Gemcitabine In Patients Research Articles

Phase I Dose-Finding Study of Vandetanib in Combination with Gemcitabine in Locally Advanced Unresectable or Metastatic Pancreatic Adenocarcinoma

Objectives: Vandetanib is an oral inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor and RET (REarranged during Transfection) signaling. The primary objective of this open-label phase I trial was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of vandetanib in combination with gemcitabine in patients with unresectable, locally advanced or metastatic pancreatic adenocarcinoma (PAC). Methods: Patients received vandetanib (100 or 300 mg/day) plus gemcitabine (1,000 mg/m² i.v. on days 1, 8 and 15 per 28-day cycle) until disease progression, unacceptable toxicity or withdrawal of patient consent. The MTD was determined by the assessment of dose-limiting toxicity (DLT) during the first 28 days of treatment. Results: Fifteen patients were treated. No DLTs occurred in the first cohort of vandetanib 100 mg (n = 3) and recruitment continued at the 300-mg dose level. At the 300-mg dose, 3 out of 12 patients (including 2 in the expansion cohort) experienced DLTs (aphasia, elevated liver enzymes and neutropenia; all of them grade 3), thus exceeding the MTD. No objective responses were observed, with stable disease being the best response in 78% of evaluable patients. Conclusions: Vandetanib 100 mg/day is the RD in combination with gemcitabine in the treatment of patients with advanced PAC.

Aerosolized Gemcitabine in Patients with Carcinoma of the Lung: Feasibility and Safety Study

We investigated the biodistribution, pharmacokinetics, safety profile, and feasibility of aerosolized gemcitabine (GCB) in patients with lung carcinoma. Eleven patients with carcinoma localized in the lungs were studied in a dose escalation study of aerosolized GCB administered 1 day/week for 9 consecutive weeks. Safety data, scintigraphic assessment of the delivered dose and pharmacokinetic monitoring were analyzed. Patients were treated with doses of between 1 mg/kg and 4 mg/kg (dose in the nebulizer), using a new inhaler device (Aeroneb Pro with an Idehaler Chamber). The total dose of GCB delivered to the patient's lung was 42±16% of the initial amount of dose in the nebulizer. Safety data showed no hematologic toxicity, nephrotoxicity or neurotoxicity. At 4 mg/kg, one patient experienced grade 4 pulmonary toxicity (bronchospasm), which was the dose-limiting toxicity. Grade 2 and 3 toxic effects included fatigue, vomiting, dyspnea, and cough. Overall response: minor response in one patient, stable disease in four patients, progressive disease in four patients. Pharmacokinetic data showed very low plasma GCB levels. Maximal plasma concentration was observed at the end of nebulization. Aerosolized gemcitabin was safe, with minimal toxicity, for patients with lung carcinoma.

A randomised phase II trial of two sequential schedules of docetaxel and cisplatin followed by gemcitabine in patients with advanced non-small-cell lung cancer

The aim of this study was to determine the activity and toxicity of two sequential chemotherapy regimens in the first-line treatment of advanced non-small-cell lung cancer (NSCLC). Eighty-eight chemonaive patients with stage IIIB/IV NSCLC were randomised to receive either three cycles of 75mg/m(2) cisplatin plus 75mg/m(2) docetaxel, both administered on day 1 every 21days, followed by three cycles of 1,200mg/m(2) gemcitabine on days 1 and 8 every 3weeks (arm A), or three cycles of 25mg/m(2) cisplatin plus 25mg/m(2) docetaxel on days 1, 8 and 15 every 28days, followed by three cycles of 1,200mg/m(2) gemcitabine on days 1 and 8 every 3weeks (arm B). Of the evaluable patients, 61% in arm A (n=41) and 36% (n=44) in arm B completed treatment as per the protocol. The best tumour response rates were as follows (arm A and arm B): complete response: 2.4 and 2.3%; partial response: 39 and 20.4%; stable disease: 26.8 and 13.6%; and progressive disease: 31.8 and 45.4%. The median progression-free and overall survival were 3.9 and 12.3months in arm A, respectively, 3.1 and 7.7months in arm B. Grade 3-4 adverse events were more common in arm A. Grade 3-4 neutropenia was the main toxicity observed (56.1% in arm A and 11.4% in arm B). Our data demonstrate the feasibility of a sequential approach of cisplatin plus docetaxel followed by single-agent gemcitabine. Weekly administration of platinum-docetaxel is associated with an improved safety profile but lower efficacy than the conventional three-weekly schedule (registration ID 2004-001044-72).

