Gemcitabine In Patients Research Articles

Randomized, Multicenter, Phase II Study of CO-101 Versus Gemcitabine in Patients With Metastatic Pancreatic Ductal Adenocarcinoma: Including a Prospective Evaluation of the Role of hENT1 in Gemcitabine or CO-101 Sensitivity

Gemcitabine requires transporter proteins to cross cell membranes. Low expression of human equilibrative nucleoside transporter-1 (hENT1) may result in gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC). CO-101, a lipid-drug conjugate of gemcitabine, was rationally designed to enter cells independently of hENT1. We conducted a randomized controlled trial to determine whether CO-101 improved survival versus gemcitabine in patients with metastatic PDAC (mPDAC) with low hENT1. The study also tested the hypothesis that gemcitabine is more active in patients with mPDAC tumors with high versus low hENT1 expression. Patients were randomly assigned to CO-101 or gemcitabine, after providing a metastasis sample for blinded hENT1 assessment. An immunohistochemistry test measuring tumor hENT1 was developed. To dichotomize the population, an hENT1 cutoff value was defined using primary PDAC samples from an adjuvant trial, and a high/low cutoff was applied. The primary end point was overall survival (OS) in the low hENT1 subgroup. Of 367 patients enrolled, hENT1 status was measured in 358 patients (97.5%). Two hundred thirty-two (64.8%) of 358 patients were hENT1 low. There was no difference in OS between treatments in the low hENT1 subgroup or overall, with hazard ratios (HRs) of 0.994 (95% CI, 0.746 to 1.326) and 1.072 (95% CI, 0.856 to 1.344), respectively. The toxicity profiles in both arms were similar. Within the gemcitabine arm, there was no difference in survival between the high and low hENT1 subgroups (HR, 1.147; 95% CI, 0.809 to 1.626). CO-101 is not superior to gemcitabine in patients with mPDAC and low tumor hENT1. Metastasis hENT1 expression did not predict gemcitabine outcome.

Adjuvant Chemotherapy With Gemcitabine and Long-term Outcomes Among Patients With Resected Pancreatic Cancer

The prognosis for patients with pancreatic cancer is poor, even after resection with curative intent. Gemcitabine-based chemotherapy is standard treatment for advanced pancreatic cancer, but its effect on survival in the adjuvant setting has not been demonstrated. To analyze whether previously reported improvement in disease-free survival with adjuvant gemcitabine therapy translates into improved overall survival. CONKO-001 (Charité Onkologie 001), a multicenter, open-label, phase 3 randomized trial to evaluate the efficacy and toxicity of gemcitabine in patients with pancreatic cancer after complete tumor resection. Patients with macroscopically completely removed pancreatic cancer entered the study between July 1998 and December 2004 in 88 hospitals in Germany and Austria. Follow-up ended in September 2012. After stratification for tumor stage, nodal status, and resection status, patients were randomly assigned to either adjuvant gemcitabine treatment (1g/m2 d 1, 8, 15, q 4 weeks) for 6 months or to observation alone. The primary end point was disease-free survival. Secondary end points included treatment safety and overall survival, with overall survival defined as the time from date of randomization to death. Patients lost to follow-up were censored on the date of their last follow-up. A total of 368 patients were randomized, and 354 were eligible for intention-to-treat-analysis. By September 2012, 308 patients (87.0% [95% CI, 83.1%-90.1%]) had relapsed and 316 patients (89.3% [95% CI, 85.6%-92.1%]) had died. The median follow-up time was 136 months. The median disease-free survival was 13.4 (95% CI, 11.6-15.3) months in the treatment group compared with 6.7 (95% CI, 6.0-7.5) months in the observation group (hazard ratio, 0.55 [95% CI, 0.44-0.69]; P < .001). Patients randomized to adjuvant gemcitabine treatment had prolonged overall survival compared with those randomized to observation alone (hazard ratio, 0.76 [95% CI, 0.61-0.95]; P = .01), with 5-year overall survival of 20.7% (95% CI, 14.7%-26.6%) vs 10.4% (95% CI, 5.9%-15.0%), respectively, and 10-year overall survival of 12.2% (95% CI, 7.3%-17.2%) vs 7.7% (95% CI, 3.6%-11.8%). Among patients with macroscopic complete removal of pancreatic cancer, the use of adjuvant gemcitabine for 6 months compared with observation alone resulted in increased overall survival as well as disease-free survival. These findings provide strong support for the use of gemcitabine in this setting. isrctn.org Identifier: ISRCTN34802808.

The addition of erlotinib to gemcitabine and cisplatin does not appear to improve median survival in metastatic pancreatic cancer.

