Cb AUC Research Articles

Final results of a randomized phase II trial of pemetrexed (P) + carboplatin (Cb) ± enzastaurin (E) versus docetaxel (D) + Cb as first-line treatment of patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC)

8037 Background: E is a selective, oral serine/threonine kinase inhibitor. The combination of PCb has shown clinical activity in two phase 2 trials of advanced NSCLC. A phase 3 trial among pts with stage IIIB/IV NSCLC showed that P + cisplatin provides similar efficacy with better tolerability than gemcitabine + cisplatin (Scagliotti, JCO, 2008). The toxicity profile observed with P + platinum doublets makes these regimens attractive for the integration of novel agents with different mechanisms of action. In the TAX 326 trial, D + cisplatin was associated with a median survival of 11.3 mos vs. 10.1 mos for vinorelbine + cisplatin (P=.04). The current open-label three- arm trial was designed to assess PCb ± E versus a control arm of DCb. Methods: Between 3/06 and 5/08, pts with stage IIIB (with pleural effusion) or IV NSCLC, ECOG PS of 0 or 1, and no prior systemic therapy were enrolled. Pts were equally randomized to 3 arms: (A) P 500 mg/m2 and Cb AUC 6 every 3 wks × 6 cycles with E given orally as a loading dose of 1200 mg or 1125 mg followed by 500 mg daily until disease progression; (B) The same regimen of PCb without E; or (C) D 75 mg/m2 and Cb AUC 6 every 3 wks × 6 cycles. Pts receiving P were administered folic acid, vitamin B12 and steroid prophylaxis. Pts on D also received steroid prophylaxis. Results: See table . Conclusions: First-line treatment with PCb was associated with a significantly longer overall survival than DCb in advanced or metastatic NSCLC. E did not add to the activity of the PCb doublet. PCbE, PCb, and DCb appeared to be well tolerated. Complete results for all patients in the study will be available at the time of the meeting. [Table: see text] [Table: see text]

A prospective evaluation of quality of life (QOL) in a phase II trial of pemetrexed (P) plus carboplatin (Cb) ± enzastaurin (E) versus docetaxel (D) plus Cb as first-line treatment of patients (pts) with advanced non-small cell lung cancer (NSCLC)

e19050 Background: E is a selective, oral serine/threonine kinase inhibitor. PCb has shown promising clinical activity in two phase 2 trials of advanced NSCLC. This open-label, three-arm trial was designed to assess PCb ± E versus a control arm of DCb. QOL may be an important consideration with the introduction of targeted agents such as E that have a different toxicity profile than traditional chemotherapeutic agents. Methods: Pts with Stage IIIB (with pleural effusion) or IV NSCLC, ECOG PS of 0 or 1, and no prior systemic therapy were enrolled. Pts were equally randomized to one of three arms: (A) P 500 mg/m2 and Cb AUC 6 every 3 wks X 6 cycles with E given orally as a loading dose of 1200 mg or 1125 mg followed by 500 mg daily until disease progression; (B) The same regimen of PCb without E; or (C) D 75 mg/m2 and Cb AUC 6 every 3 wks X 6 cycles. Pts receiving P were also administered folic acid, vitamin B12 and steroid prophylaxis. Pts on D also received steroid prophylaxis. The Functional Assessment of Cancer Therapy-Lung (FACT-L) Questionnaire and FACT-Taxane toxicity subscale were used to evaluate QOL at baseline and every 3 weeks up to 18 weeks during treatment. A best overall response of improved or worsened was defined as an increase or decrease from baseline to last patient visit of ≥ 0.5 standard deviations of baseline scores. Results: The intent-to-treat population of this study consisted of 218 randomized pts (PCE: 72, PC: 74, DC: 72). Baseline and ≥ 1 post-baseline score was obtained from 54 pts receiving PCE (75%), 62 pts receiving PC (84%), and 54 pts receiving DC (75%). QOL data are summarized in the table below. Conclusions: Across treatment groups, differences in mean scores were not statistically significant. In addition, differences in classification of improved, stable, or worsened were not statistically significant across treatment groups. [Table: see text] [Table: see text]

0181 PROACT: A randomised study comparing anastrozole with tamoxifen as neoadjuvant and adjuvant treatment in postmenopausal women with locally advanced breast cancer - a Japanese subgroup analysis

immunohistochemistry or Her2 amplification by FISH) were treated with four cycles of PCb with the dose of Cb AUC=2 and P 80mg/m2 given 3 out of every 4 weeks. Patients were encouraged to receive trastuzumab as a 4mg/kg loading dose followed by 2mg/kg weekly for 16 weeks. The primary endpoint was pathological complete response (pCR) defined as no invasive cancer in breast and axillary. Results: From May 2007 to Oct 2008, 28 patients with Her2 overexpressing breast cancer had completed preoperative therapy. 12 patients were treated with PCb plus trastuzumab (HPCb) and the rest of patients received PCb alone. 26/28 patients had stage III disease. 25/28 patients before treatment were with positive axillary node confirmed by fine needle aspiration. Except alopecia, other grade 3−4 toxicities were acceptable. 35.7% (10/28) patients experienced grade 3−4 neutropenia. No episodes of febrile neutropenia were reported. And only 1 patient suffered from grade 3 anemia. Adding trastuzumab treatment didn’t increase the incidence of grade 3−4 toxicities. No cardiac toxicity was found confirmed by left ventricular ejection fraction. 12/28 patients (42.9%) achieved pCR. 4/16 patients treated with chemotherapy alone achieved pCR with pCR rate 25.0%. However, in the trastuzumab treatment group, 8 patients achieved pCR with pCR rate as high as 66.7% (8/12). Conclusion: With pCR rate of 66.7%, this weekly paclitaxel, carboplatin and trastuzumab regimen is a highly active and low toxicity in preoperative therapy of Her2 over-expression breast cancer and deserves to further validation.

