Gemcitabine In Advanced Pancreatic Cancer Research Articles

A phase I/II study of LOAd703, a TMZ-CD40L/4-1BBL-armed oncolytic adenovirus, combined with nab-paclitaxel and gemcitabine in advanced pancreatic cancer.

4138 Background: Due to its low tumor immunogenicity and immunosuppressive microenvironment, pancreatic ductal adenocarcinoma (PDAC) remains an immunotherapeutic challenge. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, has been shown to lyse tumor cells selectively, induce anti-tumor cytotoxic T-cell responses, reduce myeloid-derived suppressor cell (MDSC) infiltration, and induce tumor regression in preclinical studies. Methods: In this phase I/II trial, patients with unresectable or metastatic PDAC were treated with intratumoral injections of LOAd703 and standard intravenous nab-paclitaxel/gemcitabine (nPG) chemotherapy. Starting on cycle 1 day 15 of nPG, LOAd703 was injected with image guidance into the primary pancreatic tumor or a metastasis every 2 weeks for 6 injections. In the event of sustained tumor control, subjects were eligible to receive up to 6 more injections. Three dose levels of LOAd703 were investigated using a BOIN dose escalation design. Primary endpoints were safety and feasibility. Results: Of the 22 subjects enrolled, 21 received at least 1 LOAd703 injection, and 18 received at least 3 LOAd703 injections (the a priori definitions of evaluability for dose limiting toxicity [DLT] and efficacy, respectively). Of the 21 subjects injected, median age was 61, 81% had stage IV disease, and 57% had already received chemotherapy for advanced disease. Median CA 19-9 was 1494. Of the 18 response evaluable subjects, 3 were treated at dose level 1 (5x10e10 VP), 4 at dose level 2 (1x10e11 VP), and 11 at dose level 3 (5x10e11 VP). The most common adverse events (AEs) attributable to LOAd703 were fever, chills, nausea, and increased liver enzymes. AEs were short-lived and grade 1/2, except for a grade 3 transaminase elevation in one subject receiving dose level 3 (the only DLT). Objective response rate (ORR) among those treated at the highest dose level was 55% (5/11 subjects), thus meeting the predefined criterion for efficacy. Among all response evaluable patients, overall response rate (ORR) was 44%, and disease control rate (DCR) was 94%. CA 19-9 decreased by ≥50% in 61% of evaluable patients. Median overall survival (OS) among the 21 subjects receiving at least 1 LOAd703 injection was 8.7 months. The proportion of T effector memory cells increased after initiation of on-protocol treatment (p = 0.0232) while the proportion of T regulatory cells and myeloid-derived suppressor cells decreased (p = 0.0410, p = 0.0256, respectively). Conclusions: Combining intratumoral injections of LOAd703 with standard nPG chemotherapy was safe and feasible. The target response rate at the highest dose level was met, and treatment-emergent immune responses were observed. A follow-up clinical trial combining LOAd703, nPG, and the anti-PDL-1 inhibitor atezolizumab is underway. Clinical trial information: NCT02705196.

First line modified Folfirinox versus gemcitabine for advanced pancreatic cancer: A single institution retrospective experience

Abstract Background Advanced pancreatic cancer (APC) is a highly lethal malignancy which has one of the worst treatment outcomes. Modified (m)FOLFIRINOX is an intense but a proven treatment approach with a survival benefit for APC. Although mFOLFIRINOX demonstrated survival benefit compared with gemcitabine monotherapy, the standard treatment in previous years, toxicity is a difficult aspect of this treatment. Methods A retrospective analysis of patients referred to Medical Oncology Clinics of Ankara Oncology Research and Training Hospital with the diagnosis of inoperable locally advanced or metastatic pancreatic cancer and treated with mFOLFIRINOX or gemcitabine monotheraphy from March 2013 to April 2018 was performed. Results Forty three patients and 37 patients were included in mFOLFIRINOX and gemcitabine groups, respectively. The mean age of the patients was 53.74 years (range: 32–69) and 65,7 years (range: 47–82) for mFOLFIRINOX and gemcitabine, respectively (95% CI, p Conclusion mFOLFIRINOX is a difficult regimen for both patients and physicians with significant toxicity with a greater survival benefit. The survival benefit was modest in this real-life experience. Patient selection bias and small sample size of this retrospective study should be considered.

