Clinical trial NCT00562978
Conditions: Lymphoma
Keywords: recurrent grade 1 follicular lymphoma recurrent grade 2 follicular lymphoma recurrent grade 3 follicular lymphoma recurrent adult diffuse large cell lymphoma recurrent adult diffuse mixed cell lymphoma recurrent adult diffuse small cleaved cell lymphoma recurrent adult immunoblastic large cell lymphoma recurrent mantle cell lymphoma stage III grade 1 follicular lymphoma stage III grade 2 follicular lymphoma stage III grade 3 follicular lymphoma stage IV grade 1 follicular lymphoma stage IV grade 2 follicular lymphoma stage IV grade 3 follicular lymphoma stage III adult diffuse large cell lymphoma stage III adult diffuse mixed cell lymphoma stage III adult diffuse small cleaved cell lymphoma stage IV adult diffuse large cell lymphoma stage IV adult diffuse mixed cell lymphoma stage IV adult diffuse small cleaved cell lymphoma stage III mantle cell lymphoma stage IV mantle cell lymphoma stage III adult immunoblastic large cell lymphoma stage IV adult immunoblastic large cell lymphoma
Sponsor: City of Hope Medical Center
Start date: 2000-05-16; Completion date: 2018-05-21
Enrollment: 54 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
RATIONALE: Radiolabeled monoclonal antibodies, such as yttrium Y 90 ibritumomab tiuxetan, can find cancer cells and carry tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as etoposide and cyclophosphamide, work in different ways to kill cancer cells or stop them from growing. Giving radiolabeled monoclonal antibodies together with etoposide and cyclophosphamide before a peripheral blood stem cell transplant may be an effective treatment for non-Hodgkin lymphoma.

PURPOSE: This phase I/II trial is studying the side effects and best dose of yttrium Y 90 ibritumomab tiuxetan when given together with etoposide and cyclophosphamide followed by an autologous stem cell transplant and to see how well it works in treating patients with non-Hodgkin lymphoma.

Detailed description:
OBJECTIVES:

* To evaluate the safety and efficacy of a new preparative regimen of yttrium Y 90 ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation (ASCT) for treatment of patients with poor-risk, relapsed, or refractory non-Hodgkin lymphoma (NHL).
* To determine the maximum tolerated dose of yttrium Y 90 ibritumomab tiuxetan which can be given with high-dose etoposide and high-dose cyclophosphamide followed by ASCT in patients with NHL.
* To perform dosimetry study to estimate the radiation dose delivered to the tumor and normal organs.
* To evaluate the short-term and long-term complications of this new preparative regimen.

OUTLINE: This is a phase I does-escalation study of yttrium Y 90 ibritumomab tiuxetan followed by an open-label phase II study.

* Preparation for transplantation: Peripheral blood stem cells (PBSCs) are collected via leukapheresis. Samples are analyzed by cytogenetic studies, immunophenotyping, and gene rearrangement. Patients with an adequate number of collected CD34-positive cells (≥ 3 times 10\^6 /kg) proceed to radioimmunotherapy.
* Radioimmunotherapy: Patients receive yttrium Y 90 ibritumomab tiuxetan IV on days -21 and -14. Patients undergo bone marrow biopsy and dose estimation on day -7.
* Chemotherapy: Patients receive etoposide IV on day -4 and cyclophosphamide IV over 2 hours on day -2.
* Transplantation: Patients undergo reinfusion of PBSCs on day 1.
* Growth factor therapy: Patients receive filgrastim (G-CSF) IV beginning on day 1 and continuing until blood counts recover.

Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically.

