Higher Number Of Pts Research Articles

Abstract P6-04-11: The foundation one assay influences clinical decision making in metastatic breast cancer

Abstract Background: Tumor DNA sequencing is now readily available in metastatic breast cancer (MBC). The purpose of this study was to determine the effect of molecular testing on clinical decision-making in MBC at an academic cancer center. Methods: We obtained the Foundation One (FO) tests that were requested from Duke Cancer Institute breast oncologists between 12/2013 and 4/2015. We examined the following: ER/PR/HER2 status, histology, biopsy site and time, #months (mons) from time tissue was obtained to testing, #lines of prior therapy prior to tissue sampling and FO testing, #mons from initial diagnosis/MBC to FO. The following variables from the FO test were abstracted: #genomic alterations, #rx with potential benefit, #clinical trials available, #variations of unknown significance (VUS). Physicians were retrospectively surveyed regarding influence of FO results on clinical treatment decisions and on clinical trial consideration. Results: To date, 58 specimens have been sent for FO testing. From the time of FO testing, the mean #of mons since initial diagnosis (dx) was 84.4(7-435) and the mean #of mons since the dx of MBC was 31.4(1-140). Pts with triple negative breast cancer (TNBC) were more likely to have FO ordered within 1 year of MBC diagnosis (OR=2.93, p=0.048). On average, pts had received 3.78 lines of rx for MBC (0-10) at the time FO was sent. The timing of tissue acquisition for FO testing was bimodal (45% had a new bx for the assay whereas 55% had the FO test on archival bx). 50% of un-resulted (unsuccessful) FO assays were from archival tissue with a mean #mons since the archival tissue was obtained of 42 mons (18-74). To date, 56% of resulted samples were from archival tissue with a mean #mons since the archival tissue was obtained of 19.6(2-75). Per the FO report: the mean #genomic alterations per pt = 6.21 (1-16); the mean #VUS per pt = 11.5 (3-30); the mean #mutation-directed rx per pt= 3.4 (0-15), the mean #mutation-directed clinical trials per pt= 9.33 (0-20). Genomic alterations occurring in ≥ 10% patients included: TP53 (48%), CCND1 (27%), FGF4 (27%), FGF19 (27%), FGFR1 (25%), PIK3CA (25%), FGF3 (25%), MYC (25%), ZNF703 (21%), ESR1 (19%), MCL1 (15%), CDH1 (13%), ERBB2 (10%), EMSY (10%), MYST3 (10%). 36 pts had invasive ductal carcinoma (IDC), 6 pts had inflammatory breast cancer (IBC), and 6 had invasive lobular carcinoma (ILC). No genomic alterations were associated with a sub-type of MBC with the exception of ESR1 mutations in ER+ IDC (100%) and CDH1 mutations in ILC (67%). Pts found to have ESR1 mutations had on average 63 mons(10-200) of endocrine therapy at the time of tissue sampling. When the breast cancer medical oncology physicians were retrospectively surveyed, 42% FO assays influenced clinical treatment decisions and 14% resulted in clinical trial enrollment. Conclusions: FO utilization is variable based on MBC sub-type and the timing of tissue collection is bimodal. ESR1 mutations were associated with history of prolonged endocrine rx treatment in ER+ IDC and CDH1 mutations were associated with ILC. FO assays frequently influenced clinical treatment decisions but did not result in a high number of pts enrolled on clinical trials. We will update our dataset with additional FO assays and clinicopathologic variables. Citation Format: Harnden KK, Kimmick GG, Marcom PK, Westbrook KE, Blackwell KL. The foundation one assay influences clinical decision making in metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-04-11.

Clinical Use of Ultrasound Superb Micro-Vascular Imaging Technique in Patients with Hemophilia Treated with Standard Radiosynovectomy. Initial Report

Introduction: Ultrasound (US) is an easily well available, non-invasive imaging technology that is used as a first-line diagnostic examination, in patients with hemophilia, who developed arthropathy due to joint bleeding. US is used both to select patients for radiosynovectomy (RS) and also for a follow-up study. It is especially important in vascular imaging, where clear and precise hemodynamic data is presented in a visual , which is more sensitive than the standard one. Clinically significant challenges exist in detecting small or microflow states without the use of contrast media, particular in pts with synovial overgrowth, which is characteristic in patients with hemophylic arthropathy. In this initial study we report the clinical use of e Superb Micro-Vascular Imaging technique ( colour -cSMI and grey scale mode mSMI ) in patients after radiosynovectomy in a short term follow-up.Materials and Methods. There were 8 pts with hemophia, advanced arthropathy and joint bleeding due to synovial overgrowth Standard qualification into RS in each case. Overall 18 RS were done, including 10 ankle, 6 elbow and 2 knee joints. All pts had initial before RS and follow-up study 1-2 months and 3-6 months after RS. All had clinical and US standard examinations, performed by the same physician. In each case the same methods of US imaging were used, including position. All examinations were performed using Aplio 400 with linear transducer (9-12MHz) (Toshiba MSC, J). All images include cine mode collected during examination were reviewed in each case. The final analysis includes an initial study compared to a follow-up of least 2 examinations using a quality scale of intensity of synovial vascularisation, based on SMI and standard evaluation including thickness of synovium, echogenity etc were evaluated.Results: All RS were without complications. Initial US indicated high vascular flow in affected joints in all pts, in a semiquantitative scale (cSMI 3.1 and mSMI 4.1 ). In the first follow-up cSMI was 2.5 and mSMI was 2.83, in second follow-up studies cSMI 2.56 and mSMI 2.56. There were no other deferrers of imaging analysis, including other US elements of synovial overgrowth reductiona, echogenic improvement etc. Clinical single pt with elbow arthropathy did not respond to RS, which was documented in both cSMI and mSMI, without any differences between initial and follow-up tests. 5 had response a clinical response and 2 had minimal clinical response.Conclusion: The new Superb Micro-Vascular Imaging technique seems to be useful in the imaging/clinical evaluation of early response in pts with hemophilic arthropathy who had radiosynovectomy. The new US approach with cSMI and mSMI is both high sensitive in detecting of microvascular blood reduction in initial stage of clinical follow-up. Further analysis with higher number of pts and longer follow-up suld be performed to assess real value of this technology DisclosuresNo relevant conflicts of interest to declare.

Treating Indolent Lymphoma in Older Adults: What Is the Right Way?

