Conditions: Mantle-Cell Lymphoma
Keywords: Non-Hodgkin's Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: no

Brief summary:
The investigator(s) hypothesize that Rituximab together with combination chemotherapy, followed by Rituximab maintenance therapy, will provide better disease control with improved response rates and overall survival in patients with previously untreated Mantle Cell Lymphoma (MCL).

Detailed description:

Arms:
arm 1: Participants in this group will receive four 21-day cycles of combination R-MACLO/IVAM induction therapy, followed by Rituximab maintenance therapy as follows:

Induction Therapy:

* Cycles 1 and 3: Rituximab, Doxorubicin, Vincristine, Cyclophosphamide, Methotrexate, Leucovorin and Granulocyte-colony stimulating factor (G-CSF)
* Cycles 2 and 4: Rituximab, Cytarabine, Ifosfamide, Mesna, Etoposide, and G-CSF.

Maintenance Therapy: Rituximab: For study participants in complete remission. Every 6 months for up to 3 years.

Total participation duration is about 4 years. Participants will be followed for survival.

Interventions: intervention 1: G-CSF intervention 2: Rituximab intervention 3: Cyclophosphamide intervention 4: Cytarabine intervention 5: Doxorubicin intervention 6: Etoposide intervention 7: Ifosfamide intervention 8: Leucovorin intervention 9: Mesna intervention 10: Methotrexate intervention 11: Vincristine
Intervention descriptions: intervention 1: Granulocyte-colony stimulating factor (G-CSF) 480 mcg subcutaneously starting on Day 13 of Cycles 1 and 3; and Day 7 of Cycles 2 and 4. intervention 2: Rituximab 375 mg/m\^2 intravenously (IV) on Day 1 for 4 Cycles during induction therapy. Participants achieving complete remission will then receive Rituximab maintenance therapy every 6 months for up to three years. intervention 3: Cyclophosphamide 800 mg/m\^2 IV on Day 1 and 200 mg/m\^2 IV on Days 2 through 5 of Cycles 1 and 3. intervention 4: Cytarabine (AraC) 2 grams/m\^2 IV on Days 1 and 2 of Cycles 2 and 4. intervention 5: Doxorubicin 45 mg/m\^2 IV bolus on Day 1 of Cycles 1 and 3. intervention 6: Etoposide (VP16) 60 mg/m\^2 IV on Days 1 through 5 of Cycles 2 and 4. intervention 7: Ifosfamide 1.5 grams/m\^2 IV on Days 1 through 5 of Cycles 2 and 4. intervention 8: Leucovorin 100 mg/m\^2 IV beginning 36 (+/-4) hours after start of Methotrexate infusion, and then 10 mg/m\^2 at 6 hour (+/- 30 min) intervals until Methotrexate level is \< 0.1 µmol/L during Cycles 1 and 3. intervention 9: Mesna 360 mg/m\^2 IV on Days 1 through 5 of Cycles 2 and 4. intervention 10: Methotrexate (MTX) 1,200 mg/m\^2 in 250 mL with Dextrose 5% in water (D5W) IV over 1 hour, followed by Methotrexate 3,000 mg/m\^2 in 1,000 mL D5W by continuous infusion over 23 (+/-2) hours on Day 10 of Cycles 1 and 3. intervention 11: Vincristine 1.5 mg/m\^2 IV push (maximum of 2 mg) on Days 1 and 8 of Cycles 1 and 3.

Protocol document:
Prot_SAP_000.pdf: 
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EPROST # 20080803
SCCC # 2008043
PHASE II STUDY OF RITUXIMAB IN COMBINATION WITH METHOTREXATE, 
DOXORUBICIN, CYCLOPHOSPHAMIDE, LEUCOVORIN, VINCRISTNE, IFOSFAMIDE, 
ETOPOSIDE, CYTARABINE AND MESNA (R-MACLO/IVAM) IN PATIENTS WITH 
PREVIOUSLY UNTREATED MANTLE CELL LYMPHOMA
PRINCIPAL INVESTIGATOR:
Izidore Lossos, M.D.,
Associate Professor of Medicine
Hematology/Oncology
SUB-INVESTIGATOR(S):
Joseph Rosenblatt M.D.
Denise Pereira, M.D.
James Hoffman, M.D.
STATISTICIAN:
Tulay Koru-Sengul, MHS, PhD
NCT #
VERSION #:
00878254
9.4
VERSION  DATE:
July 22nd, 2019
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CONTACT INFORMATION
PRINCIPAL INVESTIGATOR:
Izidore S. Lossos, MD
Professor of Medicine
Department of Medicine
Division of Hematology/Oncology
University of Miami Miller School of Medicine
SUB-INVESTIGATOR(S):
Joseph Rosenblatt M.D.
Professor
Department of Medicine
Division of Hematology/Oncology
Denise Pereira, M.D.
Department of Medicine
Division of Hematology/Oncology
University of Miami MillerSchool of Medicine
James Hoffman, MD
Assistant Professor of Medicine
Department of Medicine
Division of Hematology/Oncology
University of Miami Miller School of Medicine
STATISTICIAN:
Tulay Koru-Sengul, MHS, PhD
Associate Professor
University of Miami Miller School of 
Medicine
Division of Biostatistics at Department 
of Public Health Sciences
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TABLE OF CONTENTS
SCHEMA........................................................................................................................................5
1.1
PRIMARY OBJECTIVE .........................................................................................................8
1.2
SECONDARY OBJECTIVES...................................................................................................8
2.0
BACKGROUND.................................................................................................................8
3.0
PATIENT SELECTION ..................................................................................................10
3.1. INCLUSION CRITERIA ...........................................................................................................10
3.2
EXCLUSION CRITERIA ......................................................................................................11
3.3
ENROLLMENT PROCEDURES.......................................ERROR! BOOKMARK NOT DEFINED.
4.0
TREATMENT PLAN.......................................................................................................11
4.1
CYCLE 1...........................................................................................................................12
4.2
CYCLE 2...........................................................................................................................13
4.3
CYCLE 3...........................................................................................................................14
4.4
CYCLE 4...........................................................................................................................16
4.5
SUPPORTIVE CARE GUIDELINES.......................................................................................17
4.6
DURATION OF THERAPY...................................................................................................17
5.0
CLINICAL AND LABORATORY EVALUATIONS...................................................18
5.1
BASELINE/PRETREATMENT EVALUATIONS.......................................................................18
5.2
EVALUATIONS DURING TREATMENT:................................................................................19
5.3
POST-TREATMENT EVALUATION......................................................................................19
5.4
EARLY DISCONTINUATION OF THERAPY ...........................................................................20
6.0
DOSING DELAYS/DOSE MODIFICATIONS.............................................................20
6.1
HEMATOLOGIC TOXICITY.................................................................................................20
6.2
NON-HEMATOLOGIC TOXICITY........................................................................................21
7.0
AGENT FORMULATION AND PROCUREMENT....................................................21
7.1
RITUXIMAB (RITUXAN)....................................................................................................21
7.2
DOXORUBICIN (ADRIAMYCIN) .........................................................................................22
7.3
VINCRISTINE (ONCOVIN)..................................................................................................23
7.4
CYCLOPHOSPHAMIDE (CYTOXAN) ...................................................................................24
7.5
METHOTREXATE ..............................................................................................................24
7.6
LEUCOVORIN (FOLINIC ACID)...........................................................................................25
7.7
ETOPOSIDE (VP16) ..........................................................................................................26
7.8
IFOSFAMIDE (IFEX)...........................................................................................................26
7.9
MESNA (MESNEX)............................................................................................................27
7.10
CYTARABINE (ARAC) ......................................................................................................27
7.11
FILGRASTIM (NEUPOGEN)................................................................................................28
8.0
    MEASUREMENT OF EFFECT.................................................................................28
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9.0
ADVERSE EVENT REPORTING .................................................................................31
9.1
ADVERSE EVENT (AE) DEFINITIONS................................................................................31
10.0
DATA REPORTING........................................................................................................34
11.0
CRITERIA FOR DISCONTINUATION OF THERAPY............................................34
12.0
STATISTICAL CONSIDERATIONS............................................................................35
13.0
REFERENCES .................................................................................................................38
APPENDIX I ................................................................................................................................41
NATIONAL CANCER INSTITUTE (NCI) COMMON TOXICITY CRITERIA (CTC).........41
APPENDIX II...............................................................................................................................42
DATA AND SAFETY MONITORING PLAN.........................................................................42
APPENDIX III:............................................................................................................................43
DATA SUBMISSION SCHEDULE..........................................................................................43
APPENDIX IV .............................................................................................................................44
ABBREVIATIONS ...................................................................................................................44
APPENDIXV- STUDY CALENDAR ........................................................................................45
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SCHEMA
Patients older than 18 years and less than 72 years of age, with previously untreated mantle cell 
lymphoma and ECOG Performance Status 0-2.
TREATMENT
Treatment is given on an inpatient basis and patients should receive cycles 1 and 2 during the same 
hospitalization, followed by a 2 week resting period and then cycles 3 followed by a 1 week resting 
period, and then cycle 4.  Patients in complete remission will receive maintenance therapy with Rituximab 
every 6 months for a total of 3 years.
Cycles 1 and 3
DAY
DRUG
1
Rituximab 375 mg/m2 IV according to institutional standard protocol.
1
Doxorubicin 45 mg/m2 IV bolus according to institutional standard 
protocol.
1
Vincristine 1.5 mg/m2 IV push (maximum of 2 mg) according to 
institutional standard protocol.
1
Cyclophosphamide 800 mg/m2 IV given in 100 ml NS IV over 30 (+/- 
15) minutes according to institutional standard protocol.
2-5
Cyclophosphamide 200 mg/m2 IV given in 100 ml NS IV over 30 (+/- 
15) minutes according to institutional standard protocol.
8
Vincristine 1.5 mg/m2 IV push (maximum of 2 mg) according to 
institutional standard protocol.
10
Methotrexate 1,200 mg/m2 in 250 ml D5W IV over 1 hour (+/-30 min)
followed byMethotrexate3,000mg/m2 in 1,000 ml D5W by continuous 
infusion over 23 (+/-2) hours (130 mg/m2 every hour for 23 hours).  
