Fixed Dose Rate Gemcitabine Research Articles

Phase 2 Trial of Neoadjuvant FOLFIRINOX and Intensity Modulated Radiation Therapy Concurrent With Fixed-Dose Rate-Gemcitabine in Patients With Borderline Resectable Pancreatic Cancer

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. 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. 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). 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.

Alternate Week Gemcitabine and Capecitabine: An Effective Treatment for Patients With Pancreatic Adenocarcinoma.

Determine whether a regimen of fixed dose rate gemcitabine plus capecitabine is effective and tolerable for advanced pancreatic adenocarcinoma. We performed a retrospective analysis of 62 patients with locally advanced or metastatic pancreatic adenocarcinoma treated at the University of California San Francisco between 2008 and 2016. Treatment was an alternate week schedule of fixed dose rate 1000 mg/m gemcitabine and capecitabine 1000 mg/m (58 patients), 1200 mg/m (12 patients), or 650 mg/m (1 patient) for intended 12 cycles. We evaluated overall survival (OS), progression-free survival (PFS), radiologic response, and adverse events necessitating treatment modification. For metastatic patients, median OS was 10.3 months (95% confidence interval [CI], 6.7-12.1 months), and PFS was 5.6 months (95% CI, 2.6-7.7 months). In locally advanced patients, OS was 12.0 months (95% CI, 4.9-17.1 months), and PFS was 5.4 months (95% CI, 2.5-9.4 months). Radiologic response for metastatic disease (42 patients) was 19% objective response, 45% stable disease, and 36% progressive disease. Treatment required modification for 22 patients due to adverse events, most frequently hand-foot syndrome (18 patients). Alternate week schedule of fixed dose rate gemcitabine and capecitabine was active and tolerable for advanced pancreatic adenocarcinoma. Overall survival and PFS were comparable to first-line treatments. Importantly, adverse effects appear less severe than first-line treatments.

Efficacy and safety of neoadjuvant FOLFIRINOX for borderline resectable pancreatic adenocarcinoma: improved efficacy compared with gemcitabine-based regimen.

Borderline resectable pancreatic cancer (BRPC) is a potentially resectable disease but is associated with poorer survival compared to primary resectable disease. There has been no prospective trial that compare the efficacy of FOLFIRNOX and gemcitabine-based regimen for BRPC. Between February 2013 and December 2014, 18 patients with BRPC receiving FOLFIRINOX were reviewed retrospectively. For comparative analysis, data for all BRPC patients (n=18) in our previous phase 2 study of neoadjuvant fixed-dose rate-gemcitabine plus capecitabine were pooled. Patients received a median 6 cycles (range, 3-13) of FOLFIRINOX. Surgical resection was performed in 12 patients (67%) and R0 resection in 9 patients. Median progression-free survival (PFS) and overall survival (OS) were 16.8 (95% confidence interval [CI], 9.4-24.2) and 21.2 (95% CI, 14.2-28.2) months, respectively. Patients who underwent surgical resection showed significantly better PFS (p=0.01) and OS (p=0.003) than those unresected. In the exploratory analysis, patients receiving FOLFIRINOX showed significantly longer PFS compared to those receiving fixed-dose rate-gemcitabine plus capecitabine (median 16.8 months [95% CI, 9.4-24.2] vs. 6.5 months [1.6-11.3]; p = 0.04). There was a trend toward improved OS in patients who received FOLFIRINOX (median 21.2 months [95% CI, 14.2-28.2]) compared to those who received fixed-dose rate-gemcitabine plus capecitabine (13.6 months [11.8–15.4]; p=0.12). FOLFIRINOX was feasible and effective as neoadjuvant chemotherapy for patients with BRPC and may have improved efficacy compared to a gemcitabine-based regimen.

Biweekly gemcitabine and low-dose cisplatin in the treatment of locally advanced or metastatic pancreatic cancer patients: a single institute experience.

