Gemcitabine In Advanced Pancreatic Cancer Research Articles

Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients

Statins have potential antineoplastic properties via arrest of cell-cycle progression and induction of apoptosis. A previous study demonstrated in vitro and in vivo antineoplastic synergism between statins and gemcitabine. The present randomized, double-blinded, phase II trial compared the efficacy and safety of gemcitabine plus simvastatin (GS) with those of gemcitabine plus placebo (GP) in patients with locally advanced and metastatic pancreatic cancer. Patients were randomly assigned to receive a 3-week regimen with GS (gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus simvastatin 40 mg once daily) or GP (gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus placebo). The primary end point was time to progression (TTP). Between December 2008 and April 2012, 114 patients were enrolled. The median TTP was not significantly different between the two arms, being 2.4 months (95 % CI 0.7-4.1 months) and 3.6 months (95 % CI 3.1-4.1 months) in the GS and GP arms, respectively (P = 0.903). The overall disease control rate was 39.7 % (95 % CI 12.2-33.8 %) and 57.1 % (95 % CI 19.8-44.2 %) in the GS and GP arms, respectively (P = 0.09). The 1-year expected survival rates were similar (27.7 and 31.7 % in the GS and GP arms, respectively; P = 0.654). Occurrence of grade 3 or 4 adverse events was similar in both arms, and no patients had rhabdomyolysis. Adding low-dose simvastatin to gemcitabine in advanced pancreatic cancer does not provide clinical benefit, although it also does not result in increased toxicity. Given the emerging role of statins in overcoming resistance to anti-EGFR treatment, further studies are justified to evaluate the efficacy and safety of combined simvastatin and anti-EGFR agents, such as erlotinib or cetuximab, plus gemcitabine for treating advanced pancreatic cancer.

KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer

It has not yet been defined if KRAS has a prognostic value or is a predictive biomarker for the efficacy of erlotinib in advanced pancreatic cancer (PC). AIO-PK0104 was a phase III trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC. For this post hoc subgroup analysis, biomarker data on the KRAS exon 2 mutation status were correlated with objective response to 1st-line therapy and with overall survival after start of 2nd-line chemotherapy (OSc). KRAS codon 12 was mutated in 121 of 173 (70%) patients. The KRAS status showed no association with objective response (p=0.40), but KRAS wildtype patients had an improved OS (HR 1.68, p=0.005). A trend for a survival benefit was also observed during (non-erlotinib containing) 2nd-line chemotherapy, with a HR of 1.47 (p=0.10) for the OSc. This post hoc analysis of AIO-PK0104 supports the assumption that KRAS is rather a prognostic than a predictive biomarker in PC.

First-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancer

To investigate activity, toxicity, and prognostic factors for survival of erlotinib and fixed dose-rate gemcitabine (FDR-Gem) in advanced pancreatic cancer. We designed a single-arm prospective, multicentre, open-label phase II study to evaluate the combination of erlotinib (100 mg/d, orally) and weekly FDR-Gem (1000 mg/m(2), infused at 10 mg/m(2) per minute) in a population of previously untreated patients with locally advanced, inoperable, or metastatic pancreatic cancer. Primary endpoint was the rate of progression-free survival at 6 mo (PFS-6); secondary endpoints were overall response rate (ORR), response duration, tolerability, overall survival (OS), and clinical benefit. Treatment was not considered to be of further interest if the PFS-6 was < 20% (p0 = 20%), while a PFS-6 > 40% would be of considerable interest (p1 = 40%); with a 5% rejection error (α = 5%) and a power of 80%, 35 fully evaluable patients with metastatic disease were required to be enrolled in order to complete the study. Analysis of prognostic factors for survival was also carried out. From May 2007 to September 2009, 46 patients were enrolled (male/female: 25/21; median age: 64 years; median baseline carbohydrate antigen 19-9 (CA 19-9): 897 U/mL; locally advanced/metastatic disease: 5/41). PFS-6 and median PFS were 30.4% and 14 wk (95%CI: 10-19), respectively; 1-year and median OS were 20.2% and 26 wk (95%CI: 8-43). Five patients achieved an objective response (ORR: 10.9%, 95%CI: 1.9-19.9); disease control rate was 56.5% (95%CI: 42.2-70.8); clinical benefit rate was 43.5% (95%CI: 29.1-57.8). CA 19-9 serum levels were decreased by > 25% as compared to baseline in 14/23 evaluable patients (63.6%). Treatment was well-tolerated, with skin rash being the most powerful predictor of both longer PFS (P < 0.0001) and OS (P = 0.01) at multivariate analysis (median OS for patients with or without rash: 42 wk vs 15 wk, respectively, Log-rank P = 0.03). Additional predictors of better outcome were: CA 19-9 reduction, female sex (for PFS), and good performance status (for OS). Primary study endpoint was not met. However, skin rash strongly predicted erlotinib efficacy, suggesting that a pharmacodynamic-based strategy for patient selection deserves further investigation.

EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104

Background:We aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in pancreatic cancer (PC) patients treated with the anti-EGFR agent erlotinib within the phase 3 randomised AIO-PK0104 study.Methods:AIO-PK0104 was a multicenter trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC; primary study end point was the time-to-treatment failure after first- and second-line therapy (TTF2). Translational analyses were performed for KRAS exon 2 mutations, EGFR expression, PTEN expression, the EGFR intron 1 and exon 13 R497K polymorphism (PM). Biomarker data were correlated with TTF, overall survival (OS) and skin rash.Results:Archival tumour tissue was available from 208 (74%) of the randomised patients. The KRAS mutations were found in 70% (121 out of 173) of patients and exclusively occurred in codon 12. The EGFR overexpression was detected in 89 out of 181 patients (49%) by immunohistochemistry (IHC), and 77 out of 166 patients (46%) had an EGFR gene amplification by fluorescence in-situ hybridisation (FISH); 30 out of 171 patients (18%) had a loss of PTEN expression, which was associated with an inferior TTF1 (first-line therapy; HR 0.61, P=0.02) and TTF2 (HR 0.66, P=0.04). The KRAS wild-type status was associated with improved OS (HR 1.68, P=0.005); no significant OS correlation was found for EGFR–IHC (HR 0.96), EGFR–FISH (HR 1.22), PTEN–IHC (HR 0.77), intron 1 (HR 0.91) or exon 13 R497K PM (HR 0.83). None of the six biomarkers correlated with the occurrence of skin rash.Conclusion:The KRAS wild-type was associated with an improved OS in erlotinib-treated PC patients in this phase 3 study; it remains to be defined whether this association is prognostic or predictive.

Harnessing gemcitabine metabolism: a step towards personalized medicine for pancreatic cancer

Pancreatic cancer is a lethal malignancy with a 5-year survival rate of only 6%. Surgical resection remains the only cure, yet even after resection the 5-year survival is only 20% due to a high recurrence rate. Thus, a high proportion of patients with this disease will ultimately require systemic chemotherapy for advanced pancreatic cancer (APC). While the advent of personalized medicine has resulted in significant advances in the management of many cancer types, the standard of care for pancreatic cancer remains gemcitabine based, with very few exceptions. This article first aims to provide an overview of the benefits and limitations of gemcitabine alone, gemcitabine combinations, and different modes of administration of gemcitabine in APC. It then discusses research, suggesting that pharmacogenomic differences in enzymes that affect gemcitabine transport and metabolism can predict benefit from this drug in pancreatic cancer. Finally, the article outlines novel therapies and combinations that exploit these interindividual variations in gemcitabine metabolism to improve the efficacy of this drug in the management of APC.

O-0007 Exploratory Serum Biomarker Analyses from BO21129, a Phase II Study of Erlotinib in Second-Line Pancreatic Cancer: Potential Role of Amphiregulin?

