Study Comparing Zevalin Regimen With no Further Treatment in Patients With Diffuse Large B-cell Lymphoma.

Phase III,Open-label,Prospective,Two-armed,Multicenter Study Comparing Zevalin Regimen With no Further Treatment in Patients With Diffuse Large B-cell Lymphoma.

This study treats patients with diffuse large B-cell lymphoma whose disease is in complete remission due to previous treatment with Cyclophosphamide Doxorubicin hydrochloride Vincristine Prednisolone- Rituximab (CHOP-R). Half of the patients received Zevalin and the other half receive no further anti-cancer treatment. The two patient groups compared to determine if Zevalin given after CHOP-R therapy provides greater benefits than receiving no additional anti-cancer therapy after CHOP-R.

The objectives of this study were to evaluate the efficacy and safety of the Zevalin study regimen compared with observation alone in patients with complete remission (CR or CRu) after first-line CHOP-R, the study was to include patients 60-years-of-age or older with histologically confirmed Ann Arbor stage II, III, or IV diffuse large B-cell lymphoma

End Points:

Primary endpoint: Overall survival (OS) Secondary endpoints: Disease-free survival (DFS), health-related quality of life (HRQL) as assessed by the patient using standard questionnaires .

Number of Patients :

A total of 400 patients (200 per arm) were planned to be enrolled.

- In fact, 68 randomized patients (full analysis set; FAS) were analysed; 34 patients per each arm. The per-protocol set (PPS; 65 patients) comprised 33 patients allocated to the Zevalin arm and 32 patients allocated to the observation control arm.

Study Treatment :

The combination regimen with rituximab was designed in 2 steps as follows:

• Day 1: Initial administration of 250 mg/m^2 rituximab, followed immediately by administration of 185 megabecquerel (MBq) (5 millicurie [mCi]) of [111In]-ibritumomab tiuxetan (the latter one only in centers where biodistribution imaging or dosimetry was compulsory according to local law). In centers where biodistribution imaging or dosimetry had not been required, the first rituximab infusion was given alone.
• Day 7-9: Rituximab 250 mg/m^2, followed immediately by [90Y]-ibritumomab tiuxetan 14.8 megabecquerel/kilograms (MBq/kg) (0.4 millicurie / kilogram [mCi/kg]) (maximum dose 1184 MBq) given as a slow intravenous (I.V.) push over 10 minutes. Two treatment days one week apart followed by a 12-week safety period.

Duration of Patient Participation:

Due to the sequential design, the total duration of this study was not fixed. Originally, the study was planned in a randomized, parallel-group, group sequential design.

Objective :

The primary objective of this study was an inferential comparison between the 2 randomized groups in terms of overall survival using a group sequential triangular test ,since the study was prematurely terminated the pre-planned group-sequential nature of the study design was not applicable statistical analyses. Actually, the prominent efficacy variables for the OS and DFS were analysed in the FAS (identical to the safety analysis set) and PPS using Kaplan Meier estimates by treatment group.

Study Design :

This study was designed as a prospective, multi-center, open label, randomized, two-armed, group-sequential Phase III study. The study was planned to consist of 2 stages: an interventional Stage 1 with Screening/Baseline, treatment, safety, and follow-up periods, and a non-interventional Stage 2 consisting of a long-term follow-up period (until completion of a median observation period of 5 years). This second stage of the study was to be started only if superiority of the Zevalin study regimen could be demonstrated in the preceding Stage 1.

Pharmacokinetics/Pharmacodynamic results: Not applicable

Extent of exposure:

All 34 patients randomized to the Zevalin arm were given 2 rituximab infusions(with a median dose of 425.0 mg at each of the 2 infusion time points).Three patients underwent radioimaging studies/dosimetry and therefore were administered [111In]-ibritumomab tiuxetan at Day 1. All but 1 patient received an infusion with [90Y]-ibritumomab tiuxetan following the second infusion of rituximab. The mean dose ranged from 765.9 -1197.0 MBq.

Inclusion Criteria:

• Histologically confirmed, Ann Arbor stage II, III, or IV Diffuse large B-cell lymphoma (DLBCL) according to the Revised European American Lymphoma(REAL)/World Health Organization (WHO) classification .
• Central pathology review confirming the DLBCL diagnosis and Cluster of differentiation 20 (CD20) positivity, and no evidence of DLBCL in bone marrow
• First-line treatment of DLBCL must have been 6 or 8 cycles of standard CHOP chemotherapy in combination with rituximab .
• Complete remission(CR) or unconfirmed complete remission(CRu) according to the International Workshop Response Criteria for Non Hodgkins Lymphoma (NHL) described by Cheson et al and modified for this study after first-line treatment with CHOP-R. Computerised Tomography (CT) scans of chest, abdomen, pelvis, and neck (if applicable) must have been performed within 6 weeks after the last dose of the last course of CHOP-R. Applicability of the neck CT means that the patient had involvement of the neck region by palpation / physical examination at first diagnosis (pre-CHOP-R).
• Central radiographic review of the CT scans from before and after first-line treatment with CHOP-R fulfilling the radiological requirements for CR/CRu
• Patients 60 years of age or older at time of randomization
• WHO performance status (PS) of 0 to 2 within 1 week of randomization
• Absolute neutrophil count greater than or equal to 1.5 x 10^9/L within 1 week of randomization
• Hemoglobin greater than or equal to 10 g/dL within 1 week of randomization
• Platelets greater than or equal to 150 x 10^9/L within 1 week of randomization
• Life expectancy of 3 months or longer
• Written informed consent obtained according to local guidelines

Exclusion Criteria:

• Presence of any other malignancy or history of prior malignancy except non-melanoma skin tumors or stage 0 (in situ) cervical carcinoma
• Prior radioimmunotherapy, radiation therapy, or any other NHL therapy except first-line CHOP-R
• Presence of gastric, central nervous system or testicular lymphoma at first diagnosis
• Histological transformation of low-grade non-Hodgkin's lymphoma (NHL)
• Known seropositivity for hepatitis C virus or hepatitis B surface antigen
• Known history of Human Immunodeficiency virus (HIV) infection
• Abnormal liver function: total bilirubin > 1.5 x upper limit of normal (ULN) or Alanine Aminotransferase > 2.5 x ULN within 1 week of randomization
• Abnormal renal function: serum creatinine > 2.0 x ULN within 1 week of randomization
• Nonrecovery from the toxic effects of CHOP-R therapy
• Known hypersensitivity to murine or chimeric antibodies or proteins
• Granulocyte Colony Stimulating Factor (G-CSF) or Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) therapy within two weeks (or four weeks if pegylated) prior to screening laboratory sampling
• Concurrent severe and/or uncontrolled medical disease (e.g., uncontrolled diabetes,congestive heart failure, myocardial infarction within 6 months of study, unstable and uncontrolled hypertension, chronic renal disease, or active uncontrolled infection) which could compromise participation in the study
• Male and female patients of child-bearing potential unwilling to practice effective contraception during the study and unwilling or unable to continue contraception for 12 months after their last dose of study treatment
• Female patients who are pregnant or are currently breastfeeding
• Treatment with investigational drugs less than 4 weeks before the planned Day 1 or nonrecovery from the toxic effects of such therapy
• Surgery less than 4 weeks before the planned Day 1 or nonrecovery from the side effects of such surgery
• Concurrent systemic corticosteroid use for any reason except as premedication in case of known or suspected allergies to contrast media or as premedication for potential side effects of rituximab treatment
• Unwillingness or inability to comply with the protocol