R-MACLO-IVAM and Thalidomide in Untreated Mantle Cell Lymphoma

• Sponsor: University of Miami (Other)
• Overall Status: Completed
• CT.gov ID: NCT00450801
• Collaborator: (none)
• Enrollment: 22
• Location: 1
• Arm: 1
• Duration (Months): 135
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: To evaluate the efficacy of a new high intensity chemotherapy regimen with thalidomide maintenance in patients with newly diagnosed mantle cell lymphoma

PURPOSE: This phase II trial is studying how well giving rituximab together with combination chemotherapy followed by thalidomide works in treating patients with previously untreated mantle cell lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Drug: Rituximab; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Doxorubicin; Drug: Etoposide; Drug: Ifosfamide; Drug: Leucovorin; Drug: Methotrexate; Drug: Thalidomide; Drug: Vincristine; Drug: Mesna; Drug: Filgrastim (G-CSF); Drug: Granisetron; Drug: Decadron	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the progression-free survival of patients with previously untreated mantle cell lymphoma treated rituximab in combination with methotrexate, doxorubicin, cyclophosphamide, leucovorin, vincristine, ifosfamide, etoposide, cytarabine and mesna (MACLO/IVAM) followed by thalidomide.

Secondary

• Determine the overall survival of patients treated with this regimen.

• Determine the response rate in patients treated with this regimen.

• Determine the toxicity of this regimen in these patients.

OUTLINE: During cycle 1, patients will receive rituximab intravenous (IV), granisetron IV, decadron IV, doxorubicin IV bolus, vincristine intravenous pyelogram (IVP) on day 1; cyclophosphamide IV on day 1-5; vincristine IVP on day 8; methotrexate IV, methotrexate by continuous infusion, then leucovorin IV until methotrexate level is below 0.01 nanomolar (nM) on day 10. Patients will receive filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 13 and continuing until blood counts recover.

When absolute neutrophil count (ANC) reaches1,500/mm^{3, patients will start cycle 2. Patients will receive rituximab IV on day 1; cytarabine IV on day 1 and 2; ifosfamide IV, mesna IV, etoposide IV on day 1-5; and G-CSF SC daily beginning on day 7 and continuing until ANC is greater than 1,000 cells/mm}3.

Approximately 2-3 weeks later, patients receive another course of therapy as above.After cycle 4, patients in complete remission will take oral thalidomide until progression of disease. After completion of study treatment, patients are followed monthly for 3 months, every 3 months for 2 years, every 6 months for 3-5 years, and then annually thereafter or at study termination.

PROJECTED ACCRUAL: A total of 22 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Rituximab in Combination With Methotrexate, Doxorubicin, Cyclophosphamide, Leucovorin, Vincristine, Ifosfamide, Etoposide, Cytarabine and Mesna (MACLO/IVAM) in Patients With Previously Untreated Mantle Cell Lymphoma
• Study Start Date: Apr 1, 2004
• Actual Primary Completion Date: Jul 1, 2015
• Actual Study Completion Date: Jul 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: R-MACLO-IVAM-T Rituximab, Methotrexate, Doxorubicin, Cyclophosphamide and Vincristine (cycle 1), followed by Rituximab, Ifosfamide (and Mesna), Etoposide and Cytarabine (cycle 2). These two cycles are repeated once, and patients achieving complete repose receive maintenance Thalidomide.

