A Study of MabThera (Rituximab) Plus Standard Chemotherapy in Patients With Previously Untreated Mantle Cell Lymphoma.

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00472420
• Collaborator: (none)
• Enrollment: 48
• Locations: 7
• Arm: 1
• Actual Duration (Months): 46.9
• Patients Per Site: 6.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This single arm study will evaluate the benefit of adding MabThera to standard induction chemotherapy in patients with newly diagnosed mantle cell lymphoma. The safety and tolerability of a MabThera-containing first line regimen will also be assessed. All patients will receive MabThera (375mg/m2 iv) every 3 weeks for 8 cycles, in combination with standard chemotherapy. The anticipated time on study treatment is 3-12 months, and the target sample size is <100 individuals.

Condition or Disease	Intervention/Treatment	Phase
Mantle Cell Lymphoma	Drug: rituximab [MabThera/Rituxan]; Drug: First line chemotherapy	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label Study of the Effect of the Addition of MabThera to Standard Chemotherapy on Clinical Response in Patients With Previously Untreated Mantle Cell Lymphoma
• Actual Study Start Date: Jun 27, 2007
• Actual Primary Completion Date: May 25, 2011
• Actual Study Completion Date: May 25, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	Drug: rituximab [MabThera/Rituxan]; 375mg/m2 iv every 3 weeks; Drug: First line chemotherapy; As prescribed

Outcome Measures

Primary Outcome Measures

1. Number of Participants Achieving Complete Remission (CR) (Including Unconfirmed CR [CR(u)]) or Partial Remission (PR) [Screening, Baseline (BL), every 21 days thereafter up to Week 27, every 3 months thereafter up to Month 24, Withdrawal Visit (4 weeks after discontinuation of study treatment)]

   CR was defined by: a) disappearance of clinical/radiographic evidence of disease, disease-related symptoms, and biochemical abnormalities; b) decrease in lymph nodes (LNs) greater than (>) 1.5 centimeters (cm) in greatest transverse diameter (GTD) to less than (<) 1.5 cm, a decrease in LNs 1.1 - 1.5 cm to 1 cm or 75 percent (%) decrease in sum of the products of GTD (SPD); c) non-palpable spleen, decreased size of enlarged organs, and disappearance of nodules; and d) disappearance of bone marrow (BM) infiltrate. CR(u) was defined as fulfilling a) and c), above, with greater than or equal to (≥) 1 of the following: a) > 75% decrease in SPD of LNs > 1.5 cm, and > 75% decrease in SPD of previously confluent LNs; b) indeterminate BM, or c) confirmed CR. PR was defined by: a) 50% decrease in SPD of the 6 largest LNs; b) no increase in LNs, liver, or spleen size; c) ≥ 50% decrease in splenic and hepatic nodule SPDs; d) no measurable disease in other organs; and e) no new sites of disease.

Secondary Outcome Measures

1. Progression Free Survival (PFS) [Screening, BL, every 21 days thereafter up to Week 27, every 3 months thereafter up to Month 24, Withdrawal Visit (4 weeks after discontinuation of study treatment)]

   PFS was defined as the median time, in months, from the date of study entry to disease progression, death due to mantle cell lymphoma, or last contact. Progressive disease (PD) was defined by: a) 50% increase from nadir in the SPD of any previously identified abnormal LN, or b) appearance of any new lesion during or at the end of treatment. The 95% confidence interval (CI) was estimated using Kaplan-Meier methodology.

2. Event Free Survival (EFS) [Screening, BL, every 21 days thereafter up to Week 27, every 3 months thereafter up to Month 24, Withdrawal Visit (4 weeks after discontinuation of study treatment)]

   EFS was defined as the median time, in months, from the date of study entry disease progression, relapse, secondary malignancy, death or last contact. Relapse was defined by: a) appearance of any new lesion or a ≥ 50% increase in size of previously involved sites, or b) ≥ 50% increase in GTD of any previously identified LN >1 cm in short axis or in the SPD of more than one LN. The 95% CI was estimated using Kaplan-Meier methodology.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• histologically-proven mantle cell lymphoma;

• previously untreated disease at stage II, III and IV, requiring therapy.

