Clinical Trials /

Novel Combination Therapy in the Treatment of Relapsed and Refractory Aggressive B-Cell Lymphoma

NCT02436707

Description:

The purpose of this study is to find out what effects new combinations of treatment will have this disease. In this clinical trial, the study treatment options currently are ibrutinib plus R-GDP, or R-GDP alone.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Novel Combination Therapy in the Treatment of Relapsed and Refractory Aggressive B-Cell Lymphoma
  • Official Title: A Multi-Stage Randomized Phase II Study of Novel Combination Therapy in the Treatment of Relapsed and Refractory Aggressive B-Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: LY17
  • NCT ID: NCT02436707

Conditions

  • Lymphoma

Interventions

DrugSynonymsArms
IbrutinibIbrutinib plus R-GDP (ACCRUAL COMPLETE)
RituximabR-GDP
GemcitabineR-GDP
DexamethasoneR-GDP
CisplatinR-GDP
MesnaR-DICEP
CyclophosphamideR-DICEP
EtoposideR-DICEP
G-CSFR-DICEP

Purpose

The purpose of this study is to find out what effects new combinations of treatment will have this disease. In this clinical trial, the study treatment options currently are ibrutinib plus R-GDP, or R-GDP alone.

Detailed Description

      R-GDP has been used to treat many people with lymphoma. Ibrutinib has been shown to benefit
      people with certain types of lymphoma. They have not previously been given together.

      This research is being done to try to find new combinations of treatment that may be better
      for treating patients with this disease. It is not clear however if these treatments can
      offer better results than standard treatment.

      The standard or usual treatment of this disease is treatment with rituximab plus gemcitabine,
      dexamethasone, and cisplatin (R-GDP).
    

Trial Arms

NameTypeDescriptionInterventions
R-GDPActive ComparatorRituximab - 375 mg/m2 IV, 1.5 - 6 hours D1 (prior to cisplatin); Gemcitabine - 1000 mg/m2, IV 30 min D1, D8; Dexamethasone - 40 mg daily PO D1 - D4; Cisplatin - 75 mg/m2 IV, 1 hour D1;
  • Rituximab
  • Gemcitabine
  • Dexamethasone
  • Cisplatin
Ibrutinib plus R-GDP (ACCRUAL COMPLETE)ExperimentalIbrutinib 560 mg PO -- D1 - D21 Rituximab 375 mg/m2 IV 1.5 - 6 hours D1 (prior to cisplatin) Gemcitabine 1000 mg/m2 IV 30 min D1, D8 Dexamethasone 40 mg daily PO -- D1 - D4 Cisplatin 75 mg/m2 IV 1 hour D1
  • Ibrutinib
  • Rituximab
  • Gemcitabine
  • Dexamethasone
  • Cisplatin
R-DICEPExperimentalRituximab 375 mg/m2 IV 1.5-6hrs Day 1 and Day 5 prior to Cisplatin Mesna 1.75 g/m2 IV 24 hour Cycle 1, Day 2, Day 3 and Day 4 Cyclophosphamide, 1.75 g/m2 IV 2 hours, Day 2, Day 3 and Day 4 Etoposide 350 mg/m2 IV 2 hours, Day 2, Day 3 and Day 4 Cisplatin 35 mg/m2 IV, 2 hours, Day 2, Day 3 and Day 4 G-CSF 300 mcg (<60kg); 480 mcg (60-90kg); 600 mcg (>90kg); SC, Daily, starting Day 15 until apheresis completed.
  • Rituximab
  • Cisplatin
  • Mesna
  • Cyclophosphamide
  • Etoposide
  • G-CSF

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with histologic diagnosis for one of the following histologies according to
             the World Health Organization: documented at initial diagnosis or at relapse:

               -  Diffuse large cell lymphoma, B-cell (includes primary mediastinal B-cell
                  lymphoma, T-cell rich B-cell lymphoma);

               -  Previous indolent lymphoma (follicular lymphoma, marginal zone lymphoma,
                  including extranodal MALT lymphoma, lymphoplasmacytoid lymphoma) with
                  transformation to diffuse large B-cell lymphoma at most recent relapse (biopsy
                  proof of transformation is mandatory);

               -  Unclassifiable B-cell lymphoma with indeterminate features between diffuse large
                  B-cell lymphoma and Burkitt lymphoma.

          -  Biopsy proof of disease at initial diagnosis is mandatory. A biopsy at relapse is
             preferred but not mandatory. Participating centres must designate a local reference
             expert pathologist who will confirm the diagnosis for the patients enrolled at that
             centre.

          -  Patients must be CD20+ in order to be eligible for the study.

          -  Clinically and/or radiologically measurable disease (one site bidimensionally
             measurable). Measurements/ evaluations must be done within 28 days prior to
             randomization.

          -  Prior FDG-PET scan, if done at baseline, must be positive (known FDG-avid lymphoma)

          -  Patients with de novo aggressive B-cell lymphoma must have relapsed or progressed, or
             have biopsy proven refractory disease, after 1 prior line of therapy (R-CHOP
             chemotherapy or equivalent). Patients with histological transformation from low grade
             lymphoma may have had up to 3 prior treatment regimens. Patients with transformed low
             grade lymphoma treated with a non-anthracycline regimen may be enrolled at
             investigator discretion.

          -  Patient age is ≥16 years. Patients older than 65 years of age are not recommended for
             this study.

          -  ECOG performance status of 0, 1, 2 or 3.

          -  Patient must be considered fit for intensive chemotherapy and ASCT, and an appropriate
             candidate to receive second-line salvage chemotherapy and ASCT.