A phase I/II study of pemetrexed in combination with carboplatin in patients with platin sensitive recurrent ovarian or peritoneal cancer (PSOC)

16513 Background: Carboplatin (Cb)-based combinations are used commonly in platin-sensitive recurrent ovarian or peritoneal cancer (PSOC) (Parmar 2003, Pfisterer 2006). Pemetrexed (Pem) is a multi-targeted antifolate whose primary mechanism of action is the inhibition of thymidylate synthase (TS). Methods: The primary objective of phase I was to determine the MTD, DLT, quantitative and qualitative toxicities of combination Pem and Cb. A standard 3-patient cohort dose escalation was planned starting at Cb AUC 5 and Pem 500 mg/m2. Inclusion criteria were: women age > 18 years, contraception use if still fertile, PSOC (defined as recurrence 6 months after first-line therapy), measurable (RECIST criteria) or evaluable disease (CA125 only), adequate organ function and ability to continue follow-up. Two dose levels of Cb (AUC 5, 6) and five levels of Pem (500, 600, 700, 800, 900 mg/m2) were evaluated. DLTs were defined based on cycle 1. Results: Twenty patients, median age 57.4 years (37.3–75.3) were enrolled. Three patients had a PS of 0 and the remaining 17 patients had a PS of 1. Three patients had measurable disease and the remaining 17 patients had CA125 - only evaluable disease. There were no deaths on study. There were no protocol-defined DLTs in cycle 1 and no serious adverse events (SAEs) related to study therapy. There were 2 SAEs noted, one at dose level 1 and one at dose level 6. The 20 patients completed 112 cycles of Cb including 104 as planned and 115 cycles of Pem, including 112 as planned. Five patients required dose adjustments. Dose level 6 was well tolerated. Conclusions: Combination Cb and pemetrexed is well tolerated. However, subsequent to data lock for this trial, data from a randomized Phase II comparing 500 vs. 900 mg/m2 pemetrexed in PSOC demonstrated numerically greater Grade 3 and 4 SAEs with the 900 mg/m2 dose (data on file). A Phase II trial utilizing pemetrexed 500 mg/m2 and Cb AUC 6 is underway. Dose Level Pem mg/m 2 Cb AUC Patients per Dose Level 1 500 5 4 2 600 5 3 3 600 6 4 4 700 6 3 5 800 6 3 6 900 6 3 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company, GlaxoSmithKline, Schering-Plough Eli Lilly and Company, GlaxoSmithKline, Schering-Plough

Preliminary results of a randomized phase II trial of pemetrexed (P) + carboplatin (Cb) ± enzastaurin (ENZ) versus docetaxel (D) + Cb as first-line treatment of patients with stage IIIB/IV non-small cell lung cancer (NSCLC)

8061 Background: ENZ is a selective, oral serine/threonine kinase inhibitor. The combination of PCb has shown clinical activity in two phase 2 trials of advanced NSCLC. A phase 3 trial among pts with stage IIIB/IV NSCLC showed that P + cisplatin (C) provides similar efficacy with better tolerability than gemcitabine + C (Scagliotti, IASLC 2007; PRS-03). In the TAX 326 trial, DCb was associated with a median survival of 11.3 mos vs. 10.1 mos for vinorelbine + C (P=.04). This open-label three-arm trial was designed to assess PCb ± ENZ versus a control arm of DCb. Methods: Pts with Stage IIIB (with pleural effusion) or IV NSCLC, ECOG PS of 0 or 1, and no prior systemic therapy were enrolled. Pts were equally randomized to one of three arms: (A) P 500 mg/m2 and Cb AUC 6 every 3 wks X 6 cycles with ENZ given orally as a loading dose of 1200 mg or 1125 mg followed by 500 mg daily until disease progression; (B) The same regimen of PCb without ENZ; or (C) D 75 mg/m2 and Cb AUC 6 every 3 wks X 6 cycles. Pts receiving P were also administered folic acid, vitamin B12 and steroid prophylaxis. Pts on D also received steroid prophylaxis. Results: See table. Conclusions: PCb+ENZ, PCb, and DCb appear to be well tolerated in advanced or metastatic NSCLC. In this trial, first-line treatment with PCb ± ENZ (compared with DCb) was associated with a greater incidence of grade 3/4 anemia or thrombocytopenia but less grade 4 neutropenia and grade 2 alopecia. Updated results for all pateints in the study will be available at the time of the meeting. Characteristics/Results PCb+ENZ (Arm A) PCb (Arm B) DCb (Arm C) No. of available pts 53 55 51 Median age, yrs 67 67 65 Male gender 55% 53% 53% Brain metastasis 9% 11% 8% ECOG Performance Status – – – PS 0 47% 44% 41% PS 1 45% 46% 53% Missing 8% 11% 6% Mean no. of cycles of PCb or DCb 3.7 4.1 3.2 Dose reductions or delays – – – P or D 33% 29% 17% Cb 35% 29% 15% Mean relative dose intensity – – – P or D 89% 91% 93% Cb 85% 87% 90% Compliance with ENZ 84% – – No. pts assessed for safety 42 48 46 Neutropenia, Grade 3/4 24%/12% 23%/6% 20%/20% Anemia, Grade 3/4 7%/2% 17%/0% 0%/0% Thrombocytopenia, Grade 3/4 14%/12% 10%/8% 2%/0% Febrile neutropenia Grade 3/4 0%/0% 2%/0% 2%/2%< Fatigue, Grade 3/4 2%/0% 0%/0% 7%/0% Diarrhea, Grade 3/4 5%/0% 0%/0% 7%/0% Pain, Grade 3/4 0%/0% 4%/0% 9%/0% Alopecia, Grade 2 0% 6% 13% Elevated ALT, Grade 3/4 2%/0% 0%/0% 0%/0% Pulmonary embolus, Grade 3/4 0%/0% 0%/4% 2%/4% Dyspnea, Grade 3/4 0%/0% 2%/0% 4%/2% Dizziness, Grade 3/4 0%/0% 2%/0% 2%/0% Dehydration, Grade 3/4 2%/0% 0%/0% 9%/0% Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company