Intravenous Fluid Therapy Successfully Prevents Renal Injury by Gemcitabine in Patients With Pancreatic Cancer

Intravenous Fluid Therapy Successfully Prevents Renal Injury by Gemcitabine in Patients With Pancreatic Cancer

Phase I study of axitinib (AG-013736) in combination with gemcitabine in patients with advanced pancreatic cancer

Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, is under investigation for treatment of various solid tumors. The safety and pharmacokinetics of axitinib in combination with gemcitabine in patients with advanced pancreatic cancer was evaluated in the phase I portion of this trial. The randomized phase II portion was reported separately. Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Pharmacokinetic profiles of the drugs were obtained on cycle (C) 1 day (D) 1 (gemcitabine alone 1,000 mg/m(2)), C1D14 (steady state, axitinib alone 5 mg twice daily [BID]), and C1D15 (gemcitabine plus steady-state axitinib). Adverse events were monitored weekly at the clinic. Eight patients participated in the phase IB portion of the trial. Patients received gemcitabine on D1, D8, and D15 and continuous axitinib in a 28 day-cycle beginning C1D3. There was no dose-limiting toxicity. Common treatment-related adverse events included fatigue, diarrhea, dysphonia, and hypertension. Myelosuppression was similar to gemcitabine monotherapy. No apparent major pharmacokinetic interactions between gemcitabine and axitinib were observed. Of six patients evaluable for efficacy, three had confirmed partial responses. Axitinib (5 mg BID) and gemcitabine (1,000 mg/m(2)) were well tolerated when administered together, without any pharmacokinetic interactions, and showed encouraging antitumor activity.

A phase II randomized study of cetuximab and bevacizumab alone or in combination with gemcitabine as first-line therapy for metastatic pancreatic adenocarcinoma

The purpose of this study was to assess the efficacy and safety of bevacizumab plus cetuximab with or without gemcitabine in patients with advanced pancreatic adenocarcinoma. Patients with locally advanced or metastatic pancreatic adenocarcinoma, previously untreated, were randomized to bevacizumab (10 mg/kg q2w) plus cetuximab (400/250 mg/m(2) initial/weekly), either with (Arm A) or without (Arm B) gemcitabine (1000 mg/m(2) weekly × 3 of 4 weeks). Tumor assessments were performed q8w. Primary study endpoint was progression-free survival (PFS). Sixty-one patients were randomized to Arm A (n = 30) or Arm B (n = 31). Median treatment duration was 9 weeks in Arm A and 8 weeks in Arm B (range, 2.0-40.4). Patients in Arm A had median PFS and overall survival values of 3.55 months and 5.41 months, respectively, compared to 1.91 months and 4.17 months in Arm B. The study closed early due to lack of sufficient efficacy in both treatment arms. Although both regimens were well tolerated, patients treated with gemcitabine experienced more grade 3-4 toxicities, including proteinuria and thromboembolic events. The combination of cetuximab and bevacizumab did not result in promising activity with or without gemcitabine, suggesting that a strategy of dual EGFR/VEGF inhibition in pancreatic cancer does not warrant further development. To our knowledge, this is one of the first trials to evaluate a completely noncytotoxic regimen in the first-line treatment of advanced pancreatic cancer. (ClinicalTrials.gov number, NCT00326911).

Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704

The aim of this study is to validate the prognostic and predictive value of the non-synonymous cytidine deaminase (CDA) Lys²⁷Gln polymorphism for hematological toxicity and survival using a randomized phase III adjuvant trial (Radiation Therapy Oncology Group (RTOG) 9704) in pancreatic cancer in which one treatment arm received gemcitabine. CDA is involved in gemcitabine inactivation, and there is conflicting data on the role of the non-synonymous CDA Lys²⁷Gln polymorphism in predicting toxicity and survival in cancer patients treated with gemcitabine. RTOG 9704 randomized 538 patients after pancreatic resection to receive radiotherapy with either 5-fluorouracil (5-FU) or gemcitabine. CDA Lys²⁷Gln polymorphism genotype was analyzed. We tested an association between CDA single-nucleotide polymorphism genotype and the survival outcome by the Cox proportional hazard model adjusting for other covariates, as well as toxicity by the logistic regression model. There is statistically significant more severe hematological toxicity in patients treated with gemcitabine with either the homozygote wild-type genotype (Lys/Lys) alone (odds ratio (OR)=0.06, P=0.01), or in combination with the heterozygote (Lys/Gln; OR=0.14, P=0.03) when compared with homozygote variant genotype (Gln/Gln) when adjusted for other covariates. This was not seen in the non-gemcitabine treated arm. There are no genotype differences with respect to survival outcome. In conclusion, in this prospective randomized adjuvant study of patients with pancreatic cancer, the CDA Lys²⁷Gln polymorphism is validated as a predictive marker of gemcitabine hematological toxicity, but not with treatment response or survival.

