A Study of MabThera (Rituximab) Addition to Regularly Prescribed Chemotherapy in Patients With Untreated Mantle Cell Lymphoma.

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01144403
• Collaborator: (none)
• Enrollment: 8
• Locations: 8
• Arm: 1
• Duration (Months): 50
• Patient Per Site: 1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This multicenter, open-label study will assess the efficacy and safety of MabThera (rituximab) added to standard chemotherapy in participants with untreated Mantle Cell Lymphoma not eligible for autologous stem cell transplantation. Participants will receive MabThera (372 mg/m^2 intravenously) on Day 1 of each 28-day treatment cycle in addition to standard chemotherapy for 6 cycles. In participants experiencing complete or partial response, MabThera will be continued as consolidation therapy for 2 more cycles.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Large B-Cell Lymphoma	Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Rituximab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Multicenter Open-label Study of MabThera(Rituximab) Addition to Regularly Prescribed Chemotherapy in Patients With Untreated Mantle Cell Lymphoma
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rituximab Rituximab, 375 milligram per meter square (mg/m^2) was given intravenously on Day 1 and then every 28 days (+/-7 days) for 6 cycles, followed by 2 consolidated infusions in responders as rituximab induction therapy. Rituximab infusions were administered concomitantly with prescribed chemotherapy i.e., fludarabine, cyclophosphamide and mitoxantrone (maximum 6 cycles).	Drug: Cyclophosphamide; as prescribed, 6 cycles; Drug: Fludarabine; as prescribed, 6 cycles; Drug: Mitoxantrone; as prescribed, 6 cycles; Drug: Rituximab; 375 mg/m^2 intravenously, Day 1 of each 28-day cycle, up to 8 cycles; Other Names: Mabthera/Rituxan

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) [Up to 50 months (approximately)]

   Overall Response Rate (ORR) was determined by tumor response according to International Workshop Group to Standardize Response Criteria for mantle cell lymphoma (MCL) criteria from confirmed evaluations of both target, radiographically evaluated, and non-target lesions. A responder is defined as a subject experiencing either a complete (CR)/ unconfirmed complete (Cru), or partial response (PR) by these criteria. As per criteria; CR = disappearance of all evidence of disease; CRu = the sum of the product of the diameters (SPD) of multiple nodes decreased by at least 75%; PR = regression of measurable disease and no new sites.

Secondary Outcome Measures

1. Overall Survival (OS) [From the time of enrollment until death due to any cause (up to 50 months [approximately])]

   Overall survival is defined as time from date of enrollment to the date of death, regardless of the cause of death.

2. Progression-free Survival (PFS) [From the time of enrollment until death due to any cause (up to 50 months [approximately])]

   PFS is defined as the interval between the day of enrollment and the first documentation of progressive disease or death. Progression of disease is defined as at least a 20 percent (%) increase in the sum of longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions.

3. Number of Participant With Adverse Event (AE) [Up to 50 months (approximately)]

   An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with study treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• adult participants, >/=18 years of age

• untreated Mantle Cell Lymphoma, not eligible for Autologous Stem Cell Transplantation

• known mantle cell lymphoma international prognostic index (MIPI) at diagnosis

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• adequate hematological, renal and hepatic function

Exclusion Criteria:

• known hypersensitivity to murine proteins or chemotherapy regimen

• previous first-line therapy

• history of other malignancy within the last 5 years, except for squamous cell carcinoma, basal cell carcinoma of the skin or in situ cervical carcinoma

• active infection

• clinically significant cardiac disease

• regular corticosteroid treatment in the 4 weeks prior to first dose of study drug

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Brasov		Romania	500326
2		Bucharest		Romania	005098
3		Bucharest		Romania	022328
4		Bucuresti		Romania	030171
5		Cluj-Napoca		Romania	400015
6		Iasi		Romania	700111
7		Targu-mures		Romania	540136
8		Timisoara		Romania	300079

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01144403
• Other Study ID Numbers: ML22489; 2009-011433-27
• First Posted: Jun 15, 2010
• Last Update Posted: Oct 18, 2016
• Last Verified: Jul 1, 2016

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Mantle-Cell; Lymphoma, Large B-Cell, Diffuse; Cyclophosphamide; Rituximab; Fludarabine; Mitoxantrone

Study Results

Participant Flow

Pre-assignment Detail	A total 8 participants were enrolled from Romania.