Exclusion Criteria:

• known hypersensitivity reaction to rituximab, or known anti-murine antibody reactivity or known hypersensitivity to murine antibodies;

• active malignancy other than mantle cell lymphoma within 5 years of start of study, with the exception of resected basal cell cancer, squamous cell cancer of the skin, or in situ cancer of the cervix;

• serious disorders interfering with full standard dosing chemotherapy;

• stage I disease.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institute of Oncology, A Dept of Internal Medicine	Budapest		Hungary	1122
2	University of Debrecen Medical and Health Science Center, Institute of Internal Medicine, Hematology	Debrecen		Hungary	4032
3	Petz Aladar Megyei Korhaz; Hematologia	Gyor		Hungary	9024
4	Kaposi Mor Teaching Hospital, Dept of Internal Medicine/Hematology	Kaposvar		Hungary	7400
5	Miskolci Semmelweis Korhaz; Ii Belgyogyaszat	Miskolc		Hungary	3529
6	University of Szeged, II Dept of Internal Medicine	Szeged		Hungary	6720
7	Zala Megyei Korhaz; Ii. Belgyogyaszat	Zalaegerszeg		Hungary	8901

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: NCT00472420
• Other Study ID Numbers: ML20493
• First Posted: May 11, 2007
• Last Update Posted: Aug 15, 2017
• Last Verified: Jun 1, 2017

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Mantle-Cell; Rituximab

Study Results

Participant Flow

Arm/Group Title	Rituximab Plus (+) Chemotherapy
Arm/Group Description	Participants received rituximab, 375 milligrams per square meter (mg/m^2), intravenously (IV), on Day 1 of Cycles 1-8 (21-day cycle). Participants also received 1 of the following chemotherapies: CHOP, Cycles 1-8: cyclophosphamide, 750 mg/m^2, IV, doxorubicin, 50 mg/m^2, IV, or epirubicin, 70 mg/m^2, IV, vincristine, 1.4 mg/m^2, IV, on Day 1 of Cycles 1-8, and methylprednisolone, 16 mg/d, IV or orally (PO), on Days 1-5. OR Hyper-CVAD/M-A, Cycles 1, 3, 5, and 7: cyclophosphamide, 300 mg/m^2, IV, every 12 hours (q12h) on Days 2-4; mesna, 600 mg/m^2, IV, 1 hour before the start of cyclophosphamide on Days 2-4; doxorubicin, 50 mg/m^2, IV, or epirubicin, 70 mg/m^2, IV, on Day 5; vincristine, 1.4 mg/m^2, IV, on Days 5 and 12; and dexamethasone, IV or PO, 40 mg/day on Days 2-5 and Days 12-15. Hyper-CVAD/M-A, Cycles 2, 4, 6, and 8: methotrexate, 200 mg/m^2, IV, followed by 800 mg/m^2, IV, on Day 2; cytarabine, 3000 mg/m^2, IV over 2 hours, q12h on Day 3 (2 doses) or Days 3-4 (4 doses).
Period Title: Induction Treatment Period
STARTED	48
COMPLETED	32
NOT COMPLETED	16
Period Title: Induction Treatment Period
STARTED	32
COMPLETED	15
NOT COMPLETED	17

