bluuebunny/crossref_metadata_2025_split huggingface dataset:
ABT-869 in Combination with Paclitaxel (P) as First-Line Treatment in Patients (Pts) with Advanced Breast Cancer.
Authors: Rugo H. , Lopez-Hernandez J. , Gomez-Villanueva A. , Gupta N. , Qian J. , Qin Q. , Ricker J. , Carlson D. , Kozloff M. 
Published: December 2010

Abstract
Background: ABT-869 is a novel orally active, potent and selective inhibitor of VEGF and PDGF receptor tyrosine kinases. ABT-869 potentiates the action of P in a number of preclinical tumor models including breast carcinoma (BC). This study was conducted to assess pharmacokinetic (PK) interaction and safety of ABT-869 combined with weekly P, and to guide ABT-869 dosing in the randomized portion of the trial.Methods: Pts with measurable chemotherapy naïve metastatic or unresectable locally advanced BC were eligible for this trial. Treatment consisted of weekly P (90 mg/m2) on Day (D) 1, 8 and 15 of every 28-day cycle (C) and ABT-869 0.20 orally once daily (QD) starting on D3 of C1. Treatment continued until progressive disease (PD) or unacceptable toxicity was observed. CT scans were conducted at baseline (within 21 days prior to C1 D1) and at the end of every 3 cycles. Adverse events (AE) were graded by NCI CTCAE V3.0; efficacy was evaluated by RECIST.Results: As of May 2009, 8 pts have enrolled in this study: 5 at 0.20 mg/kg and, based on the frequent need for dose reductions in this and other ongoing trials, a second cohort has enrolled 3 out of 6 planned pts at 0.15 mg/kg. Preliminary safety and efficacy results are shown (table). Of the 5 pts dosed at 0.20 mg/kg, 2 pts had confirmed partial responses (PR) and continued on drug at reduced dose for 12 and 10 cycles, and 3 discontinued (DC); 1 due to PD, 1 withdrew consent, and 1 for AE (pulmonary embolism, cycle 2). Three pts have been dosed at 0.15 mg/kg; one is early and two have PR. The most common AEs were neutropenia (n=3), stomatitis, vomiting, ALT increased, hyperglycemia, hypokalemia and hypertension (n=2 each). These events were generally grade 1 or 2 except for neutropenia.Conclusion: The combination of ABT-869 0.20 mg/kg QD with P weekly resulted in antitumor activity (2 PR) but required frequent dose reductions due to AEs. A reduced dose of 0.15 mg/kg with weekly P is being evaluated (2 PR). Updated results of this ongoing study will be presented.Pt #Initial ABT-869 Dose (mg)Current ABT-869 Dose (mg)Cycle of Dose ReductionReason for Dose ReductionEnd Cycle 3 AssessmentsEnd Cycle 6 AssessmentsCurrent status 0.20 mg/kg 1001107.54G3 hand-footPRPRCycle 121041105.03,5G3 fatiguePRPRCycle 1010022020----DC in Cycle 2 (PD)102112.512.5--SD-DC in Cycle 4 (withdrew consent due to headaches)10221515----DC in Cycle 2 (Pulmonary embolism) 0.15 mg/kg 10231052,4G2 hand painPR-Cycle 510247.57.5--PR-Cycle 410251010----Cycle 1G= grade
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5076.
Effects of Rapamycin on Breast Cancer Cell Migration through the Cross-Talk of MAPK Pathway.
Authors: Zhao H. , Cui K. , Nie F. , Jin G. , Li F. , Wu L. , Wang L. , Brandl M. , Yilidirim N. , Zhang S. , Sun A. , Wong S. 