Phase III open-label comparison of gemcitabine/oxaliplatin versus paclitaxel/carboplatin as first line therapy for advanced non-small cell lung cancer (NSCLC)

8024 Background: Platinum-based doublets are the standard of care for advanced and metastatic NSCLC. Gemcitabine/cisplatin is one of the most active regimens; however many patients cannot tolerate the non-hematological side effects of this combination. This study was designed to compare the efficacy and tolerability of Gemcitabine + Oxaliplatin (GEMOX) to that of Paclitaxel/Carboplatin (PCb) in chemotherapy-naïve Stage IIIB/IV NSCLC patients. Methods: Newly diagnosed patients greater than 18 years of age with histologically proven NSCLC and ECOG PS ≤ 1 were randomly assigned 1:1 and stratified by stage (IIIB vs IV) in a 1:4 proportion to receive either PCb (P 225 mg/m2 day 1 followed by Cb AUC = 6) or GEMOX (GEM 1000mg/m2 days1 and 8 and OX 130 mg/m2 on day 1 after GEM) for a maximum of 6 cycles. The primary endpoint was time-to-progression (TTP), with tumor response rate, overall survival (OS), and quality of life (QoL) as secondary endpoints. Results: A total of 383 patients were randomized; 371 patients received treatment and have full safety data available (184 patients received GEMOX; 187 patients received PCb). Of the 371 patients with safety data, 204 (55.0%) were male, 193 (52.0%) < 65 years old, 340 (91.6 %) were Caucasian and 6 (1.6%) Hispanic, 193 (52.0 %) had an ECOG score = 0, 302 (81.4%) had Stage IV disease at diagnosis and 33 (8.9%) had brain metastases. Mean ± SD number of cycles completed was 4.1 ± 1.8 (range 1–6). There were 26 deaths (7.0%) within 30 days of completing treatment. At the end of the follow-up period (684 days from start of study treatment) 38 pts (10.2%) were still alive. Neutropenia (32.9%) and thrombocytopenia (17.3%) were the most common Grade 4 toxicities. Conclusions: Additional safety and full efficacy data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis

Multicenter phase II trial of carboplatin (Cb) and gemcitabine (G) followed by concurrent chemoradiation in patients with unresectable stage III non-small-cell lung cancer (NSCLC): FEV1 as prognostic marker

7558 Background: In patients (pts) with unresectable stage III NSCLC concurrent chemoradiotherapy (CRT) results in improved survival compared to sequential CRT, but comes at the cost of increased toxicity. Data from the recent HOG 01–24 trial suggest that survival of stage III NSCLC patients is correlated with the FEV1. Methods: Pts (PS 0–2) with unresectable stage III NSCLC and FEV1 ≥1.5L were treated with 3 cycles of induction chemotherapy (Cb AUC 5 on d1 and G 1,200 mg/m2 on d1 and d8 Q3 wks) followed by conventional radiotherapy (2.0 Gy/fraction, 5 fractions a week, up to a total dose of 60 Gy) with concurrent weekly cisplatin (Cis 30 mg/m2). The primary endpoint was overall survival at 2 years. An exploratory analysis the effect of FEV1 (expressed as % of predicted value) on survival was performed. Results: Between 02/2003 and 11/2005, 45 pts were enrolled. The demographics were as follows: 34/11 male/female, 14/31 stage IIIA/IIIB, median age 62 y (range 41–81 y), 31/12 FEV1 ≥70%/<70%, 42% squamous cell and 33% adenocarcinoma. All pts received at least 1 cycle CbG. CRT was started in 36 pts: median total radiation dose and duration was 60 Gy and 43 days. The overall response rate was 58% (2% CR, 56% PR). Primary grade 3/4 toxicities were neutropenia (36%), thrombocytopenia (18%), febrile neutropenia (1%). No treatment-related deaths were observed. The median progression-free (PFS) and overall survival (OS) are 11.1 m and 20.4 m. The 1-, 2- and 3-yr OS rates are 62%, 38% and 17%. An FEV1 ≥70% was associated with a better survivall: median OS of 21.6 m vs 9.0 m and 2-yr OS of 48% vs 17% in pts with FEV1 ≥70% vs FEV1 <70% (HR 0.37; 95% CI 0.09 - 0.58). The HR (95%CI) was 1.10 (0.56 - 2.18) for PS 0–1 vs 2 and 0.92 (0.47 - 1.79) for stage IIIA vs IIIB. Conclusions: Induction chemotherapy with CbG followed by CRT with concurrent weekly Cis is well tolerated and results in promising overall survival in pts with unresectable stage III NSCLC. In these pts FEV1 appears to be a important prognostic marker. No significant financial relationships to disclose.