Metastatic pancreatic cancer carries a poor prognosis, with median survival on the order of several months. There is evidence that combining gemcitabine with either erlotinib or cisplatin may be superior to single agent gemcitabine in patients with good performance (PS 0-1). We retrospectively compared outcomes of patients treated with either the three drug regimen of gemcitabine, cisplatin, and erlotinib (GCE) or the doublet of gemcitabine and cisplatin (GC) in order to assess the potential benefit of erlotinib. We also evaluated the role of erlotinib among smokers and non-smokers. We retrospectively analyzed 145 patients who presented between 2006 and 2009 with previously untreated metastatic pancreatic cancer initially treated at the M.D. Anderson cancer center with either GC or GCE. Information on tumor characteristics and overall survival time (OS) was collected by medical record review. Kaplan-Meier curves were used to estimate OS. Log rank tests were used to compare OS between groups. The Cox proportional hazards regression model was used to evaluate the ability of patient prognostic variables or treatment group to predict OS. A total of 71 patients were treated with GC, while 74 were treated with GCE. Cox analyses found no significant difference in overall survival (median 5.5 vs. 8.0 months, respectively, p-value=0.1). Small sampling numbers may have contributed to this result. One year survival was 23 % in the GCE group and 13 % in the GC group. Patients with poor performance status (PS=2-3) had worse survival as compared to patients with better performance status (PS=0-1, p=0.001). As in earlier studies, patients treated with more lines of therapy tended to have better survival (p <0.0001), and CA19-9 was found to be a significant predictor for OS (p=0.001). No statistical evidence of a survival difference was found between smokers and non-smokers in both treatment groups (p=0.72). In conclusion, though there was a trend towards improved survival with the addition of erlotinib to gemcitabine and cisplatin, this does not reach statistical significance.

Transarterial chemoembolisation (TACE) with gemcitabine: Phase II study in patients with liver metastases of breast cancer

ObjectiveEvaluation of the efficacy and tolerability of transarterial chemoembolization with gemcitabine in patients with inoperable liver metastases of breast cancer. Materials and methodsOpen-label, prospective non-randomized single-center study design; patients had previous chemotherapy including anthracyclines and/or taxanes in the metastatic setting, adequate bone marrow reserve, sufficient liver/renal function, no centralnervous system metastases, Karnovsky-performance-status >70%, and life expectancy >12 weeks. Forty-three patients were enrolled (median 58 years, range 48–71). A suspension of gemcitabine 1.200mg/m2, 2–10ml/m2 of Lipiodol, and 5ml of a degradable starch microsphere (Embocept) suspension, were administered intra-arterially up to 3 times with a 4-weaks-interval. Dose-limiting toxicit is defined as grade 4 thrombocytopenia, neutropenia, or nonhematologic toxicity>grade 3. Tumor response was evaluated by magnetic resonance (MRI) and computed tomography (CT) imaging. ResultsAll patients tolerated the treatment well; with no dose limiting toxicities. Imaging follow-up according to the RECIST-criteria (Response Evaluation Criteria in Solid Tumors) revealed a partial response in 3 patients, stable disease in 16 patients and progression in 22 patients. The progression free survival was 3.3 months.A significant correlation exists only with the factor vascularization: strongly vascularized tumors show a significantly lowered response. Patients with complete or partial response and the main fraction of the stable disease group showed in the MRI and angiography only a moderate vascularization.The resulting estimate of the total survival rate amounts to a median of 10.2 months. ConclusionTransarterial chemoembolization with gemcitabine is well tolerated and provides an alternative treatment method for patients with liver metastases of breast cancer.

Differential Pharmacokinetics of Ganitumab in Patients With Metastatic Pancreatic Cancer Versus Other Advanced Solid Cancers.

Ganitumab is an investigational, fully human monoclonal antibody antagonist of the insulin-like growth factor-1 receptor (IGF1R) that has shown trends towards improved progression-free survival and overall survival in a phase 2 pancreatic cancer clinical trial. To characterize ganitumab pharmacokinetics (PK) and identify factors affecting PK, ganitumab serum concentration data from three clinical trials were analyzed. The PK of ganitumab as monotherapy and in combination with gemcitabine in patients with pancreatic or non-pancreatic cancer were assessed with a non-linear mixed-effect model. We found that ganitumab exhibited linear and time-invariant kinetics. A two-compartment model adequately described data over a dose range of 1-20 mg/kg with good predictive capability. Typical clearance and central volume of distribution values were 1.7- and 1.3-fold higher, respectively, in patients with pancreatic cancer than in patients with other advanced solid cancers, resulting in lower ganitumab exposure. Covariate analysis was used to evaluate effects of cancer type, gemcitabine coadministration, clinical study, demographics, and laboratory values on ganitumab PK. Pancreatic cancer type was the most significant covariate on clearance along with weight, albumin, and serum creatinine. Gemcitabine coadministration did not affect ganitumab clearance. Thus, disease state can significantly affect PK and should be considered when selecting the clinically effective dose.

