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Translational Therapeutics

Modulation of autophagy: a Phase II study of vorinostat plus hydroxychloroquine versus regorafenib in chemotherapy-refractory metastatic colorectal cancer (mCRC)



In metastatic colorectal cancer (mCRC), regorafenib (RGF), a multi-kinase inhibitor with angiogenic inhibition has modest effects on survival. We reported that autophagy modulation using hydroxychloroquine (HCQ), enhances the anticancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in mCRC, is well tolerated, and has comparable activity to RGF. Thus, we conducted a prospective study of VOR/HCQ versus RGF in mCRC.


This is a randomised, controlled trial of VOR 400 mg and HCQ 600 mg orally daily versus RGF 160 mg orally daily (3 weeks on/1 week off), every 4 weeks, in patients with mCRC. Primary endpoint: median progression-free survival (mPFS). Secondary endpoints: median overall survival (mOS); adverse events; pharmacodynamic analyses.


From 2/2015-10/2017, 42 patients were randomised to VOR/HCQ and RGF. Median age was 58.4 years. mPFS on VOR/HCQ was 1.9 months versus 4.35 months with RGF (P = 0.032). There was no difference in mOS (P = 0.9). Treatment was tolerated in both arms. In both arms, there was improved anti-tumour immunity.


VOR/HCQ had an inferior PFS when compared to RGF, although there was an increase in anti-tumour immunity in mCRC. VOR/HCQ has a favourable safety profile, and immune or tumour biomarkers may be used to identify clinical benefit of autophagy modulation in mCRC.

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Fig. 1: Consort diagram for Phase II randomised controlled clinical trial for vorinostat (VOR)/hydroxychloroquine (HCQ) versus regorafenib (RGF) in refractory metastatic colorectal cancer (mCRC).
Fig. 2: Left: progression-free survival (PFS) of VOR/HCQ versus RGF.
Fig. 3: 27-plex human cytokine array of patients who received RGF versus VOR/HCQ.
Fig. 4: VOR/HCQ versus RGF in mCRC results in a reduction in T cell and regulatory T cells.

Data availability

The datasets generated and/or analysed during this study are available from the corresponding author on reasonable request


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We would like to thank Merck for providing vorinostat for the study. We would like to thank the study coordinators, Leslie Wood RN and Lisa Longoria. Preliminary results were presented at ASCO 2019 conference, Chicago, IL (poster).


All authors: Cancer Prevention Research Institute of Texas (CPRIT RP140685) funded this clinical trial. We thank Merck for providing the vorinostat for the study. SPA: NIH CA054174, NIA AG044271.

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All authors conceived and/or designed the work that led to the submission, acquired data and/or played an important role in interpreting the results, drafted or revised the manuscript, approved the final version, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Sukeshi Patel Arora.

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The authors declare no competing interests.

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All patients provided written informed consent before enrollment. This study followed the ethical principles of the Declaration of Helsinki, the International Conference on Harmonization Guidelines for Good Clinical Practice, and local regulations (European Directive 2001/20/EC and US Code of Federal Regulations Title 21). The Institutional Review Board at the University of Texas Health San Antonio approved the original protocol and all subsequent amendments.

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Arora, S.P., Tenner, L., Sarantopoulos, J. et al. Modulation of autophagy: a Phase II study of vorinostat plus hydroxychloroquine versus regorafenib in chemotherapy-refractory metastatic colorectal cancer (mCRC). Br J Cancer (2022).

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