ImClone Systems Research Articles

CETUXIMAB: From Bench to Bedside

Cetuximab (IMC-C225, Erbitux ImClone Systems Inc, New York, NY) is a recombinant, human/mouse chimeric monoclonal antibody (MAb) that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR) on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) as well as other ligands. Cetuximab binding to the EGFR blocks phosphorylation and activation of receptor-associated kinases and their associated downstream signalling (MAPK, PI3K/Akt, Jak/Stat pathways) resulting in inhibition of many cellular processes such as induction of apoptosis, cell growth, decreased Matrix Metallo-Proteinase (MMPs) and vascular endothelial growth factor (VEGF) production. Cetuximab is also able to display cytotoxic effect through antibody-dependent cellular cytotoxicity (ADCC). In vitro and in vivo experiments elucidated a wide range of biological properties attributed to cetuximab, these include: direct inhibition of EGFR tyrosine kinase activity, inhibition of cell cycle progression, inhibition of angiogenesis, invasion and metastatization processes, activation of pro-apoptotic molecules and synergic cytotoxicity effect with chemotherapy and radiotherapy. Several studies have shown cetuximab is able to inhibit growth of EGFR-expressing tumor cells in vitro as well as in nude mice bearing xenografts of human cancer cell lines. Moreover, numerous clinical trials demonstrated cetuximab efficacy in different tumor types and it is approved by Food and Drugs Administration (FDA) for use in the treatment of metastatic colorectal cancer (mCRC) as single agent or in combination with chemotherapy, for locally/regionally advanced head and neck squamous cell carcinoma (HNSCC) in combination with radiotherapy, and as monotherapy for recurrent/metastatic HNSCC after failing platinum-based chemotherapy. This review will illustrate pre-clinical and clinical data on biological properties of cetuximab focusing on the predictive markers of clinical response to this drug.

Erratum to: Controversies in the Management of Hepatic Colorectal Metastases

The educational review series ‘‘Controversies in the Management of Hepatic Colorectal Metastases’’ published in the September 2009 issue of the Annals of Surgical Oncology was supported by educational grants from sanofiaventis U.S., Bristol-Myers Squibb, and ImClone Systems Inc. Following is the list of articles that comprise this Educational Series. Controversies in the Management of Hepatic Colorectal Metastases

Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival

Previous results from our phase 3 randomised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN) at 3 years. Here we report the 5-year survival data, and investigate the relation between cetuximab-induced rash and survival. Patients with LASCCHN of the oropharynx, hypopharynx, or larynx with measurable disease were randomly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6-7 weeks or radiotherapy plus weekly doses of cetuximab: 400 mg/m(2) initial dose, followed by seven weekly doses at 250 mg/m(2). Randomisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score, T stage, N stage, and radiation fractionation. The trial was un-blinded. The primary endpoint was locoregional control, with a secondary endpoint of survival. Following discussions with the US Food and Drug Administration, the dataset was locked, except for queries to the sites about overall survival, before our previous report in 2006, so that an independent review could be done. Analyses were done on an intention-to-treat basis. Following completion of treatment, patients underwent physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months thereafter. The trial is registered at www.ClinicalTrials.gov, number NCT00004227. Patients were randomly assigned to receive radiotherapy with (n=211) or without (n=213) cetuximab, and all patients were followed for survival. Updated median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months (95% CI 32.8-69.5) versus 29.3 months (20.6-41.4) in the radiotherapy-alone group (hazard ratio [HR] 0.73, 95% CI 0.56-0.95; p=0.018). 5-year overall survival was 45.6% in the cetuximab-plus-radiotherapy group and 36.4% in the radiotherapy-alone group. Additionally, for the patients treated with cetuximab, overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0.49, 0.34-0.72; p=0.002). For patients with LASCCHN, cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone, confirming cetuximab plus radiotherapy as an important treatment option in this group of patients. Cetuximab-treated patients with prominent cetuximab-induced rash (grade 2 or above) have better survival than patients with no or grade 1 rash. ImClone Systems, Merck KGaA, and Bristol-Myers Squibb.