11+
Leucovorin 100 mg/m2 IV beginning 36 (+/-4) hours after start of 
Methotrexate infusion followed by Leucovorin 10 mg/m2 IV every 6 (+/- 
30 min) hours until Methotrexate level is< 0.1µmol/L.
13+
G-CSF 480 mcg SQ daily.
Stop G-CSF after 2 consecutive ANC >1,000 cells/mm3.  
Cycle 2 will be scheduled to begin after 2 consecutive ANC > 1,500 cells/mm³ 
and chemotherapy orders are finalized.
SPECIAL INSTRUCTIONS
Pre-medications:
Patients will be pre-medicated for nausea/vomiting or hypersensitivity according to 
institutional standards. Pre-medications may vary based on subject’s medical 
history.
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CBC:
Will be drawn every other day during Chemotherapy administration.
Starting on Day 14,CBC will be drawn every day until the end of the cycle.
Methotrexate level:
First Methotrexate level to be obtained 24 hours (+/- 2 hrs) after completion of 
Methotrexate and daily until level is < 0.1 µmol/L.
Methotrexate Precautions:
If Creatinine is > grade 3 on cycle 1 reduce Methotrexate to 75%.
Patients with Pleural Effusion, if not drained do not administer Methotrexate.
Leucovorin:
Leucovorin dose may be adjusted per PI discretion to ensure subject safety.
G-CSF:
Obtain CBC every other day, starting day 9.  GCFS will be given daily until ANC is 
1,000 cell/mm3, at which point, GCSF will be stopped and CBC drawn daily.  After 
stopping G-CSF, if WBC becomes less than 1000µL, restart G-CSF 480 g SQ 
daily for 3 days and repeat CBC.  If subject is of large body habitus, G-CSF can be 
increased to 600 µg SQ daily at discretion of treating physician, after the initial dose 
of 480 µg.  When ANC is 1,500, start cycle 2
Cycles 2 and 4
To start immediately after Cycle 1 and one to two weeks after cycle 3 once ANC is  1500 cells/mm3
DAY
DRUG
-1
NS 200 mL/hr x 12 hours (+/- 1 hr) prior to Ifosfamide
1
Rituximab 375 mg/m2 IV according to standard protocol.
1 and 2
Cytarabine 2 grams/m2 IV every 12 hours  (+/-60 mins) x 4 doses 
according to institutional standard protocol
1-5
Ifosfamide 1.5 grams/m2 IV QD x 5 days according to institutional 
standard protocol
1-5
Mesna 360 mg/m2 IV every 3 hours (+/-30 mins) x 5 days according to 
institutional standard protocol
1-5
Etoposide 60 mg/m2 IV daily x 5 days according to institutional standard 
protocol
7
G-CSF 480 g SQ daily (start Day 7) according to institutional standard 
protocol
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SPECIAL INSTRUCTIONS
Pre-medications:
Patients will be pre-medicated for nausea/vomiting or hypersensitivity according to 
institutional standards. Pre-medications may vary based on subject’s medical 
history.
Cytarabine:
Will be given over 3 hours (+/- 1 hr)
Ifosfamide:
Will be given over 1 hour (+/- 30 min) daily on days 1-5.
Ifosfamide Level:
Obtain U/A daily, hold ifosfamide if >5 RBC/HPF, resume per physician’s orders
Mesna:
Give Mesna in 50 mL D5W over 20 minutes (+/- 10 mins)
Etoposide:
Give Etoposide in 250 mL D5W over 1 hour (+/- 30 mins)
G-CSF:
After stopping G-CSF, if WBC becomes less than 1000/µL, restart G-CSF 480 g 
SQ daily for 3 days and repeat CBC. Obtain CBC every other day starting Day 9.
Scheduled Labs (cycles 2 through 4):
•
Days 1, 3 and 5:   CBC with differential. 
•
Starting Day 7:  CBC with differential every day, until ANC reaches 1500cells/mm3 for two 
consecutive days or per physician’s orders.    
•
Days 1 through 5:  Urinalysis.  
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1.0
OBJECTIVES
1.1
Primary Objective
Progression-free survival
1.2
Secondary Objectives
1.2.1
Overall survival
1.2.2
Response Rate
1.2.3
Toxicity
2.0
BACKGROUND
Mantle cell lymphoma (MCL), a subtype of non-Hodgkin’s lymphoma (NHL), was recently 
recognized as a distinct disease entity.  The term MCL was proposed in 1992 to unify previously 
defined subtypes of NHL, such as diffuse poorly differentiated lymphocytic lymphoma, 
intermediate differentiated lymphocytic lymphoma, centrocytic lymphoma, and diffuse small 
cleaved cell lymphoma, into a single disease entity 1.  According to the International Lymphoma 
Study Group (ILSG), MCL represents 6% of all NHLs 2.  MCL is derived from a subset of naive 
pre-germinal center cells, andmay present with two cytological variants:  typical (lymphocytic) or 
blastic3-4.  In addition, there are three possible patterns of involvement:  mantle-zone, nodular or 
diffuse 4.  It has been suggested that the treatment response and survival of the diffuse and nodular 
patterns are worse than those involving the mantle cell zone.  Majlis et al reported 3-year survival 
rates for mantle-zone, nodular, and diffuse type of 100%, 50%, and 55% respectively 5.  The 
monoclonal B-cells express CD19, CD20, CD22, HLA-DR, CD5, surface IgM and, in most cases, 
surface IgD.  They are negative for CD23 and CD10 (CALLA) antigens 6.
The characteristic cytogenetic abnormality in MCL is the t(11;14) (q13;q32) translocation.  Band 
11q23 includes the BCL-1 locus, which is the site of the PRAD1 (CCND1) gene encoding for cyclin 
D1.  This rearrangement results in translocation of the BCL-1 locus to the immunoglobulin heavy 
chain gene enhancer region located at 14q32, causing cyclin D1 over-expression.  Cyclin D1 
interacts with cyclin dependent kinases 4 and 6 to facilitate the progression of cell through G1 into 
S phase of proliferation 7.
If Response is at least 
Stable Disease after 
Cycles 1 and 2 
Administer 
Cycles 3 & 4
If Response is CR at the end of 
therapy  Administer Rituximab 
375 mg/m2 as weekly doses every 
6 months for a total of 3 years
If Response is PR 
Follow for 
Progression and 
Survival
If Response is CR 
Continue 
Maintenance 
Rituximab
Restage 
After 
Cycle 4
Restage 
Progression
Follow For Survival
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MCL is one of the worst types of NHL since it incorporates some of the undesirable features of both 
low-grade and high-grade lymphomas, namely incurability and rapid course respectively 7.  Most of 
the patients present with advanced stage, high international prognostic index (IPI), and extranodal 
involvement.  The incidence of Stage III and IV varies between 75 to 90% of the patients 2, 4, 6-8.  In 
addition, there is a high incidence of extranodal involvement, the most common sites being bone 
marrow (61-79%), spleen (31-60%), liver (13-30%), peripheral blood (12-30%), and gastrointestinal 
tract (18-20%) 6-9.  Central nervous system (CNS) involvement occurs in about 4% of the patients 
and is associated with poor prognosis 10.
The long-term survival for patients with MCL is generally poor, with only about 27% of the patients 
surviving 5 years after diagnosis and 11% of the patients being disease-free after 5 years.  In 
addition, the ILSG found no 5-year survivors with IPI index 4/5, placing MCL among the 
lymphomas with worse overall prognosis 2.  Despite response rates of 50% to 70% to different 
regimens, all patients eventually develop disease progression after chemotherapy, with the mean 
survival around 3 years 11. 
Several studies using combination chemotherapy with or without anthracyclines (CHOP or COP) 
showed responses between 56% and 90%, with CR rates ranging from 9% to 58%.  However, 
relapse-free survival was relatively short with average of 15 to 20 months.  Median survival in most 
studies ranged from 28 to 52 months 12.  Therapy with fludarabine alone or in combination with 
other chemotherapeutic agents has been tested in small trials.  In a recent study, Cohen et al obtained 
response rates of 66% (30% CR) in a study involving 30 patients treated with fludarabine and 
cyclophosphamide.  The overall survival for patients receiving this combination as first line therapy 
has not been reached at 43 months, although failure- free survival was 28 months 13.  In another 
study involving 29 patients, Zinzani et al achieved a 63% overall response (28% CR) using 
fludarabine alone or in combination with idarubicin14.  Rituximab has also been tested in MCL.  
Igarashi et al treated 21 patients with refractory or relapsed MCL, achieving a 31% response rate 
(no CR observed) 15.  Howard et al obtained a 96% response rate (48%n CR) in 25 patients with 
MCL, using a combination of CHOP and rituximab.  25 patients were evaluated for molecular 
remission, which was seen in 9 of them.  However, the achievement of CR or molecular remission 
did not translate into a prolonged progression-free survival, which was 16.6 months 16.  Khouri et 
al, treated patients with Hyper-CVAD, an aggressive regimen alternating cycles of 
cyclophosphamide, doxorubicin, vincristine, and dexamethasone and high-dose methotrexate and 
cytarabine.  This regimen induced a 93% response rate with 38% CR.  This therapy was followed 
by stem cell transplantation and 93% of previously untreated patients were alive at 3 years post-
transplant, 73% of them disease-free 19. 
Although encouraging results have been reported for stem cell transplant (SCT), its role in the 
treatment of patients with MCL remains unknown.  Overall 3-year survival for MCL patients 
previously treated ranges between 24% to 59%, with one study, performed by Milpied et al, 
reporting 80% overall survival at 4 years 20- 22.  Event-free survival (EFS) or progression-free 
survival (PFS) at three years however, ranges between 17% to 48%19, 22.  Stewart et al, reported a 
23% overall survival for SCT in MCL patients in first remission.  EFS/PFS however, was only 8% 
23.  There have been few small studies on the use of allogeneic SCT in MCL.  The reported overall 
survival is 55% to 62% at 2 years 24-25. 
