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Purpose This phase I study was conducted to determine the recommended dose of enzastaurin, an oral protein kinase C beta (PKCβ) inhibitor, for phase II trials. Secondary objectives were maximum-tolerated dose (MTD), pharmacokinetics (PK), toxicity, and response. Patients and Methods Patients at least 18 years of age with advanced cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1 lower received enzastaurin orally once daily at a starting dose of 20 mg. Dose escalation proceeded using a modified Simon design. Results All 47 patients enrolled (mean age, 58 years) received at least one dose of enzastaurin, with a median of two cycles (range, one to 17 cycles). Prevalent malignancies were lung (n = 10) and head and neck cancers (n = 9). Although no MTD was identified up to 700 mg/d, 525 mg was chosen as the recommended dose, and 12 additional patients were accrued at that level. Three dose-limiting toxicities (QTc changes) occurred: one at the 700-mg dose (patient discontinued), and two in the expansion cohort at the 525-mg dose. Total analytes (enzastaurin and its metabolites) exposure increased with increasing doses up to 240 mg, and appeared to plateau at 525 and 700 mg. Grade 1 chromaturia, fatigue, and other GI toxicities were the most common, while no clinically significant grade 3/4 toxicities occurred. Two deaths, unrelated to enzastaurin, occurred. Twenty-one patients (45%) achieved stable disease (SD) for two to 16 cycles. Conclusion On the basis of plasma exposures and safety data, enzastaurin 525 mg once daily is the recommended phase II dose. Enzastaurin is well tolerated up to 700 mg/d. Evidence of early activity was seen with significant stable disease.

Purpose To determine pathologic response rates to liposome-entrapped cis-bisneodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) (L-NDDP) administered intrapleurally in patients with malignant pleural mesothelioma. Patients and Methods Thirty-three patients with malignant pleural mesothelioma and free-flowing pleural effusions received intrapleural L-NDDP once every 3 weeks at a dose of 450 mg/m2. Thoracoscopic evaluation with pleural biopsies was performed before therapy and then after every two cycles. The primary end point was pathologic response as determined by thoracoscopic biopsy. Results After at least two cycles, post-treatment pleural biopsy analysis was negative in 14 patients for a pathologic response rate of 42% (95% CI, 25% to 61%). Median survival was 11.2 months. There were three treatment-related deaths secondary to peritonitis, cellulitis at the thoracoscopy site, and empyema. Grade 3 nonhematologic toxicities included infection, fever, dyspnea, and anorexia, which occurred in five (15%), one (3%), one (3%), and one (3%) patients, respectively. There were no grade 4 nonhematologic toxicities. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia occurred in five (15%), three (9%), and two (6%) patients, respectively. Two patients with pathologic responses subsequently underwent pleural decortication. Both surgical specimens revealed residual tumor in regions that were not in direct communication with the pleural space. Conclusion Intrapleural L-NDDP therapy in this patient population is feasible with significant but manageable toxicity. Although pathologic responses are highly encouraging, areas of mesothelioma that are not in direct communication with the pleural space will evade drug exposure and limit efficacy in some patients. The optimal role of intrapleural L-NDDP therapy currently remains to be determined.

Purpose Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody. Erlotinib HCl (Tarceva, OSI-774; OSI Pharmaceuticals, New York, NY) is a potent, reversible, highly selective and orally available HER-1/epidermal growth factor receptor tyrosine kinase inhibitor. Preclinical data in various xenograft models produced greater growth inhibition than with either agent alone. Additionally, both agents have demonstrated benefit in patients with previously treated non–small-cell lung cancer (NSCLC). Patients and Methods A phase I/II study in two centers examined erlotinib and bevacizumab (A+T) in patients with nonsquamous stage IIIB/IV NSCLC with ≥ one prior chemotherapy. In phase I, erlotinib 150 mg/day orally plus bevacizumab 15 mg/kg intravenously every 21 days was established as the phase II dose, although no dose-limiting toxicities were observed. Phase II assessed the efficacy and tolerability of A+T at this dose. Pharmacokinetic parameters were evaluated. Results Forty patients were enrolled and treated in this study (34 patients at phase II dose); the median age was 59 years (range, 36 to 72 years), 21 were female, 30 had adenocarcinoma histology, nine were never-smokers, and 22 had ≥ two prior regimens (three patients had ≥ four prior regimens). The most common adverse events were mild to moderate rash, diarrhea, and proteinuria. Preliminary data showed no pharmacokinetic interaction between A+T. Eight patients (20.0%; 95% CI, 7.6% to 32.4%) had partial responses and 26 (65.0%; 95% CI, 50.2% to 79.8%) had stable disease as their best response. The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months. Conclusion Encouraging antitumor activity and safety of A+T support further development of this combination for patients with advanced NSCLC and other solid tumors.

