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Background: Modified FOLFIRINOX and gemcitabine plus nab-paclitaxel (GEM-NAB) have been recommended as first-line therapies for advanced pancreatic cancer (PC). Due to the lack of evidence to directly compare them, we conducted this network meta-analysis to indirectly compare the effectiveness and toxicity of modified FOLFIRINOX and GEM-NAB.Methods: The eligible retrospective studies on treatments related to modified FOLFIRINOX and GEM-NAB up to 4 April 2020 were searched and assessed. We used the frequentist model to analyze the survival and toxicity data between different treatments. Pooled analysis for overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and events of toxicity were analyzed in this study.Results: Twenty-two studies were involved in this network meta-analysis. The comparisons on OS and PFS showed that modified FOLFIRINOX and GEM-NAB had similar treatment efficacy (OS: 1.13; 95% CI: 0.78-1.63; PFS: HR: 1.19; 95% CI: 0.85-1.67). GEM-NAB was more effective than modified FOLFIRINOX based on the result of ORR (RR: 1.43; 95% CI: 1.04-1.96). Moreover, our analysis showed a similar toxicity profile between modified FOLFIRINOX and GEM-NAB.Conclusions: The current evidence showed that modified FOLFIRINOX and GEM-NAB were similar in survival and toxicity. Many factors should be considered for in the formulation of optimal treatment, and our meta-analysis could provide some guidance to treatment selection in the first-line setting for advanced PC. [ABSTRACT FROM AUTHOR]

KRAS mutation is associated with the progression and growth of pancreatic cancer and contributes to chemo-resistance, which poses a significant clinical challenge in pancreatic cancer. Here, we developed a RT22-ep59 antibody (Ab) that directly targets the intracellularly activated GTP-bound form of oncogenic KRAS mutants after it is internalized into cytosol by endocytosis through tumor-associated receptor of extracellular epithelial cell adhesion molecule (EpCAM) and investigated its synergistic anticancer effects in the presence of gemcitabine in pancreatic cancer. We first observed that RT22-ep59 specifically recognized tumor-associated EpCAM and reached the cytosol by endosomal escape. In addition, the anticancer effect of RT22-ep59 was observed in the high-EpCAM-expressing pancreatic cancer cells and gemcitabine-resistant pancreatic cancer cells, but it had little effect on the low-EpCAM-expressing pancreatic cancer cells. Additionally, co-treatment with RT22-ep59 and gemcitabine synergistically inhibited cell viability, migration, and invasion in 3D-cultures and exhibited synergistic anticancer activity by inhibiting the RAF/ERK or PI3K/AKT pathways in cells with high-EpCAM expression. In an orthotopic mouse model, combined administration of RT22-ep59 and gemcitabine significantly inhibited tumor growth. Furthermore, the co-treatment suppressed cancer metastasis by blocking EMT signaling in vitro and in vivo. Our results demonstrated that RT22-ep59 synergistically increased the antitumor activity of gemcitabine by inhibiting RAS signaling by specifically targeting KRAS. This indicates that co-treatment with RT22-ep59 and gemcitabine might be considered a potential therapeutic strategy for pancreatic cancer patients harboring KRAS mutation. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is still a highly fatal malignancy among the most common cancers. More powerful treatments are expecting to bring hope for patients. Biweekly gemcitabine/nab-paclitaxel/S-1 (GAS) was proved safe and effective for patients with locally advanced pancreatic cancer in Japan. The objective of this study is to evaluate the feasibility and toxicity of GAS (repeated every 3 weeks) in the treatment of locally advanced or advanced pancreatic cancer and determine the recommended dose of S-1 in this combination.Methods: This is an open-label, single-arm, and single-center phase I trial. Patients who have been diagnosed with locally advanced or advanced PDAC pathologically without previous systemic treatments will be enrolled and be treated with GAS chemotherapy every 3 weeks (nab-paclitaxel 125 mg/m 2, ivgtt, day1, 8; gemcitabine 1000 mg/m2, day1, 8; different doses of S-1 within a dose escalation scheme) until the presence of disease progression (PD), intolerable adverse events (AEs), or requirement of patients and researchers. The primary endpoints are maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). The secondary endpoints include safety, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).Discussion: This trial will adjust the administration of GAS to make it more effective for Chinese patients, while exploring the toxicity and feasibility of this adjustment.Trial Registration: ChiCTR, ( ChiCTR1900027833 ). Registered 30 November 2019. [ABSTRACT FROM AUTHOR]

Background: Combination of gemcitabine and nab-paclitaxel has superior clinical efficacy than gemcitabine alone. Nevertheless, health-related quality of life. (QoL) associated with this combination therapy when administered at first-line in advanced pancreatic adenocarcinoma is unknown.Methods: A total of 125 patients were randomized to combination therapy (1000 mg/m2 gemcitabine + 125 mg/m2 nab-paclitaxel) and single-agent gemcitabine (1000 mg/m2) arms to take treatment weekly for 7 of 8 weeks, and following 3 of 4 weeks, until progression or severe toxicity. Primary endpoints were three-months of definitive deterioration free percent of patients, and QoL.Results: Overall QoL analyses showed that 34 and 58.3% of cases in gemcitabine and gemcitabine+nab-P arms had no deterioration in 3rd month QoL scores (p = 0.018). These proportions were 27.3 and 36.6% in 6th month assessments, respectively (p = 0.357). Median overall survivals in combination and single-agent arms were 9.92 months and 5.95 months, respectively (HR: 0.64, 95% CI: 0.42-0.86, p = 0.038). Median progression free survivals in these treatment arms were 6.28 and 3.22 months, respectively (HR: 0.58, 95% CI: 0.39-0.87, p = 0.008). Median time-to-deterioration were 5.36 vs 3.68 months, and objective response rates were 37.1% vs 23.7% (p = 0.009), respectively in combination and single-agent arms.Conclusions: Combination therapy with gemcitabine + nab-paclitaxel had better overall and progression-free survival than gemcitabine alone. Also, combination therapy showed increased response rate without toxicity or deteriorated QoL. Combination treatment with gemcitabine and nab-paclitaxel may provide significant benefit for advanced pancreatic cancer.Trial Registration: This study has been registered in ClinicalTrials.gov as NCT03807999 on January 8, 2019 (retrospectively registered). [ABSTRACT FROM AUTHOR]

