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TPS3114 Background: mTOR is a member of the PI3K family. Ridaforolimus (RIDA) is a mTOR inhibitor that has demonstrated tolerability as intravenous (IV) and oral formulations. PI3K/AKT/mTOR signalling is associated with resistance to taxanes. In cancer (ca) cells, inhibition of mTOR signalling counteracts AKT-mediated resistance to drugs inhibiting tubulin. Paclitaxel and carboplatin (PC) have broad activity including endometrial, ovarian, and many cancers. mTOR inhibition with PC has synergistic and additive effects in solid tumors. A common defect in endometrioid ca is mutation of PTEN, causing activation of the PI3K/AKT/mTOR pathway. RIDA improved PFS over hormonal therapy of metastatic endometrial cancer in a randomized phase II study (Oza AM, et al. J Clin Oncol. 2011;29 [suppl; abstr 5009]). In 35 patients in a phase II study of RIDA, there were 7.7% partial response (PR) and 58% with stable disease with median duration 6.6 months (Mackay H et al. J Clin Oncol. 2011;29 [suppl; abstr 5013]). Ovarian ca ultimately develops a phenotype resistant to taxanes that may be overcome with mTOR inhibition. RIDA may therefore potentiate the response of endometrial, ovarian, and other solid cancers to PC. Methods: Patients (pts) with advanced solid ca and measureable disease and up to 3 prior therapies received P (175mg/m2 IV) and C (AUC 5 to 6 mg/ml/min IV) on day (D)1 of each 3-week cycle. RIDA in escalating cohorts of 10-40 mg is administered orally daily for 5 days per week (D1-5, D 8-12, D 15-19) in phase IA cohorts. Samples for pharmacokinetics of RIDA and P and pharmacodynamics (PD) are collected. More than 1 anticipated DLT of thrombocytopenia or neutropenia in the latter part of the cycle shifts the escalation of RIDA to an alternate schedule (D1-5, D 8-12). Escalation continues in a 3X3 design until 40 mg/day of RIDA or MTD. Seven pts have been enrolled; 5 ovarian, 1 endometrial, 1 urethral ca. The second cohort of an alternate schedule has been filled and evaluation continues. Further characterization of tolerability, efficacy, and PD are planned at the MTD in the phase IB expansion cohorts of 15 ovarian/15 endometrial cancers.

7536 Background: Tigatuzumab (T), a humanized monoclonal antibody that acts as a DR5 agonist induces apoptosis in human cancer cell lines and has shown activity in a phase 1 trial; phase 2 trials are ongoing in several tumor types. In NSCLC cells, single-agent T shows anti-cancer activity. Methods: Patients (pts) with histologically/cytologically confirmed (TNM ed6) NSCLC stage IIIB/IV, measurable disease by RECIST (v1.0), and ECOG-PS 0-1 were enrolled at 15 European sites. Pts received T or placebo (PL) IV + carboplatin/paclitaxel (C/P) every 3 weeks (wks) (1 cycle) for up to 6 cycles. In the case of complete response (CR)/partial response (PR) or stable disease, T or PL was given as maintenance therapy. The dosage regimen was T 10 mg/kg or PL at wk 1/cycle 1 and 8 mg/kg or PL every 3 wks thereafter; P: 175 mg/m2 every 3 wks; C: AUC 6 every 3 wks. Primary endpoint: progression-free survival (PFS); secondary endpoints: overall survival (OS) and objective response rate (ORR) (CR + PR), safety. Efficacy was assessed in both the full population and a prospectively-defined FCGR genotype subset. Results: 97/100 pts (9.3% stage IIIB wet; 90.7% stage IV; 70.1% non-squamous; 29.9% squamous) were eligible for efficacy analyses (49 to T; 48 to PL). Median PFS (95% CI) was 5.4 months (3.3, 6.6) for T vs 4.3 months (4.1, 5.8) for PL; HR = 0.96; 95% CI: 0.6, 1.6. Median OS (95% CI) was 8.4 months (6.9, 16.3) for T vs 9.0 months (7.6, 14.5) for PL (HR = 0.95; 95% CI: 0.6, 1.6). 12 pts (24.5%) in the T arm and 11 pts (22.9%) in the PL arm had PR; no pt had CR. In a subset of pts (n = 25) with FCGR2A-H131R or FCGR3A-V158F genotypes, there was a non-significant trend towards increased PFS with T vs PL (HR = 0.47; 95% CI: 0.16, 1.35) but no difference in OS. T was well tolerated; the only increased grade 3/4 toxicity was grade 3 neutropenia (16% with T vs 4% with PL). The number of treatment cycles was similar in both treatment arms. Conclusions: T does not improve the efficacy of C/P as treatment for systemic therapy-naïve, unselected advanced NSCLC pts. T was well tolerated and is being investigated in other settings.

8580 Background: Several clinical trials adding VEGF signaling inhibitors to chemotherapy have not demonstrated any benefit over chemotherapy alone in advanced melanoma potentially due to decreased tumor cell proliferation induced by VEGF blockade. We tested the hypothesis that sequential administration of axitinib followed by carboplatin and paclitaxel may be more effective than chemotherapy alone in metastatic melanoma. Methods: We conducted a prospective phase II trial of this combination in previously treated metastatic melanoma patients. Patients had an ECOG PS 0-1, and normal organ function. Axitinib 5 mg PO bid was taken on days 1 through 14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg/m2) was administered on day 1 starting with cycle 2. FLT-PET scans were performed on 6 patients to assess tumor cell proliferation on days 1, 14, 17, and 20 of cycle 1. Results: Treatment has been well tolerated. The most common grade 3 AEs have been neutropenia, hypertension, and gastrointestinal events. Grade 4 non-hematologic AEs have not been observed. 4 of 5 patients completing FLT-PET scans to date showed increases (23% to 92%) in SUV values during the axitinib holiday. The fifth patient had a single, minimally FLT avid lesion at baseline (SUV=1.9). In 30 evaluable patients, there have been 4 confirmed PRs, 2 unconfirmed PRs, and 3 patients with 28.6, 29.3, and 29.5% decreases in tumor size by RECIST. Overall, 19 patients have had SD and 5 have had PD as the best response. With a median follow-up of 8.3 months and 17 patients still active, the median PFS is 6.9 months, and 23 patients (77%) are still alive. 26 of 30 evaluable patients have been wild type for BRAF-V600E/K mutations. Conclusions: Axitinib followed by carboplatin and paclitaxel has been well tolerated and effective in a largely BRAF wild-type metastatic melanoma population. Given the urgent need for effective therapies in this population, this regimen warrants phase III testing.