Purpose: Response of solid malignancies to therapy is usually determined by serial measurements of tumor size. The purpose of our study was to assess the consistency of measurements performed by readers evaluating lung tumors. Materials and Methods: The study group was composed of 33 patients with lung tumors more than 1.5 cm. Bidimensional (BD) and unidimensional (UD) measurements were performed on computed tomography (CT) scans according to the World Health Organization (WHO) criteria and the Response Evaluation Criteria in Solid Tumors (RECIST), respectively. Measurements were performed independently by five thoracic radiologists using printed film and were repeated after 5 to 7 days. Inter- and intraobserver measurement variations were estimated through statistical modeling. Results: There were 40 tumors with an average size of 1.8 to 8.0 cm (mean, 4.1 cm). Analysis of variance showed a significant difference (P < .05) among readers and among the measured nodules for UD and BD measurements. Interobserver misclassification rates were more than intraobserver misclassification rates using either progressive disease or response criteria. The probability of misclassifying a tumor with the WHO criteria or RECIST was greatest with interobserver measurements when criteria for progression (43% BD, 30% UD) were used and lowest with intraobserver measurements when criteria for response (2.5% BD, 3.0% UD) were used. In addition, interobserver misclassification rates were more than intraobserver misclassification rates for both regular and irregular tumors. Conclusion: Measurements of lung tumor size on CT scans are often inconsistent and can lead to an incorrect interpretation of tumor response. Consistency can be improved if the same reader performs serial measurements for any one patient.

265 Background: At tertiary cancer centers, physicians frequently request reinterpretation of imaging studies performed at outside institutions. The purposes of this study were to determine the quality of outside computed tomography (CT) scans of the chest and compare the accuracy of accompanying radiology reports from outside institutions and our multidisciplinary cancer center. Methods: Two thoracic radiologists graded the quality of 59 outside chest CT scans and generated independent reports for 52 of the scans. A third thoracic radiologist scored the outside reports and reinterpretations for quality. Fisher’s exact tests were used to compare the frequency with which crucial items appeared in outside reports and reinterpretations. Next, two outside thoracic radiologists identified discrepancies between outside reports and reinterpretations (first radiologist) and determined whether the outside report or reinterpretation was more accurate in each case (second radiologist). Finally, the impact of discrepancies on management was evaluated, largely based on NCCN guidelines. Results: Of the 59 outside CT scans, 35 (59%) were of poor quality. Reinterpretations were more likely than outside reports to include information about lymph nodes, adrenal and liver metastasis, tumor nodules, and tumor texture. In 19 of 52 cases (37%), discrepancies were identified between outside reports and reinterpretations. In 17 of these cases, the reinterpretation was superior; in 2 cases, the reinterpretation and outside report were of equal quality. Among these 17 cases, reinterpretation allowed staging in nine cases that could not be staged with information from the outside reports; resulted in upstaging without management change in one case and upstaging with management change in four cases among the five cases with staging information present in both sets of reports; and revealed a significant omission (2 cases) or error (1 case) that changed management in three cases. In total, reinterpretation resulted in significant changes to 16 of 52 (31%) of CT scans. Conclusions: Subspecialty reinterpretation of chest CT scans can substantially improve clinical management.