Background: Gemcitabine/erlotinib treatment offers limited benefit in unselected patients with pancreatic ductal adenocarcinoma (PDAC). Development of skin rash has been associated with favorable outcomes in patients treated with gemcitabine/erlotinib. This study aimed to extend knowledge on the effectiveness of gemcitabine/erlotinib in metastatic PDAC in the context of clinical practice and with focus on skin rash.Methods: This multicenter, non-interventional study enrolled 376 patients with metastatic PDAC receiving gemcitabine/erlotinib. The primary endpoint was overall survival (OS) in patients with skin rash versus no skin rash. Secondary endpoints included progression-free survival (PFS), treatment satisfaction and safety. All data were analyzed using descriptive statistics. Survival time and time to disease progression were estimated using the Kaplan-Meier method. Effectiveness endpoints were analyzed for subgroups by skin rash grade (no rash, rash grade 1, rash grade ≥ 2), duration of erlotinib treatment (≤8 weeks, > 8 weeks), Eastern Cooperative Oncology Group (ECOG) performance status at baseline (0-1, 2) and age (≤65 years, > 65 years).Results: Within the full analysis set (FAS; N = 270), 48 patients (17.8%) developed grade 1 rash, 51 patients (18.9%) grade ≥ 2 rash, while 171 patients (63.3%) did not develop a rash. Median OS of all patients was 9.11 months with an OS of 9.93 months in rash-positive and 8.68 months in rash-negative patients. Median PFS was 5.06 months for rash-positive and 4.11 months for rash-negative patients. PFS was longer in patients with rash grade ≥ 2 and in older patients (> 65 years). Examination using a multivariate Cox proportional model revealed that an age > 65 years was associated with longer OS (hazard ratio 0.640; p = 0.0327) and PFS (hazard ratio 0.642; p = 0.0026). Out of the 338 patients in the SAF, 310 patients (91.7%) experienced at least one AE, and 176 patients (52.1%) experienced skin-related side effects, all of which were CTC grade 1 to 3.Conclusions: Comparing rash-positive with rash-negative patients showed no significant difference in survival. While patients with rash grade ≥ 2 and older patients (independent of skin reactions) showed longer PFS, this did not translate into prolonged OS. The study did not reveal new safety signals.Trial Registration: ClinicalTrials.gov Identifier: NCT01782690, retrospectively registered on 4 February 2013. [ABSTRACT FROM AUTHOR]

Background and Aims: Pancreatic cancer is an aggressive malignancy with poor prognosis. Gemcitabine is the standard chemotherapeutic drug used to treat the disease; however, it has a low response rate. Therefore, there is an urgent need to develop new and safe therapies to enhance sensitivity to gemcitabine in treating pancreatic cancer.Methods: The synergistic effect of gemcitabine combined with specific B cell CLL/lymphoma 2 (Bcl-2) inhibitor ABT-199 against pancreatic cancer was tested using cell viability, cell cycle, and apoptosis assays in vitro and in an MIA Paca-2 xenograft model in vivo. Its underlying mechanism was explored using western blotting analysis of Bcl-2 family proteins.Results: ABT-199 not only enhanced the effect of gemcitabine on cell growth inhibition but also promoted gemcitabine-induced apoptosis in pancreatic cancer cell lines. Gemcitabine decreased the expression of anti-apoptotic protein Mcl-1 but increased the expression of anti-apoptotic protein Bcl-2. ABT-199 downregulated the gemcitabine-induced production of Bcl-2 and increased the expression of pro-apoptotic protein Bcl-2 interacting protein (BIM). Mouse xenograft experiments also confirmed the synergistic effect of gemcitabine and ABT-199 on tumor growth inhibition and the induction of tumor cell apoptosis.Conclusion: Our results indicated that ABT-199 improved the anti-tumor effect of gemcitabine on pancreatic cancer by downregulating gemcitabine-induced overexpression of Bcl-2. ABT-199 has already been investigated in phase 3 clinical trials for chronic lymphocytic leukemia; therefore, it may serve as a potential drug to improve the sensitivity of pancreatic cancer to gemcitabine. [ABSTRACT FROM AUTHOR]

Purpose: New chemotherapies have become available for the treatment of advanced pancreatic cancer and have led to changes in its standard treatments. Since pancreatic cancer is becoming more common as a result of population aging, there is a need for diversification of chemotherapy.Methods: Between March 2014 and April 2017, FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (G-nab) was used as first-line therapy to treat 27 patients with locally advanced and metastatic pancreatic cancer at our hospital. In this study, we retrospectively evaluated their clinical characteristics, survival outcomes and adverse events.Results: Twelve of the 27 patients were treated with FFX, and the other 15 patients were treated with G-nab. The disease control rate was 86.7% in the G-nab group and 75% in the FFX group. Median OS time was 8.9 months in the FFX group and 11.8 months in the G-nab group. The 1-year survival rate was 46.6% in the G-nab group and 16.6% in the FFX group. The second-line treatment rate was 40% in the G-nab group and 66.7% in the FFX group. The grade 3-4 neutropenia rate was 20% in the G-nab group and 25% in the FFX group. No patients developed febrile neutropenia, or severe nausea, diarrhea, or anorexia. The peripheral sensory neuropathy rate was 73.3% in the G-nab group and 75% in the FFX group.Conclusions: Although G-nab and FFX are effective treatments for advanced pancreatic cancer, the G-nab group had a higher 1-year survival rate, and G-nab can be more safely administered to older patients. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the safety and efficacy of mocetinostat (a Class I/IV HDAC inhibitor) in combination with gemcitabine in patients with solid tumors, including pancreatic cancer.Methods: In this open-label, non-randomized Phase I/II study (NCT00372437) sequential cohorts of patients with solid tumors received gemcitabine (1000 mg/m2, day 1 of three consecutive weeks, 4-week cycles) and oral mocetinostat [50-110 mg, three times per week (TIW)]. The maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) was determined based on dose-limiting toxicities in Cycle 1 (Phase I study). The MTD/RP2D was further evaluated in patients with advanced pancreatic cancer (Phase II study) using a two-stage design. The Phase II primary endpoint was overall response rate (ORR).Results: Forty-eight patients were enrolled into the Phase I (n = 25) and Phase II (n = 23) studies. In the Phase I study, the MTD/RP2D was mocetinostat 90 mg TIW + gemcitabine 1000 mg/m2. Grade ≥ 3 treatment-related adverse events (AEs) were reported by 81% of all patients, the most frequent being fatigue (38%) and thrombocytopenia (19%). The ORR was 11% in the Phase I study (n = 2 patients with pancreatic cancer, responses lasting for 16.8 and 4.0 months, respectively). As no responses were seen in the Phase II cohort, the study was terminated.Conclusions: Mocetinostat TIW in combination with gemcitabine was associated with significant toxicities in patients with advanced pancreatic cancer. The level of clinical activity of this treatment combination was not considered high enough to merit further testing in this setting. [ABSTRACT FROM AUTHOR]

Purpose: Although gemcitabine is a mainstay of pancreatic cancer therapy, it is only moderately effective, and it would be desirable to measure drug uptake in patients. 1-(2'-deoxy-2'-fluoroarabinofuranosyl) cytosine (FAC), is an analog of gemcitabine, and when labeled with F-18, it may be a potential surrogate PET tracer for the drug.Procedures: [18F]FAC was synthesized to a radiochemical purity of >96 %. The human tumor lines AsPC1, BxPC3, Capan-1, Panc1, and MiaPaca2 were grown orthotopically in nude mice. KPC mice that conditionally express oncogenic K-ras and p53 mutations in pancreatic tissue were also used. The intra-tumoral distributions of [14C]gemcitabine and [18F]FAC were mapped with autoradiography. The inter-tumor correlation between [14C]gemcitabine and [18F]FAC was established in the orthotopic tumors. Expression of the equilibrative and concentrative nucleoside transporters (ENT, CNT) in vitro was detected by western blotting. Drug uptake was characterized in vitro using [3H]gemcitabine and the effect of transporter inhibition on gemcitabine and FAC uptake was investigated. The relative affinity of cells for gemcitabine and FAC was tested in competition assays. The cell lines differed in sensitivity to transport inhibitors and in competition studies. There was a good in vivo correlation between the total uptake of [18F]FAC and [14C]gemcitabine, measured across all orthotopic tumors. Using the KPC and BxPC3 models, we found that [14C]gemcitabine and [18F]FAC were largely co-localized.Conclusions: In the lines examined here, [18F]FAC uptake correlates well with gemcitabine in vivo, supporting the notion that [18F]FAC can serve as a PET radiotracer surrogate to determine the uptake and distribution of gemcitabine within pancreatic tumors. [ABSTRACT FROM AUTHOR]

Purpose: Following a previously published pre-clinical validation, this phase I study evaluated the safety, maximum tolerated dose, anti-tumour activity and immune status of a gemcitabine-chloroquine combination as a first- or late-line treatment in patients with metastatic or unresectable pancreatic cancer.Methods: In this 3 + 3 dose escalation study, patients received a single weekly standard dose of intravenous gemcitabine, followed by single weekly oral intake of 100, 200 or 300 mg of chloroquine. Tumour response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. Immune status was evaluated by RT-PCR to measure the relative expression of immune-related genes in peripheral blood mononuclear cells (PBMCs).Results: Overall, nine patients [median age 72 years; interquartile range (IQR), 68-78 years] were treated. No dose-limiting toxicities as defined in the protocol were observed. Three patients experienced partial response, and two patients had stable disease. The median time to progression was 4 months (95% CI 0.8-7.2), and the median overall survival was 7.6 months (95% CI 5.3-9.9). Among 86 assayed immune genes, three were significantly differentially expressed in PBMCs from responding versus non-responding patients: interferon-gamma receptor-1, toll-like receptor 2, and beta-2 microglobulin.Conclusions: The addition of chloroquine to gemcitabine was well tolerated and showed promising effects on the clinical response to the anti-cancer chemotherapy. Based on these initial results, the efficacy of the gemcitabine-chloroquine combination should be further assessed. [ABSTRACT FROM AUTHOR]

