlled polyclonal activation of T cells that, ideally, is exquisitely dependent on the presence of target cells. Otherwise, overt production of inflammatory cytokines and secondary reactions may occur as side effects, as can be observed with constitutively T-cell activating monoclonal antibodies to CD3 or CD28, and with bispecific antibodies bearing Fc gamma portions. Here we analyzed 2 distinct bispecific single-chain antibody constructs of the BiTE class, called MT110 and MT103 (or MEDI-538), for conditional T-cell activation. In the presence of target-expressing cell lines, low picomolar concentrations of the BiTE molecules were sufficient to stimulate a high percentage of peripheral human T cells to express cytokines and surface activation markers, enter into cell cycle, and induce redirected lysis of target cells. However, in the absence of target cells, the 2 BiTE molecules even at high concentrations did not detectably activate T cells. Our data show that T cell activation by monomeric forms of MT110 and MT103 is highly conditional in that it is strictly dependent on the presence of cells expressing the proper target antigen. BiTE molecules therefore qualify for a highly controlled polyclonal T-cell therapy of cancer.

141 POSTER Effect of population and gender on chemotherapeutic agent-induced cytotoxicity

Abstract: Large interindividual variance is observed in both response and toxicity associated with chemotherapy. Our goal is to identify factors that contribute to chemotherapy-induced toxicity. To this end, we used EBV-transformed B-lymphoblastoid HapMap cell lines derived from 30 Yoruban trios (African descent) and 30 Centre d' Etude du Polymorphisme Humain (CEPH) trios (European descent) to evaluate population- and gender-specific differences in cytotoxicity of carboplatin, cisplatin, daunorubicin, and etoposide using a high-throughput, short-term cytotoxicity assay. The IC(50) was compared for population- and gender-specific differences for the four drugs. We observed large interindividual variance in IC(50) values for carboplatin, cisplatin, daunorubicin, and etoposide for both Yoruban and CEPH populations (range from 8- to 433-fold). Statistically significant differences in carboplatin and daunorubicin IC(50) were shown when comparing Yoruban cell lines (n = 89) to CEPH cell lines (n = 87; P = 0.002 and P = 0.029, respectively). This population difference in treatment induced cytotoxicity was not seen for either cisplatin or etoposide. In the Yoruban population, cell lines derived from females were less sensitive to platinating agents than males [median carboplatin IC(50), 29.1 versus 24.6 micromol/L (P = 0.012); median cisplatin IC(50), 7.0 versus 6.0 micromol/L (P = 0.020) in female and male, respectively]. This difference was not observed in the CEPH population. These results show that population and gender may affect risk for toxicities associated with certain chemotherapeutic agents.

Antisense-mediated downregulation of anti-apoptotic proteins induces apoptosis and sensitizes head and neck squamous cell carcinoma cells to chemotherapy

Abstract: We have earlier reported that the inhibition of apoptosis in head and neck squamous cell carcinomas (HNSCC) is because of upregulated expression of Bcl-2, Bcl-X(L) and Survivin. Hence, we addressed the question whether antisense approach towards these inhibitors of apoptosis could restore the apoptosis in HNSCC. Further, we wanted to see whether chemotherapeutic efficacy of Cisplatin and Etoposide could be enhanced by using these drugs in combination with antisense oligonucleotides in human laryngeal carcinoma HeP2 and tongue carcinoma Cal27 cells. The effect of these antisense oligonucleotides was examined on the mRNA expression by RT-PCR and on protein expression by Western blotting. Apoptosis was measured by flowcytometry, TUNEL assay and caspase-3 activity assay. Treatment of HeP2 and Cal27 cells with 400 nM antisense oligonucleotides against Bcl-2, Bcl-X(L) and Survivin for 48 hrs decreased their expression both at the mRNA as well as at the protein level, resulting in the induction of apoptosis. Treatment of HeP2 and Cal27 cells with these antisense oligonucleotides augmented Cisplatin and Etoposide induced apoptosis. Our findings emphasize the importance of Bcl-2, Bcl-X(L) and Survivin as survival factors in HNSCC cells. Antisense treatment against these survival factors in combination with lower doses of chemotherapy offers potential as a less toxic chemoadjuvant therapy.