Gemcitabine in combination with low-dose cisplatin has shown promising activity in pancreatic cancer with manageable toxicities. The purpose of this study is to assess the activity of a combination of gemcitabine and low-dose cisplatin in the first-line treatment of metastatic and locally advanced pancreatic cancer patients. We conducted a retrospective analysis of all patients diagnosed with metastatic and locally advanced pancreatic cancer who received a combination of gemcitabine and cisplatin in the first-line setting. Patients with baseline cytopenias and elevated liver function tests were included. Patients received cisplatin at 20mg per square meter followed by gemcitabine at a dose of 1000mg per square meter at fixed dose rate every 2weeks. Patients were treated until disease progression or unacceptable toxicities. A total of 58 patients were included in the analysis. The median progression-free survival was 4.4months [95% confidence interval (CI) 3.6-6.4], and median overall survival was 6.7months (95% CI 4.4-10.9). Thirty-eight patients (66%) experienced at least one grade 3 or 4 toxicity. The most common grade 3 or 4 toxicity was hematologic toxicity (25 patients, 43%). Biweekly fixed dose rate gemcitabine combined with low-dose cisplatin shows interesting activity in advanced pancreatic cancer. This regimen is an acceptable alternative for patients ineligible for gemcitabine plus nab-paclitaxel (i.e., those with elevated bilirubin at baseline) or clinical trials. Additionally, this regimen should be considered as a first-line option for those patients with breast cancer susceptibility gene mutations (BRCA1 and/or BRCA2).

Fixed Dose Rate versus Standard Dose Rate Infusion of Gemcitabine and Cisplatin in Advanced Stage Non-Small Cell Lung Cancer

Background: Comparing the efficacy and safety of gemcitabine at a fixed-dose rate (FDR) infusion (10 mg/m2/min) with the standard dose rate infusion in patients with locally advanced and metastatic non-small squamous cell carcinoma (NSCLC). Methods: The study randomized 60 patients with confirmed diagnosis of NSCLC to receive gemcitabine at a dose of 1000 mg/m2 on days 1 and 8 given as a 30-min infusion (Arm A) or at a rate of 10 mg/m2/min (Arm B). Cisplatin 75 mg/m2 was administered intravenously on day 2 in both arms. Results: No difference in overall response rate (46.6% versus 43.3%). Median time to progression for Arm A was 7 months (95% CI, 6.207 - 7.793 months), versus 6 months for Arm B (95% CI, 4.990 - 7.010 months). Median survival time was comparable [12 months (95% CI, 8.588 - 15.412 months) versus 11 months (95% CI, 9.066 - 12.934 months)] respectively. Two-year survival (18% versus 11%, p = 0.38) was detected. No treatment related deaths occurred. Main hematological toxicities were grade I and II neutropenia, in 36.7% and 53.3% respectively (p = 0.044). Grade III anemia was observed in 10% and 6.7% in both arms respectively (p = 0.024). Grade I and II nausea and vomiting was observed in 50% and 46.7%. Conclusions: FDR gemcitabine in combination with cisplatin had equivalent efficacy and more severe hematologic toxicities compared to the standard 30-min gemcitabine infusion with cisplatin in patients with advanced NSCLC.

Gemcitabine fixed-dose rate infusion for the treatment of pancreatic carcinoma: a meta-analysis of randomized controlled trials.

BackgroundPre-clinical evidence shows that fixed dose rate (FDR) infusion of gemcitabine could optimize plasma concentration of gemcitabine, while the clinical efficacy and toxicity of FDR infusion of gemcitabine in advanced pancreatic carcinoma has not been systematically investigated. Thus, this meta-analysis was designed to ascertain this issue.MethodsDatabases of EMBASE, PubMed, and Cochrane Library were searched for eligible randomized controlled trials (RCTs). RCTs comparing FDR and standard 30-min infusion of gemcitabine in advanced pancreatic carcinoma were included. The primary endpoints were treatment efficacy (overall response rate, 1-year survival rate, median survival, and time to treatment failure) and toxicities were secondary endpoints (neutropenia, thrombocytopenia, anemia, and vomiting). Relative risks or mean differences and corresponding 95% confidence intervals (CIs) were calculated.ResultAfter careful and rigorous selection, 3 eligible RCTs including 764 patients of advanced pancreatic adenocarcinoma were included in this meta-analysis. For treatment efficacy, FDR gemcitabine provided significantly longer median survival over standard gemcitabine (Mean Difference = 1.24 months, 95% CI: 0.39-2.09), while there was no statistical difference in other endpoints of treatment efficacy. For toxicities, patients with FDR gemcitabine experienced significantly more grade 3/4 hematological toxicities than those received standard gemcitabine (neutropenia, thrombocytopenia, and anemia), while there was no difference for vomiting.ConclusionCompared with standard 30-min infusion, FDR gemcitabine provide longer median survival, but increased the risk of hematological toxicities for patients with advanced pancreatic adenocarcinoma.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_214Electronic supplementary materialThe online version of this article (doi:10.1186/s13000-014-0214-8) contains supplementary material, which is available to authorized users.