e14666 Background: Localized esophageal adenocarcinoma is usually treated with multi-modality therapy, i.e., chemotherapy or chemoradiotherapy (CRT) followed by surgery. Standard treatment for localized squamous cell carcinoma is controversial as definitive CRT can offer the same overall survival as CRT followed by surgery. Cisplatin and infusional 5FU is the accepted chemotherapy in combination with RT. However this regimen is cumbersome to administer and is associated with significant toxicities. Based on recent data combining weekly paclitaxel with radiotherapy in both the neoadjuvant and definitive settings we report our early experience with this regimen. Methods: All patients (pts) were staged with CT, EUS and PET/CT. Pts with localized, operable or inoperable disease were included. CRT consisted of paclitaxel 50mg/m2 and carboplatin AUC = 2 on days 1, 8, 15, 22, 29, 35 with concurrent RT (5 days/wk, 41.4-50.4Gy). Results: From December 2010 to January 2012, 24 pts: male/female 20/4, median age 67 yrs (29-88), adeno/squamous carcinoma 14/10, lymph node involvement (21pts) were treated. 13 pts treated with neoadjuvant (NA) intent, 11 pts underwent definitive CRT. In the NA group grade 3/4 toxicities were non-hematologic: cardiac (1pt), fatigue (1pt), 2 pts died from progression of disease prior to surgery. Eight pts have undergone surgery (3 awaited). RO resection rate 87.5%, 1 pt had a pCR, 4 pts had a near pCR. At 3mth follow-up 3 pts had no clinical or radiological evidence of disease, 5 pts await repeat imaging. In the definitive group grade 3/4 toxicities included hematologic: neutropenic fever (1pt), non-hematologic: esophagitis (3pts). At 3mth follow-up 7 pts have stable disease, 4 pts await repeat imaging. Dysphagia improved in 21 pts, worsened in 3 pts, and 5 pts required a feeding tube (4 prior to CRT). Conclusions: Carboplatin and paclitaxel combined with radiotherapy is a tolerable regimen in either the neo-adjuvant or definitive setting for locally advanced esophageal cancer. Rates of toxicity compare favorably to standard cisplatin and infusional 5FU. Prospective data with long-term follow-up using this regimen have been reported in the neo-adjuvant setting and are awaited in the definitive setting.

10625 Background: The identification of resistance mechanisms for conventional chemotherapy in lung cancer is of fundamental importance not only for personalization of chemotherapy but also for the subsequent development of novel targeted approaches to overcome this resistance. Currently, there is no clinically validated test for the prediction of response to tubulin-targeted agents in NSCLC. Our previous preclinical work identified Checkpoint with Forkhead and Ringfinger domain” (CHFR) as a predictor of taxane cytotoxicity in in vitro models. The current work assessed the translational significance of this finding in a cohort of US veterans treated at a single-institution. Methods: We studied a cohort of patients with advanced NSCLC treated with taxane-containing frontline regimens at the Atlanta VA Medical Center between 2000 and 2009. Archived paraffin-embedded tissue was retrieved and stained for CHFR expression using standard immunohistochemical techniques. Level of protein expression was assessed by light microscopy and scored for intensity of CHFR staining. Intensity of staining was correlated with clinical outcome including objective response and median overall survival using Chi-Square test and Cox proportional models. Results: We analyzed tumor samples from 45 eligible patients with median age 62.6 years, M/F (44/1). In this cohort, high expression of CHFR is strongly associated with adverse outcomes: the risk for progressive disease (PD) after first-line chemotherapy with carboplatin-paclitaxel was 54% in patients with CHFR-high vs. only 18% in those with CHFR-low tumors (HR 3.1; 95% CI 1.09-9.04; p=0.02). Median overall survival was strongly correlated with response to first-line therapy (clinical benefit: 9.24 months; PD: 4.7 months; p

7549 Background: MONET1 evaluated overall survival (OS) in patients (pts) with nonsquamous NSCLC receiving motesanib (an oral VEGFR 1, 2 and 3, PDGFR and Kit inhibitor) plus C/P compared with pts receiving placebo plus C/P. Analysis of the total population (N=1090) showed that motesanib + C/P did not significantly improve OS vs C/P alone (primary endpoint). Here we present results of a subgroup analysis of Asian pts. Methods: Asian pts (Japan, S. Korea, Philippines, Hong Kong, Taiwan, Singapore) with stage IIIB/IV or recurrent nonsquamous NSCLC and no prior systemic therapy for advanced NSCLC were analysed. Pts were randomized to up to six 3-wk cycles of C (AUC 6 mg/mL·min) and P (200 mg/m2) with either motesanib 125 mg QD (Arm A) or placebo QD (Arm B) orally continuously. Results: 227 Asian pts (incl. 106 Japanese pts) with nonsquamous NSCLC were randomized (Arm A/B, n=110/117); 198 had adenocarcinoma (n=97/101). Median age was 60 y (range 30–78); 80% had stage IV disease. At the time of analysis, 139 pts had died (118 pts with adenocarcinoma). Pts received a median of 164 days of motesanib vs 125 days of placebo (vs 106 and 126 days in non-Asian pts). Median follow-up was 63 wks. Efficacy results are shown in the table. Motesanib/placebo-related AEs were seen in 94/74% of pts respectively; Gr ≥3 related AEs in 48/22%. Most common emergent AEs were (Arm A/B) alopecia (78/76%), diarrhea (63/33%), and nausea (55/43%); gallbladder disorders (Gr 1–2) were seen in 9/2% of pts. Gr ≥3 AEs more frequent in Arm A vs B included neutropenia (36/22%) and hypertension (13/3%). Emergent Gr 5 events were seen in (Arm A/B) 5/4% vs 16/11% in non-Asian pts. Conclusions: In contrast to non-Asian pts, in the subgroup of Asian pts with advanced nonsquamous NSCLC, motesanib plus C/P treatment was associated with increased OS, PFS, and objective response rates (ORR) compared with C/P alone, with no excess of treatment-related mortality. [Table: see text]