Baseline Characteristics

Arm/Group Title	Rituximab + Chemotherapy
Arm/Group Description	Participants received rituximab, 375 mg/m^2, IV, on Day 1 of Cycles 1-8 (21-day cycle). Participants also received 1 of the following chemotherapies: CHOP, Cycles 1-8: cyclophosphamide, 750 mg/m^2, IV, doxorubicin, 50 mg/m^2, IV, or epirubicin, 70 mg/m^2, IV, vincristine, 1.4 mg/m^2, IV, on Day 1 of Cycles 1-8, and methylprednisolone, 16 mg/d, IV or PO, on Days 1-5. OR Hyper-CVAD/M-A, Cycles 1, 3, 5, and 7: cyclophosphamide, 300 mg/m^2, IV, q12h on Days 2-4; mesna, 600 mg/m^2, IV, 1 hour before the start of cyclophosphamide on Days 2-4; doxorubicin, 50 mg/m^2, IV, or epirubicin, 70 mg/m^2, IV, on Day 5; vincristine, 1.4 mg/m^2, IV, on Days 5 and 12; and dexamethasone, IV or PO, 40 mg/day on Days 2-5 and Days 12-15. Hyper-CVAD/M-A, Cycles 2, 4, 6, and 8: methotrexate, 200 mg/m^2, IV, followed by 800 mg/m^2, IV, on Day 2; cytarabine, 3000 mg/m^2, IV over 2 hours, q12h on Day 3 (2 doses) or Days 3-4 (4 doses).
Overall Participants	48
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	70.20
Sex: Female, Male (Count of Participants)
Female	16 33.3%
Male	32 66.7%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Achieving Complete Remission (CR) (Including Unconfirmed CR [CR(u)]) or Partial Remission (PR)
Description	CR was defined by: a) disappearance of clinical/radiographic evidence of disease, disease-related symptoms, and biochemical abnormalities; b) decrease in lymph nodes (LNs) greater than (>) 1.5 centimeters (cm) in greatest transverse diameter (GTD) to less than (<) 1.5 cm, a decrease in LNs 1.1 - 1.5 cm to 1 cm or 75 percent (%) decrease in sum of the products of GTD (SPD); c) non-palpable spleen, decreased size of enlarged organs, and disappearance of nodules; and d) disappearance of bone marrow (BM) infiltrate. CR(u) was defined as fulfilling a) and c), above, with greater than or equal to (≥) 1 of the following: a) > 75% decrease in SPD of LNs > 1.5 cm, and > 75% decrease in SPD of previously confluent LNs; b) indeterminate BM, or c) confirmed CR. PR was defined by: a) 50% decrease in SPD of the 6 largest LNs; b) no increase in LNs, liver, or spleen size; c) ≥ 50% decrease in splenic and hepatic nodule SPDs; d) no measurable disease in other organs; and e) no new sites of disease.
Time Frame	Screening, Baseline (BL), every 21 days thereafter up to Week 27, every 3 months thereafter up to Month 24, Withdrawal Visit (4 weeks after discontinuation of study treatment)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Rituximab + Chemotherapy
Arm/Group Description	Participants received rituximab, 375 mg/m^2, IV, on Day 1 of Cycles 1-8 (21-day cycle). Participants also received 1 of the following chemotherapies: CHOP, Cycles 1-8: cyclophosphamide, 750 mg/m^2, IV, doxorubicin, 50 mg/m^2, IV, or epirubicin, 70 mg/m^2, IV, vincristine, 1.4 mg/m^2, IV, on Day 1 of Cycles 1-8, and methylprednisolone, 16 mg/d, IV or PO, on Days 1-5. OR Hyper-CVAD/M-A, Cycles 1, 3, 5, and 7: cyclophosphamide, 300 mg/m^2, IV, q12h on Days 2-4; mesna, 600 mg/m^2, IV, 1 hour before the start of cyclophosphamide on Days 2-4; doxorubicin, 50 mg/m^2, IV, or epirubicin, 70 mg/m^2, IV, on Day 5; vincristine, 1.4 mg/m^2, IV, on Days 5 and 12; and dexamethasone, IV or PO, 40 mg/day on Days 2-5 and Days 12-15. Hyper-CVAD/M-A, Cycles 2, 4, 6, and 8: methotrexate, 200 mg/m^2, IV, followed by 800 mg/m^2, IV, on Day 2; cytarabine, 3000 mg/m^2, IV over 2 hours, q12h on Day 3 (2 doses) or Days 3-4 (4 doses).
Measure Participants	48
CR	19 39.6%
PR	8 16.7%

2. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the median time, in months, from the date of study entry to disease progression, death due to mantle cell lymphoma, or last contact. Progressive disease (PD) was defined by: a) 50% increase from nadir in the SPD of any previously identified abnormal LN, or b) appearance of any new lesion during or at the end of treatment. The 95% confidence interval (CI) was estimated using Kaplan-Meier methodology.
Time Frame	Screening, BL, every 21 days thereafter up to Week 27, every 3 months thereafter up to Month 24, Withdrawal Visit (4 weeks after discontinuation of study treatment)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Rituximab + Chemotherapy
Arm/Group Description	Participants received rituximab, 375 mg/m^2, IV, on Day 1 of Cycles 1-8 (21-day cycle). Participants also received 1 of the following chemotherapies: CHOP, Cycles 1-8: cyclophosphamide, 750 mg/m^2, IV, doxorubicin, 50 mg/m^2, IV, or epirubicin, 70 mg/m^2, IV, vincristine, 1.4 mg/m^2, IV, on Day 1 of Cycles 1-8, and methylprednisolone, 16 mg/d, IV or PO, on Days 1-5. OR Hyper-CVAD/M-A, Cycles 1, 3, 5, and 7: cyclophosphamide, 300 mg/m^2, IV, q12h on Days 2-4; mesna, 600 mg/m^2, IV, 1 hour before the start of cyclophosphamide on Days 2-4; doxorubicin, 50 mg/m^2, IV, or epirubicin, 70 mg/m^2, IV, on Day 5; vincristine, 1.4 mg/m^2, IV, on Days 5 and 12; and dexamethasone, IV or PO, 40 mg/day on Days 2-5 and Days 12-15. Hyper-CVAD/M-A, Cycles 2, 4, 6, and 8: methotrexate, 200 mg/m^2, IV, followed by 800 mg/m^2, IV, on Day 2; cytarabine, 3000 mg/m^2, IV over 2 hours, q12h on Day 3 (2 doses) or Days 3-4 (4 doses).
Measure Participants	48
Median (95% Confidence Interval) [months]	30.456

