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Background: The prognosis of patients with advanced biliary tract cancer who have progressed on gemcitabine plus cisplatin is dismal. We aimed to investigate the efficacy and safety of second-line liposomal irinotecan plus fluorouracil and leucovorin in patients with metastatic biliary tract cancer that has progressed on gemcitabine plus cisplatin.Methods: This multicentre, open-label, randomised, phase 2b (NIFTY) study was done at five academic institutions in South Korea and included patients aged 19 years or older with histologically or cytologically confirmed metastatic biliary tract cancer that had progressed on first-line gemcitabine plus cisplatin and an Eastern Cooperative Oncology Group performance status of 0 or 1. By use of an interactive web-based response system integrated with an electronic data capture system, patients were randomly assigned (1:1) using permuted blocks (block size 4) to receive either intravenous liposomal irinotecan (70 mg/m2 for 90 min) plus intravenous leucovorin (400 mg/m2 for 30 min) and intravenous fluorouracil (2400 mg/m2 for 46 h) every 2 weeks or leucovorin and fluorouracil only every 2 weeks, and were stratified by primary tumour site, previous surgery with curative intent, and participating centre. Study treatment was continued until the patient had disease progression or unacceptable toxicities, or withdrew consent. The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival. The primary endpoint and safety were assessed in the full analysis set and the safety analysis set, respectively, both of which comprised all randomly assigned patients who received at least one dose of the study treatment. This trial is registered with ClinicalTrials.gov, NCT03524508, and enrolment is complete.Findings: Between Sept 5, 2018, and Feb 18, 2020, 193 patients were screened for eligibility, of whom 174 (88 in the liposomal irinotecan plus fluorouracil and leucovorin group and 86 in the fluorouracil plus leucovorin group) were enrolled and included in the full analysis and safety analysis sets. At a median follow-up of 11·8 months (IQR 7·7-18·7), the median BICR-assessed progression-free survival was significantly longer in the liposomal irinotecan plus fluorouracil and leucovorin group (7·1 months, 95% CI 3·6-8·8) than in the fluorouracil and leucovorin group (1·4 months, 1·2-1·5; hazard ratio 0·56, 95% CI 0·39-0·81; p=0·0019). The most common grade 3-4 adverse events were neutropenia (21 [24%] of 88 in the liposomal irinotecan plus fluorouracil and leucovorin group vs one [1%] of 86 in the fluorouracil and leucovorin group) and fatigue or asthenia (11 [13%] vs three [3%]). Serious adverse events occurred in 37 (42%) patients receiving liposomal irinotecan plus fluorouracil and leucovorin and 21 (24%) patients receiving fluorouracil and leucovorin. There were no treatment-related deaths.Interpretation: Adding liposomal irinotecan to fluorouracil and leucovorin significantly improved BICR-assessed progression-free survival in patients with advanced biliary tract cancer. Liposomal irinotecan plus fluorouracil and leucovorin could be considered a standard-of-care second-line therapy for advanced biliary tract cancer.Funding: Servier and HK inno.N Translation: For the Korean translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

Background: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours.Methods: We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m2, gemcitabine 875 mg/m2 and cisplatin 60 mg/m2.Results: Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m2 (days 2 and 9) + gemcitabine 1000 mg/m2 (days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease.Conclusions: Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs.Clinical Trial Identifier: NCT02157792. [ABSTRACT FROM AUTHOR]

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]

Tumour-associated macrophages have been implicated in pancreatic ductal adenocarcinoma (PDAC) therapy response and Extracellular vesicles (EVs) shed by macrophages might have a role in this process. Here, we demonstrated that large EVs released by anti-inflammatory human macrophages decreased PDAC cellular sensitivity to gemcitabine. Using proteomic analysis, chitinase 3-like-1 (CHI3L1) and fibronectin (FN1) were identified as two of the most abundant proteins in the cargo of macrophages-derived EVs. Overexpression of CHI3L1 and FN1, using recombinant human proteins, induced PDAC cellular resistance to gemcitabine through ERK (extracellular-signal-regulated kinase) activation. Inhibition of CHI3L1 and FN1 by pentoxifylline and pirfenidone, respectively, partially reverted gemcitabine resistance. In PDAC patient samples, CHI3L1 and FN1 were expressed in the stroma, associated with the high presence of macrophages. The Cancer Genome Atlas analysis revealed an association between CHI3L1 and FN1 gene expression, overall survival of PDAC patients, gemcitabine response, and macrophage infiltration. Altogether, our data identifies CHI3L1 and FN1 as potential targets for pharmacological inhibition in PDAC. Further pre-clinical in vivo work is warranted to study the possibility of repurposing pentoxifylline and pirfenidone as adjuvant therapies for PDAC treatment. [ABSTRACT FROM AUTHOR]

Aberrant glycosylation in pancreatic cancer has been linked to cancer development, progression and chemoresistance. However, the role of glycogene, such as galactosyltransferase, in pancreatic cancer remains unknown. Herein, we establish beta-1.4-galactosyltransferase 1 (B4GALT1) as a clinical marker and regulator of chemoresistance. Clinically, high B4GALT1 expression correlates with poor survival, enhanced tumor size, increased lymph node metastasis, elevated cancer progression and enhanced incidence of relapse in PDAC patients. Expression of B4GALT1 is up-regulated in gemcitabine resistant patient derived organoids as well as chemoresistant cancer cell lines, while genetic perturbation of its expression in PDAC cell lines regulates cancer progression and chemoresistance. Mechanistically, we show that elevated p65 activity transcriptionally up-regulates B4GALT1 expression, which then interacts with and stabilizes cyclin dependent kinase 11 isomer CDK11p110 protein via N-linked glycosylation, in order to promote cancer progression and chemoresistance. Finally, depletion of B4GALT1 rescues the response of chemoresistant cells to gemcitabine in an orthotopic PDAC model. Overall, our data uncovers a mechanism by which p65-B4GALT1-CDK11p110 signalling axis determines cancer progression and chemoresistance, providing a new therapeutic target for an improved pancreatic cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model.Methods: We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer.Results: Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes.Conclusions: Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine. [ABSTRACT FROM AUTHOR]

Background: The Phase 2 SCALOP trial compared gemcitabine with capecitabine-based consolidation chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC).Methods: Thirty-five systematically identified circulating biomarkers were analysed in plasma samples from 60 patients enroled in SCALOP. Each was measured in triplicate at baseline (prior to three cycles of gemcitabine-capecitabine induction chemotherapy) and, for a subset, prior to CRT. Association with overall survival (OS) was determined using univariable Cox regression and optimal thresholds delineating low to high values identified using time-dependent ROC curves. Independence from known prognostic factors was assessed using Spearman correlation and the Wilcoxon rank sum test prior to multivariable Cox regression modelling including independent biomarkers and known prognostic factors.Results: Baseline circulating levels of C-C motif chemokine ligand 5 (CCL5) were significantly associated with OS, independent of other clinicopathological characteristics. Patients with low circulating CCL5 (CCL5low) had a median OS of 18.5 (95% CI 11.76-21.32) months compared to 11.3 (95% CI 9.86-15.51) months in CCL5high; hazard ratio 1.95 (95% CI 1.04-8.65; p = 0.037).Conclusions: CCL5 is an independent prognostic biomarker in LAPC. Given the known role of CCL5 in tumour invasion, metastasis and the induction of an immunosuppressive micro-environment, targeting of CCL5-mediated pathways may offer therapeutic potential in pancreatic cancer.Clinical Trial Registration: The SCALOP trial was registered with ISRCTN, number 96169987 (registered 29 May 2008). [ABSTRACT FROM AUTHOR]

Background: The Wee1 (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in patients with ovarian cancer.Methods: In this double-blind, randomised, placebo-controlled, phase 2 trial, women with measurable recurrent platinum-resistant or platinum-refractory high-grade serous ovarian cancer were recruited from 11 academic centres in the USA and Canada. Women were eligible if they were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, a life expectancy of more than 3 months, and normal organ and marrow function. Women with ovarian cancer of non-high-grade serous histology were eligible for enrolment in a non-randomised exploratory cohort. Eligible participants with high-grade serous ovarian cancer were randomly assigned (2:1), using block randomisation (block size of three and six) and no stratification, to receive intravenous gemcitabine (1000 mg/m2 on days 1, 8, and 15) with either oral adavosertib (175 mg) or identical placebo once daily on days 1, 2, 8, 9, 15, and 16, in 28-day cycles until disease progression or unacceptable toxicity. Patients and the team caring for each patient were masked to treatment assignment. The primary endpoint was progression-free survival. The safety and efficacy analysis population comprised all patients who received at least one dose of treatment. The trial is registered with ClinicalTrials.gov, NCT02151292, and is closed to accrual.Findings: Between Sept 22, 2014, and May 30, 2018, 124 women were enrolled, of whom 99 had high-grade serous ovarian cancer and were randomly assigned to adavosertib plus gemcitabine (65 [66%]) or placebo plus gemcitabine (34 [34%]). 25 women with non-high-grade serous ovarian cancer were enrolled in the exploratory cohort. After randomisation, five patients with high-grade serous ovarian cancer were found to be ineligible (four in the experimental group and one in the control group) and did not receive treatment. Median age for all treated patients (n=119) was 62 years (IQR 54-67). Progression-free survival was longer with adavosertib plus gemcitabine (median 4·6 months [95% CI 3·6-6·4] with adavosertib plus gemcitabine vs 3·0 months [1·8-3·8] with placebo plus gemcitabine; hazard ratio 0·55 [95% CI 0·35-0·90]; log-rank p=0·015). The most frequent grade 3 or worse adverse events were haematological (neutropenia in 38 [62%] of 61 participants in the adavosertib plus gemcitabine group vs ten [30%] of 33 in the placebo plus gemcitabine group; thrombocytopenia in 19 [31%] of 61 in the adavosertib plus gemcitabine group vs two [6%] of 33 in the placebo plus gemcitabine group). There were no treatment-related deaths; two patients (one in each group in the high-grade serous ovarian cancer cohort) died while on study medication (from sepsis in the experimental group and from disease progression in the control group).Interpretation: The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. This therapeutic approach might be applicable to other tumour types with high replication stress; larger confirmatory studies are required.Funding: US National Cancer Institute Cancer Therapy Evaluation Program, Ontario Institute for Cancer Research, US Department of Defense, Princess Margaret Cancer Foundation, and AstraZeneca. [ABSTRACT FROM AUTHOR]