The safety and efficacy of cisplatin plus gemcitabine in recurrent ovarian cancer

The activity and synergy for the combination treatment of cisplatin and gemcitabine has been identified in a variety of human tumor cells, including ovarian cancer cells, and has been widely approved for the treatment of non-small cell lung cancer, pancreatic cancer and biliary tract cancer. As the gastrointestinal symptoms with cisplatin therapy are commonly considered to negatively affect the quality of life of patients more than those experienced with carboplatin therapy, carboplatin is generally preferred over cisplatin in combination therapy. This study evaluated the safety and efficacy of cisplatin plus gemcitabine in patients with recurrent ovarian cancer. Patients with recurrent ovarian, peritoneal or fallopian tube cancer, who had failed with multiple other chemotherapy agents, including platinum, received cisplatin (30 mg/m(2)) plus gemcitabine (750 mg/m(2)) on days 1 and 8 of every 28 days for between 1 and 4 cycles. In total, 18 patients were treated with cisplatin and gemcitabine between 2006 and 2011. There were 1 complete and 5 partial responses, producing an overall response rate of 33.4 %. Median overall survival was 11.0 months. Grade 4 neutropenia and thrombocytopenia were seen in 11.1 and 22.2 % of patients, respectively. Non-hematological toxicity was less than Grade 1. Non-hematological toxicity with combined cisplatin and gemcitabine therapy was considered tolerable and did not impede patient quality of life. However, this drug combination should be monitored for hematologic toxicity.

Novel agents and future prospects in the treatment of pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is one of the most aggressive malignancies and the fourth leading cause of cancer-related mortality in the United States. The majority of patients are diagnosed at advanced stage with inoperable locally advanced tumors or metastatic disease, and palliative chemotherapy remains the best therapeutic option for these patients. Despite intensive clinical and pre-clinical research over the last few years, the combination of the anti-metabolite drug gemcitabine with the targeted agent erlotinib, is considered standard of care in the treatment of these patients, with only minimal or modest efficacy. Therefore, novel therapeutic approaches are currently under clinical investigation in an attempt to produce more definite results for this fatal disease. In this paper we summarize five most interesting research abstracts as presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting. In two studies, nimotuzumab, a monoclonal antibody against epidermal growth factor receptor (EGFR) (Abstract #4009) and bavituximab, a monoclonal antibody against phosphatidylserine (Abstract #4054) are tested in combination with gemcitabine in patients with advanced pancreatic cancer. Abstract #4012 is a study of gemcitabine with vismodegib, a novel hedgehog pathway inhibitor, whereas in Abstract #4035, toxicity and efficacy results of sunitinib in combination with gemcitabine in patients with pancreatic adenocarcinoma are presented. Lastly, safety results of pimasertib, a novel mitogen-activated protein kinase kinase (MEK) inhibitor, combined with the standard gemcitabine are presented in Abstract #4041.

This Month in Adult Urology

No AccessJournal of UrologyThis Month in Adult Urology1 Oct 2013This Month in Adult Urology William D. Steers William D. SteersWilliam D. Steers More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.07.007AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "This Month in Adult Urology." The Journal of Urology, 190(4), pp. 1151–1152 References 1 : Upper tract imaging surveillance is not effective in diagnosing upper tract recurrences in patients followed for nonmuscle invasive bladder cancer. J Urol2013; 190: 1187. Abstract, Google Scholar 2 : Tumor lesion diameter on diffusion weighted magnetic resonance imaging could help predict insignificant prostate cancer in patients eligible for active surveillance: preliminary analysis. J Urol2013; 190: 1213. Abstract, Google Scholar 3 : Salvage surgery after failed treatment of synthetic mesh sling complications. J Urol2013; 190: 1281. Link, Google Scholar 4 : SWOG S0353: phase II trial of intravesical gemcitabine in patients with nonmuscle invasive bladder cancer and recurrence after 2 prior courses of intravesical bacillus Calmette-Guérin. J Urol2013; 190: 1200. Link, Google Scholar 5 : Cost-effectiveness of fluorescence in situ hybridization in patients with atypical cytology for the detection of urothelial carcinoma. J Urol2013; 190: 1181. Link, Google Scholar © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 190Issue 4October 2013Page: 1151-1152 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information William D. Steers More articles by this author Expand All Advertisement PDF DownloadLoading ...

