TY - JOUR
T1 - Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-Mesothelin (CRS-207) with or without Nivolumab in Patients with Pancreatic Cancer
AU - Tsujikawa, Takahiro
AU - Crocenzi, Todd
AU - Durham, Jennifer N.
AU - Sugar, Elizabeth A.
AU - Wu, Annie A.
AU - Onners, Beth
AU - Nauroth, Julie M.
AU - Anders, Robert A.
AU - Fertig, Elana J.
AU - Laheru, Daniel A.
AU - Reiss, Kim
AU - Vonderheide, Robert H.
AU - Ko, Andrew H.
AU - Tempero, Margaret A.
AU - Fisher, George A.
AU - Considine, Michael
AU - Danilova, Ludmila
AU - Brockstedt, Dirk G.
AU - Coussens, Lisa M.
AU - Jaffee, Elizabeth M.
AU - Le, Dung T.
N1 - Funding Information:
T. Tsujikawa is an employee/paid consultant for Konica Minolta and Ono Pharmaceutical. T. Crocenzi reports receiving commercial research grants from Bristol-Myers Squibb and AstraZeneca. E.J. Fertig is an employee/paid consultant for Champions Oncology. R.H. Vonderheide is an employee/paid consultant for Medimmune, Celldex, Lilly, and Verstem, and reports receiving other commercial research support from Lilly, Apexigen, Inovio, Fibrinogen, and Janssen. A.H. Ko is an employee/paid consultant for Erytech, and reports receiving commercial research grants from Aduro Biotech, BMS, Celgene, Haloqyme, Merck, Merrimack, and Roche/Genentech. M.A. Tempero is an employee/paid consultant for Advance Medical, EcoR1 Capital, LLC., Elicio Therapeutics, Karyopharm Therapeutics, CPRIT, Bristol-Myers Squibb, AstraZeneca, FibroGen, Inc., Immunovia, and Merck & Co., Inc., and reports receiving commercial research grants from Celgene and Halozyme. G.A. Fisher is an employee/paid consultant for Merck, AstraZeneca, and Genentech/Roche. D.G. Brockstedt is an employee/paid consultant for and holds ownership interest (including patents) in Aduro Biotech. L. M. Coussens is an employee/paid consultant for Oregon Health & Science University, Cell Signaling Technologies, Syndax Pharmaceuticals, Inc., Carisma Therapeutics, Inc., Verseau Therapeutics, Inc., Zymeworks, Inc., CytomX Therapeutics, Inc., Starr Cancer Consortium, Lustgarten Foundation for Pancreatic Cancer Research, P30 Koch Institute for Integrated Cancer Research, Massachusetts Institute of Technology (honorarium), Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Care Center at Johns Hopkins (honorarium), Dana Farber Cancer Center Breast SPORE (honorarium), University of California, Moores Cancer Center (honorarium), NIH/NCI Frederick National Laboratory Advisory Committee (FNLAC, daily honorarium), Cell Signaling Technologies, Susan G Komen Foundation, Komen scholar (honorarium); reports receiving commercial research grants from Syndax Pharmaceuticals and Innate Pharma; reports receiving other commercial research support from Cell Signaling Technologies (reagent support), Syndax Pharmaceuticals (reagent support), and Deciphera Pharmaceuticals, LLC; is an advisory board member/unpaid consultant for Cancer Research Institute (CRI), The V Foundation for Cancer Research, Starr Cancer Consortium, and Pharmacyclics, Inc: Steering Committee for PCYC-1137-CA (NCT02436668). E.M. Jaffee is an employee/paid consultant for CSTONE, DragonFly, Genocea, Achilles, and Adaptive Biotech; reports receiving commercial research grants from BMS, Aduro Biotech, and Amgen; holds ownership interest (including patents) in Aduro Biotech; and is an advisory board member/unpaid consultant for the Lustgarten Foundation, Parker Cancer Institute, and the National Cancer Advisory Board. D.T. Le reports receiving commercial research grants from BMS and Aduro Biotech. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
The study and analyses were funded by the Pancreatic Cancer Action Network-AACR Research Acceleration Network Grant, supported by the Fredman Family Foundation, Grant Number 14-90-25-LE, a Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant (SU2C-AACR-DT14-14; D.T. Le, E.M. Jaffee, T. Tsujikawa, and L.M. Coussens), Aduro Biotech (D.T. Le and E.M. Jaffee), Bristol-Myers Squibb (D.T. Le and E.M. Jaffee), the Bloomberg Kimmel Institute (D.T. Le and E.M. Jaffee), and NCI/NIH SPORE P50CA062924 (D.T. Le and E.M. Jaffee) and CA62924 (D.T. Le and E.M. Jaffee). Kelly Gemmill assisted in article preparation. Stand Up to Cancer is a division of the Entertainment Industry Foundation. The abovementioned Dream Team grant is administered by the American Association for Cancer Research, the Scientific Partner of SU2C.