e14712 Background: Esophageal and gastroesophageal junction (GEJ) adenocarcinoma is increasingly treated with trimodality therapy. We present our experience using carboplatin/paclitaxel and radiotherapy followed by surgery. Methods: Consecutive patients with distal esophageal/GEJ adenocarcinoma (≥T2 or N+) treated from July 2010 to October 2011 were identified. All patients received neoadjuvant carboplatin/paclitaxel with concurrent radiotherapy (CRT) to 50.4 Gy using an IMRT technique and then Ivor Lewis esophagogastrectomy. PET/CT was performed prior to and after CRT. Patient/treatment characteristics and tumor response were analyzed. Results: Over this timeframe,17 patients completed trimodality therapy using this regimen. All were male with a median age of 59 years (45-72). All tumors were grade 2-3 adenocarcinoma with mean tumor length of 4.4 cm (1-9). A median of 6 cycles (5-9) neoadjuvant carboplatin/paclitaxel were administered, 3 patients received additional adjuvant therapy. Average time from diagnosis to CRT completion was 78 days (44-141) and from CRT end to surgery was 62 days (35-92). Neoadjuvant CRT was well tolerated with mean weight loss of 3.5 kg. All pts had R0 resections. No anastomotic leaks or perioperative mortality occurred. Mean hospital stay was 13.6 days (8-28). Pathologic complete response (pCR) was seen in 41% of patients, microscopic residual disease (isolated tumor cells or

7521 Background: First-line EGFR-TKI in advanced BAC yielded a 2.9 to 4-month PFS in Phase II trials. We have suggested that EGFR-TKI had a reduced activity in M-BAC but that C/P and pemetrexed cou...

7063 Background: The addition of gemcitabine (G) to doublet chemotherapy with carboplatin (C) and paclitaxel (P) has demonstrated to improve clinical outcome of advanced stage IIIB and IV NSCLC in ...

8528 Background: Axitinib is a potent inhibitor of VEGFR, PDGFR, and c-Kit with impressive single agent activity in advanced melanoma. We tested the hypothesis that axitinib may increase the effect...

TPS218 Background: In ECOG 4599, bevacizumab was continued as maintenance therapy following 6 cycles of PCB. This study led to the approval of PCB followed by B for first-line treatment of advanced non-squamous NSCLC by the FDA. Switch maintenance therapy with Pm has recently demonstrated survival benefit for non-squamous NSCLC. Therefore ECOG 5508 will compare the efficacy of continuation of B vs. switch to Pm or the BPm combination after 4 cycles of PCB. Methods: The primary objective is to compare OS with B, Pm or BPm as maintenance therapy in pts with advanced stage NSCLC. Secondary objectives include PFS, response, toxicity and correlative studies focusing on polymorphisms, population pharmacokinetics and expression levels association with these outcomes. Eligibility criteria: ECOG PS 0 or 1 and adequate hematologic, renal and hepatic function, no brain metastases. All eligible pts receive PC (200 mg/m2, AUC=6 on day 1 every 3 wks) + B 15mg/kg day 1 (PCB) every 3 weeks. After 4 cycles pts with CR/PR/...

5083 Background: Weekly paclitaxel (wP) with 3 weekly or weekly carboplatin (wC) are the most active regimens in serous gynaecological cancers (Van der Berg 2009, Katsuma 2009). wCP has also been s...

7008 Background: CALGB 9633 randomized surgically resected stage IB NSCLC patients to carboplatin/paclitaxel (CP) or observation (OBS). A retrospective assessment suggested a survival benefit in patietns with tumors > 4.0 cm in size (G. Strauss JCO 2008). KRAS mutations were associated with lack of benefit from adjuvant chemotherapy in the JBR.10 trial. The impact of KRAS mutations on outcome in CALGB 9633 was evaluated. Methods: Pretreatment tumor specimens from CALGB 9633 were evaluated for presence of KRAS (codons 12, 13, 61) mutations using mass spectrometry. Outcomes based on presence/absence of KRAS mutations were evaluated. Results: Tumor specimens were available for KRAS genotyping from 267/344 (78%) patients (CP: 139; OBS: 128). KRAS mutations were detected in 71 (27%) of all KRAS evaluable patients: CP: 35 pts (25%); OBS 36 pts (28%). KRAS mutations were more common in adenocarcinomas vs. non-adeno (41% vs. 11%; p < 0.0001) and in ≥ 4.0 cm vs. < 4 cm (32% vs. 18%; p = 0.0144). 5 yr OS (90% CI) f...

7503 Background: EGFR kinase inhibitors are effective in never-smokers with NSCLC especially in those harboring EGFR mutations. In a prior phase III study (TRIBUTE) ECP was associated with improved RR, PFS, and OS compared to CP but only in never-smokers. CALGB 30406 prospectively evaluated E and ECP in never/light former smokers with chemotherapy-naive advanced lung adenoca and evaluated the impact of EGFR mutations on outcome. Methods: Chemotherapy-naive, never, or light former (≤ 10 pack years, > 1 yr since cessation) smokers, with advanced lung adenoca were randomized to E alone (150 mg/day) or ECP (E 150 mg/day given continuously; C [AUC = 6] and P (200 mg/m2) both q21 days) for 6 cycles followed by E. Primary endpoint was PFS in both arms. Collection of pretreatment tumor for assessment of EGFR mutations was mandatory. Results: Between 8/05 and 4/09 188 pts were accrued; 182 pts randomized (E=82; ECp=100) and treated. Baseline characteristics (E/ECP) were well balanced: Female: 61%/58%; Caucasian: 7...

3080 Background: Reolysin is an isolate of reovirus, a RNA virus which replicates in cells with activated Ras signaling pathway while sparing normal cells. We conducted a phase I/II dose escalation...