Predictors of early recurrence in postmenopausal women with hormone receptor positive breast cancer in the BIG 1-98 trial

Abstract: BACKGROUND Aromatase inhibitors are considered standard adjuvant endocrine treatment of postmenopausal women with hormone receptor-positive breast cancer, but it remains uncertain whether aromatase inhibitors should be given upfront or sequentially with tamoxifen. Awaiting results from ongoing randomized trials, we examined prognostic factors of an early relapse among patients in the BIG 1-98 trial to aid in treatment choices. PATIENTS AND METHODS Analyses included all 7707 eligible patients treated on BIG 1-98. The median follow-up was 2 years, and the primary end point was breast cancer relapse. Cox proportional hazards regression was used to identify prognostic factors. RESULTS Two hundred and eighty-five patients (3.7%) had an early relapse (3.1% on letrozole, 4.4% on tamoxifen). Predictive factors for early relapse were node positivity (P < 0.001), absence of both receptors being positive (P < 0.001), high tumor grade (P < 0.001), HER-2 overexpression/amplification (P < 0.001), large tumor size (P = 0.001), treatment with tamoxifen (P = 0.002), and vascular invasion (P = 0.02). There were no significant interactions between treatment and the covariates, though letrozole appeared to provide a greater than average reduction in the risk of early relapse in patients with many involved lymph nodes, large tumors, and vascular invasion present. CONCLUSION Upfront letrozole resulted in significantly fewer early relapses than tamoxifen, even after adjusting for significant prognostic factors.

Genetic risk profiles for cancer susceptibility and therapy response

Abstract: Cells in the body are permanently attacked by DNA-reactive species, both from intracellular and environmental sources. Inherited and acquired deficiencies in host defense mechanisms against DNA damage (metabolic and DNA repair enzymes) can modify cancer susceptibility as well as therapy response. Genetic profiles should help to identify high-risk individuals who subsequently can be enrolled in preventive measures or treated by tailored therapy regimens. Some of our attempts to define such risk profiles are presented. Cancer susceptibility: Single nucleotide polymorphisms (SNPs) in metabolic and repair genes were investigated in a hospital-based lung cancer case—control study. When evaluating the risk associated with different genotypes for N-acetyltransferases (Wikman et al. 2001) and glutathione-S-transferases (Risch et al. 2001), it is mandatory to distinguish between the three major histological subtypes of lung tumors. A promoter polymorphism of the myeloperoxidase gene MPO was shown to decrease lung cancer susceptibility mainly in small cell lung cancer (SCLC) (Dally et al. 2002). The CYP3A4*1B allele was also linked to an increased SCLC risk and in smoking women increased the risk of lung cancer eightfold (Dally et al. 2003b). Polymorphisms in DNA repair genes were shown to modulate lung cancer risk in smokers, and reduced DNA repair capacity elevated the disease risk (Rajaee-Behbahani et al. 2001). Investigations of several DNA repair gene variants revealed that lung cancer risk was only moderately affected by a single variant but was enhanced up to approximately threefold by specific risk allele combinations (Popanda et al. 2004). Therapy response: Interindividual differences in therapy response are consistently observed with cancer chemotherapeutic agents. Initial results from ongoing studies showed that certain polymorphisms in drug transporter genes (ABCB1) differentially affect response outcome in histological subgroups of lung cancer. Stronger beneficial effects were seen in non-small cell lung cancer (NSCLC) patients following gemcitabine and in SCLC patients following etoposide-based treatment. Several DNA repair parameters (polymorphisms, RNA expression, and DNA repair capacity) were measured in vitro in lymphocytes of patients before radiotherapy and correlated with the occurrence of acute side effects (radio-hypersensitivity). Our initial analysis of several repair gene variants in breast cancer patients (n=446) who received radiotherapy revealed no association of single polymorphisms and the development of side effects (moist desquamation of the irradiated normal skin). The risk for this side effect was, however, strongly reduced in normal weight women carrying a combination of XRCC1 399Gln and APE1 148Glu alleles, indicating that these variants afford some protection against radio-hypersensitivity (Chang-Claude et al. 2005). Based on these data we conclude that specific metabolic and DNA repair gene variants can affect cancer risk and therapy outcome. Predisposition to hereditary cancer syndromes is dominated by the strong effects of some high-penetrance tumor susceptibility genes, while predisposition to sporadic cancer is influenced by the combination of multiple low-penetrance genes, of which as a major challenge, many disease-relevant combinations remain to be identified. Before translating these findings into clinical use and application for public health measures, large populationbased studies and validation of the results will be required.