Phase I study of a combination therapy of gemcitabine and candesartan in patients with advanced pancreatic cancer: GECA-1 study.

e14555 Background: Increasing evidence indicates a role of the local rennin-angitensin system (RAS) in tumor growth, suggesting potential of RAS as a target for cancer treatment. Our retrospective analysis showed inhibition of RAS was associated with better progression-free survival and overall survival in patients with advanced pancreatic cancer receiving gemcitabine (Br J Cancer. 2010;103:1644-8). This study was conducted to investigate the maximum-tolerated dose (MTD) of candesartan, an angiotensin receptor blocker, in combination with gemcitabine in patients with advanced pancreatic cancer (UMIN-CTR 000002152). Methods: Candesartan was administered orally at escalating dose (4 mg, 8 mg, 16 mg and 32 mg) qd daily and gemcitabine was administered 1,000 mg/m2 30min i.v. day 1, 8, 15, repeated every 4 weeks. There were no dose escalations within each patient. Eligible criteria were unresectable locally advanced or metastatic pancreatic cancer without any prior treatment, ECOG PS 0-2, normal renal function and without hypertension or hypotension. DLT was defined as grade 4 hematological toxicities, Grade 2 hypotension, abnormal creatinine or potassium and grade 3 or 4 other non-hematological toxicities. MTD was defined when 2 or more patients in a cohort of 3 patients or when 3 or more patients in a cohort of 6 patients experienced DLT. Results: Between July 2009 and Oct 2010, 14 patients (4 mg: 3 patients, 8 mg: 3 patients, 16 mg: 6 patients, 32 mg: 2 patients) were enrolled in this trial. The median age, 60, male:female, 5:9, PS 0:1, 8:6, locally advanced, 43%. One of 6 patients at 16 mg demonstrated DLT of grade 4 neutropenia and 2 of 2 patients at 32mg demonstrated DLT of grade 2 hypotension. Tumor response by RECIST was SD in 11, PD in 1, and NE in 2. Response rate was 0% but disease control rate (DCR) was 79%. Median progression-free survival (PFS) was 8.1 months and 1-year survival was 65% after a median observational period of 9.8 months. Conclusions: The recommended dose of candesartan in combination with gemcitabine was 16 mg. The results of DCR and PFS appeared promising.

Lenalidomide in combination with gemcitabine in patients with untreated metastatic carcinoma of the pancreas: A Sarah Cannon Research Institute phase II trial.

e14640 Background: Lenalidomide is an oral Imid immunomodulatory compound with both anti-angiogenic and immunomodulatory properties. The objectives of this phase II study were to assess the safety, tolerability, and anti-tumor activity, including response rate, progression-free (PFS), and overall survivals (OS), of lenalidomide combined with gemcitabine in patients (pts) with untreated metastatic pancreas cancer. Methods: Eligibility included: previously untreated metastatic adenocarcinoma of the pancreas (locally advanced disease excluded); ECOG PS 0-2; adequate organ function. Prophylactic anticoagulation was required (ASA, LMWH, or warfarin). Pts received lenalidomide 25mg PO days 1-21 and gemcitabine 1,000 mg/m2 IV days 1, 8, and 15 of 28-day cycles. Results: Between 5/2009 – 4/2010, 72 patients (median age 64 years; 49 [68%] male; 30 [42%] ECOG PS 0; 41 [57%] ECOG PS 1) began combination therapy at 9 sites, and received median of 2 cycles (range: 0-17+). Grade 3/4 hematologic toxicity included thrombocytopenia (15 pts, 21%) and neutropenia (12 pts, 17%), with no febrile neutropenia. Common non-hematologic toxicities were fatigue (49%), nausea (33%), anorexia (21%), constipation (19%), and rash (19%). Hematologic toxicity resulted in dose reduction of gemcitabine and lenalidomide in 33 pts (46%) and 27 pts (38%), respectively; an additional 17 and 32 patients required dosing interruption. Despite prophylactic anticoagulation (79% ASA, 13% LMWH, 5% warfarin), 13 pts (18%) developed grade 3/4 venous thromboembolic events. Three patients remain on treatment. Fifty pts (69%) have ended treatment for disease progression or death due to disease; other reasons for treatment discontinuation included: symptomatic deterioration (6), intercurrent illness (6), patient choice (6), and toxicity (1). Eight patients (11%) achieved partial response. PFS and OS were 2.5 (95% CI 1.9-3.5) and 4.73 (95% CI 3.4-6) months, respectively. Six-month OS was 38% (95% CI 27-50%). Conclusions: Compared to expected results with gemcitabine alone, the addition of lenalidomide did not improve the survival of patients with untreated metastatic pancreatic cancer.

