A Comprehensive Review of Vorinostat (Suberoylanilide Hydroxamic Acid): A First-in-Class Histone Deacetylase Inhibitor

Abstract

Vorinostat, also known as suberoylanilide hydroxamic acid (SAHA), is a first-in-class, orally bioavailable small molecule that functions as a pan-histone deacetylase (HDAC) inhibitor. Its primary mechanism of action involves the chelation of a zinc ion within the catalytic site of Class I, II, and IV HDACs, leading to enzymatic inhibition. This results in the hyperacetylation of core nucleosomal histones and other non-histone proteins, which promotes a more open chromatin structure and alters the expression of a subset of genes critical for cell cycle control, differentiation, and apoptosis. This report details the scientific and clinical profile of Vorinostat. On October 6, 2006, Vorinostat, under the brand name Zolinza®, received landmark approval from the U.S. Food and Drug Administration (FDA) for the treatment of cutaneous manifestations in patients with progressive, persistent, or recurrent cutaneous T-cell lymphoma (CTCL) following two systemic therapies. This approval was based on a pivotal Phase IIb study demonstrating an objective response rate of approximately 30%. Beyond its approved indication, Vorinostat has been extensively investigated across a broad spectrum of other malignancies, including solid tumors and hematologic cancers, typically in combination with other anticancer agents, and as a latency-reversing agent in HIV infection research. The characteristic safety profile of Vorinostat is manageable but significant, dominated by fatigue, gastrointestinal toxicities (diarrhea, nausea), and myelosuppression (thrombocytopenia, anemia). As a foundational epigenetic therapeutic, Vorinostat has not only provided a valuable treatment option for a rare cancer but has also validated HDACs as a therapeutic target, paving the way for the development of an entire new class of anticancer drugs.

Section 1: Introduction: A First-in-Class Epigenetic Modulator

The field of oncology has been progressively shaped by paradigm shifts in the understanding of cancer biology, from the initial focus on cytotoxic agents to the era of targeted therapies directed at specific oncogenic mutations. The development of Vorinostat represents another such inflection point: the validation of epigenetic dysregulation as a tractable therapeutic target. Epigenetics refers to heritable changes in gene expression that do not involve alterations to the underlying DNA sequence itself. One of the central mechanisms of epigenetic control is the post-translational modification of histone proteins, which package DNA into chromatin and regulate its accessibility for transcription.

The genesis of Vorinostat can be traced back to a seminal observation made in 1966 by Dr. Charlotte Friend, who discovered that the common laboratory solvent dimethyl sulfoxide (DMSO) could induce terminal differentiation in murine erythroleukemia cells, effectively reverting them to a non-malignant state.[1] This finding suggested that cancer was not merely a state of irreversible genetic damage but could also be a reversible disorder of gene expression. Intrigued by this potential, Memorial Sloan-Kettering researcher Dr. Paul Marks collaborated with Columbia University chemist Dr. Ronald Breslow to rationally design and synthesize more potent chemical analogs of DMSO, with the goal of harnessing this differentiation-inducing property for cancer therapy.[1] This systematic optimization process led to the discovery of suberoylanilide hydroxamic acid (SAHA), a compound that was subsequently found to be a potent inhibitor of a class of enzymes known as histone deacetylases (HDACs).[1]

This discovery was monumental. It provided a direct molecular link between a chemical agent and the modulation of the epigenetic machinery. The subsequent development of SAHA, later given the nonproprietary name Vorinostat, culminated in its landmark approval by the U.S. Food and Drug Administration (FDA) on October 6, 2006.[1] Marketed as Zolinza®, Vorinostat became the first HDAC inhibitor approved for clinical use, establishing a new class of anticancer agents and validating HDACs as a legitimate therapeutic target. This approval was a testament to a drug development paradigm that began with a cellular phenotype—differentiation—and subsequently identified the molecular target, a contrast to many modern approaches that begin with a known target and design inhibitors against it. This report provides a comprehensive and exhaustive review of Vorinostat, detailing its molecular profile, its multifaceted mechanism of action, its clinical pharmacology and efficacy, its extensive investigational history, its safety profile, and its unique regulatory trajectory, thereby contextualizing its role in modern oncology and future therapeutic development.

Section 2: Molecular Profile and Physicochemical Characteristics

The precise identification and characterization of a pharmaceutical agent are fundamental to its scientific study and clinical application. Vorinostat is well-defined by a comprehensive set of chemical identifiers, a distinct molecular structure that underpins its mechanism of action, and specific physicochemical properties that dictate its formulation and handling.

Nomenclature and Identifiers

Vorinostat is known by several names and is cataloged under numerous registry systems, reflecting its journey from a laboratory compound to a marketed drug.

