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Clinical Trial
. 2016 May;119(2):312-8.
doi: 10.1016/j.radonc.2016.04.013. Epub 2016 Apr 19.

Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer

Emily Chan  1 , Lori R Arlinghaus  2 , Dana B Cardin  1 , Laura Goff  1 , Jordan D Berlin  1 , Alexander Parikh  1 , Richard G Abramson  2 , Thomas E Yankeelov  3 , Scott Hiebert  1 , Nipun Merchant  4 , Srividya Bhaskara  5 , Anuradha Bapsi Chakravarthy  6
Affiliations
Clinical Trial

Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer

Emily Chan et al. Radiother Oncol. 2016 May.

Abstract

Background and purpose: This single institution phase I trial determined the maximum tolerated dose (MTD) of concurrent vorinostat and capecitabine with radiation in non-metastatic pancreatic cancer.

Material and methods: Twenty-one patients received escalating doses of vorinostat (100-400mg daily) during radiation. Capecitabine was given 1000mg q12 on the days of radiation. Radiation consisted of 30Gy in 10 fractions. Vorinostat dose escalation followed the standard 3+3 design. No dose escalation beyond 400mg vorinostat was planned. Diffusion-weighted (DW)-MRI pre- and post-treatment was used to evaluate in vivo tumor cellularity.

Results: The MTD of vorinostat was 400mg. Dose limiting toxicities occurred in one patient each at dose levels 100mg, 300mg, and 400mg: 2 gastrointestinal toxicities and one thrombocytopenia. The most common adverse events were lymphopenia (76%) and nausea (14%). The apparent diffusion coefficient (ADC) increased in most tumors. Nineteen (90%) patients had stable disease, and two (10%) had progressive disease at time of surgery. Eleven patients underwent surgical exploration with four R0 resections and one R1 resection. Median overall survival was 1.1years (95% confidence interval 0.78-1.35).

Conclusions: The combination of vorinostat 400mg daily M-F and capecitabine 1000mg q12 M-F with radiation (30Gy in 10 fractions) was well tolerated with encouraging median overall survival.

Keywords: HDAC inhibitor; Magnetic resonance imaging; Neoadjuvant therapy.

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Conflict of interest statement

Conflicts of interest

Emily Chan, M.D., Ph.D.: Advisory boards for Merrimack, Amgen, Bayer, Taiho, Castle Biosciences, Genentech, Lilly, Imclone.

Lori R. Arlinghaus, Ph.D.: None.

Dana Cardin, M.D.: Advisory board for Merrimack.

Laura Goff, M.D.: Research funding: Astellas Pharma, Millenium, Roche, Amgen, Pfizer, Onyx.

Jordan D. Berlin, M.D.: None.

Alexander Parikh, M.D.: None.

Richard G. Abramson, M.D.: ICON Medical Imaging, consultant.

Thomas E. Yankeelov, Ph.D.: None.

Scott Hiebert, Ph.D.: None.

Nipun Merchant, M.D.: None.

Srividya Bhaskara, Ph.D.: None.

A. Bapsi Chakravarthy, MD: Bayer/Onyx.

Figures

Fig. 1
Fig. 1
Study schema. Subjects received capecitabine, vorinostat and radiation (30 Gy in 10 fractions) followed by two additional weeks of vorinostat. Subjects deemed unresectable were given the option of continuing capecitabine and vorinostat or coming off study and receiving standard of care treatment with their oncologist.
Fig. 2
Fig. 2
Vorinostat results in increased lysine acetylation of H3 in PBMCs: Abbreviations: XRT, Radiation; C, Capecitabine; V, Vorinostat.
Fig. 3
Fig. 3
DW-MRI pre and post start of therapy shows increase in ADC: pre-treatment DW-MRI was obtained prior to therapy. Post therapy DW-MRI was obtained after one week of chemoradiation. Images were obtained on a 3T MRI.
See this image and copyright information in PMC

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