Triapine, a novel inhibitor of the M2 subunit of ribonucleotide reductase (RR), is a potent radiosensitizer. This phase 1 study, sponsored by the National Cancer Institute Cancer Therapy Evaluation Program, assessed the safety and tolerability of triapine in combination with radiation (RT) in patients with locally advanced pancreas cancer (LAPCA).We evaluated 3 dosage levels of triapine (24 mg/m2, 48 mg/m2, 72 mg/m2) administered with 50.4 Gy of RT in 28 fractions. Patients with LAPCA received triapine thrice weekly, every other week during the course of RT. Dose-limiting toxicity (DLT) was assessed during RT and for 4 weeks after its completion. Dynamic contrast-enhanced magnetic resonance imaging and serum RR levels were evaluated as potential predictors for early response.Twelve patients were treated. Four patients (1 nonevaluable) were enrolled at dosage level 1 (DL1), 3 patients at DL2, and 5 patients (2 nonevaluable) at DL3. No DLTs were observed, and the maximum tolerated dose was not reached. Two patients (17%) achieved partial response, and 6 patients (50%) had stable disease. One patient underwent R0 resection after therapy. Ninety-two percent of patients (100% at DL3) experienced freedom from local tumor progression. In 75% of patients who eventually experienced progression, metastases developed without local progression. RR levels did not seem to predict outcome. In 4 patients with available data, dynamic contrast-enhanced magnetic resonance imaging may predict early response or resistance to therapy.The combination of triapine at 72 mg/m2 3 times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA.

14617 Background: Platelet derived growth factor receptor alpha (PDGFRα) plays a critical role in tumorigenesis and tumor progression. PDGFRα and its ligands are expressed by an array of tumors and supportive stroma, and the integrity of this axis results in the proliferation of tumors, supportive stroma and blood vessels. IMC-3G3 is a recombinant human IgG1 MAb targeted to PDGFRα and induces prominent anticancer effects in vitro and on human tumor xenografts in vivo. Methods: This Phase 1, multicenter study of IMC-3G3 administered intravenously in patients (pts) with advanced refractory or untreatable cancer plans to enroll 5 cohorts of 3–6 pts. The primary objectives were to determine the MTD and safety profile. Cohorts 1–3 received 4 weekly infusions of 4, 8, and 16 mg/kg IMC-3G3 per cycle and are reported here. Future cohorts (Cohorts 4 and 5) will receive IMC-3G3 every 2 weeks at doses of 15 and 20 mg/kg. Results: Thirteen pts have enrolled to date (11 male, 2 female; 9 prostate cancer, 1 bladder/transitional cell carcinoma, 1 endometrial cancer, 1 SCLC, and 1 carcinoid unspecified). Eight pts were treated > 10 weeks; 2 pts at 16 mg/kg are ongoing at 18 and 26 weeks, respectively. One pt at 4 mg/kg who experienced a PSA decrement of > 50% was treated for 39 weeks until discontinuing due to disease progression. No dose-limiting toxicities were observed at any dose level in cycle 1. The most frequently reported AE has been fatigue (2 of 12 pts). No Grade 3/4 IMC-3G3-related events were reported. Following the final infusion of cycle 1, as IMC-3G3 dose was escalated from 4 to 8 to 16 mg/kg; A) the mean t1/2 remained relatively constant (126–138 hrs), B) mean Cmax and AUCinf increased in a greater-than-dose-proportional manner, suggesting nonlinear IMC-3G3 pharmacokinetics (Cmax = 139, 297, and 1198 μg/mL; AUCinf = 23686, 48149, and 130302 hr*μg/mL for the 4, 8, and 16 mg/kg cohorts respectively), and C) mean clearance decreased (0.196–0.132 mL/hr/kg), suggesting saturation of IMC-3G3 elimination was being approached. Conclusions: Enrollment continues with evaluation of 15 and 20 mg/kg every 2-weeks based on supportive PK data and toxicity profiles. Preliminary safety, PK, and biological activity data support further IMC-3G3 disease-directed development. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration ImClone Systems ImClone Systems ImClone Systems

