Single-agent Gemcitabine Research Articles

Metuzumab enhanced chemosensitivity and apoptosis in non-small cell lung carcinoma

ABSTRACTTargeted therapeutics is used as an alternative treatment of non-small cell lung cancer (NSCLC); however, treatment effect is far from being satisfactory, and therefore identification of new targets is needed. We have previously shown that metuzumab inhibit tumor growth in vivo. The present study was performed to investigate the anti-tumor efficacy of metuzumab combined with gemcitabine and cisplatin (GP), paclitaxel and cisplatin (TP) or navelbine and cisplatin (NP) regimens in multiple NSCLC cell lines. Our results demonstrate that, in comparison to single agent metuzumab or GP treated cells, metuzumab combined with GP display inhibitory effects on tumor growth. Furthermore, we found that metuzumab elevated the sensitivity of cell lines to gemcitabine, which was identified by MTT assay. Flow cytometric analysis showed that metuzumab combined with gemcitabine (GEM) treatment led to an obvious G1 arrest and an elevated apoptosis in A549, NCI-H460 and NCI-H520 cells. Western blot analysis also demonstrated a significantly reduced level of cyclin D1, Bcl-2, and an obviously increase level of Bax and full-length caspase-3 in A549, NCI-H460 and NCI-H520 cells treated with metuzumab/gemcitabine combination in comparison with single agent treated cells. In addition, metuzumab/gemcitabine treated A549, NCI-H460 and NCI-H520 cells also demonstrated a significantly increase in deoxycytidine kinase (dCK) protein level compared with single agent metuzumab or gemcitabine treated cells. Xenograft models also demonstrated that this metuzumab/gemcitabine combination led to upregulation of dCK. Taken together, the mechanisms of metuzumab combined with GP repress tumor growth were that the combined treatment significantly inhibited the tumor cell proliferation, apoptosis and cell cycle in vitro and in vivo and at least partially by induction of dCK expression. Our results suggested that metuzumab could significantly enhance chemosensitivity of human NSCLC cells to gemcitabine. Metuzumab/gemcitabine combination treatment may be a potentially useful therapeutic regimen for NSCLC patients.

MTE27.01 Treatment of Lung Cancer Patients with Poor Performance Status

MTE27.01 Treatment of Lung Cancer Patients with Poor Performance Status

Abstract B62: Evaluation of scheduling for triple therapy gemcitabine/CHEK1 inhibitor/WEE1 inhibitor in pancreatic cancer models

Abstract Sensitization of cancer cells to gemcitabine (Gem) has been shown with checkpoint kinase CHEK1 (CHK1) and WEE1 inhibitors. Our aim is to determine, using in vitro and in vivo models, the optimal regime for application of the triple combination in pancreatic cancer. First, we have investigated the dual combinations of Gem + either CHEK1 or WEE1 inhibitors in growth inhibition assays in vitro. Synergistic growth inhibition was identified using both Bliss Independence and Loewe models, in MIA PaCa-2 cells at 10 – 30 nM Gem + 300 – 1000 nM CHEK1 inhibitor MK8776; or 10 – 30 nM Gem + 30 – 100 nM WEE1 inhibitor MK1775. The synergistic concentrations were submaximal, i.e. below the single agent GI50 concentrations, which were 30 nM for Gem, 6 μM for MK8776, and 500 nM for MK1775. The Panc-1 cell line is more resistant to Gem as a single agent, but synergy was evident: in colony forming assays the dual combination of either 30 nM gem + 300 nM MK1775 or 30 nM Gem + 1 μM MK8776 inhibited colony formation by 97 +/- 1.6 % and 91 +/- 2% respectively. Single agent Gem inhibited colony formation by only 23 +/- 4 % and MK1775 or MK8776 did not inhibit colony formation at these concentrations. Next, we investigated scheduling of the Gem/CHEK1i/Wee1i triple combination, at the synergistic concentrations, with kinetic live-cell imaging assays. MIA PaCa-2 cells treated continuously with 10 nM Gem plus 1 μM MK8776 showed durable growth inhibition over 72 hours. However, if both drugs were washed off after 24 hours the Gem + CHEK1i-treated cells recovered and began to proliferate within 24 hours. Different schedules of the trio were tested, and the most durable growth inhibition (> 5 days) was obtained when Gem + MK8776 were washed off at 24 hours and replaced with 300 nM MK1775, whereas 300 nM MK1775 in the absence of Gem + MK8776 pretreatment did not significantly inhibit growth, compared to control. Different scheduling options were also tested in Panc-1 cells in colony forming assays, and again the most effective schedule was Gem + MK8776 for 24 hours, followed by MK1775. MIA PaCa-2 xenograft studies are now underway, initially with the dual combination, to be followed with the drug trio of simultaneous Gem + MK8776, followed by MK1775. To reduce the likelihood of toxicity, Gem doses lower than the typical “full” dose (100 mg/kg IP twice per week) were tested. We found that 25 mg/kg Gem twice in a day (8h apart), twice per week was not well tolerated even as a single agent, but both 25 and 50 mg/kg Gem once in a day, twice per week was tolerated when co-dosed with 25 mg/kg MK8776, and when this combination was followed 8 hours later by 60 mg/kg MK1775 (OG). A pharmacokinetic study revealed that plasma Gem (dFdC) concentrations were not altered by co-dosing Gem with MK8776, but intratumor dFdCTP (the active intracellular metabolite of Gem) was elevated at 1 – 8 hours after the 25 mg/kg Gem + MK8776 dose (AUC0 –last 49 +/- 7.9 hr.pmoles/mg tissue) compared to mice with 25 mg/kg Gem alone (AUC0-last 21 +/- 2.6 hr.pmoles/mg tissue). CHEK1 target inhibition was demonstrated in vivo, with abrogation of Gem-induced CHEK1 S296 autophosphorylation for at least 4h post Gem + MK8776 dosing, using Western blot analyses of tumor lysate. There was also increased γH2AX and pRPA32 S4/8 at 4 - 8 hours post-dose with Gem + MK8776 compared to Gem alone, indicating enhanced DNA damage. Pharmacodynamic and efficacy studies with the triple combination, will determine whether enhanced efficacy can be observed, when compared to full dose, single agent gemcitabine (100 mg/kg IP twice per week). Citation Format: Siang-Boon Koh, Frances M. Richards, Yann Wallez, Duncan I. Jodrell.{Authors}. Evaluation of scheduling for triple therapy gemcitabine/CHEK1 inhibitor/WEE1 inhibitor in pancreatic cancer models. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B62.

