Therapy For Advanced Pancreatic Cancer Research Articles

Safety and Efficacy of Gemcitabine, Docetaxel, Capecitabine, Cisplatin as Second-line Therapy for Advanced Pancreatic Cancer After FOLFIRINOX.

The aim of this monocentric study was to evaluate the efficacy and tolerability of a polychemotherapy regimen based on gemcitabine, docetaxel, capecitabine, cisplatin (PDGX) as second-line for advanced pancreatic cancer after FOLFIRINOX. Patients received FOLFIRINOX as first-line regimen were retrospectively identified between January 2016 and January 2019. After disease progression or unacceptable toxicity, patients eligible for second-line therapy were treated in our center by PDGX. During this period, 18 patients received PDGX regimen as second-line therapy. Main grade 3 toxicities were hematologic, which required dose adaptation in 14/18 patients. No toxic death was observed. Median second-line progression-free survival (PFS) and overall survival (OS) were 2,91 and 5,3 months, respectively. Total OS from the initiation of first-line was and 11,9 months. Second-line PDGX regimen after FOLFIRINOX failure is feasible, with notable toxicity profile and is associated with poor clinical outcomes.

TRYbeCA-1: A randomized, phase III study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441).

TPS4666 Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study inpatients with advanced pancreatic cancer whose disease progressed following first-line treatment(NCT02195180). Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is a randomized, open-label Phase 3 trial (N = ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage III-IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. A hazard ratio in OS of 0.725 is being targeted which represents a conservative estimate based on the Phase 2b data and is viewed as being highly clinically relevant. An IDMC is established to review safety at regular intervals andto review efficacy data at the planned interim and final analyses. IDMC last reviewed the trial in October 2019 and suggested the trial continue as planned. Clinical trial information: NCT03665441 .

TRYbeCA-1: A randomized, phase III study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441).

TPS783 Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study inpatients with advanced pancreatic cancer whose disease progressed following first-line treatment. Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is a randomized, open-label Phase 3 trial (N = ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage III-IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. A hazard ratio in OS of 0.725 is being targeted which represents a conservative estimate based on the Phase 2b data and is viewed as being highly clinically relevant. An IDMC will be established to review safety at regular intervals andto review efficacy data at the planned interim and final analyses. Clinical trial information: NCT03665441.

Theranostic nanoparticles enabling the release of phosphorylated gemcitabine for advanced pancreatic cancer therapy.

Gemcitabine (GEM) has been the recommended first-line drug for patients with pancreatic ductal adenocarcinoma cancer (PDAC) for the last twenty years. However, GEM-based treatment has failed in many patients because of the drug resistance acquired during tumorigenesis and development. To override resistance to GEM in pancreatic cancer, we developed a visualisable, photothermally controlled, drug release nanosystem (VPNS). This nanosystem has NaLuF4:Nd@NaLuF4 nanoparticles as the luminescent core, octabutoxyphthalocyanine palladium(ii) (PdPc) as the photothermal agent, and phosphorylated gemcitabine (pGEM) as the chemodrug. pGEM, one of the active forms of GEM, can circumvent the insufficient activation of GEM in cancer cell metabolism. The NaLuF4:Nd@NaLuF4 nanoparticles were employed to visualise the tumor lesion in vivo by their near-infrared luminescence. The near-infrared light-triggered photothermal effect from PdPc could trigger the release of pGEM loaded in a thermally responsive ligand and simultaneously enable photothermal cancer treatment. This work presents an effective method that suppresses the growth of tumour cells with dual-mode treatment and enables the improved treatment of orthotopic nude mice afflicted with pancreatic cancer.