Arms: arm 1: * Preparation for AHSCT: Peripheral blood stem cells (PBSCs) are collected via leukapheresis. Samples are analyzed by cytogenetic studies, immunophenotyping, and gene rearrangement. Patients with an adequate number of collected CD34-positive cells (≥ 3 times 10\^6 /kg) proceed to radioimmunotherapy.
* Radioimmunotherapy: Patients receive yttrium Y 90 ibritumomab tiuxetan and undergo bone marrow biopsy and dose estimation.
* Chemotherapy: Patients receive etoposide IV and cyclophosphamide IV
* AHSCT: Patients undergo reinfusion of PBSCs.
* Growth factor therapy: Patients receive filgrastim (G-CSF) IV. Treatment continues in the absence of disease progression or unacceptable toxicity. arm 2: * Preparation for AHSCT: Peripheral blood stem cells (PBSCs) are collected via leukapheresis. Samples are analyzed by cytogenetic studies, immunophenotyping, and gene rearrangement. Patients with an adequate number of collected CD34-positive cells (≥ 3 times 10\^6 /kg) proceed to radioimmunotherapy.
* Radioimmunotherapy: Patients receive yttrium Y 90 ibritumomab tiuxetan and undergo bone marrow biopsy and dose estimation.
* Chemotherapy: Patients receive etoposide IV and cyclophosphamide IV
* AHSCT: Patients undergo reinfusion of PBSCs.
* Growth factor therapy: Patients receive filgrastim (G-CSF) IV. Treatment continues in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: filgrastim intervention 2: cyclophosphamide intervention 3: etoposide intervention 4: AHSCT intervention 5: yttrium Y 90 ibritumomab tiuxetan
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 A PHASE I/II TRIAL OF ESCALATING DOSE OF YTTRIUM-90-LABELED ANTI-CD20 MONOCLONAL 
ANTIBODY IN COMBINATION WITH HIGH-DOSE ETOPOSIDE AND CYCLOPHOSPHAMIDE 
FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION FOR PATIENTS WITH POOR 
RISK/RELAPSED B-CELL NON-HODGKIN’S LYMPHOMA 
 
NCT00562978 
 
Document Date 03/28/2014 


 
06/20/07 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 EAST DUARTE ROAD 
DUARTE, CA 91010 
DEPARTMENT OF HEMATOLOGY / BONE MARROW TRANSPLANTATION 
05/10/00 
TITLE: 
A PHASE I/II TRIAL OF ESCALATING DOSE OF YTTRIUM-90-LABELED ANTI-CD20 
MONOCLONAL ANTIBODY IN COMBINATION WITH HIGH-DOSE ETOPOSIDE AND 
CYCLOPHOSPHAMIDE FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION FOR 
PATIENTS WITH POOR RISK/RELAPSED B-CELL NON-HODGKIN’S LYMPHOMA 
CITY OF HOPE PROTOCOL NUMBER/VERSION NUMBER: 
IRB# 98153 
VERSION 17 
10/29/03, 04/06/04,  DATE(S) OF AMENDMENT(S)/REVISION(S): 
06/16/04 
Amendment 
1 – 01/31/00 – Version 01 
Amendment 
8 – 02/08/01 – Version 08 
Amendment 
2 – 05/10/00 – Version 02 
Amendment 
9 – 05/03/01 – Version 09 
Amendment 
3 – 06/05/00 – Version 03 
Amendment 10 – 08/07/01 – Version 10 
Amendment 
4 – 07/13/00 – Version 04 
Amendment 11 – 05/30/02 – Version 11 
Amendment 
5 – 09/08/00 – Version 05 
Amendment 12 – 10/29/03 – Version 12 
Amendment 
6 – 10/25/00 – Version 06 
Amendment 13 – 04/06/04 – Version 13 
Amendment 
7 – 12/20/00 – Version 07 
Amendment 14 – 06/16/04 – Version 14 
Amendment    15  –   06/20/07  –   Version 15 
Amendment    16  –   04/18/12  –   Version 16 
(title page only change) 
Amendment   17  –   03/28/14   --  Version 17  
 
 
 
 
 
 
 
          
SITE: 
Lymphoma 
HISTOLOGY: 
Low and Intermediate Grade CD20 (+) 
STAGE (IF APPLICABLE): 
II, III, IV 
MODALITY: 
Chemotherapy/Radioimmunotherapy 
TYPE: 
Phase I/II 
PRINCIPAL INVESTIGATOR: 
06/16/04 
Auayporn Nademanee, M.D. 
Department of Hematology/Hematopoietic Cell Transplantation 
COLLABORATING INVESTIGATOR: 
Andrew Raubitschek, M.D. 
Department of Radioimmunotherapy 
PARTICIPATING CLINICIANS: 
06/16/04 
Stephen J. Forman, M.D. 
Department of Hematology/Hematopoietic Cell Transplantation 
10/29/03 
Joycelynne Palmer, Ph.D. 
Department of Biostatistics 
PARTICIPATING INSTITUTIONS: 
City of Hope National Medical Center 
INVESTIGATIONAL NEW DRUG (IND) NUMBER: 
BB-IND 8836 
 