Purpose: S-1 has systemic activity for locally advanced pancreatic cancer (LAPC). Here, the efficacy and safety of induction gemcitabine (GEM) and S-1 (GS) followed by chemoradiotherapy (CRT) and systemic chemotherapy using S-1 for LAPC were assessed.Methods: The treatment consisted of four cycles of induction GS (S-1 60, 80, or 100 mg/day based on body surface area for 14 days every 3 weeks plus GEM 1000 mg/m2 on days 8 and 15), followed by S-1 (80, 100, or 120 mg/day based on body surface area on days 1-14 and 22-35) and concurrent radiotherapy (50.4 Gy in 28 fractions). Maintenance chemotherapy with S-1 was started 1-4 weeks after CRT until disease progression or unacceptable toxicity was observed. The primary endpoint was 1-year survival.Results: A total of 30 patients with LAPC were enrolled. The median survival and progression-free survival were 21.3 and 12.7 months, respectively. Overall survival rates at 1, 2, 3, and 4 years were 73.3, 36.7, 23.3, and 16.7%, respectively. The median survival of 23 patients who received CRT was 22.9 months, with a 3-year survival rate of 30.4%. The two most common grade 3 or 4 adverse events during induction GS were neutropenia (63.3%) and biliary tract infection (20%). Toxicities during CRT or maintenance chemotherapy were generally mild.Conclusions: This regimen was feasible and highly active resulting in encouraging survival in patients with LAPC. Further investigations are warranted to elucidate the effectiveness of this treatment strategy in future studies. Clinical trials information: UMIN000006332. [ABSTRACT FROM AUTHOR]

Purpose: Transforming growth factor-beta inhibitors may enhance the antitumor activity of gemcitabine with acceptable safety and tolerability. This open-label, multicenter, non-randomized phase 1b study assessed the safety/tolerability, pharmacokinetics, and tumor response of galunisertib plus gemcitabine in Japanese patients with advanced or metastatic pancreatic cancer.Methods: During each 28-day cycle, galunisertib 150 mg was administered orally twice daily (300 mg/day) for 14 days, followed by 14 days of rest. Gemcitabine 1000 mg/m2 was intravenously given on Days 8, 15, and 22. Safety was assessed by the incidence of dose-limiting toxicities (DLTs) in the first cycle and treatment-emergent adverse events (TEAEs). Efficacy was assessed by antitumor activity and changes in carbohydrate antigen 19-9 (CA19-9).Results: No DLTs were reported. All 7 enrolled patients had ≥1 TEAE, of which the most common included anorexia, decreased neutrophil count, and decreased white blood cell count. Grade ≥3 TEAEs were observed in 6 patients; 4 patients had Grade ≥3 TEAEs (decreased neutrophil, white blood cell, and lymphocyte count; hypophosphatemia) considered possibly related to study drug(s). The pharmacokinetic profile of galunisertib in combination with gemcitabine was similar to that previously observed for galunisertib alone. The clinical response [complete response (CR), partial response (PR), or stable disease] rate was 42.9%, and the median progression-free survival was 64 days; no CR/PR were achieved.Conclusion: Galunisertib plus gemcitabine had an acceptable safety/tolerability profile with evidence of efficacy in Japanese patients with advanced or metastatic pancreatic cancer. [ABSTRACT FROM AUTHOR]

Purpose: To determine a recommended dose for a biweekly combination neoadjuvant chemotherapy including gemcitabine, nab-paclitaxel, and S-1 (GAS) for patients with locally advanced pancreatic ductal adenocarcinoma (LAPC).Methods: Patients with borderline resectable or unresectable LAPC without distant metastasis were eligible for this study. The planned dosages of gemcitabine (mg/m2, day 1), nab-paclitaxel (mg/m2, day 1), and S-1 (mg/day, days 1-7) were 800/100/60-100 at level 1, and 1000/125/60-100 at level 2. The treatment cycle was repeated every 2 weeks, and patients were assessed for resectability and response to the treatment after 6 cycles. This study was registered with UMIN Clinical Trial Registry (UMIN000016630).Results: We enrolled 16 patients with LAPC in this study. At dose level 1, one of 8 patients experienced dose-limiting toxicity (DLT). One of the next 8 patients also experienced DLT at dose level 2. Based on these results, level 2 was considered the recommended dose for this regimen. Pancreatectomy with curative intent could be performed in 13 of the 16 patients. R0 resection was performed in 12 of 13 patients.Conclusion: In conclusion, recommended doses for a biweekly GAS chemotherapy regimen were determined as nab-paclitaxel: 125 mg/m2, gemcitabine: 1000 mg/m2 on day 1, S-1: <1.25 m2, 60 mg; 1.25-1.5 m2, 80 mg; >1.5 m2, 100 mg twice a day on days 1-7. GAS chemotherapy showed good preliminary efficacy with mild toxicity in this study, and warrants a further phase 2 trial to investigate the efficacy of the GAS regimen for LAPC. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to determine whether checkpoint kinase 1 inihibitor (CHK1), LY2603618, and gemcitabine prolong overall survival (OS) compared to gemcitabine alone in patients with unresectable pancreatic cancer.Methods: Patients with Stage II-IV locally advanced or metastatic pancreatic cancer were randomized (2:1) to either 230 mg of LY2603618/1000 mg/m2 gemcitabine combined or 1000 mg/m2 gemcitabine alone. OS was assessed using both a Bayesian augment control model and traditional frequentist analysis for inference. Progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics (PK), and safety (Common Terminology Criteria for Adverse Events [AEs] v 3.0) were also evaluated.Results: Ninety-nine patients (n = 65, LY2603618/gemcitabine; n = 34, gemcitabine) were randomized (intent-to-treat population). The median OS (months) was 7.8 (range, 0.3-18.9) with LY2603618/gemcitabine and 8.3 (range, 0.8-19.1+) with gemcitabine. Similarly, in a Bayesian analysis, the study was not positive since the posterior probability that LY2603618/gemcitabine was superior to gemcitabine in improving OS was 0.3, which did not exceed the prespecified threshold of 0.8. No significant improvements in PFS, ORR, or duration of response were observed. Drug-related treatment-emergent AEs in both arms included nausea, thrombocytopenia, fatigue, and neutropenia. The severity of AEs with LY2603618/gemcitabine was comparable to gemcitabine. The LY2603618 exposure targets (AUC(0-∞) ≥21,000 ng∙hr/mL and Cmax ≥2000 ng/mL) predicted for maximum pharmacodynamic response were achieved after 230 mg of LY2603618.Conclusions: LY2603618/gemcitabine was not superior to gemcitabine for the treatment of patients with pancreatic cancer.Trial Registration: NCT00839332 . Clinicaltrials.gov. Date of registration: 6 February 2009. [ABSTRACT FROM AUTHOR]

