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

• Sponsor: Spectrum Pharmaceuticals, Inc (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00322218
• Collaborator: Bayer (Industry)
• Enrollment: 68
• Locations: 90
• Arms: 2
• Duration (Months): 31
• Patients Per Site: 0.8
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Large Cell, Diffuse	Drug: Zevalin	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase III,Open-label,Prospective,Two-armed,Multicenter Study Comparing Zevalin Regimen With no Further Treatment in Patients With Diffuse Large B-cell Lymphoma.
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zevalin 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.	Drug: Zevalin; 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.; Other Names: Ibritumomab tiuxetan
No Intervention: Observational 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).

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) [5 years or until patient dies or lost to follow up]

   The primary analysis was based on the full analysis set (FAS). Actually, the prominent efficacy variable OS was analysed in the FAS (identical to the safety analysis set) and Per Protocol Set using Kaplan Meier estimates by treatment group. "Overall survival" was defined as the median time interval (in months)from randomization to death from any cause.This time-to-event variable was censored at the date of the last known follow-up visit (provided that the patient was still alive at that time).

Secondary Outcome Measures

1. Proportion of Participants With Disease Free Survival (DFS) [5 years or until patient disease progresses or lost to follow up]

   DFS was analysed in the FAS (identical to the safety analysis set) and Per Protocol set using Kaplan Meier estimates by treatment group.Disease-free survival was defined as the median time interval (in months) from randomization to the date of relapse (as assessed by the investigator) or death from any cause. This time-to-event variable was also censored at the date of the last known follow-up visit (provided that the patient was still alive at that time).

2. The Health-related Quality of Life (HRQL) [Up to Month 36]

   HRQL questionnaire consists of 27 questions each scores ranging from 0 - 4. The minimum score was 0 which is termed as 'worst imaginable health state' and the maximum score for a patient was 100 which is termed as 'best imaginable health state'. The descriptive classification defines health status in terms of 5 dimensions: mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. Each dimension is subdivided into 3 levels: no problem, some or moderate problems, unable or extreme problems.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Mesa	Arizona	United States
2	Research Site	Phoenix	Arizona	United States
3	Research Site	Scottsdale	Arizona	United States
4	Research site	Bakersfield	California	United States
5	Research Site	Berkeley	California	United States
6	Research Site	Beverly Hills	California	United States
7	Research Site	Burbank	California	United States
8	Research Site	Duarte	California	United States
9	Research site	Los Angeles	California	United States
10	Research site	Newport Beach	California	United States
11	Research Site	San Diego	California	United States
12	Research site	Vallejo	California	United States
13	Research site	Aurora	Colorado	United States
14	Research site	Newark	Delaware	United States
15	Research site	Saint Petersburg	Florida	United States
16	Research Site	Coeur d'Alene	Idaho	United States
17	Research site	Chicago	Illinois	United States
18	Research site	Joliet	Illinois	United States
19	Research Site	Morris	Illinois	United States
20	Research site	Overland Park	Kansas	United States
21	Research Site	Shreveport	Louisiana	United States
22	Research site	Baltimore	Maryland	United States
23	Research site	Boston	Massachusetts	United States
24	Research site	Detroit	Michigan	United States
25	Research Site	Rochester	Minnesota	United States
26	Research Site	Saint Louis Park	Minnesota	United States
27	Research Site	Commack	New York	United States
28	Research Site	East Setauket	New York	United States
29	Research Site	Durham	North Carolina	United States
30	Research Site	Philadelphia	Pennsylvania	United States
31	Research Site	Aberdeen	South Dakota	United States
32	Research Site	Dallas	Texas	United States
33	Research Site	Houston	Texas	United States
34	Research Site	Norfolk	Virginia	United States
35	Research Site	Graz		Austria
36	Research Site	Innsbruck		Austria
37	Research Site	Brugge		Belgium
38	Research Site	Gent		Belgium
39	Research Site	Leuven		Belgium
40	Research Site	Edmonton	Alberta	Canada
41	Research Site	Ottawa	Ontario	Canada
42	Research Site	Toronto	Ontario	Canada
43	Research Site	Montreal	Quebec	Canada
44	Research Site	Helsinki		Finland
45	Research Site	Oulu		Finland
46	Research Site	Creteil		France
47	Research Site	Dijon		France
48	Research Site	Lille Cedex		France
49	Research Site	Limoges		France
50	Research Site, Cedax	Lyon		France
51	Research Site	Paris Cedex		France
52	Research Site	Toulouse Cedex		France
53	Research Site	Chemnitz		Germany
54	Research Site	Jena		Germany
55	Research Site	Karlsruhe		Germany
56	Research Site	Mainz		Germany
57	Research Site	Rostock		Germany
58	Research Site	Wurzburg		Germany
59	Research Site	Budapest		Hungary
60	Research Site	Debrecen		Hungary
61	Research Site	Szeged		Hungary
62	Research Site	Dublin		Ireland
63	Research Site	Galway		Ireland
64	Research Site	Bologna		Italy
65	Research Site	Milan		Italy
66	Research Site	Perugia		Italy
67	Research Site	Pisa		Italy
68	Research Site	Torino		Italy
69	Research Site, Yonsei	Seoul		Korea, Republic of
70	Research Site	Seoul		Korea, Republic of
71	Research Site	Gdansk		Poland
72	Research Site	Krakow		Poland
73	Research Site	Poznan		Poland
74	Research Site	Warsaw		Poland
75	Research Site	Coimbra		Portugal
76	Research Site	Lisbon		Portugal
77	Research Site	Porto		Portugal
78	Research Site	Singapore		Singapore
79	Research Site	Madrid		Spain
80	Research Site	Pamplona		Spain
81	Research Site	Salamanca		Spain
82	Research Site	Sevilla		Spain
83	Research Site	Malmo		Sweden
84	Research Site	Uddevalla		Sweden
85	Research Site	Umea		Sweden
86	Research Site	Bern		Switzerland
87	Research Site	St Gallen		Switzerland
88	Research Site	Bangkok		Thailand
89	Research Site	Leicester		United Kingdom
90	Research Site	London		United Kingdom