• Systematic Chemical Names: The International Union of Pure and Applied Chemistry (IUPAC) name for the compound is N'-hydroxy-N-phenyloctanediamide.[4] An alternative chemical name is 8-(hydroxyamino)-8-oxo-N-phenyl-octanamide.[7]
• Common and Trivial Names: Its official nonproprietary names are Vorinostat (United States Adopted Name, International Nonproprietary Name [INN]).[1] It is widely known in research literature by its developmental abbreviation, SAHA, which stands for suberoylanilide hydroxamic acid.[1]
• Brand Name: The commercial product is marketed by Merck & Co. under the brand name Zolinza®.[1]
• Developmental and Code Names: During its development, it was referred to by codes such as MK-0683 and L-001079038.[7]
• Registry Numbers: It is uniquely identified by its CAS (Chemical Abstracts Service) Number, 149647-78-9.[4] Other key database identifiers include its DrugBank ID (DB02546), PubChem Compound ID (5311), and FDA UNII (Unique Ingredient Identifier) (58IFB293JI).[1]

Chemical Structure and Formula

Vorinostat is a dicarboxylic acid diamide derived from the coupling of suberic acid with aniline and hydroxylamine.[8]

• Molecular Formula: C14​H20​N2​O3​.[4]
• Molecular Weight: 264.32 g/mol.[6]
• Structural Identifiers:
• InChI: InChI=1S/C14H20N2O3/c17-13(15-12-8-4-3-5-9-12)10-6-1-2-7-11-14(18)16-19/h3-5,8-9,19H,1-2,6-7,10-11H2,(H,15,17)(H,16,18).[4]
• InChIKey: WAEXFXRVDQXREF-UHFFFAOYSA-N.[6]
• SMILES: C1=CC=C(C=C1)NC(=O)CCCCCCC(=O)NO.[4]
• Pharmacophore Analysis: The structure of Vorinostat established the classic pharmacophore for many subsequent HDAC inhibitors. It consists of three essential components: (1) a hydrophobic "cap" group (the phenyl ring) that interacts with the surface of the enzyme, (2) a hydrophobic linker (the six-carbon alkyl chain derived from suberic acid), and (3) a zinc-binding group (the hydroxamic acid, -C(=O)NOH), which is the functional moiety that coordinates with the zinc ion in the enzyme's active site.[1]

Physicochemical Properties

The physical and chemical properties of Vorinostat are critical for its formulation as an oral drug and for its use in research settings.

• Appearance: It is a white to off-white or tan crystalline powder or solid.[8]
• Melting Point: Vorinostat has a defined melting point of 161-162°C.[8]
• Solubility: It is poorly soluble in water but is soluble in organic solvents, most notably dimethyl sulfoxide (DMSO), where concentrations of up to 100 mM can be achieved.[2] It has limited solubility in ethanol (2 mg/mL).[13] This solubility profile necessitates its formulation in capsules for oral administration and the use of DMSO for most in vitro laboratory work.
• Stability: The solid compound is stable for at least two years when stored at -20°C. Solutions prepared in DMSO can be stored at -20°C for up to six months to three years, depending on the supplier's recommendation.[8]

The table below consolidates the key molecular and physicochemical identifiers for Vorinostat.

Table 1: Summary of Vorinostat Identifiers and Physicochemical Properties

Parameter	Value	Source(s)
IUPAC Name	N'-hydroxy-N-phenyloctanediamide	4
Common Name	Suberoylanilide hydroxamic acid (SAHA)	8
Brand Name	Zolinza®	11
CAS Number	149647-78-9	8
DrugBank ID	DB02546	4
Molecular Formula	C14​H20​N2​O3​	13
Molecular Weight	264.32 g/mol	8
Appearance	White to tan powder	8
Melting Point	161-162°C	8
Solubility (DMSO)	≥15 mg/mL to 100 mM	2
Solubility (Ethanol)	2 mg/mL	13
Solubility (Water)	Poorly soluble / Insoluble	10
Storage Temp.	-20°C (long term)	8

Section 3: Mechanism of Action: Reversing Epigenetic Silencing

Vorinostat exerts its therapeutic effects by fundamentally altering the epigenetic landscape of cancer cells. Its mechanism is centered on the inhibition of histone deacetylases (HDACs), enzymes that play a pivotal role in gene regulation.

The Epigenetic Landscape: Histone Acetylation and Gene Regulation

The expression of genes is tightly controlled by the structural organization of chromatin. This structure is dynamically regulated by the competing activities of two enzyme families: histone acetyltransferases (HATs) and histone deacetylases (HDACs).[18] Histone proteins have tails rich in positively charged lysine residues, which allow them to bind tightly to the negatively charged phosphate backbone of DNA. This electrostatic interaction results in a condensed chromatin structure (heterochromatin) that is generally inaccessible to the transcriptional machinery, leading to gene silencing.

HATs catalyze the transfer of an acetyl group to the ε-amino group of lysine residues on histone tails. This acetylation neutralizes the positive charge, weakening the histone-DNA interaction and causing the chromatin to relax into a more open conformation (euchromatin). This relaxed state allows transcription factors and RNA polymerase to access the DNA, facilitating gene expression.[18] Conversely, HDACs remove these acetyl groups, restoring the positive charge on the lysines and promoting the re-condensation of chromatin into a transcriptionally silent state.[18] The balance between HAT and HDAC activity is therefore crucial for normal cellular function.

