Clinical trial NCT00732498
Conditions: Lymphoma
Keywords: contiguous stage II grade 1 follicular lymphoma contiguous stage II grade 2 follicular lymphoma contiguous stage II grade 3 follicular lymphoma noncontiguous stage II grade 1 follicular lymphoma noncontiguous stage II grade 2 follicular lymphoma noncontiguous stage II grade 3 follicular lymphoma recurrent grade 1 follicular lymphoma recurrent grade 2 follicular lymphoma recurrent grade 3 follicular lymphoma stage III grade 1 follicular lymphoma stage III grade 2 follicular lymphoma stage III grade 3 follicular lymphoma stage IV grade 1 follicular lymphoma stage IV grade 2 follicular lymphoma stage IV grade 3 follicular lymphoma
Sponsor: University of Arizona
Start date: 2006-05-15; Completion date: 2018-10-15
Enrollment: 28 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Radiolabeled monoclonal antibodies, such as yttrium Y 90 ibritumomab tiuxetan, can find cancer cells and carry cancer-killing substances to them without harming normal cells. Giving combination chemotherapy together with rituximab and yttrium Y 90 ibritumomab tiuxetan may kill more cancer cells.

PURPOSE: This phase II trial is studying giving combination chemotherapy followed by rituximab and yttrium Y 90 ibritumomab tiuxetan to see how well it works in treating patients with relapsed stage II, stage III, or stage IV follicular non-Hodgkin lymphoma.

Detailed description:
OBJECTIVES:

Primary

* To evaluate the 1-year progression-free survival of patients with relapsed stage II-IV follicular non-Hodgkin lymphoma treated with ESHAP chemotherapy for cytoreduction followed by yttrium Y 90 ibritumomab tiuxetan radioimmunotherapy.
* To evaluate the median time to progression in these patients.

Secondary

* To evaluate the overall and complete response rates in patients treated with this regimen.

OUTLINE:

* ESHAP chemotherapy: Patients receive ESHAP chemotherapy comprising etoposide IV over 1 hour, methylprednisolone IV, cisplatin IV on days 1-4, and cytarabine IV over 2 hours on day 1. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity.
* Radioimmunotherapy: Between 4-6 weeks after completion of ESHAP chemotherapy, patients receive rituximab IV followed by indium In 111 ibritumomab tiuxetan IV over 10 minutes on day 1. Patients with \< 25% bone marrow involvement and expected biodistribution proceed to treatment. Patients receive rituximab IV followed by yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes on day 7, 8, or 9.

After completion of study treatment, patients are followed periodically.

Arms: arm 1: Etoposide, Methylprednisolone, Cytarabine, Cisplatin (ESHAP) infusion X 2 Cycles followed by Rituximab and In-Zevalin or Y-Zevalin.
Interventions: intervention 1: Methylprednisolone intervention 2: Etoposide intervention 3: Cytarabine intervention 4: Cisplatin intervention 5: Rituximab intervention 6: In-Zevalin intervention 7: Y-Zevalin
Intervention descriptions: intervention 1: 250 mg/m2/day IV over 1 hour days 1,2,3,4 every 28 days for 2 cycles. If bone marrow \<25% involved and expected biodistribution after 2 cycles yttrium-90-ibritumomab tiuxetan (Zevalin) to be administered. intervention 2: 40 mg/day IV over 1 hour days 1,2,3,4 every 28 days for 2 cycles. If bone marrow \<25% involved and expected biodistribution after 2 cycles yttrium-90-ibritumomab tiuxetan (Zevalin) to be administered. intervention 3: 2000 mg/m2 IV over 2 hours days 4 every 28 days for 2 cycles. If bone marrow \<25% involved and expected biodistribution after 2 cycles yttrium-90-ibritumomab tiuxetan (Zevalin) to be administered. intervention 4: 25 mg/m2/day IV at 1mg/min days 1,2,3,4 every 28 days for 2 cycles. If bone marrow \<25% involved and expected biodistribution after 2 cycles yttrium-90-ibritumomab tiuxetan (Zevalin) to be administered. intervention 5: 250 mg/m2 slow IV over days 1, then 7,8 or 9 prior to In Zevalin. Rituximab + Zevalin regimen is given 4-6 weeks after completion of 2 cycles of ESHAP. Treatment can be completed within 7-9 days in an outpatient setting. intervention 6: 5 mCi slow IV push over 10 minutes days 1. Given within 4 hours after Rituximab. intervention 7: Platelet counts from 100,000/mm3 to 149,000/mm3 will receive 0.3 mCi/kg. Platelet counts from \>/= 150,000/mm3 will receive 0.4 mCi/kg, not to exceed 32 mCi Y Zevalin. Slow IV push over 10 minutes, days 7,8 or 9 given within 4 hours after Rituximab.

Protocol documents:
Prot_SAP_000.pdf: 
 
Amendment #9: 08/28/2017 
 [1] 
 
PHASE II TRIAL OF YTTRIUM-90-IBRITUMOMAB TIUXETAN  (ZEVALIN®) 
RADIOIMMUNOTHERAPY AFTER CYTOREDUCTION WITH ESHAP CHEMOTHERAPY 
IN PATIENTS WITH RELAPSED FOLLICULAR NON-HODGKIN’S LYMPHOMA 
(PROTOCOL # 106-P158; 009-004-ZEV) 
 
The University of Arizona Cancer Center 
1515 N. Campbell Ave. 
Tucson, AZ 85724 
 
 
PRINCIPAL INVESTIGATOR: 
 
Daniel O. Persky, MD 
 
 
 
 
PROTOCOL DATE: 
 
 
Amendment #9: 28 August 2017 
 
• Amendment #8: 19 April 2017 
• Amendment #7: 7 January 2013 
• Amendment #6:  28 June 2010  
• Amendment #5:  21 May 2010 
• Amendment #4: 1 April 2010 
• Amendment #3: 15 January 2009 
• Amendment #2: 27 April 2007 
• Amendment #1: 1 March 2006 
• Initial Protocol: 15 April 2005 
 


 
Amendment #9: 08/28/2017 
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Protocol Signature Page 
Protocol Title: 
PHASE II TRIAL OF YTTRIUM-90-IBRITUMOMAB TIUXETAN  (ZEVALIN®) 
RADIOIMMUNOTHERAPY AFTER CYTOREDUCTION WITH ESHAP CHEMOTHERAPY IN 
PATIENTS WITH RELAPSED FOLLICULAR NON-HODGKIN’S LYMPHOMA 
 
Protocol Version/Date: 
28 August 2017 
I agree to conduct the study as outlined in the protocol and to comply with all the terms and conditions 
set out therein. I confirm that I will conduct the study in accordance with FDA and ICH GCP guidelines 
and all other applicable regulatory requirements. I also will ensure that sub-investigator(s) and other 
relevant members of my staff have access to copies of this protocol. 
 
______________________________________ 
 
 
______________________ 
Signature of Principal Investigator 
 
 
 
 
Date of Signature 
 
Daniel O. Persky, MD 
Printed Name of Principal Investigator 
 
The University of Arizona Cancer Center 
Institution 
 
1515 N. Campbell Ave. 
Address 
 
Tucson, AZ 85724 
City, State, Zip


 
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TABLE OF CONTENTS 
Title Page…………………………………………………………………………... 01 
Protocol Signature Page……………………………………………………………. 02 
Table of Contents…………………………………………………………………... 03 
Study Schema………………………………………………………………………. 06 
 
1.BACKGROUND / RATIONALE……………………………………………….. 07 
 
 
1.A. Non-Hodgkin’s Lymphoma…………………………................................. 07 
 
 
1.B. Overview of Chemotherapy for Follicular Non-Hodgkin’s Lymphoma….. 07 
 
 
1.C. Monoclonal Antibody Therapy of B-Cell Non-Hodgkin’s Lymphoma…... 08 
 
 
 
1.C.1. Rituximab…………………………………………………………… 08 
 
 
1.D. Radioimmunotherapy of Lymphoma…………………………………….. 09 
 
 
 
1.D.1. Iodine I 131-Anti B1 Antibody Clinical Experience……………….. 10 
 
 
 
1.D.2. 90Y Zevalin………………………………………………………….. 12 
 
 
1.E. Rationale for Current Protocol……………………………………………. 16 
 
2. OBJECTIVES…………………………………………………………………… 18 
 
3. STUDY DESIGN……………………………………………………………….. 18 
 
 
3.A. Treatment Summary………………………………………………………. 18 
 
 
3.B. Study Duration……………………………………………………………. 18 
 
4. STUDY POPULATION………………………………………………………… 18 
 
 
4.A. Inclusion Criteria………………………………………………………….. 18 
 
 
4.B. Exclusion Criteria…………………………………………………………. 20 
 
 
4.C. Number of Patients to be Enrolled………………………………………... 21 
 
 
4.D. Patient Enrollment Procedures……………………………………………. 21 
 
5. STUDY PROCEDURES………………………………………………………... 21 
 
 
5.A. Screening / Baseline Evaluations…………………………………………. 21 
 
 
5.B. Evaluations During ESHAP Treatment Period…………………………… 23 
 
 
 
5.B.1. ESHAP C1, D1……………………………………………………... 23 
 
 
 
5.B.2. ESHAP C2, D1……………………………………………………... 23 
 
 
 
5.B.3. ESAHP C2, D29……………………………………………………. 23 
 
 
5.C. Evaluations During the 111In Zevalin Imaging Period…………………….. 24 
 
 
 
5.C.1. Day 1………………………………………………………………... 24 
 
 
 
5.C.2. Days 2, 3, 4 and 5…………………………………………………… 24 
 
 
 
5.C.3. Days 7, 8 or 9……………………………………………………….. 25 


 
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5.C.4. Day 35………………………………………………………………. 25 
 
 
5.D. Restaging………………………………………………………………….. 26 
 
 
 
5.D.1. 3 Months Post 90Y-Zevalin Infusion………………………………... 26 
 
 
5.E. Follow-Up Evaluations……………………………………………………. 26 
 
 
 
5.E.1. Short-Term Follow-Up……………………………………………… 26 
 
 
 
5.E.2. Long-Term Follow-Up……………………………………………… 27 
 
 
5.F. Disease Progression / Off Study Evaluations……………………………... 27 
 
6. DRUG INFORMATION……………………………………………………….. 28 
 
 
6.A. ESHAP Drug Information and Adverse Events…………………………... 28 
 
 
 
6.A.1. Cisplatin…………………………………………………………….. 28 
 
 
 
6.A.2. Cytosine Arabinoside……………………………………………….. 29 
 
 
 
6.A.3. Etoposide……………………………………………………………. 31 
 
 
 
6.A.4. Methylprednisolone sodium succinate……………………………… 33 
 
 
6.B. Rituximab Drug Information and Adverse Events……………………….. 34 
 
 
6.C. 111-Indium Zevalin and 90-Y-Zevalin Drug Information  
 
 
 
 
and Adverse Events…………………………………………………39 
 
7. TREATMENT PLAN…………………………………………………………… 42 
 
 
7.A. ESHAP Regimen Dosing…………………………………………………. 42 
 
 
7.B. Rituximab, 111-Indium Zevalin and 90-Y-Zevalin Administration……… 42 
 
8. TOXICITIES TO BE MONITORED and DOSE ADJUSTMENTS……………45 
 
 
8.A. ESHAP Toxicities and Dose Modifications………………………………45 
 
 
8.B. Rituximab Antibody Toxicities and Dose Modification…………………..46 
 
 
8.C. 111In Zevalin and 90Y Zevalin Toxicities and Dose Adjustments………….48 
 
9. ADVERSE EVENT REPORTING……………………………………………… 48 
 
10. CONCOMITANT MEDICATIONS…………………………………………… 49 
 
11. REMOVAL OF PATIENTS FROM STUDY………………………………….50 
 
12. STATISTICAL CONSIDERATIONS…………………………………………50 
 
 
12.A. Study Design…………………………………………………………….. 50 
 
 
12.B. Sample Size……………………………………………………………… 50 
 
 
12..C. Method of Analysis…………………………………………………….. 50 
 
13. STUDY ADMINISTRATION………………………………………………… 51 
 
 
13.A. Review and Consent Requirements……………………………………... 51 
 
 
13.B. Registration Procedure………………………………………………….. 52 


 
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13.C. Study Records – Data Collection & Recording…………………………. 52 
 
 
13.D. Patient Confidentiality…………………………………………………... 52 
 
 
13.E. Monitoring……………………………………………………………….. 52 
 
14. REFERENCES………………………………………………………………… 55 
 
15. APPENDICIES………………………………………………………………… 61 
 
 
Appendix A: Study Calendar………………………………………………….. 62 
 
 
Appendix B: Performance Status Scale……………………………………….. 63 
 
 
Appendix C: Adult Toxicity Criteria………………………………………….. 64 
 
 
Appendix D: International Workshop Standardized Response Criteria for  
 
 
 
 
 
Evaluation of Clinical Responses in NHL………………… 65 
 
 
Appendix E: SAE & MedWatch Forms……………………………………….. 68 
 
 
Appendix F: Ann Arbor Staging System………………………………………. 78 
 
 
Appendix G: Guidelines for the Establishment of Radionuclide Dose 
 
 
 
 
 
Calibrator Settings Using MDS Nordion Yttrium –  
 
 
 
 
 
[90] Chloride………………………………………………. 79 
 
 
Appendix H: Preparation and Dispensing Information for 111In Zevalin 
 
 
 
 
 
and 90Y Zevalin…………………………………………….. 83 
 
 
Appendix I: Data Acquisition for 111In Zevalin………………………………... 90 
 
 
Appendix J: Amendment #1 Summary of Changes……………………………. 91 
 
 
Appendix K: Amendment #2 Summary of Changes…………………………... 92 
 
 
Appendix L: Amendment #3 Summary of Changes…………………………… 93 
 
 
Appendix M: Amendment #4 Summary of Changes……………………………114 
      Appendix N: Amendment #5 Summary of Changes……………………………115 
      Appendix O: Amendment #6 Summary of Changes……………………………115 
Appendix P: Amendment #7 Summary of Changes……………………………115 
 
 
 
 
 
 
 


 
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Study Schema 
 
 
 
 
Relapsed follicular lymphoma 
                                (Bulky Stage II, Stage III, Stage IV) 
                                (First, second, third, or fourth relapse) 
 
 
                                           ESHAP x 2 cycles 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
         
 
 
 
 
 
  Restage  
 
 
 
 
 
       Bone marrow < 25% involved  
 
Bone marrow > 25% involved 
 
and expected biodistribution 
 
         or altered biodistribution 
 
 
 
 
 
     
 
 
 
 
 
 
 
           
 
 
 
 
 
 
 
 
 
 
Zevalin 
 
 
 
      Off study (treatment failure) 
 
 
 
 
 
     
 
 
 
 
 
Restage 
          Follow-up per protocol 
 
 
 
 


 
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1 BACKGROUND/RATIONALE 
1.A Non-Hodgkin’s Lymphoma 
The non-Hodgkin’s lymphomas (NHL) are a diverse group of lymphoid neoplasms that collectively rank 
fifth in cancer incidence and mortality in the United States.[1, 2]  The incidence and prevalence of NHL 
has risen 150% over the past few decades.[3, 4]  The incidence of NHL increases with age and males are 
affected about 1.5 times more often than females. 
The majority of non-Hodgkin’s lymphomas is of B-cell origin and can be categorized according to the 
International Working Formulation (IWF) or the Revised European American Lymphoma (REAL) 
classification.[5-7]  The use of the WHO modified REAL classification of non-Hodgkin’s lymphomas is 
strongly encouraged.  The estimated median survival time for patients with follicular lymphoma is 7-10 
years from initial diagnosis. [8 –13] 
Transformation of low-grade NHL to a more aggressive subtype has been reported to occur in about 25% 
- 60% of patients over time.[9, 10, 14,15]  Patients with low-grade NHL usually present with advanced 
disseminated disease.[11, 12, 16,17]  Chemotherapy treatment with or without radiotherapy can lead to 
remissions; however, virtually all treated patients repeatedly relapse[18] with shorter remissions following 
each subsequent course of chemotherapy.[9-13, 19]   Although there have been several additions to the 
oncologist’s chemotherapy repertoire, no chemotherapeutic regimen has been shown to be superior to 
another in prolonging survival in follicular NHL, [14, 20-22] and there has been little to no change in 
survival in the past 30 years. 
 
Thus, follicular non-Hodgkin’s lymphomas (NHL) pose a particularly difficult dilemma for clinicians 
and new treatment strategies are needed. 
 
 
1.B Overview of Chemotherapy for Follicular Lymphoma     
 
With the exception of a small fraction of patients (10% - 15%) with truly localized disease, as noted 
above most patients with indolent lymphoma do not achieve long-term remissions. [23,24]   Because 
conventional chemotherapy regimens have not been shown to improve survival in this disease compared 
with a policy of expectant therapy, [23]   many asymptomatic patients are followed with “watchful 
waiting.”   Symptomatic patients are commonly treated with oral alkylating agents (e.g., chlorambucil), 
or with an alkylating agent (cyclophosphamide) in combination with a vinca alkaloid and corticosteroids 
(CVP), but studies have not demonstrated a survival advantage for patients treated with these regimens.   
 
 
Because of the curative potential of anthracycline-based regimens (e.g., CHOP) for aggressive NHL, 
CHOP has been tested extensively by the Southwest Oncology Group (SWOG) in patients with indolent 
lymphomas. [25-28] Four hundred fifteen patients with low-grade malignant lymphomas were treated with 
CHOP (with or without BCG and/or levamisole) between 1972 and 1983 on SWOG-7204, SWOG-7426, 
and SWOG-7713.  Approximately 90% of these patients achieved objective responses, including 61%-
78% with complete remissions. [25-27] With a median follow-up of 12.8 years, the median survival was 
6.9 years.  [28] Toxicities included myelosuppression, nausea, paresthesias, infection, and cardiomyopathy 
(<5%).  Unfortunately, these studies failed to demonstrate a plateau on the survival curves of patients 
treated with CHOP, indicating that by itself CHOP has little curative potential for indolent lymphomas, 
in contrast to its efficacy for diffuse large cell lymphomas.[28]  Whether cures with CHOP are possible for 
patients with follicular lymphomas remains controversial, with conflicting studies from several 
institutions.[29-32]  Nevertheless, all investigators agree on the necessity of developing better treatment for 
patients with indolent lymphomas.   
 


 
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Newer chemotherapy agents (fludarabine, 2-chlorodeoxyadenosine) have shown considerable activity in 
patients with relapsed low-grade lymphomas; however, no study has demonstrated that these drugs are 
curative in indolent lymphomas or that survival is prolonged by their use.  SWOG-9501 investigated the 
combination of fludarabine plus mitoxantrone in patients with newly diagnosed follicular lymphomas.  
This regimen was well tolerated and produced a high response rate, but the survival curves do not appear 
superior to those obtained with other regimens, including CHOP. [33]  Other chemotherapy regimens 
which have been found to be effective for relapsed indolent lymphoma include ESHAP, [34, 35] which has 
published response rates ranging from 36% to as high as 82%. 
 
 
High-dose chemoradiotherapy with bone marrow or peripheral blood stem cell transplantation is 
commonly employed for treatment of patients with relapsed lymphomas of all types.  Preliminary data 
from the Dana Farber Cancer Institute suggest the disease-free survival after transplantation for follicular 
lymphomas relates to the quality of initial morphological remission obtained and the ability to decrease 
the number of cells bearing clonal rearrangements of the bcl-2-oncogene (which is present in 80% of 
newly diagnosed follicular lymphomas).[36]  However, the curability of indolent lymphomas with stem 
cell transplantation and the advisability of performing this procedure are controversial.   
 
1.C Monoclonal Antibody Therapy of B-Cell Non-Hodgkin’s Lymphoma 
Attempts to treat B-cell malignancies with immunotherapy using monoclonal antibodies reactive against 
B-cell antigens, began over a decade ago.[37-41]  In early studies using murine monoclonal antibodies, 
responses were limited by the development of human anti-mouse antibody (HAMA), by the relative 
inability of mouse antibodies to recruit human immune effector mechanisms for tumor killing, and by 
down-regulation of the target antigen.[42]  Efficacy could also be limited by circulating free antigen.  
Recent approaches that have been taken to improve the clinical outcome of immunotherapy include: 
• use of chimeric, humanized, or PRIMATIZED® antibodies to reduce antibody immunogenicity 
(HAMA); 
• choice of target antigen that does not modulate, internalize, and/or shed from the cell surface; 
• use of new high-yield manufacturing procedures allowing higher dosing levels; 
• use of radioimmunoconjugates and other immunotoxins. 
 
 
1.C.1 Rituximab 
Rituximab (Rituxan, MabThera) is a chimeric IgG1 kappa monoclonal antibody, with mouse 
variable and human constant regions.  It specifically recognizes the CD20 antigen expressed on normal 
B cells and most malignant B-cell lymphomas.[43] The CD20 antigen is a suitable target for treatment of 
B-cell lymphomas because it does not circulate in the plasma as free protein that could block targeting of 
an antibody to lymphomas,[44] does not internalize upon anti-CD20 antibody binding, and does not shed 
from the cell surface after antibody binding.[45] 
In vitro studies have demonstrated that rituximab binds human complement and lyses lymphoid B-cell 
lines through CDC (complement dependent cytotoxicity) and antibody-dependent cellular cytotoxicity.  
Rituximab has also been shown to have antiproliferative effects in tritiated thymidine incorporation 
assays and to directly induce apoptosis, while other anti-CD19 and CD20 antibodies do not.[46] 
Rituximab (Rituxan) is licensed in the United States as therapy for patients with relapsed or refractory 
low-grade or follicular, CD20 positive, B-cell non-Hodgkin’s lymphoma (NHL) (See the appropriate 


 
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Appendix for the Package Insert); in Europe, rituximab (MabThera) is licensed as therapy for patients 
with stage III-IV follicular lymphoma who are chemo resistant or are in their second or subsequent 
relapse after chemotherapy.  In an open-label, single arm, multi-center pivotal trial, 166 patients with 
relapsed disease received four weekly infusions of 375 mg/m2 rituximab.[47]  Ninety-one percent of 
patients (151 of 166) were evaluable for efficacy and an overall response rate of 50% with 6% CR and 
44% PR was achieved.  Median time to progression for responders was 13.2 months.[48, 49]  Other studies 
have demonstrated the activity of rituximab in patients with both treated and untreated lymphomas. [50, 
51]  Despite the encouraging clinical results and success of rituximab, 40%-50% of patients with indolent 
lymphomas and 60%-70% of patients with aggressive lymphomas fail to respond to single-agent 
rituximab, only 5%-10% of patients attain complete remissions, and the median duration is only 
approximately 1 year.  Consequently, many investigators have begun exploring methods of enhancing 
the potency of antibodies, including combining them with chemotherapy and conjugating them to toxins 
or radionucleotides.   
Czuczman conducted a pilot trial administering CHOP chemotherapy (cyclophosphamide, doxorubicin, 
vincristine, prednisone) with rituximab to 40 patients with indolent lymphoma.  Objective remissions 
were observed in 38 patients (95%), including 22 CRs (55%), with a median time-to-treatment failure of 
more than 29 months.[52]  In SWOG 9800, 85 evaluable patients with previously untreated advanced 
stage indolent lymphoma who were treated with 6 cycles of CHOP followed by four doses of rituximab 
were reported by Maloney et al [53]  to have an overall response rate of 72% with 54% complete 
remissions and a 2-year progression-free survival rate of 74%.  CHOP plus rituximab is currently being 
further evaluated in previously untreated advanced indolent lymphoma in SWOG 0016, a randomized 
phase III trial (SWOG 0016) comparing CHOP plus rituximab with CHOP plus Iodine-131 
Tositumomab (Bexxar). 
 
1.D   Radioimmunotherapy of Lymphoma 
Radiolabeled monoclonal antibodies are efficacious in treating NHL for the following reasons: 
lymphocytes and lymphoma cells are inherently sensitive to radiotherapy[54]; the local emission of 
ionizing radiation by radiolabeled antibodies may kill cells with or without the target antigen in close 
proximity to the bound antibody; and penetrating radiation may obviate the problem of limited access in 
bulky or poorly vascularized tumors. 
Early investigations of therapeutic radiolabeled antibodies for B-cell lymphoma were performed with 
iodinated antibodies.[55-60]  (Detailed below in Section 1.D.1)  However, the development and 
improvement of methods for attaching metal chelating groups to proteins have made it possible to study 
other potentially useful radioisotopes such as 90Yttrium (90Y). (Detailed below in Section 1.D.2.)  
90Yttrium has several advantages over 131I and for these reasons, has been selected for this study.  
As a pure, high-energy, beta-emitting isotope, 90Y can deliver more energy to the tumor (2.3 MeV versus 
0.6 MeV of beta energy for 131I) and the longer pathlength (χ90 = 5 mm versus 1 mm for 131I)[61] may 
allow tumor cells in the vicinity of the antibody-bound cell to be killed without direct binding of the 
antibody.[62]  These characteristics may be especially advantageous in the treatment of poorly 
vascularized tumors.  The shorter half-life of 90Y (2.7 days versus 8 days for 131I) approximates the 
biological half-life of the radiolabeled antibody, which may minimize toxicity to nontarget organs.  
Because 131I emits penetrating gamma rays (0.35 MeV), patients receive an increased whole body dose.  
In addition, patients require the following: 1) shielding to protect hospital staff, 2) restrictions in travel, 
activities, the use of bedroom and bathroom facilities to limit exposure to family and the public, and 3) 
possible hospitalization.  Furthermore, dehalogenation of 131I leads to accumulation of free iodine in the 


 
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thyroid, posing the risk of hypothyroidism; this risk is present in patients treated with prophylactic 
potassium iodide as well.  The isotope, 90Y, is a pure beta emitter and can therefore be given on an 
outpatient basis without patient restrictions. 
While the beta emitter, 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 efficiency.[63-66]  Characteristics 
of 90Y and 131I are summarized in Table1. 
Table 1. 
Comparative Properties of 90Y and 131I 
Properties 
90Y 
131I 
Energy 
Beta emitter (2.3 MeV) 
Gamma (0.36 MeV)/Beta (0.6 MeV) emitter 
Path Length 
5 - 10 mm 
1 - 2 mm for beta component 
Administration 
Always outpatient 
Can require hospitalization 
Half-life 
64 hours 
192 hours 
 
 
1.D.1  Iodine-131 Anti-B1 Antibody Clinical Experience 
In the initial Phase I/II, open-label study of non-myeloablative doses of Iodine-131 anti-B1 
antibody for the treatment of patients with B-cell NHL of all histologic types, [67-69]  59  patients were 
enrolled.  Twenty-eight patients had low-grade NHL, 14 had transformed low-grade NHL, 15 had 
intermediate-grade NHL, and 2 had high-grade NHL.  The median time from diagnosis was 45 months, 
the median number of prior therapies was four, 88% had stage III or IV disease, 36% had bulky disease, 
51% had an elevated LDH, and 24% had failed bone marrow transplant (BMT).  Patients received one to 
three dosimetric doses followed by a therapeutic dose.  The dosimetric dose(s) involved the IV 
administration of 5 mCi of Iodine-131 anti-B1 antibody to determine the rate of whole body clearance so 
that a whole body radiation dose (cGy) could be calculated.  Each dosimetric dose was preceded by 0, 
95, or 475 mg of unlabeled antibody.  Therapeutic dose-escalation was initiated at 25 cGy and adjusted 
in 10 cGy increments until the maximum tolerated dose (MTD) was reached.  Fifty-three of the 59 
patients received a therapeutic dose.  The MTD was 75 cGy for patients who had not undergone BMT.  
Based on all data published in August 2000, a response was observed in 42/59 (71%) patients and a 
complete response (CR) was observed in 20/59 (34%) patients.  The median progression free survival 
(PFS) was 12 months for responders and 20.3 months for those who achieved a CR.  Seven of the 59 
patients were in CR at time of publication.  Responses were observed in 50% of post-BMT patients and 
52% of bulky disease patients.  A response was observed in 24/28 (86%) patients and a CR was 
observed in 13/28 (46%) patients with low-grade NHL.  A response was observed in 11/14 (79%) 
patients and a CR was observed in 7/14 (50%) patients with transformed low-grade NHL.  Dose-
dependent pharmacokinetics were observed.  The mean tumor dose was 14.5 times the whole body dose.  
The dose-limiting toxicity was hematologic: three patients developed a platelet count < 10,000 
cells/mm3 and two patients had an absolute neutrophil count (ANC) < 100 cells/mm3.  The most 
prevalent non-hematologic toxicities were transient, mild to moderate fever, nausea, asthenia, and chills.  
Ten of 59 (17%) patients developed human anti-murine antibodies (HAMA).   
 
In the Phase II, multicenter, (dosimetry validation) open-label study of non-myeloablative doses of 
Iodine-131 anti-B1 antibody for the treatment of patients with low-grade B-cell lymphomas and 


 
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transformed low-grade lymphomas, [70]  37 patients had low-grade NHL and 10 had transformed low-
grade NHL.  The median time from diagnosis was 41 months, the median number of prior therapies was 
four, 91% had Stage III or IV disease, 44% had bulky disease, 44% had an elevated LDH.  Patients 
received one dosimetric dose followed by a therapeutic dose.  The dosimetric dose involved the IV 
administration of 450 mg of unlabeled antibody and 35 mg (5 mCi) of Iodine-131 anti-B1 antibody to 
determine the rate of whole body clearance so that a whole body radiation dose (cGy) could be 
calculated.  The therapeutic dose involved IV administration of 450 mg of unlabeled antibody and 35 mg 
of Iodine-131 anti-B1 antibody with radioactive Iodine-131 titrated to deliver 75 cGy.  Forty-five of the 
47 patients received a single dosimetric and therapeutic dose of Iodine-131 anti-B1 antibody as 
described in the protocol.  A response was observed in 27/47 (57%) patients and a complete response 
(CR) was observed in 14/47 (30%) patients.  The median duration of response was 248 days (95% 
confidence interval: 136 days to upper limit not reached) and median duration of CR was not reached 
(95% with ongoing responses ranging from 245-606 days.  A CR was observed in 9/37 (24%) patients 
with low-grade NHL.  A response was observed in 6/10 (60%) patients and a CR was observed in 5/10 
(50%) patients with transformed NHL.  The mean tumor dose was 10.6 times the whole body dose.  The 
dose-limiting toxicity was hematologic:  five patients developed a platelet count <10,000 cells/mm3 and, 
mild to moderate asthenia, nausea and fever.  Only one of 46 (2%) patients developed HAMA following 
treatment as assessed by centralized validated HAMA assay. 
 
Press and colleagues studied myeloablative doses of the same radioiodinated antibody (anti-B1, Coulter 
Pharmaceuticals) with autologous stem cell support in Phase I and II trials in Seattle. [71,72]  Twenty-nine 
patients with multiple relapsed B cell lymphomas were treated with single agent I-131-anti-CD20 (B1) 
antibody (2.5 mg/kg, 280 to 785 mCi) followed by autologous hematopoeitic stem cell rescue between 
2/90 and 7/94.  Objective responses occurred in 86% of patients, including 79% complete responses.  
Early toxicities included Grade 4 myelosuppression in all patients, Grade 2-3 nausea in 8 of 29, and fatal 
sepsis in one.  Reversible cardiopulmonary failure was the dose-limiting non-hematopoietic toxicity (2 
pt.), occurring at an estimated absorbed lung dose of 27 Gy.  Overall survival and progression-free 
surviving patients had long-term objective impairment of performance status or cardiopulmonary 
function, though one patient with a pre-existing anthracycline-induced cardiomyopathy remained on 
digoxin (with an ejection fraction of 69%) four years after radioimmunotherapy.  No serious delayed 
cardiopulmonary complications occurred.  Late toxicities were minimal, except for elevation of the 
thyroid stimulating hormone level in 59% of the subjects.  Two patients who had been heavily pretreated 
with alkylating agents and external beam irradiation developed acute leukemia eight years after 
radioimmunotherapy.  Two patients developed secondary solid neoplasms 3 years after treatment (1 
noninvasive transitional cell carcinoma of the bladder; 1 metastatic colon cancer). 
 
In SWOG 9911, 90 eligible previously untreated patients with advanced indolent lymphoma treated with 
six cycles of CHOP followed 4-8 weeks later by tositumomab/iodine I 131 tositumomab (anti-CD20 
antibody) [73, 74] had an overall response rate to the entire treatment regimen of 90%, including 67% 
complete remissions and 23% partial remissions. Twenty-seven (57%) of the 47 fully evaluable patients 
who achieved less than a CR with CHOP had an improved remission status after tositumomab/iodine I 
131 tositumomab.  With a median follow-up of 2.3 years, the 2-year progression-free survival was 
estimated to be 81%, with a 2-year overall survival of 97%.   Treatment was well tolerated.  Reversible 
myelosuppression was the main adverse event and was more severe during CHOP chemotherapy than 
following radioimmunotherapy.   As noted above, CHOP plus I –131 tositumomab is being evaluated 
further in advanced previously untreated indolent lymphoma in the randomized, phase III trial S0016.  


