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BACKGROUND. S-1 is a promising oral fluoropyrimidine. The authors obtained extended Phase II safety and efficacy data in a multicenter setting for the S-1 plus cisplatin combination: The experimental arm of the global Phase III First-Line Advanced Gastric Cancer Study (FLAGS) is being compared with 5-fluorouracil/cisplatin. METHODS. Eligible patients had untreated, histologically confirmed advanced gastric cancer (AGC), a Karnofsky performance status (KPS) ≥70%, adequate organ function, and provided written consent. Patients received S-1 (25 mg/m2 twice daily on Days 1 through 21) plus cisplatin (75 mg/m2 on Day 1) every 28 days. The confirmed overall response rate (CORR) also was designated by an external review. The time to progression (TTP), median survival (MS), and safety were assessed. RESULTS. All 72 patients were assessed for safety and survival, and 64 patients were assessed for CORR. The median KPS was 90%. The median number of treatment cycles was 4. The CORR was 55% (95% confidence interval [95% CI], 42–67%). The median duration of response was >5 months. At 6 months, only an estimated 38% of patients had cancer progression. The estimated MS was 10.4 months (95% CI, 8.6–12.9 months). At least 1 serious adverse event occurred in 44% of patients. The frequent grade 3 or 4 toxicities (using the National Cancer Institute Common Toxicity Criteria), which occurred in >10% of patients, included fatigue/asthenia (24%), emesis (17%), nausea (15%), diarrhea (13%), and neutropenia (19%). Complicated neutropenia (1.4%) and grade 4 diarrhea (1.4%) were rare. CONCLUSIONS. The current extended data confirmed that S-1 combined with cisplatin had a highly desirable safety profile. The efficacy against AGC, according to an external review, was encouraging. FLAGS is expected to complete its accrual of 1050 patients by December 2007. Cancer 2007. © 2006 American Cancer Society.

Purpose S-1 plus cisplatin is considered highly active in Japanese gastric cancer patients. We conducted a phase II multi-institutional trial, in the West, in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma to evaluate activity and safety of this combination. Methods Patients received cisplatin intravenously at 75 mg/m2 on day 1 and S-1 orally at 25 mg/m2/dose bid (50 mg/m2/d) on days 1 to 21, repeated every 28 days. Patients with histologic proof of gastric or gastroesophageal junction adenocarcinoma with a Karnofsky performance status (KPS) of ≥ 70% and near-normal organ function were eligible. All patients provided a written informed consent. To observe a 45% confirmed overall response rate (ORR), 41 assessable patients were needed. Results All 47 patients were assessed for safety and survival, and 41 patients were assessed for ORR. The median age was 56 years and median KPS was 80%. The median number of chemotherapy cycles was four. The confirmed ORR was 51% (95% CI, 35% to 67%) and it was 49% by an independent review. At the 6-month interval, 71% of patients were alive, with a median survival time of 10.9 months. Frequent grade 3 or 4 toxicities included fatigue (26%), neutropenia (26%), vomiting (17%), diarrhea (15%), and nausea (15%); however, stomatitis (2%) and febrile neutropenia (2%) were uncommon. There was one (2%) treatment-related death. Conclusion S-1 plus cisplatin is active against gastric cancer and has a favorable toxicity profile. A global phase III study of S-1 plus cisplatin versus fluorouracil plus cisplatin currently is accruing patients.

3091 Background: INCB028060 is a potent and selective inhibitor of c-MET receptor tyrosine kinase (RTK). This first-in-human study aims to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and potential efficacy of INCB028060. Methods: In a standard 3+3 escalation, patients (pts) age =18 years with advanced solid tumors are treated with INCB028060 orally once (QD) or twice daily on a continuous 28-day schedule. C-MET inhibition is evaluated by adding c-MET overexpressing SNU-5 human gastric cancer cells to pts whole blood and then analyzing for inhibition of phospho-c-MET by ELISA. Results: At this time 17 pts have been treated across dose levels of 10, 20, 50, and 70 mg/once daily. Median age is 63 years, median ECOG PS is 0, and the most common tumor types are colorectal (4), NSCLC (3), and prostate/HCC/cholangiocarcinoma (2 each). One pt with breast cancer and diffuse liver metastases treated at 50 mg QD developed grade 3 AST elevation on C1D22, having had grade ...

e14117 Background: Achieving complete pathological response (CPR) with neoadjuvant chemoradiation may predict a higher likelihood of long-term survival in patients with operable rectal cancer. Howe...