Gemcitabine Single Agent for Recurrent Post Bladder Preservation Therapy and in Metastatic Transitional Cell Carcinoma of Urinary Bladder in Elderly Patients with Renal Impairment

Purpose : The objectives of the study are to evaluate efficacy (ORR, PFS, & OS) and toxicity of single-agent gemcitabine in recurrent post conservative therapy and in the metastatic transitional cell carcinoma of the urinary bladder in elderly patients with a renal impairment. Patients and Methods: Between March 2014 and September 2016 , Fourteen patients have recurrent post conservative therapy & in metastatic transitional cell cancer of the urinary bladder in elderly patients with renal impairment were included to receive single-agent gemcitabine (1,000 mg/m2) administered weekly times three on a 4-week cycle. The median age was 74.5 years. The majority of patients (57.2%) have metastatic disease at diagnosis also a majority of patients (57.2%) have a solitary metastatic disease. The median overall treatment period was 14 weeks (range: 4-24 weeks). Results: Overall response rate was 35.7% (CR 7.1% + PR 28.6%). Median-Progression Free Survival was 20 weeks (95% CI: 95% CI: 8.313- 31.687). Median Overall survival rates were 40 weeks (95% CI: 28.313-51.687). 50% of patients experienced at least one grade 1 or 2 neutropenia and 71.5% of patients developed thrombocytopenia and no patient (0%) required hospitalization during therapy for neutropenic fever or dehydration . 50% patients required treatment delayed at least one week due to treatment toxicity. Conclusion: The single agent Gemcitabine had significant improvement in response rate, progression-free survival and overall survival with good tolerance and manageable toxicity.

A modified regimen of biweekly gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer is both tolerable and effective: a retrospective analysis.

Treatment with nab-paclitaxel with gemcitabine demonstrates a survival advantage when compared with single-agent gemcitabine. However, the combination is associated with significant toxicities, leading to a high rate of drug discontinuation. We implemented a modified regimen of gemcitabine and nab-paclitaxel (mGNabP) in an attempt to minimize toxicities while maintaining efficacy. A total of 79 evaluable patients with metastatic pancreatic adenocarcinoma (mPC) treated with a modified regimen of gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 15 of every 28-day cycle were identified from our prospective database. A total of 57 patients received this regimen as first-line treatment and were evaluated for toxicities, progression-free survival (PFS), and overall survival (OS). Overall, 22 patients with advanced or metastatic PC treated with the modified regimen outside the first-line setting were only evaluated for toxicities. The median OS and PFS were 10 months [95% confidence interval (CI) 5.9-13 months] and 5.4 months (95% CI 4.1-7.4 months) for patients that received the modified regimen as first-line therapy. Neurotoxicity occurred in 27% with only 1.6% of patients experiencing grade ⩾3 toxicity. The incidence of grade ⩾3 neutropenia was 19%, resulting in growth factor support in 12% of patients. This rate was similar in patients who received the modified regimen for first-line treatment of mPC versus the overall group. A modified regimen of biweekly nab-paclitaxel with gemcitabine is associated with a lower cost, acceptable toxicity profile and appears to be relatively effective in pancreatic cancer. Prospective randomized studies confirming its potential benefits compared with standard weekly mGNabP are warranted.

