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1005 Background: B in combination with weekly paclitaxel or docetaxel (D) as 1st-line therapy for MBC has improved progression-free survival (PFS) compared with the respective taxane alone in two large Phase III trials. This study investigated the addition of B to standard 1st-line chemotherapy regimens for MBC. Methods: Patients were randomized in 2:1 ratio to receive B + chemotherapy or placebo (pl) + chemotherapy. Prior to randomization, investigators chose capecitabine (Cap) (2000 mg/m2 x 14d), taxane (T) (nab-paclitaxel [260 mg/m2] or D [75 or 100 mg/m2], q3wk), or anthracycline (Ant)-based chemotherapy (q3wk). B or pl was administered at 15 mg/kg q3wk. Key eligibility criteria included MBC or locally-recurrent disease, no prior cytotoxic treatment, ECOG PS 0 or 1, HER2-negative disease and no CNS metastases. The primary endpoint was investigator-assessed PFS. Secondary endpoints included overall survival (OS), objective response rate (ORR), independent review of PFS, and safety. At progression, all patients were eligible for B with 2nd line chemotherapy. The Cap cohort and the pooled T or Ant (T + Ant) cohort were independently powered and analyzed in parallel using two-sided stratified log-rank test (Cap: 80% power to detect HR=0.75; T + Ant: 90% power to detect HR=0.7). Results: RIBBON-1 enrolled 1237 patients (Cap, 615; T, 307; Ant, 315) from 12/05 to 8/07 in 22 countries with a median follow-up of 15.6 months in the Cap cohort and 19.2 months in the T + Ant cohort. The results are summarized below. OS data are limited with only 33% of events. Safety was consistent with results of prior B trials. Conclusions: The addition of B to Cap, T; or Ant-based chemotherapy regimens used in 1st-line treatment of MBC resulted in statistically-significant improvement in PFS with a safety profile comparable to prior Phase III studies. [Table: see text] [Table: see text]

e14554 Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor. Preclinical studies have shown synergistic antitumor activity with the combination of trastuzumab plus vinorelbine in metastatic breast cancer.The recommended dose of neratinib in monotherapy is 240 mg. In this phase 1 study, a combination dose of neratinib plus vinorelbine that is tolerable was determined in patients (pts) with solid tumors. Methods: This is an open-label, 2-part study of ascending multiple daily oral doses of neratinib (160 mg, 240 mg) in combination with 25 mg/m2 IV vinorelbine (administered on days 1, 8 every 3 wks). Tumor measurements were made every 6 wks by modified RECIST criteria. Results: 6 pts have been treated at each dose level. Data for 12 pts (5 pts still ongoing) as of 30 Oct 2008 are presented (median age [range] of 53.5 [38–75] yrs; 83% female). The median duration of treatment [range] was 1.9 [1.5–2.7] m. There was only 1 dose limiting toxicity (DLT) of grade 3 neuropathy (pt had preexisting grade 1 neuropathy) at 160 mg neratinib-25 mg/m2 vinorelbine, so the dose was escalated to 240 mg neratinib- 25 mg/m2 vinorelbine. In this cohort, there were no DLTs, and since the neratinib and vinorelbine doses reached full standard doses there was no need for further dose escalation. AEs, any causality, all grades in ≥ 15% of pts included diarrhea (92%), nausea (67%), constipation (50%), fatigue (42%), vomiting and anthralgia (33% each), abdominal pain and anorexia, (25% each), anemia and neutropenia (17% each). Grade ≥3 AEs that occurred in ≥1 pt included neutropenia (2 pts), pneumonia (1 pt) and peripheral neuropathy (2 pts). Preliminary efficacy data show that 1 pt with stomach cancer had stable disease, lasting ≥21 weeks. Conclusions: The combination of 240 mg neratinib and 25 mg/m2 vinorelbine was found to be tolerable and to demonstrate early evidence of clinical benefit in pts with solid tumors, to be assessed further in pts with metastatic ErbB-2+ breast cancer in part 2. [Table: see text]