Background: Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose.Methods: This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing.Findings: Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0-19·4; cohort B1 22·0 months [21·4-22·7], cohort B2 18·2 months [17·0-18·9], cohort C1 17·9 months [14·3-19·7], cohort C2 15·9 months [12·7-16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3-4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2).Interpretation: APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population.Funding: Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb. [ABSTRACT FROM AUTHOR]

Background: Gram-negative bacteria mediated gemcitabine resistance in pre-clinical models. We determined if intratumoural lipopolysaccharide (LPS) detection by immunohistochemistry is associated with outcome in advanced pancreatic ductal adenocarcinoma (PDAC) treated with gemcitabine and non-gemcitabine containing 1st-line chemotherapy.Methods: We examined LPS on tumour tissue from 130 patients treated within the randomised AIO-PK0104 trial and a validation cohort (n = 113) and analysed the association of LPS detection to patient outcome according to treatment subgroups.Results: In 24% of samples from the AIO-PK0104 study LPS was detected; in LPS-positive patients median OS was 4.4 months, compared to 7.3 months with LPS negative tumours (HR 1.732, p = 0.010). A difference in OS was detected in 1st-line gemcitabine-treated patients (n = 71; HR 2.377, p = 0.002), but not in the non-gemcitabine treatment subgroup (n = 59; HR 1.275, p = 0.478). Within the validation cohort, the LPS positivity rate was 23%, and LPS detection was correlated with impaired OS in the gemcitabine subgroup (n = 94; HR 1.993, p = 0.008) whereas no difference in OS was observed in the non-gemcitabine subgroup (n = 19; HR 2.596, p = 0.219).Conclusions: The detection of intratumoural LPS as surrogate marker for gram-negative bacterial colonisation may serve as a negative predictor for gemcitabine efficacy in advanced PDAC.Clinical Trial Registry: The Clinical trial registry identifier is NCT00440167. [ABSTRACT FROM AUTHOR]

Background: Personalised medicine strategies may improve outcomes in pancreatic ductal adenocarcinoma (PDAC), but validation of predictive biomarkers is required. Having developed a clinical trial to assess the ATR inhibitor, AZD6738, in combination with gemcitabine (ATRi/gem), we investigated ATM loss as a predictive biomarker of response to ATRi/gem in PDAC.Methods: Through kinase inhibition, siRNA depletion and CRISPR knockout of ATM, we assessed how ATM targeting affected the sensitivity of PDAC cells to ATRi/gem. Using flow cytometry, immunofluorescence and immunoblotting, we investigated how ATRi/gem synergise in ATM-proficient and ATM-deficient cells, before assessing the impact of ATM loss on ATRi/gem sensitivity in vivo.Results: Complete loss of ATM function (through pharmacological inhibition or CRISPR knockout), but not siRNA depletion, sensitised to ATRi/gem. In ATM-deficient cells, ATRi/gem-induced replication catastrophe was augmented, while phospho-Chk2-T68 and phospho-KAP1-S824 persisted via DNA-PK activity. ATRi/gem caused growth delay in ATM-WT xenografts in NSG mice and induced regression in ATM-KO xenografts.Conclusions: ATM loss augments replication catastrophe-mediated cell death induced by ATRi/gem and may predict clinical responsiveness to this combination. ATM status should be carefully assessed in tumours from patients with PDAC, since distinction between ATM-low and ATM-null could be critical in maximising the success of clinical trials using ATM expression as a predictive biomarker. [ABSTRACT FROM AUTHOR]

Background: The efficacy and safety of the anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab, as compared with those of platinum-based chemotherapy, as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC) with PD-L1 expression are not known.Methods: We conducted a randomized, open-label, phase 3 trial involving patients with metastatic nonsquamous or squamous NSCLC who had not previously received chemotherapy and who had PD-L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune cells as assessed by the SP142 immunohistochemical assay. Patients were assigned in a 1:1 ratio to receive atezolizumab or chemotherapy. Overall survival (primary end point) was tested hierarchically according to PD-L1 expression status among patients in the intention-to-treat population whose tumors were wild-type with respect to EGFR mutations or ALK translocations. Within the population with EGFR and ALK wild-type tumors, overall survival and progression-free survival were also prospectively assessed in subgroups defined according to findings on two PD-L1 assays as well as by blood-based tumor mutational burden.Results: Overall, 572 patients were enrolled. In the subgroup of patients with EGFR and ALK wild-type tumors who had the highest expression of PD-L1 (205 patients), the median overall survival was longer by 7.1 months in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months; hazard ratio for death, 0.59; P = 0.01). Among all the patients who could be evaluated for safety, adverse events occurred in 90.2% of the patients in the atezolizumab group and in 94.7% of those in the chemotherapy group; grade 3 or 4 adverse events occurred in 30.1% and 52.5% of the patients in the respective groups. Overall and progression-free survival favored atezolizumab in the subgroups with a high blood-based tumor mutational burden.Conclusions: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type. (Funded by F. Hoffmann-La Roche/Genentech; IMpower110 ClinicalTrials.gov number, NCT02409342.). [ABSTRACT FROM AUTHOR]

Purpose: The use of concurrent doublet chemotherapy with radiation for locoregionally advanced cervical cancer (LACC) is limited by gastrointestinal and hematologic toxicity. By reducing radiation dose to bowel and bone marrow, image guided intensity modulated radiation therapy (IG-IMRT) may improve chemotherapy tolerance. The goal of this study was to determine whether IG-IMRT could lead to improved tolerance to concurrent cisplatin and gemcitabine for LACC.Methods and Materials: We conducted an open-label, nonrandomized, prospective phase 1 dose escalation trial at a tertiary academic cancer center (ClinicalTrials.gov identifier: NCT01554410). We enrolled patients with stage IB-IVA cervical cancer, with either an intact cervix or posthysterectomy with residual/recurrent pelvic or paraortic nodal involvement, undergoing radical pelvic or extended field chemoradiation therapy. Treatment consisted of chemoradiation with IG-IMRT (45-47.6 Gy, 25-28 fractions to the pelvis ± paraortic nodes with simultaneous nodal boost to 53.2-59.4 Gy, 28 fractions) plus 5 cycles of concurrent weekly cisplatin 40 mg/m2 with escalating doses of gemcitabine (50, 75, 100, or 125 mg/m2). Cohorts were separated preregistration according to whether the patient received pelvic or extended field IG-IMRT and whether gemcitabine followed (CG) or preceded (GC) cisplatin delivery. Dose-limiting toxicity (DLT) events were monitored up to 30 days after chemoradiation therapy. The primary endpoint was maximum tolerated dose (MTD) resulting in DLT probability ≤20%.Results: Between February 2011 and June 2019, 35 patients were registered. Overall, 7 patients (20.0%) experienced DLTs. For the pelvic field cohort, the estimated MTD was 100 mg/m2 with GC sequencing, which is higher than the previously reported MTD for this regimen. The extended field cohort was closed after 2 of 3 patients experienced a DLT at the first dose level.Conclusions: IG-IMRT can permit higher doses of concurrent gemcitabine with cisplatin and pelvic radiation for LACC. However, acute toxicity remains a factor with this regimen, depending on radiation volume and chemotherapy sequencing. [ABSTRACT FROM AUTHOR]

Background: Patients with borderline resectable pancreatic cancer (BRPC) have poor prognosis with upfront surgery.Methods: This was a single-arm Phase 2 trial for clinical and biomarker analysis. The primary endpoint is 1-year progression-free survival (PFS) rate. Patients received 8 cycles of neoadjuvant modified (m) FOLFIRINOX. Up to 6 cycles of gemcitabine were given for patients who underwent surgery. Plasma immune cell subsets were measured for analysing correlations with overall survival (OS).Results: Between May 2016 and March 2018, 44 chemotherapy- and radiotherapy-naïve patients with BRPC were included. With neoadjuvant mFOLFIRINOX, the objective response rate was 34.1%, and curative-intent surgery was done in 27 (61.4%) patients. With a median follow-up duration of 20.6 months (95% confidence interval [CI], 19.7-21.6 months), the median PFS and OS were 12.2 months (95% CI, 8.9-15.5 months) and 24.7 months (95% CI, 12.6-36.9), respectively. The 1-year PFS rate was 52.3% (95% CI, 37.6-67.0%). Higher CD14+ monocyte (quartile 4 vs 1-3) and lower CD69+ γδ T cell (γδ TCR+/CD69+) levels (quartiles 1-3 vs 4) were significantly associated with poor OS (p = 0.045 and p = 0.043, respectively).Conclusions: Neoadjuvant mFOLFIRINOX followed by postoperative gemcitabine were feasible and effective in BRPC patients. Monocyte and γδ T cells may have prognostic implications for patients with pancreatic cancer. ClinicalTrials.gov identifier: NCT02749136. [ABSTRACT FROM AUTHOR]

