A Phase II Study of Yttrium-90-Labeled Anti-CD20 Monoclonal Antibody in Combination With High-Dose Beam Followed by Autologous Stem Cell Transplantation for Poor Risk/Relapsed B-Cell Lymphoma
Phase: PHASE2
Conditions: Lymphoma
Sponsor: City of Hope Medical Center

 
 
CITY OF HOPE NATIONAL MEDICAL CENTER 
DEPARTMENT OF HEMATOLOGY AND HEMATOPOIETIC CELL TRANSPLANTATION 
 
TITLE: A PHASE II STUDY OF YTTRIUM-90-LABELED ANTI-CD20 MONOCLONAL ANTIBODY IN 
COMBINATION WITH HIGH-DOSE BEAM (BCNU, ETOPOSIDE, CYTARABINE AND MELPHALAN) 
FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION FOR PATIENTS WITH POOR 
RISK/RELAPSED B-CELL LYMPHOMA 
 
City of Hope Protocol #/Version:                IRB# 07076         
 
    Version:  
21 
 
 
Date(s) of Amendment(s)/Revision(s):  
 
 
 
 
Initial Review 
COH Protocol Dated 10/19/07 
       Version:  00 
 
 
 
Initial Approval 
COH Protocol Dated 2/4/08 
       Version:  00 
 
 
 
Amendment #1 
COH Protocol Dated 4/01/08 
       Version:  01 
 
 
 
Amendment #2 
COH Protocol Dated 11/19/08 
       Version:  02 
 
 
 
Amendment #3 
COH Protocol Dated 04/17/09 
       Version:  03 
 
 
 
Amendment #4 
COH Protocol Dated 10/29/09 
       Version:  04 
 
 
 
Amendment #5 
COH Protocol Dated 11/12/09 
       Version:  05 
 
 
 
Amendment #6 
COH Protocol Dated 02/22/10 
       Version:  06 
 
 
 
Amendment #7 
COH Protocol Dated 05/05/10                 Version:  07 
 
 
 
Amendment #8 
COH Protocol Dated 06/10/10 
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Amendment #9 
COH Protocol Dated 10/11/10 
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                                           Amendment #12   COH Protocol Dated 02/01/12 
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Amendment #13   COH Protocol Dated 06/29/12 
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Amendment #14 COH Title Page Dated 01/15/13 
        Version: 14 
 
Amendment #15 COH Title Page Dated 01/24/13 
        Version: 15 
 
Amendment #16 COH Protocol Dated 02/04/13 
        Version: 16 
 
Amendment #17 COH Protocol Dated 06/17/13 
        Version: 17 
 
Amendment #18  COH Protocol Dated 02/10/14 
        Version: 18 
 
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                                   Amendment #21 COH Title Page Dated 12/15/14 
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Modality: 
Chemotherapy/Radioimmunotherapy 
 
Type:  
 
 
 
 
Phase II 
 
Principal Investigator: 
Amrita Krishnan, M.D.  
 
Collaborating Investigator(s): 
Jeffery Wong, M.D.  
Auayporn P. Nademanee, M.D. 
Stephen J. Forman, M.D. 
Joycelynne M. Palmer, Ph.D. 
 
Participating Clinicians: 
 
 
Ahmed Aribi, M.D., Ravi Bhatia, M.D.,  
Ji-Lian Cai, M.D., Robert Chen, M.D., Warren 
Chow, M.D., Len Farol, M.D., Myo Htut, M.D., 
Chatchada Karanes, M.D. Samer Khaled, M.D., 
Ryotaro Nakamura, M.D., Margaret R. O’Donnell, 
M.D., Nitya Nathwani, M.D., Pablo Parker, M.D., 
Leslie Popplewell, M.D., Michael Rosenzweig, 
M.D., Firoozeh Sahebi, M.D., Tanya Siddiqi, M.D., 
Eileen Smith, M.D., David S. Snyder, M.D., George 
Somlo, M.D., Ricardo Spielberger, M.D., Anthony 
Stein, M.D., Dave Yamauchi, M.D., Haris Ali, M.D., 

 
 
Amandeep Salhotra, M.D., Vinod Pullarkat, M.D., 
Ibrahim Aldoss, M.D., Elizabeth Budde, M.D., Thai 
Cao, M.D., Jinhua Park, M.D., Ph.D., Dave 
Yamauchi, M.D., Jasmine Zain, M.D., Alex Herrera, 
M.D., Monzr Al Malki, M.D., Matthew Mei, M.D., 
Savita Dandapani, M.D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
TABLE OF CONTENTS 
   1.0 BACKGROUND AND RATIONALE ................................................................................ 1 
   2.0 STUDY OBJECTIVES ..................................................................................................... 6 
   3.0 STUDY DESIGN ............................................................................................................. 7 
   4.0 DRUG FORMULATION .................................................................................................. 7 
   5.0 STAGING CRITERIA .................................................................................................... 11 
   6.0 INCLUSION CRITERIA ................................................................................................. 12 
   7.0 EXCLUSION CRITERIA ................................................................................................ 13 
   8.0 TREATMENT PLAN ...................................................................................................... 13 
   9.0 STUDY CALENDAR - PREPARATIVE REGIMEN AND PBSCT .................................. 18 
 10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS .................................. 20 
 11.0 
STATISTICAL CONSIDERATIONS .............................................................................. 21 
 12.0 
REGISTRATION GUIDELINES ..................................................................................... 23 
 13.0 
RECORDS TO BE KEPT AND DATA SUBMISSION SCHEDULE ............................... 23 
 14.0 
DATA MANAGEMENT ................................................................................................. 23 
 15.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................... 23 
16.0  
DATA SAFETY MONITORING PLAN: RISK LEVEL 3 ................................................. 24 
 17.0 
REFERENCES .............................................................................................................. 26 
 
Appendix 
I  
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 
Appendix 
II 
Modified Bearman Toxicity Scale 
Appendix 
III 
Additional Assays to be Performed on Previously Collected Samples  
 

 
 
1.0 
BACKGROUND AND RATIONALE 
 
Non-Hodgkin lymphomas are the sixth most common cause of cancer-related deaths in the United States.  
The incidence of NHL has increased by 50% over the past 15 years.  The incidence of both indolent and 
aggressive lymphomas increases with age making these the most commonly diagnosed lymphoid 
malignancies in patients over 60 years of age.1 Despite the use of aggressive combination chemotherapy 
regimens, approximately 30-40% of the patients with intermediate- and high-grade NHL do not achieve a 
complete remission (CR) or suffer a relapse after attaining a remission.2 High-dose chemotherapy or 
chemo/radiotherapy followed by autologous bone marrow or stem cell transplantation (ASCT) has been 
shown to induce long-term disease control in about 10-50% of patients with relapsed and refractory 
intermediate- and high-grade lymphoma.3 The benefit of high-dose therapy and ASCT has been proven to 
be superior to conventional salvage chemotherapy in a randomized study of 215 patients with 
chemotherapy-sensitive NHL in relapse reported by the Parma study group.4 The 5-yr event-free survival 
(EFS) was 46% for ASCT group compared to 12% for the salvage therapy without transplantation (p= 
0.001).  Thus, high-dose therapy and ASCT has become a potential curative modality for patients with 
recurrent aggressive lymphoma. However, not all the patients derive long-term benefit from this treatment 
and recurrent disease remains the single most common cause of treatment failure after high-dose therapy 
and ASCT. Therefore, new therapeutic approaches within the ASCT setting are needed. 
 
Patients with low-grade NHL have an indolent clinical course and are not cured by current treatment 
approaches.  Although most patients can achieve a complete remission with standard treatment, the 
median duration of first CR ranges from 12 to 36 months.  Although relapsed low-grade lymphoma may 
still respond to salvage therapy, the duration of subsequent remissions progressively decreases.  High-
dose therapy and ASCT has been shown to improve survival and increase the duration of remission in 
some patients with relapsed low-grade NHL.5 However, because of the long natural history and the 
continued pattern of relapse post ASCT in some studies, the role of high-dose therapy and ASCT as a 
potential curative treatment for patients with relapsed low-grade lymphoma has not been clearly 
established.  
 
Mantle cell lymphoma, one of the categories of low-grade lymphoma, remains one of the most difficult 
clinical challenges. Response rates with initial chemotherapy such as CHOP-Rituxan are over 90%, 
however, progression free survival remains short.6 Therefore, new treatment strategies are needed to 
improve long-term survival. One of the explored strategies is the use of high dose therapy and autologous 
stem cell transplant as upfront consolidation. The optimal conditioning regimen for the consolidative phase 
remains a subject of study. 
 
The incidence of lymphoma increases with age. Furthermore, the prognosis of lymphoma in older patients 
tends to be worse. This is due to a combination of factors; the biology of the disease, comorbidities that 
lead to increased toxicity with conventional chemotherapy or that require dose reduction of chemotherapy. 
The early transplant trials such as the PARMA study included younger patients (<60yrs). However, many 
of our patients are beyond this age range. For these patients with poor risk or relapsed lymphoma, new 
options are needed. Novel conditioning regimens that combine radioimmunotherapy with high dose 
chemotherapy are one such option. 
 
1.1 
Results of High-Dose Chemo/Radiotherapy and ASCT for NHL 
Several high-dose therapy regimens have been used as preparative regimens for NHL and so far, none of 
these regimens have emerged to be the best regimen.  However, since NHL is radiosensitive and based 
on the experience of acute leukemia, the combination of total body irradiation (TBI) and cyclophosphamide 
(Cy) has been widely used as a preparative regimen for patients with lymphoid malignancies.  In an attempt 
to reduce relapse rates, etoposide has been added to the TBI and Cy regimen because of its known activity 
in lymphoma. The results of phase I and II studies of TBI 12.0 Gy, etoposide 60 mg/kg and Cy 100 mg/kg 
conducted at City of Hope7, Stanford University8 and Fred Hutchinson Cancer Research Center (FHCRC)9 
demonstrated the activity of this regimen in patients with lymphoid malignancies. The transplanted-related 
mortality within the first 100 days was 7-8% and the common causes of death were veno-occlusive disease 
(VOD), diffuse alveolar hemorrhage, and infection.  The major transplant-related morbidities were 
mucositis and skin, toxicities which were fully reversible.  Utilizing this regimen, Stanford reports 5-year 
event free survival (EFS) and overall survival (OS) probabilities of 52% (95% confidence interval (CI): 42-

 
 
62%) and 61% (95%CI: 50-73%) respectively for 134 NHL patients who underwent ASCT at their 
institution.  
 
Between 2/87 and 8/98, 264 patients with intermediate or high grade non-Hodgkin lymphoma underwent 
ASCT at City of Hope Bone Marrow Transplant Program. Ninety-four patients underwent ASCT in first 
complete/partial remission, 40 in induction failure, and 130 in relapse or subsequent remission. Seventy-
nine percent of patients received the combination of total body irradiation, high dose etoposide and 
cyclophosphamide as conditioning regimen. Carmustine was given instead of TBI for patients who were 
not able to receive TBI due to prior radiation, or if their age was greater than 60 years with borderline 
performance status. With a median follow-up of 4.4 years for the surviving patients (1-12.8 yrs.), the 5-
year Kaplan-Meier estimates of probability of overall survival, progression-free survival, and relapse are 
55% (95% CI: 49-61), 47% (95%CI: 40-53%) and 47% (95%CI: 40-54%) respectively. In univariate 
analysis, patients who received a total-body irradiation tended to have fewer relapses after transplant and 
improved survival but this was no longer significant at multivariable analysis. There were 27 deaths (10%) 
from non-relapse mortality, including 10 patients due to secondary malignancy. This result has been 
confirmed in the Southwestern Oncology Group cooperative trial.  Despite its effectiveness, the relapse 
rates of 34-53% remain high. Thus, more effective preparative regimens are needed. 
 
Options for new regimens include adding new agents or incorporating post transplant maintenance 
strategies. The limitation of adding new agents in the high dose setting is minimizing overlapping organ 
toxicity. Thus, targeted radioimmunotherapy against CD20 is an attractive option as it has relatively low 
toxicity to normal organs except the bone marrow. 
 
1.2      Anti-CD20 
Anti-CD20 (anti-B1) is a murine monoclonal antibody of isotype IgG2a, raised against cryopreserved 
Burkitt lymphoma cells. The antibody reacts against the B1 antigen, an epitope of the CD20 developmental 
cell surface protein.   CD20 is a 35 kD cell surface phosphoprotein found on 95% of normal mature B cells 
and more than 90% of B-cell non-Hodgkin lymphomas and B-cell chronic lymphocytic leukemias tested, 
but not on T cells, plasma cells, uncommitted hematopoietic-precursors stem cells, dendritic cells, 
granulocytes, monocytes, or erythrocytes, or on tumors of T cell, myeloid or erythroid origin.  CD20 is not 
shed and does not modulate from the surface after binding of antibody. 
 