The safety of IPI-926, a novel hedgehog pathway inhibitor, in combination with gemcitabine in patients (pts) with metastatic pancreatic cancer.

4114 Background: IPI-926 is a novel, selective, oral, natural product-derived small molecule that targets the Hedgehog (Hh) pathway by inhibiting Smoothened (Smo). Inhibition of Smo can repress malignant activation of the Hh pathway, resulting in decreased desmoplasia and improved delivery of chemotherapy to pancreatic tumors. Methods: A phase Ib/II trial is underway to evaluate the safety profile and efficacy of IPI-926 in combination with gemcitabine. Eligible pts with previously untreated metastatic pancreatic cancer and ECOG performance status 0-1 had IPI-926 administered orally daily (QD) for a 28-day cycle, in 3 to 6 pt cohorts. IV gemcitabine (1,000 mg/m2) was administered once weekly for 3 weeks followed by 1 week off. DLTs were evaluated during Cycle 1. Results: As of Dec 2010, 15 pts with a median age of 67 years (range 58-83) have been enrolled in the phase Ib portion of this trial at dose levels of IPI-926 ranging from 110-160 mg QD, and a median of 3 cycles completed (1-6). No Grade 4/ 5 adverse events (AE) have been observed related to either study drug, and no IPI-926-related serious AEs have been noted. The most common IPI-926-related AEs observed include fatigue (40% total, 0% Grade 3), nausea (40%, 0%), ALT increased (13%, 7%), AST increased (13%, 7%), anemia (13%, 0%), and vomiting (13%, 0%). The observed safety profile for gemcitabine has been consistent with published data. The one DLT observed to date (130 mg of IPI-926) was Grade 3 AST increase, which was asymptomatic, resolved with dose interruption, and did not recur after dose reduction. No apparent drug interaction between IPI-926 and gemcitabine has been observed to date. Preliminary data include 3 radiographic partial responses in the 9 pts with post-baseline scans. Conclusions: IPI-926 in combination with gemcitabine has been well tolerated to date in patients with metastatic pancreatic cancer, without unexpected toxicity, and preliminary evidence of clinical activity has been observed. The phase Ib portion of this trial is now fully enrolled with ongoing pt treatment and data collection. Clinical evaluation of this combination continues in a randomized, double blind, placebo controlled phase II trial.

A multicenter, randomized, controlled study of CO-1.01 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and low tumor expression of human equilibrative nucleoside transporter-1 (hENT1) determined by metastasis biopsy.

TPS144 Background: Gemcitabine (Gem) is standard of care therapy for mPDAC, however many patients do not benefit. Gem requires a transporter protein, hENT1, to enter cells. Reduced tumor hENT1 expression predicts poor outcome after Gem therapy (Farrell). CO-1.01 is a Gem-elaidic acid conjugate which is able to enter cells independently of transporters. This clinical study tests the hypothesis that CO-1.01 is more effective than Gem at prolonging survival in patients with mPDAC and low tumor expression of hENT1 (NCT01124786). Methods: Patients with mPDAC, with no prior palliative chemotherapy are eligible. A screening biopsy of metastatic tumor tissue from every patient, assessed by a central pathology laboratory as adequate for future immunohistochemical measurement of hENT1, is required before randomization and then banked. 54/250 patients have been randomized 1:1 to Gem or CO-1.01. The primary endpoint is overall survival in the prospectively defined hENT1 low subgroup (see below). A fully validated hENT1 IHC assay (class I device) has been developed and a scoring system (modified H score) is being developed in parallel to the randomized study. The H-score cut-off that predicts poor clinical outcome with Gem is being derived from independent, large randomized controlled studies of Gem vs comparator for adjuvant treatment of PDAC. This cut-off will be applied, blinded and prospectively, to the screening metastasis biopsies to identify the patients in the primary endpoint population (hENT1 low subgroup). Additional exploratory analyses include pharmacogenetic analysis of Gem metabolizing enzymes, and pharmacogenomic analyses of tumor tissues. To our knowledge, this is the first randomized study in mPDAC that mandates metastatic tumor tissue collection to allow prospective testing of an efficacy hypothesis in a molecularly-defined subset of patients. The design of the study will enable robust investigation of the relationship between hENT1 tumor expression and clinical outcomes. Farrell J. Gastroenterology 2009:136;187

Molecular markers of the EGFR pathway in erlotinib-treated patients with advanced pancreatic cancer (APC): Translational analyses of a randomized, cross-over AIO phase III trial.