Fixed-dose rate gemcitabine alone or alternating with FOLFIRI.3 (irinotecan, leucovorin and fluorouracil) in the first-line treatment of patients with metastatic pancreatic adenocarcinoma: An AGEO randomised phase II study (FIRGEM)

BackgroundFluorouracil and irinotecan-based, and gemcitabine-based regimens, are the standard of care in the first-line treatment of patients with metastatic pancreatic cancer. New approaches are needed to improve survival and quality of life. Whether a sequential approach alternating irinotecan, fluorouracil and gemcitabine may be effective and tolerable in patients with metastatic pancreatic cancer is unknown. MethodsIn this randomised, multicentre, open-label, phase 2 trial, patients with metastatic pancreatic adenocarcinoma, World Health Organisation (WHO) performance status 0–1, and bilirubin levels <1.5 upper limit of normal values (ULN) were randomised 1:1 to receive as first-line treatment either FOLFIRI.3 (irinotecan, leucovorin and fluorouracil) alternating with fixed-dose rate gemcitabine as 2-month periods (FIRGEM, arm A), or fixed-dose rate gemcitabine alone (arm B). Treatment was continued until disease progression or limiting toxicity. The primary end-point was the crude progression-free survival (PFS) rate at 6months. The study is registered with EudraCT (N° 2006-005703-34). ResultsBetween October 2007 and March 2011, 98 patients were enroled. The observed 6-month PFS rate was 43.5% (95% confidence interval (CI), [28.6–58.4%]) in arm A reaching the Fleming decision rules criteria to reject H0 and 26.1% (95% CI [12.9–39.3%]) in arm B.Objective response rates were 37% (23–51%) in arm A and 10% (1–19%) in arm B. Median PFS (5.0 versus 3.4months, hazard ratio (HR)=0.59 [0.38–0.90]) and overall survival (11.0 versus 8.2months, HR=0.71 [0.46–1.10]) were higher in arm A compared to arm B. The most frequent grade 3–4 toxicities were neutropenia (49%/24%; febrile neutropenia, 4%/0% in arms A/B), diarrhoea (arm A, 12% and arm B, 0%), and nausea/vomiting (8%/4%). No toxic deaths occurred. ConclusionThe FIRGEM strategy appears to be effective and feasible in patients with metastatic pancreatic cancer.

680P - Phase Ii Study of a Combination Chemotherapy with Weekly Docetaxel and Gemcitabine in Previously Treated Metastatic Esophageal Squamous Cell Cancer

ABSTRACT Aim: This multicenter, phase II study was conducted to assess the efficacy and safety of weekly docetaxel plus fixed-dose rate (FDR) gemcitabine as second-line chemotherapy in patients with metastatic esophageal squamous cell carcinoma (SCC). Methods: Esophageal SCC patients with documented progression after fluoropyrimidine-based first-line chemotherapy were treated with docetaxel 35 mg/m2 and gemcitabine 1,000 mg/m2 iv at FDR (10 mg/m2/min) on days 1 and 8. Treatment was repeated every 21 days until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint was response rate (RR), and secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS). Results: A total of 33 patients were registered onto this prospective study. Combination or weekly docetaxel and FDR gemcitabine was well tolerated: the most common treatment-related adverse events were anemia (97%), fatigue (64%) and neutropenia (55%). Grade 3 or 4 neutropenia was developed in 13 patients (39%) and three episodes of febrile neutropenia were observed. One patient with lung and extensive lymph node metastases died of respiratory failure after receiving fourth cycles of chemotherapy, and the possibility of drug-induced pneumonitis could not be completely excluded. The overall RR was 30% with one complete and 9 partial responses. Stable disease was documented in 19 patients (58%). The median PFS and OS were 6 (95% CI 5-8) and 9 (95% CI 7-11) months, respectively. Conclusions: The weekly combination of docetaxel and FDR gemcitabine showed a promising antitumor activity and tolerability in previously treated, metastatic esophageal SCC. Disclosure: All authors have declared no conflicts of interest.

Efficacy and safety of fixed dose rate gemcitabine infusion in combination with docetaxel in patients with relapsed/refractory soft tissue sarcoma

