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PURPOSE MDX-210 is a bispecific antibody that binds simultaneously to type I Fc receptors for immunoglobulin G (IgG) (Fc gamma RI) and to the HER-2/neu oncogene protein product. MDX-210 effectively directs Fc gamma RI-positive effector cells such as monocytes and macrophages to phagocytose or kill tumor cells that overexpress HER-2/neu. The goals of this phase Ia/Ib trial were to determine the maximum-tolerated dose (MTD) and/or the optimal biologic dose (OBD) of MDX-210. PATIENTS AND METHODS Patients with advanced breast or ovarian cancer that overexpressed HER-2/neu were eligible for treatment. Cohorts of three patients received a single intravenous (IV) infusion of MDX-210 at increasing dose levels from 0.35 to 10.0 mg/m2. RESULTS Treatment was well tolerated, with most patients experiencing transient grade 1 to 2 fevers, malaise, and hypotension only. Two patients experienced transient grade 3 hypotension at 10.0 mg/m2. Transient monocytopenia and lymphopenia developed at 1 to 2 hours, but no other hematologic changes were observed. Doses of MDX-210 > or = 3.5 mg/m2 saturated > or = 80% of monocyte Fc gamma RI and produced peak plasma concentrations > or = 1 microgram/mL, which is greater than the concentration for optimal monocyte/macrophage activation in vitro. Elevated plasma levels of the monocyte products tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and neopterin were observed with maximal levels at doses > or = 7.0 mg/m2. Localization of MDX-210 in tumor tissue was demonstrated in two patients. One partial and one mixed tumor response were observed among 10 assessable patients. CONCLUSION MDX-210 is immunologically active at well-tolerated doses. The MTD and OBD is 7 to 10 mg/m2.

e23168Background: Genetic profiling of tumors is quickly increasing as are trials targeting genetic alterations. Furthermore, genetic alterations are a relatively permanent part of a tumor profile,...

1550 Background: Genetic profiling of tumors is a powerful approach to predict drug sensitivity and resistance. However, oncologists are often unfamiliar with interpretation of genetic data. We est...

7022 Background: Aerodigestive tract cancer (ADT) is the leading cause of cancer-related death in the US. New effective treatments are needed. Among a panel of drugs causing growth inhibition of lung cancer cells and repression of cyclin D1, the histone deacetylase inhibitor V was found most potent. To translate studies into the clinic, a window of opportunity trial of V was conducted. Methods: Pts with resectable ADT received 400 mg V once daily orally for 7 days prior to surgical resection. Serum samples were obtained before the last V dose and at the time of biopsy. Tumor tissue was immediately snap-frozen in liquid nitrogen, stored at -70°C, homogenized in three parts PBS (1:3g/v). V was quantitated with a LC-MS/MS assay. Post- versus pre-treatment tumor biopsies were scored for necrosis, acute and chronic inflammation, and immunohistochemical changes in Ki-67, cyclin E, cyclin D1, EGFR, phospho-EGFR, p21, p27 and caspase. Results: 15 pts enrolled, 9 pts took V for a median of 7 days (3-9), underwent resection and had adequate pretreatment samples. Median age 66, 4 women, 4 former, 5 current smokers, 1 squamous cell lung carcinoma, 8 adenocarcinoma (1 esophageal). PK analyses confirmed plasma (8pts) and tumor (7pts) concentrations above the detection limits. There was considerable interindividual variation in plasma V concentrations (7.3-192.4 ng/ml; CV 95%), at 178-500 min from last V dose, and in intratumoral V levels (15.0-80.3 ng/g; CV 59%). All pts had wild-type EGFR, 4 pts had KRAS codon 12 mutations, 78% showed reduced Ki-67 expression, 50% had decreased cyclin E, 78% exhibited necrosis, chronic or acute inflammation in the post-treatment biopsies. Most cases with KRAS mutations had biomarker responses. Changes in multiple biomarkers were observed across the range of intratumoral V levels. Conclusions: This is the first report of V concentrations in human tumors. Preoperative treatment with V achieved intratumoral concentrations comparable to serum with evidence of necrosis, decreased Ki-67 and cyclin E, and other biomarker responses in resected ADT. The results demonstrate the value of window of opportunity trials in the investigation of novel cancer therapeutics.

7062 Background: Lung cancer is the most common cause of cancer mortality in the United States and novel treatments are needed. We previously engineered murine transgenic cyclin E models that recap...

