Alberts, Steven R.

446 Background: MutKRAS and mutBRAF are important predictive and prognostic markers, respectively, in colorectal cancer (CRC). However, little is known about why some tumors harbor these mutations. N0147 is a phase III adjuvant trial for stage III CRC patients (N=3397) in which patients completed questionnaires and tumor variables and KRAS/BRAF mutation status was assessed. Methods: 2,323/3,397 patients who were enrolled prior to a 2008 amendment requiring KRAS testing completed a Patient Questionnaire. Primary tumors were assessed for mutKRAS and mutBRAF using standard methods; MMR status was determined using IHC. Multivariate analysis was performed to identify predictors of mutation status. Results: 60% and 86% of mutKRAS and mutBRAF tumors were right-sided, respectively. MutKRAS was less likely if there was a family history of CRC and in ever-smokers, and was nearly mutually exclusive with mutBRAF. MutBRAF was associated with deficient MMR (dMMR), high grade histology, and 4+ positive lymph nodes at surgery. MutBRAF was more likely in patients age > 70, retired persons, ever-smokers, but was less likely in non-whites and men. Conclusions: Smoking, family history of CRC, and dMMR status are associated with lower frequency of mutKRAS , but higher mutBRAF. Both mutations tend to be right sided, and mutBRAF is more common in the elderly, females, and non-Hispanic whites. [Table: see text]

314 Background: Small bowel adenocarcinoma (SB-ACA) is rare, having little prospective data guiding management. A prior phase I study evaluated UGT1A1 genotype specific dosing of oxaliplatin, irinotecan, and capecitabine. Our prospective, multicenter clinical trial assessing tumor response in pts having metastatic SB-ACA, used a similar dosing strategy. Methods: Genotypes were determined via central lab. Previously untreated pts were dosed by UGT1A1*28 genotypes 6/6, 6/7, and 7/7 receiving 100/85/85 mg/m2 oxaliplatin d1, 150/150/75 mg/m2 irinotecan d1, and 1600/400/200 mg/m2 capecitabine (BID) d2-15 of 21 days. The study design was such that 1 confirmed response in 16 pts expanded enrollment to 33 pts, with 7 required for demonstrating efficacy. Results: 28 pts (13-6/6, 10-6/7, 5-7/7) have been enrolled [75% male, mean age 62.5 (range 41-77)]. Location of primary included: duodenum (63%), jejunum (26%), and ileum (7%), with pts having >1 metastatic site (abdominal-41%, bone-7%, liver-56%, lung-30%, nodal-52%, subcutaneous-4%, other-19%). Gr 3+ treatment related toxicity was not significantly different by genotype (50%-6/6, 44%-6/7, 20%-7/7, p=0.48) and included (pts): diarrhea(5), vomiting(5), leukopenia(5), neutropenia(7), and nausea(6). 57% (13 of 23) pts achieved responses during therapy, with a confirmed response rate of 39% (95% CI 0-58%). 18 have died, with a median follow-up of 8.3 mos (range 0-43). Conclusions: UGT1A1 genotype directed dosing with oxaliplatin, irinotecan, and capecitabine appears to result in prolonged response in this population. Larger studies are needed to determine comparability to CapeOx alone or if response/toxicity differs among genotypes. Supported by NIH Grant CA25224, Sanofi-Aventis, and Pfizer. [Table: see text]

271 Background: Epidermal growth factor inhibitors show some benefit in the treatment of advanced pancreatic cancer. A trial to evaluate the incorporation of Pmab into a conventional multimodality regimen and continuation as maintenance therapy was conducted in pts with LA disease. Methods: Pts with ECOG PS 0-1, preserved organ function and tumor encompassed within standard radiation fields were eligible. Pmab 6 mg/kg on days 1, 15, 29 and continuous infusion 5-FU 225 mg/m2/d or capecitabine 825 mg/m2 were given with RT. Pts then received weekly gemcitabine 1000 mg/m2 and Pmab on days 1, 15 for three 4-week cycles. Maintenance Pmab was then continued for additional 6 months. RT consisted of 45 Gy to the tumor and regional nodes with a 5.4 Gy boost using conformal techniques. Primary endpoint of one-year survival (OS) with secondary endpoints progression-free survival (PFS), confirmed tumor response, and adverse events (at least possibly related) are reported. Results: 51 pts (23 M: 28 F) were enrolled with a median age of 65 (range: 43-84). Twenty-two pts (43%) received at least 1 cycle of post-chemo-RT, while 29 patients only received chemo-RT. All 51 pts have ended treatment with pts going off study because of: progression (39%), adverse events (27%), refusal (25%), and other reasons (8%). Frequently occurring maximum grade 3/4 AEs across the entire treatment course (chemo-RT + post-chemo-RT chemo) are shown below. With a median follow-up of 12.3 months, survival at 12 months is 50.2% (95% CI: 37.9-66.5%), median survival 12.1 mos (95% CI: 6.8-15.9) and median PFS 7.4 mos (95% CI: 3.7-8.6). Confirmed response rate was 5.9% (1-CR, 2-PR). Conclusions: The addition of Pmab to a conventional chemo-RT regimen provides benefit in terms of median survival. This is similar to reports of other EGFR inhibitors in LA disease. Adverse events, especially during the chemo-RT portion, were considerable and affected administration of subsequent systemic maintenance therapy. [Table: see text]