3. Secondary Outcome

Title	Event Free Survival (EFS)
Description	EFS was defined as the median time, in months, from the date of study entry disease progression, relapse, secondary malignancy, death or last contact. Relapse was defined by: a) appearance of any new lesion or a ≥ 50% increase in size of previously involved sites, or b) ≥ 50% increase in GTD of any previously identified LN >1 cm in short axis or in the SPD of more than one LN. The 95% CI was estimated using Kaplan-Meier methodology.
Time Frame	Screening, BL, every 21 days thereafter up to Week 27, every 3 months thereafter up to Month 24, Withdrawal Visit (4 weeks after discontinuation of study treatment)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Rituximab + Chemotherapy
Arm/Group Description	Participants received rituximab, 375 mg/m^2, IV, on Day 1 of Cycles 1-8 (21-day cycle). Participants also received 1 of the following chemotherapies: CHOP, Cycles 1-8: cyclophosphamide, 750 mg/m^2, IV, doxorubicin, 50 mg/m^2, IV, or epirubicin, 70 mg/m^2, IV, vincristine, 1.4 mg/m^2, IV, on Day 1 of Cycles 1-8, and methylprednisolone, 16 mg/d, IV or PO, on Days 1-5. OR Hyper-CVAD/M-A, Cycles 1, 3, 5, and 7: cyclophosphamide, 300 mg/m^2, IV, q12h on Days 2-4; mesna, 600 mg/m^2, IV, 1 hour before the start of cyclophosphamide on Days 2-4; doxorubicin, 50 mg/m^2, IV, or epirubicin, 70 mg/m^2, IV, on Day 5; vincristine, 1.4 mg/m^2, IV, on Days 5 and 12; and dexamethasone, IV or PO, 40 mg/day on Days 2-5 and Days 12-15. Hyper-CVAD/M-A, Cycles 2, 4, 6, and 8: methotrexate, 200 mg/m^2, IV, followed by 800 mg/m^2, IV, on Day 2; cytarabine, 3000 mg/m^2, IV over 2 hours, q12h on Day 3 (2 doses) or Days 3-4 (4 doses).
Measure Participants	48
Median (95% Confidence Interval) [months]	40.049

