Pancreatic Cancer Pts Research Articles

Effect of cytidine deaminase (CDA)–related biomarkers on overall survival in patients with advanced pancreatic cancer receiving gemcitabine (GEM) monotherapy.

e14645 Background: CDA metabolizes GEM to an inactive metabolite, 2’,2’-difluorodeoxyuridine (dFdU). We have already reported the impact of CDA-related biomarkers on GEM-induced toxicities (Sugiyama, J Clin Oncol. 2007; and Ueno, Br J Cancer. 2009). This study was intended to clarify the effects of CDA-related phenotypic and genetic biomarkers on the overall survival of advanced pancreatic cancer pts treated with GEM monotherapy. Methods: Using advanced pancreatic cancer (stage IV) pts enrolled in the first study (n=73) and the second study (n=98) who received a 30-minute intravenous GEM infusion at a dose of 1,000 mg/m2, the overall survival was analyzed for associations with the pharmacokinetic parameters of GEM and dFdU, plasma CDA activity and nonsynonymous SNPs of CDA {79A>C (CDA*2) and 208G>A (CDA*3) } as well as the pts’ background factors. Results: In the first study, overall survival was significantly longer in pts with longer mean residence time (MRT) of GEM and lower plasma concentration of dFdU at 0.5hr (C0.5) than in pts with a shorter GEM MRT and higher dFdU C0.5 (p=0.0138 and p=0.0011, respectively). Low plasma CDA activity and heterozygous CDA*3 were also significantly associated with prolonged overall survival (p=0.0062 and p=0.0247, respectively). After adjusting with the pts’ background factors, CDA related biomarkers were still significantly associated with overall survival in the multivariate Cox proportional hazard models. Association of low plasma CDA activity with prolonged overall survival was also confirmed by the second study (p=0.0061). Conclusions: In GEM monotherapy, reduced CDA activity correlated well with prolonged survival of advanced pancreatic cancer pts. CDA*3 is one of the factors that reduced the CDA activity in Japanese pts. 1st study 2nd study No. of pts MST P value No. of pts MST P value Plasma CDA activity High 18 5.3 mo 0.0062 42 5.1 mo 0.0061 Low 16 8.1 mo 37 8.6 mo CDA*2 Negative 44 6.1 mo 0.2546 56 7.1 mo 0.3819 Positive 26 4.5 mo 30 7.2 mo CDA*3 Negative 65 5.4 mo 0.0247 81 6.9 mo 0.1771 Positive 5 17.3 mo 5 11.7 mo

Final results of a phase I study of the combination of a novel cell cycle inhibitor ON 01910.Na with gemcitabine in patients with advanced pancreatic and other solid tumors.

3101 Background: ON 01910.Na (ON) is a novel multitargeted inhibitor of several regulatory pathways including polo-like kinase 1 (Plk1) and PI-3 kinases, with synergistic preclinical activity when combined with gemcitabine (G; Jimeno et al, 2008, 2009), prompting a phase I clinical evaluation. Methods: Patients (pts) had histologically confirmed solid tumors refractory to standard therapy. G was administered as a 30-min infusion on days 1, 8 and 15 of a 28-day cycle. ON was administered as a 2-h infusion on days 1, 4, 8, 11, 15, and 18. Assessments included safety, response, pharmacokinetic interaction studies at the MTD, and pharmacodynamics in tumor at the MTD. The MTD was further confirmed in an expansion cohort enriched in advanced pancreatic cancer pts. Results: Thirty-six pts (median age 61; median ECOG PS 1) received a median of 3 cycles (6 pts ongoing) at 5 dose levels: (G/ON mg/m2: 750/600 n=6; 1,000/600 n=5; 750/1,200 n=3; 1,000/1,200 n=3; 1,000/1,800 n=19). Only those toxicities that were expected from G were observed in patients treated with the combination, and included thrombocytopenia, neutropenia, elevated AST/ALT, nausea, vomiting, and fatigue. One DLT was documented (death at Day 18 at the 1,800 mg/m2 ON dose). Antitumor activity was seen in one G-pretreated Hodgkin lymphoma pt (PR), 2 ovarian cancer pts (1 G-pretreated with 50% decrease in CA125; 1 G-naïve with 50% decrease in CA125 and 12% tumor regression), one NSCLC pt (SD at 24 weeks) and one thymic cancer pt (PR at 32 weeks). Additionally, 18 advanced pancreatic cancer (PC) pts were enrolled. Tumor regression (including one confirmed PR in a G-pretreated pt) was noted in 7/13 evaluable pts and CA 19-9 decrease in 8/13 pts. Median progression-free survival was 19 weeks and overall survival 48 weeks at 1,200 and 1,800 mg/m2 ON doses (n=12) in the subset of 16 metastatic PC pts, 11 of whom were previously treated with G. Conclusions: ON 01910.Na 1,800 mg/m2 and gemcitabine combination is well tolerated. Anti-tumor activity in G-pretreated pts with advanced PC provide the rationale for a phase II evaluation in metastatic PC pts. Final results will be presented and molecular data including PI3K mutation status.

A phase I study of two different schedules of nab-paclitaxel (nab-P) with ascending doses of vandetanib (V) with expansion in patients (Pts) with pancreatic cancer (PC).