1004 Background: Neratinib (HKI-272) is an orally administered irreversible pan-ErbB receptor tyrosine kinase inhibitor. In an ongoing phase II study, the preliminary objective response rate was 26% in patients with ErbB2+ advanced breast cancer with prior trastuzumab therapy. This study assessed the safety and preliminary efficacy of the combination of neratinib plus trastuzumab. Methods: Patients with advanced ErbB2+ breast cancer that progressed following trastuzumab therapy were enrolled. The primary endpoint was 16-week progression free survival rate (PFS). In part 1 (dose escalation), patients received neratinib 160 mg or 240 mg daily plus trastuzumab 4 mg/kg IV loading dose then 2 mg/kg weekly. In part 2, patients received weekly trastuzumab with neratinib 240 mg daily. Timed blood samples were collected for PK analyses. PK analysis is ongoing. Results: 45 patients (part 1 n = 8; part 2 n = 37) were enrolled (mean age 52 yr); 9 are active. In part 1, cohorts 1 and 2 were fully enrolled with 4 patients each. No dose limiting toxicities were observed. Most common AEs, any grade, were diarrhea (91%), nausea (51%), anorexia (40%), vomiting (38%), and asthenia (27%). Grade 3/4 AEs were diarrhea (13%), nausea (4%), vomiting (4%). Two patients receiving neratinib 240 mg reported AEs leading to withdrawal. No AEs of congestive heart failure and no significant drops of left ventricular ejection fraction were reported. Among 33 patients evaluable for efficacy, objective response rate was 27% (95% CI, 13% - 46%); 16-week PFS rate (for part 2) 47% (95% CI, 29% - 63%); median PFS was 19 weeks (95% CI 15 - 32 weeks). Conclusions: Neratinib plus trastuzumab was well tolerated with no significant or unexpected toxicities, and demonstrated clinical activity. [Table: see text]

1051 Background: Lapatinib is an effective anti-HER-2 therapy in LAMBC pts, currently investigated in the adjuvant setting. Following anthracyclines, taxanes and capecitabine, VNR is an active agent in metastatic setting. Its main toxicity consists of neutropenia and may challenge the standard weekly, day D1 and D8 regimen. We investigated the combination of L + VNR, seeking the recommended dose for further phase II studies and the potential pharmacokinetic (PK) interactions. Methods: Women with a HER-2+ LAMBC, in progression after ≤ 2 lines of trastuzumab-based treatment were treated with a 7D (D-7 to D0) loading dose of L before starting VNR on a D1 and D8 q3w IV regimen. L was given orally continuously. Primary prophylaxis of febrile neutropenia (FN) with G-CSF was not permitted. Dose levels (DL, L [mg]/VNR [mg/m2]) ranged from 750/20 to 1250/30 with 3 pts/DL (6 in case of dose-limiting toxicity [DLT]). DLT was defined on tolerance at cycle 1 and included grade (gr) 4 neutropenia (PN) ≥ 7D, FN, thrombocytopenia (gr4 or symptomatic gr3), omission of D8 for haematological toxicity, and any drug-related gr3–4 non-haematological toxicity. PK samples were collected on 7 points on D1 of cycle 1 for L and VNR dosages. Results: From August 2007 to December 2008, 15 evaluable pts were enrolled (median age 58 [46–75], 43% PS 0, 8 pts previously exposed to only 1 line of trastuzumab) and 65 cycles were administered. Toxicity is available for 13 pts. Of 3 pts treated at DL4 (1000/25), 2 developed a DLT: 1 FN and 1 gr4 PN > 7D. Other significant toxicities (% pts) included gr2 anaemia 8%, gr4 PN 46%, gr1 diarrhoea 62%, gr2 nausea/vomiting 8%, gr1 skin rash 23%, gr2 transaminases 23%; no decrease of cardiac function occurred. From DL1 to DL3 (750/20, 1000/22.5), total body clearance of VNR decreased by 50% (32 ± 19 L/h vs 17 ± 7 L/h). Conclusions: Maximal tolerated dose has been reached at 1000/22.5 for the combination of L with VNR given on a D1 and D8 q3w schedule. Given a potential PK interference which would yield to higher exposure to VNR, an intermediate DL is going to be explored (1250/22.5) to allow an accurate definition of the recommanded dose of the combination for future phase II comparison studies. [Table: see text]