363 Background: Irinotecan (CPT-11) has demonstrated antitumor activity against metastatic colorectal cancer used alone or with 5-fluorouracil (5FU)/leucovorin (LV). Two arms with CPT-11, 5FU, and LV (FOLFIRI) +/- cetuximab (Cmab) were originally included in N0147. However, after CALGB 89803 (J Clin Oncol. 25:3456, 2007), PETACC-3 (J Clin Oncol. 27:3117, 2009), and Accord02 (Ann Oncol. 20:674, 2009) showed no benefit to the three-drug combination in adjuvant therapy, the CPT-11 arms of N0147 were discontinued. We report the outcomes for patients given FOLFIRI +/- Cmab. Methods: Following a signed informed consent patients with resected stage III colon cancer were randomized to one of 6 arms including 12 biweekly cycles of CPT-11 180 mg/m2 d1 with LV 400 mg/m2, 5FU 400 mg/m2 bolus IV, then 46-hr IV 5FU 2,400 mg/m2 on d1-2 without (Arm B, FOLFIRI) or with Cmab (Arm E) 400 mg/m2 d1 cycle 1 then Cmab at 250 mg/m2 d1 and 8. Primary endpoint was 3-year disease-free survival (DFS). Secondary endpoints included overall survival (OS) and toxicity. Results: 156 patients (Arm B-111, Arm E-45) were enrolled; median follow-up on 81 patients in Arm B was 60.3 months and 58.2 months in Arm E for 41 patients. wtKRAS (vs mt) status was associated with improved DFS (HR=0.6 [95% CI 0.4-1.1], p = 0.09) and OS (HR 0.7 [95% CI 0.4-1.5], p = 0.38). The addition of Cmab improved DFS and OS in the overall group and within wtKRAS pts. Grade greater than III non-hematologic adverse effects were significantly increased in the Cmab arm (46% vs. 64%, p = 0.05). Conclusions: In this randomized phase III trial adjuvant FOLFIRI resulted in a 3-year DFS lower than that expected for FOLFOX. Trends for improved DFS and OS with the addition of Cmab were observed in patients with resected stage III colon cancer patients, regardless of KRAS status. Supported by NIH Grant CA25224, Bristol-Myers Squibb, ImClone, Sanofi-Aventis, and Pfizer. [Table: see text] [Table: see text]

261 Background: Mapatumumab is a fully human agonist monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1). Sorafenib targets Mcl-1, a key TRAIL resistance protein, and accordingly could enhance mapatumumab's pro-apoptotic activity. Based on this and on preclinical data on mapatumumab in HCC cell lines, the current dose-escalation study is evaluating mapatumumab in combination with sorafenib in patients with advanced HCC. Methods: Eligible patients had advanced HCC, Child-Pugh A or Model for End-Stage Liver Disease score < 15, and were positive for hepatitis B surface antigen or hepatitis C antibody. Intravenous mapatumumab was administered at 3, 10 or 30 mg/kg every 21 days with sorafenib (400 mg twice daily) until disease progression or unacceptable toxicity. Dose-limiting toxicities (DLTs) included events considered at least possibly related to mapatumumab and/or its interaction with sorafenib. Tumor measurements were performed every 2 cycles. Dose escalation required at least 3 patients in a cohort to receive >= 50% of full-dose sorafenib in the first 2 cycles. Results: To date, 19 patients have been enrolled in the 3 mg/kg (n=6), 10 mg/kg (n=9) and 30 mg/kg (n=4) cohorts and have received a median of 4 cycles (range 1 to 24 cycles); 4 patients have received >= 11 cycles. The maximum tolerated dose has not been reached. DLTs that prompted expansion of the 3 mg/kg and 10 mg/kg cohorts were elevations of amylase and/or lipase (1 at 3 mg/kg, 1 at 10 mg/kg). Other Grade 3-4 events considered at least possibly related to mapatumumab and/or its interaction with sorafenib included hepatic pain (1/17), thrombocytopenia (1/17), increased aspartate aminotransferase (1/17), increased lipase (1/17), and increased gamma-glutamyltransferase (1/17). Two patients have had a partial response and 4 patients have had stable disease lasting > 12 weeks, based on investigator assessment. Conclusions: Mapatumumab was well-tolerated at doses up to 30 mg/kg in combination with sorafenib in patients with HCC and viral hepatitis. A randomized phase II study of this combination in patients with advanced HCC is planned. [Table: see text]