To evaluate the efficacy and safety of fixed dose rate (FDR) gemcitabine infusion in combination with docetaxel in patients with relapsed/refractory soft tissue sarcoma. Clinicopathological data of 28 patients with relapsed/refractory soft tissue sarcoma treated in our hospital from April 2008 to August 2013 were reviewed in this study. The patients received 900 mg/m² gemcitabine with a FDR infusion (10 mg/m²/min) in a total dose of 900 mg/m² on days 1 and 8, and 75 mg/m² docetaxel intravenously over 60 min on day 8 of a 21-day cycle. When irradiation was conducted before drug therapy, the dose of gemcitabine was reduced to 675 mg/m² on days 1 and 8. The clinicopathological characteristics, short-term response, long-term survival status and toxicity were analyzed retrospectively. The 28 patients received a total of 118 cycles of therapy (range 1-8 cycles, median 4 cycles per patient). No patient achieved complete response (CR), 4 partial responses (PR) and 11 stable diseases (SD), with an overall response rate (ORR) of 14.3% and clinical benefit rate (CBR) of 53.6%. The median progression-free survival (PFS) was 3.2 months and the median overall survival (OS) was 8.5 months. PFS and OS were correlated with the response to this treatment regimen (P < 0.0001). Patients with clinical benefit had significantly better PFS and OS than the patients with progressive disease (P < 0.05 for all). The ORR, CBR, PFS and OS were better in patients with leiomyosarcoma than in patients with other histological subtypes in this study, but the differences were not significant (P > 0.05 for all). Grade 3-4 neutropenia, anemia and thrombocytopenia were 50.0%, 17.9% and 14.3%, respectively. Only one patient (3.6%) had febrile neutropenia. Grade 3 non-hematologic toxicities were nausea/vomiting (3.6%) and mucositis (3.6%). No grade 4 non-hematologic toxicities were observed. Almost all non-hematologic toxicities were grade 1-2 and manageable. The fixed dose rate (FDR) gemcitabine infusion in combination with docetaxel is an effective treatment regimen for patients with relapsed/refractory soft tissue sarcoma, and with tolerable adverse reactions.

Phase II Study of Induction Fixed-Dose Rate Gemcitabine and Bevacizumab Followed by 30 Gy Radiotherapy as Preoperative Treatment for Potentially Resectable Pancreatic Adenocarcinoma

Eighty percent of patients with resected pancreatic ductal carcinoma (PDC) experience treatment failure within 2 years. We hypothesized that preoperative fixed-dose rate (FDR) gemcitabine (GEM) combined with the angiogenesis inhibitor bevacizumab (BEV) and accelerated 30 Gy radiotherapy (RT) would improve outcomes among patients with potentially resectable PDC. This phase II trial tested induction FDR GEM (1,500 mg/m(2)) plus BEV (10 mg/kg IV) every 2 weeks for three cycles followed by accelerated RT (30 Gy in 10 fractions) plus BEV directed at gross tumor volume plus a 1-2 cm vascular margin. Subjects underwent laparoscopy and resection after day 85. Therapy was considered effective if the complete pathologic response rate exceeded 10 % and the margin-negative resection rate exceeded 80%. Fifty-nine subjects were enrolled; 29 had potential portal vein involvement. Two grade 4 (3.4%) and 19 grade 3 toxicities (32.8%) occurred. Four subjects manifested radiographic progression, and 10 had undetected carcinomatosis. Forty-three pancreatic resections (73%) were performed, including 19 portal vein resections (44%). Margin-negative outcomes were observed in 38 (88%, 95% confidence interval [CI] 75-96), with one complete pathologic response (2.3%; 95% CI 0.1-12). There were seven (6 grade 3; 1 grade 4) wound complications (13%). Median overall survival for the entire cohort was 16.8 months (95% CI 14.9-21.3) and 19.7 months (95% CI 16.5-28.2) after resection. Induction therapy with FDR GEM and BEV, followed by accelerated BEV/RT to 30 Gy, was well tolerated. Although both effectiveness criteria were achieved, survival outcomes were equivalent to published regimens.

Randomized phase II trial of gemcitabine versus gemcitabine and imatinib mesylate in patients with previously treated metastatic breast cancer.