Introduction: The treatment of hematological malignancies in older adults is an emerging and important issue due to the aging population trend as well as drug-related toxicities in pts (pts) with comorbidities. Indolent lymphomas constitute a subgroup of incurable non-Hodgkin lymphomas characterized by multiple relapses. Anthracycline containing chemo-immunotherapy regimens (ACR) such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) are very active in indolent lymphomas, resulting in a long progression-free survival (PFS). Due to their high rate of associated toxicities, such regimens are less likely to be given to the elderly population. Currently, there is no consensus regarding the treatment of indolent lymphomas in older adults. The present study assessed overall survival (OS), time to next treatment (TNT) and treatment-associated toxicity in this distinctive subpopulation of pts with indolent lymphoma, aiming to develop an optimal approach to the management of such pts.Methods: This retrospective cohort analysis included pts with indolent lymphoma (histology diagnosis of follicular lymphoma, marginal zone lymphoma, Waldenstrom's macroglobulinaemia and indolent lymphoma not otherwise specified) aged ≥60 at therapy initiation (1st line) treated with either an ACR or a non-ACR at the Rambam Department of Hematology and Bone Marrow Transplantation between the years 2000 and 2012. All regimens included rituximab. OS, TNT and treatment-related toxicity (neutropenic fever and hospital admission due to noninfectious causes during the treatment period) were assessed.Results: Forty three pts treated with an ACR and 55 pts receiving a non-ACR were included in the analysis. Clinical characteristics, response to therapy and treatment modification data are presented in table 1. The median age was 67 years in the ACR group and 73 years in the non-ACR group; median duration of the follow-up was 4.3 years (range 0.1-11.9 years). No difference in terms of high risk co-morbidity score, defined as modified Charlson co-morbidity score ≥5 (Charlson et al, 1987), was found between the ACR group and the non-ACR group. Significantly more pts with follicular lymphoma were treated with ACR compared to non-follicular indolent lymphomas. There was no difference in CR rate between the ACR and non-ACR groups. In a univariate analysis, OS was found to be significantly higher in the ACR group, but in the multivariate analysis, OS appeared to be influenced only by age. The cause of death was disease-related in 8 pts (100% of deaths) in the ACR group and in 7 pts (64%) in the non-ACR group (data on the cause of death were available for 11 out of 18 pts from the non-ACR group). The median TNT was longer in the ACR cohort, but the difference did not reach statistical significance. No difference was found between the ACR and non-ACR groups in terms of major treatment-related toxicities assessed by the number of hospital admissions because of infection or other causes. Dose adjustments and treatment delays were far more frequent in the ACR cohort. This study is limited by its retrospective nature, the small number of patients and a significantly higher number of pts with follicular lymphoma treated in the ACR group.Conclusions: The present analysis of a cohort of older adults with indolent lymphoma treated with chemo-immunotherapy regimens in routine clinical practice has demonstrated that ACR was safe and efficacious. When approaching older adults suffering from indolent lymphoma, the considerations of quality of life (time without the need of further treatment, the minimal number of hospital admissions and minimal number of infections requiring hospitalization) should play a major role in treatment decision-making. In the current study, ACR was not inferior to non-ACR in terms of toxicity. A trend to an improved OS and longer TNT was demonstrated in the ACR group. The patient age should not deter physicians from using ACR in older adults.Table 1ParametersACR N=43Non-ACR N=55P valueAge, median67730.05Pts with modified Charlson comorbidity score ≥5 (%)7 (17)10 (19)0.55Pts with follicular lymphoma (%)33 (77)27 (49)0.007CR rate (%)30 (70)33 (60)0.44-year OS, %8167<0.04Median time to next treatment, months90550.2Dose adjustments65370.008Treatment delays57370.06 DisclosuresNo relevant conflicts of interest to declare.

Hypertension treatment: Does the awareness of patients really affect the goal?

Objective: Hypertension (HT) represents the most important cardiovascular (CV) risk factor, but the target blood pressure is not reached in the majority of hypertensive treated patients (pts). Moreover, HT values and adherence to treatment are seldom evaluated during “everyday life”. This work was conducted during public events out of medical setting and aimed to improve the awareness against CV risk factors. The sample of population was evaluated in order to: assess the prevalence of HT and that of treated “target patients”, comparing these findings with literature; and evaluate the awareness of HT as a major CV risk factor. Methods: 1350 subjects were evaluated (mean age 58 years, median 60, range 8–102, male/female ratio = 0.86). CV risk factors, HT management and comorbidities were collected and blood pressure (BP) was measured according to ESH/ESC 2007 guidelines. Adherence to treatment was evaluated according to the Morisky Scale. Results: Among the 1350 subjects, 765 (57%) declared themselves “normotensive” and 582 (43%) “hypertensive”. In 981 (73%), BP was <140/90 mm Hg, while in 365 (27%) it was ≥140/90: among these last, 221 belonged to the group of “hypertensive”, thus representing “non-target patients” (NTpts) (38%), while “target” patients (Tpts) were 360 (62%). No differences in terms of risk factors and number of medications taken were found when comparing NTpts versus Tpts (with the exception of coronary artery disease, more represented in target pts, p < 0.03). In both groups a number of pts did not remember the anti-hypertensive therapy (20% and 19% respectively, p = 0.69). Despite these findings, adherence to treatment was generally high (Morisky score 3–4 in 79 out of 101 evaluable pts). Conclusions: Despite the possible bias related to the methodology of the survey, our data are consistent with those reported in literature regarding HT prevalence in Italy. On the contrary, the rate of Tpts was significantly higher compared to the literature (62% vs 30–35%) and rather close to the goal of 70% advocated by the Italian Society of Hypertension (SIIA) within 2015. The high number of pts who did not remember the treatment (almost 20%) apparently did not correspond to a failed BP control (p not significant between Tpts and NTpts). Moreover, the evaluation of adherence to treatment revealed high scores in 78% of pts. According to our data, not completely corresponding to the literature, it is possible to hypothesize that in the population of the Southern Bergamo Province, the poor awareness of pts about CV risk does not significantly affect the BP goal.

Other Cancers in Patients With Chronic Lymphocytic Leukemia Requiring Therapy: Association With Prognostic Factors and Impact on Survival

