Clinical trial NCT00058422
Conditions: Lymphoma
Keywords: noncontiguous stage II adult diffuse large cell lymphoma stage III adult diffuse large cell lymphoma stage IV adult diffuse large cell lymphoma
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2003-02-10; Completion date: 2019-11-14
Enrollment: 65 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Monoclonal antibodies such as rituximab and yttrium Y 90 ibritumomab tiuxetan can locate cancer cells and either kill them or deliver radioactive cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining rituximab and combination chemotherapy with yttrium Y 90 ibritumomab tiuxetan may kill more cancer cells.

PURPOSE: Phase II trial to study the effectiveness of combining rituximab and combination chemotherapy with yttrium Y 90 ibritumomab tiuxetan in treating older patients who have B-cell lymphoma that has not been previously treated.

Detailed description:
OBJECTIVES:

* Determine the progression-free and overall survival of patients age 60 and over with previously untreated diffuse large B-cell lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) combined with yttrium Y 90 ibritumomab tiuxetan.
* Determine the incidence of adverse experiences, hematologic toxicity (WBC, hemoglobin, and platelet nadirs; and transfusion requirements), cardiac toxicity (incidence of left ventricular dysfunction and cardiomyopathy by echocardiography), and the development of human antimouse antibody/human anti-chimeric antibody in patients treated with this regimen.
* Determine the predictive value of detecting minimal residual disease by molecular techniques for future relapse/recurrence in patients treated with this regimen.
* Determine the response rate of patients treated with this regimen.
* Determine the red blood cell transfusion requirements, change in hemoglobin from baseline, and incidence of anemia with prophylactic darbepoetin alfa support in patients treated with this regimen.
* Determine the conversion rate to complete remission in patients treated with ibritumomab tiuxetan who achieve a partial remission post-R-CHOP.
* Determine the effect of darbepoetin alfa on the quality of life of these patients.

OUTLINE: This is an open-label, nonrandomized study.

* Chemotherapy: Patients receive rituximab IV over 2-5 hours, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1; oral prednisone on days 1-5 or 2-6; and filgrastim (G-CSF) subcutaneously (SC) on days 7-15. Patients also receive darbepoetin alfa SC on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
* Radioimmunotherapy: Patients receive rituximab IV over 3-5 hours and indium In 111 ibritumomab tiuxetan (IDEC-In2B8) IV over 10 minutes on day 0.

Patients undergo gamma camera imaging at 2-24 hours and 48-72 hours after the injection of IDEC-In2B8 to observe the flow of ibritumomab tiuxetan. If the flow is deemed safe, then patients receive yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes on day 7.

Quality of life is assessed at baseline, before course 5 of chemotherapy, before radioimmunotherapy, and at 3 months.

Patients are followed every 3 months for 1 year and then every 6 months for 4 years.

PROJECTED ACCRUAL: A total of 65 patients will be accrued for this study.

Arms: arm 1: Chemotherapy: Patients receive rituximab IV over 2-5 hours, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1; oral prednisone on days 1-5 or 2-6; and filgrastim (G-CSF) subcutaneously (SC) on days 7-15. Patients also receive darbepoetin alfa SC on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Radioimmunotherapy: Patients receive rituximab IV over 3-5 hours and indium In 111 ibritumomab tiuxetan (IDEC-In2B8) IV over 10 minutes on day 0.

Patients undergo gamma camera imaging at 2-24 hours and 48-72 hours after the injection of IDEC-In2B8 to observe the flow of ibritumomab tiuxetan. If the flow is deemed safe, then patients receive yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes on day 7. Quality of life is assessed at baseline, before course 5 of chemotherapy, before radioimmunotherapy, and at 3 months. Patients are followed every 3 months for 1 year and then every 6 months for 4 years.
Interventions: intervention 1: darbepoetin alfa intervention 2: filgrastim intervention 3: rituximab intervention 4: cyclophosphamide intervention 5: doxorubicin hydrochloride intervention 6: prednisone intervention 7: vincristine sulfate intervention 8: indium In 111 ibritumomab tiuxetan intervention 9: yttrium Y 90 ibritumomab tiuxetan
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None intervention 8: None intervention 9: None

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
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A PHASE II STUDY OF R-CHOP AND IBRITUMOMAB TIUXETAN 
(ZEVALIN®) FOR ELDERLY PATIENTS WITH PREVIOUSLY UNTREATED 
DIFFUSE LARGE B-CELL LYMPHOMA 
 
 
Principal Investigator: 
Paul A. Hamlin, M.D.* 
Co Principle Investigator: 
Andrew D. Zelenetz, M.D., Ph.D.* 
 
Responsible Investigators: 
Craig Moskowitz, M.D.* 
Neeta Pandit-Tasker, M.D.* 
Steven Horwitz, M.D.* 
Joseph Jurcic, M.D.* John 
Gerecitano, MD*         
Tarun Kewalramani, M.D.* 
Ariela Noy, M.D.* 
M. Lia Palomba, M.D.* 
Carol S. Portlock, M.D.* 
David Straus, M.D.* 
 
Cardiology: 
Nancy Roistacher, MD 
 
Nuclear Medicine: 
Steven Larson, M.D. 
Neeta Pandit-Tasker, M.D.* 
 
 
Immunology Pharmacy: 
Scott Freswick, Pharm.D. 
Radiochemistry: 
Ron Finn, Ph.D. 
Hematopathology: 
Daniel Filippa, M.D. 
Julie Feldstein, M.D. 
 
MEMORIAL SLOAN-KETTERING CANCER CENTER 
1275 York Avenue 
New York, NY 10021 


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COLLABORATING INSTITUTIONS: 
MD ANDERSON CANCER CENTER - University of Texas 
 
Principle Investigator: 
Maria Alma Rodriguez, MD* 
1515 Holcombe Boulevard, #68 
Houston, TX, 77030 
phone: 713.792.2860  fax: 713.794.5656 
mrodriguez@notes.mdacc.tmc.edu 
 
Responsible Investigators (Consenting individuals) 
 
 
Luis Fayad, MD 
Frederick Hagemeister, MD 
Larry Kwak, MD, PhD 
Peter McLaughlin, MD 
Sattva Neelapu, MD 
Barbara Pro, MD 
Jorge Romaguera, MD 
Felipe Samaniego, MD 
Anas Younes, MD 
 
DRUG MANUFACTURERS: 
Biogen Idec, Inc.. Pharmaceuticals 
Corporation 
3030 Callan Road 
San Diego, CA 92121 
Phone 858-431-8500 
Fax 858-431-8887 
 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Fax 805 499 9472 
 
 
 
Revised 8/22/02 


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TABLE OF CONTENTS 
Page 
1. PROTOCOL SUMMARY 
3 
2. OBJECTIVES AND SCIENTIFIC AIMS 
4 
3. BACKGROUND AND RATIONALE 
4 
4. STUDY DESIGN 
10 
5. THERAPEUTIC AGENTS 
11 
6. CRITERIA FOR PATIENT ELIGIBILITY 
24 
7. RECRUITMENT PLAN 
26 
8. PRETREATMENT EVALUATION 
27 
9. TREATMENT PLAN 
27 
10. EVALUATION DURING TREATMENT 
31 
a. Chemotherapy Phase (I) Table 
33 
b. Radioimmunotherapy Phase (II) Table 
36 
11. ADVERSE EXPERIENCES 
37 
12. CRITERIA FOR THERAPEUTIC 
39 
RESPONSE/OUTCOME ASSESSMENT 
13. CRITERIA FOR REMOVAL FROM STUDY 
41 
14. BIOSTATISTICS 
41 
15. SUBJECT REGISTRATION AND 
43 
RANDOMIZATION PROCEDURES 
16. DATA MANAGEMENT ISSUES AND QUALITY 
44 
ASSURANCE 
17. PROTECTION OF HUMAN SUBJECTS 
45 
18. INFORMED CONSENT PROCEDURES (see Appendix 
46 
I) 
19. REFERENCES 
46 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 02-090A(9) 
 
11/07 
Patients age ≥60 with untreated High- 
Int. and High risk by aaIPI DLBCL 
• 
No prior therapy (1 cycle RCHOP 
allowed) 
R-CHOP x 6 cycles every 21 days 
with CSF support and 
Darbepoetin alfa 4.5 g/kg/q3w 
Rituxan 250 mg/m2, over 3-5 hours 
on day 0 followed by imaging dose 
111In ibritumomab tiuxetan 
90Y-ibritumomab 
tiuxetan 0.4 mCi/Kg 
 
 
1.0 
PROTOCOL SUMMARY 
 
This is a multi-institutional, non-randomized, open-label, phase II study of 6 cycles of 
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) 
followed by 90Y-ibritumomab tiuxetan, a 90Y-labeled anti-CD20 murine antibody, in 
patients 60 years or older with previously untreated high risk diffuse large B-cell 
lymphoma. 
 
In part I of the study, patients will receive R-CHOP chemotherapy at standard doses 
every 21 days for a total of 6 cycles with pegfilgrastim (or G-CSF) and prophylactic 
Darbepoetin alfa support. 
 
In part II of the study, patients will receive a loading dose of rituximab, 250 mg/m2, over 
3-5 hours on Day 0. This is followed by an imaging dose of 111In ibritumomab tiuxetan. 
Two or three gamma camera images will be taken at 2-24 hours, 48-72 hours, and, if 
needed, 90-120 hours after injection of 111In ibritumomab tiuxetan. On Day 7, a second 
loading dose of rituximab 250 mg/m2 over 3-5 hours will be given, immediately followed 
by 90Y-ibritumomab tiuxetan. Patients with baseline platelet counts 150,000 will receive 
a 0.4 mCi/kg dose, and patients with platelet counts of 100,000-149,000 will receive a 0.3 
mCi/kg dose. The dose is given via slow IV push over 10 minutes. 
 
SCHEMA: 
 
 
 
 
 
PART I 
 
Restaging 4-5 weeks 
post D1 last R-CHOP 
 
 
PART II 
6-9 weeks after 
Day 0 
D1 of last R-CHOP 
(*Patients with BM<25% 
Involved proceed to RIT) 
Gamma imaging 
Day 7 
 
 
 
 
 
                            90Y-ibritumomab 
tiuxetan 0.3 mCi/Kg 
Maximum 
Dose 32 mCi 
Amended:9/ 
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Rituxan 250 mg/m2 over 
3-5 hours 
PLT=100,000 
-149,999 
PLT 
≥150,000 


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2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
The primary efficacy endpoints for this study evaluating the sequential administration of 
6 cycles of R-CHOP with pegfilgrastim (or G-CSF) and Prophylactic Darbepoetin alfa 
support followed by 90Y-ibritumomab tiuxetan for patients 60 years of age or older with 
previously untreated high-intermediate or high risk by the age adjusted International 
prognostic index (aaIPI = 2 or 3, respectively) diffuse large B-cell lymphoma are to 
determine: 
• progression free survival (PFS) 
• overall survival (OS) 
 
The primary safety endpoints are to determine: 
• the incidence of adverse experiences 
• hematologic toxicity (white blood cell, hemoglobin, and platelet nadir; transfusion 
requirements) 
• cardiac toxicity – the incidence of LV dysfunction and cardiomyopathy as 
assessed by echocardiography 
 
The secondary efficacy endpoints of the study are to determine: 
• the predictive value of detecting minimal residual disease by molecular 
techniques for future relapse/recurrence 
• the treatment response rate for R-CHOP 
• Event free survival (EFS) 
• The packed red blood cell transfusion requirements, change in hemoglobin (Hgb) 
from baseline, and incidence of anemia (CTC grading) with Prophylactic 
Darbepoetin alfa support. Hgb response and correction with darbepoetin alfa is 
defined as: an increase of 2.0 gm/dl from baseline and an Hgb 12.0 g/dl, 
respectively, in the absence of RBC transfusion in the preceding 21 days. 
• A comparison of baseline FACT-An QOL scores with subsequent evaluations will 
be performed to correlate the impact of darbepoetin alfa on this QOL measure. 
• The conversion rate to CR with 90Y-ibritumomab tiuxetan for patients with a PR 
post R-CHOP 
• the effects of sequential R-CHOP and 90Y-ibritumomab tiuxetan on hematopoietic 
progenitor cells as determined by stem cell assays performed by Dr. Malcolm 
Moore’s laboratory. 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
Introduction 


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Diffuse large B-cell lymphoma (DLBCL) is a potentially curable subtype of non- 
Hodgkin’s lymphoma (NHL) with an increasing frequency in elderly patients. In the 
International NHL Prognostic Factors Project, age was found to be an important adverse 
prognostic factor, affecting both relapse-free and overall survival. For elderly patients in 
that study, 5-year survival rates for low, low intermediate, high-intermediate, and high 
risk disease were 56%, 44%, 37%, and 21%, respectively (see table).1 Other smaller, 
earlier studies have also confirmed the poor prognosis seen in elderly patients.2-5 The 
reasons for the poor outcomes in elderly patients are unclear. DLBCL may be inherently 
more biologically aggressive in elderly patients than in younger patients. Co-morbid 
conditions in the elderly often complicate treatment, leading to poorer outcomes.6 
Increased treatment-related toxicities are seen in the elderly, and can be life-threatening 
(e.g., neutropenic sepsis) or can lead to dose reductions which result in lower dose 
intensity and a higher rate of treatment failure.7,8 
 
Table 4 Age-Adjusted index, patients >60 (n=761)1 
Risk 
# of risk 
Factors 
% of 
patients 
CR Rate 
(%) 
RFS (%) 
At 2 yrs. 
RFS (%) 
At 5 yrs. 
OS (%) 
@ 2yr 
OS (%) 
@ 5yr 
Low 
0 
18 
91 
75 
46 
80 
56 
Low-Int. 
1 
31 
71 
64 
45 
68 
44 
High-Int 
2 
35 
56 
60 
41 
48 
37 
High 
3 
16 
36 
47 
37 
31 
21 
 
Based on the Shipp data (1) for patients >60 years of age, CR rates range from 36-91% 
depending on the aaIPI group. For patients with High Intermediate and High Risk 
disease, only 56% and 36% respectively will attain a CR with CHOP therapy. Of these 
patients attaining a CR, between 59% and 63% will relapse by 5 years despite obtaining 
an initial CR. Attempts to improving this scenario have been the focus of many 
subsequent trials. 
 
Supportive care advances with CHOP 
 
Several efforts have been made at improving treatment outcomes in elderly patients with 
DLBCL. The use of hematopoietic growth factors with CHOP chemotherapy has shown 
promise in the management and prevention of febrile neutropenia. The NCCN 
recommends all patients aged 70 years or older and treated with CHOP chemotherapy 
receive prophylactic pegfilgrastim or G-CSF support. In a retrospective series of 50 
consecutive elderly patients with DLBCL treated with CHOP and G-CSF, Donnelly et al 
reported a high dose intensity and response, with overall survival rates comparable to the 
cohort of patients under the age of 60 used to established the age-adjusted International 
Prognostic Index (IPI).9 Improved response rates and dose-intensity were also reported in 
a recent prospective cohort of 20 elderly patients.10 


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Less information is available on the impact of anemia following chemotherapy. 
Traditional cutoffs for transfusion have included hemoglobin (Hgb) <8g/dl in the absence 
of coronary artery disease and <10g/dl in the presence of coronary artery disease to 
prevent myocardial ischemia. More recent evidence in non-hematologic malignancies 
suggests amelioration of cancer related fatigue and quality of life declines with 
maintenance of Hgb levels between 11-13 g/dl. 11. The NCCN has recommended elderly 
patients receiving chemotherapy have Hgb maintained 12g/dl. Maintenance of 
functionality in the elderly population is paramount, with deterioration of ADLs leading to 
dependence, inability to receive additional therapy, and potentially requiring 
institutionalization. 
 