15180 Background: For metastatic pancreatic cancer, no combination chemotherapy has been shown to improve survival significantly in comparison to single agent gemcitabine. A novel combination with oxaliplatin 60 mg/m2, irinotecan 90 mg/m2, cetuximab 250 mg/m2 (OIC) given every two weeks appears to produce a high rate of radiographic response. Since our reporting (ASCO 2007 GI Conference), we continue to see a high rate of clinical and radiographic responses (50% by Recist Criteria). We therefore decided to look carefully on the survival data of OIC versus control (mainly gemcitabine single agent or in combination with other agents). Methods: We retrospective reviewed patients seen from 10/2002 to 10/2006 with diagnosis of metastatic pancreatic cancer. The survival duration was calculated from the date of diagnosis to the date of death. We included only patients whose dates of death could be confirmed with death certificates. Results: A total of 37 patients were identified. 11 of those were in the OIC arm and 26 were treated with other regimens (17 with gemcitabine-based regimens, 9 with either capecitabine or 5-FU-based regimens) that function as control. The range of survival duration was 4 - 28 months for OIC arm and 1 - 28 months for the control. Median survival was 10 months for the OIC arm versus 5 months for the control. Conclusions: OIC regimen produces a high rate of tumor response and may have a survival advantage with this retrospective analysis. We believe it is a regimen deserves further evaluation. No significant financial relationships to disclose.

3592 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. This phase I study assesses the safety, tolerability and pharmacokinetics (PK) of SU in combination with capecitabine (C). Methods: Pts with advanced solid tumors not amenable to curative therapy, previously treated with =2 prior chemotherapy regimens, and ECOG PS =1 were eligible. Prior antiangiogenic therapy was not permitted. Three SU schedules were evaluated: 4 wks on treatment followed by 2 wks off in 6-wk cycles (4/2 schedule); 2 wks on followed by 1 wk off in 3-wk cycles (2/1 schedule), and continuous dosing (CD schedule). In all cases C was administered orally bid on days 1–14. SU and C doses were alternately escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) of SU for all schedules using a standard 3 + 3 design. PK and antitumor efficacy were also assessed. Results: A total of 50 pts have been enrolled; 28 pts have been treated on the 4/2 schedule: SU 50 mg + C 1,000 mg/m2, and SU 37.5 mg + C 1,250 mg/m2 were not tolerated. Dose limiting toxicities (DLTs) included: grade 3 myalgia (n=1), grade 3 fatigue (n=2), and grade 3 hand- foot syndrome (n=2). The MTD for the 4/2 schedule was SU 37.5 mg/day + C 1,000 mg/m2. No DLTs nor dose reductions were observed among 9 pts treated at the MTD. Preliminary PK data do not indicate drug-drug interactions between SU and C. 3 pts (1 each with breast cancer, neuroendocrine carcinoma, and thyroid carcinoma) achieved confirmed partial responses. On the 2/1 schedule patients are being accrued to SU 37.5 or 50 mg + C 1,000 mg/m2 and doses of SU 37.5 mg + C 1,000 mg/m2 or SU 25 mg + C 1,250 mg/m2 are being explored on the CD schedule. Conclusions: The combination of SU 37.5 mg/day (4/2 schedule) with C 1,000 mg/m2 in pts with advanced solid tumors appears tolerable. SU may be administered in combination with C with no apparent drug-drug interaction. Subsequent cohorts will define the MTD of SU administered on the 2/1 and CD schedules. Further studies of this combination in breast cancer are warranted. No significant financial relationships to disclose.