Aberrant HDAC Activity in Cancer

A growing body of evidence has demonstrated that this delicate epigenetic balance is frequently disrupted in cancer. Many malignancies, particularly those of hematologic and epithelial origin, are characterized by the overexpression or aberrant recruitment of HDACs to the promoters of key genes.[18] This leads to a state of localized or global histone hypoacetylation, resulting in the inappropriate silencing of genes that are critical for controlling cell growth, promoting differentiation, and inducing programmed cell death (apoptosis). The silencing of these tumor suppressor genes is a key driver of the malignant phenotype.[18]

Molecular Inhibition by Vorinostat

Vorinostat was developed to counteract this aberrant epigenetic silencing by directly inhibiting HDAC activity.

Target Specificity

Vorinostat is classified as a "pan-HDAC inhibitor" due to its broad activity against multiple HDAC isoforms. It potently inhibits enzymes in Class I (HDAC1, HDAC2, HDAC3), Class II (specifically HDAC6), and Class IV (HDAC11).[1] Its half-maximal inhibitory concentrations (

IC50​) against these enzymes are in the low nanomolar range, indicating high potency.[10] Notably, Vorinostat does not inhibit the Class III HDACs, also known as sirtuins, which are NAD⁺-dependent and have a different catalytic mechanism.[17] This broad spectrum of activity ensures that Vorinostat can effectively target the dysregulated HDAC activity present in a wide variety of cancer cells. However, this lack of specificity is also a defining characteristic of the drug. While ensuring robust target engagement, the simultaneous inhibition of multiple HDAC isoforms, each with distinct biological roles, may contribute to the spectrum of observed toxicities and limit the achievable therapeutic window, a factor that could explain its varied success in clinical trials outside of its primary indication.

Binding Mechanism

Crystallographic studies have elucidated the precise molecular interaction between Vorinostat and its target enzymes. The hydroxamic acid functional group of Vorinostat acts as a potent chelator that binds with high affinity to the zinc (Zn2+) ion located deep within the catalytic pocket of the HDAC active site.[1] This interaction, coupled with contacts between the drug's alkyl chain and the hydrophobic tunnel of the active site, effectively blocks substrate access and inactivates the enzyme's deacetylase function.[17]

Downstream Cellular Consequences

The inhibition of HDACs by Vorinostat triggers a cascade of downstream molecular and cellular events that collectively contribute to its antitumor activity.

Histone Hyperacetylation and Transcriptional Reprogramming

The most direct and immediate consequence of Vorinostat treatment is the global accumulation of acetylated histones, including H2A, H2B, H3, and H4.[2] This hyperacetylation can be readily detected in both cancer cell lines and patient-derived tissues, serving as a reliable pharmacodynamic biomarker of drug activity.[16] The resulting chromatin relaxation leads to the transcriptional re-expression of a subset of previously silenced genes, estimated to be between 2% and 10% of the genome.[24] Critically, this includes the reactivation of tumor suppressor genes, such as the cyclin-dependent kinase inhibitor

p21 (CDKN1A), and genes involved in apoptosis and cell differentiation.[17]

Non-Histone Protein Targets and Pleiotropic Effects

The biological effects of Vorinostat extend beyond histones. HDACs deacetylate a wide array of non-histone proteins, and their inhibition by Vorinostat leads to the hyperacetylation and functional alteration of these targets as well. This pleiotropy is central to its complex mechanism. Key non-histone targets include:

• Transcription Factors: Acetylation of tumor suppressors like p53 and oncogenic transcription factors like Bcl-6 can modulate their activity and stability.[17]
• Chaperone Proteins: Acetylation of Heat shock protein 90 (Hsp90), a master chaperone for numerous oncoproteins, can impair its function, leading to the degradation of its client proteins.[17]
• Cytoskeletal Proteins: Acetylation of α-tubulin affects microtubule stability and function, which can disrupt cell division and intracellular transport.[17]

The fact that Vorinostat's effects are mediated through this diverse set of non-histone targets, in addition to its primary effect on chromatin, helps explain its varied activity across different cancer types. The specific anti-tumor effect in a given cell may depend not just on the re-expression of tumor suppressors but also on the destabilization of the particular oncoproteins or cellular structures that the cell is most reliant upon. This complexity also makes it challenging to identify a single, universal biomarker that can predict response to therapy.

Cellular Outcomes

The culmination of these molecular changes manifests in several key anti-cancer cellular outcomes:

• Cell Cycle Arrest: Vorinostat induces cell cycle arrest, most commonly in the G1 phase. This is primarily mediated by the transcriptional upregulation of the p21 protein, which inhibits cyclin/CDK complexes and prevents progression through the cell cycle.[16]
• Induction of Apoptosis: The drug triggers programmed cell death through multiple pathways. It can upregulate components of the extrinsic pathway, such as the TRAIL death receptors, and modulate the intrinsic pathway by downregulating anti-apoptotic proteins (e.g., Bcl-2) and upregulating pro-apoptotic proteins.[14]
• Inhibition of Angiogenesis: In hypoxic tumor environments, Vorinostat can suppress the expression of key angiogenic factors like hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF), thereby inhibiting the formation of new blood vessels needed for tumor growth.[17]
• Modulation of Immunity: Vorinostat has been shown to downregulate immunosuppressive cytokines such as Interleukin-10 (IL-10), potentially enhancing the host anti-tumor immune response.[17]
• Activation of Autophagy: In some contexts, Vorinostat can also induce autophagy, a cellular self-degradation process that can either promote survival or contribute to cell death depending on the context.[2]

Section 4: Clinical Pharmacology: Pharmacokinetics and Metabolism

The clinical utility of a drug is determined not only by its mechanism of action but also by its pharmacokinetic profile—how the body absorbs, distributes, metabolizes, and eliminates it. Vorinostat possesses a relatively straightforward pharmacokinetic profile characterized by oral bioavailability, metabolism independent of the major cytochrome P450 system, and a short half-life.