Abstract #1090 Background Breast cancer is the leading solid tumor responsible for meningeal carcinomatosis (MC) and the incidence is rising. To date, there is no standard of care and few prospective trials. Intrathecal treatment is provided but the modalities remain controversial. Methods From our data base we recorded 91 patients with breast MC admitted to Institut Curie between 2000-2007. Lumbar punction was performed in all patients for cerebrospinal fluid (CSF) cytology, protein level and dosage of CYFRA 21. Intra-thecal treatment: methotrexate 15 mg day1 to 5 and hydrocortisone acetate day 1 with oral folinic acid rescue day 1 to 5 every two weeks. Results Median age was 53 years (range 30-78). Tumor type was ductal carcinoma (63%), lobular (28%), ER positive 74%, HER2 overexpressed 10% and triple negative 31%. All patients presented other metastatic site: bone (67%), liver (42%) lung (29%), brain (38%). The median interval between primary tumor and diagnosis of MC was 60 months. Amongst the 80 patients treated (87%) with intra-thecal MTX, clinical response was observed in 88% of cases. There was a strong correlation between clinical response and survival (p 1 year) or patients for whom treatment will have no impact on survival (< 3 months). Conclusion: This score has to be confirmed in prospective study and new modalities of treatments need to be evaluated according to the biology of disease. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1090.

Abstract #406 Background: Resistance to trastuzumab (H) is associated with loss of PTEN and AKT/mTOR activation. Preclinically, RAD001, an oral inhibitor of mTOR, enhances the efficacy of H suggesting that RAD001 could reverse resistance to H. Methods: Vinorelbine (V) was administered at a dose of 25 mg/m2, IV over 10-15 min on days 1 and 8 q3w. H 4 mg/kg loading dose administered IV over 90 min on Day 1 (if pt was not already receiving H), followed by weekly H 2 mg/kg IV over 30 min. In the daily RAD001 arm, 3 cohorts were planned (2.5, 5 and 10mg) and in the weekly RAD001 arm, 4 cohorts were planned (20, 30, 50 and 70mg). Treatment continued until progression or unacceptable toxicity. Results: As of June 10 2008, 28 heavily pretreated pts were enrolled: 15 to 5mg/d, 6 to 20mg/w and 7 to 30mg/w cohorts. All pts received prior taxanes. Median number of prior CT regimens was 3 (range: 1-5). The main safety events were grade 2 and 3 stomatitis which led to dose reduction of RAD001 in 3 pts and dose interruption in 3. Grade 4 and 3 Neutropenia were seen in 24 pts (leading to dose reduction of V in 11 pts). Twenty two pts have been evaluated for efficacy (table 1). 1 pt had a CR (45+ weeks), 2 pts had PR (35+, 38 weeks), 15 pts SD (Median 26+, range 8+ to 58 weeks) and 4 pts PD. Clinical benefit rate (CR+PR+SD > 24 wks) is 55%+. Conclusions: Initial findings show that RAD001 is generally well tolerated in combination with V and H and shows promising anticancer activity and clinical benefit in heavily pretreated patients with HER2+ advanced breast cancer. Updated results will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 406.

1057 Background: RAD001 (everolimus) is an oral inhibitor of the mTOR serine-threonine kinase, a downstream component of the PI3K/AKT signaling pathway playing a critical role in regulation of protein synthesis and ultimately cell growth, proliferation, and angiogenesis. RAD001 shows activity in breast cancer patients (pts) as both monotherapy and in combination with letrozole. Preclinical models demonstrate that RAD001 enhances the efficacy of trastuzumab. Loss of PTEN and AKT/mTOR activation have been reported to mediate resistance to trastuzumab. Methods: Vinorelbine was administered at a dose of 25 mg/m2, IV over 10–15 min on days 1 and 8 q3w. Trastuzumab 4 mg/kg loading dose administered IV over 90 min on day 1 (if pt was not already receiving trastuzumab), followed by weekly trastuzumab 2 mg/kg IV over 30 min. In the daily RAD001 arm, 2 cohorts were planned (5 and 10mg) and in the weekly RAD001 arm, 4 cohorts were planned (20, 30, 50 and 70mg). Treatment continues until progression or unacceptable t...

1078 Background: BM are frequently accompanied by a variety of NSS. Development of a systematic assessment tool for NSS may aid in the evaluation of clinical benefit. Based on a list of tumor-relat...

1070 Background: Larotaxel (L), a semi-synthetic taxoid, has shown preclinical and clinical activity against taxane-resistant BC, and it presents the ability to cross the blood brain barrier. In HE...