Gemcitabine in Patients With Intraductal Papillary Mucinous Neoplasm With an Associated Invasive Carcinoma of the Pancreas

The standard chemotherapy for invasive ductal carcinoma of the pancreas (IDC) is gemcitabine; however, the efficacy of gemcitabine in invasive intraductal papillary mucinous neoplasm with an associated invasive carcinoma of the pancreas (IPMN-IC) is still unknown. Because it is difficult to distinguish between IPMN-IC and IDC based only on radiological findings in advanced unresectable cases, recurrent cases after surgical resection were analyzed to identify the efficacy of gemcitabine monotherapy for IPMN-IC. Between 1992 and 2010, 128 patients with IPMN-IC and 548 patients with IDC underwent pancreatic resection at the National Cancer Center Hospital. Twelve patients with IPMN-IC and 73 patients with IDC had recurred after surgery and subsequently underwent gemcitabine at the standard dosage. The disease-control rates were comparable between the IPMN-IC and IDC patients (58.3% vs 59.4%). The median progression-free survival was 2.8 and 4.1 months in the IPMN-IC and IDC patients, respectively (P = 0.46). Also, no statistically significant difference in the median survival times was observed between the 2 groups (9.3 vs 8.8 months, respectively; P = 0.09). Among patients who had IPMN-IC and IDC with recurrent disease after resection, there was no significant difference in treatment outcomes after gemcitabine.

Disrupting Cytokine Signaling in Pancreatic Cancer

Etanercept blocks tumor necrosis factor α (TNF-α), a proinflammatory cytokine that plays a role in cancer-related cachexia and tumor growth. A phase I/II study was conducted to assess the tolerability and efficacy of gemcitabine and etanercept in advanced pancreatic cancer. Twenty-five patients received etanercept 25 mg subcutaneously twice weekly with gemcitabine. A control cohort of 8 patients received gemcitabine alone. The primary end point was progression-free survival at 6 months. Blood specimens were analyzed for TNF-α, IL-1β, IL-6, interferon-γ, IL-10, and NF-κβ activation. The trial is registered with ClinicalTrials.gov, number NCT00201838. Thirty-eight patients participated in this study. In the gemcitabine-etanercept cohort, grade 3/4 drug-related toxicities included leucopenia (3) and neutropenia (6). There were 3 (12%) patients with partial response and 8 (32%) patients with stable disease. The rate of progression-free survival at 6 months was 28% [n = 7; 95% confidence interval (CI), 20%-36%]. Median time to progression was 2.23 months (95% CI, 1.86-4.36 months) and median overall survival was 5.43 months (95% CI, 3.30-10.23 months). Clinical benefit rate was 33% of the evaluable patients. A correlation was seen between IL-10 levels and clinical benefit. Etanercept added to gemcitabine is safe but did not show significant enhancement of gemcitabine in patients with advanced pancreatic cancer.

Phase I Trial of AEG35156 an Antisense Oligonucleotide to XIAP Plus Gemcitabine in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

AEG35156 is an antisense oligonucleotide (ASO) that targets the X-linked inhibitor of apoptosis mRNA. Preclinical studies showed potent activity of AEG35156 in combination with gemcitabine in pancreatic ductal adenocarcinoma (PDA). A phase I study was conducted to establish the maximum-tolerated dose, safety, and antitumor activity of AEG35156 plus gemcitabine in metastatic PDA. Fourteen patients with metastatic PDA were enrolled. Nine patients were treated at 350 mg IV and 5 patients at 500 mg IV of AEG35156, 3 weeks on/1 week off of a 28-day cycle. Gemcitabine was administered at 1000 mg/m(2) IV over 30 minutes immediately after AEG35156 in both groups. Because of perceived neurotoxicity dose deescalation to 350 mg was recommended. All 14 patients were evaluable for tolerability and toxicity. Toxicities include neutropenia (grade 3/4, 6 patients), thrombocytopenia (grade 3, 2 patients), peripheral neuropathy (grade 3, 2 patients), fatigue (grade 3, 4 patients), ascites (grade 3, 2 patients), and nausea/vomiting (grade 4, 2 patients). Five patients (45%) experienced stable disease with a median progression-free survival of 58 days (95% CI, 52-107 d). The maximum-tolerated dose is AEG35156 500 mg plus gemcitabine 1000 mg/m(2) given on days 1, 8, and 15 every 28 days. AEG35156 plus gemcitabine failed to show significant clinical activity in advanced PDA.

Randomized multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and a prospective evaluation of the of the association between tumor hENT1 expression and clinical outcome with gemcitabine treatment.