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Due to unsatisfactory results obtained with both conventional chemotherapy and SCT, it has become 
clear that new high-dose intense chemotherapeutic regimens are needed to improve the survival 
rates for patients with MCL.  Similar intensity protocols have been used for treatment of Burkitt’s 
lymphoma.  Magrath treated patients with Burkitt’s lymphoma using the CODOX-M protocol, 
which consisted of cyclophosphamide, doxorubicin, prednisone, vincristine, high-dose 
methotrexate and intrathecal methotrexate, alternating with IVAC (ifosfamide, etoposide, high-dose 
cytarabine and intrathecal methotrexate).  This regimen resulted in excellent disease control and was 
relatively well tolerated in both children and adults 17.  Mead et al used this same regimen in 52 
patients with Burkitt’s lymphoma.  All patients developed grade 3 and 4 neutropenia and 64% of 
the patients developed grade 3 and 4 thrombocytopenia.  The only other significant side effect was 
mucositis, observed in about 40% of the cases 18. 
 We have therefore developed a similar intense protocol combining most of the agents that 
demonstrated activity in MCL in an attempt to provide a better disease control with improved 
response rates and overall survival.
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death has been 
reported in some patients with hematologic malignancies treated with rituximab.  The majority of 
patients received rituximab in combination with chemotherapy.  The median time to the diagnosis 
of hepatitis was approximately 4 months after the initiation of rituximab and approximately one 
month after the last dose.
Patients achieving a complete remission to induction therapy will receive maintenance therapy with 
Rituximab for 3 years that was recently shown to prolong progression free survival in other subtypes 
of lymphoma.  
In an initial phase II study of R-MACLO-IVAM 22 patients were enrolled. 21 completed therapy 
and all achieved complete remission and one patient died of sepsis on day 14.  Seventeen patients 
remain alive and relapse-free with a median follow up of 33 months. Although the results are very 
promising, we did observe some toxicity, including grade 2 elevation of creatinine post methotrexate 
and intolerability of thalidomide in many patients. The proposed study comes to address these 
toxicities while trying to preserve regimen efficacy.
3.0
PATIENT SELECTION
3.1. Inclusion Criteria
3.1.1
Previously untreated, histologically confirmed mantle cell lymphoma,
3.1.2
Measurable or evaluable disease (at least one site with >1.5 cm in diameter
3.1.3
All stages are eligible
3.1.4
Age > 18 years 
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3.1.5
ECOG performance status 0, 1, or 2
3.1.6
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
3.1.7
Serum creatinine< 1.5 mg/dl
3.1.8
Ability to give informed consent
3.1.9
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
3.1.10
Life expectancy greater than 6 months
3.2
Exclusion Criteria
3.2.1
Previous chemotherapy, immunotherapy or radiotherapy for this mantle cell 
lymphoma
3.2.2
Concurrent active malignancies, with the exception of in situ carcinoma of the 
cervix and basal cell carcinoma of the skin
3.2.3
Grade 3 or 4 cardiac failure and/or ejection fraction < 50.
3.2.4
Psychological, familial, sociological or geographical conditions that do not 
permit treatment and/or medical follow-up required to comply with the study 
protocol.
3.2.5
Patients with a known history of HIV or AIDS
3.2.6
Presence of hepatitis or HBV infection
3.2.7
Pregnant or breast-feeding women.
3.2.8
CNS involvement 
4.0
TREATMENT PLAN
Treatment will be administered in the hospital, with the first and second cycles occurring during the 
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same admission. 
4.1
Cycle 1
DAY
DRUG
1
Rituximab 375 mg/m2 IV according to standard protocol.  
1
Doxorubicin 45 mg/m2 IV bolus according to institutional standard 
protocol.
1
Vincristine 1.5 mg/m2 IV push (maximum of 2 mg) according to 
institutional standard protocol.
1
Cyclophosphamide 800 mg/m2 IVgiven in 100 ml NS IV over 30 (+/- 15) 
minutes according to institutional standard protocol.
2-5
Cyclophosphamide 200 mg/m2 IVgiven in 100 ml NS IV over 30 (+/- 15) 
minutes according to institutional standard protocol.
8
Vincristine 1.5 mg/m2 IV push (maximum of 2 mg) according to 
institutional standard protocol.
10
Methotrexate 1,200 mg/m2 in 250 ml D5W IV over 1 hour (+/-30 min)
followed by 
Methotrexate 3,000 mg/m2 in 1,000 ml D5W by continuous infusion over 
23 (+/-2) hours (130 mg/m2 every hour for 23 hours).  
11+
Leucovorin 100 mg/m2 IV beginning 36 (+/-4)hours after start of 
Methotrexateinfusion followed by Leucovorin 10 mg/m2 IV every 6 (+/- 30 
min) hours until Methotrexate level is< 0.1µmol/L.
13+
G-CSF 480 mcg SQ daily.
Stop G-CSF after 2 consecutive ANC >1,000 cells/mm3.  
Cycle 2 will be scheduled to begin after 2 consecutive ANC > 1,500 cells/mm³ 
and chemotherapy orders are finalized.
SPECIAL INSTRUCTIONS
Pre-medications:
Patients will be pre-medicated for nausea/vomiting or hypersensitivity according to 
institutional standards.Pre-medications may vary based on subject’s medical history.
CBC:
Will be drawn every other day during Chemotherapy administration.
Starting on Day 14,CBC will be drawn every day until the end of the cycle.
Methotrexate level:
First Methotrexate level to be obtained 24 hours (+/- 2 hrs) after completion of 
Methotrexate and daily until level is < 0.1 µmol/L.
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Methotrexate Precautions:
If Creatinine is > grade 3 on cycle 1 reduce Methotrexate to 75%.
Patients with Pleural Effusion, if not drained do not administer Methotrexate.
Leucovorin:
Leucovorin dose may be adjusted per PI discretion to ensure subjects safety.
G-CSF:
After stopping G-CSF, if WBC becomes less than 1000µL, restart G-CSF 480 g SQ 
daily for 3 days and repeat CBC.  If subject is of large body habitus, G-CSF can be 
increased to 600 µg SQ daily at discretion of treating physician, after the initial dose 
of 480 µg.
*G-CSF dosage may be changed based on clinical consideration of treating physician.
4.2
Cycle 2
To start immediately after Cycle 1 once ANC is  1500 cells/mm3 (see above)
DAY
DRUG
-1
NS 200 mL/hr x 12 hours (+/- 1 hr) prior to Ifosfamide
1
Rituximab 375 mg/m2 IV according to institutional standard protocol.
1 and 2
Cytarabine 2 grams/m2 IV every 12 hours  (+/-60 mins) x 4 doses 
according to institutional standard protocol
1-5
Ifosfamide 1.5 grams/m2 IV QD x 5 days according to institutional 
standard protocol
1-5
Mesna 360 mg/m2 IV every 3 hours (+/-30 mins) x 5 days according to 
institutional standard protocol
1-5
Etoposide 60 mg/m2 IV daily x 5 days according to institutional standard 
protocol
7
G-CSF 480 g SQ daily (start Day 7) according to institutional standard 
protocol
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SPECIAL INSTRUCTIONS
Pre-medications:
Patients will be pre-medicated for nausea/vomiting or hypersensitivity according to 
institutional standards. Pre-medications may vary based on subject’s medical history.
Cytarabine:
Will be given over 3 hours (+/- 1 hr)
Ifosfamide:
Will be given over 1 hour (+/- 30 min) daily on days 1-5.
Ifosfamide Level:
Obtain U/A daily, hold ifosfamide if >5 RBC/HPF.
Mesna:
Give Mesna in 50 mL D5W over 20 minutes (+/- 10 mins)
Etoposide:
Give Etoposide in 250 mL D5W over 1 hour (+/- 30 mins)
G-CSF:
After stopping G-CSF, if WBC becomes less than 1000/µL, restart G-CSF 480 g SQ 
daily for 3 days and repeat CBC.Obtain CBC every other day starting Day 9.
*G-CSF dosage may be changed based on clinical consideration of treating physician.
4.3
Cycle 3
To start 7-14 days after discharge from hospital
DAY
DRUG
1
Rituximab 375 mg/m2 IV according to institutional standard protocol.
1
Doxorubicin 45 mg/m2 IV bolus according to institutional standard protocol.
1
Vincristine 1.5 mg/m2 IV push (maximum of 2 mg) according to institutional 
standard protocol.
1
Cyclophosphamide 800 mg/m2 IVgiven in 100 ml NS IV over 30 (+/- 15) 
minutes according to institutional standard protocol.
2-5
Cyclophosphamide 200 mg/m2 IVgiven in 100 ml NS IV over 30 (+/- 15) 
minutes according to institutional standard protocol.
8
Vincristine 1.5 mg/m2 IV push (maximum of 2 mg) according to institutional 
standard protocol.
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10
Methotrexate 1,200 mg/m2 in 250 ml D5W IV over 1 hour (+/-30 min)
followed by
Methotrexate 3,000mg/m2 in 1,000 ml D5W by continuous infusion over 23 
(+/-2) hours (130 mg/m2 every hour for 23 hours).
11+
Leucovorin 100 mg/m2 IV beginning 36 (+/-4)hours after start of 
Methotrexateinfusion followed by Leucovorin 10 mg/m2 IV every 6 (+/- 30 
min) hours until Methotrexate level is< 0.1µmol/L.
13+
G-CSF 480 mcg SQ daily.
Stop G-CSF after 2 consecutive ANC >1,000 cells/mm3.
Cycle 2 will be scheduled to begin after 2 consecutive ANC > 1,500 cells/mm³ 
and chemotherapy orders are finalized.
SPECIAL INSTRUCTIONS
Pre-medications:
Patients will be pre-medicated for nausea/vomiting or hypersensitivity according to 
institutional standards.Pre-medications may vary based on subject’s medical history.
CBC:
Will be drawn every other day during Chemotherapy administration.
Starting on Day 14,CBC will be drawn every day until the end of the cycle.
Methotrexate level:
First Methotrexate level to be obtained 24 hours (+/- 2 hrs) after completion of 
Methotrexate and daily until level is < 0.1 µmol/L.