4047 Background: Within a cross-over phase III trial, we compared gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in patients with treatment-naive APC (Boeck S et al, ASCO 2010, LBA4011). Valid translational data are still lacking from APC phase III trials. Methods: 281 patients (pts) were randomized; archival formalin fixed paraffin embedded (FFPE) tumor tissue was available from 208 pts. We centrally analysed KRAS exon 2 mutation status (PCR), EGFR expression (immunohistochemistry, IHC and fluorescence in-situ hybridization, FISH), PTEN expression (IHC), as well as the EGFR intron 1 polymorphism [PM] (PCR) and the EGFR exon 13 R497K PM (PCR). Translational biomarker data were correlated (either as dichotomous or continuous variables, respectively) with overall survival (OS) by using Kaplan-Meier estimates and the log rank test. Results: KRAS mutations (all in codon 12) were found in 121/173 pts (70%), EGFR expression was detected in 174/181 pts (96%) by IHC, and 77/166 pts (46%) had an EGFR gene amplification by FISH; 30/171 pts (18%) had a loss of PTEN expression. Median number of CAn repeats in the intron 1 PM (allele 1+2, n=186) was 34 (range 28-41) and 112/194 pts (58%) had the GG wildtype sequence for the exon 13 R497K PM of the EGFR gene. EGFR intron 1 PM showed no correlation with EGFR expression either by IHC (p=0.264) or FISH (p=0.311). Median OS for all 208 pts was estimated with 6.2 months. In univariate biomarker analyses KRAS mutation status was significantly associated with OS (HR 1.68, 95% CI 1.17-2.41, p=0.005); no significant correlation was found for EGFR-IHC (HR 1.01, p=0.985), EGFR-FISH (HR 1.22, p=0.252), PTEN-IHC (HR 0.77, p=0.216), EGFR intron 1 PM (HR 1.02, p=0.540) or EGFR exon 13 R497K PM (HR 0.83, p=0.231). None of the 6 molecular biomarkers analysed correlated with the occurrence of skin rash. Conclusions: Translational research with archival FFPE tissue is feasible in APC phase III trials. Molecular markers of the EGFR pathway may be associated with treatment outcome in erlotinib-treated pts with APC.

Phase II trial of postoperative adjuvant gemcitabine and cisplatin chemotherapy followed by chemoradiation with gemcitabine in patients with resected pancreatic cancer.

4094 Background: Despite potentially curative resection for pancreatic carcinoma the 5-year survival in these patients is less than 20%. Progression of disease can occur both locally and in distant sites. Effective multimodality adjuvant treatment protocol is needed for these patients receiving curative resection. Methods: Patients with curatively resected pancreatic adenocarcinoma (stage IB ~ IIB, AJCC 6th ed.), ECOG PS of 0-2, and no prior chemo- or radiotherapy were eligible. Treatment consisted of chemotherapy with gemcitabine (GEM) 1,200mg/m2 (D1,8) and CDDP 60mg/m2 (D1) every 3 weeks for 2 cycles. Subsequently, patients without progression received chemoradiotherapy (CRT) (50.4 Gy/ 28 Fx) with concurrent weekly gemcitabine (300mg/m2/week). GEM 1,200mg/m2 were given on day 1, 8 every 3 weeks for 4 cycles after CRT. The primary endpoint was to evaluate one year disease free survival (DFS) rate. The secondary endpoints were median DFS, overall survival (OS), and safety. Results: From Oct. 2005 to Sep. 2009, we enrolled 74 patients with curatively resected pancreas cancer (median age 61, M:F = 48:26 ). At the median follow up duration of 45 months (range 10.2 ~ 64.6 months), six patients withdrew consent, 11 patients confirmed disease progression during treatment and 57 patients completed CRT followed by systemic chemotherapy. One-year DFS rate was 62.1%. Fifty-two patients (70.3%) were diagnosed with recurrence. Most of the recurrences were systemic disease (49 patients, 66.2% of all patients). Median DFS was 17.4 months and median OS was 33.6 months in all patients. The stage (73.3% in IIA, 55.6% in IIB, p<0.001) and the nodal status (71.0% in N0, 55.6% in N1, p=0.01) at the time of diagnosis were significantly related with DFS. Toxicities were generally tolerable, 53 events of grade 3 or 4 hematologic toxicity were reported and four patients experienced febrile neutropenia. Conclusions: Adjuvant GEM-CDDP chemotherapy followed by GEM-RT and maintenance GEM showed promising efficacy and good tolerability in curatively resected pancreatic cancer.

Final results of a phase I study of the combination of a novel cell cycle inhibitor ON 01910.Na with gemcitabine in patients with advanced pancreatic and other solid tumors.