ABSTRACT Introduction Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor, is approved in combination with gemcitabine for advanced pancreatic cancer. As the use of biomarkers to guide treatment decisions for targeted therapies is an area of increasing interest, a post-approval commitment was made to investigate potential biomarkers for erlotinib in pancreatic cancer. This randomised, placebo-controlled, multicentre, phase II study examined whether any biomarkers were predictive of differential outcomes with erlotinib monotherapy in advanced pancreatic cancer. The primary data for this study have been presented previously and showed no correlation between any of the pre-specified biomarkers investigated and the primary endpoint of progression-free survival (PFS) with erlotinib. Here we present the results of exploratory analyses on serum biomarkers. Methods Serum samples were collected from patients at baseline, 3 weeks, and after treatment discontinuation. Randomisation was stratified by ECOG PS, region and smoking status, and the initial estimation of hazard ratio for the treatment effect was by unadjusted Cox regression. After observing imbalances in some baseline characteristics, additional post-hoc analyses using a stepwise model selection algorithm were performed to assess for any impact on PFS and OS. Serum biomarker analyses were conducted on amphiregulin, EGF, TGF-a, and sHer-2. Exploratory analyses of efficacy were performed in ‘low’ and ‘high’ subgroups, as compared to the median of each soluble marker in the overall population. Efficacy was analysed in subgroups using both the initial unadjusted analysis, as well as the post-hoc model that was developed in the overall population. Results Data on baseline serum markers were available for 199 out of 207 patients for amphiregulin and TGF-a, and 202 out of 207 patients for EGF and sHer-2. The adjusted post-hoc analysis of serum biomarkers showed that erlotinib provided a significant benefit in terms of PFS and OS in patients with high levels of amphiregulin (Table). Validation of results for other markers is ongoing and data will be presented. Conclusion Exploratory adjusted analyses of serum markers showed that patients with high serum amphiregulin concentrations achieved a significant benefit in both PFS and OS. The observation that patients with elevated baseline levels of amphiregulin obtained benefits in both PFS and OS with erlotinib may suggest potential for this biomarker in pancreatic cancer. Table 1 .

Does Health-Related Quality of Life Improve for Advanced Pancreatic Cancer Patients Who Respond to Gemcitabine? Analysis of a Randomized Phase III Trial of the Cancer and Leukemia Group B (CALGB 80303)

Context Gemcitabine for advanced pancreatic cancer (APC) is palliative and the prognosis is poor, making health-related quality of life (HRQOL) particularly important. Objectives We evaluated HRQOL with the EuroQol (EQ-5D™) in patients with APC participating in Cancer and Leukemia Group B 80303, a multicenter, double-blind, randomized trial comparing overall survival (OS) between two treatment arms: gemcitabine with bevacizumab or gemcitabine with placebo. Methods A consecutive subsample of patients was invited to complete the EQ-5D surveys. Because neither clinical nor HRQOL outcomes differed based on the study arm, analyses were pooled. Changes in mean scores from baseline to eight weeks and the prognostic value of the EQ-5D were evaluated. Results Mean index scores remained stable (0.78 at baseline [ n = 267], 0.79 at eight weeks [ n = 186], P = 0.34, Wilcoxon signed rank test), attributable to a modest deterioration of physical function domain scores coincident with small improvements in pain and anxiety/depression scores. A small decline in visual analogue scale scores was observed (70.7 vs. 68.2, P = 0.026). HRQOL changes within chemotherapy response strata revealed stable index scores but a trend of worsened physical function among patients with disease progression compared with those with stable or improved disease. Visual analogue scale scores trended downward over time irrespective of chemotherapy response status, with a statistically meaningful deterioration in patients who progressed (68.9 vs. 64.4, P = 0.029). Baseline scores from both EQ-5D scales were significant predictors of OS in Cox proportional hazard models. Conclusion Response to gemcitabine treatment in APC is not associated with appreciable improvement of global HRQOL. Small improvements in pain and mood are observed despite progressive functional decline. Those who respond to gemcitabine may experience a slight slowing of functional deterioration.

Novel Strategy with Gemcitabine for Advanced Pancreatic Cancer

5-fluorouracil (5-FU) is widely used in chemotherapy for gastric and colorectal cancer, but gemcitabine (GEM), and not 5-FU, is approved as a standard drug for use in pancreatic cancer. Interindividual variation in the enzyme activity of the GEM metabolic pathway can affect the extent of GEM metabolism and the efficacy of GEM chemotherapy. Human equilibrative nucleoside transporter 1 (hENT1) is recognized as a major transporter of GEM into cells. In addition, a factor that activates hENT1 is the inhibition of thymidylate synthase (TS), one of the 5-FU metabolic enzymes; TS inhibition mediates depleting intracellular nucleotide pools, resulting in the activation of the salvage pathway mediated through hENT1. In this paper, the role of 5-FU in GEM-based chemotherapy for pancreatic cancer is discussed with special emphasis on enzymes involved in the 5-FU and GEM metabolic pathways and in the correlation between GEM responsiveness and the expression of 5-FU and GEM metabolic enzymes.