Systemic Chemotherapy in Advanced Pancreatic Cancer

Pancreatic cancer remains one of the most lethal cancers. These patients often have multiple symptoms, and integrated supportive care is critical in helping them remain well for as long as possible. Fluorouracil-based chemotherapy is known to improve overall survival (OS) by approximately 3 months, compared to the best supportive care alone. A 1997 study comparing gemcitabine and fluorouracil treatment of advanced pancreatic cancer patients showed an improvement in OS of 1 month in patients receiving gemcitabine. Over the next 10 years, multiple randomized studies compared single-agent gemcitabine with combination chemotherapy and showed no effective survival improvement. However, the addition of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, was associated with a significant improvement in OS of approximately 2 weeks. However, adoption of this regimen has not been widespread because of its limited effect and added toxicity. Two clinical trials have recently prolonged OS in advanced pancreatic cancer patients by almost 1 year. The first compared FOLFIRINOX with gemcitabine alone, and was associated with a significant improvement in median survival. The second compared gemcitabine and nab-paclitaxel with gemcitabine alone, and was associated with improvements in OS. At present, these regimens are considered standard treatment for patients with good performance statuses.

Abstract A47: A patient-derived xenograft model of pancreatic cancer in mice to develop novel adjuvant therapies

Abstract Background: Eighty percent of patients with pancreatic ductal adenocarcinoma (PDAC) die from their disease within five years of surgical resection, likely due to presence of occult metastases at diagnosis. We have developed a patient-derived xenograft (PDX) model in mice to investigate the behavior of occult metastatic cells in the liver microenvironment and derive novel adjuvant therapies. Methods: Five PDAC tumors (215, 366, 608, 654 and 738) were resected from patients and implanted orthotopically in mice. Tumors were harvested, cell lines generated and transduced with luciferase, then injected into spleens of mice to generate microscopic liver metastases, then primary tumors removed via splenectomy. Bioluminescence imaging of mice and histologic analysis and flow cytometry of livers were utilized to characterize each tumor's distinct pattern of cell clearance and outgrowth kinetics. Affymetrix gene expression of tumors was performed. Mice were treated with adjuvant therapy following resection of primary tumors in the spleen and time-to-progression (TTP) and overall survival (OS) were measured. Results: Each PDX cell line demonstrated unique and reproducible clearance in the liver and outgrowth kinetics as measured by bioluminescence imaging. Distinct differences in gene expression were identified in tumors exhibiting rapid vs. delayed outgrowth. The MEK inhibitor trametinib (0.3 mg/kg oral daily) prolonged TTP and OS vs. control (OS - Tumor 608: 114 vs. 43 days, p<0.001; Tumor 366: MS not achieved vs. 167 days, p=0.0488). In a randomized preclinical trial, sequential therapy with gemcitabine followed by trametinib provided a survival advantage and increased TTP when compared with control and single agent gemcitabine treatment. Conclusions: This PDX PDAC model of occult metastasis allows characterization of hepatic clearance of tumor cells and outgrowth kinetics. Metastatic outgrowth appears to be dependent upon distinguishable tumor cell-specific factors. Trametinib effectively inhibits KRAS-MEK-ERK signaling, delays outgrowth of occult metastases and prolongs survival of mice. Utilization of this model will help further define the complex interaction of PDAC cells and the metastatic microenvironment of the liver. Citation Format: Matthew G. Mullen, Timothy E. Newhook, James M. Lindberg, Sara J. Adair, Edik M. Blais, Alex D. Michaels, Edward B. Stelow, Jason A. Papin, J. Thomas Parsons, Todd W. Bauer. A patient-derived xenograft model of pancreatic cancer in mice to develop novel adjuvant therapies. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A47.

The Role of MicroRNAs in Resistance to Current Pancreatic Cancer Treatment: Translational Studies and Basic Protocols for Extraction and PCR Analysis.