Anti-CD20 has been used extensively as a therapeutic agent for use in bone marrow purging.  Clinical use 
of this antibody in marrow purging has shown it to be selective in eradicating B-cell lymphomas as well as 
normal B cells, while leaving other lymphocyte population intact.  Some subpopulation of B cell precursors 
is left intact, as evidence by engraftment of the normal B cell compartment. 
 
1.3 
Yttrium-90 
Yttrium-90 (Y90, Zevalin) is a chimeric antibody with a murine variable portion and a human IgG1 kappa 
constant portion that recognizes the CD20 antigens expressed on normal B cells and most malignant B-
cell lymphomas.  Yttrium 90 shows specificity for the CD20 antigen and binds with an apparent affinity of 
4.3 x 10-9M.  Yttrium-90 has also been reported to induce apoptosis and to sensitize drug-resistant human 
B-cell lymphoma cell lines to cytotoxic chemotherapy. 
 
1.4 
Radionuclides for Radioimmunotherapy 
Yttrium-90 (90Y) (ZEVALIN) may be an ideal radionuclide for radioimmunotherapy since it emits beta 
particles that are more potent than those delivered by 131I.  It is a pure beta emitter, making it a safer 
reagent for medical personnel to administer than 131I.  In addition, the short half-life also facilitates the use 
of 90Y in combination with other agents; i.e. chemotherapy or total body radiation, as well as allows for high 
dose rates at localized sites.  Unfortunately, 90Y cannot be used for radioimmunoscintigraphy due to its 
absence of gamma emissions.  Indium-111 has been substituted as an imaging reagent to show tumor 
localization in patients scheduled for 90Y therapy, on assumption that its biodistribution closely mimics that 
of 90Y.  Using In-111 labeling, other murine monoclonal antibodies have been used successfully in clinical 
trials for cutaneous T-cell lymphoma and chronic lymphocytic leukemia, melanoma, and colon cancer. 
 
Prior to the establishment of Yttrium-90 for clinical use, Iodine-131 had been the gold standard for 

 
 
radioimmunotherapy due to its long track record in treating thyroid carcinoma. However, there are 
disadvantages to Iodine-131, which include its long half-life, the risks of radiation exposure to health care 
personnel and the nonspecific radiation to normal organs from the gamma components of Iodine-131. 
 
1.5 
Results of 131I anti-B1 Monoclonal Antibody with Autologous Bone Marrow Support 
The use of radio-labeled monoclonal antibody (MAb) at myeloablative radiation dose followed by 
autologous stem cell rescue has been explored by investigators from The Fred Hutchinson Cancer 
Research Center.  Press et al10 conducted a trial utilizing a higher dose of 131I labeled anti-CD20 antibody 
with autologous bone marrow rescue in 43 patients with B-cell lymphoma in relapse.  In this study, 
sequential biodistribution studies were performed with escalating doses of antibody (0.5, 2.5, and 10 
mg/kg) trace-labeled with 5 to 10 mCi of 131I.  Patients whose tumors were estimated to receive greater 
doses of radiation than liver, lungs, or kidneys (a favorable biodistribution) were eligible for the therapeutic 
infusion of 131I labeled antibody.  Of the 43 patients, 24 had a favorable biodistribution, and 19 received 
therapeutic infusion of 234-777 mCi of 131I-labeled antibodies (58-1168 mg) followed by autologous marrow 
infusion.  Sixteen patients achieved a CR, two had a partial response, and one had a minor response.  
Nine of the complete responders have remained in continuous CR for 3 to 53 months.  Toxicities include 
myelosuppression, nausea, infection and two episodes of cardiopulmonary toxicity.  In this study, 
cardiopulmonary toxicity was the dose limiting, non-hematopoietic toxicity of high-dose 131I-labeled 
antibody. 
 
In an attempt to reduce toxicity to normal tissues and to directly deliver higher dose of radiation to tumor 
sites, 131I-labeled-anti-CD20 MAb has been incorporated into high-dose therapy regimen instead of TBI.  
Press et al11 reported results of a phase I/II study to define the MTD of an 131I- labeled anti-B1 monoclonal 
antibody which can be given with high-dose etoposide and cyclophosphamide in conjunction with ASCT 
in 38 (26 low-grade; 12 aggressive) NHL patients. Patients were treated in cohorts of 4 patients each with 
131I-anti-B1 antibody doses (2.5 mg/kg, 318-840 mCi) calculated to deliver 20-27 Gy of radiation to dose-
limiting, critical normal organs, followed by etoposide (0 or 60 mg/kg), cyclophosphamide (100 mg/kg), and 
ABMT (15 patients) or ASCT (22 patients).  Of the 37 evaluable patients, 33 (89%) were currently alive 
and 29 (78%) were progression-free after a median follow-up of 1.5 yr.  Toxicities included grade 4 
myelosuppression  in all patients, grade 2-3 nausea in 26 (70%), pulmonary infiltrate in 4 and grade 3 VOD 
in 2 patients.  There were four deaths; 3 from progressive NHL and 1 from disseminated varicella. These 
results suggest that 131I- anti-B1 antibody can be given at doses delivering up to 25 Gy to critical normal 
organs, with pulmonary and gastrointestinal toxicities being dose-limiting. 
 
1.6 
Results of Bexxar (131I Anti-CD20 Monoclonal Antibody) in combination with High Dose 
Chemotherapy followed by Autologous Stem Cell Rescue 
In a phase I trial, Vose and colleagues from Nebraska Medical Center evaluated the addition of standard 
dose Bexxar (131I-Anti-CD 20) given sequentially with BEAM (BCNU, etoposide, Ara-C and melphalan) 
followed by ASCT in patients with primary induction failure or chemo-refractory recurrent non-Hodgkin 
lymphoma.17 Twenty-three patients were included in this pilot study. There were no treatment-related 
deaths. The overall response rate was 66% with complete response rate of 57% and partial remission rate 
of 9%. With a median follow-up of 38 months, the overall survival was 55% and event free survival was 
39% respectively. Short and long term toxicities were similar to BEAM alone. This suggests that the 
combination of Bexxar with high dose chemotherapy can be administered without increased toxicity. 
 
While the superiority of this approach over conventional radiation based regimens has not been proven, 
retrospective studies comparing high dose radioimmunotherapy (RIT) versus total body irradiation based 
(TBI) regimens suggest a benefit. Gopal et al performed a multivariate comparison of 125 patients with 
follicular lymphoma treated with high dose RIT with 131I.The RIT regimen had a lower 100 day transplant 
related mortality and improved OS compared to TBI based regimens.28 This suggests that further study of 
these RIT based conditioning regimens is warranted. 
1.7  
Therapeutic Use of Anti-CD20 Antibody and Yttrium90 Anti-CD20 Antibody 
A Phase I dose escalation pharmacokinetic trial of anti-CD 20 given as a single intravenous infusion using 
doses ranging from 10 mg/m 2 to 500 mg/m2 in patients with relapsed or refractory low-grade lymphoma 
was reported by Maloney et al.14 The median half-life of the free antibody at doses ranging from 100 mg/m2 
to 500 mg/m2 was 4.4 days (range 1.6-10.5 days).  In Phase II clinical studies, anti-tumor activity has been 

 
 
observed in patients with relapsed or refractory low-grade or follicular B-cell NHL. The majority of adverse 
events was mild to moderate and included fever, fatigue, chills and nausea, which were primarily 
associated with the initial infusions.  No quantifiable human anti-mouse antibodies (HAMA) or human anti-
chimeric antibodies (HACA) were observed. Depletion of peripheral B-cells occurred rapidly following the 
first infusion with recovery beginning 6 months post-treatment. Despite this depletion of B-cells, there was 
minimal change in serum IgG, IgM, and IgA levels and no increase in the frequency or severity of infectious 
complications.  Anti-tumor activity was observed at various disease sites, including peripheral blood, bone 
marrow, lymph nodes, spleen and abdominal masses. 
 
A phase III trial to assess the safety and efficacy of anti-CD20 antibody, 375 mg/m2, given once weekly for 
four doses in 166 patients with relapsed or refractory low-grade or follicular NHL was reported by 
McLaughlin et al.15 The overall response rate in 151 evaluable patients was 50% (9CR; 67 PR).  The 
median duration of response has not been reached after a median follow-up of 9+ months. Conversion to 
negative bcl-2 status occurred in 57% of patients who were positive at baseline and subsequently 
reevaluated after the fourth infusion. No positive HAMA responses were observed in 67 patients evaluated 
and the incidence of HACA was less than 1%. Severe neutropenia and thrombocytopenia were observed 
in less than 2% of patients. Anti-CD20  has also been studied in 44 patients with relapsed diffuse large B-
cell and mantle cell lymphoma. The overall response rate was 31%, with a 10% CR rate. Thus anti-CD20 
monoclonal antibody has become a very effective salvage therapy for CD20+ B-cell low- and intermediate-
grade NHL and this treatment has become an important addition to our armamentarium. 
 
Anti-CD20 has also been studied in combination with chemotherapy. Czuczman et al conducted a Phase 
II multi-center study evaluating the safety and anti-tumor activity of anti CD20 375 mg/m2 for six doses in 
combination with six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) 
chemotherapy in 40 patients with low-grade NHL.16 Combination therapy appeared safe and toxicity profile 
observed was consistent with that seen with CHOP alone. No HAMA or HACA responses were observed. 
The overall response rate in 35 patients who completed treatment was 100% (21 CR; 14 PR).  The median 
time to disease progression has not been reached with follow-up time of 9-27+ months. Seven of eight 
patients who were bcl-2 positive at baseline by polymerase chain reaction (PCR) became negative in both 
peripheral blood and bone marrow following treatment.  
 
Several randomized trials have now confirmed the superiority of combining chemotherapy with 
immunotherapy. The GELA trial and the MINT trial confirmed the superiority of CHOP rituximab over CHOP 
alone in both event free survival and overall survival in elderly patients and in younger patients with diffuse 
large cell lymphoma.17,18 
 
Yttrium-90 Clinical Studies 
A Phase I/II dose escalation study of 90Y-murine anti-CD20 monoclonal antibody (MAb) in patients with 
recurrent B-cell lymphoma was performed by Knox et al.19 The primary objectives of the study were: (a) to 
determine the effect of the preinfusion of unlabeled anti-CD20 MAb on the biodistribution of 111In-anti-CD20 
MAb; (b) to determine the maximal tolerated dose of 90Y-anti-CD20 MAb that does not require bone marrow 
transplantation; and (c) to evaluate the safety and antitumor effect of 90Y-anti-CD20 MAb in patients with 
recurrent B-cell lymphoma.  Eighteen patients with relapsed low- or intermediate-grade non-Hodgkin 
lymphoma were treated.  Biodistribution studies with 111In-anti-CD20 MAb were performed prior to therapy. 
Groups of three or four patients were treated at dose levels of approx 13.5, 20, 30, 40, and 50 mCi 90Y-
anti-CD20 MAb.  Three patients were retreated at the 40 mCi dose level. The use of unlabeled antibody 
affected the biodistribution favorably. Nonhematological toxicity was minimal. The only significant toxicity 
was myelosuppression.  The overall response rate following a single dose of 90Y-anti-CD20 MAb therapy 
was 72%, with six complete responses and seven partial responses, and freedom from progression of 3-
29+ mo following treatment.  Radioimmunotherapy with less than or equal to 50 mCi 90Y-anti-CD20 MAb 
resulted in minimal non-hematologic toxicity and durable clinical responses in patients with recurrent B-
cell lymphoma.  Doses of less than or equal to 40 mCi 90Y-anti-CD20 MAb were not myeloablative. 
 
A phase II study by Witzig et al established the activity of Yttrium-90 in patients with rituximab refractory 
follicular lymphomas. Fifty-seven patients were treated. The patients first received a dose of rituximab, 
375mg/m2, day 1 and day 8 to deplete peripheral blood B cells. The first 28 patients had indium-111 
imaging performed on day 1 (see below).20 The estimated radiation doses were acceptable allowing for 

 
 
Yttrium 90 treatment in all the patients. The overall response rate was 74% (15% CR 59% PR). The time 
to progression for responders was 8.7 months. The therapy was well tolerated. The adverse events were 
primarily hematologic and transient. No patient discontinued therapy because of an adverse event. The 
incidence of grade 4 neutropenia was 35% though only 7% of patients required hospitalization for fever. 
 