Background: High-grade serous ovarian cancers show increased replication stress, rendering cells vulnerable to ATR inhibition because of near universal loss of the G1/S checkpoint (through deleterious TP53 mutations), premature S phase entry (due to CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic drivers (through MYC amplification and other mechanisms). We hypothesised that the combination of the selective ATR inhibitor, berzosertib, and gemcitabine could show acceptable toxicity and superior efficacy to gemcitabine alone in high-grade serous ovarian cancer.Methods: In this multicentre, open-label, randomised, phase 2 study, 11 different centres in the US Experimental Therapeutics Clinical Trials Network enrolled women (aged ≥18 years) with recurrent, platinum-resistant high-grade serous ovarian cancer (determined histologically) and Eastern Cooperative Oncology Group performance status of 0 or 1, who had unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting. Eligible patients were randomly assigned (1:1) to receive intravenous gemcitabine (1000 mg/m2) on day 1 and day 8, or gemcitabine plus intravenous berzosertib (210 mg/m2) on day 2 and day 9 of a 21-day cycle until disease progression or intolerable toxicity. Randomisation was done centrally using the Theradex Interactive Web Response System, stratified by platinum-free interval, and with a permuted block size of six. Following central randomisation, patients and investigators were not masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival, and analyses included all patients who received at least one dose of the study drugs. The study is registered with ClinicalTrials.gov, NCT02595892, and is active but closed to enrolment.Findings: Between Feb 14, 2017, and Sept 7, 2018, 88 patients were assessed for eligibility, of whom 70 were randomly assigned to treatment with gemcitabine alone (36 patients) or gemcitabine plus berzosertib (34 patients). At the data cutoff date (Feb 21, 2020), the median follow-up was 53·2 weeks (25·6-81·8) in the gemcitabine plus berzosertib group and 43·0 weeks (IQR 23·2-69·1) in the gemcitabine alone group. Median progression-free survival was 22·9 weeks (17·9-72·0) for gemcitabine plus berzosertib and 14·7 weeks (90% CI 9·7-36·7) for gemcitabine alone (hazard ratio 0·57, 90% CI 0·33-0·98; one-sided log-rank test p=0·044). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (14 [39%] of 36 patients in the gemcitabine alone group vs 16 [47%] of 34 patients in the gemcitabine plus berzosertib group) and decreased platelet count (two [6%] vs eight [24%]). Serious adverse events were observed in ten (28%) patients in the gemcitabine alone group and nine (26%) patients in the gemcitabine plus berzosertib group. There was one treatment-related death in the gemcitabine alone group due to sepsis and one treatment-related death in the gemcitabine plus berzosertib group due to pneumonitis.Interpretation: To our knowledge, this is the first randomised study of an ATR inhibitor in any tumour type. This study shows a benefit of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer. This combination warrants further investigation in this setting.Funding: US National Cancer Institute. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the efficacy and safety of platinum plus gemcitabine (P/G) combinations as postoperative adjuvant chemotherapies for non-small cell lung cancer.Methods: Patients with postoperative stage IB-IIIA non-small cell lung cancer were randomly assigned to receive either cisplatin plus gemcitabine (GP arm) or carboplatin plus gemcitabine (GC arm) every 3 weeks for four cycles. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints were safety, feasibility, overall survival (OS), and biomarker analyses.Results: A total of 102 patients were randomized (stage IB, 22%; II, 36%; IIIA, 42%; histology: 74% adenocarcinoma). Of the 51 patients in each arm, 37 (73%) completed 4 cycles. During follow-up (median 5.8 years; range 0.1-9.7 years), estimated DFS and OS rates at 2 years were 59.6% and 86.3% with GP and 68.0% and 86.3% with GC, respectively. No significant difference in DFS was noted between arms (P = 0.163), although 3-, 4-, and 5-year DFS rates were higher with GC. Hematological toxic effects were comparable and non-hematological toxic effects were infrequent. DFS was significantly higher in the excision repair cross-complementation group 1 (ERCC1)-low group than in the ERCC1-high group for the GP arm (P = 0.045).Conclusion: Both P/G combination regimens were feasible and well-tolerated, and thus may represent valid options for postoperative adjuvant treatment of non-small cell lung cancer. Although no significant differences in DFS were evident between regimens, the present data favor the adoption of GC for further evaluation.Clinical Trial Registration: UMIN-CTR ( https://www.umin.ac.jp/ctr/ ) identifier: UMIN000000913. [ABSTRACT FROM AUTHOR]

Background: Therapeutic options are limited for advanced, metastatic biliary tract cancer. The pivotal NAPOLI-1 trial demonstrated the superior clinical benefit of nanoliposomal irinotecan (Nal-IRI) in gemcitabine-pretreated patients with metastatic pancreatic ductal adenocarcinoma; however, the antitumor activity of Nal-IRI in biliary tract cancer is unknown. This is the first report describing the efficacy of Nal-IRI in biliary tract cancer.Methods: In this multicenter retrospective cohort analysis, we identified patients with metastatic biliary tract adenocarcinoma who were treated with Nal-IRI in combination with 5-fluorouracil and folinic acid following tumor progression under standard therapy at one of the study centers between May 2016 and January 2019. We assessed disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).Results: There were 14 patients; the median age at the time of diagnosis and the median age at the initiation of Nal-IRI were 59.3 and 60.0 years, respectively. Nal-IRI in combination with 5-fluorouracil and folinic acid was administered as second-, third-, fourth-, and fifth-line treatment in 6 (43%), 5 (36%), 2 (14%), and 1 (7%) patient with metastatic disease, respectively. The objective DCR with Nal-IRI was 50% (7/14 patients). Six patients (43%) had partial response, and one patient (7%) had stable disease. Progressive disease was observed in seven patients. The median PFS and median OS following Nal-IRI initiation were 10.6 and 24.1 months, respectively.Conclusions: This retrospective analysis provides the first evidence that Nal-IRI might exhibit a clinical meaningful antitumor activity in metastatic biliary tract cancer. [ABSTRACT FROM AUTHOR]

Background: Nab-paclitaxel plus gemcitabine (nabP+gemcitabine) offers modest survival gains for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Sequential scheduling of nabP+gemcitabine in a PDAC mouse model improved efficacy; this hypothesis was tested in a clinical trial.Methods: Patients with previously untreated metastatic PDAC were randomised to receive nabP+gemcitabine administered either concomitantly on the same day, or sequentially, with gemcitabine administered 24 h after nabP. The primary outcome measure was progression-free survival (PFS). Secondary outcome measures were objective response rate (ORR), overall survival (OS), safety, quality of life (QoL) and predictive biomarkers.Results: In total, 71 patients received sequential (SEQ) and 75 concomitant (CON) treatment. Six-month PFS was 46% with SEQ and 32% with CON scheduling. Median PFS (5.6 versus 4.0 months, hazard ratio [HR] 0.67, 95% confidence interval [95% CI] 0.47-0.95, p = 0.022) and ORR (52% versus 31%, p = 0.023) favoured the SEQ arm; median OS was 10.2 versus 8.2 months (HR 0.93, 95% CI 0.65-1.33, p = 0.70). CTCAE Grade ≥3 neutropaenia incidence doubled with SEQ therapy but was not detrimental to QoL. Strongly positive tumour epithelial cytidine deaminase (CDA) expression favoured benefit from SEQ therapy (PFS HR 0.31, 95% CI 0.13-0.70).Conclusions: SEQ delivery of nabP+gemcitabine improved PFS and ORR, with manageable toxicity, but did not significantly improve OS.Clinical Trial Registration: ISRCTN71070888; ClinialTrials.gov (NCT03529175). [ABSTRACT FROM AUTHOR]

Background: The goal of this study was to characterize the efficacy and safety of stereotactic body radiation therapy (SBRT) versus conventionally fractionated radiation therapy with concurrent chemotherapy (CFRT) for the definitive treatment of locally advanced pancreatic cancer. The primary outcome measure was efficacy, defined by 2-year overall survival (OS). Secondary outcomes were incidence of any grade 3/4 toxicity and 1-year OS.Methods: A PICOS/PRISMA/MOOSE selection protocol was used to identify eligible studies. Inclusion criteria were: 1) patients diagnosed with locally advanced N0-1 M0 pancreatic cancer; 2) CFRT 1.8 to 2.0 Gy/fraction with chemotherapy per protocol or SBRT ≥5 Gy/fraction in ≤5 fractions; 3) either no control group or another definitive chemotherapy or radiation therapy arm; 4) at least 1 of the outcome measures reported; and 5) single or multi-arm phase 2/3 prospective study for CFRT and/or phase 1/2 or retrospective study for SBRT. Neoadjuvant and/or adjuvant chemotherapy was prescribed per protocol specifications. Weighted random effects meta-analyses were conducted using the DerSimonian and Laird method to characterize summary effect sizes for each outcome.Results: A total of 470 studies were initially screened; of these, 9 studies assessed SBRT and 11 studies assessed CFRT. For SBRT, the median dose was 30 Gy, and the most common regimen was 30 Gy/5 fractions. For CFRT, doses ranged from 45 to 54 Gy in 1.8- to 2.0-Gy fractions, with the majority of studies delivering 50.4 Gy in 28 fractions with concurrent gemcitabine. The random effects estimate for 2-year OS was 26.9% (95% CI, 20.6%-33.6%) for SBRT versus 13.7% (95% CI, 8.9%-19.3%) for CFRT and was statistically significant in favor of SBRT. The random effects estimate for 1-year OS was 53.7% (95% CI, 39.3%-67.9%) for SBRT versus 49.3% (95% CI, 39.3%-59.4%) for CFRT, and was not statistically significant. The random effects estimate for acute grade 3/4 toxicity was 5.6% (95% CI, 0.0%-20.0%) for SBRT versus 37.7% (95% CI, 24.0%-52.5%) for CFRT and was statistically significant in favor of SBRT. The random effects estimate for late grade 3/4 toxicity was 9.0% for SBRT (95% CI, 3.3%-17.1%) versus 10.1% (95% CI, 1.8%-23.8%) for CFRT, which was not statistically significant.Conclusion: These results suggest that SBRT for LAPC may result in a modest improvement in 2-year OS with decreased rates of acute grade 3/4 toxicity and no change in 1-year-OS or late toxicity. Further study into the use of stereotactic body radiation therapy for these patients is needed. [ABSTRACT FROM AUTHOR]

