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ABSTRACT BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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. CLINICAL TRIAL REGISTRATION NCT02316340. Access through your institution Buy or subscribe This is a preview of subscription

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ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS PEVONEDISTAT (MLN4924): MECHANISM OF CELL

DEATH INDUCTION AND THERAPEUTIC POTENTIAL IN COLORECTAL CANCER Article Open access 21 July 2020 PHASE I TRIAL OF HYDROXYCHLOROQUINE TO ENHANCE PALBOCICLIB AND LETROZOLE EFFICACY IN

ER+/HER2− BREAST CANCER Article Open access 26 January 2025 CITRINO: PHASE 1 DOSE ESCALATION STUDY OF ANTI-LAG-3 ANTIBODY ENCELIMAB ALONE OR IN COMBINATION WITH ANTI-PD-1 DOSTARLIMAB IN

PATIENTS WITH ADVANCED/METASTATIC SOLID TUMOURS Article Open access 27 February 2025 DATA AVAILABILITY The datasets generated and/or analysed during this study are available from the

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bevacizumab in front line treatment of metastatic colorectal cancer. J Clin Oncol. 2017;35(15_suppl):3545. Article  Google Scholar  Download references ACKNOWLEDGEMENTS 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). FUNDING 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, USA Sukeshi Patel

Arora, Laura Tenner, John Sarantopoulos, Jay Morris, Qianqian Liu, Jenny A. Mendez, Tyler Curiel, Joel Michalek & Devalingam Mahalingam * Feinberg School of Medicine at Northwestern

University, Chicago, IL, USA Devalingam Mahalingam Authors * Sukeshi Patel Arora View author publications You can also search for this author inPubMed Google Scholar * Laura Tenner View

author publications You can also search for this author inPubMed Google Scholar * John Sarantopoulos View author publications You can also search for this author inPubMed Google Scholar *

Jay Morris View author publications You can also search for this author inPubMed Google Scholar * Qianqian Liu View author publications You can also search for this author inPubMed Google

Scholar * Jenny A. Mendez View author publications You can also search for this author inPubMed Google Scholar * Tyler Curiel View author publications You can also search for this author

inPubMed Google Scholar * Joel Michalek View author publications You can also search for this author inPubMed Google Scholar * Devalingam Mahalingam View author publications You can also

search for this author inPubMed Google Scholar CONTRIBUTIONS 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. CORRESPONDING AUTHOR Correspondence to Sukeshi Patel Arora. ETHICS DECLARATIONS COMPETING INTERESTS

The authors declare no competing interests. ETHICS APPROVAL AND CONSENT TO PARTICIPATE 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. CONSENT TO

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SUPPLEMENTARY INFORMATION SUPPLEMENT FIGURE 1S SUPPLEMENT TABLE 1S AJ-CHECKLIST RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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_ 127, 1153–1161 (2022). https://doi.org/10.1038/s41416-022-01892-6 Download citation * Received: 28 January 2022 * Revised: 15 May 2022 * Accepted: 09 June 2022 * Published: 23

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