Comparisons of different neoadjuvant chemotherapy regimens with or without stereotactic body radiation therapy for borderline resectable pancreatic cancer: study protocol of a prospective, randomized phase II trial (BRPCNCC-1)

BackgroundFew patients with pancreatic cancer may be candidates for immediate surgical resection at the initial diagnosis. Even if patients with borderline resectable pancreatic cancer (BRPC), micrometastases may occur before surgery. Therefore, neoadjuvant therapy is vital for improved survival, which has been confirmed in previous studies that neoadjuvant chemotherapy with or without radiotherapy provides superior overall compared with upfront surgery. However, question of whether the addition of radiotherapy to neoadjuvant chemotherapy can improve prognosis compared with chemotherapy alone is a challenging matter. Moreover, most of previous studies only adopted conventional radiotherapy as the neoadjuvant modality though stereotactic body radiation therapy (SBRT) has been proven effective and commonly employed in pancreatic cancer. Also, no studies have evaluated the efficacy of S-1 as the neoadjuvant chemotherapy regimen for BRPC albeit similar prognosis has been found between S-1 and gemcitabine in advanced pancreatic cancer. Hence, the aim of this study is to investigate whether neoadjuvant chemotherapy plus SBRT results in better outcomes compared with neoadjuvant chemotherapy alone and also compare the efficacy of gemcitabine plus nab-paclitaxel with SBRT and S-1 plus nab-paclitaxel with SBRT.MethodsPatients with biopsy and radiographically confirmed BRPC, no prior treatment and severe morbidities are enrolled. They will be randomly allocated into three groups: neoadjuvant gemcitabine plus nab-paclitaxel, neoadjuvant gemcitabine plus nab-paclitaxel with SBRT and neoadjuvant S-1 plus nab-paclitaxel with SBRT. Standard doses of gemcitabine and nab-paclitaxel are used. The radiation dose of SBRT is 7.5-8Gy/f for 5 fractions. Surgical resection will be performed 3 weeks after SBRT. Artery first approach pancreaticoduodenectomy or radical antegrade modular pancreatosplenectomy will be used for the tumor in the head or body and tail of the pancreas, respectively. The primary endpoint is overall survival. The secondary outcomes are disease free survival, pathological complete response rate, R0 resection rate and incidence of adverse effects.DiscussionIf results show the survival benefits of neoadjuvant chemotherapy plus SBRT and similar outcomes between S-1 and gemcitabine, it may provide evidence of clinical practice of this modality for BRPC.Trial registrationThe study has been registered in ClinicalTrial.gov (NCT03777462).

A Phase 2 Study of PCI-27483, a Factor VIIa Inhibitor in Combination with Gemcitabine for Advanced Pancreatic Cancer

Objectives: Tissue factor overexpression is associated with tumor progression, venous thromboembolism, and worsened survival in patients with cancer. Tissue factor and activated factor VII (FVIIa) complex may contribute to tumor invasiveness by promoting cell migration and angiogenesis. The study objective was to evaluate safety, pharmacokinetics, and efficacy of PCI-27483, a selective FVIIa inhibitor. Methods: This was an open-label, multicenter phase 2 trial of patients with advanced pancreatic cancer. Part A of the study was an intrapatient dose escalation lead-in portion in patients concurrently receiving gemcitabine, and in part B, patients were randomized 1: 1 to the recommended phase 2 dose combination PCI-27483–gemcitabine versus gemcitabine alone. Results: Target international normalized ratio (between 2.0–3.0) was achieved following PCI-27483 treatment. Overall safety of PCI-27483–gemcitabine (n = 26) was similar to gemcitabine alone (n = 16), with a higher incidence of mostly low-grade bleeding events (65% vs. 19%). Progression-free survival (PFS) and overall survival (OS) were not significantly different between patients treated with PCI-27483–gemcitabine (PFS: 3.7 months, OS: 5.7 months) and those treated with gemcitabine alone (PFS: 1.9 months, OS: 5.6 months). Conclusions: Targeted inhibition of the coagulation cascade was achieved by administering PCI-27483. PCI-27483–gemcitabine was well tolerated, but superiority to single agent gemcitabine was not demonstrated.

Outcomes of patients with borderline-resectable pancreatic cancer treated with FOLFIRINOX versus gemcitabine plus nab-paclitaxel.

