Novel Combination Therapy in the Treatment of Relapsed and Refractory Aggressive B-Cell Lymphoma
Novel Combination Therapy in the Treatment of Relapsed and Refractory Aggressive B-Cell Lymphoma
The purpose of this study is to find out what effects new combinations of treatment will have
 this disease. New promising treatment strategies will be added to this study as they are
 available to be compared against the standard treatment.
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 study uses a "pick the winner" design to facilitate efficient screening of novel
 combination treatment regimens and select those meeting pre-specified criteria for testing in
 the phase III setting. All novel treatment options will be compared against the standard
 treatment for this disease: rituximab plus gemcitabine, dexemthasone, and cisplatin (R-GDP).
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.