N of 1 case reports of exceptional responders accrued from pancreatic cancer patients enrolled in first-in-man studies from 2002 through 2012.

Ignacio Garrido-Laguna,Katherine Geiersbach,Nan Hu,Danielle Tometich,Kai Wang,Jian Ying,Sunil Sharma,Jonathan Whisenant,Jeffrey S Ross

doi:10.18632/oncoscience.141

Ignacio Garrido-Laguna, Katherine Geiersbach + Show 7 more

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https://doi.org/10.18632/oncoscience.141

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Abstract

To identify exceptional responders among patients with advanced pancreatic cancer enrolled in first-in-man (FIM) studies. A Scopus search identified 66 FIM studies that enrolled at least one patient with advanced pancreatic cancer between 2002-2012. Descriptive statistics were used to summarize categorical variables. We also screened CRKL amplifications in the FoundationOne™ pancreatic cancer database. Most FIM studies included targeted therapies (76 vs. 24%). The most common targeted therapy involved cell cycle inhibitors (24%). Pharmacodynamic analyses were more frequently done in trials with targeted therapies (70 vs. 31%, p=0.006). Response rates were similar. Treatment-related death was 0.5%. Skin, cardiovascular and metabolic grade 3-4 toxicities were more frequent with targeted therapies. Four exceptional responses were identified including a complete response to bosutinib (Src Inhibitor) and partial responses to trametinib (MEK inhibitor) (2 patients) and CHR-3996 (histone deacetylase inhibitor). We found that CRKL amplifications, a potential biomarker for Src inhibitors, are present in 1% of PDA. We retrospectively identified extraordinary responses among patients with advanced PDA enrolled in FIM studies with Src, HDAC and MEK inhibitors. We identified CRKL amplifications are present in 1% of PDA and need to be evaluated as predictive biomarker for Src inhibitors.

Highlights

Pancreatic ductal adenocarcinoma (PDA) is a devastating disease
We retrospectively identified extraordinary responses among patients with advanced PDA enrolled in FIM studies with Src, histone deacetylase inhibitor (HDAC) and MEK inhibitors
We identified CRKL amplifications are present in 1% of PDA and need to be evaluated as predictive biomarker for Src inhibitors

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDA) is a devastating disease. It is the fourth most common cause of death by cancer in the United States (US). 46,420 new cases will be diagnosed in the US in 2014 and 39,540 patients will succumb to the disease.[1] It is estimated that it will become the second deadliest cancer by 2020.[2] The 5-year overall survival rate is less than 5%.[3] Modest improvements in survival have recently www.impactjournals.com/oncoscience been achieved with combinations of cytotoxic agents. 50% of them will be eligible for second-line therapy or enrollment on early clinical trials.[6] While evidence supporting the use of second-line therapy is limited, phase 1 and first-in-man (FIM) trials can be considered for eligible patients. While evidence supporting the use of second-line therapy is limited, phase 1 and first-in-man (FIM) trials can be considered for eligible patients. [7,8,9]

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