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5500 Background: IC is associated with lower distant failure (DF) rates in SCCHN but an improvement in overall survival (OS) has not been validated. The goal of this trial was to determine whether IC prior to chemoradiotherapy (CRT) improves survival compared to CRT alone. Methods: In this phase 3, open-label trial, subjects with pathologically confirmed SCCHN; N2/N3 disease without metastases; no prior therapy; KPS ³ 70%; and intact organ function were randomized to CRT alone (CRT arm) [5 days of D (25 mg/m2), F (600 mg/m2), hydroxyurea (500 mg BID), and RT (150 cGy BID) followed by a 9 day break] or to 2 cycles of IC [D (75 mg/m2), P (75 mg/m2), F (750 mg/m2 day 1-5)] followed by the same CRT (IC arm). Primary endpoint was OS. Secondary endpoints included DF free survival, failure pattern, and recurrence-free survival (RFS). 280 subjects provided 80% power to detect a hazard ratio HR=0.5 for OS (a=0.05). Results: 280 subjects were accrued from 2004-09 with minimum follow-up 24 months. Of 142 patients randomized to IC, 91% received 2 cycles and 87% continued to CRT. Treatment adherence during CRT was high for docetaxel and hydroxyurea, but fewer than 75% of the patients received target dose of 5FU in both arms. RT was delivered without major deviations in 94% and 95% of patients on IC and CRT arms, respectively. The most common grade 3-4 toxicities during IC were febrile neutropenia (9%) and mucositis (8%), and during CRT (both arms combined) they were mucositis (45%), dermatitis (19%), and leukopenia (17%). Only grade 3-4 leukopenia and neutropenia rates were significantly higher in IC (p=0.002 and p=0.02, respectively). Table shows efficacy. Conclusions: High survival rates were observed in both arms. Further analysis and follow-up may provide insight into why the significant decrease in DF did not translate into improved OS. [Table: see text]

Introduction: The Aurora kinases represent a family of serine/threonine kinases important in regulating cell cycle progression. Aurora-A is required for centrosome function and mitotic spindle assembly. Aurora-A phosphosphorylation supports the activity of many proteins involved in cell proliferation and survival, including important EGFR effectors such as AKT and RAS. High expression of Aurora A has been shown in patients with breast, lung, gastrointestinal, genitourinary, and gynecological cancers. The Aurora kinases are known to promote tumor formation and progression, which has led investigators to develop multiple inhibitors of Aurora kinases for clinical use. The expression of Aurora-A kinase in head and neck cancers is not well understood. We assessed the overall survival (OS) for a cohort of patients with squamous cell carcinoma of the head and neck (SCCHN) based upon Aurora-A and phospho-Aurora-A kinase expression (reflecting active Aurora-A). We also related this to SCCHN subtype, using p16 expression as a surrogate for human papillomavirus association, because of the recognition that p16 + cancers have far superior prognosis. Methods: Tumor tissue from 89 patients with SCCHN operated on at the Fox Chase Cancer Center was analyzed for Aurora-A and phospho-Aurora-A expression. Aurora kinase expression was determined using AQUATM, with the median values used to distinguish over-expressers. Aurora-A and phospho-Aurora-A expression was correlated with T and N stage and OS, in p16+ versus p16- tumors The p16 status was determined by immunohistochemistry. Results: T stage was inversely related to Aurora-A expression when adjusted for p16 status (Spearman's rho -0.24, p = 0.04). Aurora-A expression was not related to N stage (Spearman's rho -0.03, p = 0.79). OS was 36 months for over-expressers of Aurora-A and 92 months for patients with low levels of Aurora-A expression (HR 1.9, 95% CI 1.05-3.46). 20 patients were positive for p16 by IHC. There was no difference in survival amongst p16 positive patients based on Aurora-A expression (53.3 months vs 57.2 months, p = 0.679). Amongst the 69 p16 negative patients, OS was 93.6 months for patients with low levels of Aurora-A expression and 35.9 months for those with elevated levels of Aurora-A (HR 1.84, 95% CI 0.89-3.79). There was a trend towards improved survival in patients with lower levels of phospho-Aurora-A expression (63.9 vs 57.6 months, p = 0.129). Conclusions: Increased expression of Aurora-A in this cohort of SCCHN patients is associated with a significant decrease in OS. Increased expression of Aurora-A in patients with p16 positive tumors does not seem to impact survival, though the number of patients was small. Aurora-A represents a possible therapeutic target in patients with SCCHN. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 721. doi:1538-7445.AM2012-721