 
Amendment #9: 08/28/2017 
 [12] 
1 D. 2 90Y Zevalin  
a.  Background 
90Y Zevalin is a unique compound composed of the following: a murine IgG1 kappa 
monoclonal 
antibody 
ibritumomab 
(IDEC-2B8); 
the 
linker 
chelator 
tiuxetan 
(isothiocyanatobenzyl MX-DTPA); and the radioisotope 90Y that is securely chelated via the 
linker.  Like its unlabeled chimeric counterpart, rituximab, 90Y Zevalin targets the CD20 antigen 
present on 95% of B cell lymphomas.[75]  111In Zevalin is the 111Indium-labeled murine 
monoclonal antibody used for imaging and dosimetry.  Rituximab, a chimeric mouse/human 
antibody, is given initially to clear peripheral B lymphocytes and optimize biodistribution of the 
radiolabeled antibody. 
In single-dose safety studies with ibritumomab (IDEC-2B8) performed in mice and guinea pigs, 
no overt toxicity was seen within seven days of dosing.  Tumor localization studies with 111In 
Zevalin performed in athymic mice demonstrated that concentrations of 111In Zevalin increased 
steadily in tumor, but did not accumulate in blood or other tissues.  Biodistribution studies 
performed in mice with 90Y Zevalin demonstrated minimal bone accumulation (< 1.5% injected 
dose/gram after 3 days). 
b. Zevalin® Clinical Experience 
Zevalin radioimmunotherapy has been evaluated in seven clinical trials (see Table 2). The 
first two trials (106-01 and 106-02) differed from subsequent trials in the following ways: 
• The murine ibritumomab antibody was used instead of the chimeric rituximab antibody as the 
cold antibody infused prior to Zevalin 
• Dosing was based on total mCi rather than mCi/kg 
• Stem cells were collected prior to radioimmunotherapy 
Because of these differences, 106-01 and 106-02 have been excluded from the integrated safety 
summary. 
Table 2.    
Summary Zevalin Clinical Trials 
Study 
Type 
Patient Population 
Description 
No. of 
Patients  
90Y Zevalin 
Intended Dose 
106-01 
106-02 
Phase I/II 
Low- or intermediate-
grade B-cell lymphoma 
Dose-escalating 
18 
10 - 50 mCi 
106-03 
Phase I/II 
Low- or 
intermediate-grade or 
mantle cell NHL 
Dose-escalating 
51 
0.2, 0.3, 0.4 
mCi/kg 
106-04 
Phase III 
Randomized 
LG/F/T NHL  
Zevalin 
vs.Rituximab 
control 
73 
70 
0.4 mCi/kg 
N/A 
106-05 
Phase II 
LG/F/T NHL 
mild thrombocytopenia  
Single arm 
30 
0.3 mCi/kg 
106-06 
Phase III 
Nonrandomized 
Rituximab refractory 
follicular NHL 
Prior treatment 
served as control 
57 
0.4 mCi/kg 
106-98 
Open label 
LG/F/T NHL 
Open label 
138 
0.3-0.4 mCi/kg 


 
Amendment #9: 08/28/2017 
 [13] 
LG/F/T NHL = low-grade, follicular or transformed non-Hodgkin’s lymphoma; N/A = not applicable 
b.1 Summary of Safety Results 
The safety profile of Zevalin is summarized for patients who received 90Y Zevalin 
as a mCi/kg dose in five clinical trials (106-03, 106-04, 106-05, 106-06, 106-98; N = 349).  Results 
revealed that adverse events (AEs) are primarily hematologic with Grade 4 neutropenia, 
thrombocytopenia, and anemia occurring in 30%, 10% and 4.0% of patients, respectively. Most 
nonhematologic AEs were Grade 1 or 2 and the incidence was comparable to that seen with rituximab 
therapy.  Median serum immunoglobulins remain largely within the normal range and a low incidence of 
severe infection was noted despite a 6-month reversible depletion of B cells.  Incidence of 
HAMA/HACA is low and a HAMA or HACA response did not result in unusual toxicity.  
Myelodysplasia has been reported for 1.4% of patients, well within the expected background rate for this 
heavily pretreated patient population. [x, 76] 
b.2 Summary of Efficacy Results 
Knox administered Yttrium-90-labeled anti-CD20 antibodies to 18 patients with 
relapsed B cell lymphomas (4 treated with Y-90-tositumomab antibody and 14 with ibritumomab 
tiuxetan) in escalating single doses of 13.5 to 50 mCi.[77]  Six complete remissions and seven partial 
responses were observed (overall response rate, 72%), with a median response duration of 6 months.  
Four patients developed human anti-mouse antibodies (HAMA).  Grade 4 myelosuppression was seen at 
doses above 50 mCi of 7-90, but no other serious toxicities were observed.   
 
In a multi-center Phase I/II trial dose-finding study (106-03), Witzig et al treated 
51 patients with relapsed or refractory non-Hodgkin’s lymphoma with Ibritumomab Tiuxetan (Y2B8, 
Zevalen).[78]  Eligibility criteria included an ANC > 1,500/mm3, platelets > 100,000/mm3 and bone 
marrow involvement < 25%.  Median age was 60 years.  Patients had a median of two prior regimens 
(range, 1-7).  In the phase I portion of the trial, patients received either 100 or 250 mg/m2 of unlabeled 
rituximab (to clear peripheral B-cells and improve biodistribution) followed by Indium-111-
ibritumomab tiuxetan (5 mCi on Day 1 for imaging and Y-90-ibitumomab tiuxetan 0.2, 0.3, or 0.4 
mCi/kg on Day 8.  The optimal dose of unlabeled rituximab was determined to be 250 mg/m2 and 0.4 
mCi/kg was the maximally tolerated dose of Yttrium-90.  In an intent-to- treat analysis the overall 
response rate was 67%, including 26% CRs and 41% PRs.  Thirty-four patients with low grade 
lymphoma achieved an 82% overall response rate  (26% CRs, 56% PRs), 43% of 14 aggressive 
lymphomas responded, and none of the three patients with mantle cell disease responded. Estimated time 
to progression for intent to treat was 12.9 months and estimated median duration of response was 11.7 
months. Hematologic toxicity was dose-limiting.   Thrombocytopenia was the most common 
hematologic event.  Hematologic toxicity was transient and reversible.  Only one patient developed an 
immune response. 
 
Witzig et al [79,80] (106-04) conducted a randomized phase III trial in 143 patients with relapsed 
or refractory low-grade, follicular, or CD 20+ transformed NHL.  Patients received either ibritumomab 
tiuxetan, 0.4 mCi/kg (maximum of 32 mCi) or rituximab, 375 mg/m2 weekly for 4 weeks.  Eligibility 
required an ANC > 1,500/mm3, a platelet count > 100,000/mm3, and bone marrow involvement < 25%.  
As assessed by International Workshop Response Criteria, [81] patients who received ibritumomab 
tiuxetan achieved an overall response rate (ORR) of 80% (73 patients) compared with 56% (70 patients) 
for patients on the rituximab arm (p = 0.002).  Complete response (CR) rates were 30% for the 
ibritumomab tiuxetan group and 16% for the rituximab group (p = 0.04), with an additional 4% of 


 
Amendment #9: 08/28/2017 
 [14] 
patients in each arm achieving an unconfirmed CR.  The estimated (Kaplan-Meier) median duration of 
response was 14.2 months versus 12.1 months, respectively (p = 0.6) and time to progression (TTP) was 
11.2 versus 10.1 months, respectively (p = 0.173).  For the 113 patients with follicular histology (113 of 
the 143 patients), the overall response rate was 86% in the 90-Y- ibritumomab tiuxetan group versus 
55% in the rituximab group (P < 0.001), and the estimated median TTP was 12.6 months for the 90-Y-
ibritumomab tiuxetan group and 10.2 months for the rituximab group (P = 0.062). The estimated median 
DR for patients with follicular lymphoma patients treated with 90-Y ibritumomab tiuxetan was 18.5 
months versus 12.1 months for the rituximab control group (P = 0.371.   Durable responses of > 6 
months were 64% versus 47% (P = 0.030), respectively.  Although the differences in duration of 
response and TTP were not significant between arms, ORR and CR were significantly higher in the 
ibritumomab tiuxetan group.  Time to progression was longer in CR/CRu patients treated with 90-Y-
ibritumomab.   Within the group of patients with follicular lymphoma 74% had DR >  6 months, 59% > 
9 months, and 47% > 12 months on the 90-Y-ibritumomab tiuxetan arm.  Reversible hematologic 
toxicity was seen in patients treated with ibritumomab tiuxetan.   
 
 
In an open-label trial, [82, 82a] 54 patients with follicular lymphoma were accrued to learn whether 
patients who had failed to achieve a partial remission or CR (complete response) to rituximab or had a 
response that lasted less than 6 months would respond to radioimmunotherapy with Y-90-ibritumomab 
tiuxetan.  The median age was 54 years and patients had received a median of four prior regimens.  
Forty-four percent of patients had bulky disease (defined as > 7 cm) and 32% had bone marrow 
involvement.  Using the International Workshop Response Criteria, the overall response rate was 74% 
with Y-90-ibritumomab tiuxetan and the complete response rate was 15%.  The duration of response was 
7.7 months for ibritumomab tiuxetan compared to 4 months for prior rituximab in these patients (p < 
0.001).  Median time to progression had not been reached at the time of the report.  
 
A fourth study, based on findings in the phase I portion of Study 106-03, confirmed the safety of 
the dose of 0.3 mCi/kg (11 MBq/kg) (maximum 32 mCi (1.2 GBq) in patients with mild 
thrombocytopenia (100,000 to 149,000 platelets/mm3) and demonstrated significant clinical activity in 
this population with an 83% ORR (37% complete response, 6.7% complete response unconfirmed, and 
40% partial response as assessed by International Workshop Criteria). [83]   Patients with follicular 
lymphoma had an overall response rate of 92%, and estimated median TTP of 10.8 months (12.6 months 
for responders). 
 
Long-term follow-up information for the patients with B-cell NHL from the four registrational 
trials of Zevalin conducted between 1996 and 1999 has become available.   
In 2002, Gordon et al [84] reported on long-term follow-up of the patients with diffuse mixed and diffuse 
large cell lymphoma (all of whom had had prior CHOP or CHOP-like regimens) treated in the phase I/II 
study. The median age of this group was 58 years and the overall response rate was 58% (33% CRs).  At 
35.5 months of follow-up (range, 2.4-40+ months), the median duration of response had not been 
reached.  Toxicity was primarily hematologic with Grade 4 neutropenia in 17% and thrombocytopenia in 
8%.  Hematologic toxicity was reversible.  
 
More recently [85] follow-up for the entire group of 51 patients in the phase I/II study was 
reported. The overall response rate (ORR) in all patients was 73% (51% CR/Cru, 22% PR).  The ORR in 
patients with follicular lymphoma was 85% and 58% in patients with diffuse large B-cell lymphoma.  
Median time to progression (TTP) in responders was 12.6 months and DR was 11.7 months.  Median 
TTP and duration of response (DR) for CR/Cru patients were 13.4 months and 12.4 months, 


 
Amendment #9: 08/28/2017 
 [15] 
respectively.  Median TTP and DR for CR/Cru patients treated at the 0.4 mCi/kg (14.8 MBq/kg) dose 
were 28.3 and 27.5 months, respectively.  Median TTP and DR for patients in CR who were treated at 
the 0.4 mCi/kg (14.8 MBq/kg) dose was 45.0 and 44.0 months, respectively.  Median TTP in DLBCL 
patients was 4.6 months in all 12 patients, including 7 responders and 5 nonresponders.  Median DR in 
the seven responders was 49.8 months.  The reason for the large difference between TTP and DR in 
DLCL group is that the rapid progression in the nonresponders lowered the median TTP.  Median 
follow-up in this study is 28.5 months for all patients and 63 months for ongoing responders.  Nine 
patients (24% of responding patients) (five with FL and four with DLCL) had a TTP of more than 3 
years.  Five of the 9 patients (14% of all responders) (3 with FL and 2 with DLCL) are still in remission 
(DR range, 60-70+ months).    
 
Schilder et al [86] provide long-term follow-up data for the 211 patients with B-cell NHL treated 
in the four registrational trials of 90-Y ibritumomab conducted between 1996 and 1999.  Of these 
patients, 153 patients (73%) had follicular lymphoma (FL).  With ongoing follow-up, long-term durable 
responses (> 12 months) were reported for 37% of all 211 patients and for 39% of patients with 
follicular lymphoma.   Median DR and TTP for long-term responder patients were 28 months (range, 11-
80) and 29 months (range, 12-82), respectively, with a median follow-up of 50 months (range, 13-82).  
The median DR to the last prior therapy for LTR patients was 12 months.  The CR and CRu among LTR 
patients was 65%, and the median DR and TTP were 29 and 31 months, respectively, for CR/CRu 
patients.  In ongoing responders, the median DR is 52 months (range, 48-80).  Compared to the overall 
LTR patients, LTR patients with FL had similar disease characteristics, DR, TTP, and CR/CRu rates.  
Failure to respond to the therapy given immediately prior to treatment with Zevalin did not appear to 
affect the ability to achieve long-term responses with the agent.    
 
 
c. Summary of Dosimetry Results 
Dosimetry has been performed on a total of 205 patients.  A central analysis of the dosimetry 
data was completed for 179 of those patients.  Initial MIRDOSE3 estimates of radiation absorbed dose to 
uninvolved organs and red marrow, completed at the clinical site, were used to determine patient 
eligibility for RIT.  All patients studied with dosimetry met the protocol defined criteria for proceeding 
with 90Y Zevalin treatment, with estimated radiation absorbed doses below the maximum allowable of 
2000 cGy for uninvolved organs and 300 cGy for red marrow.  Subsequent to 90Y Zevalin treatment, a 
central dosimetry analysis was performed by a collaboration between Oak Ridge Associated Universities 
(ORAU) and the Mayo Clinic. This provided a uniform analysis of the patient blood and imaging data. 
A 5 mCi tracer dose of 111In Zevalin was used for imaging and dosimetry.  The radiation 
absorbed doses from 111In Zevalin and 90Y Zevalin were estimated from blood and imaging data 
obtained during the week following 111In Zevalin injection.  The radiation absorbed doses from 111In 
Zevalin were minimal.  The median estimated radiation absorbed doses from 5 mCi 111In Zevalin were 
15 cGy to spleen, 11 cGy to liver, 5 cGy to lungs, 3 cGy to kidneys, and 2 cGy to red marrow.  The 
radiation absorbed doses from 90Y Zevalin were more significant.  The median radiation absorbed doses 
from 90Y Zevalin were 742 cGy to spleen, 450 cGy to liver, 211 cGy to lungs, 23 cGy to kidneys, and 62 
cGy to red marrow.  The mean whole blood effective half-life of 90Y Zevalin was 27 +/- 5 hours. 
Hematologic toxicity did not correlate with any of the dosimetric or pharmacokinetic parameters 
analyzed, including blood derived red marrow dose, sacral image-derived red marrow dose, total body 
dose, blood effective half-life, or blood AUC.  Patients were effectively screened for safe treatment 
using clinical selection criteria including percent bone marrow involvement with NHL (< 25%), baseline 


 
Amendment #9: 08/28/2017 
 [16] 
platelet count (> 100,000 cells/mm3).  Patients were treated safely using individualized dosing based on 
patient weight and platelet count.  
These findings indicate that dosimetry is not necessary for the safe administration of 90Y Zevalin 
in this defined patient population. 
 
1.E Rationale for Current Protocol 
As detailed above, radioimmunoconjugates are effective treatments in relapsed/refractory follicular 
lymphoma when used as single agents and can result in prolonged disease control.  These remissions can 
be extremely durable in patients with the greatest reduction in tumor burden.  Radioimmunoconjugates 
used as consolidative treatment following a course of initial chemotherapy for patients with newly 
discovered follicular lymphoma produce durable remissions and appear to have changed the overall 
survival in this disease for the first time in 30 years.  
 
Subset analyses of I-131 tositumomab studies have shown that the response rate is greater in individuals 
with decreased disease burden.  In the University of Michigan experience of 59 patients treated for 
relapsed NHL, those with non-bulky disease had a higher response (82%) than did those with bulky 
disease (52%).  Complete response was better in patients with no bulk vs. bulky disease, 37% vs. 29% 
respectively. [87]  A multicenter phase III study published in 2001 demonstrated similar results.  This 
study showed that patients with decreased tumor burden had improved response (81%) vs. patients with 
greater tumor burden (39%). [88] Finally, a recently published study of I-131 tositumomab in recurrent 
indolent and transformed B-cell NHL showed again the importance of reduced tumor volume.  In this 
study patients with decreased tumor mass had a 100% overall response rate (ORR) vs. a 60% ORR in 
patients with increased tumor mass. [89]   
 
Long-term outcome information for patients with relapsed/refractory indolent lymphoma treated with Y-
90-ibritumomab tiuxetan indicates that durable long-term responses (> 5 years) can be obtained in a 
significant proportion of patients with follicular lymphoma and that improvements in CR rates improve 
TTP. [85, 86] 
 
The recent analysis by the Southwest Oncology Group of long-term outcomes obtained in sequential 
Southwest Oncology Group clinical trials for previously untreated indolent lymphoma since 1974, [90] 
clearly demonstrates the impact of monoclonal antibody therapy in the management of follicular 
lymphoma.    In this analysis, all previously untreated, advanced stage follicular lymphoma patients 
treated with three sequential treatment approaches (CHOP chemotherapy +/- non-specific 
immunostimulants (SWOG 7426 and 7713, 1974-1978); ProMACE-MOPP +/- interferon (SWOG 8809, 
1988-1994); and CHOP followed by monoclonal antibody (MoAb) therapy (SWOG 9800 [CHOP-
Rituximab] and SWOG 9911 [CHOP-I-131 tositumomab, 1998-2000) were evaluated for 4-year 
progression free survival (PFS) and 4-year overall survival (OS) by treatment strategy.  Results are 
shown below in Tables 3a and 3b. 
 


 
Amendment #9: 08/28/2017 
 [17] 
TABLE 3a. 
Progression-Free Survival by Treatment Strategy 
TREATMENT 
N 
DEATH/PROGRESSION 4-YR PFS 
CHOP + MoAb 
179 
75 
61% 
ProMACE 
425 
290 
48% 
CHOP 
356 
257 
46% 
 
TABLE 3b. 
Overall Survival by Treatment Strategy 
TREATMENT 
N 
DEATH 
   4-YR OS 
CHOP + MoAb 
179 
18 
91% 
ProMACE 
425 
189 
79% 
CHOP 
356 
226 
69% 
 
These results demonstrate that PFS remained unchanged until the recent studies that utilized CHOP 
followed by a monoclonal antibody for initial treatment.  In contrast to PFS, OS has increased with each 
subsequent treatment strategy.  These data are consistent with the hypotheses that initial therapy with 
chemotherapy followed by a monoclonal antibody has significant impact on PFS (p = 0.005) and OS (p 
< 0.0001). [90]  
 
Our hypothesis is that radioimmunocongugates significantly change outcome for patients with follicular 
lymphoma when given in the situation of minimal residual disease.   We propose to test this hypothesis 
prospectively in previously treated patients using a phase II trial design evaluating the combination of 
ESHAP chemotherapy (methylprednisolone, etoposide, cisplatin, cytarabine) followed by Zevalin.  For 
this prospective test of cytoreduction of the tumor burden followed by radioimmunoconjugate therapy, 
an outpatient formulation of ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) will be 
used as a means of reducing the mass of disease.  We propose to use this regimen for a few reasons.  
First, ESHAP has very good efficacy as a salvage regimen in treating relapsed low-grade lymphomas.  
One study [35] showed a 75% ORR and 36% CR rate in patients with relapsed disease.  
 
Second, although ESHAP is very active in low-grade NHL, it is not often utilized by community 
oncologists as a salvage regimen.  Therefore, most pretreated patients have not seen these agents and 
therefore their lymphomas should be responsive to ESHAP.  After treatment with two cycles of 
preparative ESHAP most patients should have minimal residual disease and therefore have higher 
response to Zevalin.  It is our hypothesis that tumor mass reduction with standard chemotherapy in 
relapsed follicular lymphoma will result in a significant prolongation of time to progression following 
Zevalin therapy, changing the natural history of relapsed disease. 
 
 
The TTP and OS results of this study will be compared with reported outcomes in published trials of 
Zevalin alone to assess whether there is sufficient improvement to merit further study of this approach in 
this setting.  We have designed the trial to detect an increase in 1-year PFS from a historical value of 
50% to 67.3%, which corresponds to an increase in median TTP from 12 months to 21 months.  


 
Amendment #9: 08/28/2017 
 [18] 
2 OBJECTIVES 
 
 
 
2.A Primary Objectives 
2.A.1 To evaluate the 1-year progression-free survival (PFS) of patients with relapsed     
follicular non-Hodgkin’s lymphoma (NHL) treated with ESHAP chemotherapy for 
cytoreduction 
(2 
cycles) 
followed 
by 
Ibritumomab 
tiuxetan 
(Zevalin) 
radioimmunotherapy. 
 
2.A.2 To evaluate the median TTP of patients with relapsed follicular NHL treated with  
ESHAP chemotherapy for cytoreduction (2 cycles) followed by Ibritumomab tiuxetan 
(Zevalin) radioimmunotherapy.  
 
2.B Secondary Objective 
    2.B.1 To evaluate the overall (ORR) and complete response rates (CR) of patients with relapsed 
follicular NHL treated with ESHAP chemotherapy for cytoreduction (2 cycles) followed by 
Ibritumomab tiuxetan (Zevalin) radioimmunotherapy.   
 
3 STUDY DESIGN 
 
3.A Treatment Summary 
After informed consent has been obtained, patients will undergo screening to assure eligibility for the 
study.  After two cycles of ESHAP have been given, patients will be restaged to determine response.  
Patients with residual involvement of more than 25% of bone marrow after the two cycles of ESHAP 
will be taken off treatment and followed for time to progression and survival.  Patients experiencing 
disease stabilization or reduction with less than 25% residual bone marrow involvement will undergo 
imaging for biodistribution.  If biodistribution is acceptable, then patients will receive the Zevalin 
treatment and undergo a second disease evaluation for response assessment.  Thereafter, patients will be 
followed at 6 month intervals (Short-term follow-up) for 2 years, and then annually (Long-Term follow-
up) for an additional 3 years  
 
3.B Study Duration 
The estimated active accrual period for this study is 5 years.  After completion of treatment, patients will 
be followed for 5 years to allow determination of study endpoints. 
 
4 STUDY POPULATION 
 
4.A Inclusion Criteria 
 
 
4.A.1 All patients must have a history of relapsed follicular non-Hodgkin’s lymphoma.  Patients 
must be in first, second, third, or fourth relapse.  
 
 
4.A.2 Lymphomas must express the CD20 antigen as demonstrated by either flow cytometry or 
immunoperoxidase staining of paraffin sections using anti-CD20 antibodies.   
 


 
Amendment #9: 08/28/2017 
 [19] 
 
4.A.3 Patients must have bulky Stage II, Stage III, or Stage IV extent of disease by the Ann 
Arbor classification (see Appendix F).   Bulky disease is defined as any tumor measuring 
10.0 cm or greater or occupying > one-third of the chest diameter.   
 
 
4.A.4 All  patients must have bidimensionally measurable disease (as defined in Appendix D) 
documented within 28 days prior to C1, Day 1.   
 
            
4.A.5 Pathology Review:  Adequate sections from the diagnostic specimen or core needle 
biopsies which are large enough to show architecture (bone marrow biopsies and fine-
needle aspirates are insufficient) is desirable. At a minimum, a report documenting the 
diagnosis is required. 
 
            
4.A.6 Patients must have a unilateral or bilateral bone marrow aspirate and biopsy performed 
within 28 days prior to Cycle 1, Day 1.   
 
            
4.A.7 Patients must have a CT or PET scan of chest, abdomen, and pelvis within 28 days prior 
to Cycle 1, Day 1.   
 
 
4.A.8 Patients must have an LDH and β-2 microglobulin within 28 days prior to  
  
 
Cycle 1, Day 1.  
  
 
4.A.9 Patients must have received prior chemotherapy for lymphoma.   
(Patients must have had at least 1, but no more than 4 prior chemotherapy regimens for 
lymphoma.   This includes investigational agents and/or other antibody therapy.  All prior 
therapy must have been completed at least 3 weeks prior to registration.  Patient who 
previously received rituximab must have completed this therapy 6 weeks prior to 
registration.  If rituximab is given as a single agent after relapse, it is considered a 
separate regimen and will be counted as such.  If the rituximab is given in combination 
for either the first or second relapse or as consolidation after a chemotherapy regimen 
without an intervening relapse, it will considered part of the combination regimen and 
counted as one prior therapy.  Patients must have recovered from any prior-therapy-
related toxicities prior to Cycle 1, Day 1.) 
 
 
 
 
4.A.10  All patients must have a Zubrod performance status of 0, 1, or 2  
 
 
(see Appendix B). 
 
 
4.A.11 Patients must be 18 years old or older.   
 
 
4.A.12 Patients must have absolute neutrophil count (segmented neutrophils and bands)  1,500 
/µL and platelets > 100,000/µL within 28 days prior to Cycle 1, Day 1 unless decreased 
counts have been shown to be due to marrow involvement with NHL. 
 
NOTE:  For progression to treatment with Zevalin:  Patients must have < 25% bone marrow 
involvement with lymphoma as determined after cycle 2 of ESHAP.   For patients without bone 
marrow involvement, there must be adequate bone marrow reserves as defined under 
EXCLUSION.  (These criteria must be strictly met for adequate patient safety.)   


 
Amendment #9: 08/28/2017 
 [20] 
Additionally, patients must have:  
• serum creatinine value < 2.0 and total bilirubin < 2.0. 
• Platelet counts ≥ 150,000/mm3, these patients will receive a dose of 0.4 mCi/kg of Zevalin 
• Platelet counts from 100,000/mm3 to 149,000/mm3, these patients will receive a 0.3 mCi/kg 
dose of Zevalin 
            4.A.13 Patients with renal insufficiency or renal failure (serum creatinine > 2.0 mg/dL; creatinine 
clearance < 50 ml/min) are not eligible for this study.  A serum creatinine or creatinine 
clearance must be obtained within 28 days prior to Cycle 1, Day 1.  
 
  
 
4.A.14 Pregnant or nursing women may not participate.  Women or men of reproductive 
potential must agree to use an effective contraceptive method as determined by the 
treating physician from the time of Cycle 1, Day 1 to 6 months after receiving the 
Zevalin.  
  
 
4.A.15 No prior malignancy is allowed except for adequately treated basal cell or squamous cell 
skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-
free for 5 years.  
 
4.A.16 If Day 28 falls on a weekend or holiday, the limit may be extended to the next working 
day.  In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0.  Therefore, if a test is done on a Monday, the Monday 4 
weeks later would be considered Day 28.  This allows for efficient patient scheduling 
without exceeding the guidelines.   
 
 
4.A.17 All patients must be informed of the investigational nature of this study and give written 
informed consent in accordance with institutional and federal guidelines.   
 
4.A.18  Expected survival ≥ 3 months 
4.B Exclusion Criteria 
 
4.B.1 Patients with impaired bone marrow reserve, as indicated by one or more of the 
following: 
 
                  •    Platelet count  < 100,000 cells/mm3 
 
                  •    Hypocellular bone marrow (cellularity < 10%)   
 
• Marked (> 10%) reduction in bone marrow precursors of one or more cell lines 
(granulocytic, megakaryocytic, erythroid) (beyond that which would be expected for the 
patient’s age and bone marrow cellularity 
 
 
                  •    History of failed stem cell collection 
 
4.B.2 Prior radioimmunotherapy 


 
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4.B.3 Presence of CNS lymphoma. Patients must not have clinical evidence of central nervous 
system (CNS) involvement by lymphoma.   
 
 
4.B.4 Patients with abnormal liver function:  total bilirubin > 2.0 mg/dL 
 
 
4.B.5 Patients with abnormal renal function: serum creatinine > 2.0 mg/dL or creatinine 
clearance < 50 ml/min. 
 
 
4.B.6 Patients who have received prior external beam radiation therapy to > 25% of active bone 
marrow (involved field or regional) 
 
 
4.B.7 Patients who have received G-CSF or GM-CSF therapy within 2 weeks prior to treatment 
 
 
4.B.8 Serious nonmalignant disease or infection which, in the opinion of the investigator and/or 
the sponsor, would compromise other protocol objectives 
 
 
4.B.9 Major surgery, other than diagnostic surgery, within 4 weeks 
 
 
 
4.B.10 Patients with pleural effusion 
 
4.C Number of Patients to be Enrolled   
All patients who receive at least one dose of chemotherapy ESHAP  will be considered evaluable 
and will be included in the analysis.   Fifty-two evaluable patients are needed.  Although it is 
considered highly unlikely that a patient who has given consent (enrolled) for treatment would 
not be treated, if this were to occur, an additional patient would be enrolled to meet the goal of 
52 evaluable patients. 
 
4.D Patient Enrollment Procedure 
All ethical, regulatory, technical, and scientific approvals must be in place before study 
registrations will be accepted.   All patients will be registered centrally with the Clinical Research 
Coordinator based in the Arizona Cancer Center at 520-694-9053.  The Clinical Research 
Coordinator will assign each patient a sequential number. Prior to registration, the fully signed 
informed consent must be presented and all inclusion and exclusion criteria will be reviewed 
with the registering investigator or designee.  All source documentation needed to confirm 
eligibility must be available for this review. 
 
5 STUDY PROCEDURES 
 
5.A Screening/Baseline Evaluations 
Unless otherwise specified, the following evaluations must be performed within 28 days prior to C1, D1: 
5.A.1  
Medical history, including documentation of all prior lymphoma treatments and 
documentation of the rationale for treatment of the patient's lymphoma with Zevalin 


 
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5.A.2 
Physical examination, including vital signs (BP, temperature & pulse), height, weight, 
Body Surface Area (BSA) & performance status (Appendix B). 
5.A.3 
Disease Assessment 
• Total of all measurable indicator lesions 
• CT or PET scan of the chest, abdomen and pelvis is recommended for baseline 
response evaluation. 
      5.A.4 
Laboratory tests including: 
• Complete blood count (CBC) with differential and platelet count  
• Serum chemistries - BUN, creatinine, total bilirubin, alkaline phosphatase, LDH, 
SGOT (AST), SGPT (ALT) 
• Serum beta-2-microglobulin 
• Pregnancy test (serum) for women of childbearing potential 
• Hepatitis B screen (encouraged by Good Medical Practice, but not required) 
      5.A.5 
Unilateral or Bi-lateral bone marrow biopsy and aspirate for histology and determination 
of percent bone marrow involvement 
      5.A.6 
Bone marrow cytogenetics (Results are not required prior to enrollment). This can also be 
done with the repeat Bone Marrow biopsy and aspirate at Cycle 2, Day 29. This does not 
have to be done at each Bone Marrow biopsy and aspirate, but does need to be completed 
at either, Baseline or Cycle 2, Day 29. 
5.A.7 
Pathology Review: All patients registered on this study are encouraged to undergo 
pathology review.  The purpose of this review is to verify the histologic diagnosis of an 
indolent non-Hodgkin lymphoma and that the patients are CD20 positive.  Any excess 
tissue will be retained by the Arizona Cancer Center (unless the patient denies consent).   
a  Pathology materials are to be submitted to:  
Lisa Rimsza, M.D. 
Department of Pathology 
The University of Arizona Cancer Center 
1501 N. Campbell Avenue 
Tucson, AZ 85724-0001 
Phone: (520) 626-2212 
b The following materials would constitute best available material for review:  
• Representative H&E stained slides form the diagnostic biopsy.  (Note: 
Needle aspirates are not adequate for this submission.  Consult Dr. Rimsza 
if adequacy of the specimen is in question.) 
• One representative paraffin block which will be conserved (no more than 
eight additional slides will be cut).  
• One copy of the pathology report.   
 


 
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5.B  Evaluations During ESHAP Treatment Period 
For the purpose of toxicity assessment, the treatment period will include the time from the first ESHAP 
infusion to 30 days following Zevalin infusion.  Evaluations during the 2 cycles of ESHAP are outlined 
in Appendix A. 
 
 
5.B.1 ESHAP Cycle 1, Day 1 
a. Begin ESHAP Treatment (Please refer to Section 7A for ESHAP administration) 
 
 
5.B.2 ESHAP Cycle 2, Day 1 
a. History & Physical examination, including vital signs (BP, temperature & pulse), height, 
weight, Body Surface Area (BSA), and performance status (Appendix B). 
 
b. Laboratory tests including: 
• 
Complete blood count (CBC) with differential and platelet count  
• 
Serum chemistries - BUN, creatinine 
 
c. Toxicity Assessment: Adverse events are to be recorded on an ongoing basis and on 
appropriate source documents at the clinical site and in the patient's case report form.  
 
 
 
5.B.3 ESHAP Cycle 2, Day 29  
a. History & Physical examination, including vital signs (BP, temperature & pulse), height, 
weight, Body Surface Area (BSA) & performance status (Appendix B).  
 
b. Laboratory tests including: 
• 
Complete blood count (CBC) with differential and platelet count  
• 
Serum chemistries - BUN, creatinine 
 
c. Unilateral or Bi-lateral bone marrow biopsy and aspirate for histology and determination 
of percent bone marrow involvement 
 
d. Bone marrow cytogenetics. Does not have to be done at each Bone Marrow biopsy and 
aspirate, but does need to be completed at either, Baseline or Cycle 2, Day 29. 
 
e. Disease Assessment: 
• 
Total of all measurable indicator lesions. 
• 
CT or PET scan of the chest, abdomen and pelvis  
 
f. Toxicity Assessment: Adverse events are to be recorded on an ongoing basis and on 
appropriate source documents at the clinical site and in the patient's case report form.  


