Belinostat (Beleodaq)

Number: 0887

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses belinostat (Beleodaq) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

1. Criteria for Initial Approval

   Aetna considers belinostat (Beleodaq) medically necessary for the treatment of the following indications:

   1. T-Cell Lymphomas

      For treatment of T-cell lymphomas with any of the following subtypes:

      1. Peripheral T-cell lymphoma [including the following subtypes: anaplastic large cell lymphoma, peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, enteropathy associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, nodal peripheral T-cell lymphoma with TFH phenotype, or follicular T-cell lymphoma] when both of the following criteria are met:

         1. The requested drug will be used as a single agent; and
         2. The requested drug is used for relapsed or refractory disease or for palliative intent; or

      2. Hepatosplenic T-cell lymphoma when both of the following criteria are met:

         1. The requested drug will be used a single agent; and
         2. The member has had two or more previous lines of chemotherapy; or

      3. Extranodal NK/T-cell lymphoma, when all of the following criteria are met:

         1. The requested drug will be used as a single agent; and
         2. The member has relapsed or refractory disease; and
         3. The member has had an inadequate response or contraindication to asparaginase-based therapy (e.g., pegaspargase); or
            

      4. Adult T-cell leukemia/lymphoma (ATLL) when both of the following criteria are met:

         1. The requested drug is used as a single agent, and
         2. The requested drug is used for subsequent therapy; or

      5. Breast implant-associated anaplastic large cell lymphoma (ALCL) when both of the following criteria are met:

         1. The requested drug is used as a single agent; and
         2. The requested drug is used for subsequent therapy.
            

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of belinostat (Beleodaq) therapy medically necessary for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

3. Related Policies

   1. CPB 0740 - Pralatrexate (Folotyn)
   2. CPB 0865 - Romidepsin (Istodax)

Dosage and Administration

Belinostat is available as Beleodaq in 500 mg, lyophilized powder in single‐use vials for reconstitution and for intravenous infusion. 

Peripheral T-cell lymphoma

The recommended dosage of belinostat (Beleodaq) is 1,000 mg/m² administered over 30 minutes by intravenous infusion once-daily on days 1 to 5 of a 21-day cycle. Cycles can be repeated until disease progression or unacceptable toxicity. Treatment discontinuation or interruption with or without dosage reductions by 25 % may be needed to manage adverse reactions.

Source: Acrotech Biopharma, 2020

Experimental and Investigational

Aetna considers concomitant use of belinostat with Folotyn (pralatrexate), Istodax (romidepsin), Ninlaro (ixazomib), or Zolinza (vorinostat) experimental and investigational because the effectiveness and safety of these combinations has not been established.

Aetna considers belinostat experimental and investigational for the treatment of the following hematologic malignancies and solid tumors (not an all-inclusive list) because its effectiveness for these indications has not been established:

• Acute lymphoblastic leukemia
• Acute promyelocytic leukemia
• Acute myeloid leukemia
• Atopic dermatitis
• B-cell lymphomas (including diffuse large B cell lymphoma and mantle cell lymphoma)
• Bladder cancer
• Bone cancer
• Breast cancer
• Carcinoma of unknown primary site
• Cervical cancer
• Chordoma
• Colon cancer
• Fallopian tube cancer
• Gastric cancer
• Glioblastoma
• Head and neck cancer
• Hepato-cellular carcinoma
• Hodgkin lymphoma
• Lung cancer (including lung squamous cell carcinoma, non-small cell lung cancer, and small cell lung cancer)
• Mesothelioma
• Multiple myeloma
• Myelodysplastic syndrome
• Neuroendocrine tumor
• Ovarian cancer
• Pancreatic cancer
• Peritoneal carcinoma
• Prostate cancer
• Rectal cancer
• Renal cancer
• Rhabdomyosarcoma
• Soft tissue sarcoma
• Thymic tumor
• Thyroid cancer.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Belinostat (Beleodaq):
Other CPT codes related to the CPB:
96413 - 96417	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
J9032	Injection, belinostat, 10 mg
Other HCPCS codes related to the CPB:
Ixazomib (Ninlaro) - no specific code:
J9307	Injection, pralatrexate, 1 mg
J9319	Injection, romidepsin, lyophilized, 0.1 mg
ICD-10 codes covered if selection criteria are met:
C82.00 – C82.99	Follicular lymphoma
C84.40 – C84.7A	Peripheral T-cell lymphoma, not classified
C84.60 – C84.69	Anaplastic large cell lymphoma, ALK-positive
C84.70 – C84.79, C84.7A	Anaplastic large cell lymphoma, ALK-negative
C86.0	Extranodal NK/T-cell lymphoma, nasal type
C86.1	Hepatosplenic T-cell lymphoma
C86.2	Enteropathy-type (intestinal)T-cell lymphoma
C86.5	Angioimmunoblastic T-cell lymphoma
C91.50 - C91.52	Adult T-cell lymphoma/leukemia (HTLV-1-associated)
ICD-10 codes not covered for indications listed in the CPB (not all inclusive):
C16.0 – C16.9	Malignant neoplasm of stomach
C18.0 - C18.0	Malignant neoplasm of colon
C20	Malignant neoplasm of rectum
C22.0	Liver cell carcinoma[hepatocellular carcinoma]
C25.0 - C25.9	Malignant neoplasm of pancreas
C34.00 - C34.92	Malignant neoplasm of lung [small cell lung cancer]
C37	Malignant neoplasm of thymus
C40.00 – C41.9	Malignant neoplasm of bone and articular cartilage of limbs
C45.0	Mesothelioma of pleura
C45.7	Mesothelioma of other sites [stomach and lungs]
C48.1 - C48.8	Malignant neoplasm of peritoneum
C49.0 - C49.9	Malignant neoplasm of connective and soft tissue
C50.011 - C50.929	Malignant neoplasm of breast
C53.0 - C53.9	Malignant neoplasm of cervix uteri
C56.1 - C56.9	Malignant neoplasm of ovary
C57.00 - C57.02	Malignant neoplasm of fallopian tube
C61	Malignant neoplasm of prostate
C67.0 - C67.9	Malignant neoplasm of bladder
C7A00 - C7A.8	Malignant neuroendocrine tumors
C71.0 - C71.9	Malignant neoplasm of brain [glioblastoma]
C72.0 - C72.9	Malignant neoplasm of other and unspecified parts of the nervous system [chordoma]
C73	Malignant neoplasm of thyroid gland
C76.0	Malignant neoplasm of head, face and neck
C81.00 0 C81.99	Hodgkin lymphoma
C83.00 - C83.09 -	Small cell B-cell lymphoma
C83.10 - C83.19	Mantle cell lymphoma
C83.30 - C83.39	Diffuse large B-cell lymphoma
C85.10 - C85.19	Unspecified B-cell lymphoma
C85.20 - C85.29	Mediastinal (thymic) large B-cell lymphoma
C90.00 - C90.02	Multiple myeloma
C91.00 - C91.02	Acute lymphoid leukemia [ALL]
C92.00 - C92.02	Acute myeloid leukemia
D46.9	Myelodysplastic syndrome, unspecified
L20.81 - L20.9	Atopic dermatitis

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Treatment of adult patients with relapsed or refractory peripheral T-cell lymphoma (PTCL)

Compendial Uses

• T-Cell Lymphomas

  • Hepatosplenic T-cell lymphoma
  • Extranodal NK/T-cell lymphoma
  • Adult T-cell leukemia/lymphoma (ATLL)
  • Breast implant associated anaplastic large cell lymphoma (ALCL)

Belinostat is available as Beleodaq (Acrotech Biopharma LLC) and is a histone deacetylase (HDAC) inhibitor with a sulfonamide-hydroxamide structure. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. In vitro, Beleodaq (belinostat)caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Beleodaq (belinostat) shows preferential cytotoxicity towards tumor cells compared to normal cells. Beleodaq (belinostat) inhibited the enzymatic activity of histone deacetylases at nanomolar concentrations (<250 nM) (Acrotech Biopharma, 2020).

Per the prescribing information, belinostat (Beleodaq) carries the following warnings and precautions:

• Hematologic toxicity
• Infection
• Hepatotoxicity
• Tumor lysis syndrome
• Embryo-fetal toxicity.

The most common adverse reactions (>25%) are nausea, fatigue, pyrexia, anemia, and vomiting (Acrotech Biopharma, 2020).

Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas (PTCLs) comprise a diverse group of rare diseases in which lymph nodes become cancerous.  Peripheral T-cell lymphomas represent approximately 10 to 15 % of non-Hodgkin’s lymphomas in North America; and these rare malignancies have a poor prognosis.  As a consequence of lack of randomized controlled trials (RCTs), standard therapy for PTCL has not been established.  First-line treatment with anthracycline-based poly-chemotherapy followed by consolidation with high-dose chemotherapy and autologous stem cell transplant in responding patients has demonstrated good feasibility with low toxicity in prospective studies and is widely used in eligible patients.  In relapsed and refractory patients, who are not candidates for stem cell transplantations, therapeutic options are limited and are usually palliative.  Several new agents are currently under investigation to improve the outcome of PTCL in the first-line and salvage settings.  Belinostat, a novel histone deacetylase (HDAC) inhibitor of both class I and class II HDAC enzymes, has demonstrated broad anti-neoplastic activity in pre-clinical studies and promising results in advanced relapsed/refractory lymphomas. 

Beleodaq (belinostat) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with relapsed or refractory peripheral T‐cell lymphoma (PTCL). This indication is approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease‐related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

McDermott and Jimeno (2014) stated that several HDAC molecules have been found to be over-expressed in PTCL; and therefore, HDAC inhibition has been an important new target in treating these malignancies that have traditionally had poor outcomes and limited treatment response.  Phase I studies were tested across a broad range of hematologic malignancies and solid tumors and showed stability of disease with low rates of adverse events.  This made it acceptable to proceed with further testing in specific tumor types to further determine effectiveness.  Two phase II studies have been completed with belinostat given intravenously in the relapsed/refractory PTCL setting with at least 25 % overall response and minimal toxicities.  These findings have led to a request for accelerated approval to the U.S. Food and Drug Administration (FDA) for belinostat in this setting. 

On July 3, 2014, the FDA approved belinostat (Beleodaq) for the treatment of patients with PTCL; the approval was rendered under the agency’s accelerated approval program. The safety and effectiveness of belinostat was evaluated in a clinical study involving 129 patients with relapsed or refractory PTCL.  All subjects were treated with belinostat until their disease progressed or side effects became unacceptable.  Results showed 25.8 % of subjects had achieved complete response (CR) or partial response (PR) after treatment.  The most common side effects seen in belinostat-treated participants were anemia, fatigue, fever, nausea and vomiting.

Belinostat is a member of HDAC inhibitors that have been tested as a single agent and in combination with other chemotherapies and biological agents in the treatment of solid tumors and other types of hematologic malignancies.  However, its effectiveness in these settings has not been established.

In a phase I study, Lassen and co-workers (2010) determined the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of belinostat with carboplatin and paclitaxel and the anti-tumor activity of the combination in solid tumors.  Cohorts of 3 to 6 patients were treated with escalating doses of belinostat administered intravenously once-daily, days 1 to 5 q21 days; on day 3, carboplatin (area under the curve (AUC) 5) and/or paclitaxel (175 mg/m2) were administered 2 to 3 hours after the end of the belinostat infusion.  In all, 23 patients received 600 to 1,000 mg/m2/day of belinostat with carboplatin and/or paclitaxel.  No DLT was observed.  The maximal administered dose of belinostat was 1,000 mg/m2/day for days 1 to 5, with paclitaxel (175 mg m(-2)) and carboplatin AUC 5 administered on day 3.  Grade III/IV adverse events were (n; %): leucopenia (5; 22 %), neutropenia (7; 30 %), thrombocytopenia (3; 13 %) anemia (1; 4 %), peripheral sensory neuropathy (2; 9 %), fatigue (1; 4 %), vomiting (1; 4 %) and myalgia (1; 4 %).  The pharmacokinetics of belinostat, paclitaxel and carboplatin were unaltered by the concurrent administration.  There were 2 PR (1 rectal cancer and 1 pancreatic cancer).  A third patient (mixed Mullerian tumor of ovarian origin) showed a complete CA-125 response.  In addition, 6 patients showed a stable disease (SD) lasting greater than or equal to 6 months.  The authors concluded that the combination was well-tolerated, with no evidence of pharmacokinetic interaction.  They stated that further evaluation of anti-tumor activity is needed.

Grassadonia et al (2013) stated that hydroxamate-based HDAC inhibitors (Hb-HDACIs), such as vorinostat, belinostat and panobinostat, have been previously shown to have a wide range of activity in hematologic malignancies such as cutaneous T-cell lymphoma and multiple myeloma.  Recent data showed that they synergize with a variety of cytotoxic and molecular targeted agents in many different solid tumors, including breast, prostate, pancreatic, lung and ovarian cancer.  Hb-HDACIs have a quite good toxicity profile and are now being tested in phase I and II clinical trials in solid tumors with promising results in selected neoplasms, such as HCC.

Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia

Dai et al (2011) investigated interactions between belinostat and bortezomib in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells.  Co-administration of sub-micromolar concentrations of belinostat with low nanomolar concentrations of bortezomib sharply increased apoptosis in both AML and ALL cell lines and primary blasts.  Synergistic interactions were associated with interruption of both canonical and non-canonical nuclear factor (NF)-κB signaling pathways, e.g. accumulation of the phosphorylated (S32/S36) form of IκBα, diminished belinostat-mediated RelA/p65 hyper-acetylation (K310), and reduced processing of p100 into p52.  These events were accompanied by down-regulation of NF-κB-dependent pro-survival proteins (e.g., XIAP, Bcl-xL).  Moreover, belinostat/bortezomib co-exposure induced up-regulation of the BH3-only pro-death protein Bim.  Significantly, shRNA knock-down of Bim substantially reduced the lethality of belinostat/bortezomib regimens.  Administration of belinostat ± bortezomib also induced hyper-acetylation (K40) of α-tubulin, indicating histone deacetylase inhibitor 6 inhibition.  Finally, in contrast to the pronounced lethality of belinostat/bortezomib toward primary leukemia blasts, equivalent treatment was relatively non-toxic to normal CD34(+) cells.  The authors concluded that these findings indicated that belinostat and bortezomib interact synergistically in both cultured and primary AML and ALL cells and raise the possibilities that up-regulation of Bim and interference with NF-κB pathways contribute to this phenomenon.  They also suggested that combined belinostat/bortezomib regimens warrant further attention in acute leukemia.

Kirschbaum et al (2014) performed a phase II study of belinostat in patients with acute myeloid leukemia (AML).  In this open-label phase II study, patients with relapsed/refractory AML, or newly diagnosed patients with AML over the age of 60, were eligible.  Belinostat was administered intravenously at a dose of 1,000 mg/m2 daily on days 1 to 5 of a 21-day cycle until progression or unacceptable toxicity.  The primary end-point was CR rate, with secondary end-points of ORR (CR + PR), time to treatment failure, OS and safety.  A total of 12 eligible patients with AML were enrolled, of whom 6 had received at least 1 prior line of therapy.  No CR or PR was seen; 4 patients had SD for at least 5 cycles.  Grade 3 non-hematological toxicities occurred in 4 patients.  The authors concluded that belinostat as monotherapy has minimal single-agent effect in AML on this dosing schedule.

Acute Promyelocytic Leukemia

Valiuliene et al (2015) stated that belinostat (Bel) has proved to be a promising cure in clinical trials for solid tumors and hematological malignancies. However, insight into molecular effects of Bel on acute promyelocytic leukemia (APL) is still lacking. In this study, these researchers investigated the effect of Bel alone and in combination with differentiation inducer retinoic acid (RA) on human promyelocytic leukemia NB4 and HL-60 cells. These investigators found that treatment with Bel, depending on the dosage used, inhibited cell proliferation, whereas in combination with RA enhanced and accelerated granulocytic leukemia cell differentiation. They also evaluated the effect of used treatments with Bel and RA on certain epigenetic modifiers (HDAC1, HDAC2, PCAF) as well as cell cycle regulators (p27) gene expression and protein level modulation. These investigators showed that Bel in combination with RA up-regulated basal histone H4 hyper-acetylation level more strongly compared to Bel or RA alone. Furthermore, chromatin immune-precipitation assay indicated that Bel induced the accumulation of hyper-acetylated histone H4 at the p27 promoter region. Mass spectrometry analysis revealed that in control NB4 cells, hyper-acetylated histone H4 was mainly found in association with proteins involved in DNA replication and transcription, whereas after Bel treatment it was found with proteins implicated in pro-apoptotic processes, in defense against oxidative stress and tumor suppression. The authors concluded that the findings of this study provided some novel insights into the molecular mechanisms of Bel action on APL cells.