Published: December 2010

Abstract
Phase I/II clinical studies with rapamycin analogs in breast and other cancers have demonstrated favorable responses. However, little is known on the effects of the mTOR inhibitor on breast cancer cell metastasis, which is a major cause of morbidity and death. We developed a highly sensitive 3-dimensional (3D) proliferation/invasion assay using quantitative bioluminescence (BL) imaging and applied this assay to evaluate the effects of rapamycin on the triple negative breast cancer cell line MDA-MB231. Without cytotoxicity of rapamycin on this cell line, rapamycin at 10nM inhibited the cell migration/invasion, but not at 1nM and 100nM, which was confirmed by the time-lapse single cell tracking analysis. The quantification of cytoskeleton changes showed most potent effects of 10nM rapamycin on the MDA-MB231 cells, with the formation and rearrangement of specialized cell membrane structures and actin fiber implicated in cell motility. Then, the Panorama Cell Signaling Antibody Microarray, enabling the global comparative analysis of cell signal proteins simultaneously, was exploited to analyze the effects of rapamycin on the cellular signaling network of the MDA-MB231 breast cancer cell line. 100nM rapamycin activated the MAPK pathway obviously, through the attenuated negative feedback of activated S6K1 to PI3K-Raf, which increased the expressions of activated Jun N-terminus kinase (JNK), Erk1/2, MEK-1, Raf-pS621, and MAPK-activated protein kinase 2 (MAPKAPK2) in the cells exposed to 100nM rapamycin. MEK inhibitor U0126 or PD98059 could restore the anti-migration effects of 100nM rapamycin on the MDA-MB231 cells. Furthermore, the combination of MEK inhibitors and rapamycin performed synergism on inhibiting the cell proliferation and migration/invasion. Accordingly, rapamycin at a certain dose suppresses MDA-MB231 cell migration/invasion, and the co-targeting of mTOR and MAPK pathways enhances the inhibition on cell proliferation and migration/invasion, underscoring the potential therapeutic utility of rapamycin, and rapamycin combining with MAPK inhibitors in triple negative breast cancer progression, and the results highlight the cross-talk homeostasis of mTOR and MAPK pathways in cancer treatment.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5080.
Pooled Analysis of Cardiac Safety in Patients Treated with Pertuzumab.
Authors: Suter T. , Brammer M. , Ross G. , Lenihan D. 
Published: December 2010

Abstract
Background: Pertuzumab, a monoclonal antibody, is a human epidermal growth factor receptor 2 (HER2)-dimerisation inhibitor directed to the dimerisation epitope of HER2, with promising activity when given with trastuzumab to patients with HER2-positive metastatic breast cancer following progression on trastuzumab.1 As anti-HER2 treatment has been associated with cardiac dysfunction, we investigated the incidence of reduced left ventricular ejection fraction (LVEF) and congestive heart failure (CHF) in patients treated with pertuzumab as single agent or in combination with cytotoxic or anti-HER therapy.Methods: We analysed patients in completed Phase II studies with pertuzumab. Cardiac dysfunction was defined as: 1) reduced LVEF (baseline normal: LVEF reduced ≥10% absolute and to below 50%); 2) symptomatic CHF: any symptoms suggestive of CHF counted (severity then classified according to New York Heart Association).Results: In 554 patients analysed, the overall incidence of reduced LVEF was 5.8% and of CHF 0.7%. Individual data for patients in different treatment protocols are shown in Table 1. PatientsReduced LVEFCHF (n)(n/%)(n/%)Pertuzumab as single agent (24% with prior anthracyclines)30221/7.01/0.3Pertuzumab with cytotoxic therapy1756/3.42/1.1Pertuzumab with trastuzumab (71% with prior anthracyclines)775/6.51/1.3 The majority of patients with reduced LVEF or symptomatic CHF had significant improvement or return to baseline function on follow-up or with standard cardiac medication.Conclusions: Overall, the incidence of cardiac dysfunction in Phase II studies of patients treated with pertuzumab was low. When combined with trastuzumab in selected patients, there is no apparent indication that pertuzumab exacerbates the known risk of reduced LVEF and CHF with trastuzumab.2 These data suggest that the combination of pertuzumab with trastuzumab or chemotherapy for HER2-positive breast cancer appears safe from a cardiac perspective with appropriate monitoring in ongoing studies.References1. Gelmon K et al. Poster 1026 presented at the 44th ASCO Annual Meeting, Chicago, Illinois, USA, 30 May-3 June, 20082. Muehlbauer S et al. Abstract presented at SABCS 2008; abs 6136
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5088.