5563 Background: Conventional dosing of C (400 mg/m2 loading dose, 250 mg/m2 weekly) yields response rate of approximately 13% among pts with R/M HNSCC. Conventional weekly dosing of C may not satu...

7548 Background: The median age of newly diagnosed NSCLC patients (pts) in the US is 71 and more than 60% of newly diagnosed pts are 65 years of age or older. The ‘fit elderly’ (PS 0-1) derive the ...

e21173 Background: The tumor suppressor p16 is a biomarker for HPV-related head and neck squamous cell cancer, especially in patients (pts) without prior tobacco use. Retrospective analyses of NSCL...

5539 Background: We previously found that low nuclear ERCC1 measured by AQUA with the antibody (ab) 8F1 is associated with a higher survival (75.6 months) compared to high nuclear ERCC1 (28.4 month...

7066 Background: Stage IIIA NSCLC comprises a heterogenous group of tumors due to differences in primary tumor size and the size and location of nodal disease. The optimal therapeutic approach rema...

7067 Background: NSCLC patients (Pts) with T4 and/or N3 disease are categorized as stage IIIB NSCLC. Chemoradiation (CRT) is the standard of care for pts with dry (without malignant pleural effusio...

Introduction: We analyzed SCCHN archival tissue in order to determine if baseline ERCC1 levels as measured by AQUA is associated with prognosis, benefit from adjuvant treatment or T stage in patients with resectable SCCHN. Experimental Procedures: Tissue microarrays containing head and neck squamous cell carcinoma samples obtained from patients treated at Fox Chase Cancer Center from 1990-2002 were constructed. Slides were stained by a modified indirect immunofluorescence method. Sections were incubated with ERCC1 antibody (8F1, Lab Vision) and wide-spectrum screening rabbit cytokeratin antibody (Dako Z0622). Prolong Gold mounting medium (P36931; Molecular Probes) containing 4,6-Diamidino-2-phenylindole (DAPI) was used to define tissue nuclei. A binary image (tumor mask) was created from the cytokeratin image of each histospot. ERCC1 levels were measured using fluorescent immunohistochemistry on the HistoRx PM-2000 image analysis platform and the data analyzed using AQUA algorithms. The in situ biomarker profiling system generated quantitative measurements of patient protein levels based on AQUA scores derived from fluorescent output of labeled markers. Tumor mask, nuclear, and cytoplasmic ERCC1 expression were measured. Baseline demographic and prognostic information was compared using Student's t-test for continuous variable or Fisher's exact tests for categorical variable. Analysis for overall survival was performed using Kaplan-Meier method, with comparisons using the log-rank test. Cox proportional hazard models were also used to examine the effect of ERCC1 after adjusted for the pathological T stage. Results: Tissue was analyzed from 109 patients (70 male, 39 females). Primary sites included tongue (34), glottic (15), retromolar trigone (10), tonsil (5), pyriform sinus (3), oral cavity (36), other (6). 33 were treated with surgery. 76 received adjuvant radiation or platinum based chemoradiation. The ERCC1 expression by AQUA score was defined as high versus low at the 30th percentile (262.37 in nuclear compartment, 161.31 in cytoplasmic compartment, 361.09 in tumor mask). In the 33 patients treated with surgery alone, there was no association with ERCC1 status and survival. In this group, low ERCC1 levels in all 3 compartments was associated with a higher T stage and tumor size (p=0.05 in nuclear, p=0.003 in tumor mask, p=0.05 in cytoplasm). Among the 76 patients who received adjuvant radiation/chemoradiation, low ERCC1 measured in the nuclear compartment was associated an increased survival (p=0.02). Conclusions: Low nuclear ERCC1 expression as defined by AQUA score in SCCHN is associated with greater T stage and benefit to adjuvant therapy with radiation/chemoradiation. We are developing a study to guide treatment selection for recurrent/metastatic disease based on ERCC1 status. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2804.

