Updated results of a phase 1 study combining the matrix metalloproteinase 9 inhibitor GS-5745 with gemcitabine and nab-paclitaxel in patients with advanced pancreatic cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 363-363 ◽  
Author(s):  
Johanna C. Bendell ◽  
Manish R. Patel ◽  
Carrie Baker Brachmann ◽  
Xi Huang ◽  
Julia D. Maltzman ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Matrix Metalloproteinase ◽  
Pancreatic Adenocarcinoma ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Matrix Metalloproteinase 9 ◽  
Phase 1 Study ◽  
Metastatic Setting ◽  
Metalloproteinase 9

363 Background: GS-5745 is a monoclonal antibody inhibitor of matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. We present data from patients (pts) with advanced pancreatic adenocarcinoma enrolled in an ongoing multi-indication phase 1 study (NCT01803282) evaluating GS-5745. Methods: Following a monotherapy dose finding stage, pts with locally advanced or metastatic pancreatic cancer received gemcitabine (G) + nab-paclitaxel (Abraxane, A) and GS-5745 800 mg IV every 2 weeks. Treatment continued until disease progression, unacceptable toxicity or withdrawal of consent. Response was assessed every 8 weeks per RECIST version 1.1 criteria. Results: As of April 2016, 36 pts were enrolled (1 continues to receive GS-5745). The most frequently observed adverse events (AEs) of any grade include fatigue (75%), alopecia (55.6%), peripheral edema (55.6%) and nausea (50%). Grade ≥ 3 AEs observed in ≥ 10% of pts included neutropenia (25%), anemia (19.4%) and fatigue (13.9%). The median progression free survival (PFS) for all pts is 7.8 (90% confidence interval (CI) = [6.1, 11]) months (mos), median duration of response (DOR) is 5.8 mos and the objective response rate (ORR) is 44.4%. Of the 31 pts who were treatment naïve in the metastatic setting, median PFS is 9.2 (90% CI = [6.1, 11]) mos, median DOR 5.8 mos and the ORR 51.6%. Median baseline circulating MMP9 was 44.3 (range 12.4-549.6) ng/mL and 31 of 32 patients with post-baseline samples had undetectable MMP9 levels within 8 weeks. Conclusions: GS-5745+GA demonstrated numerically higher ORR and PFS compared to historical data without additional toxicity. Additionally, reductions in circulating MMP9 levels post treatment suggest target engagement by GS-5745 . These results suggest this combination may warrant additional study in first line metastatic pancreatic adenocarcinoma. Clinical trial information: NCT01803282.

Updated results of a phase 1 study combining the matrix metalloproteinase 9 inhibitor GS-5745 and mFOLFOX6 in patients with advanced gastric/gastroesophageal junction cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 108-108 ◽  
Author(s):  
Manish A. Shah ◽  
Alexander Starodub ◽  
Jordan Berlin ◽  
Carrie Baker Brachmann ◽  
Xi Huang ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Matrix Metalloproteinase 9 ◽  
Dose Finding ◽  
Phase Iii ◽  
Matrix Remodeling ◽  
Treatment Naïve ◽  
Metalloproteinase 9

108 Background: GS-5745 is a monoclonal antibody inhibitor of matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. We present updated data from a phase I study of patients (pts) with advanced gastric/gastroesophageal adenocarcinoma (GC) treated with GS-5745 and mFOLFOX6 (NCT01803282). Methods: Following a monotherapy dose finding stage, pts with Human Epidermal Growth Factor Receptor 2 (HER2)-negative advanced or metastatic GC received mFOLFOX6 and GS-5745 (800 mg IV) every 2 weeks. Treatment continued until disease progression, unacceptable toxicity or withdrawal of consent. Response was assessed every 8 weeks per RECIST version 1.1 criteria. Results: As of April 2016, 40 pts were enrolled in the expanded cohort (12 continue to receive GS-5745). The most frequently observed adverse events (AEs) of any grade include nausea (62.5%), fatigue (60%), diarrhea (45%), peripheral neuropathy (45%) and neutropenia (37.5%). Grade ≥ 3 AEs observed in ≥ 10% of pts include neutropenia (20%) and nausea and neutrophil count decreased (10% each). Among 29 treatment naïve pts, median progression free survival (PFS) is 12 (90% confidence interval (CI) 5.5-18) months (mos), median duration of response (DOR) 10.6 mos and objective response rate (ORR) of 55.2%. For all pts (n=40), PFS is 7.8 (90% CI 5-13.9) mos, median DOR 10.1 mos and ORR of 50%. Median baseline circulating MMP9 was 44.7 (range 16.8-1395.3) ng/mL and all 34 patients with post-baseline samples had undetectable MMP9 levels within 8 weeks. Conclusions: The combination of GS-5745 with mFOLFOX6 is well tolerated and demonstrates activity, particularly in treatment naïve pts. Reduction in circulating MMP9 level after treatment with GS-5745 suggests specific target engagement. A phase III registration study of mFOLFOX6 +/- GS-5745 in treatment naïve metastatic GC pts is underway. Clinical trial information: NCT01803282.