1012 Background: CNS disease is a major problem among pts treated with H for stage IV HER2+ breast cancer with a reported incidence of 28–43%. This study was designed to characterize further the activity reported with lapatinib in an initial phase II trial in women with HER2+ disease metastatic to brain (Lin et al ASCO ‘06). Methods: Eligible pts had HER2+ breast cancer, prior H therapy and cranial RT, ECOG PS 0–2, and radiographic evidence of progressive brain metastases with at least one measurable (LD = 10mm) brain lesion. Pts received lapatinib 750 mg PO BID. Brain MRIs were obtained at 3.0 mm slices without gaps in the axial dimension. The primary endpoint was CNS response as defined by a = 50% volumetric (vol) reduction of CNS lesions in the absence of: new lesions, need for increased dose of steroids, progressive neurological signs/symptoms (NSS), or progressive extra-CNS disease. CNS disease progression was defined as either a = 40% vol increase from nadir, increase in steroid requirements, or progression of NSS. Results: The study exceeded its accrual goal of 220 pts in < 1 year; 238 pts were enrolled from Jan-Nov 06. Preliminary data from the initial 104 pts have undergone independent radiology review. 8 pts (7.7%) met vol criteria for partial response with a median absolute vol reduction of CNS disease of 3.6 cm3 (range 0.4 to 29.7 cm3). Exploratory analysis revealed that 17 of the initial 104 pts (16.3%) experienced a = 20% vol reduction of CNS disease with a median absolute vol reduction of 3.3cm3. The median time to vol progression in these 17 pts was 16 wks (range 12 -24 wks). Analysis of efficacy and tolerability based upon protocol defined criteria from all 238 pts will be presented. Conclusions: Preliminary data from this large multicenter trial provides evidence that lapatinib has activity based on vol reductions in pts with progressive HER2+ CNS disease following prior H-based systemic therapy and cranial RT. Definitive conclusions will be based on the entire database. Additional studies are warranted incorporating lapatinib in combination with other therapies and/or in a less refractory setting to optimize its use in HER2+ CNS disease. [Table: see text]

2527 Background: Glutathione-S-transferases (GST) regulate the cellular response to oxidative stress and various anticancer agents. We recently underlined the importance of oxidative stress in the side effects of taxanes [Alexandre et al,J Natl Cancer Inst 2006;98:236–44], and investigated the relationship between the GST isoforms M1, T1 and P1 genes polymorphisms and docetaxel-induced peripheral neuropathy. Methods: We retrospectively analysed GST polymorphisms in a cohort of cancer patients (pts) treated with docetaxel and entered in a clinical trial database. A clinical neurologic evaluation (according to the NCI-CTC v2.0) was performed at baseline and at each treatment cycle. The GST M1 (null genotype), GST T1 (null genotype), and GST P1 (Ile105Val and Ala114Val) polymorphisms were determined using PCR, followed by either sequencing or RFLP techniques. The relationship between GST polymorphisms and grade = 2 neurosenrory toxicity (NST) as primary endpoint was studied, using the Chi2-square (with Yates correction) and the Fischer’s two-tailed exact test. Results: Fifty-eight pts were included : F/M: 29/29; median age: 61 years (range: 47–75). Primary tumor: 27.6% breast, 27.6% prostate, 24.1% lung and 20.7% other cancers. Pts received docetaxel 75–100 mg/m2 given as single-agent. A total of 261 cycles were administered (median/pt: 4, range 2–12). Ten pts developed grade = 2 NST. Twenty-seven pts (47%) were homozygous for the GST P1 105Ile allele, and 31 pts were either homozygous or heterozygous for the GST P1 105Val allele. Grade = 2 NST was significantly more common in pts with GST P1 105Ile/105Ile genotype (8/27 pts, 30%) compared with patients with 105Ile/105Val or 105Val/105Val GSTP1 genotype (2/31 pts, 6,5%; P = 0.047). Pts who were genotyped as GST P1 105Ile/105Ile had a higher risk of developing a grade = 2 NST than did those with other GSTP1 genotypes (OR 6.11; 95% CI, 1.17–31.94; P < 0.05). Conclusions: We found a significant correlation between GST P1 105Ile homozygous genotype and the development of a docetaxel-induced peripheral neuropathy. No significant financial relationships to disclose.

