NCT04025931

Chidamide Combined With Toripalimab in Sarcoma

A Single-arm, Multi-center, Open, Phase II Study of Chidamide Combined With Toripalimab in Refractory and Advanced Soft-tissue Sarcoma

• Status: Unknown
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 74 (estimated)
• Sponsor: Sun Yat-sen University · Academic / Other
• Sex: All
• Age: 14 Years – 70 Years
• Healthy volunteers: Not accepted

Summary

Soft tissue sarcoma is a relatively rare malignant tumor with an incidence of about 1-2/100,000. The best way to obtain evidence-based medical evidence is to participate in clinical trials with new drugs (especially targeted drugs and immunotherapy). Chidamide, an oral subtype-selective histone deacetylase inhibitor monotherapy was effective on the patients with hematological tumors by inhibiting HDAC activity and other ways, showing good anti-tumor activity. Histone deacetylase inhibitors (HDACi) may also reverse drug resistance or inefficiency of immunoassay inhibitors, and combination therapy has shown preliminary efficacy in a variety of tumors.Because of the poor prognosis of advanced soft tissue sarcoma, there is no standard second-line treatment. Therefore, we think it is necessary to explore the feasibility of combination of chidamide and Toripalimab monoclonal antibody in advanced, refractory and progressive soft tissue sarcoma after failure of standard treatment, and look forward to further improving the efficacy of soft tissue sarcoma.

Detailed description

Histone deacetylase inhibitor (HDACI) can inhibit many kinds of hematological tumors by inhibiting HDAC activity and other ways, showing good anti-tumor activity. Chidamide is a new chemical structure benzamide HDAC inhibitor developed independently in China. It has the selectivity of HDAC subtypes and unique efficacy. In a phase II clinical study of Chidamide in the treatment of peripheral T-cell lymphoma in China in 2009, 79 patients with recurrent or refractory lymphoma had ORR of 27.9%. The 2016 edition of the Chinese Expert Consensus on Chidamide in the Treatment of PTCL discussed in detail the treatment of Chidamide alone or in combination with other drugs. The representative drug of immunological checkpoint inhibitors is programmed death 1 (PD-1/PD-L1). PD-1/PD-L1 immunotherapy activates the body's own immune system to attack cancer cells by blocking the PD-1/PD-L1 pathway with drugs. Immunotherapy show its long-term control of cancer and its effectiveness in a variety of cancers. In a multicenter phase II clinical trial, 80 patients with bone and soft tissue sarcoma were treated with single drug of PD-1 antibody Pembrolizumab. The results showed that all the patients with soft tissue sarcoma achieved therapeutic effect were undifferentiated pleomorphic sarcoma and liposarcoma. The overall objective remission rate was 18% (7/40), suggesting that Pembrolizumab alone does not fully activate suppressed T cells, and may need to be combined to improve the efficacy. Recent studies have shown that combination of epigenetic regulators, such as histone deacetylase inhibitors (HDACi), can overcome some major drug resistance constraints and ensure patient safety. Pre-clinical data based on mouse models strongly support the feasibility and effectiveness of combination therapy. In vitro and in vivo studies, combined use of pan- or class I selective HDACi can benefit further. Chidamide is mainly targeted at subtypes 1, 2, 3 and 10 of HDAC class I and class II B. It has a regulatory effect on the abnormal epigenetic function of tumors. By inhibiting the related HDAC subtypes to increase the acetylation level of chromatin histone, chromatin remodeling is initiated, which changes the gene expression of multiple signal transduction pathways (i.e. epigenetic changes), thereby inhibiting the cell cycle of tumors, inducing apoptosis of tumors, and having overall regulatory activity on cellular immunity. Induction and enhancement of natural killer cells (NK) and antigen-specific cytotoxic T cells (CTL) mediated tumor killing. Chidamide can also enhance the mechanism of dendritic cells presenting and maturing tumor antigens, inhibiting regulatory T cells (Treg) and MDSC cells, and promote the anti-tumor immune function through regulating the micro-environment of tumor immunosuppression. Because of the poor prognosis of advanced soft tissue sarcoma, there is no standard treatment for second-line treatment. Therefore, we think it is necessary to explore the feasibility of combination of chidamide and Toripalimab in advanced, refractory and progressive soft tissue sarcoma after failure of standard treatment, and look forward to further improving the efficacy of soft tissue sarcoma.

Conditions

• Sarcoma

Interventions

Type	Name	Description
DRUG	chidamide and toripalimab	The eligible patients with advanced soft tissue sarcoma were treated with chidamide combined with toripalimb. Chidamide 30mg orally twice a week; Toripalimab 240 mg (fixed dose) every three weeks. Repeat every three weeks. Patients with disease control (CR + PR + SD) and tolerable adverse reactions continued to take medication until the researchers concluded that patients were not suitable to continue medication or the efficacy evaluation was disease progression (PD). No other antineoplastic treatment can be given during the treatment.

Timeline

• Start date: 2020-01-19
• Primary completion: 2023-12-30
• Completion: 2024-12-30
• First posted: 2019-07-19
• Last updated: 2023-12-29

Locations

1 site across 1 country: China