Which cyclin E prevails as prognostic marker for breast cancer? Results from a retrospective study involving 635 lymph node negative breast cancer patients

Abstract: PURPOSE To evaluate the prognostic value of cyclin E with a quantitative method for lymph node-negative primary breast cancer patients. PATIENTS AND METHODS mRNA transcripts of full-length and splice variants of cyclin E1 (CCNE1) and cyclin E2 (CCNE2) were measured by real-time PCR in frozen tumor samples from 635 lymph node-negative breast cancer patients who had not received neoadjuvant or adjuvant systemic therapy. RESULTS None of the PCR assays designed for the specific splice variants of the cyclins gave additional prognosis-related information compared with the common assays able to detect all variants. In Cox multivariate analysis, corrected for the traditional prognostic factors, high levels of cyclin E were independently associated with a short distant metastasis-free survival [hazard ratio (HR), 3.40; P < 0.001 for CCNE1 and HR, 1.76; P < 0.001 for CCNE2, respectively]. After dichotomizing the tumors at the median level of 70% tumor cells, the multivariate analysis showed particularly strong results for CCNE1 in the group of 433 patients with stroma-enriched primary tumors (HR, 5.12; P < 0.001). In these tumors, the worst prognosis was found for patients with estrogen receptor-negative tumors expressing high CCNE1 (HR, 9.89; P < 0.001) and for patients with small (T1) tumors expressing high CCNE1 (HR, 8.47; P < 0.001). CONCLUSION Our study shows that both CCNE1 and CCNE2 qualify as independent prognostic markers for lymph node-negative breast cancer patients, and that CCNE1 may provide additional information for specific subgroups of patients.

595 POSTER Insulin-like growth factor-I secreted from prostate stromal cells mediates tumor-stromal cell interactions of prostate cancer

Abstract: Prostate cancer shows high expression of type I insulin-like growth factor (IGF-I) receptor (IGF-IR) and prostate stromal cells (PrSC) produce IGF-I. Although high plasma level of IGF-I is a risk factor of prostate cancer, the significance of the prostate stromal IGF-I in the regulation of prostate cancer remains elusive. Here we show that the stromal IGF-I certainly regulates the development of prostate cancer. Coinoculation of PrSC increased the growth of human prostate cancer LNCaP and DU-145 tumors in severe combined immunodeficient mice. The conditioned medium of PrSC, as well as IGF-I, induced phosphorylation of IGF-IR and increased the growth of LNCaP and DU-145 cells. PrSC, but not LNCaP and DU-145 cells, secreted significant amounts of IGF-I. Coculture with PrSC increased the growth of DU-145 cells in vitro but the pretreatment of PrSC with small interfering RNA of IGF-I did not enhance it. Furthermore, various chemical inhibitors consisting of 79 compounds with approximately 60 different targets led to the finding that only IGF-IR inhibitor suppressed the PrSC-induced growth enhancement of DU-145 cells. Thus, these results show that the prostate stromal IGF-I mediates tumor-stromal cell interactions of prostate cancer to accelerate tumor growth, supporting the idea that the IGF-I signaling is a valuable target for the treatment of prostate cancer.