Erythropoietin given weekly has been shown to significantly increase Hgb levels, 
decrease transfusion requirements, and improve functional status and fatigue. 14% and 
19% of patients in the GELA study had grade 3 or 4 anemia with R-CHOP and CHOP 
therapy, respectively.12 Although data for grade I and II anemia with CHOP are largely 
unreported, one study of 174 patients reported a 49% incidence of grade I/II anemia and 
17% grade III 13. The maintenance of adequate Hgb levels is desirable, but 
erythropoietin therapy necessitates weekly injections. Darbepoetin Alfa (Aranesp) is a 
biochemically distinct form of recombinant human erythropoietin, containing additional 
sialic acid residues that prolong the serum half-life. 14 Darbepoetin alfa has been 
demonstrated to have a dose dependent relationship and can feasibly be administered on a 
reduced frequency schedule with combination chemotherapy, still retaining efficacy 
benefits.15 
 
D. Kotasek et. Al. reported updated results of a randomized, double-blind, placebo 
controlled, phase I/II dose finding study of Aranesp administered once every three weeks 
in solid tumor patients. 16 259 patients were randomized to receive either Aranesp 
(doses: 4.5-15 g/kg/q3wk) or placebo. Results for the first four dosing cohorts were 
reported, demonstrating a 51% response rate at the 4.5 g/kg/q3wk dose, with a mean 
change in hemoglobin of 0.6 gm/dl and a 52% response rate at the 6.75 g/kg/q3wk dose, 
with a mean change in hemoglobin of 1.2 gm/dl. Increasing the dose to 9.0 and 12 
g/kg/q3k results in a dose response increase in the response rate and change in 
hemoglobin (61%/1.3 gm/dl and 71%/2.6gm/dl respectively). The ability to administer 
darbepoetin alfa in concert with R-CHOP would prove both cost effective regarding 
resource allocation and improve patients convenience by deceasing the number of 
hospital visits (from every week to every three weeks). Subsequently, Reardon et. Al. 
(ASH #3783, Blood 102(11), Nov 16,2003), p20B) reported on 112 patients effectively 
treated with 300 micrograms every 3 weeks. We plan to investigate the ability of 
Aranesp, delivered at a more convenient dosing schedule q3 weeks in conjunction with 
R-CHOP, to ameliorate the anemia associated with chemotherapy and 
radioimmunotherapy. 
 
Rituximab monoclonal antibody therapy 


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Anti-CD20 monoclonal antibody therapy has been one of the most important advances in 
the management of B-cell lymphoid malignancies over the past few years. Rituximab, a 
chimeric anti-C20 antibody, exerts its anti-tumor effect by directly inducing apoptosis, by 
activating complement, and by antibody dependent cell-mediated cytotoxicity. It has been 
shown to produce objective responses in approximately 50% of patients with relapsed or 
refractory low-grade or follicular NHLs.17 In patients with relapsed or refractory 
aggressive lymphomas (including DLBCL), Coiffier and colleagues found a response rate 
of 31% when an 8-week course of rituximab is used.18 
 
Coiffier et al recently reported 24 month median follow-up of the GELA study which 
randomized 399 elderly patients with newly diagnosed DLBCL to receive either 8 cycles 
of CHOP or CHOP with rituximab (R-CHOP). Sixty percent of the patients had age- 
adjusted international prognostic index (aaIPI) high-intermediate or high-risk disease. 
The complete response rates in the R-CHOP cohort were significantly higher (76% vs. 
63%), and at a median followup of 18 months the event-free survival (62% vs. 43%) and 
overall survival (73% vs. 61%) was also significantly improved, with statistical 
significance continuing at 24 months 12,19. 
 
The GELA data was updated at ASH 2003 and continues to hold true with 4 years 
median followup (Figure below). Event free survival for high-risk patients by IPI is 
roughly 45% at 48 months. Consequently, the magnitude of rituximab’s benefit appears 
to be less in the high-risk groups compared with the low risk groups.. These results are 
encouraging, and represent an important advance in the management of elderly patients 
with DLBCL. However, significant room for improvement remains. 


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R-CHOP 
CHOP 
Low risk: P < 0.001 
0.0 
0.0 
0.0   0.5   1.0   1.5   2.0   2.5   3.0   3.5   4.0   4.5   5.0   5.5 
0.0   0.5   1.0   1.5   2.0   2.5   3.0   3.5   4.0   4.5   5.0   5.5 
Years 
Years 
1.0
High risk: P < 0.01 
0.8
0.6
R-CHOP 
0.4
0.2
CHOP 
 
 
(Coiffier, ASH 2003) 
 
 
Toxicity of R-CHOP 
 
The addition of Rituximab to CHOP chemotherapy was well tolerated and not associated 
with significant increases in toxicity. The grade 3 and 4 adverse events were consistent 
with expected toxic effects of CHOP, occurring with similar frequency. Hematologic 
toxicity was not associated with increased neutropenic infections (12% R-CHOP vs 20% 
CHOP) nor increased grade 3 or 4 anemia (14% R-CHOP vs 19% CHOP). 12. Increased 
cardiac toxicity (47% for R-CHOP vs. 35% for CHOP) predominantly reflected increased 
grade 1 events related to rituximab infusion (24% RCHOP vs 13% CHOP) with an 
equivalent incidence of grade 3 and 4 events (8 %) in both groups.12 
 
Anthracycline induced cardiomyopathy remains a rare but serious dose related 
consequence of therapy with doxorubicin. The risk of cardiomyopathy has been reported 
to be increased in patients > age 70, with hypertension, with coronary artery disease, and 
with combination chemotherapy. Elderly patients are likely to experience congestive 
heart failure at a lower cumulative dose.20 Given the unknown cardiotoxicity of 
sequential R-CHOP and RIT, we will prospectively evaluate echocardiographic 
determinations of LV function. 
 
Radioimmunotherapy 
Event-Free Survival according to aaIPI 
1.0 
0.8 
0.6 
0.4 
0.2 


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Radioimmunotherapy represents an emerging therapeutic modality that involves the 
conjugation of radionuclides to monoclonal antibodies in an attempt to enhance tumor 
cell kill and treatment outcomes. The monoclonal antibody maintains its anti-tumor 
efficacy and is augmented by the addition of a beam of gamma or beta radiation directed 
at tumor tissue adjacent to the target binding site. In the case of lymphoid malignancies, 
the radionuclides most commonly conjugated to anti-CD20 antibodies are iodine-131 
(131I) and yttrium-90 (90Y). Limitations of I131 use include hypothyroidism and the 
inconvenience of gamma radiation, which necessitates isolation precautions for several 
days following its administration. Potential advantages of 90Y include ease of 
administration since it is a pure beta emitter, which facilitates outpatient administration, 
and a longer path length of 5-10 mm, which results in improved cell kill in adjacent tumor 
tissue. While 90Y provides therapeutic advantages, it cannot be used for imaging. The 
gamma emitter 111In has been successfully used as an imaging agent prior to the 90Y- 
labeled antibody. A dose of 5 mCi 111In-labeled antibody is one that balances safety and 
imaging efficacy 21-24, allowing for the determination of expected biodistribution with 
the therapeutic dose. 
 
Ibritumomab tiuxetan is a murine immunoglobulin G1 kappa monoclonal antibody 
(ibritumomab) covalently bound to MX-DTPA (tiuxetan) that chelates the radioisotope 
90Y. In a phase I/II trial involving patients with relapsed or refractory low-grade or 
transformed low-grade NHL, the maximum tolerated dose (MTD) was 0.4 mCi/kg (or 0.3 
mCi/kg for patients with baseline platelet counts of 100,000-149,000). The overall 
response rate for the 51 patients treated at the MTD was 67% (26% CR, 41% PR). For 
patients who transformed to intermediate-grade disease (n=14), the overall response rate 
was 43%.25 These results appear superior to immunotherapy alone when used in a 
similar patient population. The final results of a phase III study were presented at the 
ASH 2000 meeting which randomized 143 patients with relapsed or refractory low-grade 
or transformed low grade NHL to receive rituximab or 90Y- ibritumomab tiuxetan. The 
overall response rate was 80% in the radioimmunotherapy arm vs. 56% in the rituximab 
arm (p=0.002), and the CR rate was significantly improved (30% vs. 16%, p=0.04). 
Response durations did not significantly differ between the two arms.26 
 
The effect of radioimmunotherapy on stem cell precursors is currently not known. 
Preliminary reports from the Mayo Clinic have demonstrated the feasibility of 
administering additional chemotherapy for relapse post Zevalin, as well as reporting 5/6 
successful peripheral blood stem cell mobilizations following Zevalin (all patients 
regaining adequate counts post ASCT).27 We plan to evaluate stem cell progenitor 
assays before and after radioimmunotherapy in this group of transplant ineligible patients 
(see Appendix D). 
 
Hypothesis 
 
The number of elderly patients and the incidence of NHL in this population continue to 
increase annually. Elderly patients (age >60) have a poorer prognosis with standard 


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CHOP chemotherapy compared with younger patients and historically have been under- 
represented in clinical trials. The data from the GELA demonstrate that the addition of 
immunotherapy (rituximab) to CHOP may improve outcomes in elderly patients with 
DLBCL. Supportive care measures such as G-CSF and Prophylactic Darbepoetin help to 
maintain dose intensity and minimize toxicity. Elderly patients age >65 and many aged 
60-65 are not candidates for potentially curative second-line transplant regimens should 
they have relapsed or refractory disease. Therefore, it is paramount that new regimens be 
designed to improve upon the quality and durability of the upfront treatment. Preliminary 
data show superior response rates with radioimmunotherapy over standard immunotherapy 
when used alone in low-grade and transformed NHL, raising the possibility                   
that combinations with chemotherapy could improve results. 
 
In follicular lymphoma, where BCL-2 represents a useful marker to assess for minimal 
residual disease, patients with PCR positive CRs (molecular residual disease) who are 
were treated with rituximab following CHOP and subsequently achieved PCR negativity 
had superior freedom from recurrence compared with those patients never achieving PCR 
negativity (57% vs 20%; p<0.001). 28 This lends credence to the premise that relapses 
result from residual but clinically undetectable disease. In a similar vein, the presence of 
minimal residual disease in intermediate and high grade lymphoma patients following 
ASCT, as detected by PCR IgH gene rearrangements, was associated with relapse in 6/6 
cases, while 13/13 PCR negative patients remained in CR 29 We plan to prospectively 
evaluate the prognostic significance of minimally residual disease present after R-CHOP 
and RIT (See Appendix C) and to give additional therapy in the form of RIT to in hopes 
of targeting minimal residual disease and improving durable remissions. 
 
Consequently, we hypothesize that the addition of targeted consolidative 
radioimmunotherapy following R-CHOP treatment may decrease future relapses and 
improve survival. We propose a phase II study evaluating the feasibility, efficacy, and 
safety of a sequential program of R-CHOP with pegfilgrastim or G-CSF and Prophylactic 
Darbepoetin alfa support followed by consolidation with 90Y-ibritumomab tiuxetan. We 
will prospectively evaluate for molecular evidence of minimally residual disease, 
correlating this data with future outcome, and assess the impact of this regimen on bone 
marrow progenitor cells. The safety of RIT following R-CHOP will also be investigated. 
 
 
4.0 
STUDY DESIGN 
 
This is a multi-institution, non-randomized, open-label, phase II study of 6 cycles of 
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) 
followed by 90Y-ibritumomab tiuxetan, a 90Y-labeled anti-CD20 murine antibody, in 
patients 60 years or older with high risk (aaIPI 2 or 3), previously untreated diffuse large 
B-cell lymphoma. 
 
In part I of the study, patients will receive R-CHOP chemotherapy at standard doses 
every 21 days for a total of 6 cycles with G-CSF growth factor support. In addition, 


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prophylactic Darbepoetin alfa will be administered every 3 weeks throughout the duration 
of this study. After the 4th and 6th cycles, patients will be assessed for treatment   
response. Intrathecal chemotherapy prophylaxis will be given for patients deemed at risk. 
Bone marrow examinations will also be performed to assess for minimal residual disease 
(See Appendix C) and hematopoietic progenitor cell assays (See Appendix D). Patients 
with a confirmed or unconfirmed complete response and patients with a partial response 
(who continue to be ineligible for autologous stem cell transplantation) will proceed to the 
radioimmunotherapy (RIT) part (part II) of the study. Pre-RIT, patients will be re- staged 
and must have a bone marrow biopsy with <25% involvement by lymphoma,        
adequate cellularity, and preserved cardiac function. Earlier work has shown that 
rituximab levels are not immediately cleared from tumor binding sites. 30. Consequently, 
90Y-ibritumomab tiuxetan therapy will be delayed 6-9 weeks after completion of R- 
CHOP in order to expose more CD20 binding sites. Rituximab and B-cell levels will be 
measured following R-CHOP and prior to RIT. 
 
In part II of the study, 6-9 weeks (42-63 days) after D1 of the last R-CHOP cycle, 
patients will receive a loading dose of rituximab, 250 mg/m2, over 3-5 hours on Day 0. 
This is followed immediately by a 10 minute IV push infusion of 1.6 mg of 111In 
ibritumomab tiuxetan (containing 5 mCi of 111In). Imaging will be obtained 2-24 hours 
following 111In ibritumomab tiuxetan infusion. Whole body anterior and posterior images 
will be acquired. Imaging will be repeated at 48-72 hours. The 111In imaging will be done 
to ensure expected biodistribution, rather than tumor dosimetry. Additionally, since this 
study is evaluating the role of 90Y-ibritumomab tiuxetan following chemotherapy in 
patients who may be in clinical remission, tumor uptake is not required for patient 
eligibility for 90Y-ibritumomab tiuxetan administration. On Day 7, a second loading dose 
of rituximab 250 mg/m2 over 3-5 hours will be given, immediately followed by 90Y- 
ibritumomab tiuxetan. Patients with baseline platelet counts 150,000 will receive a 0.4 
mCi/kg dose, and patients with platelet counts of 100,000-149,999 will receive a 0.3 
mCi/kg dose. The dose is given via slow IV push over 10 minutes. 
 
Patients will be followed weekly during RIT. The nadir with 90Y ibritumomab tiuxetan is 
expected starting week 6-8. Patients will then be assessed for treatment response at week 
12-13. Bone marrow examinations to assess for minimal residual disease and 
hematopoietic progenitor cell assays will be repeated. 
 