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TABLE OF CONTENTS 
 1.0 
BACKGROUND RATIONALE 
1 
 2.0 
OBJECTIVES 
8 
 3.0 
STUDY DESIGN 
8 
 4.0 
DRUG FORMULATION 
9 
 5.0 
STAGING CRITERIA 
12 
 6.0 
ELIGIBILITY CRITERIA 
13 
 7.0 
EXCLUSION CRITERIA 
14 
 8.0 
TREATMENT PLAN 
14 
 9.0 
STUDY DESIGN AND RULES FOR DOSE ESCALATION 
18 
10.0 
STUDY CALENDAR - PREPARATIVE REGIMEN AND PBSCT 
21 
11.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
22 
12.0 
STATISTICAL CONSIDERATIONS 
23 
13.0 
REGISTRATION GUIDELINES 
24 
14.0 
RECORDS TO BE KEPT AND DATA SUBMISSION SCHEDULE 
24 
15.0 
GENDER AND MINORITIES 
25 
16.0 
DATA MANAGEMENT 
25 
17.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
25 
18.0 
REFERENCES 
26 
Appendix I  
Common Toxicity Criteria (CTC) 
A1 
Appendix II 
Toxicity Module 
A38 
Appendix III 
Infection Module 
A39 
Appendix IV 
Performance Status Scales/Scores 
A40 
Appendix V 
RTOG/EORTC Late Radiation Morbidity Scoring Scheme A41 
Appendix VI 
BMT Complex/Multi-Component Events 
A44 
 


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1.0 
BACKGROUND RATIONALE 
Non-Hodgkin’s lymphomas (NHLs) 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 old.1  Despite the use of 
aggressive combination chemotherapy regimens, approximately 30-40% of patients with 
intermediate- and high-grade NHL does not achieve complete remission (CR) or suffers relapse 
after attaining 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  Recently, the benefit of high-dose therapy and ASCT proved to be 
superior to conventional salvage chemotherapy in a randomized Parma study of 215 patients with 
chemotherapy-sensitive NHL in relapse.4  The 5-year event-free survival (EFS) was 46% for the 
ASCT group as 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 patients derive long-term benefits from this 
treatment and recurrent disease remains the single most common cause of treatment failure post-
high-dose therapy and ASCT.  Therefore, new therapeutic approaches are needed. 
Patients with low-grade NHL have indolent clinical courses 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.  Relapsed low-grade 
lymphoma may still respond to salvage therapy.  But the duration of subsequent remissions 
progressively decreases.  High-dose therapy and ASCT has been shown to improve survival and 
to 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. 
Recently, the role of radioimmunotherapy for treatment of NHL has emerged.  Radioisotope-
labeled monoclonal antibodies provide a mechanism by which radioactivity can be directly 
targeted to tumors sites while sparing normal tissues.  B-cell lymphomas are attractive targets for 
radioimmunotherapy because of their radiosensitivity, their well-defined surface antigens and the 
availability of multiple monoclonal antibodies to those antigens. 


