Randomized phase III study on the effect of early intensification of rituximab in combination with 2-weekly CHOP chemotherapy followed by rituximab maintenance in patients with diffuse large B-cell lymphoma

Phase 1

Conditions: diffuse large B-cell lymphoma
MedDRA version: 21.0Level: LLTClassification code 10012820Term: Diffuse large B-cell lymphoma NOSSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2006-005174-42-NL

Lead Sponsor: HOVON Foundation

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 600

Inclusion Criteria

For first randomization:
- Patients with a confirmed histologic diagnosis of diffuse large B-cell lymphoma (DLBCL) based upon a representative histology specimen according to the WHO classification (see appendix A)
- DLBCL must be CD20 positive
- Ann Arbor stages II-IV (see appendix C)
- Age 18-65 years and age-adjusted IPI 1-3 OR age 66-80 years and age-adjusted IPI 0-3
- WHO performance status 0 – 2 (see appendix E)
- Written informed consent

For second randomization:
Patients achieving a CR (or FDG-PET negative PR/CRu) after 6 (elderly) or 8 (young patients) cycles of R-CHOP14 will be randomized to maintenance treatment with rituximab or no further treatment.
- Patients in complete remission or FDG-PET negative partial remission/unconfirmed complete remission at least 4 weeks after the last cycle of R-CHOP14 (including last rituximab administration)
- Time interval since last cycle of R-CHOP14 (including last rituximab administration) between 4 and 8 weeks
- No rituximab-related adverse event necessitating stopping of rituximab administration
- No active infection
- Written informed consent
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 300
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 300

Exclusion Criteria

-Age 18-65 (inclusive) years and aa-IPI 0 (no risk factors)
-Intolerance of exogenous protein administration
-Severe cardiac dysfunction (NYHA classification III-IV, see appendix F) or LVEF < 45%
- Congestive heart failure or symptomatic coronary artery disease or cardiac arrhythmias not well controlled with medication. Myocardial infarction during the last 6 months
- Severe pulmonary dysfunction (vital capacity or diffusion capacity < 50% of predicted value) unless clearly related to NHL involvement
- Patients with uncontrolled asthma or allergy, requiring systemic steroid treatment
- Significant hepatic dysfunction (total bilirubin >= 30mmol/l or transaminases >= 2.5 x upper normal limit), unless related to NHL
- Significant renal dysfunction (serum creatinine >= 150 umol/l or clearance <= 60 ml/min), unless related to NHL
- Clinical signs of severe cerebral dysfunction
- Suspected or documented Central Nervous System involvement by NHL
- Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to study drugs
- Testicular DLBCL
- Primary mediastinal B cell lymphoma
- Transformed indolent lymphoma
- (EBV) post-transplant lymphoproliferative disorder
- Secondary lymphoma after previous chemotherapy or radiotherapy
- Major surgery, other than diagnostic surgery, within the last 4 weeks
- Patients with active uncontrolled infections
- Patients known to be HIV-positive
- Active chronic hepatitis B or C infection
- Serious underlying medical conditions, which could impair the ability of the patient to participate in the trial (e.g. ongoing infection, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease)
- Life expectancy < 6 months
- Prior treatment with chemotherapy, radiotherapy or immunotherapy for this lymphoma, except a short course of prednisone (< 1 week) and/or cyclophosphamide (< 1 week and not in excess of 900 mg/m2 cumulative) or local radiotherapy in order to control life threatening tumor related symptoms
- History of active cancer during the past 5 years, except basal carcinoma of the skin or stage 0 cervical carcinoma

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess in a prospective, multicenter, randomized phase III study in patients with DLBCL the effect of early intensification of rituximab combined with 2-weekly CHOP +G-CSF (CHOP14) in comparison to no intensification of rituximab on the response rate (complete remission and FDG-PET negative partial remission/unconfirmed complete remission) and time to reach response<br>;Secondary Objective: To assess in a prospective, multicenter, randomized phase III study in patients with DLBCL the efficacy of maintenance treatment with rituximab in comparison to no further treatment on failure free survival<br>;Primary end point(s): Response rate (complete remission and FDG-PET negative partial remission or unconfirmed complete remission) ;Timepoint(s) of evaluation of this end point: 200 and 400 evaluable patients and end of trial.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): -Failure free survival measured from the date of registration. Patients still alive or lost to<br>follow up are censored at the last day they were known to be alive<br>- Overall survival measured from the time of registration<br>- Time to reach response<br>- Toxicity;Timepoint(s) of evaluation of this end point: end of trial

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