The optimal management of laryngeal carcinoma requires tumor treatment and preservation of laryngeal functions, such as swallowing and voice quality. Radiotherapy (RT) can fulfill both criteria, although it remains important to identify predictors of radioresistance and reduce unnecessary irradiation. Insulin-like growth factor-1 receptor (IGF-1R) is a transmembrane receptor that plays a key role in cancer development, although its prognostic value after RT remains unknown. We evaluated the predictive value of IGF-1R expression for RT response in patients with early glottic squamous cell carcinoma.We retrospectively reviewed 43 patients with T1N0 and T2N0 glottic squamous cell carcinoma who were treated with RT alone. Biopsy specimens were stained using an anti-IGF-1R antibody, and we evaluated the relationships between IGF-1R expression and T classification or tumor recurrence. We also evaluated the loco-regional control (LRC) rate and the prognostic value of various clinical factors.All cases achieved complete response after the initial RT, and 10 (23.3%) patients experienced local tumor recurrence. Twenty-five patients (58.1%) exhibited high IGF-1R expression, although the level of IGF-1R expression was not correlated with T classification. Local recurrence was observed in 36% (9/25) of patients with high IGF-1R expression and in only 5% (1/18) of patients with low IGF-1R expression (p < 0.05). The 2-year LRC rate was 94.1% for the low IGF-1R expression group, compared to 49.8% for the high IGF-1R expression group (p = 0.04). Anterior commissure involvement and IGF-1R expression were independent adverse factors for LRC.High IGF-1R expression was more common among patients with recurrent early glottic carcinoma, which suggests that there is a biological relationship between IGF-1R expression and RT response. Thus, IGF-1R may be a useful screening parameter for RT response in laryngeal carcinoma.

14630 Background: VEGFR-1 is expressed on both tumor vasculature and a wide range of human tumors. IMC-18F1 is a recombinant human monoclonal IgG1 antibody that directly targets VEGFR-1 so as to block ligand binding and, in turn, downstream VEGFR-1 signaling. VEGFR-1 activation is also critical for epithelial-mesenchymal transformation and is a mediator of circulating hematopoietic progenitor cells that condition the microenvironment enabling the growth of tumor metastases. Methods: This Phase 1 study of IMC- 18F1 was designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of IMC-18F1 administered weekly at doses of 2, 3, 6, and 12 mg/kg IV (Cohorts 1–4). If safety, PK, and pharmacodynamic data supported less frequent dosing, then schedules of 15 mg/kg every 2 weeks and 20 mg/kg every 3 weeks (Cohorts 5 and 6) were to be evaluated. Results: A total of 14 patients have received treatment as part of Cohorts 1–4. To date, there have not been IMC-18F1-related, grade > 2 adverse events (AE) nor dose- limiting toxicities observed. The most common AEs considered at least possibly-related to study drug include fatigue (n = 5), nausea (n = 3), and anemia (n = 2). Following the final infusion in Cycle 1; the mean half-life of IMC-18F1 increased with increasing dose (85.9 - 205.4 hrs); the mean clearance decreased with increasing dose (0.208–0.067 mL/hr/kg), suggesting that saturation of elimination was being approached. Cmax and AUCinf increased in a greater-than-dose-proportional manner, indicating that the PK of IMC-18F1 was nonlinear. Conclusions: Enrollment on this study continues, with an evaluation of 15 mg/kg every-2-week and 20 mg/kg every-3- week schedules based on supportive PK and toxicity profiles. The preliminary safety, PK, and biological activity data support further disease- directed development of IMC-18F1. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration ImClone Systems Incorporated ImClone Systems Incorporated

Tibial dyschondroplasia (TD) is a metabolic cartilage disease of young poultry in which endochondral bone formation is disrupted leading to the retention of a non-calcified, avascular plug of cartilage in the tibial growth plate. Chicks aged 7 days were fed either a control diet or one containing thiram 100 ppm for 48 h to induce TD. Cell multiplication in the growth plate was determined thereafter with bromodeoxyuridine (BrdU) labelling, and metabolic changes by measuring alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP), and glutathione (GSH) activities. The effect on chondrocyte maturation was examined by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of gene expression. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) and DNA fragmentation were used to determine the effects of thiram on cell survival. The results showed that thiram-induced TD was not due to the multiplication of cells in the post-proliferative zones. Thiram did not affect ALP activity, which would have indicated a loss of calcification potential, but it reduced both TRAP and the glutathione concentrations, suggesting that the growth plate metabolism and remodelling functions were adversely affected. Thiram appeared to have no effect on the expression of type X collagen, transglutaminase, RUNX2, or matrix metalloproteinase-2 (MMP) genes suggesting that it did not alter the maturation potential of chondrocytes. On the contrary, the expressions of MMP-13 and vascular endothelial growth factor (VEGF) genes were “up-regulated,” suggesting that thiram has pro-angiogenic activity. However, TUNEL assay showed that thiram induced endothelial cell apoptosis in the capillary vessels of the growth plates, as early as 10 days of age, when TD was not visually evident. The vascular death increased on subsequent days accompanied by massive death of chondrocytes in the transition zone of the growth plate. The induction of apoptosis in the growth plate was also demonstrated by DNA fragmentation. It was concluded that thiram induced TD not through an increase in the multiplication of chondrocytes in the transition zone and not by altering the expression of genes causing the arrest of chondrocytes in a prehypertrophic state, but by creating a metabolic dysfunction which led to the destruction of blood capillaries in the transition zone chondrocytes.

4065 Background: Cetuximab is a chimeric IgG1 Mab that targets the human epidermal growth factor receptor (EGFR). Most clinical trials using cetuximab in mCRC treated patients (pts) with EGFR positive tumors determined by immunohistochemistry (IHC). The intensity of EGFR immunostaining (IS) has not been related to the activity of cetuximab, and objective responses have been reported in pts with EGFR negative tumors. Potential reasons will be presented. Methods: This phase II multicenter study enrolled pts with refractory EGFR-undetectable mCRC who have received at least 1 standard fluoropyrimidine-containing chemotherapy regimen and an ECOG PS<2. Local results of EGFR by IHC were confirmed centrally. EGFR-undetectable disease is defined as no membrane staining above background for all tumor cells examined in a well preserved tissue section. Pts received weekly cetuximab infusions (400/250mg/m2 initial/weekly dose) and were evaluated for tumor response every 6 weeks. The primary outcome was overall response rate (ORR), and secondary outcomes included disease control rate, time to progression, survival, and safety. Results: 85 of the 88 patients enrolled received at least 1 dose of cetuximab and are evaluable for response. 86% of patients failed both oxaliplatin- and irinotecan-containing regimens, whereas 7%, 6%, and 1% failed only irinotecan-, oxaliplatin-, or fluoropyrimidine-containing regimens, respectively. To date, 6 pts had confirmed partial responses (PR): ORR=7% (95% CI=3–15%) as assessed by investigator. One pt has an unconfirmed PR and 7 pts are ongoing. There have been 4 cetuximab-related adverse events (Aes)>grade 3: infusion related reaction, hypomagnesaemia, dyspnea and skin rash. Two pts discontinued treatment due to Aes: 1 each with an infusion related reaction (above) and a small bowel obstruction. Efficacy endpoints will also be determined by an independent review. Conclusions: These preliminary results indicate that cetuximab monotherapy is active in refractory mCRC pts with EGFR undetectable disease. This activity is comparable to cetuximab monotherapy in EGFR-detectable, refractory mCRC, confirming that EGFR IHC is an unreliable indicator of cetuximab activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration ImClone ImClone ImClone

A33 Background: VEGFR-2 is a key regulator of angiogenesis and cancer cell growth. IMC-1121B is a recombinant human IgG1 MAb targeted to VEGFR-2. Anti-VEGFR-2 antibodies are effective in binding to the VEGFR-2, thereby inhibiting action of VEGF in a variety of preclinical leukemia and solid tumor models.