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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.  But so far, 
none of these regimens have emerged as the best regimen.  However, since NHL is radio-
sensitive and based on experience with acute leukemia, the combination of total body irradiation 
(TBI) and cyclophosphamide (Cy) has been widely used as a preparative regimen for some 
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 Hope6, Stanford University7 and Fred Hutchinson Cancer Research Center (FHCRC)8 
demonstrate the activity of this regimen in patients with lymphoid malignancies.  The transplant-
related mortality within 100 days was 7-8%, with the common causes of death being 
venoocclusive disease (VOD), diffuse alveolar hemorrhage and infection.  The major transplant-
related morbidities were mucositis and skin toxicities, which were fully reversible.  The 5-year 
EFS and overall survival (OS) were 52% [95% Confidence interval (CI) 42-62%] and 61% (95% 
CI 50-73%), respectively for 134 patients with NHL who underwent ASCT utilizing this regimen 
at Stanford.  These results have been confirmed in the Southwestern Oncology Group 
cooperative trial.  Despite its effectiveness, the relapse rate of 34-53 % remains considerably 
high.  Thus, new preparative regimens need to be explored. 
1.2 
Radionuclides for Radioimmunotherapy 
Iodine-131 (131I) has been the gold standard for radioimmunotherapy due to its long track record 
in treating thyroid carcinomas, its well-defined radiochemistry, its clinical availability, and its 
potential for both radioimmunoscintigraphy and radioimmunotherapy.  131I has been employed in 
the majority of reported clinical trials of radioimmunotherapy.  However, there are disadvantages 
to 131I, including its long 8-day half life, the risks of radiation exposure to health care providers 
and the non-specific irradiation to normal organs from gamma components of 131I. 
Yttrium-90 (90Y) 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.  In addition, the short half-life of 90Y facilitates 
its use in combination with other agents, i.e. chemotherapy or total body radiation, and allows for 
high dose rates at localized sites.  Unfortunately, 90Y cannot be used for 
radioimmunoscintigraphy due to its absence of gamma emissions.  Indium-111 (111In) has been 
substituted as an imaging reagent to show tumor localization in patients scheduled for 90Y 
therapy, based on its biodistribution which is close to that of 90Y.  111In-labeled murine 
monoclonals have been used successfully in clinical imaging trials for cutaneous T-cell 
lymphoma, chronic lymphocytic leukemia, melanoma, and colon cancer. 
1.3 
Anti-CD 20 
Anti-CD20 (anti-B1) is a murine monoclonal antibody of isotype IgG2a, raised against 
cryopreserved Burkitt’s 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’s lymphomas 
and B-cell chronic lymphocytic leukemias tested, but not on T-cells, plasma cells, uncommitted 


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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. 
1.4 
IDEC-C2B8 
IDEC-C2B8 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.  IDEC-C2B8 shows specificity for the CD 20 antigen and binds 
with an apparent affinity of 4.3 x 10-9M.  IDEC-C2B8 has also been reported to induce apoptosis 
and to sensitize drug-resistant human B-cell lymphoma cell lines to cytotoxic chemotherapy. 
A phase I dose escalation pharmacokinetic trial of IDEC-C2B8 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.9  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 abdomen. 
A phase III trial to assess the safety and efficacy of IDEC-C2B8 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.10  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.  IDEC-
C2B8 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. 
IDEC-C2B8 has also been studied in combination with chemotherapy.  Czuczman et al11 


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conducted a phase II multi-center study evaluating the safety and anti-tumor activity of IDEC-
C2B8 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.  
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.  This combined therapy is being 
investigated in previously untreated patients with intermediate- and high-grade NHL. 
1.5 
Results of Radiolabeled Antibodies in the Treatment of Non-Hodgkin’s Lymphoma  
Most recent radioimmunotherapy trials for lymphoma have utilized 131I-labeled anti-B1 (anti-
CD20) antibody.  Kaminski et al12 first reported on a trial utilizing multiple treatments with low 
dose 131I-labeled anti-B1 antibody in ten patients who had a CD20 positive B-cell lymphoma in 
whom primary therapy had failed.  Six of the nine treated patients had tumor responses, including 
patients with bulky or chemotherapy-resistant diseases.  Four patients had complete remissions 
(CR), and two had partial responses.  The follow-up time was relatively short, but no disease 
progression was observed in the four patients who achieved a CR at 8-11 months.  Toxicity was 
minimal with mild or no myelosuppression. 
Based on these results, a phase I/II study of 131I-labeled anti-B1 was conducted in 58 heavily pre-
treated patients with NHL (28 low-grade, 14 transformed low-grade, 15 intermediate-grade, and 
2 high-grade).13  The median number of prior therapy was 4, 88% had stage III or IV disease, 
36% had bulky disease, 51% had an elevated LDH level and 14 had failed BMT.  Patients 
received 1-3 dosimetric doses followed by a therapeutic dose.  The dosimetric dose involved the 
IV administration of 5 mCi of 131I anti-B1 antibody to determine the rate of whole body clearance 
so that a whole body radiation dose could be calculated.  Each dosimetric dose was preceded by 
0, 95, or 475 mg of unlabeled antibody.  Therapeutic dose escalation was initiated at 25 cGy and 
adjusted in 10 cGy increment until the MTD.  The MTD was 75 cGy for patients who had not 
undergone BMT.  The overall response rate in these heavily pre-treated patients was 71% with a 
CR rate of 34%.  The median duration of response was 271 days (95% CI; 40-394 days) and the 
median duration of CR was 566 days.  Response was observed in both low-grade and 
transformed low-grade NHL as well as in patients with bulky disease and patients who had 
relapsed post-BMT. 
Further trials of 131I-labeled anti-B1 antibody at non-myeloablative doses has been studied in 4 
separate clinical trials (phase I and II, single and multi-center) in 113 patients with low-grade 
NHL including 25 with transformed low-grade NHL.14  Patients received a single dosimetric 
dose of 450 mg of unlabeled anti-B1 infusion over one hour followed by 35 mg radiolabeled with 
5 mCi 131I over ½ hour.  The therapeutic dose was administered 7 to 14 days after the dosimetric 
dose and consisted of the same unlabeled and labeled antibody doses.  The overall response rate 
was 77% with a CR rate of 45% and 67% of the complete responders were in continuous 
remission for > 4 years.  Reversible hematologic toxicity was the dose- limiting toxicity. ANC < 
100/mm3 was observed in 2.6% of patients and platelets < 10,000/mm3 in 5.3%.  The nadir 