Predictors of long-term survival in lung cancer patients (p) included in the randomized Spanish Lung Cancer Group 0008 phase II trial using concomitant chemoradiation with docetaxel (D) and carboplatin (Cb) plus induction (I) or consolidation (C) chemotherapy (CT) with docetaxel and gemcitabine (G)

7574 Background: There is little information about prognostic variables associated with long term survival in stage III NSCLC p treated with concomitant chemoradiotherapy. Methods: Unresectable stage III p with IK ≥ 70, forced expiratory volume in 1 second (FEV1) of ≥ 1L and weight loss < 5% were initially randomized to sequential treatment (arm A), concurrent CT/TRT followed by consolidation CT (arm B) or induction CT followed by CT/TRT (arm C). Based on RTOG 9410 results, arm A was closed and the study continues with two concomitant arms (B, C). All p receive 2 cycles of D 40 mg/m2 d1, 8 plus G 1,200 mg/m2 d1, 8 as I or C therapy. Concomitant treatment includes D 20 mg/m2 and Cb AUC 2 weekly plus 60 Gy TRT. In order to identify factors that affected survival duration an univariate analysis and a Cox proportional hazards regression were performed including the following variables: age (< 70 or > 70), sex, ECOG (0 vs 1), FEV1 (>2 L vs 1–2 L), stage III (A vs B), N disease (N0 vs N1–2 vs N3), Hb level (≥12 gr/dl vs < 12 gr/dl), RT treatment completed (yes vs no), I or C plus concomitant treatment completed (yes vs no) and prolonged RT delay (≥ 7 days vs > 7 d). Results: From May 01 to Jun 06, 151 p were included (A: 19, B: 66, C: 66). Efficacy and survival data were already presented. With a median follow-up of 23 months (m), no statistically significant differences in terms of MST (13.7 m [B] and 14.6 m [C]) or 4-years survival (27% [B] and 34% [C]) were found. In the Cox regression analysis only RT treatment completed (p < 0.0001) and I or C plus concomitant treatment completed (p < 0.0001) were associated with improved survival. Conclusions: Based in this retrospective analysis neither age, sex, ECOG nor clinical parameters are good predictors for OS in p candidate to concomitant treatment whereas finishing the treatment is needed for achieve long term results. No significant financial relationships to disclose.

Pemetrexed (P) alone or in combination with platinum for malignant pleural mesothelioma (MPM): Efficacy and toxicity of the International Expanded Access Program (EAP) in Spanish patients (p)

19038 Background: A landmark phase III study reported a significant survival benefit for P+cisplatin (cis) versus cis alone in MPM (Vogelzang et al. JCO 2003). EAP provided access to P alone or P plus a platinum for 3311 MPM p in 13 countries. Safety and efficacy data for Spanish p are summarized in this abstract. Methods: From Feb 2003 to May 2005, 225 advanced MPM p were enrolled at 26 sites in Spain. P 500 mg/m2 was given alone or in combination with either cis 75 mg/m2 or carboplatin (Cb) AUC 5 once every 21 days with standard pre-medication (vitamin B12, folic acid, and dexamethasone). Results: 221 MPM p were evaluable for safety and 180 (113 chemonaïve; 67 pre-treated) for efficacy. Median age, 60 yrs (range: 25–89); 78.7% male; 73.3%, Karnofsky score ≥80. Response rate: 27% in the P group, 27.5% in the P+cis group and 30.4% in the P+Cb group, with a clinical benefit rate of 51.4%, 65.5% and 78.6%, respectively. Median time to progression (TTP): 6.9 months (m) in the P group and 8 m in the P+cis group. Median survival (MS): 14.1 m in the P group and 13.4 m in the P+cis group (figure). Neither TTP nor MS could be estimated in the P+Cb group due to high censoring rate. 1-year survival: 67.2% for the P group, 57.1% for the P+cis group, and 62.8% for the P+Cb group. Hematological toxicity was tolerable. Conclusions: Treatment with P plus a platinum resulted in improved survival in MPM compared to cis or Cb alone, with a manageable toxicity, supporting the findings of the phase III study. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Lilly Oncology

Elderly subgroup analysis of a randomized phase 3 trial of gemcitabine (G) in combination with carboplatin (Cb) or paclitaxel (P) compared to paclitaxel plus carboplatin in advanced (stage IIIB, IV) non-small cell lung cancer (NSCLC)

7665 Background: Efficacy and safety of platinum-based chemotherapy doublets in elderly (ELD) NSCLC pts with good PS have been reported to be similar to those in younger pts (N-ELD). However, little data exists about which of the standard regimens are suitable for the ELD. To compare efficacy and safety of doublet regimens in the ELD, we conducted a retrospective age-specific subgroup analysis of our Phase 3 randomized trial comparing 3 regimens for advanced NSCLC (Treat, et al: Abst#7025, Proc ASCO 2005). Methods: A Phase 3 study in advanced (Stage IIIB/IV) NSCLC chemonaive patients with ECOG PS &lt;2 was designed to compare the efficacy of a G-containing platinum regimen GCb (G 1000 mg/m2 IV D 1, 8 plus Cb AUC 5.5, D 1) to a nonplatinum G doublet GP (G 1000 mg/m2 IV D 1,8 plus P 200 mg/m2, D 1) and a reference regimen of PCb (P 225 mg/m2 plus Cb AUC 6.0, D 1). Outcome data of ELD pts (age =70) vs. N-ELD pts (age &lt;70) were compared. Survival (OS) was the primary endpoint with secondary endpoints being response rate (RR), time to progression (TTP) and toxicity. Data from all 3 arms were pooled for this analysis. Results: A total of 314 ELD and 746 N- ELD pts were analyzed (GCb 111/245, GP 100/251, PCb 103/250). There were no significant differences in the OS or TTP distributions in ELD compared to N-ELD pts ( Table 1 ). In general, the incidence and grade of toxicity in ELD vs. N-ELD were comparable. ELD experienced moderately higher incidences of Grade 3–4 constitutional (12.6% vs. 7.1%), neurologic (16.1% vs. 8.9%), and pulmonary (12.3% vs. 7.9%) toxicities compared with N-ELD pts. Conclusion: Use of G-containing doublets as first-line chemotherapy showed similar efficacy to the standard PCb regimen in ELD and N-ELD patients with advanced/metastatic NSCLC as defined by OS, RR, and TTP. ELD tolerated these regimens well despite experiencing slightly more toxicity than younger patients. No significant financial relationships to disclose. [Table: see text]