Drug: Rituximab; Rituximab 375 mg/m2 IV, Days 1 of all cycles; Other Names: Rituxan ; Drug: Cyclophosphamide; Cyclophosphamide 800 mg/m2 IV, Day 1, Cyclophosphamide 200 mg/m2 IV Days 2 - 5, Cycles 1 and 3. Cyclophosphamide will be given in 100 cc NS IV over 30 minutes.; Other Names: Cytoxan ; Drug: Cytarabine; Cytarabine 2 grams/m2 IV every 12 hours x 4 doses, Days 1 and 2, Cycles 2 and 4.; Other Names: AraC ; Drug: Doxorubicin; Doxorubicin 45 mg/m2 IV bolus, Day 1, Cycles 1 and 3; Other Names: Adriamycin ; Drug: Etoposide; Etoposide 60 mg/m2 IV daily x 5 days, Cycles 2 and 4; Other Names: VP16 ; Drug: Ifosfamide; Ifosfamide 1.5 grams/m2 IV once a day (QD) x 5 days, Cycles 2 and 4; Other Names: Ifex ; Drug: Leucovorin; Leucovorin 180 mg/m2 IV beginning 36 hours after start of methotrexate infusion and then 12 mg/m2 IV every 6 hours until methotrexate level is below 0.01 nM. Day 10, Cycles 1 and 3.; Other Names: Folinic Acid ; Drug: Methotrexate; Methotrexate 1,200 mg/m2 in 250 cc 5 percent dextrose in water (D5W) IV over 1 hour followed by Methotrexate 5,520 mg/m2 in 1,000 cc D5W by continuous infusion over 23 hours (240 mg/m2 every hour for 23 hours). Day 10, Cycles 1 and 3.; Other Names: amethopterin ; Drug: Thalidomide; Maintenance therapy.; Other Names: Thalomid ; Drug: Vincristine; Vincristine 1.5 mg/m2 IVP (maximum of 2 mg), Day 1 and 8 , Cycles 1 and 3.; Other Names: Oncovin ; Drug: Mesna; Mesna 360 mg/m2 IV every 3 hours x 5 days, Cycles 2 and 4; Other Names: Mesnex ; Drug: Filgrastim (G-CSF); G-CSF 480 mcg subcutaneous (SQ) starting Day 13 (Cycles 1 and 3), Day 7 (Cycles 2 and 4); Other Names: Neupogen ; Drug: Granisetron; Granisetron 1 mg IV on Day 1, Cycle 1 and 3; Other Names: Sancuso Granisol ; Drug: Decadron; Decadron 10 mg IV on Day 1, Cycles 1 and 3; Other Names: Maxidex Ozurdex Baycadron

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival Rate [Up to 5 years]

   Percentage of participants achieving progression-free survival at 1, 3 and 5 years after the start of protocol therapy, based upon the International Working Group Response Criteria for Non-Hodgkin's Lymphoma (NHL). Progression is defined as a ≥ 50% increase from nadir in the product of the two largest perpendicular diameters (PPD-size) of any previously identified abnormal node, or appearance of any new lesion.

Secondary Outcome Measures

1. Overall Survival Rate [Up to 5 years]

   Percentage of participants who are alive up to five years after receipt of protocol therapy.

2. Response Rate [Up to 5 years]

   Percentage of participants achieving complete response (CR) to protocol therapy according to International Working Group Response Criteria for Non-Hodgkin's Lymphoma (NHL) using the CT imaging method. Patients were classified by best tumor response; CR was defined as normalization of the lactate dehydrogenase (LDH), complete disappearance of disease-related symptoms and lymph nodes, and clearance of lymphoma from involved organs; complete response unconfirmed (CRu) as a residual lymph node greater than 1.5 cm in greatest transverse diameter that had regressed by more than 75% or an indeterminate bone marrow examination; partial response (PR) as greater than 50% reduction in the involved lymph nodes, or disappearance of the involved lymph nodes but persistent bone marrow involvement; relapse/progression as new or increased lymph nodes, organomegaly, or reappearance of bone marrow involvement.

3. Number of Patients Experiencing Adverse Events. [Up to 5 years]

   Number of patients experiencing adverse events during the course of protocol therapy.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Previously untreated, histologically confirmed mantle cell lymphoma.

• Measurable or evaluable disease.

• All stages are eligible.

• Age > 18 years.

• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.

• Adequate hepatic function:

• Bilirubin < 3 mg/dL.

• Transaminases (SGOT and/or SGPT) < than 2.5 times the upper limit of normal for the institution, unless due to lymphomatous involvement.

• Serum creatinine < 1.5 mg/Dl.

• Ability to give informed consent.

• Women of childbearing potential must have a negative pregnancy test within 72 hours of entering into the study. Males and females must agree to use adequate birth control if conception is possible during the study. Women must avoid pregnancy and men avoid fathering children while in the study.

• Life expectancy greater than 6 months.

Exclusion Criteria:

• Previous chemotherapy, immunotherapy or radiotherapy for this lymphoma

• Concurrent active malignancies, with the exception of in situ carcinoma of the cervix and basal cell carcinoma of the skin.

