Previous Chemotherapy For Metastatic Disease Research Articles

Abstract P4-10-25: Pretreatment serum metabolome predicts PFS in first-line trastuzumab-treated metastatic breast cancer

Abstract Background: Cancer cells have altered metabolism, which contributes to their ability to proliferate, survive in unusual microenvironments, and invade other tissues. Measuring the complete set of metabolites in an individual (i.e. the metabolome) provides a functional readout for cellular pathways. Further, changes in the metabolome can be correlated with disease status, prognosis and progression. Using a metabolomics platform and machine learning algorithms, biomarker signatures can be identified to predict response to therapy. Metabolite analysis of pretreatment plasma has shown promise for predicting response in a small retrospective study of the CDK 4/6 inhibitors palbociclib and ribociclib in hormone receptor-positive metastatic breast cancer (Zhang B et al, ASCO 2019 Abstr 3043). HER2-positive metastatic breast cancer patients have significant heterogeneity in response and progression-free survival (PFS) to HER2-targeted therapy. Here we retrospectively evaluated the pretreatment serum metabolome for association with PFS in a cohort of trastuzumab-treated metastatic breast cancer patients from a single institution. Methods: Pretreatment serum from 26 HER2-positive trastuzumab-naive metastatic breast cancer patients who were treated with first-line trastuzumab and chemotherapy were included in this exploratory analysis. Metabolites were extracted from previously frozen serum (1 mL) using ice-cold methanol and chloroform. The resulting metabolites were isolated and quantified using an unbiased, non-destructive, nuclear magnetic resonance (NMR)-based profiling platform (Olaris, Inc., Cambridge, MA). The serum was analyzed via 1D 1H NMR and 2D 13C-1H heteronuclear single quantum coherence spectroscopy (HSQC) using customized non-uniform sampling (NUS) techniques and processed with proprietary Olaris software. Supervised and unsupervised machine learning algorithms were used to identify patients with shorter and longer PFS to trastuzumab-based therapy. Results: The median PFS for this cohort was 301 days. Patients were subdivided into early progressors (PFS < 301 days) and late progressors (PFS ≥ 301 days). 23 metabolite resonance levels were statistically different between the two groups (KW test p<0.05, 11 metabolites expected by chance). Using advanced machine learning we constructed a model based on 5 metabolite resonances that showed significant discriminatory ability with an AUC of 0.964 using receiver-operating curve (ROC) analysis. 21 of the 26 patients received trastuzumab and chemotherapy as a first-line therapy, while the remaining 5 patients received first-line trastuzumab with subsequent chemotherapy, after 1 or more lines of previous chemotherapy for metastatic disease. We repeated our analysis using only the first-line therapy subgroup and identified a partially overlapping set of metabolite resonances that could nearly perfectly discriminate early and late progressors with an AUC of 0.973. Further efforts are underway to confirm the identity of these metabolites. Conclusions: Metabolic profiling of pretreatment serum using NMR was successful in identifying a biomarker signature that predicted PFS to trastuzumab in HER2-positive metastatic breast cancer. Expanded metabolome analysis is warranted in larger cohorts and clinical trials to confirm that this serum biomarker signature predicts PFS to trastuzumab therapy, particularly in the first-line setting. Further, by identifying the metabolites and metabolic pathways that differ between early and late progressors, it may be possible to identify novel targets and/or suggest combination treatments in the HER2-positive metastatic breast cancer setting. Citation Format: Elizabeth O'Day, Kim Leitzel, Suhail M Ali, Bo Zhang, Chen Dong, Haiwei Gu, Xiajian Shi, Joseph J Drabick, Leah Cream, Monali Vasekar, Hyma V Polimera, Vinod Nagabhairu, Prashanth Moku, Ashok Maddukuri, Harry Menon, Neha Pancholy, Walter P Carney, Wolfgang Koestler, Allan Lipton. Pretreatment serum metabolome predicts PFS in first-line trastuzumab-treated metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-25.

Exemestane and Everolimus combination treatment of hormone receptor positive, HER2 negative metastatic breast cancer: A retrospective study of 9 cancer centers in the Campania Region (Southern Italy) focused on activity, efficacy and safety.

Exemestane (Exe) in combination with Everolimus (Eve) represents an important treatment option for patients diagnosed with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC), which was previously treated with non-steroidal aromatase inhibitors (NSAI). Data from unselected populations may be useful for defining the optimal therapeutic algorithm within a clinical setting. Data from 264 HR+, HER2-MBC patients who received Exe-Eve treatment in combination, following the failure of NSAIs was retrospectively analyzed. Different lines of endocrine treatment (ET) were investigated to evaluate the efficacy and toxicity of the treatment within the ‘everyday clinical practice’ population. The disease control rate (DCR) was 73.1%, with no statistically significant difference among the different settings. At a median follow-up of 42 months, the median progression free survival (PFS) was 11.6, 9.7 and 7.5 months for patients treated with Exe-Eve as first, second or third line therapy, respectively. There was a statistically significant correlation with younger age, no previous adjuvant chemotherapy (CT), no previous adjuvant endocrine therapy (ET), HT duration ≥36 months, involvement of liver and/or lung, no prior CT for metastatic disease and PS=0 at the start of treatment. The median overall survival (OS) was 33.0 months; at a median follow-up of 67 months, the median OS was 43.1, 31.7 and 27.9 months in patients treated with Exe-Eve in first, second or third line therapy, respectively. On multivariate analysis, diabetes and previous CT for metastatic disease were revealed to correlate with a worse outcome. Conversely, the presence of mucositis was significantly associated with long-term survival. Overall, Exe-Eve was typically well tolerated and the majority toxicities were G1 or 2, while treatment discontinuation due to unacceptable toxicity was only required in 5.7% of patients. Despite the limitations due to the observational nature of this study, the findings suggest that treatment with Exe-Eve is an active and safe therapeutic option for endocrine-sensitive MBC patients in a real-world clinical setting, regardless of treatment lines.

Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer (EORTC 75111-10114): an open-label, randomised, phase 2 trial from the Elderly Task Force/Breast Cancer Group

Despite the high incidence of metastatic breast cancer and its related mortality in the elderly population, our knowledge about optimal treatment for older patients with cancer is far from adequate. We aimed to evaluate the efficacy of dual anti-HER2 treatment with or without metronomic chemotherapy in older patients with HER2-positive metastatic breast cancer. We did a multicentre, open-label, randomised, phase 2 trial in 30 centres from eight countries in Europe, in patients with histologically proven, HER2-positive metastatic breast cancer, without previous chemotherapy for metastatic disease, who were 70 years or older, or 60 years or older with confirmed functional restrictions defined by protocol, and had a life expectancy of more than 12 weeks and a performance status according to WHO scale of 0-3. Eligible patients were randomly assigned (1:1) by an online randomisation system based on the minimisation method to receive metronomic oral cyclophosphamide 50 mg per day plus trastuzumab and pertuzumab, or trastuzumab and pertuzumab alone. Trastuzumab was given intravenously with a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Pertuzumab was given intravenously with a loading dose of 840 mg, followed by 420 mg every 3 weeks. Patients were stratified by hormone receptor positivity, previous HER2 treatment, and baseline geriatric screening. The primary endpoint was investigator-assessed progression-free survival at 6 months as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A difference of 10% or greater between the two groups was sought. Efficacy analyses were by intention to treat; safety was assessed in all patients who received at least one dose of study treatment. In case of progression, all patients were offered trastuzumab emtansine. This trial is registered with ClinicalTrials.gov, number NCT01597414, and is completed. Between July 2, 2013, and May 10, 2016, 80 patients, of whom 56 (70%) had a potential frailty profile according to the geriatric screening G8 score (≤14), were randomly assigned to receive trastuzumab and pertuzumab (n=39) or trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (n=41). Estimated progression-free survival at 6 months was 46·2% (95% CI 30·2-60·7) with trastuzumab and pertuzumab versus 73·4% (56·6-84·6) with trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (hazard ratio [HR] 0·65 [95% CI 0·37-1·12], p=0·12). At a median follow-up of 20·7 months (IQR 12·5-30·4), the median progression-free survival was 5·6 months (95% CI 3·6-16·8) with trastuzumab and pertuzumab versus 12·7 months (6·7-24·8) with the addition of metronomic oral cyclophosphamide. The most frequent grade 3-4 adverse events were hypertension (in six [15%] of 39 patients in the trastuzumab and pertuzumab group vs five [12%] of 41 in the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group), diarrhoea (four [10%] vs five [12%]), dyspnoea (two [5%] vs four [10%]), fatigue (three [8%] vs two [5%]), pain (two [5%] vs two [5%]), and a thromboembolic event (0 [0%] vs four [10%]). Severe cardiac toxicities were occasionally observed in both groups. In the trastuzumab and pertuzumab group four patients died without progression, due to cardiac arrest during treatment (n=1), peritoneal infection (n=1), respiratory failure (n=1), and sudden death without a specified cause (n=1). In the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group, one patient died from heart failure. Addition of metronomic oral cyclophosphamide to trastuzumab plus pertuzumab in older and frail patients with HER2-positive metastatic breast cancer increased median progression-free survival by 7 months compared with dual HER2 blockade alone, with an acceptable safety profile. Trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, followed by trastuzumab emtansine after disease progression, might delay or supersede the need for taxane chemotherapy in this population. F Hoffmann-La Roche.

Abstract OT2-2-07: A phase II study of S-1 (14 days' administration followed by 7 days' rest) for metastatic breast cancer

