NCI-CTC Grade Research Articles

Elderly subgroup analysis of a randomized phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for first‐line treatment of advanced nonsmall cell lung carcinoma (TAX 326)

Controversy continues over whether elderly patients with advanced nonsmall cell lung carcinoma (NSCLC) should receive platinum-based chemotherapy. TAX 326 reported improved survival with docetaxel-cisplatin (DC) versus vinorelbine-cisplatin (VC) for advanced NSCLC. DC and docetaxel-carboplatin (DCb) were better tolerated than VC. We analyzed the efficacy and toxicity in patients ages < 65 and > or = 65 years. Chemotherapy-naive, TNM Stage IIIB-IV NSCLC patients were randomized to DC (docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2), d1 q3w), DCb (docetaxel 75 mg/m(2) and carboplatin area under the concentration-time curve 6 mg/mL.min, d1 q3w), or VC (vinorelbine 25 mg/m(2), d1, 8, 15, and 22 and cisplatin 100 mg/m(2), d1 q4w). Of 1218 patients, 401 were age > or = 65 years (149/118/134 DC/DCb/VC arms). In the elderly, median survival was 12.6 versus 9.9 months, 1-year survival was 52% versus 41%, 2-year survival was 24% versus 17% for DC versus VC, respectively. DCb survival results were similar to those for VC: median, 9.0 months; 1-year, 38%; 2-year, 19%. Survival outcomes were similar between elderly and younger patients across treatment arms. Compared with younger patients, elderly patients reported moderately higher incidences of NCI CTC (version 1.0) Grade 3-4 asthenia, infection, and pulmonary toxicities across treatment arms, and diarrhea and sensory neurotoxicity for cisplatin-containing arms. Most hematologic toxicities occurred with similar incidences between elderly and younger patients, although neutropenia was slightly increased in elderly patients. First-line docetaxel-cisplatin chemotherapy showed similar activity in elderly and younger patients with advanced/metastatic NSCLC; elderly patients tolerated docetaxel-platinum well despite experiencing slightly more toxicity than younger patients.

Hyperthermia combined with radiation in treatment of locally advanced prostate cancer is associated with a favourable toxicity profile

Purpose: Hyperthermia is used to treat several pelvic tumours. An important step in establishing a broader role for hyperthermia in treatment of prostate cancer is verification of an acceptable toxicity profile. In this report, short- and long-term toxicity profiles of a completed phase II trial of transrectal ultrasound hyperthermia combined with radiation in treatment of locally advanced prostate cancer are presented.Methods and materials: Thirty-seven patients enrolled on a phase II study of external beam radiation ± androgen suppression with two transrectal ultrasound hyperthermia treatments were assessed for short- and long-term toxicity. Prostatic and anterior rectal wall temperatures were monitored. Rectal wall temperatures were limited to 40°C (19 patients), 41°C (three patients) and 42°C (15 patients). Univariate logistic regression was used to estimate the log hazard of developing NCI CTC Grade 2 toxicity based on temperature parameters. Hazard ratios, 95% confidence intervals, p-values for statistical significance of each parameter and proportion of variability explained for each of the parameters were calculated.Results: Median follow-up was 42 months. Both short- and long-term GI toxicity were limited to grade 2 or less. Acute grade 2 proctitis was greater for patients with allowable rectal wall temperature of >40°C. Eleven of 18 patients in this group had acute grade 2 proctitis vs three of 19 patients with rectal wall temperatures limited to 40°C (p = 0.004). Long-term grade 2 GI and GU toxicity occurred in 5% and 19% of patients. No late grade 3 or greater toxicity occurred. Late GI and GU toxicity were not associated with the allowable rectal wall temperature.Conclusion: Transrectal ultrasound hyperthermia combined with radiation for treatment of advanced clinically localized prostate cancer is safe and well tolerated.

Phase II trial of carboplatin and paclitaxel in cisplatin‐pretreated advanced transitional cell carcinoma

The purpose of the study was to assess the efficacy and toxicity of carboplatin and paclitaxel administered every 3 weeks in patients with advanced urothelial carcinoma, previously treated with cisplatin-based therapy. Eligibility included metastatic or locally advanced unresectable transitional cell carcinoma of the urothelial tract. Prior chemotherapy, except taxanes, was permitted within 12 months. Adequate hematologic, hepatic, and renal function and a performance status of 0-2 were required. Treatment consisted of paclitaxel 200 mg/m2 intravenously for 3 hours followed by carboplatin, target area under the curve = 5 repeated every 3 weeks. Forty-four patients were enrolled. Thirty-four (77%) patients had a performance status of 0 or 1. Twenty-five (57%) of the patients had received prior neoadjuvant or adjuvant chemotherapy, and 19 (43%) had received it for metastatic disease. In all, 181 cycles were administered (median, 3.5 cycles; range, 1-11 cycles). The predominant NCI CTC (version 2.0) Grades 3 and 4 toxicities consisted of myelosuppression in 28 patients and neuropathy in 11 patients. There were no treatment-related deaths. Of the 44 patients, 1 (2%) had a complete response, 2 (5%) had a partial response, and 4 (9%) had an unconfirmed partial response, for an overall response rate of 16% (95% confidence interval [CI] 7-30%). The median progression-free survival was 4 months (95% CI 3-5 months) and the median survival was 6 months (95% CI 5-8 months). Carboplatin and paclitaxel combination is well tolerated and has modest activity in platinum refractory advanced urothelial carcinoma. Effective regimens need to be developed in cisplatin-pretreated urothelial carcinoma.