Publisher Copyright:
©2020 American Association for Cancer Research.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2020/7/15
Y1 - 2020/7/15
N2 - Purpose: Two studies in previously treated metastatic pancreatic cancer have been completed combining GVAX pancreas vaccine (GM-CSF–secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes–expressing mesothelin). In the current study, we compared Cy/GVAX followed by CRS-207 with (Arm A) or without nivolumab (Arm B). Patients and Methods: Patients with pancreatic adenocarcinoma who received one prior therapy for metastatic disease and RECIST measurable disease were randomized 1:1 to receive treatment on Arm A or Arm B. The primary objective was to compare overall survival (OS) between the arms. Additional objectives included assessment of progression-free survival, safety, tumor responses, CA19-9 responses, and immunologic correlates. Results: Ninety-three patients were treated (Arm A, 51; Arm B, 42). The median OS in Arms A and B were 5.9 [95% confidence interval (CI), 4.7–8.6] and 6.1 (95% CI, 3.5–7.0) months, respectively, with an HR of 0.86 (95% CI, 0.55–1.34). Objective responses were seen in 3 patients using immune-related response criteria (4%, 2/51, Arm A; 2%, 1/42, Arm B). The grade ≥3 related adverse event rate, whereas higher in Arm A (35.3% vs. 11.9%) was manageable. Changes in the microenvironment, including increase in CD8þ T cells and a decrease in CD68þ myeloid cells, were observed in long-term survivors in Arm A only. Conclusions: Although the study did not meet its primary endpoint of improvement in OS of Arm A over Arm B, the OS was comparable with standard therapy. Objective responses and immunologic changes in the tumor microenvironment were evident.
AB - Purpose: Two studies in previously treated metastatic pancreatic cancer have been completed combining GVAX pancreas vaccine (GM-CSF–secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes–expressing mesothelin). In the current study, we compared Cy/GVAX followed by CRS-207 with (Arm A) or without nivolumab (Arm B). Patients and Methods: Patients with pancreatic adenocarcinoma who received one prior therapy for metastatic disease and RECIST measurable disease were randomized 1:1 to receive treatment on Arm A or Arm B. The primary objective was to compare overall survival (OS) between the arms. Additional objectives included assessment of progression-free survival, safety, tumor responses, CA19-9 responses, and immunologic correlates. Results: Ninety-three patients were treated (Arm A, 51; Arm B, 42). The median OS in Arms A and B were 5.9 [95% confidence interval (CI), 4.7–8.6] and 6.1 (95% CI, 3.5–7.0) months, respectively, with an HR of 0.86 (95% CI, 0.55–1.34). Objective responses were seen in 3 patients using immune-related response criteria (4%, 2/51, Arm A; 2%, 1/42, Arm B). The grade ≥3 related adverse event rate, whereas higher in Arm A (35.3% vs. 11.9%) was manageable. Changes in the microenvironment, including increase in CD8þ T cells and a decrease in CD68þ myeloid cells, were observed in long-term survivors in Arm A only. Conclusions: Although the study did not meet its primary endpoint of improvement in OS of Arm A over Arm B, the OS was comparable with standard therapy. Objective responses and immunologic changes in the tumor microenvironment were evident.
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U2 - 10.1158/1078-0432.CCR-19-3978
DO - 10.1158/1078-0432.CCR-19-3978
M3 - Article
C2 - 32273276
AN - SCOPUS:85086445264
VL - 26
SP - 3578
EP - 3588
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 14
ER -