Purpose: Following promising responses to the DNA methyltransferase (DNMT) inhibitor 5-fluoro-2'-deoxycytidine (FdCyd) combined with tetrahydrouridine (THU) in phase 1 testing, we initiated a non-randomized phase 2 study to assess response to this combination in patients with advanced solid tumor types for which tumor suppressor gene methylation is potentially prognostic. To obtain pharmacodynamic evidence for DNMT inhibition by FdCyd, we developed a novel method for detecting expression of tumor suppressor protein p16/INK4A in circulating tumor cells (CTCs).Methods: Patients in histology-specific strata (breast, head and neck [H&N], or non-small cell lung cancers [NSCLC] or urothelial transitional cell carcinoma) were administered FdCyd (100 mg/m2) and THU (350 mg/m2) intravenously 5 days/week for 2 weeks, in 28-day cycles, and progression-free survival (PFS) rate and objective response rate (ORR) were evaluated. Blood specimens were collected for CTC analysis.Results: Ninety-three eligible patients were enrolled (29 breast, 21 H&N, 25 NSCLC, and 18 urothelial). There were three partial responses. All strata were terminated early due to insufficient responses (H&N, NSCLC) or slow accrual (breast, urothelial). However, the preliminary 4-month PFS rate (42%) in the urothelial stratum exceeded the predefined goal-though the ORR (5.6%) did not. An increase in the proportion of p16-expressing cytokeratin-positive CTCs was detected in 69% of patients evaluable for clinical and CTC response, but was not significantly associated with clinical response.Conclusion: Further study of FdCyd + THU is potentially warranted in urothelial carcinoma but not NSCLC or breast or H&N cancer. Increase in the proportion of p16-expressing cytokeratin-positive CTCs is a pharmacodynamic marker of FdCyd target engagement. [ABSTRACT FROM AUTHOR]

Objectives: This prospective trial was performed to verify whether microwave ablation (MWA) in combination with chemotherapy could provide superior survival benefit compared with chemotherapy alone.Materials and Methods: From March 1, 2015, to June 20, 2017, treatment-naïve patients with pathologically verified advanced or recurrent non-small cell lung cancer (NSCLC) were randomly assigned to MWA plus chemotherapy group or chemotherapy group. The primary endpoint was progression-free survival (PFS), while the secondary endpoints included overall survival (OS), time to local progression (TTLP), and objective response rate (ORR). The complications and adverse events were also reported.Results: A total of 293 patients were randomly assigned into the two groups. One hundred forty-eight patients with 117 stage IV tumors were included in the MWA plus chemotherapy group. One hundred forty-five patients with 113 stage IV tumors were included in the chemotherapy group. The median follow-up period was 13.1 months and 12.4 months, respectively. Median PFS was 10.3 months (95% CI 8.0-13.0) in the MWA plus chemotherapy group and 4.9 months (95% CI 4.2-5.7) in the chemotherapy group (HR = 0.44, 95% CI 0.28-0.53; p < 0.0001). Median OS was not reached in the MWA plus chemotherapy group and 12.6 months (95% CI 10.6-14.6) in the chemotherapy group (HR = 0.38, 95% CI 0.27-0.53; p < 0.0001) using Kaplan-Meier analyses with log-rank test. The median TTLP was 24.5 months, and the ORR was 32% in both groups. The adverse event rate was not significantly different in the two groups.Conclusions: In patients with advanced NSCLC, longer PFS and OS can be achieved with the treatment of combined MWA and chemotherapy than chemotherapy alone.Key Points: • Patients treated with MWA plus chemotherapy had superior PFS and OS over those treated with chemotherapy alone. • The ORR of patients treated with MWA plus chemotherapy was similar to that of those treated with chemotherapy alone. • Complications associated with MWA were common but tolerable and manageable. [ABSTRACT FROM AUTHOR]

Background: Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs.Methods: We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2-T4 pN0-N3 M0 or pTany N1-3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m2) or carboplatin (area under the curve [AUC]4·5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m2) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analysed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants.Findings: Between June 19, 2012, and Nov 8, 2017, we enrolled 261 participants from 57 of 71 open study sites. 132 patients were assigned chemotherapy and 129 surveillance. One participant allocated chemotherapy withdrew consent for data use after randomisation and was excluded from analyses. Adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0·45, 95% CI 0·30-0·68; p=0·0001) at a median follow-up of 30·3 months (IQR 18·0-47·5). 3-year event-free estimates were 71% (95% CI 61-78) and 46% (36-56) for chemotherapy and surveillance, respectively. 55 (44%) of 126 participants who started chemotherapy had acute grade 3 or worse treatment-emergent adverse events, which accorded with frequently reported events for the chemotherapy regimen. Five (4%) of 129 patients managed by surveillance had acute grade 3 or worse emergent adverse events. No treatment-related deaths were reported.Interpretation: Gemcitabine-platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population.Funding: Cancer Research UK. [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: TG01 is the first cancer immunotherapy targeting KRAS oncogenic mutations. This study assessed the safety and efficacy of TG01/GM-CSF in patients with resected pancreatic adenocarcinoma.Methods: Patients with stage I or II pancreatic adenocarcinoma who had undergone surgical resection (R0 or R1) received adjuvant gemcitabine with TG01/GM-CSF using two schedules of vaccination. Immune response was defined as a positive delayed-type hypersensitivity (DTH) response and/or positive T-cell proliferation assay.Results: Thirty-two patients were enrolled between February 2013 and May 2016. Nineteen were treated with the high antigen burden, with four serious adverse reactions considered possibly related to TG01 treatment, including three allergic reactions. On this basis, a further 13 patients received a modified vaccination schedule with reduced antigen burden, with no serious adverse events related to TG01. Ninety-five percent patients in the main cohort and 92% in the modified cohort had a positive immune response. Median overall survival (OS) was 33.1 months, and median disease-free survival (DFS) was 13.9 months for the main cohort. For the modified cohort, the median OS was 34.3 months and median DFS was 19.5 months.Conclusions: TG01/GM-CSF with gemcitabine was well tolerated, with high levels of immune activation. OS and DFS compare favourably with published data for adjuvant gemcitabine.Clinical Trial Registration: This clinical trial was registered at ClinicalTrials.gov (NCT02261714). [ABSTRACT FROM AUTHOR]

Background: Both gemcitabine and bendamustine have been evaluated in patients with recurrent/refractory Hodgkin lymphoma but to the authors' knowledge not as a doublet. The authors completed a phase 1/2 trial to identify the optimal dose and frequency of administration and to assess the efficacy of this combination in patients with recurrent/refractory Hodgkin lymphoma.Methods: Patients were treated up to a maximum dose of gemcitabine (1000 mg/m2 on day 1) and bendamustine (120 mg/m2 on days 1 and 2), which was determined to be the recommended phase 2 dose, administered every 21 days for up to 6 cycles. Patients could discontinue study therapy after 2 cycles to proceed with autologous or allogeneic stem cell transplantation.Results: No dose-limiting toxicities were identified, but 4 patients experienced grade 3 to 5 pulmonary adverse events (toxicity was graded according to Common Terminology Criteria for Adverse Events [version 4]). A total of 26 patients were enrolled having completed a median of 4 prior lines of therapy (range, 1-7 lines), including 13 patients at the recommended phase 2 dose, in whom the overall response rate was 69% and the complete response rate was 46%. The median progression-free survival for the phase 2 patients was 11 months (95% CI, 3 months to not reached), and the median overall survival for this group had not been reached at the time of last follow-up (95% CI, 4 months to not reached).Conclusions: This doublet was found to be tolerable and effective, but patients must be monitored closely for pulmonary toxicity. The authors currently are evaluating this doublet in combination with nivolumab. [ABSTRACT FROM AUTHOR]