299 Background: Pancreatic cancer is a major cause of cancer-related death. Less than 20% of patients have resectable disease at diagnosis. Patients with borderline-resectable pancreatic cancer (BRPC) are at high risk of incomplete resection with upfront surgery. Currently there is no standard induction chemotherapy regimen exists for BRPC. Both FOLFIRINOX (5-FU, irinotecan, oxaliplatin) and gemcitabine/nab-paclitaxel (GnP) have shown better efficacy than gemcitabine in advanced pancreatic cancer. The current study aims to assess outcomes of real-world patients with BRCP who received induction FOLFIRINOX or GnP. Methods: In this population-based multicenter retrospective cohort study patients with biopsy proven BRPC as defined by the pancreatic surgical team diagnosed from 2011-2017, in the province of Saskatchewan, Canada, who received FOLFIRINOX or GnP were assessed. Kaplan Meier methods and log rank tests were performed for survival analyses. Results: Of 161 patients with pancreatic cancer who received FOLFIRINOX or GnP during the study period, 20 eligible patients with BRPC, with median age of 65 yrs (54-79) and M:F 14:6, were identified. 85% had pancreatic head tumours with a median CA19-9 of 470 u/mL. Of eligible patients, 10 each received FOLFIRINOX or GnP. No significant differences were found between the two groups, except more patients in FOLFIRINOX group had a WHO performance status of 0 (50% vs. 10%, p = 0.057) and had a higher body mass index (27.0 vs. 23.0, p = 0.027). Eleven patients showed partial response (5–FOLFIRINOX and 6–GnP), three progressed during treatment. Five patients (4–FOLFIRINOX, 1–GnP, p = NS) underwent curative surgery. Five patients (1–FOLFIRINOX, 4–Gnp) had radiation and four underwent Nanoknife procedure (3–FOLFIRINOX, 1–GnP). The median progression free survival was 17 months in FOLFIRINOX (95% CI: 5.3-28.6) versus nine months (3.0-15) in GnP group (p = 0.26). The median overall survival was 32 months in FOLFIRINOX (not reach) versus 16 months (9.3-22.7) in GnP group (p = 0.15). Conclusions: The current study suggests that patients with BRPC who received FOLFIRINOX tends to have better outcomes. Future study are warranted to establish a preferred systemic therapy for BRPC.

18F-FDG PET/CT response in a phase 1/2 trial of nab-paclitaxel plus gemcitabine for advanced pancreatic cancer

BackgroundPositron emission tomography (PET) is poised to become a useful imaging modality in staging and evaluating therapeutic responses in patients with metastatic pancreatic cancer (mPC). This analysis from a phase 1/2 study examined the utility of early PET imaging in patients with mPC treated with nab-paclitaxel plus gemcitabine.MethodsTumors were measured by [18F]2-fluoro-2-deoxyglucose PET/computed tomography (CT) in patients who received nab-paclitaxel 100 (n = 13), 125 (n = 38), or 150 (n = 1) mg/m2 plus gemcitabine 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Lesion metabolic activity was evaluated at baseline and 6 and 12 weeks postbaseline.ResultsFifty-two patients had baseline and ≥1 follow-up PET scan. The median maximum standardized uptake values per pancreatic lesion in the nab-paclitaxel 100 mg/m2 and 125 mg/m2 cohorts were 5.1 and 6.5, respectively. Among patients who had a metabolic response by PET, those who received nab-paclitaxel 125 mg/m2 had a 4-month survival advantage over those who received 100 mg/m2. All patients in the nab-paclitaxel 125 mg/m2 cohort experienced an early complete metabolic response (CMR; 34%) or partial metabolic response (PMR; 66%). In the nab-paclitaxel 125 mg/m2 cohort, investigator-assessed objective response rates were 77% and 44% among patients with a CMR and PMR, respectively, with no correlation between PET and CT response (Spearman rs = 0.22; P = 0.193). Patients in the nab-paclitaxel 125 mg/m2 cohort with a CMR experienced a significantly longer overall survival vs those with a PMR (median, 23.0 vs 11.2 months; P = 0.011), and a significant correlation was found between best percentage change in tumor burden by PET and survival: for each 1% decrease in PET score, the risk of death decreased by 2%.ConclusionsThe majority of primary pancreatic tumors and their metastases were PET avid, and PET effectively measured changes in tumor metabolic activity at 6 and 12 weeks. These results support the antitumor activity of nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 for treating mPC and the utility of PET for measuring treatment response. Treatment response by PET analysis may be considered when evaluating investigational agents in mPC.Trial registrationNCT00398086.

Does "OPTINAB" strategy ("stop-and-go") work in treatment of advanced pancreatic cancer (APC) with nab-paclitaxel-gemcitabine?

