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Purpose:As monotherapies, eribulin (chemotherapy) and pembrolizumab (immunotherapy) have shown promise for patients with metastatic triple-negative breast cancer (mTNBC). This phase Ib/II study examined eribulin plus pembrolizumab as a potential mTNBC treatment in first-line and later-line settings.Patients and Methods:In this open-label, single-arm, phase Ib/II study, eligible patients had mTNBC, measurable disease, and ≤2 prior systemic anticancer therapies in the metastatic setting. Patients were enrolled by number of prior systemic anticancer therapies (stratum 1: 0 vs stratum 2: 1–2) in the metastatic setting and further analyzed by tumor programmed death-ligand 1 (PD-L1) expression status. All patients received intravenous eribulin 1.4 mg/m2 on day 1 and day 8, plus intravenous pembrolizumab 200 mg on day 1, of 21-day cycles. The primary objectives were the safety, tolerability, and objective response rate (ORR) of this combination.Results:The study included 167 patients (phase Ib, n = 7; phase II, n = 160). The most common treatment-emergent adverse events were fatigue (66%), nausea (58%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). ORRs were 25.8% [95% confidence interval (CI): 15.8–38.0] for stratum 1 (n = 66) and 21.8% (95% CI: 14.2–31.1) for stratum 2 (n = 101). Patients with PD-L1–positive tumors (combined positive score ≥1) had numerically higher ORR than those with PD-L1–negative tumors, particularly in stratum 1 [stratum 1: 34.5% (95% CI: 17.9–54.3) vs 16.1% (95% CI: 5.5–33.7); stratum 2, 24.4% (95% CI: 12.9–39.5) vs 18.2% (95% CI: 8.2–32.7)].Conclusions:Eribulin plus pembrolizumab was generally well tolerated and showed promising antitumor activity in mTNBC. Efficacy outcomes appeared influenced by line of therapy and PD-L1 status.

Supplementary Information

Purpose: Dysregulated cyclin-dependent kinases are important to the growth of some sarcomas. Flavopiridol is a pan-CDK inhibitor that has been shown to potentiate chemotherapy. As such, we explored the potentiation of doxorubicin by flavopiridol in sarcoma, in vitro and in vivo, and conducted a phase I trial of flavopiridol with doxorubicin in patients with advanced sarcomas.Experimental Design: Sarcoma cell lines and xenografts were treated with flavopiridol alone and in combination with doxorubicin. In the phase I study, doxorubicin and flavopiridol were administered on two flavopiridol schedules; a 1-hour bolus and split dosing as a 30-minute bolus followed by a 4-hour infusion.Results: Preclinically, flavopiridol potentiated doxorubicin. In vivo, doxorubicin administered 1 hour before flavopiridol was more active than doxorubicin alone. Clinically, 31 patients were enrolled on protocol and flavopiridol was escalated to target dose in two schedules (90 mg/m2 bolus; 50 mg/m2 bolus + 40 mg/m2 infusion) both in combination with doxorubicin (60 mg/m2). Dose-limiting toxicities were neutropenia, leukopenia, and febrile neutropenia but no maximum tolerated dose was defined. Flavopiridol pharmacokinetics showed increasing Cmax with increasing dose. Response Evaluation Criteria in Solid Tumors (RECIST) responses included two partial responses, however, stable disease was seen in 16 patients. Of 12 evaluable patients with progressive well- and dedifferentiated liposarcoma, eight had stable disease greater than 12 weeks.Conclusions: The sequential combination of doxorubicin followed by flavopiridol is well tolerated on both schedules. Disease control was observed in well- and dedifferentiated liposarcoma specifically, a disease in which CDK4 is known to be amplified. Clin Cancer Res; 18(9); 2638–47. ©2012 AACR.

PDF file - 66K, Cumulative grade 2 or greater hematologic toxicity throughout all cycles.

89 Background: Combination treatment with regorafenib (80–120 mg/day, PO, 3 wks on/1 wk off) plus nivolumab (480 mg IV Q4W) showed manageable safety but modest efficacy in a phase 2 study of 70 pts from North America with pMMR/MSS chemotherapy-resistant metastatic CRC (mCRC). Five pts had a partial response (PR; objective response rate [ORR]: 7%); all did not have liver metastases at baseline (n = 5/23; ORR: 22%). One pt had a confirmed complete response (CR) after the primary completion analysis of the study (ASCO 2021). This retrospective exploratory analysis investigated the potential association between specific biomarkers and anti-tumor activity, and how those biomarkers are modulated by treatment with regorafenib plus nivolumab. Methods: In formalin-fixed paraffin-embedded tumor samples obtained at baseline and Cycle (C) 2 Day (D) 8, immune-related biomarkers were assessed via immunohistochemistry (IHC), and RNA sequencing was used for gene expression profiling/gene signatures. Pre-/on-treatment blood samples were collected to measure circulating tumor DNA (ctDNA) and soluble biomarkers. Results: A total of 40 and 27 baseline tumor samples and 14 and 5 paired tumor samples at baseline/C2D8 were available for IHC and RNA sequencing, respectively. Higher baseline protein and mRNA expression of biomarkers for pre-existing immune sensitivity (eg, effector T cells) trended with anti-tumor activity. These biomarkers were expressed at lower levels in pts with liver metastases vs those without liver metastases at baseline. Cytotoxic T cell density was elevated on C2D8 but did not correlate with anti-tumor activity. Increased mean variant allelic frequency in ctDNA at C2D1 predominated in pts with progressive disease (PD), while clearance of ctDNA at C2D1 was only noted for the one pt with a CR. High clonal tumor mutational burden in ctDNA showed a numerical trend with anti-tumor activity (PD vs. SD/PR; P=0.058) and PFS (P = 0.072). Baseline serum levels of select markers related to angiogenesis (eg, vascular endothelial growth factor [VEGF] D) were associated with inferior anti-tumor activity (P = 0.002). Serum levels of immune-related soluble biomarkers (eg, tumor necrosis factor alpha) increased on treatment (P < 0.005), while levels of soluble VEGF receptor 2 decreased (P < 0.001). Conclusions: This study of pts with MSS mCRC treated with regorafenib plus nivolumab suggests that baseline tumor biomarkers for pre-existing immune sensitivity trended with anti-tumor activity, whereas select baseline peripheral biomarkers related to angiogenesis trended with inferior anti-tumor activity. Pharmacodynamics effects were observed, yet no significant correlation with anti-tumor activity was found. Due to the small sample size and retrospective nature, these analyses are hypothesis-generating. Clinical trial information: NCT04126733.