Population Pharmacokinetics of Trastuzumab-DM1, a First-in-Class HER2 Antibody-Drug Conjugate Given Every 3 Weeks (q3w) and Weekly (qw) to Patients with HER2-Positive Metastatic Breast Cancer (MBC).
Authors: LoRusso P. , Girish S. , Burris H. , Beeram M. , Vukelja S. , Modi S. , Yi J. , Wang B. , Saad O. , Gupta M. 
Published: December 2010

Abstract
BackgroundTrastuzumab-DM1 (T-DM1) is a first-in-class HER2 antibody–drug conjugate (ADC) in development for the treatment of HER2-postive MBC. T-DM1 is composed of trastuzumab (Herceptin®), DM1, an inhibitor of tubulin polymerization derived from maytansine, and the stable MCC linker that conjugates DM1 and trastuzumab. T-DM1 has been tested at multiple dose levels in a Phase I trial: q3w (0.3–4.8 mg/kg) and weekly (1.2–2.9 mg/kg), and in two subsequent Phase II trials with T-DM1 administered as a single agent at 3.6 mg/kg q3w. A population pharmacokinetic (PK) model for T-DM1 conjugate was developed using pooled PK data from these trials to estimate typical PK parameter values and inter-patient variability in patients with HER2-positive MBC. The model was further developed to explore and quantify the effect of body size and pathophysiologic covariates on the pharmacokinetics of T-DM1 to better understand the clinical factors that might affect safety for individual patients.MethodsFor the current analysis, 2935 T-DM1 serum concentration–time datapoints from 167 patients were simultaneously fitted using NONMEM® software. T-DM1 concentration-time data to date are best described using a two-compartment linear model. All relevant and plausible covariates likely to have an effect on T-DM1 systemic exposure, e.g., body size covariates (body weight [BW], body surface area [BSA], and body mass index [BMI]), albumin, liver enzymes, creatinine clearance, tumor burden, baseline trastuzumab levels, HER2ECD, concomitant medications, etc., will be explored for possible correlation with the parameters in the model. In addition, the effect of selected covariates on the pharmacokinetics of DM1 is also explored.ResultsEstimated PK parameters for T-DM1 from the base population PK model with data available to date are: clearance (CL) 0.75 L/day, central distribution volume (V1) 3.37 L, peripheral volume (V2) 1.04 L, and inter-compartmental clearance (Q) 0.92 L/day. Inter-individual variability on CL, V1, and V2 was 26%, 17%, and 66%, respectively. Preliminary univariate covariate analysis suggests that body size metric (BSA, WT, BMI) has an influence on exposure of T-DM1. Albumin and tumor burden also appear to influence the clearance of T-DM1. Additional covariate analysis is ongoing. Results of the updated PK model and covariate analysis based on ongoing Phase II trials will be presented at the meeting.ConclusionsModerate inter-individual variability for the estimated PK parameters was observed. The model incorporating all available PK data from Phase I and II trials will help identify clinical factors, from the covariates studied, that affect the pharmacokinetics of T-DM1 and thus potentially, the safety of T-DM1 in individual patients.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5099.
Phase II Study of a HER-2/Neu (HER2) Intracellular Domain (ICD) Vaccine Given Concurrently with Trastuzumab in Patients with Newly Diagnosed Advanced Stage Breast Cancer.
Authors: Disis M. , Dang Y. , Bates N. , Higgins D. , Childs J. , Slota M. , Coveler A. , Jackson E. , Waisman J. , Salazar L. 