MPACT demonstrated a survival benefit of nab-paclitaxel plus gemcitabine versus gemcitabine in advanced pancreatic cancer (APC). However, sensory peripheral neuropathy is a dose-limiting toxicity and neuromodulators have shown limited, if any activity in ameliorating neuropathy. In colorectal cancer, the OPTIMOX ("stop-and-go") approach offered a strategy to reduce neuropathy. No data exist to support this strategy for nab-paclitaxel in APC. Retrospective study of APC patients who developed grade 3 neuropathy during nab-paclitaxel plus gemcitabine was done. Nab-paclitaxel was held and then reinstituted upon radiological or tumor marker progression. Duration of disease control (DCC) was measured. We named this strategy "OPTINAB". Seven patients out of 27 (25%) developed grade 3 neuropathy after an average of 4.2months; nab-paclitaxel was suspended while gemcitabine was continued. Maintenance gemcitabine continued for a mean of 2.8months. Upon progression (radiologic or CA19-9) nab-paclitaxel was re-instituted with gemcitabine. One patient could not tolerate nab-paclitaxel due to worsening of neuropathy while other six continued the combo with mean progression-free survival 2 (PFS2) of 2.2months. The six patients continued nab-paclitaxel for a mean of PFS2 of 2.2months (range 1-4months). Nab-paclitaxel resulted in improvement of an average DDC with an average of (7.0+2.2=) 8.2months (range 8-13months). Average overall survival for this group was 11.7months (range 9.5-17months). Reintroduction of nab-paclitaxel resulted in an average DDC of 9.4months. Average overall survival (OS) for this group was 11.7months. "OPTINAB" approach improved PFS2 in these patients and was feasible as majority of the patient tolerated nab-paclitaxel. Although it is a small study, it supports the need for a randomized, prospective study to test the concept of "OPTINAB".

Nab-Paclitaxel and Gemcitabine in Advanced Pancreatic Cancer: The One-year Experience of the National Cancer Institute of Naples.

Pancreas adenocarcinoma is the sixth cause of cancer-related death worldwide with an increasing mortality in the Western countries. Recently, the association between nab-paclitaxel (nab-P) and gemcitabine (GEM) has significantly improved progression-free and overall survival. Patients affected by metastatic pancreas adenocarcinoma were treated at the Department of Abdominal Oncology of the National Cancer Institute of Naples from July 2015 to July 2016 with nab-P at 125 mg per square meter of body-surface area followed by GEM at 1,000 mg per square meter on days 1, 8 and 15 every 4 weeks. Computed tomography (CT) was performed every three months of therapy. Toxicity was graded with National Cancer Institute-Common Toxicity Criteria (NCI-CTC) v4.0. Objective responses were evaluated with Response Evaluation Criteria in Solid Tumors (RECIST). Analysis of time-to-progression is only descriptive. Pain was evaluated with a visual analogue scale (VAS). Twenty-three patients were treated. Median age was 67 years (range=45-81); 8 patients were ≥70 years old. Performance status (PS) Eastern Cooperative Oncology Group (ECOG) was 2 in 8 patients, 1 in 10 and 0 in 5. Twelve patients presented with diffuse hepatic metastases, 4 with carcinosis, 7 with more than one organ involvement. Nab-P was reduced at 100 mg per square meter in all patients. The most common G3/G4 adverse events were neutropenia (13.0% G4, 8.6% G3; none was febrile), neuropathy (30.4% G3) and asthenia (G3 17.3%). The disease control rate was 43.4% (partial response+stable disease (PR+SD) 10/23). The median time-to-progression was 7.9 months (95% confidence interval (CI)=5.8-11.2). After three months of therapy the PS improved in 14 patients, as well as pain in 18 patients. We present an experience with nab-P and GEM association in a series with poor PS and highly metastatic disease relatively to a previous randomized study. The schedule is feasible, with nab-P at 100 mg per square meter achieving a good disease control rate, as well as a clinical benefit.

Nab-paclitaxel and gemcitabine in advanced pancreatic cancer: The one-year experience of the National Cancer Institute of Naples.

