Delving into the Latest Updates on Tinostamustine with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Bendamustine-vorinostat fusion molecule, Tinostamustine (USAN/INN)

+ [5]

Target

DNA x HDACs

Mechanism

DNA inhibitors(DNA inhibitors), HDAC inhibitors(Histone deacetylase inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases+ [7]

Active Indication

Follicular LymphomaMantle-Cell LymphomaAdvanced Malignant Solid Neoplasm+ [13]

Inactive Indication

Recurrent Multiple Myeloma

Originator Organization

Mundipharma EDO GmbH

Active Organization

Mundipharma Research Ltd.

Hangzhou Minsheng Pharmaceutical Co., Ltd.

Inactive Organization

Mundipharma EDO GmbH

Drug Highest PhasePhase 2

First Approval Date-

RegulationSpecial Review Project (CN), Orphan Drug (EU)

Login to view timeline

Structure/Sequence

Molecular FormulaC19H28Cl2N4O2

InChIKeyGISXTRIGVCKQBX-UHFFFAOYSA-N

CAS Registry1236199-60-2

The study is designed as an open label, multi-center, Phase 1 study of single agent tinostamustine, used as adjuvant treatment in patients with newly diagnosed GBM who are MGMT unmethylated and have completed concomitant treatment with temozolomide and radiation. Treatment with adjuvant tinostamustine will start within 5 weeks of completion of concomitant temozolomide and radiation. The study is designed to define the MTD by evaluating toxicities during dose escalation. Tinostamustine will be administered on Day 1 of a 21-day treatment cycle.
The total number of treatment cycles is 12 for patients who continue to benefit from treatment without disease progression or intolerable toxicity. Patients will enter a "3+3" design with dose escalation/de-escalation depending on safety from the last treated cohort.

Start Date01 Jul 2022

Sponsor / Collaborator

Mundipharma Research Ltd.

CTR20181208

/ RecruitingPhase 1

注射用NL-101治疗复发难治非霍奇金淋巴瘤的Ⅰ期临床试验

[Translation] Phase I clinical trial of NL-101 for injection in the treatment of relapsed and refractory non-Hodgkin's lymphoma

主要目的：评价注射用NL-101单次及连续2天给药在复发难治非霍奇金淋巴瘤患者中的安全性、耐受性。次要目的：NL-101及其主要代谢产物在人体内的药代规律；NL-101在复发难治非霍奇金淋巴瘤患者中的初步疗效；分析单次、连续2天和多周期重复给药的剂量与毒性的相关性，以确定Ⅱ期研究的推荐剂量。

[Translation]

Primary objective: To evaluate the safety and tolerability of NL-101 for injection in patients with relapsed or refractory non-Hodgkin's lymphoma after single or two-day administration. Secondary objectives: To evaluate the pharmacokinetic patterns of NL-101 and its major metabolites in humans; To evaluate the preliminary efficacy of NL-101 in patients with relapsed or refractory non-Hodgkin's lymphoma; To analyze the correlation between the dose and toxicity of single, two-day and multiple-cycle repeated administrations, in order to determine the recommended dose for Phase II studies.

Start Date17 Apr 2019

Sponsor / Collaborator

Hangzhou Minsheng Pharmaceutical Co., Ltd.

NCT03903458

/ Unknown statusPhase 1IIT

Open Label, Non-randomized, Phase IB Study to Characterize Safety, Tolerability and Recommended Dose of Tinostamustine and Nivolumab in Patients With Refractory, Locally Advanced or Metastatic MelAnoma

This trial is a first-in-human drug combination with the first-in-class alkylating histone deacetylase inhibition (HDACi) fusion molecule Tinostamustine (EDO-S101) and the anti-PD-1 monoclonal antibody Nivolumab in patients with refractory, locally advanced or metastatic melanoma.

Start Date07 Mar 2019

Sponsor / Collaborator

Kantonsspital St. Gallen

100 Clinical Results associated with Tinostamustine

Login to view more data

100 Translational Medicine associated with Tinostamustine

Login to view more data

100 Patents (Medical) associated with Tinostamustine

Login to view more data

23

Literatures (Medical) associated with Tinostamustine

01 Jan 2025·Hematological Oncology

Safety and Efficacy of Tinostamustine in a Subpopulation of Patients With Relapsed/Refractory Hodgkin Lymphoma From a Phase I Trial

Article

Author: Sureda, Anna ; De Filippi, Rosaria ; Zinzani, Pier Luigi ; Manamley, Nick ; Zijlstra, Josée M. ; Janik, Tomas ; Pinto, Antonio ; Hilgier, Kasia ; Mutsaers, Pim ; Tournilhac, Olivier ; Ghesquières, Hervé ; Morschhauser, Franck