3101 Background: ON 01910.Na (ON) is a novel multitargeted inhibitor of several regulatory pathways including polo-like kinase 1 (Plk1) and PI-3 kinases, with synergistic preclinical activity when combined with gemcitabine (G; Jimeno et al, 2008, 2009), prompting a phase I clinical evaluation. Methods: Patients (pts) had histologically confirmed solid tumors refractory to standard therapy. G was administered as a 30-min infusion on days 1, 8 and 15 of a 28-day cycle. ON was administered as a 2-h infusion on days 1, 4, 8, 11, 15, and 18. Assessments included safety, response, pharmacokinetic interaction studies at the MTD, and pharmacodynamics in tumor at the MTD. The MTD was further confirmed in an expansion cohort enriched in advanced pancreatic cancer pts. Results: Thirty-six pts (median age 61; median ECOG PS 1) received a median of 3 cycles (6 pts ongoing) at 5 dose levels: (G/ON mg/m2: 750/600 n=6; 1,000/600 n=5; 750/1,200 n=3; 1,000/1,200 n=3; 1,000/1,800 n=19). Only those toxicities that were expected from G were observed in patients treated with the combination, and included thrombocytopenia, neutropenia, elevated AST/ALT, nausea, vomiting, and fatigue. One DLT was documented (death at Day 18 at the 1,800 mg/m2 ON dose). Antitumor activity was seen in one G-pretreated Hodgkin lymphoma pt (PR), 2 ovarian cancer pts (1 G-pretreated with 50% decrease in CA125; 1 G-naïve with 50% decrease in CA125 and 12% tumor regression), one NSCLC pt (SD at 24 weeks) and one thymic cancer pt (PR at 32 weeks). Additionally, 18 advanced pancreatic cancer (PC) pts were enrolled. Tumor regression (including one confirmed PR in a G-pretreated pt) was noted in 7/13 evaluable pts and CA 19-9 decrease in 8/13 pts. Median progression-free survival was 19 weeks and overall survival 48 weeks at 1,200 and 1,800 mg/m2 ON doses (n=12) in the subset of 16 metastatic PC pts, 11 of whom were previously treated with G. Conclusions: ON 01910.Na 1,800 mg/m2 and gemcitabine combination is well tolerated. Anti-tumor activity in G-pretreated pts with advanced PC provide the rationale for a phase II evaluation in metastatic PC pts. Final results will be presented and molecular data including PI3K mutation status.

Efficacy and safety of a phase II study of sorafenib plus gemcitabine in advanced hepatocellular carcinoma.

e14633 Background: Currently, the only standard systemic treatment for advanced hepatocellular carcinoma (HCC) is sorafenib monotherapy. In searching for an improved regimen of systemic treatment, we chose to use gemcitabine which has a modest activity but acceptable toxicity in advanced HCC to combine with sorafenib. Here we report the first efficacy and safety analysis of this novel combination in the treatment of advanced HCC. Methods: The study is a single arm sorafenib plus gemcitabine in patients with metastatic or unresectable HCC. Pathological diagnosis of HCC is mandatory. Treatment includes 4-week cycle of gemcitabine (1,000 mg/m2 day 1, 8, 15) to maximum of 6 cycles together with sorafenib (200 mg twice daily). Patient would continue sorafenib until disease progression or withdrawal from other reason. The primary endpoint is the progression free survival (PFS). Results: Forty five patients were eligible. Almost all patients had Child-Pugh score A (42/45, 93.3%). There were 28/45 (62.2%) patients who had hepatitis B virus associated HCC and 23/45 (51.1%) who had extrahepatic metastases. The overall response rate was 2/39 (5.1%) without complete response and the disease control rate was 30/39 (76.9%). The median PFS was 3.7 (3.5, 3.8) months with the longest time of treatment over 16 months. The median overall survival was at 12 (7.5, 16) months. Reported grade 3/4 treatment related adverse events (AE) include 33% thrombocytopenia, 15.6% neutropenia, and 15.6% hand-foot skin reaction. The study regimen was well tolerated with 4 patients discontinued from the treatment due to adverse events. There was one death during study treatment. Conclusions: The combination of sorafenib and gemcitabine in advanced HCC has a moderate clinical efficacy and encouraging long survival with acceptable toxicities comparing to th sorafenib monotherapy. Future studies in a larger randomized population are warranted.