467 INVITED The targeted oncology platform at ImClone Systems: novel receptor blocking antibody therapeutics and approaches

467 INVITED The targeted oncology platform at ImClone Systems: novel receptor blocking antibody therapeutics and approaches

87 POSTER Correlation analysis utilizing measurements of tumor biomarkers and antibody efficacy against EGFR, IGF1R and VEGFR2 receptors in multiple tumor models

Specific insulin-like growth factor-I receptor (IGF-IR) targeting emerged in recent years as a promising therapeutic strategy in cancer. Endometrial cancer is the most common gynaecological cancer in the Western world. The aim of this study was to evaluate the potential of cixutumumab (IMC-A12, ImClone Systems), a fully human monoclonal antibody against the IGF-IR, to inhibit IGF-I-mediated biological actions and cell signalling events in four endometrial carcinoma-derived cell lines (ECC-1, Ishikawa, USPC-1 and USPC-2). Our results demonstrate that cixutumumab was able to block the IGF-I-induced autophosphorylation of the IGF-IR. In addition, the PI3K and MAPK downstream signalling pathways were also inactivated by cixutumumab in part of the cell lines. Prolonged (24 h and 48 h) exposures to cixutumumab reduced IGF-IR expression. Furthermore, confocal microscopy of GFP-tagged receptors shows that cixutumumab treatment led to IGF-IR redistribution from the cell membrane to the cytoplasm. Antiapoptotic effects were evaluated by cleavage of caspase 3 and PARP, and mitogenicity and transformation by proliferation and cell cycle assays. Results obtained showed that cixutumumab abrogated the IGF-I-stimulated increase in proliferation rate, and increased caspase-3 and PARP cleavage, two markers of apoptosis. Of importance, cixutumumab had no effect neither on insulin receptor (IR) expression nor on IGF-I activation of IR. In summary, in a cellular model of endometrial cancer cixutumumab was able to inhibit the IGF-I-induced activation of intracellular cascades, apoptosis and proliferation.

TAKEOVER Bristol-Myers goes straight to ImClone shareholders with higher bid

Bristol-Myers Squibb Chairman James M. Cornelius sidestepped ImClone Systems’ management last week by presenting a sweetened buyout offer directly to ImClone shareholders. Bristol-Myers is now willing to pay $62.00 per share, or $4.7 billion, to buy the 83.4% of its drug development partner that it doesn’t already own. In a written response, ImClone Chairman Carl C. Icahn called the hostile offer “absurd” and said Cornelius is being misleading. Although Cornelius alleges that ImClone has resisted meaningful discussions, Icahn insisted that the company has been happy to discuss better offers. The public haggling has gone on for nearly two months, since Bristol-Myers first made an unsolicited $60.00-per-share bid that ImClone’s directors called inadequate. Soon after, Icahn, who owns about 13.5% of ImClone’s stock, announced that an unnamed large pharmaceutical firm had made a conditional $70.00-per-share offer (C&EN, Sept. 15, page 20). Apparently fed up with waiting, Cornelius wrote in a Sept. 22 letter t...

Which adjuvant systemic treatments (AdjRx) would medical oncologists (MOs) wish to receive if they had colon cancer (CCa)? A survey of 150 physicians

4049 Background: Decisions about AdjRx for CCa lead some patients (Pts) to ask MOs what they would do in the same situation. We wished to understand how often Pts ask MOs what therapy they would choose as a Pt and how MOs respond. Methods: 150 US-based MOs were recruited for a survey focused on several AdjRx scenarios. MOs were asked how they manage CCa and what treatment they would choose for themselves in the described situations. Results: MOs (median age 48, 75% male) estimated that 41% of Pts with CCa ask how they would be treated, and 70% of MOs regularly provide an answer. For Stage III CCa, oxaliplatin-based chemotherapy or clinical trial participation were more common choices than off-study chemo/biologic therapy (Table 1). Trials evaluating bevacizumab were favored over studies with cetuximab (p<0.01). For Stage II CCa with only eight nodes examined, 86% of MOs would receive AdjRx. 47% of MOs would receive AdjRx for lower-risk Stage II CCa, but when presented only with a set of recurrence risks derived from Adjuvant! Online for a similar case, 97% would want AdjRx. Overall, MO recommendations to Pts were identical for 73% of responses. Conclusions: Although it is unclear if MOs should communicate their potential treatment choices to Pts, many do so when asked, and generally recommend treatments they would elect as Pts. Most MOs would not receive off-study biologics even for high-risk Stage III disease, and clinical trials evaluating these agents were more common choices. About half of MOs would be treated in a situation perceived qualitatively as “low-risk Stage II,” yet almost all would be treated based on the quantitative risk reductions for a similar case as described in Adjuvant! Online. This suggests that MOs would receive treatment for a modest reduction in recurrence risk if they were convinced there was that benefit. More research is required to better understand these complex issues. Table 1: MO treatment preferences if they were diagnosed with colon cancer Treatment Stage III Higher- risk Stage II Lower-risk Stage II 2/18 node-positive 15/18 node-positive 0/8 nodes No high risk features, 0/18 nodes Risk-calculation data presented only1 FOLFOX/CAPOX 51% 27% 56% 17% 86% Clinical trial: FOLFOX vs FOLFOX/bevacizumab 31% 42% N/A2 N/A N/A Clinical trial: FOLFOX vs FOLFOX/cetuximab 3% 3% N/A N/A N/A Chemotherapy + bevacizumab 3 13%4 27%5 0% 0% 0% 5-FU/LV alone 1% 0% 14% 13% 4% Capecitabine alone 1% 1% 14% 17%6 7% No chemotherapy 0% 0% 16% 53%7 3% 1 According to Adjuvant! Online (age 55, Grade I, T3N0M0 with > 10 nodes identified). Baseline five-year recurrence risk = 13%; risk with fluoropyrimidine = 10.5%; risk with oxaliplatin/fluoropyrimidine = 8.1% 2 N/A = Not applicable, case asked for non-protocol treatment only 3 FOLFOX + bevacizumab = 11% and 26% for 2/18N+ and 15/18N+ cases, respectively 4 Significantly different from MO patient recommendation of 7% (p<0.05) 5 Significantly different from MO patient recommendation of 11% (p<0.05) 6 Significantly different from MO patient recommendation of 8% (p<0.05) 7 Significantly different from MO patient recommendation of 70% (p<0.05). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Inc, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Genentech BioOncology, Genomic Health, ImClone Systems, Merck and Company Inc, Novartis Pharmaceuticals Corporation, Pfizer Inc, Response Genetics Inc, Roche Laboratories Inc, sanofi-aventis Adjuvant! Inc Amgen Inc, Bristol-Myers Squibb Company, Genentech BioOncology, Pfizer Inc, Roche Laboratories Inc, sanofi-aventis Amgen Inc, AstraZeneca Pharmaceuticals LP, CTEP, ImClone Systems, NCI/NIH, sanofi-aventis, SWOG Amgen Inc, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Eli Lilly, Genentech BioOncology, ImClone Systems, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche Laboratories Inc, sanofi-aventis