Background: A randomized clinical trial has found that the addition of erlotinib to gemcitabine (GEM-E) for pancreatic cancer led to a modest increase in survival. The aim of this national population-based retrospective study was to compare the effectiveness of GEM-E to GEM alone for pancreatic cancer patients in real clinical practice.Methods: Patients with pancreatic cancer (ICD-10: C25) with prescription claims of gemcitabine or erlotinib between Jan 1, 2007 and Dec 31, 2012 were retrospectively identified from the Korean Health Insurance claims database. To be included in the study population, patients were required to have had a histological or cytological diagnosis within one year before chemotherapy. Patients treated with prior radiotherapy, surgery, or chemotherapy were excluded to reduce heterogeneity. Overall survival from the initiation of therapy and the medical costs of GEM-E and GEM were compared.Results: A total of 4,267 patients were included in the analysis. Overall survival was not significantly longer in patients treated with GEM-E (median 6.77 months for GEM-E vs. 6.68 months for GEM, p = 0.0977). There was also no significant difference in the respective one-year survival rates (27.0 % vs. 27.3 %; p = 0.5988). Multivariate analysis using age, gender, and comorbidities as covariates did not reveal any significant differences in survival. Based on this relative effectiveness, the incremental cost per life year gained over GEM was estimated at USD 70,843.64 for GEM-E.Conclusions: GEM-E for pancreatic cancer is not more effective than GEM in a real-world setting, and it does not provide reasonable cost-effectiveness over GEM. [ABSTRACT FROM AUTHOR]

Purpose: Addition of either nab-paclitaxel or erlotinib to gemcitabine to treat advanced pancreatic cancer has demonstrated overall survival benefit. This study was conducted to evaluate the tolerability and safety of combining all three drugs and assess preliminary evidence of efficacy.Methods: In this open-label, phase 1b study, patients with previously untreated, advanced pancreatic cancer were treated in 28-day cycles with intravenous gemcitabine/nab-paclitaxel on days 1, 8, and 15, and once daily oral erlotinib. A standard "3 + 3" design was used. Dose level 1 (DL1) for gemcitabine (mg/m(2))/nab-paclitaxel (mg/m(2))/erlotinib (mg) was 1000/125/100, respectively, with de-escalation to DL-1 (1000/100/100), DL-2b (1000/75/100), and DL-3 (1000/75/75). The maximum tolerated dose (MTD) was defined by occurrence of dose-limiting toxicity (DLT) in ≤1 of six patients within the first cycle. Efficacy was assessed with CT scans performed at two-cycle intervals.Results: Nineteen patients were enrolled. DLTs occurred in two patients at DL1, three patients at DL-1, two patients at DL-2b, and one patient at DL-3. The MTD for the combination of gemcitabine/nab-paclitaxel/erlotinib was DL-3 (1000/75/75). In analyses of efficacy among 14 evaluable patients, partial responses were observed in four of six patients at DL1, one of two patients at DL-2b, and two of six patients at DL-3.Conclusion: The addition of erlotinib to gemcitabine and nab-paclitaxel is not tolerable at standard single-agent dosing of all drugs. However, significant clinical activity was noted, even at DL-3. Further study of the combination will need to incorporate reduced dosing. [ABSTRACT FROM AUTHOR]

