GEM-refractory Pancreatic Cancer Research Articles

A Retrospective Study of Gemcitabine Plus Nab-Paclitaxel for Advanced Pancreatic Cancer Refractory to Gemcitabine Monotherapy.

This study aimed to investigate the efficacy and safety of gemcitabine (GEM) plus nab-paclitaxel (nab-PTX), termed GnP, which is limited, in patients with advanced pancreatic cancer (PC) who show good tolerance to GEM monotherapy prior to being refractory to it. We retrospectively analyzed the data of patients with locally advanced or metastatic PC who received GEM followed by GnP between December 2014 and March 2019, regardless of the treatment line. A total of 14 patients who received GnP after becoming refractory to GEM were included in this study. Eight patients were included in the nab-PTX-naïve group, seven of whom were treated with GEM monotherapy as first-line chemotherapy, and one was refractory to GEM monotherapy after modified FOLFIRINOX treatment. The other six patients were included in the nab-PTX reintroduction group. In this group, all patients received GnP followed by GEM maintenance therapy to prevent adverse events, such as peripheral neuropathy and fatigue. Two patients in the nab-PTX-naïve group showed partial response and none in the reintroduction group; median progression-free survival was 7.6 and 1.4 months and median overall survival was 9.4 and 6.2 months, respectively. In the safety analysis, grade 3 anemia and peripheral neuropathy were observed in one patient in the nab-PTX reintroduction group, while the remaining adverse events were of grade 1 or 2. GnP is safe and effective even in patients with GEM-refractory PC, and GEM treatment followed by GnP can be an effective treatment option for patients with nab-PTX-naïve PC.

TAS-118 (S-1 plus leucovorin) versus S-1 in gemcitabine-refractory advanced pancreatic cancer: A randomized, open-label, phase III trial (GRAPE trial).

4099 Background: Addition of oral leucovorin (LV) to S-1 significantly improved progression-free survival (PFS) in a previous randomized phase II trial in Japanese patients (pts) with gemcitabine (GEM)-refractory advanced pancreatic cancer (PC). TAS-118 is an oral drug containing S-1 and LV. This phase III trial conducted in Japan and Korea compared overall survival (OS) between GEM-refractory advanced PC pts treated with TAS-118 and S-1. Methods: GEM-refractory PC pts were randomized in a 1:1 ratio to receive TAS-118 (S-1; 40-60 mg and LV; 25 mg bid for 1w, q2w) or S-1 (S-1; 40-60 mg bid for 4w, q6w). The primary endpoint was OS. The secondary endpoints included PFS, overall response rate, disease control rate, duration of response, and safety. Results: Five hundred and eighty-six pts were eligible for efficacy assessment (TAS-118: n=296 and S-1: n=290). Baseline characteristics were well balanced between the treatment arms. TAS-118 did not result in a statistically significant improvement in OS compared with that achieved with S-1 (median OS, 7.6 months vs. 7.9 months; hazard ratio [HR], 0.98; 95% CI, 0.82 to 1.16; P=0.756). However, it significantly improved PFS compared to that achieved with S-1 (median PFS, 3.9 months vs. 2.8 months; HR, 0.80; 95% CI, 0.67 to 0.95; P=0.009). Pre-planned subgroup analysis of OS showed significant interactions between the treatment effects and pancreatic resection (P=0.025), and between the treatment effects and country (P=0.004). Grade 3/4 drug-related adverse events (≥5% incidences) in TAS-118 and S-1 arms included diarrhea (7.0% vs. 7.3%), anorexia (6.7% vs. 5.0%), stomatitis (6.7% vs. 0.7%), and anemia (3.3% vs. 5.0%). Conclusions: The primary endpoint was not met. Further, the interactions between the treatment effects and pancreatic resection, and between the treatment effects and country, might affect the results. Clinical trial information: 132172. [Table: see text]

Retrospective analysis of fixed dose rate infusion of gemcitabine and S-1 combination therapy (FGS) as salvage chemotherapy in patients with gemcitabine-refractory advanced pancreatic cancer: inflammation-based prognostic score predicts survival.

