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Purpose Treatment options for neuroendocrine tumors (NETs) remain limited. This trial assessed the progression-free survival (PFS) of bevacizumab or interferon alfa-2b (IFN-α-2b) added to octreotide among patients with advanced NETs. Patients and Methods Southwest Oncology Group (SWOG) S0518, a phase III study conducted in a US cooperative group system, enrolled patients with advanced grades 1 and 2 NETs with progressive disease or other poor prognostic features. Patients were randomly assigned to treatment with octreotide LAR 20 mg every 21 days with either bevacizumab 15 mg/kg every 21 days or 5 million units of IFN-α-2b three times per week. The primary end point was centrally assessed PFS. This trial is registered with ClinicalTrials.gov as NCT00569127. Results A total of 427 patients was enrolled, of whom 214 were allocated to bevacizumab and 213 to IFN-α-2b. The median PFS by central review was 16.6 months (95% CI, 12.9 to 19.6 months) in the bevacizumab arm and was 15.4 months (95% CI, 9.6 to 18.6 months) in the IFN arm (hazard ratio [HR], 0.93; 95% CI, 0.73 to 1.18; P = .55). By site review, the median PFS times were 15.4 months (95% CI, 12.6 to 17.2 months) for bevacizumab and 10.6 months (95% CI, 8.5 to 14.4 months) for interferon (HR, 0.90; 95% CI, 0.72 to 1.12; P = .33). Time to treatment failure was longer with bevacizumab than with IFN (HR, 0.72; 95% CI, 0.58 to 0.89; P = .003). Confirmed radiologic response rates were 12% (95% CI, 8% to 18%) for bevacizumab and 4% (95% CI, 2% to 8%) for IFN. Common adverse events with bevacizumab and octreotide included hypertension (32%), proteinuria (9%), and fatigue (7%); with IFN and octreotide, they included fatigue (27%), neutropenia (12%), and nausea (6%). Conclusion No significant differences in PFS were observed between the bevacizumab and IFN arms, which suggests that these agents have similar antitumor activity among patients with advanced NETs.

551 Background: Sorafenib inhibits various pro-angiogenesis pathways including PDGFR-B, a factor associated with resistance to anti-VEGF therapy. A previous phase II trial in patients with chemorefractory metastatic CRC demonstrated a 63% disease control rate with a combination of bevacizumab (BEV) and sorafenib. This phase I trial sought to determine the MTD of BEV and sorafenib combined with standard cytotoxic therapy for advanced gastrointestinal (GI) cancers. Methods: Patients with advanced GI malignancies appropriate for irinotecan-based therapy were enrolled (14 with CRC, 3 gastroesophageal). A standard 3 + 3 design was used with 3 escalating sorafenib dose levels (DL): (1) 200 mg po daily, days 3-7, 10-14; (2) 200 mg po twice daily, days 3-6, 10-13; and (3) 200 mg po twice daily, days 3-7, 10-14. FOLFIRI: irinotecan 180 mg/m2 d1, leucovorin 400 mg/m2 d1, 5-fluorouracil (FU) bolus 400 mg/m2 d1, 5-FU infusion 2400 mg/m2d1-2 and BEV 5 mg/kg d1. 1 cycle = 14 days. Results: Seventeen pts were enrolled, median age of 56 (range 32 and 81). Two pts were replaced, as they did not complete DLT evaluation, leaving 15 evaluable pts. Four evaluable pts at DL1 and 6 pts at DL2 had no DLTs. At DL 3, the first cohort of 3 pts did not experience any DLTs. In the second cohort of 3 pts, 2 pts experienced DLTs (asymptomatic G3 hypophosphatemia, G3 dehydration and diarrhea). MTD was determined to be DL2: sorafenib 200 mg PO twice daily, days 3-6, 10-13 combined with FOLFIRI and BEV at standard doses. Of the 15 evaluable pts, 4 pts had PR, 8 pts had SD as best response, 1 pt had PD, and 2 pts discontinued treatment prior to first tumor assessment. The median number of cycles was 10 (range 1-37). Three pts with CRC had disease control > 12 months. Conclusions: The MTD of this regimen is sorafenib 200 mg PO twice daily, days 3-6,10-13 combined with standard doses of FOLFIRI and BEV. Dual VEGF inhibition combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies. Supported by CA69912 and CA15083. Clinical trial information: NCT01383343.