The dosimetry from the Witzig trial as well as other single agent studies of Yttrium-90 was reported by 
Wiseman et al.21 Forty-two patients with low- and intermediate-grade NHL received Yttrium-90 following 
injection of unlabeled rituximab (cold antibodies) followed by 2 mg of mouse anti-CD20 antibody labeled 
with 5 mCi 111In (IDEC-In2B8).  90Y 0.2, 0.3, or 0.4 mCi/kg was given 7 days following 111In.  The patients 
had 111In dosimetry performed by serial whole body gamma camera imaging, urine collection and blood 
sampling at 0, 2, 6, 24, 48, 72, 96 and 144 hours.  The highest mean calculated 90Y radiation dose to a 
normal organ was spleen with 24.16 rads/mCi (0.6-67.0), followed by liver with 17.2 rad/mCi (9.4-39.2) 
and lungs with 12.9 rads/mCi (4.2-67.7).  90Y dose of 0.4 mCi/kg was the MTD for bone marrow toxicity 
(thrombocytopenia and neutropenia).  These results suggest that: 1) no organ was irradiated beyond safety 
levels; 2) 111I can serve as a predictor of 90Y; 3) rituximab dose of 250 mg/m2 has been established as the 
“cold” antibody with added benefits of its therapeutic effect; and 4) bone marrow toxicity was the dose-
limiting effect with full and predictable recovery. 
 
The use of Yttrium-90 as a single agent in older patients with refractory NHL has been studied. Schilder at 
al reported on an integrated analysis of four clinical trials comprising 211patients. They were in three 
cohorts; <60yrs, 60-69 yrs, >70 yrs. Complete remission rates and hematologic toxicities were similar 
across the cohorts. This suggested that Yttrium-90 is effective and well tolerated in older patients.22 
 
1.8  
Yttrium-90 and High Dose Chemotherapy 
The use of dose escalated IDECY2B8 combined with high dose chemotherapy is an ongoing study at 
Northwestern University.23 To date, 33 patients have been treated. Because of the dose increase of the 
Yttrium, dosimetry monitoring is required to deliver patient specific defined radiation doses to critical 
organs. A report of the 33 patients treated with Yttrium-90 and high dose BEAM (BCNU, Etoposide, 
Cytarabine, Melphalan) was presented at the American Society of Clinical Oncology meeting by Jane 
Winter. The investigators noted that the most common grade 3-4 toxicities were infection, fever, and 
stomatitis. Engraftment times were similar to BEAM alone. This suggests that the combination of this 
isotope with high dose chemotherapy is well tolerated. However, the need for dosimetry makes the Winter 
protocol a more difficult regimen to utilize. Furthermore, it is unclear that increasing the Yttrium-90 dose 
provides any clinical benefit. 
 
1.9  
Study Proposal 
Therefore, our pilot trial at the City of Hope utilized standard dose Yttrium-90 in combination with high dose 
BEAM. The protocol treated 38 patients with a combination of standard dose Yttrium-90 (0.4 mCi/kg) and 
high dose BEAM (BCNU, Etoposide, Cytarabine, Melphalan) chemotherapy. Data on 24 patients with 
adequate follow-up was presented at the American Society of Clinical Oncology meetings.24 The patient 
population was older than our standard transplant population (median age 60 yrs). The toxicity profile of 
this regimen was similar to high dose BEAM alone. The major toxicity was pulmonary (grade 3) in three 
patients. This included interstitial pneumonitis and sepsis associated respiratory distress. Engraftment 
times were similar to high dose BEAM alone. At the time of reporting, with a median follow-up of 13.0 
months, progression free survival was 74%. 
 
We propose to expand upon this initial experience in a larger series of patients. Our pilot study established 
the safety of this regimen and suggested short-term efficacy. However, given the small numbers of patients 
spread among diverse histologies, the long-term efficacy of this regimen is still unproven. For example, we 
conducted a retrospective analysis of patients> 50 years of age who were treated with high dose BEAM 
versus those treated with Zevalin plus high dose BEAM. This analysis was presented at the American 
Society of Hematology Meeting in 2006.  Analysis of patients with diffuse large cell lymphoma showed a 
significant difference in ZBEAM vs. BEAM, with the two year OS/PFS in the ZBEAM group of 88%/62% 
versus 65%/67% in the BEAM group. In contrast, no significant difference was seen between the 
conditioning regimens for patients with mantle cell lymphoma. The number of patients with follicular 
lymphoma or transformed lymphoma was too small in both groups to make a comparison. We therefore 
wish to further study the effects of ZBEAM conditioning in a larger number of patients with different 

 
 
histologies. This new study will enroll patients with poor risk or relapsed follicular lymphoma (grade1-3), 
mantle cell lymphoma, diffuse large B-cell lymphoma and transformed low-grade lymphoma. There will be 
no upper age limit but organ function criteria must be met. We will assess the effects of this novel 
preparative regimen on disease progression among the various lymphoma histologies. Short- and long- 
term transplant related complications with specific attention to pulmonary, hematologic and hepatic 
function based on our pilot study experience will be assessed. 
 
The study will also focus on costimulatory receptors, namely, PD-1, CTLA-4, CD28, ICOS, OX40 and 4-
1BB (CD137), and will be performed on blood samples collected at various time points before and after 
the AHSCT regimen, using either FACS analysis or mRNA Q-PCR.  The results may contribute to a better 
understanding of immune factors important in outcome.  To date, we have shown that the PD-1 molecule 
was up-regulated in HCT subjects before the development of CMV disease.  Similar techniques will be 
used for the expression of the other costimulatory receptors.  NOTE THAT, DUE TO FUNDING, 
PATIENTS ENROLLED AFTER 6/20/12 WILL NOT BE INCLUDED IN THE COSTIMULATORY 
MOLECULE ANALYSIS.  
Lastly, with the marked improvement in survival, coupled with an increase in the intensity of treatment for 
patients with malignancies, therapy-related AML or MDS (t-MDS/AML) has become a serious and growing 
clinical problem. The incidence of t-MDS/AML ranges between 6-18% following treatment of various 
malignancies such as Hodgkin disease and non-Hodgkin lymphoma (both after conventional 
chemotherapy and following bone marrow or stem cell transplantation), breast cancer, testicular and 
ovarian cancers and acute lymphoblastic leukemia.25-27 Therefore, because of the need for continued 
prospective monitoring for long term therapy related complications such as myelodysplasia and therapy 
related AML, all patients will be co-enrolled on protocol 98117, ‘Molecular Pathogenesis of Therapy 
Related Leukemia’.  
 
2.0 
STUDY OBJECTIVES 
 
This is a phase II study designed to evaluate hematopoietic recovery, early and late transplant related 
toxicity, disease progression/relapse, progression free/relapse free survival, overall survival and therapy 
related MDS/AML among patients with poor risk/relapsed follicular lymphoma (grade1-3), mantle cell 
lymphoma, diffuse large B-cell lymphoma, and transformed low-grade lymphoma who undergo RIT based 
ASCT. 
 
2.1 
To estimate the progression free/relapse free survival and overall survival probabilities among 
patients with poor risk/relapsed follicular lymphoma (grade1-3), mantle cell lymphoma, diffuse large 
B-cell lymphoma, and transformed low-grade lymphoma who undergo RIT based ASCT. 
2.2 
To evaluate hematopoietic recovery, using neutrophil (ANC500 x103/L, ANC1000 x103/L) and 
unmaintained platelet (20 x103/L, 100 x103/L) engraftment as primary criterion, following RIT 
based ASCT. 
2.3 
To characterize early and late pulmonary, cardiac and hepatic toxicities during the first 100 days 
post ASCT and again one year post ASCT. 
2.4 
To evaluate the response rate and the disease progression/relapse rate in patients treated with RIT 
based ASCT. 
2.5 
To evaluate long-term incidence of myelodysplasia and therapy related AML with this new 
preparative regimen. 
2.6 
To descriptively compare the outcomes of patients treated on this protocol to a comparable patient 
population treated with chemotherapy alone. 
2.7 
To perform exploratory studies on expression of costimulatory molecules before and after RIT 
based ASCT.  Refer to Section 9.0 (Study Calendar) for costimulatory molecule assay time points. 
NOTE THAT, DUE TO FUNDING, PATIENTS ENROLLED AFTER 6/20/12 WILL NOT BE 
INCLUDED IN THE COSTIMULATORY MOLECULE ANALYSIS. 
    
 
 
3.0 
STUDY DESIGN 
 

 
 
This is an open-label clinical study of a new preparative regimen followed by autologous stem cell support 
in patients with relapsed- refractory- NHL.  Patients with low and intermediate-grade NHL who have 
relapsed following conventional chemotherapy or have failed to achieve remission, or have poor risk 
disease and who are candidates for high-dose therapy and ASCT will be eligible for this study. All patients 
will receive Yttrium-90 in combination with high-dose BEAM followed by ASCT. Yttrium-90 will be given at 
a fixed dose of 0.4 mCi/kg and there will not be any dose escalation. 
 
All patients will have peripheral blood stem cells collected with the target CD34+ of 5.0x106/kg. The 
mobilization regimen for stem cell collection will be at the discretion of the treating physician. Patients will 
undergo pre-therapy imaging studies on day –21 and therapy on day -14.  BCNU will be given on day –7 
and –6; cytarabine and VP-16 (etoposide) will be given between day -5 to day - 2 and Melphalan on day -
1. PBSC will be infused on day 0. 
 
4.0 
DRUG FORMULATION 
 
4.1 
Rituximab (Rituxan®) 
a. 
Drug Formulation and Procurement 
Rituxan is commercially available and jointly marketed by Biogen IDEC, Inc. and Genentech 
USA, Inc.  Rituxan is supplied as 100 mg and 500 mg of sterile, preservative-free, single-use 
vials.  Single unit 100 mg carton contains one 10 mL vial of Rituxan (10 mg/mL).  NDC 50242-
051-21.  Single unit 500 mg carton contains one 50 mL vial of Rituxan (10 mg/mL).  NDC 
50242-053-06. 
 
b. 
Drug Toxicity (See Rituxan package insert for more information www.rituxan.com) 
Warnings:   
Fatal Infusion Reactions: Deaths within 24 hours of Rituxan infusion have been reported. These 
fatal reactions followed an infusion reaction complex, which included hypoxia, pulmonary 
infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or 
cardiogenic shock. Approximately 80% of fatal infusion reactions occurred in association with 
the first infusion.  Patients who develop severe infusion reactions should have Rituxan infusion 
discontinued and receive medical treatment. 
Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal 
outcome has been reported in the setting of TLS following treatment of non-Hodgkin's 
lymphoma (NHL) patients with Rituxan. 
Severe Mucocutaneous Reactions: Severe mucocutaneous reactions, some with fatal outcome, 
have been reported in association with Rituxan treatment.  
Progressive Multifocal Leukoencephalopathy (PML):  JC virus infection resulting in PML and 
death has been reported in patients treated with Rituxan. 
 
Infusion Reactions:  Mild to moderate infusion reactions consisting of fever and chills/rigors 
occurred in the majority of patients during the first Rituxan infusion. Other frequent infusion 
reaction symptoms included nausea, pruritus, angioedema, asthenia, hypotension, headache, 
bronchospasm, throat irritation, rhinitis, urticaria, rash, vomiting, myalgia, dizziness, and 
hypertension. These reactions generally occurred within 30 to 120 minutes of beginning the first 
infusion, and resolved with slowing or interruption of the Rituxan infusion and with supportive 
care (diphenhydramine, acetaminophen, IV saline, and vasopressors). The incidence of infusion 
reactions was highest during the first infusion and decreased with each subsequent infusion. 
 
Infectious Events:  Rituxan induced B-cell depletion in 70% to 80% of patients with NHL and 
was associated with decreased serum immunoglobulins in a minority of patients; the 
lymphopenia lasted a median of 14 days (range, 1 — 588 days). Infectious events occurred in 
31% of patients: 19% of patients had bacterial infections, 10% had viral infections, 1% had 
fungal infections, and 6% were unknown infections. Incidence is not additive because a single 
patient may have had more than one type of infection. Serious infectious events (Grade 3 or 4), 
including sepsis, occurred in 2% of patients. 
 

 
 
Hematologic Events:  Grade 3 and 4 cytopenias were reported in 48% of patients treated with 
Rituxan; these include: lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), 
and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1 — 588 
days) and of neutropenia was 13 days (range, 2 — 116 days). A single occurrence of transient 
aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following 
Rituxan therapy were reported. 
 
Pulmonary Events:  135 patients (38%) experienced pulmonary events in clinical trials. The 
most common respiratory system adverse events experienced were increased cough, rhinitis, 
bronchospasm, dyspnea, and sinusitis. In both clinical studies and post-marketing surveillance, 
there have been a limited number of reports of bronchiolitis obliterans presenting up to 6 months 
post-Rituxan infusion and a limited number of reports of pneumonitis (including interstitial 
pneumonitis) presenting up to 3 months post-Rituxan infusion, some of which resulted in fatal 
outcomes. The safety of resumption or continued administration of Rituxan in patients with 
pneumonitis or bronchiolitis obliterans is unknown. 
 