4007 Background: Gemcitabine requires membrane transporter proteins to cross the cell membrane. Low expression of the human equilibrative nucleoside transporter-1 (hENT1) may play a role in gemcitabine resistance in PDAC. CO-101 (also known as CP-4126), a lipid-drug conjugate of gemcitabine, was rationally designed to enter cells independently of hENT1 and to circumvent transporter-mediated resistance. We conducted a randomized, controlled trial (LEAP) in patients with mPDAC to determine whether CO-101 improved survival vs gemcitabine in patients with low hENT1 tumors. The study also prospectively tested the hypothesis that gemcitabine is more active in patients with hENT1 high than hENT1 low tumors in metastatic disease. Methods: Patients were randomized to CO-101 or gemcitabine. An immunohistochemistry test measuring tumor hENT1 expression was developed in parallel with the recruitment phase of LEAP. To dichotomize the population, a hENT1 cut-off was defined using primary PDAC tumor samples from an adjuvant trial. LEAP participants provided a metastasis sample during screening for blinded hENT1 assessment, and the cut-off was applied to these samples. The primary endpoint of the study was overall survival in the low hENT1 subgroup. Results: 367 patients were enrolled, with metastasis hENT1 status available for 358/367 (97.5%). 232/357 (65%) were hENT1 low. There was no difference in overall survival between CO-101 and gemcitabine in the hENT1 low subgroup, or overall, with hazard ratios of 0.994 [95% CI 0.746, 1.326] and 1.072 [95% CI 0.856, 1.344] respectively. Within the gemcitabine arm, there was no difference in survival between the hENT1 high and low subgroups (HR 1.147 95% CI 0.809, 1.626). The observed side effect profile was typical of gemcitabine and was similar in both treatment arms, in the hENT1 low subgroups and overall. Conclusions: CO-101 is not superior to gemcitabine in patients with mPDAC and low tumor hENT1 expression. Metastasis hENT1 expression did not predict gemcitabine treatment outcome in patients with mPDAC. Clinical trial information: NCT01124786.

Circulating cytokines and angiogenic factors (CAF) as markers of clinical response in the study of trametinib (T) plus gemcitabine (G) versus placebo (P) plus gemcitabine for patients (pts) with untreated metastatic adenocarcinoma of the pancreas (MEK113487).

4042 Background: T is a reversible and highly selective allosteric inhibitor of MEK1/MEK2. The addition of T to G did not improve overall survival (OS) as first-line treatment for pts with metastatic adenocarcinoma of the pancreas (ASCO GI 2013 #291). CAF profiles have shown potential for identification of prognostic and predictive markers in cancer pts (Tran, Lancet, 2012). Methods: Plasma samples (n = 144 baseline [BL]; n = 112 day 15) from pts who consented to participate in MEK113487 study were analyzed for 30 CAFs (ANG2, IGFBP3, IL2R, IP10, MMP2, MMP9, OPN, PDGFBB, SCF, TIMP1, IL6, MIP1B, SDF1, TRAIL, VEGF, MIP3A, MCP2, FGFB, IL8, VEGFR1, IL10, IL1A, IL12P40, PIGF, EGF, IL1B, TNFA, IL4, MIP1A, MCP3) using SearchLight multiplex assays in a CLIA-certified laboratory. Change from BL was assessed using either paired t tests or Wilcoxon tests. BL and change from BL CAF levels were tested for association with clinical outcome using proportional hazards regression within arm (P &lt; .01 for significance) and between arms (treatment arm by CAF level interaction, P &lt; .05 for significance). Results: Lower levels (&lt; median) of BL ANG2, IL6, TIMP1, and IL8 were associated with an average of 5 mo longer OS in both the T+G and G arms. Lower BL levels (less than first quartile) of IGFBP3 and PDGFBB were associated with 6 mo longer OS in the T+G arm, while higher levels (greater than third quartile) of IGFBP3 and PDGFBB were associated with 4.8 mo longer OS in the G arm. A combined model of low IGFBP3 and/or PDGFBB showed improved survival for T+G vs G (median OS, 10.3 vs 5.6 mo). Decreases of ANG2 and IL2R levels at day 15 from BL were observed in the T+G arm only; additional results will be presented. Conclusions: This study suggests that plasma CAF profiling may aid in the prognostic evaluation of pts, assessing therapeutic response, and identifying pathways modulated by treatment in pancreatic cancer pts. Low IGFBP3 and PDGFBB may identify patients who receive greater benefit from T+G compared with G in this population and merit further investigation as predictive markers. Clinical trial information: NCT01231581.

A phase II trial of a cremophor-free, polymeric micelle formulation of paclitaxel and gemcitabine in patients with advanced non-small cell lung cancer.

e19129 Background: Non-platinum doublet paclitaxel and gemcitabine has shown efficacy on par with platinum-based doublet regimens as first-line chemotherapy in advanced non-small cell lung cancer patients. Genexol-PM is a Cremorphor EL(CrEL)-free polymeric micelle formulation of paclitaxel. This study was designed to evaluate the efficacy and safety of Genexol-PM and gemcitabine combination in advanced non-small cell lung cancer patients. Methods: This is a single-arm, single-center phase II study. Patients with advanced NSCLC received Genexol-PM at 230mg/m2 on day 1 and gemcitabine 1000mg/m2 on day 1 and day 8 of a 3-week cycle as first-line chemotherapy. Six cycles of chemotherapy were administered unless there is a disease progression. The primary endpoint was response rate. Results: Forty-three patients received the study drugs with median of 4 cycles per patient (range, 1-6). Among 35 patients who received more than one cycle, mean dose intensity of CrEL-free paclitaxel and gemcitabine was 209 mg/m2/3-week and 1,853 mg/m2/3-week respectively. Overall response rate was 46.5%. The median progression free survival was 4.0 months (95% CI 2.0-6.0 months) and median overall survival was 14.8 months (95% CI 9.1-20.5 months). 18 patients (51%) experienced grade 3/4 adverse events, including neutropenia or febrile neutropenia (n=7), pneumonia (n=3), asthenia (n=3), peripheral neuropathy (n=2), diarrhea (n=1), skin rash (n=1), myalgia (n=1), pulmonary thromboembolism (n=1), LV dysfunction (n=1), and dyspnea with sudden death (n=1). Adverse events leading to drug discontinuation were occurred in 9 patients, among which 2 patients were died of adverse events (pneumonia, dyspnea with sudden death). Conclusions: CrEL-free paclitaxel in combination with gemcitabine demonstrated comparable antitumor activity with less emetogenicities in non-small cell lung cancer patients. Clinical trial information: NCT01770795.

