This is a single-arm Phase 1/2 study (NCT00392353) sponsored by the National Cancer Institute (NCI), involving 28 patients with myelodysplastic syndromes (MDS) and some acute myeloid leukemia (AML). It began in November 2006. According to ClinicalTrials.gov, recruitment was completed as of February 2026, but the study remains active and is not recruiting, with ongoing follow-up. The study design involved administering azacitidine and oral vorinostat every 28 days to evaluate safety, determine the recommended dose, and assess response rates and time to leukemia conversion. Given its long-term, unresolved status, it is more of a study preserving the clinical evidence of an early epigenetic combination strategy rather than a new commercial catalyst.

The drug and its biological rationale: Vorinostat, the active ingredient in Zolinza, inhibits histone deacetylases (HDACs), increasing acetylation of histones and transcriptional regulatory proteins, thereby inducing differentiation and apoptosis of tumor cells. Azacitidine, the active ingredient in Vidaza, is a hypomethylating agent (HMA) that inhibits DNA methyltransferases (DNMTs), restoring abnormally suppressed gene expression. Researchers hypothesized that simultaneously inducing DNA demethylation and histone acetylation could improve the low response rates and resistance observed with azacitidine monotherapy. Initial results, including 14 MDS and 6 AML patients, reported a complete remission (CR) rate of 45% and a complete hematologic remission (CRi) rate of 9%, but these were small, single-arm results, necessitating validation in a comparative trial.

Subsequent validation and competitive landscape: Subsequent randomized studies failed to replicate the initial signals. The RAvVA study, which compared 259 adult AML/MDS patients, found that adding vorinostat did not improve overall response rate (ORR) or overall survival (OS), with p-values of 0.84 and 0.32, respectively. Similarly, the SWOG S1117 study in high-risk MDS/chronic myelomonocytic leukemia showed that the azacitidine/vorinostat arm had a CR rate of 18%, which was not superior to the azacitidine monotherapy arm (26%). Currently, the key standard of care for non-intensive treatment of AML is the combination of Venclexta (venetoclax, a BCL-2 inhibitor) and azacitidine, and for MDS, azacitidine/decitabine and risk-stratified ruspertacept/lenalidomide are the main competitive options.

Regulatory, market, and investment implications: The FDA approved Vidaza for MDS on May 19, 2004, and the EMA approved it on December 17, 2008. Zolinza was approved for cutaneous T-cell lymphoma on October 6, 2006. The European application for Zolinza was withdrawn by Merck on February 13, 2009, after the CHMP concluded that the benefit-risk profile was not sufficiently demonstrated. There have been no FDA approvals or AdComm votes for this MDS/AML combination. In 2024, the global AML therapeutics market is estimated at USD 3.5 billion, and the MDS therapeutics market is estimated at USD 2.4 billion, representing significant commercial potential. However, the vorinostat combination has not demonstrated a clear advantage in randomized data. Therefore, the direct value-creation potential for Merck & Co. and Bristol Myers Squibb is limited, and the research value lies in epigenetic biomarkers and patient selection hypotheses.

Why it matters: This study initially showed promising results in Phase 1/2, with CR rates of 45% and CRi rates of 9%. However, subsequent randomized AML studies involving 259 patients showed that adding vorinostat did not improve ORR or OS (p=0.84 and p=0.32, respectively), highlighting the limitations of single-arm data. From an investment perspective, despite targeting the USD 3.5 billion AML market and the USD 2.4 billion MDS market, the vorinostat combination failed to establish a basis for replacing the venetoclax/azacitidine standard of care. For researchers, the key takeaway is that patient selection based on molecular characteristics such as CDKN2A, IDH1, and TP53 may be more important than DNMT/HDAC dual inhibition in future development. For the industry, this serves as a case study demonstrating that long-term, active, small, early-stage clinical trials are less valuable than randomized survival data and clear biomarker strategies in determining asset value.