The purpose of this study was to assess the efficacy and safety of fixed dose rate infusion of gemcitabine and S-1 combination therapy (FGS) in patients with gemcitabine (GEM)-refractory pancreatic cancer (PC) and to explore independent variables associated with survival. We retrospectively reviewed consecutive patients with GEM-refractory PC who received FGS at our institution from March 2009 to December 2013. GEM was administered by fixed dose rate intravenous infusion of 1,200mg/m(2) as a 120-min infusion on day 1, and S-1 was administered orally twice a day at a dose of 40mg/m(2) on days 1-7. Cycles were repeated every 14days. Sixty-one patients with GEM-refractory PC received FGS. Sixteen patients received FGS as third-line treatment. Twenty-nine patients (48%) had a history of S-1 administration. The objective response rate was 13%, and the disease control rate was 49%. The median progression-free survival time was 2.7months, and the median overall survival time was 6.0months. Major Grade 3 or 4 adverse events included neutropenia (15%), diarrhea (3%), anorexia (2%), and fatigue (2%). A high inflammation-based prognostic score (modified Glasgow prognostic score (mGPS), which incorporates C-reactive protein and albumin), a performance status >0, and serum carbohydrate antigen 19-9 level >2,000IU/ml were independently associated with a poor outcome. FGS might be effective and well tolerated as salvage chemotherapy in a practical setting. The inflammation-based prognostic score is a simple and reliable indicator of survival in the setting of salvage chemotherapy.

Randomized phase II study of best available fluoropyrimidine compared with continuation of gemcitabine (Gem) monotherapy in patients with Gem-refractory pancreatic cancer.

287 Background: Gem is a standard chemotherapy for unresectable pancreatic cancer (PC) patients (pts); however there is no standard regimen for Gem-refractory PC pts. We often continue to administer Gem for Gem-refractory PC pts because Gem is less toxic. The aim of this study is to elucidate the efficacy of second line treatment in PC. Methods: The pts who were treated with standard dose of Gem and diagnosed disease progression with radiographic findings were randomly allocated to arm A (to treat with best available fluoropyrimidine) or arm B (to continue to treat with standard dose of Gem). Each doctor could choose one of the available fluoropyrimidine (5FU, UFT and S-1) in arm A. Results: We collected 80 patients from Jan, 2004 to Sep, 2008 into this trial. 27 pts (67.5%) were treated with S-1, 8 pts (20%) with UFT and 5 pts (12.5%) with 5FU in arm A. Response Rate were 10% in arm A and 0% in arm B, respectively. Disease Control Rate were 50% and 17.5%, Progression Free Survival Time were 113 days and 50 days (p<0.1050) and Overall Survival Time were 226 days and 161 days (p<0.0384), respectively. Conclusions: Fluoropyrimidine statistically improve survival time in Gem-refractory PC pts, compared to continue Gem. Clinical trial information: UMIN000002154.

Phase I/II study of gemcitabine as a fixed dose rate infusion and S-1 combination therapy (FGS) in gemcitabine-refractory pancreatic cancer patients

There is no standard regimen for gemcitabine (Gem)-refractory pancreatic cancer (PC) patients. In a previous phase II trial, S-1 was found to exhibit marginal efficacy. Gem administration by fixed dose rate infusion of 10 mg/m(2)/min (FDR-Gem) should maximize the rate of intracellular accumulation of gemcitabine triphosphate and might improve clinical efficacy. We conducted the phase I/II of FDR-Gem and S-1 (FGS) in patients with Gem-refractory PC. The patients received FDR-Gem on day 1 and S-1 orally twice daily on days 1-7. Cycles were repeated every 14 days. Patients were scheduled to receive Gem (mg/m(2)/week) and S-1 (mg/m(2)/day) at four dose levels in the phase I: 800/80 (level 1), 1,000/80 (level 2), 1,200/80 (level 3) and 1,200/100 (level 4). Forty patients were enrolled in the phase II study at recommended dose. The recommended dose was the level 3. In the phase II, a partial response has been confirmed in seven patients (18%). The median overall survival time and median progression-free survival time are 7.0 and 2.8 months, respectively. The common adverse reactions were anorexia, leukocytopenia and neutropenia. This combination regimen of FGS is active and well tolerated in patients with Gem-refractory PC.

A multinational phase II study of PEP02 (liposome irinotecan) for patients with gemcitabine-refractory metastatic pancreatic cancer.