Immunogenicity:  The observed incidence of antibody positivity in an assay is highly dependent 
on the sensitivity and specificity of the assay and may be influenced by several factors including 
sample handling, concomitant medications, and underlying disease. For these reasons, 
comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other 
products may be misleading.  In clinical studies of patients with low-grade or follicular NHL 
receiving single-agent Rituxan, human antichimeric antibody (HACA) was detected in 4 of 356 
(1.1%) patients and 3 had an objective clinical response. These data reflect the percentage of 
patients whose test results were considered positive for antibodies to Rituxan using an enzyme-
linked immunosorbant assay (limit of detection = 7 ng/mL). 
 
c. 
Drug Storage, Reconstitution and Stability 
Rituxan vials are stored in the refrigerator at 2-8C (36-46F).  Do not use beyond expiration 
date stamped on carton.  Rituxan vials should be protected from direct sunlight.  Do not freeze 
or shake.  Refer to the “Preparation for Administration” section of the Rituxan package insert 
(www.rituxan.com) for information on the stability and storage of solutions of Rituxan diluted for 
infusion. 
 
4.2 
Ibritumomab Tiuxetan (Zevalin®) 
a. 
Drug Formulation and Procurement 
Zevalin is commercially available from Spectrum Pharmaceuticals.  Each of the two Zevalin kits 
contains four vials that are used to produce a single dose of either In-111 Zevalin or Y-90 
Zevalin, as indicated on the outer container label: 
1. One (1) Zevalin vial containing 3.2 mg of Ibritumomab Tiuxetan in 2 mL of 0.9% sodium 
chloride solution; a sterile, pyrogen-free, clear, colorless solution that may contain 
translucent particles; no preservative present. 
2. One (1) 50 mM Sodium Acetate Vial containing 13.6 mg of sodium acetate trihydrate in 
2 mL of Water for Injection; a sterile, pyrogen-free, clear, colorless solution; no 
preservative present. 
3. One (1) Formulation Buffer Vial containing 750 mg of Albumin (Human), 76 mg of 
sodium chloride, 28 mg of sodium phosphate dibasic dodecahydrate, 4 mg of pentetic 
acid, 2 mg of potassium phosphate monobasic and 2 mg of potassium chloride in 10 mL 
of Water for Injection adjusted to pH 7.1 with either sodium hydroxide or hydrochloric 
acid; a sterile, pyrogen-free, clear yellow to amber colored solution; no preservative 
present. 
4. One (1) empty Reaction Vial, sterile, pyrogen-free. 
 
b. 
Drug Toxicity  (See Zevalin package insert for more information www.zevalin.com) 
Warnings:   
Fatal Infusion Reactions: Deaths have occurred within 24 hours of Rituximab infusion, an 
essential component of the Zevalin® therapeutic regimen. These fatalities were associated with 

 
 
an infusion reaction symptom complex that included hypoxia, pulmonary infiltrates, acute 
respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. 
Approximately 80% of fatal infusion reactions occurred in association with the first Rituximab 
infusion.  Patients who develop severe infusion reactions should have Rituximab, In-111 
Zevalin, and Y-90 Zevalin infusions discontinued and receive medical treatment. 
Prolonged and Severe Cytopenias: Y-90 Zevalin administration results in severe and prolonged 
cytopenias in most patients. The Zevalin therapeutic regimen should not be administered to 
patients with ≥ 25% lymphoma marrow involvement and/or impaired bone marrow reserve. 
Severe Cutaneous and Mucocutaneous Reactions: Severe cutaneous and mucocutaneous 
reactions, some with fatal outcome, have been reported in association with the Zevalin 
therapeutic regimen. Patients experiencing a severe cutaneous or mucocutaneous reaction 
should not receive any further component of the Zevalin therapeutic regimen and should seek 
prompt medical evaluation. 
 
The most serious adverse reactions caused by the Zevalin therapeutic regimen include 
prolonged and severe cytopenias, infections (predominantly bacterial in origin), hemorrhage 
while thrombocytopenic (resulting in deaths), and allergic reactions (bronchospasm and 
angioedema). In addition, patients who have received the Zevalin therapeutic regimen have 
developed myeloid malignancies and dysplasias.  Fatal infusion reactions have occurred 
following the infusion of Rituximab.  In postmarketing reports, cutaneous and mucocutaneous 
reactions have been associated with the Zevalin therapeutic regimen.  Please refer to the 
BOXED WARNINGS and WARNINGS sections of the package insert for detailed descriptions of 
these reactions.  17 of 40 Isolated reports of extravasation with subsequent infusion site 
reaction, like dermatitis, desquamation and site ulcer have been received. In addition, isolated 
post-marketing reports have been received showing that Zevalin-associated radiation might 
cause damage to lymphoma-surrounding tissue and complications due to lymphoma swelling 
(see PRECAUTIONS in the package insert). The most common toxicities reported were 
neutropenia, thrombocytopenia, anemia, gastrointestinal symptoms (nausea, vomiting, 
abdominal pain, and diarrhea), increased cough, dyspnea, dizziness, arthralgia, anorexia, 
anxiety, and ecchymosis. Hematologic toxicity was often severe and prolonged, whereas most 
non-hematologic toxicity was mild in severity.  
 
c. 
Drug Storage, Reconstitution and Stability 
Store at 2-8C (36-46F).  Do not freeze.  The radiolabeled solutions should be used within 6 
hrs and should be held at 2-8C until administered. 
 
4.3 
Etoposide (Vepesid®, VP-16) (epipodophyllotoxin,etoposide,4'-demethyl-9(4,6-o-ß) d-
ethylideneglycopyranoside).   
 
a. 
Drug Formulation and Procurement 
Etoposide is commercially available from various manufacturers, 100 mg/5 ml solution in 100 mg, 
500 mg vials. 
 
b. 
Drug Toxicity 
Myelosuppression, primarily granulocytopenia, is the dose-limiting toxicity.  Gastrointestinal toxicity 
at high doses includes nausea, emesis and mucositis.  Reversible hepatotoxicity may occur at very 
high doses.  The acute side effects of occasional bronchospasm and hypotension are avoided by 
slow intravenous administration. 
 
c. 
Drug Storage, Reconstitution and Stability 
The contents of the ampule are diluted with 50 volumes of NaCl solution for injection, USP, and 
administered by slow intravenous infusion.  Patients will receive the drug through a central venous 
catheter at a rate of 100 mg/m2/1 hour. 
 
4.4 
Carmustine (BiCNU®) (1, 3-bis-(2-chloroethyl) 1- nitrosourea) (NSC-409962) 
 

 
 
a. 
Description 
BCNU is a lipid soluble agent, which has alkylating properties plus an isocyanate metabolite, which 
interferes with DNA and RNA synthesis. 
 
b. 
Toxicology 
Human toxicities:  The major toxicity of BCNU at this dose is myelosuppression.  Transient 
abnormal liver function tests occur infrequently but are self-limited.  Fatal hepatic necrosis has been 
described with much higher doses (1200 mg/m²) and in patients with accumulated dosage.  Renal 
toxicity has been described with chronic administration of BCNU.  As with pulmonary toxicity, the 
dose per course and schedule of drugs may be important co-variables along with the total 
accumulated dose.  Rarely, seizures and obtundation have been reported in patients with brain 
tumors treated with BCNU, but this was presumed to be due to tumor rather than drug toxicity. 
 
c. 
Pharmacology 
Kinetics:  IV BCNU is rapidly degraded to active metabolites. 60% to 70% is excreted in the urine 
in 96 hours and 10% as respiratory CO2. Because of the high lipid solubility, it crosses the blood-
brain barrier readily. 
 
Formulation:  BCNU is an alkylating agent which is supplied by Bristol Laboratories as a lyophilized 
powder (100 mg vial) containing no preservatives.  Due to its water insolubility, it is to be 
reconstituted with the diluent provided (3-ml absolute ethanol) followed by 27-ml sterile water to a 
final concentration of 3.3 mg/ml in 10% ethanol. 
 
Storage and Stability:  Stability upon reconstitution (less than 8% potency is lost) is 8 hours at room 
temperature or 40 hours if refrigerated and protected from light when stored in the original amber 
vial. BCNU solution may be further diluted to a concentration of 0.2 mg/ml with 5% dextrose or 
0.9% sodium chloride injection, USP, and will be stable for 48 hours if refrigerated and an additional 
8 hours at room temperature under normal room fluorescent light.  BCNU has a low melting point 
requiring refrigeration at all times prior to reconstitution.   Do not use if an oil film is present at the 
bottom of vial. 
 
Administration:  BCNU should be administrated by IV drip over 1 to 2 hours. Unpublished data 
suggest decreased availability when administrated in plastic infusion containers. 
 
Supplier:  BCNU is commercially available and should be purchased by a third party. 
 
4.5 
Melphalan (L-phenylalanine mustard, L-PAM, Alkeran) 
 
a. 
Drug Formulation and Procurement 
In common with other nitrogen mustards, melphalan reacts with DNA to produce either DNA-DNA 
or DNA-protein cross-linked products, probably by binding at the N-7 position of guanine. 
Melphalan is commercially available by Buroughs Wellcome Company. 
 
b. 
Drug toxicity 
The dose-limiting toxicity of melphalan is myelosuppression.  Other toxicities after IV melphalan 
include mucositis, nausea, vomiting and diarrhea.  Alopecia is generally seen only with high doses 
associated with bone marrow transplant settings.  Rarely reported reactions include pulmonary 
fibrosis, skin rash, vasculitis, and allergic reactions.  With high dose chemotherapy, gastrointestinal 
toxicity becomes dose limiting.  At such high doses, elevated transaminases, syndrome of 
inappropriate antidiuretic hormone secretion, depression, interstitial pneumonitis, and hepatic 
veno-occlusive 
disease 
have 
been 
reported. 
Acute 
nonlymphocytic 
leukemia 
and 
myeloproliferative syndromes may occur as secondary cancers from any alkylating agent such as 
melphalan.  Amenorrhea, permanent in many cases, has been noted with melphalan used in 
premenopausal women undergoing adjuvant therapy for breast cancer.  Azoospermia would be 
expected, but is not well documented in the literature. 
 
c. 
Drug Storage, Reconstitution and Stability: 

 
 
Melphalan is provided in sterile vials containing 50 mg lyophilized drug as the hydrochloride salt.  
It is formulated with 20 mg povidone per 50 mg vial.  Sterile diluent is supplied, which contains per 
10 ml: sodium citrite 0.20 g, propylene glycol 6 ml, ethanol (95%) 0.52 ml, sterile water q.s. 10 ml.  
Reconstitute each 50 ml vial by rapidly injecting 10ml diluent provided.  Immediately shake vial 
vigorously until a clear solution is obtained.  This provides a 5mg/ml solution.  Intact vials are stored 
at room temperature (15-30C) protected from light.  Once reconstituted with the diluent provided, 
the solution is chemically and physically stable at room temperature for 90 minutes.  Melphalan, 
when reconstituted with the diluent provided and subsequently diluted in NS to a concentration of 
0.1-0.45mg/ml is chemically and physically stable for 60 minutes at room temperature.  Do not 
refrigerate.  Reconstituted, undiluted melphalan has been administered via central line using doses 
of 70-200mg/m2 over 2 to 20 minutes. 
 
4.6 
Cytosine Arabinoside (Cytarabine, Ara-C, cytosar) 
 
a. 
Drug Formulation and Procurement 
Deoxycytidine analogue, which is metabolized to Ara-CTP, a substance that inhibits DNA 
polymerase.  It is S-phase-specific, and thus affects DNA synthesis.  It has an initial half-life of 
about 15 minutes, with a secondary phase of about 2 hours.   Rapidly catabolized by hepatic 
cytidine deaminases to Ara-U. Ara-C is commercially available. 
 
b. 
Drug Toxicity 
Acute DLT – severe leukopenia and thrombocytopenia.  Nausea and vomiting may be dose limiting 
at higher doses.  Other adverse reactions include immunosuppression, anorexia, stomatitis, mild 
oral ulceration, flu-like syndrome with fever and alopecia.  Diarrhea, fever, somnolence, 
conjunctivitis, ataxia, encephalopathy, or veno-occlusive disease can also develop.   Chronic 
administration may cause mild gonadal dysfunction. 
 
c. 
Drug Storage, Reconstitution and Stability 
A freeze-dried powder available in 100 mg and 500 mg vials with diluent, which contains 0.9% 
benzyl alcohol in water. The unreconstituted form of the drug is stable at room temperature for at 
least two years.  Reconstitute with 5 mil of diluent to 100-mg vial and 10 ml to the 500-mg vial.  Also 
available in 1g and 2g vials without diluent. Reconstitute with 10 ml and 20-ml sterile water or 
bacteriostatic water. The reconstituted solution is stable at room temperature for 48 hours.  
Commercially available from various manufacturers in 100 mg, 1 g and 2 g vials. 
 
5.0 
STAGING CRITERIA 
The Ann Arbor staging criteria will be used.  Stage is determined based on extent of disease at the 
time of diagnosis. 
 