Background: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]). Patients and methods: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours. Results: A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p = 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4–4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3–1.6) for placebo (HR = 0.64, 95% CI: 0.38–1.07; p = 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6–4.2) months for brivanib and 2.0 months (95% CI: 1.2–2.7) for placebo (HR: 0.56, 95% CI: 0.26–1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6–4.2) and was 2.0 months (95% CI: 1.2–2.7) in those randomised to placebo (HR = 0.54, 95% CI: 0.25–1.17; p = 0.11). Conclusion: Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib., SCOPUS: ar.j, info:eu-repo/semantics/published

Introduction. Soft Tissue Sarcoma (STS) is a rare malignancy of mesodermal tissue, with international incidence estimates between 1.8 and 5 per 100,000 per year. Understanding quality of life (QoL) and the detrimental impact of disease progression is critical for long-term care and survival. Objectives. The primary objective was to explore the relationship between disease progression and health-related quality of life (HRQoL) using data from Eisai’s study (E7389-G000-309). Methods. This was a 1 : 1 randomized, open-label, multicenter, Phase 3 study comparing the efficacy and safety of eribulin versus dacarbazine in patients with advanced STS. The QoL analysis was conducted for the baseline and progression populations using the European Organization for Research and Treatment of Cancer 30-item core QoL questionnaire (EORTC QLQ-C30). Results. There were no statistical differences between the two treatment arms at baseline for any domain (p>0.05; n=452). Of the 399 patients who experienced disease progression (unadjusted and adjusting for histology), dacarbazine patients had significantly lower Global Health Status, Physical Functioning scores, and significantly worse Nausea and Vomiting, Insomnia, and Appetite Loss (p<0.05). Conclusions. These results indicate differences in HRQoL overall and at progression between dacarbazine and eribulin patients, with increases in symptom severity observed among dacarbazine patients.

BACKGROUND: HSP90 inhibition leads to proteosomal degradation of activated KIT and has in vitro activity against gastrointestinal stromal tumors (GIST). BIIB021 is an oral non-ansamycin HSP90 inhibitor. We carried out a phase II study of BIIB021 in patients with GIST refractory to imatinib and sunitinib. PATIENTS AND METHODS: The primary end-point was metabolic partial response (mPR) as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET). The secondary end-points were pharmacokinetic assessments of BIIB021 and pharmacodynamic assessments of HSP70. Twenty-three patients were treated on two schedules: 12 pts received 600 mg twice a week (BIW) and 11 patients received 400 mg three times a week (TIW). All had prior imatinib and sunitinib but stopped>14 days before starting BIIB021. RESULTS: The median age was 59 years (33-88 years), 61% male, 44% Eastern Cooperative Oncology Group 1 (ECOG1). The best response was PR by FDG-PET for five patients (3/12 at 600 mg BIW and 2/9 at 400 TIW) for an overall response rate of 22%. The response duration was 25-138 days. Adverse events (AEs) were mild to moderate. The mean Cmax was 1.5 micromol and the mean AUC was 2.9 micromol h. Cmax>1.5 micromol was associated with a decrease in standardized uptake value (SUVmax). HSP70 increased substantially following treatment. CONCLUSIONS: This study met its primary end-point. BIIB021 leads to objective responses in refractory GIST patients. Pharmacodynamic studies confirmed HSP90 inhibition. Further evaluation of BIIB021 in GIST is warranted.

Background. Patients with recurrent synovial sarcomas have few options for systemic therapy. Since they express large amounts of endogenous CT (cancer testis) antigens such as NY-ESO-1, we investigated the clinical activity of single agent anti-CTLA4 antibody ipilimumab in patients with advanced or metastatic synovial sarcoma.Methods. A Simon two-stage phase II design was used to determine if there was sufficient activity to pursue further. The primary endpoint was tumor response rate by RECIST 1.0. Patients were treated with ipilimumab 3 mg/kg intravenously every 3 weeks for three cycles and then restaged. Retreatment was possible for patients receiving an extra three-week break from therapy. Sera and peripheral blood mononuclear cells were collected before and during therapy to assess NY-ESO-1-specific immunity.Results. Six patients were enrolled and received 1–3 cycles of ipilimumab. All patients showed clinical or radiological evidence of disease progression after no more than three cycles of therapy, for a RECIST response rate of 0%. The study was stopped for slow accrual, lack of activity, and lack of immune response. There was no evidence of clinically significant either serologic or delayed type hypersensitivity responses to NY-ESO-1 before or after therapy.Conclusion. Despite high expression of CT antigens by synovial sarcomas of patients treated in this study, there was neither clinical benefit nor evidence of anti-CT antigen serological responses. Assessment of the ability of synovial sarcoma cell lines to present cancer-germ cell antigens may be useful in determining the reason for the observed lack of immunological or clinical activity.

BACKGROUND: Data regarding the role of anthracyclines and taxanes as first-line treatments of metastatic angiosarcoma are limited. METHODS: Records of 117 metastatic angiosarcoma patients who were treated with either doxorubicin or weekly paclitaxel were reviewed. RESULTS: Seventy-five patients (64%) were treated with weekly paclitaxel and 42 (36%) with single-agent doxorubicin. Patients in the weekly paclitaxel group were older and more frequently had angiosarcomas arising from the skin. In the doxorubicin group, 34 patients were evaluable for response: 2 (6%) had complete response, 8 (23.5%) had partial response, 10 (29.5%) had stable disease, and 14 (41%) had progressive disease. In the weekly paclitaxel group, 68 patients were evaluable for response: 9 (13%) had complete response, 27 (40%) had partial response, 20 (29.5%) had stable disease, and 12 (17.5%) had progressive disease. Objective responses to weekly paclitaxel were more frequent in cutaneous angiosarcomas, whereas tumor location did not impact response to doxorubicin. Median progression-free survival (PFS) was 4.9 months (95% confidence interval [95% CI], 3.9-6.0 months). Median overall survival (OS) was 8.5 months (95% CI, 6.4-10.7 months). On multivariate analysis, ECOG performance status (PS) was the sole independent factor associated with PFS and OS. CONCLUSIONS: First-line single-agent doxorubicin and weekly paclitaxel seem to have similar efficacy in metastatic angiosarcomas. Cutaneous angiosarcomas respond favorably to weekly paclitaxel. Best supportive care should be considered in patients with poor PS.