          -  Life expectancy > 90 days.

          -  Laboratory Requirements: (must be done within 14 days of randomization)

        Hematology:

          -  Granulocytes (AGC) ≥ 1.0 x 10^9/L (independent of growth factor support)

          -  Platelets ≥ 100 x 10^9/L (50 x 10^9/L if bone marrow involvement by lymphoma,
             independent of transfusion support)

        Biochemistry:

          -  AST and ALT ≤ 3x ULN

          -  Serum total bilirubin ≤ 1.5x ULN (≤ 5x ULN if Gilberts Disease)

          -  Serum Creatinine ≤ 1.5x ULN (or estimated GFR of ≥ 40 mL/min/1.73m2 using Cockcroft
             Gault formula).

        Women must be post-menopausal, surgically sterile or use reliable forms of contraception
        while on study. Women of child bearing potential and men who are sexually active must be
        practicing a highly effective method of birth control during and after the study consistent
        with local regulations regarding the use of birth control methods for subjects
        participating in clinical trials. Men must agree to not donate sperm during and after the
        study. These restrictions apply for 12 months (1 year) after the last dose of study drug.

          -  Women of childbearing potential must have a pregnancy test taken (either by serum
             beta-human chorionic gonadotropin [B-hCG]) or urine) and proven negative within 14
             days prior to randomization. Women who are pregnant or breastfeeding are ineligible
             for this study.

        Patient consent must be appropriately obtained in accordance with applicable local and
        regulatory requirements. Each patient must sign a consent form prior to enrollment in the
        trial to document their willingness to participate.

        Patients must be accessible for treatment and follow up. Patients randomized on this trial
        must be treated and followed at the participating centre. This implies there must be
        reasonable geographical limits (for example: 1 ½ hour's driving distance) placed on
        patients being considered for this trial. Investigators must assure themselves the patients
        randomized on this trial will be available for complete documentation of the treatment,
        response assessment, adverse events, and follow-up.

        In accordance with CCTG policy, protocol treatment is to begin within 5 working days of
        patient randomization.

        Exclusion Criteria:

          -  Patients with a history of other malignancies, except: adequately treated non-melanoma
             skin cancer and superficial bladder cancer, curatively treated in-situ cancer of the
             cervix or breast, or localized excised prostate cancer, other solid tumours curatively
             treated with no evidence of disease for ≥ 3 years.

          -  Active and uncontrolled central nervous system involvement, meningeal or parenchymal.
             Patients with CNS disease at initial presentation and who are in a CNS CR at the time
             of relapse are eligible. MRI scanning and / or lumbar puncture should be performed if
             there is clinical suspicion of active CNS disease.

          -  Major surgery performed within 10 days of randomization.

          -  Known history of human immunodeficiency virus (HIV), active Hepatitis C Virus
             infection, active Hepatitis B Virus infection or any uncontrolled active systemic
             infection requiring intravenous (IV) antibiotics. Patients with Hepatitis B serology
             suggestive of infection are eligible if they are HBV DNA negative and concurrently
             treated with anti-viral therapy. Patients with a past history of hepatitis C who have
             eradicated the virus are eligible.

          -  Patients who have been vaccinated with live, attenuated vaccines within 4 weeks of
             randomization.

          -  Clinically significant cardiovascular disease such as uncontrolled or symptomatic
             arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
             Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by
             the New York Heart Association Functional Classification.

          -  Any serious active disease or co-morbid medical condition, including psychiatric
             illness, judged by the local investigator to preclude safe administration of the
             planned protocol treatment or required follow-up.

          -  Any other serious intercurrent illness, life threatening condition, organ system
             dysfunction, or medical condition judged by the local investigator to compromise the
             subject's safety, interfere with the absorption or metabolism of ibrutinib capsules,
             or preclude safe administration of the planned protocol treatment or required
             follow-up, including (for example):

               -  active, uncontrolled bacterial, fungal, or viral infection;

               -  clinically significant cardiac dysfunction or cardiovascular disease.

          -  Pregnant or lactating females, or women of childbearing potential not willing to use
             an adequate method of birth control for the duration of the study.

          -  Patients are not eligible if they have a known hypersensitivity to the study drugs or
             their components.
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:16 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Measure overall response rate
Time Frame:2 years
Safety Issue:
Description:To determine the overall response rate (complete and partial response) to novel combination therapy in patients with relapsed and refractory aggressive B cell lymphoma

Secondary Outcome Measures

Measure:Number and severity of adverse events
Time Frame:2 years
Safety Issue:
Description:To evaluate the tolerability and toxicity of novel combinations. Adverse events will be monitored on an ongoing basis by the central office and their frequencies reported annually at investigators' meetings. Safety and tolerability will be reviewed in the first six patients assigned to ibrutinib plus R-GDP as part of a safety run-in. Ibrutinib dose will be reduced for subjects subsequently enrolled if necessary
Measure:Transplantation rate
Time Frame:2 years
Safety Issue:
Description:A non-inferiority analysis of transplantation rate will be conducted with 10% non-inferiority margin. The one-sided 80% asymptotic confidence limit of the difference in transplantation rate will be calculated between treatment and control arms.
Measure:Stem cell collection rate
Time Frame:2 years
Safety Issue:
Description:Stem cell collection rate defined as collection of ≥ 2 x 106 CD34+ cells/kg.
Measure:Event free Survival Rate
Time Frame:2 years
Safety Issue:
Description:• Event free survival (EFS) at one year defined as time from study entry to any treatment failure including disease progression, or discontinuation of treatment for any reason
Measure:Overall Survival
Time Frame:2 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Canadian Cancer Trials Group

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