Background: The current study aimed to evaluate the outcomes of patients with unresectable non-metastatic locally advanced pancreatic adenocarcinoma (LAPA) who did not benefit from resection considering the treatment strategy in the clinical settings.Methods: Between 2010 and 2017, a total of 234 patients underwent induction chemotherapy for LAPA that could not be treated with surgery. After oncologic restaging, continuous chemotherapy or chemoradiation (CRT) was decided for patients without metastatic disease. The Kaplan-Meier method was used to determine overall survival (OS), and the Wilcoxon test to compare survival curves. Multivariate analysis was performed using the stepwise logistic regression method.Results: FOLFIRINOX was the most common induction regimen (168 patients, 72%), with a median of 6 chemotherapy cycles and resulted in higher OS, compared to gemcitabine (19 vs. 16 months, hazard ratio (HR) = 1.2, 95% confidence interval: 0.86-1.6, P = .03). However, no difference was observed after adjusting for age (≤75 years) and performance status score (0-1). At restaging, 187 patients (80%) had non-metastatic disease: CRT was administered to 126 patients (67%) while chemotherapy was continued in 61 (33%). Patients who received CRT had characteristics comparable to those who continued with chemotherapy, with similar OS. They also had longer progression-free survival (median 13.3 vs. 9.6 months, HR = 1.38, 95% confidence interval: 1-1.9, P < .01) and limited short-term treatment-related toxicity.Conclusions: The median survival of patients who could not undergo surgery was 19 months. Hence, CRT should not be eliminated as a treatment option and may be useful as a part of optimised sequential chemotherapy for both local and metastatic disease. [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: The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma and Hh signalling.Methods: Patients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel. Vismodegib was added starting on the second cycle. The primary endpoint was progression-free survival (PFS) as compared with historical controls. Tumour biopsies to assess pCSC, stroma and Hh signalling were obtained before treatment and after cycle 1 (gemcitabine and nab-paclitaxel) or after cycle 2 (gemcitabine and nab-paclitaxel plus vismodegib).Results: Seventy-one patients were enrolled. Median PFS and overall survival (OS) were 5.42 months (95% confidence interval [CI]: 4.37-6.97) and 9.79 months (95% CI: 7.85-10.97), respectively. Of the 67 patients evaluable for response, 27 (40%) had a response: 26 (38.8%) partial responses and 1 complete response. In the tumour samples, there were no significant changes in ALDH + pCSC following treatment.Conclusions: Adding vismodegib to chemotherapy did not improve efficacy as compared with historical rates observed with chemotherapy alone in patients with newly diagnosed metastatic pancreatic cancer. This study does not support the further evaluation of Hh inhibitors in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01088815. [ABSTRACT FROM AUTHOR]

Background: Retrospective studies suggest a survival benefit when platinum-based chemotherapy is administered to patients with pancreatic cancer harbouring a germline mutation in BRCA1, BRCA2 or PALB2 (mut-positive PDAC). However, the objective response rate (ORR) and real-world progression free survival (rwPFS) achieved with such treatment remain ill-defined.Methods: Twenty-six patients with advanced-stage mut-positive PDAC who had been treated with platinum-based therapy were matched by age, race and sex to 52 platinum-treated control PDAC patients. Responses to therapy were determined by RECIST v1.1, performed by blinded radiology review. Measured outcomes included ORR and rwPFS.Results: The ORR in mut-positive patients was 58% compared to 21% in the control group (p = 0.0022). There was no significant difference in ORR between platinum regimens in mut-positive patients (p = 0.814), whereas in control patients, the only observed responses were to FOLFIRINOX. rwPFS was 10.1 mo. for mut-positive patients and 6.9 mo. for controls (HR 0.43; 95% CI 0.25-0.74; 0.0068).Conclusion: Mut-positive PDAC has a high ORR and prolonged rwPFS to platinum-based chemotherapy. These findings may have implications particularly in the neoadjuvant setting, and for future clinical trial design, and highlight the importance of early germline testing in patients with PDAC. [ABSTRACT FROM AUTHOR]

Background: Intimal sarcoma (InS) is an exceedingly rare neoplasm with an unfavorable prognosis, for which new potentially active treatments are under development. We report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with InS.Methods: Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis. Patients with MDM2-positive InS who were treated with anthracycline-based regimens, gemcitabine-based regimens, or pazopanib between October 2001 and January 2018 were selected. Local pathological review was performed to confirm diagnosis. Response was assessed by RECIST1.1. Recurrence-free survival (RFS), progression-free survival (PFS) and overall survival were computed by Kaplan-Meier method.Results: Seventy-two patients were included (66 anthracycline-based regimens; 26 gemcitabine-based regimens; 12 pazopanib). In the anthracycline-based group, 24 (36%) patients were treated for localized disease, and 42 (64%) patients were treated for advanced disease. The real-world overall response rate (rwORR) was 38%. For patients with localized disease, the median RFS was 14.6 months. For patients with advanced disease, the median PFS was 7.7 months. No anthracycline-related cardiac toxicity was reported in patients with cardiac InS (n = 26). For gemcitabine and pazopanib, the rwORR was 8%, and the median PFS was 3.2 and 3.7 months, respectively.Conclusion: This retrospective series shows the activity of anthracycline-based regimens in InS. Of note, anthracyclines were used in patients with cardiac InS with no significant cardiac toxicity. The prognosis in patients with InS remains poor, and new active drugs and treatment strategies are needed. [ABSTRACT FROM AUTHOR]

Purpose: Triple-negative breast cancer (TNBC) is an aggressive, lethal, and heterogeneous subtype of breast cancers, tending to have lower 5-year survival rates than other BC subtypes in response to conventional chemotherapies. This study's aim was to identify advanced regimens to effectively control TNBC tumor development.Methods: We investigated the combination of the DNA synthesis inhibitor gemcitabine, the DNA-damaging agent cisplatin, and the histone deacetylase inhibitor romidepsin to control a variety of breast cells in vitro. We studied the toxicity of drug doses and administration schedules to determine tolerable combination regimens in immune-deficient nude and -competent BALB/c mice. We then studied the efficacy of tolerable regimens in controlling TNBC cell-derived xenograft development in nude mice. By reducing clinically equivalent doses of each agent in combination, we formulated tolerable regimens in animals. We verified that the tolerable triple combination gemcitabine plus romidepsin + cisplatin regimen more efficacious than double combination regimens in controlling xenograft tumor development in nude mice.Results: A triple combination of gemcitabine + romidepsin + cisplatin synergistically induced death of the TNBC M.D. Anderson-Metastatic Breast cancer (MDA-MB) 231 and MDA-MB468, as well as Michigan Cancer Foundation (MCF) 7, MCF10A, and MCF10A-Ras cells. Cell death induced by gemcitabine + romidepsin + cisplatin was in a reactive oxygen species-dependent manner.Conclusion: Considering the high costs for developing a new anticancer agent, we used the FDA-approved drugs gemcitabine, romidepsin (is approved for T-cell lymphoma and is under clinical trial for TNBC), and cisplatin to economically formulate an efficacious and safe combination regimen. The highly efficacious gemcitabine plus romidepsin + cisplatin regimen should be poised for efficient translation into clinical trials, ultimately contributing to reduced mortality and improved quality of life for TNBC patients. [ABSTRACT FROM AUTHOR]

Purpose: Preoperative therapy in borderline resectable pancreatic cancer (BRPC) is intended to increase R0 resection rates. An optimal approach in BRPC is yet to be defined.Methods and Materials: Patients with BRPC, confirmed adenocarcinoma, performance status ≤1, and adequate organ function enrolled in a single-institution, phase 2 trial. Patients received FOLFIRINOX × 6 cycles, then radiation therapy (50 Gy in 25 fractions) concurrent with fixed-dose rate gemcitabine (1 g/m2 over 100 minutes) followed by 2 additional gemcitabine infusions. Computed tomography scans were performed at 2-month intervals during treatment. Patients without distant disease were offered surgical exploration. The primary objective was R0 resection rate with an alternate hypothesis of 55%. Secondary objectives included median progression-free survival (PFS), median overall survival (OS), response rate, and safety. The trial registration number is NCT01661088.Results: Twenty-five patients with median age of 60 years (range, 47-77 years) enrolled from November 2011 through January 2017. Twenty-one (84%) completed FOLFIRINOX and 19 (76%) completed all protocol therapy. Treatment-related grade 3 to 4 toxicities included neutropenia (40%), nausea and vomiting (28%), diarrhea (16%), and fatigue (12%). Eighteen patients (72%) underwent laparotomy, 13 (52%) were resected (all R0). The median PFS and OS in 25 patients were 13.1 months (95% confidence interval [CI], 7.3-24.7) and 24.4 months (95% CI, 12.6-40.0), respectively. For resected patients, median PFS was 21.6 months (95% CI, 8.2-37.1) and OS was 37.1 months (95% CI, 15.4-not reached).Conclusions: Neoadjuvant therapy with FOLFIRINOX, followed by intensity modulated radiation therapy concurrent with fixed-dose-rate gemcitabine in BRPC is feasible and tolerated. Although the alternate hypothesis was not met, the OS of the resected cohort was favorable. [ABSTRACT FROM AUTHOR]