Randomized phase II trial of gemcitabine versus gemcitabine and imatinib mesylate in patients with previously treated metastatic breast cancer.

1091 Background: Gemcitabine (GEM) as a standard 30-min infusion has activity as a single-agent in metastatic breast cancer (mbc). Prolonged infusion of GEM at a fixed dose rate (FDR) of 10 mg/m2/min is associated with greater formation of active metabolite and may result in improved antitumor activity. Imatinib mesylate (IM)-mediated inhibition of PDGFR reduces tumor interstitial fluid pressure allowing for improved chemotherapy penetration into tumors. We evaluated the addition of IM to FDR GEM in patients (pts) with previously treated mbc. Methods: This was a randomized phase II trial in mbc pts who progressed after 1 but no more than 2 prior cytotoxic regimens. Eligibility included measurable disease; no prior GEM or IM exposure. Group 1 received FDR GEM IV 1250 mg/m2 at 10 mg/m2/min (over 120 min) on days 3 and 10 every 21 days; Group 2 received the same FDR GEM dose and schedule plus IM 400 mg orally daily on days 1-5 and 8-12 every 21 days. Primary endpoint was time to progression (TTP). Sample size of 40 pts per group was needed to detect an 8 mo increase in TTP with the combination (80% power, α = .05, 2-sided). Secondary endpoints included ORR and safety. Results: Between 5/2006-4/2011, 44 pts were randomized (22 per group). Study closed early due to slow accrual. Median age 54 (31-75); median ECOG PS 1 (0-2); 52% were hormone receptor-positive and HER2-negative; 27% triple-negative, and 20% HER2-positive. Median number of cycles was 2 in Group 1 (range 1-12) and 3.5 in Group 2 (range 1-13). Most common adverse events (%) of any grade, Group 1 vs Group 2 were neutropenia (68 vs. 78), anemia (48 vs. 65), thrombocytopenia (24 vs. 47), nausea (40 vs. 52) and vomiting (24 vs. 21). One gr 4 thrombotic thrombocytopenic purpura occurred in Group 2. Median TTP were 2 mo (95% CI: 1-5 mo) in Group 1 and 2.5 mo (95% CI: 1-5 mo) in Group 2 (p = 0.3 log rank test). ORR was 9.1% in each group (95% CI: 1.6-30.6%), with 2 PRs in each group. Stable disease (≥ 3 mo) was 32% in Group 1 and 41% in Group 2. Conclusions: This study was underpowered to draw any conclusion regarding a difference in TTP between the two groups at the time it was prematurely closed. Combination of IM and FDR GEM showed a trend to increased toxicity compared to FDR GEM alone. Clinical trial information: NCT00323063.

HENT1 tumor levels to predict survival of pancreatic ductal adenocarcinoma patients who received adjuvant gemcitabine and adjuvant 5FU on the ESPAC trials.

4006 Background: Some studies in patients with resected pancreatic cancer have suggested that expression of the human equilibrative nucleoside transporter (hENT1) may be predictive of improved survival from gemcitabine but these have either been based on retrospective non-randomized studies or in one study the principal treatment was chemoradiation. The samples collected from the adjuvant ESPAC1/3 randomized trials have provided a unique opportunity to assess to REMARK standards the therapeutic predictability of hENT1 in patients undergoing resection for pancreatic cancer. Methods: Tissue Microarrays (TMAs) were prepared using paraffin embedded tumor specimens from patients randomized to gemcitabine or 5FU/Folinic acid in the ESPAC-1 and -3 trials. Cores were given an H-Score depending on the level of staining with the 10D7G2 anti-hENT1 antibody. Groups were compared using Kaplan-Meier and Cox proportional hazards. Results: Scores were obtained for 176 gemcitabine treated and 176 5FU treated patients. The overall median H-Score was 48 and patients were classified as having high hENT1 if the mean score for their cores was above this. Median overall survival for gemcitabine treated patients was 23.4 (95% CI: 18.3, 26.0) months versus 23.5 (95% CI: 19.8, 27.3) months for 5FU treated patients (χ21 = 0.24, P = 0.623). In the gemcitabine group A significantly lower survival (χ21 = 9.87, P = 0.002) was noted with low hENT1 (median survival 17.1 (95% CI: 14.3, 23.8) versus 26.2 (95% CI: 21.2, 31.4) months). Median survival was 25.6 (95% CI: 20.1, 27.9) and 21.9 (95% CI: 16.0, 28.3) months respectively for high and low hENT1 in the 5FU group, a non-significant difference (χ21 = 0.83, P = 0.362). Multivariate analysis confirmed hENT1 expression as a predictive marker in gemcitabine (Wald χ2 = 7.10, P = 0.008) but not 5-fluorouracil (Wald χ2 =0.34, P = 0.560) groups. Conclusions: The study supports use of gemcitabine in patients with high tumor hENT1 expression and 5-fluorouracil in patients with low hENT1.

