Conditions: Lymphoma, Large Cell, Diffuse
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 68
Healthy volunteers: no

Brief summary:
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.

Detailed description:
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.

Arms:
arm 1: Patients received Zevalin.

Zevalin Therapeutic Regimen:

Day 1: Initial administration of 250 mg/m\^2 rituximab, followed immediately by administration of 185 MBq of \[111In\]-ibritumomab tiuxetan ,in centers where 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 MBq/kg given as a slow intravenous push over 10 minutes.

Two treatment days one week apart were followed by a 12-week safety period. arm 2: Patients in this arm did not receive any reference therapy; they remained free of any anti-lymphoma therapy and were observed for relapse. This was non-interventional Stage consisting of a longterm follow-up period (until completion of a median observation period of 5 years).

Interventions: intervention 1: Zevalin
Intervention descriptions: intervention 1: Zevalin study treatment regimen consisted of 2 rituximab i.v. infusions (Day 1 and Day 7-9) and one \[90Y\]-ibritumomab tiuxetan infusion in connection with the second rituximab infusion.

The core treatment regimen in the Zevalin arm was:

Day 1: Rituximab i.v. infusion 250 mg/m\^2

Day 7-to 9: Rituximab i.v. infusion 250 mg/m\^2 immediately followed by \[90Y\]-ibritumomab tiuxetan 14.8 MBq/kg (0.4 mCi/kg) with a maximum dose of 1184 MBq (32 mCi),administered as slow intravenous push over 10 minutes.

Protocol document: