Overall survival in a trial of orally administered CCR2 inhibitor CCX872 in locally advanced/metastatic pancreatic cancer: Correlation with blood monocyte counts.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 92-92 ◽  
Author(s):  
David Linehan ◽  
Marcus Smith Noel ◽  
Aram F. Hezel ◽  
Andrea Wang-Gillam ◽  
Ferry Eskens ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Treatment Period ◽  
Peripheral Blood ◽  
Locally Advanced ◽  
Suppressor Cells ◽  
Peripheral Blood Monocyte ◽  
Blood Monocyte ◽  
Metastatic Pancreatic Cancer ◽  
Myeloid Derived Suppressor Cells

92 Background: The CCL2-CCR2 signaling axis may facilitate migration of myeloid derived suppressor cells to pancreatic cancer resulting in an immune suppressive tumor microenvironment. CCR2 inhibition in patients with non-metastatic pancreatic cancer was previously reported to decrease tumor-infiltrating macrophages/Treg cells and increase effector T cells (Nywening et al, 2016). Here, a CCR2 specific antagonist CCX872 was used in combination with FOLFIRINOX to treat subjects with locally advanced or metastatic, non-resectable pancreatic cancer in a multi-center study. Methods: Fifty subjects (ECOG score ≤ 2) were enrolled, receiving FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) once every two weeks (maximum 12 cycles) plus 150 mg CCX872 QD or BID for 12 weeks. Subjects showing at least stable disease at the end of the 12-week treatment period were eligible to CCX872 treatment until disease progression. In this ongoing study, all subjects are followed for overall survival (OS). Blood samples were taken at baseline and at intervals throughout the active treatment period for hematologic and flow cytometric analysis of circulating immune cell populations. Results: The all-subjects OS at 18 months is 29%. This compares favorably with previously published data: i.e., OS of only 18.6% at 18 months for FOLFIRINOX regimen alone (Conroy et al, 2011). Peripheral blood monocyte counts at baseline inversely correlate with OS (p = 0.0071, Hazard ratio = 1.169) with CCX872 and FOLFIRINOX combination therapy. Overall, circulating monocytes, inflammatory monocytes and monocytic myeloid derived suppressor cells were reduced by treatment. Conclusions: CCX872-B plus FOLFIRINOX resulted in an OS of 29% at 18 months with no safety issues. Better OS was associated with lower peripheral blood monocyte counts at baseline. Clinical trial information: NCT02345408.

Modified IPCW model: A method for adjusting for bias in the estimation of overall survival due to the use of second and third line therapies in locally advanced or metastatic pancreatic cancer patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15787-e15787
Author(s):  
N. E. Iznaga Escobar ◽  
Patricia Lorenzo Luaces ◽  
Lizet Sanchez Valdes ◽  
Carmen Valenzuela Silva ◽  
Tania Crombet Ramos ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Cox Regression ◽  
Locally Advanced ◽  
Secondary Analysis ◽  
Metastatic Pancreatic Cancer ◽  
Fixed Dose ◽  
Line Treatment ◽  
Newly Diagnosed

e15787 Background: Nimotuzumab, a unique and affinity differentiated anti-EGFR antibody had been used in combination with gemcitabine on the treatment of pancreatic cancer patients. The aim of the study was to evaluate overall survival. Methods: Patients with newly diagnosed, locally advanced or metastatic pancreatic cancer, KPS ≥ 70 %, 18-72 years old, with adequate renal and liver function were included. Pts received gemcitabine 1000 mg/m2and nimotuzumab or placebo fixed dose of 400 mg once a wk, for 3 wks, followed by a 1-wk rest (d1, 8, 15, q28) until disease progression or unacceptable toxicity. The primary endpoint was OS and secondary PFS, ORR, CBR, safety and QoL. For OS determination, a KM log-rank test was used and a modified IPCW with a cox regression as a secondary analysis. On this evaluation using a modified IPCW model, 41.7% of pts from treatment arm and 42.7% from control arm who received 2nd and 3rd line treatment were censored after progression, while pts that did not receive 2nd and 3rd line treatment were weighted to compensate for the bias created by censoring switchers to 2nd and 3rd line treatment. Results: 192 pancreatic cancer pts were recruited. Ninety-six pts (62 male and 34 female) with a median age of 67 years, range (31, 83) were randomized to treatment arm and 96 pts (57 male and 39 female) with a median age of 64 years, range (41, 82) were randomized to control arm. In the primary analysis, median OS [95% CI] in the treatment arm was 8.57 mo [5.93, 10.90] vs 6.03 mo [4.97, 7.60] in the control arm. The HR [95% CI], 0.83 [0.62, 1.12] and p = 0.23 and when a modified IPCW model as a secondary analysis was used to remove the effect of 2nd and 3rd line therapies, the median OS was statistically significant with a HR [95% CI], 0.81 [0.67, 0.98] and a p = 0.030. The median PFS [95% CI] was 4.43 mo [3.67, 6.00] in the treatment arm vs 3.47 mo [2.60, 4.03] in the control arm with a HR [95% CI] 0.68 [0.51, 0.92] and p = 0.012. Conclusions: A modified IPCW model had proven that addition of nimotuzumab to gemcitabine increases median overall survival of newly diagnosed chemotherapy-naïve locally advanced or metastatic pancreatic cancer patients. Clinical trial information: NCT00561990.

scholarly journals Impact of New Chemotherapy Regimens on the Treatment Landscape and Survival of Locally Advanced and Metastatic Pancreatic Cancer Patients

2020 ◽  
Vol 9 (3) ◽  
pp. 648 ◽  
Author(s):  
Markus Kieler ◽  
Matthias Unseld ◽  
Daniela Bianconi ◽  
Martin Schindl ◽  
Gabriela V. Kornek ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Median Overall Survival ◽  
Systemic Treatment ◽  
Locally Advanced ◽  
Survival Rates ◽  
Cox Proportional Hazards Model ◽  
Metastatic Pancreatic Cancer ◽  
Line Treatment ◽  
First Line

Background: New chemotherapy regimens for the treatment of metastatic pancreatic cancer have changed the therapy paradigm. We aimed to assess their impact on the treatment landscape and clinical outcome at our academic institution. Methods: In this single institutional posthoc registry analysis, we assessed characteristics and survival rates from all patients with locally advanced and metastatic pancreatic cancer who started a systemic treatment between 01/2011 and 12/2017. Survival analyses were performed by Kaplan-Meier and Cox proportional hazards model. Results: A total of 301 patients started a systemic treatment in the observation period. In the first line treatment, we observed a shift from the four different main regimens (gemcitabine/nab-paclitaxel, modified FOLFIRINOX, gemcitabine/oxaliplatin +/− erlotinib or gemcitabine alone) to gemcitabine/nab-paclitaxel and modified FOLFIRINOX that add up to more than 80% of administered first line treatments in each of the time cohorts (2011–2013 vs. 2014–2017). The rate for first line modified FOLFIRINOX treatment was balanced between the two groups (19% and 15%). Median overall survival differed significantly between the two time cohorts (8.89 versus 11.9 months, p = 0.035). Survival rates for different first to second line treatment sequences (modified FOLFIRINOX to gemcitabine/nab-paclitaxel, gemcitabine/nab-paclitaxel to fluoropyrimidines plus nanoliposomal irinotecan, or gemcitabine/nab-paclitaxel to fluoropyrimidines plus oxaliplatin) were not significantly different and median overall survival ranged from 14.27 to 15.64 months. Conclusion: Our study provides real-world evidence for the effectiveness of the new chemotherapy regimens and underscores the importance of the choice of the front-line regimen when considering different sequencing strategies.

scholarly journals Randomized Phase III Study of Gemcitabine Plus S-1, S-1 Alone, or Gemcitabine Alone in Patients With Locally Advanced and Metastatic Pancreatic Cancer in Japan and Taiwan: GEST Study

2013 ◽  
Vol 31 (13) ◽  
pp. 1640-1648 ◽  
Author(s):  
Hideki Ueno ◽  
Tatsuya Ioka ◽  
Masafumi Ikeda ◽  
Shinichi Ohkawa ◽  
Hiroaki Yanagimoto ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Locally Advanced ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Metastatic Pancreatic Cancer ◽  
Phase Iii Study