4124 Background: nab-P is an albumin bound paclitaxel. V is a potent inhibitor of VEGFR 2, RET and EGFR. Preclinical data reveal enhanced nab-P activity with concurrent VEGF inhibition. Primary objective was to determine the maximum tolerated dose (MTD). A secondary objective was to assess preliminary efficacy in pts with PC. Methods: Pts were randomized to one of 2 cohorts. Dose of nab-P was fixed (Cohort A: nab-p 100 mg/m2 IV weekly for 3 wks q 28 days; Cohort B: nab-P 260 mg/m2 IV q 3 wks) while 3 doses of V were evaluated (100 mg, 200 mg, 300 mg orally daily). A 3+3 design was used. Expansion at the MTD (15 pts) was planned in both cohorts. Cohort A expansion was restricted to PC pts who failed gemcitabine based therapy. Two single nucleotide polymorphisms (SNPs), SPARC rs1059829 and rs3210714, were evaluated by PCR-RFLP on genomic DNA extracted from peripheral whole blood in 25 pts. Results: Dose escalation results were presented at ASCO 2010 (J Clin Oncol 28:15s, 2010 suppl; abstr 3059).There was one DLT at each dose level in cohort A (grade 3 rash in 2 pts, grade 4 neutropenia in 1 pt). No DLTs observed in cohort B. MTD was nab-P 100 mg/m2 IV weekly for 3 /4 wks and V 300 mg daily in cohort A; nab-P 260 mg/m2 IV q 3 wks and V 300 mg daily in cohort B. 29 pts with PC were treated: 9 (cohort A dose escalation), 15 (cohort A dose expansion) and 5 (cohort B). Median age was 62; 16 males, 13 females. Median number of prior treatments 2 (range 1-4). 22 pts with PC were evaluable for response: 6 (27.5%) PR, 10 (45%) SD and 6 (27.5%) PD. Median PFS was 5.3 mo (95% CI: 3.7-7.3) and median OS 8.2 mo (95% CI: 6.2 -11.5). No statistically significant association was found between SNPs in SPARC and clinical outcome. Conclusions: Both schedules of nab-P with V are well tolerated. The MTD for both cohorts is the maximum planned dose. The preliminary efficacy in a cohort of pts with refractory PC is promising and warrants further evaluation. Grade 3 or 4 toxicities for all pts in all cycles Cohort A% Cohort B% Neutropenia 31 48 Diarrhea 13 12 Leukopenia 10 16 Acneiform rash 15 8 Fatigue 10 4 Hypertension 5 12 Prolonged QTC 5 8 Thombosis 8 4 Joint pain 5 4 Muscle pain 5 4 Anorexia 5 0 Dyspnea 5 0 Nausea 5 0 Pruritus 5 0

Contribution of environment and genetics to oxidative stress in pancreatic cancer (PC) patients (pts).

211 Background: Several risk factors have been identified as contributors to PC development, including tobacco and alcohol use, and exposure to environmental chemicals. A common denominator of these risk factors is the ability to induce oxidative stress/damage. An individual's genetic makeup may also contribute to oxidative stress, as oxidative stress/damage genes exhibit single nucleotide polymorphisms (SNPs), which can alter protein expression or activity. The goal of this study was to (1) determine if increased oxidative stress/damage is observed in PC pts and (2) to assess the contribution of environmental and genetic factors to oxidative stress/damage parameters. Methods: An oxidative stress/damage profile was generated from blood samples of newly diagnosed PC pts (n=20), from non-cohabiting genetic relatives (n=20) and/or from non-genetic relatives living in the same household (n=20). This profile consisted of measurement of total antioxidant capacity (Trolox equivalent antioxidant capacity, TEAC), direct and oxidative DNA damage (COMET), and malondialdehyde (MDA) levels. Expression of SNPs in selected oxidative stress/response genes was also evaluated. Environmental and dietary/lifestyle information was collected using a detailed questionnaire. Results: PC pts, when compared to healthy nonrelated but cohabitating relatives, displayed a significant increase in direct DNA damage (p=0.002), while oxidative DNA damage, TEAC and MDA levels were similar. When comparing PC pts to healthy genetic relatives, increased levels of TEAC, direct and oxidative DNA damage approached or were statistically significant (p = 0.061, 0.002, and 0.062 respectively). Analysis of 26 selected SNPs in oxidative stress/ damage genes in the PC pts vs healthy controls revealed that expression of CYP2A6 (L160H), rs1801272, and TNF (-308G>A), rs1800629, approached statistical significance (p=0.05 and 0.20 respectively). Conclusions: Increased oxidative DNA damage observed in PC pts vs healthy related, but non-cohabitating relatives, suggests that environmental exposures contribute to oxidative stress. In combination with a specific genetic background, environmental influences may increase the risk of PC. No significant financial relationships to disclose.

A phase Ib study of the MEK inhibitor GSK1120212 combined with gemcitabine in patients with solid tumors: Interim results.