Background: Desmoid tumors (deep fibromatoses) are clonal connective tissue malignancies that do not metastasize, but have a significant risk of local recurrence, and are associated with morbidity and occasionally mortality. Responses of desmoid patients to sorafenib on an expanded access program led us to review our experience. Methods: After Institutional Review Board (IRB) approval, we reviewed data for 26 patients with desmoid tumors treated with sorafenib. Sorafenib was administered at 400 mg oral daily and adjusted for toxicity. Results: Sorafenib was the first-line therapy in 11/26 patients and the remaining 15/26 had received a median of 2 prior lines of therapy. Twenty-three of 26 patients had shown evidence of progressive disease by imaging, whereas 3 patients had achieved maximum benefit or toxicity with chemotherapy. Sixteen of 22 (∼70%) patients reported significant improvement of symptoms. At a median of 6 months (2–29) of treatment, the best response evaluation criteria in solid tumors (RECIST) 1.1 response included 6/24 (25%) patients with partial response (PR), 17/24 (70%) with stable disease, and 1 with progression and death. Twelve of 13 (92%) patients evaluated by MRI had > 30% decrease in T2 signal intensity, an indirect metric for increased fibrosis and loss of cellularity. Eighty percent of patients with radiological benefit had extra-abdominal desmoids. Discussion: Sorafenib is active against desmoid tumors. A prospective, randomized clinical trial of sorafenib against other active agents is warranted. Loss of MRI T2 signal may be a useful surrogate for defining responses, but requires validation by examination of tumor pathology. Clin Cancer Res; 17(12); 4082–90. ©2011 AACR.

Inflammatory myofibroblastic tumor (IMT) is a distinctive mesenchymal neoplasm characterized by a spindle-cell proliferation with an inflammatory infiltrate. Approximately half of IMTs carry rearrangements of the anaplastic lymphoma kinase (ALK) locus on chromosome 2p23, causing aberrant ALK expression. We report a sustained partial response to the ALK inhibitor crizotinib (PF-02341066, Pfizer) in a patient with ALK-translocated IMT, as compared with no observed activity in another patient without the ALK translocation. These results support the dependence of ALK-rearranged tumors on ALK-mediated signaling and suggest a therapeutic strategy for genomically identified patients with the aggressive form of this soft-tissue tumor. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

We present a challenging case of a previously healthy 23-year-old man who developed an inflammatory myofibroblastic tumour of the hard palate, harbouring a rearrangement of the anaplastic lymphoma kinase (ALK) locus. Despite surgical intervention, radiotherapy and ALK-inhibition therapy, the tumour recurred locally and metastasised to regional lymph nodes, and the patient passed away roughly 9 months after diagnosis from local progression. The rapid progression of this patient’s disease and its resistance to treatment demonstrate the potentially aggressive clinical course of inflammatory myofibroblastic tumours. ALK-inhibition therapy was unsuccessful in this ALK-positive tumour, highlighting the need for further investigation of markers predictive of disease progression and treatment response.

Sarcomas comprise a heterogeneous group of mesenchymal neoplasms. They can be grouped into 2 general categories, soft tissue sarcoma and primary bone sarcoma, which have different staging and treatment approaches. This review includes a discussion of both soft tissue sarcomas (malignant fibrous histiocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma, dermatofibrosarcoma protuberans, angiosarcoma, Kaposi sarcoma, gastrointestinal stromal tumor, aggressive fibromatosis or desmoid tumor, rhabdomyosarcoma, and primary alveolar soft-part sarcoma) and primary bone sarcomas (osteosarcoma, Ewing sarcoma, giant cell tumor, and chondrosarcoma). The 3 most important prognostic variables are grade, size, and location of the primary tumor. The approach to a patient with a sarcoma begins with a biopsy that obtains adequate tissue for diagnosis without interfering with subsequent optimal definitive surgery. Subsequent treatment depends on the specific type of sarcoma. Because sarcomas are relatively uncommon yet comprise a wide variety of different entities, evaluation by oncology teams who have expertise in the field is recommended. Treatment and follow-up guidelines have been published by the National Comprehensive Cancer Network (www.nccn.org).

Purpose Bevacizumab improves survival in several solid tumor malignancies when combined with chemotherapy. We evaluated the efficacy and safety of the addition of bevacizumab to chemotherapy in the treatment of gastric and gastroesophageal junction (GEJ) adenocarcinoma. Patients and Methods Forty-seven patients with metastatic or unresectable gastric/GEJ adenocarcinoma were treated with bevacizumab 15 mg/kg on day 1, irinotecan 65 mg/m2, and cisplatin 30 mg/m2 on days 1 and 8, every 21 days. The primary end point was to demonstrate a 50% improvement in time to progression over historical values. Secondary end points included safety, response, and survival. Results Patient characteristics were as follows: median age 59 years (range, 25 to 75); Karnofsky performance status 90% (70% to 100%); male:female, 34:13; and gastric/GEJ, 24:23. With a median follow-up of 12.2 months, median time to progression was 8.3 months (95% CI, 5.5 to 9.9 months). In 34 patients with measurable disease, the overall response rate was 65% (95% CI, 46% to 80%). Median survival was 12.3 months (95% CI, 11.3 to 17.2 months). We observed no increase in chemotherapy related toxicity. Possible bevacizumab-related toxicity included a 28% incidence of grade 3 hypertension, two patients with a gastric perforation and one patient with a near perforation (6%), and one patient with a myocardial infarction (2%). Grade 3 to 4 thromboembolic events occurred in 25% of patients. Although the primary tumor was unresected in 40 patients, we observed only one patient with a significant upper gastrointestinal bleed. Conclusion Bevacizumab can be safely given with chemotherapy even with primary gastric and GEJ tumors in place. The response rate, time to disease progression (TTP), and overall survival are encouraging, with TTP improved over historical controls by 75%. Further development of bevacizumab in gastric and GEJ cancers is warranted.