Interim outcome analysis of a prospective phase I trial of surgical resection with intracavitary hyperthermic cisplatin and gemcitabine for patients with resectable malignant pleural mesothelioma.

7588 Background: We completed a phase I trial of cisplatin and dose-escalated gemcitabine in a hyperthermic intra-operative lavage (IOHC) following extrapleural pneumonectomy (EPP arm) or extended pleurectomy (PD arm). Primary and secondary endpoints including gemcitabine MTD (1000 mg/m2 with 175 mg/m2 cisplatin) and pharmacokinetics, toxicity and mortality were reported (IMIG congress, 9/11-14/2012, abstract IIB.4 [1]). To define phase II indications, we explored patient outcome in comparison to published phase II results of a similar trial using cisplatin IOHC alone following EPP (J Thorac Cardiovasc Surg 2009, 138:405 [2]). Methods: The protocol was registered and IRB approved. Informed consent was obtained. Overall survival was calculated from the date of surgery to the date of death or censored at the date of most recent contact. Patients who were treated on the EPP arm at 500 to 1000 mg/m2 gemcitabine dose levels were included, grouped by epithelial (E) or non-epithelial (NE) histological subtype. Median, 1-year and 2-year survival was estimated using Kaplan-Meier methods. Results: 141 patients were registered. Median age was 65 (43-85) and 22 (21%) were women. Histology was epithelial (63), biphasic (32), and sarcomatoid (8). Two patients died perioperatively (2%). 59 patients were treated on the EPP arm of which the 27 (13 censored) treated at 500 to 1000 mg/m2 gemcitabine were studied. Qualitative comparison with a prior phase II trial of cisplatin IOHC (ref [2]) suggests incremental survival benefit to adding gemcitabine for patients with epithelial but not non-epithelial tumor histology (Table). Conclusions: Patients with epithelial histology tumors who require EPP for macroscopic complete resection appear likely to benefit from the addition of gemcitabine and should be included in a phase II investigation of this combination. Patients with non-epithelial biopsy who require EPP should be considered for other treatment strategies. Clinical trial information: NCT00571298. [Table: see text]

Phase I/II study of PCI-27483, a coagulation factor VIIa (FVIIa) inhibitor, in combination with gemcitabine in patients with advanced pancreatic cancer.

e15014 Background: Tissue factor (TF) up-regulation is associated with increased tumor invasiveness and progression, worsened prognosis and increased thromboembolism (VTE). Activation of protease activated receptors by TF:FVIIa complex leads to increases in IL-8, VEGF and other invasiveness promoting factors. PCI-27483 (P), a selective FVIIa inhibitor, reduced pancreatic adenocarcinoma (PCa) xenograft growth in mice at doses producing 2.5 - 3.0 x PT changes. Methods: Escalating doses of P combined with gemcitabine (G) targeting peak (2 hr post) INR = 3.0 was studied in Phase I preceding randomization to G+P at the determined dose vs. G alone in Phase II. Eligible patients (pts) had measurable locally advanced or metastatic PCa, ECOG PS 0-1, and normal PT/aPTT, and no history of VTE. G was given IV at 1 G/m2 q wk X3 every 4 wks, and P was self-administered SC bid continuously. Tumor evaluation including spiral CTs were performed at baseline and q 8 wks. Results: In phase I, 8 pts were enrolled and the targeted INR was attained at 1.2 mg/kg. In phase II, 34 patients were randomized, 16 to G and 18 to G+P. The randomized arms were well balanced; overall 88% had metastatic disease; most had liver involvement. Among pts randomized to P+G, mean ± SD 2-hr post injection INR was 3.1 ± 1.2 on D8 and 2.8 ± 1.0 on D22 (n=13). P dosing was continued for up to 96 wks; mean ± SD: 17 ± 24 wks. Dose reduction to maintain target INR was required for 6 pts. Overall tolerability and safety of G+P was similar to that of G, with a higher incidence of mostly low grade bleeding events and decreased Hgb. Efficacy measures of G vs G+P pts were not significantly different (Table). Conclusions: PCI-27483 +G was well tolerated at doses of P up to 1.5 mg/kg bid. The safety profile of the combination was consistent with that expected of each agent. While the clinical endpoints were not achieved in pancreatic cancer, the targeted inhibition of the coagulation cascade was achieved. Clinical trial information: NCT01020006. [Table: see text]

Phase Ib study evaluating safety and pharmacokinetics (PK) of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 monohydrate (LY) when combined with gemcitabine in patients with advanced cancer.

