S0213 Chemotherapy Plus Rituximab in Treating Patients With Mantle Cell Lymphoma

• Sponsor: Southwest Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00041132
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 56
• Arm: 1
• Duration (Months): 105

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Combining rituximab with chemotherapy may kill more cancer cells.

PURPOSE: Phase II pilot study to study the effectiveness of combining chemotherapy with rituximab in treating patients who have newly diagnosed mantle cell lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Biological: filgrastim; Biological: rituximab; Drug: cyclophosphamide; Drug: cytarabine; Drug: dexamethasone; Drug: doxorubicin; Drug: leucovorin; Drug: methotrexate; Drug: vincristine	Phase 2

Detailed Description

OBJECTIVES:

• Determine the 1-year progression-free survival probability in patients with previously untreated mantle cell lymphoma treated with courses of rituximab and cyclophosphamide, doxorubicin, vincristine, and dexamethasone alternating with courses of rituximab and high-dose cytarabine and methotrexate with leucovorin calcium.

• Determine the response rate (complete unconfirmed and complete and partial responses) and survival of patients treated with this regimen.

• Determine the toxicity of this regimen in these patients.

• Correlate chromosomal breakpoints, translocated immunoglobulin regulatory sequences, and cyclins D1, D2, and D3 with response and progression-free survival in patients treated with this regimen.

• Correlate gene expression (measured by DNA microarray analysis) with response and progression-free survival in patients treated with this regimen.

OUTLINE: This is a pilot, multicenter study.

• Courses 1, 3, 5, and 7: Patients receive rituximab IV on day 1 (courses 1, 3, and 5 only); cyclophosphamide IV over 3 hours twice a day on days 2-4; doxorubicin IV over 24 hours on days 5-7; vincristine IV on days 5 and 12; dexamethasone orally or IV four times a day on days 2-5 and 12-15; and filgrastim (G-CSF) subcutaneously (SC) daily beginning on day 8 and continuing until blood counts recover.

• Courses 2, 4, 6, and 8: Patients receive rituximab IV on day 1 (courses 2, 4, and 6 only); high-dose methotrexate IV over 24 hours on day 2; high-dose cytarabine IV over 2 hours twice a day on days 3-4; oral leucovorin calcium 4 times a day on days 3-10; and G-CSF SC daily beginning on day 5 and continuing until blood counts recover.

Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients are followed within 30 days, every 3 months for 2 years, and then every 6 months for 3 years. Patients with disease progression are followed annually for up to 5 years from study entry.

PROJECTED ACCRUAL: Approximately 50 patients will be accrued for this study within 25 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Trial of Hyper-CVAD and Methotrexate/ARA C Plus Rituximab in Patients With Previously Untreated Mantle Cell Lymphoma
• Study Start Date: Sep 1, 2002
• Actual Primary Completion Date: Nov 1, 2007
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Hyper-CVAD + MTX/Ara-C + Rituximab 21-day cycles of Hyper-CVAD and high-dose methotrexate/cytarabine are alternated beginning with Hyper-CVAD for a maximum of 8 cycles. Rituximab is given for cycles 1-6. Hyper-CVAD (cycles 1,3,5,7): rituximab 375 mg/m^2 on day 1, mesna 600 mg/m^2 on days 2-4, cyclophosphamide 300 mg/m^2 on days 2-4, doxorubicin 16.6 mg/m^2/day on days 5-7, vincristine 1.4 mg/m^2 on days 5 and 12, dexamethasone 40 mg on days 2-5 and 12-15, and filgrastim 5 ug/kg on days 8-21. Methotrexate/Ara-C (cycles 2,4,6,8): rituximab 375 mg/m^2 on day 1, methotrexate 1000 mg/m^2 over days 2-3, Ara-C 12 g/m^2 over days 3-4, leucovorin 170 mg over days 3-5, and G-CSF 5 ug/kg on days 5-21.

