Clinical trial NCT00290498
Conditions: Lymphoma
Keywords: Non-Hodgkin's Lymphoma B-Cell Non-Hodgkin's Lymphoma Lymphoma Cyclophosphamide Cytarabine Doxorubicin Hyper-CVAD Methotrexate Prednisone Rituximab Vincristine R-CHOP R-HCVAD Dexamethasone Decadron Leucovorin Ara-C Cytosar Cytoxan DepoCyt Cytosine arabinosine hydrochloride AD Hydroxydaunomycin hydrochloride Neosar
Sponsor: M.D. Anderson Cancer Center
Start date: 2005-08-01; Completion date: 2017-08-11
Enrollment: 67 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The overall goal of this clinical research study was to find out which of two different chemotherapy drug combinations, R-CHOP and R-HCVAD, is more effective in treating B-cell lymphoma.

At this point, all participants will now be assigned to the R-HCVAD arm of the study. Researchers will study the safety and effectiveness of this drug combination.

Detailed description:
This study originally involved 2 different study drug regimens, R-CHOP and R-HCVAD. R-CHOP is made up of rituximab, cyclophosphamide, vincristine, and prednisone, and is the most common treatment for patients with non-Hodgkin's lymphoma. This combination was compared with R-HCVAD, which is made up of rituximab, doxorubicin, cyclophosphamide, vincristine, and dexamethasone.

Rituximab (Rituxan®) is a humanized monoclonal antibody against cluster of differentiation antigen 20 (CD20) (a receptor in the surface of malignant B-cell lymphocytes). The drug has activity against aggressive and nonaggressive NHL of B-cell origin, and has been used in combination with chemotherapy. Cyclophosphamide is a type of drug know as an alkylating agent. Vincristine is a type of drug called vinca alkaloids. It is typically used in lymphomas, leukemias, and other tumors. Prednisone is a type of steroid. Dexamethasone is a steroid that may have activity against lymphomas. Methotrexate is an anti-cancer drug and a folic acid antagonist. It is used to treat solid tumors, lymphomas, leukemias, and autoimmune diseases.

When this study began, participants were randomly assigned (as in the flip of a coin) to 1 of 2 arms: Arm A (R-HCVAD alternating with a combination of rituximab, methotrexate, and Ara-C) or Arm B (R-CHOP). From this point on, all new participants will be treated with the Arm A combination, which has shown to be better.

If you are found to be eligible to take part in this study, you will be given the study drugs in 21-day cycles. The cycles will alternate between R-HCVAD and a combination of rituximab, methotrexate, and Ara-C. During Cycle 1 (the R-HCVAD cycle), you will receive rituximab through a needle in your vein (intravenously, or "IV"), on Day 1. The infusion will take about 1 hour. Cyclophosphamide will be given by IV every 12 hours for 3 days. Each infusion of cyclophosphamide will take about 3 hours. Doxorubicin will be given as a 15-minute infusion on Day 5 with the supervision of a nurse. Your doctor may also choose to give you the doxorubicin over 24-48 hours using a small pump that you will carry around your waist in a "fanny pack." You will not have to stay in the hospital to receive this study drug. Vincristine will be given by IV, on Days 5 and 12. Each vincristine infusion will take about an hour. Dexamethasone will be given by mouth (as a pill, capsule, or tablet) on Days 2-5 and 12-15. You will also be given other standard medications to help prevent possible side effects of these medications (such as nausea, vomiting, or rash).

In Cycle 2 (the rituximab-methotrexate-Ara-C cycle), you will receive rituximab on Day 1. You will receive methotrexate by IV (after finishing the rituximab) on Days 2 and 3. The infusion will take about 24 hours. You will be given a small "fanny pack" with a pump inside that will slowly infuse the drug. You do not have to stay in the hospital while the drug is being given. You will be given Ara-C every 12 hours on Days 3-4 (a total of 4 doses). You will be given other standard medications to help prevent possible side effects of these medications (such as nausea, vomiting, or rash) during this cycle also.

Leucovorin is given 12 hours after each methotrexate infusion. It is used to stop the action of the methotrexate and to prevent/lessen any side effects that the methotrexate may cause.

During treatment, you will have blood draws (between 2-3 tablespoons) every week for routine tests. Every 4 weeks during treatment , you will be asked questions about your medical history and have a physical exam to check for any side effects. Every 2 cycles (about every 8 weeks), you will have bone marrow biopsies performed (if they were positive before starting on this study), until they come back negative. You will have a positron emission tomography (PET) scan to see if the tumor is responding. Once the PET scan comes back negative, it will be up to your physician to decide if you need additional PET scan tests, and when. You will have CT scans of the chest, abdomen, pelvis, and neck every 2 cycles, if they were positive at the beginning of the study also. You may have additional testing done while on this study, if your physician feels that it is needed (for example, if it is needed to check for side effects).

You may receive additional medication called "CNS prophylaxis" before receiving the study treatments. Your doctor will discuss these medications with you. The "CNS prophylaxis" consists of an alternating dose of either doxorubicin or methotrexate. The methotrexate will be given either by IV pump or by a "lumbar puncture" (a needle inserted into the space between the vertebrae in your back to infuse the drug directly into the spinal area). The doxorubicin will be given by IV. Changes in the dose level of CNS prophylaxis will be approved if you are at risk for or are experiencing serious side effects.

You will receive the study drugs for up to 6-8 cycles on an outpatient basis. This means you will not have to be admitted to the hospital to receive the study drugs. You may be taken off study if the disease gets worse. If you experience intolerable side effects while taking any of the study drugs, your study doctor may decide to delay your treatment for up to 3 weeks (one study cycle) or to continue your therapy on the drugs at a lower dose. If the side effects become very severe, your doctor may decide to take you off of the study and stop the medication.

At the end of your scheduled treatments, you will be asked to return to the clinic for follow-up visits every 6 months for the first, second, third, and fourth year after treatment on this study. You will then be followed every year after that. If your doctor feels it is necessary, you may have blood tests (about 3-5 teaspoons) performed at these visits. You will have bone marrow biopsies every other year for the first 2 years, if they were positive before you started on this study, and then every year after that. At these visits, you will be asked about any side effects you may have experienced and whether or not your cancer has come back. If your doctor feels there is a chance that the cancer has come back, he or she may schedule x-rays or scans in order to check. You will also be asked about any other therapies you may be having to treat your cancer, if it has come back.

If you are taken off study for any reason, you will be asked to come back to the clinic for an end-of-treatment visit within 4 weeks from the last treatment. This visit will include a physical exam, routine blood tests (about 5-8 teaspoons), a blood-pregnancy test for women who are able to get pregnant, an ECG, and a chest x-ray.

This is an investigational study. All of the study drugs are approved by the FDA for the treatment of lymphoma. Up to 66 patients will take part in this study. All of the patients will be enrolled at MD Anderson.