• Grade 3 or 4 cardiac failure and/or ejection fraction < 50.

• Psychological, familial, sociological or geographical conditions that do not permit treatment and/or medical follow-up required to comply with the study protocol.

• Patients with a known history of HIV or AIDS

• Presence of hepatitis or hepatitis B virus (HBV) infection

• Pregnant or breast-feeding women.

• Central nervous system (CNS) involvement

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Miami Sylvester Comprehensive Cancer Center - Miami	Miami	Florida	United States	33136

Sponsors and Collaborators

• University of Miami

Investigators

• Study Chair: Izidore S. Lossos, MD, University of Miami Sylvester Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Izidore Lossos, Professor, University of Miami
• ClinicalTrials.gov Identifier: NCT00450801
• Other Study ID Numbers: 20030165; SCCC-2003027; WIRB-20051242
• First Posted: Mar 22, 2007
• Last Update Posted: Nov 10, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by Izidore Lossos, Professor, University of Miami: contiguous stage II mantle cell lymphoma; noncontiguous stage II mantle cell lymphoma; stage I mantle cell lymphoma; stage III mantle cell lymphoma; stage IV mantle cell lymphoma
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Mantle-Cell; Leucovorin; Cytarabine; Thalidomide; Cyclophosphamide; Ifosfamide; Rituximab; Doxorubicin; Methotrexate; Etoposide; Vincristine; Granisetron

Study Results

Participant Flow

Arm/Group Title	R-MACLO-IVAM-T
Arm/Group Description	Rituximab, Methotrexate, Doxorubicin, Cyclophosphamide and Vincristine (cycle 1), followed by Rituximab, Ifosfamide (and Mesna), Etoposide and Cytarabine (cycle 2). These two cycles are repeated once, and patients achieving complete repose receive maintenance Thalidomide.
Period Title: Overall Study
STARTED	22
COMPLETED	21
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	R-MACLO-IVAM-T
Arm/Group Description	Rituximab, Methotrexate, Doxorubicin, Cyclophosphamide and Vincristine (cycle 1), followed by Rituximab, Ifosfamide (and Mesna), Etoposide and Cytarabine (cycle 2). These two cycles are repeated once, and patients achieving complete repose receive maintenance Thalidomide.
Overall Participants	22
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56.5
Age, Customized (participants) [Number]
< 50 years	6 27.3%
50 - 59 years	8 36.4%
60 - 69 years	5 22.7%
70 - 79 years	3 13.6%
Sex: Female, Male (Count of Participants)
Female	4 18.2%
Male	18 81.8%
Region of Enrollment (participants) [Number]
United States	22 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival Rate
Description	Percentage of participants achieving progression-free survival at 1, 3 and 5 years after the start of protocol therapy, based upon the International Working Group Response Criteria for Non-Hodgkin's Lymphoma (NHL). Progression is defined as a ≥ 50% increase from nadir in the product of the two largest perpendicular diameters (PPD-size) of any previously identified abnormal node, or appearance of any new lesion.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R-MACLO-IVAM-T
Arm/Group Description	Rituximab, Methotrexate, Doxorubicin, Cyclophosphamide and Vincristine (cycle 1), followed by Rituximab, Ifosfamide (and Mesna), Etoposide and Cytarabine (cycle 2). These two cycles are repeated once, and patients achieving complete repose receive maintenance Thalidomide.
Measure Participants	21
1 year progression-free survival	91 413.6%
3 year progression-free survival	78 354.5%
5-year progression-free survival	69 313.6%

2. Secondary Outcome

Title	Overall Survival Rate
Description	Percentage of participants who are alive up to five years after receipt of protocol therapy.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R-MACLO-IVAM-T
Arm/Group Description	Rituximab, Methotrexate, Doxorubicin, Cyclophosphamide and Vincristine (cycle 1), followed by Rituximab, Ifosfamide (and Mesna), Etoposide and Cytarabine (cycle 2). These two cycles are repeated once, and patients achieving complete repose receive maintenance Thalidomide.
Measure Participants	21
1-year rate overall survival Rate	96 436.4%
2-year overall survival Rate	96 436.4%
3-year overall survival rate	96 436.4%
4-year overall survival rate	87 395.5%
5-year overall survival rate	87 395.5%