18054 Background: Transcriptional repression of cyclin D1 occurs during responses to erlotinib (E) both in vitro and in vivo. Cyclin D3 has overlapping function with cyclin D1 but has distinct transcriptional regulation. Methods: The expression of cyclin D3 was compared in E sensitive cell lines (H358, H441) and an E resistant cell line (A549). Cyclins D1, D2, and D3 were independently overexpressed in E sensitive NIH 3T3 cells by plasmid transfection. Biopsy tissues from a proof-of-principal clinical trial of E were assessed for cyclin D3 expression. Results: A549 cells were resistant to E and expressed high levels of cyclin D3 RNA and protein compared to E sensitive cell lines. Overexpression of cyclin D1 and cyclin D3 conferred partial resistance to E in NIH 3T3 cells while cyclin D2 had no significant effect. Comparison of cyclin D3 immunostaining in tumor biopsies from patients before and after treatment with E revealed an increase in the percentage of cyclin D3 expressing cells following treatment with E. Conclusions: Cyclin D3 confers resistance to E in vitro and in vivo. Drugs such as retinoids and rexinoids that target cyclin D3 expression may prove useful for enhancing sensitivity to E. No significant financial relationships to disclose.

15527 Background: ACC is a rare malignancy with a very poor prognosis. Surgery is the only potential curative option. Gefitinib is an oral EGFR inhibitor that may have activity in solid tumors that express EGFR. ACC over expresses EGFR in a high proportion of cases. Methods: From April 2004 through December 2006, the ACC Working Group conducted a phase II trial of Gefitinib as second line, monotherapy in patients with pathologically confirmed unresectable ACC who had progressed on mitotane or chemotherapy. All prior systemic therapy was discontinued 28 days prior to starting gefitinib. Patients were ineligible if: had received prior therapy with any EGFR inhibitor, pregnant or breast feeding, had other co-existing malignancies (other than basal cell carcinoma or cervical cancer in situ), had an ECOG PS > 2, absolute neutrophil counts < 1,500, or platelets < 20,000. Patients were not allowed concomitant use of phenytoin, carbamazepine, rifampicin, barbiturates, or St John’s Wort. Patients took gefitinib 250 mg orally once a day. Each cycle was 21 days with radiological assessment every 6 weeks.Response rate as determined by RECIST criteria was the primary endpoint. Results: 19 patients accrued to the study (18 with measurable disease and 1 without). Pt Characteristics: Female 79% (15/19); Median age 48 (range 26–74); 84% (12 female and 4 male =15/19) of the patients had steroid secreting tumors. Grade 3 toxicity was noted in 2 patients and included, hypertension and lower extremity edema and elevated liver transaminases. No grade 4 toxicities occurred. Of 19 patients evaluable, there were no complete responders, partial responders or patients with stable disease (0% response rate; 95% CI: 0%-18%). Conclusions: Gefitinib demonstrated no activity in patients with unresectable ACC. This study is now closed. This study demonstrated the ability to successfully accrue to a trial of novel agents in rare tumors in a multicenter setting. [Table: see text]

7136 Background: Bexarotene (Targretin) is a selective retinoid X receptor (RXR) agonist that appears to prolong survival in pts with NSCLC. To determine mechanisms of action, preclinical studies and a short-term, proof-of-principle clinical trial were performed. Methods: BEAS-2B immortalized human bronchial epithelial cells were treated with bexarotene and effects on EGFR and cell cycle regulatory proteins were determined by Western analyses. To evaluate bexarotene tissue pharmacokinetic (PK) and pharmacodynamic effects, 12 pts with pathologically confirmed stage I and II NSCLC were enrolled. Subjects were given 300 mg/m2/day of bexarotene orally for 7 to 9 days prior to surgical resection. Resected tumor tissue was evaluated for biomarker expression and tumor tissue bexarotene concentrations. Plasma bexarotene concentrations were measured at the time of resection. Biomarker changes were assessed immunohistochemically comparing pre- and post-treatment tissues by pathologists blinded to the tissue origin ...

4770 Background: Primary neoplasms of the adrenal cortex are extremely rare malignancies, estimated to represent 0.05–0.2% of all cancers diagnosed in the United States annually. These cancers carr...

3093 Background: Erlotinib (OSI-774, Tarceva™) is an epidermal growth factor receptor (HER1) tyrosine kinase inhibitor (TKI) with clinical activity in lung cancer. Mechanisms engaged during clinical response to erlotinib need to be determined. Methods: Using cultured human bronchial epithelial cells, in vitro effects of erlotinib were investigated. Cells were treated with erlotinib and effects on HER1 and cell cycle regulatory proteins were determined by immunoblot analyses. To evaluate further molecular changes in patient tumor specimens, a phase II pharmacokinetic and pharmacodynamic trial was performed in patients with aerodigestive tract cancers, who were candidates for serial tumor sampling. Five patients were enrolled and 4 patients were evaluable (3 NSCLC, 1 laryngeal SCC). Each received erlotinib at an oral dose of 150mg daily. Detailed plasma pharmacokinetics were performed on days 1 and 8. Tissue and plasma concentrations were determined at the second tissue sampling on day 9. Changes in the des...