13020 Background: Elderly patients (>70 years) may present different pharmacokinetic profile for many drugs , mainly because of altered elimination due to renal function or metabolic decreases. Methods: Docetaxel, 50 to 85 mg/m2, median 70 mg/m2, was infused during 1 hr to 44 patients, aged 70 to 83 years, median 76.5 years. Three blood samples per patient were obtained according to a limited sampling strategy (Baille et al. Clin Cancer Res 1997, vol. 3, 1535–38). Covariates of interest were carefully recorded, age, body weight, body surface area, gender, serum creatinine, orosomucoid, serum albumin. These data were then analysed using NONMEM V to a) obtain individual Bayesian estimates of docetaxel clearance, b) re-analyse the data in order to estimate population parameters for this elderly population, c) show possible covariate effects on the pharmacokinetic parameters. Results: Median docetaxel CL from Bayesian estimation was 29.1 (2.5–97.5% quantiles 12–49) L/h. When the population was re-analysed per se, docetaxel CL was 29.2 (2.5–97.5% quantiles 17–35) L/h. The inter- subject variability for CL was 25% (precision 32%).. No covariate effect was observed on CL. Conclusions: Docetaxel clearance in elderly patients is slightly decreased, 29 L/h versus 36.8 L/h (reported in 547 patients, mean age 56 years, 5–95% quantiles 39–71 years). The inter-subject-variability of CL in elderly patients was decreased to 25% versus 47.5% in the 547 patients population. A pharmacokinetic- pharmacodynamic modelling of neutrophil counts versus time will be performed in these elderly patients in order to point a possible different sensitivity of this population to the myelosuppressive effects of docetaxel. No significant financial relationships to disclose.

10710 Background: X (Xeloda) is an oral fluoropyrmidine with consistently high activity in MBC, a good safety profile with little myelosuppression and no alopecia, and the convenience of oral administration. The addition of X to docetaxel in anthracycline-pretreated pts also increases survival. This non-randomized phase II study was conducted to evaluate the efficacy, safety and impact on quality of life (QoL) of X in pts with MBC pretreated with anthracyclines and taxanes. Main findings from this trial have been published previously [Fumoleau et al. Eur J Cancer 2004;40:536–42]. Here we present mature data after a follow-up of 48 months. Methods: Pts with anthracycline- and taxane-pretreated MBC received X 1250 mg/m2 twice daily on days 1–14 every 3 weeks for a median of 6 cycles (range 1–15). Results: Baseline characteristics of the 126 pts enrolled were typical of a pretreated MBC population. X achieved complete/partial response or stable disease in 63% of patients (overall response rate, 28%). Median time to progression was 4.9 months (95% CI: 4.0–6.4).Median duration of response was 5.9 months (95% CI: 4.5–12.7). The only grade 3/4 events occurring in ≥ 10% of patients were diarrhea (10%) and HFS (21%). The most common grade 3/4 laboratory abnormality was granulocytopenia (14%). After a follow-up of 48 months, 8 patients are still alive. Updated median overall survival is 15.9 months (95% CI: 13.5–21.3). 1-, 2- and 3-year survival rates are 63%, 37% and 17%, respectively. QoL assessment showed that X treatment was associated with an increase in mean Global Health Score up to cycle 6, with the increase maintained at subsequent evaluations. Conclusions: X is highly active in patients with anthracycline- and taxane-pretreated MBC, leading to a long median survival of 15.9 months. X is also well tolerated and improves QoL. [Table: see text]

10637 Background: The presence of CTCs in blood from metastatic breast cancer patients before first line chemotherapy and persistence of CTCs after initiation of treatment, are predictive of shorter overall survival (Cristofanilli M; et al, 2005, J Clin Oncol 23:1420–1430). CTCs could be used as a surrogate marker. The aim of this study was to determine if CTC were present in the blood of patients who received neoadjuvant chemotherapy (CT) for large operable and locally advanced breast cancer, before initiation of CT (preCT) and at the end of CT before surgery (postCT). Methods: 7.5 ml of blood were obtained on CellSave tube from patients included in an ongoing randomized phase II trial. All patients received 4 cycles of Epirubicin-Cyclophosphamide every 3 weeks followed by 4 cycles of docetaxel associated with or not trastuzumab for HER2 positive patients and with or not celecoxib for HER2 negative patients. CTCs were immunomagnetically separated and fluorescently stained with the CellSearch kit. Cells were classified using the CellSpotter Analyzer as CTCs if they stained positive for DAPI (nuclear dye), and cytokeratin 8, 18 and 19, and if they stained negative for the leucocyte-specific antibody CD45. Results: From 10/2004 to 12/2005, preCT blood samples were obtained in 60 patients, analyzed in 56 for technical reasons. At least one CTC was detected in 15/56 (27%, CI 95%: 15.5–38.5%), 1 to 17 cells per sample (median 1.5). With a threshold of 2 cells, 8/56 (14%, CI 95%: 5–23%) patients were classified positive. At time of analysis, pre CT and post CT samples from the same patient were available for 19 patients. Six had >1 CTC/sample before CT (31.5%) and only one (1/6, 17%) remained positive after CT. Thirteen were negative for CTC before CT and 2/13 (15%) became positive after CT, with only one cell per sample. Conclusions: CTCs can be detected in blood of patients with large operable or locally advanced breast cancer before initiation of neoadjuvant CT and can be monitored during treatment. Longer follow-up and a larger number of patients are expected before correlating these data with tumor response and survival. No significant financial relationships to disclose.