Methotrexate Precautions:
If Creatinine is > grade 3 on cycle 1 reduce Methotrexate to 75%.
Patients with Pleural Effusion, if not drained do not administer Methotrexate.
Leucovorin:
Leucovorin dose may be adjusted per PI discretion to ensure subjects safety.
G-CSF:
After stopping G-CSF, if WBC becomes less than 1000µL, restart G-CSF 480 g 
SQ daily for 3 days and repeat CBC.  If subject is of large body habitus, G-CSF can 
be increased to 600 µg SQ daily at discretion of treating physician, after the initial 
dose of 480 µg.
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*G-CSF dosage may be changed based on clinical consideration of treating physician.
4.4
Cycle 4
To start immediately within one to two weeks after Cycle 3 once ANC is  1500 cells/mm3
(see above)
DAY
DRUG
-1
NS 200 mL/hr x 12 hours (+/- 1 hr) prior to Ifosfamide
1
Rituximab 375 mg/m2 IV according to institutional standard protocol.
1 and 2
Cytarabine 2 grams/m2 IV every 12 hours  (+/-60 mins) x 4 doses 
according to institutional standard protocol
1-5
Ifosfamide 1.5 grams/m2 IV QD x 5 days according to institutional 
standard protocol
1-5
Mesna 360 mg/m2 IV every 3 hours (+/-30 mins) x 5 days according to 
institutional standard protocol
1-5
Etoposide 60 mg/m2 IV daily x 5 days according to institutional standard 
protocol
7
G-CSF 480 g SQ daily (start Day 7) according to institutional standard 
protocol
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SPECIAL INSTRUCTIONS
Pre-medications:
Patients will be pre-medicated for nausea/vomiting or hypersensitivity according to 
institutional standards. Pre-medications may vary based on subject’s medical history.
Cytarabine:
Will be given over 3 hours (+/- 1 hr)
Ifosfamide:
Will be given over 1 hour (+/- 30 min) daily on days 1-5.
Ifosfamide Level:
Obtain U/A daily, hold ifosfamide if >5 RBC/HPF.
Mesna:
Give Mesna in 50 mL D5W over 20 minutes (+/- 10 mins)
Etoposide:
Give Etoposide in 250 mL D5W over 1 hour (+/- 30 mins)
G-CSF:
After stopping G-CSF, if WBC becomes less than 1000/µL, restart G-CSF 480 g SQ 
daily for 3 days and repeat CBC.Obtain CBC every other day starting Day 9.
*G-CSF dosage may be changed based on clinical consideration of treating physician.
4.5
Supportive Care Guidelines
All antibiotics may be administered as clinically indicated.
4.6
Duration of Therapy
Treatment will consist of up to 4 cycles of therapy.  Response assessment by CT and PET 
scans will be performed post Cycle 2.  Once the final cycle  of therapy is completed, 
response evaluation will be performed based on pre-study CT scans, PET/ Scan/endoscopy 
or any staging scans that were positive at baseline. (PI approval required if treating with 
less than 4 cycles).
Subjects in complete remission will be given Rituximab 375 mg/m2 IV, per institution 
guidelines, as 4 weekly doses every 6 months for a total of 3 years or until  progression of 
disease or if the subject is unable to tolerate further treatment.  Rituximab should begin 6 
months from date of discharge +/- 21 days.  Maintenance therapy, premedications can be 
changed based on clinical consideration from treating physician.  Timelines for giving 
premedications are given per institutional guidelines.    Subject may be discharged after 
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administration of Rituximab, once stable.  
5.0
Clinical and Laboratory Evaluations
5.1
Baseline/Pretreatment Evaluations
The following will be obtained no more than 28 days prior to the initiation of therapy (See 
Appendix 5):
5.1.1
Complete medical history to include:
5.1.1.1
Date of initial diagnosis of lymphoma.  A copy of the pathology report 
must be available in the medical record.
5.1.1.2
Presence or absence of “B”-symptoms (unexplained fevers, night 
sweats, involuntary weight loss greater than 10% normal body weight)
5.1.1.3
History of other symptoms related to mantle cell lymphoma.
5.1.1.4
History of drug allergies
5.1.1.5
Medication list to include all medications taken within 30 days of study 
entry.
5.1.2
Complete physical examination: includes ECOG performance score, vital signs, 
weight, height, neurologic examination, careful measurement of all palpable 
peripheral lymph nodes, and measurement of other sites of disease present on 
physical examination.
5.1.3
Laboratory tests:
5.1.3.1
Hematology: CBC, platelet count, and differential
5.1.3.2
Blood chemistries: to include sodium, potassium, chloride, CO2, 
creatinine, calcium, uric acid, total bilirubin, AST, ALT, alkaline 
phosphatase, total protein, albumin, LDH, Hepatitis B and C, Beta-2 
microglobulin.
5.1.3.3
Urine pregnancy test for women of child bearing age within 72 hours of 
study entry 
5.1.4
Other tests
5.1.4.1
EKG
5.1.4.2
MUGA or Echocardiogram 
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5.1.5
Staging Evaluation (-28 to D1):  The following will be done for baseline.
5.1.5.1
CT scan of the chest with contrast.
5.1.5.2
Bone scan/bone films if clinically indicated.
5.1.5.3
CT of the abdomen and pelvis with contrast.
5.1.5.4
Brain CT or MRI scan if clinically indicated
5.1.5.5
Pet scan.
5.1.5.6
Colonoscopy with or without upper endoscopy, if clinically indicated.
5.1.5.7
Bone Marrow Biopsy and Aspirate.
5.2
Evaluations during treatment:
See Appendix 5 for a study calendar
5.2.1
Physical examination including ECOG performance score, weight and vital signs 
will be repeated on day 1 (+/- 3 days) of each chemotherapy cycle.  Disease 
measurable on physical examination should be measured in two dimensions.
5.2.2
  CBC and differential will be repeated at the start of each chemotherapy cycle.
5.2.3
CMP, Bicarbonate, creatinine, BUN, liver function tests (including total 
bilirubin, alkaline phosphatase, AST, ALT, and LDH will be obtained at the start 
of each chemotherapy cycle.
5.2.4
For cycles 2 and 4 only – daily U/A during Ifosfamide therapy.
5.2.5
Restaging evaluation: 
After second cycle – CT scan of chest, abdomen, pelvis and Neck and PET scans 
will be obtained.  
At the end of the treatment (after final 
cycle) – all staging exams that were positive at baseline will be repeated.  CT, 
PET scan in all the patients and bone marrow biopsy and aspiration and 
colonoscopy/endoscopy, if clinical involvement was present at initial staging.
5.3
Maintenance Treatment Evaluations
The studies listed below (5.3.1-5.3.5) are required at the indicated intervals until disease 
progression or death (whichever occurs first).  Patients who have disease progression and 
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are alive are followed for survival only – no additional studies are required after disease 
progression.
For all patients who achieve CR after their final cycle of in-patient therapy, the following 
studies should be obtained monthly for the first 3 months, then every 3 months for 2 years, 
then every 6 months for years 3 through 5 and yearly thereafter:
5.3.1
Medical History
5.3.2
Complete physical examination: includes ECOG performance score, vital signs, 
weight,  body surface area (during Rituximab treatment), neurologic 
examination, careful measurement of all palpable peripheral lymph nodes, and 
measurement of other sites of disease present on physical examination.
5.3.3
CBC, CMP, LDH and Beta-2.
The following studies should be obtained every 3 months for years 1 and 2, every 6 months 
for 3-5 years, then annually after year 5 or more frequently if clinically indicated:
5.3.4
Restaging evaluation (CT as indicated) will be performed
5.3.5
Bone Marrow biopsy and aspiration, if clinically indicated.
Windows for maintenance therapy, as well as follow-up visits are (+/- 21 days)
5.4
Early discontinuation of therapy
Patients going off study prior to completion of therapy will have a complete physical 
examination, and blood drawn for the following studies: CBC with differential and 
platelets, Electrolytes, creatinine, BUN, liver function tests (including total bilirubin, 
alkaline phosphatase, AST, ALT, LDH, Uric Acid and Beta-2 microglobulin.
6.0
Dosing Delays/Dose Modifications
6.1
Hematologic Toxicity
No dose modifications will be made for hematologic toxicity. We do expect severe 
pancytopenia and thrombocytopenia.
6.1.1
Day One Counts for each cycle of chemotherapy
6.1.1.1
If ANC < 1000 cells/mm3 delay chemotherapy for up to 2-3 weeks.  If 
by 4 weeks ANC has not increased to 1500 cells/mm3 the patient will 
be withdrawn from treatment at the discretion of the PI.
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6.2
Non-Hematologic Toxicity
6.2.1
Doxorubicin – If severe cardiotoxicity develops (ejection fraction less than 40% 
or symptomatic heart failure), this agent will be discontinued.
6.2.2
Vincristine – will be discontinued in the case of grade 3 or 4 neurotoxicity.
6.2.3
Methotrexate – dose will be decreased by 25% in the case of grade 3 or 4 renal 
toxicity.  Dose will be omitted per PI discretion in case of undrained pleural 
effusion.  
6.2.4
Cytarabine – will be discontinued in the case of grade 3 or 4 neurotoxicity 
attributed to Cytarabine. 
6.2.5
Cyclophosphamide and Ifosfamide – will be discontinued if hemorrhagic 
cystitis occurs.
7.0
Agent Formulation and Procurement
7.1
Rituximab (Rituxan)
Rituximab is a chimeric anti-CD20 antibody that targets the CD20 antigen present during 
most phases of B cell development.
7.1.1
Drug preparation:  Rituximab is present in 100 and 500 mg single-use vials 
formulated in 25 nM sodium citrate. It should be diluted in 0.9% sodium chloride 
or 5% dextrose to a final concentration of 1 to 4 mg/mL.
7.1.2
Administration:  This agent is given only by IV route. 