Vitkeviciene and associates (2019) stated that APL is characterized by PML-RARA translocation, which causes the blockage of promyelocyte differentiation.  Conventional treatment with retinoic acid and chemotherapeutics is quite satisfactory.  However, there are still patients who relapse or develop resistance to conventional treatment.  To propose new possibilities for acute leukemia treatment, these researchers examined the potential of HDAC inhibitor and histone methyl transferase (HMT) inhibitor to enhance conventional therapy in-vitro and ex-vivo.  NB4 and HL60 cell lines were used as an in-vitro model; APL patient bone marrow mononuclear cells were used as an ex-vivo model.  Cell samples were treated with belinostat (HDAC inhibitor) and 3-deazaneplanocin A (HMT inhibitor) in combination with conventional treatment (retinoic acid and idarubicin).  These investigators demonstrated that the combined treatment used in the study had slightly higher effect on cell proliferation inhibition than conventional treatment.  Furthermore, enhanced treatment showed stronger effect on induction of apoptosis and on suppression of metabolism.  Moreover, the treatment accelerated granulocytic cell differentiation and caused chromatin re-modelling (increased H3K14 and H4 acetylation levels).  In-vitro and ex-vivo models showed similar response to the treatment with different combinations of 3-deazaneplanocin A, belinostat, retinoic acid, and idarubicin.  The authors concluded that these findings suggested that 3-deazaneplanocin A and belinostat enhanced conventional APL treatment and could be considered for further investigations for clinical use.

Advanced Thymic Epithelial Tumors

In a phase II clinical trial, Giaccone and colleagues (2011) examined the effectiveness of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors.  Patients with advanced thymic epithelial malignancies in whom at least 1 line of platinum-containing chemotherapy had failed were eligible for this study.  Other eligibility criteria included adequate organ function and good performance status.  Belinostat was administered intravenously at 1 g/m2 on days 1 to 5 of a 21-day cycle until disease progression or development of intolerance.  The primary objective was response rate in patients with thymoma.  Of the 41 patients enrolled, 25 had thymoma, and 16 had thymic carcinoma; patients had a median of 2 previous systemic regimens (range of 1 to 10 regimens).  Treatment was well-tolerated, with nausea, vomiting, and fatigue being the most frequent adverse effects.  Two patients achieved PR (both had thymoma; response rate, 8 %; 95 % CI: 2.2 % to 25 %), 25 had SD, and 13 had progressive disease; there were no responses among patients with thymic carcinoma.  Median times to progression and survival were 5.8 and 19.1 months, respectively.  Survival of patients with thymoma was significantly longer than that of patients with thymic carcinoma (median not reached versus 12.4 months; p = 0.001).  Protein acetylation, regulatory T-cell numbers, and circulating angiogenic factors did not predict outcome.  The authors concluded that belinostat has modest anti-tumor activity in this group of heavily pre-treated thymic malignancies.  However, the duration of response and disease stabilization is intriguing, and additional testing of belinostat in this disease is warranted.

Atopic Dermatitis

Liew and colleagues (2020) noted that atopic dermatitis (AD) is a common chronic inflammatory skin disease.  Skin barrier defects contribute to disease initiation and development; however, underlying mechanisms remain elusive.  To understand the underlying cause of barrier defect, these investigators examined aberrant expression of specific microRNAs (miRNAs) in AD.  Delineating the molecular mechanism of dysregulated miRNA network, they focused on identification of specific drugs that can modulate miRNA expression and repair the defective barrier in AD.  A screen for differentially expressed miRNAs between healthy skin and AD lesional skin resulted in the identification of miR-335 as the most consistently down-regulated miRNA in AD.  Using in silico prediction combined with experimental validation, these investigators characterized down-stream miR-335 targets and elucidated the molecular pathways by which this microRNA maintains epidermal homeostasis in healthy skin.  miR-335 was identified as a potent inducer of keratinocyte differentiation; it exerts this effect by directly repressing SOX6.  By recruiting SMARCA complex components, SOX6 suppresses epidermal differentiation and epigenetically silences critical genes involved in keratinocyte differentiation.  In AD lesional skin, miR-335 expression was aberrantly lost.  SOX6 was abnormally expressed throughout the epidermis, where it impaired skin barrier development.  These researchers demonstrated that miR-335 was epigenetically regulated by histone deacetylases; a screen for suitable histone deacetylase inhibitors identified belinostat as a candidate drug that could restore epidermal miR-335 expression and rescue the defective skin barrier in AD.  The authors concluded that belinostat is of clinical significance not only as a candidate drug for AD treatment, but also as a potential means of stopping the atopic march and further progression of this systemic allergic disease.

B-Cell Lymphoma (e.g., Diffuse Large B Cell Lymphoma and Mantle Cell Lymphoma

Havas and associates (2016) stated that diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 % 5-year survival rate, highlighting a need for new therapeutic approaches; and HDACi are novel therapeutics being clinically-evaluated in combination with a variety of other drugs.  However, rational selection of companion therapeutics for HDACi is difficult due to their poorly-understood, cell-type specific mechanisms of action.  These researchers developed a pre-clinical model system of sensitivity and resistance to the HDACi belinostat using DLBCL cell lines.  In the current study, these investigators demonstrated that cell lines sensitive to the cytotoxic effects of HDACi underwent early mitotic arrest prior to apoptosis.  In contrast, HDACi-resistant cell lines completed mitosis after a short delay and arrest in G1.  To force mitotic arrest in HDACi-resistant cell lines, these researchers used low-dose vincristine or paclitaxel in combination with belinostat and observed synergistic cytotoxicity.  Belinostat curtailed vincristine-induced mitotic arrest and triggered a strong apoptotic response associated with down-regulated MCL-1 expression and up-regulated BIM expression.  Resistance to microtubule targeting agents (MTAs) has been associated with their propensity to induce polyploidy and thereby increase the probability of genomic instability that enables cancer progression.  Co-treatment with belinostat effectively eliminated a vincristine-induced, actively cycling polyploid cell population.  The authors concluded that the findings of this study demonstrated that vincristine sensitized DLBCL cells to the cytotoxic effects of belinostat and that belinostat prevented polyploidy that could cause vincristine resistance; these observations provided a rationale for using low-dose MTAs in conjunction with HDACi as a potential therapeutic strategy for treatment of aggressive DLBCL.

Nguyen and colleagues (2017) examined interactions between volasertib and belinostat in DLBCL and mantle cell lymphoma (MCL) cells in-vitro and in-vivo.  Exposure of DLBCL cells to very low concentrations of volasertib in combination with belinostat synergistically increased cell death (apoptosis).  Similar interactions occurred in GC-, ABC-, double-hit DLBCL cells, MCL cells, bortezomib-resistant cells and primary lymphoma cells.  Co-exposure to volasertib/belinostat induced a marked increase in M-phase arrest, phospho-histone H3, mitotic errors, cell death in M-phase, and DNA damage.  Belinostat diminished c-Myc mRNA and protein expression, an effect significantly enhanced by volasertib co-exposure.  c-Myc knock-down increased DNA damage and cell death in response to volasertib, arguing that c-Myc down-regulation plays a functional role in the lethality of this regimen.  Notably, PLK1 knock-down in DLBCL cells significantly increased belinostat-induced M-phase accumulation, phospho-histone H3, γH2AX, and cell death.  Co-administration of volasertib and belinostat dramatically reduced tumor growth in an ABC-DLBCL flank model (U2932) and a systemic double-hit lymphoma model (OCI-Ly18), accompanied by a pronounced increase in survival without significant weight loss or other toxicities.  The authors concluded that these findings indicated that PLK1/HDAC inhibition warrants attention as a therapeutic strategy in non-Hodgkin’s lymphoma (NHL).  These researchers stated that based upon the present findings, a phase I clinical trial of volasertib (or other PLK1 inhibitors) in combination with an HDACI such as belinostat for patients with relapsed/refractory NHL appears justified.  In addition to testing the tolerability of this regimen, and identifying the recommended phase II dose (RP2D), such a trial could help to examine if post-treatment pharmacodynamic changes in tumor cells can recapitulate those observed pre-clinically.  Consequently, plans to develop this strategy further in patients with NHL are currently underway.

Puvvada and co-workers (2017) noted that aggressive lymphomas (aNHL) including DLBCL have poor outcomes in relapsed refractory patients.  Prior studies have demonstrated that loss of major histocompatibility complex class II (MHCII) expression in DLBCL is associated with poor survival.  In a single-arm, single-center, open-label, phase-II clinical trial, these researchers examined if PXD-101 (belinostat) would increase MHCII expression, synergize with ibritumomab tiuxetan (Zevalin), and improve clinical outcomes.  The primary end-point was ORR in aNHL patients treated with 2 cycles of PXD-101 followed by re-staging computed tomography (CT) and 1 cycle of Zevalin.  A total of 5 patients were enrolled, and all were heavily pre-treated.  Therapy was well-tolerated, with nausea and vomiting being the most frequent adverse events (AEs).  All patients progressed after receiving therapy; the study did not achieve the required ORR to proceed to the next stage.  The authors concluded that the pleotropic effects of HDACi and lack of clinical biomarkers precluded a priori identification of responding patients.  These investigators stated that while they reported a negative trial of PXD-101 in combination with Zevalin, this study highlighted the importance of a clinically feasible biomarker.