Abstract 3896 Chronic lymphocytic leukemia (CLL) is associated with an increased incidence of other cancers (OC). Potential risk factors for OC in CLL include immune disturbances, shared risk factors, genetic predisposition and chemotherapy. While reports on OC in patients with CLL have been typically descriptive in nature, detailed information regarding the clinical features of OC, relationship with the time of diagnosis of CLL, patient characteristics, prognostic factors and survival have been missing. We report an analysis of OC in pts with CLL requiring therapy, with a post therapy observation time of 5 years or longer. We reviewed our database and selected pts with CLL seen at our center who underwent treatment and who have a follow-up of at least 5 years after therapy. We studied pts with an OC either before or after the diagnosis and/or treatment of CLL and compared them with patients without OC. Richter's transformation of CLL was not considered an OC in this analysis. A total of 1,364 pts with CLL referred between 1963 and 2007 with a median follow up time of 8.2 years (range 5–28) were studied. Among these, we identified 324 pts (24%) with OC. Sixty-eight pts were diagnosed with >1 OC [2 OC (62 pts), 3 OC (4 pts) or 4 OC (2 pts)], for a total of 400 individual OC. Of the 324 pts with OC, OC preceded the diagnosis of CLL in 117 pts (36%), with a median time from OC to CLL of 80 (0–455) months, OC occurred after the diagnosis of CLL but before treatment in 49 pts (15%), with median time from CLL to OC of 22 (0–131) months. OC occurred after treatment of CLL in 158 pts (49%), with a median time from treatment to OC of 94 (0–304) months. The type, frequency and timing of OC are summarized in [table 1][1]. Clinical characteristics and traditional prognostic factors were not significantly different between pts with and without OC, with the exception of age, as pts with OC are older than pts without OC at the time of referral (median age: 60 vs 55 years, p 5 years, the incidence of OC is 24%. Among pts with OC, there is a trend for higher number of pts with del11q. In pts with OC, OC itself is a major cause of death, while the vast majority of deaths among pts without OC are caused by CLL or CLL-related complications. | Site of OC | 1st case | Total cases | OC prior/at CLL | OC after CLL | |:---------------------------------------:| --------------- | ----------- | --------------- | ------------ | --- | | After diagnosis | After treatment | | NMSC[1][2] | 124 | 144 | 41 | 26 | 77 | | PROSTATE | 43 | 54 | 18 | 7 | 29 | | MELANOMA | 26 | 34 | 16 | 2 | 16 | | BREAST | 23 | 26 | 14 | 2 | 10 | | MDS/AML[2][3] | 16 | 18 | | | 18 | | LUNG | 14 | 21 | | 1 | 20 | | NEUROENDOCRINE | 3 | 6 | 1 | | 5 | | HEAD AND NECK | 12 | 16 | 3 | 2 | 11 | | UROTHELIAL CELL CANCERS | 11 | 12 | 7 | 2 | 3 | | GI[3][4] (including pancreas and liver) | 10 | 18 | 4 | 3 | 11 | | KIDNEY | 10 | 11 | 4 | 3 | 4 | | NHL[4][5] and MM[5][6] | 8 | 12 | | | 12 | | TESTIS/OVARY | 6 | 6 | 4 | | 2 | | THYROID | 6 | 7 | 5 | 1 | 1 | | SARCOMAS | 4 | 5 | 4 | | 1 | | UTERUS | 2 | 3 | 3 | | | | OTHERS[6][7] | 6 | 7 | 3 | | 4 | | TOTALS | 324 | 400 | 127 | 49 | 224 | * [↵][8]1 non-melanoma skin cancers; * [↵][9]2 myelodysplastic syndrome/acute myeloid leukemia; * [↵][10]3 gastrointestinal; * [↵][11]4 non-Hodgkin's lymphoma; * [↵][12]5 multiple myeloma; * [↵][13]6 includes: brain, nasopharyngeal, penis carcinoma, mesothelioma, unknown primary. Table 1. Distribution of OC (1364 pts). Disclosures: No relevant conflicts of interest to declare. [1]: #T1 [2]: #fn-1 [3]: #fn-2 [4]: #fn-3 [5]: #fn-4 [6]: #fn-5 [7]: #fn-6 [8]: #xref-fn-1-1 [9]: #xref-fn-2-1 [10]: #xref-fn-3-1 [11]: #xref-fn-4-1 [12]: #xref-fn-5-1 [13]: #xref-fn-6-1

SAT0228 Performance of MRI Compared to Conventional Radiographs in the Detection of Structural Lesions in the Sacroiliac Joints in Patients With Recent Onset Axial Spondyloarthritis

BackgroundStructural lesions are visible on MRI T1-weighted images of the sacroiliac (SI) joints. However, radiographs are currently the established method to detect structural lesions (SL).ObjectivesTo compare the performance of MRI...

Early stage “T2N0” breast cancer: Does it consist two different “T2” stages?

e11595 Background: Lymph node negative stage IIA early breast cancer (BC) patients (pts) according to TNM classification consists T2N0 tumors reprsenting a wide range of size (&gt;2-5 cm). We aimed to compare clinicopathological features and prognosis of T2N0 stage pts with tumor size larger vs smaller than 4 cm. Methods: Data of 2200 BC pts followed between years 1998 and 2012 at our institute were analysed, retrospectively. pT2N0 stage BC pts (T:2 to 4,9 cm) were divided into 2 subgroups as 2 to 3,9 cm (T2a) and 4 to 4,9 cm (T2b). Clinicopathological features and survival analyses were evaluated. Results: There were 268 (80%) T2a and 65 (20%) T2b pts among T2N0 (n=333) population. All but 2 pts in T2a (99%) and all pts in T2b subgroups were female. Mean age of diagnosis was 50.8±11 and 46.2±10.1 years in T2a and T2b subgroups, respectively (p= 0.003). Number of premenopausal pts were higher in T2b (n=39, 60%) compared to T2a (n=100, 37%) subgroup (p= 0.003). There were no differences in histopathological subtypes, tumor grade, ER, PR, HER-2 status, adjuvant radiotherapy and chemotherapy regimens, -cycle numbers, endocrine, and trastuzumab treatments between T2a and T2b subgroups. Higher number of pts in T2a subgroup was treated with breast conserving surgery [110 (%41.2) vs 11 (%16.9)] and higher number of pts in T2b subgroup were treated with mastectomy [T2a= 158 (%58.8) vs T2b= 54 (%83.1)]. Disease recurrence was seen in 25 pts in T2a and 13 pts in T2b subgroups. Median progression free survival (PFS) could not be reached in T2a subgroup. Median PFS was 96.5 (min – max: 66 – 127) months in T2b subgroup (p= 0.02). There were no differences in PFS and number of events between goups when all pts analysed according to menopausal status and surgical treatment type. Overall survival data could not be analyzed due to small number of events (5 pts in T2a and 1 patient in T2b subgroups were died). Conclusions: T2N0 subgroup of stage IIA BC consists a wide range of tumor size between &gt;2 to 4.9 cm. Pts with T2b (≥4 cm) tumors had shown worse prognosis compared to patients with T2a (&lt;4cm) tumors and might be treated with more agressive adjuvant chemotherapy. This finding might be helpful for treatment decisions but must be evaluated in studies with larger number of pts.

Gender differences in comprehensive geriatric assessment (CGA): Results from the IN-GHO registry.

9553 Background: Elderly cancer patients (pts) are a heterogeneous population. As chronological age does not provide sufficient information on individual limitations and resources, a CGA helps to describe the heterogeneity in a structured way. Assessment instruments might be sensitive to gender differences. We therefore analyzed the IN-GHO registry for gender associated differences in results of CGA. Methods: The internet based IN-GHO registry prospectively collects data of elderly cancer pts from &gt; 100 centres in Germany and Austria. Data from 1,580 pts aged 70+ years were analyzed comparing results between female (n=883) and male (n=697) pts by Chi-square or Mann-Whitney U test. Analyses included results from CGA, physicians´ rating (fit vs. compromised vs. frail) and pts´ self rating of fitness for treatment (Likert scale 1 = very fit to 6 = very unfit), type (combination vs. monotherapy vs. no), and dosage (full vs. adapted) of treatment. Results: Mean age was 76.7 years (range 70-97), 71.5% had a solid tumor, and 28.5% a hematological malignancy. Mean age was slightly but significantly higher in women than in men (76.9 vs. 76.4; p=0.02), reflected in a higher number of pts. aged 80+ (26.5% vs. 21.1%; p=0.013). No gender differences were observed in physicians´ rating and pts´ self rating of fitness for therapy, or in type or dosage of treatment. Furthermore, no gender associated differences were noted in Karnofsky-Performance-Scale, comorbidity (Charlson-Comorbidity-Score), polypharmacy, and cognition (Mini-Mental-Status-Examination). Gender associated differences, however, were noted in body mass index (more women in categories &lt;19 and &gt;35), mean ADL (91.7 vs. 93.4, p=0.03), mean IADL (6.9 vs. 6.7 (p=0.049), and timed-up-and-go test (&lt; 10 seconds 36.1% vs. 43.6%, p=0.005). The main differences between women and men in ADL and IADL scores were noted in the item bathing (ADL) and food preparation, housekeeping, and laundry (IADL). Conclusions: The internet based registry is a valuable tool to gain data on prognostic factors, treatment, and outcome in old cancer pts. In several items of CGA, significant differences exist between women and men.