 
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5.C Evaluations During the Zevalin Imaging & Treatment Period 
Ibritumomab Tiuxetan Indium (111In Zevalin) regimen is administered 4 – 6 weeks after completion of 
ESHAP. 
 
5.C.1 Day 1 
a. History & Physical examination, including vital signs (BP, temperature & pulse), 
height, weight, Body Surface Area (BSA), and performance status are to be 
performed within 28 days of Rituximab & Zevalin administration.  (Appendix B). 
b. Toxicity Assessment: Adverse events are to be recorded on an ongoing  
basis and on appropriate source documents at the clinical site and in the patient's 
case report form.  
c. Laboratory tests including: 
• Complete blood count (CBC) with differential and platelet count  
• Serum chemistries - BUN, creatinine 
 
The above mentioned tests and assessment are to be performed within 28 days of 
Rituximab & Zevalin administration. 
 
d. Rituxaimab Infusion (250 mg/m2) &  111In Zevalin (Ibritumomab Tiuxetan Indium) 
infusion. (Please refer to section 7.B for detailed treatment administration) 
5.C.2 Days 2, 3, 4 and 5 
a. Gamma Scan: A scan is to be performed at 48-72 hours after 111In Zevalin 
(Ibritumomab Tiuxetan Indium) infusion. Another optional scan may be performed at 90-120 
hours after 111In Zevalin (Ibritumomab Tiuxetan Indium) infusion.  
CAUTION WILL BE TAKEN IN THE HANDLING OF ALL RADIOACTIVE SAMPLES 
ACCORDING TO STANDARD PROCEDURES AND PRACTICES AT THE CLINICAL 
SITE. 
The purpose of 111In Zevalin (Ibritumomab Tiuxetan Indium) imaging is twofold: 
• To evaluate biodistribution of whole body gamma camera images 
• To assess whether biodistribution is acceptable to proceed with 90Y Zevalin (Ibritumomab 
Tiuxetan Ytrium-90) radioimmunotherapy. 
 
The biodistribution of 111In Zevalin (Ibritumomab Tiuxetan Indium) 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.  Images should be acquired using a large field of view gamma camera quipped with a 
medium energy collimator.  Whole body anterior/posterior planar images should be acquired using a 
large field-of-view gamma camera and medium energy collimators.  Suggested gamma camera settings: 
256 x 1024 matrix; dual energy photopeaks set at 172 and 247 keV; 15% symmetric window; scan speed 
of 10 cm/min for the 48-72 hour scan, and 7-10 cm/min for subsequent scans.  


 
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 Expected biodistribution: 
• Activity in the blood pool areas (heart, abdomen, neck, and extremities) may be faintly 
visible. 
• Moderately high to high uptake in normal liver and spleen. 
• Moderately low or very low uptake in normal kidneys, urinary bladder, and normal 
(uninvolved) bowel. 
• Non-fixed areas within the bowel lumen that change position with time; delayed imaging 
as described above may be necessary to confirm gastrointestinal clearance. 
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.  Tumor visualization on 
the 111In Zevalin (Ibritumomab Tiuxetan Indium) scan is not required for 90Y Zevalin (Ibritumomab 
Tiuxetan Ytrium-90) therapy. 
 Altered biodistribution 
• Intense localization of radiotracer in the liver and spleen and bone marrow indicative of 
reticuloendothelial system uptake 
• Increased uptake in normal organs (not involved by tumor) such as: 
o Diffuse uptake in normal lung more intense than the liver. 
o Kidneys with greater intensity than the liver on the posterior view. 
o Fixed areas (unchanged with time) of uptake in the normal bowel greater than 
uptake in the liver. 
o In less than 0.5% of patients receiving 111In Zevalin (Ibritumomab Tiuxetan 
Indium), prominent bone marrow uptake was observed, characterized by clear 
visualization of the long bones and ribs. 
If a visual inspection of the gamma images reveals an altered biodistribution, the patient should 
not proceed to the 90Y Zevalin (Ibritumomab Tiuxetan Ytrium-90) dose.  The safety and efficacy of the 
administration of 90Y Zevalin (Ibritumomab Tiuxetan Ytrium-90)in patients with prominent marrow 
uptake is not known.  Possible causes of prominent bone marrow uptake, such as bone marrow 
involvement by lymphoma, increased marrow activity due to recent hematopoietic growth factor 
administration, and increased reticuloendothelial uptake in patients with HAMA and HACA, should be 
considered.  Re-assessment of biodistribution after correction of underlying factors should be performed.  
90Y Zevalin (Ibritumomab Tiuxetan Ytrium-90) should not be administered to patients with persistently 
prominent marrow uptake on the repeat biodistribution scans.  
 
5.C.3 Day 7, 8 or 9 
a. Rituximab Infusion & 90Y Zevalin (Ibritumomab Tiuxetan Ytrium-90) Infusion (Please 
refer to section 7.B for detailed treatment administration) 
 
5.C.4  Day 35 (+/- 7 days) 
 
 
 
a. Laboratory tests including: 
Complete blood count (CBC) with differential and platelet count. To be done every week 
until any count abnormalities have passed nadir. 
 


 
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5.D Restaging 
5.D.1 3 Months Post- 90Y Zevalin (Ibritumomab Tiuxetan Ytrium-90) Infusion 
The following tests/evaluations will be obtained 3 months (+/- 7 days) post 90Y Zevalin 
Infusion: 
a.   History & Physical examination, including vital signs (BP, temperature & pulse), 
height, weight, Body Surface Area (BSA) & performance status (Appendix B).  
b.   Laboratory tests including: 
• Complete blood count (CBC) with differential and platelet count  
• Serum chemistries - BUN, creatinine 
• LDH 
c. Disease Assessment: 
• Total of all measurable indicator lesions. 
• CT or PET scan of the chest, abdomen and pelvis  
d. Toxicity Assessment: Adverse events are to be recorded on an ongoing basis and on 
appropriate source documents at the clinical site and in the patient's case report form.  
5.E Follow-Up Evaluations  
5.E.1 Short-Term Follow-Up Period 
 
a. The following tests/evaluations will be obtained at 6-month intervals (+/- 7 days) for 
a period of 2 years (24 months) following the Zevalin: 
• History & Physical examination, including vital signs (BP, temperature & 
pulse), height, weight, Body Surface Area (BSA), and performance status 
(Appendix B). 
• Laboratory tests including: 
o Complete blood count (CBC) with differential and platelet count  
o Serum chemistries - BUN, creatinine 
o LDH 
• Disease Assessment (Only required at 6-month intervals for a period of 2 
years (24 months) following Zevalin): 
o Total of all measurable indicator lesions. 
o CT or PET scan of the chest, abdomen and pelvis (Restaging of 
disease by CT scan is recommended every 6 months up to Month 24, 
then annually until year 5). 
 
 


 
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5.E.2 Long-Term Follow-Up Period 
a.   The following tests/evaluations will be obtained annually (+/- 30 days) for an 
additional 3 years after the completion of the Short-Term Follow-Up period: 
• History & Physical examination, including vital signs (BP, temperature & 
pulse), height, weight, Body Surface Area (BSA), and performance status 
(Appendix B). 
• Laboratory tests including: 
o Complete blood count (CBC) with differential and platelet count  
o Serum chemistries - BUN, creatinine 
o LDH 
• Disease Assessment: 
o Total of all measurable indicator lesions. 
o CT or PET scan of the chest, abdomen and pelvis 
 
Once the patients have completed  the Short-Term Follow-Up period they will continue to 
be followed for 3 years on an annual basis (+/- 30 days) for survival and disease status. Patients 
should be followed by physical exam and, if clinically indicated by Good Medical Practice, CT 
or PET scans.  Patients will be followed for 3 years or until patient starts alternate treatment or is 
removed from study to allow determination of study endpoints. 
 
5.F Disease Progression Evaluations/Off-Study 
Patients who develop disease progression during the treatment period and who do not begin other 
anti-cancer therapy will continue to be followed for routine safety and efficacy for a total of 30 days 
following any discontinuation of treatment for any cause. 
5.F.1 Tests to be Performed When a Patient is Determined to Have Disease Progression or 
is Removed from the Study for any Reason 
 
The following tests will be performed within 4 weeks after a patient has demonstrated 
progression of disease, or removed from study: 
It is strictly mandated that patients not be given other myelosuppressive anti-neoplastic 
agents until recovery from hematologic nadir.  
These tests do not have to be repeated if they were performed within 7 days prior to 
documentation of disease progression. 
a. History & Physical examination, including vital signs (BP, temperature & pulse), 
height, weight, Body Surface Area (BSA), and performance status (Appendix B). 
b. Laboratory tests including: 
• Complete blood count (CBC) with differential and platelet count  
• Serum chemistries - BUN, creatinine 


 
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• LDH 
c.Disease Assessment (if patient is removed from the study for a cause other than 
progressive disease): 
• Total of all measurable indicator lesions. 
• CT or PET scan of the chest, abdomen and pelvis 
d.Toxicity Assessment: Adverse Events (AE) are to be recorded on an  
ongoing basis until resolved or determined to be permanent. All  
AEs are to be documented on appropriate source documents at the  
clinical site and in the patient's case report form. 
 
6 DRUG INFORMATION 
 
6.A. 
ESHAP Regimen Drug Information 
6.A.1.  Cisplatin (CDDP) (Platinol) (NSC-119875)  
a. 
DESCRIPTION  
Cis-diamminedichloroplatinum (Patinol or cisplatin) is a heavy metal complex 
and is water-soluble.  It is a white lyophilized powder with a molecular weight of 
300.1. 
b. 
TOXICOLOGY 
Human Toxicology:  Human toxicity includes anorexia, nausea, vomiting, renal 
toxicity (with an elevation of BUN, creatinine, serum uric acid and impairment of 
endogenous creatinine clearance, as well as renal tubular damage), ototoxicity 
(with hearing loss which initially is in the high-frequency range, as well as 
tinnitus), peripheral neuropathy and hyperuricemia.  Much more severe and 
prolonged toxicity has been observed in patients with abnormal or obstructed 
urinary excretory tracts.  Raynaud’s phenomena and digital ischemia has been 
described. 
 
Anaphylactic-like 
reactions 
including 
facial 
edema, 
bronchoconstriction, tachycardia and hypotension may occur within minutes of 
administration.  Myelosuppression, often with delayed erythrosuppression, is 
expected.  In the high-dose treatment regimen with osmotic diuresis, the nadir of 
white cells and platelets occurred regularly at about two weeks with recovery 
generally at about three weeks after the initiation of therapy.  Rare complications 
are alopecia, seizures, loss of taste and allergic reactions.  Tetany may occur due 
to hypomagnesemia and/or hypocalcemia.  Other electrolyte disturbances may 
occur.  At high doses patients have experienced optic neuritis, papilledema, 
cerebral blindness, blurred vision, and altered color perception.  Patients have also 
experienced cardiac abnormalities, elevated SGOT and rash.  Subsequent courses 
should not be given until serum creatinine returns to normal if elevated.  
Audiometric analyses should be monitored and courses withheld until auditory 
acuity is within normal limits.  The occurrence of acute leukemia has been 
reported rarely in patients treated with anthracycline/alkylator combination 
chemotherapy. 


 
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 [29] 
 
Pregnancy and Lactation:  Cisplatin can cause fetal harm when administered to a 
pregnant woman.  In mice, cisplatin is teratogenic and embryotoxic.  No 
information is available on the excretion of this drug in human milk.  Because 
many drugs are excreted in human milk and because of the potential for serious 
adverse reactions in nursing infants, it is recommended that nursing be 
discontinued. 
 
c. 
PHARMACOLOGY 
Kinetics:  After a single IV dose, increased concentration is found in the liver, 
kidneys and a small and large intestines.  Plasma levels of cisplatin decay in a 
biphasic mode with an initial half-life of 25-49 minutes, and a secondary phase 
ranging from 58 to 73 hours.  This prolonged phase is due to protein binding 
which exceeds 90% of the radioactivity in the second phase.  Urinary excretion is 
incomplete with only 27 to 43% of the radioactivity excreted in the first five days.  
The initial fractions of radioactivity are largely unchanged drugs.  Although this 
drug seems to act as an alkylating agent, there are data to indicate that its mode 
and sites of actions are different from those of nitrogen mustard and the standard 
alkylating agents.  Cisplatin penetrates into CNS poorly.    
 
Formulation:  Cisplatin is available as 10 mg and 50 mg vials of dry powder 
which are reconstituted with 10 ml and 50 ml of Sterile Water for Injection USP, 
respectively.  Cisplatin is also available as an aqueous solution, 1 mg/ml, in 50 or 
100 ml vials. 
 
Storage and Stability:  The intact vials may be stored at room temperature (15-25 
degrees C) for the lot life indicated on the package.  Do not refrigerate.  Once 
reconstituted, the solution should be kept at room temperature to avoid 
precipitation.  The reconstituted solution is stable for 20 hours at room 
temperature, although, due to lack of preservatives, the solution should be used 
within eight hours of reconstitution.  The solution may be further diluted in a 
chloride-containing vehicle such as D5NS, NS, or D5-1/2 NS (precipitate occurs 
in D5w). 
 
Administration:  In this protocol, cisplatin will be given immediately after 
preparation as an intravenous infusion over a 60 minute period.  Needles or 
intravenous sets containing aluminum parts that may come in contact with 
cisplatinum (Platinol) should not be used for preparation or administration, 
as a black precipitate is formed with 30 minutes. 
 
Supplier:  Cisplatin is commercially available for purchase by a third party.   
 
6.A.2     Cytosine Arabinoside (Ara-C) (Cytarabine) (Cytosar U) (NSC-63878)  
a. 
DESCRIPTION 
Ara-C is chemically 4-amino-1-S-D-arabino-furanosyl-2 (1H)-primidinone.  Ara-
C is metabolized to its active form, ara-CTP.  The ara-CTP functions as an 
inhibitor of DNA polymerase.  Ara-C exhibits cell phase specificity, killing cells 


 
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undergoing DNA synthesis (S phase) and may also block cells from progressing to 
S phase from G1.  Extensive chromosomal damage, including chromatid breaks, 
occurs.  Ara-C appears to be most effective in tumors with high growth fraction. 
 
b. 
TOXICOLOGY 
Human Toxicology:  Side effects of ara-C include myelosuppression, nausea, 
vomiting, diarrhea, anorexia, anal ulceration, stomatitis, rash, headache, fever, 
myalgia, malaise, bone pain, chest pain, hepatic and renal dysfunction, and 
alopecia.  Central nervous system toxicity, i.e., signician cerebral and cerebellar 
dysfunction, progression to coma, has been seen with high doses.  Severe 
cardiomyopathy has been reported with high dose ara-C in combination with 
cyclophosphamide.  Progressive ascending paralysis has occurred in two patients 
receiving IV and intrathecal ara-C.  Marked keratoconjuncitivitis has also 
occurred with high doses.   
 
The most frequently reported reactions after intrathecal administration were 
nausea, vomiting and fever.  Paraplegia and meningitis has been reported with 
intrathecal administration.  Ara-C given intrathecally may cause systemic toxicity 
and careful monitoring of the hemopoietic system is indicated.  If used 
intrathecally of if high dose therapy is used, do not use a diluent containing benzyl 
alcohol. 
 
Ara-c can cause fetal harm when administered to a pregnant woman, however, 
there are no adequate and well-controlled studies in pregnant women. 
 
c. 
PHARMACOLOGY 
Kinetics:  Ara-C is metabolized by deoxycytidine kinase and related kinases to 
nucleotide triphosphate, which is an active inhibitor of DNA polymerase.  
Deoxyccytidine prevents or delays cytotoxic activity.  The active form is 
converted to nontoxic uracil derivatives by pyrimidine nucleoside deaminases.  
The balance of kinase and deaminase levels appears to be an important factor in 
sensitivity/resistance of the cell to ara-C.  After IV injection, plasma 
disappearance of ara-C is biphasic.  Initial half-life is 10 minutes, delayed half-life 
if 1-3 hours.  After 24 hours, 80% is excreted in the urine as its inactive 
metabolite, ara-U.  After a single IV administration of ara-C, levels in CSF are 
low.  With intrathecal administration, half-life is 2 hours.  There is little 
conversion to ara-U because of low CSF levels of diaminase.  Drug interaction of 
ara-C has been reported with digoxin, gentamycin and fluorocytocine. 
 
Formulation:  Ara-C is supplied as a sterile powder in 100 mg and 500 mg vials 
for injection.  Ara-C is also available in 1 and 2 gram vials.  The drug should be 
reconstituted with sterile water for injection. 
 
Storage and Stability:  The sterile powder should be stored at room temperature 15 
degrees to 30 degrees C (59-86 degrees).  The resulting solution has a stability of 
48 hours if stored at ROOM TEMPERATURE.  Do not use if even a slight haze 


 
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develops.  The reconstituted solution may be further diluted in 5% Dextrose or 
sodium chloride injection. 
 
Administration:  Ara-C is usually administered by continuous IV infusion, but IV 
bolus and subcutaneous use have their place in treating certain leukemic responses 
(i.e., maintenance or remission). 
 
Supplier:   Ara-C is commercially available and therefore should be purchased by 
the third party.   
 
6.A.3     Etoposide (VP-16) (Vespesid) (Ethylidene-Lignan P.) (NSC-141540)  
a.      DESCRIPTION 
 
 
 
Chemistry:  VP 16 is a semi-synthetic podophyllotoxin derivative  
from the plant podophyllum pletatum, and has antineoplastic properties in 
experimental animals, and in man.  The empiric formula C29H32O13 has a 
molecular weight of 588. 
 
Mechanism of Action:  The epipodophyllotoxins exert phase specific spindle 
poison activity with metaphase arrest, but in contrast to the vinca-alkaloids, have 
an additional activity of inhibiting cells from entering mitosis.  Suppression of 
titrated thymidine, uridine, and leucine incorporation in human cells in tissue 
culture suggests effects against DNA, RNA and protein synthesis. 
 
Animal Tumor Data:  Significant antitumor effect has been demonstrated in 
L1210, mouse sarcoma 37 and 180, Walker carcinosarcoma and Erlich ascites 
tumor.  With the L1210 system, activity was schedule-dependent, having greater 
effect with a twice-weekly administration than with daily dosing or the 
administration of single large doses.  The drug is active given intraperitoneally or 
orally in L1210.  No effect was demonstrated against intracerebrally inoculated 
1210. 
 
b.      TOXICOLOGY 
Animal Toxicology:  The predominant toxicities of VP-16 in animal studies 
involve the hematopoietic system, with toxicity to the liver and GI tract occurring 
only at doses producing profound myelosuppression.  Anemia, Leukopenia, and 
lymphoid involution occur in mice, rats, and monkeys.  Acute toxicity 
investigations have been complicated by the toxicity of the solvent system.  The 
LD-50 of the solvent plus drug approached that of the solvent alone.  
Immunosuppressive effects occur with an inhibition of antibody production in 
mice and monkeys, and prevention of experimental allergic encephalomyelitis in 
rats (cell-mediated immunity). 
 
Human Toxicology:  Reversible myelotoxicity has been uniformly observed to be 
the major toxicity of VP-16 and to represent the only clinically significant side 
effect.  Following a single IV injection, peak myelotoxicity occurs at seven to nine 
days.   Following daily IV injections for five to seven days, myelotoxicity is 
maximal between 12 – 16 days from the initiation of therapy.  Bone marrow 


 
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suppression is mainly manifested as granulocytopenia, with thrombocytopenia 
transient modest nausea, vomiting and diarrhea, are common.  Other reactions 
could include aftertaste, rash, pigmentation, pruritis, abdominal pain, constipation 
and dysphagia.  Occasional alopecia is reported.  VP-16 does not produce 
phlebitis, or nephrotoxicity.  Rarely, anaphylactic-like reactions have been 
reported, as well as, hypotension.  Hypotension can be managed by infusing the 
drug over at least a 30-minute period.  Occasionally, chills, fever, peripheral 
neurotoxicity, stomatitis, hepatotoxicity, transient cortical blindness and radiation 
recall dermatitis may be a result of VP-16 administration.  The occurrence of 
acute leukemia has been reported rarely in patients treated with VP-16 in 
association with other anti-neoplastic agents.  VP-16 can cause fetal harm when 
administered to pregnant women. 
 
Pregnancy and Lactation:  Etoposide can cause fetal harm when administered to a 
pregnant woman.  Etoposide has been shown to be teratogenic in mice and rats.  
In these studies, etoposide caused dose-related maternal toxicity, embryotoxicity, 
and teratogenicity.  Fetal abnormalities included decreased weight, major skeletal 
abnormalities, 
exencephaly, 
encephalocele, 
anopthalmia, 
and 
retarded 
ossification.  No information is available on excretion of this drug in human milk.  
Because many drugs are excreted in human milk and because of the potential for 
serious adverse reactions in nursing infants, it is recommended that nursing be 
discontinued. 
 
c.      PHARMACOLOGY  
Kinetics:  After IV administration, disposition is biphasic with initial half-life of 
1.5 hours and terminal half-life of 4 – 11 hours.  Drug does not accumulate in 
plasma following daily administration of 100 mg/M2 for 4 – 5 days.  Drug crosses 
blood-brain barrier poorly.  Recovery after IV administration of radiolabeled 
etoposide in the urine ranges from 42 – 67% and feces from 0 – 16%.  The 
mutogenic and genotoxic potential has been established in mammalian cells. 
 
Formulation:  100 mg of VP-16 is supplied as 5 ml of solution in Sterile Multiple 
Dose Vials for injection.  The pH of the yellow clear solution is 3 – 4.  Each ml 
contains 20 mg VP-16, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg polysorbate 
80/tween 80, 650 mg polyethylene glycol 300, and 30.5% (v/v) alcohol.  VP-16 
must be diluted prior to use with either 5% Dextrose Injection, USP, or o.9% 
sodium Chloride Injection, USP.  The time before precipitation occurs depends on 
concentration, however, when at a concentration of 0.2 mg/ml it is stable for 96 
hours at room temperature and at o.4 mg/ml it is stable for 48 hours. 
 
Storage and Stability:  The drug is available as a box of 10 vials that are stored at 
room temperature.  Each vial should be kept in the box to protect it from light.  
VP-16 is less stable in 5% Dextrose injection and precipitation is reported. 
 
Administration:  VP-16 has a minimum infusion time of 30 minutes to reduce 
hypotension.  In this protocol, VP-16 will be given over 60 minutes.   
 


 
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 [33] 
Supplier:  VP-16 is commercially available for purchase by a third party.   
 
6.A.4      Methylprednisolone sodium succinate (Solu-Medrol) 
a. 
DESCRIPTION 
Methylprednisolone is a glucocorticoid that is given intravenously.   
 
b. 
TOXICOLOGY 
Human Toxicology: Possible adverse effects associated with methylprednisolone 
are: fluid and electrolyte disturbances, congestive heart failure in susceptible 
persons, hypertension, euphoria, personality changes, insomnia, mood swings, 
depression, exacerbation of infection (e.g., tuberculosis), exacerbation or 
symptoms of diabetes, psychosis, muscle weakness, osteoporosis, vertebral 
compression fractures, pancreatitis, esophagitis, peptic ulcer, dermatologic 
disturbances, convulsions, vertigo and headache, endocrine abnormalities, 
ophthalmic changes, and metabolic changes.  Some patients have experienced 
itching and other allergic, anaphylactic or other symptoms including fever, 
myalgia and arthralgia.  Phenytoin, phenobarbitol and ephedrine enhance 
metabolic clearance of corticosteroids.   
 
Corticosteroids should be used cautiously in patients with hypothyroidism, 
cirrhosis, ocular herpes simplex, existing emotional instability or psychotic 
tendencies, 
nonspecific 
ulcerative 
colitis, 
diverticulitis, 
fresh 
intestinal 
anastomoses, peptic ulcer, renal insufficiency, hypertension, osteoporosis and 
myasthenia gravis.  Immunization procedures (especially smallpox vaccination) 
should not be undertaken in patients on corticosteroids.   
 
c. 
PHARMACOLOGY 
Kinetics: Methylprednisolone is extremely soluble in water.  It is well-suited for 
intravenous use and high levels are obtained rapidly.  Glucocorticoids have salt-
retaining properties.  The anti-inflammatory property of this drug is its ability to 
modify the body’s immune system.  On the other hand, glucocorticoids suppress 
the body’s response to viral as well as bacterial infections.  Equivalent doses are 
as follows:  
 
Methylprednisolone 
Dexamethasone 
Prednisone 
Hydrocortisone Cortisone 
4 mg 
0.75 mg 
5 mg 
20 mg 
25 mg 
 
 
Formulation:  Several formulations are available.  Act-O-Vial comes in 40 
mg/mL, 125 mg/2 mL, and 500 mg/4 mL.  Another available formulation is 500 
mg/8 mL.   
 
Storage and Stability: The unreconstituted product may be stored at room 
temperature 20° to 25° C.  The product in solution can also be stored at room 
temperature.  The solution must be used within 48 hours.  The product must be 
protected from light.   


 
Amendment #9: 08/28/2017 
 [34] 
 
Administration:  Methylprednisolone is administered by the intravenous route.   
 
Supplier: Methylprednisolone is commercially available and should be purchased 
by third party.  
 
 
6.B Rituximab Drug Information 
 
 
6.B.1 DESCRIPTION 
 
Rituximab is a mouse/human chimeric monoclonal antibody consisting of human IgG1 heavy 
and kappa light chain constant regions with murine variable regions from the murine IgG1 kappa anti-
human CD20 monoclonal antibody rituximab. The rituximab antibody is produced by a Chinese hamster 
ovary transfectoma. 
 
 
6.B.2 TOXICOLOGY 
 
Human Toxicology: Single doses of up to 500 mg/m2 and weekly x 4 doses of 375 mg/m2 have 
been administered without dose limiting toxicity. Adverse events are most common during the initial 
antibody infusion and usually consist of Grade 1, or 2 fever (73%), asthenia (16%), chills (38%), nausea 
(19%), vomiting (11%), rash (14%), and t umor site pain (3%). Grade 1 or 2 hypotension (8%) may be 
treated with IV fluids. Hematologic toxicity is usually mild and reversible. Transient decreases in the 
WBC or platelet count have been observed – especially in patients with high levels of circulating tumor 
cells or bone marrow involvement. Two patients have had late-onset Grade 4 neutropenia at four and ten 
months that was attributed to an unknown cause, were transient and resolved. Infections (Grade 1 and 2) 
have not been related to dose level. Symptoms are generally associated with the initial antibody 
infusions and diminish in frequency with each successive infusion. 
 
 
Infusion Reaction: An infusion-related symptom complex consisting of fever and chills/rigors 
has occurred in the majority of patients during the first rituximab infusion. Other frequent infusion-
related symptoms include nausea, uticaria, fatigue, headache, pruritis, bronchospasm, dyspnea, sensation 
of tongue or throat swelling (angioedema), rhinitis, vomiting, hypotension, flushing, and pain at disease 
sites. These reactions generally occurred within 30 minutes to 2 hours of beginning the first infusion, and 
resolved with slowing or interruption of the rituximab infusion and with supportive care (IV saline, 
diphenhydramine, and acetaminophen). 
 
 
Tumor Lysis Syndrome: Rituximab rapidly decreases benign and malignant CD20 positive cells. 
Tumor lysis syndrome has been reported to occur within 12 to 24 hours after the first rituximab infusion 
in patients with high numbers of circulating malignant lymphocytes. Patients with high tumor burden 
(bulky lesions) may also be at risk. Patients at risk for developing tumor lysis syndrome should be 
followed closely and appropriate laboratory monitoring performed. 
 
Other viral infections:  The following additional serious viral infections, either new, reactivated, or made 
more severe have been reported in some patients receiving rituximab in combination with chemotherapy.  
These viral infections include JC virus (which can lead to progressive multifocal leukoencephalopathy 
[PML], a rare and often fatal disease), cytomegalovirus (CMV), herpes simplex virus, parvovirus B19, 
varicella zoster virus, West Nile virus, and hepatitis C.  In some cases, the viral infections occurred up to 
18 months after discontinuation of the rituximab and resulted in death.  Because there are no warning 


 
Amendment #9: 08/28/2017 
 [35] 
signs of PML, you should contact your study doctor immediately if you experience major changes in 
vision or unusual eye movements, loss of balance or coordination, or periods of disorientation or 
confusion.  You should also contact your study doctor right away if you have a persistent cough, fever, 
chills, congestion, or any flu-like symptoms while receiving rituximab (or several months after 
discontinuation of rituximab therapy).  These symptoms may be signs of a serious infection. 
 
The following risks were updated per the Cancer Therapy Evaluation Program’s (CTEP), National 
Cancer Institute (NCI) Action Letter dated June 16th, 2010. 
Likely 
• Fever 
• Reaction that can occur during or following infusion of the drug.  The reaction may include 
fever, chills, rash, low blood pressure, and difficulty breathing. 
• Decreased number of a type of white blood cell (lymphocyte) 
• Chills 
 
Less Likely 
• Lack of enough red blood cells (anemia) 
• Thickening of blood/serum as found in Waldenstrom’s macroglobulinemia (a cancer of certain 
blood cells) 
• Fever associated with dangerously low levels of a type of white blood cell (neutrophils) 
• Heart attack caused by a blockage of a blood vessel supplying part of the heart 
• Fast heartbeat; regular rhythm 
• Fast heartbeat usually originating in an area located above the ventricles 
• Belly Pain 
• Diarrhea 
• Nausea or the urge to vomit 
• Vomiting 
• Swelling of the arms and/or legs 
• Fatigue or tiredness 
• Pain 
• Allergic reaction by your body to the drug product that can occur immediately or may be delayed.  
The reaction may include hives, low blood pressure, wheezing, swelling of the throat and 
difficulty breathing. 
• Infection  
• Awakening of viruses which have been latent/dormant 
• Infection in HIV positive patients 
• Decreased number of a type of white blood cell (neutrophil/granulocyte) 
• Decreased number of a type of blood cell that help to clot blood (platelet) 
• Decrease in the total number of white blood cells (leukocytes) 
• Increased blood sugar level 
• Decreased blood level of calcium 
• Decreased blood level of potassium 
• Joint pain 
• Back pain 


 
Amendment #9: 08/28/2017 
 [36] 
• Muscle pain 
• Pain in the area of the tumor 
• Dizziness (or sensation of lightheadedness, unsteadiness, or giddiness) 
• Headache or head pain 
• Abnormal drowsiness or sluggishness, an unusual lack of energy 
• Convulsion or seizure 
• Sudden or traumatic injury to the kidney 
• Stuffy or runny nose, sneezing 
• Sudden constriction of the small airways to the lung that can cause wheezing and shortness of 
breath 
• Cough 
• Shortness of breath 
• Decrease in the oxygen supply to a tissue 
• Inflammation of the lungs that may cause difficulty breathing and can be life threatening 
• Sore throat 
• Excess sweating 
• Itching 
• Skin rash with the presence of macules (flat discolored area) and papules (raised bump) 
• Swelling of body tissue underneath the skin 
• Hives 
• Sudden reddening of the face and/or neck 
• High blood pressure 
• Low blood pressure 
 
 
Rare, but Serious 
Serious, life-threatening allergic reaction requiring immediate medical treatment by your doctor. The 
reaction may include extremely low blood pressure, swelling of     the throat, difficulty breathing, and 
loss of consciousness.  
• Group of signs and symptoms due to rapid breakdown of tumor that can occur after treatment of 
cancer has started that causes increased levels of blood potassium, uric acid, and phosphate, 
decreased levels of blood calcium, and kidney failure. 
• Disease affecting brain tissue, caused by a virus (specifically the JC virus: Jacob Cruetzfeld virus). 
• Severe potentially life-threatening damage to the lungs which can lead to fluid in the lungs. 
• Severe reaction of the skin and gut lining that may include rash and shedding or death of tissue. 
• Potentially life-threatening condition affecting less than 10% of the skin in which cell death causes 
the epidermis (outer layer) to separate from the dermis (middle layer).  
• Life-threatening condition affecting greater than 30% of the skin in which cell death causes the 
epidermis (outer layer) to separate from the dermis (middle layer). 
 
Refer 
to 
the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/reporting/adeers.html for further clarification.  


 
Amendment #9: 08/28/2017 
 [37] 
Note: Rituximab in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
 
6.B.3 PHARMACOLOGY 
 
Pharmacokinetics: In prior studies patients treated at the 375 mg/m2 dose levels exhibited 
detectable antibody concentrations throughout the treatment period. Most patients exhibited increasing 
pre-infusion antibody concentrations with each subsequent infusion. In nine patients, the T1/2 following 
the first antibody infusion was 59.8 hours (11.1 – 104.6 hr) with a Cmax of 271 mcg/mL.  
 
 
Formulation: Rituximab antibody will be provided on 100 mg (10mL) and 500 mg (50ml) 
pharmaceutical grade vials at a concentration of 10 mg of protein per mL (actual concentration should be 
noted on the product label). 
 