Absorption and Distribution

Vorinostat is formulated as a 100 mg capsule for oral administration, which should be taken with food to improve tolerability.[25] Following oral administration, it is absorbed into the systemic circulation. In plasma, Vorinostat exhibits moderate protein binding of approximately 71%.[1] Exploratory analyses have suggested that gender, race, and age do not have clinically meaningful effects on the pharmacokinetics of Vorinostat.[28]

Metabolism

The metabolism of Vorinostat is a key feature of its clinical pharmacology, as it proceeds via two primary pathways that do not involve the cytochrome P450 (CYP) enzyme system.[1]

• Primary Metabolic Pathways: The first major pathway is glucuronidation, which results in the formation of vorinostat O-glucuronide. The second pathway involves hydrolysis of the amide bond, followed by β-oxidation of the resulting carboxylic acid, which ultimately yields 4-anilino-4-oxobutanoic acid.[1]
• Metabolite Activity and Exposure: A critical aspect of Vorinostat's metabolism is that both of these major metabolites are pharmacologically inactive.[1] Although their exposure in plasma at steady-state is substantially higher than that of the parent drug (mean exposure is 4-fold higher for the O-glucuronide and 13-fold higher for 4-anilino-4-oxobutanoic acid), they do not contribute to the drug's efficacy or toxicity profile.[27]
• Independence from CYP450 System: In vitro studies have definitively shown that Vorinostat undergoes negligible biotransformation by CYP enzymes.[1] This is a highly significant clinical advantage. Patients with cancer are frequently prescribed multiple concomitant medications (polypharmacy), many of which are substrates, inhibitors, or inducers of the CYP450 system. A drug that bypasses this major pathway for drug-drug interactions is much more predictable in its behavior. This favorable profile minimizes the need for complex dose adjustments and reduces the risk of unexpected toxicity or loss of efficacy when Vorinostat is co-administered with other agents, making it an attractive partner for combination therapy regimens. This pharmacological property likely provided confidence for the large number of combination clinical trials that have been conducted.

Elimination

Vorinostat is cleared from the body primarily through the metabolic pathways described above.

• Route of Elimination: Renal excretion of the active, unchanged drug is not a significant route of elimination. Less than 1% of an administered dose is recovered as unchanged Vorinostat in the urine, confirming that its clearance is almost entirely dependent on metabolism.[27]
• Half-Life: Vorinostat has a short terminal elimination half-life of approximately 2 hours.[1] The O-glucuronide metabolite has a similarly short half-life, while the 4-anilino-4-oxobutanoic acid metabolite has a longer half-life of around 11 hours.[1] The short half-life of the active parent drug necessitates at least once-daily dosing to maintain drug concentrations above the therapeutic threshold. This pharmacokinetic property also implies that the drug does not accumulate significantly with repeated dosing and that acute, concentration-dependent toxicities should resolve relatively quickly after the drug is discontinued. This likely influenced the exploration of different dosing schedules in clinical trials, such as daily administration versus intermittent schedules (e.g., 5 days per week), in an effort to optimize the balance between sustained efficacy and patient tolerability.[26]

Pharmacodynamics

Pharmacodynamic studies have confirmed that orally administered Vorinostat achieves concentrations sufficient to engage its target in vivo. At clinically relevant doses, evidence of histone hyperacetylation—the key biomarker of HDAC inhibition—has been demonstrated in peripheral blood mononuclear cells and in tumor tissue from treated patients.[10] This provides direct evidence that the drug reaches its intended site of action and exerts its primary biological effect.

Section 5: Clinical Efficacy in the Treatment of Cutaneous T-Cell Lymphoma (CTCL)

The clinical development of Vorinostat culminated in its approval for a specific, difficult-to-treat patient population, establishing its role as a valuable therapeutic option in dermatologic oncology.

Approved Indication

Vorinostat (Zolinza®) is approved by the U.S. FDA for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies.[1] CTCL is a rare type of non-Hodgkin's lymphoma where malignant T-cells primarily affect the skin, causing patches, plaques, and tumors, often accompanied by severe pruritus (itching).[11] The approval is for adult patients (18 years of age or older) and encompasses advanced stages of the disease, including Mycosis Fungoides (MF) and Sézary Syndrome (SS).[29]

Pivotal Phase IIb Trial (NCT00091559)

The FDA approval was primarily based on the results of a pivotal, multicenter, open-label, single-arm Phase IIb clinical trial.[29]

• Study Design and Population: The trial enrolled 74 patients with advanced CTCL (MF or SS) who were refractory to or had relapsed after other therapies. The majority of patients (82%) had advanced-stage disease (Stage IIB or higher).[33]
• Dosing Regimen: Patients received Vorinostat at a dose of 400 mg administered orally once daily with food.[29]
• Primary Endpoint: The primary measure of efficacy was the Objective Response Rate (ORR), assessed by changes in skin disease using the Severity-Weighted Assessment Tool (SWAT).[33]

Efficacy Results

The trial demonstrated clinically meaningful activity for Vorinostat in this heavily pretreated patient population. The key efficacy outcomes are summarized in Table 2 below.