238 Background: Dual inhibition of the EGFR pathway using erlotinib and the monoclonal antibody panitumumab results in greater antitumor activity in preclinical pancreatic cancer models. A trial evaluating this approach was conducted. Methods: A safety analysis was initially performed with 6 patients at P 4 mg/kg every two weeks, E 100 mg daily, G 1000 mg/m2 weekly of a 28-day cycle. PGE was well tolerated with a grade 3 fatigue as only dose-limiting toxicity. Patients (pts) were then randomized to either PGE or GE alone. Eligibility included: no prior chemo, ECOG PS 0-1, bilirubin <2x UL, AST <2.5x UL. CT scans every 2 cycles. Results: 93 pts (46-GE; 47-PGE) were randomized from January to August, 2010. Median age 61 years and 65% male. ECOG PS 0 (51%) and PS 1 (49%). No significant differences in baseline characteristics observed between treatment arms. 81 pts evaluable for AEs; 37 (46%) had a maximum grade 3 (at least possibly related to treatment), and 12 (15%) maximum grade 4 or 5. Treatment arms similar with respect to the overall AEs with exception grade 1-3 acneiform rash, GE (65%) vs. PGE (85%). Commonly occurring grade 4 AEs (at least possibly related) consisted of thrombosis (3 pts) and thrombocytopenia (2 pts). Two grade 5 events occurred in PGE arm—duodenal hemorrhage (possibly related) and pancolitis with multisystem failure (unlikely). An additional PGE pt died 30 days off study (grade 5 CHF, possibly). 54 patients (67%; 31-GE, 23-PGE) ended treatment; 38 (70%) for disease progression (24-GE; 14-PGE). Other reasons for treatment discontinuation: AEs (9; 17%), pt refusal (4; 7%), death on study (2; 4%), other (1). In 81 pts with at least 1 cycle of chemotherapy, the median PFS for GE 2.0 months and 3.3 months for PGE. Accrual for the study was recently completed and overall and 6-month survival data will be presented. Conclusions: This study involved an initial run-in design to define tolerable doses of dual EGFR inhibitors, PGE, in pancreatic cancer patients. Although preliminary, the randomized phase II portion has been completed and differences between GE and PGE in terms of relevant clinical outcomes, PFS, are observed. No significant financial relationships to disclose.

CRA3507 Background: FOLFOX is standard adjuvant therapy for stage III CC. Adding Cmab to FOLFOX benefits pts with metastatic CC WT KRAS tumors. N0147 assessed the potential benefit of Cmab added to FOLFOX. Methods: 21-56 days following resection and informed consent, KRAS status was centrally determined. Pts with wtKRAS CC were randomized to 12 biweekly cycles of oxaliplatin 85 mg/m2 d1, with leucovorin 400 mg/m2, 5FU 400 mg/m2 bolus IV, then 46-hr IV 5FU 2,400 mg/m2 on d1-2 (mFOLFOX6), without (arm A) or with Cmab (arm D) 250 mg/m2 d1&8, with Cmab at 400 mg/m2, cycle 1, d1. Primary endpoint was 3-yr disease free survival (DFS). Secondary endpoints included overall survival (OS) and toxicity. Planned accrual of 2,070 wtKRAS pts provided 90% power to detect hazard ratio (HR) of 1.33 with 2-sided α=0.05; with interim analyses after 25%, 50%, and 75% of planned events. Results: 1,760 wtKRAS pts (Arm A-858, Arm D-902) were enrolled at the time of closure; median follow-up on 1,624 pts is 15.9 months. Trial closed to accrual when preplanned interim analysis after 50% of planned events demonstrated no benefit to addition of Cmab. 3-yr DFS favored FOLFOX alone (HR 1.18, 95% CI 0.92-1.52; p=0.33). No benefit of Cmab was observed in any subgroups assessed. Any grade ≥ 3 AE, diarrhea, and failure to complete 12 cycles was significantly increased in arm D. Increased toxicity and greater differences in all outcomes were observed in pts aged ≥ 70 ( Table ). Conclusions: In this randomized phase III trial the addition of Cmab to mFOLFOX6 was of no benefit for pts with resected stage III wtKRAS CC. Supported by NIH Grant CA25224, Bristol-Myers Squibb, ImClone, Sanofi-Aventis, and Pfizer. [Table: see text] [Table: see text]