1091 Background: Gemcitabine (GEM) as a standard 30-min infusion has activity as a single-agent in metastatic breast cancer (mbc). Prolonged infusion of GEM at a fixed dose rate (FDR) of 10 mg/m2/min is associated with greater formation of active metabolite and may result in improved antitumor activity. Imatinib mesylate (IM)-mediated inhibition of PDGFR reduces tumor interstitial fluid pressure allowing for improved chemotherapy penetration into tumors. We evaluated the addition of IM to FDR GEM in patients (pts) with previously treated mbc. Methods: This was a randomized phase II trial in mbc pts who progressed after 1 but no more than 2 prior cytotoxic regimens. Eligibility included measurable disease; no prior GEM or IM exposure. Group 1 received FDR GEM IV 1250 mg/m2 at 10 mg/m2/min (over 120 min) on days 3 and 10 every 21 days; Group 2 received the same FDR GEM dose and schedule plus IM 400 mg orally daily on days 1-5 and 8-12 every 21 days. Primary endpoint was time to progression (TTP). Sample size of 40 pts per group was needed to detect an 8 mo increase in TTP with the combination (80% power, α = .05, 2-sided). Secondary endpoints included ORR and safety. Results: Between 5/2006-4/2011, 44 pts were randomized (22 per group). Study closed early due to slow accrual. Median age 54 (31-75); median ECOG PS 1 (0-2); 52% were hormone receptor-positive and HER2-negative; 27% triple-negative, and 20% HER2-positive. Median number of cycles was 2 in Group 1 (range 1-12) and 3.5 in Group 2 (range 1-13). Most common adverse events (%) of any grade, Group 1 vs Group 2 were neutropenia (68 vs. 78), anemia (48 vs. 65), thrombocytopenia (24 vs. 47), nausea (40 vs. 52) and vomiting (24 vs. 21). One gr 4 thrombotic thrombocytopenic purpura occurred in Group 2. Median TTP were 2 mo (95% CI: 1-5 mo) in Group 1 and 2.5 mo (95% CI: 1-5 mo) in Group 2 (p = 0.3 log rank test). ORR was 9.1% in each group (95% CI: 1.6-30.6%), with 2 PRs in each group. Stable disease (≥ 3 mo) was 32% in Group 1 and 41% in Group 2. Conclusions: This study was underpowered to draw any conclusion regarding a difference in TTP between the two groups at the time it was prematurely closed. Combination of IM and FDR GEM showed a trend to increased toxicity compared to FDR GEM alone. Clinical trial information: NCT00323063.

Phase I dose-escalation study and population pharmacokinetic analysis of fixed dose rate gemcitabine plus carboplatin as second-line therapy in patients with ovarian cancer

ObjectiveThis phase I study of fixed dose rate (FDR) gemcitabine and carboplatin assessed the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, pharmacokinetic (PK)/pharmacodynamic (PD) profile and preliminary anti-tumor activity in patients with recurrent ovarian cancer (OC). MethodsPatients with recurrent OC after first line treatment were treated with carboplatin and FDR gemcitabine (infusion speed 10mg/m2/min) on days 1, 8 and 15, every 28days. Pharmacokinetics included measurement of platinum concentrations in plasma ultrafiltrate (pUF) and plasma concentrations of gemcitabine (dFdC) and metabolite dFdU. Intracellular levels of dFdC triphosphate (dFdC-TP), the most active metabolite of gemcitabine, were determined in peripheral blood mononuclear cells (PBMCs). Population pharmacokinetic modeling and simulation were performed to further investigate the optimal schedule. ResultsTwenty three patients were enrolled. Initial dose escalation was performed using FDR gemcitabine 300mg/m2 (administered at infusion speed of 10mg/m2/min) combined with carboplatin AUC 2.5 and 3. Excessive bone marrow toxicity led to a modified dose escalation schedule: carboplatin AUC 2 and dose escalation of FDR gemcitabine (300mg/m2, 450mg/m2, 600mg/m2 and 800mg/m2). DLT criteria as defined per protocol prior to the study were not met with carboplatin AUC 2 in combination with FDR gemcitabine 300–800mg/m2 because of myelosuppressive dose-holds (especially thrombocytopenia and neutropenia). ConclusionsFDR gemcitabine in combination with carboplatin administered in this 28days schedule resulted in increased grade 3/4 toxicity compared to conventional 30-minute infused gemcitabine. A two weekly schedule (chemotherapy on days 1 and 8) would be more appropriate.