A phase I/II study of the Src inhibitor saracatinib (AZD0530) in combination with gemcitabine in advanced pancreatic cancer

This phase I/II study of saracatinib in combination with gemcitabine in patients with advanced pancreatic cancer was conducted by the NCIC Clinical Trials Group. The aims were to define the recommended phase II dose (RP2D) of saracatinib when combined with gemcitabine, and assess the efficacy of this combination in advanced pancreatic cancer. Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and no prior chemotherapy. In phase I saracatinib was escalated in combination with gemcitabine (1000 mg/m(2)) to determine the recommended phase II dose (RP2D). The study was then expanded to a single arm phase II trial using a Simon 2-stage design. The primary endpoint was objective tumor response (OR) plus stable disease ≥ 4 months (SD4) rate; if ≥ 8 patients had OR+SD4, the study would proceed to stage 2. Thirteen patients were enrolled into the phase I portion of this study. Saracatinib 175 mg PO daily was chosen as the RP2D in combination with gemcitabine. Twenty-one additional patients were then enrolled at the RP2D (phase II). Of the 22 response evaluable patients treated at the RP2D, 9 patients (40.9%) had progressive disease, 6 patients (27.3%) had stable disease for less than 4 months, 5 patients (22.7%) had SD4, and 2 patients (9.1%) had a partial response to treatment. Objective criteria for continuing to stage 2 were thus not met and the trial was closed following the accrual of 34 patients. Saracatinib 175 mg daily in combination with gemcitabine is well tolerated but the combination did not improve efficacy over what would be expected from gemcitabine alone.

Reviewing the safety of erlotinib in non-small cell lung cancer

Importance of the field: Erlotinib, a potent inhibitor of EGFR activity, is approved as a monotherapy for the treatment of advanced NSCLC and in combination with gemcitabine for advanced pancreatic cancer. The oral administration and manageable toxicity of erlotinib, along with its similar efficacy to chemotherapy, make it an important option as either maintenance therapy or in second-/third-line for patients with NSCLC who have previously received first-line chemotherapy. It is also an emerging option in other treatment settings in NSCLC.Areas covered in this review: This review summarizes safety data from major clinical trials of erlotinib in patients with advanced NSCLC, as well as post-marketing data obtained in the 5 years since this drug was first approved.What the reader will gain: An understanding of the common toxicities expected with erlotinib in patients with advanced NSCLC.Take home message: Erlotinib is a well-tolerated treatment option for patients with advanced NSCLC. The main adverse events of rash and diarrhea are typically mild or moderate in severity, and rarely lead to treatment withdrawal. When necessary, rash and diarrhea can be easily managed prophylactically, by active intervention or through dose reduction.

Gastrointestinal bleeding during anti-angiogenic peptide vaccination in combination with gemcitabine for advanced pancreatic cancer.

Most pancreatic cancer patients are diagnosed at the advanced stages, and no therapy is superior to gemcitabine alone. To confirm the feasibility and efficacy of a novel clinical intervention using tumor vessel-specific anti-angiogenic peptide vaccination, we conducted a clinical phase I/II trial using HLA-A*2402/A*0201-restricted vascular endothelial growth factor receptor type 1 (VEGFR1)-derived peptide vaccination in combination with gemcitabine for advanced pancreatic cancer (http://www.clinical-trials.gov; NCT00683358 and NCT00683085). Four of the enrolled patients (n=2 for HLA-A*2402 and n=2 for HLA-A*0201 protocol, respectively), defined as having progressive disease according to the Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v.1.0), failed to respond to the therapy. Another two patients enrolled in HLA-A*2402 protocol dropped out of the study due to rapid disease progression. Grade 2-3 hematologic toxicities were observed in all cases, but the treatment was well tolerated with minimal systemic adverse events. One case in HLA-A*2402 protocol and another case in HLA-A*0201 protocol suffered complicated gastrointestinal (GI) bleeding during vaccination. The causal relationship between GI bleeding and VEGFR1-peptide vaccination is unclear according to the pathologic examination. These studies terminated prematurely because of the advanced stage of the disease in the enrolled patients on entry to the study. Despite GI bleeding, peptide vaccination provides a feasible treatment option for many advanced pancreatic cancer patients.