Bone Cancer

de Nigris et al (2021) noted that a great interest in the scientific community is focused on the improvement of the cure rate in patients with bone malignancies that have a poor response to the 1st-line of treatments.  Novel treatments currently include epigenetic compounds or molecules targeting epigenetic-sensitive pathways.  These investigators provided an exhaustive review of such agents in these clinical settings.  Carefully designed pre-clinical studies selected several epigenetic drugs, including inhibitors of DNA methyltransferase (DNMTIs), such as decitabine; HDACIs such as entinostat, belinostat; lysine-specific histone demethylase (LSD1) such as INCB059872 or FT-2102 (outasidenib); inhibitors of isocitrate dehydrogenases, and enhancer of zeste homolog 2 (EZH2), such as EPZ6438 (tazemetostat) to enhance the therapeutic effect, the prevalent approach in phase-II clinical trial is the association of these epigenetic drug inhibitors, with targeted therapy or immune checkpoint blockade.  The authors concluded that the optimization of drug dosing and regimens of phase-II clinical trials may improve the clinical effectiveness of such novel therapeutic approaches against these devastating cancers.

These researchers stated that an important issue in this field is determining the adequate time for response, because the epigenetic re-programming takes longer to become apparent than the actions of traditional chemotherapies.  Furthermore, long-term clinical benefits must be rigorously evaluated using careful follow-up measurements of response to subsequent therapies.  Moreover, since epigenetic modifications could contribute to identifying within a population of different susceptibilities to a disease and treatments, there is a need to evaluate the individual epigenetic signature, to establish the best protocol among drug regimens, adequate control of pain, and the appropriate strong clinical endpoints.  This effort could be optimized by personalized therapy in the context of the network medicine integrated approach tailored to the frailty of the individual patient suffering bone malignancies.

Carcinoma of Unknown Primary Site

In a randomized, phase II clinical trial, Hainsworth et al (2015) evaluated the effectiveness of belinostat when added to paclitaxel/carboplatin in the empiric first-line treatment of patients with carcinoma of unknown primary site (CUP). Previously untreated patients with CUP were randomized to receive belinostat plus paclitaxel/carboplatin (group A) or paclitaxel/carboplatin alone (group B) repeated every 21 days. Patients were re-evaluated every 2 cycles, and those without disease progression continued treatment for 6 cycles. Patients in group A then continued receiving single-agent belinostat, whereas patients in group B stopped treatment. The primary end-point was PFS: The authors postulated that the addition of belinostat would improve PFS from 5 months (expected with paclitaxel/carboplatin) to 8 months. A total of 89 patients were randomized (group A, n = 44; group B, n = 45), and the demographics and disease characteristics were balanced between the 2 groups. The addition of belinostat to paclitaxel/carboplatin did not improve PFS (group A, 5.4 months [95 % CI: 3.0 to 6.0 months]; group B, 5.3 months [95 % CI: 2.8 to 6.6 months]; p = 0.85); OS was 12.4 months for group A versus 9.1 months for group B (p = 0.20). The response rate favored the belinostat group (45 % versus 21 %; p = 0.02). Belinostat resulted in a modest increase in treatment toxicity. The authors concluded that the addition of belinostat to paclitaxel/carboplatin did not improve the PFS of patients with CUP who were receiving first-line therapy, although the patients who received belinostat had a higher investigator-assessed response rate. They stated that future trials in CUP should focus on specific subsets, defined either by the predicted tissue of origin or by the identification of targetable molecular abnormalities.

Chordomas

Scheipl et al (2013) noted that chordomas are rare malignancies of the axial skeleton.  Therapy is mainly restricted to surgery.  These researchers investigated HDAC inhibitors as potential therapeutics for chordomas.  Immunohistochemistry (IHC) was performed using the HDAC 1-6 antibodies on 50 chordoma samples (34 primary tumors, 16 recurrences) from 44 patients (27 males, 17 females).  Pan-HDAC-inhibitors vorinostat (SAHA), panobinostat (LBH-589), and belinostat (PXD101) were tested for their effectiveness in the chordoma cell line MUG-Chor1 via Western blot, cell cycle analysis, caspase 3/7 activity (MUG-Chor1, UCh-1), cleaved caspase-3, and PARP cleavage; p-values below 0.05 were considered significant.  Immunohistochemistry was negative for HDAC1, positive for HDAC2 in most (n = 36; 72 %), and for HDACs 3 to 6 in all specimens available (n = 43; 86 %); HDAC6 expression was strongest.  Vorinostat and panobinostat, but not belinostat caused a significant increase of G2/M phase cells and of cleaved caspase-3 (p = 0.0003, and p = 0.0014 after 72 hours, respectively), and a peak of caspase 3/7 activity.  PARP cleavage confirmed apoptosis.  The presented chordoma series expressed HDACs 2-6 with strongest expression of HDAC6.  The authors concluded that vorinostat and panobinostat significantly increased apoptosis and changed cell cycle distribution in-vitro.  They stated that HDAC-inhibitors should be further evaluated as therapeutic options for chordoma.

Colon Cancer

Na and colleagues (2011) investigated the anti-tumor effect of PXD101 (belinostat) combined with irinotecan in colon cancer.  HCT116 and HT29 colon cancer cells for cell viability assay were treated with PXD101 and/or SN-38, the active form of irinotecan.  Anti-tumor effects of HCT116 and HT29 xenografts treated with these combinations were evaluated.  [(18)F]FLT-PET was used to detect early responses to PXD101 and irinotecan in colon cancer.  PXD101 and SN38 possessed dose-dependent anti-proliferative activity against HCT116 and HT29 cells and exerted a synergistic effect when used in combination.  In xenografted mice, PXD101 in combination with irinotecan dramatically inhibited tumor growth without causing additive toxicity.  Apoptotic effects on xenograft tumors were greater with combined treatment than with irinotecan alone.  [(18)F]FLT-PET imaging revealed a 64 % decrease in [(18)F]FLT uptake in tumors of HCT116 xenograft-bearing mice treated with a combination of PXD101 and irinotecan, indicating a decrease in thymidine kinase 1 (TK1) activity.  These results were supported by Western blot analyses showing a decrease in tumor thymidine kinase 1 protein levels, suggesting that [(18)F]FLT-PET can be used to non-invasively detect early responses to these agents.  The authors concluded that these data showed that PXD101 (belinostat) increased the cytotoxic activity of irinotecan in in-vitro and in-vivo colon cancer models and suggested these agent combinations should be explored in the treatment of colon cancer.

Concomitant Use of Ixazomib and Belinostat

Passero and colleagues (2020) noted that ixazomib activity and transcriptomic analyses previously established in T cell lymphoma (TCL) and Hodgkin lymphoma (HL) models predicted synergistic activity for HDAC inhibitory combination.  These researchers determined the mechanistic basis for ixazomib combination with the HDAC inhibitor, belinostat, in HL and TCL cells lines (ixazomib-sensitive/resistant clones) and primary tumor cells.  In ixazomib-treated TCL and HL cells, transient inhibition followed by full recovery of proteasomal activity observed was accompanied by induction of proteasomal gene expression with NFE2L2 (also termed NRF2) as a prominent upstream regulator.  Down-regulation of both NFE2L2 and proteasomal gene expression (validated by quantitative real time polymerase chain reaction [rt-PCR]) occurred with belinostat treatment in Jurkat and L428 cells.  In addition, CRISPR/Cas9 mediated knockdown of NFE2L2 in Jurkat cells resulted in a significant decrease in cell viability with ixazomib compared with untreated control cells.  Using transcriptomic and proteasomal activity evaluation of ixazomib, belinostat, or ixazomib + belinostat treated cells, these investigators observed that NFE2L2, proteasome gene expression and functional recovery were abrogated by ixazomib + belinostat combination, resulting in synergistic drug activity in ixazomib-sensitive and -resistant cell lines and primary cells.  The authors concluded that these findings suggested that the synergistic activity of ixazomib + belinostat was mediated via inhibition NFE2L2-dependent proteasomal recovery and extended proteasomal inhibition culminating in increased cell death.