Abstract Background S-1, an orally administered fluorinated pyrimidine (FP), improves overall survival in the adjuvant setting of gastric and pancreatic cancer. It is also effective for metastatic breast cancer (Yamamoto et al. Anticancer Res 30:3827-32, 2010). Although S-1 is usually administered for 28 days followed by 14 days’ rest, severe adverse events are often observed by Day 15. By altering the schedule into 14 days’ administration followed by 7 days’ rest, discontinuation of treatment can often be avoided in daily practice. This schedule maintains the same dose intensity. Equally, an anti-tumor effect and fewer adverse events are observed in 14 days’ administration followed by 7 days’ rest than in 28 days’ administration followed by 14 days’ rest for the treatment of squamous cell carcinoma of the head and neck (Tsukuda et al. Br J Cancer 93:884-889, 2005). In order to reduce the occurrence and severity of adverse events of S-1, we paid attention to dose reduction according to the renal function of patients. S-1 is comprised of tegafur, 5-chloro-2, 4-dihydroxy-pyridine(CDHP) and potassium oxonate. CDHP enhances the serum concentration of 5-FU by inhibiting dihydropyrimidine dehydrogenase (DPD), and it is excreted by the kidneys. Therefore, an accumulation of DPD in patients with renal dysfunction escalates the serum concentration of 5-FU and induces more severe adverse events. Thus, the dosage of S-1 should be reduced according to renal function. Trial design This is a phase II trial to evaluate the efficacy and toxicity of S-1 (14 days’ administration followed by 7 days’ rest) for metastatic breast cancer. S-1 is administered orally twice daily at a dose of 40-60 mg depending on the BSA and creatinine-clearance from Days 1 to 14, which is followed by 7 days’ rest. This treatment is repeated until disease progression. (Trial registration :UMIN 000014096) Eligibility criteria Patients with histologically confirmed breast cancer, and recurrent and /or metastatic disease are included. Patients with HER2-positive (IHC:3+ or FISH+) tumor are excluded. Patients within 2 lines of previous chemotherapy for metastatic disease are allowed. Eligible patients are aged between 20 years and 80 years with a performance status of 0 to 2 and adequate organ function. Specific aims The primary endpoint is the response rate, and the secondary endpoints are disease control rate, progression-free survival, time to failure, toxicities and feasibility. Statistical methods The sample size was calculated using the Simon method, with a type I error of 5% and a study power of 90%. The unpromising response rate was 15% and the promising rate was 42%. The required number of patients was estimated to be 23. Target accrual Accrual of 25 patients was planned to produce a minimum of 23 evaluable patients. Patient accrual started in June 2014. Citation Format: Akira Hirano, Akinori Hattori, Kaoru Ogura, Hiroaki Inoue, Fumie Okubo, Mari Kamimura, Shiho Sakaguchi, Jun Kinoshita, Reiko Miyamoto, Norie Jibiki, Yoshihiko Naritaka, Tadao Shimizu. A phase II study of S-1 (14 days' administration followed by 7 days' rest) for metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-2-07.

Abstract P3-10-02: Gemcitabine with cisplatin or paclitaxel in metastatic triple-negative breast cancer

Abstract Background: There is still no standard chemotherapy for patients with metastatic triple-negative breast cancer (mTNBC). Our previous phase II pilot trial with first-line gemcitabine and cisplatin combination (GP) in patients with mTNBC (clinicaltrials.gov Identifier: NCT00601159) showed a median progression-free survival (PFS) of 6.2 months. In this Chinese Breast Cancer Study Group (CBCSG) 006 trial (clinicaltrials.gov Identifier: NCT01287624) we explored in a randomized trial the role of the less costly GP regimen versus the standard GT [Gemcitibine + paclitaxel] chemotherapy for the metastatic breast cancer as a first line treatment for mTNBC. Trial objectives: progression free survival [PFS]; overall survival [OS]; and toxicity. Methods: In the trial with a hybrid trial design incorporating a formal test of superiority as well as noninferiority, mTNBC patients with no previous chemotherapy for metastatic disease were randomly assigned to receive either GP regimen (G/P: 1250 mg/m2 d1,8/ 75 mg/m2 d1) or the GT regimen (same G; T: 175 mg/m2 d1). Results: Between Jan. 2011 and Nov., 2013, 236 patients were randomized [118 patients / arm], and all received at least one dose of assigned chemotherapy. As of Mar. 20, 2014, the intent-to-treat analysis showed 201 recurrences and 97 deaths. Objective response rates of GP vs GT were 67.9% vs. 50.4% (P= 0.008), with median PFS of 232 vs. 194 days (HR=0.692, 95% CI 0.523-0.915; P= 0.009). Overall survival of patients from the GP vs. the GT arms was median 672 vs. 556 days (HR=0.902, 95% CI 0.605-1.344; P= 0.611). Significant differences in grade 3/4 adverse events were seen for nausea, vomiting, anemia and thrombocytopenia [GP vs. GT, 6.8 vs. 0.8%; 11.0 vs. 0.8%; 33.1 vs. 51.0%; and 32.2 vs. 2.5%, respectively]. In addition, assessment of adverse events of any grade showed the GP regimen had more anorexia, constipation, hypomagnesemia and hypokalemia, while GT regimen had significantly more alopecia and peripheral neuropathy. The delivered relative dose intensity was > 90% for all three drugs, with the total number of delivered cycles of chemotherapy in GP and GT arms being 654 and 648 [average 5.54 and 5.49 /patient], respectively. Conclusions: 1.The Gemcitabine + Platinum is superior to Gemcitabine + Paclitaxel in terms of objective response rates and duration of PFS. 2.While grade 3 / 4 nausea & vomiting, and anemia, were heavier for the GP combination, the delivery of chemotherapy and average number of cycles delivered were comparable between the two arms. 3.Overall survival data will be updated on the conference to indicate the long-term effect of the somehow more toxic GP regimen, which shows nevertheless superiority of response rates and of the PFS over the more costly GT regimen. Citation Format: Xichun Hu, Binghe Xu, Li Cai, Zhonghua Wang, Biyun Wang, Jian Zhang, Yuee Teng, Zhongsheng Tong, Yueyin Pan, Yongmei Yin, Changping Wu, Zefei Jiang, Xiaojia Wang, Guyin Lou, Donggeng Liu, Jifeng Feng, Jianfeng Luo, Jiong Wu, Zhimin Shao, Joseph Ragaz. Gemcitabine with cisplatin or paclitaxel in metastatic triple-negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-10-02.

Phase I/IB trial of eribulin and everolimus in patients with triple-negative metastatic breast cancer.