S1019 A Randomized Phase II Study Designed to Compare Toxicity and Dose Intensity Between Four-Week Versus Three-Week Schedule of Gemcitabine for Advanced Pancreatic Cancer

Purpose: The aim of this phase II study is to compare toxicity and dose intensity (DI) between four-week (4w) and three-week (3w) schedule of gemcitabine (GEM) for advanced pancreatic cancer (PC). Methods: Patients with histologically or cytologically proven locally advanced and/or metastatic PC were assigned to receive GEM in 4w schedule or 3w schedule. The protocol of GEM was as follows: 4w schedule (1,000mg/m2 on days 1, 8 and 15 of each 28-day cycle), 3w schedule (1,000mg/m2 on days 1 and 8 of each 21-day cycle). If grade 3 to 4 hematological toxicity (only a platelate count was defined = 50%, age between 20 and 80 years, and adequate organ function. Written informed consent was obtained from all patients. The primary endpoint was a compliance rate of protocol regimen within eight weeks after initiation of chemotherapy, which was defined as the proportion of patients without a dose reduction or a delay in administration of GEM. Secondary endpoints were DI, safety, response rate and overall survival. Results: A total of 90 patients (4w: 3w schedule= 45: 45) were enrolled between January 2006 and October 2008. Baseline patient and disease characteristics were similar in both schedules. Median age was 67 (range, 49-79) years in 4w schedule vs. 66 (range, 33-79) years in 3w schedule; p=0.67. KPS (70-80: 90-100%) was (4: 41) vs. (5: 40); p=0.99. Disease (locally advanced: metastatic) was (7: 38) vs. (7: 38); p=0.99. The eight week-compliance rate of protocol regimen was the same; 53.3% (24/45) in both schedules. However, median duration of accumulative rate for adverse events tended to be extended in 3w schedule; 35days (6-334) vs. 49 (6-414), p=0.20. Consequently, the mean received DI was equivalent in both schedules; 588 +/130 mg/m2/week vs. 550 +/116, p=0.14. Grade 3-4 neutropenia was a major adverse event in both schedules; 37.7% (17/ 45) vs. 35.5 (16/45); p=0.82, in contrast, thrombocytopenia was significantly increased in 4w schedule; 26.6% (12/45) vs. 4.4 (2/45); p=0.009. Tumor response rate was 14.2% (5/ 35) vs. 17.1(6/35); p=0.92, and the disease control rate (PR, SD) was 60.0% (27/45) vs. 62.2 (28/45); p=0.82. Median survival time was 206 (33-802) days vs. 250 (39-681); p= 0.84. Conclusions: These results support the efficacy and safety in 3w schedule of GEM for PC.

Gemcitabine-based Cytotoxic Doublets Chemotherapy for Advanced Pancreatic Cancer: Updated Subgroup Meta-analyses of Overall Survival

Previous meta-analyses showed a survival advantage with gemcitabine (GEM)-based combinations over GEM in advanced pancreatic cancer. Therefore, it would be valuable to explore the specific active regimens based on a subgroup meta-analysis. Updated data by comprehensive search of the literature from databases and conference proceedings. Subgroup meta-analysis compared GEM with GEM-based doublets chemotherapy in terms of 6-month overall survival (OS) and 1-year OS. Eighteen randomized controlled trials with 4237 patients were included, which were divided into five subgroups: GEM/capecitabine, GEM/cisplatin, GEM/5-fluorouracil, GEM/irinotecan and GEM/oxaliplatin. In each subgroup, risk ratios (RRs) for 6-month OS were 0.85 (P = 0.04), 0.99 (P = 0.88), 0.95 (P = 0.46), 1.03 (P = 0.77) and 0.80 (P = 0.001), respectively, and RRs for 1-year OS were 0.94 (P = 0.14), 0.99 (P = 0.75), 0.96 (P = 0.19), 1.00 (P = 0.97) and 0.93 (P = 0.05), respectively. A meta-analysis of the trials with adequate information on performance status (PS) was performed in four trials with 1325 patients. Patients with a good PS did not show a survival benefit when receiving combination chemotherapy. RRs for 6-month and 1-year OS were 0.82 (P = 0.18) and 0.93 (P = 0.08). In contrast, application of combination chemotherapy to patients with a poor PS appeared to be harmful. RRs were 1.17 (P = 0.04) for 6-month OS and 1.09 (P = 0.04) for 1-year OS. The meta-analysis indicated a significant survival benefit when GEM was either combined with capcitabine or oxaliplatin. On the basis of a preliminary subgroup analysis, pancreatic cancer patients with a poor PS appeared to have a worse survival benefit from GEM-based cytotoxic doublets.

