Background Valproate (VPA) is an orally available histone deacetylase (HDAC) inhibitor and avelumab is a therapeutic anti-PD-L1 monoclonal antibody. VPA is known to arrest the growth of transformed cells and has also been shown to enhance the efficacy of chemotherapy in virus-associated solid tumors (VAST) by increasing lytic viral gene expression. We hypothesized that combining VPA with avelumab may be an effective therapeutic strategy for the treatment of patients with VAST.

Methods We designed a single-arm, basket phase II feasibility trial. Patients with EBER+ nasopharyngeal (n=12) or p16+ oropharyngeal (8), cervical (7), anal (6), penile (3) or vaginal (2) carcinoma were enrolled. Patients received oral VPA (target serum concentration ug/mL) with avelumab 10 mg/kg intravenously until progression of disease, or a maximum of two years’ duration. Objective response rate (ORR) was a co-primary endpoint with feasibility while safety, progression-free and overall survival (PFS/OS) were secondary outcomes under study.

Results 39 patients were enrolled. Treatment was feasible; of 39 patients just two did not complete the pre-defined threshold of four treatment cycles. Approximately one-half of patients received first-line (metastatic) treatment, the remainder of patients had received ≥1 line(s) of therapy at the time of enrolment. ORR by RECIST 1.1 was 21% across the entire cohort; of interest, two of three patients with penile cancer achieved a sustained, partial response. Treatment responses were seen in all patient cohorts, except those with vaginal squamous cell carcinoma. All observed treatment responses have been durable in nature. For the all-patient analysis, median PFS and OS were 6.9 and 21.7 months, respectively. Treatment was well tolerated, with a safety profile consistent with that observed with PD-(L)1 blockade. We identified novel predictive biomarkers; the expression of galectin-9 on peripheral monocytes negatively correlated with efficacy, and increased serum IL8/IL18 and CD71+ erythrocyte precursor cells also predicted poor treatment outcomes.

Conclusions We report feasibility, efficacy and safety results of a completed phase II trial combining HDAC and PD-L1 inhibition. Encouragingly, despite enrolling patients with prior therapy ORR were similar in this trial to those seen historically in untreated patients, and no new safety concerns were identified by combining HDAC inhibition with PD-L1 blockade. Ongoing biomarker analyses may be helpful in identifying patients for whom combination therapy could be considered.

Acknowledgements The authors would like to acknowledge the support of the Alberta Cancer Foundation, as well as EMD Serono. Most importantly, the authors wish to thank the patients and their families who participated in this clinical trial.

Trial Registration This clinical trial was registered with the National Institute of Health (NIH); clinical trial registration number NCT03357757.

Ethics Approval This clinical trial was approved by the Health Research Ethics Board of Alberta (HREBA) Cancer Committee (approval number HREBA.CC-17-0374).