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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Lymphoma

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R-MACLO-IVAM-T<br>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<br>* Rituximab 375 mg/m2 IV, Days 1 of all cycles<br>* Other names: Rituxan;Drug: Cyclophosphamide<br>* 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.<br>* Other names: Cytoxan;Drug: Cytarabine<br>* Cytarabine 2 grams/m2 IV every 12 hours x 4 doses, Days 1 and 2, Cycles 2 and 4.<br>* Other names: AraC;Drug: Doxorubicin<br>* Doxorubicin 45 mg/m2 IV bolus, Day 1, Cycles 1 and 3<br>* Other names: Adriamycin;Drug: Etoposide<br>* Etoposide 60 mg/m2 IV daily x 5 days, Cycles 2 and 4<br>* Other names: VP16;Drug: Ifosfamide<br>* Ifosfamide 1.5 grams/m2 IV once a day (QD) x 5 days, Cycles 2 and 4<br>* Other names: Ifex;Drug: Leucovorin<br>* 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.<br>* Other names: Folinic Acid;Drug: Methotrexate<br>* 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.<br>* Other names: amethopterin;Drug: Thalidomide<br>* Maintenance therapy.<br>* Other names: Thalomid;Drug: Vincristine<br>* Vincristine 1.5 mg/m2 IVP (maximum of 2 mg), Day 1 and 8 , Cycles 1 and 3.<br>* Other names: Oncovin;Drug: Mesna<br>* Mesna 360 mg/m2 IV every 3 hours x 5 days, Cycles 2 and 4<br>* Other names: Mesnex;Drug: Filgrastim (G-CSF)<br>* G-CSF 480 mcg subcutaneous (SQ) starting Day 13 (Cycles 1 and 3), Day 7 (Cycles 2 and 4)<br>* Other names: Neupogen;Drug: Granisetron<br>* Granisetron 1 mg IV on Day 1, Cycle 1 and 3<br>* Other names: Granisol;Drug: Decadron<br>* Decadron 10 mg IV on Day 1, Cycles 1 and 3<br>* Other names: Baycadron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival Rate | 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. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Rate | Percentage of participants who are alive up to five years after receipt of protocol therapy. | Up to 5 years | 
| Response Rate | 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. | Up to 5 years | 
| Number of Patients Experiencing Adverse Events. | Number of patients experiencing adverse events during the course of protocol therapy. | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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