First-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancer

To investigate activity, toxicity, and prognostic factors for survival of erlotinib and fixed dose-rate gemcitabine (FDR-Gem) in advanced pancreatic cancer. We designed a single-arm prospective, multicentre, open-label phase II study to evaluate the combination of erlotinib (100 mg/d, orally) and weekly FDR-Gem (1000 mg/m(2), infused at 10 mg/m(2) per minute) in a population of previously untreated patients with locally advanced, inoperable, or metastatic pancreatic cancer. Primary endpoint was the rate of progression-free survival at 6 mo (PFS-6); secondary endpoints were overall response rate (ORR), response duration, tolerability, overall survival (OS), and clinical benefit. Treatment was not considered to be of further interest if the PFS-6 was < 20% (p0 = 20%), while a PFS-6 > 40% would be of considerable interest (p1 = 40%); with a 5% rejection error (α = 5%) and a power of 80%, 35 fully evaluable patients with metastatic disease were required to be enrolled in order to complete the study. Analysis of prognostic factors for survival was also carried out. From May 2007 to September 2009, 46 patients were enrolled (male/female: 25/21; median age: 64 years; median baseline carbohydrate antigen 19-9 (CA 19-9): 897 U/mL; locally advanced/metastatic disease: 5/41). PFS-6 and median PFS were 30.4% and 14 wk (95%CI: 10-19), respectively; 1-year and median OS were 20.2% and 26 wk (95%CI: 8-43). Five patients achieved an objective response (ORR: 10.9%, 95%CI: 1.9-19.9); disease control rate was 56.5% (95%CI: 42.2-70.8); clinical benefit rate was 43.5% (95%CI: 29.1-57.8). CA 19-9 serum levels were decreased by > 25% as compared to baseline in 14/23 evaluable patients (63.6%). Treatment was well-tolerated, with skin rash being the most powerful predictor of both longer PFS (P < 0.0001) and OS (P = 0.01) at multivariate analysis (median OS for patients with or without rash: 42 wk vs 15 wk, respectively, Log-rank P = 0.03). Additional predictors of better outcome were: CA 19-9 reduction, female sex (for PFS), and good performance status (for OS). Primary study endpoint was not met. However, skin rash strongly predicted erlotinib efficacy, suggesting that a pharmacodynamic-based strategy for patient selection deserves further investigation.

Optimizing the Administration of Fixed-Dose Rate Gemcitabine Plus Capecitabine Using an Alternating-week Schedule

This multisite study sought to optimize the dosing, schedule, and administration of fixed-dose rate (FDR) gemcitabine plus capecitabine for advanced pancreatic and biliary tract cancers using an alternating-week dose schedule of both agents. Patients with previously untreated advanced pancreatic and biliary tract cancers with Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. For the dose-finding portion, a standard 3+3 dose-escalation schema was used, with the gemcitabine dose kept at 1000 mg/m(2) administered by FDR (10 mg/m(2)/min) on day 1 of each 14-day cycle, and capecitabine given on days 1 to 7 at doses ranging from 800 to 1500 mg/m(2) twice daily. Primary study objective was determination of maximum tolerated dose (MTD). The cohort at MTD was expanded for further efficacy assessment. A total of 45 patients (median age 61 y; 93% pancreatic/7% biliary; 84% with metastatic disease) were enrolled. Median number of cycles received was 11.5. The MTD using this dose schedule was FDR gemcitabine 1000 mg/m(2) plus capecitabine 1000 mg/m(2) bid, due to a high incidence of late hand-foot syndrome observed at the next higher dose level. Most common nonhematologic adverse events related to treatment included nausea/vomiting (overall rate, 64%; all grade 1/2) and hand-foot syndrome (overall rate, 60%; grade 3, 22%). The incidence of grade 3/4 hematologic adverse events was 24%. Six of 41 evaluable patients (14.6%) had a partial response; 18 of 31 patients (58%) with elevated baseline CA 19-9 level had ≥50% biomarker decline during treatment. Estimated median time to tumor progression and overall survival were 5.5 and 9.8 months, respectively (5.5 and 10.1 mo in the metastatic pancreatic cancer cohort). This dosing schedule of FDR gemcitabine plus capecitabine is active in patients with advanced pancreatobiliary cancers. Given its favorable toxicity profile and convenience, this regimen represents an appropriate front-line option for this patient population and may serve as the foundation on which new investigational agents are added in future trial design.

Fixed-Dose Rate Gemcitabine Plus Capecitabine as Second-Line Treatment for Metastatic Pancreatic Cancer Patients Pretreated with Oxaliplatin