Palliation of haemorrhaging and ulcerated cutaneous tumours using electrochemotherapy

Abstract: By short, intense electric pulses it is possible to cause cell permeabilisation (electroporation) and this can be used to deliver chemotherapy to tumours (electrochemotherapy). Preclinical studies have shown effects on vasculature of electroporation and electrochemotherapy, in particular in tumours. The effect on normal vasculature is a brief reflexory constriction; however in the fragile and abundant vasculature of tumours, a direct anti-vascular effect has been shown. This finding is mirrored in the clinical observation that bleeding, ulcerated lesions cease to bleed after application of electric pulses, and stay dry while the involution of tumours due to uptake of the cytotoxic agent takes place. Ulcerated, bleeding lesions are not uncommon in cancer patients, and cause discomfort due to bleeding and also stigmatisation when lesions are in visible areas. This report describes a case with ulcerated, bleeding lesions where the use of electrochemotherapy has led to efficient and immediate relief of symptoms.

Effective treatment of an extensive recurrent breast cancer which was refractory to multimodal therapy by multiple applications of electrochemotherapy

Abstract: The application of combined chemotherapy and cancer cell permeabilising electric pulses (electrochemotherapy) has been demonstrated here to be clinically effective in the treatment and control of extensive breast cancer. In this case study the application has proven to be successful in the palliative treatment of a patient with recurrent breast wall cancer nodules, where conventional modes of treatment were ineffective in reducing or eliminating the cancer. This novel therapy offers a new surgical approach for the treatment and elimination of previously refractory cancers, improving the survival and quality of life options available to cancer patients.

Current perspectives on the epidemiology of gastrointestinal stromal tumours

Abstract: Gastrointestinal stromal tumours (GISTs) are rare mesenchymal malignancies of the gastrointestinal (GI) tract that are a distinct disease entity based on their molecular pathogenesis, immunohistochemical staining, and responsiveness to targeted therapy. The annual incidence of GIST is 11 to 15 cases per million in studies based on Caucasian populations, with GISTs detected at autopsy and those with a low malignancy potential included. GISTs vary in malignant potential ranging from small, incidentally detected turnours with excellent outcome, to aggressive sarcomas. The appearance and behaviour of GISTs can differ depending on the location within regions of the GI tract. Approximately one third of GISTs worldwide are in the high-risk category for malignant potential, and an inverse correlation between level of risk and survival of GIST patients has been observed. KIT, or more rarely PDGFRA, gene mutations are key to GIST oncogenesis. Criteria for identification of GIST, based on immunoreactivity for the CD117 epitope expressed on KIT, have improved the accuracy of GIST diagnosis and contributed to recognition of GIST as a distinct disease entity. Other markers for diagnostic specificity for GIST are under consideration. Improved diagnosis has led to a slight increase in the observed incidence rate of GIST, which has stabilised in recent years. GISTs are refractory to conventional chemotherapy and surgery was the most effective therapy for GIST prior to the development of the targeted therapy imatinib. Although surgery remains first-line therapy for primary GIST, imatinib is indicated as frontline therapy for metastatic or unresectable GIST.

Successful repetitive treatments by electrochemotherapy of multiple unresectable Kaposi sarcoma nodules

Abstract: We report the successful treatment of a 66-year-old man with failure of conventional local and general treatments for Kaposi sarcoma. He had a poor quality of life because of large ulcerated lesions on both legs. After the first electrochemotherapy session, the largest and the most painful lesions were cleared. Later on, repetitive electrochemotherapy sessions combined with the alternate use of imiquimod application led to an excellent local control with no secondary effect. This case demonstrates that electrochemotherapy can be safely and successfully repeated, with persistent excellent antitumour effects.