Phase II ECOG trial of irinotecan/docetaxel with or without cetuximab in metastatic pancreatic cancer: Updated survival and CA19–9 results

4642 Background: Gemcitabine (G) is standard for metastatic pancreatic cancer (PC), with median survivals of 6 months (m). We conducted this randomized phase II trial to determine the activity of this non-G regimen, and whether combining it with cetuximab (C ) was feasible and active. Primary endpoint was response. 50% fall in CA19–9 is examined as a response surrogate in this update because restaging was not performed in 32% of pts; we previously demonstrated 50% fall in CA19–9 to correlate with survival (p=.02). Methods: Pts required histologic confirmation of adenocarcinoma of the pancreas, distant metastases, ECOG PS 0–1, normal. bilirubin, written informed consent, and were randomly assigned to Arm A or B. CT or MR within 4 weeks (wk) was used for tumor measurement. Pts on Arm A received docetaxel 35 mg/m2 and irinotecan 35 mg/m2 weekly x 4 in a 6 wk cycle. Pts on Arm B received the same therapy, with C (400 mg/m2 wk 1, 250 mg/m2 weekly thereafter). Pts not receiving therapeutic anticoagulation received enoxaparin 40 mg per day. Pts were restaged (RECIST) after 2 cycles (12 weeks). Results: In eligible, treated pts (Arm A = 44, Arm B = 43) (EGFR = 97%): Median age Arm A: 60.2, Arm B: 60.6 years. Arm A 55% male, 34% PS 0. Arm B 86% male, 44% PS 0. Mean number of cycles Arm A = 2.8, Arm B = 3.3. Dominant grade ¾ toxicities were neutropenia, nausea, diarrhea. 32% pts were never restaged (related to baseline PS, p =.03). Responses were seen in 4.5%: Arm A (90% CI 1.5%, 18.4%) and 7%, Arm B (90% CI 2.3%, 19.3%). CA19–9 fell 50% from baseline in 30% Arm A, 39% Arm B (p=0.47). Median progression-free survival Arm A 3.9 m, Arm B 4.5 m. Median overall survival (OS), with 89% of pts known to have died, 6.5m in Arm A. With 98% of pts known to have died in Arm B, OS 5.3 m. Median OS for pooled arms was greater for pts with lesser EGFR immunoreactivity than for pts with 3+ staining on > 50% of cells (p= 0.086). Conclusions: Weekly I/D ± C is associated with grade 3/4 neutropenia/diarrhea. The study did not meet the goal of 4 responding pts in either arm; however, the rate of restaging was markedly lower than projected. The surrogate response endpoint of 50% fall in CA19–9 is exploratory: 11 pts in Arm A and 14 in Arm B experienced a 50% decline in CA19–9. Non-G containing therapy is active in metastatic PC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Bristol-Myers Squibb, ImClone Systems, Pfizer, sanofi-aventis Bristol-Myers Squibb, ImClone Systems, Pfizer