Gastric Cancer

Demirtas et al (2022) stated that gastric cancer (GC) is a prevalent disease worldwide with high mortality and poor treatment success. Early diagnosis of GC and forecasting of its prognosis with the use of biomarkers are directly relevant to achieve both personalized/precision medicine and innovation in cancer therapeutics. Gene expression signatures offer one of the promising avenues of research in this regard, as well as guiding drug re-purposing analyses in cancers. Using publicly accessible gene expression datasets from the Gene Expression Omnibus and the Cancer Genome Atlas (TCGA), these investigators reported original findings on co-expressed gene modules that are differentially expressed between 133 GC samples and 46 normal tissues, which hold potential for novel diagnostic candidates for GC. Furthermore, these researchers found 2 co-expressed gene modules were significantly associated with poor survival outcomes revealed by survival analysis of the RNA-Seq TCGA datasets. They identified STAT6 (signal transducer and activator of transcription 6) as a key regulator of the identified gene modules. Lastly, potential therapeutic drugs that may target and reverse the expression of the identified altered gene modules examined for drug re-purposing analyses and the unraveled compounds were further examined in the literature by the text mining method. These investigators found several re-purposed drug candidates, including trichostatin A, vorinostat, parthenolide, panobinostat, brefeldin A, belinostat, and danusertib. Through text mining analysis and literature search validation, belinostat and danusertib were suggested as possible novel drug candidates for the treatment of GC. The authors concluded that these findings collectively informed multiple aspects of GC medical management, including its precision diagnosis, forecasting of possible outcomes, as well as drug re-purposing for innovation in GC medicines in the future.

Glioblastoma

Kusaczuk and colleagues (2016) stated that HDAC inhibitors (HDACi) are now intensively investigated as potential cytostatic agents in many malignancies.  These investigators provided novel information concerning the influence of belinostat (Bel) on glioblastoma LN-229 and LN-18 cells.  They found that LN-229 cells stimulated with 2 μmol/L of Bel for 48 hours resulted in 70 % apoptosis, while equivalent treatment of LN-18 cells resulted in only 28 % apoptosis.  In LN-229 cells this effect was followed by up-regulation of pro-apoptotic genes including Puma, Bim, Chop and p21 . In treated LN-18 cells only p21 was markedly over-expressed.  Simultaneously, LN-229 cells treated with 2 μmol/L of Bel for 48 hours exhibited down-regulation of molecular chaperones GRP78 and GRP94 at the protein level.  In contrast, in LN-18 cells Western blot analysis did not show any marked changes in GRP78 nor GRP94 expression.  Despite noticeable over-expression of p21, there were no signs of evident G1 nor G2/M cell cycle arrest, however, the reduction in number of the S phase cells was observed in both cell lines.  The authors concluded that these findings suggested that Bel can be considered as potential anti-glioblastoma agent.  To the authors’ knowledge this was the 1st report presenting the effects of belinostat treatment in glioblastoma cell lines.

Xu et al (2022) noted that glioblastoma (GBM) is highly aggressive and has a poor prognosis.  Belinostat is a histone deacetylase inhibitor with blood-brain barrier (BBB) permeability, anti-GBM activity, and the potential to enhance chemoradiation.  In a pilot study, these researchers examined the effectiveness of combining Bel with standard-of-care (SOC) therapy.  A total of 13 patients were enrolled in each of control and Bel cohorts.  The Bel cohort was given a belinostat regimen (500 to 750 mg/m2 1×/day × 5 days) every 3 weeks (weeks 0, 3, and 6 of radiation therapy [RT]).  All patients received temozolomide  (TMZ) and RT.  RT margins of 5 to 10 mm were added to generate clinical tumor volumes and 3 mm added to create planning target volumes.  Median OS was 15.8 months for the control cohort and 18.5 months for the Bel cohort (p = 0.53).  The recurrence volumes (rGTVs) for the control cohort occurred in areas that received higher radiation doses than that in the Bel cohort.  For those Bel-treated patients who experienced out-of-field recurrence, tumors were detectable by spectroscopic MRI (sMRI) before RT.  Recurrence analysis suggested better in-field control with Bel.  The authors concluded that the findings of this study highlighted the potential of Bel as a synergistic therapeutic agent for GBM.  It may be especially beneficial to combine this radio-sensitizing effect with spectroscopic MRI-guided RT.

The authors stated that due to limitations in the study including a small sample size (n = 13) in each cohort, a wide range of survival responses to Bel, as well as toxicities from initially larger doses of administered Belt, further investigation is needed larger cohorts with manageable Bel dosing regimens to discern the true effect size of this treatment.  In this study, Bel was only administered during RT.  Since an HDACi such as Bel is a reversible drug and epigenetic modification-induced stress remains, these researchers hypothesized that extended use of Bel during the maintenance period after RT may further improve outcomes in patients.  This will require future testing to examine the safety and effectiveness of Bel when combined with adjuvant TMZ.  Based on the findings of this pilot study, these researchers are planning a multi-site trial with a larger cohort of patients that will also include maintenance Bel after sMRI-guided RT.

Hairy Cell Leukemia

Lupi and colleagues (2021) stated that experience with angiotensin-receptor neprilysin inhibitors (ARNI) in oncologic patients with heart failure (HF) is limited. These investigators reported a case of ARNI started as 1st-choice therapy in a patient with relapsing hairy cell leukemia (HCL) and HF with depressed left ventricular ejection fraction (LVEF). A middle-aged man, previously treated with rituximab for HCL, was scheduled for cardiologic screening before starting a new anti-neoplastic therapy for cancer relapse. The patient had symptomatic HF with reduced LVEF and high NT-proBNP levels. In this patient, early ARNI treatment was well-tolerated and produced a rapid and durable improvement of symptoms, LVEF and NT-proBNP levels. Consequently, the oncologic team could start an experimental treatment with obinutuzumab, with complete HCL remission. The authors concluded that in this patient with HCL and HF, ARNI therapy was safe and effective, contributing to un-delayed cancer treatment.

Hepatocellular Carcinoma (HCC)

Yeo and colleagues (2012) noted that epigenetic aberrations have been reported in hepato-cellular carcinoma (HCC).  In a phase I/II clinical trial, these researchers determined dose-limiting toxicity (DLT) and MTD of belinostat for patients with unresectable HCC.  They assessed pharmacokinetics (phase I study) and assessed activity of and explored potential biomarkers for response (phase II study).  Major eligibility criteria included histologically confirmed unresectable HCC, ECOG performance score less than or equal to 2, and adequate organ function.  Phase I consisted of 18 patients; belinostat was given intravenously once-daily on days 1 to 5 every 3 weeks; dose levels were 600 mg/m2 per day (level 1), 900 mg/m2 per day (level 2), 1,200 mg/m2 per day (level 3), and 1,400 mg/m2 per day (level 4).  Phase II consisted of 42 patients.  The primary end-point was PFS, and the main secondary end-points were response according to Response Evaluation Criteria in Solid Tumors (RECIST) and OS.  Exploratory analysis was conducted on pre-treatment tumor tissues to determine whether HR23B expression is a potential biomarker for response.  Belinostat pharmacokinetics were linear from 600 to 1,400 mg/m2 without significant accumulation.  The MTD was not reached at the maximum dose administered.  Dose level 4 was used in phase II.  The median number of cycles was 2 (range of 1 to 12).  The PR and SD rates were 2.4 % and 45.2 %, respectively.  The median PFS and OS were 2.64 and 6.60 months, respectively.  Exploratory analysis revealed that disease stabilization rate (CR plus PR plus SD) in tumors having high and low HR23B histo-scores were 58 % and 14 %, respectively (p = 0.036).  The authors concluded that epigenetic therapy with belinostat demonstrated tumor stabilization and is generally well-tolerated.  HR23B expression was associated with disease stabilization.  The clinical effectiveness of belinostat for HCC awaits results from phase III clinical trials.

Lung Cancer

Balasubramaniam and colleagues (2018) stated that the standard-of-care for advanced small cell lung cancer (SCLC) is chemotherapy with cisplatin+etoposide (C+E).  Most patients have chemo-sensitive disease at the outset, but disease frequently relapses and limits survival.  Efforts to improve therapeutic outcomes in SCLC and other neuroendocrine cancers have focused on epigenetic agents, including the histone deacetylase inhibitor belinostat.  In a single-center, phase-I clinical trial, these researchers determined the MTD of the combination of belinostat (B) with C+E.  Belinostat was administered as a 48-hour continuous IV infusion on days 1 to 2; cisplatin was administered as a 1-hour IV infusion on day 2; and etoposide was administered as a 1-hour IV infusion on days 2, 3, and 4.  A total of 28 patients were recruited in this trial.  The MTD was belinostat 500 mg/m/24 hour, cisplatin 60 mg/m, and etoposide 80 mg/m.  The combination was safe, although some patients were more susceptible to AEs.  Hematologic toxicities were most commonly observed.  Objective responses were observed in 11 (39 %) of 28 patients and 7 (47 %) of 15 patients with neuroendocrine tumors (including SCLC).  Patients carrying more than 3 copies of variant UGT1A1 (*28 and *60) had higher serum levels of belinostat because of slower clearance; DNA damage peaked at 36 hours after the initiation of belinostat, as did global lysine acetylation, but returned to baseline 12 hours after the end of infusion.  The authors concluded that the combination of B+C+E was safe and active in SCLC and other neuroendocrine cancers; future phase-II clinical trials should consider genotyping patients for UGT1A1*28 and UGT1A1*60 and to identify patients at an increased risk of AEs.