Abstract B22: Trybeca-1: A randomized, phase 3 study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441)

Abstract Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs), is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized phase 2b study in patients with advanced pancreatic cancer whose disease progressed following first-line treatment (NCT02195180). Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression-free survival (PFS). The safety profile of eryaspase was acceptable. The results of this phase 2b study provided a rationale for initiating this confirmatory phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is an international, randomized, open-label phase 3 trial (N= ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anticancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1, stage IV disease, documented evidence of disease progression, available tumor tissue, and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. A hazard ratio in OS of 0.725 is being targeted, which represents a conservative estimate based on the phase 2b data and is viewed as being highly clinically relevant. An IDMC will be established to review safety at regular intervals and to review efficacy data at the planned interim and final analyses. Citation Format: Pascal Hammel, Rosanna Berardi, Eric Van Cutsem, Jaime Feliu, Richard Greil, Harpreet Wasan, Jean-Philippe Metges, Peter Nygren, Pia Österlund, Marcus Noel, Thomas Seufferlein, Geert-Jan Creemers, Anu Gupta, Sophie Salesse, Nigel Biswas-Baldwin, Hedy Dion, Hagop Youssoufian, Iman El-Hariry, Manuel Hidalgo. Trybeca-1: A randomized, phase 3 study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441) [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B22.

Mutant KRAS G12V-specific TCR Transduced T Cell Therapy for Advanced Pancreatic Cancer

Mutant KRAS G12V-specific TCR Transduced T Cell Therapy for Advanced Pancreatic Cancer

P-098 - TRYbeCA-1: A randomized, phase 3 study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441)

Introduction: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs), is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study in patients with advanced pancreatic cancer whose disease progressed following first-line treatment (NCT02195180). Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression-free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is an international, randomized, open-label, phase 3 trial (N= ∼500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. A hazard ratio in OS of 0.725 is being targeted which represents a conservative estimate based on the phase 2b data and is viewed as being highly clinically relevant. An IDMC will be established to review safety at regular intervals and to review efficacy data at the planned interim and final analyses. Results: N/A - TiP abstract Conclusion: N/A - TiP abstract

Outcomes and Characteristics of Patients Receiving Second-line Therapy for Advanced Pancreatic Cancer.

There is limited randomized data to guide second-line chemotherapy selection in advanced pancreatic cancer (APC). We aimed to characterize predictors and outcomes of second-line chemotherapy in patients with APC. We identified all patients with APC [locally advanced (LAPC) or metastatic (MPC)] who received ≥1 cycle of first-line chemotherapy between January 2012 and December 2015 across 6 cancer centers in British Columbia, Canada. Baseline characteristics and survival outcomes were summarized. Of 676 patients with APC (31% LAPC, 69% MPC) who received ≥1 cycle of chemotherapy, 164 (24%) received second-line chemotherapy. These patients were younger, with lower ECOG and higher CA19-9 at presentation, compared with patients who did not receive second-line chemotherapy. There were no differences in rates of second-line chemotherapy between LAPC and MPC (28% vs. 23%; P=0.18). Only first-line FOLFIRINOX was associated with second-line chemotherapy. Median overall survival (OS) from second-line chemotherapy was longer with second-line gemcitabine/nab-paclitaxel than fluoropyrimidine or gemcitabine (7.9 vs. 5.1 vs. 4.3 mo; P=0.008). On multivariable analysis, longer OS from second-line chemotherapy was associated with gemcitabine/nab-paclitaxel, lower ECOG, and LAPC. In this population-based cohort, first-line FOLFIRINOX was the strongest predictor of second-line chemotherapy. Duration of therapy remains short and novel treatments are urgently needed.

Trybeca-1: A randomized, phase 3 study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441).

TPS471 Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study inpatients with advanced pancreatic cancer whose disease progressed following first-line treatment(NCT02195180). Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is an international, randomized, open-label Phase 3 trial (N = ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. An HR in OS of 0.725 is being targeted representing a conservative estimate based on the P2b data and is viewed as being highly clinically relevant. An IDMC will be established to review safety at regular intervals and to review efficacy data at the planned interim and final analyses. Clinical trial information: NCT03665441.