Pancreatic ductal adenocarcinoma (PDAC) is a common cause of cancer death and has the worst prognosis of any major malignancy, with less than 5 % of patients alive 5-years after diagnosis. The therapeutic options for metastatic PDAC have changed in the past few years from single agent gemcitabine treatment to combination regimens. Nowadays, FOLFIRINOX or gemcitabine with nab-paclitaxel are new standard combinations in frontline metastatic setting in PDAC patients with good performance status. MicroRNAs (miRNA) are small, noncoding RNA molecules affecting important cellular processes such as inhibition of apoptosis, cell proliferation, epithelial-to-mesenchymal transition (EMT), metastases, and resistance to common cytotoxic and anti-signaling therapy in PDAC. A functional association between miRNAs and chemoresistance has been described for several common therapies. Therefore, in this review, we summarize the current knowledge on the role of miRNAs in the resistance to current anticancer treatment used for patients affected by metastatic PDAC.

Gemcitabine-Based Chemoradiation in the Treatment of Locally Advanced Head and Neck Cancer: Systematic Review of Literature and Meta-Analysis.

Platinum-based concurrent chemoradiation (CCRT) improves locoregional control and overall survival of locoregionally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) when compared to radiotherapy alone, but this approach is hampered by significant toxicity. Therefore, alternative ways to enhance the radiation effects are worth investigating. Gemcitabine (2',2'-difluorodeoxycytidine), in addition to its activity against a variety of solid tumors, including SCCHN, is one of the most potent radiosensitizers, and it has an overall favorable safety profile. In this paper, the clinical experience with gemcitabine-based chemoradiation in the treatment of patients with LA-SCCHN is reviewed. We conducted a review of the literature on the clinical experience with radiotherapy combined with either single-agent gemcitabine or gemcitabine/cisplatin-based polychemotherapy for the treatment of patients with LA-SCCHN. We also searched abstracts in databases of major international oncology meetings from the last 20 years. A meta-analysis was performed to calculate pooled proportions with 95% confidence intervals (CIs) for complete response rate and grade 3-4 acute mucositis rate. A total of 13 papers were eligible for the literature review. For schedules using a gemcitabine dose intensity (DI) below 50 mg/m(2) per week, the complete response rate was 86% (95% CI, 74%-93%) with grade 3-4 acute mucositis rate of 38% (95% CI, 27%-50%) and acceptable late toxicity. In one of the studies employing such low DIs, survival data were provided showing a 3-year overall survival of 50%. Compared with DI ≥50 mg/m(2) per week, there was no difference in the complete response rate (71%; 95% CI, 55%-83%; p = .087) but a significantly higher (p < .001) grade 3-4 acute mucositis rate of 74% (95% CI, 62%-83%), often leading to treatment interruptions (survival data provided in 8 studies; 3-year overall survival, 27%-63%). Late toxicity comprising mainly dysphagia was generally underreported, whereas information about xerostomia and skin fibrosis was scarce. This review highlights the radiosensitizing potential of gemcitabine and suggests that even very low dosages (less than 50 mg/m(2) per week) provide a sufficient therapeutic ratio and therefore should be further investigated. Refinements in radiation schemes, including intensity-modulated radiation therapy, in combination with low-dose gemcitabine and targeted agents, such as cetuximab, are currently being investigated. Cisplatin-based concurrent chemoradiation (CCRT) has become the standard treatment of locally advanced head and neck cancer (LAHNC). This approach is hampered by significant toxicity. This paper reviews the studies using gemcitabine as an alternative radio-sensitizer for CCRT in patients with LAHNC. In this capacity, despite its mild intrinsic toxicity, gemcitabine comes with high rates of severe mucositis when used in dosages exceeding 50 mg/m(2) per week. CCRT with low-dose gemcitabine provides a sufficient therapeutic ratio, combining clinical activity, similar to the higher-dose regimens, with lower toxicity. Further investigation is warranted.

Gemcitabine in patients previously treated with platinum-containing chemotherapy for refractory thymic carcinoma: radiographic assessment using the RECIST criteria and the ITMIG recommendations

The key drugs for chemotherapy of thymic carcinoma are gradually being revealed in phase II and conventional retrospective studies. Gemcitabine is regarded as one of these key drugs according to the findings of clinical trials in which it was combined with capecitabine. However, the activity of single-agent gemcitabine concerning refractory thymic carcinoma remains unclear. We conducted a retrospective review of the medical records of refractory thymic carcinoma patients previously treated with platinum-containing chemotherapy between 1980 and 2014. Of all 11 patients in this study, the objective response rate regarding gemcitabine was 36.4% [95% confidence interval (CI) 15.2-64.6] using the RECIST criteria and the response criteria proposed by the ITMIG. The median progression-free survival time was 4.3months (95% CI 0.7-11.0). The survival time from the start of gemcitabine treatment was 28.5months (95% CI 5.5-47.8), and from the start of first-line chemotherapy was 46.5months (95% CI 7.3-47.8). Gemcitabine achieved a moderate response and has the potential to be used as a key drug for thymic carcinoma. Some patients treated with gemcitabine demonstrated prolonged cancer control even in later lines of chemotherapy.