Context There is no consensus about second-line chemotherapy for pancreatic cancer. The addition of oxaliplatin to 5-fluorouracil/folinic acid improved outcome in gemcitabine refractory patients. However, first-line options for these patients are changing and combination chemotherapy containing oxaliplatin such as FOLFIRINOX is frequently used. Objective We performed a phase II trial to evaluate the activity of a regimen with fixed-dose rate gemcitabine and capecitabine (FDR GEM-CAP) as second-line treatment for metastatic pancreatic cancer patients pretreated with oxaliplatin. Methods Patients with cytological or histological diagnosis of pancreatic adenocarcinoma, with ECOG performance status (PS) 0 or 1, who progressed after first-line chemotherapy including oxaliplatin were enrolled into the study and treated with capecitabine 650 mg/m 2 bid on days 1 to 14 plus FDR gemcitabine 800 mg/m 2 infused in 80 minutes on days 1 and 8, with cycles repeated every 21 days. The main end-point of the study was the percentage of patients free of progression at 2 months after beginning of chemotherapy; with a p0=0.50 and p1=0.70, an α=0.10 and β=0.20, a total of 20 patients should be necessary for the analysis. Results Twenty patients were enrolled; M/F=9/11; PS 0/1=13/7. Median age was 60 years (range 42-75 years). First-line treatment was gemcitabine plus oxaliplatin (GEMOX) in 13 patients and FOLFIRINOX in 7. The median number of cycles of second-line FDR GEM-CAP was 4 (range 2-14), with a total of 108 cycles administered. The only grade 3 toxicity recorded was anemia in 1 patient. Only 9 cycle delays (8.3%) were needed for toxicity. Among 18 patients so far evaluable for response, 2 partial responses (11.1%) and 7 stable diseases (38.9%) have been observed. The trial met its primary end-point; median progression-free survival was 4.3 months with a percentage of patients free of progression at 2 months of 79%. Median overall survival from the beginning of second-line was 12 months. Conclusion The combination of FDR GEM-CAP as we used is well tolerated and active in metastatic pancreatic cancer patients and could be an interesting second-line option for selected patients treated with first-line FOLFIRINOX.

A phase I study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors

Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G. Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m(2) over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured. Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m(2) (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome. This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.

Phase II clinical trial of induction chemotherapy with fixed dose rate gemcitabine and cisplatin followed by concurrent chemoradiotherapy with capecitabine for locally advanced pancreatic cancer

5-FU-based concurrent chemoradiotherapy (CRT) has been the mainstay of treatment for locally advanced pancreatic cancer (LAPC) for the past decades, but the prognosis remains dismal. Patients with pathologically confirmed LAPC of the pancreas, an ECOG PS of 0-2 and no prior chemo- or radiotherapy were eligible. The treatment consisted of induction (IND) chemotherapy with a fixed dose rate gemcitabine 1,000 mg/m(2) on days 1 and 8 and CDDP 60 mg/m(2) on day 1 every 3 weeks for 3 cycles. Subsequently, the patients without progression received CRT of 55.8 Gy/31 fractions with capecitabine 650 mg/m(2) twice daily. Gemcitabine was given for 3 cycles after CRT. The primary endpoint was time to progression. Thirty-seven patients with LAPC were enrolled. Median age was 55 years, there were 20 males and 17 females, and ECOG PS was 0 in 6 and 1 in 31. Three patients (9.7 %) achieved partial responses after IND chemotherapy. Twenty-five patients received CRT with a mean radiation dose of 54.0 Gy, with one additional patient achieving a partial response. The median time to progression was 7.2 months (95 % CI, 4.4-10), and the median overall survival was 16.8 months (95 % CI, 12.9-20.7). The grade 3/4 toxicities included neutropenia (29 %/6.5 %), thrombocytopenia (3.2 %/0 %) and anemia (9.7 %/0 %) during the IND phase and grade 3 neutropenia and diarrhea occurring in one and two patients during CRT phase. IND chemotherapy with gemcitabine and cisplatin followed by CRT with capecitabine and maintenance gemcitabine was well tolerated and exhibited promising efficacy for the treatment of LAPC.

A Phase I/II Trial of Intensity Modulated Radiation (IMRT) Dose Escalation With Concurrent Fixed-dose Rate Gemcitabine (FDR-G) in Patients With Unresectable Pancreatic Cancer

Local failure in unresectable pancreatic cancer may contribute to death. We hypothesized that intensification of local therapy would improve local control and survival. The objectives were to determine the maximum tolerated radiation dose delivered by intensity modulated radiation with fixed-dose rate gemcitabine (FDR-G), freedom from local progression (FFLP), and overall survival (OS). Eligibility included pathologic confirmation of adenocarcinoma, radiographically unresectable, performance status of 0-2, absolute neutrophil count of ≥ 1,500/mm(3), platelets ≥ 100,000/mm(3), creatinine <2 mg/dL, bilirubin <3 mg/dL, and alanine aminotransferase/aspartate aminotransferase ≤ 2.5 × upper limit of normal. FDR-G (1000 mg/m(2)/100 min intravenously) was given on days -22 and -15, 1, 8, 22, and 29. Intensity modulated radiation started on day 1. Dose levels were escalated from 50-60 Gy in 25 fractions. Dose-limiting toxicity was defined as gastrointestinal toxicity grade (G) ≥ 3, neutropenic fever, or deterioration in performance status to ≥ 3 between day 1 and 126. Dose level was assigned using TITE-CRM (Time-to-Event Continual Reassessment Method) with the target dose-limiting toxicity (DLT) rate set to 0.25. Fifty patients were accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or dehydration (7); duodenal bleed (3); duodenal perforation (1). The recommended dose is 55 Gy, producing a probability of DLT of 0.24. The 2-year FFLP is 59% (95% confidence interval [CI]: 32-79). Median and 2-year overall survival are 14.8 months (95% CI: 12.6-22.2) and 30% (95% CI 17-45). Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months. High-dose radiation therapy with concurrent FDR-G can be delivered safely. The encouraging efficacy data suggest that outcome may be improved in unresectable patients through intensification of local therapy.