Purpose: Efficacy and safety of nab-paclitaxel plus gemcitabine have not been clarified in Japanese patients with metastatic pancreatic cancer. No pharmacokinetic profile of co-administration of nab-paclitaxel and gemcitabine has been reported. We conducted a phase I/II study of the efficacy, safety, and pharmacokinetics in Japanese patients with metastatic pancreatic cancer.Methods: The patients were administered 125 mg/m(2) nab-paclitaxel followed by 1000 mg/m(2) gemcitabine on day 1, 8, and 15 every 4 weeks. Treatment was continued until disease progression, unacceptable adverse events, or withdrawal of consent, whichever occurred first. The primary endpoints were tolerability in phase I and overall response rate according to RECIST in phase II.Results: A total of 34 patients were enrolled. At the time of 1-year follow-up analysis since the last patient enrollment, the objective response rate by independent review committee was 58.8% (20 of 34 patients; 95% confidence interval [CI], 40.7-75.4%). The median progression-free survival and median overall survival were 6.5 months (95% CI, 5.1-8.3) and 13.5 months (95% CI, 10.6--not reached), respectively. Main adverse drug reactions of grade 3 or higher were neutropenia (70.6%), leukopenia (55.9%), anemia (14.7%), lymphocytopenia (14.7%), thrombocytopenia (14.7%), and peripheral sensory neuropathy (11.8%). There were no treatment-related deaths and no marked differences in pharmacokinetics of combined paclitaxel and gemcitabine in historical comparison between co-administration and monotherapies.Conclusions: Nab-paclitaxel plus gemcitabine regimen showed highly promising efficacy with manageable safety profile under careful observation and with appropriate supportive care in Japanese patients with metastatic pancreatic cancer.Clinical Trial Number: JapicCTI-121987. [ABSTRACT FROM AUTHOR]

Background: Chk1 inhibitors have emerged as promising anticancer therapeutic agents particularly when combined with antimetabolites such as gemcitabine, cytarabine or hydroxyurea. Here, we address the importance of appropriate drug scheduling when gemcitabine is combined with the Chk1 inhibitor MK-8776, and the mechanisms involved in the schedule dependence.Methods: Growth inhibition induced by gemcitabine plus MK-8776 was assessed across multiple cancer cell lines. Experiments used clinically relevant "bolus" administration of both drugs rather than continuous drug exposures. We assessed the effect of different treatment schedules on cell cycle perturbation and tumor cell growth in vitro and in xenograft tumor models.Results: MK-8776 induced an average 7-fold sensitization to gemcitabine in 16 cancer cell lines. The time of MK-8776 administration significantly affected the response of tumor cells to gemcitabine. Although gemcitabine induced rapid cell cycle arrest, the stalled replication forks were not initially dependent on Chk1 for stability. By 18 h, RAD51 was loaded onto DNA indicative of homologous recombination. Inhibition of Chk1 at 18 h rapidly dissociated RAD51 leading to the collapse of replication forks and cell death. Addition of MK-8776 from 18-24 h after a 6-h incubation with gemcitabine induced much greater sensitization than if the two drugs were incubated concurrently for 6 h. The ability of this short incubation with MK-8776 to sensitize cells is critical because of the short half-life of MK-8776 in patients' plasma. Cell cycle perturbation was also assessed in human pancreas tumor xenografts in mice. There was a dramatic accumulation of cells in S/G₂ phase 18 h after gemcitabine administration, but cells had started to recover by 42 h. Administration of MK-8776 18 h after gemcitabine caused significantly delayed tumor growth compared to either drug alone, or when the two drugs were administered with only a 30 min interval.Conclusions: There are two reasons why delayed addition of MK-8776 enhances sensitivity to gemcitabine: first, there is an increased number of cells arrested in S phase; and second, the arrested cells have adequate time to initiate recombination and thereby become Chk1 dependent. These results have important implications for the design of clinical trials using this drug combination. [ABSTRACT FROM AUTHOR]

Background: Only a few clinical trials have been conducted in patients with advanced pancreatic cancer after failure of first-line gemcitabine-based chemotherapy. Therefore, there is no current consensus on the treatment of these patients. We conducted a randomised phase II study of the modified FOLFIRI.3 (mFOLFIRI.3; a regimen combining 5-fluorouracil (5-FU), folinic acid, and irinotecan) and modified FOLFOX (mFOLFOX; a regimen combining folinic acid, 5-FU, and oxaliplatin) regimens as second-line treatments in patients with gemcitabine-refractory pancreatic cancer.Methods: The primary end point was the 6-month overall survival rate. The mFOlFIRI.3 regimen consisted of irinotecan (70 mg m(-2); days 1 and 3), leucovorin (400 mg m(-2); day 1), and 5-FU (2000 mg m(-2); days 1 and 2) every 2 weeks. The mFOLFOX regimen was composed of oxaliplatin (85 mg m(-2); day 1), leucovorin (400 mg m(-2); day 1), and 5-FU (2000 mg m(-2); days 1 and 2) every 2 weeks.Results: Sixty-one patients were randomised to mFOLFIRI.3 (n=31) or mFOLFOX (n=30) regimen. The six-month survival rates were 27% (95% confidence interval (CI)=13-46%) and 30% (95% CI=15-49%), respectively. The median overall survival periods were 16.6 and 14.9 weeks, respectively. Disease control was achieved in 23% (95% CI=10-42%) and 17% patients (95% CI=6-35%), respectively. The number of patients with at least one grade 3/4 toxicity was identical (11 patients, 38%) in both groups: neutropenia (7 patients under mFOLFIRI.3 regimen vs 6 patients under mFOLFOX regimen), asthaenia (1 vs 4), vomiting (3 in both), diarrhoea (2 vs 0), and mucositis (1 vs 2).Conclusion: Both mFOLFIRI.3 and mFOLFOX regimens were tolerated with manageable toxicity, offering modest activities as second-line treatments for patients with advanced pancreatic cancer, previously treated with gemcitabine. [ABSTRACT FROM AUTHOR]