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typically occurred at week 5-6 with recovery by week 8-9.  The most common non-hematologic 
toxicities were transient mild to moderate fever, nausea, asthenia, and chills.  None of the 
patients developed HAMA.  These results suggest that 131I-labeled anti-B1 is safe and effective 
and may induce prolonged CR in heavily pre-treated low-grade and transformed low-grade NHL. 
1.6 
Results of 131I anti-B1 Monoclonal Antibody with Autologous Bone Marrow Support 
Although promising results have been reported with radiolabeled MAb for NHL, these results 
may be improved by using higher dose or myeloablative radiation dose.  The use of radiolabeled 
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 al15 conducted a 
trial utilizing 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 al16 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 a cohorts of 4 patients each with doses of 131I-anti-B1 antibody (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 death; 3 from progressive NHL and 1 from 
disseminated Varicella.  These results suggest that 131I- anti-B1 antibody can be given at doses 
delivering  25 Gy to critical normal organs, with pulmonary and gastrointestinal toxicities being 
dose-limiting.  Although additional studies are needed, 131I-anti-B1 antibody can be safely given 
in combination with high-dose chemotherapy in an autologous stem cell transplant setting for 
NHL. 
1.7 
90Y -Anti-CD20 Radioimmunotherapy for Relapsed NHL 
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.17  The primary objectives 


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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's 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 
nonhematological 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. 
Results of a phase I/II study utilizing chimeric antibody Rituximab as the unlabeled clearing 
antibody and 90Y conjugated anti-CD20 (IDEC-Y2B8, conjugated to the parent murine 
monoclonal 2B8) was recently reported.  In the study reported by Witzig et al18, the first portion 
of the study compared 100 mg/m 2 with 250 mg/m 2of Rituximab as the clearing dose and 
compared dosimetry imaging capabilities.  It was determined that 250 mg/m2 of Rituximab was 
the optimal dose to be used.  In the second portion of the phase I study, the dose of IDEC-Y2B8 
was escalated from 0.2 mCi/kg to 0.4 mCi/kg. No bone marrow or stem cell harvest was 
required.  None of the patients treated at 0.2, 0.3 and 0.4 mCi/kg whose baseline platelet count > 
150,000/mm3 developed grade 4 hematologic toxicity, whereas 3 of 6 patients treated at 0.2 or 
0.3 mCi/kg with baseline platelet counts between 100,000 to 150,000/mm3 developed transient 
grade 4 hematologic toxicity. 
The dosimetry from this phase I/II trial of IDEC-Y2B8 was reported by Wiseman et al.19  Forty-
two patients with low- and intermediate-grade NHL received IDEC-Y2B8 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 111I.  
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 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. 
Outcomes from this trial have been compiled in a submitted publication.19  The overall response 
rate (ORR) for the intent-to-treat population (n = 51) was 67% (26% CR, 41% PR); for the low-
grade group (n = 34) 82% (27% CR, 56% PR); 43% for intermediate grade (n = 4); and 0% for 
mantle cell (n = 3).  Responses were seen in patients with bulky (> 7 cm) disease (41%) and 