278 Background: GSK1120212 (212) is a reversible, allosteric inhibitor of MEK1/MEK2. The objectives of this open-label, single-arm study are to evaluate the safety, pharmacokinetics (PK), and anti-tumor activity of 212 + gemcitabine (gem), and to determine the recommended phase II regimen (RP2R) in patients (pts) with advanced solid tumors. Methods: 212 (1-2.5mg) is given continuously, orally, once daily. Gem (1,000mg/m2) is infused on days 1, 8, and 15 every 28 days. Doses are escalated to the maximum tolerated dose (MTD) and followed by an expansion cohort to confirm the RP2R tolerability. Results: 28 pts received ≥ 1 dose of 212 + gem, including 8 pancreatic, 6 breast, and 4 non-small cell lung (NSCLC) cancer pts. The MTD and RP2R is 2mg 212 + 1,000mg/m2 gem. Dose-limiting toxicities (DLTs) are G3/G4 febrile neutropenia (n=2), G3 AST elevation (n=2), and G2 uveitis (n=1). 16 serious adverse events (SAEs) were reported; 5 were considered to be related to study drugs (1 pneumonitis, 3 febrile neutropenia, 1 dyspnea). All DLTs and SAEs have resolved. The most common AEs at the RP2R (n=18) were rash (78%), fatigue (67%), thrombocytopenia (61%), neutropenia (50%), decreased appetite (50%), nausea (44%), diarrhea and constipation (39%); all ≤ G2 except thrombocytopenia (17% ≥ G3) and neutropenia (33% ≥ G3). Co-administration did not affect the PK profiles of 212 or gem. 25 pts had measurable disease at baseline. 1 pancreatic cancer pt with previous radiotherapy and 2 cycles of gem achieved a partial response and stayed on study for 6 months. 3 additional pancreatic cancer pts reported stable disease; 2 of which were on the study for 3.5-5 months and the third pt continues in the study. 1 triple-negative breast cancer pt, refractory to chemotherapy, and 1 parotid cancer pt experienced a complete response of their target lesions. Conclusions: 212 + gem is tolerable with an acceptable safety profile in this pt population, with evidence of clinical activity in pancreatic cancer. A randomized phase II study in previously untreated patients with metastatic pancreatic cancer is underway to investigate the clinical activity of this combination. [Table: see text]

1H NMR–based metabolic profiling of serum for the detection of pancreatic cancer.

193 Background: Pancreatic cancer (PC) is one of the leading causes of cancer deaths with a 5-yr mortality rate of 95%, and the lack of a suitable early detection method contributes to its poor prognosis. Metabolomics, the analysis of the metabolic profiles in biological samples such as serum and urine is emerging as an important tool to complement other “omic” techniques. In an effort to identify potential biomarkers for PC, we analyzed serum from PC patients (pts) focusing on altered metabolic profiles using 1H nuclear magnetic resonance (NMR). Methods: The metabolite profiles from serum samples consisting of 55 PC pts and 32 healthy controls were analyzed using NMR combined with advanced supervised and unsupervised multivariate statistical methods such as partial least squares discriminant analysis (PLSDA) and principal component analysis (PCA). A number of metabolite markers selected based on p values and logistic regression rank the importance of each potential marker. Statistically significant metabolites between cancer and controls were used to build a prediction model. Results: Based on multivariate logistic regression analysis of 20 targeted metabolites, 10 metabolite markers were selected from the variable selection process and used to build a regression model with high accuracy (AUROC >0.99), a sensitivity of 95% and specificity of 95% using a training set of samples. When the model was tested on an independent set of patient samples, it yielded a sensitivity of 95% and a specificity of 100% (AUROC >0.98). Box and whisker plots for individual markers verified the high performance of all 10 markers. Conclusions: The high sensitivity of the metabolic profile that distinguishes PC pts from controls indicates the potential utility of 1H NMR metabolic profiling for the early detection of PC. The investigation has identified perturbations in several pathways such as glycolysis and amino acid metabolism, highlighting their contribution to disease onset. This study demonstrates the potential of metabolite profiling as an important tool toward detecting PC development. Future studies will involve metabolite validation on high risk pts, and additional mass spectrometry based metabolic discovery efforts. No significant financial relationships to disclose.

Phase I study of AMG 479, a fully human monoclonal antibody against the type 1 insulin-like growth factor receptor (IGF-1R), in Japanese patients (pts) with advanced solid tumors.

318 Background: AMG 479 is a fully human monoclonal antibody against human IGF-1R that inhibits the survival and proliferative signals driven by IGF-1 and -2. Methods: Patients (Pts) were enrolled into 1 of 3 dose cohorts (6, 12 or 20 mg/kg) of single-agent AMG 479 administered intravenously Q2W. Dose-limiting toxicity (DLT) was assessed for the first 28 days. The primary objectives were to assess the safety, tolerability, and pharmacokinetics (PK) of AMG 479 in Japanese pts with advanced solid tumors. An exploratory pharmacodynamic (PD) analysis was done to investigate the relationship between exposure and changes in the level of circulating factors in IGF-1R pathway (IGFBP-3 and total IGF-1). Results: Nineteen pts with ECOG 0-1 (6 in cohort 1 and 3, 7 in cohort 2) received at least 1 dose of AMG 479. Median age was 58.0 years. Tumor types included: breast (4), gastric (3), rectal (2), NSCL (2), thymic (2), and other cancers (6). Enrollment has been completed; 5 pts remained on study as of 15 March 2010. No DLTs were observed. Three serious adverse events (SAE) were reported, only respiratory tract haemorrhage in a subject with thymic carcinoma was considered by the investigator to be related to AMG 479. The most common grade ≥3 AEs were neutropenia (21%), leukopenia (16%) and lymphopenia (11%). There was a trend of dose-dependency on severity of thrombocytopenia, but not on that of neutropenia. No neutralizing anti-AMG 479 antibodies were detected. PK was dose-linear and similar to PK in non-Japanese pts. Tumor response data were available for 17 pts. Stable disease (defined as a lack of progression at the first 8-week assessment) as best response was reported in 6 pts and progressive disease was reported in 11 pts. Exploratory PD marker analysis demonstrating exposure dependent changes will be presented. Conclusions: AMG 479 up to 20 mg/kg was tolerable in Japanese pts with advanced solid tumors. The AE and PK profiles were similar to those previously observed in non-Japanese pts. An international phase 3 study in metastatic pancreatic cancer pts is planned based on the promising results from phase 1b/2 study (ASCO 2010, Abs 4035). [Table: see text]