TPS2637 Background: Eribulin mesylate is a synthetic analog of halichondrin B via tubulin-based anti-mitotic mechanism, leads to G2/M cell cycle arrest, disruption of mitotic spindles, apoptotic cell death and inhibits the phosphorylation of AKT in TNBC cells. Everolimus inhibits mTOR pathway. With mTOR inhibition, pAKT is enhanced, seen at 24 hours with everolimus alone in TNBC cell lines Ser473 and SKBR3. Combination of eribulin and everolimus suppressed both pAKT and pS6K1 at 24 hours. Based on our preclinical findings, we hypothesize that everolimus and eribulin will have a synergistic effect with inproved clinical activity in metastatic TNBC. Objectives: phase I/IB trial of everolimus plus eribulin in metastatic TNBC. Phase I determines the safety & tolerability and the recommended Phase II dose (RP2D), while the Phase IB will evaluate event free survival rate at RP2D. Methods: Eligibility: Metastatic TNBC who progressed on anthracyclines/taxanes, and previous chemotherapy for metastatic disease (up ...

Phase II study of helical tomotherapy in the multidisciplinary treatment of oligometastatic colorectal cancer.

653 Background: Complete metastasectomy provides a real chance for long-term survival in patients with oligometastatic colorectal cancer (CRC). For patients who are not amenable for metastasectomy, we demonstrated in a previous study the feasibility of moderately hypofractionated intensity-modulated and image-guided radiotherapy (RT) by helical tomotherapy. Aiming at higher response rates, we evaluated in this study helical tomotherapy delivering 50 Gy in daily fractions of 5 Gy. Methods: Inoperable CRC patients with ≤ 5 metastases were enrolled. No limitations concerning dimension or localization of the metastases were imposed. Whole body PET-CT was performed at baseline and 3 months after the initiation of RT to evaluate the metabolic response rate according to PERCIST v 1.0. Side effects were scored using the NCI CTC AE v 3.0 scale. Results: We report the results of the first 22 patients. Thirteen patients (59%) received previous chemotherapy for metastatic disease, displaying residual (n=7) or progressive (n=6) metabolic active metastatic disease at time of inclusion. A total of 51 metastases were treated. Most common sites were the lung, liver and lymphnodes. One patient (5%) experienced grade 3 dysphagia; 2 patients (9%) and 1 patient (5%) grade 2 dysphagia and diarrhea, respectively. Twenty patients were evaluated by post-treatment PET-CT. Five and 6 patients achieved a complete and partial metabolic response, resulting in an overall metabolic response rate of 55%. At a median follow-up of 11 months, 17 patients (77%) developed progressive disease, of which 3 isolated local progression. Five patients (23%) are in remission in all irradiated areas without evidence of distant recurrence. Interestingly, those 5 patients received previous chemotherapy with residual oligometastatic disease at time of inclusion. Conclusions: Ten fractions of 5 Gy resulted in a promising 55% metabolic response rate with limited toxicity. Helical tomotherapy is an attractive modality in the multidisciplinary approach of oligometastatic CRC, more specifically in the consolidation of residual and inoperable oligometastatic disease in patients previously treated with chemotherapy.

Phase II Multicenter Trial of Albumin-Bound Paclitaxel and Capecitabine in First-Line Treatment of Patients With Metastatic Breast Cancer

BackgroundCapecitabine, a tumor-activated oral fluoropyrimidine, and albumin-bound paclitaxel (ab-paclitaxel) have substantial single-agent activity in patients with metastatic breast cancer (MBC). Taxane and antimetabolite doublets have improved efficacy compared with single agents. This phase II open-label trial was designed to test the safety and efficacy of capecitabine and ab-paclitaxel in previously untreated MBC. Patients and MethodsPatients received capecitabine (825 mg/m2 orally twice daily, approximately 12 hours apart, on days 1 to 15) and ab-paclitaxel (125 mg/m2 intravenously on days 1 and 8 of each cycle with no premedication) every 3 weeks. The primary endpoint was overall objective response rate (ORR), with evaluation performed after every 2 cycles. Entry criteria included measurable MBC, human epidermal growth factor receptor 2 (HER2) negativity, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, no previous chemotherapy for metastatic disease, and > 6 months since adjuvant fluoropyrimidine or paclitaxel treatment. ResultsFifty patients received at least 1 dose of study drug, with 46 patients evaluable for efficacy evaluation. Three hundred seventy-four cycles of therapy were delivered. Eighty percent of patients completed 8 cycles. The ORR was 61% (complete response [CR], 4%; partial response [PR], 57%), and 7 patients had sustained (≥ 24 weeks) stable disease for a clinical benefit rate of 76.1%. The median progression-free survival (PFS) was 10.6 months, and the median overall survival was 19.9 months. The most common adverse events (AEs) that were ≥ grade 3 were pain, hand-foot syndrome, and neutropenia. ConclusionThe combination of weekly ab-paclitaxel plus daily capecitabine orally at these doses and scheduling was well tolerated and showed substantial efficacy.

Selective internal radiation therapy (SIRT) for treatment of patients with breast cancer with metastatic liver disease.