Published: December 2010

Abstract
HER2 is a tumor antigen in breast cancer and several trials have demonstrated that breast cancer patients can be immunized against this protein. We have developed HER2 peptide based vaccines that are aimed at eliciting CD4+ Th1 tumor antigen specific T cell responses. Th1 effectors provide immunologic memory, enhance cross priming which will allow the elaboration of tumor specific CD8+ T cells, and stimulate epitope spreading which we have shown to be a potential biomarker of clinical response. 52 patients will be enrolled with the primary objective to determine relapse free survival after active immunization. Eligible patients are newly diagnosed with Stage III (B or C) or Stage IV breast cancer and begin vaccination within 6 months of starting maintenance trastuzumab. This interim report will present data on the first 25 patients enrolled; 21 stage IV and 4 locally advanced patients. The vaccine is well tolerated with all adverse events (AE) being Grade I or 2. The most common AE is injection site reaction. Moreover, the combination of HER2 vaccination with trastuzumab did not result in additive cardiac toxicity in these patients. Immune responses were evaluated by IFN-gamma ELISPOT. To date, 88% of patients immunized developed significant immunity to the components of the ICD vaccine. The majority, 75%, developed robust immunity to the HER2 protein. Our group has recently demonstrated that a broadening of immunity throughout the HER2 protein, to components of the protein that weren't in the vaccine, i.e. epitope spreading, may be associated with improved survival in vaccinated patients. 63% of immunized patients demonstrated evidence of intramolecular epitope spreading. We questioned whether such high frequencies of homing Type 1 T cells might modulate the immunosuppressive tumor microenvironment, so we evaluated whether circulating serum immunosuppressive cytokines were impacted by immunization. TGF-beta is an immunosuppressive cytokine secreted by tumor stroma and regulatory T cells. We found that the levels of serum TGF-beta decreased significantly in the majority of patients after vaccination. We further analyzed the correlation between the change of serum levels of TGF-beta post vaccination and HER2 ICD vaccine-induced T cell responses. We found that the greater the magnitude of the HER2 specific T cell response, as demonstrated by IFN-gamma secretion, the greater the decrease in serum TGF-beta (p=0.0045, r=0.742). The correlation between the increased epitope spreading T cell response and decreased levels of TGF-beta was even more significant (p=0.0003). The median overall survival has not been reached with 100% of patients alive at this time. Relapse free survival data will be presented.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5102.
Response Rates in Non-Anthracycline Versus Anthracycline Exposed Patients with Metastatic Breast Cancer Treated with Lapatinib.
Authors: Rugo H. , Johnston S. , Preston A. , Kemner A. , Stein S. , Gomez H. 
Published: December 2010

Abstract
Introduction: Anthracycline free regimens are increasingly used as adjuvant therapy for HER2 positive breast cancer due to concerns related to cardiac toxicity. Lapatinib plus capecitabine is approved for the treatment of patients with prior exposure to anthracyclines, taxanes and trastuzumab. With this recent shift in treatment practice, an exploratory analysis was performed to evaluate whether prior anthracycline exposure had an effect on clinical benefit in patients treated with lapatinib.Methods: The activity of lapatinib was examined in 7 completed studies (2 Phase III, 5 Phase II) in which lapatinib was administered as monotherapy or in combination with paclitaxel, bevacizumab, or letrozole for the treatment of HER2 positive metastatic breast cancer. In each study, patients were grouped by prior anthracycline exposure to evaluate the clinical activity of lapatinib containing regimens, as measured by overall response rate (RR).Results: In 7 studies, 192 of 593 patients were exposed to prior anthracycline. 401 patients were not. Lapatinib was administered as monotherapy in 3 studies and in combination in 4 studies. Within in each study, RR were similar in both groups (no prior anthracycline and prior anthracycline). In the combination of lapatinib plus letrozole, overall RR was higher in patients not exposed to prior anthracyclines (36.1% versus 18%). Cardiac data to be presented. Recognizing the limitations of patient numbers and cross study comparisons, as a whole, the results of this analysis indicate that patients had similar overall response rates to lapatinib regardless of exposure to prior anthracycline.Summary of Response Rate Response Rate by Prior Exposure to Prior AnthracyclineStudyTreatment ArmsNo Prior Anthracycline, % (n/N)Prior Anthracycline, % (n/N)Total, % (n/N)EGF30001 (HER2+)lapatinib+paclitaxel56.7 (17/30)63.6 (14/22)59.6 (31/52)EGF30008 (HER2+)lapatinib+letrozole36.1 (22/61)18.0 (9/50)27.9 (31/111)EGF20009lapatinib QD22.4 (11/49)30.0 (6/20)24.6 (17/69) lapatinib BID30.2 (13/43)34.6 (9/26)31.9 (22/69)EGF102580lapatinib42.9 (18/42)N/A42.9 (18/42)EGF103009lapatinib10.6 (15/141)N/A10.6 (15/141)EGF103890lapatinib+bevacizumab16.7 (3/18)8.8 (3/34)11.5 (6/52)EGF105764lapatinib+paclitaxel76.5 (13/17)77.5 (31/40)77.2 (44/57) Conclusions: With the increasing availability of agents to treat breast cancer, it is common that many patients do not receive prior anthracycline treatment for their disease. In this exploratory analysis, it appears the clinical activity of lapatinib is maintained in patients with no prior anthracycline exposure; and as observed in the lapatinib plus letrozole combination study, may even increase the overall response rate.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5105.