Efficacy and cost of peripheral blood stem cell (PBSC) mobilization with low-dose cyclophosphamide (LD-CY) compared with plerixafor (P) in multiple myeloma (MM) patients (pts) treated with novel induction therapies.

7040 Background: Efficacy and cost effectiveness of P vs. LD-CY mobilization in MM pts treated with novel induction therapies is not known. Methods: We analyzed the mobilization outcomes of 107 consecutive pts who underwent a planned, single autograft within 1-year of starting induction therapy with novel agents (thalidomide, lenalidomide, bortezomib) between 2003-2012. Pts undergoing mobilization with LD-CY/G-CSF (1.5gm/m2) (n=74) were compared against those receiving P/G-CSF (0.24mg/kg) (n=33). Efficacy of PBSC mobilization was assessed by evaluating peak peripheral blood (PB) CD34+ cell counts, CD34+ cell yield on day1 of collection, total CD34+ cell collection, and total number of apheresis sessions. Mobilization failure was defined as failure to collect ≥2 x106 cells/kg body weight. Mobilization costs were calculated per patient in both groups. Centers for Medicare and Medicaid Services reimbursement rates and Red Book Average Wholesale Price were used for cost determination. Results: At baseline, the LD-CY and P cohorts were well balanced. Compared to LD-CY, P use was associated with higher median peak PB CD34+ cell count (68/µl vs. 36/µl, p=0.048), CD34+ yield on day 1 of collection (6.9 x106/kg vs. 2.4 x106/kg, p=0.001), and total CD34+ cell yield (11.6 x106/kg vs. 7x106/kg, p=0.001). Median numbers of apheresis sessions were 2 in each group (p=0.17). In pts with prior lenalidomide use, mobilization failure rate in the LD-CY group was higher compared to the P group (20% vs. 0%, p=0.01). P group had a higher number of pts collecting ≥10x106/kg CD34+ cells (60.6% vs. 31%, p=0.01). Rate of infectious complications, transfusion requirements and hospitalizations was similar in both groups. The average total cost of mobilization in the P group was significantly higher compared to the LD-CY group ($28,980 vs. $19,627, p-value&lt;0.0001). Conclusions: Our data indicates that although associated with a significantly higher total mobilization cost, plerixafor produced a more robust PBSC mobilization, without any collection failures.

Other Cancers in Patients with Chronic Lymphocytic Leukemia Requiring Therapy: Association with Prognostic Factors and Impact On Survival

AbstractAbstract 3896Chronic lymphocytic leukemia (CLL) is associated with an increased incidence of other cancers (OC). Potential risk factors for OC in CLL include immune disturbances, shared risk factors, genetic predisposition and chemotherapy. While reports on OC in patients with CLL have been typically descriptive in nature, detailed information regarding the clinical features of OC, relationship with the time of diagnosis of CLL, patient characteristics, prognostic factors and survival have been missing. We report an analysis of OC in pts with CLL requiring therapy, with a post therapy observation time of 5 years or longer. We reviewed our database and selected pts with CLL seen at our center who underwent treatment and who have a follow-up of at least 5 years after therapy. We studied pts with an OC either before or after the diagnosis and/or treatment of CLL and compared them with patients without OC. Richter’s transformation of CLL was not considered an OC in this analysis. A total of 1,364 pts with CLL referred between 1963 and 2007 with a median follow up time of 8.2 years (range 5–28) were studied. Among these, we identified 324 pts (24%) with OC. Sixty-eight pts were diagnosed with >1 OC [2 OC (62 pts), 3 OC (4 pts) or 4 OC (2 pts)], for a total of 400 individual OC. Of the 324 pts with OC, OC preceded the diagnosis of CLL in 117 pts (36%), with a median time from OC to CLL of 80 (0–455) months, OC occurred after the diagnosis of CLL but before treatment in 49 pts (15%), with median time from CLL to OC of 22 (0–131) months. OC occurred after treatment of CLL in 158 pts (49%), with a median time from treatment to OC of 94 (0–304) months. The type, frequency and timing of OC are summarized in table 1. Clinical characteristics and traditional prognostic factors were not significantly different between pts with and without OC, with the exception of age, as pts with OC are older than pts without OC at the time of referral (median age: 60 vs 55 years, p<.0001). We next analyzed the distribution of the newer prognostic parameters in these two groups. Fifty-three % of pts with OC had unmutated IGHV genes, 65% were ZAP70+, 22% CD38+, 8% had del17p, 27% del11q, 22% +12, 20% negative FISH, and 23% del13q. Sixty-one % of pts without OC had unmutated IGHV genes, 58% were ZAP70+, 26% CD38+, 6% had del17p, 17% del11q, 22% +12, 26% negative FISH, and 29% del13q. A trend toward significance (p.07) for a higher incidence of del11q was observed in pts with OC. At the time of this analysis 536 (39%) pts have died and 828 (61%) are alive. One hundred seventy six/324 (54%) pts with OC are alive, vs 652/1040 (63%) pts without OC (p<.007). Median overall survival (OS) has not been reached in either pt group at a median follow up of 95 (61–284) months for pts with OC and 98 (61–340) months for pts without OC. Causes of death were: progression of CLL (99), CLL-related complications (121), OC (43), complications of stem cell transplant (16), events unrelated to CLL (39) and unknown causes (218). In pts with OC, the OC itself was the cause of death in 37%. Other causes of death were CLL/CLL-related complications in 44%, complications of stem cell transplant in 8%, and events unrelated to CLL in 11%. In contrast, in pts without OC CLL/CLL-related complications accounted for 83% of deaths, complications of stem cell transplant for 4%, and events unrelated to CLL for 13%. In conclusion, in pts with CLL requiring therapy and with post therapy follow up of >5 years, the incidence of OC is 24%. Among pts with OC, there is a trend for higher number of pts with del11q. In pts with OC, OC itself is a major cause of death, while the vast majority of deaths among pts without OC are caused by CLL or CLL-related complications.Table 1Distribution of OC (1364 pts).Site of OC1st caseTotal casesOC prior/at CLLOC after CLLAfter diagnosisAfter treatmentNMSC1124144412677PROSTATE435418729MELANOMA263416216BREAST232614210MDS/AML216180018LUNG14210120NEUROENDOCRINE36105HEAD AND NECK12163211UROTHELIAL CELL CANCERS1112723GI3 (including pancreas and liver)10184311KIDNEY1011434NHL4 and MM58120012TESTIS/OVARY66402THYROID67511SARCOMAS45401UTERUS23300OTHERS667304TOTALS324400127492241non-melanoma skin cancers;2myelodysplastic syndrome/acute myeloid leukemia;3gastrointestinal;4non-Hodgkin's lymphoma;5multiple myeloma;6includes: brain, nasopharyngeal, penis carcinoma, mesothelioma, unknown primary. Disclosures:No relevant conflicts of interest to declare.

