Abstract CT190: A Phase II basket study of hypomethylating agent oral cc-486 and durvalumab in advanced solid tumors (METADUR)
Authors: Taylor Kirsty , Yau Helen Loo , Wang Ben X. , Bedard Philippe L. , Razak Albiruni R. , Hansen Aaron R. , Spreafico Anna , Cescon Dave , Butler Marcus O. , Oza Amit M. , Lheureux Stephanie , Stjepanovic Neda , Wang Lisa , As Brendan Van , Boross-Harmer Sarah , Pugh Trevor , Siu Lillian L. , Carvalho Daniel D. De 
Published: August 2019

Abstract
Background
Aberrant DNA methylation contributes to cancer initiation and progression. In preclinical models of solid tumors, chronic low dose administration of DNA hypomethylating agents can induce T-cell mediated immune activation responses by stimulating expression of endogenous retroviral elements, culminating in an IFN-mediated response. The addition of physiological levels of vitamin C may potentiate viral mimicry and increase anti-tumor immune priming. Immunologically ‘cold’ tumors were selected to evaluate whether these strategies can enhance their otherwise poor responses to immune checkpoint blockade.
Methods
PD-L1/PD-1 inhibitor naïve patients (pts) with advanced microsatellite stable colorectal cancer (MSS CRC); platinum resistant ovarian cancer (OC); estrogen receptor positive, HER2 negative breast cancer (ER+HER2- BC) were enrolled in this single institution, multi-cohort, investigator-initiated trial. The initial regimen (regimen A) consisted of oral CC-486 300mg QD Days 1-14 (cycles 1-3 only) in combination with durvalumab 1500mg IV Day 15, in 28 day-cycles. A protocol amendment (regimen B) after 19 patients changed CC-486 to 100 mg QD Days 1-21 (cycles 1-3), added oral vitamin C 500mg QD continuously and kept durvalumab 1500mg IV Day 15, in 28-day cycles. Adverse events (AEs) assessed by CTCAEv4.03 grade (G); tumor response by RECIST 1.1 every 2 cycles; paired tumor biopsies at baseline and cycle 2 days 10-14; and serial peripheral blood mononuclear cells (PBMCs) for immune-profiling (IP) and epigenetic analysis. PD-L1 by IHC was assessed using SP263 assay, positivity defined by TC&gt;25%.
Results
A total of 28 pts with MSS CRC (n=15), OC (n=4), ER+HER2- BC (n=9) were enrolled, 19 pts treated on regimen A, 9 on regimen B. Median age was 56 (range 36-78), ECOG 0:1=7:21, 100% had ≥3 prior lines of therapy, all tumors were PD-L1 negative. Best response was SD (3/28 pts received 3, 3 and 4 cycles respectively) with DCR 7.1%. Median follow-up of 4.7 months, mPFS was 1.9 months (95% CI 1.5-2.3) and mOS was 5 months (95% CI 4.5-10). Three patients (all regimen A) experienced DLTs (2 G4 neutropenia and 1 G3 anemia). Fifteen patients (54%) experienced G1/2 fatigue, 46% experienced G1/2 nausea, vomiting or diarrhea. Toxicity was comparable with addition of vitamin C. Initial analysis of PBMCs by flow cytometry in 3 of 4 OC pts demonstrated an increase in PD-1 and Ki67 expression in CD8 T cells only following administration of durvalumab. EPIC methylation array on 4 pts’ paired tumors and LINE 1 assay on 19 pts’ serial PBMCs (regimen A) demonstrated minimal change in global methylation.
Conclusion
No meaningful clinical responses to CC-486 plus durvalumab were observed. Tumor tissue and PBMCs both demonstrate minimal global DNA demethylation, with or without physiological dose vitamin C. Incremental immune activation beyond PD-L1 blockade was not demonstrated. Clinical trial information: NCT02811497
Citation Format: Kirsty Taylor, Helen Loo Yau, Ben X. Wang, Philippe L. Bedard, Albiruni R. Razak, Aaron R. Hansen, Anna Spreafico, Dave Cescon, Marcus O. Butler, Amit M. Oza, Stephanie Lheureux, Neda Stjepanovic, Lisa Wang, Brendan Van As, Sarah Boross-Harmer, Trevor Pugh, Lillian L. Siu, Daniel D. De Carvalho. A Phase II basket study of hypomethylating agent oral cc-486 and durvalumab in advanced solid tumors (METADUR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT190.