FACT-anemia quality of life (QOL) evaluations will be performed at baseline, at Part I 
restaging (between cycles 4&5), post/chemotherapy/pre-RIT restaging, and following RIT 
(week 12-13). Correlation of FACT-anemia scores with hematologic parameters and 
impact of RIT will be assessed. 
 
The primary efficacy endpoints for this study are to determine the progression free 
survival (PFS) and overall survival (OS) of the sequential administration of 6 cycles of R- 
CHOP with pegfilgrastim (or G-CSF) and Prophylactic Darbepoetin alfa support   
followed by 90Y-ibritumomab tiuxetan for patients 60 years of age or older with 
previously untreated diffuse large B-cell lymphoma. 


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The secondary efficacy endpoints of the study are to determine the predictive value of 
detecting minimal residual disease by molecular techniques for future relapse/recurrence, 
the treatment response rate for R-CHOP, the packed red blood cell transfusion 
requirements, incidence of anemia, and change in hemoglobin (Hgb) from baseline with 
Prophylactic Darbepoetin alfa support, impact of anemia and darbepoetin alfa use on 
QOL measures, impact of RIT on QOL measures, cardiotoxicity as assessed by 
echocardiography, the conversion rate to CR with 90Y-ibritumomab tiuxetan for patients 
with a PR post R-CHOP, the effects of sequential R-CHOP and 90Y-ibritumomab 
tiuxetan on hematopoietic progenitor cells. 
 
The safety endpoints are to determine the incidence of adverse experiences, hematologic 
toxicity (e.g., white blood cell, hemoglobin, and platelet nadir) anduse of supportive care. 
 
5.0 
THERAPEUTIC AGENTS 
 
5.1 Cyclophosphamide 
5.1.1 Description, Pharmacology, Storage and Preparation 
Cyclophosphamide, a nitrogen mustard derivative, is a polyfunctional 
agent. The drug is a monohydrate, white crystalline powder and is soluble 
in water and in alcohol. Cyclophosphamide is biotransformed principally in 
the liver to active alkylating metabolites by a mixed function     
microsomal oxidase system. It is eliminated primarily in the form of 
metabolites; however, 5-25% of the dose is excreted in urine as unchanged 
drug. The elimination half-life after oral administration is 3-12 hours. The 
preparation and storage of cyclophosphamide should follow the 
manufacturer’s recommendations. 
5.1.2 Toxicities 
Toxicities from cyclophosphamide consist of nausea and vomiting, 
anorexia, diarrhea, abdominal discomfort, alopecia, skin rash, leukopenia, 
thrombocytopenia, anemia, hemorrhagic cystitis, interstitial pneumonitis, 
and urinary bladder fibrosis. Cyclophosphamide causes dose-limiting 
myelosuppression and hemorrhagic cystitis. Myelosuppression consists of 
leukopenia and thrombocytopenia. Leukopenia nadir and time of recovery 
usually occur at 8-14 days and 18-25 days, respectively. Development of 
hemorrhagic cystitis is dependent on the dose of cyclophosphamide and 
the duration for therapy. Prophylactic measures, including forced diuresis 
and hydration, have been shown to be effective in preventing bladder 
toxicity. 
 
Secondary malignancies, mostly bladder carcinomas and acute leukemias, 
have been shown to be associated in patients treated with 
cyclophosphamide alone or in conjunction with other agents or modalities. 
Occurrence of secondary malignancies may occur several years after 
treatment. 


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Cyclophosphamide decreases serum pseudocholinesterase concentrations 
and may prolong the neuromuscular blocking activity of succinylcholine, 
especially in very ill patients receiving large intravenous doses of 
cyclophosphamide. If a patient is to receive anesthesia, the 
anesthesiologist should be notified if the patient has received 
cyclophosphamide within 10 days of the procedure. 
 
Cyclophosphamide is a know teratogen and impairs oogenesis and 
spermatogenesis. Sterility may occur in both sexes and may be 
irreversible. 
5.2 Doxorubicin 
5.2.1 Description, Pharmacology, Storage and Preparation   
Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures 
of Streptomyces peucetius. It exerts its action by intercalating between 
base pairs of the DNA double helix and by inhibition of topoisomerase II, 
causing double strand DNA breaks. Free radical formation has been 
implicated in doxorubicin cardiotoxicity by means of Cu (II) and Fe (III) 
reduction at the cellular level. Rapid plasma uptake occurs after slow 
biliary metabolism and excretion. The majority of the drug is protein 
bound and independent of plasma concentration. Doxorubicin has a 
terminal half-life of 20-48 hours. The preparation and storage of 
doxorubicin should follow the manufacturer’s recommendations. 
5.2.2 Toxicities 
The dose-limiting toxicity of doxorubicin is irreversible cardiotoxicity. 
Signs and symptoms of cardiotoxicity are cardiac arrhythmias, decreased 
left ventricular ejection fraction, congestive heart failure, and 
cardiorespiratory decompensation such as dilatation of the heart, pleural 
effusion, and venous congestion. Doxorubicin administration should not 
exceed cumulative lifetime doses of 550 mg/m2. Myelosuppression 
consisting of leukopenia is common, with a nadir of 10-14 days. Other 
adverse effects include nausea, mucositis, stomatitis, alopecia, 
extravasation, hyperpigmentation of nail beds, red-orange discoloration of 
urine, and erythematous streaking of veins. 
 
There is inadequate information as to what effect doxorubicin has on 
fertility in males. Doxorubicin falls into U.S. Food and Drug 
Administration Pregnancy Category D 
5.3 Vincristine 
5.3.1 Description, Pharmacology, Storage and Preparation  
Vincristine is a naturally occurring vinca alkaloid. Vincristine sulfate is 
the salt of a dimeric alkaloid from Catharanthus roseus, the common 
periwinkle plant. Vincristine sulfate is a white, off-white, or slightly 
yellow hygroscopic, amorphous, or crystalline powder that is freely 
soluble in water and slightly soluble in alcohol. It is reconstituted to a 


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concentration of 1 mg/mL. Vincristine exerts its effects by inhibiting 
mitosis, causing an arrest of cell division in the metaphase stage. 
Vincristine is metabolized in the liver by the hepatic cytochrome P450 in 
the CYP3A family. Vincristine has a triphasic pattern of elimination 
occurring at 5 minutes, 2.3 hours, and 85 hours. The terminal half-life of 
vincristine ranges between 19 and 155 hours. About 80% of the injected 
dose appears in the feces and 10-20% is found in the urine. The 
preparation and storage of vincristine should follow the manufacturer’s 
recommendations. 
5.3.2 Toxicities 
Patients receiving vincristine commonly experience alopecia. One dose- 
limiting side effect is peripheral neurotoxicity, as manifested by neuritic 
pain, paresthesias, decrease in deep tendon reflexes, foot drop, jaw pain, 
back pain, constipation, and paralytic ileus. These symptoms may 
disappear with a reduction in dosage. Vestibular and auditory damage can 
also occur and are usually manifested as dizziness, nystagmus, or loss of 
hearing. 
 
Vincristine may result in azoospermia in males. Vincristine is a U.S. Food 
and Drug Administration's Pregnancy Category D 
 
5.4 Prednisone 
5.4.1 Description and Pharmacology 
Prednisone is a synthetic glucocorticoid. It is often used to enhance the 
effects of other cancer agents when used in combination. Given in 
pharmacologic doses, prednisone exerts anti-inflammatory and 
immunosuppressive effects on the blood and lymphatic system. At the 
cellular level, prednisone appears to halt DNA synthesis by mediating the 
inhibition of glucose transport or phosphorylation. In consequence, this 
causes a decrease in available intracellular energy and thereby impedes 
mitotic division. Prednisone is rapidly absorbed from the gastrointestinal 
tract when administered orally and has a short duration (3-4 hours) of 
pharmacologic effects. Animal studies demonstrate that it is rapidly 
distributed to muscles, liver, skin, intestine, and kidneys upon ingestion. 
5.4.2 Toxicities 
Prednisone exerts numerous effects on the body: euphoria, mood swings, 
fluid retention, adrenocortical insufficiency, muscle pain or weakness, 
muscle wasting, increased susceptibility to infections, hypokalemia, 
hypercortisolism, amenorrhea, glucose intolerance, hyperglycemia, 
nausea, vomiting, anorexia, increased appetite, weight gain, gastric 
ulceration, ulcerative esophagitis, insomnia, headache, restlessness, 
increased motor activity, impaired wound healing, osteopenia, 
osteoporosis, avascular necrosis, skin atrophy and thinning, acne, and 
increased sweating. 


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Patients must be instructed to use glucocorticoids cautiously if they have 
any infections, impending surgery, hypothyroidism, cirrhosis, mental 
instability, congestive heart failure, peptic ulcer disease, diverticulitis, 
nonspecific ulcerative colitis, recent intestinal anastomoses, seizures, 
osteoporosis, herpes simple infections of the eye, and thromboembolic 
disorders. 
 
5.5. Neupogen® (Filgrastim, G-CSF) and Neulasta(TM) (pegFilgrastim or pegylated 
filgastrim) 
5.5.1. Description and pharmacology- Neupogen: 
NEUPOGEN® is a human protein, which is involved in the promotion of 
the growth and maturation of granulocytic progenitors and the stimulation 
of functional activity. 
Formulation: Available as a recombinant DNA product supplied as 1 or 2 
ml vials containing clear colorless sterile protein solution. 
Storage: It can be stored at 2-6°C and is stable for at least 30 months. 
5.5.2. Description and pharmacology- Neulasta: 
Pegfilgrastim is the pegylated form of recombinant methionyl human G- 
CSF (filgrastim). Pegfilgrastim is produced by covalently binding a 20- 
kilodalton (kD) monomethoxypolyethylene glycol molecule to the N- 
terminal methionyl residue of filgrastim 
Formulation: 6 MG/0.6 ML SOL. A single fixed dose of 6 milligrams 
(mg) subcutaneously, given once per chemotherapy cycle, is effective and 
is recommended. 
Storage: The manufacturer recommends storage of Neulasta(TM) syringes 
at 2 to 8 degrees C (36 to 46 degrees F), avoidance of freezing or shaking, 
and leaving syringes in the carton provided until time of use to protect 
from light (Prod Info Neulasta(TM), 2002). 
5.5.3. Toxicity: 
Bone pain, exacerbation of preexisting autoimmune disorders, transient 
and reversible changes in alkaline phosphatase, uric acid and LDH. 
Contraindications: Prior hypersensitivity to Escherichia coli-derived 
proteins, filgrastim, or pegfilgrastim 
5.5.4. Supplier: Amgen, Inc. 
 
5.6. Rituximab 
For a complete description of rituximab, please refer to the 
Rituxan→  Package Insert in Appendix A. 
 
A very rare side effect is an infection of the brain called progressive 
multifocal leukoencephalopathy (PML). It is almost always fatal 
 
 
5.7. 90Y and 111I-Ibritumomab Tiuxetan 
5.7.1. Origin of the IDEC-2B8/ibritumomab cell line 


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The murine anti-CD20 monoclonal antibody 2B8.H11.G2.G9 
(ibritumomab tiuxetan ) is an IgG1 kappa antibody. The selection of the 
monoclonal antibody ibritumomab tiuxetan was based upon the 
observations that: ibritumomab tiuxetan specifically recognizes and binds 
to human B-cell lines and normal human peripheral blood lymphocytes in 
the same relative proportion as the highly characterized and commercially 
available anti-CD20 antibodies anti-Leu16 and B1; anti-Leu16 and B1 
were effectively inhibited by approximately equal concentrations of 
ibritumomab tiuxetan ; Ibritumomab tiuxetan exhibited no cross-reactivity 
with T-lymphocyte populations. 
 
The ibritumomab tiuxetan antibody was previously expressed by a murine 
hybridoma cell line and produced in hollow-fiber bioreactors. Currently, 
ibritumomab tiuxetan is produced in Chinese hamster ovary (CHO) cells 
in suspension culture. The CHO-expressed ibritumomab tiuxetan antibody 
differs from the murine hybridoma product in that one amino acid (at 
position 238 in the heavy chain) has been changed from a lysine to a 
methionine. The CHO master Cell Bank has been fully characterized and 
found to be negative for mycoplasma, infectious virus, and replicating 
viruses. Types A and C retroviral particles were observed by electron 
microscopy. 
 
5.7.2. Investigational Drug Nomenclature 
IDEC Pharmaceuticals code designation: IDEC-Y2B8 (IDEC 106); IDEC- 
2B8-MX-DTP (IDEC-129), IDEC-In2B8 (IDEC-105) 
Generic name: 90Y-ibritumomab tiuxetan, 111In-ibritumomab tiuxetan 
IND numbers: BB-IND 4850 – IDEC-Y2B8/IDEC-In2B8 
MF number: BB-MF – IDEC-Y2B8/IDEC-In2B8 
 
5.7.3. Clinical Formulation 
For a complete description of the preparation and dispensing of 90Y and 
111I-Ibritumomab tiuxetan, please refer to Appendix G. The radiolabeling 
kit is provided by Biogen Idec, Inc.. and all compartments are tested to be 
sterile and pyrogen-free. The kit consists of the following components: 
• 2 mL glass vial containing 2 mL (3.2 mg) of IDEC-Y2B8-MX- 
DTPA at 1.6 mg/mL in low metal normal saline 
• 2 mL glass vial containing 2 mL low metal 50nM sodium acetate 
• 10 mL glass vial containing 10 mL formulation buffer (PBS 
containing 7.5% human serum albumin and 1mM DTPA, pH 7.2) 
• 10 mL glass vial (empty) 
5.7.4. Storage 
The radiolabeling kits should be stored in a secure refrigerator at 2-8C. 
Ibritumomab tiuxetan solutions are stable at 2-8C for up to 8 hours 
following preparation. Ibritumomab tiuxetan solutions are stable at 2-8C 
for up to 12 hours following preparation. Due to the relatively short half- 


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life of the 90Y and 111In isotopes, if not used soon after calibration time, 
the actual doses will have decayed and will required recalculation. 
 
5.7.5. Toxicities 
The adverse events described are summarized from the aggregated clinical 
experience with 349 patients enrolled on 5 trials and is reflected in the 
Product Information: Zevalin ™, ibritumomab tiuxetan (Biogen Idec, Inc.., 
2/02) 
 
Hematologic Toxicity: The most common side effects were hematologic. 
Hematologic toxicity was transient and reversible. 61% of patients with a 
platelet count of at least 150,000 cells/ mm3 prior to therapy developed 
thrombocytopenia with a platelet count less than 50,000 cells/ mm3; 
median 41,000 cells/ mm3; 57% of patients developed neutropenia with an 
absolute neutrophil count (ANC) of less than 1000 cells/ mm3 (median  
800 cells/ mm3). In patients with mild thrombocytopenia at baseline 
(platelet count of 100,000 to 149,000 cells/ mm3), 78% developed severe 
thrombocytopenia (median platelet count 24,000 cells/ mm3) and 74% 
developed severe neutropenia (median ANC 600 cells/ mm3). Median time 
to platelet nadir was 53 days with a median duration of 35 days; median 
ANC nadir was at 62 days with a median duration of 22 days. Twenty-two 
percent of patients received platelet transfusions; 20% received red blood 
cell transfusions; 13% received filgrastim; and 8% received erythropoietin. 
Severe cytopenia extended beyond 12 weeks after administration              
of ibritumomab tiuxetan in less than 5% of patients. 
 