1225O - A Randomized Phase 2 Study of Erlotinib Plus Pemetrexed vs Erlotinib or Pemetrexed Alone as Second-Line Treatment for Never-Smoker Patients with Non-Squamous Advanced Non-Small Cell Lung Cancer (NSCLC)

ABSTRACT Background Erlotinib (E) and Pemetrexed (P) are approved second-line treatments in patients (pts) with relapsed NSCLC and may be effective in combination. This randomized phase 2 study compared the efficacy and safety of E + P vs either agent alone, as second-line treatment in never-smoker pts with advanced non-squamous NSCLC. Methods From Nov 2007 to Jul 2010, never-smoker NSCLC, ECOG Performance Status (PS) ≤2 pts who had failed 1 prior chemotherapy regimen were enrolled and randomized to either: E 150 mg daily, P 500 mg/m2 day 1, or P 500 mg/m2 day 1 plus E 150 mg daily on days 2 to 14 of a 21-day cycle, continued until discontinuation criteria were met. The primary endpoint of progression-free survival (PFS) was analyzed using a sequential approach. A multivariate Cox model was used to perform a global comparison across the 3 arms with pairwise comparisons between treatments using contrasts within the model. If the global null hypothesis was rejected at a 2-sided 0.2 significance level (SL), then 2 pairwise comparisons of E + P vs E or P were conducted. Statistical significance was claimed if both pairwise and global null hypotheses were rejected at a 2-sided 0.05 SL. Results A total of 240 non-squamous pts (Male, 34.6%; East Asian, 55.4%; ECOG PS 0-1, 92.9%) were included. A statistically significant difference in PFS was found across the 3 arms (global p = 0.003), with E + P significantly better than both single agents (HR (95% CI) for E + P vs E was 0.57 (0.40, 0.81), p = 0.002; for E + P vs P was 0.58 (0.39, 0.85), p = 0.005). Median PFS (95% CI) was 7.4 months (4.4, 12.9) in E + P, 3.8 (2.7, 6.3) in E and 4.4 (3.0, 6.0) in P. Safety analyses showed a higher number of pts with ≥1 TEAE with CTCAE grade 3/4 toxicity in E + P (n = 45; 60.0%) than in P (n = 10; 28.9%) or E (n = 22; 12.0%), the majority being neutropenia, anemia, rash and diarrhea. Conclusions Erlotinib + Pemetrexed significantly improved PFS compared to either agent alone in this clinically selected population. E + P had more toxicity, but was clinically manageable. Further analysis of the EGFR mutational status will help to understand and predict which pts will benefit most from this approach. Disclosure X. Wang: I am employee of Eli Lilly and Company. S. Altug: I am employee of, and hold stock/stock options in, Eli Lilly and Company. M. Orlando: “I am employed by and hold stock in Eli Lilly & Company”. All other authors have declared no conflicts of interest.

Vemurafenib (V) in BRAF V600E metastatic melanoma (mM): Analysis of 507 patients (pts) enrolled in the French temporary authorization for use (ATU).

8591 Background: V, a selective BRAF inhibitor, significantly improves OS in BRAF mutated mM. ATU is an exceptional measure making available drugs that have not yet been granted a Marketing Authorisation. We provide demographic data of pts treated by V in the ATU. Methods: V 960 mg BID was given to pts with unresectable stage IIIC or IV BRAF V600E mM. Genotyping was done on the national network of molecular genetics platforms funded by the Institut National du Cancer. Data were prospectively collected. Results: From Apr 2011 to Jan 2012, 83 sites enrolled 507 pts. 80% were treated by oncodermatologists. Pts characteristics at baseline are summarized below. Safety and efficacy data are being evaluated. Conclusions: Around 2 out of 3 patients with a BRAF mutated mM were enrolled in France in the ATU highlighting a large access to BRAF genotyping and to V. Demographic data differs from literature and clinical trials for: site of primary melanoma (reverse trunk/extremity ratio) and inclusion of pts with brain metastasis or PS&gt;2 (excluded in CT). A high number of pts had risk factors for NMSC emphasizing the importance of the communication between oncologists and dermatologists for managing V therapy. [Table: see text]

The impact of HER2 positivity on survival in metastatic gastric and GEJ cancer.

17 Background: HER2 positive (+) gastric (GC) and GEJ adenocarcinoma (AC) has been associated with a worse survival outcome. This study examines the survival rate of patients (pts) with metastatic HER2 (+) GC and GEJ AC in the province of BC. Methods: Formalin fixed embedded tissue from pts with resected GC or GEJ AC from 2004−2011 were identified retrospectively through the BC Cancer Agency registry and prospectively for pts with a new diagnosis of advanced disease. Biopsies and resection samples were analyzed via previously validated methods. IHC scores of 3 were considered (+), 2 were equivocal and 0/1 were negative (−). 10% cut-off was used to determine (+) samples. Equivocal staining was considered (+) via FISH or SISH with a ratio of &gt; 2.2 considered amplified. Pt characteristics were abstracted to an anonymized database. Kaplan meier curves were calculated to evaluate overall survival from time of diagnosis or relapse to death for pts with Her 2 (+) or (-) disease. Results: 164 of 294 pts were identified with metastatic or relapsed GC (49%) or GEJ (51%) AC without traztumumab treatment. 21 (13%) of pts were HER2 (+) either by IHC, FISH or SISH. See Table for pt characteristics. The HER2 (+) group was older (median age 68 yrs vs 60), more GEJ (62% vs 49% p=1.23), and a higher number of pts that did not receive treatment (52% vs. 27% p=5.09). Median survival was not significantly different among HER2 (+) and (−) disease (4.0 mo vs. 7.3 mo, p=0.089). Conclusions: The rate of HER2 positivity is similar to that seen in trial data. HER2 positivity trends to a worse prognosis but was not significant in this study. [Table: see text]

High Number of Copy Number Alterations and Over-Expression of Genes Involved in the Response Mechanisms to Genotoxic Stress Both Characterize Newly Diagnosed Multiple Myeloma (MM) Patients Carrying Amplified MDM4 and/or Deleted p53,