11 Background: Currently there are no serum markers of response to AA. We performed a proteome based analysis of serum from prostate cancer patients, followed by mapping of candidate markers to networks based on known molecular interactions in Ingenuity Knowledge Base (IKB). Methods: Isobaric mass tags for relative and absolute quanititation (iTRAQ) analyzed by reverse-phase liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS) was performed in serum of 3 non-localized prostate cancer cohorts. The first cohort included 15 paired untreated hormone-sensitive “pre AA” and 3-month “post AA” specimens; the second included 10 “early AA failure” (median failure time: 11 months) and the third included 10 “late AA failure” specimens (median failure time: 95 months). Differentially expressed candidate proteins were identified by comparisons of (i) paired pre/post AA proteomes and (ii) post AA proteome with the combined AA failure cohorts at a False Discovery Rate of 0.2. To facilitate biological interpretation of multiple candidates identified in the comparisons, IPA was used. Candidate markers implicated in IPA networks with statistical significance were pursued in a second, independent patient cohort for association with time to AA failure using univariate Cox regression analysis. Results: Median PSA for pre/post AA first cohort were 3.15 and 0.29 ng/ml. Median PSA for the second and third cohorts were 27.3 and 4.3 ng/ml. Between post AA and AA failure cohorts, 149 proteins were differentially expressed. Between early and late AA failure 98 proteins were differentially expressed; 47 proteins were common in both comparisons. Network enrichment analysis of the 47 proteins by IPA identified four interaction networks (p<0.01), one of which highlighted a role for 17-β-estradiol (E1). Gas chromatography used for measuring 3-month post AA initiation serum E1, estrone (E2) and testosterone levels (N=38) detected high E1, E2 levels associated with longer time to AA failure (P=0.07 for E1; P=0.08 for E2) in the independent cohort. Conclusions: A global proteomic analysis identified post AA initiation serum E1, E2 levels as potential response markers, which needs validation.

249 Background: Evaluating tumor specific pathologic and genetic profiles in mCRPC stage is difficult due to the limited availability of mCRPC tissue. We describe findings from a prospective cohort study performed to obtain concomitant histopathology and genetic information in mCRPC. Methods: Patients with mCRPC initiating abiraterone acetate therapy underwent 2 serial (3 months apart) metastatic (met) site needle core biopsies (NCB1/2). Bone lesions were biopsied using 11-13G core needles and 18G core biopsy devices were used for non-osseous masses. Up to 4 cores were obtained at each biopsy with the 1st core (S1) sent for DNA sequencing, the 2nd (S2) for RNA sequencing, and the 3rd/4th (X3, X4) submitted for xenograft implantation. From each, 1-2 mm segments were separated and formalin-fixed for histopathologic examination (HPE). Results: A total of 54 patients, enrolled between June 2013 and July 2014, underwent 94 NCB (54 NCB1, 40 NCB2), rendering a total of 259 samples (94 S1; 75 S2; 59 X3 and 31 X4) of which 85 (32%) were positive (pos) for tumor by HPE. Positivity for tumor in S1, S2, X3, and X4 cores was 42%, 33%, 22%, and 19%, respectively. At least one core pos for met tumor was observed in 62% NCB1 and 52% NCB2 (overall 52/94; 56%). Met sites biopsied include bone (71), lymph nodes (18), liver (3), penile (1) and pelvic (1) soft tissues. HPE revealed met adenocarcinoma in 44/52, and poorly differentiated carcinoma in 8/52. Gleason grade applied to the met ranged from 3+4 to 5+5. 45/85 pos samples (53%) had > 50% tumor cellularity. Pos NCB in bone lesions was observed in 23/71 (32%), compared to 17/23 (73%) of non-bone sites (p=.0004). 85 S1 samples yielded DNA material, of which 66 (77%) had ≥10% tumoral DNA. 24 cases with negative HPE had ≥10% tumoral DNA; 7 cases with pos HPE had <10 tumoral DNA. In all, 76/94 (81%) NCB yielded tumor material either by HPE or DNA analysis. Conclusions: NCB of mCRPC is feasible and provides adequate tissue for pursuing HPE and sequencing studies. HPE of extracted material correlates with DNA sequencing data and provides complementary information on tumor features. Bone lesions yield significantly less tumoral material than non-osseous sites.

