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Azacitidine and Rituximab-GDP Immunochemotherapy in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

NCT03719989

Description:

This phase II clinical trial aims at evaluating the efficacy and safety of azacitidine followed by rituximab-GDP immunochemotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients who were treated with from 1 to 4 lines of prior therapies for relapsed/refractory DLBCL wee eligible. azacitidine will be treated one week prior to conventional rituximab-gemcitabine, dexamethasone, cisplatin (R-GDP) immunochemotherapy. Patients will be treated every 21 days as one cycle, and up to 6 cycles. The primary endpoint of this study is objective response rate according to the Lugano response criteria for non-Hodgkin lymphoma, and secondary endpoints are safety, complete response, progression-free survival, and overall survival.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Azacitidine and Rituximab-GDP Immunochemotherapy in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma
  • Official Title: A Phase II Study of Epigenetic Priming Using Azacitidine Followed by Rituximab-GDP Immunochemotherapy in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: EPIC
  • NCT ID: NCT03719989

Conditions

  • Diffuse Large B Cell Lymphoma
  • Relapsed Non Hodgkin Lymphoma
  • Refractory Non-Hodgkin Lymphoma

Interventions

DrugSynonymsArms
azacitidine plus R-GDPN/ETreatment arm

Purpose

This phase II clinical trial aims at evaluating the efficacy and safety of azacitidine followed by rituximab-GDP immunochemotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients who were treated with from 1 to 4 lines of prior therapies for relapsed/refractory DLBCL wee eligible. azacitidine will be treated one week prior to conventional rituximab-gemcitabine, dexamethasone, cisplatin (R-GDP) immunochemotherapy. Patients will be treated every 21 days as one cycle, and up to 6 cycles. The primary endpoint of this study is objective response rate according to the Lugano response criteria for non-Hodgkin lymphoma, and secondary endpoints are safety, complete response, progression-free survival, and overall survival.

Detailed Description

      This phase II clinical trial aims at evaluating the efficacy and safety of azacitidine
      followed by rituximab-GDP immunochemotherapy in patients with relapsed/refractory diffuse
      large B-cell lymphoma (DLBCL). This study is designed with the expectation of correction of
      aberrant hypermethylation of tumor suppressor genes by preceding use of low dose azacitidine
      thereby re-sensitizing chemosensitivity of tumor cells. Patients who were treated with from 1
      to 4 lines of prior therapies for relapsed/refractory DLBCL wee eligible. Planned initial
      doses of the current regimen are as follows;

      azacitidine S.C 25 mg/m2 D1,2,3,4,5 rituximab I.V. 375 mg/m2 D8 gemcitabine I.V. 1,000 mg/m2,
      D8,15 dexamethasone I.V. or P.O. 40 mg D8,9,10,11 cisplatin 70 mg/m2 I.V. D8

      Patients will be treated every 21 days as one cycle, and up to 6 cycles of treatment will be
      conducted. Especially, first 3~6 patients will be regarded as 'lead-in safety cohort' and
      their safety will be reviewed by an independent data and safety monitoring board (DSMB). The
      primary endpoint of this study is objective response rate according to the Lugano response
      criteria for non-Hodgkin lymphoma, and secondary endpoints are safety, complete response,
      progression-free survival, and overall survival.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment armExperimentalThis study is sing-arm study. Therefore, all enrolled patients will be treated with azacitidine plus R-GDP regimen
  • azacitidine plus R-GDP

Eligibility Criteria

        Inclusion Criteria:

          1. age from 19 to 75 years

          2. diagnosed as diffuse large B-cell lymphoma according to the World Health Organization
             2016 criteria

          3. with any measurable lesion by radiologic studies (direct measurement is allowed in
             cases of (sub)cutaneous lesions)

          4. patients who were initially treated with rituximab plus cyclophosphamide, doxorubicin,
             vincristine, and prednisone (CHOP) or other rituximab-containing immunochemotherapy
             and relapsed or refractory to prior treatment

          5. previously treated with from1 to 4 lines of therapy

               -  autologous stem cell transplant (ASCT) will be counted as 1 line of therapy

               -  in cases of previously treated with ASCT, patients 1) who elapsed at 60 days and
                  2) who have lower risk of severe bone marrow suppression and infectious
                  complication, judged by physician