ABSTRACTA significant unmet need remains for patients with Hodgkin lymphoma (HL) who fail to respond to first‐line treatment or experience an early relapse. Tinostamustine, a novel alkylating deacetylase inhibitor, inhibits tumor cell growth and slows disease progression in models of hematological malignancies and solid tumors. This was a Phase I, multicenter, open‐label, two‐stage trial investigating the safety and efficacy of tinostamustine in patients ≥ 18 years with relapsed/refractory (R/R) hematological malignancies, including HL. Stage 1 involved dose‐escalation to determine the maximum tolerated dose (MTD) of tinostamustine, optimal infusion time and recommended Phase II dose (RP2D). Stage 2 confirmed the safety and efficacy of the RP2D in expansion cohorts of selected R/R hematological malignancies. Ten patients with heavily pre‐treated HL entered dose‐escalation, with nine patients experiencing treatment‐emergent adverse events (TEAEs) considered to be related to study treatment—primarily hematological toxicities. MTD was 100 mg/m2 tinostamustine over 60 min and signals of efficacy were observed for patients with HL. In Stage 2, all 20 patients with HL experienced ≥ 1 TEAE, which were principally hematological or gastrointestinal. There were no tinostamustine‐related deaths in either stage of the study. Overall response rate in Stage 2 was 37% (2 complete responses, 5 partial responses; 95% confidence interval [CI]: 16%, 62%) and median progression‐free survival 3.8 months (95% CI: 2.2–9.4 months). Tinostamustine is a promising new therapeutic approach for the treatment of patients with R/R classical HL with limited options. This study demonstrates a predictable and manageable safety profile with signals of efficacy.Trial Registration: ClinicalTrials.gov identifier: NCT02576496

01 Aug 2024·Journal of Zhejiang University-SCIENCE B

Genome-wide CRISPR screening identifies critical role of phosphatase and tensin homologous (PTEN) in sensitivity of acute myeloid leukemia to chemotherapy

Article

Author: Chen, Boxiao ; Zhang, Jiawei ; Lin, Liming ; He, Xin ; Gan, Yichao ; Wang, Luyao ; Tao, Jingjing ; Li, Shu ; Gao, Feiqiong ; Meng, Ying ; Fan, Yili ; Xu, Yang ; Lu, Zhimin ; Xin, Dijia

Although significant progress has been made in the development of novel targeted drugs for the treatment of acute myeloid leukemia (AML) in recent years, chemotherapy still remains the mainstay of treatment and the overall survival is poor in most patients. Here, we demonstrated the antileukemia activity of a novel small molecular compound NL101, which is formed through the modification on bendamustine with a suberanilohydroxamic acid (SAHA) radical. NL101 suppresses the proliferation of myeloid malignancy cells and primary AML cells. It induces DNA damage and caspase 3-mediated apoptosis. A genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) library screen revealed that phosphatase and tensin homologous (PTEN) gene is critical for the regulation of cell survival upon NL101 treatment. The knockout or inhibition of PTEN significantly reduced NL101-induced apoptosis in AML and myelodysplastic syndrome (MDS) cells, accompanied by the activation of protein kinase B (AKT) signaling pathway. The inhibition of mammalian target of rapamycin (mTOR) by rapamycin enhanced the sensitivity of AML cells to NL101-induced cell death. These findings uncover PTEN protein expression as a major determinant of chemosensitivity to NL101 and provide a novel strategy to treat AML with the combination of NL101 and rapamycin.

01 Dec 2023·European Journal of Medicinal Chemistry

Hydroxamic acid hybrids: Histone deacetylase inhibitors with anticancer therapeutic potency

Review

Author: Hou, Haodong ; Zhou, Bo ; Pan, Yuan ; Gao, Jingyue ; Gao, Feng

Histone deacetylases (HDACs), a class of enzymes responsible for the removal of acetyl functional groups from the lysine residues in the amino-terminal tails of core histones, play a critical role in the modulation of chromatin architecture and the regulation of gene expression. Dysregulation of HDAC expression has been closely associated with the development of various cancers. Histone deacetylase inhibitors (HDACis) could regulate diverse cellular pathways, cause cell cycle arrest, and promote programmed cell death, making them promising avenues for cancer therapy with potent efficacy and favorable toxicity profiles. Hybrid molecules incorporating two or more pharmacophores in one single molecule, have the potential to simultaneously inhibit two distinct cancer targets, potentially overcome drug resistance and minimize drug-drug interactions. Notably, hydroxamic acid hybrids, exemplified by fimepinostat and tinostamustine as potential HDACis, could exert the anticancer effects through induction of apoptosis, differentiation, and growth arrest in cancer cells, representing useful scaffolds for the discovery of novel HDACis. The purpose of this review is to summarize the current scenario of hydroxamic acid hybrids as HDACis with anticancer therapeutic potential developed since 2020 to facilitate further rational exploitation of more effective candidates.