Radiation Therapy and Simultaneous Chemotherapy for Recurrent Cervical Carcinoma

To evaluate the efficacy and toxicity in patients with recurrence of cervical cancer treated with radiotherapy and simultaneous chemotherapy. Between 1987 and 2001, 24 patients with recurrent cervical carcinoma were treated with concurrent chemoradiotherapy. Nine patients had incomplete tumor resection prior to radiation therapy. Irradiation was delivered to a total dose of 60 Gy, in three patients with central recurrences supplemented by brachytherapy. One patient was treated with brachytherapy alone. Simultaneous chemotherapy was done as a combined therapy of 5-fluorouracil-(5-FU, 600 mg/m(2)/d1-5, 29-33) and cisplatin (20 mg/m(2)/d1-5, 29-33; 16/24 patients) or of 5-FU (1,000 mg/m(2)/d1-5, 29-33) and mitomycin C (10 mg/m(2)/d2, 30; 1/24 patients). Cisplatin alone (25 mg/m(2)/d1-5) and carboplatin alone (800 mg/m(2)/d1-5) were administered in 5/24 patients (21%) and 2/24 patients (8%). The 5-year local recurrence-free survival rate was 37%, disease-free survival 33%, and overall survival 34%. Grade 3 toxicity (NCI-CTC grade 3) occurred mainly as diarrhea (38%), leukopenia (33%), and nausea (21%). Severe toxicity (grade 4) was not seen in any of the patients. Radiation therapy with simultaneous chemotherapy for recurrences of cervical cancer is an effective treatment with acceptable toxicity.

A phase I study to determine the effect of tamoxifen on the pharmacokinetics of a single 250 mg oral dose of gefitinib (IRESSA) in healthy male volunteers

To determine the effect of tamoxifen on the pharmacokinetics of a single 250 mg oral dose of gefitinib (IRESSA) in healthy volunteers. An open-label, single-center, phase I study in healthy male volunteers. Each volunteer received a single 250 mg oral dose of gefitinib on day 1. On days 11-14, oral loading doses of 60 mg tamoxifen were administered, followed by 20 mg tamoxifen for a further 16 days to maintain steady-state exposure. On day 24, volunteers received a second single 250 mg oral dose of gefitinib. The last dose of tamoxifen was given on day 30. Pharmacokinetic and safety assessments were conducted throughout the trial. A total of 18 volunteers were recruited. The presence of tamoxifen did not have a clinically significant effect on the primary variables AUC and Cmax of gefitinib, nor on the secondary variables AUC(0-t), tmax, t1/2, and lambdaz. The geometric least square mean values for AUC were 3,407.6 versus 3,397.9 ng.h/ml in the absence and presence of tamoxifen, respectively (90% CL 0.894, 1.112) and for Cmax were 110.8 versus 103.6 ng/ml, respectively (90% CL 0.786, 1.111). The combination of gefitinib with tamoxifen was generally well tolerated by the volunteers. There were no serious adverse events and no volunteer discontinued the study due to an adverse event. NCI-CTC grade 1/2 drug-related adverse events were observed in seven volunteers, including loose stools and skin events associated with gefitinib, and lethargy and headache, flushing, and dizziness associated with tamoxifen. This study suggests that tamoxifen has no significant effect on the pharmacokinetics, tolerability, or safety of a single 250 mg oral dose of gefitinib. Therefore, in clinical investigations of this combination, no dose adjustment of gefitinib is indicated.

A multicenter phase 2 study of irinotecan (CPT-11) and doxifluridine (5’-DFUR), an intermediate form of capecitabine, for metastatic colorectal cancer (MCRC)

3698 Background: We previously reported interim results of a multicenter Phase II study of sequential CPT-11 and 5’-DFUR combination therapy in patients with MCRC (2005 Gastrointestinal Cancer Symposium abst#250). We report here the time to progression (TTP) of MCRC. Methods: Patients with histologically proven MCRC; measurable disease according to RECIST; ECOG PS 0–1; and adequate born marrow, renal and hepatic functions were included. No prior CPT-11 chemotherapy was employed and a regimen of fluoropyrimidine-based chemotherapy was introduced. In the present study, patients received CPT-11 at a dose of 150 mg/m2 iv on days 1 and 15, and 5’-DFUR at a dose of 800 mg/body po on days 3–14 and 17–28 of a 5-week treatment cycle. Toxicity was evaluated every cycle using NCI-CTC. Results: From February 2003 to June 2004, 67 patients were enrolled in this study. Patient characteristics were: male/female, 41/26; median age, 65 years (range, 28–74 years); and ECOG PS 0/1, 59/8; Metastatic locations including multiple metastases: liver 35, lung 14, lymph nodes 17, others 7. No prior chemotherapy had given to 54 patients (80.6%). To date, 64 patients were evaluated for toxicity and 55 patients for efficacy. NCI-CTC grade 3–4 adverse events were: neutropenia, 21.9%; fatigue, 10.4%; leukopenia, 6.0%; anorexia, 4.5%, diarrhea, 4.5%, and nausea/vomiting, 3.0%. Objective response rate was 32.7% (18/55 patients) with one CR, 17 PR, 24 SD and 13 PD. Median TTP was 120 days while median overall survival has not been calculated yet. Conclusions: Sequential CPT-11 and 5’-DFUR combination therapy was well tolerated and showed efficacy against MCRC, providing good QOL of the patients. The updated analysis will be presented at the meeting. No significant financial relationships to disclose.