The balance between risks and benefits: Long-term use of aromatase inhibitors

Abstract: The third-generation aromatase inhibitors (AIs) are gradually displacing tamoxifen as the preferred adjuvant endocrine treatment for hormone-receptor-positive early breast cancer in postmenopausal women, having demonstrated superior efficacy in clinical trials. However, for the AIs to gain widespread acceptance in the adjuvant setting, good long-term tolerability must also be demonstrated, particularly as many women with early breast cancer can now expect to live for over a decade after initial diagnosis. Tamoxifen has been widely used in this setting for over 30 years, and the side effects associated with its long-term use are well documented. Many adverse events that occur with tamoxifen are predictable consequences of its antiestrogenic actions, including hot flushes and mood disturbances. However, tamoxifen also has estrogenic properties in some tissues, which are associated with desirable and undesirable effects. Of particular importance, tamoxifen can cause unwanted gynecological events, including an increased risk of developing endometrial cancer, and thromboembolic disease. Conversely, tamoxifen protects against postmenopausal bone loss, modestly lowers cholesterol levels and may protect against cardiac disease. As the number of women treated with AIs increases, long-term safety data relating to these agents will gradually accumulate. Safety data are currently available from early adjuvant trials comparing an AI with tamoxifen during the first 5 years after surgery (sequential and substitution strategies), and from the extended adjuvant setting, comparing letrozole with placebo after completion of 5 years of tamoxifen therapy (the MA.17 trial). In early adjuvant studies, the use of tamoxifen as a comparator can complicate the analysis of safety data, particularly in tissues where tamoxifen has beneficial, estrogenic effects. Studies in the early adjuvant setting have shown that AIs are generally well tolerated and are associated with a lower incidence of vaginal bleeding, thromboembolic disease and endometrial cancer than tamoxifen. Results from these studies have suggested that AIs are associated with musculoskeletal side effects, including bone loss, osteoporosis and fractures, cardiovascular disease and hypercholesterolemia. However, analysis of safety data from MA.17, with a placebo control, showed no evidence of adverse effects of letrozole on the cardiovascular system or lipid profiles. When the data from early and extended adjuvant studies are considered together, it can be concluded that the increased incidences of hypercholesterolemia and cardiovascular disease seen in patients taking an AI probably reflect the lack of the protective effects of tamoxifen in these patients rather than a detrimental effect of the AI. Bone loss is a predictable consequence of the near-complete elimination of circulating estrogen achieved by third-generation AIs in postmenopausal women. In the MA.17 trial, although more women on letrozole reported new, self-diagnosed osteoporosis than those on placebo, the number of clinical fractures did not differ significantly between the two treatment arms, however, further follow-up is needed. Furthermore, ongoing studies are evaluating the role of bisphosphonates and other agents to better characterize and potentially ameliorate AI-associated bone loss in postmenopausal women. The adverse events associated with AI use are predictable and manageable. On the basis of current data, the tolerability of AIs in the adjuvant setting appears as good as that of tamoxifen, and some serious adverse events associated with tamoxifen use are avoided. Further studies and longer follow-up from current trials will help to determine in more detail the long-term effects of this class of drugs.

Long lasting complete response in melanoma treated by electrochemotherapy

Abstract: The optimal treatment of multiple cutaneous and subcutaneous metastases of melanoma still remains unresolved. There are many different possible treatment modalities. We present a case of melanoma on the calf in which multiple cutaneous and subcutaneous metastases were treated by electrochemotherapy with cisplatin. They completely responded for eight years. After eight years two new metastatic nodules occurred and were treated by electrochemotherapy with cisplatin and again complete response was achieved. The case presents the advantages of electrochemotherapy of multiple cutaneous and subcutaneous metastases of melanoma, its relative simplicity, its minimal side effects and the possibility to treat recurrent disease as many times as needed, with long lasting complete responses.