5518 Background: Reirradiation (ReRT) with concurrent chemotherapy is a radical but potentially curative treatment modality for locally recurrent, non-metastatic SCCHN. ReRT studies commonly use sp...

e18089 Background: Motesanib is an orally administered small-molecule antagonist of VEGF receptors (1, 2, and 3), PDGF, and c-kit receptors with antiangiogenic and direct antitumor activity. A drug...

8041^ Background: The IRESSA Pan Asia Study (IPASS) demonstrated superiority of G vs C/P for progression-free survival (PFS) in 1,217 chemonaïve, never/light ex-smokers with WHO PS 0–2, adenocarcinoma histology and stage IIIB/IV NSCLC. PFS favored C/P initially then G, likely driven by different outcomes according to EGFR mutation (M) status. Planned analyses of pts recruited in China are reported. Methods: 372 pts in China (31% of overall population) were randomized to G 250 mg/day (n=184) or C (AUC 5 or 6)/P (200 mg/m2) (n=188). Primary objective was to assess PFS in ITT population; a treatment by country interaction test (China vs other) was performed. Secondary endpoints were overall survival (OS), objective response rate (ORR, RECIST), QoL (FACT-L, TOI), symptom improvement (LCS) and tolerability. Results: PFS results for pts in China did not significantly differ from other pts (interaction test p=0.4265). G demonstrated numerically longer PFS vs C/P; effect was not constant over time, favoring C/P initially then G. Preliminary OS (28% maturity; follow-up ongoing) was similar for G and C/P. ORR was significantly higher with G (45%) than C/P (30%). QoL improvement rates were higher with G than C/P (FACT-L 44 vs 34%; TOI 45 vs 25%); symptom improvement rates were similar (LCS 48 vs 42%). G had a more favorable tolerability profile than C/P. Conclusions: For pts in China, efficacy and tolerability data were generally consistent with the overall population. G demonstrated improved efficacy (PFS and ORR), similar OS, higher QoL and similar symptom improvement rates and more favorable tolerability profile compared with C/P in chemonaïve, never/light ex-smokers with advanced NSCLC and adenocarcinoma histology. In IPASS, EGFR mutation status appeared to be a strong predictive biomarker for G efficacy compared with C/P. [Table: see text] [Table: see text] ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519–521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .

8015 Background: Cetuximab (CX) plus platinum-based chemotherapy improves overall survival (OS) in advanced NSCLC (FLEX). SWOG previously showed that EGFR FISH is associated with efficacy outcomes in patients (pts) receiving CB/P/CX (S0342). Bevacizumab (B) plus chemotherapy also increases survival (E4599) in eligible pts. Given the biologic rationale for combining EGFR and VEGFR targeted agents, S0536 investigated the safety and efficacy of carboplatin (CB), paclitaxel (P) and CX plus B. Methods: Eligibility: treatment-naïve advanced stage non-squamous cell NSCLC, no requirement for EGFR positivity, PS 0–1, no brain metastases or hemoptysis. Treatment: CB AUC 6, P 200 mg/m2, B 15 mg/kg IV day 1 every 3 weeks, CX 400 mg/m2 day 1 then 250 mg/m2 weekly for up to 6 cycles; then B 15 mg/kg every 3 weeks and CX 250 mg/m2 weekly until progression. Primary endpoint: feasibility defined by the frequency and severity of ≥grade 4 hemorrhagic toxicities. Secondary endpoints: response rate, progression-free survival (PFS), OS and toxicity. Results: 110 pts enrolled from August 2006 to September 2007; 104 assessable. Pt characteristics: median age 64 years (42–78), Male/Female 52/52, PS 0/1 43/61, stage IIIB/IV 9/95, adenocarcinoma: 81, current/former smoker: 82. Overall toxicities were acceptable and comparable to S0342 and E4599. Primary endpoint was met: grade ≥4 hemorrhage: 2% (95% CI: 0–7%). There were 4 treatment-related deaths: lung hemorrhage (2), infection (1), unknown (1). Partial response (PR): 51/95 assessable (54%; 43%-64%); Stable disease (SD): 22/95 (23%). Disease control rate (PR+SD): 77%. With median follow up of 15 months (mos), PFS is 7 mos (18 pts remain progression-free) and OS is 14 mos. 1 year survival is 57% (47–67%). EGFR IHC by H score (>0 vs 0) showed a nonsignificant trend toward improved survival: 15 vs 11 mos (p=0.14). Conclusions: CB/P, CX plus B demonstrates safety, tolerability and efficacy in advanced NSCLC and is the most active regimen studied to date in SWOG. Additional S0536 biomarker studies including EGFR FISH will be presented. S0819, a Phase III trial of CB/P ± CX (plus B in eligible pts) is under development and is designed to validate EGFR FISH as a predictive biomarker. [Table: see text]

7560 Background: Recent studies have demonstrated that adjuvant chemotherapy provides a survival benefit in patients with resected NSCLC. In Japan, uracil-tegafur has been recognized as a standard adjuvant strategy for resected NSCLC, however, carboplatin based adjuvant chemotherapy has not been fully evaluated for the treatment of NSCLC patients in an adjuvant setting. The present phase III study assessed the efficacy and safety of carboplatin/paclitaxel and oral uracil-tegafur as the first study to compare intravenous and oral drugs in resected stage IB-IIIA NSCLC. Methods: The patients with pathological stage IB-IIIA NSCLC who underwent complete resection were randomized 1:1 to carboplatin (AUC 5) /paclitaxel (175 mg/m2) every 3 week for 4 cycles (A arm) or uracil-tegafur (250 mg/m2) daily for 2 years (B arm). The primary endpoint was overall survival (OS) and secondary endpoints were disease-free survival and toxicity. The accrual of 200 patients per arm is required to demonstrate an improvement of OS (15% increase) in the A arm compared to B arm. Randomization was stratified by histology and tumor stage. An interim analysis was planned to perform on the first 200 patients recruited and data of survival and toxicity were examined in the first 100 patients. Results: Between November 2004 and November 2008, 200 patients from 31 Japanese centers were randomized and the first 100 patients were included for interim analysis. Median age was 69 (range; 50–80) years. Ninety-eight patients had PS of 0–1 and 2 patients had PS of 2. Sixty-seven patients were male and 23 patients were female. Sixty patients had adenocarcinoma, 30 had squamous cell carcinoma, and 10 had other histologies. Disease stage was IB in 53, IIA in 14, IIB in 19, and IIIA in 14 patients. Toxicities observed during adjuvant chemotherapy were well tolerable. There was no toxic death. The median survival time of A and B arms combined was 4.1 year. Monitoring Committees approved to continue the present study. Conclusions: The present phase III trial with carboplatin/paclitaxel or uracil-tegafur is feasible with manageable toxicity. The study is on course to achieve its primary endpoint. [Table: see text]