Purpose The present phase III study was designed to investigate the noninferiority of S-1 alone and superiority of gemcitabine plus S-1 compared with gemcitabine alone with respect to overall survival. Patients and Methods The participants were chemotherapy-naive patients with locally advanced or metastatic pancreatic cancer. Patients were randomly assigned to receive only gemcitabine (1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle), only S-1 (80, 100, or 120 mg/d according to body-surface area on days 1 through 28 of a 42-day cycle), or gemcitabine plus S-1 (gemcitabine 1,000 mg/m2 on days 1 and 8 plus S-1 60, 80, or 100 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle). Results In the total of 834 enrolled patients, median overall survival was 8.8 months in the gemcitabine group, 9.7 months in the S-1 group, and 10.1 months in the gemcitabine plus S-1 group. The noninferiority of S-1 to gemcitabine was demonstrated (hazard ratio, 0.96; 97.5% CI, 0.78 to 1.18; P < .001 for noninferiority), whereas the superiority of gemcitabine plus S-1 was not (hazard ratio, 0.88; 97.5% CI, 0.71 to 1.08; P = .15). All treatments were generally well tolerated, although hematologic and GI toxicities were more severe in the gemcitabine plus S-1 group than in the gemcitabine group. Conclusion Monotherapy with S-1 demonstrated noninferiority to gemcitabine in overall survival with good tolerability and presents a convenient oral alternative for locally advanced and metastatic pancreatic cancer.

Monocytosis Has Adverse Prognostic Significance and Impacts Survival in Patients with T-Cell Lymphomas.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2647-2647
Author(s):  
Stefano Sacchi ◽  
Alessia Bari ◽  
Tamar Tadmor ◽  
Luigi Marcheselli ◽  
Eliana Valentina Liardo ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Peripheral Blood ◽  
Cell Lymphoma ◽  
Negative Impact ◽  
Peripheral Blood Monocyte ◽  
Blood Monocyte ◽  
Monocyte Count ◽  
T Cell Lymphomas ◽  
Peripheral Blood Monocyte Count

Abstract Abstract 2647 New data concerning the important role of microenvironment on lymphoma growth are emerging, and in recent years surrogate biomarkers have been identified as prognostic factors for survival in non-Hodgkin lymphoma (NHL). Unlike follicular (FL), diffuse B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), there is still no specific internationally accepted risk stratification scoring system for peripheral T-cell lymphomas (PTCL), and the International Prognostic Index (IPI) or the Prognostic Index for T-cell lymphomas (PIT) model are been used to identify higher risk cases of PTCL. Here we retrospectively analyzed the relevance of the well recognized prognostic parameters for T-NHL in 172 patients with different types of PTCL. In 94 cases in whom peripheral blood monocyte count (PBMC) at diagnosis was available, we evaluated whether monocytosis (PBMC >800/mm3) could be used as a simple prognostic factor for overall survival (OS) and outcome in PTCL. For the entire group with a median follow-up of 19 months (range 1–168 months), the 5-years OS was 42%, and the median OS 48 months. Monocytosis was present in 23% of the evaluable cases and patients with high PBMC (>800/mm3) at diagnosis had a worse OS (median 12 months) compared to those with PBMC < 800/mm3.This difference showed strong statistical significance (p=0.003) (Fig 1) and the Hazard ratio (HR) for PBMC >800/mm3, stratified by histopathological subtype, was 2.81. In particular 3-years OS of patients with PBMC >800/mm3 with anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, and peripheral T-cell lymphoma not otherwise specified was 50%, 25%, and 12%, respectively compared to 86%, 65%, and 50% for those patients with PBMC <800/mm3. In univariate analysis age >60y, advanced stage, bone marrow involvement, ECOG PS >1, LDH>UNL, PBMC >800/mm3, hemoglobin <12 gr/dL, albumin <3.5 gr/L were associated with inferior OS. In multivariate analysis, monocytosis alone retained a negative prognostic value even when adjusted for PIT and stratified by histolopathological subtype (HR 2.41, p=0.015). In this study, as in others on B-NHL and HL, monocytosis had an independent negative impact on survival in patients with T-NHL. This data, which provide convincing support for the use of monocytosis as a simple prognostic parameter, now need to be further validated in a larger cohort of patients with T-NHL. Figure 1: Overall survival (OS) of 94 patients with PTCL according to peripheral blood monocyte count (PBMC): monocytosis (PBMC >800/mm3) has a negative impact on OS (p=0.003) Figure 1:. Overall survival (OS) of 94 patients with PTCL according to peripheral blood monocyte count (PBMC): monocytosis (PBMC >800/mm3) has a negative impact on OS (p=0.003) Disclosures: No relevant conflicts of interest to declare.