1135 Background: Selective internal radiation therapy (SIRT) has become a treatment option as salvage therapy for liver-dominant metastasis which is also used in patients (pts) with breast cancer. It is based on hepatic arterial infusion of resin microspheres containing the pure ß-emitter Yttrium-90. The goal of this cohort analysis was evaluate the clinical efficacy of SIRT and to define biomarkers predicting response to this new option. Methods: We retrospectively analyzed data from 40 pts with breast cancer (39 female, 1 male) at a median age of 60.3 yrs (31-73 yrs) who had received SIRT for metastatic liver disease from 2002-2009. We used survival analysis techniques (Kaplan-Meier estimator and Cox regression models) for this exploratory study. Results: 13 pts (33.3%) were premenopausal, 23 (59.0%) postmenopausal, and 3 (7.7%) perimenopausal; 14 pts (36.8%) overexpressed HER2/neu; 27 pts (71.1%) were hormone receptor positive; 39 pts (97.5%) had received previous chemotherapy for metastatic disease, 34 (87.2%) hormone therapy. 37 pts (94.9%) had received anthracyclines, and 34 (89.5%) taxanes before SIRT. Median time from diagnosis of breast cancer to SIRT was 6.8 yrs (1.1-27.3 yrs). In 19 pts (47.5%), metastasis was limited to the liver, 21 (52.5%) pts had liver-predominant metastasis (21 bone, 7 non-regional lymph nodes, 4 lung, 5 others). Overall response rate (ORR) in the liver was 45.5% (95% CI: 0.29-0.62). Stable disease for more than 8 weeks was achieved in 12.1% of pts. Median PFS in the liver was 3.3 mo (1.8-32.8 mo), and median TTP 3.5 mo (1.8-32.8 mo). Median overall survival (OS) was 8.2 mo. Bivariate Cox regression models (using the Wald test) for baseline biomarkers before SIRT revealed a significant correlation of CEA (p=0.022), CA 15-3 (p=0.006), and LDH (p=0.012) with OS. No correlation was observed for C-reactive protein levels (p=0.74). Conclusions: This analysis of SIRT applied in breast cancer pts with metastatic liver disease indicates substantial clinical activity of this treatment option in highly pretreated breast cancer pts. CEA, CA 15-3, and LDH baseline levels in serum before SIRT appear to be predictors for OS. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration SIRTEX

Final results from an open-label, randomised, phase II study of adecatumumab (MT201), a fully human anti-EpCAM antibody, in patients with metastatic breast cancer

3588 Background: High-level expression of the epithelial cell adhesion molecule (EpCAM) has been associated with unfavourable prognosis in various cancers. Adecatumumab was developed as a low-affinity IgG1 antibody targeting EpCAM-positive cancer cells. Methods: EpCAM-positive metastatic breast cancer patients without CNS metastases, with no indication for trastuzumab were eligible; an initial restriction to a maximum of one previous chemotherapy for metastatic disease was subsequently removed. 109 EpCAM- positive patients were enrolled. Patients were stratified into high- and low-level EpCAM expression (n = 74 and 35, respectively) according to immuno-histochemistry testing, and subsequently randomised to receive either high-dose (6 mg/kg/q2w) or low-dose (2 mg/kg/q2w) adecatumumab (n = 54 and 55, respectively). Primary endpoint was clinical benefit rate (CBR = objective response + stable disease) at week 24 with secondary parameters exploring time to progression (TTP) and safety. Results: The primary endpoint (CBR at week 24: >25%) was not met in any of the 4 groups according to central radiological review. Exploratory analyses of the Kaplan-Meier curves, however, showed a lower probability for tumor progression in patients receiving high dose adecatumumab (HR: 0.67 [0.47–0.94]; p=0.047). A similar trend was also observed in patients with high-level EpCAM expression (HR: 0.71 [0.49–1.03]; p=0.116). Further (retrospective) analysis using more stringent criteria for the definition of high-level EpCAM expression indicated an inverse correlation of staining intensity and frequency with probability of progression. An increased incidence of CTC grade 1 and 2 AE was found in the high-dose group with main side effects being gastrointestinal and constitutional symptoms. Conclusions: The observation of dose- and target-dependent activity of adecatumumab warrants further investigation. Definition of the optimum dose and regimen as well as exploration of the predictive value of EpCAM testing will be key in future development. No significant financial relationships to disclose.

Preliminary results of phase II study of irinotecan and capecitabine combination as first line chemotherapy for advanced and metastatic gastric cancer

14030 Background: Chemotherapy has a proven palliative role in advanced gastric cancer. The most widely investigated single-agent chemotherapy is 5-fluorouracil with partial response rates up to 20%. Single-agent irinotecan achieved response rates of 18%-23%. We investigated the combination Irinotecan plus Capecitabine for previously untreated locally advanced or metastatic gastric cancer. Methods: We conducted a phase II study with the combination of Irinotecan 80 mg/m2 on day 1, 8, and 15, and capecitabine 625 mg/m2 twice daily on days 1 to 14 repeated every 4 weeks. Patients were evaluated every second cycle. Previous chemotherapy for metastatic disease was not allowed. Patients must have measurable disease, ECOG PS < 2, life expectancy > 2 months, adequate hematological, liver and renal functions. Response was evaluated according to RECIST and toxicities according to NCI common toxicity criteria 3.0. Results: Between February 2002 and December 2005 31 patients were enrolled (20 male and 11 female). The median age was 57 years [range 37–74 years]. 142 cycles were administered with a median of 4.6 cycles per patient [range 1–10 cycles]. 29 patients were evaluable for response, and two are on ongoing treatment. Partial response rate was 38.5% . 9 patients (29%) had stable disease. Overall tumor control rate was 67.5%. Median time to progression and overall survival were 5.8 months [range- 1–16] and 10.58 months [range- 1–21] respectively. There was no grade III-IV reported toxicity including no hand and foot syndrome. Conclusions: Irinotecan and capecitabine in combination show an interesting tumor control rate (67.5%) with extremely well tolerated toxicity in patients with extensive gastric cancer. No significant financial relationships to disclose.