Arms: arm 1: R-HCVAD + R-MTX/Ara-C ((Rituximab-HCVAD (rituximab, doxorubicin, cyclophosphamide, vincristine, and dexamethasone) alternating with Rituximab-Methotrexate-Cytarabine)) arm 2: R-CHOP ((Rituximab-CHOP (Rituximab, cyclophosphamide, vincristine, and prednisone))

No longer recruiting for this study arm.
Interventions: intervention 1: Rituximab intervention 2: Cyclophosphamide intervention 3: Doxorubicin intervention 4: Vincristine intervention 5: Dexamethasone intervention 6: Methotrexate intervention 7: Cytarabine intervention 8: Prednisone
Intervention descriptions: intervention 1: Arm A: Rituximab 375 mg/m² by vein on day 1, Cycle 1 and alternating cycles. Arm B: Rituximab 375 mg/m² on day 1, Cycle 2 and alternating cycles. intervention 2: Arm A: Cyclophosphamide 300 mg/m\^2 by vein (IVPB) over 3 hours every 12 hours x 6 doses on Days 2-4, Cycle 1 and alternating cycles.

Arm B: Cyclophosphamide 750 mg/m² by vein day 1 intervention 3: Arm A: Doxorubicin 50 mg/m\^2/day by vein over 15 minutes (12 hours after last dose of cyclophosphamide) on Day 5, Cycle 1 and alternating cycles. intervention 4: Arm A: Vincristine 1.4 mg/m\^2 (maximum 2 mg) by vein (IVPB) on Days 5 (1-24 hours after last cyclophosphamide) and on day 12, Cycle 1 and alternating cycles.

Arm B: Vincristine 1.4 mg/m\^2 (maximum 2 mg) by vein (IVPB) on Days 5 (1-24 hours after last cyclophosphamide) and on day 12 of each cycle. intervention 5: Arm A: Dexamethasone 40 mg by vein or by mouth daily x 4 on Days 2-5 and on days 12-15 of cycle 1 and alternating cycles. intervention 6: Arm A: Methotrexate after finishing Rituximab, 200 mg/m2 by vein over 2 hours, then 800 mg/m2 by vein over 22 hours day 1 cycle 2. intervention 7: Arm B: Cytarabine 3 g/m\^2 by vein over 2 hours every 12 hours X 4 doses on days 3 \& 4, cycle 2 and alternating cycles. intervention 8: Arm B: Prednisone 100 mg by mouth (as a pill, capsule, or tablet) once a day on Days 1-5, each cycle.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 2005-0054
Revised September 17, 2012
Page 1
THE UNIVERSITY OF TEXAS
M.D. ANDERSON CANCER CENTER
DIVISION OF MEDICINE
TITLE:  A Phase II randomized Study of Rituxan-HCVAD alternating with Rituximab-
methotrexate-cytarabine vs. standard Rituximab CHOP every 21 days for Patients with Newly 
Diagnosed with high risk aggressive B-cell non-Hodgkin’s lymphomas in patients 60 year-old or 
younger 
1.0
OBJECTIVES
2.0
BACKGROUND
3.0
BACKGROUND DRUG INFORMATION 
4.0
PATIENT ELIGIBILITY
5.0
PROTOCOL TREATMENT PLAN
6.0
PRETREATMENT EVALUATION (See Appendix F)
7.0
EVALUATION DURING STUDY (See Appendix F)
8.0
CRITERIA FOR RESPONSE
9.0
STATISTICAL CONSIDERATIONS
10.0
DATA AND PROTOCOL MANAGEMENT
11.0
REPORT OF ADVERSE EVENTS
12.0
REFERENCES
Appendices
Informed Consent


Protocol 2005-0054
Revised September 17, 2012
Page 2
1.0
OBJECTIVES
1.1
To evaluate the Overall response rate (ORR), Complete Response (CR + Cru), 
Disease-free survival (DFS), and progression-free survival (PFS) rate following 
therapy with Rituxan-HCVAD alternating with Rituximab with high-dose 
methotrexate/ara-C and standard R-CHOP in patients with newly diagnosed B-cell
aggressive non-Hodgkin’s lymphomas younger than 60 years old and with 
adjusted IPI 2 or higher adverse prognostic features.  Progression-free survival 
will be done for 3-years
1.2
Secondary objectives include: overall survival, toxicity profile.
2.0
BACKGROUND
2.1
Aggressive Non-Hodgkin’s lymphomas
Aggressive NHL is the most common of the NHL diagnosed in the USA.  Ninety 
to 95% of these will be of B-cell origin, and half of the patients will be younger 
than 60 years old.  Many prognostic factors have been evaluated for patients with 
this condition, but the most commonly used is the International Prognostic Index 
(IPI).  The IPI1 has been adjusted in patients 60 years old or younger, and includes 
Stage I- II vs. III-IV, normal vs. elevated Lactic dehydrogenase (LDH), and 
Performance Status 0-1 vs. more than 1. For each one of these adverse prognostic 
features, patients received one adverse point; if none of these features are present, 
the score would be 0 and the patient would be at low risk for relapse.  The 
disease-free survival and survival rates for the four groups of patients 60 years old 
or younger is summarized in the table below:
Age-Adjusted IPI index in patients 60 years old or younger:
N=1274
CR rate (%)
% 5-yr DFS
% 5-yr survival
0 (22% of patients)
92
86
83
1 (32% of patients)
78
66
69
2 (32% of patients)
57
53
46
3 (14% of patients)
46
58
32
Therefore, almost half of the younger patients with aggressive lymphomas (FLCL, 
DLCL, Immunoblastic lymphomas) will present with poor prognostic features, 
and less than half of these will be alive at 5 year.  The main cause of death is 
recurrent large cell lymphoma.  This group of patients with two or more poor risk 
prognostic factors should be target for investigational therapies.  
2.2. Rituximab-CHOP
Rituximab is a new chimeric antibody directed against CD20, a surface protein on 
B-cell lymphoma cells, and some normal B-lymphocytes.  This drug has activity 
as a single agent in indolent and aggressive NHL.2-5 In vitro studies showed an 
increase in sensitivity of different cell lines to chemotherapy agents, when 
Rituximab was added.  Recently, investigators have reported overall responses 
values of more than 90% in treatment of follicular lymphomas by Czuczman et al 
(CHOP-R),6 McLaughlin (FND-R),7 Zinzani (FN-R),8 in aggressive NHL by Julie 