7503 Background: Thalidomide (T) is an oral angiogenesis inhibitor with anti-tumor activity in hematological malignancies. Given that antiangiogenic drugs such as bevacizumab have proven activity in advanced NSCLC, ECOG conducted a phase III study to compare the effects of the addition of thalidomide to paclitaxel/carboplatin/radiation therapy (PC/RT) on overall survival (OS) in pts with newly diagnosed stage III NSCLC. Secondary endpoints included time to progression (PFS) and toxicity. Methods: Pts were required to have inoperable stage IIIA or IIIB (no pleural effusion) NSCLC and a PS of 0 or 1. Pts were randomized to receive 2 cycles of P (225 mg/m2)+ C (AUC=6) every 3 wks or PC + thalidomide starting at 200 mg daily with the possibility of dose escalation. This was followed by weekly C (AUC=2), P (45 mg/m2) and concurrent RT (60 Gy) ± T. Pts on PC/RT + T continued thalidomide for 24 mo. or until disease progression. Results: 277 eligible pts were randomized to PC/RT and 272 pts to PC/RT + T. Median age was 63; 61% of pts had stage IIIB disease, 35% had squamous histology, and 46% were PS 0. The third planned interim analysis was conducted with 403 of 506 planned deaths (73.9%) for full analysis and the trial was stopped early by the ECOG Data Monitoring Committee for futility. The median overall survival for the no T arm was 15.3 mo. (12.4–20.2 mo.) compared to 16.0 mo for the T arm (14.4–18.3 mo.); hazard ratio = 0.985 (0.81–1.19); p = 0.88. Median PFS for the no T arm was 7.6 mo. (6.6–8.7 mo.) compared to 8.0 mo. for the T arm (7.1–9.1 mo.), p>0.05. The most common toxicity on both arms was myelosuppression. 11% of pts on the T arm had a grade 3–5 thrombosis/embolism, compared to [Table: see text]

e20667 Background: Eltrombopag is an oral, small molecule, non-peptide, TPO-receptor agonist studied for the treatment of thrombocytopenia (TCP) due to various causes, including chemotherapy (CT)-induced TCP and is approved for the treatment of chronic ITP in the US. Since eltrombopag is excreted primarily through the liver and liver function is an important safety parameter, HB lab values and AEs were analyzed in a double-blind, placebo (pbo)-controlled, multicenter ph II study. Methods: The safety of eltrombopag was evaluated in adults with advanced solid tumors (mainly NSCLC and ovarian). Pts received up to 8 cycles of Carb (AUC 5–6 IV) + Pac (175–225 mg/m2 IV), both administered on day 1 q 21 days. 183 pts were randomized to eltrombopag 50, 75, 100mg, or pbo (1:1:1:1). Eltrombopag or pbo were taken from Day 2 - 11 in each cycle of CT. Results: Baseline characteristics, prior medical conditions and number of CT cycles during the study were similar between the treatment groups. At baseline, one pt reported liver metastases (75mg group). Similar numbers of pts had HB lab abnormalities in all groups ( table ). Additionally, HB AEs (34 AEs) occurred in 15 pts across all treatment groups ( table ). Conclusions: In this study, eltrombopag did not increase the incidence of HB AEs or HB lab abnormalities compared to pbo. [Table: see text] [Table: see text]

9596 Background: A randomized phase II trial (JCO 26:5407–15, 2008) compared carboplatin-paclitaxel (CP) with vandetanib (VEGFR-EGFR inhibitor) monotherapy (V) and V plus CP (VCP) 1st-line for advanced NSCLC (N=181). PFS was superior for VCP vs CP (HR 0.76). We performed analyses of quality of life (QOL) and its correlations with plasma concentrations of cytokines and angiogenic factors (CAF) among the participants in this trial. Methods: QOL was serially measured by Functional Assessment of Cancer Therapy-Lung (FACT-L) and Trial Outcome Index (TOI) scores. Concentrations of 35 plasma CAFs were measured at baseline and multiple timepoints during treatment with multiplexed bead suspension arrays and ELISAs. We performed exploratory analyses for the following associations: (1) QOL with plasma CAF levels at baseline; (2) changes in QOL with changes in plasma CAF levels. Spearman correlation coefficient, log-rank test and mixed linear models were applied in the analyses. P-value < 0.05 was considered significant. Results: Baseline QOL and plasma samples were both available for 120 patients. Lower baseline FACT-L scores (inferior QOL) were associated with higher pre-treatment plasma levels of INF-γ, IL-1RA, IL-6, IL-12, IL-15, TNF-α, RANTES, MIG, MIP-1β, MMP-9, bFGF, VEGF and sVEGFR-2 (all P [Table: see text]

19113 Background: Combination chemotherapies have demonstrated response rate (RR) of 30–50% with median survival of only approx 10 months for patients with stage IIIB/ IV NSCLC. Therefore it is imp...