A phase II study of isoflavones, erlotinib, and gemcitabine in advanced pancreatic cancer

The EGFR/Akt/NF-κB signalling pathway is frequently deregulated in pancreatic cancer and contributes to cell growth, metastasis and chemoresistance. An isoflavone, genistein, inactivates Akt and NF-κB and enhances the anti-tumor activity of erlotinib and gemcitabine in experimental systems of pancreas cancer. This phase II study was undertaken to determine the effects of adding isoflavone to a regimen of gemcitabine and erlotinib on survival in patients with advanced pancreatic cancer. Eligibility included previously untreated patients with advanced pancreatic adenocarcinoma. Patients received gemcitabine 1,000 mg/m² on days 1, 8, and 15, and erlotinib 150 mg once daily P.O. on day 1 to day 28. Soy isoflavones (Novasoy®) were administered at a dose of 531 mg twice daily P.O. starting day -7 until the end of study participation. Twenty patients with advanced pancreas cancer were enrolled (median age 57.9 years). Sixteen patients had stage IV disease. The median number of cycles was 2 per patient. The median survival time was 5.2 months (95% CI, 4.6-N/A months). The probability of survival at 6 months was 50% (95% CI, 32-78%). The addition of soy isoflavones to gemcitabine and erlotinib did not appear to increase the survival of patients with advanced pancreatic cancer.

A phase Ib/IIa trial to evaluate the CCK2 receptor antagonist Z-360 in combination with gemcitabine in patients with advanced pancreatic cancer

Aim To evaluate the combination of the gastrin antagonist Z-360 and gemcitabine for advanced pancreatic cancer. Methods Previously untreated patients with PC were randomly allocated to Z-360 120 mg, 240 mg or placebo. Z-360/placebo was given on day –3 and gemcitabine 1000 mg/m 2 commenced on day 1 followed by Z-360 on day 2. Thereafter Z-360/placebo was given twice daily concurrently with standard dose of gemcitabine. Pharmacokinetics for both drugs was measured alone and in combination. Toxicity, response and quality of life were also recorded. Results Thirty-three patients with a median age of 62 years were randomised of which six had locally advanced disease and 26 had metastatic disease. Analysis of the area under the plasma concentration versus time curve (AUC), the maximum observed concentration (Cmax(obs)) and the time of the maximum observed concentration (Tmax(obs)) for Z-360, gemcitabine and 2,2-difluorodeoxyuridine (dFdU), could not exclude an effect on the systemic exposure to Z-360, gemcitabine and dFdU when co-administration of Z-360 and gemcitabine was compared with single agent administration. The most commonly reported adverse events were nausea, abdominal pain, vomiting and fatigue. At the end of the study, 62.5%, 25% and 60% had stable disease in the 120 mg, 240 mg and placebo group, respectively. A higher proportion of patients in Z-360 groups reported improvement in pain. Conclusions Z-360 is safe and well tolerated when combined with gemcitabine. A Phase III trial is needed to determine whether the combination of Z-360 and gemcitabine is superior to gemcitabine alone in advanced PC.

Abstract B225: Use of RNAi to identify targets for further improving the antitumor activity of gemcitabine and nab-paclitaxel combination therapy in patients with advanced pancreatic cancer