FOLFIRINOX is a cost-effective combination chemotherapy in first-line for advanced pancreatic Cancer

ObjectivesThe analysis was conducted to assess the effect of front-line combination chemotherapies on progression free survival (PFS). MethodsThe analysis was restricted to phase III randomized controlled trials (RCTs) in first-line therapy for advanced pancreatic cancer. The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) was applied to the above phase III RCTs. We have also calculated differences in PFS between the different arms of each trial and the pharmacological costs necessary to get the benefit in PFS, for each trial. ResultsOur study evaluated 11 phase III randomized controlled trials (RCTs), including 4572 patients. Combining the costs of therapy with the measure of efficacy represented by the PFS, we have obtained 74.12 € per month of PFS gained for 5-FU, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX), 90.14 per month of PFS gained for gemcitabine and oxaliplatin (GEMOX) and 4708.70 € per month of PFS gained for the combination of gemcitabine plus nab-pacliatxel against gemcitabine alone. ConclusionsCombining pharmacological costs with the measure of efficacy represented by PFS, FOLFIRINOX is a cost-effective first-line for advanced pancreatic cancer.

Efficacy and safety of gemcitabine plus anti-angiogenesis therapy for advanced pancreatic cancer: a systematic review and meta-analysis of clinical randomized phase III trials.

Purpose: Pancreatic cancer is a common digestive neoplasm with a high fatality rate. We performed this systematic review and meta-analysis of clinical randomized phase III trials to explore the efficacy and safety of gemcitabine plus anti-angiogenesis therapy versus gemcitabine monotherapy for locally advanced or metastatic pancreatic cancer.Methods: We searched PubMed, Embase and the Cochrane Library to identify eligible studies. Data were collected for the period from January 1, 2000 to August 20, 2018. Hazard ratios (HRs) and odds ratios (ORs) were used as main evaluation parameters.Results: A total of eight eligible studies with 3,586 individuals were included in the present meta-analysis. The results showed that the combination of gemcitabine plus anti-angiogenesis therapy had a significant effect on progression-free survival (HR = 0.92, 95% CI: 0.86 - 1.00, P = 0.04), but led to no significant difference in the overall survival (HR = 0.96, 95% CI: 0.88 - 1.05, P = 0.38). In terms of safety, gemcitabine plus anti-angiogenesis therapy did not increase the rate of grade 3-4 common adverse effects except for hypertension.Conclusions: Although gemcitabine plus anti-angiogenesis therapy might prolong the progression-free survival in locally advanced or metastatic pancreatic cancer, these successful results did not translate into a significant improvement in the overall survival or change in the clinical guidelines.

Local Phototherapy Synergizes with Immunoadjuvant for Treatment of Pancreatic Cancer through Induced Immunogenic Tumor Vaccine.

Purpose: To develop a synergistic combination therapy for advanced pancreatic cancer, using local phototherapy and immunotherapy, and to determine the efficacy and mechanism of the novel combination therapy using a highly metastatic pancreatic tumor model in mice.Experimental Design: Mice bearing Panc02-H7 pancreatic tumors (both subcutaneous and orthotopic) were treated with noninvasive or interventional photothermal therapy, followed by local application of an immunoadjuvant. Tumor growth and animal survival were assessed. Immune cell populations within spleen and tumors were evaluated by FACS and IHC, and cytokine levels were determined by ELISA.Results: Up to 75% of mice bearing subcutaneous tumors treated with combination therapy had complete tumor regression. Local photothermal therapy exposed/released damage-associated molecular patterns, which initiated an immunogenic tumor cell death, resulting in infiltration of antigen-presenting cells and Th1 immunity. Concomitant application of immunoadjuvant amplified Th1 immunity, especially the tumor-specific cytotoxic T lymphocyte response, with increased quantity and quality of T cells. Combination therapy also induced tumor-specific immune memory, as demonstrated by resistance to tumor rechallenge and production of memory T cells. For the treatment of orthotopic tumor, the combination therapy significantly reduced the primary tumors and metastases, and prolonged the animal survival time.Conclusions: This study indicated that combination of local phototherapy and immunotherapy induced a systemic immunity against established tumors and metastases in an aggressive, preclinical pancreatic tumor model, leading to a potential clinical method for patients with advanced pancreatic cancer. Clin Cancer Res; 24(21); 5335-46. ©2018 AACR.