Adverse Events

Time Frame	Adverse events (AEs) were recorded throughout the study up to 3 months after the last study drug administration.
Adverse Event Reporting Description	All participants who received at least 1 dose of study treatment were included in the safety analysis.
Arm/Group Title	Rituximab + Chemotherapy
Arm/Group Description	Participants received rituximab, 375 mg/m^2, IV, on Day 1 of Cycles 1-8 (21-day cycle). Participants also received 1 of the following chemotherapies: CHOP, Cycles 1-8: cyclophosphamide, 750 mg/m^2, IV, doxorubicin, 50 mg/m^2, IV, or epirubicin, 70 mg/m^2, IV, vincristine, 1.4 mg/m^2, IV, on Day 1 of Cycles 1-8, and methylprednisolone, 16 mg/d, IV or PO, on Days 1-5. OR Hyper-CVAD/M-A, Cycles 1, 3, 5, and 7: cyclophosphamide, 300 mg/m^2, IV, q12h on Days 2-4; mesna, 600 mg/m^2, IV, 1 hour before the start of cyclophosphamide on Days 2-4; doxorubicin, 50 mg/m^2, IV, or epirubicin, 70 mg/m^2, IV, on Day 5; vincristine, 1.4 mg/m^2, IV, on Days 5 and 12; and dexamethasone, IV or PO, 40 mg/day on Days 2-5 and Days 12-15. Hyper-CVAD/M-A, Cycles 2, 4, 6, and 8: methotrexate, 200 mg/m^2, IV, followed by 800 mg/m^2, IV, on Day 2; cytarabine, 3000 mg/m^2, IV over 2 hours, q12h on Day 3 (2 doses) or Days 3-4 (4 doses).
All Cause Mortality
	Rituximab + Chemotherapy
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Rituximab + Chemotherapy
	Affected / at Risk (%)	# Events
Total	25/48 (52.1%)
Blood and lymphatic system disorders
Thrombocytopenia	4/48 (8.3%)
Febrile neutropenia	3/48 (6.3%)
Pancytopenia	4/48 (8.3%)
Anaemia	6/48 (12.5%)
Granulocytopenia	1/48 (2.1%)
Neutropenia	1/48 (2.1%)
Bone marrow failure	1/48 (2.1%)
Agranulocytosis	4/48 (8.3%)
Cardiac disorders
Arrythmia	1/48 (2.1%)
Atrial fibrillation	1/48 (2.1%)
Ventricular tachycardia	1/48 (2.1%)
Acute coronaria syndrome	1/48 (2.1%)
Heart injury	1/48 (2.1%)
Gastrointestinal disorders
Nausea	1/48 (2.1%)
Diarrhoea	1/48 (2.1%)
General disorders
Pyrexia	3/48 (6.3%)
Disease recurrence	1/48 (2.1%)
Infections and infestations
Septic shock	1/48 (2.1%)
Pneumonia	4/48 (8.3%)
Sepsis	2/48 (4.2%)
Sinusitis	1/48 (2.1%)
Periproctal abscess	1/48 (2.1%)
Encephalomalacia	1/48 (2.1%)
Metabolism and nutrition disorders
Hyperglycaemia	2/48 (4.2%)
Musculoskeletal and connective tissue disorders
Muscular weakness	1/48 (2.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Progression of pre-existing cancer	1/48 (2.1%)
Nervous system disorders
Transient ischaemic attack	1/48 (2.1%)
Renal and urinary disorders
Renal failure acute	1/48 (2.1%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/48 (2.1%)
Pleurlopneumonia	1/48 (2.1%)
Pneumothorax	1/48 (2.1%)
Bronchospasm	1/48 (2.1%)
Skin and subcutaneous tissue disorders
Urticaria, perioral tingling	1/48 (2.1%)
Surgical and medical procedures
Tumour excision	1/48 (2.1%)
Vascular disorders
Deep vein thrombosis	2/48 (4.2%)
Haemorrhage	1/48 (2.1%)
Hypertensive crisis	1/48 (2.1%)
Other (Not Including Serious) Adverse Events
	Rituximab + Chemotherapy
	Affected / at Risk (%)	# Events
Total	23/48 (47.9%)
Blood and lymphatic system disorders
Bacteremia	1/48 (2.1%)
Thrombocytopenia	4/48 (8.3%)
Agranulocytosis	5/48 (10.4%)
Pancytopenia	2/48 (4.2%)
Anaemia	1/48 (2.1%)
Febrile neutropenia	1/48 (2.1%)
Neutropenia	1/48 (2.1%)
Bone marrow toxicity	1/48 (2.1%)
Cardiac disorders
Carotid sinus syndrome	1/48 (2.1%)
Eye disorders
Ulcus corneae	1/48 (2.1%)
Gastrointestinal disorders
Diarrhoea infectious	1/48 (2.1%)
Diarrhoea	2/48 (4.2%)
Nausea	1/48 (2.1%)
Choking sensation	1/48 (2.1%)
General disorders
Chills	4/48 (8.3%)
Pyrexia	3/48 (6.3%)
Chilliness	1/48 (2.1%)
Pain	1/48 (2.1%)
Hepatobiliary disorders
Hepatic function abnormal	1/48 (2.1%)
Infections and infestations
Herpes zoster	1/48 (2.1%)
Helicobacter test positive	1/48 (2.1%)
Pneumonia	2/48 (4.2%)
Oral thrush	1/48 (2.1%)
Prostatitis	1/48 (2.1%)
Gastroenteritis	1/48 (2.1%)
Herpes labialis	1/48 (2.1%)
Upper respiratory tract infection	1/48 (2.1%)
Injury, poisoning and procedural complications
Patella fracture	1/48 (2.1%)
Renal and urinary disorders
Renal failure	1/48 (2.1%)
Respiratory, thoracic and mediastinal disorders
Hydrothorax	1/48 (2.1%)
Skin and subcutaneous tissue disorders
Pruritus cutaneous	1/48 (2.1%)
Toxicoderma	1/48 (2.1%)
Toxic skin eruption	1/48 (2.1%)
Vascular disorders
Thrombophlebitis	1/48 (2.1%)

Limitations/Caveats

[Not Specified]

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.