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splenomegaly (50%).  Kaplan-Meier estimate of time-to-progression in responders and duration 
of response is 12.9+ months and 11.7+ months, respectively.  Adverse events were primarily 
hematologic and correlated with baseline extent of marrow involvement with NHL and baseline 
platelet count.  Only one patient developed an anti-antibody response (HACA/HAMA). 
1.8 
Study Proposal 
The high-dose therapy regimen of FTBI 1200 cGy, etoposide 60 mg/kg and Cy 100 mg/kg has 
been used extensively at City of Hope as a preparative regimen for patients with hematological 
malignancies.  Given the relatively high relapse rate associated with this regimen, the effective 
anti-lymphoma therapy of IDEC-C2B8, and the safety and feasibility of IDEC-Y2B8 with the 
ability to directly deliver radiation to tumors sites, we propose to study a new preparative 
regimen in patients with relapsed NHL which will utilize 90Y-labeled anti-CD20 antibody 
(IDEC-Y2B8) instead of TBI in combination with high-dose etoposide and cyclophosphamide.  
We plan to conduct a phase I/II trial to define the maximum tolerated dose (MTD) of IDEC-
Y2B8 that can be given with high-dose etoposide and cyclophosphamide followed by ASCT, and 
to define the response rate and toxicities associated with this regimen.  To avoid liver toxicity, 
etoposide dose will be started at 40 mg/kg and escalated to 60 mg/kg and the dose of Cy will be 
fixed at 100 mg/kg. 
05/03/01, 06/16/04 The patient will undergo a dosimetry study with IDEC-In2B8 to confirm favorable localization of 
isotope one week prior to administration of therapeutic dose IDEC-Y2B8.  Serial gamma camera 
images will be obtained at the end of the infusion, 24 hours, 48 hours, 72 - 96 hours, 120 hours 
and 144 hours post-infusion.  At each time point, one whole body and 4 spot planar scans will be 
acquired with the Toshiba dual head camera.  In addition, two SPECT images will be obtained at 
48 and 72 -96 hour time points.  Nuclear Medicine images will be used to estimate the 
distribution of activity in various organs, especially liver, lungs, kidney, heart and spleen.  Blood 
samples will be drawn prior to IDEC-C2B8 and at approximately 0 hours (immediately prior to 
IDEC-In2B8), 2 hours, 4 - 6 hours, 24 hours, 48 hours, 72 - 96 hours, 120 hours and 144 hours 
following antibody infusion.  These samples will be used to analyze antibody clearance and bone 
marrow dose estimates.  Urine samples will be collected daily for six days to analyze 
radioisotope clearance. 
05/03/01, 08/07/01, 
06/16/04 
Favorable biodistribution will be defined as tumor dose greater than any normal organ, except 
spleen and bone marrow, ie. liver, lung, kidney.  For patients in CR at time of transplantation, no 
specific tumor localization is required as long as Ga 67 scan and/or FDG-PET scan is negative.  
Tumor dose will be calculated from multiple gamma camera images and blood/urine 
pharmacokinetics.  If the patient shows favorable biodistribution, the therapeutic dose will be 
administered on day -14.  Serial gamma camera images will be obtained at the end of the 
infusion, 24 hours, 48 hours, 72 - 96 hours, 120 hours and 144 hours post-infusion.  At each time 
point, one whole body and 4 spot planar scans will be acquired with the Toshiba dual head 
camera.  Nuclear Medicine images will be used to confirm estimates of the distribution of 
activity in various organs, especially liver, lungs, kidney, heart and spleen.  Blood samples will 
be drawn prior to IDEC-C2B8 and at approximately 0 hours (immediately prior to IDEC-In2B8 / 
IDEC-Y2B8), 2 hours, 4 - 6 hours, 24 hours, 48 hours, 72 - 96 hours, 120 hours and 144 hours 
following antibody infusion.  These samples will be used to analyze antibody clearance and bone 