Table 2: Efficacy Outcomes from Pivotal Phase IIb Trial in CTCL (NCT00091559)

Efficacy Endpoint	Value / Result	Description / Context	Source(s)
Objective Response Rate (ORR), Overall	29.7%	Response rate across all 74 enrolled patients.	33
ORR, Stage IIB or Higher	29.5%	Response rate in the primary target population with advanced disease.	33
Type of Response	All initial responses were Partial Responses (PR)	One patient subsequently achieved a Complete Response (CR) after 281 days.	33
Median Time to Response (TTR)	56 days (range: 28-171)	Patients who responded typically showed evidence of improvement within 2 months.	33
Median Duration of Response (DOR)	Not reached (≥185 days)	The response was durable, lasting at least 6 months at the time of analysis.	33
Median Time to Progression (TTP)	148 days (overall)	The median time until disease progression for all patients was nearly 5 months.	33
Pruritus (Itching) Relief	32.3% of patients	A significant portion of patients with moderate-to-severe baseline pruritus experienced relief.	33

The overall objective response rate of approximately 30% was considered significant in this refractory setting.[29] Responses were observed relatively quickly, with a median time to response of just under two months. Furthermore, these responses were durable, with a median duration of at least six months.[33]

A particularly important finding was the effect on pruritus, one of the most debilitating symptoms of CTCL. Nearly one-third of patients with significant baseline itching experienced relief. Notably, this symptomatic improvement was observed in both patients who achieved an objective tumor response and those who did not, suggesting that Vorinostat may have a direct effect on the pathways mediating pruritus, independent of its tumor-shrinking capabilities.[33] This provides a meaningful quality-of-life benefit for patients.

Based on this evidence, the National Comprehensive Cancer Network (NCCN) guidelines include Vorinostat as a preferred systemic therapy (Category 2A recommendation) for patients with recurrent or advanced mycosis fungoides and Sézary syndrome.[29]

Section 6: Investigational Landscape: Vorinostat Beyond CTCL

While Vorinostat's only approved indication is for CTCL, its novel epigenetic mechanism of action spurred a vast and diverse program of clinical investigation across a wide range of other diseases. The prevailing strategy in this investigational landscape has been to use Vorinostat not as a standalone agent, but as a "rational combination" partner. The underlying hypothesis is that by "priming" the cancer cell's epigenome—relaxing chromatin and altering gene expression—Vorinostat can sensitize tumors to the cytotoxic or targeted effects of other therapies. This has led to numerous trials in solid tumors, other hematologic malignancies, pediatric cancers, and even non-oncologic indications like HIV infection.

Solid Tumors

• Glioblastoma (GBM): Given the preclinical evidence that HDAC inhibitors can act as radiosensitizers, Vorinostat was evaluated in combination with standard-of-care temozolomide and radiation for newly diagnosed GBM. The Alliance N0874/ABTC 02 Phase I/II trial found the combination to be acceptably tolerable but ultimately failed to meet its primary efficacy endpoint of improving overall survival (median OS was 16.1 months).[34] However, this trial yielded a critical finding for the field. Correlative RNA sequencing of baseline tumor tissue identified two gene expression signatures: a resistance signature (sig-79) that was associated with shorter survival, and a sensitivity signature (sig-139) associated with longer survival.[34] Although the overall trial was negative, this discovery was a major step forward, suggesting that the failure may have been one of patient selection rather than drug activity. It provides a potential roadmap for future trials where such biomarkers could be used to enrich for patients most likely to benefit, transforming a "one-size-fits-all" approach into a precision medicine strategy.
• Malignant Pleural Mesothelioma: Vorinostat has been studied in combination with first-line chemotherapy (pemetrexed and cisplatin) in a Phase I/II study.[35] While early Phase I data showed some evidence of efficacy, it remains an investigational use.[29]
• Non-Small Cell Lung Cancer (NSCLC): A Phase II/III trial was conducted combining Vorinostat with the chemotherapy doublet of paclitaxel and carboplatin. Early reports suggested the combination led to improved response rates and survival outcomes compared to chemotherapy alone.[1]
• Breast Cancer: A pilot study (NCT01695057) explored a neoadjuvant (pre-surgery) strategy in patients with triple-negative breast cancer. The goal was to determine if Vorinostat could induce the expression of the estrogen receptor (ER) and progesterone receptor (PR), potentially making these aggressive tumors susceptible to hormonal therapies.[36]
• Other Solid Tumors: A multitude of Phase I trials have explored the safety and feasibility of combining Vorinostat with various standard chemotherapies, including gemcitabine, capecitabine, and FOLFOX (fluorouracil, leucovorin, oxaliplatin), in patients with advanced solid tumors.[37]