Single Agent Gemcitabine As a Salvage Regimen in Patients with Relapsed/Refractory Hodgkin's Lymphoma after Autologous Stem Cell Transplantation

The aim of this study was to evaluate the efficacy and safety of gemcitabine as a salvage regimen in patients with relapsed or refractory Hodgkin's lymphoma after autologous stem cell transplantation (ASCT). Fifteen patients were enrolled. All patients had received ≥ 2 prior chemotherapy regimens, had an ECOG performance status ≤ 2, had adequate organ function and had undergone ASCT. Patients received intravenous gemcitabine (1000 mg/m2) on days 1 and 15, every 4 weeks. The median age was 26 years (range, 18-44) and 8 (53%) were female. Eight (53%) had primary refractory disease. All had previous platinum-based salvage chemotherapy (IIVP, 7; ICE, 5; DHAP, 3). All (100%) had relapsed/refractory disease following ASCT as their last treatment. Eleven (73%) had refractory/progressive disease after ASCT. None had previous brentuximab vedotin treatment. Median number of previous lines of chemotherapy was 2 (range, 2-3). Median number of gemcitabine cycles administered to the patients was 4 (range, 2-6). Treatment response was assessed with PET-CT in majority of the patients before and 2-3 cycles after gemcitabine, and those patients who demonstrated a response continued to receive a maximum of 6 courses of gemcitabine or bridged to allogeneic SCT. Of 15 patients, 1 (7%) had complete response, 5 (33%) had partial response and the remaining patients had refractory/progressive disease with an overall response rate of 40%. The median time to progression for responding patients was 3 months (range, 2-7 months). Two patients were successfully bridged to allogeneic SCT. Main toxicity was hematological. Grade ≥ 3 hematologic toxicity occurred in 8 patients: thrombocytopenia (40%), neutropenia (33%) and anemia (7%). Three patients had grade 4 thrombocytopenia and 2 had grade 4 neutropenia. Dose reduction was necessary in 3 patients and treatment cycle postponed in 2 patients because of hematological toxicity. Five patients (33%) needed G-CSF support. Two patients developed febrile neutropenia. No treatment-related deaths occurred. Gemcitabine was shown to be an active salvage regimen in patients with relapsed/refractory Hodgkin's lymphoma after ASCT, producing an overall response rate of 40%. Although, the median PFS time was short, some patients can be bridged to allogeneic SCT. Hematological toxicity was common. DisclosuresOff Label Use: Gemcitabine in Hodgkin's Lymphoma.

Lenalidomide Exhibits Activity in Mantle Cell Lymphoma through Increased NK Cell Mediated Cytotoxicity