Nab-paclitaxel plus S-1 as first-line followed by S-1 maintenance for advanced pancreatic adenocarcinoma: a single-arm phase II trial

PurposeWe conducted a single-arm prospective phase II study to determine the efficacy and safety of the first-line treatment of advanced pancreatic cancer with nab-paclitaxel and S-1 followed by S-1 maintenance therapy.MethodsNab-paclitaxel was administered intravenously on days 1 and 8 at 120 mg/m2. S-1 at 120 mg/day (for surface area ≥ 1.5 m2), 100 mg/day (for surface area between 1.25–1.5 m2), and 80 mg/day (for surface area < 1.25 m2) were given two times daily on days 1–14 every 3 weeks. Patients who achieved response and stable disease after 6 cycles were given S-1 maintenance treatment in the same schedule until disease progression or unacceptable toxicity developed. The primary endpoint was objective response rate (ORR), and the secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Between 01/2015 and 07/2017, 32 patients were enrolled.ResultsThe ORR in the intention-to-treat (ITT) population (N = 32) was 53.1%, and the DCR was 87.5%. In the 30 evaluable patients, the ORR and DCR were 56.7 and 93.3%, respectively. The median follow-up time was 18 (range 12–36) months, the median PFS was 6.2 (range 4.4–8) months, and the median OS was 13.6 (range 8.7–18.5) months. The incidence of grade 3/4 neutropenia was 27.6%. Other grade 3 adverse events included 1 (3.1%) hand–foot syndrome, 1 (3.1%) rash and 2 (6.3%) diarrheas.ConclusionsNab-paclitaxel and S-1 regimen has presented encouraging ORR, OS, and manageable toxicities as first-line therapy for advanced pancreatic cancer.

Venous thromboembolism and pancreatic cancer

Pancreatic cancer (PC) is a devastating malignancy with an overall 5-year survival of 8% for all stages combined. Most of the PC patients diagnosed have an advanced disease (40%) or metastatic stage (40%), which eliminates surgery as a potentially curative treatment. The disease course is often complicated by venous thromboembolism (VTE) events, which per se account for significant morbidity and mortality, with significantly worsen survival. PC is associated with the highest risk of VTE among all cancer patients. We review the literature data to address the incidence and clinical outcomes of VTE in PC patients. VTE incidence varies from 5 to 41% according to epidemiological studies and is as high as 57% in postmortem series. Since 2013, international clinical practice guidelines recommend primary thromboprophylaxis with a grade 1B level of evidence as an adjuvant therapy in advanced PC. A recent meta-analysis of randomized controlled trials investigating the benefit and risk of low-molecular-weight heparins (LMWH) in ambulatory advanced PC patients under chemotherapy showed that the incidence of VTE was 2.1% in patients treated with LMWH and 11.2% in controls (risk ratio, 0.18; 95% CI, 0.083-0.39; P<0.0001). In conclusion, improved earlier diagnosis and effective management of VTE, a frequent and life-threatening complication in PC, is warranted to improve PC patient outcomes.

Endoscopic Ultrasound‑Guided Antitumor Therapy for Advanced Pancreatic Cancer

Endoscopic Ultrasound‑Guided Antitumor Therapy for Advanced Pancreatic Cancer

Outcomes and characteristics of patients receiving second-line therapy for advanced pancreatic cancer.