10056 Background: The combination of G and D has shown efficacy against refractory STS (Hensley, JCO 2002). STS have a high content of VEGF, which is associated with poor prognosis. This phase I/II study assesses the safety, tolerability, efficacy, and pharmacodynamics (PD) of B in combination with G+D, given on a two-weekly schedule to minimize adverse events (AEs). We are reporting the phase I results. Methods: Untreated pts with advanced or recurrent STS and ECOG PS =2 were eligible. Some pts were treated in a neoadjuvant setting, when surgically appropriate. Planned doses were G 1,000, 1,250, and 1,500 mg/m2, D 50 mg/m2, and B 5 mg/kg iv, every 2 wks. G doses were escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) of G with fixed doses of D and B. MTD was assessed on the first 2 cycles (1 cycle = 2 wks). Treatment was continued until progression or unacceptable toxicity. For neoadjuvant therapy, B was given only for 4 cycles, followed by 4 cycles without B in anticipation of surgery and pts came off study at that point. PD and antitumor efficacy were also assessed. Results: Nine pts have been treated on the phase I escalation arm, including 3 in the neoadjuvant setting. There were no dose limiting toxicities. After 4 cycles with G at 1,500 mg/m2, there was 1 asymptomatic grade 4 bowel perforation at the site of the tumor in a pt with initially inoperable leiomyosarcoma (LMS). After emergency surgery, the pt is free of disease. Observed grade 1 and 2 AEs include alopecia, diarrhea, fatigue (5 each), rigors (4), nausea, dyspnea, headaches (3 each), chest pain, epistaxis, stomatitis, anemia (2 each), rash, hypertension, neuropathy, leukopenia (1 each). There were 1 CR (angiosarcoma), 2 PR, (myxoid sarcoma, undifferentiated sarcoma), 4 NC (2 LMS, liposarcoma, PNST), and 2 PD (myxoid sarcoma, PNST). Necrosis was observed, including in NC disease. Three pts are free of disease after surgery. Conclusions: The combination of G, D, and B given every 2 weeks is safe and has demonstrated some activity in pts with advanced or recurrent STS. The phase II arm is ongoing at G 1,500 mg/m2 with 4 pts already enrolled. Mature data including PD will be reported at the meeting. No significant financial relationships to disclose.

4083 Background: We obtained additional phase II safety and efficacy data in a multi-center setting on an active regimen of S-1 plus cisplatin; the experimental arm of the global phase III First-Line Advanced Gastric cancer Study (FLAGS). Methods: Eligible patients had untreated advanced gastric cancer (AGC), histologic proof, KPS ≥70%, adequate organ function, and gave written consent. Patients received S-1 (25mg/m2 p.o. bid on days 1–21) plus cisplatin (75mg/m2 i.v. on day 1) every 28 days. All reported confirmed overall response rate (C-ORR), response durations, and time-to-progression (TTP) are externally reviewed. Results: All 72 patients were assessed for safety and 64 for efficacy. The median age was 56 years and median KPS was 90%. Median no. of cycles was 4. C-ORR was 50% (95% CI, 37%-63%). Median duration of response is >6 months. At 6 months, only 35% of patients have had cancer progression. Median survival (n=72) is 10.5 months (95% CI, 9.3 to NR). At least one SAE occurred in 43% of patients. The frequent grade 3 or 4 adverse events (occurring in >10% of patients) included: fatigue/asthenia (26%), vomiting (21%), nausea (18%), diarrhea (17%), neutropenia (18%), anorexia (11%), and dehydration (11%). Febrile neutropenia (1.4%) and grade 4 diarrhea (1.4%) were rare. Conclusions: These extended data confirm that S-1 plus cisplatin has a very desirable safety profile and impressive efficacy data in AGC. FLAGS will complete accrual of >700 patients by March of 2007. (Supported by Taiho Pharma-USA). [Table: see text]