7098 Background: Patients with CLL that develop Richter’s syndrome (RS) have a very poor prognosis. Similarly, pts with CLL that have clinical and histological features (increased large cells/prolymphocytes in CLL tissue biopsy) of increased aggressiveness (defined as accelerated phase CLL, AP) have a poor prognosis. In order to identify prognostic factors in pts with AP and RS, collectively referred to as TC, we reviewed our center experience. Methods: Pts with TC and complete evaluation including biopsy and concomitant FDG/PET were included. Pts with de novo TC were excluded as their prognosis is substantially superior versus previously treated pts. Pts with N+ or M+ concurrent solid tumors were also excluded. Since FDG/PET-derived SUV reflects tumor proliferative rate, we used SUVmax≥10 to indicate high-risk disease (Falchi, Blood. 2012;120: abstr # 927). We identified factors associated with outcome and performed a multivariable model for OS. Results: One hundred eighty-three consecutive pts with TC (99 with AP and 84 with RS) were evaluated at MDACC between 2002 and 2012. Demographic and clinical characteristics were similar between pts with AP and pts with RS. 30% and 77% of pts with AP and RS, respectively had an SUVmax≥10. Approximately half of the pts were treated with intensive chemoimmunotherapy after the TC diagnosis. CR rates were 21% and 16% and overall response rates were 37% and 26% for pts with AP and RS, respectively. At the time of this analysis 144/183 pts have died, for a median OS of 9.6 months (7.9-14.7). Age ≥65, B symptoms, LDH, β2-microglobulin, del17p, SUVmax≥10, extensive disease by FDG/PET (SUVmax≥5 on both sides of the diaphragm), PS≥2 bulky disease and high Ki67 correlated with shorter OS. In multivariable analysis SUV uptake (max≥10), PS higher than 1 and bulky nodal disease (>5 cm) retained independent significance. Conclusions: Based on our experience, an SUVmax of 10 or higher, PS higher than 1 and bulky nodal disease (>5 cm) are the most important factors predicting outcome in pts with TC. A prognostic model for survival is being developed for pts with TC.

e19645 Background: The natural history of isolated gonadal vein thrombosis (GVT) occurring in cancer patients (pts) is not well described in the medical literature. GVT in cancer pts it is of uncertain clinical significance. Methods: Utilizing a software program allowing a searchable database of radiology reports, the computerized tomographic scan (CT) reports of pts at a single cancer center from January 1, 2004 to June 30, 2011, were searched for the term “gonadal vein thrombus”. Pts included in this analysis had a diagnosis of cancer, isolated GVT (i.e. no evidence of thrombosis at another site), and at least six months of follow-up information. Results: 162 cancer pts with GVT were identified for analysis [median age 57.8 ± 12 years, right GVT 89 pts (54.9%), left GVT 59 pts (36.4%), bilateral 14 pts (8.6%)]; the majority of the pts (96, 59.3%) had a non-gynecologic malignancy. At the time of diagnosis of GVT the majority of pts were receiving chemotherapy (84, 51.9%); 70 pts (43.2%) had surgery within the prior six months (the most common being hysterectomy, 127 pts, 78.6%). The majority of pts in this study had metastatic disease (93, 57.4%) as well as active cancer (138, 85.1%, defined as GVT occurring at the time of cancer diagnosis, disease recurrence, metastatic disease, or treatment for cancer within the prior six months); median follow-up time was 22 months. A minority of pts received anticoagulation (28pts, 17.2%). Twenty-two pts (13.6%) developed a recurrent venous thromboembolic event (VTE); these events were pulmonary embolism (12 pts, 7.4%), deep venous thrombosis (5 pts, 3.1%), inferior vena cava thrombosis (4 pts, 2.5%). Median time to development of re-thrombosis was 7 months (range 2-13.5 months). Active cancer was the only risk factor significantly associated with recurrent VTE (p = 0.047); pts with prior hysterectomy had a significantly reduced risk of recurrent VTE (p = 0.036). Conclusions: Incidental isolated GVT identified in cancer pts has a high risk of recurrent VTE (13.6%). Based upon specific pts risk factors for VTE, treatment of an incidentally detected GVT in cancer pts with anticoagulation, as per guidelines for other VTE sites, may be indicated.