 
Storage and Stability: Rituximab should be stored at 2 - 8°C. Do not freeze or store at room 
temperature. The product is a protein- HANDLE GENTLY AND AVOID FOAMING. The avoidance of 
foaming during product handling, preparation and administration is important, as foaming may lead to 
the denaturing of the product proteins. 
 
 
Administration: Prepare the rituximab infusion solution as follows: 
1. If a delay in administration of the infusion occurs after the product is prepared, the 
properly identified container may be kept refrigerated at 2 - 8°C for up to six hours. 
2. Use sterile, non-pyrogenic, disposable containers, syringes, needles, stopcocks and 
transfer tubing, etc. 
3. Transfer of the rituximab from the glass vial should be made by using a suitable 
sterile graduated syringe and large gauge needle. 
4. Transfer the appropriate amount of rituximab from the graduated syringe, into a 
partially filled IV pack containing sterile, pyrogen-free 0.9% sodium chloride 
solution, USP (saline solution). The final concentration of rituximab in saline solution 
should be a maximum of 1 mg/ml. Mix by inverting the bag gently. DO NOT USE A 
VACUUM APPARATUS to transfer the product from the syringe to the plastic bag. 
5. Place an IV administration set into the outflow port of the bag containing the infusion 
solution. 
6. NOTE:  DO NOT USE evacuated glass containers which require vented 
administration sets because this causes foaming as air bubbles pass through the 
solution. 
The administration of rituximab will be accomplished by slow IV infusion.  CAUTION:  DO NOT 
ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.  IV pumps such as the IMED 960 may be 
used with the rituximab infusion.  DO NOT INFUSE CONCOMITANTLY with another IV solution or 
IV medications.  Prime the line with the rituximab solution such that approximately 30 mL are delivered.  
This will saturate the filter and tubing. 
 


 
Amendment #9: 08/28/2017 
 [38] 
6.C Ibritumomab (IDEC-2B8) Drug Information 
6.C.1 Origin of the Ibritumomab (IDEC-2B8) Cell Line 
The murine anti-CD20 monoclonal antibody 2B8.H11.G3.G9, ibritumomab (IDEC-2B8), is an 
IgG1 kappa antibody.  The selection of the monoclonal antibody ibritumomab was based upon 
observations that: ibritumomab specifically recognized and bound 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; ibritumomab exhibited no cross-
reactivity with T-lymphocyte populations.  
Ibritumomab was previously expressed by a murine hybridoma cell line and produced in hollow-
fiber bioreactors.  Currently, ibritumomab is produced in Chinese hamster ovary (CHO) cells in 
suspension culture.  The CHO-expressed ibritumomab 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. 
6.C.2 Investigational Drug Nomenclature 
• Biogen Idec, Incorporated code designation: Zevalin (Ibritumomab tiuxetan) 
• Generic name: Ibritumomab tiuxetan 
• IND numbers: BB-IND 4850 - Zevalin 
• MF number:  BB-MF 7087 - Zevalin 
6.C.3 Clinical Formulation 
The radiolabeling kit is provided by Biogen Idec and all components are tested to be sterile and 
pyrogen-free.  The kit consists of the following components: 
• 3 mL glass vial containing 2 mL (3.2 mg) of Zevalin (ibritumomab tiuxetan) at 
1.6 mg/mL in low metal normal saline 
• 3 mL glass vial containing 2 mL low-metal 50 mM sodium acetate 
• 10 mL glass vial containing 10 mL formulation buffer (PBS containing 7.5% human 
serum albumin and 1 mM DTPA, pH 7.2) 
o 10 mL glass vial (empty) 
6.C.4 Storage 
The radiolabeling kits should be stored in a secure refrigerator at 2 - 8°C.  Zevalin solutions are 
stable at 2 - 8°C for up to 8 hours for 90Y Zevalin and up to 12 hours for 111In Zevalin following their 
preparation.  Due to the relatively short half life of the 90Y isotope, if not used soon after calibration 
time, the actual dose will have decayed and will require recalculation.  For proper Rituxan storage 
instructions see the package insert in the appropriate Appendix. 
6.C.5   111In Zevalin and 90Y Zevalin Treatment Protocol  
The 111In and 90Y isotope order form must be completed and faxed to the designated isotope 
vendor preceding the initial Rituxan infusion.  Patients will receive an initial infusion of 250 mg/m2 
Rituxan.  (111 In Zevalin, 90-Y-Zevalin, and Rituximab will not be provided by Biogen Idec 


 
Amendment #9: 08/28/2017 
 [39] 
Incorporated). Immediately following, patients will receive a fixed dose of 5.0 mCi of 111In Zevalin.  If 
the biodistribution is altered such that the safety risk would be unacceptable, the patient will be taken off 
study and not proceed with 90Y Zevalin radioimmunotherapy.  On Day 7, 8 or 9, patients must receive a 
second infusion of 250 mg/m2 of Rituxan and either 0.4 mCi/kg or 0.3 mCi/kg of Zevalin based on most 
recent platelet counts.  The exact dose of Zevalin will be based on the patient’s weight during the most 
recent evaluation according to Table 4.  The maximum dose is not to exceed  32 mCi of 90Y.  
Table 4. 
Dosing of Zevalin 
 Platelet Counts ≥ 150,000/mm3 
 Platelet Counts 100,000/mm3 to 149,000/mm3 
0.4 mCi 90Y/kg 
Dose will be calculated using actual body weight 
Not to exceed 32 mCi (Maximum Dose) 
0.3 mCi 90Y/kg 
Dose will be calculated using actual body weight 
Not to exceed 32 mCi (Maximum Dose) 
 
6.C.6  Zevalin Adverse Events 
For an extensive review of adverse events refer to the Investigational Brochure.  Safety data, 
except where indicated, are based upon 349 patients treated in 5 clinical studies with ZEVALIN.  In all 
cases, the ZEVALIN regimen included two doses of RITUXAN.  See the RITUXAN package insert for 
specific adverse event (AE) information for that product.   
 
Table 5 lists most common nonhematologic adverse events in ≥ 5% of patients.  The table does 
not include hematologic AEs of neutropenia, thrombocytopenia, and anemia (See Table 6, Hematologic 
Toxicity). 
 
Table 5 
Incidence of Nonhematologic† Adverse Events in ≥ 5 % of Patients in Clinical Trials with 
ZEVALIN Regimen During the Treatment Period*(N = 349) 
  
All Grades 
Grade 3/4 
  
N (%) 
N (%) 
Any Adverse Event 
318 (91.1) 
70 (20.1) 
Body as a Whole 
280 (80.2) 
41 (11.7) 
Asthenia 
149 (42.7) 
9 (2.6) 
Infection 
100 (28.7) 
16 (4.6) 
Chills 
82 (23.5) 
1 (0.3) 
Fever 
58 (16.6) 
2 (0.6) 
Abdominal Pain 
54 (15.5) 
9 (2.6) 
Pain 
44 (12.6) 
3 (0.9) 
Headache 
43 (12.3) 
2 (0.6) 
Throat Irritation 
33 (9.5) 
0 (0.0) 
Back Pain 
27 (7.7) 
2 (0.6) 
Flushing 
20 (5.7) 
0 (0.0) 
Cardiovascular System 
58 (16.6) 
12 (3.4) 
Hypotension 
22 (6.3) 
3 (0.9) 
Digestive System 
168 (48.1) 
10 (2.9) 
Nausea 
107 (30.7) 
2 (0.6) 
Vomiting 
41 (11.7) 
0 (0.0) 
Diarrhea 
31 (8.9) 
1 (0.3) 
Anorexia 
27 (7.7) 
0 (0.0) 


 
Amendment #9: 08/28/2017 
 [40] 
  
All Grades 
Grade 3/4 
  
N (%) 
N (%) 
Hemic and Lymphatic System 
50 (14.3) 
12 (3.4) 
Ecchymosis 
25 (7.2) 
1 (0.3) 
Metabolic and Nutritional Disorders 
79 (22.6) 
12 (3.4) 
Peripheral Edema 
28 (8.0) 
2 (0.6) 
Musculoskeletal System 
63 (18.1) 
2 (0.6) 
Arthralgia 
26 (7.4) 
2 (0.6) 
Myalgia 
23 (6.6) 
1 (0.3) 
Nervous System 
94 (26.9) 
7 (2.0) 
Dizziness 
35 (10.0) 
1 (0.3) 
Respiratory System 
125 (35.8) 
11 (3.2) 
Dyspnea 
47 (13.5) 
7 (2.0) 
Increased Cough 
36 (10.3) 
0 (0.0) 
Rhinitis 
22 (6.3) 
0 (0.0) 
Skin and Appendages 
96 (27.5) 
2 (0.6) 
Pruritus 
32 (9.2) 
1 (0.3) 
Rash 
29 (8.3) 
1 (0.3) 
Special Senses 
25 (7.2) 
1 (0.3) 
Urogenital System 
21 (6.0) 
1 (0.3) 
*Treatment period is the time interval from first infusion to 30 days  after ZEVALIN treatment.   
†Hematologic toxicities of neutropenia, thrombocytopenia, and anemia are shown in Table 6. 
Note:  All adverse events are included, regardless of relationship. 
 
The following adverse events occurred in ≥ 1% but < 5% of patients during the treatment period:  
bronchospasm (4.9%), insomnia (4.9%), constipation (4.6%), angioedema (4.3%), urticaria (4.0%), 
anxiety (3.7%), dyspepsia (3.7%), increased lactic dehydrogenase (3.7%), sweats (3.7%), petechia 
(3.4%), sinusitis (3.2%), night sweats (3.2%), enlarged abdomen (2.9%), epistaxis (2.9%), 
hyperglycemia (2.9%), tachycardia (2.9%), hyperesthesia (2.6%), bone pain (2.6%), neck pain (2.6%), 
paresthesia (2.6%), conjunctivitis (2.3%), dehydration (2.3%), depression (2.3%), hypertension (2.3%), 
malaise (2.3%), increased SGOT (2.3%), skin disorder (2.3%), allergic reaction (2.0%), increased BUN 
(2.0%), leg cramps (2.0%), dry mouth (2.0%), melena (2.0%), pancytopenia (2.0%), somnolence (2.0%), 
gastrointestinal disorder (1.7%), hypocalcemia (1.7%), tumor pain (1.7%), increased alkaline 
phosphatase (1.7%), increased SGPT (1.7%), voice alteration (1.7%), increased creatinine (1.4%), 
edema (1.4%), pleural effusion (1.4%), rectal hemorrhage (1.4%), myasthenia (1.4%), stomatitis (1.4%), 
decreased weight (1.4%), agitation (1.1%), amblyopia (1.1%), dysphagia (1.1%), dysuria (1.1%), 
gastrointestinal 
hemorrhage (1.1%), 
gum 
hemorrhage (1.1%), 
hypokalemia 
(1.1%), 
hypoproteinemia (1.1%), urinary incontinence (1.1%), lymphadenopathy (1.1%), axilla pain (1.1%), 
injection site pain (1.1%), palpitation (1.1%), vasodilation (1.1%), and abnormal vision (1.1%). 
All Grade 3 and 4 events occurring in < 5% of patients (except for those noted in Table 5) consisted of 
pancytopenia (1.7%), allergic reaction (1.1%), dehydration (1.1%), gastrointestinal hemorrhage (0.9%), 
hyperglycemia (0.9%), melena (0.9%), tumor pain (0.9%), increased alkaline phosphatase (0.6%), 
ascites (0.6%), constipation (0.6%), increased lactic dehydrogenase (0.6%), increased SGPT (0.6%), 
malaise (0.6%), apnea (0.6%), bilirubinemia ( 0.6%), hypoxia ( 0.6%), deep thrombophlebitis ( 0.6%), 
hypochromic 
anemia 
(0.3%), 
angioedema 
(0.3%), 
anxiety (0.3%), 
depression 
(0.3%), 
hypoproteinemia (0.3%), increased SGOT (0.3%), insomnia (0.3%), neck pain (0.3%), pleural effusion 
(0.3%), somnolence (0.3%), tachycardia (0.3%), urticaria (0.3%), anemia hemolytic ( 0.3%), arterial 
anomaly ( 0.3%), arrhythmia (0.3%), arthritis (0.3%), cachexia (0.3%), convulsion (0.3%), coronary 
artery disorder, (0.3%), easy bruisability (0.3%), lung edema (0.3%), pulmonary embolus (0.3%), 
encephalopathy (0.3%), granulocytosis (0.3%), congestive heart failure (0.3%), hematemesis (0.3%), 


 
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subdural hematoma (0.3%), hepatic failure (0.3%), hypercalcemia (0.3%), hyperuricemia, (0.3%), 
increased prothrombin (0.3%), myocardial ischemia (0.3%), jaundice (0.3%), kidney failure (0.3%), 
migraine (0.3%), neuritis (0.3%), intestinal obstruction (0.3%), eye pain (0.3%), respiratory 
disorder (0.3%), supraventricular tachycardia (0.3%), vaginal hemorrhage (0.3%), and increased venous 
pressure (0.3%). 
Hematologic Events:  Hematologic toxicity has been frequently observed in clinical trials, and is 
dose-limiting.  Table 6 presents the incidence and duration of Grade 3 and 4 hematologic toxicity for 
patients with mild thrombocytopenia at baseline who were treated at 0.3 mCi/kg (11.1 MBq/kg), and for 
those with normal baseline platelet count treated at 0.4 mCi/kg (14.8 MBq/kg), up to the maximum dose 
of 32 mCi (1184 MBq).  
 
Table 6 
Hematologic Toxicity 
 
Median 
Nadir 
Patients 
with 
Grade 3 
Toxicity 
Patients 
with 
Grade 4 
Toxicity 
Days Within  
Grade 3 or 4*  
(Median for all 
Patients) 
Days Within  
Grade 3 or 4*  
(Median for  
Patients with  
Grade 3 or 4 Nadir) 
0.3 mCi/kg; 11.1 MBq/kg dose (maximum 32 mCi; 1184 MBq) 
ANC (cells/mm3) 
600 
40% 
35% 
23.0 
29.0 
Platelets (/mm3) 
24,000 
66% 
14% 
29.0 
34.5 
Hemoglobin (g/dL) 
10.0 
12% 
8% 
0.0 
14.0 
0.4 mCi/kg; 14.8 MBq/kg dose (maximum 32 mCi; 1184 MBq) 
ANC (cells/mm3) 
800 
28% 
30% 
14.0 
22.0 
Platelets (/mm3) 
41,000 
52% 
10% 
15.0 
24.0 
Hemoglobin (g/dL) 
10.5 
14% 
3% 
0.0 
14.0 
*ANC < 1000 cells/mm3, platelets < 50,000/mm3, and hemoglobin < 8.0 g/dL 
 
Infectious Events: During the first 3 months after initiating ZEVALIN therapy, 28.7% (100/349) of 
patients developed infections, which were Grade 1 or Grade 2 in 24% (84 patients).  Nine (2.5%) 
patients developed Grade 3 infections comprising urinary tract infection, febrile neutropenia, sepsis, 
pneumonia, cellulitis, colitis, diarrhea, osteomyelitis, and upper respiratory tract infection.  Grade 4 
infections were reported for 2.0% (7 patients) and comprised sepsis, empyema, pneumonia, febrile 
neutropenia, fever, and biliary stent-associated cholangitis.  During follow-up from 3 months to 4 years 
after the start of treatment with ZEVALIN, 6.0% (21 patients) developed infections, which were Grade 1 
or Grade 2 in 3% (12 patients).  Six patients (2.0%) had Grade 3 infections comprising urinary tract 
infection, bacterial or viral pneumonia, febrile neutropenia, perihilar infiltrate, pericarditis, and 
intravenous drug-associated viral hepatitis.  Three patients (1.0%) had Grade 4 infections comprising 
bacterial pneumonia, respiratory disease, and sepsis. 
Secondary Malignancies:  A total of 1.7% of patients (6/349) developed secondary malignancies 
following treatment with ZEVALIN.  One (0.3%) patient developed a Grade 1 meningioma, and 
5 (1.4%) developed myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). 


 
Amendment #9: 08/28/2017 
 [42] 
NOTE:  Past-marketing experiences of erythema multiforme, Stevens-Johnson syndrome, toxic 
epidermal necrolysis, bullous dermatitis, and exfoliative dermatitis were reported in patients who 
received received the Zevalin® therapeutic regimen, which includes Rituximab, In-111 Zevalin® and 
Y-90 Zevalin®. Some of these events were fatal.  The onset of the reactions was variable: in some 
cases acute, days in others, and delayed (3-4 months).  Biogen Idec has, therefore, revised the 
BOXED WARNINGS, WARNINGS, and ADVERSE REACTIONS sections of the Prescribing 
Information for Zevalin® to describe severe cutaneous or mucocutaneous reactions in patients 
receiving Zevalin®.  Patients experiencing a severe cutaneous or mucocutaneous reaction should 
not receive any further components of the Zevalin® therapeutic regimen and should seek prompt 
medical evaluation. 
 
7 TREATMENT PLAN 
All patients who qualify for this study will receive chemotherapy with ESHAP followed by treatment 
with Zevalin 
7.A ESHAP REGIMEN DOSING 
 
ESHAP chemotherapy:  Patients will receive 2 cycles of cytoreductive chemotherapy according to the 
schedule described below.  (Table 7) 
 
 
 
TABLE 7 
ESHAP CHEMOTHERAPY PLUS ZEVALIN 
DRUG 
DOSE 
ROUTE 
DAYS 
INTERVAL 
 
Etoposide 
 
40 mg/m2/ day 
 
IV infusion over 1 hour 
 
1,2,3,4 
 
q 28 days for 2 cycles 
 
Methylprednisolone 
 
250 mg/day 
 
IV push 
 
1,2,3,4 
 
q 28 days for 2 cycles 
 
Cytarabine 
 
2000 mg/m2 
 
IV infusion over 2 hours 
 
4 
 
q 28 days for 2 cycles 
 
Cisplatin 
 
25 mg/m2/day 
 
IV infusion at 1mg/min 
 
1,2,3,4 
 
q 28 days for 2 cycles 
 
• The cycle length will be 28 days if bone marrow recovery allows.  If recovery requires an 
additional week, then the second cycle will be postponed for a week.   
• Either pegfilgastrim or filgastrim may be given at the investigator’s discretion. 
 
7.B   RITUXIMAB , 111IN ZEVALIN,  AND 90Y ZEVALIN ADMINISTRATION 
The rituximab + ibritumomab tiuxetan regimen is given 4-6 weeks after completion of the second 
cycle of ESHAP. Treatment can be completed within 7 - 9 days in an outpatient setting 
 
TABLE 8 
Rituximab , 111In Zevalin,  AND 90Y Zevalin Administration 


 
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AGENT 
DOSE 
ROUTE 
DAYS 
NOTES 
 
 
Rituximab 
 
 
250 mg/m2 
 
 
Slow IV 
 
 
1, then 7, 8 or 9 
 
Give prior to  
111In Zevalin 
 
 
111In Zevalin 
 
 
5 mCi 
 
Slow IV push 
over 10 
minutes 
 
 
1 
 
Give within 4 hours 
after rituximab 
 
 
90Y Zevalin 
 
Depends on 
platelet count 
(see Section 
7.B.3) 
 
Slow IV push 
over 10 
minutes 
 
 
7, 8, or 9 
 
Give within 4 hours 
after rituximab 
 
 
7.B.1 Rituxan & 111In Zevalin Administration 
1.6 mg of 111In Zevalin (5.0 mCi of 111In) will be used for radioimaging.  The imaging dose of 
111In Zevalin will be administered by a 10-minute slow IV push injection immediately following the 
infusion of Rituxan. 111In Zevalin may be directly injected by stopping the flow from the IV bag and 
injecting the radiolabeled antibody directly into the line.  A 0.22 micron filter must be on line between 
the patient and the infusion port.  Flush the line with at least 10 mL of normal saline after 111In Zevalin 
has been injected.  (See Appendix H). 
a. Oral premedication (2 tablets [325 mg] of acetaminophen and 50 - 100 mg oral 
diphenhydramine hydrochloride) may be administered 30 - 60 minutes prior to starting 
each infusion of rituximab. 
7.B.2  Radioimaging Schedule 
Imaging (see Appendices H & I) will be conducted at the clinical site on each patient prior to 
receiving 90Y Zevalin. Within 48-72 hours following the 111In Zevalin administration, whole body 
anterior and posterior images of the patient must be acquired.  If desired, a second image can be obtained 
at 90 - 120 hours to support the decision.  If the patient has an altered biodistribution, the patient will be 
taken off study before proceeding to 90Y Zevalin radioimmunotherapy. 
a. Whole-body gamma camera images to assess biodistribution of ibritumomab tiuxetan are 
obtained as described below after the first infusion of rituximab followed by In-111 
ibritumomab tiuxetan.  
Scan 1 
Hours 48 -72 
Optional Scan 
Hours 90 - 120 
 
b. If ibritumomab tiuxetan biodistribution is acceptable, therapy continues on Day 7, 8, or 9 
with a second infusion of rituximab followed by Y-90 ibritumomab tiuxetan as noted in 
Table 8. 
 
c. Altered biodistribution:  Y-90 ibritumomab tiuxetan should not be administered to 
patients with altered biodistribution of In-111 ibritumomab tiuxetan.  The expected 
biodistribution of In-111 ibritumomab tiuxetan includes easily detectable uptake in the 


 
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blood pool areas 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 image; and 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.  Altered biodistribution of In-111 ibritumomab tiuxetan can be 
characterized by diffuse uptake in normal lung more intense than the liver on the posterior 
view of the second or third day image; or intense areas of uptake throughout the normal 
bowel comparable to uptake by the liver on the second or third day images. 
 
 
 
7.B.3 Rituxan & 90Y Zevalin Administration 
90Y Zevalin will be administered following the second Rituxan infusion Day 7, 8 or 9 (See 
Appendix H). Each patient will receive one therapeutic dose of Zevalin according to the dosing schema 
(see Table 4 or Section 7.B.3b).    
Please note:  Patients with platelet counts from 100,000/mm3 to 149,000/mm3 will receive 0.3 
mCi/kg and patients with platelet counts > 150,000/mm3 will receive 0.4 mCi/kg, not to exceed 32 mCi 
90Y Zevalin.  90Y Zevalin will be administered intravenously as a slow IV push over 10 minutes.  90Y 
Zevalin 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. Flush the line with at least 10 mLs of normal saline after 90Y Zevalin has been infused.  
(See Appendix H for radioincorporation methods) 
There is no provision for additional treatment courses for patients entered into this protocol. 
 
a. Oral premedication (2 tablets [325 mg] of acetaminophen and 50 - 100 mg oral 
diphenhydramine hydrochloride) may be administered 30 - 60 minutes prior to 
starting each infusion of rituximab. 
 
b. Y-90 ibritumomab tiuxetan should be dosed at 0.4 mCi/kg (14.8 MBq/kg) actual 
body weight for patients with platelets counts ≥ 150,000/mm3 and at 0.3 mCi/kg 
(11.1 MBq/kg) actual body weight for patients with platelet counts of 100,000 - 
149,000/mm3.  The prescribed, measured and administered dose of Y-90 
ibritumomab tiuxetan must not exceed the absolute maximum allowable dose of 
32.0 mCi (1,184 MBq), regardless of the patient’s body weight.  Do not give Y-
90 ibritumomab tiuxetan to patients with a platelet count < 100,000/mm3. 
 
c. Radiation Safety Precautions are minimal:  No isolation required. Observe the 
following guidelines for 7 days after Y-90 Zevalin Patients should wash their hands 
thoroughly after urinationThe use of a condom is recommended during sexual 
intercourse to avoid transfer of body fluids.  Avoid deep kissing.  Throughout 
therapy and for up to 12 months following treatment, effective contraception is 
recommended. 
 


 
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d. Granulocyte colony stimulating factors may be given at the discretion of the 
treating physician to prevent or mitigate unacceptable granulocytopenia associated 
with fever, or granulocytopenia less than 500 granulocytes/µl.  The use of G-CSF 
must be documented on the treatment summary form.  Any toxicities associated 
with G-CSF must also be documented on the adverse event form. 
 
8 TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS 
 
This study will utilize the CTC (NCI Common Toxicity Criteria) Version 3.0 for toxicity and Adverse 
Event reporting.  A copy of the CTC Version 3.0 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov).  All appropriate treatment areas should have access to a copy of the 
CTC Version 3.0. 
 
8.A   ESHAP  Toxicities & Dose Modification 
In the case of multiple toxicities, dose modifications should be based on the most severe dose-limiting 
toxicity. 
 
8.A.1 Hematologic Toxicity:  
The ESHAP regimen should be given as described in Section 7.A if the granulocytes are > 1,500 
cells/µL and the platelets are > 100,000 cells/µL by the time the next cycle is due.  If the blood 
counts have not recovered, treatment should be delayed by an additional week and counts 
repeated unless low peripheral counts are due to tumor.  If, after 2 weeks, counts have not yet 
recovered, the patient should be treated at 75% of the last dose received of etoposide and 
cytarabine.   
 
8.A.2 Grade 3 or 4 Infection:  
(NCI Common Toxicity Criteria Version 3.0) due to chemotherapy-related neutropenia requires a 
decrease in the doses of etoposide and cytarabine to 75% of the last dose received.  Re-escalation 
is at the discretion of the treating physician.  In this study, filgrastim or peg-filgrastim may be 
administered to prevent neutropenia at the discretion of the treating physician.    
 
The use of filgrastim or peg-filgrastim must be documented on the treatment flow sheets.  Any 
toxicities associated with either of these agents must also be documented on the treatment flow 
sheets.  
8.A.3 Impaired Renal Function:  
All patients with serum creatinine levels < 1.3 or creatinine clearance (CrCl) > 60 mL/min will 
receive full doses of all drugs.  If the creatinine is 1.4 – 2.0 or the CrCl is 30 – 60 mL/min then 
the doses of cytarabine, etoposide, and cisplatin should all be reduced by 50%.   A creatinine 
clearance of < 30 mL/min will require holding all treatment.    Re-escalation to full dose is at the 
discretion of the treating physician if the serum creatinine level drops to < 1.3 or the CrCl > 50 
mL/min.   
TABLE 9 
Cytarabine, Etoposide & Cisplatin Reductions According to Renal Function 
CrCl 
Etoposide Dose 
Cytarabine Dose 
Cisplatin Dose 


 
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> 60 mL/min 
100% 
100% 
100% 
30-60 mL/min 
50% 
50% 
50% 
10-30 mL/min 
0% 
0% 
0% 
< 10 mL/min 
0% 
0% 
0% 
 
 
8.A.4 Neuropathy:  
Patients experiencing Grade 3 cisplatin neuropathy (e.g., loss of motor function) will have the 
dose reduced by 50% for all further cycles of ESHAP.  Patients experiencing Grade 4 neuropathy 
will have the cisplatin omitted from all further cycles of ESHAP.  Patients experiencing Grade 3 
cytarabine neuropathy with ESHAP cycle 1 will have the dose reduced by 50% for cycle 2.  
Patients experiencing Grade 4 or worse cytarabine neuropathy will have the cytarabine omitted 
from all further cycles. 
 
8.B Rituximab Antibody  Toxicities & Dose Modifications  
 
8.B.1 Fevers: 
Patients may experience transient fever and rigors with infusion of chimeric anti-CD20 
antibody.  If Grade 3 fever (or Grade 2 fever with rigors) or Grade 2 rigors are noted, the 
antibody infusion should be temporarily discontinued, the patient should be observed, and the 
severity of the side effects should be evaluated.  The patient should be treated according to the 
best available local practices and procedures.  Following observation, when fever resolves to 
Grade 2 or less and rigors to Grade 1 or less, the infusion should be continued, initially, at 1/2 
the previous rate.  Following the antibody infusion, the IV line should be kept open for 
medications, as needed. 
 
8.B.2 Hypersensitivity: 
Hypotension, bronchospasm or angioedema have occurred as part of an infusion-related 
symptom complex.  If a Grade 3 or greater hypersensitivity/allergic reaction occurs, rituximab 
infusion should be interrupted and may be resumed at a 50% reduction in rate when symptoms 
have completely resolved.  Treatment with diphenhydramine and acetaminophen is 
recommended; additional treatment with bronchodilators or IV saline may be used at the 
physician's discretion.  Precautionary hospitalization for patients experiencing severe infusion 
symptoms which do not resolve after discontinuation of the cycle is recommended. 
 
8.B.3 Observation post Infusion 
If there are no complications, the IV line may be discontinued after 1 hour of observation.  If 
complications occur during the rituximab infusion, the patient should be observed for 2 hours 
after the completion of infusion.  If a patient experiences a Grade 3 toxicity that persists until 
the next scheduled infusion, the patient must discontinue treatment until toxicities have 
resolved to Grade 2 or less. If treatment is delayed for more than 3 weeks, call the Study 
Coordinator. 
 
8.B.4 Tumor Lysis Syndrome: 
Appropriate medical therapy should be provided for patients who develop tumor lysis 
syndrome.  Following treatment for and resolution of tumor lysis syndrome, subsequent 


 
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rituximab therapy may be administered in conjunction with prophylactic therapy for this 
syndrome.  Contact the Study Coordinator prior to resuming treatment in these patients. 
 
TABLE 10 
Rituximab Infusion rate Adjustment 
 
Fever 
 
Rigors 
 
Mucosal Congestion/ Edema 
 
% Drop in Systolic BP 
Infusion Rate 
Adjustment 
 
Grade 1 
 
Grade 1-2 
 
Grade 1-2 
 
30 – 49 
 
Decrease By 50% 
 
Grade > 2 
 
Grade > 3 
 
Grade > 3 
 
> 50% 
 
Stop  infusion* 
*Temporarily discontinue infusion until adverse experiences have reversed (generally 15 to 30 minutes) 
and then resume infusion at 25 – 50% of initial rate.  
 
8.B.5 Hepatitis B Reactivation with Related Fulminant Hepatitis and Other Viral Infections: 
Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active  
HBV infection and for signs of hepatitis throughout their study participation.  Patients with any  
evidence of active hepatic disease or known HBV infection should be managed as clinically  
appropriate and should only receive rituximab if they have control of the infection and are  
adequately informed of the risks.  Patients who have never received vaccination for HBV, and  
have not had serologic testing for HBsAg, should be tested for surface antigen positivity. 
 
In patients who develop progressive multifocal leukoencephalopathy (PML), rituximab should be  
discontinued and reductions or discontinuation of concomitant immunosuppressive therapy and  
appropriate treatment, including antiviral therapy, should be considered.  Physicians should  
consider PML in any patients presenting with new onset neurologic manifestations, particularly  
in patients with systemic lupus erythematosis (SLE) or lymphoid malignancies.  Consultation  
with a neurologist, brain MRI, and lumbar puncture should be considered as clinically indicated.   
There are no known interventions that can reliably prevent PML or adequately treat PML if it  
occurs.  
 
8.B.6 Severe mucocutaneous reactions:   
All patients on or off rituximab therapy should be closely monitored for signs and symptoms  
suggestive of severe cutaneous and mucocutaneous reactions.  Should these symptoms arise,  
discontinue rituximab therapy (if applicable) and support as clinically indicated.  
 
8.B.7 Cardiovascular events:   
Patients with rheumatoid arthritis (RA) are at increased risk for cardiovascular events compared  
with the general population.  Patients with RA should be monitored through the infusion, and  
rituximab should be discontinued in the event of a serious or life-threatening event. 
 
8.B.8: Arrhythmias: 
Patients who develop clinically significant arrhythmias should undergo cardiac monitoring 
during and after subsequent infusions of rituximab.  Patients with pre-existing cardiac conditions 
including arrhythmias and angina have had recurrences of these events during rituximab therapy 
and should be monitored throughout the infusion and immediate post-infusion period.  Patients 


 
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off rituximab therapy should be closely monitored for signs and symptoms suggestive of life-
threatening cardiac events and supported as clinically indicated.  
 
8.B.9 Bowel Obstructions and Perforation:   
Complaints of abdominal pain, especially early in the course, should prompt a thorough  
diagnostic evaluation and appropriate treatment.  If the patients experiences a bowel obstruction  
or perforation, discontinue rituximab therapy.  Patients off rituximab therapy should be closely  
monitored for signs and symptoms suggestive of bowel obstruction and supported as clinically  
indicated.  
 
8.B.10 Renal:  
Discontinuation of rituximab should be considered for those patients with rising serum creatinine  
or oliguria. 
 
8.C   111In Zevalin & 90Y Zevalin Toxicities & Dose Modifications 
 
The ibritumomab tiuxetan (Zevalin) regimen may cause severe and potentially fatal infusion reactions 
that usually occur with the first rituximab infusion.  Signs and symptoms may include hypotension, 
angioedema, hypoxia or bronchospasm, and may require interruption of rituximab, 111In Zevalin or 
90Y Zevalin administration.  The infusion may be restarted at the physician's discretion. 
During the administration of treatment, emergency support for anaphylaxis is to be readily available, 
including a try for epinephrine, diphenhydramine, hydrocortisone, a laryngoscope, and an 
endotracheal tube.   
 
8.C.1 Use of Colony Stimulating Factors (CSF) and Platelet and Red Blood Cell Transfusions:   
 
Colony Stimulating Factors (CSF) should be administered only in accordance with published  
 
ASCO guidelines. 
Use of CSF under these conditions will be at the discretion of the treating  
 
investigator, but must be recorded on the flow sheets.  
 