A Phase II Trial of Fixed-Dose Rate Gemcitabine plus Capecitabine in Metastatic/Advanced Biliary Tract Cancer Patients

Background: This phase II trial was conducted to determine the activity and safety of the combination of fixed-dose rate (FDR) gemcitabine and capecitabine in metastatic biliary tract cancer (BTC) patients. Methods: Patients with unresectable BTC who had pathologically confirmed adenocarcinoma, no prior chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status ≤1 and measurable disease were enrolled. Treatment consisted of FDR gemcitabine at 800 mg/m² on days 1 and 8 every 21 days with capecitabine administered orally b.i.d. in equal doses (650 mg/m² b.i.d.) for 14 days (28 doses). Results: Between May 2005 and February 2009, 30 patients were enrolled. The median age was 67 years (45–76) and there were 14 males. Thirty patients were evaluable for response and toxicity. A total of 221 cycles were administered (median 7, range 2–16). One patient achieved complete response and 7 patients achieved partial response, giving an overall response rate of 26.7% in the intention-to-treat population. Twelve patients (40.0%) had stable disease. The median progression-free survival was 6.33 months. The median overall survival was 10.8 months. Grade 3/4 neutropenia and thrombocytopenia were noted in 13 and 7% of the patients, respectively. Grade 2/3 nonhematologic toxicities were asthenia (54% of patients), diarrhea (17%), stomatitis (23%) and hand-foot syndrome (7%). There was no treatment-related death. The drugs taken were skipped at least once in 45% of the patients and the dose was reduced in 26% of them. Conclusions: The combination of FDR gemcitabine and capecitabine in this 3-week cycle is safe and seems to have a good activity in advanced biliary cancer.

Phase II trial of fixed-dose rate gemcitabine, bevacizumab, and concurrent 30 gy radiotherapy as preoperative treatment for potentially resectable pancreatic adenocarcinoma.

258 Background: Effective multimodality treatment for localized pancreatic cancer is elusive. We hypothesized that preoperative fixed-dose rate (FDR) gemcitabine (GEM) combined with short-course radiotherapy (RT) and the angiogenesis inhibitor bevacizumab (BEV) would improve margin negative surgical outcomes and complete pathological response rates. Methods: Multisite phase II trial evaluating all potentially-resectable pancreatic adenocarcinoma without major arterial involvement or portal venous occlusion. Dual primary endpoints included complete pathological response and margin negative resection rates of 10% and 80%. Subjects received FDR GEM on days 1, 15, and 29 combined with BEV (10 mg/kg IV), followed on day 43 by BEV and concurrent 30 Gy RT (3 Gy/fraction) over 10 days. After restaging, subjects underwent laparoscopy and possible resection after day 85. Stopping criteria required continuous monitoring of serious wound complications. Results: 58 subjects enrolled, of which 29 (50%) had suspected venous involvement. 57 completed treatment without dose-limiting toxicity or delays in surgery. Two grade 4 (3.4%) and 17 grade 3 toxicities (28.8%) occurred. Four patients progressed before surgery. 54 subjects underwent laparoscopy; ten had unexpected carcinomatosis, and one was unresectable. 43 subjects were resected (74%; 33 pancreatico-duodenectomy, 8 distal pancreatectomy, 1 total pancreatectomy, 1 Appleby); 19 (44%) required portal vein resection. Margin negative outcome was achieved in 38 (88%, 95% CI: 75%-96%) with one complete pathological response (2.3%; 95% CI: 0.1%- 12%) and seven (6 grade 3; 1 grade 4) wound complications (13%). Median overall survival (OS) was 16.3 months (95% CI: 13.9 -22.1) and 21.3 months (95% CI: 15.0-32.9) after resection. Median progression-free survival (PFS) was 5.7 months (95% CI: 3.9-9.1) and 9.9 months (95% CI: 5.7 to 14.1) after resection, with 7 local and 21 distant recurrences. Conclusions: Combination therapy was well-tolerated and was within statistical design parameters for the primary endpoints despite a significant proportion of borderline tumors.