Prognostic significance of xCT gene single nucleotide polymorphisms (SNPs) in patients (pts) with advanced pancreatic cancer (PC) treated with gemcitabine (GEM) plus platinum analogues (PLAT).

4065 Background: The plasma membrane xc- cystine/glutamate transporter mediates cellular uptake of cystine in exchange for intracellular glutamate and is highly expressed by PC cells. The xCT gene, encoding the cystine-specific xCT protein subunit of xc-, is important in regulating intracellular glutathione levels, critical for cancer cell protection against oxidative stress, tumor growth and resistance to chemotherapeutic agents including PLAT. Methods: We have investigated the relationship between xCT gene SNPs and overall survival (OS) of pts with PC treated with GEM ± PLAT. We examined 4 SNPs of the xCT gene in 269 advanced PC pts who received first line GEM with or without cisplatin or oxaliplatin. Genomic DNA was isolated from peripheral blood mononuclear cells. Genotyping was performed using Taqman real-time PCR assays. The association between SNPs and OS was analyzed by Kaplan-Meier plot, log-rank test and Cox proportional hazard regression models and corrected for previously identified prognostic factors, including CA 19-9, stage, and performance status. Results: A statistically significant correlation was noted between the 3’ untranslated region (UTR) xCT SNP rs7674870 and OS: Median survival time (MST) was 10.9 and 13.6 months, respectively, for the TT and TC/CC genotypes (p = 0.027). Stratified analysis showed the genotype effect was significant in pts receiving GEM+PLAT therapy (n = 145): MST was 10.5 vs. 14.1 months for the TT and TC/CC genotypes, respectively (p = 0.013). This effect remained statistically significant after adjusting for clinical factors (hazard ratio: 0.60, 95% CI, 0.40-0.89 and p = 0.011). The genotype effect was not significant in pts receiving GEM alone (n = 124): MST was 10.9 months for TT and 12.0 months for TC/CC genotypes (p = 0.47). None of the 3 synonymous SNPs examined were associated with outcome. Conclusions: The 3’ UTR xCT SNP rs7674870 may correlate with OS in PC pts receiving GEM+PLAT therapy. These data suggest that polymorphic variants of xCT may have predictive value, and that the xc- transporter may represent an important target for therapy in PC. No significant financial relationships to disclose.

Safety and efficacy results from the first-in-human study of the oral MEK 1/2 inhibitor GSK1120212.

2503 Background: GSK1120212 is a potent and selective allosteric inhibitor of MEK1/2. The objectives of this study are to define the maximum tolerated dose (MTD), and to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and response rate of GSK1120212 in advanced solid tumors and lymphoma. Methods: GSK1120212 is given orally, once daily (QD). This is a three-part study:Part 1, dose-escalation; Part 2, expansion in selected tumor types to evaluate recommended phase II doses (RP2D); Part 3, PK-PD assessment using tumor biopsies or FDG-PET. Results: 84 patients (pts) have received ≥ 1 dose of GSK1120212, including 29 melanoma and 15 pancreatic cancer pts. The MTD is 3 mg QD and the current RP2D is 2 mg QD. Dose-limiting toxicities are rash (N=2), diarrhea (N=1), central serous retinopathy (N=2) and are reversible. At doses ≥ RP2D (N=77), the most common adverse events are rash (77%; 42% G1, 30% G2, 5% G3) and diarrhea (45%; 34% G1, 9% G2, 3% G3). GSK1120212 has a small peak: trough ratio of ∼ 2 and an effective half life of ∼ 4.5 days. Steady state is reached by ∼ day 15. Tumor biopsy data showed reduction of pERK and Ki67 by > 90% at the 2 mg dose level. SUVmax was reduced by 23-48% after a 2-week treatment at 0.5 mg QD and 1 mg QD in 4 melanoma pts with evaluable FDG-PET data. In the 20 evaluable melanoma pts of known BRAF status, 5 partial responses (PRs) were observed, all having ≥ 50% tumor reduction; 3 have stayed ≥ 30 weeks on study, the other 2 are ongoing. In the 11 BRAF mutant melanoma pts, 3 PRs, 5 stable disease (SD; 2 with ≥ 20% tumor reduction, including a pt previously treated with the BRAF inhibitor, PLX4032), and 3 progressive disease (PD) were observed. Two of the 3 PDs were due to new brain lesions. In 9 BRAF wild-type melanoma pts, 2 PRs, including a pt with a GNAQ mutation, and 3 SDs were achieved. In 9 evaluable pancreatic cancer pts, 6 SDs were observed. Three of these SDs had CA19-9 decrease of >70%, of which 2 had 16% and 27% tumor reduction. Conclusions: The long effective half life and small peak:trough ratio of GSK1120212 allow constant target inhibition within a narrow range of exposure. The RP2D is well tolerated and associated with durable clinical activity in specific tumor types. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline

Phase I/II study of TH-302 in combination with gemcitabine in patients with solid tumors including advanced pancreatic cancer.

e13519 Background: TH-302 is a 2-nitroimidazole hypoxia-activated prodrug of the DNA alkylator, bromo-isophosphoramide mustard. In preclinical models, TH-302 was active alone and enhanced the activity of gemcitabine (Gem). A phase I/II study was conducted to investigate TH-302 in combination with full dose Gem. Methods: This study used standard solid tumor eligibility criteria except patients (pts) must not have received prior Gem. Pts received IV TH-302 followed by Gem (1,000 mg/m2) on Days 1, 8 and 15 of a 28 day cycle. A standard 3+3 pts design was used with a TH-302 starting dose of 240 mg/m2. An expansion component was planned for first-line pancreatic cancer pts at the MTD. The objectives of the study were to determine the MTD/RP2D of TH-302 and Gem and to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of the combination. Results: 38 pts [20M/18F, median age: 62y (range 41-82), ECOG PS 0/1: 31/7] were enrolled at 8 sites and treated at TH-302 dose of 240 (7 pts), 340 (16), 400 (...

Phase II study of PHY906 plus capecitabine (CAP) in pts with gemcitabine-refractory pancreatic cancer (PC) and measurement of cytokines.

e14540 Background: Oral CAP offers convenience as a palliative chemotherapeutic option, however, diarrhea and HFS may compromise its efficacy. Pts in USA cannot tolerate CAP 1,250 mg/m2 BID D1-14 without experiencing toxicities. PHY906, a traditional Chinese botanical formula has shown synergistic anti-tumor activity with CAP as well as cytoprotective anti-diarrheal effect in preclinical and phase I studies (ASCO 2007, 2008). These data provide a strong rationale for extending this combination into PC. Methods: PC pts with prior gemcitabine received CAP 1,500 mg/m2 BID D1-7 and PHY906 800 mg/m2 BID D1-4 q 2 wks. AEs were assessed per NCI CTCAE v3.0 and response per RECIST q 6 wks. Primary objective was OS and secondary aim to determine effect of PHY906 on cytokines and chemokines including IL-2, IL-4, IL-5, IL-6, IL-10, MCP-1, TNF-a, IFN-g, VEGF, FGF-B, GM-CSF, G-CSF using a cytometric bead array assay. Results: Twenty-five pts were enrolled: 25 received study drug (evaluable for safety); 23 received at least 1 cycle (evaluable for efficacy). Median age was 60yr (range 45-84), 10 F and 15 M, with a median ECOG PS of 1 (range 0-2). Predominant AEs included grade 3 diarrhea (n = 3), grade 3 fatigue (n = 3) and grade 3 HFS (n = 1). Among 23 pts, 2 achieved PR (9%), 10 had stable disease (43%) resulting in disease control rate of 52%. All intent-to-treat pts reached mPFS of 10 wks (r: 0.4-51) and mOS of 12 wks (r: 0.4-63). For 18 pts who received > = 2 cycles, mPFS was 13 wks and mOS 31 wks. 9-mth survival rate was 22%. Preliminary correlative studies showed that none of the cytokines except serum IL-6 was reversely correlated with survival. QOL data is currently under evaluation. Conclusions: This is the first clinical study to evaluate a botanical drug PHY906 plus CAP in PC. Our results suggest that PHY906 can increase therapeutic index of CAP by reducing diarrhea and HFS. This combination appears a safe and feasible salvage therapy after gemcitabine failure and warrants further investigation in a randomized study against CAP. Recent studies have indicated role of IL-6 in tumor progression and tumor cachexia, suggesting a need to investigate its relation to pathophysiology of PC and development of anti-IL-6 therapeutics. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration PhytoCeutica PhytoCeutica Bayer, Bristol-Myers Squibb, Genentech, Novartis, Roche, sanofi-aventis Enzon, Merck, PhytoCeutica, Roche, Taiho Pharmaceutical

S1449: Uncovered Self-Expanding Metal Stents (SEMS) for Jaundiced Pancreatic Cancer Patients Are Appropriate Regardless of Stage

Until recently, plastic endoprostheses were routinely used for initial clearance of jaundice in pancreatic cancer patients (pts) until surgical candidacy or palliative care was established. Recent experience suggests all stages of pancreatic cancer pts have the potential to benefit from SEMS in view of their superior performance and low risk. Given that use in palliative pts is cost effective, we report growing experience with SEMS placement in surgical or borderline surgical pts.