6013 Background: Interrupting the epidermal growth factor receptor (EGFR) signaling pathway has shown promise in a variety of cancers and preclinical data has demonstrated possible synergy with platinums and taxanes. Treatment options for recurrent/metastatic HNSCC are limited. A study of cisplatin and docetaxel showed a response rate of 40% and 9.6 month median survival. Erlotinib, an EGFR tyrosine kinase inhibitor, had a 4.3% response rate as single agent in HNSCC. Because of the possible synergy and efficacy, we proposed to study the combination of cisplatin, docetaxel and erlotinib in advanced HNSCC. Methods: Patients (pts) were required to have adequate performance status, measurable disease, no prior EGFR therapy, and may have received prior induction, concomitant or adjuvant chemotherapy, but not for recurrent/metastatic disease. Sites of disease included squamous cell head and neck sites excluding nasopharynx and sinus. Treatment included docetaxel 75 mg/m2 and cisplatin 75 mg/m2 intravenously every 3 weeks and erlotinib 150 mg by mouth daily. All agents were started on day 1. Pts were treated with growth factor support. Results: The trial has completed accrual to 50 pts. 47 pts are available for analysis at this time. Median age is 56 years (range 39–72). ECOG PS is 0, 1, 2 (6, 29, 2 pts). 43 pts are evaluable for efficacy. All responses were confirmed via RECIST. Complete responses have been in observed in 4 pts, partial responses in 25 pts and 12 pts have stable disease for an overall response rate of 67% and disease control rate of 95%. After a follow-up of 19 months, median overall survival was 11 months (8.61, 22.5, 95% CI) and progression free survival was 6.01 months (4.37, 8.25). 6 pts had grade 3/4 febrile neutropenia, 4 pts had grade 3/4 dehydration, 3 pts had grade 3 diarrhea, and 2 pts had grade 3/4 GI bleeding. The most common grade 1–2 toxicities were diarrhea, nausea, and rash. Conclusions: The combination of cisplatin, docetaxel and erlotinib is well tolerated and has very encouraging activity in recurrent/metastatic HNSCC. Tissues are being collected and analyzed for correlative markers including downstream EGFR pathway markers (p-akt, mek, k-ras). Final efficacy and biomarker results will be presented at the annual meeting. No significant financial relationships to disclose.

7527 Background: Æ-941 is a shark cartilage extract with antiangiogenic properties. We conducted a placebo-controlled trial testing Æ-941, with IC and CRT, in unresectable stage III NSCLC. Methods: Eligibility criteria included performance status (PS) < 2, weight loss < 10%. Subjects received one of two treatment regimens depending on site of enrollment: carboplatin (C) (AUC 6) and paclitaxel (P) (200 mg/m2) × 2 cycles followed by CRT (60 Gy/30 fractions) with weekly C (AUC 2) and P (45 mg/m2) × 6 doses or cisplatin (CDDP) (75 mg/m2, d1) and vinorelbine (V) (30 mg/m2, d1 and 8) × 2 cycles followed by CRT (60 Gy/30 fractions) with CDDP (75 mg/m2, day 1) and V (15 mg/m2, d1 and 8) × 2 cycles. Subjects were randomized to receive Æ-941 (Arm A) or placebo (Arm B), 120 mL orally twice daily, at the start of IC and continuing after CRT as maintenance therapy. Randomization was stratified for stage, gender, and type of chemotherapy. The primary endpoint was overall survival (OS), with a planned sample size of 756 subjects providing 80% power to detect a 25% difference in OS, assuming a control arm median survival time (MST) of 13 months, type I error 0.05. Results: Between 6/00 and 2/06, 384 subjects were enrolled onto the trial and randomized. In 2/06 the trial was closed to new patient entry due to insufficient accrual. This final analysis is based on 379 randomized and eligible subjects (188 arm A, 191 arm B). Subject characteristics: 60% male, median age 63 years (range 37–84), 56% stage IIIB, 58% C-based chemotherapy, median follow-up 3.7 years. There was no significant difference in OS between arms A and B, with MSTs of 14.4 (95% CI 12.6–17.9) and 15.6 (95% CI 13.8–18.1) months, respectively (log-rank p=0.73). OS by pre-specified stratification factors: stage IIIB vs IIIA (MST 13.9 vs. 17.4 months, p=0.25), C vs. CDDP chemotherapy (MST 14.4 vs. 16.7 months, p=0.13), and male vs. female (MST 15.7 vs. 15.1 months, p=0.74). The study drug was well tolerated. Fewer subjects in arm A experienced grade 3 or higher adverse events (66% vs. 77%, p=0.018). Conclusions: The addition of Æ−941 to IC and CRT does not improve OS in patients with unresectable stage III NSCLC. No significant financial relationships to disclose.