Evaluation of tumor gene expression and K-Ras mutations in FFPE tumor tissue as predictors of response to cetuximab in metastatic colorectal cancer

3512 Background: The anti-EGFR monoclonal antibody cetuximab shows activity in a subset of patients with metastatic colorectal cancer (mCRC). This study was conducted to discover and validate markers that are found to be associated with disease control and improved progression-free survival (PFS) time in patients treated with cetuximab. Methods: Formalin-fixed paraffin-embedded primary tumors of 226 patients from three studies of cetuximab monotherapy in advanced mCRC were retrospectively assayed for K-Ras mutations and for expression of candidate genes. The expression of K-Ras sequences (7 mutations and 1 wild-type) and 102 candidate genes were measured by quantitative RT-PCR. Statistical associations of mutation and gene expression with disease control (CR+PR+SD) or PFS were determined. Results: 82 (36%) of the 226 analyzed samples had K-Ras mutations. Patients whose tumors did not have K- Ras mutations had a significantly higher disease control rate (60%) than those with K-Ras mutations (23%) (p<< 0.001). Among all 226 patients, quantitative expression of 40 genes was significantly associated with disease control (p<0.05) after adjusting for multiplicity. Among 144 patients without K-Ras mutation, 31 genes were significantly associated with disease control (p<0.05) after adjusting for multiplicity. Genes that were strongly associated with disease control in both analyses included genes encoding the EGFR ligands epiregulin (EREG) and amphiregulin (AREG). Based on these results, we have developed multi-gene predictors that incorporate EREG and AREG, which when used in conjunction with K-Ras mutation status increase the ability to predict who might benefit from cetuximab treatment over K-Ras mutation status alone. Conclusions: A multi-parameter marker test comprising of K-Ras mutation status in combination with the expression levels of a small number of genes could be developed further to select patients for cetuximab therapy. Applicability of this test to cetuximab combination therapy should be explored. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb, Genomic Health, Inc., ImClone Systems, Inc. Bristol-Myers Squibb, Genomic Health, Inc., ImClone Systems, Inc.

Variability in the reporting of dermatologic adverse reactions (dADRs) to EGFR inhibitors cetuximab (C) and panitumumab (P) in the treatment of metastatic colorectal cancer (mCRC)

15045 Background: The epidermal growth factor receptor inhibitors(EGFRIs) C and P have demonstrated clinical activity against mCRC. Despite these benefits, up to 90% of patients experience dADRs, which can decrease their quality of life and alter antineoplastic therapy, both of which can affect outcome. There is anecdotal evidence suggesting inconsistency in the reporting of these events in clinical trials, which has led to deficient data on incidence and risk factors. Thus, our study examines the variability of EGFRI induced dADR reporting in mCRC clinical trials. Methods: The Pubmed MEDLINE database was searched for relevant information. Search terms included “C” and “P”, and “colorectal cancer”, and limited to Phase II-III clinical trials. Data obtained included regimen, number of discrete dADRs, and rash-survival correlation. Results: All dADRs reported were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE V.3.0). Our search yielded 31 results for C and 7 for P. Of 31 C trials, 11 (35%) reported between 1 and 3 dADRs. One dADR was reported in 6 trials (55%), 2 dADRs in 4 (36%) and 3 dADRs (rash, paronychia, and pruritus) were reported in 1 (9%). Rash was reported in all (11 of 11) trials, paronychia in 5 of 11, and pruritus in 1 of the 11. Of 7 P trials, 3 (43%) reported between 2–7 dADRs. Two dADRs were reported in 1 trial (33%), 6 dADRs in 1 (33%), and 7 dADRs (rash, pruritus, dry skin, paronychia, dermatitis acneiform, skin desquamation, skin fissures, and erythema) in 1 (33%). All of the reports mentioned rash as a side effect. However, they were not consistent in the manner in which rash was reported. CTCAE toxicity grading was completely reported in 82% of C trials and 100% of P. The use of tabulated data to report dADRs was present in 82% of C trials and 100% of P trials. Of note, a positive rash-survival correlation was noted in 45.5% of C trials and 66% of P. Conclusions: Our results indicate that there is considerable variability of EGFRI-induced dADR reporting in mCRC trials. This impedes the ability of Oncologists to provide accurate pre- therapy counseling to their patients. To improve data reliability, current standards should be revised. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Inc, ImClone Systems, Onyx Pharma Amgen Inc, Bayer Pharmaceuticals, ImClone Systems

Phase 1 study of IMC-3G3, an IgG1 monoclonal antibody targeting PDGFRα in patients with advanced solid malignancies

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

Economic impact associated with the management of dermatologic adverse drug reactions (dADRs) induced by EGFR inhibitors (EGFRIs) in lung cancer