Retrospective single center review of toxicity and efficacy of a modified FOLFIRINOX regimen in patients with locally advanced and metastatic pancreatic cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 490-490 ◽  
Author(s):  
Bhargavi Pulluri ◽  
Joan Skelly ◽  
Maura Meredith Barry
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Medical Center ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Median Number ◽  
Metastatic Pancreatic Cancer ◽  
Grade 3 ◽  
Number Of Treatment

490 Background: Conroy et al. (N Engl J Med 364:1817–1825, 2011) have shown significantly better overall survival with FOLFIRINOX compared to gemcitabine in metastatic pancreatic cancer patients (MPC). However, given the toxicity associated with FOLFIRINOX treatment, different institutions have adapted varying modifications to the original regimen. Methods: We performed a retrospective review of dose, toxicity, and efficacy of FOLFIRINOX in patients with unresectable locally advanced pancreatic cancer (LAPC) and MPC treated between Jan 2011 and Dec 2015 at University of Vermont Medical Center. Results: 43 patients were treated, of which 33 did not receive any prior treatment (6 LAPC, 27 MPC). 41 patients received dose attenuation with 1st cycle. Median relative dose of irinotecan, oxaliplatin and 5-FU were less than reported by Conroy (69 vs. 81%, 70 vs. 78% and 71 vs. 82%). Median number of treatment cycles 7.8 (range 1 to 41). Median progression free survival in our MPC cases compared to Conroy’s data was 5.7 vs. 6.4 months; overall survival at 6 and 12 months were 78 vs. 75.9% and 41 vs. 48.4% respectively. Grade ¾ toxicities were less, including neutropenia (p<0.001), fatigue (p =0.01) and neuropathy (p=0.04). One patient had grade 3 pneumonitis related to oxaliplatin. Conclusions: Our findings suggest that dose attenuation of 5-FU, irinotecan and oxaliplatin improve tolerability with fairly similar outcome as reported by Conroy et al. [Table: see text]

Irinotecan Plus Gemcitabine Results in No Survival Advantage Compared With Gemcitabine Monotherapy in Patients With Locally Advanced or Metastatic Pancreatic Cancer Despite Increased Tumor Response Rate

2004 ◽  
Vol 22 (18) ◽  
pp. 3776-3783 ◽  
Author(s):  
Caio M. Rocha Lima ◽  
Mark R. Green ◽  
Robert Rotche ◽  
Wilson H. Miller ◽  
G. Mark Jeffrey ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Tumor Progression ◽  
Tumor Response ◽  
Response Rate ◽  
Locally Advanced ◽  
Phase Iii ◽  
Metastatic Pancreatic Cancer ◽  
Tumor Response Rate ◽  
Grade 3

Purpose This phase III, randomized, open-label, multicenter study compared the overall survival associated with irinotecan plus gemcitabine (IRINOGEM) versus gemcitabine monotherapy (GEM) in patients with chemotherapy-naive, locally advanced or metastatic pancreatic cancer. Patients and Methods IRINOGEM patients received starting doses of gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2 given weekly for 2 weeks every 3-week cycle. GEM patients received gemcitabine 1,000 mg/m2 weekly for 7 of 8 weeks (induction) and then weekly for 3 of 4 weeks. The primary end point of the trial was survival. Secondary end points included tumor response, time to tumor progression (TTP), changes in CA 19-9, and safety. Results In each arm, 180 randomly assigned patients comprised the intent-to-treat population evaluated for efficacy; 173 IRINOGEM and 169 GEM patients were treated. Median survival times were 6.3 months for IRINOGEM (95% CI, 4.7 to 7.5 months) and 6.6 months for GEM (95% CI, 5.2 to 7.8 months; log-rank P = .789). Tumor response rates were 16.1% (95% CI, 11.1% to 22.3%) for IRINOGEM and 4.4% (95% CI, 1.9% to 8.6%) for GEM (χ2 P < .001). Median TTP was 3.5 months for IRINOGEM versus 3.0 months for GEM (log-rank P = .352). However, subset analyses in patients with locally advanced disease suggested a TTP advantage with IRINOGEM versus GEM (median, 7.7 v 3.9 months). CA 19-9 progression was positively correlated with tumor progression. The incidence of grade 3 diarrhea was higher in the IRINOGEM group but grade 3 to 4 hematologic toxicities and quality-of-life outcomes were similar. Conclusion IRINOGEM safely improved the tumor response rate compared with GEM but did not alter overall survival.

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