Protocol 2005-0054
Revised September 17, 2012
Page 3
Vose et al (CHOP-R),9 in mantle cell lymphoma by Romaguera et al (R-
HCVAD),10 and in Burkitt’s and Burkitt’s like lymphoma by Deborah Thomas et 
al (R-HCVAD)11.  Coiffier et al also reported results from a randomized study in 
Diffuse Large B-cell Lymphoma (DLBCL) patients older than 60 year-old with 
Ann Arbor stage II or higher, comparing standard treatment with CHOP 
(cyclophosphamide, vincristine, doxorubicin, prednisone) versus CHOP + 
Rituximab (375 mg/m²).  The patients treated in the R-CHOP arm had better 
response, complete response, disease-free survival, and overall survival rates than 
did those on the conventional arm, without any additional toxicity.  For that 
reason, in most of the centers in USA, and according to NCCN recommendations, 
R-CHOP is considered an acceptable treatment for low-grade and aggressive NHL 
including DLBCL, follicular large cell lymphomas, and immunoblastic 
lymphomas.  In this study, R-CHOP will be considered a standard treatment arm, 
and will be administered for a total of 6-8 cycles.12
2.3.  Rituxan-HCVAD
The combination of Rituximab-HCVAD has been used at M.D. Anderson in more 
than 100 patients with mantle cell lymphoma.  More than 90% of the patients 
treated with this protocol responded to the treatment with a mortality rate of 4%.  
Initially, HCVAD was designed for the treatment of Burkitt’s lymphomas in 
pediatric patients.  Subsequently, this protocol was adopted at M.D. Anderson 
Cancer Center for the treatment of acute lymphoblastic leukemias, lymphoblastic 
lymphomas, Burkitt’s, and Burkitt’s-like lymphoma-leukemia.  In these studies, 
this combination chemotherapy produced responses in Burkitt’s Lymphoma 
/leukemia, the results have been promising with an 81% CR rate, a 61% 
continuous CR rate, and a 3 year survival of 49%.11 For mantle cell lymphoma, a 
similar regimen has resulted in a 92% CR rate and a failure-free survival of 80% 
at 2 years of follow-up for patients 65 years of age or younger.10 In the same 
study patients over 65 years received a two-thirds dose reduction of Ara-C, 
achieving a CR rate of 90% and a median failure-free survival of 15 months.  The 
R-HCVAD regimen consists in two alternating chemotherapy regimens. The first 
half of this regimen is HCVAD, which includes cyclophosphamide being given at 
a relatively higher dose and on a hyper fractionated schedule, doxorubicin, 
vincristine and dexamethasone. This regimen is alternated with high doses of 
methotrexate and Ara-C.  For our study, our regimen will be Rituximab-HCVAD 
alternating with Rituximab-Methotrexate-Ara-C for a total of 6-8 cycles (3-4
cycles of each one).
2.3. CNS prophylaxis.
Prophylaxis for leptomeningeal disease will be given in patients considered at risk 
for CNS involvement.  Guidelines are summarized below, unless the clinician 
decides otherwise: patients who will receive intrathecal prophylaxis for CNS 
disease will be those who have any of the following conditions:
a.
Patients with involvement of the spinal canal.
b. Involvement of the bone marrow with aggressive lymphoma.
c.
Testicular aggressive lymphoma.
d. Two or more extranodal sites involved,


Protocol 2005-0054
Revised September 17, 2012
Page 4
e.
Diffuse bone involvement.
f.
Sinus or parasinus disease (or any risk for local extension)
CNS prophylaxis consists of intrathecal chemotherapy with every cycle of 
chemotherapy, alternating methotrexate 12 mg with ara-C 100 mg (if intrathecal 
chemotherapy is given by Ommaya reservoir, the dose of methotrexate will be 
reduced to 6 mg).   The clinician may give variations of those doses and 
treatments according to patient’s tolerance.
2.4.  Radiation therapy to the involved field will be given to patients with stage I, 
and II if clinically appropriate, and stage III or IV if the investigator felt necessary.
3.0
BACKGROUND DRUG INFORMATION
3.1.1. Rituximab.
Rituximab (Rituxan®) is a humanized monoclonal antibody against CD20 a receptor in 
the surface of malignant B-cell lymphocytes.  The drug has activity against aggressive 
and non-aggressive NHL of B-cell origin, and has been used in combination with 
chemotherapy.  The drug is administered intravenously at doses of 375 mg to 500 mg/m².  
Side effects are as follows:
Hematologic Events: In clinical trials, Grade 3 and 4 cytopenias were reported in 48% of 
patients treated with RITUXAN; these include: lymphopenia (40%), neutropenia (6%), 
leukopenia (4%), anemia (3%), and thrombocytopenia (2%).  The median duration of 
lymphopenia was 14 days (range, 1 to 588 days) and of neutropenia was 13 days (range, 2 
to 116 days).  A single occurrence of transient aplastic anemia (pure red cell aplasia) and 
two occurrences of hemolytic anemia following RITUXAN therapy were reported. 
In addition, there have been a limited number of postmarketing reports of prolonged 
pancytopenia, marrow hypoplasia, and late onset neutropenia (defined as occurring 40 
days after the last dose of RITUXAN) in patients with hematologic malignancies.  In 
reported cases of late onset neutropenia (NCI-CTC Grade 3 and 4), the median duration 
of neutropenia was 10 days (range 3 to 148 days).  Documented resolution of the 
neutropenia was described in approximately one-half of the reported cases; of those with 
documented recovery, approximately half received growth factor support.  In the 
remaining cases, information on resolution was not provided.  More than half of the 
reported cases of delayed onset neutropenia occurred in patients who had undergone a 
prior autologous bone marrow transplantation.  In an adequately designed, controlled, 
clinical trial, the reported incidence of NCI-CTC Grade  3 and 4 neutropenia was higher 
in patients receiving RITUXAN in combination with fludarabine as compared to those 
receiving fludarabine alone (76% [39/51] vs. 39% [21/53]).
Administration:   Dilute to an appropriate concentration of 1 to 4 mg/mL into an infusion 
bag containing either 0.9% Sodium Chloride USP or 5% dextrose in water USP.  Gently 
invert the bag to mix the solution.  Discard any unused portion left in the vial.
Dosage form:  Injection: 100 mg (10 mL); 500 mg (50 mL). 


Protocol 2005-0054
Revised September 17, 2012
Page 5
3.1.2. Cyclophosphamide:
Cyclophosphamide is an alkylating agent.  The usual dose goes from 50 mg/day to 60 
mg/kg/day in transplant patients.  Main side effects include cytopenias, nausea, vomiting, 
hemorrhagic cystitis, alopecia.  
Administration: oral or intravenously.  Intravenously, the drug is diluted in a 
concentration not higher than 20 mg/mL.  Standard IVPB fluid: 250 mL.  Maximum 
IVPB rate; 15 minutes; can be administered as IV push (2-5 minutes infusion) if ordered 
by physician.  Room temperature stability is 48 hours (extrapolated stability policy
considering % drug lost over time).  Refrigerator stability: 28 days.  Specials precautions: 
Keep the drug in refrigerator.  
Dosage Forms:  
Injections 100 mg, 200 mg, 500 mg, 1 g, 2 g.
Tablet: 25 mg, 50 mg.
3.1.3. Vincristine.
One of the vinca alkaloids.  Used in lymphomas, leukemias, and other tumors.   Main side 
effects include constipation, and peripheral neuropathy.
Usual dose is 1.4 mg/m² to a maximum of 2 mg  (some protocols use higher doses).
Administration: intravenously.  Maximum concentration 1 mg/mL.  Standard IV dose is 
50 mL administered IVPB over 15 minutes.  Can be given IV push.
Room temperature stability: 21 days.
Refrigeration stability:  21 days.
Special precautions:  Avoid extravasation.
Dosage forms: Injection: 1 mg/mL (1 mL).
3.1.4. Doxorubicin Hydrochloride
Anthracyclin, main side effects are nausea, vomiting, alopecia, cytopenias, 
cardiomyopathy.
Administration:  intravenously, usual dose 25 mg/m² to 75 mg/m²
Maximum concentration 5 mg/mL
Standard IVPB fluid: 50 mL
Maximum IVPB rate:  15 minutes.  Can be administered IV Push.  
Avoid extravasation.
Dosage forms:  Injection 10 mg, 50 mg, 150 mg, 200 mg.
3.1.5. Dexamethasone:
Dexamethasone is an  steroid  with multiple clinical applications and multiple ways of 
administration.  Has activity against lymphoproliferative disorders among another 
malignancies.  The usual dosage is 0.5 to 40 mg.  
Administration: Oral or intravenously.
Dosage form:  Injection, as sodium phosphate, 4 mg/mL (5mL), 24 mg (5 mL).  Tablets 
0.5 mg, 0.75 mg, 2 mg, 4 mg, and 10 mg. 
3.1.6. Methotrexate
Antineoplastic drug, folic acid antagonist.  Used for solid tumors, lymphomas, leukemias, 
autoimmune diseases.  Main toxicity is mucositis, cytopenias, renal failure, liver toxicity.
Administration:  Oral and intravenous.
Maximum concentration 25 mg/mL.  Standard IVPB fluid: 50 mL.  Maximum IVPB rate 