Ibritumomab tiuxetan should not be administered to patients with 25% or 
greater lymphoma marrow involvement and/or impaired bone marrow 
reserve (prior myeloablative therapies); platelet count less than 100,000 
cells/ mm3; neutrophil count less than 1500 cells/ mm3; bone marrow with 
15% or less cellularity or marked reduction in bone marrow precursors; or 
patients with a history of failed stem cell collection. Ibritumomab tiuxetan 
therapy should not be considered in patients with a platelet count of less 
than 100,000 cells/ mm3; dose reduction is required in patients with 
platelet counts of 100,000 to 150,000 cells/ mm3. 
 
In a Phase I/II study of n=51 patients 25 median nadirs for the 0.4 mCi/kg 
dose group were 50,000/mm3 platelets, 1100 /mm3 granulocytes and 9.9 
g/dL hemoglobin. For patients in the 0.4 mCi/kg group whose nadirs fell 
below 50,000/mm3 platelets, 1100/mm3 granulocytes or 9.9 g/dL 
hemoglobin, the median time to recovery for these values was 14 days, 
10.5 days, and 9.5 days, respectively. Five patients (10%) developed 
platelet nadirs <10,000/mm3. Fourteen patients (27%) developed 
granulocyte nadirs <500/mm3. Six patients received red blood cell 
transfusions, 3 received granulocyte colony-stimulating factor, and 10 


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patients received platelet transfusions. A significant correlation was noted 
between percent bone marrow involvement with NHL at baseline and 
hematologic toxicity. 
 
Secondary Malignancies: Three cases of acute myelogenous leukemia, 2 
cases of myelodysplastic syndrome, and 1 case of a grade 1 meningioma 
were reported. 
Cardiovascular effects: Hypotension was reported in 6% of patients and 
was grade 3/4 in 1%; peripheral edema was reported in 8% and was grade 
3/4 in 1%. 
Central nervous system: The following nervous system adverse events 
were reported (% all grades, % grade 3/4): asthenia (43%, 3%), headache 
(12%, 1%), dizziness (10%, less than 1%), and insomnia (5%, 0%) 
Gastrointestinal effects: The following gastrointestinal adverse events were 
reported (% all grades, % grade 3/4): nausea (31%, 1%), abdominal pain 
(16%, 3%), vomiting (12%, 0%), throat irritation (10%, 0%), diarrhea 
(9%, less than 1%), anorexia (8%, 0%), abdominal enlargement (5%, 0%), 
and constipation (5%, 0%). 
Nausea, abdominal pain, and anorexia have been described by some non- 
Hodgkin's lymphoma patients (less than 10%) during or following the 
radioimmunotherapy protocol 25. Some of these effects have been 
reported with rituximab mono-immunotherapy, and the contributing role 
of rituximab pretreatment is unclear. 
Increases in serum bilirubin have been observed occasionally following 
the radioimmunotherapy protocol 25. There have been no reports of 
clinical hepatotoxicity. 
Respiratory effects: The following respiratory adverse events were 
reported (% all grades, % grade 3/4): dyspnea (14%, 2%), increased cough 
(10%, 0%), rhinitis (6%, 0%), and bronchospasm (5%, 0%) 
Dermatologic effects: The following dermatologic adverse events were 
reported (% all grades, % grade 3/4): pruritus (9%, less than 1%), rash 
(8%, less than 1%), flushing (6%, 0%), and angioedema (5%, less than 
1%). 
Flushing, pruritus, and urticaria have been observed in some non- 
Hodgkin's lymphoma patients (less than 10%) during or following the 
radioimmunotherapy protocol 25. These effects have been reported during 
rituximab mono-immunotherapy; the contribution of rituximab 
pretreatment is unclear. 


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Infectious Complications: In clinical trials (n=349), 29% of patients 
developed infections during the first 3 months after receiving ibritumomab 
tiuxetan therapy. Serious infections developed in 3% of patients and life- 
threatening infections developed in 2% of patients. In long-term follow-up 
from 3 months to 4 years after ibritumomab tiuxetan therapy, infections 
developed in 6% of patients with 2% serious infections and 1% life- 
threatening infections.31 
Musculoskeletal effects: The following musculoskeletal adverse events 
were reported (% all grades, % grade 3/4): back pain (8%, 1%), arthralgia 
(7%, 1%), myalgia (7%, less than 1%). 
Back pain and arthralgia have been described by some non- Hodgkin's 
lymphoma patients (less than 10%) during or following the 
radioimmunotherapy protocol 25. These effects have been reported with 
rituximab monoimmunotherapy, and the contributing role of rituximab 
pretreatment is unclear. 
Infusion Reactions: Fatal infusion-related reactions have occurred within 
24 hours of rituximab infusion; 80% of fatal reactions were associated 
with the first rituximab infusion. Fatal reactions were associated with a 
symptom complex that included hypoxia, pulmonary infiltrates, ARDS, 
myocardial infarction, ventricular fibrillation, or cardiogenic shock. 
Severe infusion reactions typically occur within 30 to 120 minutes after 
administration of rituximab and may include symptoms of hypotension, 
angioedema, hypoxia, and bronchospasm. 
Medications for the treatment of anaphylactic and other hypersensitivity 
reactions should be available. Administration of rituximab and Indium- 
111 or Yttrium-90 ibritumomab tiuxetan should be discontinued and 
medical treatment should be administered to patients who develop severe 
infusion reactions. 
In clinical trials (n=349), allergic reactions occurred in 2% of patients and 
were severe or life threatening in 1%, and severe or life-threatening apnea 
occurred in 1% of patients. Angioedema occurred in 5% of patients and 
was severe or life- threatening angioedema in less than 1% of patients; 
urticaria occurred in 4% of patients and was severe in less than 1% of 
patients. 
Decreases in immunoglobulin levels (by at least 50%) have occurred 
rarely after therapy 25. 
Geriatric Patients: In clinical trials (n=349), there were no differences in 
safety or effectiveness between patients 65 years of age and over (n=132), 
patients 75 years of age and over (n=41), and younger patients; greater 


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sensitivity of some older patients cannot be ruled out (Prod Info 
Zevalin(TM), 2002). 
 
 
 
 
Dosimetry data collected from 56 patients in a phase I/II study were used 
to estimate the radiation dose to normal organs and bone marrow from 
90Y-ibritumomab tiuxetan treatment. Patients received 111In-ibritumomab 
tiuxetan on Day 0, followed by a therapeutic dose of 90Y-ibritumomab 
tiuxetan on Day 7. Following administration of 111In-ibritumomab tiuxetan, 
periodic whole body images were performed acquiring anterior and 
posterior images. Time-activity curves for each organ were derived by 
drawing regions of interest. From the area under the curve, residence times 
were determined and entered into the MIRDOSE3 computer software 
program to estimate absorbed radiation dose of 90Y-ibritumomab tiuxetan 
to each organ. An additional centralized dosimetry analysis was performed 
subsequently to provide a consistent analysis of data collected from the 7 
clinical sites where the study was performed. In all patients, normal organ 
and red marrow radiation doses were estimated to be well under the 
protocol-defined upper limit of 2000 cGy and 300 cGy, respectively. 
Patients with spleen involvement by lymphoma were allowed to exceed 
the 2000 cGy upper limit. Estimated median tumor absorbed dose as 
determined by data in 18 tumors in 9 patients was 1712 cGy (range 575- 
6710). The estimated absorbed radiation dose to organs, by dosing group, 
is shown in the Table below. 
Estimated 90Yttrium (0.4 mCi/kg) Absorbed Radiation Dose to 
Organs (N=30) 
Liver 
Spleen 
Lungs 
Bladder 
Wall 
Red 
Marrow 
Bone 
Surfaces 
Kidneys 
All 
Other 
Organs 
Patients 
(N) 
35 
30 
35 
35 
35 
35 
35 
35 
Median 
(cGy) 
358 
709 
275 
73 
63 
56 
43 
43 
Range 
173- 
300- 
136- 
38- 
30- 
28- 
24- 
24- 
(cGy) 
779 
2448 
442 
158 
120 
96 
61 
61 
 
 
 
 
5.8Darbepoetin alfa 


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5.8.1 Other Names: 
Aranesp™ 
 
5.8.2 Description: 
Darbepoetin alfa is an erythropoiesis stimulating protein closely related to 
erythropoietin that is produced in Chinese hamster ovary (CHO) cells by 
recombinant DNA technology. Darbepoetin alfa is a 165-amino acid 
protein that differs from recombinant human erythropoietin in containing  
5 N-linked oligosaccharide chains, whereas recombinant human 
erythropoietin contains 3. The 2 additional N-glycosylation sites result 
from amino acid substitutions in the erythropoietin peptide backbone. The 
additional carbohydrate chains increase the approximate molecular weight 
of the glycoprotein from 30,000 to 37,000 daltons. Because of this 
increased carbohydrate content, darbepoetin alfa has a 3-fold longer 
circulating mean residence time and 3- to 4-fold greater biological activity 
in animal models compared with rHuEPO. Details of these clinical trials 
as well as the chemistry, pre-clinical pharmacology, pharmacokinetics and 
toxicology of darbepoetin alfa are contained in the darbepoetin alfa 
investigator’s brochure. 
 
5.8.3 Packaging and Formulation: 
HSA-free (polysorbate) darbepoetin alfa will be manufactured and 
packaged by Amgen. Darbepoetin alfa will be provided as a clear, 
colorless, sterile protein solution containing x µg of darbepoetin alfa per 
mL (to be defined by Amgen) and the following excipients: 0.05 mg 
polysorbate 80, 2.12 mg sodium phosphate monobasic monohydrate, 0.66 
mg sodium phosphate dibasic anhydrous, and 8.18 mg sodium chloride in 
Water for Injection, USP (per 1 mL) at pH 6.2 ± 0.2. The vials supplied 
will contain approximately 1.0 mL of study medication and are for single- 
dose use only. 
 
5.8.4 Labeling: 
Information presented on the label for study medication will comply with 
the local regulatory requirements. 
 
5.8.5 Storage Conditions and Stability: 
The supplied darbepoetin alfa must be stored in a refrigerator. The 
stability of darbepoetin alfa has been demonstrated for at least 24 months 
when stored at a temperature between 2° to 8°C (36° to 46°F). Further 
stability testing is ongoing. Exposure to temperatures above or below this 
range and vigorous shaking should be avoided because this may denature 
the protein. Vials of darbepoetin alfa must not be used if any particulate 
matter or discoloration is observed. 


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5.8.6 Expiration Dating: 
As per standard practice for experimental biologic pharmaceuticals, 
Amgen will conduct periodic stability assays to monitor product stability 
and determine appropriate expiration dating of the study drug. The 
appropriate Amgen representative shall communicate this information to 
the investigator. 
 
5.8.7 Darbepoetin alfa (Aranesp®) will be administered at a dose of 300 
micrograms (mcg) every 3 weeks for anemic patients. Anemia will be 
defined as Hgb< 11.0 g/dL. Non-Anemic patients (Hgb 11.0gm/dL) will 
be monitored and initiate Darbepoetin alfa if they become anemic. 
 
5.8.8 Dose Adjustments: 
• Dose escalation is permitted after 6 weeks (2 doses). The dose should 
be escalated to 500mcg q3w if the Hgb remains below 10.0 g/dL and 
the increase in Hgb from baseline is less than 1.0 g/dL after 6 weeks. 
Physician discretion regarding dose escalation should be exercised if 
the Hgb is above 10g/dL; for example, if after 6 weeks of treatment the 
Hgb is below the baseline value. 
• The dose should should be held if the Hgb is ≥ 11.5 g/dl. A target 
hemoglobin of 11-11.5 g/dl is sought. 
• Any other dose modifications should be made in accordance with the 
modified Aranesp® package insert as follows: 
o If Hgb increases by more than 1.0 g/dL in a 2-week period (or 
1.5 g/dL in a 3-week period) immediately preceding the next 
dose, the dose should be reduced by approximately 40%. 
o If Hgb ≥ 11.5 g/dl at the time of the next dose, the planned 
doses should be temporarily withheld until the Hgb falls to less 
than 11.0 g/dL. At this point Aranesp® should be reinitiated at 
a dose approximately 40% below the previous dose. 
 
5.8.9 Overdose: 
There is no clinical experience of overdose with darbepoetin alfa. 
 
5.8.10 Preparation and Administration: 
Using aseptic techniques, attach a sterile needle to a sterile syringe. 
Remove the flip top from the vial containing darbepoetin alfa and wipe the 
septum with a disinfectant. Insert the needle into the vial, and withdraw 
the desired volume of solution into the syringe. 
 
• Do not shake darbepoetin alfa. Vigorous shaking may denature 
darbepoetin alfa, rendering it biologically inactive. 


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• Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration. Do not 
use any vials exhibiting particulate matter or discoloration. 
 
• Do not dilute darbepoetin alfa. 
 
• Do not administer darbepoetin alfa in conjunction with other drug 
solutions. 
 
• Darbepoetin alfa is packaged in single-use vials and contains no 
preservative. Discard any unused portion. Do not pool unused  
portions. 
 
5.8.11 Availability: 
Darbepoetin alfa is being supplied by Amgen, Inc. 
 
5.8.12 Drug Shipment, Re-Supply, and return: 
A completed and signed Drug Request Form must be faxed, at least 3 days 
prior to the expected delivery date, to Clinical Logistics, Amgen, Inc., 
805-499-9697. The study drug will be shipped to the investigator's 
institution; the quantity amount and condition of the drug received should 
be documented on the proof of receipt letter. The proof of receipt letter 
should be faxed to Amgen Clinical Logistics at the number indicated on 
the letter and the original retained in the pharmacy files. 
 
At the end of the study, or as directed, all study drug vials, including 
unused, partially used, or empty vials, will be returned to Amgen. The 
vials should be counted and placed in a box clearly marked with 
EXTRAMURAL on the outside of the box and sealed with tamper evident 
tape. Accompanying paperwork should be attached to the outside of the 
box. Ship to: 
Amgen Inc. 
Returned Clinical Drug, Room 124A 
One Amgen Center Drive 
Thousand Oaks, CA 91320. 
 
5.8.13 Toxicity: 
Aranesp™ is contraindicated in patients with: 
• uncontrolled hypertension 
 
• known hypersensitivity to the active substance or any of the 
excipients 


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5.8.14 Potential risks and discomforts: 
Darbepoetin alfa is generally well tolerated. Some of the side effects 
reported in clinical studies were in subjects with kidney disease, dialysis 
treatment, or cancer with and without chemotherapy, and may not have 
been not be due to darbepoetin alfa treatment. These events were more 
common in subjects with chronic kidney disease than in subjects with 
cancer. 
 