Introduction: Lenalidomide (Len) is indicated for the treatment of relapsed/refractory (R/R) Mantle Cell Lymphoma (MCL) in the United States and Switzerland. Len binds to the cullin 4 ring E3 ubiquitin ligase complex resulting in ubiquitination and subsequent proteasomal degradation of lymphoid transcription factors Aiolos and Ikaros leading to stimulation of immune cells, such as T-cells. Clinical trial CC-5013-MCL-002 (NCT00875667) is a randomized open-label phase II study in R/R MCL patients in which Len was given orally at 25 mg/day on days 1-21 of each 28-day cycle until progression (N=170). The control arm consisted of investigator choice of single-agent rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine (N=84). We explored the immune effects of Len treatment in MCL patients enrolled in CC-5013-MCL-002 and further investigated our findings in in vitro MCL co-culture models. Methods: Peripheral blood samples for exploratory analysis were collected at Cycle 1 Day 1 (C1D1, pre-treatment), Cycle 1 Day 4 (C1D4), Cycle 2 Day 15 (C2D15) and at treatment discontinuation. Flow cytometric profiling of T, B and natural killer (NK) cell subsets was performed and differences were analyzed for correlation with clinical outcomes (response rate and progression free survival [PFS]). Cell dependent cytotoxicity was measured in 1) anti-CD3 stimulated peripheral blood mononuclear cells (PBMC) treated with vehicle or 1-10000 nM Len for 3 days and incubated with target tumor cells for an additional 4 hours followed by an apoptosis assay as measured by Annexin V/ToPro-3 flow cytometry and 2) negatively selected CD56+ NK cells stimulated with IL-2 and treated with Len (1 nM to 10 μM) for 18 hrs and incubated with target tumor cells for an additional 4 hours followed by apoptosis assay. Results: At baseline, no significant differences were observed in the absolute levels of immune subsets when comparing non-responders (NR) and responders (R) in either Len (NR=11, R=23) or control (NR=4, R=5) arms. However, in the Len arm, significantly elevated (adj. p The mechanism whereby NK cell modulation contributes to clinical benefit demonstrated by Len in patients was further explored in in vitro co-culture systems with MCL cell lines. Len treated PBMC co-cultured with Jeko-1, Granta-519, and Mino MCL cell lines resulted in 38-47.5% more apoptosis compared to DMSO (p≤0.001). We examined the effect of Len on Aiolos and Ikaros protein expression in CD56+ NK and CD3+ T cells within anti-CD3 antibody stimulated PBMCs treated with DMSO or various concentrations of Len (1 nM to 10 μM) for 72 hours. Degradation of both Aiolos (40%) and Ikaros (95%) was observed after drug treatment in CD56+ NK cells. Aiolos and Ikaros levels were also monitored in CD3+ T cells and showed decreased levels after Len treatment, consistent with previous reports (Gandhi, 2014; Kronke, 2014). Furthermore, purified CD56+ NK cell mediated cytotoxicity produced a similar pro-apoptotic effect as the PBMC assay in all MCL cell lines versus DMSO (p≤0.01). Supernatants from co-cultures of NK cells with MCL cell lines showed significantly elevated granzyme B levels as compared to DMSO controls (p≤0.0001), suggesting that the apoptotic effects observed are induced by granzyme B. Conclusions: Lenalidomide is an immune modulating agent and NK cell modulation in particular may play a role in its clinical activity in MCL. A significant increase in proportions of NK cell subsets (vs total lymphocytes) at C1D4 versus baseline was observed and is a potential response indicator of favorable clinical outcome in R/R MCL patients treated with Len. In vitro, Len enhances cell mediated cytotoxicity of MCL cell lines in two co-culture model systems. Understanding NK cell mediated mechanism(s) has potential to enhance guiding patient selection strategies and rational combination therapies of lenalidomide in MCL. Disclosures Hagner:Celgene: Employment, Equity Ownership. Chiu:Celgene: Employment, Equity Ownership. Ortiz-Estevez:Celgene: Employment, Equity Ownership. Biyukov:Celgene: Employment, Equity Ownership. Brachman:Celgene: Employment, Equity Ownership. Trneny:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, expenses, Research Funding. Morschhauser:Genentech Inc./Roche: Other: Advisory boards. Stilgenbauer:AbbVie, Amgen, Boehringer-Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Roche: Consultancy, Honoraria, Research Funding. Milpied:Celgene: Honoraria, Research Funding. Musto:Sandoz: Consultancy; Celgene: Honoraria; Roche: Honoraria; Sanofi: Consultancy; Genzyme: Consultancy; Novartis: Honoraria; Janssen: Honoraria; Mundipharma: Honoraria. Martinelli:AMGEN: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; ROCHE: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy. Heise:Celgene: Employment, Equity Ownership. Daniel:Celgene: Employment, Equity Ownership. Chopra:Celgene: Employment, Equity Ownership. Carmichael:Celgene: Employment, Equity Ownership. Trotter:Celgene Corporation: Employment. Gandhi:Celgene: Employment, Equity Ownership. Thakurta:Celgene Corporation: Employment, Equity Ownership.

Current Treatment Options for Metastatic Pancreatic Adenocarcinoma.

Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death and have extremely poor prognosis. Although, declining trends for some major cancers, death rates are rising in both sexes for pancreatic cancer. Surgical resection is the only curative treatment of pancreatic cancer, but only 10 to 20 percent of patients are candidates for curative surgery. Fifty to sixty percent of patients with pancreatic cancer diagnosed in metastatic stage and 5-year overall survival (OS) rate is less than 5% for metastatic pancreatic cancer. Gemcitabine was the first chemotherapeutic agent that superior to 5-Fluorouracil. In most of the phase II trials combination gemcitabine with cytotoxic chemotherapy or targeted therapy showed promising results, but phase III trials with gemcitabine in combination with cisplatin, oxaliplatin, capacitabine, pemetrexed, irinotecan, bevacizumab, aflibercept, axitinib and cetuximab failed to improve primary endpoint OS. Monotherapy with S-1 demonstrated noninferiority to gemcitabine in OS and S-1 approved for pancreatic cancer in Japan. In a randomized phase II/III ACCORD trial median progression free survival (PFS), response rate (RR), median OS and quality of life were significantly prolonged in FOLFIRINOX arm compared to gemcitabine alone arm. In phase III (MPACT) trial, like FOLFIRINOX regimen, median PFS, RR and OS significantly prolonged with the combination nab-paclitaxel and gemcitabine compared to gemcitabine arm alone. As a targeted agent erlotinib is the first and only agent that demostrate signifiacnt activity with gemcitabine combination in patients with metastatic pancreatic cancer. Gemcitabine plus erlotinib combination significantly prolonged PFS and OS compared to gemcitabine alone arm. Although some combination regimens showed significant OS benefit compared to single-agent gemcitabine, the median OS was less than 1 year. On these grounds, future directions are needed to integrate new targeted agents and combination protocols for metastatic pancreatic cancer.