497 Background: Pancreas adenocarcinoma is the sixth cause of cancer-related death worldwide and the mortality is increasing in the Western Countries. Recently, the association between nab-paclitaxel (nab-P) and gemcitabine (GEM) has significantly improved progression-free (PFS) and overall survival (OS) compared to GEM monotherapy (PFS: 5.5 vs 3.7 months; OS: 8.5 vs 6.7 months). Methods: Patients affected by metastatic pancreas adenocarcinoma were treated at the Department of Abdominal Oncology of the National Cancer Institute of Naples from July 2015 to July 2016 with nab-P at 125 mg per square meter of body-surface area followed by GEM at 1000 mg per square meter on days 1, 8, and 15 every 4 weeks. Computed tomography (CT) was done every three months of therapy. Toxicity was graded with NCI-CTC criteria v4.0. Objective responses were evaluated with RECIST. Analysis of time-to-progression is only descriptive. Pain was evaluated with a visual analogic scale. Results: Twenty-three patients were treated. Median age was 67 years (range: 45-81); 8 patients were ≥ 70 years old. Performance Status (PS) ECOG was 2 in 8 patients, 1 in 10 and 0 in 5. Twelve patients presented with diffuse hepatic metastases, 4 with carcinosis, 7 with more than one organ involvement. They received a median number of 13 administrations (range: 3-32) of therapy. During therapy Nab-P was reduced at 100 mg per square meter in all patients. The most common G3/G4 adverse events were neutropenia (13.0% G4, 8.6% G3, none was febrile), neuropathy (30.4% G3) and asthenia (G3 17.3%). The disease control rate was 43.4% (PR+SD 10/23); PR was registered in three patients (response rate: 13.0%). Twelve patients progressed and seven dead at September 20. The median time-to-progression was 7.9 months (95% confidence interval 5.8-11.2). After three months of therapy the PS improved in 14 patients as well as pain in 18 patients. Conclusions: We present an experience with nab-P and GEM association in a series with poor PS and highly metastatic disease relatively to the previous randomized study. The schedule is feasible with nab-P at 100 mg per square meter and it achieves a good disease control rate as well as a clinical benefit.

A UGT1A1 genotype-guided dosing study of modified FOLFIRINOX (mFOLFIRINOX) in previously untreated patients (pts) with advanced gastrointestinal malignancies.

427 Background: FOLFIRINOX improves survival compared with gemcitabine in advanced pancreatic cancer (PC), but with significant toxicity (Conroy, NEJM 2011). UGT1A1 clears SN-38, the active metabolite of irinotecan (IRI); UGT1A1*28 polymorphism reduces enzymatic activity and predisposes to severe IRI toxicity. We hypothesized that dosing mFOLFIRINOX based on UGT1A1 genotype would improve tolerability. The primary objective of this study (NCT01643499) was to determine whether genotype-guided dosing of IRI in mFOLFIRINOX is tolerable. A secondary objective was to describe objective response rates (ORR) in PC and biliary tract cancers (BTC). Methods: mFOLFIRINOX was given every 14 days. CT scans were obtained every 8 weeks. UGT1A1 *1/*1, *1/*28, and *28/*28 pts received initial IRI doses of 180, 135, and 90 mg/m2, respectively. 5-FU dose was 2400 mg/m2 over 46 hours (no bolus); leucovorin 400 mg/m2; oxaliplatin 85 mg/m2. In cohort 1 (tolerability cohort by genotype), prophylactic pegfilgrastim was not allowed in cycle 1 (28 days) unless clinically indicated. In cohort 2 (expansion tolerability cohort in PC and BTC), prophylactic pegfilgrastim was given. DLT during cycle 1 was defined as Grade (Gr) 3/4 neutropenia with fever; Gr 4 neutropenia lasting ≥ 5 days; Gr 4 thrombocytopenia, or Gr 3/4 non-hematologic toxicity despite optimal medical management. Doses were tolerable if the DLT rate during cycle 1 was ≤ 33% with 70-80% statistical confidence. Results: In cohort 1, DLTs were observed in 2/15 (13%) *1/*1 pts; 2/16 (13%) *1/*28 pts; 3/9 (33%) *28/*28 pts. In cohort 2, DLTs were observed in 6/19 (32%) PC pts and 4/19 (21%) BTC pts. DLTs in cohort 1 (some pts with multiple): neutropenic fever (5); Gr 3 fatigue (4); Gr 3 diarrhea (2). DLTs in cohort 2: Gr 3 fatigue (3); Gr 3 diarrhea (3); Gr 3 nausea/vomiting (2); Gr 5 sepsis without neutropenia (1); Gr 5 multi-organ failure (1); neutropenic fever (1); Gr 3 anorexia (1). To date, ORR is 13/39 (33%) in PC and 6/28 (21%) in BTC. Conclusions: mFOLFIRINOX is not tolerable in PC and BTC, even with UGT1A1 genotype-guided dosing of IRI and prophylactic pegfilgrastim. More needs to be done to improve the tolerability of this regimen. Clinical trial information: NCT01643499.