 
Platelet transfusions should be administered only in patients with Grade 3 or 4 thrombocytopenia  
 
with obvious bleeding.  The use of platelet and red cell transfusions under these conditions will  
 
be at the discretion of the treating physician, but must be recorded on the flow sheets.   
 
 
For treatment or dose modification related questions, please contact Dr. Persky at (520) 626- 
 
8908.  
 
Unexpected or fatal toxicities (including suspected reactions) must be reported to the Study  
Coordinator, the ACC DSMB, the IRB, Biogen Idec, and the FDA. The procedure for reporting  
adverse reactions is outlined in Section 9.  
 
9 ADVERSE CLINICAL EVENT REPORTING 
 
Throughout the course of the study, every effort should be made to remain alert to possible adverse 
experiences.  Adverse events should be recorded using the toxicity criteria of the NCI Clinical 
Cooperative Groups and the Cancer Treatment Evaluation Program(Appendix C).  Adverse events not 
listed in toxicity criteria should be rated as either mild, moderate, severe, maximal/life threatening as 


 
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Grades 1, 2, 3, 4 respectively.  In the event of an adverse experience, appropriate medical intervention 
should be provided and if necessary, the investigational agent (Zevalin) should be discontinued. 
All adverse events regardless of the relationship to the study drug(s) whether observed by the 
investigator or reported by the patient, will be recorded with details of the duration and intensity of each 
episode, the action taken with respect to test drug and the patient outcome, on an appropriate source 
document at the clinical site. The investigator will evaluate each adverse experience as to its relationship 
to the test drug and as to whether or not it was serious. 
All abnormal laboratory results will be appraised by the investigator as to clinical significance.  For any 
laboratory abnormality considered clinically significant, details should be recorded on an appropriate 
source document including the action taken with respect to the test drug and the patient outcome. 
Adverse events occurring after the initiation of other anti-cancer therapy will not be followed, unless the 
therapy is initiated and the adverse event occurs within 30 days following the Zevalin drug infusion. 
 
9.A Reporting of Serious Adverse Events to the Principal Investigator, ACC DSMB, the IRB and, 
if necessary, the FDA 
Any serious or unexpected adverse event (including death) due to any cause whether or not related to the 
study drug(s) must be immediately reported to the principal investigator, ACC DSMB, the IRB and drug 
manufacturer.  The Principal Investigator must immediately complete the SAE form and arrange to have 
it faxed in a timely manner to the Drug Safety and Risk Management Department of Biogen Idec 
Incorporated (877-462-1532).  See Appendix  E for SAE form. 
It is the responsibility of the Investigator-Sponsor to IMMEDIATELY REPORT ALL SERIOUS OR 
UNEXPECTED ADVERSE IMMEDIATELY TO THE IRB CHAIR (AS PER INSTITUTION 
POLICY) AND, IF APPROPRIATE, TO THE FDA BY COMPLETING AND SUBMITTNG A 
MEDWATCH FORM (FDA FORM 3500A).  The Investigator-Sponsor must promptly provide a copy 
of the MedWatch form to Biogen Idec at the same time it is submitted to the FDA.  Completed FDA 
3500A reports should be faxed to the Drug Safety and Risk Management Department of Biogen 
Idec Incorporated (877-462-1532).  See Appendix E for additional information and a blank copy of 
the MedWatch form. 
Serious adverse events occurring after initiation of other anti-cancer therapy do not need to be reported, 
unless the therapy is initiated and the event occurs within 30 days following the infusion of the study 
drug or the event is felt to be related to the study drug.  An exception to this is the occurrence of  
myelodysplastic syndrome, leukemia, or other malignancy, which should be reported immediately. 
 
10 CONCOMITANT MEDICATIONS 
Patients should receive full supportive care including transfusions of blood and blood products, 
antibiotics, anti-emetics, etc., where applicable.  It is strictly mandated that patients not be given 
other myelosuppressive anti-neoplastic agents until recovery from hematologic nadir. 
Patients receiving concurrent oral anticoagulant therapy should have this medication discontinued when 
the platelet counts fall below 30,000 cells/mm3.  Oral anticoagulant therapy may be resumed upon signs 
of platelet recovery, at the discretion of the investigator. 
 


 
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11 REMOVAL OF PATIENTS FROM THIS STUDY 
11.A Criteria for Discontinuation of a Patient’s Study Participation 
The date of discontinuation and reason(s) for patient discontinuation from the study will be recorded in 
the CRF.  All evaluations which are required at the final study visit must by conducted for each patient 
who discontinues treatment, regardless of the reason (see Section 5.F.1). 
• Disease Progression:  Patients will be taken off study if they have progressive disease (PD) or 
clinically significant deterioration at any time during the study. 
 
• Personal Reasons:  Patients may choose to withdraw from the study at any time. 
 
• Clinical Judgment of the Investigator:  A patient may be withdrawn from the study, if in the 
opinion of the investigator, it is not in the patient’s best interest to continue. 
 
• Requiring other anti-neoplastic therapies 
 
12 STATISTICAL CONSIDERATIONS 
12.A Study Design 
This is a two- institution phase II trial to determine the efficacy and safety of the ESHAP-Zevalin 
combination therapy for the management of relapsed (CD 20+) follicular lymphoma.  Patients must have 
received at least one, but no more than 2 prior treatments for follicular lymphoma.    
 
The primary objective of this phase II clinical trial is to evaluate the 1-year progression-free survival 
(PFS) of patients with relapsed follicular NHL treated with ESHAP chemotherapy for cytoreduction (2 
cycles) followed by Y-90 ibritumomab tiuxetan (Zevalin) radioimmunotherapy, compared to what would 
be expected historically for patients treated with Zevalin without prior cytoreduction.  For this patient 
population, a 1-year PFS of 67.3% will be considered highly encouraging, compared to an historical rate 
around 50%.  These values correspond to approximate median times to progression of 21 months and 12 
months, respectively, assuming exponential survival.  
 
12.B.  Sample Size 
The planned sample size of 52 evaluable patients is based on testing the null hypothesis that the true 1-
year PFS is ≤50%, versus an alternative hypothesis that the true rate is ≥67.3% with this therapeutic 
approach.  Based on the number of patients seen at the Arizona Cancer Center with relapsed follicular 
lymphoma requiring treatment, the anticipated accrual rate is 2 patients per month.   It is estimated that 
accrual to the study would be completed within 26 months.  All patients who receive at least one dose of 
chemotherapy will be considered evaluable and included in the analysis.  In the unlikely event that an 
enrolled patient does not receive treatment, an additional patient will be registered.  
12.C    Method of Analysis 
The following are the design characteristics based on a chi-square test for one binomial population at the 
one-sided 0.10 significance level.  If the true PFS is ≤50%, then there is a maximum probability of 0.10 
of concluding that this treatment approach is sufficiently promising that it should be accepted for further 
study (false positive rate).  Alternatively, if the true PFS is ≥67.3%, then the maximum probability of 


 
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rejecting this treatment approach for further study in this setting is 0.10 (false negative rate), equivalent 
to a power of 90%. 
 
At the end of the trial, the observed PFS and response rates will be reported, along with appropriate 
confidence limits.  Kaplan-Meier methods will be used to estimate the survival curve of time-to-
progression.    Promising results at the conclusion of this trial will justify further study in a larger trial. 
 
13 STUDY ADMINISTRATION 
13.A Review and Consent Requirements 
 
13.A.1 Institutional Review Board (IRB) 
The investigator will supply all necessary documents to be submitted to the IRB and will ensure 
that the institution has a properly structured research committee.  The University of Arizona 
Human Subjects Protection Program will be the IRB of record.  Documentation of initial and 
ongoing reviews, submission of serious adverse event reports, study amendments and revisions, 
and consent form modifications will be required.  This documentation is to be forwarded to:  
• Consent Forms:  
 
 
Lora Inclan 
 
 
Clinical Research Coordinator 
 
 
The University of Arizona Cancer Center – North Campus 
 
 
Room 2111 
 
 
3838 N. Campbell Ave. 
 
 
Tucson, AZ 85719 
• Regulatory Documents: 
 
 
Kara Heard 
 
 
Lymphoma Program Regulatory Coordinator 
 
 
The University of Arizona Cancer Center, Room 1955 
 
 
1515 N. Campbell Ave 
 
 
Tucson, AZ 85724 
 
 
 
13.A.2 Patient Information and Informed Consent 
Written informed consent will be obtained for this study from all patients.  The investigator or 
his/her staff will explain the nature of the study and the risks involved to each patient prior to 
his/her inclusion in the trial.  The patient will also be informed that he/she is free to withdraw 
from the study at any time.  Original, signed informed consent forms for patients registered from 
the University of Arizona Cancer Center will be kept at The University of Arizona Cancer 
Center, North Campus, room 2111. 


 
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13.B Registration Procedure 
All ethical, regulatory, technical, and scientific approvals must be in place before study registrations will 
accepted.   All patients will be registered centrally with the Clinical Research Coordinator based at 520-
694-9053 prior to the initiation of treatment.  The Clinical Research Coordinator will assign each patient 
a sequential number prior to registration. The fully signed informed consent must be presented and all 
inclusion and exclusion criteria will be reviewed with the registering investigator or designee.  All 
source documentation needed to confirm eligibility must be available for this review.  A second phone 
registration is required prior to the initiation of Zevalin® to confirm eligibility and dose of therapy. 
 
13.C Study Records – Data Collection & Recording 
Study-specific data forms are to be found in the Clinical Research Services clinical database.   All forms 
are to be submitted centrally to the Clinical Research Coordinator at the University of Arizona Cancer 
Center at baseline, completion of ESHAP cycle 1, completion of ESHAP cycle 2, restaging at Cycle 2, 
Day 29, completion of Zevalin®, and at the follow-up intervals specified in Appendix A, including at 
time of relapse/progression, second malignancy, or death.  
13.D Patient Confidentiality 
The information obtained as a result of this research is confidential and all efforts must be made to 
ensure that the patient's anonymity will be maintained.  All records, evaluation forms, and reports will be 
identified by an identification code to maintain confidentiality.  A log of patients' codes, names and 
addresses will be kept separately.  All records are to be kept in locked files.  
13.E Monitoring 
This research study is an investigator-sponsored trial.   The Arizona Cancer Center has an NCI-approved 
Data and Safety Monitoring Plan for clinical research.  Data and systems for participating in the study 
will be monitored according to procedures outlined in that plan, with centralized patient screening and 
registration, submission and review of data, and initial verification of data as summarized below. 
Protocol Data and Safety Monitoring Plan (Medium Risk)  
Medium risk studies are intended to include all trials involving therapeutic intervention(s), which 
are not designated as high risk per NCI and the IND is not held by the investigator.  
 
Data and Safety Monitoring Plan: 
 
1. 
Identification of the DSMB obligated for oversight responsibilities: 
The Arizona Cancer Center Data and Safety Monitoring Board (DSMB) will provide ongoing 
oversight for this trial. 
 
2. 
Identification of the entity obligated for routine monitoring duties: 
Routine monitoring will be provided by the Quality Assurance/Quality Control (QA/QC) 
Program to ensure that the investigation is conducted according to protocol design and regulatory 
requirements.  
 
3. 
Monitoring progress and data review process: 
Routine monitoring of subject data will be conducted at least every six months.  
The first routine monitoring visit will include at a minimum: 
• Informed consent – 100% of cases enrolled;  


 
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• Subject eligibility - 50% of cases, up to two subjects; 
• Data review - 50% of cases, up to two subjects. 
 
All subsequent monitoring visits will consist of randomly selected subject cases based on current 
enrollment and include continuing review of previously selected cases, as applicable. 
 
A monitoring visit report and follow-up letter will be completed within two weeks of the routine 
monitoring visit; a copy will be maintained in the study file. A query/finding form will also be 
completed by the monitor to request additional source documentation, clarification, information 
or corrections to the CRF and/or regulatory records. The Clinical Research Coordinator or other 
applicable staff responsible for the study will be given a copy of this form for resolution of 
queries/findings. The query/finding form will be maintained with a copy of the visit report for 
follow-up at the next monitoring visit.  
 
The Principal Investigator will ensure the accuracy, completeness, legibility and timeliness of the 
data reported in the Case Report Form (CRF). Source documentation supporting the CRF data 
should indicate the subject’s participation in the trial and should document the dates and details 
of study procedures, adverse events, and patient status.  
 
Case report forms, which include the inclusion/exclusion criteria form, adverse event forms and 
serious adverse event forms [other forms, depending on study] should be completed with a black 
ball-point pen or typed. Corrections to the forms should not obscure the original entry and should 
be made by striking the incorrect information with a single line. Each strike should be 
accompanied by the initials of the corrector and the correction date. All subject forms and study 
files will be stored in a secure area limited to authorized staff. 
 
Note: Routine monitoring of regulatory documents and test article will be conducted at least 
annually.  
 
4. 
Process to implement study closure when significant risks or benefits are 
 
identified: 
This study may be prematurely terminated, if in the opinion of the investigator there is sufficient 
reasonable cause.   
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Failure to enter patients at an acceptable rate 
• Insufficient complete and/or evaluable data 
 
 
 
5. 
Description of adverse events and reporting procedures: 
 
 
ADVERSE EVENTS  
 
An adverse event (AE) is any untoward medical occurrence in a patient or  clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a casual 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product.  


 
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Any and all adverse events will be recorded on the UMC adverse events record form and 
reviewed by the Principal Investigator. 
 
All adverse events will be classified using either the MedDRA term or NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 3.0  
and will address: 
• Grade 
• Relationship to study drug(not related, unlikely, possible, probable, definitely)  
• Causality other than study drug (disease related, concomitant medication related, intercurrent 
illness, other)   
• Date of onset, date of resolution 
• Frequency of event (single, intermittent, continuous) 
• Event outcome (resolved, ongoing, death) 
• Action taken (none, held, dose reduced, discontinued, medication given) 
 
 
SERIOUS ADVERSE EVENTS 
 
A serious adverse event (SAE) is any untoward medical occurrence that at  any dose:  
 
1) Results in death;  
 
2) Is life-threatening; 
 
3) Requires in-patient hospitalization or prolongation of an existing hospital stay;  
 
4) Results in disability persistent or significant disability/incapacity, or: 
 
5) Is a congenital anomaly/birth defect.  
 
Note: A SAE may also be an important medical event, in the view of the investigator that 
requires medical or surgical intervention to prevent one of the outcomes listed above.  
 
All serious adverse events, regardless of attribution, and any deaths will be reported within 24 
hours of notification of the event to the sponsor and DSMB Coordinator. All serious adverse 
events, regardless of attribution, and any deaths will be reported within 5 days of notification of 
the event to the University of Arizona Human Subjects Protection  Program.  
 
 
All serious adverse events will be processed by the DSMB Coordinator monthly for initial trend 
analysis and fully reviewed by the DSMB, every six months. The DSMB coordinator will review 
the SAE reporting process to confirm reporting requirements are met. 
 
6. 
Plan for assuring data accuracy and protocol compliance: 
Routine study activity and safety information will be reported to the DSMB every six months, or 
more frequently if requested. These reports will include: 
• Study activity, cumulative and for the period under review; 
• Safety (narrative description on non-serious and serious adverse events); 
• Predetermined protocol early stopping rules for efficacy/futility;    
• Monitoring and protocol compliance; 
• Comments;  
• Attachments (AE data reviewed by the PI to compile the report, SAE letters and reports, 
results of any review(s), applicable correspondence with the IRB or other regulatory agencies.  


 
Amendment #9: 08/28/2017 
 [55] 
 
 
Data, safety and study progress will be reported to: 
• Human Subjects Protection Program (IRB) at least annually; 
• Sponsor (if applicable) at least every six months. 
 
7. 
Identification of the sponsor or funding agency, as applicable: 
The PI will immediately notify; in writing, the funding agency, if applicable, any action 
 
resulting in a temporary or permanent suspension of the study. 


 
Amendment #9: 08/28/2017 
 [56] 
 
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. 
 
 
 
 


 
 
Amendment #9: 08/28/2017 
 [62] 
APPENDIX A 
 STUDY CALENDAR  
4/1/2010 
STUDY CALENDAR    Page 1                               
 
 
 
 
 
 
Required Studies 
Baseline 
ESHAP Treatment 
Ibritumomab Tiuxetan (Zevalin) 
Regimen∞ 
Visits (weeks or days) 
Within28 
days prior 
to C1, D1 
Cycle 1 
Day 1 
Cycle 2 
Day1 
Cycle 2 
Day 29 
Day 1 
Day  
2,3,4,5 
Day 
7, 8, or 9 
Day 35  
PHYSICAL 
  
History / Physical / vital signsα 
X 
 
X 
X 
X Π 
 
 
 
Height / Weight / BSA / PS 
X 
 
X 
X 
X Π 
 
 
 
Disease Assessment 
X 
 
 
X 
 
 
 
 
Toxicity Assessment 
X 
 
X 
X 
X Π 
 
 
 
LABORATORY 
 
 
CBC / differential / platelets 
X 
 
X 
X 
X Π 
 
 
X∑ 
Serum Creatinine / BUN 
X 
 
X 
X 
X Π 
 
 
 
AST/ ALT/ Alk. Phos/ T. Bilirubin^ 
X 
 
 
 
 
 
 
 
LDH 
X 
 
 
 
 
 
 
 
ΒHCG† 
X 
 
 
 
 
 
 
 
Beta 2- microglobulin 
X 
 
 
 
 
 
 
 
Hepatitis B screen* 
X 
 
 
 
 
 
 
 
Pathology Review £ 
X 
 
 
 
 
 
 
 
Bone marrow cytogenetics¥ 
X 
 
 
X 
 
 
 
 
Bone marrow aspiration and Bx 
X 
 
 
X 
 
 
 
 
SCANS 
 
 
CT or PET Chest 
X 
 
 
X 
 
 
 
 
CT or PET Abdomen 
X 
 
 
X 
 
 
 
 
CT or PET Pelvis 
X 
 
 
X 
 
 
 
 
Gamma Scan 
 
 
 
 
 
X≠ 
 
 
TREATMENT 
 
 
ESHAP 
 
X 
X 
 
 
 
 
 
Rituximab 250 mg/m2 
 
 
 
 
X 
 
X 
 
Ibritumomab Tiuxetan Indium (111In Zevalin) 
 
 
 
 
X 
 
 
 
 
Ibritumomab Tiuxetan Ytrium-90 (90Y Zevalin) 
 
 
 
 
 
 
X 
 
α 
Vital Signs consist of BP, temperature and pulse 
†  
Baseline for women of childbearing potential 
≠  
A scan is performed at 48-72 hours after 111In Zevalin.  Another optional scan may be performed at 90- 120 hours after  
111In Zevalin.  
∞   
111In Zevalin is administered 4-6 weeks after completion of ESHAP. 
^ 
Required at Baseline and Encouraged to repeat as clinically indicated by Good Medical Practice. 
* 
Encouraged by Good Medical Practice, but not required. 
¥ 
Bone Marrow cytogenetics can be done at either Baseline or C2,D29, but must be done at least once. 
£ 
Pathology Review consists of a basic review of a pathology report. If possible submit: Representative H&E stained slides  
from the diagnostic biopsy, one representative paraffin block and one copy of the pathology report. 
∑ 
Starting Day 35 (+/- 7 days) a CBC w/ Diff and Platelet count should be done every week until nadir.  
Π 
Within 28 days prior to Rituximab & Zevalin administration..


 
 
Amendment #9: 08/28/2017 
 [63] 
 
 
STUDY CALENDAR Page 2                                      
 
 
 
 
Required Studies 
Restaging 
Short-Term Follow-Up 
Long-Term Follow-Up 
Off-Study# 
Visits (weeks or days) 
3 mos post 90Y 
Zevalin 
6 mos post 
Zevalin 
12 mos post 
Zevalin 
18 mos post 
Zevalin 
24 mos post 
Zevalin 
Follow-Up: 
Annually for 3 years£ 
Disease Progression or 
Removed from Study (within 4 
weeks) 
PHYSICAL 
  
History / physical / vital signs α 
X 
X 
X 
X 
X 
X 
X 
Height/Weight /BSA/PS 
X 
X 
X 
X 
X 
X 
X 
Disease Assessment 
X 
X 
 
X 
 
X 
X 
Toxicity Assessment 
X 
X 
X 
X 
X 
X 
X 
LABORATORY 
 
 
 
 
 
 
 
CBC/differential/platelets 
X 
X 
X 
X 
X 
X 
X 
Serum Creatinine/BUN 
X 
X 
X 
X 
X 
X 
X 
LDH 
X 
X 
X 
X 
X 
X 
X 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
CT or PET chest 
X 
X 
 
X 
 
X 
X 
CT or PET Abdomen 
X 
X 
 
X 
 
X 
X 
CT or PET pelvis 
X 
X 
 
X 
 
X 
X 
Ω  
After completion of post Zevalin restaging, follow-up exams and tests are to be repeated every 6 months for 2 years,  and then annually for up to 3 years.  
# 
Off-Study Tests to be Performed When a Patient is Determined to Have Disease Progression or is Removed from the Study for any Reason. These tests will be performed  
within 4 weeks after a patient has demonstrated progression of disease, or removed from study. These tests do not have to be repeated if they were performed within 7 days  
prior to documentation of disease progression. 
α 
Vital signs consist of BP, temperature and pulse 
£ 
Follow-up should occur every 6 months (+/- 30 days) for 2 years after the completion of the Short-Term Follow-Up period. 
† 
Continued Follow-Up should occur annually (+/- 30 days) for survival and disease status. Patients should be followed by physical exam and, if clinically indicated by Good  
Medical Practice, CT scans.  Patients will be followed for 3 years or until patient starts an alternate treatment or is removed from study to allow determination of study  
endpoints. 
 
 


 
 
 
Amendment #9: 08/28/2017 
 [64] 
APPENDIX B 
PERFORMANCE STATUS SCALE 
 
STATUS1,2 
(Karnofsky) 
SCALE 
"WHO" - STATUS3,4 
(Zubrod-ECOG) 
 
 
 
 
Normal, no complaints 
 100 
0 
Normal activity 
 
 
 
 
Able to carry on normal activity 
 90 
1 
Symptoms, but 
Minor signs or symptoms of disease 
 
 
ambulatory 
 
 
 
 
Normal activities for effort 
 80 
 
 
 
 
 
 
Cares for self, unable to carry on 
 70 
2 
Some bed time, but in  
normal activity or to do active 
 
 
bed less than 50% of 
work 
 
 
normal daytime 
 
 
 
 
Requires occasional assistance, but 
 60 
 
 
able to care for most of own needs 
 
 
 
 
 
 
 
Requires considerable assistance and 
 50 
3 
Needs to be in bed 
frequent medical care 
 
 
more than 50% of 
 
 
 
normal daytime 
 
 
 
 
Disabled, requires special care and  
 40 
 
 
Assistance 
 
 
 
 
 
 
 
Severely disabled, hospitalization 
 30 
4 
Unable to get out of 
indicated though death not 
 
 
bed 
Imminent 
 
 
 
 
 
 
 
Very sick, hospitalization necessary, 
 20 
 
 
active supportive treatment 
 
 
 
Necessary 
 
 
 
 
 
 
 
Moribund 
 10 
 
 
 
 
 
 
Dead 
 
0 
 
 
 
1. Karnofsky,D.A., Abelmann,W.H., Craver,L.F., and Burchenal,J.H.,  The use of the nitrogen 
mustards in the palliative treatment of carcinoma.  Cancer (Philad.) 1: 634, 1948. 
2. Schag,C.C., Heinrich,R.L., Ganz,P.A., Karnofsky Performance Status Revisited: Reliability, 
Validity, and Guidelines,  Clinical Oncology.  2, 187-193, 1984 
3. Zubrod,C.G., et.al. Appraisal of Methods for the Study of Chemotherapy of Cancer in Man.  
Journal of Chronic Diseases.  11: 7-33, 1960 
4. WHO Handbook for Reporting Results of Cancer Treatment.  WHO Offset Publication No.48.  
World Health Organization,  Geneva,  1979 


 
 
Amendment #9: 08/28/2017 
 [65] 
APPENDIX C 
ADULT TOXICITY CRITERIA 
COMMON TOXICITY CRITERIA (CTC) 
 
Common Terminology Criteria for Adverse Events v3.0 
(CTCAE) 
Publish Date: August 9, 2006 
Quick Reference 
The NCI Common Terminology Criteria for Adverse Events v3.0 is a descriptive terminology which can be utilized for Adverse 
Event (AE) reporting. A grading (severity) scale is provided for each AE term. 
Components and Organization 
CATEGORY 
A CATEGORY is a broad classification of AEs based on anatomy and/or pathophysiology. Within each CATEGORY, AEs are listed 
accompanied by their descriptions of severity (Grade). 
Adverse Event Terms 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or 
procedure. An AE is a term that is a unique representation of a specific event used for medical documentation and scientific 
analyses. Each AE term is mapped to a MedDRA term and code. AEs are listed alphabetically within CATEGORIES. 
Short AE Name 
The ‘SHORT NAME’ column is new and it is used to simplify documentation of AE names on Case Report Forms. 
Supra-ordinate Terms 
A supra-ordinate term is located within a CATEGORY and is a grouping term based on disease process, signs, symptoms, or 
diagnosis. A supra-ordinate term is followed by the word ‘Select’ and is accompanied by specific AEs that are all related to the 
supra-ordinate term. Supra-ordinate terms provide clustering and consistent representation of Grade for related AEs. Supra-
ordinate terms are not AEs, are not mapped to a MedDRA term and code, cannot be graded and cannot be used for reporting. 
REMARK 
A ‘REMARK’ is a clarification of an AE. 
ALSO CONSIDER 
An ‘ALSO CONSIDER’ indicates additional AEs that are to be graded if they are clinically significant. 
NAVIGATION NOTE 
A ‘NAVIGATION NOTE’ indicates the location of an AE term within the CTCAE document. It lists signs/symptoms alphabetically and 
the CTCAE term will appear in the same CATEGORY unless the ‘NAVIGATION NOTE’ states differently. 
Grades 
Grade refers to the severity of the AE. The CTCAE v3.0 displays Grades 1 through 5 with unique clinical descriptions of severity for 
each AE based on this general guideline: 
Grade 1 Mild AE 
Grade 2 Moderate AE 
Grade 3 Severe AE 
Grade 4 Life-threatening or disabling AE 
Grade 5 Death related to AE 
A Semi-colon indicates ‘or’ within the description of the grade. 
An ‘Em dash’ (—) indicates a grade not available. 
Not all Grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than five options for Grade selection. 
Grade 5 
Grade 5 (Death) is not appropriate for some AEs and therefore is not an option. 
The DEATH CATEGORY is new. Only one Supra-ordinate term is listed in this CATEGORY: ‘Death not associated with CTCAE 
term – Select’ with 4 AE options: Death NOS; Disease progression NOS; Multi-organ failure; Sudden death. 
Important: 
•  Grade 5 is the only appropriate Grade 
•  This AE is to be used in the situation where a death 
1. cannot be reported using a CTCAE v3.0 term associated with Grade 5, or 
2. cannot be reported within a CTCAE CATEGORY as ‘Other (Specify)’ 
 
Please refer to http://ctep.cancer.gov/reporting/ctc.html for specific Advese Event grading and 
reporting. 


 
 
Amendment #9: 08/28/2017 
 [66] 
APPENDIX D 
INTERNATIONAL WORKSHOP STANDARDIZED RESPONSE CRITERIA FOR NON-
HODGKIN’S LYMPHOMAS 
 
1. 
RESPONSE CLASSIFICATIONS 
The definition of “complete disappearance” of clinically detectable disease varies.  Patients 
considered disease-free have been defined by variables including complete blood count (CBC), 
clinical and radiologic findings, and sizes of lymph nodes, spleen, and liver.  Additionally, the 
lack of bone marrow involvement may be required.  Some investigators have set a minimal 
duration for the absence or reduction of disease before the response is confirmed[1-11].  In some, 
responses are reclassified retrospectively.   
Because of the considerable variation in the literature, specific, standardized guidelines for 
response assessment were recently established in a 1998 report from an International Workshop 
conducted at the NCI.  Recommendations were presented to ensure accurate and objective 
evaluation of the presence or lack of disease, and comparability among clinical trials.  The 
recommended criteria were based on lymph node biopsy and bone marrow evaluation and 
considered as anatomic definitions.  Categories were included for CR, CR/unconfirmed (CRu), 
PR, and relapse/progression [12].  Flow cytometric, cytogenetic, and molecular studies were not 
included in response definitions (Table 1). 
 
Table 1 
International Workshop Response Criteria for Non-Hodgkin’s Lymphoma 
Response 
Category 
Physical 
Examination 
Lymph Nodes 
Lymph Node 
Masses 
Bone Marrow 
CR 
Normal 
Normal 
Normal 
Normal 
CRu 
Normal 
Normal 
Normal 
Indeterminate 
 
Normal 
Normal 
> 75% decrease 
Normal or 
indeterminate 
PR 
Normal 
Normal 
Normal 
Positive 
 
Normal 
≥ 50% decrease 
≥ 50% decrease 
Irrelevant 
 
Decrease in 
liver/spleen 
> 50% decrease 
> 50% decrease 
Irrelevant 
Relapse/ 
progression 
Enlarging 
liver/spleen; 
new sites 
New or increased 
New or increased 
Reappearance  
Adapted from Cheson et al., 1999[12] 
In addition, definitions were recommended for end points of interest in clinical trials, including 
survival (overall, event-free, progression-free, and disease-free), as well as response duration, 
time to next treatment, and cause-specific death (Table 2). 
 


 
 
Amendment #9: 08/28/2017 
 [67] 
Table 2 
International Workshop Definitions of End Points for Clinical Trials 
End Point 
Response 
Category 
Definition 
Point of 
Measurement 
Overall survival 
All patients 
Death from any cause 
Entry onto trial 
Event-free survival 
CR, CRu, PR 
Failure or death from any 
cause 
Entry onto trial 
Progression-free survival 
All patients 
Disease progression or death 
from NHL 
Entry onto trial 
Disease-free survival 
CR, CRu 
Time to relapse 
First documentation 
of response 
Response duration 
CR, CRu, PR 
Time to relapse or 
progression 
First documentation 
of response 
Time to next treatment 
All patients 
Time when new treatment is 
needed 
Entry onto trial 
Cause-specific death 
All patients 
Death related to NHL 
Death 
Adapted from Cheson et al., 1999[12] 
 
2. 
MEASURES OF DURATION 
• Time to Progression:  measured from the date of first study treatment to the first date when 
progressive disease is documented. 
a. Progressive Disease (PD)-Free Interval (Duration Of Response):  measured, in a 
responder, from the date when a CR, CCR or PR is first noted to the first date at 
which progressive disease is observed.  An ongoing PD-free interval occurs when 
there is a responder for whom progressive disease has not been noted. 
3. 
MEASURABLE LESIONS 
• Measurable lesions will be assessed bidimensionally at baseline for determining the efficacy 
of study treatment.  Measurable lesions must be measured at baseline by the method which 
will be used for routine tumor measurement during the study.  The patient must have at least 
one lesion of 2 cm or larger in its longer diameter. 
 
4. 
DEFINITION OF MEASURABLE DISEASE 
b. The extent of disease is measurable if the patient has one or more lesions that are 
clearly demarcated and may be represented with clearly defined margins as 
measured in centimeters.  These measurements will be bidimensional (two longest 
perpendicular measures per lesion) meeting the minimum requirement:  1) at least  
1.5 cm in a single dimension for all lesions and 2) at least 2.0 cm in a single 
dimension for at least one lesion.  All other lesions will be followed as evaluable 
disease. 
5. 
MEASUREMENT OF LESIONS 
c. Measurable lesions must be measured at baseline by the method that will be used 
for routine measurements during the study.  Each measurable lesion will be 
consistently measured bidimensionally for the duration of the study.  In addition, 


 
 
Amendment #9: 08/28/2017 
 [68] 
the routine method of measurement for any measurable lesion, e.g., X-ray, CT 
scan, etc. will remain the same for each evaluation throughout the course of the 
study.  Measurements will be performed using a ruler or calipers and will be 
recorded in centimeters. 
REFERENCES 
1. 
World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. 
Offset Publication. Geneva: World Health Organization 1979; Report Nbr: 48, 5-41. 
2. 
Oken M, Creech R, Tormey D, Horton J, Davis T, McFadden E, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982;5:649-55. 
3. 
Redman J, Cabanillas F, Velásquez W, McLaughlin P, Hagemeister F, Swan Jr. F, et al. 
Phase II trial of fludarabine phosphate in lymphoma: an effective new agent in low-grade 
lymphoma. J Clin Oncol 1992;10(5):790-4. 
4. 
Hochster H, Kyungmann K, Green M, Mann R, Neiman R, Oken M, et al. Activity of 
fludarabine in previously treated non-Hodgkin's low-grade lymphoma:  results of an 
Eastern Cooperative Oncology Group study. J Clin Oncol 1992;10(1):28-32. 
5. 
Falkson C. Fludarabine:  a phase II trial in patients with previously treated low-grade 
lymphoma. Am J Clin Oncol 1996;19(3):268-70. 
6. 
Hiddemann W, Unterhalt M, Pott C, Wormann B, Sandford D, Freund M, et al. 
Fludarabine single-agent therapy for relapsed low-grade non-Hodgkin's lymphomas: a 
phase II study of the German Low-Grade Non-Hodgkin's Lymphoma Study Group. Semin 
Oncol 1993;20(5 Suppl 7):28-31. 
7. 
Hickish T, Serafinowski P, Cunningham D, Oza A, Dorland E, Judson I, et al. 
2-chlorodeoxyadenosine: evaluation of a novel predominantly lymphocyte selective agent 
in lymphoid malignancies. Br J Cancer 1993;67(1):139-43. 
8. 
Saven A, Lee T, Kosty M,  Piro L. Cladribine and mitoxantrone dose escalation in 
indolent non-Hodgkin's lymphoma. J Clin Oncol 1996;14(7):2139-44. 
9. 
Cabanillas F, Hagemeister F, McLaughlin P, Velásquez W, Riggs S, Fuller L, et al. 
Results of MIME salvage regimen for recurrent or refractory lymphoma. J Clin Oncol 
1987;5(3):407-12. 
10. 
Meyer R, Browman G, Samosh M, Benger A, Bryant-Lukosius D, Wilson W, et al. 
Randomized phase II comparison of standard CHOP with weekly CHOP in elderly 
patients with non-Hodgkin's lymphoma. J Clin Oncol 1995;13(9):2386-93. 
11. 
Velásquez W, Cabanillas F, Salvador P, McLauglin P, Fridrik M, Tucker S, et al. 
Effective salvage therapy for lymphoma with cisplatin in combination with high-dose 
Ara-C and dexamethasone (DHAP). Blood 1988;71(1):117-22. 
12. 
Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, et al. Report of 
an international workshop to standardize response criteria for non-Hodgkin's lymphoma. 
J Clin Oncol 1999;17(4):1244-53. 