Hematologic Malignancies

• Multiple Myeloma: A large Phase III trial investigated Vorinostat in combination with the proteasome inhibitor bortezomib for patients with progressive multiple myeloma. Merck announced that this study met its primary endpoint, demonstrating a statistically significant improvement in progression-free survival for the combination arm.[22] Despite this positive result, Vorinostat has not received regulatory approval for this indication and its use in myeloma is considered investigational.[29]
• Non-CTCL Lymphomas: Vorinostat has been tested in various other lymphoma subtypes. Completed trials include combinations with the CHOP chemotherapy regimen in T-cell non-Hodgkin's lymphoma, with azacitidine in diffuse large B-cell lymphoma (DLBCL), and with the monoclonal antibody rituximab in indolent B-cell lymphomas.[39]
• Myelodysplastic Syndromes (MDS): Encouraging results were reported from a Phase II trial that combined Vorinostat with the chemotherapy agents idarubicin and cytarabine.[1]
• Acute Myeloid Leukemia (AML): An earlier Phase II study of Vorinostat in AML failed to demonstrate sufficient efficacy.[1]

Pediatric Cancers

The use of Vorinostat has also been explored in pediatric oncology, where epigenetic dysregulation is a known driver of several cancers.

• Neuroblastoma: A Phase I trial (NCT01208454) evaluated the combination of Vorinostat and isotretinoin for children with high-risk, refractory, or recurrent neuroblastoma.[41] Research in this area is ongoing, with active trials continuing to explore its role.[42]
• Relapsed Pediatric Cancers: A Phase I/II dose-escalation study was conducted in Europe to determine a safe and effective dose for children with various relapsed solid tumors, lymphomas, or leukemias.[35]

HIV Latency Reversal

In a completely different therapeutic area, Vorinostat is being investigated as a key component of the "shock and kill" strategy aimed at curing HIV infection. The HIV virus can lie dormant in a latent state within the genome of long-lived memory T-cells, creating a viral reservoir that is invisible to the immune system and unaffected by standard antiretroviral therapy (ART).[7] The "shock" part of the strategy involves using a latency-reversing agent (LRA) to reactivate the latent virus, forcing it to express viral proteins. Vorinostat, through its ability to open up chromatin, is a potent LRA. Several Phase I/II clinical trials have demonstrated that Vorinostat can successfully disrupt HIV-1 latency

in vivo, inducing the expression of viral RNA from the latent reservoir in patients on stable ART.[6] This remains an active and promising area of research.

The following table provides a summary of key investigational trials for Vorinostat.

Table 3: Overview of Key Clinical Trials of Vorinostat in Non-CTCL Indications

Indication	Trial Identifier / Name	Phase	Combination Agent(s)	Key Finding / Status	Source(s)
Glioblastoma, Newly Diagnosed	Alliance N0874/ABTC 02	I/II	Temozolomide + Radiation	Tolerable but failed to meet primary OS endpoint. Identified predictive biomarkers.	34
Multiple Myeloma, Progressive	Phase III (Merck)	III	Bortezomib	Met primary endpoint of improving progression-free survival.	22
Malignant Pleural Mesothelioma	UCL/08/0359	I/II	Pemetrexed + Cisplatin	Investigational combination.	35
Non-Small Cell Lung Cancer (NSCLC)	Phase II/III	II/III	Paclitaxel + Carboplatin	Early data suggested improved response and survival.	1
Triple-Negative Breast Cancer	NCT01695057	Pilot	Neoadjuvant Monotherapy	Studied ability to induce ER/PR expression before surgery.	36
Diffuse Large B-cell Lymphoma (DLBCL)	NCT01120834	I/II	Azacitidine	Investigated combination in relapsed/refractory disease.	39
Neuroblastoma, High-Risk/Recurrent	NCT01208454	I	Isotretinoin	Investigated combination in pediatric patients.	41
HIV Latency Reversal	NCT01319383	I/II	Antiretroviral Therapy (ART)	Successfully disrupted HIV latency and induced viral expression.	7

Section 7: Safety, Tolerability, and Risk Management

The clinical application of Vorinostat requires a thorough understanding of its safety profile and a proactive approach to risk management. While generally manageable, the drug is associated with a distinct set of adverse reactions, some of which are serious and require careful monitoring and intervention.

Overview of Common Adverse Reactions

The most frequently reported adverse reactions (occurring in ≥20% of patients in clinical trials) are systemic and gastrointestinal in nature. These include:

• Diarrhea
• Fatigue
• Nausea
• Thrombocytopenia (low platelet count)
• Anorexia (loss of appetite)
• Dysgeusia (altered or metallic taste) [12]

Serious Warnings and Precautions

The FDA-approved prescribing information for Zolinza® includes several important warnings and precautions that highlight the most significant risks associated with its use.