Ann Arbor Classification (AJCC Manual for Staging of Cancer, 6th ed. 2002)  

 
 
STAGE I 
Involvement of a single lymph node region (I); or localized involvement of a single 
extralymphatic organ or site in the absence of any lymph node involvement (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 extralymphatic organ or site in association with regional 
lymph node involvement with or without involvement of other lymph node regions on the 
same side of the diaphragm (IIE).   
STAGE III 
Involvement of lymph node regions on both sides of the diaphragm (III), which also may be 
accompanied by extralymphatic extension in association with adjacent lymph node 
involvement (IIIE) or by involvement of the spleen (IIIS) or both (IIE,S). 
STAGE IV 
Diffuse or disseminated involvement of one or more extralymphatic organs, with or without 
associated lymph node involvement; or isolated extralymphatic organ involvement in the 
absence of adjacent regional lymph node involvement, but in conjunction with disease in 
distant site(s).  The location of Stage IV disease is identified further by specifying the site 
according to the notations listed below. 
A = Asymptomatic 
B = Fever, sweats, weight loss > 10% of body weight 
S=spleen; 
L=pulmonary 
(lung); 
M=bone 
marrow; 
H=hepatic; 
Pcard=pericardium; 
P=pleura; 
W=waldeyer’s (tonsil, naso-oropharynx); O=osseous (bone); GI=gastrointestinal; D=skin; Softis=soft 
tissue; Thy=thyroid 
 
5.1 
Definitions of Disease Sensitivity 
Patients are grouped into one of three groups based on sensitivity of disease: 
1. 
Induction failure: patients who did not achieve a CR or PR from induction chemotherapy; 
2. 
Resistant Relapse:  patients who did not achieve a CR or PR from the most recent standard 
salvage chemotherapy;  
3. 
Sensitive Relapse:  patients who did achieve a CR or PR from the most recent standard 
salvage chemotherapy. 
 
5.2 
Poor Risk Disease Criteria 
 
Patients are classified as having poor risk disease if they meet one or more of the following criteria 
1. 
Age-adjusted international prognostic index (IPI) High (3 risk factors) or High-Intermediate 
(2 risk factors) based on the following risk factors: stage III-IV, elevated serum lactate 
dehydrogenase level (LDH) and ECOG performance status 2-4. 
2. 
Patients with follicular lymphoma (grade 1-3) or diffuse large B-cell lymphoma who fail to 
achieve a complete remission after adequate induction chemotherapy regimen(s).  
3. 
Patients with mantle cell lymphoma histology will be considered poor risk.  This will include 
patients in first complete remission. 
4. 
Patients with transformed lymphoma including those in first remission will be considered 
poor risk. 
 
6.0 
INCLUSION CRITERIA  
6.1 
Age  18   
6.2 
All patients must have biopsy proven diagnosis of low- and intermediate-grade NHL working 
formulation B, C, D, E, F, and G; including mantle cell lymphoma. Patients with transformed 
lymphoma are also eligible.  
6.3 
Demonstrated monoclonal CD20 positive B-cell population in lymph nodes and/or bone marrow 
6.4 
Patients must have relapsed after achieving a complete or partial response to prior therapy, have 
never responded to prior therapy or have poor risk disease (see definition, section 5.2) 
6.5 
Patients with prior bone marrow involvement must have bone marrow aspiration and biopsy within 
60 days prior to stem cell collection which shows 10% lymphomatous involvement of total cellularity.  
Alternatively, patients with prior bone marrow involvement should have a normal bone marrow study 

 
 
which shows <10% lymphomatous involvement within 28 days before salvage chemotherapy. 
6.6 
Normal renal function test with serum creatinine of <ULN, and a creatinine clearance of >60 ml/min 
(measured or calculated) 
6.7 
Adequate pulmonary function as measured by FEV1 >60% of predicted measured, or a DLCO 
50% of predicted measured 
6.8 
Cardiac ejection fraction of > 50% by echocardiogram or MUGA scan.  The LVEF from the prestudy 
ECHO or MUGA may be used for eligibility purposes, even if the prestudy stress test indicates a 
lower LVEF. 
6.9 
Adequate liver function tests with a bilirubin of 1.5 x ULN and SGOT or SGPT 2 x ULN 
6.10     Negative human immunodeficiency virus antibody 
6.11 
ECOG performance status =0 or 1; KPS 80 
6.12 
No active CNS disease or prior history of CNS disease 
6.13 
Patients must have recovered from last therapy and should be at least four weeks from systemic 
chemotherapy on the day of administration of Y2B8.   
6.14 
After the last systemic therapeutic chemotherapy (Cytoxan, administered only for stem cell 
mobilization is not considered therapeutic) and prior to initiation of high dose treatment, the patient 
should have a baseline CT scan and PET scan done.  An FDG/CT scan is sufficient (however, if 
clinically indicated, an additional diagnostic CT may be ordered).  EXCEPTION: If scans were done 
and were negative for disease just prior to priming chemotherapy (therapeutic or nontherapeutic) 
and subsequent stem cell harvest, they do not need to be repeated prior to initiation of high dose 
treatment. 
 
 
7.0 
EXCLUSION CRITERIA 
 
7.1 
Presence of human anti-Zevalin antibody (HAZA).   
7.2 
Prior radioimmunotherapy 
7.3 
Failure to collect adequate number of CD34+ cells 3 x106 /kg 
7.4 
Abnormal cytogenetic study not related to the underlying lymphoma on the bone marrow aspirate 
sample prior to stem cell collection. If cytogenetics were not performed on the marrow aspirate prior 
to stem cell collection, cytogenetics on the peripheral blood may be performed. 
7.5 
Prior bone marrow transplantation 
7.6 
Prior malignancy except for: 
 
adequately treated basal cell or squamous cell skin cancer 
 
adequately treated noninvasive carcinoma 
 
other cancer from which the patient has been disease-free for at least five years. 
7.7 
Active evidence of Hepatitis B or C infection; Hepatitis B surface antigen positive  
7.8 
Patients who have had prior radiation to the lung will be excluded from the study, although 
mediastinal irradiation will be permitted if minimal lung is in the treatment volume. 
7.9 
Patients who have received >500cGy radiation to the kidneys will be excluded from the study. 
7.10 
Patients who are pregnant or lactating. 
 
8.0 
TREATMENT PLAN 
Prior to receiving the Yttrium-90 the patient will undergo a blood draw for Rituxan levels and a pre-
therapy imaging study with IDEC-In2B8 to confirm favorable localization of isotope, one week prior 
to the administration of the therapeutic dose. This will consist of an infusion of 5 mCi IDEC-In2B8 
following 250 mg/m2 Rituxan on day –21 followed by whole body gamma camera images obtained 
at approximately 1-24 hours post infusion, approximately 48-72 hours post infusion and an optional 
third scan at approximately 90-120 hours post infusion.  Exceptions to this time frame will be made 
if the optional scan falls on a weekend day or a holiday.  Rituxan 250 mg/m2 will be administered 
on day -21 if Rituxan levels are <10 ug/ml (refer to Table 1 below).  Blood samples will be obtained 
at approximately 0, 2 and 4-6 hours, as well as 1, 2, 3-4, 5 and 6 day(s)  post infusion of the 
antibody.  These samples will be used for analysis of antibody clearance and bone marrow dose 
estimation. Blood samples may be waived at the discretion of the PI.  Patients with unfavorable 
biodistribution, such as localization to the spleen or failure in renal clearance of the isotopes, will 
 

 
 
be excluded from the study due to the concerns of increase in toxicity. 
 
If the patient does not show unfavorable biodistribution, Rituxan levels will be drawn on day -15 or 
on day -16 (refer to Table 1 below).  A non-myeloablative dose of Yttrium- 90 will be administered 
on day -14.  If the Rituxan levels are <10 ug/ml then patients will receive Rituxan 250 mg/m2 prior 
to the Yttrium-90 (refer to Table 1 below).  Blood samples will be obtained at approximately 0, 2 
and 4-6 hours, as well as 1, 2, 3-4, 5 and 6 day(s) post infusion of the antibody. These samples will 
be used for analysis of antibody clearance and bone marrow dose estimation. Blood samples may 
be waived at the discretion of the PI.  High dose BEAM will be given between day –7 and day –1 
followed by re-infusion of autologous peripheral stem cells.   
 
Table 1.  Guide for administration of Day -21 and Day -14 Rituxan: 
 
Day -23 or -22) Rituxan 
level* 
Give 
Day 
-21 
Rituxan? 
Day -16 or -15 Rituxan level* Give Day -14 Rituxan? 
>10 ug/ml 
No 
>10 ug/ml 
No 
<10 ug/ml 
Yes 
<10 ug/ml 
Yes 
*Note:  On Monday holidays, the Rituxan level will be drawn the Friday before.  If the level is ≥15 g/ml, another 
sample on Monday does not need to be drawn (because the level will not have decreased to less than 10 ug/ml by 
Monday).  Additionally, if the value is <10 g/ml, another sample on Monday again does not need to be drawn 
(because the patient will be receiving Rituxan according to the table above).  However, if the value is ≥10 g/ml but 
<15 g/ml, then a Rituxan level draw will be repeated on Monday.   
 
 
8.1  
Outline of the preparative regimen 
Day -23 or -22  
Blood draw for Rituxan levels* See note below Table 1 above 
Day-21 
 
 
Pre-therapy imaging with 5 mCi IDEC-In2B8 following 250 
mg/m2 Rituxan or no Rituxan (depending on day -23 or -22 Rituxan levels; 
refer to table guide above) 
Day -16 or -15  
Blood draw for Rituxan levels* See note below Table 1 above 
Day-14 
 
 
IDEC-Y2B8 0.4 mCi/Kg following 250 mg/m2 Rituxan or no 
Rituxan (depending on day -16 or -15 Rituxan levels; refer to table guide 
above).  Note: Max dose is 40 mCi. 
Day-7 
 
 
BCNU 150mg/m2 
Day-6 
 
 
BCNU 150mg/m2 
Day-5 to -2 
 
Etoposide 100mg/m2 BID for 4 days 
Ara-C 100mg/m2 BID for 4 days 
Day-1 
 
 
Possible Rituxan 250 mg/m2 (refer to guide table below). 
Then Melphalan 140mg/m2 
Day 0 
 
Peripheral Stem Cell Reinfusion 
Day+5 
 
 
Start G-CSF 5mcg/kg 
Day +8 
 
 
Rituxan 250 mg/m2 (this will be administered regardless of 
previous Rituxan doses) 
 
Table 2.  Guide for administration of Day -1 and Day +8 Rituxan: 
 

 
 
Received Rituxan Day -
21? 
Received Rituxan Day -
14? 
Give Rituxan Day -
1? 
Give 
Rituxan 
Day 
+8? 
No 
No 
Yes 
Yes 
Yes 
Yes 
No 
Yes 
Yes 
No 
No 
Yes 
No 
Yes 
No 
Yes 
 
8.2 
Pre-Transplant Therapy 
a. 
Autologous Stem Cell Collection and Cryopreservation 
Patients will have a permanent indwelling central venous catheter inserted and peripheral blood 
stem cells (PBSCs) will be collected via leukapheresis as conducted according to current standard 
operating procedures. (The HCT Manual SOP for Stem Cell Mobilization can be found at   
http://www.coh.org/hct%5Fsop/docs/B.003.02_Mobilization_of_Peripheral_Blood.pdf accessibility 
verified on 04.February.2008).  PBSCs will be collected after mobilization by: 1) growth factors i.e. 
G-CSF 10 µg/kg/d or 2) chemotherapy with growth factors.  A minimum of 3.0 x 106/kg CD34+ 
should be collected.  
 
 
Radioimmunotherapy 
8.31 
On day -23 or -22, blood will be drawn for Rituxan levels (refer to Table 1 above).  Patients with 
Rituxan levels <10ug/ml will receive Rituxan 250 mg/m2 prior to the IDEC-In2B8 infusion.   
On day –21, 5mCi IDEC-In2B8 will be given following 250 mg/m2 Rituxan or no Rituxan (depending 
on day -23 or -22 Rituxan level as noted above.) 
a. 
Prior to receiving the Yttrium-90 the patient will undergo a pre-therapy imaging study with 
IDEC-In2B8 to confirm favorable localization of isotope, one week prior to the administration 
of the therapeutic dose. The objective of the imaging study is to confirm the expected 
biodistribution as an additional safety measure. Patients with unfavorable distribution 
(altered biodistribution) will be excluded from the study due to the concerns of increase in 
toxicity. Altered biodistribution on imaging is rare, which includes 1) Diffuse uptake in normal 
lung, more intense than the cardiac blood pool on the first day image or more intense than 
the liver on the second or third day image; 2) Kidneys with greater intensity than the liver 
on the posterior view of the second or third day image; 3) Intense areas of uptake throughout 
the normal bowel comparable to uptake by the liver on the second or third day images. 
b. 
Rituxan, 250 mg/m2, is to be administered by slow intravenous infusion having been diluted 
to 1-4 mg/ml in saline.  Initial infusion should be through a dedicated line at a rate of 50 
mg/hr, or 100 mg/hr if the patient has had prior Rituxan.  If hypersensitivity or infusion-
related events do not occur, escalate the infusion rate in 50 mg/hr increments (or 100 mg/hr 
increments if the patient has had prior Rituxan) every 30 minutes to a maximum rate of 400 
mg/hr.  If hypersensitivity or infusion-related events develop, the infusion should be 
temporarily slowed or interrupted.  The infusion can be continued at one-half the previous 
rate when symptoms abate. The calculated dose will be based on actual body weight. 
c. 
IDEC-In2B8 Administration - 2 mg of IDEC-In2B8 (5.0 mCi of 111In) will be administered for 
the pre-therapy imaging portion of the protocol.  The imaging dose will be administered over 
10 minutes by slow IV injection immediately following the infusion of Rituxan (if Rituxan is 
given). A 0.22 micron filter must be on the line between the patient and the infusion port.  
Flush the line with at least 10 mls of normal saline after the IDEC-In2B8 has been infused. 
d. 
As stated in 8.31.a, if the patient has unfavorable (altered) bio-distribution as documented 
by pre-therapy imaging study, he/she will be taken off-study.  
 