435 Background: Recent trials have demonstrated improved outcomes in the 1st-line treatment of advanced pancreatic cancer (APC). However, there is limited randomized data to guide 2nd-line chemotherapy (CT) selection. We aimed to characterize predictors and outcomes of 2nd-line CT in patients (pts) with APC. Methods: We identified all pts with APC (locally advanced (LAPC) or metastatic (MPC)) who received ≥1 cycle of 1st-line CT between January 1, 2012 and December 31, 2015 across 6 centers in British Columbia, Canada. Baseline characteristics and survival outcomes were summarized. Results: Of 676 pts with APC (31% LAPC, 69% MPC) who received ≥1 cycle of CT, 164 (24%) received 2nd-line CT. These pts were younger (median 63.7 vs. 67.4 years; p= 0.01), had a lower ECOG (77% ECOG 0-1 vs. 51% ECOG ≥2; p&lt; 0.001), and higher CA19-9 (median 1034 vs. 829; p= 0.01) compared to patients who did not receive 2nd-line CT. There were no differences in rates of 2nd-line CT between LAPC and MPC (28% vs. 23%; p= 0.18). On logistic regression, only 1st-line FOLFIRINOX (OR 5.90, p&lt; 0.001) was associated with 2nd line CT. CT regimens are summarized by line (Table). Median duration of 2nd-line CT was 3 cycles (range 1-30). Median overall survival (mOS) from diagnosis of patients with 2nd-line CT was 16 months. mOS from 2nd-line CT was longer with 2nd-line gemcitabine/nab-paclitaxel than fluoropyrimidine or gemcitabine (7.9 vs. 5.1 vs. 4.3 months; p= 0.008). On multivariate analysis, longer OS from 2nd-line CT was associated with gemcitabine/nab-paclitaxel (vs. single agent CT), lower ECOG, LAPC (vs MPC), and lower CA 19-9 (HRs 0.49, 0.67, 0.58, 0.38, respectively). Conclusions: In this population-based cohort, pts treated with 2nd line CT were younger, have better ECOG, similar rates of LAPC vs. MPC, and achieved a median OS of 16 months. 1st-line FOLFIRINOX was the strongest predictor of 2nd-line CT. Gemcitabine/nab-paclitaxel was associated with superior 2nd line OS compared to gemcitabine/fluoropyrimidine. [Table: see text]

Points to keep in mind when carrying out clinical trials in Japan on advanced pancreatic cancer cases without alternative treatments: Analysis of 367 cases.

243 Background: We commenced a physician-led clinical trial to examine the efficacy of a combined treatment of peptide vaccine therapy for advanced pancreatic cancer that has no effective treatment. During this trial, there were inquiries from 367 cases, of which 145 cases (40%) were examined at our outpatient clinic. The purpose of this study was to examine these cases in detail and to consider the points to be noted in executing clinical trials for poor prognosis cases. Methods: We examined the timing of inquiry, medical condition, the person(s) they inquired, and other relevant information regarding the 367 subjects who made inquiries. For the 145 cases visited the outpatient clinic of our hospital, we examined their medical condition, treatment and whether or not they have participated in a clinical trial. Results: 140 of the 367 cases (38%) of inquiry were concentrated within the first two months after the start. During these two months, there was a concentration of patients who had completed standard treatments and were a few months into BSC, but were unable to participate in the clinical trial due to deterioration of their general condition. Many of the inquiries were made by family members (spouse or child) of the patients, around twice the number of inquiries made by patients themselves. Even among the 145 subjects that were examined in the outpatient clinic of our hospital, severe cases, in particular, were seen several months after the start of the study. There were many cases that required urgent hospitalization during outpatient visits or patients whose general condition rapidly deteriorated during the screening tests. 23 cases (16%) underwent the clinical trial. Conclusions: In clinical trials such as this one, which handles cases with poor prognosis, many of the subjects are in poor general condition at the inquiry stage, and most of these inquiries are concentrated immediately after the start of the study. Therefore, it is very important to deal with inquiries and make judgments during the outpatient examination on whether or not clinical trial participation is possible.

SWI/SNF aberrations sensitize pancreatic cancer cells to DNA crosslinking agents.

While gemcitabine has been the mainstay therapy for advanced pancreatic cancer, newer combination regimens (e.g. FOLFIRINOX) have extended patient survival, though carry greater toxicity. Biomarkers are needed to better stratify patients for appropriate therapy. Previously, we reported that one-third of pancreatic cancers harbor deletions or deleterious mutations in key subunits of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex. The SWI/SNF complex mobilizes nucleosomes on DNA, and plays a key role in modulating DNA transcription and repair. Thus, we hypothesized that pancreatic cancers with SWI/SNF aberrations might exhibit compromised DNA repair, and show increased sensitivity to DNA damaging agents. Here, we studied human pancreatic cancer cell lines with deficient (or else exogenously reconstituted) SWI/SNF subunits, as well as normal pancreatic epithelial cells following SWI/SNF subunit knockdown. Cells were challenged with DNA damaging agents, including those used in current combination regimens, and then cell viability assayed. We found that pancreatic cells with SWI/SNF dysfunction showed markedly increased sensitivity to DNA damaging agents, and in particular DNA crosslinking agents (cisplatin and oxaliplatin). Assaying clearance of γH2AX confirmed that SWI/SNF dysfunction impaired DNA damage response/repair. Finally, by analyzing pancreatic cancer patient data from The Cancer Genome Atlas, we found that pancreatic cancers with SWI/SNF deficiency (subunit mutation and/or decreased expression) were associated with extended patient survival specifically when treated with platinum containing regimens. Thus, SWI/SNF dysfunction sensitizes pancreatic cancer cells to DNA crosslinking agents, and SWI/SNF mutation status may provide a useful biomarker to predict which patients are likely to benefit from platinum-containing chemotherapy regimens.