Gemcitabine plus taxane combinations in metastatic breast cancer:a comprehensive review

Gemcitabine and the taxanes (paclitaxel and docetaxel) exhibit a synergistic anticancer activity and are active in the treatment of metastatic breast cancer. Many trials have investigated the efficacy and toxicity of gemcitabine plus paclitaxel, including one Phase III trial. Gemcitabine has also been studied in combination with docetaxel and again, in a Phase III trial. In first-line Phase II trials, 61% of patients responded to gemcitabine plus paclitaxel therapy and 64% have responded to gemcitabine plus docetaxel. Response rates were lower among patients who had received previous chemotherapy for metastatic disease (46% and 52%, respectively). Toxicity of the gemcitabine plus paclitaxel regimens was generally low, with few cases of neutropenia or non-haematological toxicity. Gemcitabine plus docetaxel was seen to be slightly more toxic in terms of neutropenia and fatigue. Results of a randomised Phase III registration trial of gemcitabine plus paclitaxel versus single-agent paclitaxel show a clear advantage for the combination in terms of survival, with little added toxicity. Gemcitabine plus paclitaxel improved overall survival by approximately 25% compared with paclitaxel alone. A Phase III trial comparing gemcitabine plus docetaxel with capecitabine plus docetaxel showed similar efficacy results, with more toxicity in the capecitabine arm. The efficacy of triplet combinations of gemcitabine plus paclitaxel plus an anthracycline or trastuzumab are being explored in the metastatic and neoadjuvant setting with excellent response results. Two very large trials in Europe and the US are evaluating the incorporation of gemcitabine into sequential adjuvant therapy in post-operative breast cancer.

Gemcitabine in Combination with Paclitaxel for the Treatment of Metastatic Breast Cancer

Gemcitabine and paclitaxel are active drugs in the treatment of patients with metastatic breast cancer which seem to have synergistic anticancer activity. Seven Phase II trials of gemcitabine/paclitaxel and one Phase III trial have been published. Two dosing or admistration schedules have been preferred in the clinical development of the combinations: gemcitabine on days 1 and 8 plus paclitaxel on day 1 or 8, every 3 weeks or gemcitabine plus paclitaxel on day 1, every 2 weeks. In first-line Phase II trials, up to 71% of patients responded to gemcitabine/paclitaxel therapy. Response rates were lower among patients who had received previous chemotherapy for metastatic disease (46%). Responses were observed in patients refractory to docetaxel monotherapy. Toxicity of gemcitabine/paclitaxel regimens has been low, with infrequent neutropenia or nonhematologic toxicity. In the randomized Phase III registration trial, the gemcitabine/paclitaxel combination demonstrated a clear advantage over paclitaxel alone in terms of the primary end point of survival and other efficacy end points, with manageable toxicity. Gemcitabine/paclitaxel showed a survival advantage of approximately 22% over paclitaxel alone (hazard ratio of 0.775). Gemcitabine plus paclitaxel represents an active and well-tolerated treatment alternative for first-line treatment of anthracycline-treated metastatic breast cancer. Triplet combinations, in which an anthracycline or trastuzumab are added to gemcitabine/paclitaxel, are being explored in the metastatic and neoadjuvant settings with excellent results. In addition, gemcitabine/paclitaxel is being evaluated in two large adjuvant multicenter studies.

Gemcitabine (G) plus capecitabine (C) versus G alone in locally advanced or metastatic pancreatic cancer. A randomized phase III study of the Swiss Group for Clinical Cancer Research (SAKK) and the Central European Cooperative Oncology Group (CECOG)

LBA4010 Background: While G is a widely accepted treatment for pts with advanced pancreatic cancer, C has shown single agent activity and promising efficacy in combination with G in phase II studies. Therefore, we compared the combination of G + C with G alone in a randomized phase III study. Methods: Major eligibility criteria: KPS ≥ 60, WBC ≥ 3.5 x 109/l, platelets ≥ 100 x 109/l, hemoglobin ≥ 10.0 g/dl, sufficient liver function (bilirubin/ASAT/ALAT/ alkaline phosphatase < 5 x upper normal limit), creatinine clearance ≥ 30 ml/min and no previous chemotherapy for metastatic disease. Stratification factors: locally advanced/metastatic disease, absence/presence of pain, institution, KPS 60–80/90–100. The primary endpoint is overall survival. Secondary endpoints are quality of life, clinical benefit response, objective tumor response, duration of response, time to progression and safety. Pts were randomized to receive G 1000 mg/m2 i.v. over 30’ d 1+8 and C 650 mg/m2 orally q12hrs d 1–14, q3w, or G 1000 mg/m2 weekly x7, 1w rest and then weekly x3, q4w. Treatment continued until progression or for 6 months and could be resumed upon progression. The study was designed to detect an increase of median survival from 5 to 7 months. The survival analysis will be conducted after more than 80% of patients have died. An independent safety monitoring board is monitoring the trial data. Results: From June 2001 to June 2004, 319 pts with advanced disease from 30 institutions in 8 countries were randomized. 80% of all pts had metastatic disease, 67% had pain requiring pain medication and 84% had a KPS of 90 or 100 with a well-balanced distribution. Results on the primary and the secondary endpoints will be presented for both treatment groups during the meeting. Conclusions: To be reached after data becomes available. Supported in part by Hoffmann-La Roche and Eli Lilly Switzerland Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche Roche Lilly

Pegylated Liposomal Doxorubicin and Cyclophosphamide as First-Line Therapy for Patients with Metastatic or Recurrent Breast Cancer