Second-line pemetrexed–oxaliplatin combination for advanced pancreatic adenocarcinoma

e15597 Background: Few regimens showed efficacy in advanced pancreatic cancer patients (pts) who had failed a first-line gemcitabine-based therapy. However, there is growing evidence suggesting that second-line treatment may provide further disease control in selected pts. Both pemetrexed and oxaliplatin demonstrated activity in this setting, and their combination resulted safe and tolerable.Methods: Pancreatic cancer pts with advanced disease, PS>60, age>18 years, who progressed after a gemcitabine-based therapy were enrolled in a phase II trial, and treated with pemetrexed 500 mg/mq followed by oxaliplatin 120 mg/mq, day 1 every 3 weeks, together with adequate oral folinic acid and intramuscular vitamin B12 supplementation. Accordingly to the Simon Minimax two-stage study design, an accrual of 31 patients was planned, with a minimum response rate considered of interest of 25%, α level 0.10 and β level 0.10. Results: To date, 16 patients have been treated. Of them, 12 progressed during or shortly after gemcitabine (13) or gemcitabine-cisplatin combination (3), with a median time to progression of 186 days. 62 cycles were delivered, with a median of 4 cycles per patient (range 2–8). Overall, the regimen was well tolerated: most common adverse events were mild-to-moderate sensory neurotoxicity and gastrointestinal disturbances. We reported grade 3 anemia, grade 3 thrombocytopenia, and grade 3 fatigue in 1 patient each. Three among the treated patients died within 30 days from last delivered cycle due to progressive disease. Confirmed partial (3) or minor responses (6) were observed in 9 out of 15 evaluable pts, with a median decrease in the Ca 19.9 value of 43% among those who responded. Median progression-free survival was 99 days. At the time of analysis, 3 out of 16 patients are still on treatment.Conclusions: The preliminary results suggest that second-line pemetrexed-oxaliplatin combination is well tolerated and reasonably active, and allow the continuation of the study until the full sample of 31 pts. No significant financial relationships to disclose.

A phase Ib study to evaluate the safety and efficacy of AMG 655 in combination with gemcitabine (G) in patients (pts) with metastatic pancreatic cancer (PC)

4501 Background: AMG 655 is an investigational, fully human agonist monoclonal antibody (IgG1) that binds human death receptor 5 (DR5), activates caspases, and induces apoptosis in sensitive tumor cells. In preclinical PC models, cooperative activity is observed when G is added to AMG 655. We performed a multi-center phase I trial to evaluate AMG 655 + G in metastatic PC pts. The primary endpoint was dose-limiting toxicity (DLT). Secondary endpoints included toxicity, pharmacokinetics, antibody formation, objective response rate, progression-free survival (PFS), 6-month and overall survival. Methods: Eligible pts had previously untreated metastatic PC and ECOG PS 0 or 1. Pts enrolled into sequential cohorts and received AMG 655 3 or 10 mg/kg IV days (D) 1 and 15 and G 1000 mg/m2 IV D 1, 8, and 15 every 28 D. CT scans were obtained Q8 weeks. Results: 13 pts (3 mg/kg cohort = 6; 10 mg/kg cohort = 7) enrolled from 7/07–11/07. Pt characteristics: females 61%; ECOG PS 1 69%; median age 65 (range 35–81); liver metastases 77%. Median number of cycles: 6 (range 2–12). There were no DLT. Nine (69%) pts had grade 3–4 toxicity, the most common were: thrombocytopenia (4 pts), neutropenia (2 pts), and abdominal pain (2 pts). No anti-AMG 655 antibodies were detected. After one 3 or 10 mg/kg dose of AMG 655 after G, the Cmax and AUC of AMG 655 were similar to those in the first- in-human single-agent study (LoRusso JCO 2007; 25: abstract 3534). Preliminary data indicate no effect of AMG 655 on PK of G. Partial response 31% (4 pts, 2 unconfirmed); stable disease 38%. Median PFS: 5.3 months (95% CI, 3.5, 6.2); 6-month survival rate: 76.2% (95% CI: 42.7%-91.7%). Conclusions: AMG 655 + G is well-tolerated and may have activity in metastatic pancreatic cancer. A randomized phase II trial of G ± AMG 655 at 10-mg/kg is currently enrolling. [Table: see text]

Results of a phase I trial of KX2–391, a novel non-ATP competitive substrate-pocket directed SRC inhibitor, in patients with advanced malignancies

3511 Background: Src kinase is central to the proliferation, apoptosis and metastasis of tumor cells. KX2–391 is a synthetic, orally bioavailable small molecule Src tyrosine kinase signaling inhibitor. KX2–391 is distinct from all other known Src kinase inhibitors in targeting the peptide substrate-binding site and not the ATP-binding site. KX2–391 is the first peptide site targeted tyrosine kinase inhibitor to enter clinical trials. KX2–391 has a much wider spectrum of solid tumor activity in vitro, and is more potent in mouse xenografts, as compared to other multikinase Src/Abl inhibitors. Methods: This multi-center Phase 1 trial utilized the standard 3+3 design to determine the Maximum Tolerated Dose (MTD), safety, and pharmacokinetics (PK) of KX2–391 in pts with refractory solid tumors. Results: To date, 32 pts (12 m 20 f, median age 59 (range 31–78)) have been enrolled in 7 dose cohorts. Dose limiting toxicities (DLTs), which were all reversible within 7 days, occurred in 4 pts and included elevated ALT and AST, neutropenia, and fatigue. 22 pts experienced no Grade 3 or 4 adverse events. Other Grade 1/2 adverse events include: hypokalemia, anemia, elevated AST, fatigue, dyspnea, fever, vomiting, constipation, hematuria, and lymphopenia. The MTD is 40 mg BID on a 3 out of 4 weeks dosing schedule. 7 pts had prolonged stable disease for 4 months or longer including 2 pts with papillary thyroid carcinoma, 2 with carcinoid, and 1 each with prostate, pancreas, and head and neck cancer. Both the prostate and pancreatic cancer pts had dramatic decreases in their biomarkers (PSA went from 205 ng/ml to 39 ng/ml, and CA19–9 went from 38,838 U/ml to 267 U/ml, respectively). The PK profile demonstrated dose-proportionality, a half-life of 4.5 hrs and a Tmax of 1 hr with no evidence of accumulation with multiple doses. Conclusions: KX2–391 has a favorable PK profile, is well-tolerated, demonstrates preliminary evidence of biologic activity and should be further evaluated in Phase II trials. [Table: see text] [Table: see text]