Protocol 2005-0054
Revised September 17, 2012
Page 6
is 15 minutes.  Can be administered i.v.  push.  Room temperature stability 7 days.  
Refrigeration stability:  15 weeks.
Dosage Forms: 25 mg/mL (2 mL, 4 mL, 8 mL, and 10 mL).
3.1.7. Cytarabine Hydrochloride 
Antineoplastic agent.  Main side effects are myelosuppression, nausea, fever, ataxia, 
neurological problems as confusion.  Used for lymphomas, leukemias.
Administration intravenously or intrathecal.  
Dosage intrathecal is 5-100 mg intrathecal.
Intravenously, the dose varies from 100 mg/m²/day by continuous infusion x 7 days to 3 
g/m² every 12 hours for 8 doses.
Administration:  Maximum concentration: 100 mg/mL.  Standard IVPB fluids 500 cc.  
Maximum IVPB rate 15 minutes.  Can be given IV push.  Dose more than 1 g/m² should 
be given in more than 2 hours.
Room temperature stability: 28 days.
Refrigeration stability: 25 days.
Dosage Forms:  100 mg, 500 mg, and 1 g. 
3.1.8. Leucovorin calcium (Folinic Acid)
Antidote for folic acid antagonists, treatment of megaloblastic anemia.
Administration I.V., I.M., oral.
Maximum concentration 25 mg/mL
Maximum IVPB rate: 15 minutes.  Can be given IV push.
Room temperature stability:  15 days.
Refrigeration stability: 15 days
Dosage forms:  Injection 3 mg/mL (1 mL); 50 mg vial; 100 mg vial; 300 mg vial.
Tablet: 5 mg; 10 mg; 15 mg; and 25 mg.
3.1.9. Intrathecal  Methotrexate and Intrathecal Ara-C
See 3.1.6. and 3.1.7.  Intrathecal administration requires de use of preservative-free 
solution.  Doses will be 6 mg-12 mg of methotrexate, and 50 mg-100 mg of intrathecal 
ara-c.
4.0
PATIENT ELIGIBILITY 
Inclusions:
4.1
Confirmed diagnosis of previously untreated large B-cell Non Hodgkin’s, Large 
Cell Lymphoma and B-Cell with high grade features. Other aggressive lymphomas 
such as Primary Mediastinal large B-cell Lymphomas will be also allowed to be 
included.   
4.2
Patients with performance status of 0-2 (Zubrod Scale – see Appendix E).
4.3
Serum bilirubin <1.5 mg/dl and serum creatinine < 2.0 mg/dl unless due to 
lymphoma; ANC >1000/mm3 and platelets >100,000/mm3 unless due to 
lymphoma.
4.4
Cardiac ejection fraction 50% or greater.
4.5
Ages 16 – 60  (since CHOP-R is not studied enough in younger patients and is not 
considered standard of care.


Protocol 2005-0054
Revised September 17, 2012
Page 7
4.6
Patients must be willing to receive transfusions of blood products.
4.7
Age adjusted International Prognostic Index Score of 2 or more 
4.8
Previous steroids are allowed (if used to relieve some symptoms such as SVC, 
etc).
Exclusions:
4.9
Pregnancy, secondary to teratogenicity of the involved chemotherapy agents
4.10
Positive HIV serology secondary to poor tolerance to this intense chemotherapy 
regimen
4.11
Burkitt’s lymphomas, and Mantle cell lymphoma, transformed follicular center 
cell lymphoma, follicular grade III.
4.12
Any clinical or cytological diagnosis of CNS involvement
4.13
Any co-morbid medical, such as Child’s Class C liver cirrhosis, end-stage renal 
disease, and symptomatic congestive heart failure, or psychiatric illnesses that 
preclude treatment with intense dose chemotherapy as determined by the primary 
investigator.
4.14
Concurrent or previous malignancy whose prognosis is poor (< 90% probability of 
survival at 5 years)
4.10
Active Hepatitis B or C.  Chronic carriers for Hepatitis B will be excluded.
5.0
PROTOCOL TREATMENT PLAN 
(added 4/21/2009)  A Bayesian adaptive algorithm (Berry, 1995) was originally used for 
this protocol.  The trial is now redesigned as a single-arm phase II clinical trial to evaluate 
the efficacy of the combination regimen of Rituximab-HCVAD alternating with 
Rituximab-Methotrexate-Cytarabine in patients 60 years old or younger with newly 
diagnosed high risk aggressive B-cell non-hodgkin’s lymphomas.  Therefore patients will 
no longer be randomized and patients will no longer be randomized to receive R-CHOP.
The patients will now only receive treatment as in section 5.1 of the protocol, previously 
named ARM A:
General:  All patients will be registered utilizing the MD Anderson Clinical Oncology 
Research System (CORe) system.  Patients will be randomized utilizing the ‘Clinical 
Trial Conduct Web Site.” Cycles of R-HCVAD and Rituximab- Methotrexate/Ara-C will 
be alternated starting with R-HCVAD (in case of pleural effusion or ascitis, the 
methotrexate-ara-C cycle will be delayed until resolution of the effusion, and the patient 
will be receive another cycle of R-HCVAD again).  The second arm (Arm –B) will be 
treated with standard Rituximab-CHOP every 21 days. (no longer applicable as of 
amendment dated 3/19/2009.)
5.1 CHEMOTHERAPY (Given every 21 days) See Section 5.2 for dose modifications.
ARM A:  R-HCVAD/R-MTX-Ara-C
Cycle 1 (R-HCVAD) 
A.
Rituximab 375 mg/m² on day 1 (can be delayed up to day 8 in patients 
with leukemic phase of the lymphoma).
B.
Cyclophosphamide 300 mg/m2 IVPB over 3h Q12h x 6 doses.
Cyclophosphamide may be started after the infusion of the Rituximab is 
finished.