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab, 375 milligram per meter square (mg/m^2) was given intravenously on Day 1 and then every 28 days (+/-7 days) for 6 cycles, followed by 2 consolidated infusions in responders as rituximab induction therapy. Rituximab infusions were administered concomitantly with prescribed chemotherapy i.e., fludarabine, cyclophosphamide and mitoxantrone (maximum 6 cycles). Cyclophosphamide: as prescribed, 6 cycles Fludarabine: as prescribed, 6 cycles Mitoxantrone: as prescribed, 6 cycles Rituximab [Mabthera/Rituxan]: 375 mg/m^2 intravenously, Day 1 of each 28-day cycle, up to 8 cycles
Period Title: Overall Study
STARTED	8
COMPLETED	3
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab, 375 milligram per meter square (mg/m^2) was given intravenously on Day 1 and then every 28 days (+/-7 days) for 6 cycles, followed by 2 consolidated infusions in responders as rituximab induction therapy. Rituximab infusions were administered concomitantly with regularly prescribed chemotherapy i.e., fludarabine, cyclophosphamide and mitoxantrone (maximum 6 cycles). Cyclophosphamide: as prescribed, 6 cycles Fludarabine: as prescribed, 6 cycles Mitoxantrone: as prescribed, 6 cycles Rituximab [Mabthera/Rituxan]: 375 mg/m^2 intravenously, Day 1 of each 28-day cycle, up to 8 cycles
Overall Participants	8
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.50 (7.964)
Sex: Female, Male (Count of Participants)
Female	3 37.5%
Male	5 62.5%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR)
Description	Overall Response Rate (ORR) was determined by tumor response according to International Workshop Group to Standardize Response Criteria for mantle cell lymphoma (MCL) criteria from confirmed evaluations of both target, radiographically evaluated, and non-target lesions. A responder is defined as a subject experiencing either a complete (CR)/ unconfirmed complete (Cru), or partial response (PR) by these criteria. As per criteria; CR = disappearance of all evidence of disease; CRu = the sum of the product of the diameters (SPD) of multiple nodes decreased by at least 75%; PR = regression of measurable disease and no new sites.
Time Frame	Up to 50 months (approximately)

Outcome Measure Data

Analysis Population Description

Efficacy population included all the participants who had received at least one dose of study treatment.

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab, 375 milligram per meter square (mg/m^2) was given intravenously on day 1 and then every 28 days (+/-7 days) for 6 cycles, followed by 2 consolidated infusions in responders as rituximab induction therapy for mantle cell lymphoma. Rituximab infusions were administered concomitantly with regularly prescribed chemotherapy i.e., fludarabine, cyclophosphamide and mitoxantrone (maximum 6 cycles). cyclophosphamide: as prescribed, 6 cycles fludarabine: as prescribed, 6 cycles mitoxantrone: as prescribed, 6 cycles rituximab [Mabthera/Rituxan]: 375 mg/m^2 intravenously, day 1 of each 28-day cycle, up to 8 cycles
Measure Participants	8
Number [percentage of participants]	87.5 1093.8%

2. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival is defined as time from date of enrollment to the date of death, regardless of the cause of death.
Time Frame	From the time of enrollment until death due to any cause (up to 50 months [approximately])

Outcome Measure Data

Analysis Population Description

Efficacy population included all the participants who had received at least one dose of study treatment.

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab, 375 milligram per meter square (mg/m^2) was given intravenously on Day 1 and then every 28 days (+/-7 days) for 6 cycles, followed by 2 consolidated infusions in responders as rituximab induction therapy. Rituximab infusions were administered concomitantly with prescribed chemotherapy i.e., fludarabine, cyclophosphamide and mitoxantrone (maximum 6 cycles). Cyclophosphamide: as prescribed, 6 cycles Fludarabine: as prescribed, 6 cycles Mitoxantrone: as prescribed, 6 cycles Rituximab [Mabthera/Rituxan]: 375 mg/m^2 intravenously, Day 1 of each 28-day cycle, up to 8 cycles
Measure Participants	8
Median (95% Confidence Interval) [days]	927

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS is defined as the interval between the day of enrollment and the first documentation of progressive disease or death. Progression of disease is defined as at least a 20 percent (%) increase in the sum of longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions.
Time Frame	From the time of enrollment until death due to any cause (up to 50 months [approximately])

Outcome Measure Data

Analysis Population Description

Efficacy population included all the participants who had received at least one dose of study treatment.

