Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in China

Lu, Xianping; Ning, Zhiqiang; Li, Zhibin; Cao, Haixiang; Wang, Xinhao

doi:10.5582/irdr.2016.01024

Cited by 137 publications

(89 citation statements)

References 23 publications

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“…the CFDA for treatment of PTCL, 9 belinostat by the FDA for the use against PTCL, 10 and for combination treatment, panobinostat by the FDA and EMA for the treatment of multiple myeloma. 11 Those and many others, broad-spectrum HDACi as well as selective HDACi, are in clinical trials either as monotherapy or in combination in hematological and solid tumor indications, either as monotherapy or in combination.…”

Section: Chidamide In China Bymentioning

confidence: 99%

“…Furthermore, significantly elevated expression levels of HDACs have been observed in a broad range of hematological malignancies, for example, elevated expression levels of HDACs 1, 2, and 6 in patients with cutaneous T‐cell lymphoma (CTCL) . Consequently, a variety of HDACi have been approved for hematological malignancies: As monotherapy, vorinostat by FDA for the treatment of cutaneous T‐cell lymphoma (CTCL), romidepsin by the FDA for the treatment of CTCL and peripheral T‐cell lymphoma (PTCL), chidamide in China by the CFDA for treatment of PTCL, belinostat by the FDA for the use against PTCL, and for combination treatment, panobinostat by the FDA and EMA for the treatment of multiple myeloma . Those and many others, broad‐spectrum HDACi as well as selective HDACi, are in clinical trials either as monotherapy or in combination in hematological and solid tumor indications, either as monotherapy or in combination …”

Section: Introductionmentioning

confidence: 99%

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Phase I study of domatinostat (4SC‐202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies

Tresckow

Sayehli

Aulitzky

et al. 2019

European J of Haematology

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Objectives Domatinostat (4SC‐202) is a selective class I histone deacetylase inhibitor (HDACi). This phase I study investigated safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity in patients with advanced hematological malignancies. Methods Domatinostat was administered orally once (QD) or twice daily (BID) on days 1‐14 with 7 days off or continuously days 1‐21 in a 3 + 3 design at 7 dose levels from 25 to 400 mg total daily dose (TDD). Twenty‐four patients were treated with domatinostat. Results No formal maximum tolerated dose (MTD) was determined. One dose‐limiting toxicity (DLT, grade 4 hypercalcemia) occurred during 200 mg BID continuous treatment. Six patients were reported with ≥ grade 3 treatment‐related adverse events (TRAE; grade 3 hematological in three patients, grade 3 and grade 4 liver enzyme increase in 2 patients, grade 4 pulmonary embolism, and grade 4 hypercalcemia in one patient each). Higher grade hepatic TRAE occurred in the 200 mg BID continuous treatment cohort. Out of 24 patients, 1 achieved a complete response, 1 achieved a partial response, and 18 had stable disease as best response. Conclusion Administration of domatinostat was safe, well tolerated with signs of antitumor activity. Four hundred milligram TDD in a 200 mg BID schedule (14 + 7) is the recommended phase II dose for monotherapy.

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Section: Chidamide In China Bymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phase I study of domatinostat (4SC‐202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies

Tresckow

Sayehli

Aulitzky

et al. 2019

European J of Haematology

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“…Additional indications for Romidepsin are currently being evaluated as a combinatorial treatment, for instance, with Bortezomib, Carfilzomib (both proteasome inhibitors), 5-Azacytidine, or CHOP. Chidamide, as well as acting as an HDAC inhibitor, is so far only approved for PTCL treatment in China and used as a monotherapy or in combination with chemotherapy [164,165]. …”

Section: Current Therapies and Novel Approachesmentioning

confidence: 99%

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

Orlova

Wingelhofer

Neubauer

et al. 2017

Expert Opinion on Therapeutic Targets

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Introduction: Hematopoietic neoplasms are often driven by gain-of-function mutations of the JAK-STAT pathway together with mutations in chromatin remodeling and DNA damage control pathways. The interconnection between the JAK-STAT pathway, epigenetic regulation or DNA damage control is still poorly understood in cancer cell biology. Areas covered: Here, we focus on a broader description of mutational insights into myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas, since sequencing efforts have identified similar combinations of driver mutations in these diseases covering different lineages. We summarize how these pathways might be interconnected in normal or cancer cells, which have lost differentiation capacity and drive oncogene transcription. Expert opinion: Due to similarities in driver mutations including epigenetic enzymes, JAK-STAT pathway activation and mutated checkpoint control through TP53, we hypothesize that similar therapeutic approaches could be of benefit in these diseases. We give an overview of how driver mutations in these malignancies contribute to hematopoietic cancer initiation or progression, and how these pathways can be targeted with currently available tools.

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“…Therefore, downregulation of c-MYC and SRC kinases is important for the treatment of Ph þ B-ALL. To date, five HDAC inhibitors (vorinostat, romidepsin, belinostat, panobinostat, and chidamide) have been approved for clinical cancer treatment (30)(31)(32)(33). Among them, panobinostat (LBH589) has been reported the most active and had been approved for multiple myeloma treatment in 2015 (34).…”

Section: Introductionmentioning

confidence: 99%

Purinostat Mesylate Is a Uniquely Potent and Selective Inhibitor of HDACs for the Treatment of BCR-ABL–Induced B-Cell Acute Lymphoblastic Leukemia

Yang

Qiu

Tang

et al. 2019

Clinical Cancer Research

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Purpose: This study was to perform preclinical evaluation of a novel class I and IIb HDAC-selective inhibitor, purinostat mesylate, for the treatment of Ph þ B-cell acute lymphoblastic leukemia (B-ALL).Experimental Design: Biochemical assays were used to test enzymatic activity inhibition of purinostat mesylate. Ph þ leukemic cell lines and patient cells were used to evaluate purinostat mesylate activity in vitro. BL-2 secondary transplantation Ph þ B-ALL mouse model was used to validate its efficacy, mechanism, and pharmacokinetics properties in vivo. BCR-ABL(T315I)-induced primary B-ALL mouse model and PDX mouse model derived from relapsed Ph þ B-ALL patient post TKI treatment were used to determine the antitumor effect of purinostat mesylate for refractory or relapsed Ph þ B-ALL. Long-term toxicity and hERG blockade assays were used to safety evaluation of purinostat mesylate. Results: Purinostat mesylate, a class I and IIb HDAC highly selective inhibitor, exhibited robust antitumor activity in hematologic cancers. Purinostat mesylate at low nanomolar concentration induced apoptosis, and downregulated BCR-ABL and c-MYC expression in Ph þ leukemia cell lines and primary Ph þ B-ALL cells from relapsed patients. Purinostat mesylate efficiently attenuated Ph þ B-ALL progression and significantly prolonged the survival both in BL-2 secondary transplantation model with clinical patient symptoms of Ph þ B-ALL, BCR-ABL(T315I)-induced primary B-ALL mouse model, and PDX model derived from patients with relapsed Ph þ B-ALL post TKI treatment. In addition, purinostat mesylate possesses favorable pharmacokinetics and low toxicity properties.Conclusions: Purinostat mesylate provides a new therapeutic strategy for patients with Ph þ B-ALL, including those who relapse after TKI treatment.

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Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in China

Cited by 137 publications

References 23 publications

Phase I study of domatinostat (4SC‐202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies

Phase I study of domatinostat (4SC‐202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

Purinostat Mesylate Is a Uniquely Potent and Selective Inhibitor of HDACs for the Treatment of BCR-ABL–Induced B-Cell Acute Lymphoblastic Leukemia

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