Darbepoetin alfa injections can be associated with stinging at the injection 
site, and rare allergic reactions (e.g., skin rash, itching and hives or more 
serious allergic reactions). There is a possibility that darbepoetin alfa may 
be associated with an increased risk of cardiac events (e.g. heart attack), 
circulatory events (worsening of blood pressure, stroke, or blood clots) 
and seizure or even death. The higher risk of cardiac events may be 
associated with higher hemoglobin and/or higher rates of rise of 
hemoglobin. In one Epoetin alfa study in subjects with chronic kidney 
disease receiving dialysis, who also suffered from heart disease, there was 
a higher risk of death and thrombosis associated for those subjects who 
were assigned to maintain hemoglobin levels of 14.0 ± 1.0 g/dL. The 
reason for the increased death rate is not understood. Despite the overall 
outcome of the study, within each group, higher hemoglobin values were 
associated with better survival. 
 
5.8.15 Allergic responses: 
There may be a risk of developing an allergic reaction to darbepoetin alfa. 
Rare allergic symptoms following darbepoetin alfa treatment (eg, skin 
rash, itching and hives) have been reported, primarily in chronic renal 
failure patients. It is possible for more serious allergic reactions to occur. 
These possible reactions include a whole body rash, shortness of breath, 
wheezing, sudden drop in blood pressure, swelling around the mouth or 
eyes, rapid pulse or sweating. 
 
5.8.16 Pregnancy and lactation: 
There are no adequate and well-controlled studies in pregnant women 
(pregnancy category C), therefore, darbepoetin alfa should not be used 
during pregnancy. In addition, it is not known if darbepoetin alfa is 
excreted in human milk, therefore, lactating mothers should stop lactating 
in order to take part in this study. 
 
5.8.17 Drug Interactions: 
No formal drug interaction studies of darbepoetin alfa with other 
medications commonly used in CRF patients have been performed. 
 
5.8.18 Geriatric Use: 
Of the 1598 CRF patients in clinical studies of darbepoetin alfa, 42% were 


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age 65 and over, while 15% were 75 and over. No overall differences in 
safety or efficacy were observed between these patients and younger 
patients, but greater sensitivity of some older individuals cannot be ruled 
out. 
 
 
 
 
 
 
6 CRITERIA FOR PATIENT ELIGIBILITY 
 
Please note copies of source documentation confirming eligibility for patients 
enrolling at outside institutions must be provided to MSKCC at the time of 
registration. Please fax to: 212-557-0786 (see section 15) 
 
6.1. Patient Inclusion Criteria 
6.1.1 Patients must have reached their 60th birthday by the time of enrollment. 
Patients age 60-65 must be deemed ASCT ineligible at the time of 
enrollment. 
6.1.2 Patients must have an initial diagnosis of diffuse large B-cell lymphoma that 
is confirmed by one of the hematopathologists at the treating institution. Any 
of the following subtypes of DLBCL as described in the WHO Classification 
33 are eligible: centroblastic, immunoblastic, T-cell/histiocyte-rich, 
lymphomatoid granulomatosis type, anaplastic large B-cell, plasmablastic, 
mediastinal, or intravascular large B-cell lymphoma. Lymphomas with 
discordant histology (small cells in the bone marrow) and a DLBCL 
diagnosis will be eligible for enrollment. 
All patients must have an initial 
diagnostic specimen that is CD20-positive. 
6.1.3 Patients must have at least Ann Arbor Stage II disease and not have disease 
confined to an involved field radiation port. 
6.1.4 Patients must have high-intermediate or high-risk DLBCL as defined by an 
Age-Adjusted IPI (aaIPI) score of 2 or 3 (with 1 point each assigned for a 
ECOG>1 / KPS 70%, LDH>1x normal, and Stage III or IV) 
6.1.5 Patients must not have received prior chemotherapy, biologic therapy, or 
radiation therapy. Patients who have received steroids for 14 consecutive 
days are eligible.  Patients with a history of prior intravenous contrast 
allergy are permitted to receive steroids as a premedication. However, 
patients who have already received a single cycle of R-CHOP at standard 
dosages and otherwise meet all eligibility requirements will be allowed 
enrollment. These patients will start therapy with cycle number two of R- 
CHOP provided all pretreatment evaluations meet protocol criteria. 
6.1.6 Karnofsky performance status of at least 50% (see Appendix B). 


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6.1.7 Patients must have a total bilirubin of 2.0 mg/dL or less at the time of study 
enrollment. The patient may have a bilirubin >2.0 mg/dL if he/she has a 
history of Gilbert’s disease. 
6.1.8 Patients must have adequate renal function defined as a serum creatinine of 
1.5 mg/dL or less at the time of study enrollment. Patients with a serum 
creatinine of 1.6 mg/dL or greater are still eligible if their 12 or 24-hour 
creatinine clearance is measured at >50 mL/min. Patients who do not meet 
either criteria but have renal insufficiency that is believed to be directly 
caused by lymphomatous involvement of the kidneys or renal collecting 
system are eligible. 
6.1.9 Patients must have a cardiac ejection fraction of 50% or greater as 
determined by echocardiogram. 
6.1.10 Patients must have HIV antibody test drawn within 4-6 weeks of 
enrollment; results may be pending provided there is no history of known 
risk factors or clinical suspicion of HIV. 
6.1.11 Patients must have no concurrent uncontrolled medical problems that 
would preclude administration of chemotherapy or radioimmunotherapy. 
6.1.12 Patients receiving therapeutic doses of Coumadin may be considered 
eligible for therapy. Given the potential for thrombocytopenia on this study, 
the patient’s coagulation studies will be closely monitored. (See section 9.0) 
6.1.13 Patients must have no prior history of radiotherapy or chemotherapy for a 
cancer diagnosis within the last 5 years. 
6.1.14 Patients must have bi-dimensionally measurable disease at the time of 
study entry, defined as at least one lymph node 2.0 x 2.0 cm on physical 
examination, CT scan, or PET scan. 
6.1.15 Bone Marrow cellularity at entry must be greater than 15% as determined 
by a treating institution’s hematopathologists or specified as normocellular 
(~40%) or hyper cellular on the bone marrow biopsy report. 
6.1.16 Patients must have no known brain or leptomeningeal metastases at the 
time of study enrollment. 
6.1.17 Patients must be capable of providing written informed consent. 
 
6.2. Patient Exclusion Criteria 
6.2.1 Patients who have not reached their 60th birthday at the time of study entry 
or who are ages 60-65 and deemed potential future transplant candidates. 
6.2.2 Patients with any lymphoma subtype other than diffuse large B-cell 
lymphoma, discordant lymphomas with a DLBCL component are ineligible. 
Composite lymphomas and patients with primary effusion lymphomas are 
ineligible. 
6.2.3 Patients with Stage I or limited Stage II disease (i.e., disease confined to an 
involved field radiation port). 
6.2.4 Patients with Low or Low-Intermediate risk disease as defined by aaIPI 
scores of 0 or 1. 
6.2.5 Patients who have received prior treatment of any kind for their lymphoma, 
including chemotherapy, radiation therapy, or biologic therapy. For the 


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purposes of this trial, corticosteroids will not be considered prior therapy. 
However, patients who have already received a single cycle of R-CHOP at 
standard dosages and otherwise meet all eligibility requirements will be 
allowed enrollment. These patients will start therapy with cycle number two 
of R-CHOP provided all pretreatment evaluations meet protocol criteria. 
Patients with a history of prior severe intravenous contrast allergy are 
permitted to receive steroids as a premedication. 
6.2.6 Karnofsky performance status of less than 50%. 
6.2.7 Patients with a total bilirubin > 2.0 mg/dL without a history of Gilbert’s 
disease. 
6.2.8 Patients with a serum creatinine >1.5 mg/dL or creatinine clearance <50 
mL/min as a result of medical renal disease. 
6.2.9 Cardiac ejection fraction of <50% by echocardiogram. 
6.2.10 HIV-positivity. 
6.2.11 Concurrent uncontrolled medical problems (including uncontrolled 
hypertension) 
6.2.12 Unstable angina pectoris, recent acute myocardial infarction (within 3 
months of randomization), or congestive heart failure (> NYHA class II) 
6.2.13 Subjects with an active seizure disorder. Subjects with a previous history 
of seizure disorders will be eligible for the study, if they have had no 
evidence of seizure activity, and they have been free of anti-seizure 
medication for the previous 5 years. 
6.2.14 Patients with a history of radiotherapy or chemotherapy for a cancer 
diagnosis within the last 5 years. 
6.2.15 Patients with less than 15% bone marrow cellularity as determined by 
MSKCC hematopathologists. 
6.2.16 Brain or leptomeningeal metastases at the time of study enrollment 
6.2.17 Patients incapable of providing written informed consent. 
 
 
7 RECRUITMENT PLAN 
 
Patients will be recruited to this trial by members of the Lymphoma Service listed as 
Clinical Investigators at each participating institutions. Information regarding this 
study will be made available on the MSKCC Internet Web site. This study will be 
offered to all eligible patients referred to MSKCC, regardless of gender or ethnicity. 
Clinical Investigators on the study are expected to discuss with the patient his/her 
diagnosis, prognosis, risks and benefits of study participation, as well as treatment 
alternatives (i.e., standard treatment options) and their risks and benefits. All patients 
will be required to sign a statement of informed consent that conforms to local IRB 
guidelines. 
 
8 PRETREATMENT EVALUATION 


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8.1. History and physical examination including height, weight, and vital signs within 
7 days of study entry. 
8.2. Karnofsky performance status within 7 days of study entry. 
8.3. Complete blood count with differential within 7 days of study entry. 
8.4. Screening profile (include electrolytes, BUN, creatinine, total bilirubin, AST, 
alkaline phosphatase) and serum lactate dehydrogenase (LDH) within 7 days of 
study entry. Erythropoietin level, Ferritin, Iron, TIBC, B12 and Folate levels 
within 4-6 weeks of entry. 
8.5. Completion of a FACT-Anemia QOL scale within 7 days of study entry. 
Patients will self-administer the FACT-anemia test. See appendix K. 
8.6. CT scans of chest, abdomen, and pelvis within 4-6 weeks of study entry. If a 
patient has palpable neck adenopathy, a CT scan of the neck must also be 
performed within the same time period. 
8.7. PET scan within 4-6 weeks of study entry. 
8.8. Echocardiogram within 4-6 weeks of study entry. 
8.9. EKG 
8.10. 
12 or 24-hour urine collection for creatinine clearance for patients with a 
creatinine >1.5 mg/dL. 
8.11. 
HIV-1 antibodies drawn within 4-6 weeks of study entry. 
8.12. 
Unilateral bone marrow biopsies within 4-6 weeks of study entry. 
8.13. 
Peripheral blood (MSKCC Only) – nine 2-mL purple top tubes: 2 for 
minimal residual disease studies (to Dr. Zelenetz’ lab, K1011, see Appendix C), 7 
tubes for progenitor cell studies (to Dr. Moore’s lab, RRL717, see Appendix D) 
8.14. 
Bone marrow aspirate within 4-6 weeks of study entry (MSKCC Only) – 
five 2-mL pulls in purple top tubes. Two tubes will be sent to Dr. Zelenetz’ lab in 
K1011 (see Appendix C). Two tubes will be sent to Dr. Moore’s lab in RRL 717 
for progenitor cell studies (see Appendix D) and one tube will be sent to the flow 
cytometry lab for CD34+ count. 
8.15. 
Additionally, bone marrow evaluation for cytogenetics must be performed 
prior to RIT (preferably at baseline study, although post RCHOP is also 
acceptable). Abnormal cytogenetics by karyotype analysis that are consistent 
with myelodysplasia will exclude patients from radio-immunotherapy. (All 
Institutions) 
8.16. 
Patients being enrolled after previously receiving a single cycle of 
RCHOP will not be required to have the following tests: baseline minimal 
residual disease studies, progenitor cell analysis, CD34 Flow study. Minimal 
residual disease studies may be omitted for the duration of the trial. Progenitor 
cell analysis may commence following cycle #1 as dictated in the trial. 
 
9 TREATMENT PLAN 
9.1. Chemotherapy Phase 
9.1.1 R-CHOP Chemotherapy 
 
R-CHOP will be given at the following doses: 
• Rituximab 375 mg/m2 IVPB with premedications (see below) 


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• Cyclophosphamide 750 mg/m2 IVPB 
• Doxorubicin 50 mg/m2 IV push 
• Vincristine 1.4 mg/m2 IV push (not to exceed 2 mg per cycle) 
• Prednisone 100 mg po qd, either from Days 1-5 or 2-6 
 
The first Rituximab dose will be given over 3-5 hours to minimize 
the risk of infusion-related reactions. Subsequent doses may be 
given over a minimum of 2 hours as tolerated. 
 
Premedications for Rituximab include acetaminophen 650 mg po 
and diphenhydramine 50 mg IVPB given at least 30 minutes prior 
to infusion. Chlorpheniramine 4 mg po may be substituted for 
diphenhydramine. 
 
R-C HOP will be repeated every 21 days for a total of 6 cycles. The 
next cycle of R-CHOP can be given when the absolute neutrophil 
count is at least 1000/mm3 and the platelet is at least 75,000/mm3. 
 
Tumor lysis prophylaxis: During cycle one only, prophylactic 
Allopurinol is recommended to prevent tumor lysis syndrome in 
patients with high tumor burden (bone marrow involvement or 
LDH>500). Patients should receive 600mg PO 24 hrs. prior to the 
first rituximab, and continue 300 mg po daily for at least 7 days 
after cycle #1 of R-CHOP. Additional measures such as IV 
hydration or urinary alkalinization may be implemented as 
clinically necessary. 
 
Anti-emetic medications, including dexamethasone, will be given 
as per hospital guidelines on Day 1 of each cycle. 
 
Patients with B12 or Folate deficiency should be commenced on 
appropriate repletion therapy (B12 1000 mcg SQ q month, folic 
acid 1 mg po qd). Patients with iron deficiency (eg. Ferritin <10 
mcg/L; TSAT<15%, low iron, and high TIBC) should commence 
FeSO4 supplementation. Dosing and route as per treating 
physician. 
 
For patients requiring therapeutic anticoagulation with coumadin 
while on study, PT/PTT/INR studies should be followed closely 
with appropriate adjustments made by the treating physician. 
Patients should be considered for low-molecular heparin when 
appropriate, given the potential for fewer drug interactions. 
 
Granulocyte colony-stimulating factor will be given with each 
cycle. Neulasta 6mg SQ 24 hours after chemotherapy is preferred 


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(at MSKCC), although GCSF at 300 g for patients <70kg and 480 
g for patients 70 kg SQ starting at day 5 and continuing to day 
12 remains acceptable. Doses may be adjusted at the discretion of 
the treating physician and should follow institutional procedure. 
 
Darbepoetin alfa (Aranesp®) will be administered at a dose of 300 
micrograms (mcg) every 3 weeks for anemic patients. Anemia 
will be defined as Hgb< 11.0 g/dL. Non-Anemic patients (Hgb 
11.0gm/dL) will be monitored and initiate Darbepoetin alfa if they 
become anemic. 
 