5521 Background: Interrupting the epidermal growth factor receptor (EGFR) signaling pathway has shown promise in a variety of cancers and preclinical data has demonstrated possible synergy with platinums and taxanes. Treatment options for advanced or recurrent HNSCC are limited. A study of cisplatin and docetaxel showed a response rate of 40% and 9.6 month median survival. Erlotinib, an EGFR tyrosine kinase inhibitor, had a 4.3% response rate in HNSCC. Because of the possible synergy and efficacy, we proposed to study the combination of cisplatin, docetaxel and erlotinib in advanced HNSCC. Methods: Patients (pts) were required to have adequate performance status, measurable disease, no prior EGFR therapy, and may have received one regimen of induction, concomitant or adjuvant chemotherapy, but not for recurrent/metastatic disease. Sites of disease included squamous cell head and neck sites excluding nasopharynx and sinus. Treatment included docetaxel 75mg/m2 and cisplatin 75mg/m2, intravenously every 3 weeks and erlotinib 150 mg by mouth daily. Patients were treated with growth factor support. Results: 37 pts have been enrolled thus far. Median age is 56 years (range 39–72). Median ECOG PS is 1 (range 0–2). 32 pts are evaluable for confirmed response using RECIST criteria. Complete responses have been in observed in 3 pts, partial responses in 18 pts and 8 pts have stable disease for an overall response rate of 66% and disease control rate of 91%. Only 2 pts progressed after 2 cycles of treatment. 5 pts had grade 3/4 neutropenia (2 febrile),1 pt had grade 4 diarrhea, and 2 pts had grade 3 rash. The most common grade 1–2 toxicities were diarrhea, nausea, and rash. Conclusion: The combination of cisplatin, docetaxel and erlotinib is well tolerated and has very encouraging activity in advanced HNSCC. Data collection for response rate, duration of response and survival is ongoing. Trial accrual continues up to 50 patients and biopsies are being collected for correlative markers including downstream EGFR pathway markers (p-akt, mek, k-ras). The full data set will be presented at the annual meeting. [Table: see text]

7144 Background: AE-941(Neovastat, Aeterna Laboratories) is a standardized shark cartilage extract with antiangiogenic properties (inhibition of VEGF signaling and MMP activity, induction of endothelial cell apoptosis). An ongoing placebo-controlled trial is testing AE-941, with IC and CRT, in unresectable stage III NSCLC. Methods: Eligibility criteria include performance status (PS) < 2, weight loss < 10%. Subjects receive one of two treatment regimens depending on site of enrollment: carboplatin (C) (AUC 6) and paclitaxel (P) (200 mg/m2) x 2 cycles followed by CRT (60 Gy/30 fractions) with weekly C (AUC 2) and P (45 mg/m2) x 6 doses or cisplatin (CDDP) (75 mg/m2, d1) and vinorelbine (V) (30 mg/m2, d1 and 8) x 2 cycles followed by CRT (60 Gy/30 fractions) with CDDP (75 mg/m2, day 1) and V (15 mg/m2, d1 and 8) x 2 cycles. AE-941 or placebo (120 ml orally twice daily) is started with IC and continued after CRT as maintenance therapy. Planned sample size: 756. Results: A data safety board review of the first 4...

5565 Background: Treatment options for advanced disease are limited and for those patients failing chemotherapy, there are few viable options. Lonafarnib is a novel tricyclic peptidomimetic compound that is a potent and specific inhibitor of farnesyl protein transferase. We have previously reported clinical activity of lonafarnib in untreated HNSCC (4 of 22 patients showed response despite drug exposure for only 7–14 days). We proposed to assess the activity of lonafarnib in advanced HNSCC patients. Methods: An open-label phase II single-center study was conducted to determine the objective response rate of lonafarnib administered at 200 mg bid, enrolling patients who were incurable and who failed at least one platinum-containing regimen, but received no more than three prior regimens. Results: Fifteen patients, aged 32 to 66 (median age 57) were enrolled. All patients had baseline ECOG PS 0 or 1. Median treatment duration was 61 days (range 0–224 days). Median time to progression was 62 days. No objectiv...

7140 Background: TLK286 (Telcyta) is a novel glutathione analog prodrug activated by GST P1–1, which is overexpressed in NSCLC, releasing two electrophilic fragments that induce apoptosis. TLK286 has demonstrated significant single agent activity by RECIST in two Phase 2 NSCLC trials. In preclinical models, TLK286 is not cross resistant to docetaxel and shows synergistic inhibition in MCF-7 cells. Methods: The objectives were to determine the MTD of the TLK286/docetaxel combination and the objective response rate (ORR) by RECIST. NSCLC patients (pts) who had failed prior platinum-based therapy were treated with TLK286 at 500, 750 or 960 mg/m2 and docetaxel at 75 mg/m2 every 3 weeks until tumor progression or unacceptable toxicity. Results: At interim analysis, 30 pts (16 M, 14 F), median age 65 (range 46–80), median ECOG performance status 1, median prior regimens 1.5 (range 1–3) have received 103+ cycles (mean 3.4 cycles/pt, range 1–11). Pts failed prior therapies with: platinum (100%), paclitaxel (70%),...