Peter et al (2023) noted that Kirsten rat sarcoma virus (KRAS) oncogene, found in 20 % to 25 % of lung cancer patients, potentially regulates metabolic re-programming and redox status during tumorigenesis.  HDAC inhibitors have been examined for the treatment of KRAS-mutant lung cancer.  These investigators examined the effect belinostat at clinically relevant concentration on nuclear factor erythroid 2-related factor 2 (NRF2) and mitochondrial metabolism for the treatment of KRAS-mutant human lung cancer.  LC-MS metabolomic study of belinostat on mitochondrial metabolism was carried out in G12C KRAS-mutant H358 non-small cell lung cancer cells.  In addition, l-methionine (methyl-13 C) isotope tracer was used to examine the effect of belinostat on one-carbon metabolism.  Bioinformatic analyses of metabolomic data were carried out to identify the pattern of significantly regulated metabolites.  To study the effect of belinostat on redox signaling ARE-NRF2 pathway, luciferase reporter activity assay was conducted in stably transfected HepG2-C8 cells (containing pARE-TI-luciferase construct), followed by qPCR analysis of NRF2 and its target gene in H358 cells, which was further confirmed in G12S KRAS-mutant A549 cells.  Metabolomic study showed significantly altered metabolites related to redox homeostasis, including tricarboxylic acid (TCA) cycle metabolites (citrate, aconitate, fumarate, malate, and α-ketoglutarate); urea cycle metabolites (arginine, ornithine, argino-succinate, aspartate, and fumarate); and anti-oxidative glutathione metabolism pathway (GSH/GSSG and NAD/NADH ratio) following belinostat treatment.  13-C stable isotope labeling data indicated potential role of belinostat in creatine biosynthesis via methylation of guanidinoacetate.  furthermore, belinostat down-regulated the expression of NRF2 and its target gene NAD(P)H:quinone oxidoreductase 1 (NQO1), indicating anti-cancer effect of belinostat is mediated, potentially via Nrf2-regulated glutathione pathway.  Another HDACi panobinostat also showed potential anti-cancer effect in both H358 and A549 cells via Nrf2 pathway.  The authors concluded that belinostat was effective in killing KRAS-mutant human lung cancer cells by regulating mitochondrial metabolism which could be used as biomarkers for pre-clinical and clinical studies.

Lung Squamous Cell Carcinoma

Kong and associates (2017) noted that there have been advances in personalized therapy directed by molecular profiles in lung adenocarcinoma, but not in lung squamous cell carcinoma (SCC).  The lack of actionable driver oncogenes in SCC has restricted the use of small-molecule inhibitors.  These researchers showed that SCC cell lines displayed differential sensitivities to belinostat.  Phospho-proteomic analysis of belinostat-treated SCC cells revealed significant down-regulation of the mitogen‐activated protein kinases (MAPK) pathway, along with the induction of apoptosis.  In cisplatin-resistant cells that demonstrated aberrant MAPK activation, combined treatment with belinostat significantly inhibited cisplatin-induced ERK phosphorylation and exhibited strong synergistic cytotoxicity.  Furthermore, belinostat transcriptionally up-regulated the F-box proteins F‐box protein 3 (FBXO3) and F‐box and WD repeat domain containing 10 (FBXW10), which directly targeted son of sevenless (SOS), an up-stream regulator of the MAPK pathway, for proteasome-mediated degradation.  Supporting this, suppression of SOS/ERK pathway by belinostat could be abrogated by inhibiting proteasomal activity either with bortezomib or with siRNA knockdown of FBXO3/FBXW10.  The authors concluded that these pre-clinical data offer a novel understanding of the epigenetic mechanism by which belinostat exerts its cytotoxicity and supports the combination with cisplatin in clinical settings for chemo-refractory SCC tumors.  These researchers noted that they have described a novel mechanism of belinostat sensitivity against lung SCC, a disease in which small‐molecule inhibitors have mostly failed due to the lack of actionable driver oncogenes.  This mechanism involves the disturbance of the expressions of ubiquitin‐related proteins, which influences the activity of key survival signals, leading to an increase in cellular apoptosis.  In the context of SCC, belinostat treatment triggers the proteasomal degradation of SOS proteins and down-regulates the down-stream MAPK signaling.  They stated that HDAC inhibitors have been previously implicated in the depletion of mutant p53 through the transcriptional induction of MDM2, an E3 ubiquitin ligase that negatively regulates p53, instead of directly affecting TP53 transcription.  Likewise, a similar finding was earlier reported whereby a tyrosine kinase inhibitor (TKI), CI‐1033, significantly enhanced ubiquitination in HER2 molecule together with the inhibition of kinase activity.  These reports, along with the authors’ own experimental findings, highlighted the use of compounds that enhance drug‐induced ubiquitin modification to augment anti-neoplastic effects and warrant the use of these inhibitors in further studies.  Nevertheless, the lack of efficacy in pre-clinical xenograft models suggested that additional work is needed for clinical development of belinostat in SCC tumors 

Mesothelioma

Ramalingam and colleagues (2009) conducted a phase II study of belinostat in patients with relapsed malignant pleural mesothelioma.  Patients with advanced mesothelioma, progression with 1 prior chemotherapy regimen and Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 were eligible.  Belinostat was administered at 1,000 mg/m2 intravenously over 30 minutes on days 1 to 5 of every 3-week cycle.  The primary end-point was response rate.  The Simon 2-stage design was used.  Disease assessments were performed every 2 cycles.  A total of 13 patients were enrolled.  Baseline characteristics were: median age of 73 years; ECOG performance status 0 (n = 4), 1 (n = 8) and 2 (n = 1).  A median of 2 cycles of therapy were administered.  Disease stabilization was seen in 2 patients.  No objective responses were noted and the study did not meet criteria to proceed to the 2nd stage of accrual.  Median survival was 5 months with a median progression-free survival (PFS) of 1 month.  Salient toxicities included constipation, emesis, fatigue, and nausea.  One patient died as a consequence of cardiac arrhythmia that was deemed “possibly” related to therapy.  The authors concluded that belinostat is not active as monotherapy against recurrent malignant pleural mesothelioma.  Evaluation of combination strategies or alternate dosing schedules may be necessary for further development of this novel agent in mesothelioma.

Myelodysplastic Syndrome (MDS)

In a phase II, multi-center study, Cashen et al (2012) estimated the effectiveness of belinostat for the treatment of myelodysplastic syndrome (MDS).  Adults with MDS and less than or equal to 2 prior therapies were treated with belinostat 1,000 mg/m2 intravenously on days 1 to 5 of a 21-day cycle.  The primary end-point was a proportion of confirmed responses during the first 12 weeks of treatment.  Responding patients could receive additional cycles until disease progression or unacceptable toxicity.  A total of 21 patients were enrolled, and all were evaluable.  Patients were a median 13.4 months from diagnosis, and 14 patients (67 %) had less than 5 % bone marrow blasts.  Seventeen patients (81 %) were transfusion-dependent.  Prior therapy included azacytidine (n = 7) and chemotherapy (n = 8).  The patients were treated with a median of 4 cycles (range of 1 to 8) of belinostat.  There was 1 confirmed response-hematologic improvement in neutrophils-for an ORR of 5 % (95 % CI: 0.2 to 23).  Median OS was 17.9 months.  Grades 3 to 4 toxicities considered at least to be possibly related to belinostat were: neutropenia (n = 10), thrombocytopenia (n = 9), anemia (n = 5), fatigue (n = 2), febrile neutropenia (n = 1), headache (n = 1), and QTc prolongation (n = 1).  Because the study met the stopping rule in the first stage of enrollment, it was closed to further accrual.

Holkova et al (2021) reported the findings of a dose-escalation phase-I clinical trial of Bel and bortezomib in adult patients with acute leukemia (AML other than acute promyelocytic leukemia; ALL) or MDS or chronic myelogenous leukemia (CML) with blast crisis. A total of 38 patients received IV Bel days 1 to 5 and 8 to 12 with IV bortezomib days 1, 4, 8, and 11 every 21 days. QTc prolongation was the only identified DLT. The RP2Ds were 1.3 mg/m2 bortezomib and 1,000 mg/m2 belinostat. One patient with highly refractory MLL-ENL re-arranged bi-phenotypic AML with multiple karyotypic aberrations had a complete pathologic and karyotypic response. One patient with post-MPN AML remained on study with SD for 32 cycles. Whole-exome sequencing (WES) revealed no aberrations in the 1st patient and a hyper-mutator genotype in the 2nd; 18 patients had a best response of SD. The authors concluded that the findings of this phase-I clinical trial indicated that the limited overall effectiveness of the belinostat/bortezomib regimen in patients with relapsed/refractory AML does not warrant further clinical evaluation.