Purpose To evaluate the antitumor activity and tolerability of bevacizumab and doxorubicin in patients with metastatic soft-tissue sarcoma (STS). Patients and Methods Patients may have had up to one nonanthracycline line of therapy. Seventeen patients with metastatic STS were treated with doxorubicin at 75 mg/m2 intravenous (IV) push followed by bevacizumab 15 mg/kg IV every 3 weeks. Dexrazoxane was started for total doxorubicin dose exceeding 300 mg/m2. Results A total of 85 cycles of doxorubicin/bevacizumab were administered, median four cycles (range, one to 11), with three patients receiving one to four cycles of bevacizumab maintenance after reaching 600 mg/m2 doxorubicin. All 17 patients were assessable for response. Two partial responses (12%, 95% CI = 1% to 36%) were observed, lasting seven and 12 cycles of therapy. Eleven patients (65%) had stable disease for four cycles or more. Six patients developed cardiac toxicity grade 2 or greater, with four patients grade 2 (cumulative doxorubicin 75, 150, 300, 300 mg/m2, respectively), one grade 3 (total doxorubicin 591 mg/m2), and one grade 4 (total doxorubicin 420 mg/m2). One patient with extensive lung disease died of recurrent bilateral pneumothoraces, possibly treatment-related. Conclusion The 12% response rate for these patients was no greater than that observed for single-agent doxorubicin. However, the 65% of patients with stable disease lasting four cycles or longer suggests further study is warranted in STSs. The observed cardiac toxicity, despite close monitoring and standard use of dexrazoxane, obliges a change in the dose and/or schedule in future studies of this combination.

Background Preclinical studies have documented antitumor activity of PARP inhibition both in vitro and in vivo, against Ewing sarcoma cells. This study aimed to translate that observation into a clinical trial to assess the efficacy and tolerability of olaparib, a PARP inhibitor, in patients with advanced Ewing sarcoma (EWS) progressing after prior chemotherapy. Methods In this nonrandomized phase II trial, adult participants with radiographically measureable metastatic EWS received olaparib tablets, 400 mg orally twice daily, until disease progression or drug intolerance. Tumor measurements were determined by CT or MRI at 6 and 12 weeks after starting olaparib administration, and then every 8 weeks thereafter. Tumor response determinations were made according to RECIST 1.1, and adverse event determinations were made according to CTCAE, version 4.0. A total of 22 participants were planned to be enrolled using a conventional 2-step phase II study design. If no objective responses were observed after 12 participants had been followed for at least 3 months, further accrual would be stopped. Results 12 participants were enrolled, and all were evaluable. There were no objective responses (PR/CR), 4 SD (duration 10.9, 11.4, 11.9, and 17.9 wks), and 8 PD as best response. Of the SD, 2 had minor responses (−9% and −11.7% by RECIST 1.1). The median time to disease progression was 5.7 weeks. Further enrollment was therefore discontinued. No significant or unexpected toxicities were observed with olaparib, with only a single case each of grade 3 anemia and grade 3 thrombocytopenia observed. Conclusions This study is the first report of a prospective phase II trial to evaluate the safety and efficacy of a PARP inhibitor in patients with advanced Ewing sarcoma after failure of standard chemotherapy. Olaparib administration was safe and well tolerated when administered to this small heavily pre-treated cohort at the 400 mg BID dose, although the median duration of dosing was for only 5.7 weeks. No significant responses or durable disease control was seen, and the short average interval to disease progression underscores the aggressiveness of this disease. Other studies to combine cytotoxic chemotherapy with PARP inhibition in EWS are actively ongoing. Trial registration ClinicalTrials.gov Identifier: NCT01583543

Background Advanced GISTs are incurable, but often treatable for years with tyrosine kinase inhibitors (TKIs). The majority of GISTs harbor an oncogenic activating mutation in KIT or PDGFRA. Inhibition of this activating mutation with TKIs most often leads to durable disease control for many patients. However, almost all patients develop resistance to these TKIs, typically due to the development of secondary mutations, heralding the need for new therapeutic options. We conducted a phase II study evaluating the efficacy and toxicity of pazopanib, a broad spectrum TKI inhibiting KIT, VEGFRs (-1, -2, and -3), and PDGFR (-α and-β) in patients with advanced GIST following failure of at least imatinib and sunitinib. Methods Patients received pazopanib 800 mg orally once daily. All patients were assessed for efficacy with CT scans every 8 weeks (two cycles). Patients continued pazopanib until progression or unacceptable toxicity. The primary end point was the 24-week nonprogression [complete response+partial response+stable disease (SD)] rate (NPR) per RECIST 1.1. Secondary end points included PFS, OS, and toxicity. Results Between August 2011 and September 2012, a total of 25 patients were treated at two institutions. Median number of prior therapy was 3 (range 2–7). A total of 90 cycles of pazopanib were administered, with a median of two cycles (range 1 to 17+) per patient. Best response of SD at any time was observed in 12 (48%) patients. The NPR was 17% [95% confidence interval (CI) 4.5–37]. All but one patient discontinued protocol either due to PD (n = 19) or intolerance (n = 4). One patient with succinate dehydrogenase (SDH)-deficient GIST exhibited continuing disease control after 17 cycles. The median PFS for the entire cohort was 1.9 months (95% CI 1.6–5.2), and the median OS was 10.7 months (95% CI 3.9–NR). Conclusions Pazopanib was reasonably well tolerated with no unexpected toxicities. Pazopanib as a single agent has marginal activity in unselected heavily pretreated patients with advanced GIST.

A novel oncogene, rsc (rabbit squamous cell carcinoma), has been identified from a DMBA-induced rabbit squamous cell carcinoma using gene transfer and the nude mouse tumorigenesis assay. A full-length cDNA has been isolated and sequenced. rsc has potent tumorigenic activity in nude mice (latency

Purpose: Dysregulated cyclin-dependent kinases are important to the growth of some sarcomas. Flavopiridol is a pan-CDK inhibitor that has been shown to potentiate chemotherapy. As such, we explored the potentiation of doxorubicin by flavopiridol in sarcoma, in vitro and in vivo, and conducted a phase I trial of flavopiridol with doxorubicin in patients with advanced sarcomas. Experimental Design: Sarcoma cell lines and xenografts were treated with flavopiridol alone and in combination with doxorubicin. In the phase I study, doxorubicin and flavopiridol were administered on two flavopiridol schedules; a 1-hour bolus and split dosing as a 30-minute bolus followed by a 4-hour infusion. Results: Preclinically, flavopiridol potentiated doxorubicin. In vivo, doxorubicin administered 1 hour before flavopiridol was more active than doxorubicin alone. Clinically, 31 patients were enrolled on protocol and flavopiridol was escalated to target dose in two schedules (90 mg/m2 bolus; 50 mg/m2 bolus + 40 mg/m2 infusion) both in combination with doxorubicin (60 mg/m2). Dose-limiting toxicities were neutropenia, leukopenia, and febrile neutropenia but no maximum tolerated dose was defined. Flavopiridol pharmacokinetics showed increasing Cmax with increasing dose. Response Evaluation Criteria in Solid Tumors (RECIST) responses included two partial responses, however, stable disease was seen in 16 patients. Of 12 evaluable patients with progressive well- and dedifferentiated liposarcoma, eight had stable disease greater than 12 weeks. Conclusions: The sequential combination of doxorubicin followed by flavopiridol is well tolerated on both schedules. Disease control was observed in well- and dedifferentiated liposarcoma specifically, a disease in which CDK4 is known to be amplified. Clin Cancer Res; 18(9); 2638–47. ©2012 AACR.