190 Background: It is not known if biopsy of CRPC stage metastases alters CTC results. We evaluated pre & post biopsy CTC counts in a prospective cohort undergoing pre-chemotherapy abiraterone acetate/prednisone (AA/P). Methods: CTC enumeration was performed on 7.5mL blood using the FDA cleared immunomagnetic/immunofluorescence assay (CellSearch). Time of blood draw for CTC counts pre/post biopsy was recorded for each biopsy. Biopsies were performed using 11/13 gauge core biopsy device for bone lesions and 18 gauge core needle biopsy device for soft tissue/nodal metastases. All patients (pts) underwent two serial biopsies 3 months apart. Change in CTC counts pre/post biopsy for visits 1 and 2 were evaluated using Wilcoxon signed rank test (significance at p<0.05). Differences in CTC count change (visit1) pre/post biopsy based on metastatic site (skeletal vs. non-skeletal) was compared using Wilcoxon rank-sum test. Results: Median age of the cohort was 74 years (IQR: 68-78); median PSA at V1 was 16.4 ng/ml (IQR: 6.4-87.6); at V2 was 11.5 ng/ml (IQR: 1.8-23.7). Of 59 pts undergoing biopsies 42 were in bone and 17 in nodal/soft tissue masses. At V1, pre/post biopsy CTC counts were measured on 50 and 49 pts, respectively; at V2, pre/post CTC counts were measured on 43 and 36 pts. High volume metastatic disease at V1 was observed in 67.8 % of all pts. Table lists CTC counts and time of collection pre/post biopsy for both visits. Mean change in pre/post biopsy CTC counts for skeletal sites was 0.7 (range: -12 to 64) compared to 12.1 (range: -21 to 13) for non-skeletal sites (p=0.23). Conclusions: An increase in mean CTC counts after biopsy of CRPC metastases was observed. No significant differences in change of CTC counts based on site biopsied (skeletal versus non-skeletal) was noted. Correlation with clinical outcomes is on-going. Clinical trial information: NCT# 01953640. [Table: see text]

174 Background: AA/P is an FDA approved treatment for mCRPC. Since markers of early resistance to AA/P are unknown, we report initial findings of androgen receptor (AR) based associations with short term (12 week) progression on AA/P. Methods: mCRPC stage patients (pts) initiating pre-chemotherapy AA/P underwent metastatic site biopsies at baseline (pre AA/P) and after 12 weeks. Baseline somatic whole exome DNA, tumor gene expression for AR full length (ARFL), AR splice variant 7 (ARV7) and ARV7/ARFL ratios were compared in progessors versus non-progressors. Progression at or within 12 weeks of AA/P therapy was defined as death or disease progression by PCWG2 “composite progression (CP)” and/or “radiographic progression” endpoints. Wilcoxon rank-sum tests were used to test for differences in the two groups for comparing ARFL, ARV7 expressions and ARV7/ARFL ratios and chi square tests were used for differences in copy number variation. Results: Between 1/2013 and 6/2014, 59 pts were enrolled of which 44 have disease assessment data at the12-week time point. CP was observed in 17/44 patients. DNA seq and clinical data was available for 42/44 pts. Using radiographic progression at 12 weeks, AR Amplification/Gain was observed in 20/26 non-progressors (13 with Amplification) and in 9/16 progressors (P-value = 0.19; OR 2.5). ARFL and ARV7 gene expressions in both groups is provided in table. Conclusions: A trend towards higher ARV7/ARFL gene expression ratio in metastases was observed with early progression on AA/P. AR gain/amplification is observed less often in pts with early progression. Validation of these findings is on-going in this prospective trial. Clinical trial information: NCT# 01953640. [Table: see text]