666P - A modified regimen of nab-paclitaxel and gemcitabine in advanced pancreatic cancer

666P - A modified regimen of nab-paclitaxel and gemcitabine in advanced pancreatic cancer

Abstract 1723: Novel drug candidates CEP1430 and CEP1507 against cancer stem cells and circulating tumor cells in advanced stage pancreatic cancer

Abstract Despite improvements in treatment modalities, pancreatic cancer remains the fourth leading cause of cancer mortality in the US. The 5-year survival rate is less than 6% because of the extent of metastases at the time of diagnosis. The treatment of pancreatic cancer remains challenging however there is much optimism with targeted strategies and trial designs. The interrogation of pathway centric targets that regulate the regenerative and metastatic activities in the tumor, adequate molecular-hypothesis driven trial designs with robust prognostic and predictive markers of response are necessary for the development of effective therapeutic strategies for long term anti-tumor benefit. Here, we examined the efficacy of CEP1430 and CEP1507 to target cancer stem cells (CSC) and circulating tumor cells (CTC) in human pancreatic cancer. The pancreatic CSCs expressed the following markers(CD133,CD44,CXCR4,SSEA3/4,Oct4,ALDH,Telomerase,& Nestin). In vitro CEP1430 inhibited the growth of CSCs whereas CEP1507 inhibited CTCs that expressed the following markers [CK19, CEA, CA19-9,CK8 /18,h-TERT,C-MET,CK20,EpCAM, Vimentin, E- Cadherin, MUC1, CEA CAM5,CD45 neg]. Gemcitabine on the other hand suppressed the viability of non-CSCs (differentiated tumor Cells) by 70%. In accord, in vivo studies showed that CEP1507 when combined with gemcitabine eliminated the engraftment of human pancreatic cancer CTCs by 85% (n = 20,p<0.001). In contrast, CEP1430 in combination with gemcitabine selectively inhibited CSCs by 80% (n = 20,p<0.001) and was more effective than the individual agents. This data demonstrates that CEP1430 and CEP1507 that target CSCs and CTCs respectively may change the treatment paradigm and enhance the efficacy of gemcitabine in advanced pancreatic cancer. Further studies will evaluate the full potential of this approach to target the CSCs - and metastasis-initiating cells (CTCs) as combination therapy against locally advanced and metastatic pancreatic cancer. Citation Format: Cristian Sharma, Padmini Narayanan, Michael Sharma, Robert Rodriguez, Miriam Navel, Donna Stanton, Natalee Amezcua, Shaleekha Sharma, Mandana Amiri, Jitesh Jani, Sherven Sharma, Jay P. Sharma. Novel drug candidates CEP1430 and CEP1507 against cancer stem cells and circulating tumor cells in advanced stage pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1723.

Multicenter randomized phase II study comparing alternate-day oral therapy using S-1 with the standard regimen as a first-line treatment for patients with locally advanced and metastatic pancreatic cancer: PAN-01 study.

4107Background: S-1 is an active agent for the treatment of pancreatic cancer. GEST study has previously shown the noninferiority of S-1 to gemcitabine in advanced pancreatic cancer. However, the s...

Use of Meriva as complementary therapy of locally advanced or metastatic pancreatic cancer (PC) with gemcitabine (GEM).

e15696Background: GEM still represents one of the mostly adopted treatments for PC. Combination treatments provided some improvement in response rate (RR) and progression free survival (PFS), although almost invariably associated to increased toxicity. Aiming to find a complementary therapy to GEM in advanced PC, we tested a preparation of curcumin complexed with phospholipids (Meriva) to increase bioavailability. Curcumin has antinflammatory, antioxidant and potential antitumor properties, seemingly, descending from the activation of nuclear factor Nrf2 and inhibition of NFkB. From this pattern of nutraceutical effects of Curcumin, Meriva emerges as a good candidate for complementary therapy, while also improving quality of life (QoL). Methods: This was a single centre, single arm prospective phase II trial. Inclusion criteria were: previously untreated patients with histologically confirmed metastatic or locally advanced PC, ECOG performance status (PS) of 0-2, adequate organ function and written inform...