Data regarding the role of anthracyclines and taxanes as first-line treatments of metastatic angiosarcoma are limited.Records of 117 metastatic angiosarcoma patients who were treated with either doxorubicin or weekly paclitaxel were reviewed.Seventy-five patients (64%) were treated with weekly paclitaxel and 42 (36%) with single-agent doxorubicin. Patients in the weekly paclitaxel group were older and more frequently had angiosarcomas arising from the skin. In the doxorubicin group, 34 patients were evaluable for response: 2 (6%) had complete response, 8 (23.5%) had partial response, 10 (29.5%) had stable disease, and 14 (41%) had progressive disease. In the weekly paclitaxel group, 68 patients were evaluable for response: 9 (13%) had complete response, 27 (40%) had partial response, 20 (29.5%) had stable disease, and 12 (17.5%) had progressive disease. Objective responses to weekly paclitaxel were more frequent in cutaneous angiosarcomas, whereas tumor location did not impact response to doxorubicin. Median progression-free survival (PFS) was 4.9 months (95% confidence interval [95% CI], 3.9-6.0 months). Median overall survival (OS) was 8.5 months (95% CI, 6.4-10.7 months). On multivariate analysis, ECOG performance status (PS) was the sole independent factor associated with PFS and OS.First-line single-agent doxorubicin and weekly paclitaxel seem to have similar efficacy in metastatic angiosarcomas. Cutaneous angiosarcomas respond favorably to weekly paclitaxel. Best supportive care should be considered in patients with poor PS.

Learning Objectives After completing this course, the reader will be able to: Describe the genetic syndromes associated with pancreas adenocarcinoma.Explain the potential role of platinum-based therapy and PARP inhibitors in BRCA-mutated pancreas adenocarcinoma. CME This article is available for continuing medical education credit at CME.TheOncologist.com Background. BRCA1 and BRCA2 germline mutations are associated with an elevated risk for pancreas adenocarcinoma (PAC). Other BRCA-associated cancers have been shown to have greater sensitivity to platinum and poly(ADP-ribose) polymerase (PARP) inhibitors with better clinical outcomes than in sporadic cases; however, outcomes in BRCA-associated PAC have not been reported. Methods. Patients with a known BRCA1 or BRCA2 mutation and a diagnosis of PAC were identified from the Gastrointestinal Oncology Service, Familial Pancreas Cancer Registry, and Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center. Results. Fifteen patients, five male, with a BRCA1 (n = 4) or BRCA2 (n = 11) mutation and PAC and one patient with a BRCA1 mutation and acinar cell carcinoma of the pancreas were identified. Seven female patients (70%) had a prior history of breast cancer. Four patients received a PARP inhibitor alone or in combination with chemotherapy; three demonstrated an initial radiographic partial response by Response Evaluation Criteria in Solid Tumors whereas one patient had stable disease for 6 months. Six patients received platinum-based chemotherapy first line for metastatic disease; five of those patients had a radiographic partial response. Conclusion. BRCA mutation–associated PAC represents an underidentified, but clinically important, subgroup of patients. This is of particular relevance given the ongoing development of therapeutic agents targeting DNA repair, which may potentially offer a significant benefit to a genetically selected population. We anticipate that further study and understanding of the clinical and biologic features of BRCA-mutant PAC will aid in the identification of tissue biomarkers indicating defective tumor DNA repair pathways in sporadic PAC.

BACKGROUND: In the current study, the authors examined the outcomes of patients with desmoid tumors who received systemic therapy at a single institution to provide a basis for the examination of newer agents. METHODS: Records of patients with desmoid tumors who were treated with chemotherapy at the study institution were reviewed. The activity of nonsteroidal anti-inflammatory drugs was not addressed. Patients without measurable disease and those receiving therapy could not be documented, and those receiving prophylactic therapy were excluded. RESULTS: A total of 68 patients received 157 lines of therapy. At the time of last follow-up, 9 patients had died, 7 of progressive disease. The cohort was 62% female, with a median age of 32.5 years. Approximately 32% of the patients had Gardner syndrome. The median follow-up was 63 months, and patients received a median of 2 lines of therapy. An intra-abdominal primary tumor location was the most common (44%). The greatest Response Evaluation Criteria in Solid Tumors (RECIST) response rate was observed with anthracyclines and hormonal therapy and the lowest response was noted with single-agent dacarbazine/temozolomide or tyrosine kinase inhibitors, principally imatinib. On multivariate analysis, macroscopic nodular morphology and the presence of Gardner syndrome were the only tumor factors found to be associated with a greater time to disease progression. CONCLUSIONS: Compared with other agents, antiestrogens and anthracycline-containing regimens appear to be associated with a higher radiological response rate against desmoid tumors. Systemic therapy can be successful in patients with desmoid tumors, and is a viable option in lieu of morbid or disabling surgery.

GIST (gastrointestinal stromal tumor) is a rare soft tissue malignancy arising in the gut. It has become well known recently because of the effectiveness of anti-KIT tyrosine kinase inhibitors. From a disease that 10 years ago was only treatable with surgery, now multiple phase 2 and phase 3 trials have identified active first-line systemic therapy, appropriate dosing, an active second-line agent, and established the role of adjuvant therapy after surgery for patients with intermediate- and high-risk tumors. These are accomplishments that took decades to achieve for other more common diseases such as breast cancer or lung cancer. GIST has been the ideal disease system for studying targeted therapy in solid tumors. The progress in treating GIST has come directly from the advances that have been made in the laboratory, understanding the basic biology of tyrosine kinases, the oncogenic activity of c-KIT, and how that enzymatic activity can be inhibited. By studying model diseases such as GIST, we should be able to develop paradigms to treat more common cancers as well.