The high mobility group A1 (HMGA1) proteins are overexpressed in pancreatic cancers. They are architectural nuclear proteins, which regulate expression of multiple genes implicated in the malignant phenotype. In this study, we hypothesized that HMG A1 silencing will promote chemosensitivity in pancreatic adenocarcinoma. We studied highly malignant pancreatic adenocarcinoma cell lines (MiaPaCa2 and PANC1). Lentiviral short-hairpin RNA (shHMGA1) expression vectors targeting HMGA1 were used for generation of lentiviral particles. Stable transfectants were developed after lentiviral transduction. Nuclear expression of HMGA1 was assayed using Western blot analysis. Chemosensitivity to gemcitabine was determined by IC50 analysis. Caspase activity was quantitated using fluorometric caspase profiling. Apoptosis was assessed by flow cytometric analysis. Lentivirus-mediated RNA interference resulted in 90% silencing of HMGA1 expression in each of MiaPaCa2 and PANC1 cell lines. HMGA1 silencing enhanced chemosensitivity to gemcitabine with an approximately 50% reduction in IC50 in each cell line. Lentivirus-mediated HMGA1 silencing promoted the activation of caspases 3, 2, 9, and 8, on exposure to gemcitabine. HMGA1 silencing resulted in reduction in Akt kinase activity. Lentivirus-mediated RNA interference of HMGA1 promoted chemosensitivity to gemcitabine in pancreatic adenocarcinoma. HMGA1 may represent a novel therapeutic target in pancreatic cancer. [Copyright &y& Elsevier]

The safety and efficacy of gemcitabine and concurrent radiation to the upper abdomen followed by weekly gemcitabine in patients with resected pancreatic cancer was determined. Patients with resected adenocarcinoma of the pancreas were treated with intravenous gemcitabine administered twice-weekly (40 mg m(-2)) for 5 weeks concurrent with upper abdominal radiation (50.4 Gy in 5(1/2) weeks). At the completion of the chemoradiation, patients without disease progression were given gemcitabine (1000 mg m(-2)) weekly for two cycles. Each cycle consisted of 3 weeks of treatment followed by 1 week without treatment. Forty-seven patients were entered, 46 of whom are included in this analysis. Characteristics: median age 61 years (range 35-79); 24 females (58%); 73% stage T3/T4; and 70% lymph node positive. Grade III/IV gastrointestinal or haematologic toxicities were infrequent. The median survival was 18.3 months, while the median time to disease recurrence was 10.3 months. Twenty-four percent of patients were alive at 3 years. Only six of 34 patients with progression experienced local regional relapse as a component of the first site of failure. These results confirm the feasibility of delivering adjuvant concurrent gemcitabine and radiation to the upper abdomen. This strategy produced good local regional tumour control. [ABSTRACT FROM AUTHOR]

Background: To study the pharmacokinetics and clinical outcome of gemcitabine (2'-2'-difluoro-deoxcytidine [dFdC]) during intra-arterial versus intravenous delivery in locally advanced and regionally metastatic pancreatic cancer. Patients and methods: Seven patients with unresectable pancreatic cancer received escalating intra-arterial doses of gemcitabine ranging from 800 to 1400 mg/m², after selective embolisation of all pancreatic blood supply, except for the tumour-feeding arteries. Four patients received intravenous gemcitabine (control). Venous blood samples at different time intervals were taken throughout 270 minutes for pharmacokinetic analyses of gemcitabine and its inactive metabolite 2'-2'-difluorodeoxyuridine (dFdU). Results: Pharmacokinetic data revealed differences in plasma concentrations between intra-arterial and intravenous delivery routes. The plasma concentration-time curve of gemcitabine during and after cessation of intra-arterial pancreatic target administration through the proximal splenic artery showed a profile with an area under the plasma concentration-time curve from 0 to 270 minutes (intra-arterial 29.0 ± 0.4 vs intravenous 331.0 ± 2.7 ng • min/mL; p < 0.0001) and peak plasma concentration (intra-arterial 1.1 ± 0.2 vs intravenous 7.6 ± 2.0 ng/mL; p < 0.0001) significantly lower than that for the corresponding systemic intravenous route. A plot of ln (% of dose) versus time showed a bi-compartmentalised metabolic model for intravenous administration of gemcitabine, one indicating rapid conversion of gemcitabine to dFdU, and another at a significantly lower affinity resulting in no conversion. Hence, this could be the main reason why dFdU was not detected in the systemic circulation during pancreatic intra-arterial target delivery. Furthermore, during intravenous administration a pseudo first-order rate constant (≈0.20 min-1) for in vivo conversion of gemcitabine to dFdU was estimated, indicating a rapid cellular deamination which was not shown in the intra-arterial route. Clinically, one patient had a partial response and six patients had a stable disease after intra-arterial administration of gemcitabine. The median time to disease progression was 4 months and the median overall survival was 5 months. One patient survived for 26 months. No grade III or IV toxicity was documented. Conclusion: Intra-arterial administration of gemcitabine has a major advantage related to reduced toxicity as increasing the dose through this administration route will eventually result in pancreatic cellular drug target delivery prior to systemic availability. Despite the low number of patients recruited, the clinical results are encouraging and this approach should be tested in a randomised study. [ABSTRACT FROM AUTHOR]