Shafer et al (2023) stated that belinostat is an intravenous HDACi with FDA approval for the treatment of T-cell lymphomas.  Adavosertib is a 1st in class oral Wee1 inhibitor.  Pre-clinical studies of the combination demonstrated synergy in various human AML lines as well as AML xenograft mouse models.  In a dose-escalation, phase-I clinical trial of belinostat and adavosertib in patients with relapsed/refractory AML and MDS.  Patients received both drugs on days 1 to 5 and 8 to 12 of a 21-day cycle.  Safety and toxicity were monitored throughout the study.  Plasma levels of both drugs were measured for pharmacokinetic analysis.  Response was determined by standard criteria including bone marrow biopsy.  A total of 20 patients were enrolled and treated at 4 dose levels.  A grade-IV cytokine release syndrome (CRS) at dose level 4 (adavosertib 225 mg/day; belinostat 1,000 mg/m2) qualified as a DLT event.  The most common non-hematologic treatment-related AEs were nausea, vomiting, diarrhea, dysgeusia, and fatigue.  No therapeutic responses were observed.  The study was terminated before MTD/recommended phase-II dose determination.  The authors concluded that the combination of belinostat and adavosertib at the tested dose levels was feasible but without efficacy signals in the R/R MDS/AML population.

Nephrotic Syndrome

Dossier and colleagues (2021) noted that steroid-sensitive nephrotic syndrome (SSNS) is, in most patients, a chronic disease with 80 % experiencing at least 1 relapse after 1st flare. B-cell depletion using rituximab is effective in preventing relapse in steroid-dependent (SDNS) patients but fails to maintain long-term remission following B-cell recovery, possibly due to development of auto-reactive long-lived plasma cells. These investigators examined sequential combination of anti-CD20 antibody targeting all B-cell subsets, and anti-CD38 antibody with high plasma cell cytotoxicity in patients with uncontrolled SDNS after failure of 1 or several attempts at B-cell depletion. A total of 14 patients with median disease duration of 7.8 years received 1,000 mg/1.73 m2 obinutuzumab followed by 1,000 mg/1.73 m2 daratumumab 2 weeks later (OD sequence). Oral immunosuppression was discontinued within 6 weeks, and biological monitoring performed monthly until B-cell recovery. Median age at treatment was 11.0 [IQR 10.4 to 14.4] years. B-cell depletion was achieved in all patients, and B-cell reconstitution occurred in all at median 9.5 months following obinutuzumab injection. After median follow-up of 20.3 months (IQR 11.5 to 22.6), 5/14 patients relapsed including 4 within 100 days following B-cell repletion. Relapse-free survival (RFS) was 60 % at 24 months from obinutuzumab infusion. Mild infusion reactions were reported in 3/14 patients during obinutuzumab and 4/14 during daratumumab infusions. Mild transient neutropenia (500 to 1,000/mm3) occurred in 2/14 patients. Intravenous immunoglobulins (IVIGs) were administered to 12/14 patients due to hypogammaglobulinemia. Low IgA and IgM levels were noted in 8 and 14 patients, respectively. No severe infection was reported. The authors concluded that a combination of therapeutic monoclonal antibodies targeting the B-cell system and the production of antibodies might be effective to disrupt the chronic forms of idiopathic NS. However, a formal demonstration with a RCT comparing obinutuzumab alone versus the OD sequence is mandatory before expanding this strategy.

Ovarian Cancer

In a phase II study, Mackay et al (2010) evaluated the activity of belinostat in 2 patient populations: women with metastatic or recurrent platinum resistant (progression within 6 months) epithelial ovarian cancer (EOC) and micropapillary/borderline (LMP) ovarian tumors, both groups had received no more than 3 prior lines of chemotherapy.  Belinostat 1,000 mg/m2/day was administered intravenously on days 1 to 5 of a 21-day cycle.  Peripheral blood mononuclear cells (PBMCs) and tumor biopsies, where possible, for correlative studies were obtained prior to and following treatment.  A total of 18 patients with EOC and 14 patients with LMP tumors were enrolled in this study.  Belinostat was well-tolerated with no grade 4 toxicity (179 cycles).  Grade 3 toxicity consisted of thrombosis (n = 3), hypersensitivity (n = 1) and elevated ALP (n = 1).  One patient with LMP tumor had a PR (unconfirmed) and 10 had SD, 3 were non-evaluable.  Median PFS was 13.4 months (95 % confidence interval [CI]: 5.6 to not reached).  Best response in patients with EOC was SD (9 patients) and median PFS was 2.3 months (95 % CI: 1.2 to 5.7 months).  An accumulation of acetylated histones H3 and H4 was noted in PBMCs and in tumor tissue.  The authors concluded that belinostat is well-tolerated in both patient groups and showed some activity in patients with LMP disease.  The clinical effectiveness of belinostat for ovarian cancer awaits results from phase III clinical trials.

In a phase II study, Dizon and associates (2012) evaluated the impact of belinostat in combination with carboplatin in women with platinum-resistant ovarian cancer (including patients with fallopian tube, or primary peritoneal carcinoma).  Eligible patients had measurable, recurrent disease within 6 months of their last dose of a platinum-based combination.  Belinostat was dosed at 1,000 mg/m2 daily for 5 days with carboplatin AUC 5 on day 3 of 21-day cycles.  The primary end-point was overall response rate (ORR), using a 2-stage design.  A total of 29 women enrolled in this study and 27 were evaluable.  The median number of cycles given was 2 (range of 1 to 10).  One patient had a CR and 1 had a PR, for an ORR of 7.4 % (95 % CI: 0.9 % to 24.3 %).  Twelve patients had SD while 8 had increasing disease.  Response could not be assessed in 5 (18.5 %).  Grade 3 and 4 events occurring in more than 10 % of treated patients were uncommon and limited to neutropenia (22.2 %), thrombocytopenia (14.8 %), and vomiting (11.1 %). The median PFS was 3.3 months and overall survival (OS) was 13.7 months.  Progression-free survival of at least 6 months was noted in 29.6 % of patients.  Due to the lack of drug activity, the study was closed after the first-stage.  The authors concluded that the addition of belinostat to carboplatin had little activity in a population with platinum-resistant ovarian cancer.

Renal Cancer

Kim and colleagues (2015) examined if combining 5-fluorouracil (5-FU) with belinostat would exert a synergistic effect on renal cell carcinoma (RCC) cells in-vitro and in-vivo. These researchers used SN12C cells treated with 5-FU and/or belinostat in-vitro and in xenograft experiments in-vivo. Cell viability and death mechanisms were assessed by MTS assay and Western blot. To investigate the role of reactive oxygen species, these investigators used H2DCF-DA, reactive oxygen species scavengers and the roGFP2 construct. Belinostat potentiated the anti-cancer effect of 5-FU. It synergistically induced apoptosis by activating caspases and increasing the subG1 cell population. Effects on reactive oxygen species mediated DNA damage included decreased thioredoxin expression and increased levels of TBP-2, γ-H2AX and Ac-H3. Furthermore, belinostat attenuated the 5-FU mediated induction of thymidylate synthase via HSP90 hyper-acetylation. Co-administration of 5-FU with belinostat similarly reduced tumor volume and weight, and increased γ-H2AX and Ac-H3 levels in the SN12C xenograft model. The authors concluded that in combination with 5-FU, belinostat synergistically inhibited renal cancer cell growth by the blockade of thymidylate synthase induction and the induction of reactive oxygen species mediated DNA damage in-vitro and in-vivo. The authors concluded that the findings of this study suggested that combined treatment with belinostat and 5-FU may represent a promising new approach to renal cancer. These findings need to be validated by well-designed studies.