A phase I study of BAY 43–9006, a dual inhibitor of Raf and VEGFR kinases, in Japanese patients with solid cancers

3062 Background BAY 43–9006 is a novel inhibitor of Raf kinase and vascular endothelial growth factor (VEGF) tyrosine kinases. BAY 43–9006 has shown in vivo antitumor activity against various cancers by inhibiting tumor cell proliferation and angiogenesis. We have conducted a phase I study of BAY 43–9006 in Japanese cancer patients to decide a recommended dose and to clarify profiles of toxicities and pharmacokinetics. Methods Patients with solid tumors refractory to standard therapy, adequate organ functions, performance status of 0 or 1, and a life expectancy of ≥ 12 weeks were enrolled. Successive cohorts of patients received a single oral dose of 100 to 600 mg followed by a 7-day observation period and then received the same dose bid without interruption. Results Thirty-one patients including 10 non-small cell lung (NSCLC) and 3 renal cell cancer patients were treated. Three, 15, 6 and 7 patients were treated at 100, 200, 400 and 600 mg bid, respectively. Common drug-related adverse events were skin toxicities, laboratory data abnormalities, diarrhea and anorexia. At 200 mg bid, one patient developed grade 3 diarrhea and another two had grade 4 transient elevations of pancreatic enzymes. Grade 3/4 asymptomatic and transient elevations of pancreatic enzymes were observed in 2/3 patients at 400 and 600 mg bid, respectively. DLT definition was modified to consider not only NCI-CTC grading but also clinical significance. At 600 mg bid, dose-limiting grade 3 fatigue was observed in one patient and 5 patients experienced grade 2 hand-foot syndrome that were more painful and severe than those at 400 mg bid. The AUC and Cmax of BAY 43–9006 linearly increased with dose. At 400 mg bid, plasma trough concentrations (1.22 - 14.77 mg/L) exceeded the IC50 (1.2 mg/L) of BAY 43–9006 shown to inhibit tumor cell proliferation. Partial responses by RECIST were observed in a NSCLC patient (200 mg bid) and a renal cell cancer patient (600 mg bid). Two other NSCLC patients treated at 200 or 400 mg bid had stable disease ≥ 24 weeks. Conclusions BAY 43–9006 at 400 mg bid is recommended for phase II studies based on safety and efficacy data. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Yakuhin, Ltd. Bayer Yakuhin, Ltd.

The effect of different dose regimens in intravesical treatment of urinary bladder cancer with gemcitabine: A randomized phase II marker tumor study

4591 Background: Current intravesical treatments of Ta-T1 urinary bladder cancer have shown good efficacy, but improvement is needed. We evaluated the efficacy and toxicity of 3 different dose regimens of gemcitabine administered intravesically to patients with urinary bladder cancer. Methods: Patients with histologically proven stage Ta, grade 1/2 urinary bladder cancer and a marker lesion diameter of 0.5 to 1 cm after transurethral resection were enrolled; they received gemcitabine 2000 mg that was instilled and kept in the bladder for 1 hour. Patients were randomized to one of the following regimens: 1 dose (group A); 2 doses/week for 3 weeks (group B); or 1 dose/week for 6 weeks (group C). Response was assessed via cystoscopy 9 weeks after the end of treatment. Results: Between January 2002 and March 2004, 32 patients were enrolled; 2 were excluded due to protocol violations (groups B and C). Of the 30 randomized patients (11, group A; 10, group B; 9, group C), 1 patient was not evaluable for efficacy (group A). Nine patients (31%) reported a complete response (1, group A; 4, group B; 4, group C); an additional 9 patients (31%) had no response; and 11 (38%) had a tumor increase. All 30 patients were evaluable for toxicity. No NCI-CTC grade 3/4 toxicity was observed. Grade 1/2 nausea was reported in 5 patients (17%), and grade 1/2 fever in 2 patients (7%). One patient (3%) had grade 1 thrombocytopenia, which was reversible, and 1 of the patients with fever had grade 1 anemia, which was also reversible. Instillations were discontinued due to toxicity for only 1 patient (nausea, fever). Ten patients (33%) were unable to retain the drug for the full hour. Conclusions: As an intravesical instillation, gemcitabine showed activity and was well tolerated. The single-dose regimen does not appear to be effective. Also, twice-weekly doses do not appear to be more effective than once-weekly doses. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly

A phase II/III randomized study in advanced non-small cell lung cancer (NSCLC) with first line combination versus sequential gemcitabine (G) and docetaxel (D): Update on quality of life (QoL), toxicity, and costs