          6. ASCT ineligible or no further plan of ASCT due to previous transplantation

          7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0~2

          8. Hb ≥ 8.0 g/dL, absolute neutrophil count (ANC) ≥ 1,000/mm3, Platelet ≥ 100,000/mm3
             prior to enrollment

               -  correction of Hb by transfusion will be allowed

               -  in cases of bone marrow involvement, patients will be included if they have ANC ≥
                  500/mm3, Platelet ≥ 50,000/mm3 and no significant infection risk or transfusion
                  dependency

          9. Glomerular Filtration Rate > 60 mL/min calculated according to Cockcroft-Gault or
             Modification of Diet in Renal Disease (MDRD) equation, and total bilirubin < 2.5
             mg/dL, aspartate amino-transferase (AST) and alanine amino- transferase (ALT) < x3
             upper limit of normal (ULN)

               -  In cases of hepatic involvement of DLBCL, AST or ALT < x5 ULN will be allowed

               -  In cases of Gilbert syndrome, Direct bilirubin < 2.5 ULN will be allowed

         10. patients who agree to do highly effective contraception during and 3 months after
             treatment

         11. patients who agree not to be pregnant or breast-feeding and had a negative result for
             screening pregnancy test

         12. life expectancy > 3 months

        Exclusion Criteria:

          1. primary or secondary central nervous system DLBCL

          2. patients with or strongly suggestive of lymphomatous involvement on eye, epidural
             area, kidney/adrenal gland, breast, testes, or uterus

          3. intravascular DLBCL

          4. DLBCL transformed from low grade lymphoma

          5. high grade B-cell lymphomas other than DLBCL: primary mediastinal large B-cell
             lymphoma, high-grade B-cell lymphoma not otherwise specified (NOS), high-grade B-cell
             lymphoma with myelocytomatosis oncogene (MYC) and/or B-cell lymphoma 6 (BCL6)
             rearrangements, B-cell lymphoma, unclassifiable with features intermediate between
             DLBCL and classical Hodgkin lymphoma

          6. human immunodeficiency virus (HIV) associated DLBCL

          7. patients with liver cirrhosis of Child-Pugh Classification B or higher, or active
             hepatitis B (HBV) or hepatitis C (HCV) infection

               -  in cases of patients who are positive for HBsAg or HBcAb immunoglobulin G (IgG)
                  but no evidence of active infection, patients who are negative for HBV DNA will
                  be allowed only with adequate anti-viral prophylaxis

               -  in cases of patients who are positive for hepatitis C antibody, patients will be
                  allowed if they satisfy all other inclusion criteria and without evidence of
                  liver cirrhosis (irrespective of HCV RNA titer)

               -  patients who were diagnosed HCV less than 6 months before screening period will
                  be excluded unless they have negative result for HCV RNA

          8. patients with active infection treated with anti-microbial agents

          9. patients who were diagnosed malignancy other than lymphoma, either actively treated or
             have been received chemotherapy or radiation therapy less than 3 years from the time
             of enrollment

         10. Major surgery within 21 days (open laparotomy for diagnostic biopsy will be exempted)

         11. patients who underwent hypersensitivity, severe allergic reaction or anaphylaxis to
             rituximab or other chimeric/humanized antibodies

         12. patients who underwent hypersensitivity, severe allergic reaction or anaphylaxis
             gemcitabine, azacitidine, or cisplatin

         13. severe congestive heart failure, unstable heart or pulmonary diseases

         14. pregnant or lactating women

         15. during radiation therapy to chest area (considering previous reports of severe
             esophagitis and pneumonitis after concurrent chemoradiation with gemcitabine)

         16. with any prior experience of posterior reversible encephalopathy syndrome or
             progressive multifocal leukoencephalopathy due to rituximab

         17. with any prior experience of Stevens-Jones syndrome or toxic epidermal necrosis
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:19 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate
Time Frame:up to 3 years
Safety Issue:
Description:according to Lugano response criteria for non-Hodgkin lymphoma

Secondary Outcome Measures

Measure:Safety (adverse events and severe adverse events)
Time Frame:up to 3 years
Safety Issue:
Description:according to CTCAE V4.03 criteria
Measure:Complete response rate
Time Frame:up to 3 years
Safety Issue:
Description:according to Lugano response criteria for non-Hodgkin lymphoma
Measure:Progression-free survival
Time Frame:up to 3 years
Safety Issue:
Description:From date of enrollment until date of first documented progression or date of death from any cause, whichever came first
Measure:Overall survival
Time Frame:up to 3 years
Safety Issue:
Description:From date of enrollment until date of death from any cause

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Seoul National University Hospital

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