Background: Ontuxizumab, a humanized monoclonal antibody, targets endosialin (tumor endothelial marker 1 [TEM-1] or CD248), which is expressed on sarcoma cells and is believed to be involved in tumor angiogenesis. This is the first trial to evaluate ontuxizumab in patients with sarcoma.Methods: Part 1 was an open-label, dose-finding, safety lead-in: 4, 6, or 8 mg/kg with gemcitabine and docetaxel (G/D; 900 mg/m2 gemcitabine on days 1 and 8 and 75 mg/m2 docetaxel on day 8). In part 2, patients were randomized in a double-blind fashion in 2:1 ratio to ontuxizumab (8 mg/kg) or a placebo with G/D. Randomization was stratified by 4 histological cohorts.Results: In part 2 with 209 patients, no significant difference in progression-free survival between ontuxizumab plus G/D (4.3 months; 95% confidence interval [CI], 2.7-6.3 months) and the placebo plus G/D (5.6 months; 95% CI, 2.6-8.3 months) was observed (P = .67; hazard ratio [HR], 1.07; 95% CI, 0.77-1.49). Similarly, there was no significant difference in median overall survival between the 2 groups: 18.3 months for the ontuxizumab plus G/D group (95% CI, 16.2-21.1 months) and 21.1 months for the placebo plus G/D group (95% CI, 14.2 months to not reached; P = .32; HR, 1.23; 95% CI, 0.82-1.82). No significant differences between the treatment groups occurred for any efficacy parameter by sarcoma cohort. The combination of ontuxizumab plus G/D was generally well tolerated.Conclusions: Ontuxizumab plus G/D showed no enhanced activity over chemotherapy alone in soft-tissue sarcomas, whereas the safety profile of the combination was consistent with G/D alone. [ABSTRACT FROM AUTHOR]

Purpose: To identify patterns of local failure in patients with pancreatic cancer receiving stereotactic body radiation therapy plus chemotherapy as initial treatment, for the optimal design of target volumes encompassing a majority of local recurrences.Methods and Materials: Consecutive patients with resectable or borderline resectable but medically inoperable cancer owing to comorbidities and locally advanced pancreatic cancer undergoing stereotactic body radiation therapy and chemotherapy were reviewed. Local recurrences were plotted with respect to the celiac trunk (CT), superior mesenteric artery (SMA), and splenic artery on 1 computed tomographic scan of a template patient.Results: Five hundred and ten patients were included. Median follow-up of the entire group was 21.8 months (range, 3.1-54.9 months). Two hundred and seventeen patients had locoregional recurrences, whereas local and distant progressions were found in 293 patients. One hundred and sixty-nine (33.2%) and 144 (28.2%) patients had recurrences closer to the CT and SMA, respectively, whereas both invasions of the CT and SMA were found in 115 patients (22.5%). In addition, 33 patients (6.5%) and 49 patients (9.6%) had recurrences at the hepatic hilum and the splenic artery, respectively. Besides these patterns of failure, 138 patients (27.1%) also experienced retroperitoneal progressions. The mean distance to the CT, SMA, and retroperitoneal recurrence was 9.0, 8.3, and 11.7 mm, respectively. Multivariable analysis demonstrated that advanced pancreatic cancer, recurrences at both the CT and SMA and the hepatic hilum, CA19-9 nonresponders, and BED10 <60 Gy were predictive of worse survival.Conclusions: Areas closer to the CT, SMA, and retroperitoneal space were at a high risk of local recurrences. Nonuniform and sufficient expansions from the gross tumor volume might be necessary, and the splenic vessels abutting the tumor might also be included in the target volume without compromise of dose constraints of organs at risk. In addition, at least BED10 ≥60 Gy might be required to achieve better outcomes. [ABSTRACT FROM AUTHOR]

Recurrent primary central nervous system lymphomas (PCNSL) have a very poor prognosis. For young and fit patients, intensive chemotherapy followed by autologous stem cell transplantation could be proposed at relapse. In the other cases (unfit or elderly patients), therapeutic options are limited with no consensual regimen. The poly-chemotherapy by (R)-GEMOX is associated with anti-tumor activity in systemic lymphomas and a favorable toxicity profile. Our objective was to evaluate the activity and tolerance of (R)-GEMOX in PCNSL patients enrolled in the French nation-wide LOC cohort. We retrospectively analyzed all refractory or recurrent patients included in the LOC network who benefited from (R)-GEMOX (rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatine 100 mg/m2). Administration, tolerance, and efficacy data were analyzed. Thirteen patients, treated in five different institutions, benefited from the (R)-GEMOX regimen from February 2013 to August 2017. At the initiation of (R)-GEMOX, median age was 71.4 years old (range, 49.5-82.5) and median Karnofsky performance status (KPS) was 60 (range, 40-80). Seven patients were in second line of treatment whereas the six others were in third line or over. All patients had received methotrexate-based polychemotherapy as first-line treatment except one. Overall response rate was 38% with two complete responses and three partial responses. Median progression-free survival was 3.2 months (95%CI: 0.2-6.2), and median overall survival was 8.2 months (95%CI: 0.6-15.8). Toxicity was mainly hematological including grade ¾ neutropenia (38%), lymphopenia (23%), and thrombopenia (23%). Older age (p = 0.046) and low KPS (p = 0.054) tended to be associated with a worse prognosis. (R)-GEMOX is associated with substantial response rate and favorable toxicity profile in unfit patients with recurrent PCNSL. (R)-GEMOX could be considered to be an additional option in patients with recurrent/refractory PCNSL. [ABSTRACT FROM AUTHOR]

Background: The standard of care for patients with resected stage I to stage III pancreatic ductal adenocarcinoma (PDAC) is adjuvant gemcitabine-based chemotherapy. The role of adjuvant treatment in patients with subcentimeter, stage IA PDAC is unknown. The current study evaluated the effect of adjuvant treatment on survival outcomes among patients with American Joint Committee on Cancer/International Union Against Cancer stage IA (T1N0) resected PDAC using the National Cancer Data Base (NCDB).Methods: A retrospective review of the NCDB was conducted for patients diagnosed with T1 (tumor limited to the pancreas and measuring ≤2 cm in greatest dimension), lymph node-negative (N0), resected PDAC between 2004 and 2013. Patient demographics, histology, adjuvant treatment, and survival trends were examined. Kaplan-Meier analysis and log-rank tests were performed to determine the unadjusted association between overall survival (OS), tumor size, and treatment.Results: A total of 876 patients met the inclusion criteria. The patients had a mean age of 66.2 years (range, 32-90 years); approximately 83.3% were white (730 patients) and 53.1% were female (465 patients). Approximately 45.9% of the patients had moderately differentiated tumor histology (402 patients); 70.0% (613 patients) had tumors measuring 1 to 2 cm (T1c) and 30.0% (263 patients) had tumors measuring <1 cm (T1a/T1b). Approximately 94.2% of patients had negative surgical margins (815 patients) and 46.9% (410 patients) received adjuvant therapy. The median OS was significantly different for patients who received adjuvant therapy compared with patients who did not (70.7 months vs 46.9 months; P = .0001). For patients with tumors measuring <1 cm, survival was not found to be significantly different between patients who received adjuvant treatment compared with those who did not (not reached vs 85.3 months; P = .54). In the multivariable analysis, none of the covariates (treatment group, Charlson-Deyo Score, age, insurance, and facility status) demonstrated significant differences for patients with tumors measuring <1 cm.Conclusions: The current study is the first to demonstrate no survival benefit for adjuvant therapy in patients with resected subcentimeter PDAC. [ABSTRACT FROM AUTHOR]

Background: Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer.Methods: We randomly assigned 493 patients with resected pancreatic ductal adenocarcinoma to receive a modified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-surface area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a protocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety.Results: At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis).Conclusions: Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. (Funded by R&D Unicancer and others; ClinicalTrials.gov number, NCT01526135 ; EudraCT number, 2011-002026-52 .). [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]

Objective: The objective of this study was to perform a systematic review and meta-analysis to evaluate the two most commonly used chemotherapy regimens gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin/adriamycin, and cisplatin (MVAC) regimens for muscle-invasive bladder cancer (MIBC) patients.Methods: We searched for all studies investigating GC and MVAC for MIBC patients in PubMed, Web of Knowledge, and the Cochrane Central Search Library. A systematic review and meta-analysis were performed.Results: Our searches identified 13 studies among 2174 patients. In the meta-analysis, the pathological complete response to GC regimens was superior to MVAC regimens. No significant difference in pathological partial response was found between the two groups. GC regimens were associated with a significant decrease risk in Grade 3-4 neutropenia, mucositis, and febrile neutropenia, but a significant increase risk in Grade 3-4 thrombocytopenia. There was no significant difference in overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS) when compared GC regimens to MVAC regimens.Conclusions: GC regimens significantly improved pathological complete response compared to MVAC regimens. GC regimens were associated with a significant decrease risk in Grade 3-4 neutropenia, mucositis, and febrile neutropenia, but a significant increase risk in Grade 3-4 thrombocytopenia. There was no significant difference in OS, DSS, and DFS when compared the two regimens. [ABSTRACT FROM AUTHOR]