7057 Background: Single-agent gemcitabine (G) and docetaxel (D) are not cross-resistant and are effective in chemotherapy-naïve and pretreated patients (pts). The study was to evaluate the clinically, relevant hematologic toxicity (CRHT) in two treatment settings. Interim analysis including survival has been previously presented (ASCO 2004 abstract no. 7095). Methods: Pts received G/D in doses of 1000 mg/m2 /75 mg/m2/q3w either concomitantly in arm A: {G days 1,8 + D day 8 for 6 cycles} or sequentially in arm B: {G: days 1,8 for 3 cycles followed by D: day 1 for 3 cycles}. NCI-CTC grade 3–4 thrombocytopenia requiring transfusion, anaemia requiring transfusion or febrile neutropenia requiring IV antibiotics were defined as CRHT. Results: The table shows the characteristics, costs, and the outcome for 292 pts. In arm B pts received 69% of G and 46% of D of mean doses in arm A, respectively. In arm B CRHT appeared less often (anaemia, p=0.038 and febrile neutropenia, p=0.037, respectively). Interventions (transfusion and IV antibiotic treatment days) were more frequently with Arm A. QoL according to EORTC-LC13 measurement also favored Arm B. Overall survival as reported earlier was not different. Conclusion: Treatment costs are significantly lower if both drugs are given sequentially. Coevally there is more CRHT with concomitant drug application by higher transfusion rates and antibiotic treatment days as with sequential application. From the data available there is no indication that efficacy will differ. Arm A: combination G+D (n=152) Arm B: sequential G→D (n=140) Arm A: combination (n=552 cycles) Arm B: sequential (n=563 cycles) Baseline characteristics Toxicities: CRHT grade 3–4 (cycles) Gender (m/f) 115/37 106/24 Anaemia / transf. 14 5 Median age, years [range] 63.2 [36.6–78.7] 64.4 [39.7–81.2] Thrombocytopenia / transf. 1 1 WHO PS (0–1/1) 128/24 121/19 Febrile neutropenia / IV antibiotics 7 1 Histology: adeno/squamous/other 66/48/38 59/39/42 All interventions Stage IIIB/IV 22/130 21/119 RBC transf. (units) 81 43 Total dosage per patient in mg Platelet transf. (units) 1 2 G 12237 8407 IV antibiotics (treatment days) 400 220 D 433 201 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly, sanofi-aventis Eli Lilly, sanofi-aventis

A multicenter phase II trial of gefitinib 500 mg/day in 193 patients with advanced epidermal growth factor receptor-positive solid tumors who had failed previous chemotherapy: Interim data

3162 Background: 15 Belgian oncology centers are participating in an open-label Phase II trial of gefitinib (IRESSA) 500 mg/day in patients (pts) with advanced epidermal growth factor receptor-positive solid tumors who had failed ≥1 previous chemotherapy regimen and had no further chemotherapy treatment options. Here we report interim data. Methods: Pts received gefitinib 500 mg/day until disease progression. Objective tumor assessments, by RECIST, were made every 8 weeks and confirmed by repeat assessments ≥4 weeks later. Disease control rate (DCR) was defined as objective response (confirmed complete response or partial response [PR]) plus stable disease (SD) for ≥8 weeks. All adverse events (AEs) were reported and assessed by NCI-CTC version 2.0. Results: 193 pts have been enrolled with pancreatic cancer [21%], cervical cancer (CC) [19%], ovarian cancer (OC) [17%], sarcoma (S) [12%], cancer of unknown primary origin (U) [10%], hepatocellular carcinoma (HC) [9%], bladder cancer (BC) [7%], and endometrial cancer (EC) [4%]. At interim analysis, 184/193 pts were evaluable for response. DCR was 28%: 4 pts had PR (2 CC, 1 OC, 1 pancreatic cancer) and 48 pts had SD at 8 weeks (15 CC, 9 OC, 7 S, 5 pancreatic cancer, 5 HC, 3 EC, 2 BC, 2 U). 90% of AEs were mild to moderate. 12 NCI-CTC grade 3/4 drug-related AEs were reported in 9 pts (2 anorexia, 3 diarrhea, 3 vomiting, 1 vasculitic rash, 1 thrombocytopenia, 1 bacterial sepsis, 1 impaired liver function). All were NCI-CTC grade 3 except for 1 grade 4 anorexia. Dose reduction to 250 mg/day was required in 19% of pts. Conclusions: Gefitinib showed promising activity in pancreatic cancer, CC, and OC. Further trials of gefitinib in pancreatic cancer are ongoing. Our data in CC and OC support findings from previous gefitinib Phase I/II trials. Similar data were reported in a Phase II trial of gefitinib in advanced CC (Viens et al, Poster 1833 presented at ASCO 2003). Additionally, a Phase I trial with gefitinib reported disease control (SD) in OC (Ranson et al, J Clin Oncol 2002;20:2240–50). IRESSA is a trademark of the AstraZeneca group of companies Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca

Cetuximab with oxaliplatin and capecitabine (CAPOX)in patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapy

3669 Background: Cetuximab is an EGFR-targeting IgG1 monoclonal antibody that has demonstrated activity as single agent or in combination with irinotecan in patients with mCRC (pts) refractory to chemotherapy. Conceivably as a result of chemosenzitation, pts with irinotecan-refractory tumors are more likely to respond to the combination with irinotecan when compared to single agent cetuximab. In combination with 5FU/LV/Oxaliplatin, two recent trials reported the highest response rates ever achieved in 1st-line treatment of mCRC. Aim of this study was to evaluate efficacy and toxicity of cetuximab in combination with oxaliplatin plus capecitabine in mCRC pts refractory to oxaliplatin. Methods: Pts refractory to standard chemotherapy (incl. 5FU, oxaliplatin, and irinotecan in all pts) were assigned to treatment with cetuximab (400mg/m2 d1 followed by weekly 250mg/m2) and CAPOX: oxaliplatin (70mg/m2 d1 and 8; qd22) plus capecitabine (2000 mg/m2 d1–14; qd22). All tumors showed EGFR expression by IHC. Pts with sensory neurotoxicity > grade 1 resulting from previous oxaliplatin treatment were excluded. Tumor assessment was performed 9-weekly. Results: Since Jan 04, 15 pts have been prospectively evaluated: 9m/6f, median ECOG PS 1 [0–2], median age 59 yrs [32–75]. No. of previous treatment lines: Two 9 pts, three 5 pts, four 1 pt. Pretreatment included 5FU, oxaliplatin and irinotecan in all pts., MMC and gefitinib in 4 pts each. In 1 pt treatment was stopped due to a grade 4 hypersensitivity reaction. Further NCI-CTC grade 3/4 toxicities were (15 pts): leukopenia 1 pt, sensory neuropathy 1 pt, skin 2 pts, diarrhea 1 pt. Efficacy analysis of 15 pts: PR 27%, SD 27% (4 pts each), PD 46%. Currently median PFS is 2.5 mos (0.25+-9.6), median overall survival is 5.5+ mos (0.6–10.9+) (7 pts ongoing). Conclusion: Combination of Cetuximab plus CAPOX has significant clinical activity in patients with colorectal cancer refractory to standard chemotherapy. The observed toxicities allow treatment even in this group of heavily pretreated patients. These promising results are currently further evaluated in an expanded phase II setting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche, sanofi-aventis Roche, sanofi-aventis

A multicenter phase II study of irinotecan (CPT-11) and bolus 5-fluorouracil (5FU)/l-leucovorin (l-LV) in patients with metastatic colorectal cancer

3742 Background: A previous phase I trial in patients (pts) with metastatic colorectal cancer (CRC) demonstrated that weekly CPT-11 and bolus 5FU/l-LV administered for 3 weeks every 28 days (modified Saltz regimen) showed a promising activity without severe toxicity. We conducted a multicenter phase II trial of this regimen in pts with metastatic CRC to evaluate the objective response rate (ORR), safety profile, time to progression (TTP), and overall survival (OS). Methods: 27 pts with metastatic CRC, measurable disease, ECOG PS less than 3, and adequate organ functions were enrolled. Prior chemotherapy was allowed. Pts received weekly doses of CPT-11 (100 mg/m2) and bolus 5FU (500 mg/m2) plus l-LV (20 mg/m2) for 3 weeks. Cycles were repeated every 28 days. Results: 25 pts (10 treated and 15 untreated pts) were evaluable for response and toxicity; M/F, 12/13, median age 63 years (45–73), ECOG PS 0–1, 96%. Metastatic sites were liver 48% (n=12), lung 40% (n=10), and lymph node 36% (n=9). To date, 213 cycles were administered (median 8.5, range 2–36). There were 10 PR (40%) and 13 SD (52%), and 2 PD, resulting in ORR of 40% (CI 95%: 20.8–59.2%) and disease control rate (PR+SD) of 92%. The response rates of the pts with or without previous treatments were 20% and 53.3%, respectively. Median TTP and OS have not been achieved yet, but were 6.9 months and 17.2 months, respectively for 16 early registered pts. Neutropenia was the only NCI-CTC grade 3/4 hematological toxicity, which occurred in 52% of pts. Non-hematological toxicity was mostly grade 1/2 with only one patient (4%) having a grade 3 diarrhea. No treatment related death has been encountered. Conclusions: This weekly CPT-11/5FU/l-LV administered for 3 weeks every 28 days has manageable toxicity profile and a substantial anti-tumor activity, specifically for chemotherapy-naive patients with metastatic CRC. No significant financial relationships to disclose.

The combination of gemcitabine and cisplatin as neoadjuvant chemotherapy for early stage non-small cell lung carcinoma (NSCLC): an interim analysis of a phase II trial

7303 Background: The objectives of this ongoing, open-label, single-arm, phase II trial were to evaluate the efficacy and safety of gemcitabine/cisplatin as neoadjuvant chemotherapy in patients with operable, early stage NSCLC. Methods: Chemonaive patients >18 to 70 years old with stage IB, IIA-B, and IIIA NSCLC and an ECOG performance status (PS) of 0–1 received gemcitabine (1000 mg/m2; iv) on days 1 and 8 plus cisplatin (75 mg/m2; iv) on day 1. The treatment was administered on a 21-day treatment cycle for 3 cycles, followed by surgery or radiotherapy if medically unfit for surgery. The follow-up period was 12 months after surgery. Results: At the time of this analysis, 43 patients, with a median age of 55.8 years, were enrolled. Most patients (47%) had stage IB, while 26% of the patients had stage II and 28% had stage IIIA disease. N0 and N2 nodal disease was observed in 74% and 26% of the patients, respectively. Overall, 70% of the patients had T2 primary tumors, 26% had T3, and 2% of the patients each had T1 and T0. At baseline, 19 patients had a PS of 0 and 24 patients had a PS of 1. The PS of the patients improved in each visit during the follow-up period; 33 (77%) patients were fully active and asymptomatic (PS 0) at the final visit. Of the 38 patients evaluable for clinical tumor response, 21 (55%) had partial response and 15 (40%) had stable disease, while only 2 (5%) had progressive disease. NCI-CTC grade 3–4 hematologic toxicities included neutropenia in 24 (56%) patients and thrombocytopenia in 6 (14%) patients. Non-hematologic toxicities were acceptable. Data on 24 of 43 patients were analyzed for surgery. The tumor resection rate was 88% (21 of 24). Two of 24 patients (8%) received radiotherapy following chemotherapy. Conclusion: Preliminary results show that the combination of gemcitabine/cisplatin is an effective and tolerable neoadjuvant treatment for patients with operable, early stage NSCLC. The final analysis of the data, including pathological complete response rate as well as the expression and correlation of the prognostic factors erbB-2, VEGF, Ki67, and p53 with efficacy parameters, will be presented at the meeting. No significant financial relationships to disclose.