Abstract 3935 BackgroundThe p53 tumor suppressor pathway is tightly kept in check, or completely silenced in cancer cells. A potent inhibitor of p53 is represented by MDM4, which is critical for the control of p53 activity during the response to stress and is often amplified in several types of cancer. TP53 mutations are rare in newly diagnosed MM, while occur more frequently as late event in the course of the disease and are related to survival. Recently, the adverse prognostic impact of chr. 1q amplification, described in almost 40% of newly diagnosed MM pts, has been reported. The minimal amplified region on chr. 1q harbors MDM4. Since both del(17p) and amp(1q) identify a subgroup of high-risk MM pts, even when the novel agents are part of up-front treatment strategy, we molecularly analyzed a subgroup of MM patients treated with bortezomib-thalidomide-dexamethasone (VTD) incorporated into autologous stem cell transplantation, in order to investigate mechanisms which might be activated in myeloma plasma cells to direct and/or indirect limit the p53 function. MethodsThirty eight pts treated with VTD incorporated into autologous stem cell transplantation were analysed by means of gene expression profile (Affymetrix U133 Plus2.0 array) and unpaired analysis of copy number alterations (CNA) (Affymetrix 6.0 SNP array). Both GEP and SNP arrays experiments were performed on highly purified CD138+ bone marrow plasma cells obtained at diagnosis from each pts. The presence of CNAs in chr.1 and 17 was evaluated to identify pts carrying amp(1q) and del(17p). ResultsEighteen out of 38 pts (42%) carried a minimal amplification region of 1,1 Mb on chr.1q, which harbors MDM4. Five out of 38 pts (13%) carried a minimal deletion region of 482 Kb on chr.17, which harbors TP53. To explore the involvement of the p53 pathway in MM, pts were stratified according to the presence of amplified MDM4 and/or deleted p53 (group A, 18 pts) or the absence of both these abnormalities (group B, 20 pts). Baseline clinical characteristics were homogeneous, except for a higher rate of ≥ 3 bone lesions in pts carrying amplified MDM4 and/or deleted p53. The rate of best complete or near complete response was 89% in group A and 75% in group B. With a median follow-up of 36 months, the risk of relapse or progression was 50% for pts in group A and 25% for those in group B. The average number of aberrations per group was overall higher in group A as compared to group B (165 vs. 103 CNAs, p =0.03); indeed, the presence of amplified MDM4 and/or deleted p53 was significantly associated with a list of 95 CNAs (clustered on chr. 1, 2, 6, 8, 11, 13, 16 and 18), which included del16q (with a minimal area of deletion including WWOX), observed in 39% vs. 5% cases from group A and B, respectively (p<0.05) and chr.8 aberrations (with amplifications and or deletions, both including TRPS1) observed in 61% vs. 15% cases from group A and B, respectively (p<0.05). A comparison of expression profiles of patients carrying or not amplified MDM4 and/or deleted p53 confirmed the over-expression of MDM4 in the former group of pts and highlighted in these pts an overall activation of genes involved in the response mechanisms to genotoxic stress: indeed a significant over-expression of damage sensor genes (ATM, RAD9, RAD 50, ATRip), of damage signal mediator genes (H2AFX, 14-3-3), of genes involved in regulation of cell proliferation (CDK6, CDC25, CCND2) and of anti-apoptotic genes (BCL2, p73) was observed in pts with amplified MDM4 and/or deleted p53 (one-way ANOVA plus multiple-test correction with FDR <0,05). Finally, this group of pts significantly over-express the transcription factor YY1, which is known to interact with p53, thus inhibiting its transcriptional activity. ConclusionsPts carrying amplified MDM4 and/or deleted p53 showed a significantly higher number of CNAs and the significant over-expression of genes involved in the response mechanisms to genotoxic stress, as compared to pts lacking these chromosomal aberrations. This might account for the worse outcome of patients harboring del(17p) and/or amp(1q). The amplification of MDM4 locus and the over-expression of YY1 might contribute to maintain p53 in an OFF state by an indirect mechanism. Additional data on the role of both direct and indirect control of p53 pathway on VTD-treated MM pts prognosis, extended to an higher number of pts, will be presented during the meeting.Supported by: Fondazione Del Monte di Bo e Ra, Ateneo RFO grants (M.C.) BolognAIL. Disclosures:Cavo:Genzyme: Honoraria.

Dose-response relationship in phase I clinical trials: A European Drug Development Network (EDDN) collaboration study.

3084 Background: Alkylating agents have a strong dose effect relationship and this concept is used for development of novel cytotoxic (CTX) drugs. However, the need to reach MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study we aimed to evaluate the relationship between dose and efficacy in a large cohort of phase I patients (pts) with refractory solid tumors. Methods: We retrospectively collected data on 2232 consecutive pts treated in phase I trials in 14 European institutions in 2005 - 2007. Inclusion criteria for this analysis were: a) pts treated within single agent studies where MTD was defined; b) RECIST response available. We used logistic and Cox regression models to study the relationship of dose (as continuous variable of % of MTD) with objective response rate (ORR), disease control rate (DC) and overall survival (OS). The clinical tumor growth rate (CTGR) - a log ratio of time between advanced disease diagnosis and phase I entry to number of treatment lines- was used to identify the impact of slow growing tumors on DC. Results: 1,015 pts were eligible (MTA 72%; CTX 28%). The ORR was 3% and DC at 3 and 6 months was 25% and 11%. Median CTGR was 22 weeks. There was no difference between ORR in pts receiving MTA or CTX but the DC rate at 3 and 6 months was higher for MTA (28% and 12%) than CTX (17% and 6%; p<0.01). This difference was attributed to the higher number of pts with slow growing tumors (CTGR > 20 weeks) treated with MTA (59%) vs. CTX (48%; p=0.001). Higher doses were associated with ORR to CTX agents (median dose: responders 92% vs. non-responders 62%; OR=6.4, p=0.06) but not to MTA. There was a relationship between dose and OS for CTX agents (univariate Cox regression HR=0.63 [95%CI 0.43-0.93], p=0.02) but not for MTA (HR=1.06 [95%CI 0.87-1.27], p=0.55). However in the multivariate model adjusted for clinical and demographic variables no relationship was found between dose and OS for either MTA or CTX. Conclusions: These results support current development of novel CTX agents based on MTD. We found no direct relationship between higher doses and ORR or OS with MTA in unselected pts. There is an urgent need to identify better biomarkers to guide dose escalation trials of MTA.

Patterns of maintenance treatment (Tx) following first-line bevacizumab (bev) plus chemotherapy (CT) for metastatic colorectal cancer (mCRC): Results from a large German community-based cohort study.

502 Background: As a result of the long PFS with bev-containing combinations in first-line mCRC, discontinuation of at least one CT component after an “induction” period and continuation with “maintenance” Tx is common. It is anticipated that duration and patterns of maintenance Tx may affect PFS. Methods: We analysed induction and maintenance Tx in a large observational cohort study of bev + various first-line CT regimens. Results of the entire cohort were reported earlier [Arnold et al. ASCO GI 2010]. Results: From Jan 05 to Jun 08, 1620 patients (pts) were enrolled at 261 sites. 1,307 pts (81% of total) received bev + fluoropyrimidine-oxaliplatin (n=306, 23.5%) or fluoropyrimidine-irinotecan (n=1,001, 76.5%). While Tx reduction was not predefined, after induction 271 pts (21%) received de-escalated maintenance Tx: bev alone (n=106; 8%), or bev + CT (n=165; 13%). Median Tx duration for pts receiving bev alone was 8.7 mo for induction and 3.2 mo for maintenance. Pts receiving bev + CT maintenance had shorter induction (5.1 mo) but longer maintenance (4.4 mo). Median PFS (after induction) with bev maintenance was 10.8 mo vs. 13.5 mo for bev + CT maintenance. Data are available from 161 pts with bev + CT maintenance after induction with oxaliplatin (n=97) or irinotecan (n=64). Median total Tx duration was 9.6 mo for oxaliplatin-based induction and 10.9 mo for irinotecan-based induction; median induction duration was 4.1 and 5.5 mo, and maintenance duration was 4.3 and 4.4 mo, respectively. Median PFS (after induction) was 12.8 and 14.1 mo, respectively. Progressive disease (PD) has not yet occurred in 165 pts (62% of maintenance cohort). A high proportion of pts received Tx until PD (74% and 79%, respectively). Conclusions: Both de-escalation strategies led to long PFS and a high number of pts treated ′until PD′. A trend towards better PFS was observed in pts receiving bev + CT maintenance vs. single-agent bev. The ongoing randomized AIO KRK 0207 trial is prospectively evaluating three different maintenance strategies after induction with bev + fluoropyrimidine + oxaliplatin. [Table: see text]

Phase 1b/2 Pharmacokinetic/Pharmacodynamic (PK/PD) Study of Combination Voreloxin and Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia Patients.