 Methods: This was a multicenter, first in-human study of IMC-1121B administered intravenously once a week for 4 weeks followed by a 2-week observation period in the first treatment cycle. The primary objectives were determination of the maximum tolerated dose (MTD) and safety profile. A dose-escalation scheme was utilized and included 7 cohorts with doses ranging from 2-16 mg/kg. Cohorts of 3-7 patients with advanced refractory or untreatable cancer, no significant cardiovascular, thrombotic, or bleeding disorders, and an ECOG PS of ≤ 2 were enrolled. PK sampling was performed in the first treatment cycle before and after drug administration in weeks 1 and 4. Anti-IMC-1121B antibodies were measured pretreatment and after each cycle. Pharmacodynamic analyses included serum VEGF, soluble VEGFR-1/2 levels and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Tumor response was established at the end of cycle 1 and then after every second cycle using RECIST.
 Results: Thirty-seven pts were enrolled, 23 male and 14 female. The study is now closed to accrual after two mechanism-based dose-limiting toxicities were observed at the 16 mg/kg dose level: symptomatic hypertension and deep venous thrombosis, defining 13 mg/kg as the MTD. Other grade ≥ 2 toxicities possibly or probably related to IMC-1121B included hypertension, proteinuria, arterial emboli, anorexia, nausea, vomiting, fatigue, headache, anemia, insomnia, hyperphosphatemia, elevated transaminases and amylase, depression, and groin and back pain. Four confirmed partial responses were observed (gastric cancer [duration of response was 56 weeks], neuroendocrine [32+ weeks], melanoma [30 weeks], and uterine leiomyosarcoma [9+ weeks]). At least 9 other patients experienced prolonged stable disease > 6 months (2 colorectal, 2 thyroid, 2 prostate, 1 pancreatic, 1 biliary tract, and 1 salivary gland cancers). Four patients experienced significant pain relief with reductions in analgesic requirements, and a patient with refractory pleural effusions experienced significant reductions in fluid retention and a lower frequency of thoracenteses. Noncompartmental PK analysis revealed dose-dependent elimination and nonlinear exposure consistent with saturable clearance mechanism(s). Serum VEGF levels at the 168 hour time point consistently increased 1.5-3.5 fold for all dose groups.
 Conclusions: The MTD for this study was reached at 13 mg/kg, defined by 2 mechanism-based DLTs occurring at 16 mg/kg. IMC-1121B is well tolerated and the PK profile is typical of a MAb. Elevated serum VEGF concentrations presumably reflect displacement of the protein by IMC-1121B. Antitumor activity was observed including 4 pts with tumor regression and several others with prolonged disease stabilization. These results suggest that IMC-1121B is tolerable and biologically and clinically active thus supporting further disease-directed development.