Pancreatic cancer remains a highly chemoresistant malignancy. Gemcitabine, the most effective first-line agent available, acts by disrupting cellular replication. Caspases belong to a family of proteases that function as key components of the apoptotic death machinery. We investigated the mechanisms by which gemcitabine blocks proliferation and whether it can induce apoptosis in pancreatic cancer cells. Quiescent pancreatic cancer cells (BxPC-3) were stimulated to proliferate (10% fetal calf serum) with or without gemcitabine, PS-341 (26S proteasome inhibitor), or both. Proliferation was measured by MTT assay and apoptosis by propidium iodine staining. To determine activation of the apoptotic regulatory cell proteins, caspase-3 and cleavage of poly(ADP-ribose)polymerase (PARP) into its 85-kDa fragment were assessed by Western blotting. Gemcitabine at even low doses (10 μmol/L) significantly inhibited cellular proliferation, whereas PS-341 (10 nmol/L) had no effect. With combined treatment, PS-341 potentiated the antiproliferative effects of gemcitabine (P=0.001). At 48 hours, the apoptotic fraction was greatly enhanced by the presence of PS-341 compared with gemcitabine alone. Caspase-3 accumulated as early as 30 minutes and was associated with cleavage of PARP to its apoptotic fragment. Gemcitabine, a nucleoside analogue, may in part exert its antiproliferative effects by directing pancreatic cancer cells to a default pathway of apoptosis. 26S proteasome inhibition potentiates this effect, suggesting its potential clinical value against chemoresistance in pancreatic cancer. [Copyright &y& Elsevier]

Purpose: To investigate treatment of human pancreatic cancer cell lines and xenografts with combinations of Erbitux (IMC-C225) anti-epidermal growth factor receptor (EGFR) antibody, gemcitabine, and radiation.Methods and Materials: BxPC-3 and MiaPaCa-2 human pancreatic carcinoma cells were treated in vitro for 24 h with IMC-C225 (5 μg/mL), then exposed to epidermal growth factor (EGF) (10 mM) for 5 min. Immunoblots were screened for EGFR expression and the ability of IMC-C225 to block EGF-induced tyrosine phosphorylation of EGFR. Cells were treated with IMC-C225 (5 μg/mL) on Day 0, the IC50 dose of gemcitabine on Day 1 for 24 h, followed by 3 Gy 60Co irradiation on Day 2, or the combination of each agent. For cell proliferation, cells were counted on Day 4, and for apoptosis, cells were stained with annexin V-FITC and propidium iodide, then analyzed by FACS. Cells were treated with the same single or multiple treatments and analyzed in a clonogenic cell survival assay. The effect of IMC-C225, gemcitabine, and radiation on the growth of BxPC-3 and MiaPaCa-2 tumor xenografts was determined. Athymic nude mice bearing established s.c. tumor xenografts of 6–8 mm diameter received 6 weeks of treatment with IMC-C225 (1 mg every 3 days × 6) alone or in combination with gemcitabine (120 mg/kg i.v. every 6 days × 6), and 6 weekly fractions of 3 Gy radiation on the days after gemcitabine administration. Tumor growth was measured with Vernier calipers.Results: BxPC-3 and MiaPaCa-2 cell lines expressed low levels of EGFR. IMC-C225 inhibited EGF-induced tyrosine phosphorylation of the EGF receptor on both cell lines. Treatment of cells with a combination of IMC-C225 + gemcitabine + radiation produced the highest induction of apoptosis and inhibition of proliferation in vitro. Combination treatment with IMC-C225, gemcitabine, and radiation produced 100% complete regression of MiaPaCa-2 tumors for more than 250 days, and the greatest growth inhibition of BxPC-3 tumors compared to any single or dual treatments.Conclusions: The IMC-C225 therapy in combination with gemcitabine chemotherapy and radiation therapy demonstrated statistically significantly greater efficacy over the single and double combination therapies. This form of multimodality treatment shows potential clinical application in the treatment of pancreatic cancer in humans. [Copyright &y& Elsevier]

Background: Undifferentiated carcinoma (UC) of the pancreas is a rare subtype of pancreatic cancer. Although UC has been considered a highly aggressive malignancy, no clinical studies have addressed the efficacy of chemotherapy for unresectable UC. Therefore, we conducted multicenter retrospective study to investigate the efficacy of chemotherapy in patients with UC of the pancreas.Methods: This multicenter retrospective cohort study was conducted at 17 institutions in Japan between January 2007 and December 2017. A total of 50 patients treated with chemotherapy were analyzed.Results: The median overall survival (OS) in UC patients treated with chemotherapy was 4.08 months. The details of first-line chemotherapy were as follows: gemcitabine (n = 24), S-1 (n = 12), gemcitabine plus nab-paclitaxel (n = 6), and other treatment (n = 8). The median progression-free survival (PFS) was 1.61 months in the gemcitabine group, 2.96 months in the S-1 group, and 4.60 months in the gemcitabine plus nab-paclitaxel group. Gemcitabine plus nab-paclitaxel significantly improved PFS compared with gemcitabine (p = 0.014). The objective response rate (ORR) was 4.2% in the gemcitabine group, 0.0% in the S-1 group, and 33.3% in the gemcitabine plus nab-paclitaxel group. Gemcitabine plus nab-paclitaxel also showed a significantly higher ORR compared with both gemcitabine and S-1 (gemcitabine plus nab-paclitaxel vs. gemcitabine: p = 0.033; gemcitabine plus nab-paclitaxel vs. S-1: p = 0.034). A paclitaxel-containing first-line regimen significantly improved OS compared with a non-paclitaxel-containing regimen (6.94 months vs. 3.75 months, respectively; p = 0.041). After adjustment, use of a paclitaxel-containing regimen in any line was still an independent predictor of OS (hazard ratio for OS, 0.221; 95% confidence interval, 0.076-0.647; p = 0.006) in multiple imputation by chained equation.Conclusions: The results of the present study indicate that a paclitaxel-containing regimen would offer relatively longer survival, and it is considered a reasonable option for treating patients with unresectable UC. [ABSTRACT FROM AUTHOR]