Abstract 635Background: Voreloxin is a first-in-class anticancer quinolone derivative (AQD) that intercalates DNA and inhibits topoisomerase II, inducing apoptosis. Nonclinical studies showed synergistic activity when combined with cytarabine (ara-C). We report preliminary results of a Phase (Ph) 1b/2 study of combination voreloxin plus ara-C in relapsed/refractory AML patients. Objectives: 1) safety, tolerability and MTD of escalating doses of voreloxin in combination with ara-C; 2) voreloxin PK; 3) clinical activity by IWG; 4) pharmacodynamic (PD) markers; 5) ex vivo voreloxin resistance in bone marrow aspirates (BMA). Methods:Ph 1b/2 study with dose escalation of voreloxin given on Days 1 and 4 in combination with 2 schedules (sch) of ara-C: Sch A (A-CIV): 400 mg/m2/d continuous IV infusion ara-C X 5 days; Sch B (B-Bolus): 1 g/m2/d 2 hr IV infusion ara-C X 5 days. Voreloxin Ph 1b doses: 10 - 90 mg/m2 (A-CIV); 70 - 90 mg/m2(B-Bolus). At MTD, pts are enrolled into Ph 2 arms (dose expansion) to assess response and safety in a first relapse (1st REL) population (both sch), and a primary refractory (1oREF) population (B-Bolus only). Pre- and post-dose PBMC were probed for mechanism-based PD responses by western blot probing for DNA damage markers. Pt BMA taken prior to dosing were analyzed ex vivo for resistance to voreloxin and ara-C by a proliferation assay. Clinical response was determined by IWG criteria. Results:To date, 94 patients have been treated. Preliminary safety and overall response rate (ORR = CR + CRp) are available for Ph 1b for both cytarabine schedules and Ph 2 1st REL for A-CIV. Ph 2 B-Bolus 1st REL has completed enrollment (N=15); enrollment continues for Ph 2 B-Bolus (1oREF). Grade 3 or higher non-hematologic AEs ≥ 10% incidence were markedly reduced in Ph 1b B-bolus vs Ph1b A-CIV, notably for infection related AEs and mucositis and 30-day all-cause mortality. Activity: Tabulated results show activity with both ara-C schedules; CR+CRp seen in difficult-to-treat pt populations. In Ph 1b at doses ≥ 80 mg/m2, 1oREF pts ORR was 36% (5 of 14); all but one had failed multiple cycles of induction therapy. A high number of pts have been bridged to transplant (BMT): 8 BMT of 20 CR and 1 PR. CR + CRp have been noted in both B-Bolus Ph 2 expansions, but outcome and safety data are immature. PK/PD: Voreloxin PK were dose proportional from 10–90 mg/m2. DNA damage PD response markers, increased pDNA-PKcs and/or pCHK2, were seen in 12 of 23 patients analyzed who received ≥ 34 mg/m2 voreloxin. Ex vivo resistance assays of pts' BMA to voreloxin and ara-C suggest that voreloxin is a major contributor to the observed CRs and that the combination has enhanced activity. Conclusions: Voreloxin given in combination with continuous infusion ara-C is well-tolerated, with an encouraging number of pt successfully bridged to BMT. An ORR of 33% was observed in 1st REL pts txd with ≥ 80 mg/m2 voreloxin (all remissions were in pts txd at MTD, 80 mg/m2 voreloxin). An ORR rate of 36% was observed in 1oREF pts, a population with an historical remission rate of 10-15%. CR + CRp have been noted in both B-Bolus Ph 2 expansions, but outcome and safety data are in process. Enrollment in Ph 2 B-Bolus 1oREF patients is ongoing.DemographicsPhase1b A-CIV1b B-Bolus2 A-CIV2 B-Bolus2 B-BolusN391816156 of 25Gender71%M72%M69%MECOG 0-198%89%94%Disease StatusFrontline3%0%1st REL23%11%100%100%2nd REL15%11%1oREF33%55%100%REF REL21%22%Not available5%0%CytogeneticsPendingFavorable3%11%0%Intermediate64%28%50%Unfavorable31%22%31%Unknown3%6%6%Not available033%13%Safety–Grade 3 or Higher Adverse Events ≥ 10%Phase1b A-CIV1b B-Bolus2 A-CIVN391816Febrile N54%40%38%Pneumonia15%0%13%Sepsis/bact.38%27%56%Infections15%7%19%Upper GI13%7%6%Lower GI13%0%13%Hypokalaemia28%7%31%Hyperglycaemia13%7%13%Hypophosphataemia10%0%19%Hypoxia3%0%13%Pulmonary Hemorrhage0%0%13%Hypotension10%0%0%DLTN=2 of 7 pts at 90 mg/m2 Grade 3 diarrhea and bowel obstruction Grade 3 oral mucositis lasting ≥ 7 daysN=1 of 6 pts at 80 mg/m2and 90 mg/m2 Odynophagia Grade 3 oral mucositis lasting ≥ 7 daysMTD/Recommended Ph 2 Dose80 mg/m290 mg/m280 mg/m2Outcome1b A-CIV1b B-Bolus2 A-CIV2 B-Bolus2 B-BolusPopulationREL or REFREL or REF1st REL1st REL1oREFN391816156 of 25Median OS days (95% CI)209 (74-258)NANANANACR6363 CR, 1 CRp of 10 evaluable1 CR of 2 evaluableCRp311%CR+CRp22%23%44%TETETETE30-day all-cause mortality21%0%6%0 of 10 evaluable0 of 4 evaluable Disclosures:Lancet:Sunesis Pharmaceuticals: Study Steering Committee. Roboz:Sunesis Pharmaceuticals: Study Steering Committee. Cripe:Sunesis Pharmaceuticals: Research Funding. List:Sunesis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Fox:Sunesis: Employment. Michelson:Sunesis: Employment. Karp:Sunesis Pharmaceuticals: Research Funding.

SABRE-B: a randomized phase II trial evaluating the safety and efficacy of combining sunitinib (S) with paclitaxel (P) + bevacizumab (B) as first-line treatment for HER2-negative metastatic breast cancer (MBC): final results.