The Efficacy and Toxicity of Bevacizumab in Combination With Gemcitabine in Patients With Recurrent Ovarian Cancer

BackgroundTo evaluate the efficacy and toxicity of bevacizumab in combination with gemcitabine in patients with recurrent ovarian cancer. Patients and MethodsA retrospective analysis identified patients with recurrent ovarian cancer who received combination bevacizumab and gemcitabine. The patients received bevacizumab (15 mg/m2) every 3 weeks, plus gemcitabine (750–1000 mg/m2) on days 1 and 8 until disease progression or undue toxicity. Toxicity was assessed by using National Cancer Institute CTCAE (Common Terminology Criteria for Adverse Events) version. 3.0. Response rates were determined by serial cancer antigen 125 levels and by radiologic evaluation. ResultsTwenty-nine patients were treated with combination therapy. The median age was 51 years (range, 38–70 years); 59% had primary platinum-resistant disease. The median number of previous chemotherapy regimens was 2 (range, 1–5). Five patients experienced grade 3/4 nausea and vomiting. Four patients had grade 3/4 neutropenia. One patient had grade 3/4 proteinuria, and no patients had grade 3/4 hypertension. Eight patients had the bevacizumab infusion delayed due to proteinuria. Six patients had the gemcitabine infusion delayed or reduced due to grade 3/4 toxicity. One patient developed a colovesical fistula. Three patients developed a colon obstruction. Two patients (7%) had a complete response, and 9 patients (31%) had a partial response for an overall response rate of 38%. The median duration of response was 9.6 months (range, 1–49 months). Four patients (14%) had stable disease, and 14 patients (48%) had progressive disease. ConclusionCombination treatment with bevacizumab and gemcitabine has activity in recurrent ovarian cancer and is well tolerated. Prospective trials are needed to further characterize the role of this regimen in the treatment of recurrent ovarian cancer.

Regional Chemotherapy in Locally Advanced Pancreatic Cancer: RECLAP Trial

BackgroundPancreatic cancer is the fourth leading cause of cancer death in the United States. Surgery offers the only chance for cure. However, less than twenty percent of patients are considered operative candidates at the time of diagnosis. A common reason for being classified as unresectable is advanced loco-regional disease.A review of the literature indicates that almost nine hundred patients with pancreatic cancer have received regional chemotherapy in the last 15 years. Phase I studies have shown regional administration of chemotherapy to be safe. The average reported response rate was approximately 26%. The average 1-year survival was 39%, with an average median survival of 9 months. Of the patients that experienced a radiographic response to therapy, 78 (78/277, 28%) patients underwent exploratory surgery following regional chemotherapy administration; thirty-two (41%) of those patients were amenable to pancreatectomy. None of the studies performed analyses to identify factors predicting response to regional chemotherapy.Progressive surgical techniques combined with current neoadjuvant chemoradiotherapy strategies have already yielded emerging support for a multimodality approach to treatment of advanced pancreatic cancer.Intravenous gemcitabine is the current standard treatment of pancreatic cancer. However, >90% of the drug is secreted unchanged affecting toxicity but not the cancer per se. Gemcitabine is converted inside the cell into its active drug form in a rate limiting reaction. We hypothesize that neoadjuvant regional chemotherapy with continuous infusion of gemcitabine will be well tolerated and may improve resectability rates in cases of locally advanced pancreatic cancer.DesignThis is a phase I study designed to evaluate the feasibility and toxicity of super-selective intra-arterial administration of gemcitabine in patients with locally advanced, unresectable pancreatic adenocarcinoma. Patients considered unresectable due to locally advanced pancreatic cancer will receive super-selective arterial infusion of gemcitabine over 24 hours via subcutaneous indwelling port. Three to six patients will be enrolled per dose cohort, with seven cohorts, plus an additional six patients at the maximum tolerated dose; accrual is expected to last 36 months. Secondary objectives will include the determination of progression free and overall survival, as well as the conversion rate from unresectable to potentially resectable pancreatic cancer.Trial RegistrationClinicalTrials.gov ID: NCT01294358

Abstract 5034: Imact of KRAS mutation on clinical outcomes in pancreatic cancer patients who were treated with first-line gemcitabine-based chemotherapy