 
 
 
Amendment #9: 08/28/2017 
 [69] 
 
APPENDIX E 
 
• SAE Reporting documents 
• MedWatch forms


                 
 
 
 
 
 
                                                                                                                                                           Form Number: PV 001 
 
 
Amendment #9: 08/28/2017 
 [70] 
 
 
SERIOUS ADVERSE EVENT        
FORM (SAE) 
 
SAE Case Reference 
#________________ 
 
Biogen Idec use only 
Section A: 
 
Patient 
  Number:______________ 
Patient 
  Initials:_________ 
Site 
  Number:_______________ 
Protocol 
  Number:______________ 
  DOB:_________________ 
                        (MM/DD/YY) 
Patient Gender:   Male   Female  
Principal 
Investigator:______________________   
Date reported to Biogen 
Idec:___________________ 
                     (MM/DD/YY) 
Report Type:   Initial      Follow-up      Final 
  Onset date of event:_____________________ 
                                            (MM/DD/YY) 
 
Section B:                            CRITERIA FOR SERIOUS CLASSIFICATION 
Please check all that apply: 
 
 Death _________________________ 
                               (MM/DD/YY) 
 
     Autopsy performed?   Yes    No    
 Important medical events (may jeopardize the 
     patient and may require medical/surgical 
     intervention to prevent above outcomes) 
 Life-Threatening 
 Congenital anomaly / Birth defect 
 New / Prolonged Hospitalization 
      ____/____/____      ____/____/____ 
           Admission Date               Discharge Date 
 Other: specify______________________________ 
 Persistent / Significant Disability / ncapacity 
___________________________________________ 
Section C:                                               STUDY DRUG 
 
Investigational Drug Name: *______________________ 
 
First Treatment date:________________________ 
                                                            (MM/DD/YY) 
Date of most recent treatment:_____________________ 
                                                                          (MM/DD/YY) 
Dose, Frequency, Route:_____________________ 
Action taken on Study Drug due to Adverse Event:  (check one) 
                 None      Dose increased      Dose reduced      Interrupted      Discontinued 
 
                 IV rate increased      IV rate decreased 
Did Adverse Event abate after stopping drug? 
 Yes      No      Unknown      N/A 


                 
 
 
 
 
 
                                                                                                                                                           Form Number: PV 001 
 
 
Amendment #9: 08/28/2017 
 [71] 
Did Adverse Event reappear after reintroduction? 
 Yes      No      Unknown      N/A 
*If Investigational Drug is a combination therapy, specify other suspect component in Sections D and E 


                 
 
 
 
 
 
                                                                                                                                                           Form Number: PV 001 
 
 
Amendment #9: 08/28/2017 
 [72] 
 
 
SERIOUS ADVERSE EVENT        
FORM (SAE) 
 
SAE Case Reference 
#________________ 
 
Biogen Idec use only 
 
Patient 
  Number:______________ 
Patient 
  Initials:_________ 
Site 
  Number:_______________ 
Protocol 
  Number:______________ 
Section D:                                 Combination Therapy (Second Component) 
 
 
Investigational Drug Name: *______________________ 
 
First Treatment date:________________________ 
                                                            (MM/DD/YY) 
Date of most recent treatment:_____________________ 
                                                                          (MM/DD/YY) 
Dose, Frequency, Route:_____________________ 
Action taken on Study Drug due to Adverse Event:  (check one) 
                 None      Dose increased      Dose reduced      Interrupted      Discontinued 
 
                 IV rate increased      IV rate decreased 
Did Adverse Event abate after stopping drug? 
 Yes      No      Unknown      N/A 
Did Adverse Event reappear after reintroduction? 
 Yes      No      Unknown      N/A 
Section E:                                 Combination Therapy (Third Component) 
 
 
Investigational Drug Name: *______________________ 
 
First Treatment date:________________________ 
                                                            (MM/DD/YY) 
Date of most recent treatment:_____________________ 
                                                                          (MM/DD/YY) 
Dose, Frequency, Route:_____________________ 
Action taken on Study Drug due to Adverse Event:  (check one) 
                 None      Dose increased      Dose reduced      Interrupted      Discontinued 
 
                 IV rate increased      IV rate decreased 
Did Adverse Event abate after stopping drug? 
 Yes      No      Unknown      N/A 
Did Adverse Event reappear after reintroduction? 
 Yes      No      Unknown      N/A 
 
 
 


                 
 
 
 
 
 
                                                                                                                                                           Form Number: PV 001 
 
 
Amendment #9: 08/28/2017 
 [73] 
Section F:                        DESCRIPTION OF THE SERIOUS ADVERSE EVENT 
(Include relevant medical history and intercurrent illness) 
 
 
 
 
 
 
 
 
 
 
 
Section G:                     EVALUATION OF THE SERIOUS ADVERSE EVENT 
Key 
RELATIONSHIP TO STUDY DRUG 
GRADE 
OUTCOME AT TIME OF REPORT 
1 = Probably Related  
1 = Mild  
1 = Resolved  
4 = Worsened 
2 = Possibly Related 
2 = Moderate 
2 = Improved  
5 = Not 
Available 
3 = Unknown 
3 = Severe 
3 = Unchanged 
6 = Fatal 
4 = Not Related ** 
4 = Life Threatening 
 
 
 
ADVERSE EVENT 
(list primary diagnosis first, if possible - one per line) 
e.g. neutropenic fever 
ONSET DATE 
(MM/DD/YY) 
DATE STOPPED 
(MM/DD/YY) 
RELATIONSH
IP 
GRADE 
OUTCOME 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
**Specify on “Other Comments” section other factors that may have contributed to the adverse event.


                 
 
 
 
 
 
                                                                                                                                                           Form Number: PV 001 
 
 
Amendment #9: 08/28/2017 
 [74] 
 
 
SERIOUS ADVERSE EVENT        
FORM (SAE) 
 
SAE Case Reference 
#________________ 
 
Biogen Idec use only 
 
 
Patient 
  Number:______________ 
Patient 
  Initials:_________ 
Site 
  Number:_______________ 
Protocol 
  Number:______________ 
 
Section H:          TEST PERFORMED TO EVALUATE THE SERIOUS ADVERSE EVENT 
Tests 
Date 
(MM/DD/YY) 
Result 
If Lab, Normal 
Range/Units 
Clinically Significant 
YES 
NO 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section I:       TREATMENT ADMINISTERED TO TREAT THE SERIOUS ADVERSE EVENT 
Drug / Therapy 
Start Date 
(MM/DD/YY) 
Stop Date 
(MM/DD/YY) 
 Ongoing 
Y / N? 
Dose / Route 
Indication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Amendment #9: 08/28/2017 
 [75] 
 
 
SERIOUS ADVERSE EVENT           
FORM (SAE) 
 
SAE Case Reference 
#________________ 
 
Biogen Idec use only 
 
 
Patient 
  Number:______________ 
Patient 
  Initials:_________ 
Site 
  Number:_______________ 
Protocol 
  Number:______________ 
Section J:                                                 CONCOMITANT THERAPY 
(ongoing or completed within one week prior to onset of event) 
Do Not Include Treatments for SAE 
Drug/Therapy 
Start Date 
(MM/DD/YY) 
Stop Date 
(MM/DD/YY) 
Ongoing 
Y / N? 
Dose/Route 
Indication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section K:                                                   OTHER COMMENTS 
 
 
 
 
 
 
 
 
I have reviewed the data contained in these pages and have found it to be accurate: 
 
Principal Investigator’s Signature 
 
Date Signed 
 
 
(        ) 
Name (print) 
Title 
Phone Number 
 
(        ) 
Institution 
Fax Number 


 
       Form Approved:  OMB No. 0910-0291  Expires 12/31/94 
                                                       See OMB statement below 
Mfr. report # 
UF/ Dist report # 
                                           FDA use only 
 
 
Amendment #9: 08/28/2017 
 [76] 
 
For use by user-facilities, 
Distributors and manufacturers for 
MANDATORY reporting 
Page ___ of ___ 
A.  Patient Information 
 
C.  Suspect Medication(s) 
1. 
Patient identifier 
 
 
 
    (In Confidence) 
2. Age at time of event: 
      
 
    Or date  
   of birth: 
3. Sex 
 
   
 Female 
 
   
 Male 
4. Weight  
 
     or       
      
         
lbs.  
 
kgs.  
          
 
 Name (give labeled strength & mfr/labeler, if known) 
#1 
 
#2 
B.  Adverse Event or Product Problem 
 
2.  Dose, frequency & route used 
 
#1 
 
3. Therapy dates (if unknown, give duration) 
    from/to (or best estimate) 
 
#1 
 
1. 
 Adverse event    and/or  
 Product problem (e.g., defects/malfunctions) 
2.  Outcomes attributed to adverse event           
    (check all that apply) 
 
#2 
#2 
      
      
 
 Death 
 
 
    
 Life-threatening 
 
    
 Hospitalization – initial or prolonged 
 Disability 
 Congenital anomaly 
 Required intervention to prevent 
    permanent impairment/damage 
 Other:  
 
4. Diagnosis for use (indication) 
 
#1 
 
5. Event abated after use 
   stopped or dose reduced 
 
1# 
Yes  
No 
Doesn’t  
                             apply 
 
2# 
Yes  
No 
Doesn’t   
                             apply 
#2 
3. Date of 
    event 
    (mo/day/yr) 
 
 
to 
 
3.  Date of 
     this report 
     (mo/day/yr) 
 
6. 
LOT # (if known): 
 
#1: 
7. 
Exp. Date (if 
known): 
 
#1: 
8. 
Event reappeared after 
reintroduction: 
 
1# 
Yes  
No 
Doesn’t  
                             apply 
 
 
 
#2: 
 
#2: 
 
4. Describe event or problem: 
    Please see page two for additional information of this event.  
 
9. 
NDC # - for product problems only (if known) 
                             __                    __    
 
2# 
Yes  
No 
Doesn’t   
                             apply 
 
 
 
 10.   Concomitant medical products and therapy dates (exclude treatment of event) 
 
 
 
 
 
 
 
 
 
 
 
D.  All Manufacturers 
 
 
1. Contact office – name/address (& mfring site for devices): 
2. Phone number: 
 
 
 
      
3. Report Source: 
(check all that apply) 
  
 Foreign 
   
  
 Study 
   
  
 Literature 
  
  
 Consumer 
 
  
 Health   
       professional 
  
 User facility 
   
  
 Company 
       representative 
  
 Distributor 
  
 Other:       
       
 
 
      
 
 
 
 
 
 
1. 
Relevant tests/laboratory data, including dates: 
    Please see page three for laboratory data, including date. 
 
 
4. 
Date received by manufacturer 
  
5.  NDA # 
     IND # 
     PLA # 
6. If, IND, protocol # 
 
 
 
Pre-1938   
 Yes 
 
7. Type of report 
    (check all that apply) 
 
 7-day               
 15-day 
OTC          
 Yes 
product 
 
 
 
 
 10-day             
 periodic 
8.  Adverse event term(s) 
 
 
 
 Initial               
 follow-up # ___ 
 
6. 
Other relevant history, including preexisting conditions (e.g., allergies, race, 
pregnancy, smoking and alcohol use, hepatic/renal dysfunction, etc.): 
9. 
Mfr. report number 
 
 
 
 
E.  Initial Reporter 
 
 
  1.   Name, address & phone # 
 
 
 
 
 
 
  FDA Form 3500A (6-93) 
 
Submission of a report does not constitute an 
Admission that medical personnel, user facility, 
Distributor, manufacturer or product caused or 
Contributed to the event. 
 
2.  Health professional? 
 
     
 Yes      
  No 
3.  Occupation 
4.  Initial reporter also 
 sent report to FDA? 
 
Yes  
No  
Unk 
“An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB control number” 
 
 
 
 
 


 
       Form Approved:  OMB No. 0910-0291  Expires 12/31/94 
                                                       See OMB statement below 
Mfr. report # 
UF/ Dist report # 
                                           FDA use only 
 
 
Amendment #9: 08/28/2017 
 [77] 
 
For use by user-facilities, 
Distributors and manufacturers for 
MANDATORY reporting 
Page ___ of ___ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
       Form Approved:  OMB No. 0910-0291  Expires 12/31/94 
                                                       See OMB statement below 
Mfr. report # 
UF/ Dist report # 
                                           FDA use only 
 
 
Amendment #9: 08/28/2017 
 [78] 
 
For use by user-facilities, 
Distributors and manufacturers for 
MANDATORY reporting 
Page ___ of ___ 
 
 
 
 
 
 
 
 
  FDA Form 3500A (6-93) 
 
Submission of a report does not constitute an 
admission that medical personnel, user facility, 
distributor, manufacturer or product caused or 
contributed to the event. 
“An agency may not conduct or sponsor, and a person is not required to respond 
to, a collection of information unless it displays a currently valid OMB control 
number” 


 
 
Amendment #9: 08/28/2017 
 [79] 
APPENDIX F 
 
ANN ARBOR STAGING CRITERIA 
 
 
                      Ann Arbor Classification (AJCC Manual for Staging of Cancer, 5th edition, 1997) 
 
STAGE I 
Involvement of a single lymph node region (I) or localized involvement of a single     
extralymphoatic organ or site (IE) 
 
STAGE II 
Involvement of two or more lymph node regions on the same side of the diaphragm (II) or 
localized involvement of a single associated extralymphatic organ or site and its regional nodes 
with or without other lymph node regions on the same side of the diaphragm 
 
STAGE III 
Involvement of lymph node regions on both sides of the diaphragm (III) that may also be 
accompanied by localized involvement of an extralymphatic organ or site (IIIE) by involvement 
of the spleen (IIIS) or both (IIISE). 
 
STAGE IV 
 Disseminated (multifocal) involvement of one or more extralymphatic organs with or without 
associated  lymph node involvement, or isolated extralymphatic organ involvement with distant 
(non-regional) nodal involvement. 
 
A = Asymptomatic 
B = Fever, sweats, weight loss > 10% of body weight 
 
“BULKY” is defined as a mediastinal mass > 1/3 of the maximum chest diameter (ie, internal dimension of the 
thoracic cavity measured at its widest point per radiograph) or any other mass > cm in maximum diameter.


 
 
Amendment #9: 08/28/2017 
 [80] 
APPENDIX G 
GUIDELINES FOR THE ESTABLISHMENT OF RADIONUCLIDE DOSE 
CALIBRATOR SETTINGS USING MDS NORDION YTTRIUM-[90] CHLORIDE 
 
#1.  DOSE CALIBRATOR SETUP FOR 90Y:  Please use the following two worksheets (pages 2 and 3), 
along with the manufacturer’s reference manual, to establish dose calibrator dial settings for assaying 90Y.  Dial 
settings for 90Y are established using MDS Nordion 90Y as a standard.  MDS Nordion 90Y is accompanied by an 
Activity Concentration Sheet stating the radioactivity concentration of the product at 1200h ET on the intended 
day of use.  The radioactivity concentration is determined by a liquid scintillation technique traceable to the 
National Institute of Standards and Technology (NIST).  This traceability has been established by both 
MDS Nordion and NIST performing assays on the same 90Y sample and achieving agreement to within plus or 
minus 5%.   
#2.  GEOMETRY CHANGES:  You must establish a new dial setting when you change dispensing 
equipment.  This applies to a change in needle size, a change in syringe type, or a change in the reaction vial 
within the dose calibrator.  A change in the type of container and/or the orientation of the container within the 
dose calibrator is a change in geometry.  When using beta-emitting radionuclides a change in geometry will 
influence the dose calibrator reading. 
#3.  ACCURACY:  The accuracy of liquid transfer from the MDS Nordion 90Y vial using syringes 
commonly available in nuclear medicine departments is adequate, but not optimal.  Gravimetric or volumetric 
methods can enhance the accuracy of the transfer (Coursey et al, Nucl Med Biol 1993; 20:693-9). 
#4.  USE OF WORKSHEETS:  The worksheets on pages 2 and 3 are only for the initial determination of the 
dial settings used to assay 90Y.  Dial settings must be established for 10 mL of 90Y Zevalin in a Zevalin reaction 
vial, or the range of 90Y Zevalin volumes assayed in a 10 mL syringe.  Once the dial settings are established, keep 
these worksheets as a reference for future use.  An example of the range of dial settings used for a range of 90Y 
Zevalin volumes in a 10 mL syringe is provided on page 4. 
#5.  DAILY CALIBRATION CHECK:  On a daily basis, the dose calibrator response for each frequently 
used dial setting must be checked with a long-lived dose calibrator source.  Suggested isotopes are  
137Cs, 57Co, 60Co, or 133Ba.  Consult your health physicist. 
#6.  INITIAL ISOTOPE CALIBRATION NUMBER:  The radionuclide dose calibrator manufacturer 
must be contacted for the initial dial setting for working with 90Y. 
90Y Decay Factor Table 
Hours before 1200 h EST on the intended day of use: 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
0 
1 
1.011 
1.022 
1.033 
1.044 
1.056 
1.067 
1.079 
1.090 
0.25 
1.003 
1.013 
1.025 
1.036 
1.047 
1.058 
1.070 
1.082 
1.093 
0.50 
1.005 
1.016 
1.027 
1.039 
1.050 
1.061 
1.073 
1.084 
1.096 
0.75 
1.008 
1.019 
1.030 
1.041 
1.053 
1.064 
1.076 
1.087 
1.099 
Hours after 1200 h EST on the intended day of use: 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
0 
1 
0.989 
0.979 
0.968 
0.958 
0.947 
0.937 
0.927 
0.917 
0.25 
0.997 
0.987 
0.976 
0.966 
0.955 
0.945 
0.935 
0.925 
0.915 
0.50 
0.995 
0.984 
0.973 
0.963 
0.953 
0.942 
0.932 
0.922 
0.912 
0.75 
0.992 
0.981 
0.971 
0.960 
0.950 
0.940 
0.930 
0.920 
0.910 
To use the decay table, find the number of hours in the top and left-hand columns of the grids, then find the corresponding decay factor. 
 


 
G.81 
 
 
Amendment #9: 08/28/2017 
 [81] 
GUIDELINES FOR THE ESTABLISHMENT OF RADIONUCLIDE DOSE CALIBRATOR 
SETTINGS USING MDS NORDION YTTRIUM-[90] CHLORIDE: WORKSHEET #1 
(ZEVALIN REACTION VIAL) 
 
1. The Activity Concentration Sheet provided with each MDS Nordion 90Y vial 
includes data based on 1200h ET on the intended day of use.  Use the 90Y decay 
table on page 1 to determine the current MDS Nordion 90Y activity 
concentration, adjusting for time zone changes.  (Example:  At 1400h ET, 
2 hours post-calibration, the decay factor is 0.979.  If the Activity Concentration 
Sheet reports 84.0 mCi/mL, the current activity concentration is 
84.0 mCi/mL x 0.979 = 82.2 mCi/mL). 
_________mCi/mL 
2. Using the activity concentration determined in Step #1, calculate the volume for 
40 mCi. (Example:  40 mCi ÷ 82.2 mCi/mL = 0.49 mL).  Draw up the 
appropriated volume for 40 mCi into a 1 mL syringe with a removable needle. 
_________mL 
3. Change the needle on the 1 mL syringe.  Place the 1 mL syringe in the dose 
calibrator.  A 1 mL syringe holder may be required from your dose calibrator 
manufacturer to center the syringe in the unit.  Adjust the dial setting until the 
dose calibrator indicates 40 mCi (take into account any multiplier that may be 
required by the calibrator).  Record as Dial Setting A. 
 
4. Transfer 40 mCi into a reaction vial. 
 
 
5. Wash residual activity from the 1 mL syringe into the reaction vial with normal 
saline.  (Two 0.5 mL aliquot transfers will remove most of the retained activity in 
the needle/syringe hub). 
_________mL 
6. Place the 1 mL syringe into the dose calibrator and assay for residual activity. 
 
_________mCi 
7. Subtract the residual activity in the 1 mL syringe determined in step #6 from 
40 mCi to determine the activity transferred into the reaction vial (Example:  
40.0 mCi - 0.2 mCi = 39.8 mCi). 
_________mCi 
8. Add normal saline to the reaction vial to a total volume of 10.0 mL.  (Note:  
10.0 mL minus volume transferred in step #2 and step #5 equals the volume to 
add). 
_________mL 
9. Place the 10 mL reaction vial into the dose calibrator and adjust the dial setting 
until the display shows the activity determined in step #7.  Record as Dial Setting 
B. Record the reaction vial type and date performed. 
 
 
 
Reaction Vial  
Type:____________ 
Date: ____________ 
 
 
Dial  
Setting 
(A):
Dial 
Setting 
( )


 
G.82 
 
 
Amendment #9: 08/28/2017 
 [82] 
 
GUIDELINES FOR THE ESTABLISHMENT OF RADIONUCLIDE DOSE CALIBRATOR SETTINGS USING 
MDS NORDION YTTRIUM-[90] CHLORIDE: WORKSHEET #2 
(10 ML SYRINGE) 
 
1.  The activity concentration sheet provided with each mds nordion 90Y vial  includes 
data based on 1200h ET on the intended day of use.  Use the 90Y decay table on 
page 1 to determine the current mds nordion 90Y activity concentration, adjusting 
for time zone changes.  (example:at 1400h ET, 2 hours post-calibration, the decay 
factor is 0.979.  If the activity concentration sheet reports 84.0 mCi/mL, the 
current activity concentration is 84.0 mCi/mL x 0.979 = 82.2 mCi/mL). 
_________mCi/mL 
2.   Using the activity concentration determined by step #1, calculate the volume for 
40 mci.  (example: 40 mCi ÷ 82.2 mCi/mL = 0.49 ml).  Draw up the appropriate 
volume for 40 mCi into a 1 mL syringe with a removable needle. 
_________mL 
3.   Change the needle on the 1 mL syringe.  Place the 1 mL syringe in the dose 
calibrator.  A 1 mL syringe holder may be required from your dose calibrator 
manufacturer to center the syringe in the unit.  Adjust the dial setting until the 
dose calibrator indicates 40 mCi (take into account any multiplier that may be 
required by the calibrator).  Record as dial setting a. 
 
4.   Transfer 40 mCi into a reaction vial. 
 
 
5.   Wash residual activity from the 1 mL syringe into the reaction vial with normal 
saline.  (two 0.5 mL aliquot transfers will remove most of the activity retained in 
the needle and syringe hub). 
_________mL 
6.   Place the 1 mL syringe into the dose calibrator and assay for residual activity. 
 
_________mCi 
7.   Subtract the residual activity in the 1 mL syringe determined in step #6 from 40 
mCi to determine the activity transferred into the reaction vial (example:  40.0 
mCi - 0.2 mCi = 39.8 mCi). 
_________mCi 
8.   Add normal saline to the reaction vial to a total volume of 10.0 mL.  (note:  10.0 
mL minus volumes transferred in step #2 and step #5 equals the volume to add). 
_________mL 
9.   Calculate the activity that will be contained in 1 mL aliquots (example:  39.8 
mCi/10mL, 35.8 mCi/9mL, 31.8 mCi/8mL, etc.). 
 
10. Using a 10 mL syringe, sequentially remove 1 mL aliquots of 90Y solution from 
the reaction vial.  Assay the syringe in dose calibrator after each aliquot is 
removed.  Adjust dial setting for each volume assayed until the display shows the 
corresponding activity calculated in step #9.  Record each dial setting. 
Dial Settings (B): 
10 mL ____  5 mL  ____ 
9 mL ____  4 mL  ____ 
8 mL ____  3 mL  ____ 
7 mL ____  2 mL  ____ 
6 mL ____  1 mL  ____ 
11. Plot dial setting versus syringe volume onto graph paper (see example on page 4).  
If the slope is flat for the range of volumes, use only one dial setting to assay 90Y 
activity.  If the slope is decending or ascending, use corresponding dial settings 
for each volume, regardless of activity. 
 
12. Record the syringe type and size configuration and date completed. 
Syringe Type and Size: 
___________________   
Date:_______________  
Dial 
Setting 
 


 
G.83 
 
 
Amendment #9: 08/28/2017 
 [83] 
  
 
Dose Calibrator Set-Up for 90Y
Slope Determination for 90Y in 10 mL Syringe
15
20
25
30
35
40
45
50
55
60
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
APPROXIMATE VOLUME (mL)
DIAL SETTING  x 10 
Dose Calibrator Set-Up for 90Y:
Example Plot
Slope Determination for 90Y in 10 mL Syringe
15
20
25
30
35
40
45
50
55
60
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
APPROXIMATE VOLUME (mL)
DIAL SETTING  x 10 


 
 
Amendment #9: 08/28/2017 
 [84] 
APPENDIX H 
BIOGEN 
IDEC 
INCORPORATED 
PREPARATION 
AND 
DISPENSING 
INFORMATION FOR 111In Zevalin and 90Y Zevalin 
CAUTION:  New Drug -- Limited by Federal Law to Investigational Use Only 
 
DESCRIPTION: 
Zevalin (ibritumomab tiuxetan) is a murine monoclonal anti-CD20 antibody that will be 
radiolabeled with Indium-111 or Yttrium-90. 
 
Note: 111In Zevalin or 90Y Zevalin should not be administered until the patient has received 
the second Rituxan infusion. 
 
I. 
Components of the Zevalin (ibritumomab tiuxetan) Kit and Preparation of 111In 
Zevalin and 90Y Zevalin 
 
A. 
Radioisotopes: 111In  and 90Y used for preparing 111In Zevalin and 90Y Zevalin, will be 
obtained from vendors identified by Cell Therapeutics.  All lots of isotopes must be sterile, 
pyrogen-free and be supplied in septum vials designed to maintain these conditions.  
 
B. 
Radiolabeling Kit Components:  For clinical studies, conjugated Zevalin (ibritumomab 
tiuxetan) will be radiolabeled with either 111In for imaging or 90Y for therapy using a 
radiolabeling kit.  The radiolabeling kit is provided by Biogen Idec to the clinical site or 
radiopharmacy.  All kit components are tested for sterility and pyrogenicity. 
 
The kit is stored at 2 - 8°C (35 - 45°F) and consists of the following components: 
 
1) 
Three mL glass septum vial containing 2 mL (3.2 mg) Zevalin (ibritumomab tiuxetan) 
in low-metal normal saline at 1.6 mg/mL 
 
2) 
Three mL glass septum vial containing 2 mL low-metal 50 mM sodium acetate 
 
3) 
Ten mL glass septum vial containing 10 mL formulation buffer (1X PBS containing 
7.5% human serum albumin and 1 mM DTPA, pH 7.2) 
 
4) 
Ten mL glass septum reaction vial (empty) 
 
C. 
See the appropriate Appendix for corrected geometry of dose calibrator for Y-[90]. 
 
D. 
Preparation of 111In Zevalin:  Proper aseptic technique and precautions for handling 
radioactive materials should be employed.  Waterproof gloves shall be utilized in the 
preparation and determination of the radiochemical purity assay of 111In Zevalin.  The 
radiolabeling of 111In Zevalin shall be done according to the following directions using the 
radiolabeling kit described above. 
 


 
 
Amendment #9: 08/28/2017 
 [85] 
1) 
Before radiolabeling, bring refrigerated Zevalin (ibritumomab tiuxetan) cold kit to 
room temperature, 25° C (77° F). 
2) 
Clean the rubber stopper of all cold kit vials and the 111In chloride vial with a suitable 
alcohol swab and allow to air dry. 
3) 
Place the 111In Zevalin reaction vial in a suitable dispensing shield. 
4) 
Using a 1 mL syringe, transfer sodium acetate to the reaction vial.  The volume of 
sodium acetate added is equivalent to 1.2 times the volume of 111In chloride. 
5) 
With a 1 mL syringe, aseptically transfer 5.5 mCi of 111In chloride to the reaction vial.  
Mix completely by gently swirling and inverting the reaction vial several times, do 
not shake. 
6) 
Using a 3 mL syringe, transfer 1.0 mL Zevalin (ibritumomab tiuxetan) to the reaction 
vial.  Mix completely by gently swirling and inverting the reaction vial several times.  
Do not shake. 
7) 
Incubate the 111In Zevalin reaction vial at room temperature for thirty minutes.  
Labeling more than or less than thirty minutes may result in inadequate radiochemical 
purity. 
8) 
Using a 10 mL syringe with a large bore needle (18 - 20 G), draw formulation buffer 
that will result in a total volume of 10 mL when all components are added to the 
reaction vial.  The initial volume in the reaction vial is the volumes calculated in 
Steps 4, 5, and 6.  Ten mL minus the volumes in 4, 5, and 6, will be the volume of 
formulation buffer to add. 
9) 
At the end of the thirty-minute incubation period, add the formulation buffer to the 
reaction vial.  Gently add the formulation buffer down the side of the reaction vial.  
Do not foam, shake or agitate the mixture. 
10) Assay the 111In Zevalin reaction vial in a suitably calibrated dose calibrator. 
11) If not immediately administered to the patient, store the reaction vial containing the 
111In Zevalin at 2° to 8° C (26° to 46° F) and use within 12 hours. 
12) The percent radiochemical purity of the prepared 111In Zevalin should be determined 
before administration to the patient according to the procedure in Section II. 
13) DO NOT EXCEED THE MAXIMUM ALLOWED DOSE OF 5 mCi 111In Zevalin. 
 
E. Preparation of 90Y Zevalin:  Proper aseptic technique and precautions for handling 
radioactive materials should be employed.  Waterproof gloves shall be utilized in the 
preparation and determination of the radiochemical purity assay of 90Y Zevalin.  The 
radiolabeling of 90Y Zevalin shall be done according to the following directions using the 
radiolabeling kit described above. 


 
 
Amendment #9: 08/28/2017 
 [86] 
 
1) Before radiolabeling, bring refrigerated Zevalin (ibritumomab tiuxetan) cold kit to 
room temperature 25° C (77° F).   
2) Clean the rubber stopper of all cold kit vials and the 90Y chloride vial with a suitable 
alcohol swab and allow to air dry. 
3) Place the 90Y Zevalin reaction vial in a suitable dispensing shield. 
4) Using a 1 mL syringe, transfer sodium acetate to the reaction vial.  The volume of 
sodium acetate added is equivalent to 1.2 times the volume of 90Y chloride. 
5) With a 1 mL syringe, aseptically transfer 40 mCi of yttrium-[90] chloride to the 
reaction vial.  Mix completely by gently swirling and inverting the reaction vial 
several times, do not shake. 
6) Using a 3 mL syringe, transfer 1.3 mL Zevalin (ibritumomab tiuxetan) to the reaction 
vial.  Mix completely by gently swirling and inverting the reaction vial several times.  
Do not shake.  
7) Incubate the 90Y Zevalin reaction vial at room temperature for five-minutes.  Labeling 
more than or less than five minutes may result in inadequate radiochemical purity. 
8) Using a 10 mL syringe with a large bore needle (18 - 20 G), draw formulation buffer 
that will result in a total volume of 10 mL when all components are added to the 
reaction vial. The initial volume in the reaction vial is the volumes calculated in 
Steps 4, 5, and 6.  Ten mL minus the volumes in 4, 5, and 6, will be the volume of 
formulation buffer to add. 
9) At the end of the five-minute incubation period, add the formulation buffer to the 
reaction vial.  Gently add the formulation buffer down the side of the reaction vial.  
Do not foam, shake, or agitate the mixture. 
10) Assay the 90Y Zevalin reaction vial in a suitably calibrated dose calibrator.  
11) If not immediately administered to the patient, store the reaction vial containing 90Y 
Zevalin at 2° to 8° C (36° to 46° F) and use within eight hours. 
12) The percent radiochemical purity of the prepared 90Y Zevalin should be determined 
before administration to the patient according to the procedure in Section II. 
13) CAUTION:  DO NOT EXCEED THE MAXIMUM ALLOWED DOSE OF 
32 mCi. 
 