Purpose Pegylated liposomal doxorubicin (PLD) is an active agent for breast cancer. The efficacy and safety of PLD in combination with cyclophosphamide as first-line treatment of metastatic breast cancer (MBC) was evaluated in this phase II study. Patients and Methods Eligible patients had metastatic or recurrent breast cancer with no previous chemotherapy for metastatic disease. Patients were enrolled into 3 sequential cohorts: cohort I (n = 10) received PLD 50 mg/m 2 intravenously (I.V.) on day 1 and cyclophosphamide 100 mg/m 2 orally on days 1–14 every 28-day cycle; cohort II (n = 20) received PLD 30 mg/m 2 plus cyclophosphamide 600 mg/m 2 I.V. on day 1 every 21 days; and cohort III (n = 21) received PLD 35 mg/m 2 plus cyclophosphamide 600 mg/m 2 I.V. on day 1 every 21 days. Results An objective response was exhibited in 26 of 51 patients (4 complete responses [CRs], 22 partial responses [PRs]; 51%) in the intent-to-treat population and responses were similar among cohorts. The clinical benefit rate (CR plus PR plus stable disease) was 86%. The median duration of response was 35.1 weeks. The most common adverse events were nausea (71%), asthenia (69%), and neutropenia (67%). There was less toxicity in cohort II than in other cohorts. No clinical cardiac toxicity was observed. Only 2 of 20 patients in cohort II (10%) required treatment discontinuation as a result of adverse events. Conclusion First-line combination therapy with PLD and cyclophosphamide is active and well tolerated in patients with MBC. The recommended doses from this study are PLD 30 mg/m 2 and cyclophosphamide 600 mg/m 2 I.V. every 21 days.

Selective internal radiation therapy (SIRT) for liver metastases with concomitant systemic oxaliplatin, 5-fluorouracil and folinic acid: A phase I/II dose escalation study

3657 Background: SIR-Spheres (Sirtex Medical Limited, Sydney, Australia) contain the pure β-emitter, yttrium-90, used to selectively irradiate liver metastases from colorectal cancer. The combination of SIRT with systemic 5-fluorouracil (5-FU) and folinic acid (LV) has been shown to improve survival when compared to systemic chemotherapy alone (Van Hazel et al JSO 2004;88:78). The administration of oxaliplatin in combination with 5-FU/LV improves response rates and it is a radiosensitiser. The goal of this study was to evaluate the safety and efficacy of combining oxaliplatin and 5-FU/LV chemotherapy with SIRT Methods: Seventeen patients with liver metastases from colorectal cancer, who had not received previous chemotherapy for metastatic disease, were entered into the study. Chemotherapy consisted of the FOLFOX4 regimen, modified with an oxaliplatin dose escalated from 30 mg/m2 to 85 mg/m2 in order to assess safety and tolerability. SIR-Spheres were implanted by injection into the hepatic arterial system on days 3 or 4 of the first chemotherapy cycle. Results: Most patients experienced nausea or abdominal pain within 48 hours of SIRT. Mild peripheral neuropathy was evident in 6 of the first 11 patients, appearing between cycles 10–12. Grade 3/4 transient neutropenia was seen in 5 of 11 patients. Three NCI Grade 3 events were documented in 2 of 3 patients at the 30 mg/m2 tier (diarrhea, nausea/vomiting, fever). Six grade 3 events were seen in 4 of 8 patients in the 60 mg/m2 tier (diarrhea, nausea/vomiting, abdominal pain, fever, leukopenia, anaemia). Only one grade 3 event has been exhibited to date in 1 of 6 patients in the 85 mg/m2 tier (nausea/vomiting). Partial responses (RECIST) were seen in all of the first 11 patients. Median time to liver progression is currently 11+ months. Conclusions: The administration of SIRT in combination with oxaliplatin appears to possess an acceptable toxicity profile. The maximum tolerated dose has not been defined, but it is expected to be at least 85 mg/m2. We plan to proceed to phase III trials of chemoradiation using FOLFOX4 with or without SIRT. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sirtex

A multicenter Phase II study of bortezomib in recurrent or metastatic sarcomas

Based on evidence of activity in preclinical and Phase I studies, the authors undertook a study of bortezomib, a reversible proteasome inhibitor, for patients with metastatic sarcomas. Two arms were opened, each using a Simon two-stage design. Arm A included patients with osteogenic sarcoma, Ewing sarcoma, and rhabdomyosarcoma. Arm B accrued patients with other types of soft tissue sarcomas. Patients were not allowed to have received previous chemotherapy for metastatic disease. The initial dose of bortezomib was a 1.5 mg/m2 intravenous push twice weekly followed by a rest week. The dose was escalated to 1.7 mg/m2 if patients tolerated Cycle 1 well. The dose escalation was eliminated due to toxicity observed in the first six patients. Painful neuropathy, myalgias, and asthenia were the most significant observed toxicities. The most frequent toxicities included fatigue, diarrhea, constipation, and nausea. Pharmacodynamic data from 18 patients with complete data collection did not show consistent differences between patients with or without Grade 2 or Grade 3 neuropathy (toxicity graded according the National Cancer Institute Common Toxicity Criteria). Arm A had low accrual and was closed. One confirmed partial response among 21 evaluable patients was observed on Arm B in a patient with leiomyosarcoma. Due to the inactivity of this agent, the study was closed after the first stage of accrual. Bortezomib has minimal activity in soft tissue sarcoma as a single agent. If studied further in sarcomas, bortezomib should be investigated in combination with agents with demonstrated preclinical synergy.