A phase I trial of cabozantinib (XL184) and gemcitabine in advanced pancreatic cancer.

334 Background: Hepatocyte growth factor (HGF) and its receptor (c-Met) are activated in pancreatic ductal adenocarcinoma (PDAC). Preclinical data showed a combination of cabozantinib (cabo) and gemcitabine (gem) improved tumor control through inhibition of c-Met. We sought to determine the maximum tolerated dose (MTD) of cabo and gem in patients with advanced PDAC. Methods: Patients with unresectable or metastatic PDAC with ≤1 prior treatment and adequate organ function/performance status were eligible. Cabo was given orally once daily for 7 days and continued with gem infused IV over 30 min on days 1, 8, and 15 of a 28 day schedule. Doses were assigned in accordance with a Time to Event Continual Reassessment Method (TITE-CRM) per table below. Primary endpoint was MTD, defined as the highest dose level at which ≤25% of patients incurred a dose-limiting toxicity (DLT) in the first 35 days of therapy. Secondary endpoints included response rate, progression-free survival (PFS), and overall survival (OS). Results: Twelve patients were treated from July 2012 – May 2015. Median number of cycles given was 3 (range: 1-6). MTD was not determined. The probability of DLT was >25% for all dose levels attempted. Four of 10 evaluable patients experienced DLT (shown in table below), including grade 3 ALT/AST elevations (n=3) and thrombocytopenia (n=2). Five of 6 patients who continued therapy beyond cycle 2 incurred at least one grade 3 adverse event. Three patients had a partial response, but each discontinued therapy due to toxicity. Median PFS and OS were 4.7 (95% CI: 1.4 – 9.7) and 10.1 months (95% CI: 3.6 – 20.6), respectively, in treated patients. Conclusions: While the combination of cabo and gem demonstrated activity in PDAC, this regimen is impractical due to DLT at low doses and continuing toxicities despite dose reductions and schedule changes. Clinical trial information: NCT01663272. [Table: see text]

Evaluation of low-dose fractionated radiation therapy as a chemopotentiator of gemcitabine in advanced pancreatic cancer: results from an international multi-institutional phase II trial

Potentiation of systemic dosing of gemcitabine using very low-dose fractionated radiotherapy may improve its effect in advanced pancreatic cancer without additional toxicity as suggested by the results of our multi-institutional phase II study. Future regimens combining low-dose fractionated radiotherapy (RT) with systemic chemotherapy should be assessed for improving the chemotherapeutic benefit. Until recently, gemcitabine was considered the standard treatment for advanced pancreatic cancer despite low response rates. Efforts to improve response rates by combination therapies have had limited success and have involved using sub-systemic dosing of gemcitabine as a sensitizer for radiation. A novel paradigm, utilizing low-dose fractionated radiotherapy (LDFRT) as a potentiator of full-dose gemcitabine instead, was explored to assess safety and efficacy in treating advanced pancreatic cancer. Patients with locally advanced and metastatic pancreatic cancer were treated with 4 cycles of gemcitabine and LDFRT in a multi-institutional phase II study. Gemcitabine (1250 mg/m2 over 2 h) was administered on days 1 and 8 of a 21-day cycle. LDFRT fields included the upper abdomen from the diaphragm to the iliac crest and were administered at 60 cGy per fraction twice daily on days 1, 2, 8, and 9, with the morning fraction being delivered prior to gemcitabine infusion on days 1 and 8. Primary endpoint was objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Thirty-eight patients were enrolled in the trial, of which 23 had metastatic disease at time of enrollment. Objective response rate (CR + PR) was 8 %, and 61 % had at least stable disease. Overall median survival was 13 months and 1-year survival was 37 %. Patients with non-metastatic disease had a 1-year survival of 60 %. The most significant toxicity was hematologic, and only 3 patients were withdrawn from protocol due to toxicity. There was no reported febrile neutropenia. The use of LDFRT with systemic gemcitabine is safe, tolerable, and potentially effective. In advanced pancreatic cancer, where response rates with single-agent gemcitabine have been low, this chemopotentiation paradigm may improve survival among a poor prognostic patient cohort.

P-178 First-line chemotherapy with gemcitabine in advanced pancreatic cancer: a retrospective single-center analysis

P-178 First-line chemotherapy with gemcitabine in advanced pancreatic cancer: a retrospective single-center analysis

Generalizability of trial results to elderly Medicare patients with advanced solid tumors (Alliance 70802).