Bi-fractionated oxaliplatin (L-OHP) plus 5-fluorouracil (5FU)/leucovorin (LV) for elderly patients (pts) with advanced colorectal cancer (CRC)

3619 Background: Delivering l-OHP over 2 days together with 5FU may enhance the synergism and reduce neurotoxicity. In this study we assessed activity, toxicity and both the activity of daily living (ADL) and instrumental activity of daily living (IADL) of a bi-fractionated l-OHP plus 5FU/LV regimen as first line chemotherapy for elderly pts with metastatic CRC. Methods: Eligibility criteria included no previous chemotherapy for advanced disease, age >= 70 yrs, ECOG PS <= 2. Schedule was: l-OHP 45 mg/m2 + bolus 5FU 400 mg/m2 + 24-h infusional 5FU 600 mg/m2 + LV 200 mg/m2, days 1 and 2, every 2 weeks. Responses (WHO criteria) and ADL/IADL were assessed every 6 cycles. A two-staged Simon accrual design was adopted for this phase II study, with response rate as main endpoint (p1 45%; p0 30%). Results: From Aug ‘01 to Jul ‘04, 78 pts entered the study: M/F 54/24, median age was 75 years (r. 70–85), PS 0/1/2 in 31/38/9, liver/lung/peritoneum metastases in 58%/31%/11% of pts. A total of 651 courses were administered, with a median of 8 cycles per pt (r. 1–19). The mean weekly DI of l-OHP was 34 mg/m2 (76% of the planned). Response (77 pts evaluable) was as follow: CR in 7 (9.0%) and PR in 32 (41.5%) pts, for an overall RR of 50.5%; SD and PD both in 19 (24.7%) pts. Median duration of response was 9.0 mo. Second-line chemotherapy was delivered to 47% of pts. With a median f-u of 12.5 mo, according K-M method, median TTP and OS was 8.1 (r. 0.3–21.9) and 20.1 (r. 0.8–29.5) mo, respectively. NCI-CTC grade 3/4 toxicities were: neutropenia in 32% of pts (febrile in 2 pts), diarrhea 10%, mucositis 4%, fatigue 4%. G2 and G3 sensory neuropathy occurred in 17% and 6% of pts, respectively. Median ADL/IADL scores at T0, T6 and T12 were 6/4, 6/4, and 6/5, respectively, without significant differences. Conclusions: l-OHP and 5FU/LV was highly active and did not interfere with ADL/IADL of elderly pts with advanced CRC. The bi-fractionated delivering of l-OHP demonstrated to reduce neurotoxicity. No significant financial relationships to disclose.

Second-line chemotherapy with docetaxel for prostate-specific antigen (PSA) relapse in men with hormone-refractory prostate cancer (HRPC) previously treated with docetaxel-based chemotherapy

4682 Background: Docetaxel-based chemotherapy has demonstrated a significant survival benefit in men with HRPC. However, about 80% of patients demonstrate PSA relapse within 12 months and median time to progression is approximately 6 months after an initial response to docetaxel. Thus, we evaluated repeat treatment with low-dose docetaxel for men with HRPC and PSA progression. The primary endpoint was PSA response (PSA decrease ≥50%). Methods: Twenty-five consecutive patients with PSA progression after docetaxel-based chemotherapy were enrolled. PSA progression was defined as a continuous increase in PSA measured at 3 consecutive points 2 weeks apart and a PSA level ≥2x nadir after the first 12-week cycle or the previous chemotherapy cycle. PSA doubling time was ≤6 months in all patients. Docetaxel 35 mg/m2 was given on Days 2, 9, and 16 of a 4-week cycle x 3 cycles. Treatment was stopped in patients with stable disease or a PSA response (≥50% decrease in PSA from baseline, confirmed after 4 weeks). Patients were monitored with serial PSA measurements at 4-week intervals and the same 12-week sequence was restarted in patients with PSA progression. Patients who progressed during therapy were withdrawn and received palliative care. Results: Median baseline PSA level was 34.3 (range: 15–189) ng/mL. A PSA response was achieved by 18/25 (72%) patients; mean duration of response was 5.8 (range: 3–10) months. To date, 5 patients have undergone a second 12-week sequence of docetaxel owing to PSA progression; 3/5 (60%) subsequently achieved a PSA response (median follow-up: 8.5 (range: 3–15) months. Hematologic toxicity was acceptable: 5 patients (20%) and 3 patients (12%) had NCI-CTC grade 3–4 anemia and leukopenia, respectively. Grade 3–4 nonhematologic toxicities were nail changes (5 patients; 20%), diarrhea (3 patients; 12%), and fluid retention (3 patients; 12%). Conclusions: These results suggest that rechallenge with low-dose intermittent docetaxel may be an effective and well-tolerated treatment option in men with HRPC and PSA progression following an intial response to docetaxel-based chemotherapy. No significant financial relationships to disclose.