19094 Background: Dermatologic adverse drug reactions including rash, paronychia, xerosis, alopecia and pruritus occur in up to 75% of non-small cell lung cancer (NSCLC) patients treated with EGFRIs. In addition to the impact on psychosocial and physical health, there are also financial implications. This study seeks to evaluate the costs associated with the management of cutaneous side effects caused by EGFRIs in patients with NSCLC referred to a dermatology-based program for the management of dADRs in oncology, the SERIES (Skin and Eye Reactions to Inhibitors of EGFR and kinaseS) clinic. Methods: Medical records for a subset of 10 NSCLC patients treated with the EGFRI erlotinib was identified. Unit costs for each resource were obtained from the Red Book for pharmaceuticals and Medicare Physician Fee Schedule for outpatient services. Average total cost for treatment (including drug regimen and administration-related costs) were computed based on average wholesale drug price and procedure code, respectively. Costs were also evaluated separately for: drug treatment, clinic visits and other services such as laboratory tests and biopsies. Results: All patients (100%) developed rash in addition to paronychia (40%), xerosis (80%), pruritus (50%) and alopecia (10%). Average number of visits and treatment period was 5 and 38.7 weeks respectively. Mean total cost for treatment (including drugs, clinic visit and other services) was $2,715.56 per patient. A mean of 12.6 prescriptions (range 4–39) were filled per patient for drugs treating dADRs, imposing a mean cost of $1,347.06 per the average patient. A mean of 6.3 administration-related services (clinic visits, lab tests, biopsies) per patient (range 1–17) accounted for an average cost of $1,368.50 to the average patient. Conclusions: This study substantiates that there is a considerable financial impact in the management of EGFRI-induced dADRs in NSCLC patients. Interventions that prophylactically address such frequently occurring cutaneous toxicities are critical for the minimization of dADR treatment-related costs. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Inc, Bayer Pharmaceuticals, ImClone Systems

A phase II study of cetuximab (C225) in combination with chemoradiation (CRT) in patients (PTS) with stage IIIA/B non-small cell lung cancer (NSCLC): A report of the 2 year and median survival (MS) for the RTOG 0324 trial

7516 Background: C225 is a chimerized monoclonal antibody that targets the epidermal growth factor receptor (EGFR). NSCLC commonly expresses the EGFR, which is associated with aggressive tumor behavior and poor clinical outcome. Preclinical model systems demonstrate radiosensitization following molecular inhibition of EGFR signaling. Methods: We report a phase II trial testing the combination of C225 with CRT in unresectable stage III NSCLC with a planned sample size of 84 PTS. Eligibility criteria included Zubrod performance status (PS) ≤ 1, weight loss ≤ 5% over past 3 months, FEV1 ≥ 1.2 L, adequate hematologic, hepatic, and renal function. PTS received an initial dose of C225 (400 mg/m2) on day 1 of wk 1, then wkly doses of C225 (250 mg/m2) until completion of therapy (wks 2 - 17). During wk 2, PTS started CRT (63 Gy/35 fractions) with wkly carboplatin (C) AUC 2 and paclitaxel (P) 45 mg/m2 x 6 doses followed by C (AUC 6) and P (200 mg/m2) x 2 cycles (wks 12–17). Interim monitoring for severe (grade ≥ 3) or excessive non-hematologic toxicities occurred after PTS had been treated and followed for at least 90 days after RT. Primary endpoints include safety and compliance of concurrent C225 and CRT. Results: 93 PTS were enrolled with 87 evaluable PTS. PTS characteristics: 57% male, median age 64 years (range 42–85), 47% PS 0, 46% stage IIIA. Median follow-up is 21.6 months (M). Response rate is 62% (n=54), MS is 22.7 M, and 24 M overall survival (OS) is 49.3%(# at risk=40). Adverse events related to treatment include 20%(n=17) of PTS with grade (G) 4 hematologic toxicities, 8% (n=7 PTS) G 3 esophagitis, and 7% (n=6 PTS) G 3–4 pneumonitis. There were 5 G 5 events. Conclusions: The combination of C225 with CRT is feasible and active with MS and OS better than any previously reported by the RTOG. These results warrant confirmation in a randomized trial. Complete compliance, toxicity, and updated survival data will be reported. Supported by RTOG U10 CA21661, CCOP U10 CA37422, and Stat U10 CA32115 grants from the NCI. This abstract's contents are the sole responsibility of the authors and do not necessarily represent the official views of the NCI. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb, ImClone Systems Incorporated Bristol-Myers Squibb, ImClone Systems Incorporated Bayer, Bristol-Myers Squibb, Eli Lilly