Abstract Abstract #3126 Background: B, a humanized monoclonal antibody that neutralizes VEGF, improves progression-free survival (PFS) when combined with taxanes in 1st-line MBC. S, an oral inhibitor of receptor tyrosine kinases, including PDGFRs and VEGFRs, has shown activity in MBC. Preclinical models suggest that the addition of S to B may increase the inhibition of the VEGF signaling pathway. SABRE-B was a Phase II randomized open-label study comparing the safety and efficacy of S in combination with P/B to P/B alone.&amp;#x2028; Methods: Patients (pts) with HER2-negative MBC receiving 1st-line chemotherapy were eligible. P (90 mg/m2 qwk x 3 every 4 weeks), B (10 mg/kg q2wk) and S (25 mg qd x 21d) were administered in 28-day cycles. S dose was to be adjusted for myelosuppression, fatigue, or other treatment-related toxicities. Planned enrollment had 3 phases: an initial 2-arm phase with P/B vs. P/B/S (25 mg) to assess tolerability of S plus P/B. If P/B/S (25 mg) was tolerable, a second phase comparing P/B to P/B/S (25 mg) to P/B/S (37.5 mg) would begin. A final phase with the selected S dose would compare the clinical efficacy (PFS) of P/B/S to P/B.&amp;#x2028; Results: From 3/2007-1/2008, 46 pts were randomized, 23 to P/B and 23 to P/B/S (25 mg). At the time of this analysis, the estimated mean treatment duration was longer in the P/B arm (14.7 weeks) compared with the P/B/S arm (10.9 weeks), reflecting a higher number of pts who discontinued early in the P/B/S arm. The percentage of pts with a Grade ≥3 AE was greater in the P/B/S arm compared with P/B (73.9% vs. 39.1%) and SAEs were greater in the P/B/S arm compared with P/B (43.5% vs. 30.4%). Neutropenia, febrile neutropenia, and fatigue were the most frequently reported AEs resulting in modifications to S dosing. Seventy percent of pts had an AE resulting in S dose interruption or modification. In addition to S doses being held, 17% required S dose reduction to 12.5 mg and 30% required discontinuation of S. Pts receiving P/B/S required more interruptions in B administration compared with P/B (52% vs. 44%), and more pts receiving P/B/S discontinued B compared with P/B (22% vs. 0%) because of AEs. There was one on-treatment death with P/B/S due to disease progression. Because of poor tolerability of the addition of S (25 mg) to P/B, the second phase of enrollment (S 37.5 mg) was never initiated.&amp;#x2028; Conclusion: Given the high rate of S dose modifications and/or treatment discontinuations in the first phase of SABRE-B, it was determined that in 1st line MBC, adding S at these doses and schedules to the approved P/B regimen was not feasible and the study was closed. Targeted VEGF inhibition with B in combination with VEGFR tyrosine kinase inhibitors is of clinical interest, but will require additional clinical studies to define how to safely combine these agents. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3126.

Examining Decision Making Styles in Patients with Sickle Cell Disease (SCD) Regarding Allogeneic Stem Cell Tranplantation (ASCT)

Background: ASCT is currently the only curative option of cure for patients (pts) with sickle-cell disease. Assessing the risk and benefits of ASCT in pts with SCD is challenging due to variability in the morbidity and mortality of the disease and ASCT for individual pts. The impact of transplantation on quality of life, patient understanding of ASCT, and physician factors, all influence treatment selection. Individuals' decision-making styles can influence how patients evaluate complex treatment decisions and thus how they view ASCT.Methods: To examine how patients with SCD make treatment decisions we performed a pilot study in which we administered an 80-item questionnaire to assess pts': Desired Role in decision making, Need for Cognition, Need for Structure, Personal Fear of Invalidity, and General Decision Making style. During the visit, the research team and pt discussed the risks and benefits of ASCT and how they view their current treatment. Then, a 38-item post-visit questionnaire was administered to assess patients' strength of preference for ASCT, perceptions of physician and caregiver's preferences, and decision satisfaction. Questions were derived from previously validated questionnaires and used 5-point or 6-point Likert scale.Results: Questionnaires were administered to 25 pts (6 Sickle-Hemoglobin C (SC), 18 sickle cell anemia (SS), and 1 Sickle Beta-Thalassemia) undergoing evaluation of sickle cell disease. Patients were 18–71 years of age with 36% of pts being male. On an average, pts had experienced 4–7 episodes of sickle-cell crisis (min 0–3, max 16+). 20% of pts rated their current health as excellent/very good, 44% good, and 36% fair/poor. All pts completed all pre-visit and post-visit questions. Most pts expressed a desire that doctors make treatment decisions alone (68% agree/strongly agree) or with pt input (64%). An equally high number of pts (64%) believed they should make treatment decisions alone or with a doctor's input. 64% of pts had high scores for rational decision making style, whereas 40% scored high for an intuitive style, 24% scored high for dependent style, and only 4% high for an avoidant style of decision making (Distribution shown in table). 72% of pts felt satisfied with the information they received for decision making and 88% were satisfied with their decision. However, 44% of pts wanted clearer advice.Conclusions: Examining pts decision making styles during the process of care is feasible and can uncover pt characteristics that are relevant for improving treatment discussions. Pts in this sample tended to use rational decision making styles but wanted clearer advice. Additional studies are needed examine these factors in larger populations of pts with sickle cell disease, understand their associations with demographic variables, and design and test decision support systems that help pts and hematologists with treatment selection.General Decision Making Style (GDMS)ValuesRationalIntuitiveDependentAvoidantSpontaneousNeed for StructureNeed for CognitionMedian20191712124452Min81010672818Max25252521195863Possible Range5–255–255–255–255–2511–6618–90

Vinflunine in patients with advanced unresectable hepatocellular carcinoma and liver impairment

15023 Background: In patients (pts) with advanced hepatocellular carcinoma (HCC) and liver cirrhosis, systemic chemotherapy has most commonly been associated with a very low response rate and high toxicity leading to death from liver failure. Vinflunine (VFL) is a new microtubule inhibitor of the vinca alkaloid class which has demonstrated clinical activity in several tumour types. Methods: A phase I trial was designed to determine VFL dose adjustments in cancer pts with various degrees of liver dysfunction. A high number of pts with HCC and concomitant liver cirrhosis (Child-Pugh grades A and B) were included in the study (18/30 pts). Therefore, a subgroup analysis was carried out in order to determine the safety profile of VFL in these pts (NCI-CTC version 2.0) and to estimate its anti-tumour activity (WHO criteria). Results: Eighteen pts (15 males) of median age 60.7 [26.4–75.3] years with advanced stage and unresectable HCC were treated with VFL. All these pts were outside Milan criteria and ineligible for liver transplantation. Thirteen pts had been previously treated by chemotherapy. The WHO performance status was 0: 11 pts, 1: 5 pts, 2: 2 pts. They received a median number of 4 cycles [1.0–31.0] of different doses of VFL according to the severity of the underlying liver impairment 320 mg/m2 (3 pts), or 250 mg/m2 (6 pts) or 200 mg/m2 (9 pts). One partial response (PR) was observed while 11 pts (61.1%) had stable disease (SD) yielding a disease control rate (PR + SD) of 66.7%. The median progression free survival was 3.4 months [95% confidence interval (CI): 2.6–6.0]. Haematological toxicity: grades (G) 3 anaemia = 4 pts, G3/4 neutropenia = 11 pts, G3 thrombocytopenia = 7 pts, no febrile neutropenia. Other G3 toxicities included G3 abdominal pain (2 pts), constipation (3 pts), neutropenic infection (1 pt). Six pts experienced G3 (5 pts) or 4 (1 pt) fatigue. Conclusions: Vinflunine can be given safely at 320 mg/m2 or 250 mg/m2 or 200 mg/m2 in pts with unresectable advanced HCC with different degrees of liver impairment. The disease control rate is promising (66.7%). No significant financial relationships to disclose.