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

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.

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).

**Crossover is optional and at the discretion of the physician and in the best interest for the patient. po by mouth, C1 Cycle 1.

Fig. 2. Left: progression-free survival (PFS) of VOR/HCQ versus RGF.

Median PFS was 1.90 months (95% CI 1.87 to undefined) with VOR/HCQ versus 4.35 months (95% CI 2.63 to undefined) with RGF (P = 0.032, HR: 2.277, 95% CI: 1.058–4.898). Right: overall survival (OS) with VOR/HCQ versus RGF in mCRC. The median OS was 6.77 months (95% CI 4.0 to undefined) with VOR/HCQ versus 7.23 months [95% CI 4.8–10.8] with RGF (P = 0.90, HR: 1.05, 95% CI: 0.481–2.3). VOR   vorinostat, HCQ   hydroxychloroquine, RGF  regorafenib.

Fig. 3. 27-plex human cytokine array of patients who received RGF versus VOR/HCQ.

Assay done at Cycle 1 day 1 (C1D1, baseline) and Cycle 1 day 15 (C1D15). Low = 1–3 cycles, High = 4+ cycles completed. *P < 0.05, ~10% increase TNFa after treatment. VOR   vorinostat, HCQ   hydroxychloroquine, RGF   regorafenib.

Fig. 4. VOR/HCQ versus RGF in mCRC results in a reduction in T cell and regulatory T cells.

In the VOR/HCQ arm, there was decreased CD45RO-CD62L + (naive) T cells, but this was not observed in the RGF arm. Flow cytometry analyses of absolute numbers of various T-cell populations (CD3 + , CD4 + , CD8 + , regulatory T cells) and surface markers (CD45RO) in total PBMCs for each individual patient at baseline and after Cycle 1. P values, paired t test. VOR vorinostat, HCQ   hydroxychloroquine, RGF   regorafenib.