Infusion should be started at an initial rate of 50 mg/hour and, if no toxicity is 
observed during one hour, it should be escalated by increments of 50 mg/hour 
every 30 minutes to a maximum infusion rate of 300 mg/hour.  Patient should be 
monitored for infusion-related events, which usually occur 30 to 120 minutes 
after the start of the first infusion.  Infusion should be stopped immediately in the 
presence of signs or symptoms of an allergic reaction.  Patients should then be 
treated with corticosteroids, diphenhydramine, acetaminophen, and IV fluids.  In 
most cases, infusion can be restarted at 50% of the dose once symptoms have 
completely resolved.
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7.1.3
Side effects
Common (> 30%)
Uncommon (< 30%)
Rare (< 5%)
Chills
Fever
Fatigue
Facial flushing
Pruritus
Urticaria
Vomiting
Hypotension
Headache
Angioedema
Bronchospasm
Dyspnea
Abdominal pain
Abdominal swelling
Agitation
Anemia
Anxiety
Loss of appetite
Arthralgia
Back pain
Conjunctivitis
Cough
Diarrhea
Dry eyes
Hypertension
Insomnia
Myalgia
Pain at the injection site
Peripheral edema
Sore throat
thrombocytopenia
Angina
Cardiac arrhythmias
There is also a risk of serious virus infections occurring after discontinuation of rituximab. 
The following serious viral infections new, reactivated or exacerbated have been 
identified: 
JC 
virus 
(progressive 
multi-focal 
leukoencephalopathy, 
PML), 
cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile 
virus and hepatitis C. In some cases the viral infections occurred up to one year following 
discontinuation of rituximab and have resulted in death.
Abdominal pain, bowel obstruction and perforation, in some cases leading to death, were 
observed in patients receiving rituximab in combination with chemotherapy for diffuse 
large B-cell lymphoma.
Patients with Rheumatoid Arthritis (RA) are at an increased risk for cardiovascular events 
compared to the general population. 3 cardiovascular deaths occurred in studies where 
patients with RA were treated with rituximab. 
7.2
Doxorubicin (Adriamycin)
Doxorubicin is an antibiotic that works by intercalating into DNA, resulting in inhibition 
of DNA synthesis and function.  It also inhibits DNA topoisomerase II and inhibits 
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transcription through inhibition of DNA-dependent RNA polymerase.
7.2.1
Drug preparation: doxorubicin is available in 10, 20, 50, 100, and 150 mg vials 
for intravenous use.  It should be diluted with 0.9% sodium chloride to yield a 
final concentration of 2 mg/mL.
7.2.2
Administration:  IV Infusion. 
Since it is vesicant, administration should be slowly over 3 to 5 minutes with a 
rapid flowing IV.  Careful monitoring is necessary to avoid extravasation.  In 
case of extravasation, infusion should be immediately stopped, the extremity 
should be elevated, and ice should be applied to the involved site. 
7.2.3
Side effects
Common (> 30%)
Uncommon (< 30%)
Rare (< 5%)
Esophagitis
Hair loss
Infection
Leukopenia
Nausea
Red colored urine
Stomatitis
Vomiting
Congestive heart 
failure
Darkening of the soles 
and palms
Diarrhea
Hyperpigmentation of 
the fingernails
Uric acid nephropathy
Allergic dermatitis
Allergic reaction
Anaphylaxis
Bronchospasm
Drug fever
Hives
Shortness of breath
Skin rash
Wheezing
7.3
Vincristine (Oncovin)
Vincristine is a vinca alkaloid that works by inhibiting tubulin polymerization. It causes a 
disruption in the formation of microtubule assembly during mitosis, resulting in an arrest 
in cell division and ultimately, cell death.
7.3.1
Drug preparation: vincristine is available in 1, 2, and 5 mg vials at a concentration 
of 1 mg/mL for intravenous use. It should be diluted in 0.9% sodium chloride or 
5% dextrose.
7.3.2
Administration:  IV Infusion.
7.3.3
Side Effects
Common (> 30%)
Uncommon (< 30%)
Rare (< 5%)
Autonomic toxicity
Hair loss
Hyperuricemia
Neurotoxicity
Bloating
Cellulitis
Diarrhea
Hyponatremia
Leukopenia
Stomatitis
Thrombocytopenia
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Nausea
SIADH syndrome
Skin rash
Vomiting
Weight loss
7.4
Cyclophosphamide (Cytoxan)
Cyclophosphamide is an alkylating agent that cross-links with DNA resulting in inhibition 
of its synthesis and function.
7.4.1
Drug preparation: cyclophosphamide for intravenous use is available in 100, 200, 
500, 10000, and 2000 mg vials.  It should be diluted with sterile water.
7.4.2
Administration:  IV Infusion
7.4.3
Side Effects
Common (> 30%)
Uncommon (< 30%)
Rare (< 5%)
Loss of appetite
Darkening skin
Hyperpigmentation of 
the fingernails
Hair loss
Infection
Irregular menstrual 
periods
Leukopenia
Nausea
Stomach pain
Vomiting
Acute myocarditis
Anemia
Hemorrhagic cystitis
Diarrhea
Facial flushing
Headache
Hyperuricemia
Increased sweating
SIADH syndrome
Thrombocytopenia
Allergic dermatitis
Allergic reaction
Anaphylaxis
Angioedema
Bronchospasm
Dyspnea
Hepatitis
Hives
Hyperglycemia
Itching
Pain at the injection 
site
Skin rash
Stomatitis
7.5
Methotrexate
Methotrexate is an antimetabolite agent that works by inhibition of dihydrofolate 
reductase.
7.5.1
Drug preparation:  Methotrexate is available in 50, 100, 200, and 1000 mg single-
use vials for intravenous use. It may be further diluted in 0.9% sodium chloride.
7.5.2
Administration:  IV Infusion.
With high-dose therapy (> 1 g/m2), it is important to vigorously hydrate the 
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patient and add sodium bicarbonate in the intravenous fluid to ensure that the 
urine pH is greater than 7.0 at the time of the drug infusion. Drug levels should 
also be monitored every 24 hours, starting 24 hours after infusion.
7.2.3
Side effects
Common (> 30%)
Uncommon (< 30%)
Loss of appetite
Azotemia
Bacterial infection
Cutaneous vasculitis
Gastroenteritis
Gastric ulcers
Stomatitis
Hyperuricemia
Leukopenia
Nausea, Vomiting
Nephropathy
Thrombocytopenia
Renal failure
Acne
Oils
Cirrhosis
Demyelination
Hair loss
Itching
Pneumonitis
Pulmonary fibrosis
Skin rash
7.6
Leucovorin (folinic acid)
Leucovorin is a reduced folate which replaces intracellular stores of reduced folates 
following inhibition of dihydrofolate reductase by methotrexate or other antifolate 
analogs.
7.6.1
Drug preparation: Leucovorin is available in 50, 100, and 350 mg vials for 
intravenous or intramuscular use. Vials can be reconstituted with sterile water 
and then further diluted with 0.9% sodium chloride or 5% dextrose water.
7.6.2
Administration:  IV Infusion.  
7.6.2
Side effects are rare and include allergic reaction and seizures.
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7.7
Etoposide (VP16)
Etoposide is a topoisomerase II inhibitor.
7.7.1
Drug preparation: Etoposide is available as single-dose vials containing 
Etoposide phosphate equivalent to 100 mg of Etoposide for intravenous use. It 
should be diluted in 5 ml or 10 ml of sterile water, 0.9% sodium chloride or 5% 
dextrose water to a final concentration of 20 or 10 mg/mL.
7.7.2
Administration:  IV Infusion.
7.7.3
Side effects
Common (> 30%)
Uncommon (< 30%)
Rare (< 5%)
Anemia
Loss of appetite
Hair loss
Leukopenia
Nausea
Thrombocytopenia
Vomiting
Diarrhea
Stomatitis
weakness
Allergic dermatitis
Anaphylaxis
Angioedema
Neurotoxicity
Phlebitis
Skin rash
7.8
Ifosfamide (Ifex)
Ifosfamide is an alkylating agent.
7.8.1
Drug preparation: Ifosfamide is available in 1 g single-dose vials for intravenous 
use, prepackaged with mesna.  It should be reconstituted with sterile water and 
may be further diluted in 0.9% sodium chloride or 5% dextrose water to a final 
concentration of 0.6 to 20 mg/mL.
7.8.2
Administration:  IV Infusion
7.8.3
Side effects
Common (> 30%)
Uncommon (< 30%)
Rare (< 5%)
Dysuria
Hair loss
Encephalopathy
Hepatotoxicity
Leukopenia
Nausea
Thrombocytopenia
Urinary frequency
Hemorrhagic cystitis
Infection
Nephrotoxicity
phlebitis
Cardiotoxicity
Dyspnea
Polyneuropathy
Stomatitis
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Vomiting
7.9
Mesna (Mesnex)
Mesna is a synthetic sulfhydryl compound used to prevent ifosfamide and 
cyclophosphamide-induced hemorrhagic cystitis.
7.9.1
Drug preparation: mesna is available in 200 mg glass ampoules or as a 1000 mg 
multi-dose vial for intravenous use.  It should be diluted with 0.9% sodium 
chloride or 5% dextrose.
7.9.2
Administration:  IV Infusion. 
7.9.3
Side effects
Uncommon (< 30%)
Rare (< 5%)
Diarrhea
Nausea
Unpleasant taste
Vomiting
Allergic dermatitis
Allergic reaction
Skin rash
7.10
Cytarabine (AraC)
Cytarabine is an antimetabolite that, after phosphorylation, incorporates into DNA 
resulting in inhibition of its synthesis and function.
7.10.1
Drug preparation: cytarabine is available in 100, 500, 1000, and 2000 mg multi-
dose vials for intravenous use. It should be diluted in sterile water with benzyl 
alcohol and then further diluted with 50 to 100 ml of 0.9% sodium chloride or 
5% dextrose.
7.10.2
Administration:  IV Infusion
7.10.3
Side effects
Common (> 30%)
Uncommon (< 30%)
Rare (< 5%)
Loss of appetite
Infection
Leukopenia
Nausea
Stomatitis
Thrombocytopenia
vomiting
Neurologic toxicity
Hyperuricemia
Sensation disturbances
Bone pain
Cellulites in the site of 
injection
Chest pain
Diarrhea
Diffuse interstitial 
pneumonitis
Dizziness
Esophagitis
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7.11
Filgrastim 
(Neupogen)
Filgrastim is a colony-stimulating factor that activates the proliferation, differentiation, 
and activation of granulocyte progenitor cells.