Rhabdomyosarcoma

Marampon and colleagues (2019) described the in-vitro and in-vivo activity of belinostat on myogenic-derived PAX3/FOXO1 fusion protein positive (RH30) or negative (RD) expressing rhabdomyosarcoma (RMS) cell lines.  PXD-101 at low doses efficiently inhibited HDACs activity and counteracted the transformed phenotype of RMS by inducing growth arrest and apoptosis, affecting cancer stem cells population and inducing differentiation in RD.  Notably, PXD-101 induced oxidative stress promoting DNA damages and affected the ability of RMS to assemble mitotic spindle.  PXD-101 radio-sensitized by inducing G2 cell cycle growth arrest, enhancing the radiation's ability to induce ROS accumulation and compromising both the ability of RMS to detoxify from ROS and to repair DNA damage.  PXD-101 transcriptionally and post-transcriptionally affected c-Myc expression, key master regulator of rhabdomyosarcomagenesis and RMS radio-resistance.  All in-vitro data were corroborated by in-vivo experiments showing the cytostatic effects of PXD-101 when used alone and at low dose and its ability to promote the RT-induced killing of RMS.  The authors concluded that these findings confirmed that altered HDACs activity plays a key role in RMS genesis and suggest PXD-101 as a valid therapeutic strategy particularly in combination with RT.

Soft Tissue Sarcoma

In a phase I/II clinical trial, Vitfell-Rasmussen and colleagues (2016) determined the MTD and DLTs of belinostat (Bel) in combination with doxorubicin (Dox) in solid tumors (phase I) and RR in soft tissue sarcomas (phase II).  Belinostat was administered as a 30-min intravenous (IV) infusion on days 1 to 5 and on day 5 with Dox.  The dose escalation schedule was as follows: cohort 1: Bel 600 mg/m(2) and 50 mg/m(2) Dox, cohort 2: Bel 600 mg/m(2) and 75 mg/m(2) Dox, cohort 3: Bel 800 mg/m(2) and 75 mg/m(2) Dox, and cohort 4: Bel 1,000 mg/m(2) and 75 mg/m(2) Dox.  A total of 41 patients were included (25 in phase I, 16 in phase II).  Adverse events (AEs) were fatigue (95 %), nausea (76 %), and alopecia (63 %).  There was 1 DLT, grade 3 rash/hand and foot syndrome. MTD was Bel 1,000 mg/m(2)/day and Dox 75 mg/m(2); 4 responses were seen: 2 PR in phase I, RR of 8 %; in phase II, 1 PR/1 CR, RR of 13 %, and 9 patients (56 %) with SD.  The authors concluded that the combination was well-tolerated; RR was moderate but median time to progression was 6.0 months (95 % CI: 1.6 to 9.7 months) which was superior to some reports of single-agent Dox.  These findings need to be further investigated.

Solid Tumors

Eckschlager and colleagues (2017) stated that carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes.  Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between HDAC and histone acetyltransferases (HAT).  HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response.  Mechanisms of anti-cancer effects of HDACi are not uniform; they may be different and depend on the cancer type, HDACi, doses, etc.  HDACi appeared to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy.  HDACi vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma.  Other HDACi are in clinical trials for the treatment of hematological and solid malignancies.  The results of such studies are promising but further larger studies are needed.  The authors summarized the data on different classes of HDACi, mechanisms of their actions and discussed novel results of pre-clinical and clinical studies, including the combination with other therapeutic modalities.  Moreover, these researchers noted that despite the promising results in the treatment of cutaneous T-cell lymphoma (CTCL), vorinostat and romidepsin have not been effective in studies with different solid tumors (neuroendocrine tumor, glioblastoma multiforme, mesothelioma, refractory breast, colorectal, non-small cell lung cancer [NSCLC], prostate, head and neck, renal cell, ovarian, cervical, and thyroid cancers) and Hodgkin lymphoma.

Thyroid Cancer

Lin and associates (2013) evaluated the therapeutic effects of the histone deacetylase inhibitor PXD101 (belinostat) alone and in combination with conventional chemotherapy in treating thyroid cancer.  These researchers studied 8 cell lines from 4 types of thyroid cancer (papillary, follicular, anaplastic and medullary).  The cytotoxicity of PXD101 alone and in combination with 3 conventional chemotherapeutic agents (doxorubicin, paclitaxel and docetaxel) was measured using LDH assay.  Western blot assessed expression of acetylation of histone H3, histone H4 and tubulin, proteins associated with apoptosis, RAS/RAF/ERK and PI3K/AKT/mTOR signaling pathways, DNA damage and repair.  Apoptosis and intra-cellular reactive oxygen species (ROS) were measured by flow cytometry.  Mice bearing flank anaplastic thyroid cancers (ATC) were daily treated with intra-peritoneal injection of PXD101 for 5 days/week.  PXD101 effectively inhibited thyroid cancer cell proliferation in a dose-dependent manner.  PXD101 induced ROS accumulation and inhibited RAS/RAF/ERK and PI3K/mTOR pathways in sensitive cells.  Double-stranded DNA damage and apoptosis were induced by PXD101 in both sensitive and resistant cell lines.  PXD101 retarded growth of 8505C ATC xenograft tumors with promising safety.  Combination therapy of PXD101with doxorubicin and paclitaxel demonstrated synergistic effects against 4 ATC lines in vitro.  The authors concluded that PXD101 repressed thyroid cancer proliferation and has synergistic effects in combination with doxorubicin and paclitaxel in treating ATC.  The authors stated that these findings supported clinical trials using PXD101 for patients with this dismal disease.

Urothelial Cancers

Ismaili and co-workers (2012) stated that targeting both vascular endothelial growth factor and fibroblast growth factor pathways is a very promising strategy.  In bladder (urothelial) cancer, 2 molecules are promising, the belinostat and the bortezomib.

Waldenstrom Macroglobulinemia

Tomowiak and colleagues (2021) described the findings of a phase-II clinical trial that examined the combination of obinutuzumab and idelalisib in relapsed/refractory (R/R) Waldenstrom macroglobulinemia (WM). The objective was to determine the safety and efficacy of a fixed-duration chemotherapy-free treatment. During the induction phase, patients received obinutuzumab and idelalisib for 6 cycles, followed by a maintenance phase with idelalisib alone for less than or equal to 2 years. A total of 48 patients with R/R WM were treated with the induction combination, and 27 patients participated in the maintenance phase. The best responses, reached after a median of 6.5 months (inter-quartile range [IQR], 3.4 to 7.1; range of 2.6 to 22.1 months), were very good partial response (PR) in 5 patients, PR in 27 patients, and minor response in 3 patients, leading to ORR and major response rate (MRR) estimates of 71.4 % (95 % CI: 56.7 to 83.4) and 65.3 % (95 % CI: 50.4 to 78.3), respectively. With a median follow-up of 25.9 months, median PFS was 25.4 months (95 % CI: 15.7 to 29.0). Uni-variate analysis focusing on molecular screening found no significant impact of CXCR4 genotypes on responses and survivals but a deleterious impact of TP53 mutations on survival. Although there was no grade-5 toxicity, 26 patients were removed from the study because of side effects; the most frequent were neutropenia (9.4 %), diarrhea (8.6 %), and liver toxicity (9.3 %). The authors concluded that this phase-II clinical trial found interesting efficacy of the combination of obinutuzumab and idelalisib in symptomatic R/R WM patients, although toxicity was a major drawback. Moreover, these researchers stated that there is a need to develop new approaches in patients who are refractory to BTK inhibitors; this population may benefit from this therapeutic option, which could be examined in further clinical trials.

The authors stated that this study had several drawbacks; but suggested new treatment opportunities. First, with a median PFS of 25.5 months, these investigators reached the primary goal of demonstrating a median PFS of greater than or equal to 25 months compared with 15 months with usual therapy. Second, the sample size did not allow firm conclusions regarding the impact of genotype on efficacy, because the study was not designed for this endpoint. These findings suggested that this combination might be of interest in CXCR4MUT WM patients with advanced disease, because they demonstrated reduced response to ibrutinib. Compensatory PI3K/Akt signaling may contribute to ibrutinib resistance in the CXCR4MUT WM model, as well as in the CXCR4WT WM model, resulting in synthetic lethality toward the PI3K/Akt inhibitor. Thus, targeting of the PI3K/Akt pathway could be an option in BTK inhibitor-resistant WM patients and appeared to be a proof-of-concept regarding the efficacy of this class of compound in WM patients. Furthermore, for the 1st time, these researchers provided an estimate of the response rate or PFS achieved with a combination regimen including inhibitors of BCR-associated kinases in TP53MUT WM patients; however, the number of patients was small, and a non-statistically significant deleterious effect of TP53 mutation was observed. Third, the safety of the combination with high liver and gastro-intestinal (GI) toxicity led to early treatment discontinuation and/or a dose reduction in 50 % of the patients. Using Bayesian analysis, which quantified, via probabilistic statements, the proportion of treated patients who experienced grade-3 or garde-4 AEs, it appeared more than likely (98 %) that more than 75 % of patients could be impacted by such events. It was a limitation of further clinical use. However, considering the potential efficacy of this class of agents, next-generation PI3K inhibitors associated with obinutuzumab could overcome the toxicity profile observed in this phase-II clinical trial and may be a reasonable therapeutic option when standard therapies have been exhausted.

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References