Evaluation of low-dose fractionated radiation therapy as a chemopotentiator of gemcitabine in advanced pancreatic cancer: results from an international multi-institutional phase II trial

Potentiation of systemic dosing of gemcitabine using very low-dose fractionated radiotherapy may improve its effect in advanced pancreatic cancer without additional toxicity as suggested by the results of our multi-institutional phase II study. Future regimens combining low-dose fractionated radiotherapy (RT) with systemic chemotherapy should be assessed for improving the chemotherapeutic benefit. Until recently, gemcitabine was considered the standard treatment for advanced pancreatic cancer despite low response rates. Efforts to improve response rates by combination therapies have had limited success and have involved using sub-systemic dosing of gemcitabine as a sensitizer for radiation. A novel paradigm, utilizing low-dose fractionated radiotherapy (LDFRT) as a potentiator of full-dose gemcitabine instead, was explored to assess safety and efficacy in treating advanced pancreatic cancer. Patients with locally advanced and metastatic pancreatic cancer were treated with 4 cycles of gemcitabine and LDFRT in a multi-institutional phase II study. Gemcitabine (1250 mg/m2 over 2 h) was administered on days 1 and 8 of a 21-day cycle. LDFRT fields included the upper abdomen from the diaphragm to the iliac crest and were administered at 60 cGy per fraction twice daily on days 1, 2, 8, and 9, with the morning fraction being delivered prior to gemcitabine infusion on days 1 and 8. Primary endpoint was objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Thirty-eight patients were enrolled in the trial, of which 23 had metastatic disease at time of enrollment. Objective response rate (CR + PR) was 8 %, and 61 % had at least stable disease. Overall median survival was 13 months and 1-year survival was 37 %. Patients with non-metastatic disease had a 1-year survival of 60 %. The most significant toxicity was hematologic, and only 3 patients were withdrawn from protocol due to toxicity. There was no reported febrile neutropenia. The use of LDFRT with systemic gemcitabine is safe, tolerable, and potentially effective. In advanced pancreatic cancer, where response rates with single-agent gemcitabine have been low, this chemopotentiation paradigm may improve survival among a poor prognostic patient cohort.

1318 A randomized controlled trial of recombinant human endostatin combined with single-agent gemcitabine in the first-line treatment of the elderly patients with advanced non-small cell lung cancer

1318 A randomized controlled trial of recombinant human endostatin combined with single-agent gemcitabine in the first-line treatment of the elderly patients with advanced non-small cell lung cancer

2255 Safety and effectiveness of the combination of single chemotherapeutic agent (gemcitabine) with radiotherapy in radically resected pancreatic adenocarcinoma

2255 Safety and effectiveness of the combination of single chemotherapeutic agent (gemcitabine) with radiotherapy in radically resected pancreatic adenocarcinoma