Use of thrombin-receptor 1 (PAR-1), endostatin (ES), and interleukin-8 (IL-8) gene polymorphisms to predict tumor recurrence in patients with surgically resected gastric cancer

4559 Background: Tumor recurrence continues to be a significant problem in the management of patients with surgically resected gastric cancer. Thrombin-receptor 1 (PAR1) has been described to counter-regulate the release of endostatin (ES) and VEGF from human platelets. PAR-1 could therefore play a crucial role in the regulation of tumor angiogenesis and in turn may regulate the process of tumor invasion and metastasis. Further, interleukin-8 (IL-8) has been reported to play a major role in VEGF-independent tumor angiogenesis. We tested whether 14 functionally significant gene polymorphisms within 8 genes involved in the tumor angiogenesis pathway, will predict tumor recurrence in patients with surgically resected gastric cancer. Methods: Between 1992 and 2007 blood specimens from 105 patients (41 females and 64 males; median age=57 yrs; range=26–85 yrs) were obtained at the University of Southern California medical facilities. The median follow-up was 2.4 years (range=0.1–12.3). 47 of 105 patients (45%) developed tumor recurrence with a 5-year probability of 0.38 ± 0.06. Genomic DNA was isolated from peripheral blood and genotypes were determined using PCR-RFLP. Results: High-expression variants of PAR-1 -506 (median TTR: 1.2 yrs) and IL-8 -251 (median TTR: 1.6 yrs) as well as low-expression variants of ES +4349 (median TTR: 2.2 yrs) were associated with an increased likelihood of tumor recurrence, compared to other genotype combinations of PAR-1 (median TTR: 2.3 yrs), IL-8 (median TTR: 2.9 yrs), and ES (median TTR: 2.9 yrs). In multivariate analysis, polymorphisms in PAR-1 (adjusted p=0.04) and IL-8 (adjusted p=0.03) showed to be independent prognostic factors for TTR. Conclusions: PAR-1 I- 506D, ES G+4349A, and IL-8 T-251A polymorphisms may help to identify gastric cancer patients who are at increased risk to develop tumor recurrence. Thus targeting PAR-1, ES and IL-8 may be of clinical benefit in patients with surgically resected gastric cancer. Larger, prospective and biomarker embedded clinical trials are needed to validate these preliminary data. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb, Genentech™ BioOncology, ImClone Systems Incorporated, Merck, Pfizer Oncology, Response Genetics Genentech™ BioOncology, Merck, Pfizer Oncology, Roche, sanofi-aventis

Cox-2 inhibition and chemoradiation for squamous cell carcinoma of the head and neck

6065 Background: Concurrent chemoradiation is accepted as a standard option for locally advanced squamous cell carcinoma of the head and neck (SCCHN). Other strategies however are needed in order to improve local regional control and ultimate outcomes. Cyclo-oxygenase 2 (Cox-2) inhibition induces radiosentization and chemosentization. We conducted a Phase I/II trial using chemoradiation with Celecoxib in advanced SCCHN and reported the results after a 4 year median follow-up. Methods: From 12/02- 7/06 30 patients with locally advanced or recurrent SCCHN were entered. The objectives were to evaluate toxicity, determine the local control and disease free survival. Patients were treated with weekly carboplatin (AUC=2.0), paclitaxel (30mg/m2), radiotherapy (70Gy) and celecoxib 400mg bid. The celecoxib was started 1 week prior to the initiation of the concurrent chemoradiotherapy. Initially the celecoxib was given for a total of 2 years. After reports of concerns for cardiotoxicity, we discontinued the study 12/04. The study was restarted in 5/06. Celecoxib was used only during chemoradiotherapy thereafter. Results: Twenty-seven patients with newly diagnosed SCCHN and 3 patients with recurrent disease were treated. Seven patients were treated after study modification. The acute grade >3 toxicity was as follows: Febrile neutropenia 23%, mucositis 33%, dysphagia 63%, nausea/vomiting 17%, dermatitis 30%. Ten patients were unable to complete prescribed chemotherapy secondary to myelosuppression. There were 2 deaths during the treatment phase of the trial, both in the absence of neutropenia. One person expired secondary to delirious tremors and infection and another secondary to unknown causes. Nineteen of 30 patients are currently NED (63%) four of which required surgical salvage. Twenty of 30 patients achieved initial local control with 5 developing distant metastasis only. Conclusions: Concurrent chemoradiotherapy plus celecoxib was associated with an increased incidence of neutropenia. Control rates were similar to previously published concurrent chemoradiotherapy trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb, ImClone Systems Incorporated

A pilot study of gemcitabine (g), oxaliplatin (o), cetuximab (c) for locally advanced or metastatic pancreatic cancer