II. 
CLINICAL RELEASE TESTING FOR 111IN ZEVALIN AND 90Y ZEVALIN 
Release assay is performed at the clinical site 111In Zevalin and 90Y Zevalin. 
Radiochemical Purity:  This assay insures that an acceptable percentage of the 
radioisotope is chelated by the antibody conjugate.  An instant thin-layer chromatographic 
assay using a commercial kit (Biodex) is available for use.  In this assay, conjugated 


 
 
Amendment #9: 08/28/2017 
 [87] 
antibody remains at the origin whereas tiuxetan or DTPA-chelated indium/yttrium 
advances with the solvent front.  The amount of radioactivity remaining at the origin 
bound to the antibody conjugate is expressed as a percentage of the total amount of 
radioactivity applied to the strip.  See instructions below Steps #1 - #8. 
 
The Radiochemical Purity by Instant Thin Layer Chromatography (ITLC) shall be done 
according to the following procedure at room temperature: 
 
1. 
Required materials not supplied: 
 
• 
1 mL insulin syringe with a 25 - 26 G needle 
• 
ITLC-SG, or Biodex “Tec-Control” kit, part number 151-770 
• 
Single or multichannel analyzer 
2. Set region of interest of single or multichannel analyzer to incorporate channels 
140-1000 keV for 90Y or 140 –300 keV for 111In. 
 
3. Using a 1 mL insulin syringe, place a hanging drop (7 - 10 µL) onto the ITLC-SG strip at its 
1.4 cm mark “origin.”  Spot one strip at a time and run the procedure on three ITLC-SG 
strips.  A 1:100 dilution may be necessary if the instrument deadtime is appreciable. 
Origin Line 1.4 cm
Cut Line 3.5 cm
Solvent Front
Line  5.0 cm
       ITLC-SG Strip
6 cm
# 1
# 2
0.5 cm


 
 
Amendment #9: 08/28/2017 
 [88] 
 
4. Fill developing chamber with 0.8 mL of bacteriostatic free 0.9% NaCl.  The volume of 0.9% 
NaCl should not touch the 1.4 cm “origin” line. 
 
5. Place ITLC-SG strip into developing chamber and allow the solution to migrate past the 5 cm 
“Solvent Front” line.  Do not allow ITLC-SG strip to adhere to the side of the developing 
chamber.  See illustration below. 
6. Remove ITLC-SG strip and cut in half at the 3.5 cm “Cut-Line.”  Count each half of the 
ITLC-SG strip in a multi-channel or single channel analyzer counter for one-minute (cpm).  
Subtract background counts and use corrected counts. 
 
 
7. Calculate the radiochemical purity % as follows: 
 



 
 
Amendment #9: 08/28/2017 
 [89] 
(Radiochemical purity %) = 
 
 
 
 
 
 
8. Repeat process two times and take the average percentage of the radiochemical purity (RCP). 
The release specification for the average radiochemical purity is ≥ 95% for both 111In 
Zevalin and 90Y Zevalin. 
 
III. RECOMMENDED HANDLING AND ADMINISTRATION OF 111IN ZEVALIN 
AND 90Y ZEVALIN 
 
1. 
Refer to the appropriate section of the clinical trial protocol for details about the dose and 
dose schedule.  Note: Patients will receive an imaging dose of 5 mCi 111In Zevalin.    
Patients with most recent platelet counts from 100,000/mm3 to 149,000/mm3 will be treated 
with a 0.3 mCi/kg dose of 90Y Zevalin.  Patients with most recent platelet counts 
≥ 150,000/mm3 will be treated with 0.4 mCi/kg dose of  90Y Zevalin.   
 
2. 
Vials should be stored with proper shielding at 2 - 8°C (35 - 45°F).  Do not freeze or 
store at room temperature.  The drug is a protein -- HANDLE GENTLY AND AVOID 
FOAMING.  The avoidance of foaming during product handling, preparation and 
administration is important, as foaming may lead to the de-naturing of the product proteins. 
 
3. 
All transfer procedures require strict adherence to aseptic techniques, preferably in a 
laminar flow hood. 
 
4. 
111In Zevalin and 90Y Zevalin may be directly injected 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.   
 
NOTE:  DO NOT USE evacuated glass containers that require vented administration sets 
because this causes foaming as air bubbles pass through the solution. 
 
5. 
The administration of the radiolabeled drug will be accomplished by 10 minute IV injection 
and should be completed within the time specified in the protocol.  CAUTION:  DO NOT 
ADMINISTER AS AN INTRAVENOUS BOLUS.  Flush the line with at least 10 mLs of 
normal saline after radiolabeled product has been infused. 
 
NOTE:  IV pumps may be used with the 111In Zevalin and 90Y Zevalin injection.  DO NOT 
INJECT CONCOMITANTLY with another IV solution or IV medications.   
 
6. 
If a delay in administration occurs after the 111In Zevalin or  90Y Zevalin (in a properly 
identified container) is prepared, the radiolabeled product must be kept refrigerated after 
x 100 
(cpm #1) 
(cpm #1) + (cpm #2) 


 
 
Amendment #9: 08/28/2017 
 [90] 
preparation at 2 - 8°C (35 - 45° F) for up to twelve hours for 111In Zevalin and  eight hours 
for 90Y Zevalin.  If not used soon after the calibration time, the actual dose activity will 
have decayed and require recalculation. 
 
FOR ADDITIONAL INFORMATION CONTACT: 
Zevalin Support Services, Spectrum Pharmaceuticals, 1-866-298-8433, www.Zevalin.com 


 
 
 
Amendment #9: 08/28/2017 
 [91] 
APPENDIX I 
DATA ACQUISITION FOR 111In ZEVALIN 
Equipment and Materials 
1. 
A dual-head gamma camera with medium energy collimators is highly recommended for 
the whole body planar imaging; however, a single-head gamma camera capable of whole 
body imaging may be used. 
 
2. 
111In standards to be imaged on the whole body gamma camera. 
 
Patient 111In Zevalin Injection and Post Injection Imaging 
Injected Activity 
1. 
Just prior to infusion, verify and record the dose using a dose calibrator.  Record the time 
and date. 
2. 
Count the empty syringe after injection using the dose calibrator to determine residual 
activity to calculate and record the total activity injected. 
 
Whole Body 111In Zevalin Image Acquisition 
1. Perform a whole body scan at 48 – 72 hours and optionally at 90 - 120 hours post 111In Zevalin® 
injection.  At 48 – 72 hours, the scan speed should be at 7 - 10 cm/min (30 minute scan), and at 
90 – 120 hours, the scan speed should be 5 - 7 cm/min (40 minute scan). 
2.  Record the start times of the acquisitions on the data sheet. 
3. Each set of images should include a standard of 111In in a small plastic vial (such as a gamma-
counting vial).  A standard of approximately 50 µCi in 10 ml water should be made up prior to 
the 0 hr image and the same standard used with each planar image acquisition beginning after the 
dose is infused.  Measure the exact standard activity in a dose calibrator and record the time and 
activity.  This should correspond to the time of the start of the first scan.  Place the standard on 
the imaging table approximately 10 cm from the body, lateral to the feet.  Always place standard 
on the same side of the body for each scan.  Scan the standard with each whole body image.  
 
 
 
 
 
 
 


 
 
 
Amendment #9: 08/28/2017 
 [92] 
APPENDIX J 
Amendment #1 
(3/1/06) 
Summary of Changes 
 
• Face Page: University of Arizona/Arizona Cancer Center Co-Investigators: deletion of John 
Sweetenham, M.D., as he has left the institution, and addition of Leslie Andritsos, M.D. (Medical 
Oncology) and Lisa Gobar, M.D. (Nuclear Medicine); change of version date of the protocol to 
Amendment #1, March 1, 2006, and addition of sponsor protocol number 009-004-ZEV. 
 
• Section 5.C (Evaluations During the 111In Zevalin Imaging Period): revision  to reflect deletion of 
2-24-hour scan (see below). 
 
• Section 6.C (Zevalin® Adverse Events) and Risk section of the Model Consent Form:  Addition of new 
information relating to severe cutaneous and mucocutaneous adverse events observed in patients who 
received the Zevalin® regimen (post-marketing experiences of erythema multiforme, Stevens-Johnson 
syndrome, toxic epidermal necrolysis, bullous dermatitis, and exfoliative dermatitis). 
 
• Section 8.C (Toxicities to be Monitored and Dosage Modifications, Ibritumomab Tiuxetan Regimen):  
Addition of cautions for cutaneous and mucocutaneous reactions. 
 
• Section 7.B.1 Radioimaging Schedule: Decrease in the number of required whole-body gamma 
camera scans to assess biodistribution after the initial imaging dose on In-111 Zevalin® from two 
to one.  Scan 1 at 2-24 hours has been deleted,  
leaving the scan to be administered 48-72 hours after the In-111 Zevalin®.  As 
before, an optional subsequent scan may be performed to resolve ambiguities (90-120 hours after 
the initial imaging dose).   
 
• Model Consent Form:  Updated with regard to risks (as detailed above) and number of imaging scans 
 
• Appendix H:  Package Insert: addition of current Zevalin® Package Insert as H-2.  Added 4/18/06 
Current NCI Composite Adverse Event and Potential Risks List 
 
• Appendix K:  Updated Data Acquisition for 111-In Zevalin® (imaging times) 
 
 
 
 
 


 
 
 
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APPENDIX K 
Amendment #2 
(4/27//07) 
 
Summary of Changes 
 
• Face Page: University of Arizona/Arizona Cancer Center Co-Investigators: deletion of Leslie Andritsos, 
M.D., and addition of Daniel Persky, M.D. (Medical Oncology); change of version date of the protocol 
to Amendment #2, April 27, 2007. 
 
• Section 4.A. Inclusion Criteria:   4.A.1: Change in wording to indicate that patients may be in first, 
second, third, or fourth relapse (expanded from “first or second relapse”.  4.A.9 Change in wording to 
“…Patients must  have had at least 1, but no more than 4 prior chemotherapy regimens for 
lymphoma….” 
 
• Section 5.B  Evaluations During ESHAP Treatment and 5.C and 5.D  Evaluations During post-
Zevalin® follow-up and Appendix A:  :  Liver function tests (AST, ALT, alkaline phosphatase, total 
bilirubin), uric acid, glucose, and urinalysis will be obtained as clinically indicated, rather than required 
as part of the study.    Restaging will occur 3 months (rather than 2 months) after completion of 
Zevalin®.  Followup CT scans during the first 2 years after Zevalin® will be performed every 6 months, 
rather than every 3 months, unless clinically indicated.  Thus, the revised CT schedule is at 6, 12, 18, 
and 24 months for 2 years and then every 6 months for 2 years, and then annually.  The Zevalin® will 
be administered 4-6 weeks after completion of ESHAP (rather than 3-6 weeks).   A required week 4 
blood count after the Zevalin® treatment has also been added. The baseline anti-CD20 
immunophenotyping in Appendix A has been deleted, as this will   have been done as part of the 
original diagnostic testing before any treatment. 
 
• Section 6.B and 6.C (Drug Information) and the Model Consent have been updated to include the new 
rituximab risk information received from the Study Sponsor and NCI (attached) for this study.  The 
wording for the changes is that agreed upon by SWOG and the NCI for SWOG studies using rituximab 
or Zevalin® (which has ritiuximab as a component):   revised wording regarding severe infusion and 
hypersensitivity reactions; new information on viral infections (including the possibility of progressive 
multifocal leukoencephalopathy related to JC virus), and gastrointestinal, cardiovascular, and renal 
toxicities; new cautions related to immunization, carcinogenesis, impairment of fertility, pregnancy, and 
nursing.  APPENDIX H updated (Rituximab package insert 2/2007 update added). 
 
• Section 8 (Toxicities to be Monitored and Dosage Modifications) has been revised to provide guidance 
for monitoring for the above-noted side effects). 
 
• Model (Locally Approved) Consent Form:  This has been updated with regard to risks (as detailed 
above), number of prior therapies allowed, and timing of Zevalin® and specific study procedures. 
 


 
 
 
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APPENDIX L 
Amendment #3 
(11/1/08) 
Summary of Changes 
 
• Updated: Cover Sheet, Version date, Table of Contents 
• Inserted Protocol Signature Page 
• Updated Study Duration to 5 years 
• Re-paginated, Re-numbered Sections 
• Updated Inclusion Criteria (All changes have been reflected in the Study Calendar: Apx. 
A):  
o 4.A.2 –REMOVED: “A report providing confirmation of CD20 expression must be submitted 
per Section 5.A.” 
o 4.A.4 – Changed: “All  patients must have bidimensionally measurable disease (as defined in 
Appendix D) documented within 1 month prior to registration.  Patients with non-measurable 
disease (as defined in Appendix D) in addition to measurable disease must have all non-
measurable disease assessed within 42 days prior to registration.”  
             To: “All  patients must have bidimensionally measurable disease (as defined in 
Appendix D) documented within 28 days prior to Cycle 1, Day 1.” 
o 4.A.5 – Changed: “Pathology Review:  Adequate sections from the diagnostic specimen or 
core needle biopsies which are large enough to show architecture (bone marrow biopsies and 
fine-needle aspirates are insufficient) must be available for submission as outlined in Section 5. 
Patients are also eligible for participation in Arizona Cancer Center tumor and serum specimen 
acquisition protocols.” 
            To: “Pathology Review:  Adequate sections from the diagnostic specimen or core 
needle biopsies which are large enough to show architecture (bone marrow biopsies and fine-
needle aspirates are insufficient) is desirable. At a minimum, a report documenting the diagnosis 
is required.” 
o 4.A.6 –Changed: “Patients must have a unilateral or bilateral bone marrow aspirate and 
biopsy performed within 42 days prior to registration.” 
           To: “Patients must have a unilateral or bilateral bone marrow aspirate and biopsy 
performed within 28 days prior to Cycle 1, Day 1.” 
o 4.A.7 – Changed : “Patients must have a CT scan of chest, abdomen, and pelvis within 1 
month prior to registration.” 
            To: “Patients must have a CT scan of chest, abdomen, and pelvis within 28 days prior 
to Cycle 1, Day 1.” 
o 4.A.8 – Changed: “Patients must have an LDH and β-2 microglobulin within 1 month prior to 
registration.” 
                                    To: “Patients must have an LDH and β-2 microglobulin within 28 days prior to  
 Cycle 1, Day 1.” 


 
 
 
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o REMOVED: Formerly 4.A.10: “Patients may not have undergone bone marrow 
transplantation (BMT).” 
o 4.A.13, Now 4.A.12- Changed: “…within 14 days prior to registration…” 
           To: “…within 28 days prior to Cycle 1, Day 1…” 
o 4.A.14, Now 4.A.13 – Changed: “A serum creatinine or creatinine clearance must be 
obtained within 14 days prior to registration.” 
            To: “A serum creatinine or creatinine clearance must be obtained within 28 days prior 
to Cycle 1, Day 1.” 
o REMOVED: Formerly 4.A.15: “Patients known to be HIV-positive are not eligible.” 
o 4.A.18, Now 4.A.16 – Changed: “If Day 42 falls on a weekend or holiday, the limit may be 
extended to the next working day.  In calculating days of tests and measurements, the day a test 
or measurement is done is considered Day 0.  Therefore, if a test is done on a Monday, the 
Monday 6 weeks later would be considered Day 42.  This allows for efficient patient scheduling 
without exceeding the guidelines.” 
            To: “If Day 28 falls on a weekend or holiday, the limit may be extended to the next 
working day.  In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later 
would be considered Day 28.  This allows for efficient patient scheduling without exceeding the 
guidelines.” 
• Updated Exclusion Criteria: 
o a., Now 4.B.1 – REMOVED: “Prior myeloablative therapies with autologous bone marrow 
transplantation (ABMT) or peripheral blood stem cell (PBSC) rescue.” 
            Changed: “Hypocellular bone marrow (cellularity < 15%)” 
            To: “Hypocellular bone marrow (cellularity < 10%)” 
o c., Now 4.B.3 – REMOVED: “Any laboratory tests that are performed to assess clinical 
signs of CNS involvement must be negative within 42 days prior to registration.” 
o REMOVED - Formerly d.: “Patients with chronic lymphocytic leukemia (CLL)” 
o REMOVED – Formerly e.: “Patients with HIV or AIDS-related lymphoma” 
o REMOVED – Formerly f.: “Patients with pleural effusion” 
• 4.D – Changed: “All patients will be registered centrally with the Study Coordinator based in the 
Arizona Cancer Center Lymphoma Program Office at 520-626-6786.” 
                       To: “All patients will be registered centrally with the Clinical Research Coordinator based in the 
Arizona  
              Cancer Center at 520-694-9053.  The Clinical Research Coordinator will assign each patient a sequential                    
              number.” 
• 5.A – Changed: “Unless otherwise specified, the following evaluations must be performed within 4 
weeks prior to patient registration:” 
          To: “Unless otherwise specified, the following evaluations must be performed within 28 days prior 
to C1, D1:” 
• 
5.A.b, Now 5.A.2 – Changed: “Physical examination, including, performance status (Adult Common 
Toxicity Criteria; see the appropriate Appendix), and Tumor Assessment (see the appropriate Appendix)” 


 
 
 
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          To: “Physical examination, including vital signs (BP, temperature & pulse), height, weight, Body 
Surface Area (BSA) & performance status (Appendix B).” 
• 5.A.c, Now 5.A.3 – Changed: “CT scan or MRI of the neck, chest, abdomen and pelvis is 
recommended for baseline response evaluation” 
               To: “Disease Assessment: 
• 
Total of all measurable indicator lesions 
• 
CT scan of the chest, abdomen and pelvis is recommended for baseline response evaluation.” 
• 
5.A.d, Now 5.A.4 – Changed: “Laboratory tests including: 
• 
Complete blood count (CBC) with differential and platelet count (within 2 weeks prior to patient 
registration) 
• 
Serum chemistries - glucose, BUN, creatinine, uric acid, total bilirubin, alkaline phosphatase, 
LDH, SGOT (AST), SGPT (ALT) (within 2 weeks prior to patient registration) 
• 
Serum beta-2-microglobulin 
• 
Urinalysis:  routine dip stick 
• 
Pregnancy test (serum) for women of childbearing potential” 
                       To: “Laboratory tests including: 
• 
Complete blood count (CBC) with differential and platelet count  
• 
Serum chemistries - BUN, creatinine, total bilirubin, alkaline phosphatase, LDH, SGOT 
(AST), SGPT (ALT) 
• 
Serum beta-2-microglobulin 
• 
Pregnancy test (serum) for women of childbearing potential 
• 
Hepatitis B screen (encouraged by Good Medical Practice, but not required)” 
• 5.A.e, Now 5.A.5 – Changed: “Bi-lateral bone marrow biopsy or aspirate (within 6 weeks of patient 
registration) for histology and determination of percent bone marrow involvement.” 
        To: “Unilateral or Bi-lateral bone marrow biopsy and aspirate for histology and determination of 
percent bone marrow involvement.” 
• 
5.A.f, Now 5.A.6 – Changed: “Bone marrow cytogenetics must be performed within 6 weeks prior to 
patient registration. (Results are not required prior to enrollment.)” 
       To: “Bone marrow cytogenetics (Results are not required prior to enrollment). This can also be done 
with the repeat Bone Marrow biopsy and aspirate at Cycle 2, Day 29. This does not have to be done at 
each Bone Marrow biopsy and aspirate, but does need to be completed at either, Baseline or Cycle 2, Day 
29.” 
• 
5.A.g, Now 5.A.7 – Changed: “All patients registered on this study will undergo pathology review.” 
       To: “All patients registered on this study are encouraged to undergo pathology review.” 
• 
5.A.g.1, Now 5.A.7.a – Changed: “Pathology materials are to be submitted within 30 days of 
registration to:” 
       To: “Pathology materials are to be submitted to:” 
                   REMOVED: “An additional copy of the Protocol Specific Pathology Submission Form        


 
 
 
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                    must be submitted each time submissions are made to Dr. Rimsza.” 
• 
5.A.g.2, Now 5.A.7.b – Changed: “The following materials are to be submitted for review:” 
       To: “The following materials would constitute best available material for review:” 
• 
5.B – Changed: “ For the purpose of safety assessments, the treatment period will include the time from 
the first ESHAP infusion to 12 weeks following Zevalin infusion (see Appendix A).  Evaluations during the 
2 cycles of ESHAP are outlined in Appendix A and include Day 1 Cycle 1 pre-treatment CBC, differential, 
and platelets and Day 2 and Day 29 history and physical examination, CBC, differential, and platelets, 
serum creatinine, and BUN.  AST, ALT, alkaline phosphatase, and total bilirubin will be repeated as 
clinically indicated  (4/27/07).  Clinically significant changes should be recorded on the clinical events 
page of the CRF. On Day 29 of cycle 2 bone marrow aspiration and biopsy are repeated, as well as CT 
scans of the chest, abdomen, and pelvis.   
             Adverse events are to be recorded on an ongoing basis and on appropriate source documents at    the 
clinical site                and in the patient's case report form.  The onset of new adverse events as defined in Appendix 
E will be documented in the patient's case report form.  In addition, any transfusions of blood and blood products 
are to be recorded in the patient’s CRF. 
             In the event that a Grade 3 or 4 hematologic toxicity occurs at any time, blood samplings for follow-up 
evaluations should be performed as clinically indicated until the abnormality is resolved.”  
               To: “For the purpose of toxicity assessment, the treatment period will include the time from the first 
ESHAP infusion to 30 days following Zevalin infusion.  Evaluations during the 2 cycles of ESHAP are outlined in 
Appendix A. 
 
5.B.1 ESHAP Cycle 1, Day 1 
 
 
a. Begin ESHAP Treatment (Please refer to Section 7A for ESHAP administration) 
 
5.B.2 ESHAP Cycle 2, Day 1 
 
 
a. History & Physical examination, including vital signs (BP, temperature  
 
 
& pulse), height, weight, Body Surface Area (BSA), and performance status (Appendix 
B). 
 
b. Laboratory tests including: 
• 
Complete blood count (CBC) with differential and platelet count  
• 
Serum chemistries - BUN, creatinine 
d. Toxicity Assessment: Adverse events are to be recorded on an ongoing basis and on 
appropriate source documents at the clinical site and in the patient's case report form.  
 
 
5.B.3 ESHAP Cycle 2, Day 29  
 
 
 
a. History & Physical examination, including vital signs (BP, temperature  
 
 
 
 
& pulse), height, weight, Body Surface Area (BSA) & performance status (Appendix B).  
 
 
 
b. Laboratory tests including: 
• Complete blood count (CBC) with differential and platelet count  


 
 
 
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• Serum chemistries - BUN, creatinine 
g. Unilateral or Bi-lateral bone marrow biopsy and aspirate for histology and determination of 
percent bone marrow involvement 
h. Bone marrow cytogenetics. Does not have to be done at each Bone Marrow biopsy and aspirate, 
but does need to be completed at either, Baseline or Cycle 2, Day 29. 
i. 
Disease Assessment: 
• 
Total of all measurable indicator lesions. 
• 
CT scan of the chest, abdomen and pelvis  
j. 
Toxicity Assessment: Adverse events are to be recorded on an ongoing basis and on appropriate 
source documents at the clinical site and in the patient's case report form. 
• 
5.C  - Changed: “Evaluations During the 111In Zevalin Imaging Period 
CAUTION WILL BE TAKEN IN THE HANDLING OF ALL RADIOACTIVE SAMPLES ACCORDING TO 
STANDARD PROCEDURES AND PRACTICES AT THE CLINICAL SITE. 
Vital signs will be obtained every 15 minutes for the first hour during the Rituxan infusion, hourly during the 
remainder of the infusion, and immediately following the 111In Zevalin infusion.  If vital signs are unstable, they will 
be monitored at 5-minute intervals until stable. 
48.A. 
Evaluations During the 111In Zevalin Imaging Period 
Vital signs will be obtained every 15 minutes for the first hour during the Rituxan infusion, hourly during the 
remainder of the infusion, and immediately following the 111In Zevalin infusion.  If vital signs are unstable, they will 
be monitored at 5-minute intervals until stable. 
The purpose of 111In Zevalin imaging is twofold: 
• 
To evaluate biodistribution of whole body gamma camera images 
• 
To 
assess 
whether 
biodistribution 
is 
acceptable 
to 
proceed 
with 
90Y Zevalin radioimmunotherapy. 
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.  Images should be acquired using a large field of view 
gamma camera quipped with a medium energy collimator.  Whole body anterior/posterior planar images should be 
acquired using a large field-of-view gamma camera and medium energy collimators.  Suggested gamma camera 
settings: 256 x 1024 matrix; dual energy photopeaks set at 172 and 247 keV; 15% symmetric window; scan speed of 
10 cm/min for the 48-72 hour scan, and 7-10 cm/min for subsequent scans.  
a. Expected biodistribution: 
• 
Activity in the blood pool areas (heart, abdomen, neck, and extremities) may be faintly visible. 


 
 
 
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• 
Moderately high to high uptake in normal liver and spleen. 
• 
Moderately low or very low uptake in normal kidneys, urinary bladder, and normal (uninvolved) bowel. 
• 
Non-fixed areas within the bowel lumen that change position with time; delayed imaging as described 
above may be necessary to confirm gastrointestinal clearance. 
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.  Tumor visualization on the 111In Zevalin scan is 
not required for 90Y Zevalin therapy. 
b. Altered biodistribution 
• 
Intense localization of radiotracer in the liver and spleen and bone marrow indicative of 
reticuloendothelial system uptake 
• 
Increased uptake in normal organs (not involved by tumor) such as: 
• 
Diffuse uptake in normal lung more intense than the liver. 
• 
Kidneys with greater intensity than the liver on the posterior view. 
• 
Fixed areas (unchanged with time) of uptake in the normal bowel greater than uptake in the liver. 
• 
In less than 0.5% of patients receiving 111In Zevalin, prominent bone marrow uptake was observed, 
characterized by clear visualization of the long bones and ribs. 
If a visual inspection of the gamma images reveals an altered biodistribution, the patient should not 
proceed to the 90Y Zevalin dose.  The safety and efficacy of the administration of 90Y Zevalin in patients 
with prominent marrow uptake is not known.  Possible causes of prominent bone marrow uptake, such as 
bone marrow involvement by lymphoma, increased marrow activity due to recent hematopoietic growth 
factor administration, and increased reticuloendothelial uptake in patients with HAMA and HACA, should 
be considered.  Re-assessment of biodistribution after correction of underlying factors should be 
performed.  90Y Zevalin should not be administered to patients with persistently prominent marrow uptake 
on the repeat biodistribution scans.” 
48.B. 
         To: “Evaluations During the Zevalin Imaging & Treatment Period 
48.C. 
Ibritumomab Tiuxetan Indium (111In Zevalin) regimen is administered 4 – 6 weeks after completion of 
ESHAP. 
 
5.C.1 Day 1 
a. History & Physical examination, including vital signs (BP, temperature & pulse), height, 
weight, Body Surface Area (BSA), and performance status (Appendix B). 
b. Toxicity Assessment: Adverse events are to be recorded on an ongoing  
basis and on appropriate source documents at the clinical site and in the patient's case 
report form.  
d. Laboratory tests including: 
• Complete blood count (CBC) with differential and platelet count  


 
 
 
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 [100] 
• Serum chemistries - BUN, creatinine 
d. Rituxaimab Infusion (250 mg/m2) &  111In Zevalin (Ibritumomab Tiuxetan Indium) infusion. 
(Please refer to section 7.B for detailed treatment administration) 
Vital signs will be obtained every 15 minutes for the first hour during the Rituxan 
infusion, hourly during the remainder of the infusion, and immediately following the 111In Zevalin 
(Ibritumomab Tiuxetan Indium) infusion.  If vital signs are unstable, they will be monitored at 5-
minute intervals until stable. 
5.C.2 Days 2, 3, 4 and 5 
a. Gamma Scan: A scan is to be performed at 48-72 hours after 111In Zevalin (Ibritumomab 
Tiuxetan Indium) infusion. Another optional scan may be performed at 90-120 hours after 111In Zevalin 
(Ibritumomab Tiuxetan Indium) infusion.  
CAUTION WILL BE TAKEN IN THE HANDLING OF ALL RADIOACTIVE SAMPLES ACCORDING TO 
STANDARD PROCEDURES AND PRACTICES AT THE CLINICAL SITE. 
The purpose of 111In Zevalin  (Ibritumomab Tiuxetan Indium) imaging is twofold: 
• 
To evaluate biodistribution of whole body gamma camera images 
• 
To 
assess 
whether 
biodistribution 
is 
acceptable 
to 
proceed 
with 
90Y Zevalin (Ibritumomab Tiuxetan Ytrium-90) radioimmunotherapy. 
The biodistribution of 111In Zevalin (Ibritumomab Tiuxetan Indium) 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.  Images 
should be acquired using a large field of view gamma camera quipped with a medium energy collimator.  Whole 
body anterior/posterior planar images should be acquired using a large field-of-view gamma camera and medium 
energy collimators.  Suggested gamma camera settings: 256 x 1024 matrix; dual energy photopeaks set at 172 and 
247 keV; 15% symmetric window; scan speed of 10 cm/min for the 48-72 hour scan, and 7-10 cm/min for 
subsequent scans.  
 Expected biodistribution: 
• 
Activity in the blood pool areas (heart, abdomen, neck, and extremities) may be faintly visible. 
• 
Moderately high to high uptake in normal liver and spleen. 
• 
Moderately low or very low uptake in normal kidneys, urinary bladder, and normal (uninvolved) 
bowel. 
• 
Non-fixed areas within the bowel lumen that change position with time; delayed imaging as 
described above may be necessary to confirm gastrointestinal clearance. 


 
 
 
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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.  Tumor visualization on the 111In Zevalin 
(Ibritumomab Tiuxetan Indium) scan is not required for 90Y Zevalin (Ibritumomab Tiuxetan Ytrium-90) therapy. 
 Altered biodistribution 
• 
Intense localization of radiotracer in the liver and spleen and bone marrow indicative of 
reticuloendothelial system uptake 
• 
Increased uptake in normal organs (not involved by tumor) such as: 
o 
Diffuse uptake in normal lung more intense than the liver. 
o 
Kidneys with greater intensity than the liver on the posterior view. 
o 
Fixed areas (unchanged with time) of uptake in the normal bowel greater than uptake in 
the liver. 
o 
In less than 0.5% of patients receiving 111In Zevalin (Ibritumomab Tiuxetan Indium), 
prominent bone marrow uptake was observed, characterized by clear visualization of the 
long bones and ribs. 
If a visual inspection of the gamma images reveals an altered biodistribution, the patient should not 
proceed to the 90Y Zevalin(Ibritumomab Tiuxetan Ytrium-90) dose.  The safety and efficacy of the administration of 
90Y Zevalin (Ibritumomab Tiuxetan Ytrium-90)in patients with prominent marrow uptake is not known.  Possible 
causes of prominent bone marrow uptake, such as bone marrow involvement by lymphoma, increased marrow 
activity due to recent hematopoietic growth factor administration, and increased reticuloendothelial uptake in 
patients with HAMA and HACA, should be considered.  Re-assessment of biodistribution after correction of 
underlying factors should be performed.  90Y Zevalin (Ibritumomab Tiuxetan Ytrium-90) should not be administered 
to patients with persistently prominent marrow uptake on the repeat biodistribution scans.  
5.C.3 Day 7, 8 or 9 
a. Rituximab Infusion & 90Y Zevalin (Ibritumomab Tiuxetan Ytrium-90) Infusion (Please refer to 
section 7.B for detailed treatment administration) 
Vital signs will be obtained every 15 minutes for the first hour during the Rituxan 
infusion, hourly during the remainder of the infusion, and immediately following the 111In Zevalin 
(Ibritumomab Tiuxetan Indium) infusion.  If vital signs are unstable, they will be monitored at 5-
minute intervals until stable. 
 
5.C.4  Day 35 (+/- 7 days) 
 
 
 
a. Laboratory tests including: 
Complete blood count (CBC) with differential and platelet count. To be done every week until any count 
abnormalities have passed nadir. 


 
 
 
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• 5.C.1, Now 5.D – Changed:  
48.C.1. “Evaluations/Tests During the Zevalin Treatment Period Up to Month 3 
History and physical examination, including performance status, will be performed 8 weeks post Zevalin, 
along with repeat renal function tests (4/27/07), LDH, and CTs, X-rays for tumor assessment and rating of 
response to treatment.  For patient with persistent bone marrow involvement prior to Zevalin®, a third 
biopsy/aspirate should be done post Zevalin® to document response.” 
To: 
                   “Restaging 
48.D. 
            5.D.1  3 Months Post- 90Y Zevalin (Ibritumomab Tiuxetan Ytrium-90) Infusion 
The following tests/evaluations will be obtained 3 months (+/- 7 days) post 90Y Zevalin Infusion: 
a.   History & Physical examination, including vital signs (BP, temperature & pulse), height, 
weight, Body Surface Area (BSA) & performance status (Appendix B).  
b.   Laboratory tests including: 
• Complete blood count (CBC) with differential and platelet count  
• Serum chemistries - BUN, creatinine 
• LDH 
e. 
Disease Assessment: 
• 
Total of all measurable indicator lesions. 
• 
CT scan of the chest, abdomen and pelvis  
Toxicity Assessment: Adverse events are to be recorded on an ongoing basis and on appropriate source 
documents at the clinical site and in the patient's case report form” 
• 5.D, Now 5.E – Changed: 
“Follow-Up Evaluations From Month 3 and Beyond 
Post-Treatment Follow-Up Period 
The following tests will be obtained at 3-month intervals for a period of 2 years following the Zevalin, every 6 
months for years 3 and 4, and then annually. 
a. 
Serious adverse events, as well as any new or worsening drug related adverse events (see Appendix E. 
b. 
Interim medical history, physical examination and performance status (Adult Common Toxicity Criteria; 
Version 3.0) 
c. 
Serum chemistries:  BUN, creatinine, LDH (4/27/07). 
d. 
CBC with differential and platelet count  
e. 
Restaging of disease and Response Evaluation by physical examination 
Restaging of disease by CT scan or MRI is recommended every 6 months for the first 2 years, every 6 months for 
years 3 and 4, and then annually.   Bone marrow aspirate/biopsy should be repeated as clinically indicated.” 