452 Osteoprotegerin (OPG) and osteopontin (OPN): their usefulness in monitoring the Anastrzole (AN) treated advanced breast cancer (ABC) patients bearing bone metastases

Capecitabine, a tumor-activated oral fluoropyrimidine, and albumin-bound paclitaxel (ab-paclitaxel) have substantial single-agent activity in patients with metastatic breast cancer (MBC). Taxane and antimetabolite doublets have improved efficacy compared with single agents. This phase II open-label trial was designed to test the safety and efficacy of capecitabine and ab-paclitaxel in previously untreated MBC.Patients received capecitabine (825 mg/m2 orally twice daily, approximately 12 hours apart, on days 1 to 15) and ab-paclitaxel (125 mg/m2 intravenously on days 1 and 8 of each cycle with no premedication) every 3 weeks. The primary endpoint was overall objective response rate (ORR), with evaluation performed after every 2 cycles. Entry criteria included measurable MBC, human epidermal growth factor receptor 2 (HER2) negativity, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, no previous chemotherapy for metastatic disease, and > 6 months since adjuvant fluoropyrimidine or paclitaxel treatment.Fifty patients received at least 1 dose of study drug, with 46 patients evaluable for efficacy evaluation. Three hundred seventy-four cycles of therapy were delivered. Eighty percent of patients completed 8 cycles. The ORR was 61% (complete response [CR], 4%; partial response [PR], 57%), and 7 patients had sustained (≥ 24 weeks) stable disease for a clinical benefit rate of 76.1%. The median progression-free survival (PFS) was 10.6 months, and the median overall survival was 19.9 months. The most common adverse events (AEs) that were ≥ grade 3 were pain, hand-foot syndrome, and neutropenia.The combination of weekly ab-paclitaxel plus daily capecitabine orally at these doses and scheduling was well tolerated and showed substantial efficacy.

Docetaxel Plus Vinorelbine as Salvage Chemotherapy in Advanced Breast Cancer: A Phase II Study

Administration of a combined regimen of docetaxel plus vinorelbine every 4 weeks is feasible and shows activity in heavily pretreated patients with advanced breast cancer. To determine the activity and tolerance of docetaxel plus vinorelbine in heavily pretreated patients with advanced breast cancer. Thirty-five metastatic breast cancer patients with ECOG performance status of 0-2 received docetaxel (80 mg/m2 given intravenously) on day 1 and vinorelbine (30 mg/m2 given intravenously) on days 1 and 14, every 4 weeks. The median number of prior chemotherapy regimens was 2 (range: 1-4). Twenty-five patients (71.4%) had been treated previously using intensive therapy approaches with peripheral blood-derived stem cell (PBSC) support, including high-dose chemotherapy (11 patients), multicyclic dose-intensive chemotherapy supported with repeated PBSC infusions (seven patients), or both (seven patients). Twenty-eight patients (80%) received previous chemotherapy for metastatic disease. Adjuvant therapy in the remaining seven patients consisted of high-dose chemotherapy and PBSC support or an anthracycline-containing regimen. The total number of courses was 229, and the median number of courses per patient was 6 (range: 1-16). There was one toxic death (2.8%). Grade 3-4 toxicities included mucositis (17.1%), neutropenia (37.1%), anemia (5.7%), vomiting (2.9%), and asthenia (14.3%). Eighteen patients (58%; 95% CI: 40.6-75.4%) achieved an objective response, including four complete responses (12.9%) and 14 partial responses (45.1%). Overall response rate was 51.4% (95% CI: 34.8-67.9%). After a median follow-up of 20 months (range: 2-42), overall survival was 20 months (95% CI: 16-24), and median time to progression was 13 months (95% CI: 7-19). This combination shows activity and an acceptable toxicity profile in patients with advanced breast cancer.

A phase II study of irinotecan with 5-fluorouracil and leucovorin in patients with previously untreated gastric adenocarcinoma

A phase II study testing the safety and efficacy of irinotecan (CPT-11). 5-fluorouracil (5-FU), and leucovorin (LCV) was conducted in patients with advanced gastric adenocarcinomas. Patients with metastatic or recurrent adenocarcinoma of the gastroesophageal junction (GEJ) or stomach were entered onto this study. Previous chemotherapy for metastatic disease was not allowed. Treatment consisted of repeated 6-week cycles comprising CPT-11 125 mg/m2 intravenously (i.v.) followed immediately by LCV 20 mg/m2 i.v. and 5-FU 500 mg/m2 i.v., all given weekly for four weeks followed by a two-week rest. Thirty-eight patients were enrolled and 36 eligible patients received protocol therapy. Grade 3-5 toxicities consisted primarily of neutropenia (36%) and diarrhea (28%). Neutropenic infection was observed in 14% of patients, with 3 (8%) dying of neutropenic sepsis. The overall response rate was 22% (95% confidence interval [CI] 8.5% to 35.5%). Median survival was 7.6 months, and median time to progression was 4.4 months. This weekly regimen of CPT-11 with bolus 5-FU/LCV is active in patients with advanced adenocarcinomas of the stomach or gastroesophageal junction. While rates of grade 3-4 neutropenia and diarrhea were similar to those observed historically in patients receiving this regimen for colorectal cancer, neutropenic fever/sepsis appeared to be more frequent, and dose modifications were substantial. Future trials of this combination in patients with gastric cancer should decrease the absolute starting drug doses and/ or employ altered scheduling that better accommodates the pattern of toxicity.