HER-2 Status May Change in Recurrent Breast Cancer.
Authors: Arnaout K. , Khalife M. , Younes M. , Hanbali A. 
Published: December 2010

Abstract
Introduction:The human epidermal growth factor receptor (HER-2) is a cell membrane surface-bound receptor tyrosine kinase which has been associated with increased breast cancer recurrence and a worse prognosis. Its presence also determines which patients are candidates for targeted therapy with trastuzumab. The purpose of this retrospective study was to determine the percentage of HER-2 status change in recurrent breast cancer.Methods:In this study, we retrospectively reviewed the charts of 2,652 patients diagnosed with breast cancer in our institutution between 2003 and 2009. Forty-four patients with recurrent breast cancer and available HER-2 status at the time of diagnosis and at recurrence were identified. HER-2 status was assessed by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH). When both methods were available, we used FISH as our reference.Results:A change in HER-2 status at recurrence was observed in six patients (13.6%). One patient (2.3%) changed from negative to positive. Five patients (11.3%) had a change from positive to negative. These five patients represented 50% of the patients with positive HER-2 at the time of initial diagnosis. HER-2 status remained unchanged in thirty-eight patients (86.4%).Conclusion:A change in HER-2 status can be noted at the time of recurrence. The exact mechanism is not yet well understood, and further studies are needed to identify it. Our data support the fact that patients with recurrent breast cancer should have their HER-2 status re-evaluated, since this affects therapeutic options.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5109.
A Phase 1 Study To Assess the Safety, Tolerability and Pharmacokinetics of ARRY-380 – An Oral Inhibitor of HER2.
Authors: Chia S. , Baetz T. , D'Aloisio S. , Fernetich G. , Freeman B. , Barrett E. , Kass C. , Kang J. , Sajan B. , Moulder S. , Garrus J. 
Published: December 2010

Abstract
Background: ARRY-380 is a potent, orally active small molecule that selectively inhibits HER2 signaling in vitro and in vivo and significantly inhibits tumor growth in a variety of HER2-dependent tumor xenograft models. Based on its preclinical activity, tolerability and pharmacokinetic (PK) profile, a Phase 1 study was initiated to evaluate the safety, tolerability and PK profile of ARRY-380 as a single agent in patients with solid tumors and to establish the maximum tolerated dose (MTD).Methods: Patients with HER2 positive breast cancer or other tumor types for which published evidence of HER2 expression exists were treated with ARRY-380 as a single oral dose on Cycle 1 Day 1, followed by continuous twice-daily (BID) oral dosing starting on Cycle 1 Day 3. ARRY-380 was escalated in cohorts of 3 to 4 patients, using standard dose-limiting toxicity (DLT) criteria during Cycle 1 to determine dose escalation. Serial PK assessments were made during Cycle 1 on Days 1, 2, 3 and at steady-state on Day 15.Preliminary Results: As of June 1, 2009, 15 patients have been treated in 5 dosing cohorts at doses of 25 to 300 mg BID. Patients had a median age of 61 years (range, 37-77 years) and ECOG PS of 0 to 2. Cancer types included HER2+ breast cancer (8), colorectal (6) and salivary gland (1). No DLTs have been observed and drug-related adverse events have included Grade 1 nausea, rash and fatigue and Grade 2 fatigue in 2 patients at the 200 mg BID dose level. Preliminary PK analyses indicate a trend for increasing Cmax and AUC with increasing dose, a median Tmax of 2 hours and a mean t1/2 of 4.6 hours across all cohorts. Two patients with HER2+ breast cancer have had stable disease for ≥ 4 months with no significant toxicity. One of these two patients had a notable reduction in liver metastases (28%) after 2 cycles of ARRY-380 and is currently on study.Conclusions: ARRY-380 has demonstrated an acceptable safety and PK profile and preliminary signs of clinical benefit. Dose escalation continues to determine the MTD.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5111.