Protocol 2005-0054
Revised September 17, 2012
Page 8
C.
Mesna 600 mg/m2 IV daily over 24 hours by continuous infusion x 3 days.
Begin 1 hour prior to cyclophosphamide and complete by 12 hours after last 
dose of cyclophosphamide
D.
Doxorubicin 50 mg/m2/day IV over 15 minutes (12 hours after last dose of 
cyclophosphamide). May be given  IVPB over 15 minutes under RN 
supervision. In certain cases, if the primary physician considered 
necessary, doxorubicin can be given by continuous infusion over 48 hours. 
E.
Vincristine 1.4 mg/m2 (maximum 2 mg) IVPB on Days 5 and on day 12.
F.
Decadron 40 mg IV or P.O. daily x 4 on Days 2-5 and on days 12-15.
G.
G-CSF (Neupogen) will be started 24 hours after finishing doxorubicin 
until recovery of the Neutrophils after nadir.  Neulasta  or  Leukine (GM-
CSF)  can be used as alternatives. Patient may be taught to self administer 
the G-CSF and Neulasta injections.
H. Pre-med with Zofran 8- 32 mg IVPB daily days 2-5 (unless 
doxorubicin is given by continuous infusion)
I
Prescriptions to start 24-48 hours after end of chemotherapy 
(recommended but alternative can be used on investigator discretion):
i)
Ciprofloxacin 500 mg po BID X 10 days
ii)
Fluconazole 100 mg po daily X 10 days
iii)
Valacyclovir 500 mg po QD X 10 days
iv)
Compazine 10 mg po Q 4-6 hours PRN n/v
v)
If there is any contraindication to any of these antibiotics or anti-
emetics, alternatives can be decided by the investigator.
Cycle 2 Chemotherapy  (Mtx/Ara-c) Must be administered in inpatient setting, 
and adjust according to 5.2.1.  If Creatinine 2 patient will not 
receive this chemo and will go to R-HCVAD again.
A.
Rituximab 375 mg/m² on day 1
B.
Methotrexate after finishing Rituximab, 200 mg/m2 IV over 2 hours, then 
800 mg/m2 IV over 22 hours.  Patients with a serum creatinine > 1.5 mg/dl
will get 50% dose methotrexate (*adjust dose according to 5.2.1)
C.
Patients will receive intravenous hydration containing sodium acetate for 
alkalinization as per discretion of primary physician.
D.
Ara-C 3g/m2 IV over 2 hours Q12 hours x 4 doses on Days 3-4.  (Patients those
with a serum creatinine > 1.5 mg/dl will get only 1 gram/m² of Ara-C per dose. 


Protocol 2005-0054
Revised September 17, 2012
Page 9
(See section 5.2.1).
E.
Leucovorin rescue 50 mg po 12 hours after methotrexate infusion 
completed starting on Day 3 x 1 dose, followed by 15 mg p.o. Q6 hours 
until Methotrexate level is < 0.1.
F.
Check serum creatinine.  Check methotrexate levels at 24h and 48h post 
completion of methotrexate-if > 1 micromolar at 24 hrs or > 0.1 
micromolar at 48 hours, increase citrovorum rescue to 50 mg IV Q6 hrs 
until methotrexate < 0.1 micromolar.
G
G-CSF (Neupogen) will be started 24 hours after finishing last dose of ara-
C and if methotrexate level is < 0.1 until recovery of the Neutrophils after 
nadir.  Neulasta or Leukine (GM-CSF) can be used as alternatives.
H
Additional prescriptions (recommended, variations may happen if 
clinically indicated).  Prophylactic antibiotics should start 24-48 hours after end of 
chemotherapy.
I)
Na bicarbonate 650 mg x 2 po BID x Days 2-6- of cycle 
II)
Ciprofloxacin 500 mg po BID – start 24 hours after end of 
chemotherapy
III)
Fluconazole 100 mg po daily  – start 24 hours after end of 
chemotherapy
IV)
Pred forte 2 gtts each eye QID x 7 days (starting at Day 1 at 
discretion of physician)
V)
Valacyclovir 500 mg po QD – start 24 hours after end of 
chemotherapy
VI)
Other prophylactic antibiotics or anti-emetics can be used 
alternatively if clinically indicated. 
INTRATHECAL CHEMOTHERAPY PROPHYLAXIS:
Intrathecal chemotherapy for prophylaxis of leptomeningeal 
recurrences, will be done in patients with parasinus or sinus 
disease, base of the skull, involvement of the testicle, bone marrow 
involved with aggressive lymphoma, epidural disease, or 
involvement of the spinal canal, or patients with two or more 
extranodal sites (at the discretion of the primary clinician).
Intrathecal chemotherapy at the discretion of M.D. and number of 
intrathecal chemotheraphy optional to M.D.
Dose of Methotrexate will be 6 mg if an Ommaya reservoir is used and 12 
mg if lumbar puncture is performed.  
Dose of Ara C will be 100 mg.  
Changes in prophylaxis will be approved if toxicity happens or risk for 
serious toxicity is suspected.
Radiation Therapy:
Radiation therapy will be given in areas of involved field in patients with stage I.  
5.2.1. Dose Adjustments for Different Regimens


Protocol 2005-0054
Revised September 17, 2012
Page 10
Dose Modifications for Age and Special Circumstances
A.  Age > 60 - change schedule of ARA-C to 1g/m² IV (if patient ages to > 60      
during treatment) over 2 hours Q12h x 4 doses = 2 days (day 3 and 4).
B. Bilirubin
a.
1.2-3.0 mg/dl- Reduce doxorubicin by 50%
b. 3.1-5.0 mg/dl-Reduce doxorubicin by 75%
c.
>5.0 mg/dl-Do not use unless OK by Principal Investigator
d. > 2.0 mg/dl-Reduce Vincristine by 50%
C. Serum creatinine > 1.5 mg/dl or clearance < 60 cc/min.- Decrease intravenous 
methotrexate dose by 50% and decrease intravenous Ara-C dose to 1 gm/m2
per dose. Dose adjustment for elevated alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) reduce Vincristine by 50 %.
D.  Additional Methotrexate adjustment-
i)
If severe mucositis (grade 4) with previous dose, reduce MTX by
25% (1 dose level; see section 5.2.4)
ii)
If pleural effusion or ascites, hold MTX.
iii)
Check methotrexate levels at 24 and 48 hours:  if > 1 micromolar 
at 24h or >0.1 micromolar at 48h respectively, give citrovorum 
rescue 50mg IV Q6h till methotrexate levels < 0.1 micromolar.
E.  Additional Ara-C adjustment -
If central nervous system toxicity with previous dose, decrease Ara-C (see
section 5.2.4).
5.2.2
Dose Reduction For Hematologic Toxicity
Toxicity
Dose Modification
Day 21:
AGC>1000/mm3 or
No Change
Platelets>100,000/mm3
Day 21:
AGC 750-1000/mm3 or
Delay therapy*until AGC > 1K, 
Platelets 75-100,000/mm3
plat > 100K
Day 21:
AGC < 750/mm3 or
Delay therapy*until AGC > 1K,
platelets < 75,000/mm3
plat > 100K and decrease 1 level
*Unless BM extensively involvement by lymphoma cells
Delay > 2 weeks
Discuss with 
Chairman
Neutropenic Fever
Decrease 1 level


Protocol 2005-0054
Revised September 17, 2012
Page 11
Serious Infection or Bleeding
Discuss with Chairman 
5.2.3
For Non-Hematologic Toxicity (Appendix B)
Grade
Dose Modification
0-2
No change
3
Decrease 1 level
4
Remove from study after discussing with Chairman
5.2.4
Dose Modification During Treatment
Drug
-2
-1
0
Rituximab 375 mg/m² IV
375
375
375
Cytoxan* mg/m² IV
over 3 hrs q 12 hrs x 6
150
240
300
Vincristine* mg/m² IV 
days 5 and 12
0
1mg 
total dose
1.4 (maximum 2 mg)
Doxorubicin* mg/m² 
IVPB over 1 hr on day 5
25
40
50
Methotrexate* mg/m² as 
per instructions
500
(100) (400)
750
(150) (600)
1000
(200) (800)
Ara-C* g/m² over 2 hrs q 
12 hrs x 4 doses days 3 
and 4
1 (or 33% 
dose)
2 (or 66% 
dose)
3 (or 100% dose)
Ara-C* 1g/m² over 2 hr q 
12 hrs x 4 doses days 3 
and 4 for patients with 
serum.creatinine  > 1.5 to 
2 mg/dl
.5
.75
1
*See 5.2.1 for special instructions
Adverse effects are to be recorded on an ongoing basis and on 
appropriate source documents at the clinical site and in the patient’s 
case report form. In addition, any transfusions of blood and blood
products are to be recorded in the patient’s CRF.
In the event of grade 3 or 4 hematologic toxicity, blood samples for 
follow-up evaluations should be performed as clinically indicated until the 
abnormality is resolved.
5.2.5. ARM B:  Rituximab-CHOP (no longer applicable as of amendment dated 3/19/2009.)
Chemotherapy will be given every 21 days with doses as follow