 
 
8.32 
On day -16 or -15, blood will be drawn for Rituxan levels (refer to Table 1 above).  Patients with 
Rituxan levels <10ug/ml will receive Rituxan 250 mg/m2 prior to the IDEC-Y2B8 infusion.   
On day –14, Yttrium-90 0.4mCi/Kg will be given  following 250 mg/m2 Rituxan or no Rituxan 
(depending on day -16 or -15 Rituxan level as noted above.) 
 
a. 
Rituxan, 250 mg/m2, is to be administered by slow intravenous infusion having been diluted 
to 1-4 mg/ml in saline.  Initial infusion should be through a dedicated line at a rate of 100 
mg/hr.  If hypersensitivity or infusion-related events do not occur, escalate the infusion rate 
in 100 mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr.  If 
hypersensitivity or infusion-related events develop, the infusion should be temporarily 
slowed or interrupted.  The infusion can be continued at one-half the previous rate when 
symptoms abate. The calculated dose will be based on actual body weight. 
 
b. 
IDEC-Y2B8 Administration – IDEC-Y2B8 0.4 mCi/kg will be administered for the therapy 
portion of the protocol.  A 0.22 micron filter must be on the line between the patient and the 
infusion port.  Flush the line with at least 10 mls of normal saline after the IDEC-Y2B8 has 
been infused. The calculated dose will be based on actual body weight.  Max dose: 40 mCi. 
 
8.4 
Chemotherapy 
a. 
BCNU will be administered intravenously at dose of 150 mg/m² on day-7 and 150 mg/m2 on 
day-6, based on adjusted ideal body weight.  BCNU will be diluted with normal saline or 5% 
dextrose/water and administered over 4 hours.  Patients will be premedicated with a 
sedative and antiemetics at the discretion of the primary M.D.  All patients will receive 
loading dose of 1 gm of Dilantin on day-8 and continue 400 mg/day for 3 days beyond the 
last BCNU dose as seizure prophylaxis. 
b. 
VP-16 is to be administered twice daily on days -5,-4,-3 and -2 (total of 8 doses).  Each 
dose of VP-16 is 100mg/m2 and is calculated on adjusted ideal body weight.  VP-16 100 
mg/m2 can be diluted to 0.4 mg/ml and infused over 1 hour.  The volume of undiluted dose 
is ~ 10 ml Premeds will be given as per City of Hope SOP.  If necessary, diuretics may be 
given.  The intravenous hydration should be continued before, during, and after the VP-16.   
 
c. 
Ara-C is to be administered twice daily on days –5,-4,-3 and –2 (total of 8 doses).  Each 
dose of Ara-C is 100mg/m2 and is calculated based on adjusted ideal body weight.  Infuse 
each dose over 2 hours.  Ara-C will be mixed in D5W or NA.  The volume of undiluted dose 
is ~ 2 ml.  Appropriate antiemetics and sedatives should be given before the infusion begins. 
d. 
Melphalan 140 mg/m² is to be administered on day –1. The dose is calculated according to 
adjusted ideal body weight.  IV hydration will be continued with normal saline at a rate of 
200cc/hour and KCL 15 meq/L for a total of at least 24 hours.  Administer per COH standard 
practice. 
 
Prior to Melphalan administration on day -1, so that all patients will receive the same amount 
of Rituxan, Rituxan 250 mg/m2 will be given for certain patients only:  If the patient received 
Rituxan on both day -21 and day -14, or if the patient received Rituxan on one of those two 
days, Rituxan on day -1 will not be given.(refer to the guide table in Sec 8.1)  
e. 
Rituxan 250 mg/m2 will be given to all patients on day +8, regardless of prior Rituxan levels 
and whether or not they received Rituxan on day -21 and/or day -14. (refer to the guide 
table in Sec 8.1). 
 
8.5 
Peripheral Stem Cell Reinfusion 
 
PBSCs will be thawed and infused according to standard guideline at approximately 24 hours after 
completion of melphalan. 
 
8.6 
Growth Factor Therapy 
 

 
 
All patients will receive rh-G-CSF, 5 mcg/kg/day IV beginning on day +5, after PBSC infusion and 
continue daily until discontinued as per treating MD discretion.  
 
8.7 
Supportive Care 
All patients will be housed in private rooms during the period of granulocytopenia.  
a. 
Hyperalimentation 
All patients will receive appropriate hyperalimentation as soon as necessary after admission. This 
will be determined by the treating physician. 
b. 
Platelet Transfusion 
1. 
Indication.  Platelets are transfused to prevent bleeding and an attempt is made to 
keep the circulating level greater than 20,000/mm3 at all times.  This goal may be 
changed by the attending physician as clinically indicated. 
2. 
Irradiation.  All blood products (except the autologous stem cells) are irradiated with 
1,500 cGy prior to infusion. 
c. 
Prophylaxis of Infections: Trimethoprim-sulfamethoxazole or an alternate PCP prophylaxis 
will be administered from day -8 to day -2.  Prophylaxis should be re-instituted when graft 
function is stable as determined by the treating physician.  Prophylaxis should be continued 
for at least 6 months post transplant. Antifungal therapy should be initiated on day 0 or  +1 
and continued daily until granulocytopenia resolves. The choice of antifungal will be at the 
discretion of the treating physician. 
d. 
Treatment of Infections 
Treatment of patients on this protocol is not intended to restrict the freedom of the managing 
physician to treat suspected or documented infections.  In neutropenic patients, however, the 
following guidelines should be followed. 
1. 
All febrile, neutropenic patients should be treated with IV antibiotic(s), the choice of 
which should be guided by the patient’s clinical history, institutional practices and 
subsequent culture results. 
2. 
Patients with documented, invasive fungal infection or with persistent, unexplained 
fevers while neutropenic and on broad-spectrum antibiotic therapy should receive 
appropriate antifungal therapy. 
 
8.8 
Criteria for Removal from Protocol Treatment 
8.81     Patients may withdraw from study at any time for any reason. 
 
8.82 
All reasons for discontinuation of treatment must be documented in the flow sheets. 
8.83 
All patients will be followed for survival until death.  For patients who relapse/progress, the date of 
relapse/progression will be recorded, but these patients will no longer follow the study calendar for 
required restaging.  
 

 
 
9.0 
STUDY CALENDAR - PREPARATIVE REGIMEN AND PBSCT 
Pre-study through Day 0 
REQUIRED 
STUDIES 
Pre-
Study 
Day -23 
or -22 
Day 
–21 
Day -16 
or -15 
Day 
–14 
Day 
–7 
Day 
–6 
Day 
–5 
Day 
–4 
Day 
–3 
Day 
–2 
Day 
–1 
Day 
0 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
H&PE 
 X@ 
 
 
 
 
 
 
 
 
 
 
 
X 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC/Platelets 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
HAZA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
LDH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
LFTs 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
PT (or PT INR) 
/PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoglobulin 
levels 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CMV Titer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis Profile 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Herpes Simplex 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BMbx% 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine 
Clearance 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Rituxan Level 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Costim Assays 
 
X2 
 
 
 
X2 
 
 
 
 
 
 
 
X-RAYS & 
SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT Scans* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MUGA or 
ECHO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
DLCO/FEV1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FDG-PET Scan 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stem cell 
Collections 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Rituxan 
 
 
X1 
 
X1 
 
 
 
 
 
 
X1 
 
IDEC-In2B8 
 
 
X 
 
 
 
 
 
 
 
 
 
 
IDEC-Y2B8 
 
 
 
 
X 
 
 
 
 
 
 
 
 
BCNU 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
VP-16 & Ara-C 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
Melphalan 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PBSCT 
 
 
 
 
 
 
 
 
 
 
 
 
X 
G-CSF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
@ Include KPS pre-study. 
* CT scans of C/A/P (and neck, if clinically indicated).  Note: FDG/CT is sufficient; an additional diagnostic CT may be ordered if clinically indicated. 
% Bone marrow aspiration and biopsy, cytogenetic study and immunophenotyping  
1.  If indicated, depending on pre-Imaging dose and pre-Therapy dose Rituxan levels; refer to protocol for details 
2.  Draw two 6ml and two 4ml heparinized tubes (green tops) for an amount of whole blood of about  20ml and send to Virology Lab, Familian 
Science Bldg, Rm C209D (x63392). DUE TO FUNDING, PATIENTS ENROLLED AFTER 6/20/12 WILL NOT HAVE THIS PROCEDURE PERFORMED. 

 
 
Day 1 through day 100 
 
 
 Repeat FDG PET will be done at Day 30 if previously positive; however, if positivity is not due to lymphoma, it does not need to be repeated. 
* CT scans of C/A/P (and neck, if clinically indicated).  Note: FDG/CT is sufficient; an additional diagnostic CT may be ordered if clinically indicated. 
# Continue G-CSF daily until discontinued as per treating MD discretion.  
1.  Day 30 CT not required if pt in CR at time of transplant. 
$  Day 100 CT scans are only required if a scan was not done at day 30. 
2.  Draw two 6ml and two 4ml heparinized tubes (green tops) for an amount of whole blood of about  20ml and send to Virology Lab, Familian 
Science Bldg, Rm C209D (x63392). Costim assay on Day 21 may be drawn within +/- 7 days and the one on Day 90 may be drawn within +/- 14 
days. DUE TO FUNDING, PATIENTS ENROLLED AFTER 6/20/12 WILL NOT HAVE THIS PROCEDURE PERFORMED. 
 
 
 
 
 
 
Day 101 through year 5 
 
REQUIRED 
STUDIES 
Day 180 
YR 1 
 
YR 2 
YR 3 
YR 4 
YR 5 
PHYSICAL 
 
 
 
 
 
 
 
H&PE 
X 
X 
 
 X$ 
X 
X 
X 
LABORATORY 
 
 
 
 
 
 
 
CBC/Platelets 
X 
X 
 
X 
 
 
 
HAZA 
X 
X 
 
 
 
 
 
LDH 
X 
X 
 
X 
 
 
 
LFTs 
X 
X 
 
X 
 
 
 
Immunoglobulin 
levels 
X 
X 
 
 
 
 
 
BM% 
 
X 
 
X 
X 
X 
X 
X-RAYS & SCANS 
 
 
 
 
 
 
 
CT Scans* 
X 
X 
 
X 
 
 
X 
EKG 
 
X 
 
 
 
 
 
MUGA or ECHO 
 
X 
 
 
 
 
 
DLCO/FEV1 
 
X 
 
 
 
 
 
FDG-PET Scan 
 
X 
 
 
 
 
 
 
$ All late complications such as cataract formation and occurrence of second malignancies must be documented and reported 
* CT scans of C/A/P (and neck, if clinically indicated). Note: FDG/CT is sufficient; an additional diagnostic CT may be ordered if clinically indicated. 
% Bone marrow aspiration and biopsy, cytogenetic study and immunophenotyping.  Note: for patients with no history of bone marrow involvement 
by lymphoma, the bone marrow asp/bx is optional.  
For required followup tests, acceptable windows are: +/-14 dys for Days 30 & 60, +/- 30 dys for Days 100 & 180, and+/- 60 days for Yr 1 and 
beyond. 
 