Biological: filgrastim; 5 ug/kg; Other Names: G-CSF ; Biological: rituximab; 375 mg/m^2 on day 1 of cycles 1-6; Drug: cyclophosphamide; 300 mg/m^2 on days 2-4 of cycles 1,3,5,7; Other Names: cytoxan ; Drug: cytarabine; 12 g/m^2 over days 3-4 of cycles 2,4,6,8; Other Names: Ara-C ; Drug: dexamethasone; 40 mg on days 2-5 and 12-15 of cycles 1,3,5,7; Drug: doxorubicin; 16.6 mg/m^2/day for days 5-7 of cycles 1,3,5,7; Other Names: adriamycin ; Drug: leucovorin; 170 mg over days 3-5 of cycles 2,4,6,8; Other Names: leucovorin calcium ; Drug: methotrexate; 1000 mg/m^2 over days 2-3 of cycles 2,4,6,8; Other Names: MTX ; Drug: vincristine; 1.4 mg/m^2 on days 5 and 12 of cycles 1,3,5,7; Other Names: vincristine sulfate

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [assessed after cycle 4, after completion of treatment, then every 3 months until 1 year after registration]

   Progression-Free Survival (PFS) rate at 1 year. PFS measured from date of registration to date of first observation of progressive disease or death due to any cause. Progressive disease is a 50% increase in the sum of products of greatest diameters (SPD) of target measurable lesions over the smallest sum observed if a complete response (confirmed, or unconfirmed) was not previously achieved; appearance of a new lesion/site; unequivocal progression of non-measurable disease; or death due to disease without prior documentation of progression.

Secondary Outcome Measures

1. Response [assessed after cycle 4 and after completion of treatment (168 days)]

   Complete (CR), complete unconfirmed (CRU) and partial responses (PR). CR is complete disappearance of all measurable and non-measurable disease with the exception of nodes; no new lesions; previously enlarged organs must have regressed in size; and if bone marrow positive at baseline, it must be negative. CRU is complete disappearance of all measurable and non-measurable disease; regressed, non-palpable organs; and one or more exceptions not qualifying for CR (see protocol section 10). PR applies to patients with at least one measurable lesion who do not qualify for CR or CRU. PR is a 50% decrease in sum of products of greatest diameters (SPD) for up to six identified dominant lesions identified at baseline; no new lesions; no increase in the size of liver, spleen or other nodes; and splenic and hepatic nodules must have regressed in size by at least 50% in SPD.

2. Overall Survival [assessed after cycle 4, after completion of treatment, then every 3 months for 2 years, then every 6 months thereafter until 5 years]

   Overall Survival rate at 1 year. Time to death is from date of registration to date of death due to any cause.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 69 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically proven stage III/IV or bulky stage II mantle cell lymphoma of one of the following histologic subtypes:

• Nodular

• Diffuse

• Mantle zone

• Blastic

• Newly diagnosed and previously untreated disease

• Bidimensionally measurable disease

PATIENT CHARACTERISTICS:

Age:

• 18 to 69

Performance status:

• Zubrod 0-2

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,000/mm^3

• Platelet count at least 100,000/mm^{3 (50,000/mm}3 if marrow involvement present)

Hepatic:

• Bilirubin no greater than 1.5 mg/dL (5.0 mg/dL if hepatic involvement present)

Renal:

• Creatinine no greater than 2.0 mg/dL

• Creatinine clearance greater than 50 mL/min

Cardiovascular:

• Ejection fraction at least 50% by MUGA or 2-D echocardiogram

• No significant abnormalities by EKG

Other:

• Not pregnant or nursing

• Fertile patients must use effective contraception

• Willing to receive blood product transfusions

• No known sensitivity to E. coli-derived proteins

• No known AIDS syndrome or HIV-associated complex

• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior monoclonal antibody therapy

Chemotherapy:

• No prior chemotherapy for lymphoma

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy for lymphoma

Surgery:

• Not specified

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Southwest Oncology Group
• National Cancer Institute (NCI)

Investigators

• Study Chair: Elliot M. Epner, MD, PhD, OHSU Knight Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Southwest Oncology Group
• ClinicalTrials.gov Identifier: NCT00041132
• Other Study ID Numbers: CDR0000069445; U10CA032102; S0213
• First Posted: Jan 27, 2003
• Last Update Posted: Nov 1, 2012
• Last Verified: Oct 1, 2012

• Keywords provided by Southwest Oncology Group: stage III mantle cell lymphoma; stage IV mantle cell lymphoma; contiguous stage II mantle cell lymphoma; noncontiguous stage II mantle cell lymphoma
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Mantle-Cell; Leucovorin; Cytarabine; Dexamethasone; Cyclophosphamide; Rituximab; Doxorubicin; Methotrexate; Vincristine; Levoleucovorin