In the United States, patients who enroll in chemotherapy trials seldom reflect the attributes of the general population with cancer, as they are often younger, more functional, and have less comorbidity. We compared survival following three chemotherapy regimens according to the setting in which care was delivered (ie, clinical trial vs usual care) to determine the generalizability of clinical trial results to unselected elderly Medicare patients. Using SEER-Medicare data, we estimated survival for elderly patients (ie, age 65 years or older, n = 14097) with advanced pancreatic or lung cancer following receipt of one of three guideline-recommended first-line chemotherapy regimens. We compared their survival to that of similarly treated clinical trial enrollees, without age restrictions, with the same diagnosis and stage (n = 937). All statistical tests were two-sided. Trial patients were 9.5 years younger than elderly Medicare patients. Medicare patients were more often white and tended to live in areas of greater educational attainment than trial enrollees. For each tumor type, Medicare patients who were 75 years or older had median survivals that were six to eight weeks shorter than those of trial patients (4.3 vs 5.8 months following treatment with single agent gemcitabine for advanced pancreatic cancer, P = .03; 7.3 vs 8.9 months following treatment with carboplatin and paclitaxel for stage IV non-small cell lung cancer, P = .91; 8.2 vs 10.2 months following treatment with CDDP/ VP16 for extensive stage small cell lung cancer, P ≤ .01), whereas younger Medicare patients had survival times that were similar to those of trial patients. Results of clinical trials for advanced pancreatic cancer and lung cancers tended to correctly estimate survival for Medicare patients aged 65 to 74 years, but to overestimate survival for older Medicare patients by six to eight weeks. These estimates of Medicare patients' survival may aid subsequent patients and their oncologists in treatment decision-making.

Phase I trial of M2ES, a novel polyethylene glycosylated recombinant human endostatin, plus gemcitabine in advanced pancreatic cancer.

Pancreatic cancer is one of the most lethal and resistant to treatment of solid tumors. Combination therapies with various types of drugs against pancreatic cancer have been extensively investigated. Endostatin is a potent endogenous inhibitor of angiogenesis, which may be administered in combination with various chemotherapeutic agents in the treatment of several types of cancer. To the best of our knowledge, this phase I trial was the first clinical study to determine the tolerance, safety and efficacy of M2ES, a novel polyethylene glycosylated recombinant human endostatin, administered concurrently with full-dose gemcitabine in patients with inoperable, locally advanced or metastatic pancreatic adenocarcinoma. A total of 16 patients were treated with gemcitabine (1,000 mg/m2 on days 1, 8 and 15) and M2ES (5-45 mg/m2 on days 1, 8, 15 and 21) of each 28-day cycle. In 15 evaluable patients, the stable disease rate (SDR) was 40% (95% CI: 11.9-68.1%). In particular, a 75% SDR was observed in 3 out of 4 patients with a M2ES dose level of 7.5 mg/m2. The most noticeable M2ES-related adverse events observed during the trial were grade 2 liver function abnormalities (6.3%) and grade 1 skin rash (6.3%). No dose-limiting toxicity was observed in any patients from all the dose levels. Therefore, there was no increased toxicity associated with the addition of M2ES to gemcitabine and this combination was well tolerated.

Polychemotherapy or gemcitabine in advanced pancreatic cancer: A meta-analysis

Gemcitabine monotherapy is the cornerstone of treatment for advanced pancreatic cancer. To date, no clear survival benefit has been found when combination chemotherapy has been compared with gemcitabine alone, except in a few studies. This meta-analysis compared the efficacy of polychemotherapy with gemcitabine alone in advanced pancreatic cancer. Randomised trials comparing combination chemotherapy with gemcitabine alone were identified through electronic searches of PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials. Overall survival, reported as the hazard ratio at the 95% confidence interval, was the primary outcome measure. 29 trials (19 phase III and 10 small randomised trials) that included 8421 patients were identified. Overall, polychemotherapy significantly improved overall survival (hazard ratio=0.87; 95% CI, 0.81-0.93; P<0.0001), progression-free survival (hazard ratio=0.77; 95% CI, 0.70-0.84; P<0.00001), and response rate (risk ratio=1.71; 95% CI, 1.42-2.07; P<0.00001) compared with gemcitabine alone. Compared with gemcitabine monotherapy, combinations of two or more drugs (particularly those with novel agents or associated with >20% response rates and triplets) improved outcomes and response rate in advanced pancreatic cancer, and they could be considered a new standard of care in advanced settings.