Dose Adjustments: 
• Dose escalation is permitted after 6 weeks (2 doses). The 
dose should be escalated to 500mcg q3w if the Hgb 
remains below 10.0 g/dL and the increase in Hgb from 
baseline is less than 1.0 g/dL after 6 weeks. Physician 
discretion regarding dose escalation should be exercised if 
the Hgb is above 10g/dL; for example, if after 6 weeks of 
treatment the Hgb is below the baseline value. 
• The dose should not be escalated if the Hgb is within the 
Hgb target range of 11-11.5 g/dL. 
• Any other dose modifications should be made in 
accordance with the Aranesp® package insert as follows: 
o If Hgb increases by more than 1.0 g/dL in a 2-week 
period (or 1.5 g/dL in a 3-week period) immediately 
preceding the next dose, the dose should be reduced 
by approximately 40%. 
• If Hgb ≥ 11.5 g/dl at the time of the next dose, the planned 
doses should be temporarily withheld until the Hgb falls to 
less than 11.0 g/dL. At this point Aranesp® should be 
reinitiated at a dose approximately 40% below the previous 
dose. 
• The following events should prompt discontinuation of 
darbepoetin alfa: 
o Uncontrolled hypertension 
o Deep vein thrombosis 
 
Central Nervous System prophylaxis is recommended for all 
individuals with 1) evidence of bone marrow involvement with 
large cells on blind bone marrow biopsy, 2) radiographic evidence 
of more than one site of lytic bone involvement, or evidence of 
bone marrow involvement, 3) testicular involvement, 4) two or 
more sites of non-contiguous extranodal involvement. Either of 
the following two regimens, or a combination thereof, is 
recommended: 


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• Methotrexate, 12 mg administered intrathecally weekly for 
6 treatments during the R-CHOP course, 
• Cytasine Arabinoside, 60 mg administered intrathecally 
weekly for 6 treatments during the R-CHOP course. 
 
9.1.2 R-CHOP Schedule/Dose Modifications 
• If a patient has an absolute neutrophil count <1000/mm3 or platelet 
count of <100,000/mm3 on a scheduled treatment day, or if the 
patient develops febrile neutropenia, the next cycle of R-CHOP 
may be delayed up to 14 days as indicated. The retreatment platelet 
count should be consistent with each individual institutional 
guidelines (with a minimum cut-off of at least >75,000/mm3. ) 
 
• Vincristine doses may be reduced by 50% for Grade 2 
neurotoxicity and may be discontinued for Grade 3 or 4 
neurotoxicity 
 
• Dose reductions to R-CHOP chemotherapy for comorbidity or 
potential toxicity should be made at the discretion of the treating 
physician and may occur with Cycle #1 if necessary. Vincristine 
may be omitted in entirety from cycle 1 if potential GI toxicity 
outweighs potential benefit in the opinion of the treating MD. 
Prednisone may be given for control of symptoms prior to the start 
of chemotherapy (maximum 14 consecutive days). 
 
9.2. Radioimmunotherapy Phase 
9.2.1 Criteria to Proceed to Radioimmunotherapy Phase of Study 
• Patients must have < 25% intratrabecular space bone marrow 
involvement on a post-R-CHOP bilateral bone marrow biopsy, to be 
performed 4-6 weeks post R-CHOP and within 4 weeks of starting the 
radioimmunotherapy phase. 
• Patients must have greater than 15% cellularity of bone marrow as 
determined by MSKCC hematopathologists 
• Patients must have baseline cytogenetics that is not consistent with 
myelodysplasia (performed on a bone marrow aspiration prior to the 
initiation of Radioimmunotherapy). FISH abnormalities associated 
with MDS, whether or not morphologic or cytogenetic evidence of 
MDS is present, will also preclude Phase II treatment with RIT. These 
patients will remain on study to be followed for outcome. 
• Patients must have post-R-CHOP restaging studies within 4-5 weeks 
of completing R-CHOP showing that their disease has not progressed 
from the time of study entry. Patients with confirmed or unconfirmed 
complete response and patients with partial responses who are not 
transplant eligible are allowed to proceed. 


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• Pre-radioimmunotherapy phase Karnofsky performance status of at 
least 60%. 
• Patients must not have received any pegfilgrastim (or G-CSF) within 
the 2 weeks (14 days) and no Darbepoetin alfa within the 21 days (3 
weeks) preceding day 0 of the radioimmunotherapy phase. 
o Darbepoetin Alfa may be administered during the 
radioimmunotherapy phase of treatment starting week #3 at the 
discretion of the treating physician. Drug will be supplied by 
Amgen for this purpose. The protocol does not mandate 
colony stimulating factors during the RIT phase. 
• Patients must have acceptable hematologic function within 2 weeks of 
receiving the first loading dose of rituximab. Acceptable hematologic 
function is defined as an absolute neutrophil count 1500/mm3, 
hemoglobin 8.0 g/dL, and platelets 100,000/mm3 in the absence of 
hematopoietic growth factors for at least 14 days. 
• Patients must have no evidence of clinically significant pleural 
effusions prior to receiving the first loading dose of rituximab. 
9.2.2 Rituximab and 111In-ibritumomab tiuxetan/90Y-ibritumomab tiuxetan 
• Day 0 of the Radioimmunotherapy Phase must begin between 6 and 9 
weeks (42-63 days) after Day 1 of the last cycle of R-CHOP. 
• Rituximab administration: 
See Rituxan Package Insert (Appendix A). 
• The CBC drawn on Day 0 will serve as the reference CBC for the 
dosing of the 90Y ibritumomab tiuxetan on Day 7. An additional CBC 
should not be drawn on day 7. 
• On Day 0 of the Radioimmunotherapy Phase, patients will be 
premedicated with acetaminophen 650 mg po, diphenhydramine 50  
mg po or chlorpheniramine 4 mg po, and Ativan 0.5 mg IV 30 minutes 
prior to beginning of Rituximab infusion. (Patients need not receive 
any of the above premedications if there is a prior history of an adverse 
reaction to any of them.) Following this, rituximab 250 mg/m2        
will be infused. 
• On Day 0, immediately following the infusion of rituximab, patients 
will receive a fixed dose of 1.6 mg (5.0 mCi) of 111In-ibritumomab 
tiuxetan, given by slow IV push over 10 minutes. 
• On Day 0-1, 2-24 hours after infusion of 111In-ibritumomab tiuxetan, 
whole body gamma camera images will be taken. 
• On Day 2-3, 48-72 hours after infusion of 111In-ibritumomab tiuxetan, 
whole body gamma camera images will be taken. 
• On Day 5-7, 90-120 hours after infusion on 111In-ibritumomab 
tiuxetan, whole body gamma camera images will be taken, if deemed 
necessary. 
• On Day 7 of the Radioimmunotherapy Phase, a second rituximab 
infusion at a dose of 250 mg/m2 will be given, using the same pre- 


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medications. The Day 7 rituximab dose may be delayed up to Day 14 
if necessary. 
• Dose calibration settings will be determined by the Division of 
Nuclear Medicine according to the methods described in Appendix F. 
• 
90Y-ibritumomab tiuxetan will be administered immediately following 
the Day 7 rituximab infusion. Each patient will receive one therapeutic 
dose of 90Y-ibritumomab tiuxetan. For patients weighing >80 kg, a 
maximum dose of 32 mCi will be given. For patients weighing ≤80 kg 
with platelet counts ≥150,000/mm3, a dose of 0.4 mCi 90Y/kg will be 
given. For patients weighing ≤80 kg with platelet counts <150,000/ 
mm3, a dose of 0.3 mCi/kg will be given. 
• 
90Y-ibritumomab tiuxetan will be administered intravenously as a slow 
IV push over 10 minutes. The drug may be directly infused by  
stopping the flow from the IV bag and injecting the radiolabeled 
antibody directly into the infusion port. A 0.22 micron filter must be  
on line between the syringe and the infusion port. (The 0.22 micron 
filter is not provided by Biogen Idec, Inc.. Pharmaceuticals). Flush the 
line with at least 10 mL of normal saline after 90Y-ibritumomab 
tiuxetan has been infused. See Appendix G for radio incorporation 
methods. 
 
10 EVALUATION DURING TREATMENT 
10.1. 
Chemotherapy Phase (please refer to the Table below) 
10.1.1 Cycles 2-6 of R-CHOP: History and physical examination, assessment of 
Karnofsky Performance Status, complete blood count, comprehensive panel 
and LDH on Day 1 of each cycle. Transfusion requirements and adverse 
experiences will be recorded at each evaluation. 
10.1.2 Interim restaging: between cycles 4 and 5 of R-CHOP, a repeat CT scan of 
the chest, abdomen and pelvis and PET scan (if previously positive). Patients 
must have at least stable disease or better to be allowed to continue on study. 
10.1.3 Between cycles 4 and 5 (prior to cycle 5’s administration) patients will 
complete a FACT-anemia evaluation. 
 
10.2. 
Post-Chemotherapy / Pre-Radioimmunotherapy Restaging Evaluation (all 
to be done 4-5 weeks after Day 1 of the last cycle of R-CHOP) 
10.2.1 History, physical examination, and assessment of Karnofsky Performance 
Status 
10.2.2 CBC with differential, comprehensive profile, LDH 
10.2.3 CT scans of the chest, abdomen, and pelvis, and a PET scan (if previously 
positive). 
10.2.4 FACT-anemia evaluation form to be completed prior to the initiation of 
radioimmunotherapy 
10.2.5 Echocardiography and EKG evaluation 
10.2.6 Peripheral blood (MSKCC Only) – nine 2-mL purple top tubes: 2 for 
minimal residual disease studies (to Dr. Zelenetz’ lab, K1011, see Appendix 


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C), 7 tubes for progenitor cell studies (to Dr. Moore’s lab, RRL717, see 
Appendix D). 
10.2.7 Bone marrow aspirate studies (MSKCC Only) - five 2-mL pulls of bone 
marrow aspirate in purple top tubes will be drawn. Two tubes will be sent to 
Dr. Zelenetz’ lab in K1011 (see Appendix C). Two tubes will be sent to Dr. 
Moore’s lab in RRL 717 for progenitor cell studies (see Appendix D) and 
one tube will be sent to the flow cytometry lab for CD34+ count. 
10.2.8 Bone marrow biopsy demonstrating ≤25% BM involvement. A bilateral 
bone marrow biopsy is preferred; if a unilateral bone marrow biopsy reveals 
<10% intratrabecular space involvement, a contralateral biopsy need not be 
performed. This is mandatory at all institutions 
10.2.9 Bone marrow cellularity must be greater than 15% in order to proceed 
with Zevalin therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemotherapy Phase (I) 
Base- 
Line 
Cycle 
1a 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Restaging 
Cycle 
5 
Cycle 
6 
Post-R-CHOP 
/Pre-RIT 
Restagingb 
History, 
Physical,KPS 
X 
X 
X 
X 
X 
X 
X 
X 
CBC, diff 
X 
X 
X 
X 
X 
X 
X 
X 
Comp.Profile, 
LDH 
X 
X 
X 
X 
X 
X 
X 
X 
Erythropoietin 
level,   ferritin,   Fe, 
B12, Folate 
X 
HIV testing 
Xf 
FACT-anemiae 
X 
X 
X 
CT C-A-P 
X 
X 
X 
PET 
X 
X 
X 
ECHO/EKG 
X 
XC 
Peripheral 
blood 
(research) 
X 
Bone marrow 
X 


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Aspirate 
studies 
XD 
Bone 
marrow 
biopsy 
X 
X 
R-CHOP 
X 
X 
X 
X 
X 
X 
a History, Physical, KPS, and Labs must be performed within 7 days of 1st R-CHOP 
bRestaging post R-CHOP to be completed 4-5 weeks following cycle #6. 
cEchocardiography must be completed prior to initiation of radio-immunotherapy. 
dAspiration to include cytogenetic evaluation 
eself administered FACT-anemia QOL questionnaire to be completed by the patient 
fperformed within 4-6 weeks of enrollment 
 
10.3. 
Radioimmunotherapy Phase and Post-Radioimmunotherapy Monitoring 
10.3.1 Days 0-7 
10.3.2 The purpose of 111In-ibritumomab tiuxetan imaging is to evaluate the 
biodistribution of whole body gamma camera images and to assess whether 
biodistribution is acceptable to proceed with 90Y-ibritumomab tiuxetan 
administration. 
10.3.3 The biodistribution of 111In Zevalin should be assessed by a visual 
evaluation of whole body planar view anterior and posterior gamma images. 
A set of images at 48-72 hours after injection is required. To resolve 
ambiguities, optional images at other time points may be necessary. If the 
patient has an altered biodistribution, he/she will not receive 90Y 
Ibritumomab tiuxetan and will be taken off study. 
10.3.4 Expected biodistribution 
• Easily detectable uptake in the blood pool areas (including but not 
limited to the heart, major abdominal blood vessels, vascular areas of 
the head, lungs and pelvis) on the first day image, with less activity in 
the blood pool areas on the second or third day image. 
• Moderately high to high uptake in normal liver and spleen during the 
first day and the second or third day images. 
• Moderately low or very low uptake in normal kidneys, urinary bladder, 
and normal bowel on the first day image and the second or third day 
image. 
• Tumor uptake may be visualized in soft tissue as areas of increased 
intensity, and tumor bearing areas in normal organs may be seen as 
areas of increased or decreased intensity. Those patients in CR or CRu 
would not be expected to have any tumor visualized. 
10.3.5 Altered biodistribution 
• Diffuse uptake in normal lung more intense than the cardiac blood 
pool on the first day image, or more intense than the liver on the 
second or third day image. 
• Kidneys with greater intensity than the liver on the posterior view of 
the second or third day image. 


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• Intense areas of uptake throughout the normal bowel comparable to the 
liver on the second or third day images. 
10.3.6 Weeks 3-12 
• History and physical examination, including performance status, will be 
performed at monthly intervals for 3 months following 90Y-ibritumomab 
tiuxetan as indicated in the radioimmunotherapy calendar. 
• CBC with differential and platelet will be obtained weekly for 12 weeks 
following administration of 90Y-ibritumomab tiuxetan, or until the WBC, 
absolute neutrophil count, hemoglobin and platelet count have 
normalized. Transfusion requirements will be recorded at each 
evaluation. 
• Comprehensive profile and LDH will be obtained at monthly intervals 
for three months following administration of 90Y-ibritumomab tiuxetan. 
• In the event that a Grade 3 or 4 hematologic toxicity occurs at any time, 
blood samplings for followup evaluations should be performed as 
clinically indicated until the abnormality is resolved. Twice or thrice 
weekly platelet counts, or more if clinically appropriate, should be 
utilized when platelets are below 50K. 
10.3.7 Three (3) month evaluation (Week 12 or 13) 
• History and physical examination 
• Assessment of Karnofsky Performance Status 
• CBC, Comprehensive profile and LDH 
• FACT-an evaluation 
• CT scan of the chest, abdomen, and pelvis, and PET scan (if previously 
positive) 
• Repeat Echocardiogram to be performed between weeks 12-13. 
• Peripheral blood (MSKCC Only) – nine 2-mL purple top tubes: 2 for 
minimal residual disease studies (to Dr. Zelenetz’ lab, K1011, see 
Appendix C), 7 tubes for progenitor cell studies (to Dr. Moore’s lab, 
RRL717, see Appendix D) 
• Bone marrow aspirate studies (MSKCC Only) - five 2-mL pulls of bone 
marrow aspirate in purple top tubes will be drawn. Two tubes will be 
sent to Dr. Zelenetz’ lab in K1011 (see Appendix C). Two tubes will be 
sent to Dr. Moore’s lab in RRL 717 for progenitor cell studies (see 
Appendix D) and one tube will be sent to the flow cytometry lab for 
CD34+ count. 
• Bilateral bone marrow biopsy, if pre-RIT bone marrow biopsy was 
positive. 
10.3.8 Long term post-Radioimmunotherapy followup 
• The same studies listed in Section 10.3.7 are performed at 6 months 
post-radioimmunotherapy, 12 months, and every 12 months thereafter 
for 2 years for patients in continued CR or CRu. 
• Echocardiograms are not required after week12-13; PET is repeated only 
if previous study was positive and no evidence of progressive disease. 