Abstract Background: Gemcitabine forms the backbone of chemotherapy and a recent study showed small but significant clinical benefits of erlotinib combined with gemcitabine in patients with pancreatic ductal adenocarcinoma. However, the high frequency of KRAS mutations in this population probably limits the benefits of an EGFR inhibitor, and this limitation seems to be similar to that observed in colon cancer and non-small cell lung cancer. We undertook this study to understand the clinical significance of KRAS mutation in pancreatic cancer patients who were treated with gemcitabine-based chemotherapy. Patients &amp; Methods: We retrospectively studied 136 pancreatic cancer patients with available formalin-fixed paraffin-embedded tumor blocks from 2003 to 2009. KRAS mutations were analyzed by sequencing codons 12, 13 and 61. Results: In this study, 71 (52.2%) of the 136 pancreatic adenocarcinomas examined harbored a point mutation in codon 12 (N=70) and 61 (N =1) of KRAS. Observed point mutations at codon 12 in the order of frequency were: GGT-GAT (35G&amp;gt;A; 41 of 71 patients, 57.7 %); GGT-GTT (35G&amp;gt;T; 19 of 71 patients, 26.8%); GGT-CGT (34G&amp;gt;C; 7 of 71 patients, 10.0%); and GGT-TGT (34G&amp;gt;T; 3 of 71 patients, 4%). KRAS mutation was not associated with clinicopathological parameters such as age, sex, ECOG PS, smoking, tumor location, histologic differentiation, TNM staging, level of CA19-9 and first-line chemotherapy regimens. Patients with KRAS mutations showed a worse response and disease control rate (11.3 and 35.2%) than those with wild type KRAS (26.2 and 52.3%). KRAS mutation also adversely influenced survival of pancreatic cancer patients (mutant KRAS, 5.8 months [95% C.I. 5.1-6.5] vs. wild type KRAS, 8.0 months [95% C.I. 5.8-10.2]; p=0.001) Multivariate analysis revealed good prognostic factors for overall survival as well to moderately differentiated histology (p&amp;lt;0.001; hazard ratio (HR) = 0.437, 95% C.I. 0.301∼0.634), locally advanced disease (p&amp;lt;0.001; HR 0.417, 95% C.I. 0.255∼0.681), response to first-line chemotherapy (p=0.003; HR 0.482, 95% C.I. 0.297∼0.780) and wild type KRAS (p=0.001; HR 0.523, 95% C.I. 0.355∼0.70). Conclusions: Our results suggest that KRAS mutation may play an important role as a biomarker for response to erlotinib treatment and in determining prognosis in pancreatic cancer patients who were treated with gemcitabine-based chemotherapy. These findings should be further explored in preclinical and upcoming prospective clinical trials to potentially allow the development of new treatment algorithms to identify patients who are most likely to respond to treatment and provide a rationale for personalized medicine in pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5034. doi:10.1158/1538-7445.AM2011-5034

MicroRNA Expression as a Predictive Marker for Gemcitabine Response after Surgical Resection of Pancreatic Cancer

BackgroundTo improve the prognosis of patients after resection of pancreatic cancer, the most appropriate and efficient treatment should be provided to specific subsets of patients. Our aim was to identify promising microRNAs as markers to predict responses to gemcitabine in patients with resected pancreatic cancer.MethodsTwo gemcitabine-resistant pancreatic cancer cell lines were established, and global microRNA expression analyses was performed by quantitative reverse transcription–polymerase chain reaction (qRT-PCR). Eleven miRNAs were selected as putative predictive markers and analyzed by means of macrodissected formalin-fixed, paraffin-embedded samples obtained from 90 patients with or without gemcitabine treatment after resection of pancreatic cancer.ResultsWe identified 24 microRNAs whose expression was altered in gemcitabine-resistant cells. qRT-PCR analyses showed that patients with high miR-142-5p and miR-204 expression had significantly longer survival times than those with low miR-142-5p (P = 0.0077) and miR-204 (P = 0.0054) expression in the gemcitabine-treated group. This was not seen in the nontreated group. Multivariate analyses showed that miR-142-5p expression was an independent prognostic marker only in patients treated with gemcitabine (P = 0.034).ConclusionsmiR-142-5p is a promising predictive marker for gemcitabine response in patients with resected pancreatic cancer.

A phase II study of bortezomib and gemcitabine in relapsed mantle cell lymphoma from the National Cancer Institute of Canada Clinical Trials Group (IND 172)

Bortezomib and gemcitabine have each shown activity as single agents in mantle cell lymphoma (MCL), which is incurable. The purpose of this phase II study was to determine the efficacy and safety of the previously unstudied combination of bortezomib and gemcitabine in patients with relapsed or refractory MCL. Patients were eligible if they had relapsed MCL with 1–3 prior therapies. Patients were treated with gemcitabine 1000 mg/m2 on days 1 and 8 and bortezomib 1.0 mg/m2 IV on days 1, 4, 8, and 11, on a 21-day schedule. Twenty-six patients were evaluable for toxicity and 25 for response. The overall response rate was 60% and the median progression free survival was 11.4 months. The main adverse effects were hematological, with 40% and 48% of patients experiencing grade 3/4 thrombocytopenia and granulocytopenia, respectively. Bortezomib and gemcitabine is an active combination in relapsed and refractory MCL with clinically meaningful results. It offers a chemotherapy backbone to which other agents, less myelosuppressive, may be added.