Purpose To evaluate the potential benefit of continuous daily dosing sunitinib in patients with advanced nongastrointestinal stromal tumor (GIST) sarcomas. Patients and Methods A total of 53 patients with advanced non-GIST soft tissue sarcomas received sunitinib 37.5 mg daily. Primary end point was Response Evaluation Criteria in Solid Tumors defined response. Secondary end points were stable disease at 16 and 24 weeks. [18F]-fluorodeoxyglucose positron emission tomography was performed on a subset of 24 patients at baseline and after 10 to 14 days of therapy. Results Forty-eight patients were eligible for response. One patient (desmoplastic round cell tumor [DSRCT]) achieved a confirmed partial response (PR) and remained on study for 56 weeks. Ten patients (20%) achieved stable disease for at least 16 weeks. Metabolic PR was seen in 10 (47%) of 21 of patients. Metabolic stable disease was seen in 11 (52%) of 21. There were no unexpected toxicities observed. Conclusion Sunitinib demonstrated notable evidence of metabolic response in several patients with non-GIST sarcoma. The relevance of disease control observed in subtypes with an indolent natural history is unknown, however, the durable disease control observed in DSRCT, solitary fibrous tumor, and giant cell tumor of bone suggests that future evaluation of sunitinib in these subtypes may be warranted.

Purpose Since activity of sorafenib was observed in sarcoma patients in a phase I study, we performed a multicenter phase II study of daily oral sorafenib in patients with recurrent or metastatic sarcoma. Patients and Methods We employed a multiarm study design, each representing a sarcoma subtype with its own Simon optimal two-stage design. In each arm, 12 patients who received 0 to 1 prior lines of therapy were treated (0 to 3 for angiosarcoma and malignant peripheral-nerve sheath tumor). If at least one Response Evaluation Criteria in Solid Tumors (RECIST) was observed, 25 further patients with that sarcoma subtype were accrued. Results Between October 2005 and November 2007, 145 patients were treated; 144 were eligible for toxicity and 122 for response. Median age was 55 years; female-male ratio was 1.8:1. The median number of cycles was 3. Five of 37 patients with angiosarcoma had a partial response (response rate, 14%). This was the only arm to meet the RECIST response rate primary end point. Median progression-free survival was 3.2 months; median overall survival was 14.3 months. Adverse events (typically dermatological) necessitated dose reduction for 61% of patients. Statistical modeling in this limited patient cohort indicated sorafenib toxicity was correlated inversely to patient height. There was no correlation between phosphorylated extracellular signal regulated kinase expression and response in six patients with angiosarcoma with paired pre- and post-therapy biopsies. Conclusion As a single agent, sorafenib has activity against angiosarcoma and minimal activity against other sarcomas. Further evaluation of sorafenib in these and possibly other sarcoma subtypes appears warranted, presumably in combination with cytotoxic or kinase-specific agents.

Extraskeletal myxoid chondrosarcoma (EMC) is a genetically distinct sarcoma with a propensity for local recurrence and metastasis despite an indolent course. To the authors' knowledge, there are limited data examining chemotherapy outcomes as a guide to therapeutic decisions for unresectable disease.The clinical behavior and treatment responses of 87 patients with EMC who were seen at 2 institutions between 1975 and 2008 were examined.The median age of the patients at the time of diagnosis was 49.5 years, with a male-to-female ratio of 2:1. For patients presenting without metastases, 37% developed local recurrence (median time of 3.3 years) and 26% developed distal recurrence (median time of 3.2 years). Approximately 13% of patients presented with metastases. The 5-year, 10-year, and 15-year overall survival rates were 82%, 65%, and 58%, respectively. Twenty-one patients received 32 evaluable courses of chemotherapy. No significant radiologic or clinical responses were noted. The median time to disease progression while receiving chemotherapy was 5.2 months. The best physician-assessed response to chemotherapy was stable disease for at least 6 months in 25% of patients, stable disease for6 months in 41% of patients, and disease progression in 34% of patients. The estimated progression-free survival rates at 3 months, 4 months, 6 months, and 9 months were 69%, 65%, 40%, and 26%, respectively.This retrospective review highlights the poor response rate to chemotherapy and emphasizes aggressive control of localized disease as the primary approach to management. Although there are biases inherent in retrospective analyses, these data provide a benchmark for time to disease progression for the study of new agents for the treatment of patients with this diagnosis.

Purpose: Resistance is commonly acquired in patients with metastatic gastrointestinal stromal tumor who are treated with imatinib mesylate, often due to the development of secondary mutations in the KIT kinase domain. We sought to investigate the efficacy of second-line tyrosine kinase inhibitors, such as sorafenib, dasatinib, and nilotinib, against the commonly observed imatinib-resistant KIT mutations (KITV654A, KITT670I, KITD820Y, and KITN822K) expressed in the Ba/F3 cellular system. Experimental Design: In vitro drug screening of stable Ba/F3 KIT mutants recapitulating the genotype of imatinib-resistant patients harboring primary and secondary KIT mutations was investigated. Comparison was made to imatinib-sensitive Ba/F3 KIT mutant cells as well as Ba/F3 cells expressing only secondary KIT mutations. The efficacy of drug treatment was evaluated by proliferation and apoptosis assays, in addition to biochemical inhibition of KIT activation. Results: Sorafenib was potent against all imatinib-resistant Ba/F3 KIT double mutants tested, including the gatekeeper secondary mutation KITWK557-8del/T670I, which was resistant to other kinase inhibitors. Although all three drugs tested decreased cell proliferation and inhibited KIT activation against exon 13 (KITV560del/V654A) and exon 17 (KITV559D/D820Y) double mutants, nilotinib did so at lower concentrations. Conclusions: Our results emphasize the need for tailored salvage therapy in imatinib-refractory gastrointestinal stromal tumors according to individual molecular mechanisms of resistance. The Ba/F3 KITWK557-8del/T670I cells were sensitive only to sorafenib inhibition, whereas nilotinib was more potent on imatinib-resistant KITV560del/V654A and KITV559D/D820Y mutant cells than dasatinib and sorafenib.

Introduction. The role of vinorelbine in specific soft tissue sarcoma subtypes is unclear. We present retrospective single institution experience with single-agent vinorelbine in subjects with metastatic soft tissue malignancies.Methods. Fifty-eight patients were treated with single agent intravenous vinorelbine between April 1997 and December 2004. Doxorubicin had been administered previously to 53 subjects (91%), and the median number of lines of previous chemotherapy was 3 (range 0–7).Results. Patients received a median 6 doses of vinorelbine (range 1–65). The overall response rate was 6%(3 patients: 1 angiosarcoma, 1 epithelioid sarcoma, and 1 embryonal rhabdomyosarcoma). Fourteen patients (26%) experienced a best result of stable disease. Median time to progression was 1.8 months (95%confidence intervals 1.5–2.1 months, Kaplan-Meier estimate). Eight patients experienced grade 3 or 4 toxicity, most commonly febrile neutropenia.Conclusion. Vinorelbine demonstrates limited activity in a heavily pretreated group of soft-tissue sarcoma patients. Prospective investigation may be considered for selected sarcoma subtypes.