Toward Personalized Dosimetry with 32P Microparticle Therapy for Advanced Pancreatic Cancer

To develop a Monte Carlo model for patient-specific dosimetry of 32P microparticle localized internal radionuclide therapy for advanced pancreatic cancer. Spherical tumor geometries and a pancreatic phantom were modeled, as well as different 3-dimensional non-uniform clinical pancreatic geometries based on patient-specific ultrasound images. The dosimetry simulations modeled the dose distribution due to the energy spectrum of emitted beta particles. The average dose for small (3-cm diameter) and large (6-cm diameter) spherical tumors was 111Gy (for 7.6 MBq administered activity) and 128Gy (for 58 MBq), respectively. For the clinical 3-dimensional geometries, on the basis of patient data, the mean doses delivered to the tumor were calculated to be in the range 102 to 113Gy, with negligible dose to the pancreas for the smallest tumor volumes. The calculated dose distributions are highly non-uniform. For the largest tumor studied, the pancreas received approximately 6% of the tumor dose (5.7Gy). Importantly, we found that because the smallest tumor studied exhibited the most dynamic changes in volume in response to the treatment, the dose to tumor and pancreas is significantly underestimated if a static tumor volume is assumed. These results demonstrate the dosimetry of 32P microparticle localized internal radionuclide therapy for pancreatic cancer and the possibility of developing personalized treatment strategies. The results also highlight the importance of considering the effects of non-uniform dose distributions and dynamic change of tumor mass during treatment on the dosimetry of the tumor and critical organs.

Abstract 3809: SWI/SNF aberrations sensitize pancreatic cancer cells to DNA crosslinking agents

Abstract While gemcitabine has been the mainstay therapy for advanced pancreatic cancer, newer combination regimens (e.g. FOLFIRINOX) have extended patient survival, though carry greater toxicity. Biomarkers are needed to better stratify patients for appropriate therapy. Previously, we reported that one-third of pancreatic cancers harbor deletions or deleterious mutations in key subunits of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex. The SWI/SNF complex mobilizes nucleosomes on DNA, and plays a key role in modulating DNA transcription and repair. Thus, we hypothesized that pancreatic cancers with SWI/SNF aberrations might exhibit compromised DNA repair, and show increased sensitivity to DNA damaging agents. Here, we studied pancreatic cancer cell lines with deficient (or else exogenously reconstituted) SWI/SNF subunits, as well as normal pancreatic epithelial cells (HPDE) following SWI/SNF subunit knockdown. Cells were challenged with DNA damaging agents, including those used in current combination regimens, and then cell viability assayed. We found that pancreatic cells with SWI/SNF dysfunction showed markedly increased sensitivity to DNA damaging agents, and in particular DNA crosslinking agents (cisplatin and oxaliplatin). Assaying clearance of γH2AX foci confirmed that SWI/SNF dysfunction impaired DNA damage response/repair. Finally, by analyzing pancreatic cancer patient data (TCGA), we found that pancreatic cancers with SWI/SNF deficiency (subunit mutation and/or decreased expression) showed a strong trend towards extended survival with platinum containing chemo regimens. Thus, SWI/SNF dysfunction sensitizes pancreatic cancer cells to DNA crosslinking agents, and SWI/SNF mutation status may provide a useful biomarker to predict which patients are likely to benefit from platinum-containing chemotherapy regimens. Citation Format: Zhewei Shen, Jean Davidson, Jonathan Pollack. SWI/SNF aberrations sensitize pancreatic cancer cells to DNA crosslinking agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3809. doi:10.1158/1538-7445.AM2017-3809