647 POSTER A phase I dose-escalation study of weekly IMC-1121B, a fully human anti-vascular endothelial growth factor receptor 2 (VEGFR2) IgG1 monoclonal antibody (Mab), in patients (pts) with advanced cancer

Abstract: 3032 Background: Anti-VEGFR2 antibodies are effective in a variety of preclinical leukemia and solid tumor models. IMC-1121B is a fully human anti-VEGFR2 IgG1 Mab. METHODS Cohorts of 3-6 pts (ECOG PS ≤ 2) with advanced cancer and no significant cardiovascular, thrombotic or bleeding disorders received escalating doses of IMC-1121B. A single initial dose with extended PK sampling was followed by 4 x weekly infusions per treatment cycle starting at 2mg/kg. 7 dose levels up to a maximum of 16 mg/kg are planned. Human anti-human antibodies (HAHA) directed against IMC-1121B were assessed at baseline and before each Week 4 dose. Tumor response was assessed every 2 cycles. PD analyses include DCE-MRI, serum VEGF and sVEGFR1/2 levels, and peripheral blood mononucleocyte gene expression profiling at baseline and post-dosing. RESULTS 12 pts (8 M; 4 F), median age 58 years (range: 36-76), have entered the study: cohort 1 (2mg/kg) n=6, cohort 2 (4mg/kg) n=4 and cohort 3 (6mg/kg) n=2. No toxicities ≥ grade 2, considered definitely or probably related to study drug, have occurred. Toxicities ≥ grade 2 possibly drug-related include anorexia, vomiting, anemia, depression, fatigue, and insomnia. To date, there has been one unconfirmed partial response (melanoma) and 5 pts with stable disease for >3 months (colon: 2, breast, gastric, thyroid). Preliminary non-compartmental PK analysis reveals dose-dependent elimination and non-linear exposure, consistent with saturable clearance mechanism(s): mean t1/2 = 63.62, 93.46, 99.63 hrs, mean Cmax = 43.67, 80.25, 264 ug/mL, and AUC0-Inf = 3860, 9242, 27437 hr*ug/mL, at the 2, 4, and 6 mg/kg dose levels, respectively. CONCLUSIONS Weekly administration of IMC-1121B is well tolerated at doses up to 6mg/kg/week. There is early evidence of a non-linear dose-PK relationship. Dose escalation continues. Updated safety, PK, PD, HAHA, and efficacy data will be presented. [Table: see text].

Head-to-head: docetaxel challenges paclitaxel

Abstract: Among the novel chemotherapeutic drugs introduced in the 1990s, the taxoids have emerged as the most powerful compounds in metastatic breast cancer. For a number of years, clinical trials have investigated the efficacy of the two taxoids, docetaxel (Taxotere | and paclitaxel (Taxol| and oncologists have long asked the question whether the two agents are clinically different. However, until this time, only indirect clinical comparisons of these agents had been performed, which were imprecise owing to differences in patient populations. The TAX 311 study is the first and only head-to-head randomised phase III study to compare directly the efficacy and safety of docetaxel and paclitaxel for patients with advanced breast cancer. An early study in patients with paclitaxel-resistant breast cancer revealed differences between the taxoids and now, with the results of the newly published TAX 311 trial, it is possible to make a definitive comparison of docetaxel and paclitaxel. As previously mentioned, paclitaxel was isolated from the bark of the Pacific yew tree (Taxus brevifolia) and docetaxel was, some years later, prepared from 10-deacetylbaccatin III, isolated from the needles of the European yew tree (Taxus baccata)[1]. Despite both compounds being members of the same class of cytotoxic agent, preclinical studies demonstrated that docetaxel had a number of advantages over paclitaxel. Compared with paclitaxel, docetaxel had a wider cell-cycle activity and demonstrated a greater affinity for the (5-tubulin binding site [2]. These effects were accompanied by greater uptake and slower efflux of docetaxel from tumour cells, resulting in longer intracellular retention time and higher intracellular concentrations than those achieved with paclitaxel[3]. Compared with paclitaxel, docetaxel demonstrated more potent induction of bcl-2 phosphorylation and exhibited up to a 12-fold increase in cytotoxic activity[2,4 6]. Also, growth inhibition in human epidermal growth t%ctor receptor 2 (HER2)-positive cells was greater for docetaxel than for paclitaxel [7]. Lastly, the increased upregulation of thymidine phosphorylase observed with docetaxel and