3. Secondary Outcome

Title	Response Rate
Description	Percentage of participants achieving complete response (CR) to protocol therapy according to International Working Group Response Criteria for Non-Hodgkin's Lymphoma (NHL) using the CT imaging method. Patients were classified by best tumor response; CR was defined as normalization of the lactate dehydrogenase (LDH), complete disappearance of disease-related symptoms and lymph nodes, and clearance of lymphoma from involved organs; complete response unconfirmed (CRu) as a residual lymph node greater than 1.5 cm in greatest transverse diameter that had regressed by more than 75% or an indeterminate bone marrow examination; partial response (PR) as greater than 50% reduction in the involved lymph nodes, or disappearance of the involved lymph nodes but persistent bone marrow involvement; relapse/progression as new or increased lymph nodes, organomegaly, or reappearance of bone marrow involvement.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Participants who completed at least two cycles of therapy.

Arm/Group Title	R-MACLO-IVAM-T
Arm/Group Description	Rituximab, Methotrexate, Doxorubicin, Cyclophosphamide and Vincristine (cycle 1), followed by Rituximab, Ifosfamide (and Mesna), Etoposide and Cytarabine (cycle 2). These two cycles are repeated once, and patients achieving complete repose receive maintenance Thalidomide.
Measure Participants	21
Number (95% Confidence Interval) [percentage of participants]	100 454.5%

4. Secondary Outcome

Title	Number of Patients Experiencing Adverse Events.
Description	Number of patients experiencing adverse events during the course of protocol therapy.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R-MACLO Cycles	R-IVAM Cycles	Thalidomide Therapy
Arm/Group Description	Number of patients experiencing adverse events during the combination Rituximab, Methotrexate, Doxorubicin, Cyclophosphamide and Vincristine (R-MACLO) treatment cycles.	Number of patients experiencing adverse events during the Rituximab, Ifosfamide (and Mesna), Etoposide and Cytarabine (R-IVAM) treatment cycles.	Number of patients experiencing adverse events during Thalidomide maintenance therapy.
Measure Participants	22	22	20
Number [participants]	22 100%	22 NaN	19 NaN