13099 Background: Flavopiridol is a cyclin-dependent kinase (CDK) inhibitor. The major toxicities are secretory diarrhea and neutropenia for the 72- and 1-hour infusion schedules, respectively, fatigue, and thrombosis. Gemcitabine or irinotecan (SN-38) followed by flavopiridol at concentrations that correlate with CDK inhibition, produce sequence-dependent cytotoxic synergy with increase in apoptosis by 10–15-fold in all the cell lines tested. Both gemcitabine and irinotecan have broad activity in a number of solid tumors and may be synergistic with flavopiridol. Methods: Eligibility criteria included: patients (pts) with any advanced solid tumors; >18 years old; PS ≤ 2; life expectancy > 3 months; and normal kidney, liver, and marrow functions. Treatment consisted in gemcitabine 800 mg/m2 and irinotecan 80 mg/m2 on day 1 and flavopiridol, starting dose of 30 mg/m2 on day 2 with increment of 15 mg/m2 per dose level, repeated on days 8 and 9 for the first 6 patients, then on days 15 and 16 for the other patients (protocol was amended for inability to redose after one week). Results: Fifteen pts (12 women and 3 men) were enrolled. Characteristics were: Median age, 49 (33–77) years; Median PS 1; ethnicities, 6 whites, 3 native americans, 3 hispanics, and 3 others; Median number of prior chemotherapies, 2 (0–9). Six pts were treated on the first schedule at the first dose level, which caused 1 neutropenic sepsis and death, 1 grade 3 diarrhea, and 5 neutropenia preventing retreatment. On the q 2 week schedule, we have reached the second dose level. Side effects at flavopiridol 30 mg/m2 were all grade 1: nausea (3/3), fatigue (2/3), anorexia (1/3), and neuropathy (1/3). At 45 mg/m2 one heavily pretreated pt had DLT of diarrhea and fatigue. The other 5 pts had grade 2 fatigue (2/5), nausea (2/5), diarrhea (1/5), anorexia (1/5). Additional grade 1 side effects include thrombocytopenia, pitting edema, and pain. Response were seen a small cell tumor of the ovary, and a leiomyosarcoma of the uterus. Conclusions: The every two week dosing is well tolerated and the MTD has not yet been reached. Main side effects are consistent with known toxicity profile for irinotecan and gemcitabine. Mild pitting edema and sensory neuropathy have been noted in 2 patients each. No significant financial relationships to disclose.

14135 Background: Gemcitabine-based chemotherapy is considered standard approach for patients with metastatic pancreatic cancer but the results remain unsatisfactory with survival averaging about 6 to 10 months. Cell line study indicates more than 90% of pancreatic cancer cells express EGFR receptor. We therefore explore the use of non-gemcitabine-containing regimen and add an EGFR inhibitor. Method: We initiated a regimen with irinotecan 120 mg/m2, oxaliplatin 85 mg/m2, and cetuximab 400 mg/m2 first dose followed by 250 mg/m2 for all subsequent doses delivered every 14 days for patients with metastatic pancreatic cancer. Results: From 1/2005 to 12/2005, a total of 5 patients were treated. Two males and three females, age 59 to 78. Three presented with metastatic disease. One had Whipple’s procedure then had disease recur 2 months post-surgery. One had locally advanced disease and progressed 10 months after concurrent chemoradiation. Grade III/IV neutropenia, anemia developed in 1/5 patients. Grade III/IV diarrhea and nausea/vomiting developed in 3/5 patients. Grade III/IV fatigue, anorexia developed in 4/5 patients. The non-hematologic toxicity was the main reason for dose reduction. 4 had CT scan for response evaluation. The fifth patient completed first cycle of treatment on 1/3/2006 and had CA19–9 dropped from 15,900 to 9,398 u/ml (40% decline). By CT scan, partial response rate is 75% as shown in the table. So far, two patients have died, 5 and 10 months since initiating treatment, one from recurrent hepatic abscess and one from fungus infection. Conclusions: This combination delivered every other week appears promising for patients with metastatic pancreatic cancer. The planned phase II trial will adopt a lower dose approach with irinotecan 90 mg/m2, oxaliplatin 60 mg/m2, and cetuximab 250 mg/m2. [Table: see text] No significant financial relationships to disclose.