Protocol 2005-0054
Revised September 17, 2012
Page 12
Rituximab 375 mg/m² day 1
Cyclophosphamide 750 mg/m² intravenously day 1
Doxorubicin 50 mg/m²/ day on day 1
Vincristine 1.4 mg/m² i.v. on day 1 (maximum dose of 2 mg)
Prednisone 100 mg P.O. daily for 5 days days 1-5
Note:  Chemotherapy can be started in day 2 if clinically indicated, and 
doxorubicin can be done by continuous infusion over 48 hours in 
patients with history or risk for cardiac disease.
Dose Modifications:  For toxicities as described in 5.2.2 and 5.2.3:
Level –1 reduction of the doxorubicin, cyclophosphamide by 20%
Level –2 reduction of doxorubicin, cyclophosphamide by 50%. 
5.3
Treatment Plan and Response/Treatment Evaluation During Study
Staging after first 2 cycles (one R-HCVAD, one R-MTX/Ara-C) or R-CHOP:
-
If complete response, continue X 4 more cycles  
-
If minor or partial response, continue X 2 more cycles and re-stage
-
No change or progressive disease, off protocol 
Staging after 4 cycles: 
-
If complete or partial response, and give 2 more cycles and restage 
-
If no change, biopsy positive, off protocol
Staging after 6 cycles:
-
If complete response, give 2 more cycles and
Re-stage
-
If < PR, biopsy proven, off protocol 
Radiation Therapy:  Patients with stage I will be consolidated with radiation therapy.
5.4 CRITERIA FOR DISCONTINUATION OF TREATMENT:
1.
Patient refusal to continue to treatment
2.
Progressive disease
3.
Any reason that the primary investigator consider in best 
interest of the patient
4.
Reactivation of hepatitis B or Active Hepatitis B infection.
6.0
PRETREATMENT EVALUATION (See Appendix F) (All x-rays should be done 
within 4-6 weeks of start of treatment.) 
1.  A complete history and physical.


Protocol 2005-0054
Revised September 17, 2012
Page 13
2.  Staging : CT chest, abdomen, pelvis, CXR, PET scan, bilateral  bone marrow biopsies 
and aspirates, CXR, MUGA or Echo, EKG.  Bone marrow aspirate will be sent for 
lymphoma markers. Gallium scan or PET scan is also recommended.
3.  Laboratory studies shall include: CBC with differential and platelet count, Beta 2 
microglobulin level, Serum albumin, alkaline phosphatase, bilirubin, BUN, calcium, 
creatinine, glucose, inorganic phosphorus, LDH, SGPT, T. protein, uric acid, sodium, 
potassium, chloride, CO2, HIV testing, and Quantitative Immunoglobulins.
4.  Pregnancy test in female patients on childbearing potential.
5. Screening of patients at high risk of HBV infection to the recommended immunology 
evaluations.  High-risk patients include:  History of I.V. Drug abuse, persons born in high, men 
who have sex with men, endemic areas, dialysis patients, HIV patients, Family/household 
contacts of carriers/hepatitis B+ patients.
7.0
EVALUATION (Appendix F)
7.1
DURING STUDY  
Every cycle:  CBC differential, platelets until ANC > 1,000/mm3 and 
platelets > 20,000/mm3.  If clinically indicated, other studies may be 
performed, as determined by patients’ primary oncologist.
Every cycle:  Total protein, albumin, calcium, inorganic phosphorus, 
glucose, BUN, creatinine, uric acid, bilirubin, alkaline phosphatase, LDH, 
SGPT, and electrolytes; History and physical exam. 
Every 2 cycles:  In addition to above: unilateral BM biopsy and aspirate, if 
initially positive.  BM aspirate and biopsies will be sent for lymphoma 
markers, if initially positive, until they become negative, after that they 
will be done if clinically indicated.  PET scan will be performed, if 
initially positive, until becomes negative.  Once is negative, repeat PET 
scan will be done at the investigator discretion. CT scans, neck, 
chest/abdomen/pelvis will be performed (if initially involved).
Study treatment will be given on days specified in the protocol unless 
patient medical or logisitical problems arise.  These changes to study 
treatment schedule will be discussed with the study chairman or co-
chairman.
7.2
AFTER TREATMENT  
Full restaging of initially involved areas will be performed at least every 6 months 
during the first year from the start of treatment. After the 4th year follow up is 
yearly. Every 6 months during the 3rd, 4th year, then in one year for 5th year. 
After five years, patient will be followed yearly by survivorship clinic for 
observation. For patients with initially positive studies, BM aspiration and biopsies 
will also be done every other evaluation in the first 2 years and then yearly 
thereafter (if clinically indicated). 


Protocol 2005-0054
Revised September 17, 2012
Page 14
Serious adverse effects will be reported according to the MDACC Guidelines for 
SAE reporting (Appendix B).  The following adverse effects are expected and will 
not be reported.  They will be summarized in the updated and final results:
i)
Myelosuppression and its associated complications are part of the 
successful treatment of aggressive lymphomas.  Therefore, infections, 
bleeding and hospitalization due to this will not be reported as adverse 
drug reactions.
ii)
Readmission day 0-30 post chemotherapy to receive parenteral narcotics 
for pain relief of mucositis for parenteral control of nausea/vomiting, to 
receive blood or platelet transfusions, or for supportive measures such as 
hydration and symptom control.
8.0
CRITERIA FOR RESPONSE
Response Definitions
Complete Response (CR):  Assessed after cycles 2, 4, and 6. CR is defined as the 
disappearance of all clinical evidence of active tumor for a minimum of eight weeks.  The 
patient must be free of all symptoms. Some patients with lymphoma remain with residual 
tumor masses that, upon biopsy, are composed of collagenous tissue.  In view of this 
phenomenon, we consider 75% reduction in size of the mediastinum and/or abdominal 
mass with a negative fine-needle aspirate and a negative PET scan as CR.  In these cases, 
biopsies are strongly recommended when feasible to confirm response status.
Complete Response unconfirmed (CRu): Assessed after cycles 2, 4, and 6.  Some patients 
with lymphoma remain with residual tumor masses that, upon biopsy, are composed of 
collagenous tissue.  In view of this phenomenon, we consider 75% reduction on size of 
the mediastinum and/or abdominal mass as CRu if no other definitive test (i.e. FNA with 
a negative PET scan or biopsy) is performed.
Partial Response (PR):  Fifty percent or greater decrease in the sum of the products of all 
measured lesions persisting for at least four weeks.  No lesion may increase in size and no 
new lesion may appear.
Minor Response (MR):  More than 25% but less than 50% decrease in the sum of the 
products of all measured lesions persisting for at least four weeks.  No lesion may 
increase in size and no new lesion may appear.
No Change:  Steady state or response less than minor and no progression for at least 8 
weeks.  There may be no appearance of significant new lesions for this category.
Progressive Disease:  Unequivocal increase in the size of any measurable lesion or 
appearance of significant new lesions will constitute progressive disease.
Failure:  Any response less than a PR.
9.0
STATISTICAL CONSIDERATIONS 
A Bayesian adaptive algorithm (Berry, 1995) was originally used for this protocol (2005-
0054).  The trial is now redesigned as a single-arm phase II clinical trial to evaluate the efficacy 
of the combination regimen of Rituximab-HCVAD alternating with Rituximab-Methotrexate-