4069 Background: PEP02 is a novel nanoparticle liposome formulation of irinotecan (CPT-11) that has improved pharmacokinetics and tumor biodistribution of both CPT-11 and its active metabolite-SN38 compared to the free form drug. PEP02 has showed encouraging safety and efficacy in various tumor types, including significant antitumor activity in a human pancreatic cancer L3.6pl orthotopic nude mouse xenograft model. In previous phase I studies, PEP02 either alone or in combination with 5-FU/LV demonstrated prolonged disease control in 5 of 7 (71%) patients (pts) with gemcitabine (GEM)-refractory advanced pancreatic cancer (PC). This phase II study aims to evaluate PEP02 monotherapy as second-line treatment in pts with metastatic, GEM-refractory PC. Methods: Pts were eligible if they had metastatic pancreatic adenocarcinoma, KPS ≥ 70, and progressed following one line of GEM-based therapy. Treatment consisted of PEP02 120 mg/m2 administered as a 90-minute infusion every 3 weeks. A Simon’s 2-stage design was used with 16 pts in the first stage and 39 pts in total; primary objective was 3-month survival rate (OS3-month). Results: Between March 2009 and September 2010, 41 pts were enrolled at 3 centers in the U.S. and Taiwan. Characteristics for the 40 ITT pts: 19 M/21 F; age 39-82 yrs; 25 Asian/15 Caucasian, KPS 100/90/80/70: 7/16/7/10. Mean number of treatment cycles is 5.25 (range, 1-26). Objective response rate is 5% and disease control rate (minor response + stable disease > 2 cycles) is 50%. 10 (30.3%) of 33 pts with elevated baseline CA19-9 have had > 50% biomarker decline. The OS3-month is 75%, with median progression free survival (PFS) and OS of 9 and 21.6 weeks, respectively. There was no correlation between duration of prior GEM-based therapy and survival after PEP02 treatment. The most common G3/4 adverse events are: leucopenia/neutropenia, anemia, diarrhea, and fatigue. Conclusions: This study has already met its primary endpoint (predicted OS3-month ≥ 65%). PEP02 appears to have both activity and tolerable side effects for pts with metastatic, GEM-refractory PC, and represents a promising option for this pt population with few options.

A multinational phase II study of liposome irinotecan (PEP02) for patients with gemcitabine-refractory metastatic pancreatic cancer.

237 Background: PEP02 is a novel nanoparticle liposome formulation of irinotecan (CPT-11) that has improved pharmacokinetics and tumor biodistribution of both CPT-11 and its active metabolite-SN38 compared to the free form drug. PEP02 has showed encouraging safety and efficacy in various tumor types, including significant antitumor activity in a human pancreatic cancer L3.6pl orthotopic nude mouse xenograft model. In previous phase I studies, PEP02 either alone or in combination with 5-FU/LV demonstrated prolonged disease control in 5 of 7 (71%) patients (pts) with gemcitabine (GEM)-refractory advanced pancreatic cancer (PC). This phase II study aims to evaluate PEP02 monotherapy as 2nd-line treatment in pts with metastatic, GEM-refractory PC. Methods: Pts were eligible if they had metastatic pancreatic adenocarcinoma, KPS ≥ 70, and progressed following one line of GEM-based therapy. Treatment consisted of PEP02 120 mg/m2 administered as a 90-minute infusion every 3 weeks. A Simon's 2-stage design was used with 16 pts in the first stage and 39 pts in total; primary objective was 3-month survival rate (OS3-month). Results: Between March 2009 and August 2010, 37 pts were enrolled at 3 centers in the U.S. and Taiwan. Characteristics for the first 31 evaluable pts: 13 M/18 F; age 39-82 yrs; 19 Asian/12 Caucasian, KPS 100/90/80/70: 5/14/4/8. Mean number of treatment cycles is 5 (range, 1-22). Disease control rate (minor response + stable disease >2 cycles) is 52%. 8 of 24 pts (33%) with elevated baseline CA19-9 have had >50% biomarker decline. To date, 23/31 pts (74%) have survived > 3 months, with 4 pts still alive after 1 year. Reasons for study discontinuation: 74% progressive disease, 9% drug-related toxicity, 17% other. Preliminary safety data is available for the first stage. Most common G3/4 adverse events included: fatigue (31%), neutropenia (25%), nausea/vomiting (19%), and diarrhea (13%). Conclusions: This study has already met its primary endpoint (predicted OS3-month >65%). PEP02 appears to have both activity and tolerable side effects for pts with metastatic, GEM-refractory PC, and represents a promising option for this pt population with few standard options. [Table: see text]