Introduction: ERCC1 is a key enzyme in the nucleotide excision repair pathway and increased expression of ERCC1 is associated with cisplatin resistance in some cancers. Given the widespread use of platinum therapy for the treatment of SCCHN, we characterized the range of ERCC1 expression in SCCHN specimens using an immunofluorescence-based assay (automated quantitative analysis-tissue microarray [AQUA-TMA]). There is currently inadequate data regarding the range of ERCC1 expression in SCCHN, and how ERCC1 levels correlates with treatment outcomes, ERCC1 has been studied in SCCHN by standard immunohistochemistry, however, this method is limited by variability of techniques and subjectivity of interpretation, Therefore, there is a need for a highly quantitative technique which can be accomplished on formalin fixed paraffin embedded tissue and small samples, Our goal is to develop a reproducible assay that can eventually be incorporated into standard patient care practice. Methods: Tissue microarrays containing head and neck squamous cell carcinoma samples obtained from patients treated at Fox Chase Cancer Center from 1999–2006 were constructed. Slides were stained by a modified indirect immunofluorescence method. Sections were incubated with ERCC1 antibody (8F1, Lab Vision) and wide-spectrum screening rabbit cytokeratin antibody (Dako Z0622). Prolong Gold mounting medium (P36931; Molecular Probes) containing 4,6-Diamidino-2-phenylindole (DAPI) was used to define tissue nuclei. A binary image (tumor mask) was created from the cytokeratin image of each histospot. ERCC1 levels were measured using fluorescent immunohistochemistry on the HistoRx PM-2000 image analysis platform and the data analyzed using AQUA algorithms. The in situ biomarker profiling system generated quantitative measurements of patient protein levels based on AQUA scores derived from fluorescent output of labeled markers. Both nuclear and non-nuclear (i.e., non-membrane/cytoplasmic) ERCC1 expression was measured Results: 41 SCCHN specimens (24 oral cavity, 7 oropharynx, 5 glottic tumors, 3 unknown primary, 2 other) were analyzed. There were 25 males and 16 females and age at diagnosis ranged from 25 to 80 years (mean 64). The majority of patients were treated primarily by surgery. The range of AQUA scores was 33.66 to 1696.39 (mean 501.78, stnd deviation 284). The 25th percentile was 337.35, and the 75th percentile was 639.37. ERCC1 was predominantly nuclear (i.e., non-membrane/cytoplasmic) in the SCCHN tissue samples. Conclusions: 1) It is feasible to determine a quantitative value of ERCC1 expression with AQUA. 2) There is a wide range of ERCC1 expression in SCCHN. 3) ERCC1 is predominantly localized to the nuclear compartment. 4) Ongoing work is being done to correlate ERCC1 levels with clinical features, sensitivity to platinum therapy, and survival. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A126.

6052 Background: Unresectable/metastatic squamous cell cancer of the head and neck (SCCHN) has a poor prognosis despite standard therapy with cisplatin. Given the substantial toxicities of cisplatin and its widespread use in combination with RT in LA- SCCHN, we investigated an alternative regimen of gemcitabine (G) and pemetrexed (P). A phase II study of pemetrexed in SCCHN had a response rate (RR) of 26.5%. A phase I study of the P and G combination showed the doses and schedule below to be feasible. Methods: Eligibility stipulated measurable, incurable, unresectable recurrent/metastatic SCCHN; Karnofsky PS of > 60%, and adequate bone marrow, renal and hepatic function. One prior therapy for recurrent disease was allowed. Patients were treated with P 500 mg/m2 and G 1,500 mg/m2 every 2 weeks. Each cycle was 28 days. Primary endpoint was RR. Secondary endpoints included overall survival and toxicity. Patients were re-imaged every 2 cycles. In a 2-step design, 16 patients were to be accrued during stage 1, and 16 were projected for stage 2. If 1 or fewer responses were observed during the first stage, then the trial was to be stopped and the regimen deemed insufficiently active. Results: 17 patients were enrolled in stage 1. Median age was 64 years (range, 49–82); 10 males; 13 smokers (including 4 current smokers). 15 patients previously received definitive therapy with surgery and/or chemo-RT, and 9 had prior systemic therapy for recurrent/metastatic disease. Median number of cycles administered was 2 (range, [Table: see text]