Sponsors and Collaborators

• Spectrum Pharmaceuticals, Inc
• Bayer

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Spectrum Pharmaceuticals, Inc
• ClinicalTrials.gov Identifier: NCT00322218
• Other Study ID Numbers: 307940/106-20
• First Posted: May 5, 2006
• Last Update Posted: Jan 19, 2022
• Last Verified: Jan 1, 2022

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Large B-Cell, Diffuse

Study Results

Participant Flow

Recruitment Details	Diffuse large B-cell lymphoma (DLBCL) Patients at the age of at least 60 years and in complete remission (CR or CRu) after 6 or 8 cycles of a first-line treatment with Cyclophosphamide Doxorubicin hydrochloride Vincristine Prednisolone- Rituximab (CHOP-R) were enrolled in the study.
Pre-assignment Detail	Of the 151 screened patients 68 patients were assigned to treatment (Full analysis set, FAS). Three patients showed major protocol deviations and thus were excluded from the "per protocol set"(PPS). The PPS comprised 65 patients.

Arm/Group Title	Zevalin	Observation
Arm/Group Description	Zevalin Therapeutic Regimen: Day 1: 250 milligram per meter square (mg/m^2) Rituxan followed by 5 millicurie (mCi) 111In Zevalin. Day 7: 250 mg/m^2 Rituxan followed by 0.4 millicurie/kilogram (mCi/kg) Zevalin.	Patients in this arm were diagnosed with diffuse large B-cell lymphoma and were in complete remission after first-line CHOP-R therapy. Patients in this arm did not receive any reference therapy; they remained free of any anti-lymphoma therapy and were observed for relapse.
Period Title: Overall Study
STARTED	34	34
Per-Protocol Set	33	32
COMPLETED	31	28
NOT COMPLETED	3	6

Baseline Characteristics

Arm/Group Title	Zevalin	Observation	Total
Arm/Group Description	Zevalin Therapeutic Regimen: Day 1: 250 mg/m^2 Rituxan followed by 5 mCi 111In Zevalin. Day 7: 250 mg/m^2 Rituxan followed by 0.4 mCi/kg Zevalin.	Patients in this arm were diagnosed with diffuse large B-cell lymphoma and were in complete remission after first-line CHOP-R therapy. Patients in this arm did not receive any reference therapy; they remained free of any anti-lymphoma therapy and were observed for relapse.	Total of all reporting groups
Overall Participants	34	34	68
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	3 8.8%	6 17.6%	9 13.2%
>=65 years	31 91.2%	28 82.4%	59 86.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.2 (4.6)	68.8 (4.8)	69.5 (4.7)
Sex: Female, Male (Count of Participants)
Female	21 61.8%	19 55.9%	40 58.8%
Male	13 38.2%	15 44.1%	28 41.2%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	The primary analysis was based on the full analysis set (FAS). Actually, the prominent efficacy variable OS was analysed in the FAS (identical to the safety analysis set) and Per Protocol Set using Kaplan Meier estimates by treatment group. "Overall survival" was defined as the median time interval (in months)from randomization to death from any cause.This time-to-event variable was censored at the date of the last known follow-up visit (provided that the patient was still alive at that time).
Time Frame	5 years or until patient dies or lost to follow up

Outcome Measure Data

Analysis Population Description

This study was completed in 2008. We have exhausted all efforts and unfortunately, the data cannot be located in our records. Therefore, no data is available to report for this outcome measure.