7.11.1
Drug preparation: Filgrastim is available in single-dose, preservative-free vials 
containing 300 mcg (1 mL volume) or 480 mcg (1.6 mL volume) of G-CSF for 
intravenous or subcutaneous injection. 
7.11.2
Administration:  Subcutaneous.  
7.11.3
Side effects
Common (> 30%)
Uncommon (< 30%)
Rare (< 5%)
Arthralgia
Headache
Itching
Medullary bone pain
Myalgia
Skin rash
Leukocytosis
Pain at the site of 
injection
Allergic reaction
Anaphylactic reaction
Splenic rupture
Splenomegaly
Arrhythmias
Vasculitis
Sweet’s syndrome 
8.0
MEASUREMENT OF EFFECT
For the purposes of this study, patients should be evaluated for response at the completion of 2nd 
and final cycle of therapy; for years 1 and 2; response should be evaluated every 3 months (+/- 21 
days), years 2 through 5 every 6 months (+/- 21 days) and yearly, thereafter. Additional diagnostic 
tests will be required if clinically indicated.   
Fever
Hair loss
Headache
Hepatotoxicity
Jaundice
Malaise
Megaloblastic anemia
Muscle pain
Pruritus
Pulmonary edema
Skin rash
Thrombophlebitis
Urinary retention
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8.1
Definitions
Response 
category
Physical exam
Lymph nodes
Lymph node 
masses
Bone marrow
CR
Normal
Normal
Normal
Normal
CR (u)
Normal
Normal
Normal or > 
75% decrease
Normal 
indeterminate
PR
Normal
Normal or > 
50% decrease
Normal or > 
50% decrease
Positive or 
irrelevant
Relapse/progres
sive disease
Enlarging liver, 
spleen or other 
sites
New or 
increased
New or 
increased
Reappearance
CR – complete response; CR (u) – complete response/unconfirmed; PR  - partial response
8.2
Response Criteria
8.2.1
CR requires the following:
1. Complete disappearance of all detectable clinical and radiographic evidence 
of disease and disappearance of all disease-related symptoms if present before 
therapy, and normalization of those biochemical abnormalities (e.g. LDH) 
definitely assignable to NHL.
2. All lymph nodes and nodal masses must have regressed to normal size.  
Previously involved nodes that were between 1.1 to 1.5 cm in their greatest 
transverse diameter before treatment must have decreased to < 1 cm in their 
greatest transverse diameter after treatment, or by >75% in the sum of the 
products of the greatest diameters (SPD) may be used to confirm CR.
3. The spleen, if considered to be enlarged before therapy on the basis if a CT 
scan, must have regressed in size and must not be palpable on physical exam.  
However, no normal size can be specified because of the difficulties in accurately 
evaluating splenic and hepatic sizes.  
4. If the bone marrow was involved by lymphoma before treatment, the infiltrate 
must be cleared on repeat bone marrow aspirate and biopsy on the same site. 
8.2.2
CR/unconfirmed (CR (u)) requires the following: 
1. Residual lymph node mass greater than 1.5 cm in greatest transverse diameter 
that has regressed by more than 75% in the SPD.  Individual nodes that were 
previously confluent must have regressed by more than 75% in their SPD 
compared with the size of the original mass. 
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2. Indeterminate bone marrow (increased number or size of aggregates without 
cytologic or architectural atypia). 
8.2.3
PR requires the following:
1. > 50% decrease in SPD of the six largest dominant nodes or nodal masses.
2. No increase in the size of other nodes, liver, or spleen.
3. Splenic or hepatic nodules must regress by at least 50% in the SPD.
4. With the exception of splenic and hepatic nodules, involvement of other organs 
is considered assessable and not measurable disease.
5. Bone marrow assessment is irrelevant for the determination of a PR because it 
is assessable and not measurable disease.
6. No new sites of disease.
8.2.4
Stable disease (SD) is defined as less than a PR but not a progressive disease
8.2.5
Relapsed disease (CR or CR (u)) requires the following:
1. Appearance of any new lesion or increase by > 50% in the size of previously 
involved sites.
2. > 50% increase in greatest diameter of any previously identified node greater 
than 1 cm in its short axis or in the SPD of more than one node.
8.2.6
Progressive disease (PR or non-responders) requires the following:
1. > 50% increase from nadir in the SPD of any previously identified abnormal 
node for PRs or non-responders.
2. Appearance of any new lesion during the end of therapy.
8.3
Duration of overall response
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented.
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8.4
Duration of stable disease
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started. 
8.5
Progression-Free Survival
Upon finishing therapy, patients will be followed at 6 month (+/- 30 days) intervals to 
document the progression-free interval.
9.0
ADVERSE EVENT REPORTING
9.1
Adverse Event (AE) Definitions
Adverse events (AE’s) will use the descriptions and grading scales found in the NCI 
Common Toxicity Criteria Version 3.0 in Appendix II.
9.1.1
A serious adverse event (experience) or reaction is any untoward medical 
occurrence that at any dose: results in death, is life-threatening, requires inpatient 
hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity, or is a congenital anomaly/birth defect.
The definition of serious adverse event (experience) also includes important 
medical events.  Medical and scientific judgment should be exercised in deciding 
whether reporting is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above.  These should 
also usually be considered serious.  Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse.
9.1.2
Expected events are those that have been previously identified as resulting from 
administration of the agent.
9.1.3
An adverse event is considered unexpected when either the type of event or the 
severity of the event is not listed in: the current NCI Agent-Specific Adverse 
Event List; the investigator's brochure, drug package insert or the drug 
information section of this protocol.
9.1.4
The definition of related is that there is a reasonable possibility that the drug 
caused the adverse experience
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9.1.5
ATTRIBUTION – The determination of whether an adverse event is related to a 
medical treatment or procedure.  Attribution categories:
•
Definite – The adverse event is clearly related to the investigational 
agent(s).
•
Probable – The adverse event is likely related to the investigational 
agent(s).
•
Possible – The adverse event may be related to the investigational 
agent(s).
•
Unlikely – The adverse event is doubtfully related to the investigational 
agent(s).
•
Unrelated – The adverse event is clearly NOT related to the 
investigational agent(s).
9.1.6
Commercial agents are those agents not provided under an IND but obtained 
instead from a commercial source.
9.2
Purpose
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents.  Adverse events are reported in a routine 
manner at scheduled times during a trial (please follow directions for routine reporting 
provided in the Data Reporting Section.  Additionally, certain adverse events must be 
reported in an expedited manner for more timely monitoring of patient safety and care.  
The following sections provide information about expedited reporting.
9.2.1
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) whether the 
patient has received an investigational or commercial agent; 2) the characteristics 
of the adverse event including the grade (severity), the relationship to the study 
therapy (attribution), and the prior experience (expectedness) of the adverse 
event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization 
or prolongation of hospitalization was associated with the event.
9.2.2
Steps to determine if an adverse event is to be reported in an expedited manner:
Step 1: Identify the type of event using the NCI Common Toxicity Criteria 
(CTC) Version 3.0.
The CTC provides descriptive terminology and a grading scale for each 
adverse event listed. A copy of the CTC can be downloaded from the 
CTEP home page (http://ctep.cancer.gov). Additionally, if assistance is 
needed, the NCI has an Index to the CTC that provides help for 
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classifying and locating terms. All appropriate treatment locations 
should have access to a copy of the CTC.
Step 2: Grade the event using the NCI CTC.
Step 3: Determine whether the adverse event is related to the protocol therapy 
(investigational or commercial).
Attribution categories are as follows: Unrelated, Unlikely, Possible, 
Probable, and Definite.
Step 4: Determine the prior experience of the adverse event. 
Step 5: Review Table 9.3.1 to determine if there are any protocol-specific 
requirements for reporting of specific adverse events that require 
special monitoring.
9.3
Reporting Methods 
Table 9.3.1 Reporting for Commercial Agents
Grade 4
Grade 5a
Protocol-specific 
Requirements/
Exceptions
Attribution
Unexpected
Expected
Unexpected
Expected
Unrelated or 
Unlikely
Possible, 
Probable, or 
Definite
 
See footnote (b) for special 
requirements.
a
This includes all deaths within 30 days of the last dose of treatment with a commercial agent(s), regardless of 
attribution. Any death that occurs more than 30 days after the last dose of treatment with a commercial 
agent(s) and is attributed (possibly, probably, or definitely) to the agent(s) and is not due to cancer recurrence 
must be reported according to the instructions above.
b
The adverse events listed below do not require reporting:Grade 4 myelosuppression 
9.3.2
All serious, unusual life-threatening or lethal adverse events which may be study 
related will be reported within 24 hours by telephone to the Principal Investigator 
and must be followed by a written report which must be received by the Principal 
Investigator within 10 business days.  The Principal Investigator shall also be 
responsible for promptly notifying the local Institutional Review Board of all such 
adverse events.  For all fatal events (Grade 5) while on study or within 30 days of 
treatment, a written report will follow within 10 working days.
9.3.3
All adverse events, regardless of severity, and whether or not ascribed to the study 
drug administration, will be recorded in the appropriate section of the Case Report 
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Form.  Patients withdrawn from the study due to adverse events will be followed by 
the investigator until the outcome is determined and, when appropriate, additional 
written reports and documentation will be provided.
9.3.4 IRB Reporting 
9.4.4.1
All unexpected serious adverse events that are possibly, probably or 
definitely related to the study medications, , events that are more severe 
than anticipated, events that are more frequent than anticipated, and 
deaths must be reported to the IRB within ten (10) working days of 
being made known to the Principal Investigator.
10.0
DATA REPORTING
10.1
Records to be Kept
Case Report Forms (CRFs) will be provided for each subject.  Subjects must not be 
identified by name on any study documents.  Subjects will be identified by a Patient 
Identification Number upon registration.  