Subgroup analysis of African American patients from a randomized phase 3 trial of gemcitabine (G) in combination with carboplatin (Cb) or paclitaxel (P) compared to P plus Cb in advanced (stage IIIB, IV) non-small cell lung cancer (NSCLC)

18066 Background: A relationship between race and prognosis in patients with NSCLC has been suggested with African Americans (AA) having higher incidence and lower survival rates compared to whites (W) with a similar stage of disease. However, due to under representation of AA in clinical trials there is little data to substantiate this hypothesis. To investigate the possibility of a race effect on the efficacy and safety of standard chemotherapy doublet regimens in AA pts, we conducted a retrospective subgroup analysis of our Phase 3 randomized trial comparing 3 regimens for advanced NSCLC (Treat, et al: Abst#7025, Proc ASCO 2005). Methods: A Phase 3 study in advanced (stage IIIB/IV) NSCLC chemonaive patients with ECOG PS &lt;2 was designed to compare the efficacy of a G-containing platinum regimen GCb (G 1000 mg/m2 IV D 1, 8 plus Cb AUC 5.5, D 1) to a nonplatinum G doublet GP (G 1000 mg/m2 IV D 1,8 plus P 200 mg/m2, D 1) and a reference regimen of PCb (P 225 mg/m2 plus Cb AUC 6.0, D 1). Outcome and toxicity data of AA pts vs. W pts were compared. Survival (OS) was the primary endpoint with secondary endpoints being response rate (RR), time to progression (TTP) and toxicity. Data from all 3 arms were pooled for this analysis. Results: A total of 128 AA and 906 W pts were analyzed. There were no significant differences in the OS or TTP distributions in AA compared to W pts ( Table 1 ). The incidence and grade of hematologic toxicity in AA vs. W pts were comparable. AA demonstrated slightly lower incidences of Grade 3–4 constitutional (5.1% vs. 9.0%), hemorrhage (1.4 % vs. 2.5 %), and metabolic (4.4% vs. 7.0%) toxicities compared with W pts. Conclusions: Use of standard chemotherapy doublets as first-line chemotherapy in AA pts with advanced NSCLC demonstrated similar efficacy and safety compared to W pts treated under similar conditions. [Table: see text] No significant financial relationships to disclose.

Phase I study of the safety and pharmacokinetics (PK) of paclitaxel or paclitaxel with carboplatin administered in combination with pazopanib (GW786034)

14118 Background: Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit. Pazopanib also is a moderate inhibitor of CYP2C8 and CYP3A4 in vitro. Paclitaxel (T), a substrate for CYP2C8 and CYP3A4, administered alone and in combination with carboplatin (Cb) is highly active in breast, NSCLC, and ovarian cancers. The additive benefit of the anti-VEGF agent bevacizumab with T or T-Cb in breast and NSCLC provides strong rationale for use of a multi-targeted TKI with T or T-Cb. Methods: Pts with advanced cancer (ECOG PS 0–1) were eligible. Dose escalation was split into Part 1 [T (15–80 mg/m2) days 1, 8, 15 q 28 days plus pazopanib (400–800 mg) QD starting on day 2 of cycle 1] and Part 2 [T (80- 225 mg/m2) plus Cb AUC 6 q 21 days plus pazopanib 800 mg QD starting on day 2 of cycle 1]. Safety, PK, and clinical response were evaluated. Dose escalation occurred in cohorts of 3–6 pts based on dose-limiting toxicities (DLTs) and PK. Results: 12 pts in Part 1 received the following pazopanib/T doses (n = pts): 400 mg/15 mg/m2 (3), 800 mg/15 mg/m2 (3), 800mg /50 mg/m2 (3), 800mg /80 mg/m2 (3). Preliminary data were available from 9 pts in Part 1. Selected mean PK results for T are shown. 4 pts in Part 2 received 800mg /175 mg/m2/AUC 6 of pazopanib/T/Cb (data not yet available). Most common AEs (&gt;20%) in Part 1 were Gr 1/2 and consisted of fatigue, diarrhea, anorexia, nausea, vomiting, dysgeusia, AST elevation, rash, hypertension, and cough; Gr 3 diarrhea was reported in 1 pt. The 800mg pazopanib/80 mg/m2 T cohort in Part 1 is being expanded to 6 pts due to a DLT (dose delay of &gt; 2 wks due to an abscess). Best response (n=6 pts) in Part 1 was SD (83%) (range 1–5 cycles). Conclusions: Concomitant administration of pazopanib increased paclitaxel mean Cmax and AUC(0–8) approximately 20–35%. Determination of the MTR in Parts 1 and 2 is ongoing. These findings warrant further studies at therapeutic doses of pazopanib, paclitaxel, and carboplatin. [Table: see text] No significant financial relationships to disclose.