Abstract Pancreatic cancer remains the fourth leading cause of cancer-related deaths in the United States. Gemcitabine has been used as a standard first-line therapy for more than a decade for this deadly disease. However, the benefit of single-agent gemcitabine in advanced pancreatic cancer is small. Combination regimens including gemcitabine have provided only modest improvement. In a Phase I/II clinical trial gemcitabine plus nab-paclitaxel had significant clinical activity (Von Hoff, et al. 2009, J. Clin. Oncol. 27 (15s): Abstract #4525). To further improve the response of gemcitabine plus nab-paclitaxel therapy, we performed a high throughput RNAi (HT-RNAi) screen with a kinase-focused siRNA library consisting of siRNA oligos against 588 genes (2 siRNAs/gene) in the MIA PaCa-2 pancreatic cancer cell line. Eighty eight siRNAs targeting 82 genes were identified as positive hits (≥2 fold decrease in IC50 values). Several commercially available small molecule inhibitors of the positive hits were obtained and tested in combination with gemcitabine and nab-paclitaxel, both alone or in combination. Among the small molecule inhibitors tested, the CHK1 inhibitor, SB 218078, showed the most significant synergistic effect with gemcitabine and nab-paclitaxel, gemcitabine alone, or nab-paclitaxel alone in two pancreatic cancer cell lines, MIA PaCa-2 and PANC-1. The mechanism of SB 218078 induced sensitivity of pancreatic cancer cells to the gemcitabine and nab-paclitaxel are currently under investigation. In summary, using an HT-RNAi screen we have identified a list of gene targets that, when down-regulated by siRNA oligos, sensitize pancreatic cancer cells to the gemcitabine plus nab-paclitaxel combination therapy. Inhibitors of these targets may potentially enhance the anticancer activity of gemcitabine and nab-paclitaxel. (This work was supported by NIH/NCI Program Project grant CA109552). Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B225.

CA 19-9 Response as an Early Indicator of the Effectiveness of Gemcitabine in Patients with Advanced Pancreatic Cancer

Background: The CA 19-9 decline 8 weeks after gemcitabine administration has been shown to be a useful prognosticator of survival in patients with pancreatic cancer. We assessed the prognostic value of changes in CA 19-9 levels 4 weeks after treatment initiation on overall survival (OS) and time to progression (TTP). Methods: We evaluated 72 patients who received gemcitabine for advanced pancreatic cancer. The serum CA 19-9 level was measured routinely at baseline (CA 19-9_Pre) and after the first (4 weeks; CA 19-9_A1) and second (8 weeks; CA 19-9_A2) courses. CA 19-9 responses were categorized into quartiles using the proportional change in CA 19-9. Results: The rates of decrease in CA 19-9_A1 and CA 19-9_A2 were strongly correlated with each other (r = 0.8981, p < 0.0001). Multivariate analysis revealed that an early CA 19-9 response was prognostic of OS and TTP in addition to CA 19-9_Pre and performance status. Compared with the first quartile of an early CA 19-9 response, hazard ratios for the second, third and fourth quartiles were 0.91 (95% confidence interval, CI, 0.59–1.34), 0.71 (95% CI, 0.45–1.08), and 0.63 (95% CI, 0.41–0.94) for TTP, respectively (p for trend = 0.002), and 0.98 (95% CI, 0.61–1.49), 0.68 (95% CI, 0.40–1.08) and 0.79 (95% CI, 0.50–1.21) for OS (p for trend = 0.036). Conclusion: CA 19-9 response after the first course of gemcitabine was a prognosticator of OS and TTP in patients with advanced pancreatic cancer.

An update of a phase I/II study of the VEGF receptor tyrosine kinase inhibitor vatalanib and gemcitabine in patients with advanced pancreatic cancer

15571 Background: The VEGF pathway is the predominant mediator of angiogenesis in pancreatic cancer. Vatalanib is a small molecule tyrosine kinase inhibitor of all known VEGF receptors. We initiated a phase I/II study of vatalanib and gemcitabine for advanced pancreatic cancer. Methods: Patients with newly diagnosed unresectable or metastatic pancreatic adenocarcinoma were enrolled. Gemcitabine was given by fixed-dose rate infusion weekly × 3 in a 28-day cycle. Vatalanib was initially given orally 1250 mg once daily, then the protocol was amended to 500 mg twice daily for the phase II portion of the trial. Gemcitabine was escalated from 700 mg/m2 to the final phase II dose of 850 mg/m2. Results: To date, twenty-six patients are evaluable for toxicity and response (14M/12F; median age 62 years, range 40–82 years; median KPS 90%). Sixteen patients were enrolled in phase I and ten patients have been enrolled in phase II. Phase I dose limiting toxicities include: diarrhea, hypokalemia, neutropenia, fatigue, a...