 
 
REQUIRED STUDIES 
Day 5 
Day 7 
 
Day 8 
Day 21 
Day 30 
Day 60 
Day 90 
Day 100 
PHYSICAL 
 
 
 
 
 
 
 
 
H&PE 
 
 
 
 
X 
X 
 
X 
LABORATORY 
 
 
 
 
 
 
 
 
CBC/Platelets 
 
X 
 
 
X 
X 
 
X 
HAZA 
 
 
 
 
 
X 
 
X 
LDH 
 
 
 
 
X 
X 
 
X 
LFTs 
 
 
 
 
X 
X 
 
X 
Immunoglobulin levels 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Costim Assays 
 
 
 
X2 
X2 
X2 
X2 
 
X-RAYS & SCANS 
 
 
 
 
 
 
 
 
CT Scans* 
 
 
 
 
X1 
 
 
X$ 
EKG 
 
 
 
 
 
 
 
 
MUGA or ECHO 
 
 
 
 
 
 
 
 
DLCO/FEV1 
 
 
 
 
 
 
 
 
FDG-PET Scan 
 
 
 
 
X 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
Rituxan 
 
 
X 
 
 
 
 
 
G-CSF 
X# 
 
 
 
 
 
 
 

 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
 
Definitions 
 
a. 
Measurable Disease: Bidimensionally measurable lesions with clearly defined margins by: 
1) medical photograph (skin or oral lesion), or plain x-ray with at least one diameter 0.5 cm 
or greater (bone lesions are not included) or, 2) CT, MRI or other imaging scan with both 
diameters greater than the distance between cuts of the imaging study, or 3) palpation with 
both diameters 2 cm or greater. 
b. 
Evaluable Disease: Unidimensionally measurable lesions, masses with margins not clearly 
defined, lesions with both diameters less than 0.5 cm, lesions on scan with either diameter 
smaller than the distance between cuts, palpable lesions with either diameter less than 2 
cm, bone disease. 
c. 
Non-Evaluable Diseases: Pleural effusions, ascites, disease documented by indirect 
evidence only (e.g., by lab values). 
d. 
Objective Response, To Be Recorded at Each Evaluation: If an organ has too many 
measurable lesions to measure at each evaluation, choose three to be followed before the 
patient is entered on study.  The remaining measurable lesions in that organ will be 
considered evaluable for the purpose of objective status determination. Unless progression 
is observed, objective status can only be determined when ALL is measurable and 
evaluable sites and lesions are assessed. 
 
10.1 
 
 
Revised Response Criteria for Malignant Lymphoma 
Response Definitions for Clinical Trials (Cheson et al) 
 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance 
of all evidence 
of disease 
a) FDG-avid or PET positive prior 
to therapy; mass of any size 
permitted if PET negative 
b) Variably FDG-avid or PET 
negative; regression to normal 
size on CT. 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared on repeat 
biopsy; if indeterminate by 
morphology, 
immunohistochemistry should 
be negative 
PR 
Regression of 
measurable 
disease and no 
new sites 
50% decrease in SPD of up to 6 
largest dominant masses; no 
increase in size of other nodes 
a)FDG-avid or PET positive prior 
to therapy; one or more PET 
positive at previously involved 
site 
b) variably FDG-avid or PET 
negative; regression on CT 
50% decrease in 
SPD of nodules 
(for single nodule 
in greatest 
transverse 
diameter); no 
increase in size of 
liver or spleen 
Irrelevant if positive prior to 
therapy; cell type should be 
specified 
SD 
Failure to attain 
CR/PR or PD 
a) FDG-avid or PET positive prior 
to therapy; PET positive at prior 
sites of disease and no new sites 
on CT and PET 
b) Variably FDG-avid or PET 
negative; no change in size of 
previous lesions on CT 
 
 
Relapsed 
Disease or 
PD 
Any new lesion 
or increase by 
50% of 
previously 
involved sites 
from nadir 
Appearance of a new lesion(s) 
>1.5 cm in any axis, 50% 
increase in SPD of more than 
one node, or 50% increase 
in longest diameter of a 
previously identified node 
>1cm in short axis. 
Lesions PET positive if FDG-avid 
lymphoma or PET positive 
prior to therapy. 
 
>50% increase 
from nadir in the 
SPD of any 
previous lesions 
New or recurrent involvement 
From  “Revised Response Criteria for Malignant Lymphoma”, B.D. Cheson, et. al. J Clin Oncol 25:579-586, 2007 
 

 
 
 
10.2 
Duration of Response 
Defined as time from beginning of response (CR or PR) to disease relapse, disease progression, 
or last disease evaluation if patient in continued CR, PR. 
 
10.3 
Time to Relapse/Progression 
Defined as time from RIT based ASCT to date of first observation of progressive disease or 
relapsed disease.  
 
10.4 
Survival and Engraftment Endpoints 
a. Overall survival. Defined as the time from transplant to death due to any cause. If a patient 
is alive, survival time is censored at the time of last follow-up.  
b. Relapse-free survival. Defined as the time from transplant to the first observation of 
relapsed disease or death due to any cause, whichever occurs first. If the patient  has not 
relapsed or died, relapse-free survival is censored at the time of last follow-up. 
c. Progression-free survival. Defined as the time from transplant to first observation of 
progressive disease or death due to any cause, whichever occurs first. If the patient has 
not progressed or died, event-free survival is censored at the time of last follow-up. 
d. Engraftment. Engraftment will be monitored by measuring the duration and extent of 
myelosuppression as shown in days until ANC recovery (500,1000 x103L) and 
unmaintained platelet recovery (20K,100KL). The primary engraftment endpoint is defined 
as the first of three consecutive days on which the ANC is 500 x103/L. Patients who are 
deceased prior to day 28 post-ASCT will be considered inevaluable for engraftment. 
  
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Study Design, Sample Size Justification 
 
This is a phase II study to evaluate progression-free survival (PFS) among four poor risk non-Hodgkin 
lymphoma histologies: follicular lymphoma  (grade 1-3), mantle cell lymphoma, diffuse large B-cell 
lymphoma and transformed lymphoma. All patients enrolled in this study will be treated with 90Y-labeled 
anti-CD20 MAb (Yttrium- 90) in combination with high-dose BEAM (BCNU, cytarabine, etoposide and 
melphalan) followed by Autologous Stem Cell Transplant (ASCT).  
 
When treated with BEAM chemotherapy alone, previously reported studies show two-year PFS estimates 
for each poor-risk subgroup as follows: 
 
Non-Hodgkin lymphoma  
Poor Risk Subgroups 
2-Year PFS Probabilities1, 
Chemotherapy (BEAM) alone 
Follicular (grade 1-3) 
45% 
Mantle cell  
35% 
Diffuse large B-Cell 
45% 
Transformed  
35% 
1: Approximate values 
 
Using PFS estimates from previously reported BEAM (chemotherapy alone) studies and City of Hope Z-
BEAM/ASCT pilot studies, a total of 36 (evaluable) patients are required per stratum; however, the Diffuse 
Large B-Cell stratum will instead contain an additional 10, for a total of 46 (evaluable) patients in that 
stratum. Target accrual is thus 118 patients as the follicular and transformed lymphoma will be grouped 
together. An increase in two-year progression-free survival from historical estimates of 35% and 45% to 
55% and 65% would be detectable with 80% power, if continuous follow-up were possible on all 36 
patients. We anticipate it could take approximately 81 months to complete accrual on this study. 
 
 
 
11.2 
Phase II Monitoring 

 
 
 
Early stopping rules are incorporated to monitor toxicity, however there will be no interim analysis for 
efficacy. Toxicities will be recorded using two distinct grading systems; the modified Bearman Scale 
(Bearman, S., et al, JCO, Vol 6, No 10 (Oct), 1988, pp1562-1568. See appendix II for details) and the NCI 
CTCAE 3.0 Scale. 
 
Generally, the modified Bearman Scale will be used to define (grade) ‘early stopping’ events (toxicities), 
and the NCI CTCAE 3.0 Scale will be used for reporting adverse events. The only exception relates to how 
hematologic toxicities are graded and incorporated into the early stopping criteria. For hematologic 
toxicities, the CTCAE 3.0 Scale will be used. (The NCI CTCAE 3.0 can be found at 
http://ctep.cancer.gov/reporting/ctc.html accessibility verified on 26.March.2007) The table below will be 
consulted as relevant toxicities are encountered, so there will be no accrual-based interim analysis point. 
 
Early Stopping Criteria: For each adverse outcome, stop if the cumulative number of patients reaches or 
exceeds the following limits: 
 
 
Table of Early Stopping Criteria 
 
 
# of patients treated 
 
 
# of patients expired 
due to treatment 
related causes that 
would stop the study*  
 
# of patients with 
grade 3 toxicities that 
would require an 
evaluation for safety 
per Bearman Scale** 
Probability that the early 
stopping rule will be invoked 
given a failure rate of: 
10% 
15% 
20% 
6 
2 
2 
0.12 
0.22 
0.35 
12 
3 
3 
0.16 
0.34 
0.51 
18 
5 
5 
0.17 
0.35 
0.53 
24 
6 
6 
0.17 
0.36 
0.57 
30 
8 
8 
0.17 
0.37 
0.58 
36 
9 
9 
0.18 
0.38 
0.60 
* Note:  The stopping rules are not statistically based; expected treatment related mortality should not exceed 25%. 
** Note: For hematologic toxicities: Any grade 4 neutropenia associated with fever or infection and lasting beyond three weeks, or grade 
4 neutropenia lasting for more than 28 days per CTCAE 3.0 toxicity criteria should be counted toward the early stopping rule. 
 
Any patient who receives treatment will be evaluable for toxicity. Each patient will be assessed periodically 
according to the treatment schedule for the development of any toxicity. The toxicity rule for safety will be 
assessed as each patient reaches day +30 post transplantation and day +100 post transplantation. If more 
than the specified number of patients (noted in the table above) have significant treatment related toxicities, 
then the safety of the study will be evaluated.  
 
11.3 
Analysis of Clinical Endpoints 
 
Toxicities observed will be summarized in terms of type (organ affected or laboratory determination), 
severity (by NCI CTC and nadir or maximum values for the laboratory measure) and time of onset. For 
grade 4 neutropenia, duration will be recorded.  In accordance with the primary study objectives, we will 
perform descriptive statistical analyses on these data after the study is complete.  Costimulatory profile 
data will be used for subjects for whom these data are available.  Response rates and duration of response 
will be estimated. Confidence intervals for the response rate will be established by calculating the exact 
95% confidence limits for a binomial parameter. Additional analyses will be conducted to evaluate the post 
transplant toxicity/complication profile, and incidence of therapy induced myelodysplasia (MDS)/acute 
myeloid leukemia (AML).  
 
Descriptive statistics will be used to characterize the expression of six costimulatory molecules (PD-1, 
CTLA-4, CD28, ICOS, OX40 and 4-1BB) pre- post- RIT based ASCT. Exploratory analyses will also be 
performed to assess the impact of these molecules on the NK and T cells of lymphoma patients pre- post- 
RIT based ASCT.  NOTE THAT, DUE TO FUNDING, PATIENTS ENROLLED AFTER 6/20/12 WILL NOT 
BE INCLUDED IN THE COSTIMULATORY MOLECULE ANALYSIS.   
 

 
 
The product-limit method of Kaplan and Meier will be utilized to estimate time-to-event endpoints such as 
progression-free survival, overall survival, and time to relapse. We also may consider alternative survival 
distributions such as the accelerated failure models for poor-risk subgroups. We will consider univariate 
Cox models for the analysis of potential prognostic factors of time-to-event endpoints, including such 
factors as histologic grade, age at transplant, and disease stage as independent variables, first performing 
diagnostics to confirm the validity of the proportional hazards assumption. Descriptive comparisons with 
recent historical data from similar patient populations will be made to evaluate differences in progression-
free survival, overall survival, relapse/progression rate, and toxicities. 
 
 
12.0 
REGISTRATION GUIDELINES 
 
Once signed, informed consent has been obtained and all evaluations have been performed, patients will 
be entered on study after review of patient eligibility criteria by the assigned Clinical Research Associate 
(CRA) from the City of Hope Clinical Trials Office (CTO). Patients may be screened for registration by 
calling (626) 256-HOPE (4673) ext. 62468. 
 
Eligible patients will be identified by the nurse coordinator/CRA who will register the patient with the City 
of Hope Clinical Trials Office (CTO) between 9:00 A.M. and 5:00 P.M. pacific standard time, Monday 
through Friday. 
 
 
 
13.0 
RECORDS TO BE KEPT AND DATA SUBMISSION SCHEDULE 
 
13.1 
Confidentiality of Records 
 
The original data collection forms will be stored in secure cabinets in the CTO. All radioimmunotherapy 
associated data will be kept in the Department of Radioimmunotherapy.  
 
13.2 
Patient Consent Form 
 
At the time of registration, signed and dated copies of the patient Informed Consent form with the 
Experimental Subject’s Bill of Rights must be available (for patient, chart, and CTO.) 
 
 
14.0 
DATA MANAGEMENT 
 
The Department of Biomedical Informatics maintains a clinical research database at the City of Hope 
National Medical Center, which allows for the storage and retrieval of patient data collected from a wide 
variety of sources. The investigator will ensure that data collected conform to all established guidelines for 
coding, collection, key-entry, and verification. All patients are assigned a de-identified research participant 
number to assure patient confidentiality. Any publications or presentations will refer to patient by research 
participant number, not name. The licensed medical records department, affiliated with the institution 
where the patient receives medical care, maintains all original inpatient and outpatient chart documents.  
Patient research files are kept in a locked room and are maintained by the CTO.  Access is restricted to 
personnel authorized by the CTO.   
 
 
15.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
This study is to be approved by the Institutional Review Board according to City of Hope ethical and 
regulatory guidelines.  All patients will have signed an informed consent for participation in research 
activities, and will have been given a copy of the Experimental Subject's Bill of Rights. 
 