Study Results

Participant Flow

Arm/Group Title	Hyper-CVAD + MTX/Ara-C + Rituximab
Arm/Group Description	21-day cycles of Hyper-CVAD and high-dose methotrexate/Ara-C are alternated beginning with Hyper-CVAD for a maximum of 8 cycles. Rituximab is given for cycles 1-6. Hyper-CVAD (cycles 1,3,5,7): rituximab 375 mg/m^2 on day 1, mesna 600 mg/m^2 on days 2-4, cyclophosphamide 300 mg/m^2 on days 2-4, doxorubicin 16.6 mg/m^2/day on days 5-7, vincristine 1.4 mg/m^2 on days 5 and 12, dexamethasone 40 mg on days 2-5 and 12-15, and G-CSF 5 ug/kg on days 8-21. Methotrexate/Ara-C (cycles 2,4,6,8): rituximab 375 mg/m^2 on day 1, methotrexate 1000 mg/m^2 over days 2-3, Ara-C 12 g/m^2 over days 3-4, leucovorin 170 mg over days 3-5, and G-CSF 5 ug/kg on days 5-21.
Period Title: Overall Study
STARTED	56
Eligible	49
Eligible and Began Protocol Therapy	49
COMPLETED	26
NOT COMPLETED	30

Baseline Characteristics

Arm/Group Title	Hyper-CVAD + MTX/Ara-C + Rituximab
Arm/Group Description	21-day cycles of Hyper-CVAD and high-dose methotrexate/Ara-C are alternated beginning with Hyper-CVAD for a maximum of 8 cycles. Rituximab is given for cycles 1-6. Hyper-CVAD (cycles 1,3,5,7): rituximab 375 mg/m^2 on day 1, mesna 600 mg/m^2 on days 2-4, cyclophosphamide 300 mg/m^2 on days 2-4, doxorubicin 16.6 mg/m^2/day on days 5-7, vincristine 1.4 mg/m^2 on days 5 and 12, dexamethasone 40 mg on days 2-5 and 12-15, and G-CSF 5 ug/kg on days 8-21. Methotrexate/Ara-C (cycles 2,4,6,8): rituximab 375 mg/m^2 on day 1, methotrexate 1000 mg/m^2 over days 2-3, Ara-C 12 g/m^2 over days 3-4, leucovorin 170 mg over days 3-5, and G-CSF 5 ug/kg on days 5-21.
Overall Participants	49
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	57.4
Sex: Female, Male (Count of Participants)
Female	11 22.4%
Male	38 77.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2%
Not Hispanic or Latino	46 93.9%
Unknown or Not Reported	2 4.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 2%
White	48 98%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	Progression-Free Survival (PFS) rate at 1 year. PFS measured from date of registration to date of first observation of progressive disease or death due to any cause. Progressive disease is a 50% increase in the sum of products of greatest diameters (SPD) of target measurable lesions over the smallest sum observed if a complete response (confirmed, or unconfirmed) was not previously achieved; appearance of a new lesion/site; unequivocal progression of non-measurable disease; or death due to disease without prior documentation of progression.
Time Frame	assessed after cycle 4, after completion of treatment, then every 3 months until 1 year after registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hyper-CVAD + MTX/Ara-C + Rituximab
Arm/Group Description	21-day cycles of Hyper-CVAD and high-dose methotrexate/Ara-C are alternated beginning with Hyper-CVAD for a maximum of 8 cycles. Rituximab is given for cycles 1-6. Hyper-CVAD (cycles 1,3,5,7): rituximab 375 mg/m^2 on day 1, mesna 600 mg/m^2 on days 2-4, cyclophosphamide 300 mg/m^2 on days 2-4, doxorubicin 16.6 mg/m^2/day on days 5-7, vincristine 1.4 mg/m^2 on days 5 and 12, dexamethasone 40 mg on days 2-5 and 12-15, and G-CSF 5 ug/kg on days 8-21. Methotrexate/Ara-C (cycles 2,4,6,8): rituximab 375 mg/m^2 on day 1, methotrexate 1000 mg/m^2 over days 2-3, Ara-C 12 g/m^2 over days 3-4, leucovorin 170 mg over days 3-5, and G-CSF 5 ug/kg on days 5-21.
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	90 183.7%