2563 Background: Based on animal studies, the combination of a TGF-β inhibitor and gemcitabine is expected to enhance antitumor activity of gemcitabine. Hence, we started a combination study of LY with gemcitabine to assess the safety of this combination therapy. Methods: Gemcitabine was administered as approved and LY was given daily as intermittent dosing (14 days on/14 days off=1 cycle). A dose escalation consisting of 3 cohorts (80 mg/day, 160 mg/day, and 300 mg/day) evaluated the safety of LY in combination with gemcitabine. Toxicity was assessed using the CTCAE, version 4. Pharmacokinetic (PK) profile of LY in combination with gemcitabine was determined. Results: A total of 14 patients were evaluated (cohort 1 [n=5, 4 adenocarcinoma of colon, 1 non-small cell lung cancer, cohort 2 [n=4, adenocarcinoma, 1 each of esophageal, well differentiated, pancreas, lung], cohort 3 [n=5, 3 pancreatic, 2 rectal cancer]) in this study. The median number of cycles was 2 (range (1-6). Regardless of causality, the following treatment-emergent adverse events (TEAEs) were observed in ≥25% of patients: anemia (n=10), nausea (n=8), thrombocytopenia (n=6), neutropenia (n=6), vomiting (n=6), anorexia (n=5), fatigue (n=5), diarrhea (n=5) asthenia (n=5), pyrexia (n=4), AST increased (n=4), and constipation (n=4). Possibly related to LY, (Grade, Gr, 3/4 as mentioned) TEAEs observed were: nausea (n=5), asthenia (n=4), fatigue (n=3, 1 Gr 3), neutropenia (n=3, 1 Gr 3), anemia (n=3, 2 Gr 3 ), and in 2 patients each, thrombocytopenia (both Gr 3), headache, edema peripheral, rash, anorexia, diarrhea (1 Gr 3), mucosal inflammation, vomiting and reversible rhabdomyolysis (n=1, Gr 4). No change in the PK profile of LY was shown when LY was combined with gemcitabine. Conclusions: There were no dose limiting toxicities observed and no clinically meaningful cardiotoxicities were detected. Because of the observed manageable safety profile, LY at 300 mg/day has been advanced into a randomized Phase 2 trial in pancreatic cancer in 1st line setting to assess the antitumor activity of the combination. Clinical trial information: NCT01373164.

Phase I/II trial of carbon-ion radiotherapy with concurrent gemcitabine for patients with locally advanced pancreatic cancer.

e15008 Background: Carbon-ion radiotherapy (CIRT) offers the potential advantage of improved dose localization and enhanced biologic effect. The purpose of this trial was to establish the recommended dose of gemcitabine and CIRT, evaluating the tolerance and efficacy of gemcitabine combined with CIRT for the treatment of the patients with locally advanced pancreatic cancer. Methods: Patients with histopathologically proven, locally advanced pancreatic adenocarcinoma, which involved the celiac trunk or superior mesenteric artery without distant metastasis, were eligible for this trial. The radiation fractions were fixed at 12 fractions in 3 weeks, and the dose of gemcitabine and radiation were gradually increased. First, the dose was fixed at 43.2GyE/8 fractions and the gemcitabine dose was increased from 400, to 700 to 1000mg/m2. Subsequently, the gemcitabine dose was fixed at 1000mg/m2 and the radiation dose was increased from 43.2GyE to 55.2GyE by 5% increments. Gemcitabine was administered for 3 consecutive weeks, once a week. Results: Seventy-five patients were registered from April 2007 through February 2012. Of these patients, 71 were clinically eligible for the study. The most common Grade 3 acute toxicities were hematological toxicity (51%) and anorexia (8%). Dose limiting toxicity developed in three patients: Grade 3 gastric ulcer in 1 and Grade 4 leukopenia in 2. No other serious side effects were found. The two-year local control rate and two-year overall survival rate were 40% and 40% in all patients. The median survival time was 21 months. In the high dose group (n=47), in which patients were irradiated with at least 45.6 GyE, the two-year survival rate was 62%. Conclusions: CIRT was well tolerable even when concomitantly administered with the highest dose of gemcitabine (1000mg/m2).