Safety of low-dose aspirin (ASA) in a pooled analysis of 3 randomized, controlled trials (RCTs) of bevacizumab (BV) with chemotherapy (CT) in patients (pts) with metastatic colorectal cancer (mCRC)

3554 Background: BV (Avastin™) increases overall survival from 15.6 to 20.3 months in pts with mCRC when added to first-line irinotecan, fluorouracil, and leucovorin. In a subsequent larger pooled analysis, adding BV to CT was found to increase the risk of arterial thromboembolic events (ATEs), particularly in pts ≥65 years old with a history of atherosclerosis (Genentech, Inc., DDL, Aug 2004). Low-dose ASA is a standard therapy for primary and secondary prophylaxis of ATEs in pts at high risk of such events, and use of ASA ≤325 mg daily has been permitted in BV trials. We explored the bleeding risk associated with ASA use in mCRC trials. Methods: Analyses of pts with mCRC pooled from 3 RCTs of BV with CT were performed to explore a potential relationship between ASA use and incidence of bleeding events. ASA users were defined in 2 ways: Group A, those who reported ASA use at study enrollment (N=108); Group B, those in Group A plus those who used ASA at any time on study (N=195). Bleeding event rates by NCI-CTC grade were calculated as percent incidence unadjusted for a pt’s duration of study treatment. Conclusion: In this analysis, the use of low-dose ASA by pts with mCRC who receive CT alone or in combination with BV does not appear to increase the risk of bleeding of any severity. An exploratory analysis of the treatment effect of ASA on ATE risk in mCRC will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech, GlaxoSmithKline, ImClone, Pfizer Genentech Genentech Genentech

Feasibility of a combination of high dose chemotherapy ifosfamide, carboplatin, etoposide (ICE) plus stem cells and bevacizumab in refractory sarcoma and germ cell tumors

9070 Background: High-dose chemotherapy (HD) with ICE for 1 up to 4 cycles represents a frequently used salvage regimen for solid tumors refractory to standard dose (SD) chemotherapy. However, the activity of HD-ICE is only moderate particularly in sarcoma or in germ cell tumors unresponsive to SD -ICE. Bevacizumab (B) has some activity in sarcoma and another antiangiogenetic agent, thalidomide in refractory germ cell tumor. Furthermore B has been shown to increase the antitumor efficacy of chemotherapy in colorectal cancer, an effect which might not only be limited to 5 FU based chemotherapy. Therefore the combination of bevacizumab with sequential/intermediate/high-dose chemotherapy might be of interest. To evaluate the potential risk of the combination of HD-ICE + B we are currently performing a feasibility study in pts with progressive sarcoma and germ cell cancer. Methods: To date 5 pts (4 sarcomas, 1 germ cell tumor, including 1 pt with brain metastasis) progressive after SD-ICE (ifosfamid 1,5 g/m2 d1–3, carboplatin 150mg/m2 d1–3, etoposide 150 mg/m2 d1–3) received HD-ICE (ifosfamid 3 g/m2 d1–3, carboplatin 300mg/m2 d1–3, etoposide 300 mg/m2 d1–3) in combination with B (7,5 mg/kg - 10mg/kg) d1 with stem cell support, q 3 weeks. 5 pts were evaluable for toxicity and 4 for response. A total of 5 pts and 12 cycles (c) of chemotherapy (range 1–5) are evaluated to date. Median age was 29y (range 22–38y); female:male 2:3, ECOG 0/1 (5 pts). Results: NCI-CTC grade 3/4 toxicities: Thrombocytopenia 12/12 c, Neutropenia 12/12, nausea/vomiting 1/12, acute ifosfamide encephalopathy 1/12. In one cycle G1 epistaxis occured. There was no hypertension, mucositis over G1, no severe sustained bleeding and no thromboembolic event or severe infection. Efficacy: 1 CR, 1 PR and 2 SD were seen. Conclusions: The addition of B to HD-ICE in pts with refractory solid malignancy has interesting activity without significant increase of toxicity in particular thrombopenic bleeding and acute encephalopathy, even in the pts with brain metastasis. The study is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hoffmann-La Roche Hoffmann-La Roche

A phase-I dose-escalation study of SR271425 administered intravenously in split doses (d1-d2-d3) in patients with refractory solid tumors

3133 Background: SR271425, a novel DNA-binding cytotoxic agent has a promising broad spectrum of antitumor activity in preclinical models, independent of the schedule of administration. In addition to the usual cytotoxic related toxicities, QTc prolongation, related to Cmax, has been reported at doses >660mg/m2 in rabbit. In order to circumvent this Cmax related QTc prolongation, 5 phase I studies using different schedules of administration were initiated, testing iv infusion of 1-hour, 24-hour, weekly, and split doses. This phase I study aims to test split doses of the 1-hour regimen given d1 to d3, every 3 weeks, to establish the dose limiting toxicity (DLT), the recommended phase II dose and to characterise the PK/PD. Methods: Standard dose escalation was used. Patient’s selection was based on common phase I criteria and on specific cardiac criteria. SR271425 levels (PK samples) were measured using a turboflow LC-MS/MS method. Careful monitoring of ECGs was done and the ECGs were read centrally. Results: 3 centers have enrolled 18 highly pretreated patients to 6 dose levels from 75 to 450 mg/m2/day (from 225 to 1350mg/m2/cycle); 11 males and 7 females with median age 53, median ECOG 1, and brain, breast, lung and renal main tumor types, have received a median number of 2 cycles (range: 1–6). NCI-CTC Grade 1–2 toxicities included nausea, vomiting, asthenia, rash and yellow skin discoloration. No DLT has been reported yet especially no QTc limiting prolongation. 4 stable diseases were observed. In terms of exposure, both Cend and AUC increased in a dose related manner with no evidence of accumulation between day 1 and day 3, consistent with the mean (± SD) terminal elimination half-life of 5.11 ± 1.21 h. Conclusions: Preliminary data of this ongoing study show that split doses allow high cumulative exposure to SR271425 without significant toxicity, especially without QTc prolongation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis

A combination of low-dose prolonged infusional gemcitabine and oral treosulfan in platinum- and taxane-refractory Mullerian carcinomas: A phase II study

5064 The GeT regimen - gemcitabine (dFdC) + treosulfan (TREO) - has been found to be active in metatastic melanoma and refractory epithelial ovarian carcinoma (EOC). However, the q3w regimen with dFdC at 1250mg/m2 day 1+8 and TREO at 5000 mg/m2 day 1 was associated with myelosuppression negatively influencing dose intensity and, consecutively, progression-free survival (PFS). Since maintaining cellular accumulation appears to be crucial for long-lasting responses, this phase II trial in platinum- and taxane refractory Mullerian carcinomas (MC) was set up using a modified q2w GeT protocol with dFdC at 450 mg/m2 (3 h infusion) day 1 and oral TREO at 1000 mg/m2 day 1–4. A total of 25 patients (pts) were included (EOC: n=24; papillary-serous endometrial carcinoma: n=1). Patients had failed a median of 2 prior Ctx (1: n=9; 2: n=6; 3: n=5; 4: n=2; 5: n=2) including platinum and paclitaxel in all, anthracyclines in 9 and topotecan or dFdC in either 4 pts. A total of 145 cycles were given with a median of 6 (range: 2–10). All pts had measurable or evaluable disease according to the RECIST and Rustin criteria, repectively. All treatments were evaluable for both toxicity and response. Anemia which was never therapy-limiting was frequent but exceeded NCI-CTC grade 2 in only 8/145 cycles (6%). Leukopenia > grade 2 was not observed. In one patient, interval prolongation was necessary due to febrile urinary tract infection. In another patient, treatment was terminated due to non-lethal pulmonary embolism. Other toxicities did not exceed NCI-CTC grade 1 nor did any other patient require hospitalization due to therapy-related toxicities. A total of 9 CR and 4 PR were recorded accounting for an objective response rate of 52%; 6 pts achieved SD and 6 pts progressed on GeT. The median progression-free survival was 29 weeks. Until now, only 5 pts have died, so that the median overall survival is not yet reached. Facing the intensive pre-treatment of the pts studied, it can be concluded that the modified GeT protocol is well tolerated and exhibits a promising clinical activity in MC refractory to both platinum and taxanes that warrants further exploration in large-scaled clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration L.a.n.c.e. Inc.

Docetaxel and oxaliplatin combination as second-line treatment in patients with advanced gastric cancer

4188 Background: Chemotherapy is the only treatment option for advanced gastric cancer (AGC) patients (pts). First line regimens are able to provide a slight but significant increase of survival rates. Pts with good performance status could receive a second line, even though there are no established indications. Several new drugs, like docetaxel, irinotecan and oxaliplatin have recently been shown to be active also for AGC, but no data are available on the efficacy and safety of a newer drugs combination regimen after progression to a platinum or a non platinum-based first line chemotherapy. Methods: Pts with histologically confirmed AGC and PS (ECOG) < 2, progressed after a first line were eligible. Based on a previous phase I study (Agelakis, ASCO 2000) pts were treated with docetaxel 75 mg/m2 day 1 and oxaliplatin 80 mg/m2 day 2, every 3 weeks, until progression or unacceptable toxicity. According to the Simon design, at least one response had to be achieved among the first 18 pts, followed by a second step with 22 more pts. Results: From September 2003 until now, twenty-three pts were enrolled. Male 75%, median age 62. Metastatic site was liver in 85% and lung in 35%; primary tumor not resected in 50%. First line treatment ECF 60%, cisplatin and infusional 5-FU 30%, irinotecan and infusional 5-FU 10%. Median number of cycles 4.8. The treatment was well tolerated with no toxic deaths. The incidence of NCI-CTC grade 3–4 toxicities was low: 8 pts (40%) had grade 3–4 neutropenia, febrile neutropenia was never observed. Three pts (15%) had grade 3 asthenia and 2 (10%) grade 3 neurotoxicity. Concerning efficacy, among 20 evaluable pts 3 (15%) had a confirmed PR, 8 (40%) a SD and 9 (45%) PD. An improvement of PS and a symptoms palliation have been seen in 7 pts (35%). Median time to progression was 4.8 months. Median overall survival has not been reached yet and the study is still ongoing. Conclusions: This regimen is safe and shows an interesting profile of efficacy. If data will be confirmed in larger phase II-III studies, it should be considered a suitable option as second line therapy for AGC in pts with good PS. No significant financial relationships to disclose.