Protocol 2005-0054
Revised September 17, 2012
Page 15
Cytarabine in patients 60 years old or younger with newly diagnosed high risk aggressive B-cell 
non-hodgkin’s lymphomas.  This treatment was one of the two treatments in the original adaptive 
randomization design.  As of February 24, 2009, sixteen patients have been enrolled to this 
treatment arm.  Using the new design, the maximum sample size for the treatment of Rituximab-
HCVAD alternating with Rituximab-Methotrexate-Cytarabine is 50.
Study design:
The overall response at 4 months will be monitored using the Bayesian approach of Thall, 
Simon, Estey (1995, 1996) as extended by Thall and Sung (1998).  Historical data on similar 
patients show an overall response rate (OR) of 60%.  However, the information was down-
weighted to reflect the same marginal OR in 2 patients.  It is expected for the current trial that the 
combination drug will improve the OR to 80%.  A sample size of 50 ensures that, if the trial is 
not terminated early, a posterior 90% credibility interval for overall response rate will have width 
of 0.18 at most, under the assumption of a 80% of OR.  The probability of OR for the historical 
data is modeled by beta distribution (Beta(6, 4)).  The prior probability of OR for the 
experimental regimen is also modeled by beta distribution (Beta(1.2, 0.8)), which has the same 
a/b (a and b denote the parameters for a Beta distribution) ratio as the beta distribution for the 
historical data.  Denoting the historical probability of overall response rate by p(OR,H) the 
following decision rule will be applied:
Let E correspond to the experimental treatment, stop if  
Prob{p(OR,H)  + OR > p(OR,E) | data} > 0.9, where OR =0.20
Patients will be monitored according to the following stopping boundaries for overall response.
Number of patients evaluated
Recommend stopping if 
OR observed
20
10
30
16
40
22
50
28
The operating characteristics are summarized in the following table (based on simulations from 
10,000 trials).
True OR Rate
Prob(stop the trial early)
0.5
0.836
0.6
0.411
0.7
0.075
0.8
0.003
0.9
<0.0001
Analysis Plan
Summary statistics will be provided for continuous variables such as age.  Frequency tables will 
be used to summarize categorical variables including gender, stage, and response status.  Logistic 
regression will be utilized to assess the effect of patient prognostic factors on the response rate.  
The distributions of time-to-event endpoints including overall survival and progression free 
survival will be estimated using the method of Kaplan and Meier.  Comparison of time-to-event 
endpoints by important subgroups will be made using the log-rank test.  Cox proportional hazard 


Protocol 2005-0054
Revised September 17, 2012
Page 16
regression will be employed for multivariate analysis on time-to-event outcomes.
10.0
DATA AND PROTOCOL MANAGEMENT
10.1
Data Entry:  Patients must be registered on the Protocol Data Management 
System.
10.2
Accuracy of Data Collection:  The chairman will be the final arbiter of response or 
toxicity should a difference of opinion exist.
10.3
The principal investigator is responsible for submitting AEs to the IRB per 
MDACC standard guidelines.
11.0
REPORT OF ADVERSE EVENTS 
11.1
Adverse Event and Reporting Definitions
In the event of an adverse event, the first concern will be for the safety of the subject.  
Investigators are required to report to Genentech Drug Safety any serious adverse event,
whether expected or unexpected, regardless of causality to rituximab.  All events meeting these 
criteria will be reported for the time period beginning with any amount of exposure to rituximab 
through the protocol-defined follow-up period.  Serious criteria, definitions, and guidance for 
reporting follow.
An adverse event (AE) is any untoward medical occurrence in a subject participating in an 
investigational trial or protocol regardless of causality assessment.  An adverse event can be an 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, syndrome
or disease associated with or occurring during the use of an investigational product whether or 
not considered related to the investigational product.
Serious adverse events (SAE) are adverse events occurring at any dose which meet one or more 
of the following serious criteria:
Results in death (i.e. the AE caused or lead to death)
Is life-threatening (i.e. the AE placed the subject at immediate risk of death; it does not 
apply to an AE which hypothetically might have caused the death if it were more severe)
Requires or prolongs inpatient hospitalization (i.e. the AE required at least a 24-hour 
inpatient hospitalization or prolonged a hospitalization beyond the expected length of stay; 
hospitalizations for elective medical/surgical procedures, scheduled treatments, or routine 
check-ups are not SAEs by this criterion)
Is disabling (i.e. the AE resulted in a substantial disruption of the subject’s ability to carry 
out normal life functions)


Protocol 2005-0054
Revised September 17, 2012
Page 17
Is a congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus of a subject 
exposed to the trial drug prior to conception or during pregnancy)
It does not meet any of the above serious criteria but may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed above
SAEs include any sign, symptom or medical condition that meets any of the above criteria and 
emerges during rituximab treatment or during a post-treatment follow-up period that (1) was not 
present at the start of treatment and is not a chronic condition that is part of the patient’s medical 
history, OR (2) was present at the start of treatment or as part of the patient’s medical history but 
worsened in severity and/or frequency during therapy.
Expected adverse events are those adverse events that are listed or characterized in the current 
Investigator Brochure. 
Unexpected adverse events are those not listed in the current Investigator Brochure or not 
identified.  This includes adverse events for which the specificity or severity is not consistent 
with the description in the Investigator Brochure.  For example, under this definition, hepatic 
necrosis would be unexpected if the Investigator Brochure only referred to elevated hepatic 
enzymes or hepatitis.
11.2
Reporting of Serious Adverse Events Associated with Rituximab 
All serious adverse events (SAEs) regardless of causality to rituximab (this applies to both 
expected and unexpected events) should be recorded on a MedWatch 3500 Form (Appendix H) 
and faxed to:
Genentech Drug Safety 
Tel:
(888) 835-2555
Fax:
(650) 225-4682 or (650) 225-4683
(Please use the safety reporting fax cover sheet attached to this document for your fax 
transmission.)
AND:
Dr. Luis Fayad
Ph: 713-792-2860
Fax:  713 794-4186
AND:
Office of Protocol Research:
Phone: 713 792-2933
Fax:  713 794-4589
MedWatch 3500 Reporting Guidelines:
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information 