14126 Background: Patients with metastatic biliary cancers continue to face a very grim prognosis with no effective chemotherapy. Median survival is around 6–9 months. Irinotecan and capecitabine have modest activity against cholangiocarcinoma. Cyclooxygenase-2 (COX-2) enzyme expression is reported in many human cholangiocarcinoma cell line studies and is linked to tumor cell resistance to chemotherapy-induced apoptosis. We hypothesized that adding a COX-2 inhibitor would improve the therapeutic benefits in patients with biliary tumors. Methods: From 9/2003 to 2/2005, a total of 12 patients were treated with a combination regimen, delivered at a cycle interval of 21 days, that consisted of 120 mg/m2 irinotecan given intravenously over 60 minutes on day 1, 1500 mg/m2/day capecitabine taken orally in divided doses on days 1–14 and 400 mg/day celecoxib taken orally in divided doses on days 1–21. Results: A total of 117 treatments were administered to the 12 patients (9 females and 3 males; median age, 56 years; 10 cholangiocarcinoma and 2 gallbladder cancer). Based on the tumor marker CA19–9, 7 of the patients had a partial response (7/12, 58%). Of the seven patients for which sequential CT evaluation was available, the partial response rate was 43% (3/7) and two additional patients had stable disease. The median progression-free survival was 13 months and the median overall survival was 17 months. We encountered grade II neutropenia and anemia (2/12 each, 17%) and grade I diarrhea and hand-foot syndrome (33% and 7%, respectively). Conclusions: These data suggest that the combination of irinotecan, capecitabine and celecoxib is an effective palliative regimen for patients with metastatic biliary cancers. Further development of this regimen is severely hindered by the potential cardiovascular risk associated with long-term use of COX-2 inhibitor. No significant financial relationships to disclose.

3744 Background: Concurrent neoadjuvant chemoradiation in operable rectal cancer seeks to: decrease tumor burden; increase chance for sphincter-sparing surgery; and demonstrate tumor response to se...

4265 Background: There is no known effective chemotherapy regimen for patients with unresectable/metastatic cholangiocarcinoma. We are here to report a single institution, retrospective chart revie...

4024 Background: A Phase I study of S-1 (tegafur, oxonic acid, and CDHP) plus cisplatin performed in Western patients defined the MTD (S-1 50mg/m2/d taken orally on d 1–21 and cisplatin 75 mg/m2 gi...

2114 Purpose: 5-Fluorouracil (5-FU) has been shown to modulate DNA repair activity. This study tests (1) what is the maximum tolerated dose of capecitabine (C) given for 10 days prior to cisplatin (P) and irinotecan (I); (2) the changes in DNA repair induced by C. Patients and Methods: Patients (pt) with incurable cancers were eligible if they had normal hematologic, renal and liver functions, and had not failed 5-FU analogs or topoisomerase I inhibitors. The first cycle was P+I day 1 and I day 8 and 15, 50 mg/m2 each, to serve as control. C was started at the second cycle at a dose of 500 mg/m2/day x 10 days for the first cohort prior to P+I, which was administered on day 11, 18, and 25. Increments were by 250 mg/m2/cohort. A 3+3 design was used. Blood was drawn for DNA repair studies before the first 3 cycles and before cisplatin for the first 2 cycles. DNA repair analyses will be performed by measuring the residual cisplatin concentrations in DNAs collected from these patients. Patients stayed on study...

3161 Background:Since the approval of thalidomide by the FDA in 1998, there has been wide off-label use in oncology based on its purported cytokine modulating and anti-angiogenesis properties. We c...

4239 Background: With highly active anti-retroviral therapy, HIV-positive patients are living longer. Increased incidence of anal squamous cell carcinoma (ASCC) has been noted in these patients. Op...