Phase I/II study of gemcitabine plus S-1 with concurrent radiotherapy in patients of unresectable locally advanced pancreatic cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 261-261
Author(s):  
Tatsuya Ioka ◽  
Kazuhiro Katayama ◽  
Nobuko Ishida ◽  
Hironari Sueyoshi ◽  
Ryoji Takada ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Survival Rate ◽  
Phase I ◽  
Phase I Study ◽  
Phase 1 ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Phase 1 Study ◽  
Level 3 ◽  
Level 2

261 Background: We conducted chemoradiotherapy of gemcitabine plus S-1, key drugs for pancreatic cancer. Methods: Patients were eligible for the study if they had received a histopathological diagnosis of locally advanced pancreatic cancer and were diagnosed as unresectable by multiple clinicians including surgeons due to main arterial invasions and more. Radiation (RT) was perfomed for twenty-eight days continuously except Saturday, Sunday and National holiday in 1.8Gy once daily (total 50.4Gy). PTV was defined as GTV plus 10-15mm. Prophylactic irradiation to regional lymph nodes was not performed. Administration level of the anti-cancer drugs was referred to the following table. Results: A total of fifteen cases were enrolled to the phase I study from February, 2006 through May, 2007. RT was achieved in 13 of 15 cases (87%). Two cases of DLT occurred in level 2 (two cases of emesis) while three did in level 3 (one case of emesis and two of neutropenia of grade 4). We decided level 3 as MTD and level 2 as recommended dose. The overall response rate (more than PR) was 33.3% (5 in 15 cases) and tumor-control (more than SD) was achieved in 13 of 15 cases (87%). The one-year and two-year survival rate was 86.7% and 44.4%, respectively. Conclusions: We conducted the phase 1 study of chemoradiotherapy with two key drugs of pancreatic cancer and achieved the recommended dose in this phase I study. Ongoing study We have already finished the enrollment of 110 cases for a phase II randomized allocated study, comparing the chemoradiotherapy of administration dose decided in this phase 1 study with the combination therapy of gemcitabine plus S-1. Now we are carefully following the patients to compare two-year survival rate as a primary endpoint in phase II study. Clinical trial information: NCT01430052.

Nab-paclitaxel plus gemcitabine followed by radiotherapy with concurrent 5-FU in locally advanced unresectable pancreatic cancer: A Western Australian experience.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 430-430 ◽  
Author(s):  
Andrew Peter Dean ◽  
Nigel Spry ◽  
Alycea McGrath
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Adenocarcinoma ◽  
Median Survival ◽  
Locally Advanced ◽  
Radical Resection ◽  
Response To Therapy ◽  
Unresectable Pancreatic Cancer ◽  
Radical Radiotherapy ◽  
Metastatic Setting ◽  
Western Australian

430 Background: The optimal management of patients with locally advanced unresectable pancreatic cancer is unclear. In the metastatic setting, superior response rates have been seen with nab-paclitaxel plus gemcitabine compared to gemcitabine alone. We investigate the efficacy and safety of nab-paclitaxel plus gemcitabine followed by radical radiotherapy with concurrent 5-FU in patients with locally advanced unresectable pancreatic adenocarcinoma. Methods: A retrospective review was conducted of all patients with locally advanced unresectable pancreatic cancer treated with nab-paclitaxel plus gemcitabine, the majority proceeding to radical radiotherapy with concurrent 5-FU, at two large Western Australian metropolitan hospitals from January 2009 to December 2014. Charts were reviewed to obtain patient characteristics, efficacy and tolerability. Kaplan-Meier analysis was utilised to obtain survival curves. Results: Forty-two patients were identified as having locally advanced unresectable pancreatic adenocarcinoma, receiving nab-paclitaxel plus gemcitabine to a mean number of 5 cycles, the majority requiring dose reductions. Of these, thirty proceeded to radical radiotherapy; the majority receiving 3DCRT, 54 Gy, with concurrent 5-FU. Seven had sufficient response to therapy to be offered radical resection. Six went on to radical resection, all with R0 or close resection margins (2 with complete response). Median length of stay following surgery was 18 days, and there were no perioperative deaths. The median survival for patients proceeding with surgery was 30 months. Median survival was 23 months for those treated with chemoradiotherapy, and 10 months with chemotherapy alone. Conclusions: This retrospective investigation demonstrates that nab-paclitaxel plus gemcitabine followed by radical radiotherapy with concurrent 5-FU is a tolerable treatment option with encouraging results for patients with locally advanced unresectable pancreatic cancer. The R0 resection rate in patients that had adequate response to allow for radical resection is promising. Further studies are warranted.

Gli1 contributes to the invasiveness of pancreatic cancer through matrix metalloproteinase-9 activation

2008 ◽  
Vol 99 (7) ◽  
pp. 1377-1384 ◽  
Author(s):  
Shuntaro Nagai ◽  
Masafumi Nakamura ◽  
Kosuke Yanai ◽  
Junji Wada ◽  
Takashi Akiyoshi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Matrix Metalloproteinase ◽  
Matrix Metalloproteinase 9 ◽  
Metalloproteinase 9
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