663 Purpose: To estimate, in term of public health on the scale of a region, the cost of trastuzumab and to point out the financial impact of this new targeted therapy in the adjuvant setting. Methods: To understand the consequences of the spending on of trastuzumab at a macroeconomic level in the French hospital financing system, we decided to focus on an establishment in particular, and to analyze the increasing spending of trastuzumab at a micro-economic level, to provide a cost analysis of patients treated with trastuzumab for HER2-overexpressing metastatic breast cancer. We retrospectively reviewed 137 medical reports of patients who received trastuzumab either in combination with chemotherapy or as a single agent and in maintenance therapy. Median age of the patients was 52 years (range 32- to 79+). Eighty five percent had 3+ HER2 overexpression and fifteen percent had 2+ HER2 (FISH amplified). Results: Median survival from first treatment with trastuzumab was 38.5 months (range 0,04–53,06+). The cost of the first year treatment is in average €43,435.58 per patient, for the second year €36,419.01 and for the third year €37,198.94. Drugs cost represents 78% of the hospital stays cost for a patient and 2.9% of the budget of Institut Curie. Conclusions: This retrospective analysis showed the very high level of expenses of trastuzumab to treat metastatic breast cancers. With the adjuvant use of trastuzumab, it is expected that these expenses are going to increase exponentially. No significant financial relationships to disclose.

2046 Background: FN is a rare but severe side effect of DCX, remaining unpredictable. DCX is metabolised by CYP3A which displays high inter-individual variability. We studied the respective role of...

2113 Background: Elderly patients (>70 years) receive chemotherapy less frequently than younger and usually are excluded from clinical trials. The taxanes are among the most active agents available...

848 Background: Standard anthracycline based chemotherapy had improved survival of inflammatory breast cancer. New modalities have been developed over the past 10 years including sequential high dose chemotherapy and newer drugs such as taxanes. Methods: We analyzed a first (G1) of patients uniformly treated with conventional chemotherapy in our institution and compared to a second group (G2) receiving sequential HDC and a third group (G3) with HDC + docetacel G1: 223 pts (1977–1987) were treated at the Institut Curie on 3 consecutive protocoles with conventional doxorubicine based CT G2: 95 pts (1995–96) were enrolled onto the multicenter trial Pegase 02 consisting in four 3 weekly cycles of doxorubicine 75mg/m2 associated with CPM (6g/m2 at C1; 3g/m2 atC2) and 5FU 3g/m2 at C3 and C4 G3: 54 pts (1997–99) accrued in Pegase 05 multicenter trial received four 3 weekly cycles of D75mg/m2 + CPM 6g/m2 at C1; CPM 3g/m2 at C2, C6 and C7; docetaxel 100mg/m2 q 2W was administred at C3, C4 and C5 Median survival 3 ...

The combination of D and AD is a logical attempt to optimize MBC therapy. The ongoing phase I trial has the objective to determine the DLT, MTD and RD in previously untreated pts with CT for MBC with measurable and/or eval disease receiving AD IV bolus followed by D 1 h IV infusion q3w. Prior Adjuvant CT with anthracycline (less than 300 mg/m2) was allowed provided at least a ≥ 12 month interval before study entry. Pts were required to have normal baseline LVEF monitored every 2 cycles. Prophylactic premedication is given with 3d. steroids (starting from d-18 mg every 6 hours) and Tanakan® from the day of 1st infusion. At least 3 pts are entered by dose level. The main toxicities are as follows: D/AD mg/m2 Pts(cy) Ent/Ev Neutropenta Mucositis Pts Feb Neutro Pts DLT Pts G4 G4 m. G1 G2 G3 Pts (cy) dur.(range) 50/40 3/3 (18) 1 (2) 3 (3–3) d 1 1 0 0 0/3 60/40 8/8 (39) 8 (36) 5 (2–10) d 6 1 0 3 2/8 60/50 8/4 (10) 4 (10) 6 (3–8) d 4 0 0 2 0/4 75/50 7/0 too early Except short lasting grade IV neutropenia, no grade 3–4 non hematological toxicity was observed. No CHF nor LVEF drop outside normal limits was observed. The toxicity data allow protocol continuation at dose level IV. As of March 95, there are 26 pts included (50% received prior anthracyclines). 16 pts are evaluable for response: 7 PR (5 mess. + 2 eval.), 2 CR (l eval), 6 NC (3 still ongoing) and one Po. PK profile of D, done in all pts will be available in this ongoing study. This combination is feasible, well tolerated and seems very active in MBC.

Eligibility criteria histologically proven OC, measurable/evaluable disease, relapse/progression after at least one platinum based CT, ≤ 3 prior CT. Treatment 1 or 2 prior CT, T = 175 mg/m2 [Group A (A) = 151 pts]; 3 prior CT, T = 135 mg/m2 [Group B (B) = 41 pts] both by 3 hour IV infusion q 3 w. pts(192): median (med) age: 57 yrs (25–72); PS 0 = 74 pts, PS 1 = 88 pts, PS 2 = 34 pts. nb prior CT: 1 = 81 pts, 2 = 73 pts, 3 = 36 pts. Toxicity (% cycles): 1184 evaluable cycles (cy) (983 in A, 201 in B) with a med nb per pt of 6 in A (1–21), 5 in B (1–11). Cardiac tox.: bradycardia: (≤ 60 bpm) always asymptomatic = 13% (63 pts), hypotension (≤ 90 mm/Hg) = 3% (24 pts), drop in systolic blood pressure 30 mm/Hg = 3% (23 pts). Out of 841 cy EKG 3% were abnormal (13 pts). Minor hypersensitivity reactions (HSR): 18% (A = 19%, B = 9%) in 73 pts, flushing (12%) and skin rash (4%). In 80 cy (7%) symptomatic treatment was required but never T discontinuation. No severe HSR occurred. Hematologic tox. induced treatment delay in 4% (A = 3%, B = 6%) and dose reduction in 1%. Gr 3–4 neutropenia: A = 32%; B = 22%. Eleven pts experienced in 18 cy. any degree off ever of infection associated with a Gr 4 neutropenia, all in A. Thrombocytopenia Gr 3–4 = 1% (10 cy). Anemia Gr 3–4 = 3%, Creatininemia Gr 3 = 1 pt. Liver Tox. = 11 pts (6 with liver metastasis): ALP Gr 3–4 = 1%; ASAT Gr 3 = 0.3%. Nausea/vomiting Gr 1–2 = 13%.; Gr 3 = 2 cy. Mucositis Gr 1–2 = 4% all in A. Paresthesias (present in 45 pts at inclusion) Gr 1–2: A = 43%, B = 28%, Gr 3: A = 5 cy. Myalgias/arthralgias Gr 1–2 =18% (A = 20%, B = 7%) and Gr 3 in 3 cy. Fatique Gr 1–2 = 26%. Edema Gr. 1–2 = 6% and Gr 3 in I cy. No toxic death occurred. Efficacy 185 evaluable pts, RR = 20% (CR = 5%, PR = 15%), SO = 32% (3 pts pCR) Conclusion Taxol® given by 3 H infusion, is well tolerated. The RR seems not different from those observed with 24 H infusion.