Background: Platinum-based doublet chemotherapy regimens, preferentially gemcitabine plus cisplatin, are generally considered the first-line standard of care for patients with recurrent or metastatic nasopharyngeal carcinoma. However, no consensus has been reached regarding treatment following progression after first-line therapy. Camrelizumab (SHR-1210) is a humanised anti-programmed death-1 (anti PD-1) antibody. We present safety and preliminary antitumour activity of camrelizumab alone as second-line therapy in patients with recurrent or metastatic nasopharyngeal carcinoma and combined with gemcitabine and cisplatin as first-line therapy in this patient population.Methods: We report the results from two single-arm, phase 1 trials. Both trials included patients aged 18-70 years with histologically or cytologically confirmed nasopharyngeal carcinoma and confirmed metastatic disease or locoreginal recurrence, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients who received at least one previous line of treatment were enrolled at five academic hospitals in China into the dose-escalation and expansion trial to receive camrelizumab monotherapy intravenously at escalating doses of 1 mg/kg, 3 mg/kg, and 10 mg/kg, and a bridging dose of 200 mg per dose once every 2 weeks (monotherapy trial). Treatment-naive patients were enrolled from a single centre in China to receive six cycles of camrelizumab 200 mg (day 1), gemcitabine 1 g/m2 (days 1 and 8), and cisplatin 80 mg/m2 (day 1) every 3 weeks followed by camrelizumab 200 mg maintenance once every 3 weeks (combination trial). The primary endpoint of both trials was the safety and tolerability of the study treatment. Analyses were done per protocol. Both trials are registered with ClinicalTrials.gov, number NCT02721589 (camrelizumab monotherapy trial) and NCT03121716 (camrelizumab combination trial). Both trials are ongoing, but are no longer enrolling patients.Findings: In the camrelizumab monotherapy trial, between March 31, 2016, and Sept 20, 2017, 121 patients were assessed for eligibility, of whom 93 patients were enrolled across the dose-escalation and expansion cohorts and received at least one dose of camrelizumab (safety population). 15 (16%) of 93 patients had treatment-related adverse events of grade 3 or 4, the most common of which were elevated conjugated bilirubin concentration (three [3%] of 93 patients), stomatitis, anaemia, and increased concentrations of aspartate aminotransferase, alanine aminotransferase, and total bilirubin, each of which occurred in two (2%) patients. Eight (9%) patients had a treatment-related serious adverse event. No dose-limiting toxic effects were observed during the dose-escalation phase. 31 (34%; 95% CI 24-44) of 91 evaluable patients on camrelizumab monotherapy had an overall response with a median follow-up of 9·9 months (IQR 8·1-11·7). In the camrelizumab combination trial, between April 18, 2017, and Aug 15, 2017, 24 patients were assessed for eligibility, of whom 23 patients were enrolled and treated (safety population). 20 (87%) of 23 patients had grade 3 or 4 treatment-related adverse events: neutropenia (13 [57%] of 23 patients), anaemia (11 [48%] patients), leucopenia (11 [48%] patients), thrombocytopenia (seven [30%] patients), oedema (two [9%] patients), hyponatraemia (two [9%] patients), hypochloraemia (one [4%] patients), and rash (one [4%] patient). Two patients had treatment-related serious adverse events. No treatment-related deaths occurred in these trials. 20 (91% [95% CI 72-97]) of 22 evaluable patients had an overall response with a median follow-up time of 10·2 months (IQR 9·7-10·8).Interpretation: Camrelizumab is a well tolerated, potential treatment option for patients with recurrent or metastatic nasopharyngeal carcinoma. The combination of camrelizumab plus gemcitabine and cisplatin has a manageable toxicity profile and promising preliminary antitumour activity for this disease in treatment-naive patients. Randomised controlled trials are needed to further establish the role of immune checkpoint inhibition for nasopharyngeal carcinomas.Funding: Hengrui Medicine Co, Chinese National Natural Science Foundation project, Science and Technology Program of Guangdong, Pearl River Nova Program of Guangzhou. [ABSTRACT FROM AUTHOR]

Background: Patients with primary refractory Hodgkin's lymphoma or early relapse have a poor prognosis. Although many salvage regimens have been developed, there is no standard of care. Brentuximab vedotin and gemcitabine have been shown to be active in patients with relapsed or refractory Hodgkin's lymphoma when used as monotherapy, and each has been successfully used in combination with other agents. Preclinical data suggest that brentuximab vedotin can sensitise lymphoma cells to gemcitabine, supporting the use of the combination. We aimed to define the safety and efficacy of brentuximab vedotin with gemcitabine in children and young adults with primary refractory Hodgkin's lymphoma or early relapse.Methods: In this Children's Oncology Group, multicentre, single-arm, phase 1-2 trial, we recruited patients with Hodgkin's lymphoma from hospitals across the USA and Canada. Eligible patients were aged younger than 30 years, had no previous brentuximab vedotin exposure, and had primary refractory disease or relapse of less than 1 year from completion of initial treatment. Each 21-day cycle consisted of 1000 mg/m2 intravenous gemcitabine on days 1 and 8 and intravenous brentuximab vedotin on day 1 at 1·4 mg/kg or 1·8 mg/kg. The primary objectives were to establish the recommended phase 2 dose of brentuximab vedotin in this combination, the safety of the combination, and the proportion of patients who achieved a complete response among those treated at the recommended phase 2 level, within four cycles of treatment. This trial is registered with ClinicalTrials.gov, number NCT01780662.Findings: Between Feb 5, 2013, and Aug 19, 2016, 46 patients were enrolled, including one who was found to be ineligible, in the two phases of the study. The recommended phase 2 dose of brentuximab vedotin was 1·8 mg/kg in combination with gemcitabine 1000 mg/m2. 24 (57%) of 42 evaluable patients (95% CI 41-72) given this dose level had a complete response within the first four cycles of treatment. Four (31%) of 13 patients with a partial response or stable disease had all target lesions with Deauville scores of 3 or less after cycle 4. By modern response criteria, these were also complete responses (total number with complete response 28 [67%] of 42 [95% CI 51-80]). The most common grade 3-4 adverse events in all 42 participants treated at the recommended phase 2 dose were neutropenia (15 [36%]), rash (15 [36%]), transaminitis (9 [21%]), and pruritus (4 [10%]). There were no treatment-related deaths.Interpretation: Brentuximab vedotin with gemcitabine is a safe combination treatment with a tolerable toxicity profile for patients with primary refractory Hodgkin's lymphoma or high-risk relapse. The preliminary activity of this combination shown in this trial warrants further investigation in randomised controlled trials.Funding: National Institutes of Health and the St. Baldrick's Foundation. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the efficacy and toxicity profile of sequential intensity modulated radiation therapy (IMRT) followed by gemcitabine, dexamethasone, and cisplatin (GDP) on previously untreated high-risk, early stage upper aerodigestive tract natural killer/T-cell lymphoma (UADT-NKTCL).Methods and Materials: A phase 2 study was designed, and 40 high-risk patients with stage I(E)/II(E) UADT-NKTCL were enrolled between June 2010 and June 2014. High-risk patients were defined as those with at least 1 predefined risk factor: age >60 years, elevated serum lactate dehydrogenase, regional lymph node involvement, B symptoms, and primary tumor invasion. Patients received extended involved-site IMRT and GDP chemotherapy. The primary endpoint was the 2-year progression-free survival rate. Secondary endpoints were the 2-year overall survival rate, overall response rate, and toxicity.Results: Median follow-up time was 60.1 months. The overall response rate and complete remission rate were 97.5% and 95.0%, respectively. The 2- and 5-year progression-free survival rates were 84.7% and 79.4%, and the corresponding overall survival rates were 89.9% and 82.1%, respectively. The most frequent radiation-induced toxicities were mild mucositis and skin reaction. Grade 3/4 neutropenia (12 of 40 patients), thrombocytopenia (7 of 40), and anemia (2 of 40) were observed during chemotherapy.Conclusions: First-line IMRT followed by GDP represents an effective and well-tolerated protocol for high-risk, early stage UADT-NKTCL. [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]

Background: Pathological complete response (pCR) is associated with improved prognosis in triple-negative breast cancer (TNBC). The optimal chemotherapy regimen is unclear. Weekly nab-paclitaxel vs conventional paclitaxel or addition of carboplatin to anthracycline-taxane results in higher pCR rates with uncertain survival impact. We evaluated carboplatin vs gemcitabine with a nab-paclitaxel backbone as a short 12-week A-free regimen with a focus on early response.Methods: Patients with TNBC (estrogen receptor/progesterone receptor < 1%, human epidermal growth factor receptor 2-negative, cT1c-cT4c, cN0/+) were randomly assigned to A: nab-paclitaxel 125 mg/m2/gemcitabine 1000 mg/m2 d1,8 three times weekly (q3w); vs B: nab-paclitaxel 125 mg/m2/carboplatin AUC2 day 1,8 q3w. The trial was powered for a pCR (ypT0/is ypN0) comparison by therapy arm and early response (defined as Ki-67 decrease >30% or < 500 invasive tumor cells in the three-week serial biopsy). All statistical tests were two-sided.Results: A total of 336 patients were enrolled (48 centers, arms A/B: n = 182/154). The median age was 50 years. At baseline (A vs B), 62.6% and 62.9% had cT2-4c tumors; 86.8% and 90.9% completed therapy per protocol, respectively. pCR favored arm B (28.7%, 95% CI = 0.22 to 0.36, vs 45.9%, 95% CI = 0.38 to 0.54; 95% CI(dBA) = 6.2% to 27.9%, P = .002) and was lower in nonresponders than in early responders (19.5% vs 44.4%, P < .001) or in patients with unclassifiable early response (50.0%). The nab-paclitaxel/gemcitabine was associated with more frequent dose reductions (20.6% vs 11.9%, P = .04), treatment-related serious adverse events (11.1% vs 5.3%, P = .07), grade 3-4 infections (7.2% vs 2.6%, P = .07), and grade 3-4 ALAT elevations (11.7 vs 3.3%, P = .01).Conclusions: This first large randomized trial suggests high efficacy and excellent tolerability of a neoadjuvant nab-paclitaxel/carboplatin regimen, superior to nab-paclitaxel/gemcitabine in TNBC. De-escalation of further chemotherapy in patients with early pCR after a short anthracycline-free regimen is a promising field of future research. Early necrotic morphological changes and/or proliferation decrease after the first therapy cycle seem to be associated with subsequent pCR. [ABSTRACT FROM AUTHOR]