15510 Background: Little progress has been made in the treatment of advanced pancreatic cancer (PC). Preclinical data suggest synergism between a platinum + G, and G + C. The combination of G and erlotinib is a standard. The combination of G and platinums is associated with higher RR and PFS to G alone. Methods: The study primary endpoint was to determine the progression free survival (PFS) of GOC in patients with locally advanced or metastatic pancreatic cancer. It was expected that GOC would extend PFS from 5.8 months to 7.54 months (relative increase of 30%). Chemotherapy naïve patients with locally advanced (LA) or metastatic (M) PC with PS 0–2 and good organ function were eligible. Treatment: G, 1000 mg/m2 over 100 minutes and C, at a loading dose of 400 mg/m2 on day 1 (250 mg/m2 on day 8 and subsequent cycles), and O,100 mg/m2 on day two, every two weeks (one cycle). Patients were treated until disease progression, intolerable toxicity, or patient refusal. Efficacy evaluation was performed every 4 cycles. Results: A total of 41 evaluable patients were enrolled from June 2006 to July 2007. Median age was 62 years, (range: 44–82). Male/female: 19/22. Twenty patients (48.8%) had metastatic disease. Median PFS time was 6.9 months (95% CI=3.9–9.2). Median PFS in LA patients was 7.5 months vs. 4.5 months in M patients. Confirmed RR= 24% (95% CI=12–40%), with one (2.4%) CR and 9 (22%) PR. Clinical benefit rate (CR, PR and SD) was 75, 6% (95% CI=59.7–87.6%). One year survival was 53% (95% CI=30–71%). Median OS was 6.5 months in the M group and not reached yet in the LA group. 1-year survival for LA: 75% (95% CI=37–92%), M: 33% (95% CI=7–62%). Most frequent grade 3/4 AEs (≥ 10% of patients) included neutropenia, infection, liver enzyme elevation, fatigue, diarrhea, peripheral neuropathy, hypokalemia and thrombosis. Conclusions: GOC is an active combination with a favorable toxicity profile. The study did not meet its primary endpoint. Updated information on the primary and secondary endpoints and correlative studies on available tumor specimens will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration ImClone Systems Incorporated, Lilly Oncology, Pfizer Oncology, sanofi-aventis

Race and albuterol premedication are risk factors for hypersensitivity reactions to cetuximab

20503 Background: Cetuximab (C-mab) is a recombinant (human/mouse) epidermal growth factor receptor antibody indicated for use in patients with colorectal cancer (CRC) and head and neck cancer (HNC). Serious grade 3–4 hypersensitivity reactions (HSR) to C-mab have been reported in the frequency of 0.5%-22%. The purpose of this paper is to study risk factors for HSR to C-mab at our institution. Methods: A retrospective record review was performed of serial patients treated with C-mab at the Siteman Cancer Center, St. Louis, MO for CRC from July 2004 to July 2006 and HNC from June 2005 to August 2007. HSR were defined as allergic reactions to C-mab and were graded 1–5 according to severity, based on the Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Data regarding demographics and premedication history was collected from patient charts. Results: Fifty-one patients (27 males and 24 females) with CRC and 50 patients (38 males and 12 females) with HNC treated with C-mab were identified and their mean age was 60 ±12.07 years. Seventy (69.3%) patients were Caucasian and 31 (30.7%) were African American. All patients were pre-medicated with benadryl prior to C-mab administration. Data regarding pepcid, dexamethasone and solucortef premedication was available for 84 patients. Of these, 14(16.7%) received pepcid, 32 (38.1%) received dexamethasone and 25 (29.8%) received solucortef. Twenty four (48%) of HNC patients also received albuterol. Eleven patients (10.9%) developed HSR. Serious grade 3–4 HSR were seen in 9 patients (8.9%). Race was strongly associated with HSR. All 11 patients who developed HSR were Caucasian (Fisher’s exact p=0.017). No grade 3–4 HSR were seen in the group who received albuterol (Fisher’s exact p=0.077). There was no statistically significant effect of dexamethasone, pepcid or solucortef premedication on the risk of HSR, although the small numbers were limiting. Age and gender had no effect on the risk of HSR. Conclusions: Race is a strong predictor for HSR. Additional pre-medication with albuterol may prevent grade 3–4 HSR. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Abraxis Oncology, Amgen, Bristol-Myers Squibb, Genentech™ BioOncology, ImClone Systems Incorporated, Pfizer Oncology, sanofi-aventis

Age and ethnicity predict overall survival in patients with metastatic gastric cancer