Purpose This Phase I, multicenter, randomized study (ClinicalTrials.gov NCT01220128) evaluated the safety and immunogenicity of recombinant Wilms’ tumor 1 (WT1) protein combined with the immunostimulant AS15 (WT1-immunotherapeutic) as neoadjuvant therapy administered concurrently with standard treatments in WT1-positive breast cancer patients. Methods Patients were treated in 4 cohorts according to neoadjuvant treatment (A: post-menopausal, hormone receptor [HR]-positive patients receiving aromatase inhibitors; B: patients receiving chemotherapy; C: HER2-overexpressing patients on trastuzumab–chemotherapy combination; D: HR-positive/HER2-negative patients on chemotherapy). Patients (cohorts A–C) were randomized (2:1) to receive 6 or 8 doses of WT1-immunotherapeutic or placebo together with standard neoadjuvant treatment in a double-blind manner; cohort D patients received WT1-immunotherapeutic in an open manner. Safety was assessed throughout the study. WT1-specific antibodies were assessed pre- and post-vaccination. Results Sixty-two patients were randomized; 60 received ≥ one dose of WT1-immunotherapeutic. Two severe toxicities were reported: diarrhea (cohort C; also reported as a grade 3 serious adverse event) and decreased left ventricular ejection fraction (cohort B; also reported as a grade 2 adverse event). Post-dose 4 of WT1-immunotherapeutic, 10/10 patients from cohort A, 0/8 patients from cohort B, 6/11 patients from cohort C, and 2/3 patients from cohort D were humoral responders. The sponsor elected to close the trial prematurely. Conclusions Concurrent administration of WT1-immunotherapeutic and standard neoadjuvant therapy was well tolerated and induced WT1-specific antibodies in patients receiving neoadjuvant aromatase inhibitors. In patients on neoadjuvant chemotherapy or trastuzumab–chemotherapy combination, the humoral response was impaired or blunted, likely due to either co-administration of corticosteroids and/or the chemotherapies themselves. Electronic supplementary material The online version of this article (doi:10.1007/s10549-017-4130-y) contains supplementary material, which is available to authorized users.

BACKGROUND: Without active delivery across the blood-brain barrier (BBB), efficacy of doxorubicin in intracranial tumors is limited. Glutathione pegylated liposomal doxorubicin (2B3-101) was developed as a brain-targeted chemotherapy. In rats treated with 2B3-101 doxorubicin brain delivery was 5-fold higher as compared to pegylated liposomal doxorubicin (Doxil®/Caelyx®). This resulted in a significant improvement in glioma growth inhibition. In a Phase I dose escalation study in 37 patients with advanced solid tumors and brain metastases (n = 24) or recurrent high grade gliomas (HGG; n = 13), 2B3-101 was well tolerated up to a dose intensity of 15 mg/m2/wk, both as single agent and in combination with trastuzumab. Preliminary evidence of anti-tumor activity was observed, including 1 intracranial partial response (PR) and 16 patients with stable disease (SD) after 2 cycles. These results warranted proceeding into a Phase IIa study. METHODS: The purpose of the ongoing Phase IIa study is to evaluate the safety, tolerability and intracranial anti-tumor activity of 2B3-101 in patients with recurrent HGG and the intracranial and extra-cranial anti-tumor activity of 2B3-101 in patients with breast cancer brain metastases (BCBM) (n = 14 per group). Patients with recurrent HGG are treated with 2B3-101 60 mg/m2 iv q28d while patients with BCBM are treated with 2B3-101 50 mg/m2 iv q21d, in HER2 positive patients combined with trastuzumab (iv, 6mg/kg, q21d). Results up to March 15th 2014 are described in this abstract; in October 2014 the complete data set will be presented. RESULTS: To date, 18 patients with HGG and 10 patients with BCBM have been enrolled in the Phase IIa part of the study and have received a total of 35 (range 1-4) and 34 (range 1-7) cycles of 2B3-101, respectively. At both dose regimes, the side effects were consistent with Doxil®/Caelyx® and with the earlier Phase I results of 2B3-101. The most common adverse events (AEs) grade ≥2 related to 2B3-101 were: neutropenia (28%), palmar-plantar erythrodysesthesia (PPE) (21%), infusion reactions (21%) and oral mucositis (17%). No CNS and/or cardiac toxicity were reported. 2B3-101 cycles were administered per protocol in 92% of the HGG patients and in 62% of the BCBM patients. The main reasons for dose delays/ reductions were neutropenia (19%) and PPE (69%). The anti-tumor activity was evaluable in 13 patients with HGG and in 9 patients with BCBM. In the HGG cohort, 31% of the patients had SD as best response (RANO), including 2 patients with a response of ≥30%. In the BCBM cohort, 11% had a PR and 56% had SD as best response (RECIST). The latter group, included 3 more patients with an intracranial response of ≥20%. CONCLUSIONS: This phase I/IIa trial shows that 2B3-101 has anti-tumor activity with a tolerable safety profile in recurrent HGG and in BCBM patients. These results warrant further randomized, controlled Phase IIb studies in both patient populations.