6032 Background: Our goal was to evaluate long-term outcomes of patients with squamous cell carcinoma of the head and neck (SCCHN) treated with carboplatin, paclitaxel, and radiotherapy. Methods: We conducted a phase II trial in inoperable patients with locally advanced SCCHN. Carboplatin 100 mg/m2 and paclitaxel 40 mg/m2 were administered intravenously once a week during external beam radiotherapy (once daily, 180 cGy/fraction) for 6–7 weeks. Interstitial brachytherapy was used as a boost in selected patients with primary malignancies of the oral cavity and the oropharynx. Results: 55 patients were enrolled. 52 patients (95%) had stage IV and 51 (93%) had technically unresectable disease; 62% had an oropharyngeal primary site. 21 patients underwent brachytherapy boost. Grade 3 or 4 mucositis occurred in 30% of patients. One death occurred during treatment; it was related to complications of gastrostomy tube (G-tube) placement. Forty of 50 evaluable patients (80%) had an objective response, with a complete response rate of 52%. With a median follow-up of 69 months years for surviving patients, the 5-year progression-free survival (PFS) was 36% and the 5-year overall survival (OS) was 35%. Two of the 18 long-term survivors of >50 months were G-tube feeding dependent. Patients undergoing brachytherapy boost (n=21) had similar outcomes compared with the rest of the patients. In multivariate analysis, baseline hemoglobin levels and N stage were predictive of survival. Conclusion: Treatment with concurrent carboplatin, paclitaxel and radiation is safe and offers curative potential for poor prognosis patients with locally advanced SCCHN. No significant financial relationships to disclose.

18205 Background: Triple drug chemotherapy combinations for nonsmall cell lung cancer (NSCLC) have most recently begun to show promising results in regards to response rate and time to progression (TTP) of disease. This abstract presents data from 99 patients with advanced unresectable disease who were not felt to be candidates for concurrent radiation and chemotherapy for 1999 to 2005 treated with a split dose regimen of paclitaxel 65mg/m2 (d1, 8,15 q29 days), carboplatin AUC 2 (d1, 8,15 q29days), and gemcitabine 650 mb/m2 (d1, 8 or15 q29 days). All patients have completed a minimum of 3 courses of therapy. Methods: 57 males with mean age 72 years, and 42 females, mean age of 69 yrs with performance status of < 1. Stage III A&B-33 patients and Stage IV-56 patients. The regimen was well tolerated with 4% grade 3 to 4 neutropenia, 30% 2-to3 thrombocytopenia. There were no septic deaths, grade 3 to 4 nonhematologic toxicity included alopecia, universally, fatigue at 24% and emesis at 8%. Results: CR-14.4%, PR-31%, minimal/stable-26% with 27.6% progressive/resistant disease with a median survival time of 20.5 months. 37 patients did receive radiation therapy to the primary lesion. Conclusions: This 3-drug regimen administered in split dosing has proven to be highly active and well tolerated in good performance status patients seen in a community practice setting. This cohort of patients was representative and typical for the 85% of patients seen in community oncology practices. No significant financial relationships to disclose.

3024 Background: Chemotherapy (C) induced bone marrow suppression has been assumed to inhibit the generation of augmented immune responses. This has limited investigation of front-line C-IT in OC. Temporal relationship of IT administration relative to C has not been established. Oregovomab is a CA125 specific MAb in development as an OC adjuvant treatment to induce tumor specific immunity. Methods: Patients (pts) awaiting staging laparotomy for presumptive OC were consented to the study and contributed primary tumor samples. Qualifying pts were subsequently randomized to concurrent C-IT with antibody administered at cycles 1, 3, and 5 (Arm A) or 8 ± 2 days following cycles 1, 3, and 5 (Arm B) of standard C-P. Both arms received additional infusions of oregovomab every 12 weeks until progression; response to C-IT was assessed at 36 weeks. Results: Forty stage III/IV pts (18 Arm A; 22 Arm B) were randomized and dosed. More pts in Arm A (39%) were stage IV vs Arm B (14%) however 27% of Arm B pts had >2cm residual disease vs. 11% in Arm A. Complete clinical response (CR) to surgery and C-IT was achieved in 15 pts (83%) in Arm A and 17 pts (77%) in Arm B. For pts with = 2 cm residual disease, 88% in Arm A had = 65 U/mL CA125 prior to/at cycle 3, normalized CA125 and a CR post C-IT compared to 75% of pts in Arm B. Robust Ab2 antibody response (>100 ng/mL) was achieved in 94% of Arm A and 68% of Arm B pts. The immune response developed earlier in Arm A. After one injection of oregovomab, 31% of pts in Arm A vs. 0% in Arm B generated HAMA > 3000 ng/mL and Ab2 > 100 ng/mL (P=0.016 Fisher’s Exact Test). Such an early and vigorous response pattern has not been seen in previous oregovomab studies which have not included concomitant front-line C. There were no IT related serious adverse events. Conclusions: Contrary to expectations, concurrent C-P resulted in enhanced immune stimulation with oregovomab. Interestingly, concurrent infusion of oregovomab was more immunogenic than delayed infusion. Clinical activity was favorable and safety profiles were similar to that expected for C alone. Further randomized evaluation of front-line CP-oregovomab vs CP is warranted. [Table: see text]

7586 Background: Cetuximab, an IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) on both normal and tumor cells, has been investigated in advanced NSCLC as a single agent and in combination with chemotherapy. This ongoing randomized phase II open-label trial evaluates cetuximab in combination with carboplatin (Cb) and paclitaxel (Pac) when given in two dose schedules to patients (pts) with previously untreated stage IIIB/IV NSCLC. Methods: Eligible pts were randomized to 1 of 2 treatment arms. Cetuximab treatment was identical in both arms: 400 mg/m2 IV on day 1 and 250 mg/m2 weekly thereafter. Beginning on day 8, a schedule of Cb AUC=6 IV and Pac 225 mg/m2 IV given on a 3-week cycle was compared with a schedule of Cb AUC=6 IV q4 weeks and Pac 100 mg/m2 IV given weekly for 3 weeks of each 4-week cycle. Pts who achieve CR, PR, or SD after 4 cycles may continue weekly cetuximab monotherapy until disease progression or unacceptable toxicity. The primary objectives were to estimate median progression-free survival (PFS) and the PFS rate at 6 months. Secondary objectives included response rate. Results: The study has completed accrual, with 168 pts randomized and 165 treated. Data are available for 164 pts and confirmed responses for 155 pts. Conclusions: Cetuximab combined with Cb and Pac in both dose schedules demonstrated activity and an acceptable toxicity profile in pts with NSCLC. Final PFS and overall survival data are pending. No significant financial relationships to disclose. [Table: see text]

