Immune checkpoint blockade has led to great strides in the management of various cancers, however, durable response could be seen in approximately 20% of treated patients with most solid malignancies. Immunosuppressive entities such as transforming growth factor-β (TGF-β) in the tumor microenvironment (TME) remain a major impediment. Enhancer of zeste homolog 2 (EZH2) is the core component of the polycomb group complex, which play a major role in cellular proliferation and differentiation. EZH2 aberration has been seen in a wide range of solid tumors and hematological malignancies, affecting tumor progression and immune cells in the tumor microenvironment, and it is associated with poor clinical prognosis and outcomes. EZH2 is not only an activator of gene expression through different pathways, but also a critical epigenetic repressor through histone methylation. Therefore, EZH2 has attracted significant interest as a potential epigenetic target for cancer treatment. It is hypothesized that the combination of EZH2 inhibitors and programmed death-1 ligands/ transforming growth factor-β (PD-L1/TGFβ) blockade could enhance the efficiency of immunotherapy.~The primary objective of this study in phase Ⅰstage is to assess the safety, feasibility of EZH2 inhibitor SHR2554 in combination with anti-PD-L1/TGFβ antibody SHR1701 in advanced pretreated solid tumors and b-cell lymphomas. The second objectives include characterizing the pharmacokinetics of SHR2554 in combination with SHR1701, evaluating the preliminary efficacy of SHR2554 plus SHR1701 and the epigenetic modulating effect of SHR2554 in its combination with anti-PD-L1/TGFβ antibody. The exploratory objectives are to evaluate the pathological, immunological or clinical predictive factors for efficacy and toxicity. Based on the data of safety, efficacy and recommended dose level obtained from phase Ⅰtrial, this study moves into phase Ⅱ stage, in which enrolled subjects are randomized to SHR2554 plus SHR 1701 or SHR1701 monotherapy, to primarily evaluate the efficacy of SHR2554 plus SHR1701 and the epigenetic modulating effect of SHR2554. The second objectives include evaluating safety and other efficacy parameters, such as overall response rate (ORR), disease control rate (DCR), duration of response (DOR) and overall survival (OS). The exploratory objectives are to evaluate laboratory predicting biomarkers.
The potency of immune checkpoint blockade is limited in most solid malignancies, one possible reason for which is tumor microenvironment. Enhancer of zeste homolog 2 (EZH2) as a epigenetic target for cancer therapy has attracted significant interest. The combination of EZH2 inhibitors and programmed death-1 ligands/ transforming growth factor-β (PD-L1/TGFβ) blockade may enhance the efficiency of immunotherapy.The primary objective of this study in phase Ⅰstage is to assess the safety, feasibility of EZH2 inhibitor SHR2554 in combination with anti-PD-L1/TGFβ antibody SHR1701 in advanced pretreated solid tumors and b-cell lymphomas. The phase Ⅱ stage of this study is to primarily evaluate the efficacy of SHR2554 plus SHR1701 and the epigenetic modulating effect of SHR2554.