2. Secondary Outcome

Title	Response
Description	Complete (CR), complete unconfirmed (CRU) and partial responses (PR). CR is complete disappearance of all measurable and non-measurable disease with the exception of nodes; no new lesions; previously enlarged organs must have regressed in size; and if bone marrow positive at baseline, it must be negative. CRU is complete disappearance of all measurable and non-measurable disease; regressed, non-palpable organs; and one or more exceptions not qualifying for CR (see protocol section 10). PR applies to patients with at least one measurable lesion who do not qualify for CR or CRU. PR is a 50% decrease in sum of products of greatest diameters (SPD) for up to six identified dominant lesions identified at baseline; no new lesions; no increase in the size of liver, spleen or other nodes; and splenic and hepatic nodules must have regressed in size by at least 50% in SPD.
Time Frame	assessed after cycle 4 and after completion of treatment (168 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hyper-CVAD + MTX/Ara-C + Rituximab
Arm/Group Description	21-day cycles of Hyper-CVAD and high-dose methotrexate/Ara-C are alternated beginning with Hyper-CVAD for a maximum of 8 cycles. Rituximab is given for cycles 1-6. Hyper-CVAD (cycles 1,3,5,7): rituximab 375 mg/m^2 on day 1, mesna 600 mg/m^2 on days 2-4, cyclophosphamide 300 mg/m^2 on days 2-4, doxorubicin 16.6 mg/m^2/day on days 5-7, vincristine 1.4 mg/m^2 on days 5 and 12, dexamethasone 40 mg on days 2-5 and 12-15, and G-CSF 5 ug/kg on days 8-21. Methotrexate/Ara-C (cycles 2,4,6,8): rituximab 375 mg/m^2 on day 1, methotrexate 1000 mg/m^2 over days 2-3, Ara-C 12 g/m^2 over days 3-4, leucovorin 170 mg over days 3-5, and G-CSF 5 ug/kg on days 5-21.
Measure Participants	49
Number [participants]	42 85.7%

3. Secondary Outcome

Title	Overall Survival
Description	Overall Survival rate at 1 year. Time to death is from date of registration to date of death due to any cause.
Time Frame	assessed after cycle 4, after completion of treatment, then every 3 months for 2 years, then every 6 months thereafter until 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hyper-CVAD + MTX/Ara-C + Rituximab
Arm/Group Description	21-day cycles of Hyper-CVAD and high-dose methotrexate/Ara-C are alternated beginning with Hyper-CVAD for a maximum of 8 cycles. Rituximab is given for cycles 1-6. Hyper-CVAD (cycles 1,3,5,7): rituximab 375 mg/m^2 on day 1, mesna 600 mg/m^2 on days 2-4, cyclophosphamide 300 mg/m^2 on days 2-4, doxorubicin 16.6 mg/m^2/day on days 5-7, vincristine 1.4 mg/m^2 on days 5 and 12, dexamethasone 40 mg on days 2-5 and 12-15, and G-CSF 5 ug/kg on days 8-21. Methotrexate/Ara-C (cycles 2,4,6,8): rituximab 375 mg/m^2 on day 1, methotrexate 1000 mg/m^2 over days 2-3, Ara-C 12 g/m^2 over days 3-4, leucovorin 170 mg over days 3-5, and G-CSF 5 ug/kg on days 5-21.
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	92 187.8%