2056 Background: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. With DPD deficiency, 5-FU is discontinued. Data regarding safety of capecitabine (CAP) in this population is scarce. Methods: Patients were tested for DPD deficiency after excessive toxicities from 5-FU and CAP at UAB between 2001 and 2005. DPD activity was evaluated by PBMC radio assay, genotyping of DPYD gene by DHPLC, or 2-13C uracil breath test (UraBT). Results: Of 23 patients with GI malignancies (small intestine, gastric, pancreatic, HCC, and colorectal) evaluated, 7 (30%) were DPD deficient. Among these 7 patients, DPD activity ranged from 0.064 - 0.18 nmol/min/mg. Age ranged from 51–75 years, M:F ratio = 1.3:1, and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). Four were treated with 5-FU/LV (2 Roswell; 2 Mayo); 2 CAP (1800mg/m2); and 2 high dose bolus 5-FU (1400mg/m2) + PN401 (tri-acetyluridine). Toxicities included mucositis (71%), diarrhea (43%), nausea (29%), memory loss/altered mental status (43%), cytopenias (43%), hypotension (14%), respiratory distress (14%), acute renal failure (14%), and severe skin rashes (43%). Re-challenge with CAP in 1 patient after the Mayo regimen caused grade 3 HFS only on dorsal surfaces of hands. One patient on PN401 had a grade 3 facial rash as the worst toxicity. Genotypic analysis of the DPYD gene in the second on PN401, who had severe leucopenia, demonstrated a heterozygous mutation (IVS14+1 G>A, DPYP*2A). UraBT in 2 patients revealed 1 to be DPD-deficient (DOB50 of 112.8; PDR of 49.4%) and borderline normal values (DOB50 of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths (28%): 1 on CAP and 1 on 5-FU + PN401. Conclusions: DPD deficiency was observed in several ethnicities. Patients with CAP toxicities should also be tested for DPD deficiency. Role of PN401 in rescuing 5-FU toxicity in DPD deficiency is not clear. Screening patients for DPD deficiency prior to administration of 5-FU or CAP, using UraBT, could potentially lower risk of toxicity. Future studies should validate this technique. [Table: see text]

Table S2. Patient and tumor characteristics. (DOCX 17 kb)

Table S3. Complete list of known proteins/compounds involved in platelet degranulation. Data downloaded from Reactome. (DOCX 29 kb)

Table S4. List of known proteins associated with platelet alpha granule content release. Data downloaded from Reactome. (DOCX 22 kb)

3007 Background: LDK378 is a novel, potent and selective small molecule anaplastic lymphoma kinase (ALK) inhibitor (IC50 0.00015 μM), that does not inhibit c-MET (IC50 3.2 μM). Tumor regression has been observed in ALK-driven NSCLC xenografts. A first-in-human, Phase I study is being conducted to determine the MTD and safety profile in patients (pts) with tumors with ALK rearrangement, amplification or mutation. Other objectives were safety, PK and antitumor activity in pts with ALK-driven NSCLC, both naïve to ALK inhibitors and relapsed following previous ALK inhibitor treatment, and other ALK-positive cancers. Methods: Adult pts with advanced malignancies harboring a genetic alteration in ALK who progressed on standard therapy or for whom there was no effective therapy, were given once daily oral LDK378 on a continuous 21-day schedule. Dose escalation, starting at 50 mg/day, was guided by a Bayesian logistic regression model (BLRM) to determine the MTD. Results: At a January 5th 2012 cutoff,31 pts (primary site: lung 26 pts; breast 3 pts; other 2 pts; median age 52 years; 87% ECOG PS 0/1) were enrolled and received LDK378 at doses of 50–750 mg/day. Two dose limiting toxicities, Grade (Gr) 3 alanine aminotransferase elevation (1 pt), and Gr 3 hypophosphatemia (1 pt) occurred in 8 pts at a 400 mg dose level. BLRM allowed dose escalation, and there were no DLTs in 4 pts at 500 mg. Median duration of treatment with LDK378 was 7 weeks (range