3505 Background: IMC-A12 is a fully human IgG1 monoclonal antibody directed against the human insulin like growth factor-I receptor. The safety and maximum tolerated dose (MTD) of IMC-A12 are being evaluated in an on-going a phase I trial. Methods: Patients (pts) with ECOG PS = 2 and advanced refractory solid tumors receive IMC-A12 weekly for 4 infusions per cycle until progression. After cycle one only, there is a two week observation period. Six cohorts of IMC-A12 are planned at 3, 6, 10, 15, 21, 27mg/kg. Sampling for PK and human anti-human antibodies directed against IMC-A12 occurs before and after the first and fourth doses of each cycle. Results: Fifteen pts have been treated, 7 at 3 mg/g, 4 at 6 mg/kg, 3 at 10 mg/kg and 1 at 15 mg/kg. Data is available for the first 11 pts: 7 male, 4 female, median age 56 years (range: 45–70). Treatment related toxicities for the first 11 pts include: grade 1 pruritis, rash, discolored feces; grade 2 anemia, psoriasis, hyperglycemia, infusion-related reaction; grade 3 hyperglycemia. Four of 11 pts have stable disease: 2 at the 3 mg/kg dose remain stable for >9 months (1 male breast cancer,1 hepatocellular cancer) and 2 at the 6 mg/kg dose (1 bladder, 1 endometrial) were stable after cycle 1. One pt with prostate cancer had >25% decline in PSA and stable radiographic disease at time of study discontinuation (week 5) for DLT. Non-compartmental PK analysis reveals a mean t1/2 of 148 and 209 hrs, mean Cmax of 333 and 415 ug/mL, and mean AUC0-Inf of 51317 and 80727 hr*ug/mL at the 3 and 6 mg/kg dose levels, respectively. Target trough levels have been achieved. Conclusions: Weekly administration of IMC-A12 appears to be well tolerated and the MTD has not been reached. The PK profile is consistent with that of other Mab’s. There is early evidence of clinical activity and correlative IGF biomarker data will be available. IMC-A12 will be further evaluated in prostate, breast, and other cancers. No significant financial relationships to disclose.

C84 Background: IMC-A12 is a recombinant human Mab targeting the insulin-like growth factor-I receptor (IGF-IR). Signaling pathways critical to tumor cell proliferation and survival are mediated by the IGF-IR, which is overexpressed in multiple tumor types. In preclinical studies, IMC-A12 inhibits the growth of a variety of tumor types in vitro and in vivo. Methods: This phase I dose escalation trial was initiated to assess the safety, efficacy, and pharmacokinetic (PK) / pharmacodynamic properties of IMC-A12. Adult (age ≥ 18) patients with advanced refractory or untreatable solid tumors were eligible for inclusion if they had measurable disease and ECOG PS ≤ 2. A treatment cycle consisted of IMC-A12 administered intravenously once every 2 weeks for 4 weeks (a total of two doses per cycle), with a 2-week observation period following the first 4-week cycle only. Assessment of tumor response was performed at the end of the 2-week observation period following Cycle 1, and every 8 weeks thereafter. The starting dose in cohort 1 was 6 mg/kg; dose escalation in subsequent cohorts continued to 10 mg/kg and then to 15 mg/kg. Safety was evaluated on a weekly basis, and blood samples for PK, pharmacodynamic, and immunogenicity analyses marker were drawn throughout the study. Results: The study population included 15 patients (mean age 57.3 years) five at 6 mg/kg, eight at 10 mg/kg, and two at 15 mg/kg. PK analysis showed dose-dependent elimination and nonlinear exposure, consistent with saturable clearance mechanism(s). At the 6 and 10 mg/kg dose levels, respectively, noncompartmental PK analysis revealed a mean t1/2 of 148 and 139 hrs, mean Cmax of 554 and 734 µg/mL, mean AUC0-Inf of 69575 and 134042 hr*µg/mL, and clearance of 0.143 and 0.122 mL/hr/kg. Cmin (2 weeks post-infusion) was 146 µg/mL in the 6 mg/kg dose group and 250 µg/mL in the 10 mg/kg dose group which exceeded the target serum concentrations for IMC-A12 determined from preclinical studies. Circulating IGF-I levels increased following the first infusion; pharmacodynamic data will be presented. No evidence of anti-IMC-A12 antibody activity has been detected. Adverse events (AE) of any grade believed to be possibly, probably, or definitely related to IMC-A12 treatment have been reported in two patients, and include eructation, nausea, fatigue, headache, paresthesia, alopecia, and acneform dermatitis. No grade ≥ 3 AE were considered related to IMC-A12, and no patients discontinued therapy due to an AE. Dose escalation was halted without DLT based on achievement of target Cmin of IMC-A12. No objective responses were observed but two patients have experienced stable disease > 12 weeks: a patient with a thymoma of the right anterior mediastinum and a patient with adenocarcinoma of the ovary.Conclusions: Based on the achievement of target Cmin plasma concentrations, the recommended phase 2 dose of IMC-A12 is 10 mg/kg when administered on an every-other-week basis. The elevation of circulating IGF-I levels suggests that IMC-A12 blocks IGF-I from binding to its receptor in a clinical setting. All dose levels were well-tolerated. There has been preliminary evidence of efficacy (disease stabilization > 12 weeks) in two patients.

