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An exploratory study of metformin with or without rapamycin as maintenance therapy after induction chemotherapy in patients with metastatic pancreatic adenocarcinoma
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Katherine M. Bever1,2,3,*, Erkut H. Borazanci4,5,*, Elizabeth A. Thompson1,2, Jennifer N. Durham1,2, Kimberly Pinero4, Gayle S. Jameson4,5, Amber Vrana4, Meizheng Liu1,2, Cara Wilt1,2,3, Annie A. Wu1,2,3, Wei Fu1,6, Hao Wang1,2,6, Yafu Yin7, Jeffrey P. Leal8, Ana De Jesus-Acosta1,3, Lei Zheng1,2,3, Daniel A. Laheru1,2,3, Daniel D. Von Hoff4,5, Elizabeth M. Jaffee1,2,3, Jonathan D. Powell1,2 and Dung T. Le1,2,3
1 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
2 Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
3 The Skip Viragh Center for Pancreas Cancer at Johns Hopkins, Baltimore, MD, USA
4 Virginia Piper Cancer Center at HonorHealth, Scottsdale, AZ, USA
5 Molecular Medicine Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA
6 Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
7 Department of Nuclear Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai City, China
8 The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA
* Co-first authors
|Dung T. Le,||email:||[email protected]|
Keywords: pancreatic cancer; mTOR inhibition; maintenance therapy; metformin
Received: February 26, 2020 Accepted: April 14, 2020 Published: May 26, 2020
Purpose: Metformin combined with the mTOR inhibitor rapamycin showed potential synergistic anti-tumor activity in preclinical studies in pancreatic ductal adenocarcinoma (PDA). This phase 1b study (NCT02048384) was conducted to evaluate the feasibility and activity of metformin +/– rapamycin in the maintenance setting for unselected patients with metastatic PDA (mPDA) treated with chemotherapy.
Materials and Methods: Eligible patients with stable or responding mPDA after ≥ 6 months on chemotherapy were randomized 1:1 to metformin alone (Arm A) or with rapamycin (Arm B), stratified by prior treatment with FOLFIRINOX. Fluorodeoxyglucose (FDG) PET scans and peripheral blood mononuclear cells were obtained for exploratory analyses.
Results: 22 subjects (11 per arm) received treatment per protocol. Median PFS/OS were 3.5 and 13.2 months respectively, with 2 year OS rate of 37%; there were no differences between arms. No responses were observed by RECIST; however, decreases in FDG avidity and/or CA19-9 were observed in several long-term survivors. Treatment related adverse events of Grade ≥ 3 occurred in 0% vs 27% of patients in Arm A vs B and were asymptomatic hematologic or electrolyte abnormalities that were not clinically significant. Improved survival was associated with low baseline neutrophil: lymphocyte ratio, baseline lack of assessable disease by PET, and greater expansion of dendritic cells following treatment.
Conclusions: Metformin +/– rapamycin maintenance for mPDA was well-tolerated and several patients achieved stable disease associated with exceptionally long survival. Further prospective studies are needed to clarify the role of these agents in the maintenance setting and to enhance patient selection for such approaches.
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