A phase ii study of pelareorep (REOLYSIN®) in combination with gemcitabine for patients with advanced pancreatic adenocarcinoma

Devalingam Mahalingam, Sanjay Goel, Santiago Aparo, Sukeshi Patel Arora, Nicole Noronha, Hue Tran, Romit Chakrabarty, Giovanni Selvaggi, Andres Gutierrez, Matthew Coffey, Steffan T. Nawrocki, Gerard Nuovo, Monica M. Mita

Research output: Contribution to journalArticle

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naïve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that pelareorep complements single agent gemcitabine in PDAC.

Original languageEnglish (US)
Article number160
JournalCancers
Volume10
Issue number6
DOIs
StatePublished - Jun 1 2018

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gemcitabine
Adenocarcinoma
Oncolytic Virotherapy
Mammalian orthoreovirus 3
Survival Rate
Survival
Poisons
Mutation Rate
Neoplasms
Up-Regulation
Biomarkers
Apoptosis
Drug Therapy
Therapeutics

Keywords

  • Immuno-oncolytic virus
  • Pancreatic cancer
  • PD-L1
  • Pelareorep
  • REOLYSIN®
  • Reovirus

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Mahalingam, D., Goel, S., Aparo, S., Arora, S. P., Noronha, N., Tran, H., ... Mita, M. M. (2018). A phase ii study of pelareorep (REOLYSIN®) in combination with gemcitabine for patients with advanced pancreatic adenocarcinoma. Cancers, 10(6), [160]. https://doi.org/10.3390/cancers10060160

A phase ii study of pelareorep (REOLYSIN®) in combination with gemcitabine for patients with advanced pancreatic adenocarcinoma. / Mahalingam, Devalingam; Goel, Sanjay; Aparo, Santiago; Arora, Sukeshi Patel; Noronha, Nicole; Tran, Hue; Chakrabarty, Romit; Selvaggi, Giovanni; Gutierrez, Andres; Coffey, Matthew; Nawrocki, Steffan T.; Nuovo, Gerard; Mita, Monica M.

In: Cancers, Vol. 10, No. 6, 160, 01.06.2018.

Research output: Contribution to journalArticle

Mahalingam, D, Goel, S, Aparo, S, Arora, SP, Noronha, N, Tran, H, Chakrabarty, R, Selvaggi, G, Gutierrez, A, Coffey, M, Nawrocki, ST, Nuovo, G & Mita, MM 2018, 'A phase ii study of pelareorep (REOLYSIN®) in combination with gemcitabine for patients with advanced pancreatic adenocarcinoma', Cancers, vol. 10, no. 6, 160. https://doi.org/10.3390/cancers10060160
Mahalingam, Devalingam ; Goel, Sanjay ; Aparo, Santiago ; Arora, Sukeshi Patel ; Noronha, Nicole ; Tran, Hue ; Chakrabarty, Romit ; Selvaggi, Giovanni ; Gutierrez, Andres ; Coffey, Matthew ; Nawrocki, Steffan T. ; Nuovo, Gerard ; Mita, Monica M. / A phase ii study of pelareorep (REOLYSIN®) in combination with gemcitabine for patients with advanced pancreatic adenocarcinoma. In: Cancers. 2018 ; Vol. 10, No. 6.
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abstract = "Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18{\%} and 7{\%} respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN{\circledR}), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-na{\"i}ve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45{\%} and 24{\%}, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that pelareorep complements single agent gemcitabine in PDAC.",
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AU - Arora, Sukeshi Patel

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AU - Chakrabarty, Romit

AU - Selvaggi, Giovanni

AU - Gutierrez, Andres

AU - Coffey, Matthew

AU - Nawrocki, Steffan T.

AU - Nuovo, Gerard

AU - Mita, Monica M.

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AB - Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naïve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that pelareorep complements single agent gemcitabine in PDAC.

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