Adverse Events

Time Frame	Every week while on protocol treatment (through 8 cycles or 168 days), and 3 months after removal from protocol treatment (at between 8 and 9 months after beginning treatment).
Arm/Group Title	Hyper-CVAD + MTX/Ara-C + Rituximab
Arm/Group Description
All Cause Mortality
	Hyper-CVAD + MTX/Ara-C + Rituximab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Hyper-CVAD + MTX/Ara-C + Rituximab
	Affected / at Risk (%)	# Events
Total	4/49 (8.2%)
Gastrointestinal disorders
Colitis	1/49 (2%)
Infections and infestations
Infection with 3-4 neutropenia	1/49 (2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Second primary	1/49 (2%)
Nervous system disorders
Ataxia (incoordination)	1/49 (2%)
Other (Not Including Serious) Adverse Events
	Hyper-CVAD + MTX/Ara-C + Rituximab
	Affected / at Risk (%)	# Events
Total	48/49 (98%)
Blood and lymphatic system disorders
Anemia	45/49 (91.8%)
Febrile neutropenia	10/49 (20.4%)
PRBC transfusion	12/49 (24.5%)
Platelet transfusion	8/49 (16.3%)
Cardiac disorders
Sinus tachycardia	5/49 (10.2%)
Eye disorders
Blurred vision	4/49 (8.2%)
Dry eye	3/49 (6.1%)
Gastrointestinal disorders
Abdominal pain/cramping	3/49 (6.1%)
Constipation/bowel obstruction	23/49 (46.9%)
Diarrhea without colostomy	17/49 (34.7%)
Dyspepsia/heartburn	4/49 (8.2%)
Esophagitis/dysphagia	4/49 (8.2%)
Nausea	20/49 (40.8%)
Stomatitis/pharyngitis	26/49 (53.1%)
Vomiting	15/49 (30.6%)
General disorders
Edema	23/49 (46.9%)
Fatigue/malaise/lethargy	43/49 (87.8%)
Fever without neutropenia	20/49 (40.8%)
Hemorrhage w/ 3-4 thrombocyt	5/49 (10.2%)
Pain-other	3/49 (6.1%)
Rigors/chills	8/49 (16.3%)
Immune system disorders
Allergic reaction	5/49 (10.2%)
Infections and infestations
Infection w/o 3-4 neutropenia	15/49 (30.6%)
Infection with 3-4 neutropenia	15/49 (30.6%)
Respiratory infect w/ neutrop	3/49 (6.1%)
Respiratory infect w/o neutrop	4/49 (8.2%)
Investigations
Alkaline phosphatase increase	8/49 (16.3%)
Bilirubin increase	7/49 (14.3%)
Creatinine increase	6/49 (12.2%)
Leukopenia	44/49 (89.8%)
Lymphopenia	31/49 (63.3%)
Neutropenia/granulocytopenia	45/49 (91.8%)
SGOT (AST) increase	18/49 (36.7%)
SGPT (ALT) increase	10/49 (20.4%)
Thrombocytopenia	43/49 (87.8%)
Metabolism and nutrition disorders
Anorexia	9/49 (18.4%)
Hyperglycemia	22/49 (44.9%)
Hyperuricemia	5/49 (10.2%)
Hypoalbuminemia	12/49 (24.5%)
Hypocalcemia	13/49 (26.5%)
Hypoglycemia	5/49 (10.2%)
Hypokalemia	15/49 (30.6%)
Hypomagnesemia	5/49 (10.2%)
Hyponatremia	11/49 (22.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	7/49 (14.3%)
Bone pain	9/49 (18.4%)
Muscle weakness (not neuro)	3/49 (6.1%)
Myalgia	10/49 (20.4%)
Myalgia/arthralgia, NOS	3/49 (6.1%)
Nervous system disorders
Ataxia (incoordination)	4/49 (8.2%)
Dizziness/vertigo, NOS	7/49 (14.3%)
Headache	17/49 (34.7%)
Sensory neuropathy	26/49 (53.1%)
Taste disturbance	3/49 (6.1%)
Psychiatric disorders
Anxiety/agitation	6/49 (12.2%)
Insomnia	7/49 (14.3%)
Renal and urinary disorders
Urinary frequency/urgency	3/49 (6.1%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	3/49 (6.1%)
Cough	7/49 (14.3%)
Dyspnea	8/49 (16.3%)
Epistaxis	8/49 (16.3%)
Hypoxia	3/49 (6.1%)
Pneumonitis/infiltrates	3/49 (6.1%)
Skin and subcutaneous tissue disorders
Alopecia	35/49 (71.4%)
Dry skin	3/49 (6.1%)
Petechiae/purpura	6/49 (12.2%)
Rash/desquamation	16/49 (32.7%)
Vascular disorders
Hypotension	10/49 (20.4%)
Phlebitis	3/49 (6.1%)
Thrombosis/embolism	6/49 (12.2%)

Limitations/Caveats

[Not Specified]

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.