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• A bone marrow aspirate for MRD studies will not be required if the 
patient has had less than a complete response to therapy or has relapsed. 
Bone marrow aspirate studies for MRD will be done for up to 2 years 
post-Radioimmunotherapy (MSKCC Only) - two tubes will be sent to 
Dr. Zelenetz’ lab in K1011 (see Appendix C), and peripheral blood for 
MRD will be performed for up to 5 years. 
• Peripheral blood or bone marrow aspirate for progenitor cell studies need 
not be performed. 
• A bone marrow biopsy need only be repeated if the previous biopsy was 
positive. 
• CT scans will be preformed at 3, 6, 12, 18, 24, 30, 36, 48 and 60 months 
Post RIT. 


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Pre- 
RIT* 
Radioimmunotherapy Phase (II) 
Week # 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 
12-131 
History, 
Physical,KPS 
X 
X 
X 
X 
X 
CBC, diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comp.Profile, 
LDH 
X 
X 
X 
X 
Rituxan level 
X 
CT C-A-P 
X 
X 
FACT-an 
X 
PET 
X 
X 
ECHO 
X 
X 
Bone marrow 
Aspirate 
studies 
X 
X3 
Bone  marrow 
biopsy 
X 
X4 
Peripheral 
blood 
(research) 
X 
X5 
Rituximab 250 
mg/m2 
X 
X 
90Y- 
ibritumomab 
tiuxetan 
X 
* Pre-RIT studies overlap with the post-chemotherapy/pre-RIT studies on Part I table – 
studies do not need to be duplicated. 
1 These studies are repeated every 6 months for 5 years with the following exceptions: 
Echocardiograms are not required after week12-13; PET is repeated only if previous 
study was positive and no evidence of progressive disease. 
2 Bone marrow aspirate studies will be done for progenitor cell studies and MRD at week 
12-13. At 6 months post RIT, 12 months post-RIT and yearly followup restaging periods 
for 2 years, bone marrow aspirate studies for MRD will only be performed on patients in 
continued CR. MSKCC ONLY 
3 A bone marrow biopsy need only be performed in patients with a positive bone marrow 
biopsy on pre-RIT evaluation. Once negative, repeat bone marrow biopsies are not 
required. 
4 Peripheral blood samples for cell progenitor studies and MRD studies will be performed 
at 3 months (week 12-13) and 6 months post radioimmunotherapy; subsequently, every 6 
months stating at month 6 post-radioimmunotherapy (up to 5 years), the MRD studies will 
only be performed for patients in continued CR or CRu. MSKCC ONLY 


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11 ADVERSE EXPERIENCES 
 
The toxicities of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and 
90Y-ibritumomab tiuxetan are listed in Section 5 of the protocol. 
 
11.1. 
An objective of this study is to obtain information on the safety of the 
sequential administration of R-CHOP followed by 90Y-ibritumomab tiuxetan for 
elderly patients with previously untreated DLBCL. It is the Investigator’s 
obligation to report all adverse experiences (AE’s), regardless of association with 
study drugs. 
11.2. 
Definitions of AE’s 
11.2.1 Adverse Experience: An AE is defined as any untoward medical 
occurrence in a patient administered a pharmaceutical product and does not 
necessarily have to have a causal relationship or association with the 
treatment. An AE can therefore be any unfavorable and unintended sign, 
symptom, or significant worsening of a pre-existing sign or symptom, or 
disease temporally associated with the use of a medicinal product, whether 
or not it is considered to be related to the medicinal product. Laboratory 
abnormalities should only be recorded as AE’s if they are associated with 
clinical sequelae and/or require an intervention. 
11.2.2 Serious Adverse Experience (SAE): An SAE is considered to be any 
experience occurring at any dose that results in any of the following 
outcomes: death, a life-threatening AE (at immediate risk of death from the 
experience as it occurred), in-patient hospitalization or prolongation of 
existing hospitalization, a persistent of significant disability/incapacity, or a 
congenital anomaly/birth defect. Important medical events that may not 
result in death may be considered SAE’s when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this 
definition. 
11.2.3 Expected Adverse Experience: Any AE that is identified in Section 5 is 
considered an expected AE. 
11.2.4 Unexpected Adverse Experience: Any AE, the specificity of severity of 
which is not consistent with those listed in Section 5, is considered to be 
unexpected. 
11.3. 
Reporting AE’s 
11.3.1 During the chemotherapy phase of treatment, only grade 3 and 4 toxicities 
will be recorded. During the RIT phase of treatment, all toxicities regardless 
of grade will be recorded. All AE’s (serious and non-serious), regardless of 
relationship to study drug, are to be recorded on the AE Form (grade 3/4 
toxicities) and Toxicity Form (grades 0-4) from the time of enrollment to 3 
months after the administration of radioimmunotherapy, or until the 
administration of alternative therapy for the patient’s disease, whichever 
comes first. Subsequent to this timeframe, only AE’s that are considered by 


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the Investigator to be possibly related or probably associated with the 
administration of R-CHOP or 90Y-ibritumomab tiuxetan are to be reported. 
The severity of AE’s will be recorded on the case report form using the NCI 
Common Toxicity Criteria (version 2.0). These are found in Appendix E 
and on the internet at http://ctep.info.nih.gov. Laboratory abnormalities 
should be recorded as AE’s only if they are associated with clinical sequelae 
and/or require intervention. Patient deaths at any time are to be recorded , 
with immediate notification to the lead investigator at MSKCC (death 
certificate or Death Notice to be sent) 
11.4. 
Reporting SAE’s 
11.4.1 The Investigator is required to report all SAE’s, regardless of cause or 
relationship to study drug, that come to the attention of the investigative site 
from the time of enrollment to 3 months after the administration of 
radioimmunotherapy, or until the administration of alternative therapy for  
the patient’s disease, whichever comes first. Subsequent to this timeframe, 
only SAE’s that are considered by the Investigator to be possibly related or 
probably associated with the administration of R-CHOP or 90Y-ibritumomab 
tiuxetan are to be reported. Any SAE will be reported to the local institutions 
IRB. In addition, it will need to be sent to the other participating centers to 
report to their institution’s IRB, Biogen Idec, Inc.. Pharmacovigilance and 
Amgen as soon as possible but no later than 7 days from the onset of the 
event. 
• To the local institutional review board (IRB) 
• To MSKCC (in the case of SAE’s at collaborating institutions). To 
Paul A. Hamlin, MD (PI) Fax 646-422-2164 and Brett Wegner, RSA 
Fax: 212-557-0787 
• Direct SAE reporting must be directed to Biogen Idec, Inc.. 
Pharmacovigilance at 877-866-IDEC (4332) (phone) or (617)679-2979 
(fax). 
• Direct SAE reporting must be directed to Amgen c/o International 
Clinical Safety 866-814-1889  (fax). 
Phone reporting must be followed by a written report within 10 days using 
the SAE template from CRDB. A similar format will be provided to 
collaborating institutions for uniformity and will contain the following: 
• The initials of the subjects, patient MRN#, MSKCC protocol # and title 
• The date the event occurred 
• A description of the SAE 
• An explanation of how it was handled 
• A description of the subjects condition 
• Indication if the subject remains on study 
• Indication if the event is considered related to the treatment 
• Indication if an amendment will need to be made to the protocol and/or 
consent for as a result of the SAE 
• Institutional procedure: 


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Any SAE must be reported to the IRB as soon as possible but no later than 5 
calendar days. The IRB requires a Clinical Research Database (CRDB) AE report 
to be delivered to the Institutional SAE Manager (307 East 63rd Street, 1st Floor) 
containing the following information: 
Fields populated from the CRDB: 
• Subject’s name (generate the report with only initials if it will be sent outside 
of 
MSKCC) 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and title 
 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• Relationship of the adverse event to the treatment (drug, device, or 
intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following information: 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 
The PI’s signature and the date it was signed are required on the completed report. 
 
11.4.2 The Investigator will maintain documentation of each SAE in the 
Investigator’s Brochure/Safety Report Binder (Biogen Idec, Inc..) at the site 
and should notify the IRB of the event in a timely manner. Information 
regarding resolution of an SAE, therapies, or procedures administered to 
treat the SAE and copies of the medical records, laboratory results, or the 
test results may be requested by Biogen Idec, Inc.. Pharmaceuticals. 
11.4.3 Reporting Procedures for All Adverse Events (Amgen): 
All fatal or life-threatening events considered related to study drug by the 
investigator must be reported to Amgen within (10) calendar days. 
 
C/o International Clinical Safety 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Fax: 805-499-4495 


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The investigator should notify their Institutional Review Board (IRB) of serious 
adverse events occurring at the site and other adverse event reports received from 
Amgen, in accordance with local procedures. It will be left to the investigator’s 
clinical judgment whether or not an adverse event is of sufficient severity to 
require that the subject should be removed from treatment. A subject may also 
voluntarily withdraw from treatment due to what he or she perceives as an 
intolerable adverse event. If either of these occurs the subject must undergo an 
end-of-study assessment and be given appropriate care under medical supervision 
until symptoms cease or the condition becomes stable. 
 
12 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1. Definitions 
Response and progression of disease will be evaluated in this study using a 
modification of the international criteria proposed by the Cheson et al.34 Note: 
Lesions are either measurable or non-measurable using the criteria provided 
below. The term “evaluable” in reference to measurability will not be used 
because it does not provide additional meaning or accuracy. 
 
12.1.1 Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm with conventional techniques (PET, CT, MRI, x-ray) . 
All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
12.1.2 Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter <20 mm with conventional), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory 
breast disease, abdominal masses (not followed by CT or MRI), and cystic 
lesions are all non-measurable. 
 
 
12.2. Response Criteria 
 
Response criteria will be assessed based on the post R-CHOP and Post 90Y- 
ibritumomab tiuxetan evaluations. The criteria are as follows (GTD = Greatest 
Transverse Diameter; SPD = Sum of the Products of the Greatest Diameter): 
 
12.2.1 Complete Remission (CR): 
• No clinical, radiographic or diagnostic evidence of disease. 
• No disease related symptoms. 
• Abnormal biochemical values (eg. LDH) clearly attributable to 
lymphoma must have normalized. 


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• Lymph nodes, nodal masses regressed to “normal” size: 
• If >1.5 cm before treatment, regressed to ≤ 1.5 cm in GTD. 
• If 1.1 to 1.5 cm before treatment, regressed to ≤ 1 cm in GTD (or >75% 
in SPD). 
• Spleen and all previously enlarged organs decreased in size. Spleen 
must not be palpable on exam 
• Bone marrow free of disease on repeat aspirate and biopsy if initially 
positive. 
• Normalization of PET scans. 
12.2.2 Complete Remission/unconfirmed (CRU): 
Patients meeting the above criteria for CR with the following 
exceptions: 
• Residual node mass of >1.5 cm in GTD regressed by > 75% in SPD 
• Individual nodes previously confluent regressed by >75% in SPD 
• 
Indeterminate bone marrow (increased number or size of lymphoid 
aggregates without cytologic or architectural atypia.) 
12.2.3 Partial Remission (PR) 
• ≥ 50% decrease in SPD of the six largest dominant nodes/nodal masses. 
• No increase in size of other nodes, liver or spleen. 
• Splenic and hepatic nodes regressed at least 50% in SPD 
• No new sites of disease. 
• Bone marrow and organs other than the spleen and liver cannot be 
considered for evaluation for PR because involvement at these sites is 
considered evaluable but not measurable. 
12.2.4 Relapsed Disease (RD) 
• In patients previously CR or CRU: 
• New node 
• Size of previously involved site has increase ≥ 50% in SPD. 
• ≥ 50% increase in either: GTD of any previously identified node that was 
>1 cm in its short axis, or 
-SPD of more than one node. 
12.2.5 Stable Disease (SD) 
• Patients who have achieved less than a partial remission but who have 
not developed findings consistent with progressive disease. 
12.2.6 Progressive Disease (PD) 
• In patients previously PR or SD. 
• ≥ 50% increase from nadir in SPD of any previously identified abnormal 
node. 
• Appearance of any new lesion during or at the end of therapy. 
Note: 
• Patients with a global deterioration of their health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be classified as having “symptomatic 
deterioration.” Every effort should be made to document the objective 


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progression, even after discontinuation of treatment. 
• In some circumstances, it may be difficult to distinguish residual disease 
from normal tissue. When the evaluation of complete response depends 
on this determination, it is recommended that the residual lesion be 
investigated (fine needle aspirate/biopsy) before confirming the complete 
response status. 
 
12.3. Duration of Response 
 
• 
12.3.1 Progression-Free Survival 
• Time to progression is defined as the time of enrollment to the first 
documented progression or death. Time-to-progression analyses will 
treat patient withdrawals and interventions for reasons other than 
progression or death as independent censoring. 
12.3.2 Overall Survival 
• Overall survival is defined as the time of enrollment to the time of death or 
time of last followup. 
12.3.3 Event Free Survival 
• Event free survival is defined as the time of enrollment to the first 
documented event, with events defined as: death, relapse, progressive 
disease, secondary malignancy, or toxicity attributed to therapy and 
requiring removal from study 
 
12.4. Response Review 
• Review of response will be confirmed and validated by a selected team 
of investigators from the Department of Medicine with expertise in 
running Phase II clinical trials, and will be available for independent 
review as requested by Biogen Idec, Inc.. Pharmaceuticals. 
 
13 CRITERIA FOR REMOVAL FROM STUDY 
13.1. 
Failure to meet the eligibility criteria to receive the Radioimmunotherapy 
Phase of the treatment program. 
13.2. 
Progressive disease or stable disease during or following R-CHOP 
therapy. 
13.3. 
Failure to receive the next cycle of R-CHOP within 35 days of the last 
prior cycle of R-CHOP. 
13.4. 
Administration of selected alternative therapy (defined as corticosteroids, 
standard or investigational chemotherapy or biological therapy). 
13.5. 
Lost to followup or failure to comply with necessary follow-up as 
indicated in the protocol. 
13.6. 
Decision of the patient to withdraw from the study. 
13.7. 
If, in the opinion of the Investigator, the patient would be at unacceptably 
high risk for life-threatening toxicities by continuing on the study. 
13.8. 
Patient expires. 