• Thromboembolism: A major risk associated with Vorinostat is the development of blood clots. In clinical trials, pulmonary embolism (PE), a potentially life-threatening clot in the lungs, occurred in 5% of patients treated with the drug. Deep vein thrombosis (DVT), a clot in a deep vein (usually in the leg), has also been reported. Patients, particularly those with a prior history of thromboembolic events, must be closely monitored for signs and symptoms such as shortness of breath, chest pain, and leg swelling.[12]
• Myelosuppression: Treatment with Vorinostat can suppress bone marrow function, leading to dose-related cytopenias. Thrombocytopenia and anemia are common and can be severe (Grade 3-4). This necessitates regular blood count monitoring and may require dose reduction, interruption, or permanent discontinuation of therapy.[25]
• Gastrointestinal Toxicity: Nausea, vomiting, and diarrhea are very common side effects. These symptoms must be managed proactively with antiemetic and antidiarrheal medications. It is crucial for patients to maintain adequate hydration (at least 8 glasses or 2 liters of fluid per day) to prevent dehydration and electrolyte imbalances that can result from severe GI toxicity.[12]
• Hyperglycemia: Vorinostat can cause elevated blood glucose levels. Patients, especially those with pre-existing diabetes, require regular blood sugar monitoring. Adjustments to diet or anti-diabetic medications may be necessary.[12]
• QTc Prolongation: The drug has been observed to affect the heart's electrical activity by prolonging the QT interval on an electrocardiogram (ECG). While often asymptomatic, significant QTc prolongation can increase the risk of serious cardiac arrhythmias. Therefore, baseline and periodic ECG monitoring is recommended. Any pre-existing electrolyte abnormalities, such as hypokalemia or hypomagnesemia, should be corrected before starting treatment.[25]
• Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animal studies, Vorinostat can cause harm to a developing fetus. It is contraindicated in pregnancy. Females of reproductive potential must use effective contraception during treatment and for 6 months after the final dose. Males with female partners of reproductive potential must also use effective contraception during treatment and for 3 months after the final dose.[22]

Laboratory Monitoring and Dose Modifications

To manage these risks, a specific schedule of laboratory monitoring is required.

• Monitoring Schedule: Complete blood counts (CBC) and serum chemistry panels (including electrolytes, glucose, and creatinine) must be monitored every 2 weeks for the first 2 months of therapy, and then monthly thereafter.[26]
• Dose Modifications: The prescribing information provides a clear pathway for managing intolerance. The standard 400 mg daily dose can be reduced to 300 mg daily. If intolerance persists, the dose can be further reduced to 300 mg once daily for 5 consecutive days each week.[26] Dose adjustments are also necessary for patients with mild to moderate hepatic impairment.[28]

Drug Interactions

Two clinically significant drug interactions are highlighted in the label:

• Coumarin-Derivative Anticoagulants (e.g., Warfarin): Concomitant use with Vorinostat has been associated with prolongation of prothrombin time (PT) and International Normalized Ratio (INR). Patients on these anticoagulants require more frequent INR monitoring.[11]
• Other HDAC Inhibitors (e.g., Valproic Acid): Valproic acid, a common anti-seizure medication, also has HDAC inhibitory activity. Co-administration with Vorinostat has been linked to cases of severe thrombocytopenia and gastrointestinal bleeding. In patients receiving both drugs, platelet counts should be monitored more frequently.[12]

Table 4 provides a practical summary of the key adverse reactions and the corresponding risk management strategies.

Table 4: Summary of Adverse Reactions and Risk Management for Vorinostat

Adverse Reaction / Warning	Incidence (Grade 3-4)	Required Monitoring	Clinical Management Strategy	Source(s)
Thromboembolism (PE, DVT)	5% (PE)	Clinical signs/symptoms (chest pain, shortness of breath, leg swelling).	Monitor closely, especially in patients with a prior history of clots.	26
Myelosuppression (Thrombocytopenia, Anemia)	Dose-related	CBC every 2 weeks for 2 months, then monthly.	Dose reduction, interruption, or discontinuation as per label.	26
Gastrointestinal Toxicity (Nausea, Vomiting, Diarrhea)	Common	Clinical symptoms, hydration status, electrolytes.	Prophylactic antiemetics/antidiarrheals. Ensure adequate hydration (≥2L/day). Replace fluids/electrolytes as needed.	26
Hyperglycemia	Observed	Blood glucose every 2 weeks for 2 months, then monthly.	Adjust diet and/or anti-diabetic therapy as needed.	26
QTc Prolongation / Electrolyte Imbalance	Observed	Baseline and periodic ECG. Electrolytes (K+, Mg²⁺, Ca²⁺) at baseline and periodically.	Correct electrolyte abnormalities before starting. Seek medical attention for dizziness, palpitations, or syncope.	25
Interaction with Valproic Acid	Can cause severe thrombocytopenia/GI bleeding	More frequent platelet count monitoring.	Use with caution and increased vigilance.	26
Interaction with Warfarin	Can prolong PT/INR	More frequent INR monitoring.	Adjust warfarin dose as needed based on INR.	11
Embryo-Fetal Toxicity	Potential for fetal harm	Pregnancy status before initiation.	Counsel on risks. Mandate effective contraception for both males and females during and after treatment.	31

Section 8: Regulatory and Commercial Trajectory

The journey of Vorinostat from clinical development to market access provides a compelling case study in global pharmaceutical regulation, highlighting how different regulatory bodies can arrive at different conclusions based on the same clinical data.