Adverse Events

Arm/Group Title	R-MACLO Cycles		R-IVAM Cycles		Thalidomide Therapy
Arm/Group Description	Adverse Events occurring during the combination Rituximab, Methotrexate, Doxorubicin, Cyclophosphamide and Vincristine (R-MACLO) treatment cycles.		Adverse Events occurring during the Rituximab, Ifosfamide (and Mesna), Etoposide and Cytarabine (R-IVAM) treatment cycles.		Adverse Events occurring during Thalidomide maintenance therapy.
All Cause Mortality
	R-MACLO Cycles		R-IVAM Cycles		Thalidomide Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	R-MACLO Cycles		R-IVAM Cycles		Thalidomide Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/22 (95.5%)		21/22 (95.5%)		19/20 (95%)
Blood and lymphatic system disorders
Thrombocytopenia (Grade 3-4)	8/22 (36.4%)	8	21/22 (95.5%)	35	0/20 (0%)	0
Gastrointestinal disorders
Diarrhea (Grade 3-4)	2/22 (9.1%)	2	1/22 (4.5%)	1	1/20 (5%)	1
General disorders
Dizziness (Grade 3-4)	0/22 (0%)	0	0/22 (0%)	0	1/20 (5%)	1
Infections and infestations
Neutropenia (Grade 3-4)	12/22 (54.5%)	14	13/22 (59.1%)	20	7/20 (35%)	7
Febrile neutropenia (Grade 3-4)	9/22 (40.9%)	9	20/22 (90.9%)	20	0/20 (0%)	0
Infection (Grade 3-4)	5/22 (22.7%)	5	11/22 (50%)	14	2/20 (10%)	2
Bacteremia (Grade 3-4)	2/22 (9.1%)	2	12/22 (54.5%)	12	0/20 (0%)	0
Mucositis (Grade 3-4)	1/22 (4.5%)	1	0/22 (0%)	0	0/20 (0%)	0
Metabolism and nutrition disorders
Anemia (Grade 3-4)	7/22 (31.8%)	7	19/22 (86.4%)	27	0/20 (0%)	0
Nervous system disorders
Peripheral Neuropathy (Grade 3-4)	0/22 (0%)	0	0/22 (0%)	0	8/20 (40%)	8
Respiratory, thoracic and mediastinal disorders
Dyspnea (Grade 3-4)	1/22 (4.5%)	1	1/22 (4.5%)	1	0/20 (0%)	0
Pleural effusion (Grade 3-4)	1/22 (4.5%)	1	1/22 (4.5%)	1	0/20 (0%)	0
Erectile Dysfunction (Grade 3-4)	0/22 (0%)	0	0/22 (0%)	0	2/20 (10%)	2
Other (Not Including Serious) Adverse Events
	R-MACLO Cycles		R-IVAM Cycles		Thalidomide Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/22 (100%)		22/22 (100%)		19/20 (95%)
Blood and lymphatic system disorders
Thrombocytopenia (Grade 1-2)	7/22 (31.8%)	7	0/22 (0%)	0	0/20 (0%)	0
Cardiac disorders
Bradycardia (Grade 1-2)	0/22 (0%)	0	0/22 (0%)	0	2/20 (10%)	2
Gastrointestinal disorders
Diarrhea (Grade 1-2)	5/22 (22.7%)	5	6/22 (27.3%)	6	0/20 (0%)	0
Constipation (Grade 1-2)	6/22 (27.3%)	6	5/22 (22.7%)	7	7/20 (35%)	7
General disorders
Nausea (Grade 1-2)	9/22 (40.9%)	11	15/22 (68.2%)	18	0/20 (0%)	0
Vomiting (Grade 1-2)	4/22 (18.2%)	4	10/22 (45.5%)	10	0/20 (0%)	0
Edema (Grade 1-2)	6/22 (27.3%)	6	3/22 (13.6%)	3	4/20 (20%)	4
Headache (Grade 1-2)	9/22 (40.9%)	10	4/22 (18.2%)	6	0/20 (0%)	0
Dizziness (Grade 1-2)	2/22 (9.1%)	3	4/22 (18.2%)	5	2/20 (10%)	2
Somnolence (Grade 1-2)	0/22 (0%)	0	0/22 (0%)	0	3/20 (15%)	3
Infections and infestations
Neutropenia (Grade 1-2)	1/22 (4.5%)	1	1/22 (4.5%)	1	0/20 (0%)	0
Febrile Neutropenia (Grade 1-2)	0/22 (0%)	0	0/22 (0%)	0	0/20 (0%)	0
Infection (Grade 1-2)	1/22 (4.5%)	1	5/22 (22.7%)	5	1/20 (5%)	1
Bacteremia (Grade 1-2)	0/22 (0%)	0	0/22 (0%)	0	0/20 (0%)	0
Mucositis (Grade 1-2)	11/22 (50%)	13	8/22 (36.4%)	9	0/20 (0%)	0
Rash (Grade 1-2)	5/22 (22.7%)	5	8/22 (36.4%)	9	0/20 (0%)	0
Metabolism and nutrition disorders
Anemia (Grade 1-2)	10/22 (45.5%)	11	4/22 (18.2%)	5	0/20 (0%)	0
Hyperglycemia (Grade 1-2)	10/22 (45.5%)	11	9/22 (40.9%)	10	0/20 (0%)	0
Hypokalemia (Grade 1-2)	8/22 (36.4%)	9	11/22 (50%)	14	0/20 (0%)	0
Elevated creatinine (Grade 1-2)	6/22 (27.3%)	6	4/22 (18.2%)	4	0/20 (0%)	0
Nervous system disorders
Peripheral Neuropathy (Grade 1-2)	0/22 (0%)	0	0/22 (0%)	0	2/20 (10%)	2
Reproductive system and breast disorders
Erectile Dysfunction (Grade 1-2)	0/22 (0%)	0	0/22 (0%)	0	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea (Grade 1-2)	5/22 (22.7%)	5	5/22 (22.7%)	5	0/20 (0%)	0
Pleural Effusion (Grade 1-2)	3/22 (13.6%)	3	1/22 (4.5%)	1	0/20 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.