Protocol 2005-0054
Revised September 17, 2012
Page 18
within the Event Description (section 5) of the MedWatch 3500 
form:
Treatment regimen (dosing frequency, combination therapy)
Protocol description (and number, if assigned)
Description of event, severity, treatment, and outcome if known
Supportive laboratory results and diagnostics
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication
Follow-up information:  
Additional information may be added to a previously submitted report by any of the following 
methods:
Adding to the original MedWatch 3500 report and submitting it as follow-up
Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500 form 
Summarizing new information and faxing it with a cover letter including subject identifiers 
(i.e. D.O.B. initial, subject number), protocol description and number, if assigned, suspect 
drug, brief adverse event description, and notation that additional or follow-up information is 
being submitted  (The patient identifiers are important so that the new information is added to 
the correct initial report)
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the subject for whom and adverse event was reported.  For questions regarding 
SAE reporting, you may contact the Genentech Drug Safety representative noted above.
Study Drug Relationship:
The investigator will determine which events are associated with the use of the study drugs.  For 
reporting purposes, an AE should be regarded as possibly related to the use of the investigational 
product if the investigator believes:
There is a clinically plausible time sequence between onset of the AE and rituximab 
administration; and/or
There is a biologically plausible mechanism for rituximab causing or contributing to the AE; 
and
The AE cannot be attributed solely to concurrent/underlying illness, other drugs, or 
procedures.
11.3
Safety Reporting Requirements for IND Holders
Expedited IND Safety Reports:
For Investigator Sponsored IND Studies, some additional reporting requirements for the FDA 
apply in accordance with the guidance set forth in 21 CFR § 600.80.


Protocol 2005-0054
Revised September 17, 2012
Page 19
Events meeting the following criteria need to be submitted to the Food and Drug Administration 
(FDA) as expedited IND Safety Reports according to the following guidance and timelines:
7 Calendar-Day Telephone or Fax Report:
The Sponsor-Investigator is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the use of 
rituximab.  An unexpected adverse event is one that is not already described in the Investigator 
Brochure.  Such reports are to be telephoned or faxed to the FDA and Genentech within 7 
calendar days of first learning of the event.  Each telephone call or fax transmission (see fax 
number below) should be directed to the FDA new drug review division in the Center for Drug 
Evaluation and Research or in the product review division for the Center for Biologics 
Evaluation and Research, whichever is responsible for the review of the IND.
15 Calendar-Day Written Report:
The Sponsor-Investigator is also required to notify the FDA and all participating investigators, in 
a written IND Safety Report, of any serious, unexpected AE that is considered reasonably or 
possibly related to the use of rituximab and/or bevacizumab.
An unexpected adverse event is one that is not already described in the Investigator Brochure.  
Written IND Safety Reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32.  All safety reports previously filed with the IND 
concerning similar events should be analyzed and the significance of the new report in light 
of the previous, similar reports commented on.  
Written IND safety reports with Analysis of Similar Events are to be submitted the 
FDA, Genentech Drug Safety, and all participating investigators within 15 calendar 
days of first learning of the event. The FDA prefers these reports on a MedWatch 3500 
Form but alternative formats are acceptable (e.g. summary letter).
FDA fax number for IND Safety Reports:
1 (800) FDA 1078
All written IND Safety Reports submitted to the FDA by the Sponsor-Investigator must 
also be faxed to: 
Genentech Drug Safety 
Tel:
(888) 835-2555
Fax:
(650) 225-4682 or (650) 225-4683
(Please use the safety reporting fax cover sheet attached to this document for your fax 
transmission.)
AND:
Dr. Luis Fayad
Ph: 713-792-2860
Fax:  713 794-5656


Protocol 2005-0054
Revised September 17, 2012
Page 20
AND:
Office of Protocol Research
Phone 713 792-2933
Fax 713 794 4589
For questions related to safety reporting, contact:
Genentech Drug Safety 
Tel:
(888) 835-2555
Fax:
(650) 225-4682 or (650) 225-4683
IND Annual Reports:
In accordance with the regulation 21 CFR § 312.32, the Sponsor-Investigator shall within 
60 days of the anniversary date that the IND went into effect submit a brief report of the 
progress of the investigation.  Please refer to Code of Federal Regulations, 21 CFR § 312.32 
for a list of the elements required for the annual report.  All IND annual reports submitted 
to the FDA by the Sponsor-Investigator should be copied to Genentech.  Copies of such 
reports should be mailed to:
Genentech, Inc.
ATTN:  Brian King 
IST Coordinator 
1 DNA Way, Mailstop 88
South San Francisco, CA 94080-4990
Tel: (650) 225-6257


Protocol 2005-0054
Revised September 17, 2012
Page 21
REFERENCES:
1. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project.  A predictive 
model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993; 329: 987-994.
2. Maloney DG, Grillo-Lopez AJ, Whikte CA, et al:  IDEC-C2B8 (Rituximab) anti-CD20 
monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s. Blood 
90:2188-2195, 1997
3. McLaughlin P, Grillo-Lopez AJ, Link BK, et al:  Rituximab chimeric anti-CD20 
monoclonal antibody therapy for relapsed indolent lymphoma:  Half of patients respond 
to a four-dose treatment program.  J Clin Oncol 16:2825-2833, 1998
4. Davis TA, Grillo-Lopez AJ, White CA, et al:  Rituximab anti-CD20 monoclonal antibody 
therapy in non-Hodgkin’s lymphoma: Safety and efficacy of re-treatment.  J Clin Oncol 
18:3135-3143, 2000.
5. Blum KA, Barlett NL:  Antibodies for the treatment of diffuse large cell lymphoma.  
Semin Oncol 30{448-456, 2003
6. Czuczman MS, Grillo-Lopez AJ, White CA, et al Rituximab/CHOP chemotherapy in 
patients (pts) with low-grade lymphoma (LG/F NHL): Progression-free survival (PFS) 
after 3-year (median) follow-up.  Blood 1999; 94 (suppl 1):  99a (abstract 432)
7. McLaughlin P, Hagemeister FB, Rodriguez MA, et al.  Safety of fludarabine, 
mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV 
indolent lymphoma.  Semin Oncol 2000; 27:37-41
8. Zinzani PL, on behalf of an Italian Cooperative Study Group in Lymphoma.  A 
multicenter randomized trial of Fludarabine and Mitoxantrone Plus Rituximab vs. CHOP 
plus Rituximab as First-Line Treatment in patients with Follicular Lymphoma.  Blood
100, 2000 abstract 344
9. Vose JM, Link BK, Grossbard ML, Czuczman M, Grillo-Lopez A, Benyunes M, Gaynor 
E, Fisher RI.  Long-term follow-up of a phase II study with Rituximab in combination 
with CHOP chemotherapy in patients with previously untreated Aggressive Non-
Hodgkin’s lymphoma.  Blood 100, 2000 abstract 1396
10. Romaguera J, Cabanillas F, Dang NH, Goy A, Hagemeister FB, Fayad L, McLaughlin P, 
Pro B, Rodriguez MA, Samaniego F, Sarris AH, Younes A, Medeiros J.  Mantle cell 
lymphoma (MCL) – high rates of complete remission (CR) and prolonged failure-free 
survival (FFS) with Rituxan-HyperCVAD (R-HCVAD) without stem cell transplantation 
(SCT).  Blood 2001; 98:726a.
11. Thomas DA, Cortes J, O’Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, 
Cabanillas FF, Murphy S, Keating MJ, Kantarjian H.  Hyper-CVAD program in 
Burkitt’s-type adult acute lymphoblatic leukemia.  J Clin Oncol 1999; 17(8): 2461
12. Coiffier B, Lepage E, Briere J, et al.  CHOP chemotherapy plus rituximab compared with 
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