Based on preclinical biology (1, 2), this translational trial aimed to assess the efficacy and tolerability of the PARP inhibitor, olaparib, in patients with advanced Ewing sarcoma progressing after prior chemotherapy. In this uncontrolled phase II pilot, adult participants with radiographically measureable disease received 400 mg of olaparib capsules, twice daily, until disease progression or drug intolerance. Tumor measurements were determined by CT or MRI, at 6 and 12 weeks after starting olaparib administration, and then every 8 weeks thereafter. Tumor response determinations were made according to RECIST 1.1, and adverse event determinations were made according to CTCAE, version 4.0. A total of 22 participants were planned to be enrolled using a conventional 2-step phase II study design. If no objective responses were observed after 12 participants had been followed for at least 3 months, further accrual would be stopped. 12 participants were enrolled, and all were evaluable. A single case each of grade 3 anemia and grade 3 thrombocytopenia was observed (see Table One). Otherwise, no significant or unexpected toxicities were observed while participants were receiving study drugs. There were 0 PR/CR, 4 SD (duration 10.9, 11.4, 11.9, and 18.4 wks), and 8 PD as best response. Of the SD, 2 had minor responses (-16.7% and -11.7% by RECIST 1.1). The median time to disease progression was 5.7 weeks. Further enrollment was therefore discontinued. This study is the first report of a prospective phase II trial to evaluate the safety and efficacy of a PARP inhibitor in patients with Ewing sarcoma. Olaparib tablets were safe and well tolerated when administered to this small cohort at the 400 mg BID dose, although the median duration of dosing was for only 5.7 weeks. However, no significant responses were seen, and the short average interval to disease progression underscores the aggressiveness of this disease. Preclinical modeling supports exquisite in vivo sensitivity of this pathway in combination with chemotherapy, and such a trial of olaparib with temozolomide will begin shortly at our Center. Toxicity Type # of Patients Grade 1 2 3 4 Anemia 1 0 0 0 0 Blood and lymphatic systems disorders: other 1 1 0 0 0 Fatigue 1 1 0 0 0 Fever 1 1 0 0 0 Pain 2 1 0 1 0 Rash maculo-papular 1 1 0 0 0 Nausea 1 1 1 0 0 Vomiting 1 1 0 0 0 Urinary tract infection 1 1 0 0 0 Platelet count decreased 2 1 1 0 Hypoglycemia 1 1 0 0 0 Metabolism and nutrition disorders: other 1 1 0 0 0 Arthritis 1 1 0 0 0 Musculoskeletal and connective tissue disorder: other 1 1 0 0 0 Dizziness 1 1 0 0 0 Nervous system disorders: other 1 1 1 0 0 Cough 3 3 0 0 0 Postnasal drip 1 1 0 0 0 Respiratory, thoracic and mediastinal disorders: other 1 1 0 0 0 Hypertension 1 1 0 0 0 Total 25 19 3 0 0 Citation Format: Edwin Choy, James Butrynski, David Harmon, Jeffrey Morgan, Suzanne George, Andrew Wagner, David D'Adamo, Greg Cote, Yael Rubinstein, Cyril Benes, Daniel Haber, Jose Baselga, George Demetri. Translation of preclinical predictive sensitivity of Ewing sarcoma to PARP inhibition: Phase II study of olaparib in adult patients with recurrent/metastatic Ewing sarcoma following failure of prior chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-174. doi:10.1158/1538-7445.AM2013-LB-174

268 Background: BRCA1 and -2 germ-line mutations are associated with increased risk of PAC; approximately 5% of all cases of PAC are estimated to be due to an inherited genetic mutation (Lynch, HT, et al. Pancreatology, 2001;1(5):466-471). Other BRCA-associated cancers have demonstrated increased sensitivity to platinum chemotherapy and PARP inhibitors (PARPi) with improved clinical outcomes compared to sporadic cases (J Clin Oncol, 2008 Dec 1;26(34):5530-6). Outcomes in BRCA-associated pancreatic cancer are unknown. Methods: Patients with a known BRCA1 or -2 mutation and a diagnosis of PAC were retrospectively identified from the MSKCC Familial Pancreas Cancer Registry and via institutional database review. Outcomes and clinical characteristics were reviewed. 7 patients (1 male) with BRCA2 mutation and PAC, 4 patients (1 male) with BRCA1 mutation and PAC, were identified. Two further cases of BRCA mutation and cholangiocarcinoma were identified. Results: See Table for patient demographics. Treatment for advanced disease included a PARP inhibitor (PARPi) in 2 cases; both pts had a radiologic partial response (PR) to therapy. Five patients received platinum-based chemotherapy for advanced disease, 4 of whom had a PR. Median survival for all patients was 27.6 months. Conclusions: The use of platinum- containing chemotherapy, radiation therapy, and PARPi to target the BRCA-associated defective DNA repair mechanism is deserving of further investigation in these patients. PARPi have demonstrated promising efficacy in patients with BRCA-mutated breast and ovarian cancer and are undergoing prospective evaluation in PAC. Genetic testing in patients presenting with a personal history or strong family history of BRCA associated cancers may help to guide choice of therapy. [Table: see text] No significant financial relationships to disclose.

4152 Background: PAC in BC survivors is rare (Andersson, Acta Oncologica, 2008, 47:755-764) and may occur as part of an inherited cancer predisposition syndrome. Up to 10% of PAC patients (pts) hav...