Pemetrexed plus cisplatin (P+Cis) or pemetrexed plus carboplatin (P+Cb) for chemonaive patients (pts) with malignant pleural mesothelioma (MPM): Results of the International Expanded Access Program (EAP)

7562 Background: In a phase III study of P+Cis versus Cis, MPM pts demonstrated a significant survival benefit (12.1 mo vs 9.3 mo median survival; 50.3% vs 38.0% 1-yr survival) and clinical benefit in favor of P+Cis (Vogelzang 2003). Other studies similarly demonstrated efficacy associated with P+Cb. Before and during review by regulatory agencies, EAP provided access to P alone or P plus a platinum (Cis or Cb) for 3311 MPM pts in 13 countries. Safety and efficacy data for chemonaïve pts receiving P+platinum are summarized in this abstract. Methods: Eligible pts had histologic or cytologic diagnosis of MPM not amenable to curative treatment with surgery. P 500 mg/m2 was given in combination with either Cis 75 mg/m2 or Cb AUC 5 once every 21 days with standard pre- medication consisting of vitamin B12, folic acid, and dexamethasone. Investigator-determined response (RR) and survival data (with censoring) were recorded at the end of study participation. Myelosuppression data were also collected. Results: 1,704 chemonaïve pts received =1 dose of P+Cis (843 pts) or P+Cb (861 pts) and were evaluable for safety. For the P+Cis group, the median age was 62 yrs (range, 24–78) and 85.3% of pts were male. For the P+Cb group, the median age was 66 yrs (range, 35–89) and 80.5% of pts were male. More than 90% of pts in both groups had performance status (PS) data; 86.8% of P+Cis pts and 85.8% of P+Cb pts had Karnofsky PS =80. Among the study participants, 745 P+Cis pts and 752 P+Cb pts were evaluated for efficacy. See the table for efficacy and safety data. Conclusions: This large study confirmed the activity of P+Cis and P+Cb, demonstrating clinically similar one-year survival for the treatment of chemonaive pts with MPM. No significant financial relationships to disclose. [Table: see text]

Phase II trial of carboplatin plus cetuximab for the treatment of stage IIIB/IV non-small cell lung cancer (NSCLC)

18005 Background: Cetuximab, an IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) on both normal and tumor cells, has been investigated in advanced NSCLC as a single agent and in combination with chemotherapy. At the time of study design, triplet therapy had not demonstrated activity greater than doublets. This ongoing phase II open-label trial evaluates the doublet of cetuximab in combination with carboplatin (Cb) in patients (pts) with previously untreated stage IIIB/IV NSCLC. Methods: Eligible pts receive cetuximab 400 mg/m2 IV on day 1. Starting on day 8, pts receive cetuximab 250 mg/m2 IV weekly plus Cb AUC=6 IV q3w for 4 cycles (12 weeks). Pts who achieve CR, PR, or SD after 4 cycles may continue weekly cetuximab monotherapy until disease progression or unacceptable toxicity. The primary objective is to evaluate the response rate. Secondary objectives are to determine median progression-free survival (PFS) at 6 months and median overall survival (OS) at 1 year. Results: The study has completed accrual, enrolling and treating 57 pts, all evaluable for response. None had received prior adjuvant chemotherapy for NSCLC. All pts received cetuximab; 49 received Cb. Of the 57 pts, 55 have discontinued: 30 (52.6%) for disease progression or relapse. Drug-related adverse events occurred in 53 pts (93%). Conclusions: These preliminary data of cetuximab in combination with Cb demonstrated modest response rates with an acceptable toxicity profile in pts with advanced NSCLC. Final PFS and OS data are pending. [Table: see text] No significant financial relationships to disclose.

Concomitant chemoradiation plus induction (I) or consolidation (C) chemotherapy (CT) with docetaxel (D) and gemcitabine (G) for unresectable stage III non-small cell lung cancer (NSCLC) patients (p). Results of the randomized SLCG 0008 phase II trial

7620 Background: Neither the optimal sequence of treatment nor the best combination CT is yet well-defined in p receiving concomitant therapy Methods: P with unresectable stage III NSCLC with IK ≥ 70 and weight loss &lt; 5% were initially randomized to sequential treatment (arm A), concurrent CT/TRT followed by consolidation CT (arm B) or induction CT followed by CT/TRT (arm C). Based on RTOG 9410 results, arm A was closed and the study continues with two concomitant arms (B, C). All p receive 2 cycles of D 40 mg/m2 d1, 8 plus G 1,200 mg/m2 d1, 8 as I or C therapy. Concomitant treatment includes D 20 mg/m2 and carboplatin (Cb) AUC 2 weekly plus 60 Gy TRT. Results: From May 01 to Jun 06, 151 p were included (A: 19, B: 66, C: 66). Due to the early closing of arm A, only data of evaluable arms B and C p are shown: toxicity 127 p (B: 63, C: 64) and response 110 p (B: 53, C: 57). All groups are well-matched for baseline disease characteristics. Toxicity grade 3–4 by CTC and RTOG criteria was: esophagitis 19.5% (arm B) and 14.2% (arm C); pneumonitis 8.8 % (arm B) and 10% (arm C). Neutropenia during I or C therapy: 22% (B) and 6.2% (C). Thrombocytopenia 8% (B) and 3% (C). Neutropenia during concomitant therapy: 6.3% (B) and 6% (C). No thrombocytopenia or severe anemia was found during CT/TRT. The reduction CT rate was superior in consolidation (35%) than in induction (15%) and in arm C during concomitant therapy (22.4% C, 6.5% B). Delay of CT dose was similar in B and C arms during I or C (22% B, 20% C) but superior in arm C during concurrent treatment (19.6% B, 30.6% C). The final response rates were 57% (B) and 56.9% (C). A trend for longer time to progression (TTP) was found (B: 7.6 months (m) and C: 9.2 m; p= 0.12) but with similar overall survival (B: 14.3 m and C: 14.7 m; p=0.38). Conclusions: Non- platinum CT plus concomitant chemoradiation offer similar response rate and a favorable hematological toxicity profile in unresectable stage III NSCLC p. No differences in OS but a trend for longer TTP in the arm C (I followed by concurrent approach) has been found. Final data are pending in order to select the best sequence for further studies. No significant financial relationships to disclose.