Phase II Evaluation of a Novel Capecitabine Schedule in Combination with Lapatinib for Patients with HER2-Positive Metastatic Breast Cancer Refractory to Trastuzumab.
Authors: Gajria D. , Theodoulou M. , Feigin K. , Patil S. , Geneus S. , Drullinsky P. , D'Andrea G. , Lake D. , Norton L. , Hudis C. , Traina T. 
Published: December 2010

Abstract
BackgroundCapecitabine (C) administered for 14 days followed by a 7 day rest (14—7) in combination with lapatinib (L) improved TTP in patients with HER2(+) metastatic breast cancer (MBC) that progressed following trastuzumab (T). We applied mathematical methods to C dosing which predicted 7 days of treatment (Tx) followed by 7 days of rest (7—7) to be optimal. In animal models, C(7—7) was better tolerated than C(14—7) at higher doses and led to improved survival. A phase I study in patients (pts) with MBC concluded the MTD of C(7—7) is 2,000mg BID. To optimize the combination of C+L, we are testing C(7—7) + L.MethodsEligible pts have measurable, HER2(+) MBC with progression following trastuzumab. HER2(+)=3+ or FISH-amplified. Pts have normal LVEF by MUGA, ECOG performance status (PS) ≤2 and normal organ function. Prior therapy is limited to &lt;3 chemotherapy (CRx) regimens for MBC; prior fluoropyrimidine is not permitted. Tx = C (2,000mg orally BID, 7—7) plus L (1,250mg orally daily). Cycle length=4 weeks (wks). Pts were evaluated for toxicity every 4 wks, for response every 12 wks and for LVEF by MUGA every 12 wks. Primary endpoint: Response Rate. Secondary endpoints: toxicity by NCI CTCv3, stable disease (SD)&gt;6 months and PFS. Using a Simon optimal 2-stage design, with alpha 10% and power 90% to discriminate between RR 10% and 25%, 21 pts will be accrued to the 1st stage. If &gt;2 patients respond, 29 additional pts will be enrolled. If &gt;7/40 pts respond, then C(7—7) + L will be considered worthy of further study.ResultsAs of 5/28/09, 12 pts are enrolled; 6 are evaluable for response. Median (med) age 61 years (41-71), med ECOG PS 0 (0-2), ER/PR(+) 5, HER2(+) 12. Sites of MBC: Viscera 5, Brain 2. Med LVEF 64% (51-71%). Prior Tx: Adjuvant: CRx (7), hormone Tx (3), T (4); MBC: CRx (6), hormone Tx (4), T (8). After a med of 3 cycles (1-8), 6 pts are evaluable for response: CR 0, PR 1, SD&gt;6mo 2, SD&lt;6 mo 3. Five pts are too early for response assessment; 1 pt discontinued Tx during 1st cycle for palliative radiation without documented progression. There were no treatment-related grade 4/5 events or unexpected toxicity. Tx-related Grade (Gr) 2 or 3 toxicity in &gt;10% of pts includes: hand-foot syndrome (Gr 3: 8%, Gr 2: 17%) and diarrhea (Gr 2: 17%). There were no declines in LVEF.ConclusionCapecitabine (7—7) plus lapatinib appears well-tolerated and demonstrates activity in pts with HER2(+) MBC that has progressed following trastuzumab based therapy. Additional efficacy and safety data is expected prior to this meeting.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5113.