2

News (Medical) associated with Tinostamustine

22 Apr 2024

·www.pharmaceutical-technology.com

BioArctic partners with Eisai on Alzheimer’s treatment

The research will assess potential next-generation disease-modifying treatment for Alzheimer’s disease. Credit: Dragana Gordic via Shutterstock. Swedish research-based biopharma company BioArctic has signed an agreement with Eisai for a research evaluation focusing on BAN2802, a novel Alzheimer’s disease (AD) treatment candidate. The BAN2802 treatment combines BioArctic’s BrainTransporter technology with an undisclosed Alzheimer’s drug candidate. The BrainTransporter technology is intended to actively transport antibodies across the blood-brain barrier to enhance the treatment efficacy. Eisai, at the end of the collaboration, will assess the data generated. It can then decide to exercise an option to license BAN2802 for the treatment of Alzheimer’s disease. BioArctic and Eisai’s partnership dates back to 2005, for the development and commercialisation of drugs for Alzheimer’s disease treatment. See Also: BioMarin Pharmaceutical gets grant for treatment of adolescent PKU patients using AVPAL variant Purdue Pharma gets grant for treatment of T-cell prolymphocytic leukemia using tinostamustine Their collaboration has already resulted in the development of Leqembi (lecanemab), a drug that slows the progression of early Alzheimer’s disease. The new partnership aims to further this success in the field of Alzheimer’s disease. BioArctic CEO Gunilla Osswald said: “I am very happy that our Brain Transporter technology has continued to progress so well and that we have now entered into this first agreement utilising this platform. I believe that this technology has huge potential to improve many different projects, and support companies in their pursuit of helping people with brain disorders. “Together, we have been able to deliver lecanemab, the first fully approved disease-modifying treatment in Alzheimer’s disease in the US, Japan and China, and we look forward to continuing our fruitful collaboration and lead the development of the next generation of drugs to help patients with this devastating disease.” The research evaluation programme will be a joint financial effort. It will assess potential next-generation disease-modifying treatments for AD. BioArctic said its BrainTransporter technology facilitates the active transport of biologics across the blood-brain barrier into the brain, potentially leading to more rapid and potent treatment outcomes. Earlier this year, BioArctic and Eisai obtained approval for the amyloid beta-directed antibody Leqembi in China to treat mild cognitive impairment associated with Alzheimer’s disease and mild AD dementia.

Drug Approval

22 Apr 2024

·www.pharmaceutical-technology.com

Health Canada approves Nora Pharma for commercialisation of NIOPEG

Niopeg is a long-acting form of recombinant human granulocyte colony-stimulating factor. Credit: BlurryMe via Shutterstock. Health Canada has granted approval to Nora Pharma for the commercialisation of its first biosimilar product, Niopeg (a pegylated form of filgrastim). The Niopeg is comparable to the reference biologic drug Neulasta. Nora Pharma, a division of Sunshine Biopharma, president Malek Chamoun said: “With this product, we demonstrate to the Canadian market our determination to be a leader in the pharmaceutical sector. “This is an important milestone for our mission of bringing high-quality affordable medicines to patients across Canada.” Niopeg is a long-acting form of recombinant human granulocyte colony-stimulating factor or filgrastim. See Also: Teladoc Health gets grant for contextual video searching method for telepresence devices Purdue Pharma gets grant for treatment of T-cell prolymphocytic leukemia using tinostamustine It is specifically indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies who are receiving myelosuppressive anti-neoplastic drugs. The biosimilar Niopeg will be available in Canada in a prefilled syringe containing 6mg/0.6ml. Sunshine Biopharma CEO Dr Steve Slilaty said: “Niopeg is used to help prevent infection in people with non-myeloid cancers who are receiving chemotherapy. An example of a non-myeloid cancer is breast cancer. “Biosimilars will have a significant impact on the sustainability of drug insurance plans, ensuring patient access to these high-quality treatments for years to come.” Nora Pharma was acquired by Sunshine Biopharma in 2022. Through Nora Pharma, Sunshine Biopharma has 52 generic prescription drugs on the market in Canada. By the end of this year, Sunshine Biopharma plans to expand its product offering to a total of 60 generic prescription drugs. It is also continuing its drug development programme, which includes K1.1 messenger RNA for liver cancer, and PLpro protease inhibitor for SARS coronavirus infections.

