Two Stage Study of Combination of Chemotherapy, SHR-1210 and/or Decitabine for Relapsed/Refractory PMBCLs

Study Overview
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Brief Summary
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This is a two stage, Phase I/II clinical trial for patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL). In the first stage, the participants will receive GVD (Gemcitabine, Vinorelbine and Doxorubicine) chemotherapy and PD-1 antibody (SHR-1210) treatment. The safety and efficacy of combined regimen will be evaluated. If deemed safe and efficacious, the investigators will proceed to the second stage of the study. In the second stage, the participants will receive GVD chemotherapy and SHR-1210 treatment with low-dose Decitabine priming. The safety and feasibility of combined regimens will be evaluated in phase I study. The feasibility will be accessed.

Official Title
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Combined Chemotherapy and PD-1 Antibody(SHR-1210) With or Without Low-dose Decitabine Priming for Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL):Two Stage, Phase I/II Trail

Conditions
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Primary Mediastinal Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Decitabine
* Drug: GVD chemotherapy
* Drug: SHR-1210


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients had histologically proven PMBCL, and Radiographically measureable disease. Eastern Cooperative Oncology Group performance status 0-2 Disease recurring within 6 months after first-line chemotherapy or disease progression while receiving or persistent disease after first-line chemotherapy Bulky disease was defined as the presence of a mediastinal mass > 4.5 cm in axial diameter or extranodal lesion > 3 cm. Subjects must have received at least two prior chemotherapy regimen, and must be off therapy for at least 4 weeks prior to Day 1. Subjects with autologous hematopoietic stem-cell transplantation are eligible which must be more than 3 months. Subjects with Anti-PD-1 antibody are eligible which must be resistance. Adequate organ function. Female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study drug. Male participants of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study drug through 120 days after the last dose of study drug. Exclusion Criteria: Known clinically active central nervous system involvement. Any autoimmune disease or history of syndrome that requires corticosteroids or immunosuppressive medications. Serious uncontrolled medical disorders or active infections, pulmonary infection especially Prior organ allograft. Receiving any other form of immunosuppressive medication, except steroid. Allogeneic hematopoietic stem cell transplantation within the last 5 years. 6） Known human immunodeficiency virus (HIV). 7） Has received a live vaccine within 30 days prior to first dose of study drug. 8） Women who are pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GVD and SHR-1210 with or without Decitabine<br>This is a two stage study. For the first stage, the participants will receive the combination of GVD chemotherapy and PD-1 antibody SHR-1210. The patients enrolled into the second stage will received the combination of GVD and SHR-1210 with low-dose decitabine primed. | Drug: Decitabine<br>* Decitabine is an investigational (experimental) drug that works by depleting DNA methyltransferase 1 (DNMT1), which can increase tumor antigens and histocompatibility leukocyte antigen (HLA) expression, enhances antigen processing, promotes T cell infiltration, and boosts effector T cell function.<br>Drug: GVD chemotherapy<br>* GVD regimen is a chemotherapy regimen consisted by Gemcitabine, Vinorelbine and Doxorubicine. Patients will be administrated with Gemcitabine 0.8 g/m2, Vinorelbine 30mg and Doxorubicin 20mg/m2 intravenously infusion.<br>Drug: SHR-1210<br>* SHR-1210 is a humanized anti-PD-1 monoclonal antibody.<br>* Other names: PD-1 antibody, PD-1 inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects with treatment-related adverse events (AEs) | Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v4.03. | Up to 120 days after last administration of SHR-1210 | 
| Objective response rate (ORR) | The antitumor efficacy of the combination treatments as measured by ORR was determined using the International Working Group 2007 criteria for malignant lymphoma (J Clin Oncol. 2007 Feb 10;25(5):579-586). Clinical response of progressive disease (PD), stable disease (SD), partial remission (PR), or complete remission (CR) will be determined at each assessment. ORR is defined as the sum of CR and PR. | Enrolled patients will be followed until death, withdrawal from study, or until 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response (CR) rate | The CR rate will be estimated as the proportion of patients with response, with a 95% exact confidence interval. | Up to 2 years after completion of study treatment | 
| Median progression-free survival (PFS) time | PFS time was measured from study entry to the first documentation of disease progression or death. Disease progression was determined using the International Working Group 2007 criteria for malignant lymphoma. | Patients will be followed until disease progression, death, withdrawal from study, or until 2 years. | 
| Median overall survival (OS) time | OS time was measured from the study entry to the date of death. | Patients will be followed until death, withdrawal from study, or until 2 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed/Refractory, primary mediastinal large B-cell lymphoma, PD-1 antibody, Decitabine, GVD chemotherapy