CONKO-001: Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer (PC)

LBA4504 Background: Prognosis of patients (pts) with PC is dismal, even after curatively intended resection. Whereas gemcitabine-based chemotherapy is standard in advanced PC, the role of adjuvant chemotherapy is still under discussion. Methods: CONKO-001, a prospective, open, multicenter, controlled phase 3 study was designed to evaluate the efficacy and toxicity of gemcitabine in PC pts after complete (R0 or R1) resection. After stratification for R0/R1, nodal tumour involvement and tumour stage pts were randomized to receive either gemcitabine (G) (1g/m2 d 1, 8 and 15 every 4 weeks) for 6 months or observation (O). Pts in the observation group received no specific anticancer treatment. Primary study endpoint was disease free survival (DFS), secondary endpoints included OS and toxicity. The study was powered to detect a significant difference in DFS with 90% probability at a significance level of .05 on all eligible patients. Results: Between July 1998 and December 2004 368 pts were randomized and 354 w...

Final analysis of a randomized phase II study of bevacizumab (B) and gemcitabine (G) plus cetuximab (C) or erlotinib (E) in patients (pts) with advanced pancreatic cancer (PC)

4502 Background: Targeting several critical pathways may be more effective than single pathway blockade in a resistant cancer like PC. In preclinical PC models, combining EGFR + VEGF targeted agents is synergistic. Methods: We conducted a multicenter, randomized phase II trial of dual targeted therapy, GBC or GBE, in advanced PC pts who had: no prior therapy for metastatic disease, PS 0–2, measurable disease, no bleeding risk or duodenal invasion. Primary endpoint: response; 2 parallel, Simon 2-stage designs. Baseline correlatives: plasma VEGF, serum VEGFR2. All pts received G 1000 mg/m2 over 30’ days (D) 1, 8, 15 Q28D; B 10 mg/kg D 1, 15 Q28D. Pts, stratified by PS and site, were randomized to C 400 mg/m2 D1 then 250 mg/m2 Q7D, or E 150 mg D1–5, 8- 12, 15–26 Q28D. Results: 139 evaluable pts (GBC/GBE 68/71) enrolled at 16 sites 9/04–2/07. Pt characteristics: median age 63/63 (range 36–83/39–86); male 49%/70%; PS 0 35%/48%, 1 59%/46%, 2 6%/6%. Cycles: 343/373 (median 4/4; range 1–18/1–18). Grade 3/4 toxici...

Sorafenib (S) plus gemcitabine (G) for advanced pancreatic cancer (PC): A phase II trial of the University of Chicago Phase II Consortium

4608 Background: The ras oncogene is mutated in about 90% of PC, leading to constitutive activation of the Ras-Raf-MAPK signal transduction pathway. Sorafenib an inhibitor of B-raf, VEGFR2, and PDGFR-B, has in vitro activity against PC cell lines dependent on mutant Ras activation, and has anti-tumor activity in PC xenograft models. In a phase I trial of SG, 57% of PC patients (pts) had stable disease (SD) (Siu, 2003). Methods: We conducted a multi-center phase II trial of SG in advanced PC pts who had: no prior chemotherapy for metastatic disease, PS 0–1, measurable disease. Primary endpoint: response. The Simon 2-stage trial design required 1 response in 12 evaluable pts for 2nd stage. Pts received S 400 mg orally twice daily days (D) 1–28, and G 1000 mg/m2 over 30 minutes D 1, 8, 15 Q28D. CT scans: Q2 cycles. 17 pts enrolled at 4 sites 9/04–12/05. Pt characteristics: male 47%; median age 62 (range 50–85); PS 0 24% 1 76%; stage IV 94%; prior radiation 12%; liver metastases 81%. Results: 17 pts evaluable for toxicity, 13 for response. 61 cycles of SG have been given (median 2, range 1–12). There were no objective responses; 3 pts (23%) had SD. 1 pt with SD remains on treatment after 12 cycles. Median overall survival: 4.0 months (95% CI: 3.4, 5.9). Median progression-free survival: 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 hematologic toxicities (% pts): neutropenia 29%; thrombocytopenia 6%; neutropenic fever 0%. Grade 3 non- hematologic toxicities: thrombosis 18%; fatigue 18%; rash 12%; dehydration 12%; nausea 12%; hand-foot syndrome 12%; hypertension 6%; diarrhea 6%; GI bleeding 6%. Conclusion: The study did not meet response criteria to proceed to a second stage of accrual. SG is inactive, though well-tolerated, in advanced PC pts. Supported by NCI grant N01-CM-62201. [Table: see text]