3032 Background: Anti-VEGFR2 antibodies are effective in a variety of preclinical leukemia and solid tumor models. IMC-1121B is a fully human anti-VEGFR2 IgG1 Mab. Methods: Cohorts of 3–6 pts (ECOG PS ≤ 2) with advanced cancer and no significant cardiovascular, thrombotic or bleeding disorders received escalating doses of IMC-1121B. A single initial dose with extended PK sampling was followed by 4 x weekly infusions per treatment cycle starting at 2mg/kg. 7 dose levels up to a maximum of 16 mg/kg are planned. Human anti-human antibodies (HAHA) directed against IMC-1121B were assessed at baseline and before each Week 4 dose. Tumor response was assessed every 2 cycles. PD analyses include DCE-MRI, serum VEGF and sVEGFR1/2 levels, and peripheral blood mononucleocyte gene expression profiling at baseline and post-dosing. Results: 12 pts (8 M; 4 F), median age 58 years (range: 36–76), have entered the study: cohort 1 (2mg/kg) n=6, cohort 2 (4mg/kg) n=4 and cohort 3 (6mg/kg) n=2. No toxicities ≥ grade 2, considered definitely or probably related to study drug, have occurred. Toxicities ≥ grade 2 possibly drug-related include anorexia, vomiting, anemia, depression, fatigue, and insomnia. To date, there has been one unconfirmed partial response (melanoma) and 5 pts with stable disease for >3 months (colon: 2, breast, gastric, thyroid). Preliminary non-compartmental PK analysis reveals dose-dependent elimination and non-linear exposure, consistent with saturable clearance mechanism(s): mean t1/2 = 63.62, 93.46, 99.63 hrs, mean Cmax = 43.67, 80.25, 264 ug/mL, and AUC0-Inf = 3860, 9242, 27437 hr*ug/mL, at the 2, 4, and 6 mg/kg dose levels, respectively. Conclusions: Weekly administration of IMC-1121B is well tolerated at doses up to 6mg/kg/week. There is early evidence of a non-linear dose-PK relationship. Dose escalation continues. Updated safety, PK, PD, HAHA, and efficacy data will be presented. [Table: see text]

Over the last decade, there have been major changes in the treatment of ST-elevation myocardial infarction (STEMI). Whether these have resulted in changes in sex differences in time to treatment is unknown. We examined temporal trends in time to reperfusion therapy among men and women with STEMI.The study includes 2 cohorts of STEMI patients presenting to a large metropolitan region during the periods August 24, 2000, to August 20, 2002 (Cohort1, n = 753), and August 25, 2006, to December 31, 2008 (Cohort2, n = 885).In both cohorts, compared with men, women were significantly older and had more comorbidities. Rate of emergency medical services use among women increased from 55% in Cohort1 to 66% in Cohort2 (P = .02). Median time from symptom onset to first medical contact was 84 minutes among men and 121 minutes among women (P < .01) in Cohort1 and 59 minutes among men and 81 minutes among women (P < .01) in Cohort2. Median door-to-balloon time was significantly longer among women compared with men in Cohort2. After multivariable adjustment, female sex was associated with a 34% (or 27-minute) increase in time from symptom onset to first medical contact and with a 23% (or 13-minute) increase in time from hospital arrival to reperfusion therapy.In the last decade, there have been significant reductions in patient and system delay, especially among women. However, women continue to have longer presentation and treatment times, suggesting that there continue to be opportunities for improvement.