9523 Background: Flavopiridol, a potent cyclin dependent kinase inhibitor, has been shown in vitro to enhance doxorubicin induced apoptosis. Using the BWH dediffentiated liposarcoma xenograft model we have shown that sequential therapy with doxorubicin (D) followed 1 hour later by flavopiridol (F) is superior to doxorubicin alone (p=0.006). Single agent flavopiridol was also active in this xenograft model, but less so than the combination. Methods: We have commenced an ongoing phase I study of the combination of D and F on the basis of this preclinical data in soft tissue sarcoma with fixed dose D (60 mg/m2), followed 1 hour later by escalating doses of F (40–70 mg/m2) administered over one hour, every 3 weeks. Standard phase I eligibility criteria apply. No prior anthracycline therapy is allowed. At 300 mg/m2 D, dexrazoxane is added to D F. Patients with responsive or stable disease after cumulative D dose of 600mg/m2 can receive single agent flavopiridol. Results: Median characteristics of 7 evaluable patients: age 52 (31–65), KPS 80% (70–90), 3 males / 4 females, 0 prior regimens (range 0–2). The combination has been well-tolerated, with no dose limiting toxicity (DLT) yet. There has been 1 grade 3 bleed in the setting of progressive disease and 1 grade 4 neutropenia without fever. Grade 1 and 2 diarrhea, related to flavopiridol have been observed. Pharmacokinetic (PK) studies are ongoing. We have observed no partial responses (PR). Prolonged stable disease (SD) has been seen in 3 patients for 6, 6 and 11 months. Two patients with SD have liposarcoma. One patient with liposarcoma continues on single agent flavopiridol with stable disease after having reached the prescribed limit of D of 600 mg/m2. Conclusions: The combination of doxorubicin and flavopiridol is safe, with no unexpected toxicities. Disease stabilization in STS has been observed. This appears to be an encouraging combination in liposarcoma and is consistent with our preclinical model. Flavopiridol dose escalation is continuing. No significant financial relationships to disclose.

4020 Background: BEV improves survival in several solid tumors when combined with chemotherapy. CPT/CIS is active in gastric and GEJ cancers with a median time to progression(TTP) of 4.2 months, response rate(RR) of 30%, and median survival of ∼7 months (Pozzo Ann Onc 2004). Anti-angiogenic therapy for upper GI cancers is of concern due to a potential increased risk of perforation or GI bleed. We evaluated the efficacy and safety of the combination of CPT, CIS, and BEV in the treatment of gastric and GEJ cancers. Methods: 47 patients with previously untreated metastatic gastric or GEJ adenocarcinomas were treated with BEV 15mg/kg day 1, CPT 65mg/m2 and CIS 30mg/m2 days 1 and 8, every 21 days. The primary endpoint was TTP, with 90% power to demonstrate a 50% improvement in TTP (eg. from 5 to 7.5 months) over historical control. Safety, response, and survival were secondary endpoints. Results: Patient characteristics: median age 59 (range 25–75), KPS 90% (70%-100%), Male 34, Gastric/GEJ 27:20. With a median follow up of 9.0 months, median TTP is 9.9 months (95%CI: 6.5–11.8 months). In 33 patients with measurable disease, the RR (partial + complete) is 66.7% (95%CI: 51–83%). Median survival is 12.6 months (95%CI: 10.1–17.1 months). We observed no change in expected CPT/CIS related toxicity: eg. grade 3/4 neutropenia (29%), nausea/vomiting (10%), and diarrhea (13%). Possible BEV related toxicity includes 2 gastric perforations, 1 grade 3 peri-rectal fistula, 2 cardiac events(1 ischemia, 1 reduced ejection fraction), and 10 patients with grade 3/4 hypertension. Although the primary tumor was unresected in 35 patients, we observed only 1 patient with an upper GI bleed. Grade 3/4 thromboembolic events occurred in 25%. Conclusions: The combination of CPT/CIS/BEV is active in gastric and GEJ cancers. The toxicity profile is acceptable. The primary endpoint of improving TTP was exceeded by 100% with median TTP 9.9 months. Despite the majority of patients having their primary tumor unresected, GI bleeding was not significant. The thromboembolic and perforation rates with CPT/CIS are similar with or without BEV (Shah et al JCO 2005). Further development of BEV in gastric and GEJ cancers is clearly warranted. [Table: see text]

4025 Background: BEV is an anti-VEGF-monoclonal antibody that improves survival in colorectal cancer. CPT/CIS is an active combination in the treatment of gastric and GEJ cancers with a median time to tumor progression(TTP) of 4.5 months. We performed this study to evaluate the efficacy and safety of the combination of CPT, CIS, and BEV in the treatment of gastric and GEJ cancers. Methods: Patients with previously untreated metastatic gastric and GEJ adenocarcinomas are eligible. The primary endpoint is to improve median TTP to 7.5 months. Response, survival, and safety are secondary endpoints. Evaluable or measurable disease was required. Patients received BEV 15mg/kg on day 1, CPT 65mg/m2 and CIS 30mg/m2 on days 1 and 8, every 21 days. Response is assessed by RECIST criteria, and CTCv 3.0 was used for toxicity assessment. Results: We have enrolled 24 patients with the following characteristics: median age 55(range 25–67), KPS 80%(70–90%), Male:Female 19:5. We have observed only 3 patients with progressi...

3560 Background: Cetuximab, a chimeric anti-EGFR monoclonal antibody, has clinical activity in colorectal cancer with demonstrated safety, efficacy and additive synergy with radiation in solid tumors (head & neck, lung). A pilot trial was therefore designed to investigate the safety of cetuximab in combination with standard neoadjuvant protracted infusion 5-FU and radiation therapy in ultrasound T3–4 (uT3–4) or clinical T4 (cT4) or locally recurrent rectal adenocarcinoma. Secondary objectives of clinical activity were assessed by R0 resection and pathologic complete response (CR) rates. Methods: uT3–4 or cT4 or locally recurrent rectal adenocarcinoma patients received cetuximab 400mg/m2 day 1 (250mg/m2 weekly thereafter) and 5-FU IVCI (225mg/m2) over 5.5 weeks with concurrent pelvic radiation (5040cGy), and cetuximab (250mg/m2 Qweek) for 4 additional weeks, followed by surgical resection 1–3 weeks later. Results: Total Treated: 20 patients (ages 27 - 72), 19 uT3 patients, 1 Local Recurrence patient. Cetuximab Therapy (10 planned treatments): Too early 2 pts, ≥ 8 doses 12 pts, 5 - 8 doses 2 pts, < 5 total doses 4pts* (*cetuximab not given due to: 1 pt - acute cholecystitis from cholelithiasis; 1 pt - Grade 3 radiation perineal toxicity; 2 pts - treatment non-compliance). Radiation Therapy - 18 pts completed, 2 pts too early. Grade 3/4 Toxicities: Diarrhea 10%, Acneiform Rash (outside RT field) 15%, Stomatitis 5%, Radiation Field Dermatitis 5%, Transaminitis 5%. Surgical Outcomes: (17 pts completed surgery): R0 Resection 100%, Pathologic CR 12%. Conclusions: Cetuximab in combination with protracted infusion 5-FU and concurrent radiation is feasible without synergistic or unexpected toxicities. Further randomized investigation of this regimen in the neoadjuvant setting for rectal cancer is warranted. No significant financial relationships to disclose.