Importance: Low-grade non-muscle-invasive urothelial cancer frequently recurs after excision by transurethral resection of bladder tumor (TURBT).Objective: To determine whether immediate post-TURBT intravesical instillation of gemcitabine reduces recurrence of suspected low-grade non-muscle-invasive urothelial cancer compared with saline.Design, Setting, and Participants: Randomized double-blind clinical trial conducted at 23 US centers. Patients with suspected low-grade non-muscle-invasive urothelial cancer based on cystoscopic appearance without any high-grade or without more than 2 low-grade urothelial cancer episodes within 18 months before index TURBT were enrolled between January 23, 2008, and August 14, 2012, and followed up every 3 months with cystoscopy and cytology for 2 years and then semiannually for 2 years. Patients were monitored for tumor recurrence, progression to muscle invasion, survival, and toxic effects. The final date of follow-up was August 14, 2016.Interventions: Participants were randomly assigned to receive intravesical instillation of gemcitabine (2 g in 100 mL of saline) (n = 201) or saline (100 mL) (n = 205) for 1 hour immediately following TURBT.Main Outcomes and Measures: The primary outcome was time to recurrence of cancer. Secondary end points were time to muscle invasion and death due to any cause.Results: Among 406 randomized eligible patients (median age, 66 years; 84.7% men), 383 completed the trial. In the intention-to-treat analysis, 67 of 201 patients (4-year estimate, 35%) in the gemcitabine group and 91 of 205 patients (4-year estimate, 47%) in the saline group had cancer recurrence within 4.0 years (hazard ratio, 0.66; 95% CI, 0.48-0.90; P<.001 by 1-sided log-rank test for time to recurrence). Among the 215 patients with low-grade non-muscle-invasive urothelial cancer who underwent TURBT and drug instillation, 34 of 102 patients (4-year estimate, 34%) in the gemcitabine group and 59 of 113 patients (4-year estimate, 54%) in the saline group had cancer recurrence (hazard ratio, 0.53; 95% CI, 0.35-0.81; P = .001 by 1-sided log-rank test for time to recurrence). Fifteen patients had tumors that progressed to muscle invasion (5 in the gemcitabine group and 10 in the saline group; P = .22 by 1-sided log-rank test) and 42 died of any cause (17 in the gemcitabine group and 25 in the saline group; P = .12 by 1-sided log-rank test). There were no grade 4 or 5 adverse events and no significant differences in adverse events of grade 3 or lower.Conclusions and Relevance: Among patients with suspected low-grade non-muscle-invasive urothelial cancer, immediate postresection intravesical instillation of gemcitabine, compared with instillation of saline, significantly reduced the risk of recurrence over a median of 4.0 years. These findings support using this therapy, but further research is needed to compare gemcitabine with other intravesical agents.Trial Registration: clinicaltrials.gov Identifier: NCT00445601. [ABSTRACT FROM AUTHOR]

Background: Studies of a modified XELIRI (mXELIRI; capecitabine plus irinotecan) regimen suggest promising efficacy and tolerability profiles in the first-line and second-line settings. Therefore, we aimed to compare the efficacy and safety of the mXELIRI regimen with that of standard FOLFIRI (leucovorin, fluorouracil, and irinotecan), with or without bevacizumab in both regimens, as a second-line therapy for metastatic colorectal cancer.Methods: We did a multicentre, open-label, randomised, non-inferiority, phase 3 trial. We enrolled patients from 98 hospitals in Japan, China, and South Korea who were aged 20 years or older with histologically confirmed and unresectable colorectal adenocarcinoma, and who had withdrawn from first-line chemotherapy for metastatic colorectal cancer. We randomly assigned patients (1:1) to receive either mXELIRI with or without bevacizumab (irinotecan 200 mg/m2 intravenously on day 1 plus oral capecitabine 800 mg/m2 twice daily on days 1-14, repeated every 21 days, with or without bevacizumab 7·5 mg/kg intravenously on day 1) or FOLFIRI with or without bevacizumab (irinotecan 180 mg/m2 intravenously on day 1, leucovorin 200 mg/m2 intravenously on day 1, fluorouracil 400 mg/m2 intravenously on day 1, and a 46-h continuous intravenous infusion of fluorouracil [2400 mg/m2], repeated every 14 days, with or without the addition of bevacizumab 5 mg/kg intravenously on day 1) via a centralised electronic system. We used the minimisation method to stratify randomisation by country, Eastern Cooperative Oncology Group performance status, number of metastatic sites, previous oxaliplatin treatment, and concomitant bevacizumab treatment. Patients and clinicians were not masked to the allocated treatment. The primary endpoint was overall survival analysed on an intention-to-treat basis with a non-inferiority upper margin of 1·30 for the hazard ratio (HR). This study is registered with ClinicalTrials.gov, number NCT01996306, and is ongoing but no longer recruiting participants.Findings: Between Dec 2, 2013, and Aug 13, 2015, 650 patients were enrolled and randomly assigned to receive mXELIRI with or without bevacizumab (n=326) or FOLFIRI with or without bevacizumab (n=324). After a median follow-up of 15·8 months (IQR 8·7-24·9), a total of 490 patients had died (242 in the mXELIRI with or without bevacizumab group and 248 in the FOLFIRI with or without bevacizumab group) and the median overall survival was 16·8 months (95% CI 15·3-19·1) in the mXELIRI group and 15·4 months (13·0-17·7) in the FOLFIRI group (HR 0·85, 95% CI 0·71-1·02; pnon-inferiority<0·0001). In the per-protocol safety population, the most common grade 3-4 adverse event was neutropenia (affecting 52 [17%] of 310 patients in the mXELIRI group and 133 [43%] of 310 in the FOLFIRI group). Incidences of grade 3-4 diarrhoea were higher in the mXELIRI group (22 [7%]) than in the FOLFIRI group (ten [3%]). Serious adverse events were reported in 46 (15%) of 310 patients in the mXELIRI group and 63 (20%) of 310 in the FOLFIRI group. Two treatment-related deaths (one pneumonitis and one lung infection) were observed in the mXELIRI group and there was one treatment-related death (lung infection) in the FOLFIRI group.Interpretation: mXELIRI with or without bevacizumab is well tolerated and non-inferior to FOLFIRI with or without bevacizumab in terms of overall survival. mXELIRI could be an alternative to FOLFIRI as a standard second-line backbone treatment for metastatic colorectal cancer, at least for Asian patient populations.Funding: Chugai Pharmaceutical and F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]

Purpose: To compare a cohort of patients with platinum-resistant recurrent ovarian cancer (PROC) treated with bevacizumab and gemcitabine (Bev-Gem) to that of patients treated only with gemcitabine (Gem).Methods: Between 2011 and 2017, we identified the Bev-Gem and Gem PROC groups. The regimen included 1000 mg/m2 of Gem on days 1, 8, and 15, and 15 mg/m2 of Bev on day 1, every 4 weeks. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of the administration of Bev-Gem or Gem until disease progression or death.Results: The Bev-Gem and Gem groups included 18 and 29 patients, respectively. More patients had advanced stage disease in the Bev-Gem group (p = 0.048); no other characteristics differed between the groups. The response rates [ratio of complete remission (CR) to partial remission (PR)] of Bev-Gem and Gem were 38.9 and 3.4%, respectively (p < 0.01). The clinical benefit rates [combined percentages of CR, PR, and stable disease] of the Bev-Gem and Gem groups were 88.9 and 41.4%, respectively (p = 0.04). PFS and OS of the Bev-Gem group were superior (p < 0.01, p = 0.03, respectively). Bev-Gem was the better prognostic factor of both PFS [hazard ratio (HR) 0.17, p < 0.01] and OS (HR 0.31, p = 0.01). The frequency of hematologic and non-hematologic adverse effects was similar in each group.Conclusion: Bev-Gem regimens improved PFS and OS for PROC. Furthermore, the adverse effects of Bev-Gem were tolerable. Thus, Bev-Gem could be a candidate treatment strategy for PROC. [ABSTRACT FROM AUTHOR]

As a fundamental metabolic enzyme, anti-Thymidylate synthase (TS) strategy has been shown to be an effective therapy for human cancers. However, the genuine effects of TS in pancreatic ductal adenocarcinoma (PDA) are still conflicting. We systemically assessed the prognostic value and whether TS associated with malignant progression in PDA. Protein and mRNA expression level of TS were evaluated in en bloc PDA samples, the prognostic effect of TS expressed in cytoplasm or cytonuclear was determined separately in the first time. The impact of TS on tumor cell behaviors was assessed in in vitro assays, and the TS associated metastatic potential was further determined in two different PDA metastatic models. The retrospective clinical analysis firstly demonstrated that tumor cytonuclear TS expression was positively correlated with lymphatic metastasis and negatively correlated with the overall survival (OS) in PDA patients. The subsequent experiments further confirmed that TS depletion can effectively abate EMT (epithelial to mesenchymal) process in in vitro and decline most of the metastatic lesions in two different PDA mice models, and the deoxythymidine monophosphate (dTMP) biosynthesis malfunction resulted imbalanced dNTP pools may be the fundamental causation. Collectively, the present study suggested the prospective strategy of combined anti-TS scheme for metastatic PDA, and we strongly suggest further clinical standardization research with a large cohort to verify the prognostic value and the therapeutic potential of TS in PDA. [ABSTRACT FROM AUTHOR]