A phase II randomized selection trial evaluating concurrent chemotherapy plus cetuximab or chemotherapy followed by cetuximab in patients with advanced non-small cell lung cancer (NSCLC): Final report of SWOG 0342

7545 Background: Randomized clinical trials have failed to show a survival benefit for small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors plus chemotherapy in unselected patients with metastatic NSCLC. In contrast, pilot trials of EGFR targeted antibodies plus chemotherapy have suggested enhanced anti-tumor activity. This randomized phase II selection trial was designed to select a cetuximab-chemotherapy regimen for future evaluation in a phase III setting. Methods: Untreated patients (pts) with advanced stage NSCLC were randomized to receive paclitaxel (P) 225 mg/m2 and carboplatin (Cb) AUC=6 every 3 weeks plus concurrent cetuximab (C) 400 mg/m2 loading dose followed by 250 mg/m2, weekly for 4 cycles followed by maintenance C or sequential PCb for 4 cycles followed by C. Treatment was continued until disease progression. Eligible patients were required to have stage IIIB (pleural effusion) or IV (without brain metastases) disease, a performance status of 0–1 and adequate organ function. The primary endpoint was overall survival. The regimen with superior median survival would be considered for further evaluation provided it met a 10-month minimum. Given a true hazard ratio of 1.3, the probability of correctly choosing the superior arm would be &gt; 90%. Results: From July 2004 to June 2005, 242 eligible pts were enrolled onto the study, Final results are described below: Conclusions: Both regimens met efficacy criterion for continued evaluation though the concurrent regimen of PCb + C, had numerically higher survival, and was chosen for further study. Some toxicities were significantly increased with concurrent therapy. A phase II trial of PCb + Cetuximab + Bevacizumab is ongoing (SWOG 0536) in anticipation of a phase III trial. Molecular correlative studies of the EGFR signaling pathway including EGFR IHC, FISH and mutation analysis are underway. No significant financial relationships to disclose. [Table: see text]

Randomized phase II trial of two dose schedules of carboplatin/paclitaxel/cetuximab in stage IIIB/IV non-small cell lung cancer (NSCLC)

7586 Background: Cetuximab, an IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) on both normal and tumor cells, has been investigated in advanced NSCLC as a single agent and in combination with chemotherapy. This ongoing randomized phase II open-label trial evaluates cetuximab in combination with carboplatin (Cb) and paclitaxel (Pac) when given in two dose schedules to patients (pts) with previously untreated stage IIIB/IV NSCLC. Methods: Eligible pts were randomized to 1 of 2 treatment arms. Cetuximab treatment was identical in both arms: 400 mg/m2 IV on day 1 and 250 mg/m2 weekly thereafter. Beginning on day 8, a schedule of Cb AUC=6 IV and Pac 225 mg/m2 IV given on a 3-week cycle was compared with a schedule of Cb AUC=6 IV q4 weeks and Pac 100 mg/m2 IV given weekly for 3 weeks of each 4-week cycle. Pts who achieve CR, PR, or SD after 4 cycles may continue weekly cetuximab monotherapy until disease progression or unacceptable toxicity. The primary objectives were to estimate median progression-free survival (PFS) and the PFS rate at 6 months. Secondary objectives included response rate. Results: The study has completed accrual, with 168 pts randomized and 165 treated. Data are available for 164 pts and confirmed responses for 155 pts. Conclusions: Cetuximab combined with Cb and Pac in both dose schedules demonstrated activity and an acceptable toxicity profile in pts with NSCLC. Final PFS and overall survival data are pending. No significant financial relationships to disclose. [Table: see text]

Phase I trial of docetaxel, carboplatin and lenalidomide in patients with advanced solid tumors