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab, 375 milligram per meter square (mg/m^2) was given intravenously on Day 1 and then every 28 days (+/-7 days) for 6 cycles, followed by 2 consolidated infusions in responders as rituximab induction therapy. Rituximab infusions were administered concomitantly with prescribed chemotherapy i.e., fludarabine, cyclophosphamide and mitoxantrone (maximum 6 cycles). Cyclophosphamide: as prescribed, 6 cycles Fludarabine: as prescribed, 6 cycles Mitoxantrone: as prescribed, 6 cycles Rituximab [Mabthera/Rituxan]: 375 mg/m^2 intravenously, Day 1 of each 28-day cycle, up to 8 cycles
Measure Participants	8
Median (95% Confidence Interval) [days]	653

4. Secondary Outcome

Title	Number of Participant With Adverse Event (AE)
Description	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with study treatment.
Time Frame	Up to 50 months (approximately)

Outcome Measure Data

Analysis Population Description

Safety population included all the participants who had received at least one dose of study treatment.

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab, 375 milligram per meter square (mg/m^2) was given intravenously on Day 1 and then every 28 days (+/-7 days) for 6 cycles, followed by 2 consolidated infusions in responders as rituximab induction therapy. Rituximab infusions were administered concomitantly with prescribed chemotherapy i.e., fludarabine, cyclophosphamide and mitoxantrone (maximum 6 cycles). Cyclophosphamide: as prescribed, 6 cycles Fludarabine: as prescribed, 6 cycles Mitoxantrone: as prescribed, 6 cycles Rituximab [Mabthera/Rituxan]: 375 mg/m^2 intravenously, Day 1 of each 28-day cycle, up to 8 cycles
Measure Participants	8
Number [participants]	8 100%

Adverse Events

Time Frame	Up to approximately 50 months
Arm/Group Title	Rituximab
Arm/Group Description	Rituximab, 375 milligram per meter square (mg/m^2) was given intravenously on Day 1 and then every 28 days (+/-7 days) for 6 cycles, followed by 2 consolidated infusions in responders as rituximab induction therapy. Rituximab infusions were administered concomitantly with prescribed chemotherapy i.e., fludarabine, cyclophosphamide and mitoxantrone (maximum 6 cycles). Cyclophosphamide: as prescribed, 6 cycles Fludarabine: as prescribed, 6 cycles Mitoxantrone: as prescribed, 6 cycles Rituximab [Mabthera/Rituxan]: 375 mg/m^2 intravenously, Day 1 of each 28-day cycle, up to 8 cycles
All Cause Mortality
	Rituximab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Rituximab
	Affected / at Risk (%)	# Events
Total	3/8 (37.5%)
Infections and infestations
Pneumonia	1/8 (12.5%)
Neutropenia	1/8 (12.5%)
Injury, poisoning and procedural complications
Toxicity	1/8 (12.5%)
Other (Not Including Serious) Adverse Events
	Rituximab
	Affected / at Risk (%)	# Events
Total	8/8 (100%)
Blood and lymphatic system disorders
Anemia	3/8 (37.5%)
Leucopenia	4/8 (50%)
Neutropenia	2/8 (25%)
Thrombocytopenia	5/8 (62.5%)
ß2-microglobuline ↗	1/8 (12.5%)
C- reactive protein	1/8 (12.5%)
Cardiac disorders
Supraventricular arrhythmia	1/8 (12.5%)
Gastrointestinal disorders
Gastric Pain	1/8 (12.5%)
Hepatobiliary disorders
Hepatitis Ag HBS+	1/8 (12.5%)
Infections and infestations
Herpes	1/8 (12.5%)
Oral Candidiasis	1/8 (12.5%)
Injury, poisoning and procedural complications
Drug Eruption	2/8 (25%)
Metabolism and nutrition disorders
Hyperglycemia	1/8 (12.5%)
Nervous system disorders
Vertiginous syndrome	1/8 (12.5%)
Respiratory, thoracic and mediastinal disorders
Tracheitis	1/8 (12.5%)
Respiratory Virosis	1/8 (12.5%)
Skin and subcutaneous tissue disorders
Dermatitis Eczematous	1/8 (12.5%)
Rash	1/8 (12.5%)
Vascular disorders
Ascending Aorta Dilatation	1/8 (12.5%)

Limitations/Caveats

The study was prematurely terminated with 8 participants enrolled, all of them are included into the statistical analyses.

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.