Drug ApprovalAcquisition

100 Deals associated with Tinostamustine

Login to view more data

External Link

KEGG	Wiki	ATC	Drug Bank
D11182	-	-	DB15147

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 2	ES	Mundipharma Research Ltd.	08 Nov 2017
Advanced Malignant Solid Neoplasm	Phase 2	CA	Mundipharma Research Ltd.	08 Nov 2017
Advanced Malignant Solid Neoplasm	Phase 2	IT	Mundipharma Research Ltd.	08 Nov 2017
Advanced Malignant Solid Neoplasm	Phase 2	NL	Mundipharma Research Ltd.	08 Nov 2017
Advanced Malignant Solid Neoplasm	Phase 2	US	Mundipharma Research Ltd.	08 Nov 2017
Recurrent Lung Small Cell Carcinoma	Phase 2	ES	Mundipharma Research Ltd.	08 Nov 2017
Recurrent Lung Small Cell Carcinoma	Phase 2	NL	Mundipharma Research Ltd.	08 Nov 2017
Recurrent Lung Small Cell Carcinoma	Phase 2	CA	Mundipharma Research Ltd.	08 Nov 2017
Recurrent Lung Small Cell Carcinoma	Phase 2	IT	Mundipharma Research Ltd.	08 Nov 2017
Recurrent Lung Small Cell Carcinoma	Phase 2	US	Mundipharma Research Ltd.	08 Nov 2017

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02576496 (Pubmed \| Hematol Oncol)	Phase 1	Hodgkin's Lymphoma	-	Tinostamustine	yaautohopr(xwvsgcgpai) = Ten patients with heavily pre-treated HL entered dose-escalation, with nine patients experiencing treatment-emergent adverse events (TEAEs) considered to be related to study treatment—primarily hematological toxicities wmhbfkxiaf (jmlktupgxt ) View more	Positive	01 Jan 2025
NCT02576496 (ASH2023)	Phase 1	Cutaneous T-Cell Lymphoma	48	Tinostamustine 80 mg/m2	(wxmcghcoqw) = kzmeutnnfw czyuylsqyu (miurnmoobg, 21.1% - 78.9%) View more	-	11 Dec 2023
NCT02576496 (Phase I Trial of Tinostamustine, ASH2023)	Phase 1	Hodgkin's Lymphoma \| Multiple Myeloma \| Non-Hodgkin Lymphoma	48	Tinostamustine	(tqjhnzukvr) = dsmxevxquc qoqrmqdpti (qhjpikojle, 36.9% - 67.1%) View more	-	09 Dec 2023
NCT03903458 (ENIGMA, ESMO 12023 \| ESMO 22023) Manual	Phase 1	Melanoma	17	Tinostamustine+Nivolumab	(cerxmzwgyt) = teepsqvxob lapnaocigu (dlqccoatgw ) View more	Positive	22 Oct 2023
NCT03345485 (ASCO 12023 \| ASCO 22023) Manual	Phase 2	Advanced Malignant Solid Neoplasm	36	Tinostamustine	(mhkemnojus) = bwhyfyzqwq rdsvxosoug (xsnifnfjgm, 27.9 - 61.9) View more	Positive	31 May 2023
NCT02576496 (ASH 12021 \| ASH 22021) Manual	Phase 1	Refractory Hodgkin Lymphoma Third line	14	Tinostamustine	(svxuaffigj) = nljmriryrg jqctpgpiog (dnbtemmpgh, 13 - 65) View more	Positive	05 Nov 2021
NCT03687125 (TITANIUM1, CTgov)	Phase 1/2	Recurrent Multiple Myeloma \| Relapse multiple myeloma	6	Autologous Stem Cell Transplant (ASCT)+Tinostamustine (Tinostamustine 180 mg/m^2)	iptrldjtsh(llicyjxbpz) = hlyacicxdr jwstvklijl (xkpfodiblm, nbqgextlur - pttzjectgw) View more	-	18 Jun 2021
NCT03687125 (TITANIUM1, CTgov)	Phase 1/2	Recurrent Multiple Myeloma \| Relapse multiple myeloma	6	Autologous Stem Cell Transplant (ASCT)+Tinostamustine (Tinostamustine 220 mg/m^2)	iptrldjtsh(llicyjxbpz) = sznihscutq jwstvklijl (xkpfodiblm, twigvweozu - yqondyxqtk) View more	-	18 Jun 2021
NCT03345485 (ESMO2019)	Phase 1/2	Advanced Malignant Solid Neoplasm	22	Tinostamustine	(mbhpymybyl) = uizlhueiob iaudrybrmw (uzcpfiywlp ) View more	-	28 Sep 2019
NCT02576496 (EHA2019)	Phase 1	Hodgkin's Lymphoma \| Cutaneous T-Cell Lymphoma \| Hematologic Neoplasms \| Multiple Myeloma	27	Tinostamustine	(xwmtbiujwu) = aufaltxxnx urkbwytlew (kfdqwwoklo ) View more	-	14 Jun 2019