18123 Background: Concurrent chemoradiotherapy is standard of care for unresectable patients and the most widely cited trials include the locally advanced multi-modality protocol (LAMP) study, SWOG S9019 and S9504. Our institutional approach represents a merger between the protocols utilized in two of these phase II studies: chemoradiotherapy from the LAMP study and consolidation therapy from SWOG S9504. Methods: We identified all stage III patients treated at the NF/SG VHS from Jan 2001 to Dec 2005. Eligible patients who had unresectable stage III NSCLC were included in the analysis. We treated 34 patients with weekly paclitaxel 45 mg/m2 plus carboplatin AUC 2 and concurrent TRT 63.0 Gy over 7 weeks. Four weeks after the completion of chemoradiotherapy, docetaxel 75 mg/m2 was given every 3 weeks for 21 days for 3 cycles as consolidation. Our primary endpoints were overall and progression free survival. The secondary endpoints were response rate and toxicity. Results: With a median age of 65 years and follow-up time of 25.9 months, median overall survival was 13.7 mos. Median progression free survival was 9.8 mos. The overall response rate was 68% including 5 CRs (15%). The most common grade 3/4 toxicities included pneumonitis (21%), esophagitis (21%), neutropenia (21%) [febrile neutropenia (9%)], neuropathy (18%), anemia (15%) and hypersensitivity to paclitaxel (9%). 62% of patients were able to complete the planned treatment. There were no treatment related deaths. At the time of this analysis, 9 patients were alive (26%) including 7 without progression (21%). Conclusions: Chemoradiotherapy with weekly carboplatin and paclitaxel followed by consolidation therapy with docetaxel is associated with comparable outcomes to other combined modality regimens. Given the advanced age and co-morbidities of our population, this regimen was generally well tolerated with the expected toxicities and can be considered as an option in the treatment of patients with unresectable stage III NSCLC. No significant financial relationships to disclose.

7119 Introduction: AMG 706 is an investigational, oral, multi-kinase inhibitor with both antiangiogenic and direct antitumor activity targeting VEGF, PDGF, and Kit receptors. Panitumumab, a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFr), has shown antitumor activity and acceptable safety in pts with solid tumors. Methods: This is an ongoing, multicenter, dose finding, phase 1b study of AMG 706 with panitumumab and CP in pts with advanced NSCLC. Primary objectives were to assess the safety and PK of AMG 706; secondary objectives included drug exposure and objective response rates. Pts had stage IIIB/IV NSCLC, ECOG score of 0–1, no symptomatic or untreated CNS metastases, and no prior chemotherapy for NSCLC (segments A&C) or ≤ 1 regimen for NSCLC (segment B). AMG 706 was given orally either QD (50 mg or 125 mg) or BID (75 mg) with CP Q3W (P:200 mg/m2; C: AUC = 6 mg/mL · min; Segment A), with panitumumab (9.0 mg/kg Q3W; Segment B), or with CP+ panitumumab (Segment C). AMG 706 was dosed continuously in 21-day cycles (days 3–21 in cycle 1; days 1–21 in cycle 2 and beyond); pts were sequentially enrolled into escalating AMG 706 dose cohorts. Results: As of 9/05, 22 pts were enrolled (10 in A, 12 in B) into AMG 706 dose cohorts of 50 mg and 125 mg QD. In A and B, respectively, 7 and 6 pts were men; median (range) age was 60.5 (60, 74) and 60.5 (55.7, 71.0). One pt in the 125 mg QD cohort in Segment B had grade (gr) 5 pneumonia. Treatment-related adverse events occurring in >5% of all patients are summarized ( table ). Preliminary data showed that AMG 706 PK profiles were similar when administered with CP either 30 min or 48 hrs apart. At 50 mg QD, there was no effect of AMG 706 on the PK of P. Conclusions: Preliminary data indicate that AMG 706 can be combined safely with CP or panitumumab in pts with advanced NSCLC and that there is no effect on the PK of AMG 706 or P. Updated data will be presented. [Table: see text] [Table: see text]

17070 Background: Bexarotene (bex) is a subclass specific, synthetic rexinoid analogue, that preferentially binds and modulates the expression of RXR subclass of receptors α, β, and γ. It induces concentration-dependent repression of multiple genes (cyclin D1/D3, total EGFR, pEGFR) inhibiting cell growth, angiogenesis, invasion and metastasis, inducing differentiation, and apoptosis in tumor cells. Several phase-I/II trials suggested increased survival in patients with advanced NSCLC. Methods: Stage-IIIB with pleural effusion & Stage-IV chemo-naïve patients, ECOG 0–2, were enrolled and treated with carboplatin IV AUC-6 d-1 and paclitaxel IV 100 mg/m2 d-1, 8, 15, every 28-d for 4 cycles. Pts were randomized using a 1:1 design to bex PO 400 mg/m2/d either concurrent (C) from Day 1 or sequential (S) at the completion of chemo, for up to a year. Results: 56 patients were enrolled; median age 62.3 (range 41–86), 48 TNM Stage IV, 38 males, 50 ECOG PS 0–1. Of 51 pts evaluable for response, 30 (58%) achieved PR (C: 15 and S: 15); 16 (31%) showed SD (C: 8 and S: 8), and 5 (9.5%) had PD (C: 3 and S: 2). Thirty-two (63%) patients have expired as of 12/31/05. Based on ITT, 40 evaluable pts showed a median TTP of 169 days (C: 166.5 and S 172); The MS for the entire group is 342 days (11.42 mo (C: 12.8 and S: 10.53). Currently, 10 pts are still alive between 407 to 1036 days from registration on the trial. The treatment was well tolerated; overall, AEs were reported in 48% of pts in the S arm and 51% in the C arm. The incidence of Gr 3–4 AEs, regardless of the treatment arm, was < 5%. There were no treatment-associated deaths. Conclusions: Our data suggests a better ORR, TTP, and improvement in MS, when bex is added to carboplatin/ paclitaxel, regardless of concurrent or sequential administration, compared with chemo alone. ORR was not compromised by bex administration and in fact it was above average reported for similar phase-II & -III studies. Toxicity is easily managed. [Table: see text]