15500 Background: Patients diagnosed with metastatic gastric cancer have dismal outcome. There was a lack of established regimens to improve their survival. The prognostic role of gender, age and ethnicity on survival for patients with metastatic gastric cancer has not been determined in the U.S. It has been shown that Asians treated in Asia have overall a significant better outcome than Caucasians treated in Western world. The etiology of gastric cancer may differ among the different ethnic groups. These different etiologies include environmental factors, H.pylori infection and dietary factors which may lead to different genetic profiles of gastric cancer associated with different clinical outcome. Methods: Extracting data from the US National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registries, we compared overall survival for patients with metastatic gastric cancer by gender, age and ethnicity using multivariate Cox proportional hazards models. 15,228 patients (≥ 18 years) were identified from the years 1988- 2003. The ages of the males and females were categorized with <45, 45- 54, 55- 64, 65–74, and ≥75 years. Patients who were Native Americans, African Americans, Asians, Caucasians, and Hispanics were included. The models were adjusted for potential confouders including marital status at diagnosis, tumor site, treatment with radiation and/or surgery, and histology, and stratified by SEER registry sites and years of diagnosis. Results: Overall survival was decreased with age (p<0.001, Cox model). The median overall survival was 6 months in patients of ≤ 44 years compared to 2 months in patients who were ≥75 years. The difference of overall survival by ethnicity significantly was varied by sex (P for interaction = 0.01). Among males, Asian patients had longer overall survival, and African American patients had shorter overall survival compared to Caucasian patients (p=0.023). No significant difference in overall survival across ethnicity was found among females. Conclusions: This is the largest study of metastatic gastric cancer from SEER registries to show that age was a significant prognostic factor for overall survival in patients with metastatic gastric cancer. The influence of ethnicity on overall survival was dependent on sex. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb, Genentech™ BioOncology, ImClone Systems Incorporated, Merck, Pfizer Oncology, Response Genetics Genentech™ BioOncology, Merck, Pfizer Oncology, Roche, sanofi-aventis Dhont Family Foundation, NCI, NIH

Phase 1 study of weekly anti-vascular endothelial growth factor receptor-1 (VEGFR-1) monoclonal antibody IMC-18F1 in patients with advanced solid malignancies

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

Hand foot skin reaction (HFSR) by the multikinase inhibitors (MKIs) sorafenib and sunitinib: Impact on quality of life (QoL)

16122 Background: The MKIs sorafenib and sunitinib have shown a survival advantage in a variety of solid tumors. However, their use is hampered by the occurrence of HFSR in 20–30% of patients (pts), which may lead to dose modification or discontinuation and affect clinical outcome. This study investigated the overall impact of HFSR on QoL and its relationship with clinical severity. Methods: We analyzed the results of a dermatology-specific QoL pt reported questionnaire, the Skindex-16 (SK16). Overall SK16 scores vary from 0 (best QoL) to 96 (worst QoL). Subdomain scores for physical (0–30), emotional (0–36), and functioning (0–30) were also assessed. Clinical severity of HFSR was determined using the NCI-CTCAE v3.0. The relationship between HFSR grade and SK16 scores was determined using the Wilcoxon rank sum test. Correlation among the domains of the SK16 were assessed using the Pearson correlation coefficient. Results: 11 pts were included in the study (mean age = 59.4, range 41–84). The mean overall SK16 score among pts was 33 ± 25.9. The highest mean subdomain scores were for physical, followed by emotional (Table). Highest rated items were pain (3.45 ± 2.5), irritation (3.18 ± 2.7) and persistence of skin condition (3.36 ± 2.1). Emotional symptoms were correlated with perceived physical symptoms at r = 0.86 (p < 0.005) and functioning at r = 0.73 (p = 0.01). The worst SK16 symptom subdomain scores and overall scores were significantly associated with the highest HFSR grades (Table). Conclusions: This study suggests that HFSR has a substantial effect on overall QoL and physical symptoms are the most critical in this population. The significant increase in SK16 score with increasing NCI-CTCAE grade supports its validity as a tool in the assessment of physical symptoms in HFSR. Emotional distress proved to be an important correlate. Our study suggests that the SK16 is a valuable supplement in assessment of HFSR, as it also reflects non-physical morbidity, particularly the emotional impact of the disease. Mean SK16 Scores by HFSR Grade SK16 Subdomain NCI-CTCAE Grade 1 (N=3) 2 (N=7) 3 (N=1) All (N=11) Physical (p = 0.013) 4 15.6 23 13.1 ± 8.1 Emotional (p = 0.051) 2 15 29 12.7 ± 12.3 Functioning (p = 0.22) 4.7 6 23 7.2 ± 7.6 Overall (p = 0.042) 10.7 36.6 75 33 ± 25.9 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Bayer, ImClone Systems Incorporated, Onyx Amgen, Bayer, ImClone Systems Incorporated, Pfizer Oncology