All data on the CRF must be legibly recorded in black ink or typed.  A correction should 
be made by striking through the incorrect entry with a single line and entering the correct 
information adjacent to it.  The correction must be initialed and dated by the investigator 
or designated qualified individual.  Any requested information that is not obtained as 
specified in the protocol should have an explanation noted on the CRF as to why the 
required information was not obtained.
11.0
CRITERIA FOR DISCONTINUATION OF THERAPY 
After enrollment, the patient will be permanently withdrawn from study treatment for any of the 
following reasons:
11.1
Patients developing a life-threatening infection who are in the chemotherapy portion of 
the protocol will have chemotherapy interrupted until the infectious process has cleared.  
The subject will be withdrawn from study treatment only if chemotherapy has been held 
for more than six weeks.
11.2
Chemotherapy delays for more than six weeks, for any reason.
11.3
Severe toxicities as previously outlined. (Refer to section 9.1)
11.4
Progressive lymphoma at any time while on study.
11.5
Voluntary withdrawal.
11.6
The investigator has the right to remove subjects from study for clinical reasons, which he 
or she believes to be life-threatening or resulting in significant morbidity to the subject.
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12.0
STATISTICAL CONSIDERATION
Since we expect all patients to experience complete or partial response to the therapy, we will use 
progression-free survival (PFS) as our primary endpoint to measure efficacy.  PFS is defined as the 
time from start of treatment to the earliest one of the following events: relapse (in patients who 
achieve complete response), disease progression (in patients with partial response or stable disease), 
or death.  (See section 7 for criteria for response, relapse, and disease progression.)   All patients 
who meet eligibility criteria and receive initial treatment will be evaluable for toxicity, progression, 
and survival; patients who complete at least cycles 1 and 2 of study treatment will be evaluable for 
response.
Study size and duration. Study size is limited by the availability of eligible patients, which we 
estimate to be about 4 patients per year.  We plan to enroll a total of approximately 28 patients in 
order to base our main analyses on at least 22 (79%) evaluable patients.  Consequently, our study 
will entail an enrollment period of approximately 6 years and a minimum follow up of two years 
beyond the last patient is enrolled.  The estimated total study duration for this trial will be 8 years.
Study precision.  It is expected that study treatment will extend the median time to disease 
progression to 24 months as compared with the current standard of approximately 18 months in this 
patient population.  Assuming an exponential distribution for time to disease progression, the 
anticipated effect of study treatment is equivalent to an (absolute) increase of 9% in the proportion 
of patients alive and progression-free at 18-months from a current rate of 50% to 59% on study.
Assuming no losses to follow-up and 22 evaluable patients, our estimate of the 18-month 
progression-free survival rate using the Kaplan-Meier method [26] will have a standard error of no 
more than11% [27]. 
The following table illustrates the precision of our study for several possible outcomes.
Possible outcomes and corresponding estimates of progression-free survival based on 22 
evaluable patients
~~~~~~~~~~~~At 18 months ~~~~~~~~~~~~
Patients w/o 
progression
Proportion
Standard error
95% CI
Corresponding 
median*
11
50%
10.7%
29.1% - 70.9%
18 months
13
60%
10.4%
39.5% – 80.5%
24.4 months
15
70%
9.8%
50.9% – 89.1%
35 months
18
80%
8.5%
63.3% – 96.7%
55.9 months
#CI: Confidence interval. * Assuming progression free survival follows an exponential distribution.
The middle row in the table above represents the study objective of observing a median PFS of 
approximately 24 months.  This requires that 13 out of 22 patients survive with no evidence of 
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disease progression for at least 18 months from the start of treatment.  If this is the case, then 
our estimate of the 18-month progression free survival rate will be 60% and we will report a 
(two-sided) 95% confidence interval estimate of 39.5 to 80.5%.  
Statistical analysis: Using the Kaplan-Meier method, we will estimate both progression-free and 
overall survival rates at 6-, 12-, 18- and 24-months with corresponding two-sided 95% confidence 
intervals.  Medians, if attained, will be reported similarly.  The amount of patient follow-up will be 
characterized descriptively by the range and median for patients who experience the event 
(progression or death) and those who do not (censored observations). 
In addition to the analysis of progression-free and overall survival, patients will be classified by 
response to treatment according to the criteria in Section 7.  We will estimate the complete response 
(CR) rate with a two-sided 95% confidence interval using the exact binomial method [28]; the 
relapse rate following CR will be estimated by the method of cumulative incidence.  A detailed 
tabulation will be given of the time to response and the duration of response for each response type.  
Since our study is small, only a very strong association could be detected between response status 
(complete versus partial) and either progression-free or overall survival.  We will use the log-rank 
test to explore this association. 
Descriptive statistics will be provided for patient demographic variables (age, sex, and race) and for 
disease characteristics at baseline, including performance status.
Interim monitoring: The Research Team will continuously monitor study accruals, toxicities, and 
response to treatment.  The UM/Sylvester Comprehensive Cancer Center’s Data and Safety 
Monitoring Committee (DSMC) will monitor this protocol according to the Cancer Center’s DSM 
Plan.  In its oversight capacity, the DSMC bears responsibility for suspending or terminating this 
study. DSMC oversight of the conduct of this trial includes ongoing review of accrual and adverse 
event data, and periodic review of response. The DSMC also reviews reports from internal audits of 
protocol compliance and data integrity conducted by the University of Miami, Office of Research 
Compliance Assessment. 
The guidelines appearing in this section are offered for DSMC consideration in its review of 
accumulating study data. These guidelines were developed using Bayesian methods, which can be 
applied at any stage of enrollment without advance specification of the number of interim analyses 
to be performed, or the number of evaluable patients at the time such assessments are made [29, 
30].Under the Bayesian method, we assign a prior probability (level of belief at the start of the trial) 
to a range of possible values for the endpoint being monitored.  As data on study patients become 
available, this probability distribution is revised and the resulting posterior probability becomes the 
basis for recommending either early termination or continuation of the study.
Safety: Early stopping due to toxicity
Since we expect that most patients will experience grade 4 toxicity, trial safety will be monitored 
on the basis of treatment-related mortality. We suggest that DSMC consider stopping the study early 
if there is evidence that treatment-related mortality exceeds a rate of 10%. More specifically, DSMC 
will have evidence in favor of early termination if the posterior probability is 80% or higher that the 
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true treatment-related mortality rate exceeds 10%. The table below shows specific instances where 
this guideline is met, thus suggesting early termination due to evidence of an unacceptably high rate 
of treatment-related mortality.
Numberof treatment-
related deaths#
Total patients
Observed rate
2
3 to 8
≥ 25% (2 of 8)
3
9 to 16
≥ 19% (3 of 16)
4
17 to 22
≥ 18% (4 of 22)
#Deathwithin 30 days of receiving study treatment.
Posterior probabilities used to derive the preceding table are calculated under a prior beta 
distribution with parameters 1 = 0.2 and 2 = 1.8, which corresponds to an expected rate of 10% 
based on prior information roughly equivalent to having studied 2 patients. Furthermore, this prior 
distribution assigns a small a priori chance (27%) to the possibility that the true rate of treatment-
related mortality is 10% or greater. 
Lack of efficacy: 
We do not propose early stopping guidelines for lack of efficacy, since this is a small study and the 
primary endpoint, PFS, requires substantial follow up. Thus, interim estimates of PFS prior to 
completion of study enrollment would be imprecise and would not provide a good basis for 
considering early termination. We note further that we expect nearly all patients to achieve complete 
response and this will be monitored closely by the study team for any unexpected findings.
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13.0
REFERENCES
1. Banks PM, Chan J, Cleary ML, et al. Mantle cell lymphoma. A proposal for unification of 
morphologic, immunologic, and molecular data. Am J SurgPathol 1992 Jul;16(7):637-640.
2. The Non-Hodgkin’s lymphoma Classification Project. A clinical evaluation of the International 
Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's 
Lymphoma Classification Project. Blood. 1997; 89:3909-18.
3. Campo E, Raffeld M, Jaffe ES. Mantle-cell lymphoma. SeminHematol 1999;36:115-127.
4. Weisenburger DD, Vose JM, Greiner TC, et al. Mantle cell lymphoma. A clinicopathologic study 
of 68 cases from the Nebraska Lymphoma Study Group. Am J Hematol 2000;64:190-196.
5. Majlis A, Pugh WC, Rodriguez MA, Benedict WF. Mantle cell lymphoma: correlation of clinical 
outcome and biologic features with three histologic variants. J ClinOncol 1997;15:1664-1671.
6. Weisenburger DD, Armitage JO. Mantle cell lymphoma-- an entity comes of age. Blood 
1996;87:4483-4494.
7. Leonard JP, Schattner EJ, Coleman M. Biology and management of mantle cell lymphoma. 
CurrOpinOncol 2001; 13 :342-327. 
8. Oinonen R, Franssila K, Teerenhovi L, et al. Mantle cell lymphoma: clinical features, treatment and 
prognosis of 94 patients. Eur J Cancer 1998;34: 329-36.
9. Samaha H, Dumontet C, Ketterer N, et al. Mantle cell lymphoma: a retrospective study of 121 cases. 
Leukemia 1998;12:1281-7.
10. Oinonen R, Franssila K, Elonen E. Central nervous system involvement in patients with mantle cell 
lymphoma. Ann Hematol 1999;78: 145-149. 
11. Densmore JJ, Williams ME. Mantle cell lymphoma. Curr Treat Options Oncol 2000;1: 281-285. 
12. Meusers P, Hense J. Management of mantle cell lymphoma. Ann Hematol 1999; 78:485-494.
13. Cohen BJ, Moskowitz C, Straus D, et al. Cyclophosphamide/fludarabine (CF) is active in the 
treatment of mantle cell lymphoma. Leuk Lymphoma 2001;42:1015-1022.
14. Zinzani PL, Magagnoli M, Moretti L, et al. Fludarabine-based chemotherapy in untreated mantle 
cell lymphomas: an encouraging experience in 29 patients. Haematologica 1999;84:1002-1006. 