A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis of Cancer and Leukemia Group B (CALGB

4508 Background: In a phase II trial in 52 PC pts, GB yielded a 21% response rate and a median survival of 8.8 months (mo) (Kindler, JCO 2005). These data led CALGB to conduct a phase III trial of GB vs. GP in advanced PC pts. Methods: This randomized trial was double-blind, placebo-controlled. Eligible pts had no prior therapy for advanced disease, PS 0–2, no tumor invasion of adjacent organs, no increased bleeding risk. Primary endpoint: overall survival (OS). Stratification: PS (0/1 or 2), disease extent (locally advanced or metastatic), prior radiation (RT) (yes/no). Statistics: 90% power to detect a difference in median OS of 6 vs. 8.1 mo. Treatment: Pts received G 1,000 mg/m2 over 30 minutes days (D) 1, 8, 15 Q28D; B 10 mg/kg or P D 1, 15 Q28D. CT scans: Q2 cycles. Results: 602 pts enrolled 6/30/04–4/14/06. Based on a protocol-specified interim analysis with 64% of information on OS, the CALGB Data Safety Monitoring Board released study data in 6/06 because a futility boundary was crossed. Pts on treatment were notified and unblinded. Pt characteristics (302GB/300GP): male 58%/51%; median age 63.8/65.0; PS 2 9%/9%; stage IV 85%/84%; prior RT 11%/11%. Median follow-up: 11.3/11.7 mo. As of 12/22/06, 436 pts (224/212) have died (93% of total expected deaths at planned final analysis). Median OS 5.7/6.0 mo (95% CI: 4.9, 6.5/5.0, 6.9). Median failure-free survival 4.8/4.3 mo (95% CI: 4.3, 5.7/3.8, 5.6). Response (includes unconfirmed responses): complete (CR) 1.9%/3.0%; partial (PR) 11.2%/8.3%, stable disease (SD) 40.7%/35.7%. Disease control rate (CR/PR/SD) 54%/47%. 525 pts (268/257) are currently evaluable for toxicity. Median cycles 3.5/3.1 (p=0.09). Total mg/m2 G received 9095/8334 (p=0.22). Grade ¾ toxicity (%pts GB/GP): neutropenia 33%/30%; anemia 5%/8%; thrombocytopenia 12%/12%; hypertension 8%/2%; perforation 0.4%/0%; GI bleed 3%/2%; CVA 2%/2%; proteinuria 4%/1%; venous thrombosis 9%/9%. Conclusion: The addition of B to G does not improve survival in advanced PC. [Table: see text]

A randomized phase II study of bevacizumab (B) and gemcitabine (G) plus cetuximab (C) or erlotinib (E) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis

4040 Background: In a phase II trial of G + anti-VEGF antibody B in 52 PC pts, we reported a 21% response rate and median survival of 8.8 months (mo) (Kindler, JCO 2005). EGFR inhibitors C and E also have activity in PC. VEGF and EGFR pathways are interdependent; dual inhibition may be synergistic. Methods: We are conducting a multi-center, randomized phase II trial of GBC vs. GBE in advanced PC pts who have: no prior therapy for metastatic disease, PS 0–2, measurable disease, no tumor invasion of duodenum, no bleeding risk. Primary endpoint: response. Trial design: 2 parallel, Simon 2-stage designs; requires 6 responses in 27 evaluable pts for 2nd stage; 63 pts/arm. All pts receive G 1000 mg/m2 over 30 minutes days (D) 1, 8, 15 Q28D; B 10 mg/kg D 1, 15 Q28D. Pts are randomized to C 400 mg/m2 D1, then 250 mg/m2 Q7D, or E 150 mg D1–5, 8–12, 15–26 Q28D. CT scans: Q2 cycles. 58 pts enrolled at 13 sites 9/04–12/05. Pt characteristics: male 66%; median age 61 (range 36–82); PS: 0/1/2: 52%/40%/8%; stage IV 95%; liver metastases 76%. Results: 49 pts (GBC/GBE 24/25) are evaluable for toxicity; 51 pts (27/24) for response. 232 cycles were administered (median 4, range 1–11). Grade ¾ toxicity (%pts GBC/GBE): neutropenia 29%/28%; anemia 4%/16%, thrombocytopenia 8%/24%, DVT-PE 17%/8%, CVA 4%/4%, GI bleed 4%/12%, hypertension 4%/4%, rash 13%/4%, pneumonitis 0%/8%, diarrhea 4%/4%; grade 5: bowel perforation 0%/4%, MI- CVA 0%/4%, other cardiac 4%/0%. Response: GBC 19% (1 complete, 4 partial), GBE 21% (5 partial). Stable disease 59%/67%. Median progression-free survival 3.6/3.6 mo (95%CI: 2.7, 4.7/2.7, 5.9), 6-month survival 41%/38% (95% CI: 11%, 71%/2%, 75%). Conclusion: GBC and GBE are active in advanced PC. Toxicity, principally related to B, is moderate. The trial proceeds to a 2nd stage if 1 more response is observed in each arm. Supported by NCI grant N01-CM-17102. [Table: see text]