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14 BIOSTATISTICS 
14.1. Study Design 
This is a phase II study. The main goal is to observe the clinical efficacy in 
elderly patients (60 years or older) with previously untreated high risk (aaIPI 2 or 
3) diffuse large B cell lymphoma by assessing the induction regimen R-CHOP 
followed by 90Y-ibritumomab-tiuxetan (Zevalin). 65 patients will be enrolled in 
this study. 
 
Part I of this study is essentially standard chemotherapy in the elderly, 
recapitulating the R-CHOP GELA study. Approximately 2/3 of patients will 
achieve complete remission (CR) or partial remission (PR). Therefore, 43 
patients are expected to be eligible for part II of this study. During Part II, 
Zevalin will be administered to those patients in CR/PR with adequate 
hematologic parameters. 
 
Overall survival rates in the Shipp et al. IPI database 1 for age greater than 60 
patients at 2 years were 48% for high-intermediate risk patients and 31% for high 
risk patients. 70% and 30% of patients had high-intermediate risk and high-risk 
disease, respectively. Thus, overall the survival rate at two years for high- 
intermediate and high risk groups combined in the Shipp et at. study is 43%. This 
overall survival rate represents all patients treated – OS data for patients 
achieving a CR/PR are not reported. The 43 patients in the second part of this 
study allow us to detect a 20% difference in overall survival at two years with 
type I error 0.1 and 0.90 power. An improvement in PFS/OS >20% will be 
deemed a positive study. PFS was not calculated in the Shipp et al. study, but a 
relapse free survival rate at 2 years for high-intermediae and high-risk groups 
combined is 55.8% and will be used as an estimate for PFS. 
 
At the end of the study, Kaplan-Meier curves will be generated for overall 
survival, progression free survival and event free survival. As a second endpoint, 
the conversion rate to CR with 90Y-ibritumomab tiuxetan for patients with a PR 
post R-CHOP can be estimated. The response rate by R-CHOP can be estimated 
within +/- 12%. Finally, the predictive value of minimal residual disease for 
overall and progression free survival, as detected by molecular techniques for 
disease relapse/recurrence, will be evaluated utilizing a log-ranked analysis. 
 
In Part I, endpoints related to anemia will be evaluated in the setting of 
darbepoetin support. Descriptive statistics will report the incidence and severity 
of anemia, days of anemia, time to anemia, and change in hemoglobin from 
baseline. Hgb response and correction will be defined as: an increase of 2.0 
gm/dl from baseline and an Hgb 12.0 g/dl, respectively, in the absence of RBC 
transfusion in the preceding 21 days. 


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QOL analysis will be performed utilizing the self-administered FACT-anemia 
questionnaire, a well-validated instrument in cancer studies 11,35,36 that 
incorporates the FACT-G general assessment with symptom specific scales for 
fatigue and anemia (FACT-an). Scoring will be performed according to the 
FACT-anemia scoring schema in Appendix K. The compliance rate at each 
assessment will be estimated by the ratio of completed questionnaires actually 
completed to the number of patients alive at each assessment. Summary statistics 
will be presented for each time point and correlation with baseline hemoglobin 
levels and change in hemoglobin levels with darbepoetin evaluated. The nature  
of missing data will be evaluated and an appropriate longitudinal analysis method 
will be used to analyze the quality of life scores. 
 
14.2. 
Stopping Rule 
14.2.1 The trial will be stopped early if there is a 15% incidence of prolonged 
hematologic toxicity at the 3 month evaluation post phase II RIT. Prolonged 
hematologic toxicity will be defined as a absolute neutrophil count <1.5 
K/l, Hgb 8 gm/dl, or platelets 100,000 for patients without evidence of 
recurrent disease. If >10 patients have prolonged hematologic toxicity at the 
3 month evaluation post RIT, there will be 95% confidence that a 15% 
incidence of prolonged hematologic toxicity has been reached, necessitating 
early stopping of the protocol. 
14.2.2 The trial will be stopped early and re-evaluated if the first five consecutive 
patients experience prolonged hematologic toxicity as defined above. If the 
first three consecutive patients experience prolonged hematologic toxicity, a 
decrease in dose to 0.3 mCi/Kg may be considered. 
14.2.3 Additionally, the trial will be suspended and continued accrual will be re- 
evaluated if there are 4 or more patients among the first 20 patients who 
require hospitalization because of the administration of Zevalin. 
14.2.4 To receive 90Y-ibritumomab tiuxetan, patients must meet the criteria 
described in Section 9.1.4. The results of this study may not be applicable 
generally if a sizable fraction of patients does not go on to receive 90Y- 
ibritumomab tiuxetan. If any 11 of the first 33 patients do not proceed to 
receive 90Y-ibritumomab tiuxetan, the appropriateness of the sample size 
will be reviewed with the biostatics department at the time of the 11th 
patient. If necessary, the sample size will be adjusted and addressed in a 
protocol amendment. 
14.3. 
Sample Size and Accrual Rate 
Approximately 25-35 patients will be accrued per year. It is expected that the 
duration of the entire study should be approximately 3 years. MDACC may 
enroll a maximum of 20 patients. 
 
15  SUBJECT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
Research Participant Registration 
The following person(s) can obtain informed consent: 


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Principal Investigator: 
Paul A. Hamlin, M.D.* 
Co Principle Investigator: 
Andrew D. Zelenetz, M.D., Ph.D.* 
Responsible Investigators: 
Craig Moskowitz, M.D.* 
Steven Horwitz, M.D.* 
John Gerecitano, MD* 
Joseph Jurcic, M.D.*  
Tarun Kewalramani, M.D.* 
Ariela Noy, M.D.* 
Owen O’Connor, M.D., Ph.D.* 
M. Lia Palomba, M.D.* 
Carol S. Portlock, M.D.* 
David Straus, M.D.* 
The following person(s) can obtain informed consent at MDACC: 
Principal Investigator: 
Maria Alma Rodriguez, M.D.* 
Responsible Investigators (Consenting individuals) 
 
Luis Fayad, MD 
Frederick Hagemeister, MD 
Larry Kwak, MD, PhD 
Peter McLaughlin, MD 
Sattva Neelapu, MD 
Barbara Pro, MD 
Jorge Romaguera, MD 
Felipe Samaniego, MD 
Anas Younes, MD 
 
Confirm in the electronic medical record that the patient has received the Notice 
of Privacy Practice. This must be obtained before the eligibility confirmation and 
obtaining of the research informed consent. 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject 
Eligibility. 
 
Obtain written informed consent, by following procedures defined in section 
entitled Informed Consent Procedures. 
 
All particpants must be registered through the Protocol Participant Registration 
(PPR) Office at Memorial Sloan-Kettering Cancer Center. PPR is available 
Monday through Friday from 8:30am - 5:30pm at (646) 735-8000. The PPR fax 
numbers are (646) 735-0008 and (646) 735-0003. Registrations can be phoned in 
or faxed. The completed signature page of the informed consent form, the 
completed signature page of the Research Authorization and a completed 
Eligibility Checklist must be faxed to PPR. 


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During the registration process registering individuals will be required to answer 
specific eligibility questions and provide the following information: 
Registering Individual 
[Last, First Name] 
Notice of Privacy Status 
[Yes, No, N/A] 
Research Authorization 
[Date] 
MSKCC IRB Protocol# 
Attending of Record (if applicable) 
[Last, First Name] 
Consenting Professional 
[Last, First Name] 
Informed Consent Date 
Participant's Full Name 
[Last, First Name] 
Participant MRN 
 
 
 
For Participating Centers: 
 
Central registration for this study will take place at Memorial Sloan-Kettering 
Cancer Center. All particpants must be registered through the Protocol 
Participant Registration (PPR) Office at Memorial Sloan-Kettering Cancer 
Center. PPR is available Monday through Friday from 8:30am - 5:30pm at (646) 
735-8000. The PPR fax numbers are (646) 735-0008 and (646) 735-0003. 
Registrations can be phoned in or faxed. The completed signature page of the 
informed consent form, the completed signature page of the Research 
Authorization and a completed Eligibility Checklist must be faxed to PPR. 
 
During the registration process registering individuals will be required to answer 
specific eligibility questions and provide the following information: 
Registering Individual 
[Last, First Name] 
Notice of Privacy Status 
[Yes, No, N/A] 
Research Authorization 
[Date] 
MSKCC IRB Protocol# 
Attending of Record (if applicable) 
[Last, First Name] 
Consenting Professional 
[Last, First Name] 
Informed Consent Date 
Participant's Full Name 
[Last, First Name] 
Participant MRN 
 
 
Once eligibilty has been established, the patient is assigned an MSKCC Clinical 
Research Database (CRDB) patient number. This number is unique to the patient 
and must be written on all data correspondence for the patient. 


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16 DATA MANAGEMENT ISSUES AND QUALITY ASSURANCE 
16.1. 
A Research Study Assistant (RSA) will be assigned to the study. The 
responsibilities of the RSA include project compliance, data collection, 
abstraction and entry, data reporting, regulatory monitoring, problem resolution 
and prioritization, and coordinate the activities of the protocol study team. The 
data collected for this study will be entered into a secure database. Source 
documentation will be available to support the computerized patient record. 
16.2. 
Weekly registration reports will be generated to monitor patient accruals 
and completeness of registration data. Routine data quality reports will be 
generated to assess missing data and inconsistencies. Accrual rates, extent and 
accuracy of evaluations and followup will be monitored periodically throughout 
the study period and potential problems will be brought to the attention of the 
study team for discussion and action. Random-sample data quality and protocol 
compliance audits will be conducted by the study team, at a minimum of two 
times of year, or more frequently if indicated. All documentation of AE’s, 
records of study drug receipt and dispensation, and all IRB correspondence will 
be retained for at least 2 years after the investigation is completed. 
16.3. 
The data collected for this study will be entered into a secured database 
(Clinical Research Database, CRDB) at Memorial Sloan Kettering Cancer Center 
16.4. 
For patients treated at participating institutions, the institution will be 
responsible for filling out MSKCC Case Report forms (CRFs) and submitting 
them to MSKCC (via fax) bimonthly. Blank case report forms will be sent to the 
data managers at each site (for photocopying and use). When a patient is off- 
study, MSKCC should be alerted within 14 days, and all forms need to be sent no 
later than 4 weeks after the off-study date. Participating centers must fax CRFs  
to (212) 557-0787 to the attention of Brett Wegner. Forms can also be mailed to 
the following: Memorial Sloan Kettering Cancer Center, Clinical Trials Office, 
Brett Wegner, 633 Third Ave – 15th Floor, New York, NY 10017 
 
17 PROTECTION OF HUMAN SUBJECTS 
17.1. 
Privacy 
It is the responsibility of the Research Staff to ensure that Memorial Sloan- 
Kettering Cancer Center has on file a written acknowledgment of receipt by the 
subject of the Center’s Notice of Privacy Practices.  If the subject has not already 
done so, he/she must sign such an acknowledgment before participating in this 
study. 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form.  
The use and disclosure of protected health information will be limited to the 
individuals described in the Research Authorization form. A Research 
Authorization form must be completed by the Principal Investigator and approved 
by the IRB and Privacy Board. 
17.2. 
Potential Risks 


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Potential risks and adverse experiences associated with the drugs in this study 
program are described in Section 5. 
17.3. 
Potential Benefits 
CHOP or R-CHOP is the treatment of choice for elderly patients with DLBCL. 
However, many patients who obtain a complete or partial response to therapy will 
relapse from their disease. While some older patients can be salvaged with high- 
dose chemotherapy and an autologous stem cell transplant, others are too 
advanced in age to tolerate this procedure. In such cases, salvage treatment is 
palliative. It is hoped that by treating patients in CR or PR following R-CHOP,  
the administration of 90Y-ibritumomab tiuxetan will increase the cure rate by 
eliminating minimal residual disease, with minimal additional toxicity. 
17.4. 
Provisions for Preventing and Treating AE’s 
Treatment of febrile neutropenia and cytopenia will be in accordance with 
MSKCC guidelines. Rituximab administration will be premedicated with 
acetaminophen and diphenhydramine (or chlorpheniramine), as well as Ativan to 
prevent infusion-related AE’s. Infusion will be titrated as described in the Rituxan 
Package Insert (See Appendix A). In the event of an adverse reaction, the infusion 
will be stopped, the patient will be assessed, and treatment will be administered   
in accordance with standard medical practice. Patients will also receive      
standard anti-emetics as prophylaxis against nausea and vomiting with R-     
CHOP therapy. 
17.5. 
Alternatives/Options for Treatment 
Patients who refuse to participate in this study will be offered standard therapy, 
which includes CHOP or R-CHOP. Alternative chemotherapy regimens such as 
CEPP may be considered for patients in whom CHOP or R-CHOP would not be 
considered safe. 
17.6. 
Costs 
The patient will be responsible for all costs related to treatment and complications 
associated with R-CHOP chemotherapy. Biogen Idec, inc. Pharmaceuticals will 
provide Rituximab given during the Radioimmunotherapy Phase of the study. 
Biogen Idec, Inc.. Pharmaceuticals will provide the cost of 90Y-ibritumomab 
tiuxetan and 111In-ibritumomab tiuxetan , its preparation, and administration. 
Testing for minimal residual disease studies and progenitor cell studies will also 
be provided by Biogen Idec, Inc. The patient will be responsible for the costs of 
all scans, standard laboratory tests, and hospitalizations during the course of this 
study. 
17.7. 
Privacy and Confidentiality 
Confidentiality will be maintained within the limits of the law. Only qualified 
individuals from MSKCC, the FDA, and Biogen Idec, Inc.. Pharmaceuticals will 
be able to review patient medical records. Neither the patients’ names nor other 
identifying information will be used in reports or publications arising from this 
study. 
 
 
18 INFORMED CONSENT PROCEDURES (see Appendix I) 


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Procedures for obtaining Research Authorization: Before any protocol-specific 
procedures are carried out, investigators and/or designated staff will fully explain the 
details of the protocol, study procedures, and the aspects of patient privacy 
concerning research specific information. In addition to signing the IRB Informed 
Consent, all patients must sign the Research Authorization component of the 
informed consent form. The Research Authorization requires a separate signature 
from the patient. The original signed documents will become part of the patient’s 
medical record, and each patient will receive a copy of the signed documents. 
 
Patients potentially eligible for this trial will be informed about the nature of their 
disease and the standard treatment options will be discussed. Enrollment in this trial 
will be offered and the expected benefits and potential risks involved with this 
treatment program, including risks associated with the various agents and procedures, 
will be explained. A written informed consent form reiterating these points will be 
provided for review. Patients wishing to enroll will be required to sign three copies of 
the consent form; one will be returned to the patient, one will be filed in the patient’s 
chart, and one copy will be filed with the Clinical Trials Office. Individuals authorized 
to obtain written consent include Attending Physicians from the Lymphoma      
Service listed in Section 15. 
 
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