When results of this study are reported in medical journals or at meetings, identification of those taking 
part will be withheld.  Medical records of patients will be maintained in strictest confidence, according to 

 
 
current legal requirements.  However, they will be made available for review, as required by the Food and 
Drug Administration (FDA) or other authorized users such as the National Cancer Institute (NCI), under 
the guidelines established by the Federal Privacy Act.  
 
 
16.0  DATA SAFETY MONITORING PLAN: RISK LEVEL 3 
 
16.1        Definition of Risk Level 
 
This is a Risk Level 3 study, as defined in the “Guidance, Policy and 
Procedures for Data and Safety Monitoring for In-House Trials at City of 
Hope”, http://www.coh.org/dsmc/Pages/forms-and-procedures.aspx because 
it is a Phase II clinical trial where the risks are at least balanced by the 
potential benefit to subjects and the importance of the knowledge that may 
result. 
 
16.2 
Monitoring and Personnel Responsible for Monitoring 
 
The Protocol Management Team (PMT) consisting of the PI, Collaborating 
Investigator, CRA, protocol nurse, and statistician is responsible for monitoring the 
data and safety of this study, including implementation of any stopping rules for 
safety and efficacy.  
 
Data and safety will be reported to the COH DSMC annually.  In addition to the 
annual report, any early evaluations for safety and/or treatment related mortality will 
also be reported as these assessments are made (per guidelines set in sections 11.2 
and 11.3 of the protocol).  This report (the PMT report) will include a summary of 
accrual, adverse events and treatment related mortality.   
 
16.3 
Definitions 
 
Adverse event (AE) - An adverse event is any untoward medical experience or change of an 
existing condition that occurs during or after treatment, whether or not it is considered to be 
related to the protocol intervention.  
 
Attribution - For reporting purposes, attribution is the assessment of the likelihood that an AE 
is caused by the research agent or protocol intervention.  The attribution is assigned by the 
Principal Investigator after considering the clinical information, the medical history of the 
subject, and past experience with the research agent/intervention.  The attribution is subject to 
change as follow-up information becomes available, and it can be changed by the DSMC or by 
the IRB during the process of review. 
 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected event 
OR is an expected natural progression of any underlying disease, disorder, condition, or 
predisposed risk factor of the research participant experiencing the adverse event 
 
Serious Adverse Event (SAE) [21 CFR 312.32] is defined as any expected or unexpected 
adverse event that results in any of the following outcomes: 
 Death 
 Is life-threatening event (places the subject at immediate risk of death from the event as it 
occurred); 
 Requires in-patient hospitalization (not required as part of the treatment) or prolongation 
of existing hospitalization; 

 
 
 A persistent or significant disability/incapacity; 
 A congenital anomaly/birth defect 
 Secondary Malignancy, or 
 Any other adverse event that, based upon appropriate medical judgment, may jeopardize 
the subject’s health and may require medical or surgical intervention to prevent one of 
the outcomes listed above (examples of such events include allergic bronchospasm 
requiring intensive treatment in the emergency room or at home, blood dyscrasisas of 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse). 
 
Unanticipated problem (UP) – Any incident, experience or outcome that meets all three of the 
following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the research 
procedures described in the protocol-related documents such as the IRB approved research 
protocol, informed consent document or Investigator Brochure (IB); and b) the 
characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcomes may have been caused by 
the drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or recognized. 
 
Unexpected Adverse Event [21 CFR 312.32 (a) – An adverse event is unexpected if it is not 
listed in the investigator’s brochure and/or package insert; is not listed at the specificity or 
severity that has been observed; is not consistent with the risk information described in the 
protocol and/or consent; is not an expected natural progression of any underlying disease, 
disorder, condition, or predisposed risk factor of the research participant experiencing the 
adverse event. 
 
16.4 
Reporting of Unanticipated Problems and Adverse Events 
 
Unanticipated Problems: Unanticipated problems must be reported to the COH DSMC and 
IRB within 5 calendar days according to definitions and guidelines at 
http://www.coh.org/hrpp/Pages/hrpp-policies.aspx.  Any unanticipated problem that occurs 
during the study conduct will be reported to the DSMC and IRB by submitting electronically in 
iRIS (http://iris.coh.org). 
 
Serious Adverse Events - All SAEs occurring during this study, whether observed by the 
physician, nurse, or reported by the patient, will be reported according to definitions and 
guidelines at http://www.coh.org/hrpp/Pages/hrpp-policies.aspx and Table 1 below.  Those 
SAEs that require expedited reporting will be submitted electronically in iRIS 
(http://iris.coh.org/). 
 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that do not 
meet the criteria of serious adverse event or are not unanticipated problems will be reported only 
at the time of protocol continuation reports (see Table 1 below). 
 
All toxicities, according to the CTCAE version 3.0 and the Modified Bearman Toxicity Scale, 
will be collected from day -21 to day 100.  After day 100, all grade 3 and above toxicities 
according to the CTCAE version 3.0 (the Bearman Scale will not be used beyond day 100) will 
be collected, unless the toxicity is due to salvage therapy given after a relapse or progression 
post transplant.  Grade 4 hematologic toxicities will not be considered reportable events with the 

 
 
exception of grade 4 neutropenia associated with fever or infection and lasting beyond 3 weeks, 
and grade 4 neutropenia lasting for more than 28 days.  All SAEs will be reported until the 
patient expires or withdraws from the study, except in cases when the SAE is clearly due to 
salvage therapy given after a relapse or progression post transplant. 
 
 
Table 1:  City of Hope Adverse Event Reporting Timelines for the IRB and DSMC 
 
Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a UP 
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a 
UP   
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Required Reporting Timeframe to DSMC  
Attribution 
UNEXPECTED 
EXPECTED 
 
Death while on active treatment or within 30 days of 
last day of treatment 
Possibly, Probably, 
Definitely 
5 calendar days 
Unlikely, Unrelated 
 
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
5 calendar  days 
No reporting required* 
Unlikely, Unrelated 
No reporting required* 
No reporting required* 
 
Grades 3 and 4 AND meeting the definition of 
“serious” 
Possibly, Probably, 
Definitely 
5 calendar days 
5 calendar days 
Unlikely, Unrelated 
5 calendar days 
5 calendar days 
 
Grade 1 and 2 AND resulting in “hospitalization” 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 
*Such events are not required to be reported to the DSMC.  These events should be included with 
the SAE/AE summary provided in the IRB Annual Continuation reports. 

 
 
 
 
17.0 
REFERENCES 
 
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Appendix I 
 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 
 
http://ctep.cancer.gov/forms/CTCAEv3.pdf 

 
 
Appendix II 
 
Modified Bearman Toxicity Scale 
 
 
Grade I 
Grade II 
Grade III 
 
Cardiac  
Toxicity 
 
Mild EKG abnormality, not 
requiring medical  
intervention; or noted heart 
enlargement on chest x-ray 
with no clinical symptoms 
 
Moderate EKG abnormalities 
requiring and responding to 
medical intervention; or 
requiring continuous monitoring 
without treatment; or congestive 
heart failure responsive to 
digitalis or diuretics  
 
 
Severe EKG abnormalities 
with no or only partial 
response to medical 
intervention; or heart failure 
with no or only minor 
response to medical 
intervention; or decrease in 
voltage by more than 50%  
 
 
Bladder 
Toxicity 
 
Macroscopic hematuria after 2 
days from last chemotherapy 
dose with no subjective 
symptoms of cystitis and not 
caused by infection  
 
 
Macroscopic hematuria after 7 
days from last chemotherapy 
dose not caused by infection; or 
hematuria after 2 days with 
subjective symptoms of cystitis 
not caused by infection  
 
 
Hemorrhagic cystitis with 
frank blood, necessitating 
invasive local intervention 
with installation of sclerosing 
agents, nephrostomy or other 
surgical procedure  
 
 
Renal 
Toxicity  
 
 
Increase in creatinine up to 
twice the baseline value 
(usually the last recorded 
before start of conditioning)  
 
 
Increase in creatinine above 
twice baseline but not requiring 
dialysis  
 
 
Requirement of dialysis  
 
 
Pulmonary 
Toxicity  
 
 
Dyspnea without chest x-ray 
changes not caused by 
infection or congestive heart 
failure; or chest x-ray showing 
isolated infiltrate or mild 
interstitial changes without 
symptoms not caused by 
infection or congestive heart 
failure  
 
 
Chest x-ray with extensive 
localized infiltrate or moderate 
interstitial changes combined 
with dyspnea and not caused by 
infection or CHF; or decrease of 
PO2 (> 10% from baseline) but  
not requiring mechanical 
ventilation or > 50% O2 on 
mask and not caused by 
infection or CHF 
 
 
Interstitial changes requiring 
mechanical ventilatory 
support or > 50% oxygen on 
mask and not caused by 
infection or CHF  
 
 
Hepatic 
Toxicity 
 
Mild hepatic dysfunction with 
bilirubin ≥ 2.0 mg/dL and ≤ 6.0 
mg/dL or weight gain > 2.5% 
and < 5% from baseline, of 
non-cardiac origin; or SGOT 
increase more than 2-fold but 
less than 5-fold from lowest 
preconditioning  
 
 
Moderate hepatic dysfunction 
with bilirubin > 6.0 mg/dL and < 
20 mg/dL; or SGOT increase > 
5-fold from preconditioning; or 
clinical ascitis or image 
documented ascitis > 100 mL; 
or weight gain > 5% from 
baseline of non-cardiac origin  
 
 
Severe hepatic dysfunction 
with bilirubin > 20 mg/dL; or 
hepatic encephalopathy; or 
ascitis compromising  
respiratory function  
 
 
CNS 
Toxicity 
 
Somnolence but the patient is 
easily arousable and oriented 
after arousal  
 
 
Somnolence with confusion 
after arousal; or other new 
objective CNS symptoms with 
no loss of consciousness not 
more easily explained by other 
medication, bleeding or CNS 
infection  
 
 
Seizures or coma not 
explained (documented) by 
other medication, CNS  
infection, or bleeding  
 
 
 
 
 

 
 
Stomatitis 
 
Pain and/or ulceration not  
requiring a continuous IV  
narcotic drug  
 
Pain and/or ulceration requiring 
a continuous IV narcotic drug 
(morphine drip)  
 
Severe ulceration and/or  
mucositis requiring  
preventive intubation; or  
resulting in documented  
aspiration pneumonia with or  
without intubation  
 
 
GI Toxicity 
 
Watery stools > 500 mL but  
< 2,000 mL every day not  
related to infection  
 
 
Watery stools > 2,000 mL every 
day not related to infection; or 
macroscopic hemorrhagic 
stools with no effect on 
cardiovascular status not 
caused by infection; or subileus 
not related to infection 
 
 
Ileus requiring nasogastric  
suction and/or surgery and 
not related to infection; or 
hemorrhagic enterocolitis 
affecting cardiovascular 
status and requiring 
transfusion  
 
 
 

 
 
 Appendix III 
 
Additional Assays to be Performed on Previously Collected Samples 
 
 
 
I.  Rituxan Level Assays for IRB 01176 and IRB 07163 
 
 
This Phase II study includes serum Rituxan level assays performed pre-treatment, however the earlier Phase I 
study (IRB #01176) did not include this assay.  Moreover, those patients having received this same Zevalin-BEAM 
+ aHSCT regimen (not on clinicial trial) and participating in the retrospective chart review protocol (IRB #07163) 
also did not have Rituxan level assays done on their pre-treatment blood samples. 
 
We will perform Rituxan level analyses retrospectively, on leftover serum aliquots from previously-collected blood 
samples, which were drawn and used for the pre-treatment HAZA assay (one per patient) for those patients 
participating in the prior, Phase I study (IRB #01176) as well as those patients participating in the retrospective 
chart review protocol (IRB #07163).  The total number of samples assayed will be 63 (38 for #01176 and 25 for 
#07163). 
 
The information obtained from having the Rituxan level data on these additional patients will allow better analysis of 
potential correlations regarding pre-treatment circulating Rituxan levels and meaningful study outcomes, such as 
disease response. 
 
 
II. Additional Immunohistochemistry Staining on Pathology Specimens 
 
For each of the participating study subjects having a histology of DLBCL (including transformed histology), 
additional IHC staining on all previously collected diagnostic pathology specimens (including bone marrow, lymph 
nodes, and other tissue) will be done, in order to identify high risk molecular features and correlate with outcomes 
post Zevalin-BEAM (radioimmunotherapy) conditioning + autologous hematopoietic stem cell transplantation. 
 
The markers include but are not limited to:  CD10, bcl6, MUM1, MIB1, MUC1, MDR, p53, cyclin D2, and Bcl2. 
 
The information obtained from having this data will aid in study of the potential role of these molecular markers in 
predicting disease outcome in the cohort of patients with DLBCL (including transformed histology) treated with 
Zevalin-BEAM (RIT) conditioning prior to aHSCT.