176 Background: The purpose of the study was to determine the effectiveness of olanzapine (OLN) for the prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy (HEC). Methods: A randomized, double-blind, phase III trial was performed in chemotherapy-naïve patients receiving cisplatin, > 70 mg/m2, or cyclophosphamide-anthracycline-based chemotherapy, comparing OLN to placebo in combination with aprepitant (APR), a 5-HT3 receptor antagonist (5-HT3), and dexamethasone (DEX). The OLN regimen was 10 mg of oral OLN, 125 mg APR, a 5-HT3, and oral DEX 12 mg pre-chemotherapy, day 1, and 10 mg/day of oral OLN and 8 mg DEX on days 2-4 post-chemotherapy plus 80 mg APR on days 2, 3 post-chemotherapy. The placebo (PLA) regimen was oral placebo, pre-chemotherapy, day 1, and on days 2-4 post-chemotherapy; the APR, 5-HT3, and DEX pre- and post-chemotherapy were identical to that used in the OLN regimen. Fosaprepitant (150 mg IV), day 1 was allowed for substitution for the oral aprepitant. Palonosetron, ondansetron, or granisetron were the permitted 5-HT3 options. Nausea was measured on a 0-10 visual analogue scale, with 0 being “no nausea at all” and 10 being “nausea as bad as it can be”. No nausea was the primary endpoint and, complete response (no emesis and no use of rescue medications) was a secondary endpoint. Results: 401 patients (202 OLN, 199 PLA) were enrolled in the study. The proportion of patients who had no nausea was significantly greater for the OLN regimen compared to the PLA regimen for the acute period (24h post-chemotherapy) (74% vs. 45%, p < 0.0006), for the delayed period ( 24-120 h post-chemotherapy) (43% vs. 26%, p < 0.0006), and for the overall period (0-120 h) (39% vs. 22%, p < 0.0006). Complete response was significantly improved for the OLN patients compared to PLA patients for the acute (85% vs. 65%, p < 0.0001), the delayed (67% vs. 53%, p < 0.0078), and the overall periods (64% vs. 41%, p < 0.0001). There were no grade 3 or 4 toxicities. Conclusions: No nausea, the primary endpoint, and complete response, a secondary endpoint, were significantly improved with OLN, compared to PLA. Clinical trial information: NCT02116530.

259 Background: Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are produced by bladder cancer cell lines in vitro and expressed in human tumor tissues. Preclinical studies have also shown that bladder cancer cell lines express VEGF receptor 1 and 2 on their surface membrane. Pazopanib is a vascular endothelial receptor tyrosine kinase inhibitor with anti-angiogenesis and antitumor activity in several preclinical models. A two-stage phase II study was conducted to assess the activity and toxicity profile of pazopanib administered to patients with metastatic, urothelial carcinoma. Methods: Patients with one prior systemic therapy for recurrent, metastatic urothelial carcinoma were eligible. Patients received pazopanib at a dose of 800 mg orally daily for 4 week cycle. Results: Nineteen patients were enrolled. Median age was 66 years, with > 89% of patients presenting poorly differentiated bladder cancer. Adverse event data is available on 18 patients. No grade 4 or 5 events have been experienced. Nine patients have experienced 11 grade 3 adverse events of which 7 were deemed at least possibly related to treatment. Most common toxicities were anemia, thrombocytopenia, leucopenia and fatigue. For stage 1, none of the first 16 evaluable patients were deemed success (CR or PR) by the RECIST criteria during the first four 4-week cycles of treatment. Median progression- free survival was 1.9 months. This met the futility stopping rule of interim analysis, and therefore, the trial was recommended to be permanently closed. Correlative studies including measurement of VEGF levels in archived tissues and blood are pending. Conclusions: Pazopanib did not show activity in urothelial carcinoma patients. The role of anti-VEGF therapies in urothelial carcinoma may need further evaluation in rational combination strategies. [Table: see text]