5020 Background: Vascular endothelial growth factor (VEGF) is a major promoter of tumor angiogenesis. Bevacizumab is a recombinant humanized monoclonal antibody that neutralizes VEGF and is active in several tumor types, including epithelial ovarian cancer. Methods: We are conducting a phase II trial of carboplatin, paclitaxel and bevacizumab (CPB) in newly diagnosed patients with chemotherapy naïve, stage ≥ IC, epithelial ovarian, fallopian, primary peritoneal, or uterine papillary serous (UPSC) tumors. Patients receive carboplatin AUC of 5 IV, paclitaxel 175 mg/m2 IV, and bevacizumab 15 mg/kg IV for 6–8 cycles on a 21-day cycle. Bevacizumab is omitted in the first cycle, and continued for one year’s consolidation. Principle endpoints include response rate and progression free survival. Results: Since 3/05, 35 patients have been enrolled. Of the 30 evaluable patients, 24 have ovarian, 4 peritoneal, 1 fallopian tube cancer, and 1 UPSC (1 stage IIB, 22 stage III, and 7 stage IV), and median age is 57 (range 18–77). 133 cycles of chemotherapy have been administered with acceptable toxicity. Grade IV neutropenia has been seen in 3 cycles with 1 episode of febrile neutropenia. Grade I, II, and III HTN was observed in 1, 3, and 4 cycles, and grade I (42% hematuria 45% epistaxis) and II bleeding observed in 36 and 1 cycle(s), respectively. There has been 1 nasal perforation, 2 delayed wound healing, and no bowel perforation. 1 woman withdrew consent (for PMH diverticulitis), and 3 women have been removed for toxicity (1 autonomic neurotoxicity, 1 HTN, and 1 PE). To date, 13 patients have completed the chemotherapy phase of treatment, and only one patient has come off study for progression on consolidation bevacizumab. Conclusion: First line CBP is a highly active regimen that has been well tolerated thus far. Updated toxicity and response data will be available in the spring of 2006. [Table: see text]

7194 Background: The EGFR is often overexpressed in advanced non-small-cell lung cancer (NSCLC) - a solid tumor associated with a poor prognosis. Oncogenic k-ras mutations and raised serum VEGF predict poor outcome in NSCLC. In vitro targets of sorafenib include Raf, which is downstream of EGFR and k-ras. Sorafenib also targets the VEGFR-2/-3 tyrosine kinases, involved in tumor angiogenesis. Preclinically, sorafenib targets the tumor and tumor endothelium to inhibit tumor growth. Methods: This subanalysis of a Phase I trial with a Phase II expansion in NSCLC was performed to evaluate the safety (adverse events graded by NCI-CTC 2.0) and preliminary anti-tumor activity (response by RECIST, PFS, TTP) of oral sorafenib combined with carboplatin/paclitaxel in 15 patients with advanced, progressive NSCLC. Carboplatin (AUC 6)/paclitaxel (225 mg/m2) was administered on Day 1, and sorafenib (100, 200, or 400 mg bid) on Days 2–18 of each 21-day treatment cycle. Results: Drug-related adverse events were reported by 73% (11/15) of patients, but were mostly grade 1–2 (53%) in severity; none was grade 4. The most common drug-related events at any grade were dermatologic (Hand-foot skin reaction [20%]; rash [60%]), and gastrointestinal (diarrhea [20%]; anorexia [13%]). There were no drug-related cardiovascular adverse events. Three patients reported grade 1–2 drug-related bleeding events (epistaxis n = 2; other n = 1). Of the 14 evaluable patients, four (29%) had a confirmed PR as best response, seven (50%) had SD, and three (21%) had PD. Therefore, the disease control rate (objective response plus SD) was 79%. Duration of response was 25 weeks. Median PFS was 34 weeks. Discussion: This sorafenib combination was well tolerated and showed promising preliminary anti-tumor activity in patients with advanced, progressive NSCLC. [Table: see text]

17021 Background: NOV-002 is a proprietary formulation of oxidized glutathione that modulates production of cytokines and hematopoietic growth factors. A randomized, multi-site advanced NSCLC trial conducted in the Russian Federation showed a one-year survival rate of 63% with NOV-002 + cytotoxic chemotherapy compared to 17% with cytotoxic chemotherapy alone. Methods: Forty-four chemotherapy-naïve, Stage IIIB/IV NSCLC patients (ECOG 0–2, stratified by disease stage) were randomized to one of three groups for six months of treatment: Groups A and B: NOV-002 in combination with carboplatin and paclitaxel (C+P). For each nominal 21-day chemotherapy cycle, these groups received 60 mg of NOV-002 i.v. daily for the first 4 days, then 60 mg i.m. (A) or s.c. (B) weekdays for the next 17 days. Group C: C+P alone. Initial doses of C and P in all three groups were 225 mg/m2 and AUC 6, respectively. Initiation of repeat C+P cycles required an absence of hematologic and other toxicities in excess of pre-defined values. Primary study endpoints included tumor response (scans performed at baseline and then every two months) and safety. Results: An intent-to-treat analysis of the best overall objective tumor response (WHO criteria), showed that 11 out of 16 (69%) Group B patients demonstrated greater than 50% tumor shrinkage versus 5 out of 15 (33%) in the control group (C) (p = 0.044, logistic regression stratified on disease stage). Six out of 13 (46%) patients in Group A demonstrated an objective response. 100% of NOV-002 treated patients in Group B and 85% in Group A were able to complete four cycles of C+P compared to 50% of control patients (Group C) (p = 0.004, chi square). NOV-002 was well-tolerated in this patient population. Conclusions: These data continue to suggest increased efficacy of NOV-002 plus cytotoxic chemotherapy compared to chemotherapy alone in advanced NSCLC. [Table: see text]

R. Haddad, M. Posner, L. Wirth, S. Sonis, L. Goguen, C. Norris, C. Sullivan, L. Weeks, R. Costello, R. Tishler Medical Oncology, Dana Farber Cancer Institute, Boston, MA, Department of Oral Medicine Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, Division of Otolaryngology, Head and Neck Surgery, Brigham and Women’s Hospital, Boston, MA, Radiation Oncology, Dana Farber cancer Institute, Boston, MA