Arm/Group Title	Zevalin	Observation
Arm/Group Description	Zevalin Therapeutic Regimen: Day 1: 250 mg/m^2 Rituxan followed by 5 mCi 111In Zevalin. Day 7: 250 mg/m^2 Rituxan followed by 0.4 mCi/kg Zevalin.	Patients in this arm were diagnosed with diffuse large B-cell lymphoma and were in complete remission after first-line CHOP-R therapy. Patients in this arm did not receive any reference therapy; they remained free of any anti-lymphoma therapy and were observed for relapse.
Measure Participants	0	0

2. Secondary Outcome

Title	Proportion of Participants With Disease Free Survival (DFS)
Description	DFS was analysed in the FAS (identical to the safety analysis set) and Per Protocol set using Kaplan Meier estimates by treatment group.Disease-free survival was defined as the median time interval (in months) from randomization to the date of relapse (as assessed by the investigator) or death from any cause. This time-to-event variable was also censored at the date of the last known follow-up visit (provided that the patient was still alive at that time).
Time Frame	5 years or until patient disease progresses or lost to follow up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zevalin	Observation
Arm/Group Description	Zevalin Therapeutic Regimen: Day 1: 250 mg/m^2 Rituxan followed by 5 mCi 111In Zevalin. Day 7: 250 mg/m^2 Rituxan followed by 0.4 mCi/kg Zevalin.	Patients in this arm were diagnosed with diffuse large B-cell lymphoma and were in complete remission after first-line CHOP-R therapy. Patients in this arm did not receive any reference therapy; they remained free of any anti-lymphoma therapy and were observed for relapse.
Measure Participants	34	34
Number [proportion of participants]	0.7058 2.1%	0.7957 2.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zevalin, Observation
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.8578
	Comments
	Method	Stratified Log-Rank Test
	Comments

3. Secondary Outcome

Title	The Health-related Quality of Life (HRQL)
Description	HRQL questionnaire consists of 27 questions each scores ranging from 0 - 4. The minimum score was 0 which is termed as 'worst imaginable health state' and the maximum score for a patient was 100 which is termed as 'best imaginable health state'. The descriptive classification defines health status in terms of 5 dimensions: mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. Each dimension is subdivided into 3 levels: no problem, some or moderate problems, unable or extreme problems.
Time Frame	Up to Month 36

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zevalin	Observation
Arm/Group Description	Zevalin Therapeutic Regimen: Day 1: 250 mg/m^2 Rituxan followed by 5 mCi 111In Zevalin. Day 7: 250 mg/m^2 Rituxan followed by 0.4 mCi/kg Zevalin.	Patients in this arm were diagnosed with diffuse large B-cell lymphoma and were in complete remission after first-line CHOP-R therapy. Patients in this arm did not receive any reference therapy; they remained free of any anti-lymphoma therapy and were observed for relapse.
Measure Participants	34	34
Mean (Standard Deviation) [scores on a scale]	84.2 (14.2)	88.7 (12.6)

Adverse Events

Time Frame	Followed up until last anti-lymphoma treatment or 42 months whichever is longer.
Adverse Event Reporting Description	Only study drug-related AEs was collected until the end of Stage 1 in case of a relapse.Patients who relapsed before study treatment were to be followed up in the same way as patients in observation arm,if a patient randomized to the observation arm received treatment for a relapse, no further AE reporting was required.
Arm/Group Title	Zevalin		Observation
Arm/Group Description	Zevalin Therapeutic Regimen: Day 1: 250 mg/m^2 Rituxan followed by 5 mCi 111In Zevalin. Day 7: 250 mg/m^2 Rituxan followed by 0.4 mCi/kg Zevalin.		Patients in this arm were diagnosed with diffuse large B-cell lymphoma and were in complete remission after first-line CHOP-R therapy. Patients in this arm did not receive any reference therapy; they remained free of any anti-lymphoma therapy and were observed for relapse.
All Cause Mortality
	Zevalin		Observation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Zevalin		Observation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/34 (5.9%)		1/34 (2.9%)
Blood and lymphatic system disorders
cytopenia	2/34 (5.9%)	3	1/34 (2.9%)	1
Other (Not Including Serious) Adverse Events
	Zevalin		Observation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/34 (14.7%)		1/34 (2.9%)
Infections and infestations
Infections and manifestations	5/34 (14.7%)	5	1/34 (2.9%)	6

Limitations/Caveats

The study was prematurely terminated after 68 patients had been randomized due to a low recruitment rate that would have led to an unacceptably long study duration.No safety concerns or lack of efficacy had led to the decision to cancel the study.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.