Abstract 408: ACP-196, an orally bioavailable covalent selective inhibitor of Btk, modulates the innate tumor microenvironment, exhibits antitumor efficacy and enhances gemcitabine activity in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma exists in a complex desmoplastic microenvironment that provides stromal support for tumor growth and conceals the tumor from immune surveillance. Tumor-associated stroma comprises a mix of fibroblasts, immunosuppressive T regulatory cells (Tregs), myeloid suppressive monocytes (MDSCs) and tumor-associated macrophages (TAMs) that promote tumor growth and restrain immune-mediated tumor cell killing. The targeting of immune infiltrates may impair stromal support and enhance immune-mediated killing of pancreatic cancer cells. Bruton's tyrosine kinase (Btk) is a nonreceptor enzyme in the Tec kinase family expressed among cells of hematopoietic origin including B cells, myeloid cells, mast cells and platelets, but not T cells, where it regulates multiple cellular processes. Here we describe an unexpected finding of ACP-196, a potent, novel, second generation Btk inhibitor with improved selectivity and target coverage that binds covalently to a cysteine residue (Cys481) in the front position of the ATP-binding pocket. In an orthotopic mouse model of pancreatic cancer, KPC derived pancreatic cancer cells (KrasG12D; Trp53R172H; Pdx1-Cre) were injected into the pancreases. Vehicle, single agent ACP-196 (15 mg/kg/BID, gavage), single agent gemcitabine (50 mg/kg, IV) and combination ACP-196 with gemcitabine were evaluated for efficacy. By 4 weeks of treatment, mice in the vehicle group showed signs of health deterioration and all mice were euthanized, tumors were collected and measured. Relative to the vehicle treatment, ACP-196 monotherapy resulted in a &amp;gt;2-fold reduction in tumor growth compared with less than a 2-fold reduction with gemcitabine alone. The combination of ACP-196 and gemcitabine resulted in a further reduction in tumor growth when compared to each single agent. Interestingly, analysis of tumor tissues showed that single agent ACP-196 inhibited immunosuppressive populations of TAMs and MDSCs. Surprisingly, Treg populations were also reduced with a robust expansion of CD8+ T cells in the tumors. None of these effects were observed with gemcitabine alone. Although Btk is not expressed in T cells, this finding maybe the result of inhibiting the MDSC and TAM populations within the tumor microenvironment, a mechanism of action which is currently under investigation. Taken together, these data identify Btk as a novel target for modulating tumor immune escape and suggest that pharmacologic targeting of suppressive myeloid cells by ACP-196 induces therapeutic benefit. ACP-196 is currently being evaluated in clinical trials including frontline and salvage pancreatic cancer. Citation Format: Brian J. Lannutti, Michael Gulrajani, Fanny Krantz, Elena Bibikova, Todd Covey, Katti Jessen, Wayne Rothbaum, David M. Johnson, Roger Ulrich. ACP-196, an orally bioavailable covalent selective inhibitor of Btk, modulates the innate tumor microenvironment, exhibits antitumor efficacy and enhances gemcitabine activity in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 408. doi:10.1158/1538-7445.AM2015-408

A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer

Masitinib is a selective oral tyrosine-kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m(2)) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic. Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl-CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the 'ACOX1' subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the 'pain' subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable. The present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation. ClinicalTrials.gov:NCT00789633.

Management of the Primary Tumor and Limited Metastases in Patients With Metastatic Pancreatic Cancer

New combinations of cytotoxic chemotherapy have been proven to increase response rates and survival times compared with single-agent gemcitabine for patients with metastatic pancreatic cancer. These responses have been dramatic for a subset of patients, therefore raising questions about the management of limited metastatic disease with surgery or other ablative methods. Similarly, for patients having a complete radiographic response to chemotherapy in the metastatic compartment, whether to consider local therapy in the form of radiation or surgery for the primary tumor is now an appropriate question. Therefore, collaboration among experts in surgery, medical oncology, and radiation oncology has led to the development of guiding principles for local therapies to the primary intact pancreatic tumor for patients with limited metastatic disease and those who have had a significant response after systemic therapy.

Prognostic factors and sites of metastasis in unresectable locally advanced pancreatic cancer.

Due to differences in natural history and therapy, clinical trials of patients with advanced pancreatic cancer have recently been subdivided into unresectable locally advanced pancreatic cancer (LAPC) and metastatic disease. We aimed to evaluate prognostic factors in LAPC patients who were treated with first-line chemotherapy and describe patterns of disease progression. Patients with LAPC who initiated first-line palliative chemotherapy, 2001–2011 at the BC Cancer Agency were included. A retrospective chart review was conducted to identify clinicopathologic variables, treatment, and subsequent sites of metastasis. Kaplan–Meier and Cox-regression survival analyses were performed. A total of 244 patients were included in this study. For the majority of patients (94.3%), first-line therapy was single-agent gemcitabine. About 144 (59%) patients developed distant metastatic disease and the most frequent metastatic sites included peritoneum/omentum (42.3%), liver (41%), lungs (13.9%), and distant lymph nodes (9%). Median overall survival (OS) for the entire cohort was 11.7 months (95% CI, 10.6–12.8). Development of distant metastases was associated with significantly inferior survival (HR 3.56, 95% CI 2.57–4.93), as was ECOG 2/3 versus 0/1 (HR 1.69, 95% CI 1.28–2.23), CA 19.9 > 1000 versus ≤1000 (HR 1.59, 95% CI 1.19–2.14) and female gender, (HR 1.57, 95% CI 1.19–2.08). In this population-based study, 41% of LAPC patients treated with first-line chemotherapy died without evidence of distant metastases. Prognostic factors for LAPC were baseline performance status, elevated CA 19.9, gender, and development of distant metastasis. Results highlight the heterogeneity of LAPC and the importance of locoregional tumor control.