13027 Lenalidomide (LEN) is an immunomodulatory derivative of thalidomide with significantly greater in vitro activity and different toxicity. It may interfere with the expression of angiogenic factors (TNF-alpha &amp; IL-6), vascular endothelial growth factor (VEGF) and induce apoptosis in resistant cell lines. In preclinical trials it has shown synergy with chemotherapy. Primary objective of this study was to determine the maximum tolerated doses (MTD) of docetaxel (D) and carboplatin (Cb), combined with oral LEN. Secondary objectives were toxicity and activity. Eligibility included pathologically proven solid tumors, ≤ 2 prior chemotherapy regimens, performance status ECOG 0/1, and adequate organ function. Patients (Pts) with active brain metastases, or prior treatment with D, Cb, or LEN, were excluded. Treatment was continued for a maximum of 6 cycles, followed by optional continuation of LEN until disease progression or toxicity. MTD was defined as the dose level (dl) immediately lower than that producing dose limiting toxicity (DLT) during cycle 1 in ≥ 2 of 3–6 pts. DLT were ≥ grade (G) 3 non-hematological, or G 4 hematological toxicity. No growth factors were used during cycle 1. Four pts were treated at dl I, D 60 mg/m2, and Cb AUC 6 on Day 1, and LEN 10 mg orally daily for 14 of a 21d cycle. Dose de-escalation was done following the first cohort due to DLT. 10 pts were treated at lower dl -1, D 60 mg/m2, and Cb AUC 6 on Day 1, and LEN 5 mg orally daily for 14 of a 21d cycle. 3 of 14 pts had prior chemotherapy. Tumors included non small cell lung cancer (NSCLC) (9), and one each with thymic, rectal, apocrine carcinoma, angiosarcoma and unknown primary. The median number of cycles was 4 (range 1–6). DLTs occurred in 3 of 4 pts at dl I (G 3 electrolyte (E) (2), G 4 neutropenia (N) (1) and 1 of 10 pts at dl-1 (G 4 N). Overall G 3/4 toxicities were: N (7), thrombocytopenia (2), and E (2). There were no treatment-related deaths or irreversible toxicities. Of the evaluable pts, 5 had a partial response (5/9 NSCLC), &amp; 5 had stable disease. D 60 mg/m2, and Cb AUC 6 on Day 1, and LEN 5 mg orally daily for 14 days of a 21 d cycle is the MTD without use of prophylactic growth factors. This combination is active and further evaluation in a phase II trial is warranted. [Table: see text]

Compassionate treatment (CTr) with re-irradiation, carboplatin (Cb) and Cetuximab (C) in very advanced head and neck cancer (HNC)

13153 Background: Extremely locally advanced HNC is a dramatic clinical situation, causing pain, repeated infections, speech and swallowing impairmen, malnutrition and cosmetic disasters. Re-irradiation may partially palliate some pt, but the low dose of radiation that can safely be delivered limits this approach. Recently the combination of C and radiation has shown improvement of clinical outcome over radiation alone. Methods: We started a CTr with re-irradiation concurrent with Cb and C in pts with heavily symptomatic, pretreated HNC. CTr consisted of: RT (30 Gy) 2 Gy/d, 5 d/week given every other week; Cb AUC 6 d 1, 22 and 43; C, 400 mg/m2 loading dose and 250 mg/m2 maintenance, weekly until day 43 (6 administrations). Results: From January 04 to June 05, 8 pts pre-treated with surgery (6 pts), radiation (8) and chemotherapy (6) entered the CTr. All pts but one had bulky soft tissue invasion and 2 had skin ulceration. One had only bulky nodal relapse. One pt died after the 2nd week due to pneumonia. The other pts had a fast response to CTr: within 5–7 d from the start of therapy they reached a clinical benefit (major or complete pain relief, improvement of swallowing and/or neck movements) and subsequently a rapid tumor shrinkment. All pts achieved an objective response (complete response in 2). No significant local or systemic toxicity occurred in any of the pts, but a mild skin rush. The first 4 pts did not receive further treatment after CTr. These pts showed tumor re-growth within 4–6 weeks from the end of treatment. However one of them underwent salvage surgery and is alive and disease free 14 months after CTr. The 3 other pts received maintenance treatment with weekly C until disease progression. One of them died due to cancer unrelated causes without PD 11 weeks after RT. The 2nd pt developed PD during RT. The 3rd pt is progression-free and alive at 30 weeks from the end of RT. Overall, TTP of the 7 pts ranges between 2 and 7+ months (median 3); survival from the end of RT ranges between 3 and 14+ months (median 7+). Conclusions: CTr with re-irradiation, Cb and C seems feasible even in this poor prognosis, very advanced HNC. No additional toxicity was recorded by adding C. Palliation was achieved in almost all pts and the results deserve further investigations. No significant financial relationships to disclose.

Concurrent chemotherapy plus cetuximab or chemotherapy followed by cetuximab in advanced non-small cell lung cancer (NSCLC): A randomized phase II selectional trial SWOG 0342

7015 Background: Randomized clinical trials have failed to show a survival benefit for small molecule EGFR tyrosine kinase inhibitors plus chemotherapy in patients with advanced NSCLC. In contrast, pilot trials of EGFR targeted antibodies plus chemotherapy have suggested enhanced anti-tumor activity. This large randomized phase II trial was designed to select a cetuximab -chemotherapy regimen for future evaluation in a phase III setting. Methods: Untreated patients (pts) with stage IIIB (by pleural effusion) or IV (without brain metastases) NSCLC, with a performance status of 0–1 and adequate organ function were randomized to received paclitaxel (P) 225 mg/m2 and carboplatin (Cb) AUC=6 every 3 weeks plus cetuximab (C) 400 mg/m2 loading dose followed by 250 mg/m2, weekly for 4 cycles followed by maintenance C or the same doses of PCb for 4 cycles followed by C. C was continued until disease progression or 1 year of therapy. The primary endpoint was overall survival; the statistical design required a median survival of ≥ 10 months for a regimen to be selected for subsequent phase III trial evaluation. The probability of correctly choosing the superior arm is 91% when the true hazard ratio is 1.3. Results: From July 2004 to June 2005, 225 eligible pts were enrolled into the study. Preliminary results are described below: Conclusions: At the time of this analysis, efficacy and toxicity were similar in the two treatment arms; both regimens were well tolerated. Assuming these results are sustained, the concurrent regimen of PCb + cetuximab has met the criteria for continued evaluation. A phase II trial of PCb + cetuximab + bevacizumab (B) is in development in anticipation of a phase III trial testing PCbB ± cetuximab. Molecular correlative studies of the EGFR signaling pathway are ongoing. [Table: see text] [Table: see text]