 
 
 
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             To: 
48.E. 
“Follow-Up Evaluations  
48.E.1. 5.E.1 Short-Term Follow-Up Period 
b. The following tests/evaluations will be obtained at 3-month intervals (+/- 7 days) for a period 
of 2 years (24 months) following the Zevalin: 
• 
History & Physical examination, including vital signs (BP, temperature & pulse), 
height, weight, Body Surface Area (BSA), and performance status (Appendix B). 
• 
Laboratory tests including: 
o 
Complete blood count (CBC) with differential and platelet count  
o 
Serum chemistries - BUN, creatinine 
o 
LDH 
• 
Disease Assessment (Only required at 6-month intervals for a period of 2 years (24 
months) following Zevalin): 
o 
Total of all measurable indicator lesions. 
o 
CT scan of the chest, abdomen and pelvis (Restaging of disease by CT scan 
is recommended every 6 months up to Month 24, then annually until year 
5). 
5.E.2 Long-Term Follow-Up Period 
a.   The following tests/evaluations will be obtained every 6 months (+/- 30 days) for an  
additional 3 years after the completion of the Short-Term Follow-Up period: 
• 
History & Physical examination, including vital signs (BP, temperature & pulse), 
height, weight, Body Surface Area (BSA), and performance status (Appendix B). 
• 
Laboratory tests including: 
o 
Complete blood count (CBC) with differential and platelet count  
o 
Serum chemistries - BUN, creatinine 
o 
LDH 
• 
Disease Assessment: 
o 
Total of all measurable indicator lesions. 
o 
CT scan of the chest, abdomen and pelvis 
Once the patients have completed Long-term Follow-Up they will continue to be followed 
indefinitely on an annual basis (+/- 30 days) for survival and disease status. Patients should be followed by 
physical exam and, if clinically indicated by Good Medical Practice, CT scans.  Patients will be followed 
indefinitely or until patient starts alternate treatment or is removed from study to allow determination of 
study endpoints. 
 


 
 
 
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• 5.E, Now 5.F – Changed:  
“Disease Progression Evaluations/Off-Study 
Patients who develop disease progression during the treatment period and who do not begin other anti-cancer 
therapy will continue to be followed for routine safety and efficacy for a total of 12 weeks following the Zevalin 
treatment. 
Tests to be Performed When a Patient is Determined to Have Disease Progression or is Removed from the 
Study for any Reason 
The following tests will be performed within 4 weeks after a patient has demonstrated progression of disease.  It is 
strictly mandated that patients not be given other myelosuppressive anti-neoplastic agents until recovery from 
hematologic nadir. 
These tests do not have to be repeated if they were performed within 7 days prior to documentation of disease 
progression. 
a. 
Tumor assessment if patient is removed from the study for a cause other than progressive disease 
b. 
Physical examination, interim medical history, and performance status 
c. 
CBC with differential and platelet count 
d. 
Serum chemistries: glucose, BUN, creatinine, uric acid, total bilirubin, alkaline phosphatase, LDH, SGOT 
(AST), SGPT (ALT)  
e. 
Urinalysis:  routine dip stick 
f. 
Follow-up of all ongoing related adverse events until resolved or determined to be permanent” 
To: 
48.F. 
“Disease Progression Evaluations/Off-Study 
Patients who develop disease progression during the treatment period and who do not begin other anti-cancer 
therapy will continue to be followed for routine safety and efficacy for a total of 30 days following any 
discontinuation of treatment for any cause. 
48.F.1. 5.F.1 Tests to be Performed When a Patient is Determined to Have Disease Progression or is  
48.F.2. Removed from the Study for any Reason 
 
The following tests will be performed within 4 weeks after a patient has demonstrated progression of 
disease, or removed from study: 
It is strictly mandated that patients not be given other myelosuppressive anti-neoplastic agents until 
recovery from hematologic nadir.  
These tests do not have to be repeated if they were performed within 7 days prior to documentation of 
disease progression. 
a. History & Physical examination, including vital signs (BP, temperature & pulse), height, 
weight, Body Surface Area (BSA), and performance status (Appendix B). 
b. Laboratory tests including: 
• 
Complete blood count (CBC) with differential and platelet count  
• 
Serum chemistries - BUN, creatinine 


 
 
 
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• 
LDH 
c.Disease Assessment (if patient is removed from the study for a cause other than progressive 
disease): 
• 
Total of all measurable indicator lesions. 
• 
CT scan of the chest, abdomen and pelvis 
d.Toxicity Assessment: Adverse Events (AE) are to be recorded on an  
ongoing basis until resolved or determined to be permanent. All  
AEs are to be documented on appropriate source documents at the  
clinical site and in the patient's case report form.” 
• 6.B – Changed:  
48.G. 
“Rituximab, 111-Indium Zevalin and 90-Y-Zevalin Information 
6.B.1 
Rituximab 
For information formulation, administration and adverse events, see Rituximab package insert (Appendix 
H—updated February 2007) (4/27/07) 
 
To: 
“Rituximab Drug Information 
 
6.B.1 DESCRIPTION 
 
Rituximab is a mouse/human chimeric monoclonal antibody consisting of human IgG1 heavy and kappa 
light chain constant regions with murine variable regions from the murine IgG1 kappa anti-human CD20 
monoclonal antibody rutuximab. The rituximab antibody is produced by a Chinese hamster ovary transfectoma. 
 
6.B.2 TOXICOLOGY 
 
Human Toxicology: Single doses of up to 500 mg/m2 and weekly x 4 doses of 375 mg/m2 have been 
administered without dose limiting toxicity. Adverse events are most common during the intitial antibody infusion 
and usually consist of Grade 1, or 2 fever (73%), asthenia (16%), chills (38%), nausea (19%), vomiting (11%), rash 
(14%), and t umor site pain (3%). Grade 1 or 2 hypotension (8%) may be treated with IV fluids. Hematologic 
toxicity is usually mild and reversible. Transient decreases in the WBC or platelet count have been observed – 
especially in patients with high levels of circulating tumor cells or bone marrow involvement. Two patients have had 
late-onset Grade 4 neutropenia at four and ten months that was attributed to an unknown cause, were transient and 
resolved. Infections (Grade 1 and 2) have not been related to dose level. Symptoms are generally associated with 
the initial antibody infusions and diminish in frequency with each successive infusion. 
 
Infusion Reaction: An infusion-related symptom complex consisting of fever and chills/rigors has occurred 
in the majority of patients during the first rituximab infusion. Other frequent infusion-related symptoms include 
nausea, uticaria, fatigue, headache, pruritis, bronchospasm, dyspnea, sensation of tongue or throat swelling 
(angioedema), rhinitis, vomiting, hypotension, flushing, and pain at disease sites. These reactions generally 
occurred within 30 minutes to 2 hours of beginning the first infusion, and resolved with slowing or interruption of 
the rituximab infusion and with supportive care (IV saline, diphenhydramine, and acetaminophen). 


 
 
 
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Tumor Lysis Syndrome: Rituximab rapidly decreases benign and malignant CD20 positive cells. Tumor 
lysis syndrome has been reported to occur within 12 to 24 hours after the first rituximab infusion in patients with 
high numbers of circulating malignant lymphocytes. Patients with high tumor burden (bulky lesions) may also be at 
risk. Patients at risk for developing tumor lysis syndrome should be followed closely and appropriate laboratory 
monitoring performed. 
 
6.B.3 PHARMACOLOGY 
 
Pharmacokinetics: In prior studies patients treated at the 375 mg/m2 dose levels exhibited detectable 
antibody concentrations throughout the treatment period. Most patients exhibited increasing pre-infusion antibody 
concentrations with each subsequent infusion. In nine patients, the T1/2 following the first antibody infusion was 59.8 
hours (11.1 – 104.6 hr) with a Cmax of 271 mcg/mL.  
 
Formulation: Rituximab antibody will be provided on 100 mg (10mL) and 500 mg (50ml) pharmaceutical 
grade vials at a concentration of 10 mg of protein per mL (actual concentration should be noted on the product 
label). 
 
Storage and Stability: Rituximab should be stored at 2 - 8°C. Do not freeze or store at room temperature. 
The product is a protein- HANDLE GENTLY AND AVOID FOAMING. The avoidance of foaming during product 
handling, preparation and administration is important, as foaming may lead to the denaturing of the product 
proteins. 
 
Admministration: Prepare the rituximab infusion solution as follows: 
7. If a delay in administration of the infusion occurs after the product is prepared, the properly 
identified container may be kept refrigerated at 2 - 8°C for up to six hours. 
8. Use sterile, non-pyrogenic, disposable containers, syringes, needles, stopcocks and transfer 
tubing, etc. 
9. Transfer of the rituximab from the glass vial should be made by using a suitable sterile 
graduated syringe and large gauge needle. 
10. Transfer the appropriate amount of rituximab from the graduated syringe, into a partially 
filled IV pack containing sterile, pyrogen-free 0.9% sodium chloride solution, USP (saline 
solution). The final concentration of rituximab in saline solution should be a maximum of 1 
mg/ml. Mix by inverting the bag gently. DO NOT USE A VACUUM APPARATUS to transfer 
the product from the syringe to the plastic bag. 
11. Place an IV administration set into the outflow port of the bag containing the infusion 
solution. 
12. NOTE:  DO NOT USE evacuated glass containers which require vented administration sets 
because this causes foaming as air bubbles pass through the solution. 
The administration of rituximab will be accomplished by slow IV infusion.  CAUTION:  DO NOT ADMINISTER 
AS AN INTRAVENOUS PUSH OR BOLUS.  IV pumps such as the IMED 960 may be used with the rituximab 
infusion.  DO NOT INFUSE CONCOMITANTLY with another IV solution or IV medications.  Prime the line 
with the rituximab solution such that approximately 30 mL are delivered.  This will saturate the filter and 
tubing.” 
• 6.B & 6.C, Now 6.C – Re-numbered, Information the same 
• 
9.A.1, Now 9.A – Changed: “It is the responsibility of the Investigator-Sponsor as the IND holder to 
IMMEDIATELY REPORT ALL SERIOUS OR UNEXPECTED ADVERSE EVENTS…” 
     To: “It is the responsibility of the Investigator-Sponsor to IMMEDIATELY REPORT ALL SERIOUS 
OR UNEXPECTED ADVERSE EVENTS…” 


 
 
 
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• 13.A.a, Now 13.A.1 – Changed:  
“Review and Consent Requirements 
a. Institutional Review Board (IRB) 
The investigator will supply all necessary documents to be submitted to the IRB and will ensure that the 
institution has a properly structured research committee.  The University of Arizona Human Subjects 
Protection Program and the University of Rochester IRB  will be the IRB’s of record.  Documentation of 
initial and ongoing reviews,  submission of serious adverse event reports, study amendments and revisions, 
and consent form modifications will be required from all study sites.  This documentation is to be 
forwarded to the Study Coordinator: 
 
 
Ellen Chase, B.S. 
 
 
Arizona Cancer Center, Room 1959 
 
 
1501 North Campbell Avenue 
                        Tucson, Arizona 85724” 
To: 
“Institutional Review Board (IRB) 
The investigator will supply all necessary documents to be submitted to the IRB and will ensure that the 
institution has a properly structured research committee.  The University of Arizona Human Subjects 
Protection Program will be the IRB of record.  Documentation of initial and ongoing reviews, submission 
of serious adverse event reports, study amendments and revisions, and consent form modifications will be 
required.  This documentation is to be forwarded to:  
• 
Consent Forms:  
 
 
Lora Inclan 
 
 
Clinical Research Coordinator 
 
 
Arizona Cancer Center 
 
 
at UMC North, Room 2111 
 
 
3838 N. Campbell Ave. 
 
 
Tucson, AZ 85719 
• 
Regulatory Documents: 
 
 
Amanda Hutchison-Rzepka 
 
 
Research Specialist, Pcpl. 
 
 
Arizona Cancer Center, Room 1959 


 
 
 
Amendment #9: 08/28/2017 
 [108] 
 
 
1515 N. Campbell Ave 
 
 
Tucson, AZ 85724” 
• 13.A.b, Now 13.A.2 – Changed:  
“Original, signed informed consent forms for patients registered from the Arizona Cancer Center will be 
kept in the Arizona Cancer Center Data Management Office.  Original signed consents for patients 
registered by the University of Rochester James P. Wilmot Cancer Center will be maintained at that center, 
with a copy  forwarded to the Study Coordinator at the Arizona Cancer Center by fax  at the time of 
registration.” 
To: 
“Original, signed informed consent forms for patients registered from the Arizona Cancer Center will be 
kept at The Arizona Cancer Center at UMC, North, room 2111.” 
• 13.B – Changed: 
“Registration Procedure 
All ethical, regulatory, technical, and scientific approvals must be in place before study registrations will accepted.   
All patients will be registered centrally with the Study Coordinator based at 520-626-6786 prior to the initiation of 
treatment.  Prior to registration, the fully signed informed consent must be presented and all inclusion and 
exclusion criteria will be reviewed with the registering investigator or designee.  All source documentation needed 
to confirm eligibility must be available for this review.  A second phone registration is required prior to the 
initiation of Zevalin® to confirm eligibility and dose of therapy.” 
              To: 
48.H. 
“Registration Procedure 
All ethical, regulatory, technical, and scientific approvals must be in place before study registrations will accepted.   
All patients will be registered centrally with the Clinical Research Coordinator based at 520-694-9053 prior to the 
initiation of treatment.  The Clinical Research Coordinator will assign each patient a sequential number prior to 
registration. The fully signed informed consent must be presented and all inclusion and exclusion criteria will be 
reviewed with the registering investigator or designee.  All source documentation needed to confirm eligibility must 
be available for this review.  A second phone registration is required prior to the initiation of Zevalin® to confirm 
eligibility and dose of therapy.” 
• 13.C, Now 13.E – Changed: 
“Monitoring 
This research study is an investigator-sponsored trial.   The Arizona Cancer Center has an NCI-approved Data and 
Safety Monitoring Plan for clinical research.  Data and systems for participating in the study will be monitored 
according to procedures outlined in that plan, with centralized patient screening and registration, submission and 
review of data, and initial verification of data as summarized below. 
DATA SAFETY AND MONITORING PLAN  
The Arizona Cancer Center Data and Safety Monitoring Board (DSMB) will provide general oversight for this trial 
to ensure patient safety, data integrity and protocol compliance.  The Study Coordinator (based in the Southwest 
Oncology Group and the Lymphoma Programs) will coordinate data review and report preparation for this review.   


 
 
 
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Reports detailing clinical trial study status, serious adverse events, clinical outcomes (toxicities, responses), and 
audit findings from both sites will be submitted on at least a quarterly basis.   Serious adverse events from both sites 
will also be reported to the DSMB on a weekly basis.   The University of Arizona IRB will receive immediate 
notification of study serious adverse events and study progress reports at the time interval specified at initial review. 
 
Procedures for centralized registration of patients on this study are detailed in Section 13B.   All subjects registered 
to this study will be entered into the Arizona Cancer Center CRIS database for accrual and treatment status 
tracking.  Adverse events will also be tracked.  Patients from the University of Rochester will be assigned a unique 
number to preserve anonymity.   In addition, a registration log will be maintained at both sites using Excel to keep 
track of study number, verification of consent, date of consent. 
 
Case report forms, which include the registration form, the inclusion/exclusion criteria form, tumor measurement 
forms, response and survival assessment forms, adverse event forms, and serious adverse event forms should be 
completed with a black ball-point pen or typed. Corrections to the forms should not obscure the original entry and 
should be made by striking the incorrect information with a single line. Each strike should be accompanied by the 
initials of the corrector and the correction date. All subject forms and study files will be stored in a secure area 
limited to authorized staff. 
 
The Principal Investigator for each site will ensure the accuracy, completeness, legibility and timeliness of the data 
reported in these forms. Source documentation supporting the Case Report Form (CRF) data should indicate the 
subject’s participation in the trial and should document the dates and details of study procedures, adverse events, 
and patient status.  
 
Data and systems auditing will be performed at each of the two sites to ensure that the investigation is conducted 
according to protocol design and regulatory requirements.  Audits will be performed every 6 months at the Arizona 
Cancer Center and annually at the University of Rochester by designated Arizona Cancer Center Quality Assurance 
representatives.  An audit report will be completed within 2 weeks of the review and a copy will be maintained in the 
study file.  A visit follow-up letter (if required) detailing outstanding data and/or issues to be addressed by the 
Principal Investigator and staff within 2 weeks of the monitoring visit will be given to the Principal Investigator for 
action. A monitoring form will also be completed by the monitor to request specific corrections to the case report 
forms and/or request clarification or additional source documentation. The study coordinator responsible for the 
study will be given a copy of this form for resolution of findings. The monitor form will be maintained with a copy of 
the visit report for follow-up at the next monitoring visit.  
 
Once the study forms have undergone initial review with source documentation, data may be entered into the CRIS 
database by the study coordinator.  All computer-based subject data are password-protected. It is designed to track 
data changes so that unintentional deletions in data are not made. The Arizona Cancer Center Quality Assurance 


 
 
 
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 [110] 
and Quality Control (QA/QC) Group will be responsible for monitoring the data entered in the database every 8-12 
weeks or every 4th patient depending on frequency of enrollment. 
 
Auditing will be carried out by the Arizona Cancer Center QA/QC Group to comply with Good Clinical Practice 
guidelines. The audits will include a review of subject informed consent; consistency between data points and 
source documents, adherence to protocol, accuracy of toxicity and response assessments, completeness and 
timeliness of serious adverse event reporting and general data quality.  Although the primary endpoints in this study 
relate to progression-free survival and time to progression, determination of overall and complete response rates 
with this treatment is a secondary endpoint and confirmatory review of responses will be required. 
 
REPORTING ADVERSE EVENTS 
 
An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease temporally associated with the 
use of a medical treatment or procedure regardless of whether it is considered related to the medical treatment or 
procedure. An AE is a term that is a unique representation of a specific event used for medical documentation and 
scientific analyses. Any and all adverse events will be recorded by the Principal Investigator using the adverse 
events record form..  
 
A serious adverse event is any adverse event regardless of causality and: 1) results in death, 2) is life-threatening, 
3) requires in-patient hospitalization or prolongation of an existing hospital stay, 4) results in disability, 5) is an 
important medical event, in the view of the investigator, that requires medical or surgical intervention to prevent 
one of the outcomes listed above. All serious adverse events, regardless of attribution, and any deaths will be 
reported immediately to the Principal Investigator/ Study Coordinator at 520-626-6786 and to the local IRB within 
5 days of notification of the event.  Serious adverse events will be reported on the SAE form.  Serious adverse events 
will also be reported to Biogen Idec, Inc, as specified in Section 9 of this protocol. 
 
All adverse events will be classified using the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 3.0 and will address: 
 
-grade 
-relationship to study agent or causality/attribution (not related, unlikely, possible, probable, definitely) 
-date of onset, date of resolution 
-frequency of event (single, intermittent, continuous) 
-event outcome (resolved, ongoing, death) 
-action taken (none, medication, other) 
 
REPORTING TO AZCC DATA & SAFETY MONITORING BOARD (DSMB) 


 
 
 
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 [111] 
 
Quarterly reports will be sent to the Arizona Cancer Center Data and Safety Monitoring Board. These reports will 
include enrollment figures (# subjects consented, # screened, # screen failures, # passed), dates and results of data 
monitoring visits, a comprehensive list of all adverse events and patient status.” 
 
         To: 
48.I. 
“Monitoring 
This research study is an investigator-sponsored trial.   The Arizona Cancer Center has an NCI-approved Data and 
Safety Monitoring Plan for clinical research.  Data and systems for participating in the study will be monitored 
according to procedures outlined in that plan, with centralized patient screening and registration, submission and 
review of data, and initial verification of data as summarized below. 
Protocol Data and Safety Monitoring Plan (Medium Risk)  
Medium risk studies are intended to include all trials involving therapeutic intervention(s), which are not 
designated as high risk per NCI and the IND is not held by the investigator.  
 
Data and Safety Monitoring Plan: 
 
8. 
Identification of the DSMB obligated for oversight responsibilities: 
The Arizona Cancer Center Data and Safety Monitoring Board (DSMB) will provide ongoing oversight for 
this trial. 
 
9. 
Identification of the entity obligated for routine monitoring duties: 
Routine monitoring will be provided by the Quality Assurance/Quality Control (QA/QC) Program to 
ensure that the investigation is conducted according to protocol design and regulatory requirements.  
 
10. 
Monitoring progress and data review process: 
Routine monitoring of subject data will be conducted at least every six months.  
The first routine monitoring visit will include at a minimum: 
• 
Informed consent – 100% of cases enrolled;  
• 
Subject eligibility - 50% of cases, up to two subjects; 
• 
Data review - 50% of cases, up to two subjects. 
 
All subsequent monitoring visits will consist of randomly selected subject cases based on current 
enrollment and include continuing review of previously selected cases, as applicable. 
 
A monitoring visit report and follow-up letter will be completed within two weeks of the routine monitoring 
visit; a copy will be maintained in the study file. A query/finding form will also be completed by the 
monitor to request additional source documentation, clarification, information or corrections to the CRF 


 
 
 
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and/or regulatory records. The Clinical Research Coordinator or other applicable staff responsible for the 
study will be given a copy of this form for resolution of queries/findings. The query/finding form will be 
maintained with a copy of the visit report for follow-up at the next monitoring visit.  
 
The Principal Investigator will ensure the accuracy, completeness, legibility and timeliness of the data 
reported in the Case Report Form (CRF). Source documentation supporting the CRF data should indicate 
the subject’s participation in the trial and should document the dates and details of study procedures, 
adverse events, and patient status.  
 
Case report forms, which include the inclusion/exclusion criteria form, adverse event forms and serious 
adverse event forms [other forms, depending on study] should be completed with a black ball-point pen or 
typed. Corrections to the forms should not obscure the original entry and should be made by striking the 
incorrect information with a single line. Each strike should be accompanied by the initials of the corrector 
and the correction date. All subject forms and study files will be stored in a secure area limited to 
authorized staff. 
 
Note: Routine monitoring of regulatory documents and test article will be conducted at least annually.  
 
11. 
Process to implement study closure when significant risks or benefits are  
identified: 
Enter specifics per study phase here.                                                          
 
 
 
 
12. 
Description of adverse events and reporting procedures: 
 
 
ADVERSE EVENTS  
 
An adverse event (AE) is any untoward medical occurrence in a patient or  
clinical 
investigation 
subject administered a pharmaceutical product and that does not necessarily have a casual relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  
 
Any and all adverse events will be recorded on the UMC adverse events record form and reviewed by the 
Principal Investigator. 
 
All adverse events will be classified using either the MedDRA term or NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 3.0  
and will address: 
• 
Grade 
• 
Relationship to study drug(not related, unlikely, possible, probable, definitely)  
• 
Causality other than study drug (disease related, concomitant medication related, intercurrent illness, 
other)   


 
 
 
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• 
Date of onset, date of resolution 
• 
Frequency of event (single, intermittent, continuous) 
• 
Event outcome (resolved, ongoing, death) 
• 
Action taken (none, held, dose reduced, discontinued, medication given) 
 
 
SERIOUS ADVERSE EVENTS 
 
A serious adverse event (SAE) is any untoward medical occurrence that at  
any dose:  
 
1) Results in death;  
 
2) Is life-threatening; 
 
3) Requires in-patient hospitalization or prolongation of an existing hospital stay;  
 
4) Results in disability persistent or significant disability/incapacity, or: 
 
5) Is a congenital anomaly/birth defect.  
 
Note: A SAE may also be an important medical event, in the view of the investigator that requires medical 
or surgical intervention to prevent one of the outcomes listed above.  
 
All serious adverse events, regardless of attribution, and any deaths will be reported within 24 hours of 
notification of the event to the sponsor and DSMB Coordinator. All serious adverse events, regardless of 
attribution, and any deaths will be reported within 5 days of notification of the event to the University of 
Arizona Human Subjects Protection  
Program.  
 
 
All serious adverse events will be processed by the DSMB Coordinator monthly for initial trend analysis 
and fully reviewed by the DSMB, every six months. The DSMB coordinator will review the SAE reporting 
process to confirm reporting requirements are met. 
 
13. 
Plan for assuring data accuracy and protocol compliance: 
Routine study activity and safety information will be reported to the DSMB every six months, or more 
frequently if requested. These reports will include: 
• 
Study activity, cumulative and for the period under review; 
• 
Safety (narrative description on non-serious and serious adverse events); 
• 
Predetermined protocol early stopping rules for efficacy/futility;    
• 
Monitoring and protocol compliance; 
• 
Comments;  
• 
Attachments (AE data reviewed by the PI to compile the report, SAE letters and reports, results of any 
review(s), applicable correspondence with the IRB or other regulatory agencies.  
 
 
Data, safety and study progress will be reported to: 
• 
Human Subjects Protection Program (IRB) at least annually; 
• 
Sponsor (if applicable) at least every six months. 
 


 
 
 
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14. 
Identification of the sponsor or funding agency, as applicable: 
The PI will immediately notify; in writing, the funding agency, if applicable, any action  resulting 
in 
a 
temporary or permanent suspension of the study.” 
 
• APPENDICIES REMOVED: 
o Appendix E: Adverse Event Definitions, Documentation and Categories for 
Determining Relationship to Study Drug Administration 
 REPLACED WITH: Biogen Idec SAE forms & Medwatch Form 
o WHO Modified REAL Classification of Non-Hodgkin’s Lymphoma 
o Rituxan package Insert 
o Model Informed Consent 
o Adjusted Ideal Body Weight Calculations and Use 
o Case Report Forms 
• APPENDICIES ADDED: 
o Amendment 1 Summary of Changes 
o Amendment 2 Summary of Changes 
o Amendment 3 Summary of Changes 
• Calendar Changes (page 1): 
o 
Day 35 column added under Ibritumomab Tiuxetan (Zevalin) Regimen 
o 
Disease Assessment added to Baseline & C2, D29 
o 
Toxicity Assessment added to Baseline; C2, D1; C2, D29, Day 1 of Ibritumomab Tiuxetan 
(Zevalin) Regimen 
o 
CBC removed from C1, D1 and added to Day 35 of Ibritumomab Tiuxetan (Zevalin) Regimen 
o 
Uric Acid/Glucose/Urinalysis row removed 
o 
Hep B screen and Pathology Review separated into individual rows 
o 
Bone Marrow cytogenetics added to C2, D29 
o 
X rays as needed for tumor assessment row removed 
o 
Gamma Scan changed from 2 to only 1 
• Calendar Changes (page 2): 
o 
3 months post Zevalin changed to Restaging 3 months post Zevalin 
o 
Follow-up separated out into Short-term follow-Up and Long-Term follow-Up 
o 
Continued Follow-Up: Annually column added 
o 
Off-Study column added 
o 
Disease Assessment removed from 9, 15 and 21 mos post Zevalin 


 
 
 
Amendment #9: 08/28/2017 
 [115] 
o 
AST/ALT/Alk Phos/T.Bilirubin row removed 
o 
Uric Acid/Glucose/Urinalysis row removed 
o 
Beta 2 microglobulin, Hep B screen/pathology review, Bone Marrow cytogenetics and Bone 
marrow aspiration/bx rows removed 
o 
X rays as needed for tumor assessment row removed 
o 
Gamma scans row removed 
o 
TREATMENT AND FOLLOWUP rows removed 
 
 
APPENDIX M 
Amendment #4 
(4/1//10) 
 
Summary of Changes 
 
• Updated: Cover Sheet: Amendment #4 Version Date 4/1/2010 
• Updated Protocol Signature Page: Amendment #4 Version Date 4/1/2010 
• Table of Contents: Pg. 5 Added Appendix M Amendment #4 Summary of Changes 
• Section 4.A.7:  Pg. 19 Added PET scan 
• Section 5.A.3: Pg. 22 Added PET scan 
• Section 5.B.3.e: Pg. 24 Added PET scan 
• Section 5.C.1 Day 1: Pg. 24 History, Physical exam, BSA, performance status, toxicity 
assessment, lab tests “are to be performed within 28 days of rituximab & Zevalin 
administration.” 
• Section 5.C.3 Day 7, 8 or 9: Pg. 26-27 Removed paragraph about obtaining vital signs 
every 15 minutes during rituxan infusion. 
• Section 5.D.1: Pg. 27 Added PET scan 
• Section 5.E.1: Pg. 28 Added PET scan 
• Section 5.E.2: Pg. 28 Added PET scan 
• Section 5.F.1.c: Pg. 29 Added PET scan 
• Section 13.A.1: Pg. 51 Removed Amanda Hutchison Rzepka, Added Alex Thomas- 
regulatory documents. 
• Appendix A Study Calendar: Pg. 62 Added PET to scans; added History, Physical exam, 
BSA, performance status, toxicity assessment, lab tests “are to be performed within 28 
days of rituximab & Zevalin administration.” 
• Appendix A Study Calendar: Pg. 63 Added PET to scans. 
• Appendix H: Pg 89 Added Spectrum Pharmaceuticals. Removed Cell Therapeutics, Inc 
(CTI) 
• Appendix M: Pg. 113 Added Appendix M Amendment #4 Summary of Changes 
 


 
 
 
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APPENDIX N 
Amendment #5 
(5/21//10) 
 
Summary of Changes 
• Updated: Cover Sheet: Amendment #5 Version Date 5/21/2010 
• Updated Protocol Signature Page: Amendment #5 Version Date 5/21/2010 
• Table of Contents: Pg. 5 Added Appendix N Amendment #5 Summary of Changes 
• Section 6.B.2 Added Other Viral Infections to the Rituximab Toxicology Section. 
 
 
APPENDIX O 
Amendment #6 
(6/28//10) 
 
Summary of Changes 
• Updated: Cover Sheet: Amendment #6 Version Date 6/28/2010 
• Updated Protocol Signature Page: Amendment #6 Version Date 6/28/2010 
• Table of Contents: Pg. 5 Added Appendix O Amendment #6 Summary of Changes 
• Table of Contents: Pgs. 4-5 have been corrected to correspond with protocol page 
numbers 
• Section 6.B.2 Risks section was updated per the Cancer Therapy Evaluation Program’s 
(CTEP), National Cancer Institute (NCI) Action Letter dated June 16th, 2010. 
 
APPENDIX P 
Amendment #7 
(1/7//13) 
 
Summary of Changes 
• Updated: Cover Sheet: Amendment #7 Version Date 1/7/2013, removed Co-PIs  Daruka 
Mahadevan and Daniel Persky and added Soham D. Puvvada, MD; updated the Arizona 
Cancer Center name to “The Unversity of Arizona Cancer Center” 
• Updated Protocol Signature Page: Amendment #7 Version Date 1/7/2013 
• Table of Contents: Revised numbering; Pg. 5 Added Appendix P Amendment #7 
Summary of Changes 
• 9.A: 2nd paragraph – Removed highlight 
• 12.B: 4th sentice - Removed highlight 
• Section 13.A.1: Pg. 51 Removed Alex Thomas, Added Ruth Cañamar- regulatory 
documents. 
• Administrative changes: Reformatted document to be justified and single spacing 
throughout the entire document 
 


 
 
 
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APPENDIX Q 
Amendment #8 
(04/17/2017) 
 
Summary of Changes 
• Updated footers throughout protocol to Amendment #8: 04/19/2017 
• Updated Cover Page: Amendment #8 dated 04/19/2017; removed Dr. Thomas Miller and 
Dr. Soham Puvvada as PI and Co-PI, respectively; added Dr. Daniel Persky as PI. 
• Updated Protocol Signature Page: Amendment #8 dated 04/19/2017; updated Dr. Daniel 
Persky as PI. 
• Updated Sections 3.A, 5.E.2, and Appendix A:  Updated patient long-term follow-up 
from indefinitely to 5 years. 
• Section 8C: Removed Dr. Thomas Miller’s contact information and updated with Dr. 
Daniel Persky’s contact information. 
• Section 13.A.1:  Removed Ruth Cañamar and added Kara Heard as current regulatory 
coordinator for lymphoma team. 
 
 
APPENDIX R 
Amendment #9 
(08/28/2017) 
 
Summary of Changes 
• Updated footers and dates throughout protocol to Amendment #9: 08/28/2017 
• Updated Sections 3A, 5.E.2 and Appendix A:  Clarified that patients will continue long-
term follow-up every 6 months for 2 years, then annually for 3 years.  The scheduled 
assessments for the annual 3 year follow-up timepoints was updated to match the 
assessments performed every 6 months for 2 years.