U.S. FDA Approval

On October 6, 2006, the U.S. Food and Drug Administration (FDA) granted approval to Vorinostat, marketed under the brand name Zolinza® by its developer, Merck & Co..[1] The approved indication was for the treatment of cutaneous manifestations in patients with CTCL who have progressive, persistent, or recurrent disease on or following two systemic therapies.[26] This approval was based on the strength of the single-arm Phase IIb trial (NCT00091559), which demonstrated a clinically meaningful objective response rate of approximately 30% in a patient population with a high unmet medical need.[33]

European Medicines Agency (EMA) Application Withdrawal

In parallel, Merck Sharp & Dohme submitted a Marketing Authorisation Application to the European Medicines Agency (EMA) for "Vorinostat MSD" for a similar indication in adults with advanced CTCL.[44] However, the regulatory outcome in Europe was starkly different. On February 13, 2009, the company officially withdrew its application before a final decision was rendered.[44]

The withdrawal was prompted by major objections raised by the EMA's Committee for Medicinal Products for Human Use (CHMP). The CHMP's provisional opinion was that Vorinostat could not have been approved based on the submitted data.[44] The primary concerns revolved around the design of the pivotal study. Because it was a single-arm trial without an active comparator or placebo control, the CHMP found it difficult to adequately assess the drug's true benefit-risk balance.[44] The Committee was particularly concerned about the identified safety risks, most notably the risk of thromboembolic events. They concluded that the benefits of Vorinostat had not been sufficiently demonstrated to outweigh these risks in the context of the non-comparative trial data.[44]

This divergence in regulatory outcomes between the U.S. and Europe underscores differing regulatory philosophies. The FDA, particularly in oncology and for diseases with limited treatment options, has often utilized accelerated approval pathways that allow for approval based on single-arm trial data demonstrating a meaningful effect on a surrogate endpoint (like response rate). This approach prioritizes getting novel treatments to patients with life-threatening diseases more quickly, with the understanding that further confirmatory data may be required post-marketing. The EMA, in this case, appeared to adhere to a more stringent evidentiary standard, requiring comparative data from a randomized controlled trial to definitively establish a positive benefit-risk profile, especially when significant safety concerns like thromboembolism were present.

Orphan Drug Designation and Patent Status

To incentivize its development for rare diseases, Vorinostat was granted Orphan Drug Designation by regulatory authorities. This status was assigned for the treatment of CTCL, multiple myeloma, and malignant mesothelioma.[44] In the U.S., several patents protect Vorinostat, with expiration dates extending into the mid-to-late 2020s, including patents expiring in 2025, 2026, 2027, and 2028.[46]

Section 9: Synthesis and Future Perspectives

Vorinostat holds a significant place in the history of cancer therapy. As the first histone deacetylase inhibitor to gain regulatory approval, it single-handedly validated an entire class of epigenetic enzymes as a viable therapeutic target. Its development provided a crucial new treatment option for patients with refractory cutaneous T-cell lymphoma, a rare and debilitating disease with few effective therapies. The journey of Vorinostat from a laboratory observation with DMSO to a marketed drug is a triumph of translational science.

However, the initial hope that Vorinostat might serve as a broad-spectrum anticancer agent has been tempered by the clinical realities observed over more than a decade of investigation. While effective in the specific context of CTCL, its efficacy as a monotherapy in most other solid and hematologic malignancies has been limited. This has led to an extensive exploration of combination strategies, positioning Vorinostat as an "epigenetic sensitizer" rather than a standalone cytotoxic agent.

The central challenge and defining characteristic of Vorinostat is its nature as a pan-HDAC inhibitor. This broad activity, while ensuring target engagement, is a double-edged sword. The simultaneous inhibition of multiple HDAC isoforms, each with unique and sometimes opposing biological functions, likely contributes to both its pleiotropic anticancer effects and its spectrum of off-target toxicities. This constrains the therapeutic window, making it difficult to achieve concentrations high enough to be effective in more resistant tumors without causing unacceptable side effects.

The future of HDAC inhibition as a therapeutic strategy is therefore likely to evolve along two parallel paths:

1. Development of Isoform-Selective Inhibitors: The logical next step in the field is the creation of next-generation HDAC inhibitors that are designed to target specific HDAC isoforms (e.g., only HDAC1/2 or only HDAC6). Such selectivity holds the promise of a more refined mechanism of action, potentially leading to enhanced efficacy against specific cancer subtypes that are dependent on a particular HDAC isoform, coupled with an improved safety profile due to the sparing of other isoforms.
2. Rational Combination and Biomarker-Driven Application: For Vorinostat itself, its most promising future lies in its continued use as a component of intelligent, hypothesis-driven combination therapies. Its ability to prime the epigenome makes it a logical partner for DNA-damaging agents, targeted therapies, and immunotherapies. However, the future success of this approach will be critically dependent on moving beyond an empirical "try-it-and-see" methodology. The discovery of predictive gene expression signatures in the glioblastoma trial, despite the trial's overall negative outcome, represents the most important lesson for the field. The future is precision. Future clinical trials of Vorinostat and other pan-inhibitors must incorporate robust, prospective biomarker discovery to identify the specific genetic, epigenetic, and transcriptomic contexts in which these drugs can provide maximal benefit. Only by selecting the right patients for the right combination can the full potential of this foundational epigenetic drug be realized.

Finally, the exploration of Vorinostat as a latency-reversing agent in HIV represents a novel and potentially transformative application outside of oncology, underscoring the broad biological importance of the epigenetic pathways it modulates. Vorinostat's legacy is therefore twofold: it is both a clinically valuable drug for a specific patient population and a pioneering scientific tool that has opened the door to the vast and complex world of epigenetic therapy.

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