Clinical Trials /

Phase Ⅰ/Ⅱ Study of SHR2554 in Combination With SHR1701 in Patients With Advanced Solid Tumors and B-cell Lymphomas

NCT04407741

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • B-Cell Non-Hodgkin Lymphoma
  • Breast Carcinoma
  • Cholangiocarcinoma
  • Colorectal Adenocarcinoma
  • Esophageal Adenocarcinoma
  • Gastric Adenocarcinoma
  • Lung Adenocarcinoma
  • Pancreatic Adenocarcinoma
  • Small Intestinal Adenocarcinoma
  • Squamous Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase Ⅰ/Ⅱ Study of SHR2554 in Combination With SHR1701 in Patients With Advanced Solid Tumors and B-cell Lymphomas
  • Official Title: An Open-Label Phase Ⅰ/Ⅱ Study of EZH2 Inhibitor SHR2554 in Combination With Anti-PD-L1/TGFβ Antibody SHR1701 in Patients With Advanced or Metastatic Solid Tumors and Relapsed/Refractory B-cell Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: CHN-PLAGH-BT-055
  • NCT ID: NCT04407741

Conditions

  • Solid Tumor
  • Lymphoma

Interventions

DrugSynonymsArms
SHR2554+SHR1701SHR2554+ SHR1701
SHR1701SHR1701

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
SHR2554+ SHR1701ExperimentalDrug: SHR2554 recommended dose from phase Ⅰstudy, PO, twice a day, every 3 weeks SHR1701 30mg/kg IV over 30 minutes on day 1, every 3 weeks
  • SHR2554+SHR1701
SHR1701ExperimentalDrug: SHR1701 30mg/kg IV over 30 minutes on day 1, every 3 weeks
  • SHR1701

Eligibility Criteria

        Inclusion Criteria:

          -  1. Age from 18 to 70 years with estimated life expectancy >3 months.

          -  2. Histopathological confirmed locally advanced or metastatic systematically
             pretreated epidermal growth factor receptor (EGFR) / anaplastic lymphoma kinase (ALK)
             / c-ros oncogene 1 receptor kinase (ROS1) /BRAF negative non-small cell lung cancer
             (adenocarcinoma or squamous cell carcinoma), pancreatic adenocarcinoma,
             cholangiocarcinoma, gastrointestinal adenocarcinoma, triple-negative breast cancer and
             relapsed/refractory B-cell lymphoma (All enrolled subjects with above solid carcinoma
             are required to have received at least first-line systematic therapy and subjects with
             R/R B-cell lymphoma need a history of at least two lines of previous treatment; For
             solid carcinoma subjects enrolled in phase Ⅱ period, their previous treatment lines
             are limited to no more than four lines; Besides previously treated subjects, subjects
             with initially diagnosed pancreatic adenocarcinoma or cholangiocarcinoma are also
             eligible for enrollment in phase Ⅱ period).

          -  3. Have at least one measurable target lesion, determined by the site study team based
             on RECIST 1.1 and immune related RECIST.

          -  4. Fresh tumor samples or formalin-fixed paraffin embedded tumor archival samples
             within 3 months are necessary; Fresh tumor samples are preferred. Subjects are willing
             to accept tumor re-biopsy in the process of this study.

          -  5. Previous treatment must be completed for more than 4 weeks prior to the enrollment
             of this study, and subjects have recovered to <= grade 1 toxicity.

          -  6. Have an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 1 at
             the time of enrollment.

          -  7. Have adequate organ function, as defined in the table below, which should be
             confirmed within 2 weeks prior to the first dose of study drugs.

               -  Leukocytes greater than or equal to 3.0 ×10^9/L.

               -  Absolute neutrophil counts greater than or equal to 1.0 ×10^9/L.

               -  Platelets greater than or equal to 100 ×10^9/L.

               -  Hemoglobin greater than or equal to 90 g/L.

               -  Total bilirubin less than or equal to 2 x ULN.

               -  Serum albumin should be no less than 30 g/L.

               -  Alanine aminotransferase or Aspartate aminotransferase less than 2 x Upper Limit
                  of Normal (ULN).

               -  Measured creatinine clearance ≥ 60 mL per min.

          -  8. Previous treatment with anti-PD-1/PD-L1 antibodies or cytotoxic T lymphocyte
             associated antigen 4 (CTLA-4) inhibitors are allowed.

          -  9. Ability to understand and sign a written informed consent document.

          -  10.Women of child-bearing potential must agree to use adequate contraception (hormonal
             or barrier method of birth control; abstinence) prior to study entry, and up to 90
             days after the last dose of the drug.

        Exclusion Criteria:

          -  1. Active, known or suspected autoimmune diseases.

          -  2. Known brain metastases or active central nervous system (CNS). Subjects with CNS
             metastases who were treated with radiotherapy for at least 3 months prior to
             enrollment, have no central nervous symptoms and are off corticosteroids, are eligible
             for enrollment, but require a brain MRI screening.

          -  3. Subjects are being treated with either corticosteroids (>10 mg daily prednisone
             equivalent) or other immunosuppressive medications within 14 days of enrollment.

          -  4. History of severe hypersensitive reactions to other monoclonal antibodies.

          -  5. History of allergy or intolerance to study drug components.

          -  6. Substance abuse, medical, psychological or social conditions that may interfere
             with the patient's participation in the study or evaluation of the study results.

          -  7. History or concurrent condition of interstitial lung disease of any grade or
             severely impaired pulmonary function.

          -  8. Uncontrolled intercurrent illness, including ongoing or active systemic infection,
             symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia
             (excluding insignificant sinus bradycardia and sinus tachycardia) or psychiatric
             illness/social situations and any other illness that would limit compliance with study
             requirements and jeopardize the safety of the patient.

          -  9. History of human immunodeficiency virus (HIV) infection or acquired
             immunodeficiency syndrome (AIDS).

          -  10. Pregnant or breast-feeding. Women of childbearing potential must have a pregnancy
             test performed within 7 days before the enrollment, and a negative result must be
             documented.

          -  11. Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for
             curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial
             bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades
             lamina propria)].

          -  12. Vaccination within 30 days of study enrollment.

          -  13. Active bleeding or known hemorrhagic tendency.

          -  14. Subjects with unhealed surgical wounds for more than 30 days.

          -  15. Being participating any other trials or withdraw within 4 weeks.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Median amount of time subject survives without disease progression following the initiation of treatment
Time Frame:up to 36 months
Safety Issue:
Description:The primary endpoint is progression free survival (PFS) after treatment. PFS is defined as the time from first treatment to the date of the first documented tumor progression or death due to any cause.

Secondary Outcome Measures

Measure:Number of subjects with treatment related adverse events as assessed by CTCAE v5.0.
Time Frame:Up to 90 days after the last dose of study drugs.
Safety Issue:
Description:Establishing the safety profile following the initiation of treatment and grading these toxicities by CTCAE v5.0
Measure:The percentage of subjects respond to treatment.
Time Frame:up to 36 months
Safety Issue:
Description:Overall response rate is defined as the sum of partial responses and complete responses.
Measure:Median amount of times subjects alive after treatment
Time Frame:up tp 36 months
Safety Issue:
Description:The median overall survival (OS) time is defined as the time from enrollment to the date of death.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Chinese PLA General Hospital

Trial Keywords

  • Anti-PD-L1/TGFβ
  • EZH2
  • SHR2554
  • SHR1701
  • Advanced

Last Updated

May 27, 2020