15. Igarashi T, Kobayashi Y, Ogura M et al. Factors affecting toxicity, response and progression-free 
survival in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma treated with 
rituximab: a Japanese phase II study. Ann Oncol 2002;13:928-943.
16. Howard OM, Gribben JG, Neuberg DS, et al. Rituximab and CHOP induction therapy for newly 
diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-
free survival. J ClinOncol 2002;20:1288-1294.
17. Magrath I, Adde M, Shad A, et al.Adults and children with small non-cleaved-cell lymphoma have 
a similar excellent outcome when treated with the same chemotherapy regimenJClinOncol 1996; 
14:925-934.
18. Mead GM, Sydes MR, Walewski J, et al. An international evaluation of CODOX-M and CODOX-
M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma 
Group LY06 study. Ann Oncol 2002; 13:1264-1274. 
19. Khouri IF, Romaguera J, Kantarjian H, et al. Hyper-CVAD and high-dose methotrexate/cytarabine 
followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma. J 
ClinOncol 1998;16:3803-3809.
20. Sweetenham JW. Stem cell transplantation for mantle cell lymphoma: should it ever be used outside 
clinical trials? Bone Marrow Transplant 2001; 28:813-20.
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21. Ketterer N, Salles G, Espinouse D et al. Intensive therapy with peripheral stem cell transplantation 
in 16 patients with mantle cell lymphoma. Ann Oncol 1997; 8: 701-704.
22. Milpied N, Gaillard F, Moreau P et al. High-dose therapy with stem cell transplantation for mantle 
cell lymphoma: results and prognostic factors, a single center experience. Bone Marrow Transplant 
1998; 22: 645650.
23. Stewart DA, Vose JM, Weisenberger DD et al. The role of high-dose therapy and autologous 
hematopoietic stem cell transplantation for mantle cell lymphoma. Ann Oncol 1995; 6: 263-266.
24. Khouri IF, Lee M-S, Romaguera J et al. Allogeneic hematopoietic transplantation for mantle cell 
lymphoma: molecular remissions and evidence of graft-versus-malignancy. Ann Oncol 1999; 10: 
1293-1299.
25. Vandenberghe E, Ruiz de Elvira C, Isaacson P et al. Does transplantation improve outcome in 
mantle cell lymphoma (MCL)? A study from the EBMT. Blood 2000; 96: 482a (Abstr).
26. Parmar MKB, Machin D. survival Analysis: A Practical Approach. Cambridge, UK: John Wiley & 
Sons, 1995.
27. Collett D. Modelling Survival Data in Medical Research. London: Chapman & Hall, 1994, p26.
28. ArmitageP, Berry B, Mathews J. Statistical Methods in Medical Research, Fourth Edition, 
Oxford:Blackwell Scientific, 2002.
29. Spiegelhalter DJ, Freedman LS, Parmar MK.  Bayesian approaches to randomized trials (with 
discussion). J Royal Stat Soc Ser A 1994; 157:357-416.
30. Fayers PM, Ashby D, Parmar MKB. Tutorial in biostatistics: Bayesian data monitoring in clinical 
trials. Stat Med  1997;16:1413 - 30.
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APPENDIX I
NATIONAL CANCER INSTITUTE (NCI) COMMON TOXICITY CRITERIA (CTC)
The NCI CTC can be viewed on-line at the following NCI web site:
http://ctep.cancer.gov/reporting/ctc.html
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APPENDIX II
DATA AND SAFETY MONITORING PLAN
The Sylvester Comprehensive Cancer Center (SCCC) Data and Safety Monitoring Committee (DSMC) will 
monitor this clinical trial according to the CancerCenter’s DSM Plan.  In its oversight capacity, the DSMC 
bears responsibility for suspending or terminating this study.
DSMC oversight of the conduct of this trial includes ongoing review of accrual and adverse event data.  
The guidelines appearing in Section 12 are offered for DSMC consideration in assessing adverse events.  In 
addition, the DSMC will review reports from all audits, site visits, or study reviews pertaining to this clinical 
trial and take appropriate action.
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APPENDIX III:
DATA SUBMISSION SCHEDULE
FORM
TO BE COMPLETED
BASELINE
Eligibility Checklist
SCCC Protocol Enrollment Form
Consent Forms Signed/dated
Prior to registration
On-study Form
Within 30 days of registration
DURING PROTOCOL THERAPY
Due every week for phase I studies, every 
cycle for phase II-IV studies 
AFTER PROTOCOL THERAPY
Off Treatment Form
Within 14 days of discontinuation/completion 
of protocol therapy
FOLLOW-UP SCHEDULE (for studies with long term follow-up)
Follow-up Form
Every 3 months if < 2 years from study entry
Every 6 months is 2-5 years from study entry
Every 12 months if more than 5 years from 
study entry
Response Assessment Form
Within 
4 
weeks 
of 
knowledge 
of 
progression/relapse
Off Study Form
Within 4 weeks of knowledge of death
Subsequent Malignancy via Adverse Event Log
Within 4 weeks of knowledge of another 
malignancy
NOTE:  FORMS WILL BE CONSIDERED PAST DUE 14 DAYS AFTER THE DUE DATE.
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APPENDIX IV
ABBREVIATIONS
ANC
Absolute Neutrophil count
CR
Complete response
PR
Partial Response
G-CSF
granulocyte colony stimulating factor
HBV
Hepatitis B
IHC
Immunohistochemistry
IPI
International Prognostic Index
LDH
Lactate Dehydrogenase
MCL
Mantle Cell Lymphoma
NHL
non-Hodgkin lymphoma
NS
Normal Saline
PCR
polymerase chain reaction
PET
positron emission tomography
PR
Partial response
PD
Partial Response
R-MACLO
Rituximab,Methotrexate,Doxorubicin,Cyclophosphamide,Leucovorin, 
Vincristine
R-IVAM
Rituximab,Ifosfamide,Etoposide,Cytarabine, Mesna
SAE
severe adverse effect
SCT
Stem Cell Transplant
SD
Stable Disease
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a. Daily U/A during Ifosfamide therapy   b. If clinically indicated  c.Repeat those studies which were positive at baseline d. For patients in CR after final cycle : Rituximab (375mg/m2, IV as 4 weekly doses every 6 months for a 
total of 3yrs or until progression of disease (+/-21days).    e. These studies should be obtained monthly(+/- 21 days) for the first 3 monthsthen every 3 months (+/- 21 days), for 2 years, then 6 months(+/- 21 days) for 3-5years & 
thereafter. These studies are required at these intervals until disease progression or death (whichever occurs first).    f. These studies should be obtained every 6 months for 2 years or more frequently if clinically indicated.  g. 
Patients who have disease progression (PD) or achieve PR (after final cycle) and are alive are followed for survival only –no additional studies are required after disease progression. h. Height required at screening only.  i.  -28 to 
D1 for baseline assessment.  j.  Only concomitant medications taken while outside of the hospital are recorded.  k.  Adverse events captured 30 post off treatment or 30 days post end of maintenance portion.  L.  Conmeds are 
required only at screening/baseline visit.  M.  Only if clinically indicated
Screening
Baseline 
Visit
 Regis-
tration
Cycle 1  
Cycle 2
Restage
(after 
cycle 2)
Cycle 3
Cycle  4
Restage
(after cycle 
4)
EOT
30days 
post 
hospital 
discharge 
afterlast 
dose
Maintenance
Rituximab
Survival
Visit Window
-28 to D1
(+/- 3 
days)
(+/- 3 day)
(+/-14 
days)
(+/- 3 
day)
(+/- 3 day)
(+/-14 
days)
(+/-14 
days)
(+/- 21 days)
-
 Informed Consent
X
 -
-
-
-
-
-
-
-
-
Medical History
X
 -
-
-
-
-
-
-
-
-
Baseline
Physical Examination
X
X
X
-
X
X
-
X
Xe
-
R-MACLO
-
X
-
-
X
-
-
-
-
-
R-IVAM
         -
-
X
-
-
X
-
-
-
Treatment
RITUXIMAB
-
-
-
-
-
-
-
-
Xd
-
Electrocardiogram (EKG)
X
-
-
-
-
-
-
-
-
-
MUGA or Echocardiogram
X
-
 -
-
-
-
-
-
-
-
Weight, Heighth
X
X
X
-
X
X
-
X
Xd
-
Vital signs
X
X
X
-
X
X
-
X
Xd,e
-
ECOG status
X
X
X
-
X
X
-
X
Xd,e
-
Body Surface Area (BSA)
- 
X
X
-
X
X
-
-
Xd
-
CBC, differential, platelet count
X
X
X
-
X
X
-
X
Xd,e
-
CMP and  LDH, see protocol
X
X
X
-
X
X
-
X
Xe
-
Uric Acid
X
-
-
-
-
-
-
X
Xe
Bicarbonate
X
X
X
-
X
X
-
X
Xe
-
Beta-2 microglobulin
X
-
-
-
-
-
-
X
Xe
-
Hepatitis B
X
-
-
-
-
-
-
-
-
-
Urine Pregnancy test(72 hrs of entering 
study)
X
-
-
-
-
-
-
-
-
-
Urinalysis (U/A)
-
-
Xa
-
-
Xa
-
-
-
-
Concomitant medicationsL
X
-
-
-
-
-
-
-
-
- 
Safety
Assessments
Adverse Events Assessments (CTCAE)
X
X
X
X
X
X
X
X
-
BrainCT or MRI scanb
X
-
-
-
-
-
-
-
CT Scan (Chest, Abdomen, Pelvis with 
contrast)i
X
-
-
Xc
-
-
Xc
X
Xc,f
-
Bone Scan /bone filmsb
Xb
-
-
-
Xc
X
Xc,f
-
PET Scani
X
-
-
Xc
-
-
Xc
X
Xc,f
-
Bone Marrow Biopsy & Aspiration
X
-
-
-
-
-
Xc
Xc
Xc,f
-
Response 
Assessments
Colonoscopy(with or without 
endoscopy)
X
Submit Registration & Eligibility Checklist to CRS prior to Start of Study.
-
-
-
-
-
Xc
Xc
-
Survival
Survival g
-
-
-
-
-
-
-
-
Xg
Appendix V-Study Calendar