Increased survival using platinum analog combined with gemcitabine as compared to single-agent gemcitabine in advanced pancreatic cancer: pooled analysis of two randomized trials, the GERCOR/GISCAD intergroup study and a German multicenter study

The aim was to evaluate the efficacy of gemcitabine combined with a platinum agent compared to single-agent gemcitabine in a pooled analysis of two randomized trials. The French Multidisciplinary Clinical Research Group (GERCOR)/Italian Group for the Study of Gastrointestinal Tract Cancer (GISCAD) intergroup study comparing gemcitabine plus oxaliplatin to gemcitabine and a German multicenter trial comparing gemcitabine plus cisplatin versus gemcitabine were included in a pooled analysis based on individual patient data. Among 503 evaluable patients, 252 received gemcitabine plus a platinum analog (GP), while 251 patients were treated with gemcitabine alone. For progression-free survival (PFS), the pooled univariate analysis indicated a hazard ratio (HR) of 0.75 (P = 0.0030) in favour of the GP combination. The benefit from the GP combination was greatest in the subgroup of patients with performance status (PS) = 0 (HR = 0.64; P = 0.013). Also overall survival was significantly superior in patients receiving the GP combination (HR = 0.81; P = 0.031). Again, patients with PS = 0 appeared to have a greater benefit from treatment intensification (HR = 0.72; P = 0.063). The pooled analysis of the GERCOR/GISCAD intergroup study and the German multicenter study indicates that the combination of gemcitabine with a platinum analog such as oxaliplatin or cisplatin significantly improves progression-free survival and overall survival as compared to single-agent gemcitabine in advanced pancreatic cancer. The benefit seems to prevail in patients with a good performance status.

A randomized phase II study of axitinib (AG-013736) and gemcitabine versus gemcitabine in advanced pancreatic cancer, preceded by a phase I component

4551 Background: The current standard of care for patients (pts) with advanced pancreatic cancer (APC) is gemcitabine (GEM)- based chemotherapy. Axitinib (AG) is a potent inhibitor of vascular endothelial growth factor receptors. A phase I study of AG in solid tumors identified 5 mg BID as the therapeutic starting dose. The main objectives of this trial are to determine whether the overall survival (OS) of the combination of AG and GEM is superior to that of GEM alone as first-line therapy in pts with APC, and to determine doses of AG and GEM that can be safely administered together. Methods: 8 pts were treated on the phase 1 (P1) portion of this trial. For the phase 2 (P2) portion of the trial, 103 pts with locally advanced or metastatic disease, no prior GEM or VEGF/VEGFR inhibitors, PS 0–2 were randomized (2:1) to GEM 1,000 mg/m2 over 30 minutes on days (D) 1, 8, 15 every 28 D with or without AG at a starting dose of 5 mg po BID between Jan 06 and Aug 06. CT scans were performed every 2 cycles. Results: Data from the evaluable P1 pts (n=5) indicated that PK of GEM and AG appeared to be unchanged in combination. The GEM mean plasma exposure (AUC) was 11,348 alone vs 12,840 ng.h/mL with AG; similarly mean steady-state AG AUC was 250 alone vs 270 ng.h/mL with GEM. 3 of 8 pts had a PR. The median number of days on study drug was 158 days (range: 57–330 days) with 2 pts ongoing. Data from the randomized P2 pts: male 48%; median age 62 (36- 81); PS 0/1 vs 2: 91% vs 9%; 41% with locally advanced disease; 59% with metastatic disease. The most commonly reported adverse events are anemia (48%), alk phos elevations (48%), leukopenia (45%), neutropenia (42%), LFT elevations (39%), and thrombocytopenia (27%). The most common non-hematologic adverse events are nausea (24%), vomiting (20%), fatigue (19%), diarrhea (18%), anorexia (18%), constipation (13%), dyspnea (12%), and pyrexia (12%). 55 events have been reported in the 103 P2 pts. The pooled median OS is 203 days with a 95% CI of (158, not estimable). The median follow-up time is currently 223 days. Conclusions: AG can be safely administered at a starting dose of 5 mg BID in combination with standard dose GEM in patients with APC. Final safety and OS results by treatment arm will be presented. [Table: see text]