The role of S-1 in gemcitabine-refractory pancreatic cancer: A retrospective single-institution study

e15648 Background: S-1 was reported to be active against gemcitabine (Gem)-refractory pancreatic cancer (PaC) in Japan and was introduced in February 2005 in our institution. The aim of this study was to elucidate the impact of S-1 on prognosis of patients with Gem- refractory PaC. Methods: A total of 108 patients (pts) with advanced PaC who were treated with Gem and had disease progression (PD) at the University of Tokyo Hospital were analyzed. The introduction rates of second-line chemotherapy and the causes of introduction failure were assessed. Prognostic factors for residual survival (RS) for Gem-refractory PaC were analyzed by the Cox proportional hazard model. Results: Of 108 pts with Gem-refractory PaC, 47 pts (PreS-1 Group) had PD before February 2005, the time of S-1 introduction in our institution, and 61 pts (PostS-1 Group) after February 2005. There were no differences in baseline characteristics at PD for Gem between PreS-1 and PostS-1 Groups, except for metastasis to peritoneum more prevalent in PreS-1 Group (44.7% in PreS-1 Group and 23.0% in PostS-1 Group, p=0.023). The introduction rate of second-line chemotherapy increased from 12.8% in PreS-1 Group to 45.9% in PostS-1 Group. Second-line chemotherapy was administered in 34 pts, 29 by S-1, 4 by 5-FU-based chemoradiation, and 1 by 5-FU. The causes of introduction failure of second line chemotherapy were poor PS in 64.9%, patients’ refusal in 16.2%, infection in 2.7%, adverse effects of Gem in 1.4% and jaundice in 1.4%. RR, PFS, and OS for second-line S-1 were 17.2%, 2.5 Mo, and 7.8 Mo, respectively. PFS for Gem was not prognostic of PFS for S-1 (2.5 Mo both in pts with PFS >6Mo and in pts with PFS <6Mo for Gem). RS after PD for Gem was prolonged from 3.1 Mo in PreS-1 Group to 6.5 Mo in PostS-1 Group (p<0.001). The Cox hazard model revealed PreS-1 Group (HR2.42, p=0.001) in addition to male gender (HR1.83, p=0.019), poor PS (HR3.52, p<0.001), liver metastasis (HR2.36, p=0.037), elevated LDH (per 100U/L increase) (HR 1.30, p=0.046), elevated CRP (HR 1.14, p=0.023) at PD for Gem as poor prognostic factors of RS for Gem-refractory PaC. Conclusions: Introduction of S-1 might lead to improvement of prognosis in patients with Gem-refractory PaC. No significant financial relationships to disclose.

3544 POSTER Phase I study of gemcitabine as a fixed dose rate infusion and S-1 combination therapy in gemcitabine-refractory pancreatic cancer patients.

Purpose There is no standard regimen for gemcitabine (Gem)-refractory pancreatic cancer (PC) patients. In a previous phase II trial, S-1 was found to exhibit marginal efficacy. Gem administration by fixed dose rate infusion of 10 mg/m2/min (FDR-Gem) should maximize the rate of intracellular accumulation of gemcitabine triphosphate and might improve clinical efficacy. We conducted the phase I/II of FDR-Gem and S-1 (FGS) in patients with Gem-refractory PC.

Prognostic Factors in Patients with Gemcitabine-Refractory Pancreatic Cancer

The purpose of this study was to identify prognostic factors in patients with gemcitabine-refractory pancreatic cancer and to determine criteria for selecting candidates for second-line treatment. The records of 74 patients who were treated with gemcitabine (GEM) and followed up until disease progression were reviewed retrospectively. Sixteen clinical variables at the time of disease progression after GEM chemotherapy were chosen for analysis in this study. Univariate and multivariate analyses were conducted to identify prognostic factors associated with survival. At the time of analysis, 71 patients had died because of tumor progression. The overall median survival time was 5.1 months after first-line chemotherapy with GEM was initiated. Median survival time after disease progression was 2.0 months. Three factors, performance status, peritoneal dissemination and C-reactive protein level, were identified as independent prognostic factors in multivariate analysis. Median survival time in the good prognosis group (patients with performance status 0 or 1, no peritoneal dissemination and C-reactive protein <5.0 mg/dl) was 3.4 months. Performance status, serum level of C-reactive protein and peritoneal dissemination were identified as important prognostic factors in patients with GEM-refractory pancreatic cancer. These factors should be considered in determining the treatment following first-line chemotherapy in patients with advanced pancreatic cancer.