Table S3. Complete list of known proteins/compounds involved in platelet degranulation. Data downloaded from Reactome. (DOCX 29 kb)

Table S4. List of known proteins associated with platelet alpha granule content release. Data downloaded from Reactome. (DOCX 22 kb)

Table S2. Patient and tumor characteristics. (DOCX 17 kb)

Background Translocations of the anaplastic lymphoma kinase (ALK) gene occur in 3–8% of NSCLC. LDK378 is a novel, potent small molecule ALK inhibitor that produces tumor regressions in ALK-driven (ALK+) NSCLC xenografts. A Phase 1 study is being conducted with the primary objective of determining the MTD and safety profile in patients (pts) with ALK+ cancers. Other objectives are to assess safety, PK, and antitumor activity in pts with ALK+ NSCLC, either previously untreated with ALK inhibitors, or relapsed following ALK inhibitor treatment, and other ALK+ cancers. Methods LDK378 was administered orally once-daily on a continuous 21-day schedule, in adult pts with advanced malignancies harboring a genetic alteration in ALK who progressed on standard therapy or for whom there was no effective therapy. Dose escalation was guided by a Bayesian logistic regression model to determine the MTD, and started at 50 mg/day. Results As of 25 April2012, 56 pts (primary site: lung 50 pts [37 with prior crizotinib]; breast 4 pts; other 2 pts; median age 53 (22–76) years; 88% ECOG PS 0/1) had received LDK378 at doses of 50–750 mg/day. Of 47 pts evaluable for response (per investigator), there were 24 (51%) responses. All responses were in ALK+ NSCLC (FISH positive in ≥15% of tumor cells). In 26 pts with NSCLC who had progressed following crizotinib and were treated at ≥400 mg/day there were 21 (81%) responses. Dose limiting toxicities (DLTs) have occurred in 2/14 pts at 400 mg/day, 2/9 pts at 600 mg/day, and 1/9 pts at 750 mg/day. DLTs included diarrhea, vomiting, nausea, dehydration, and ALT elevation. The MTD was 750 mg/day. At the cutoff date, 36 (64%) pts remain on treatment. Discontinuations were due to adverse events (AEs) in 1 (2%), and disease progression in 19 (34%) pts. The most frequent AEs (all grades) were nausea 33 (59%), vomiting 30 (54%), and diarrhea 27 (48%) pts. The most frequent Grade 3/4 AE was diarrhea (5 [9%] pts). Oral absorption of LDK378 was rapid with a Tmax of 5–6 hours, and half-life was about 36 hours. Conclusions Daily oral LDK378 is well tolerated and the MTD was 750 mg/day. Striking activity was seen in ALK+ NSCLC pts treated at doses ≥400mg, who had previously progressed following crizotinib. Disclosure A.T. Shaw: I have a consultant/advisory role for Pfizer, Novartis, Chugar, Ariad, and Daiichi. D.R. Camidge: I have a compensated consultant/advisory role with Novartis Pharmacuticals Inc. S. Sharma: I have a compensated consultant/advisory role for Novartis (LEAD Summit). I have received honoraria for Novartis LEAD Summit. I have received research funding from Novartis (Phase Ib clinical trial). D.S.W. Tan: I have received research funding from Novartis. M. Goldwasser: Employment or leadership position to disclose: Associate Director Biostatistics: Novartis Pharmaceuticals. D. Dai: Employment or leadership position to disclose. Clinical Pharmacology Expert: Novartis Pharmaceuticals; Stock ownership: Myself; Novartis Pharmaceuticals. A.L. Boral: I am an employee of Novartis Institutes for Biomedical Sciences (Executive Director). I have stock ownership (Novartis). All other authors have declared no conflicts of interest.

Table S1. List of 770 screened genes. (DOCX 54 kb)