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marrow dose estimation.  Urine samples will be collected daily for six days to analyze 
radioisotope clearance.  The therapeutic dose will be administered to deliver a target dose of 
1000 cGy to the organ projected to receive the highest dose from the imaging study.  After the 
first two dose levels the dose will be increased in increments of 250 cGy until a maximum of 
2500 cGy is attained or dose limiting toxicity is encountered. 
10/29/03 
2.0 
OBJECTIVES 
05/10/00 
2.1 
To evaluate the safety and efficacy of a new preparative regimen of 90Y-labeled anti-
CD20 MAb (IDEC-Y2B8) in combination with high-dose etoposide and 
cyclophosphamide followed by ASCT for treatment of patients with relapsed/refractory 
and poor risk NHL. 
2.2 
To determine the MTD of 90Y-anti-CD20 MAb which can be given with high-dose 
etoposide 60 mg/kg and high-dose cyclophosphamide 100 mg/kg followed by ASCT in 
patients with NHL. 
2.3 
To perform dosimetry study to estimate the radiation dose delivered to the tumor and 
normal organs. 
2.4 
To evaluate the short-term and long-term complication of this new preparative regimen. 
3.0 
STUDY DESIGN 
This is an open-label phase I-II clinical and efficacy study of a new preparative regimen followed 
by autologous stem cell support in patients with relapsed and refractory NHL.  Patients with  
low-, and intermediate-grade NHL who have relapsed followed conventional chemotherapy or 
have failed to achieve remission, and who are candidates for high-dose therapy and ASCT will be 
eligible for this study. All patients will receive IDEC-Y2B8 in combination with high-dose 
etoposide and cyclophosphamide followed by ASCT.  The dose of Cy will be fixed at 100 mg/kg. 
There will be two doses escalating schema for etoposide and IDEC-Y2B8.  Etoposide will be 
started at 40 mg/kg (cohort 1) and escalate to 60 mg/kg (cohort 2).  The dose of Y2B8 will be the 
same for cohort 1 and 2, to deliver 1000 cGy to the normal organ receiving the greatest 
accumulation.  If no dose limiting toxicity is observed, while the etoposide dose remains at 60 
mg/kg, the dose of Y2B8 will be escalated to 1250 cGy, and then to a maximum of 2500 cGy, or 
until the MTD has been reached.  Therefore, there will be cohorts with 3 patients per cohort as 
follows (an additional 2 patients per cohort will be accrued if there are eligible patients available 
prior to the determination of toxicity on the current dose level): 
Cohort 1: 
Y2B8 to deliver 1000 cGy to highest normal 
organ excluding spleen and bone marrow 
 
etoposide 40 mg/kg  
 
cyclophosphamide 100 mg/kg 
Cohort 2: 
Y2B8 to deliver 1000 cGy to highest normal 
organ excluding spleen and bone marrow 
 
etoposide 60 mg/kg 
 
cyclophosphamide 100 mg/kg 


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Cohort 3: 
Y2B8 to deliver 1250 cGy to highest normal 
organ excluding spleen and bone marrow 
 
etoposide 60 mg/kg 
 
cyclophosphamide 100 mg/kg 
Cohort 4: 
Y2B8 to deliver 1500 cGy to highest normal 
organ excluding spleen and bone marrow 
 
etoposide 60 mg/kg 
 
cyclophosphamide 100 mg/kg 
Cohort 5: 
Y2B8 to deliver 1750 cGy to highest normal 
organ excluding spleen and bone marrow 
 
etoposide 60 mg/kg 
 
cyclophosphamide 100 mg/kg 
Cohort 6 to 8: 
Y2B8 to deliver 2000-2500 cGy to highest normal 
organ excluding spleen and bone marrow 
 
etoposide 60 mg/kg  
 
cyclophosphamide 100 mg/kg 
05/03/01 
All patients will have peripheral blood stem cell collected with the target CD34+ of 3.0x106/kg.  
Patients will undergo dosimetry studies on day –21 and therapy on day -14.  Etoposide will be 
given on day -4, followed by a day rest and cyclophosphamide on day -2. PBSC will be infused 
on day +1 when the radiation dose to the reinfused stem cells is estimated to be < 5 cGy. 
4.0 
DRUG FORMULATION 
4.1 
IDEC-Y2B8 
a. 
Drug Formulation and Procurement 
IDEC-2B8-MX-DTPA 
Two ml glass septum vial containing 2 ml (3.2 mg) IDEC-
2B8-MX-DTPA in low metal normal saline at 1.6 mg/ml. 
RITUXAN (IDEC-C2B8) 
Ten ml (100 mg) and/or 50 ml (500 mg) pharmaceutical 
grade glass vials at a concentration of 10 mg of protein per ml. 
111In-chloride 
5 mCi of Indium-111 chloride supplied in .05M HCl. 
90Y-chloride 
40-100 mCi Yttrium-90 chloride supplied in .05M HCl.  
10/29/03 
b. 
Drug Toxicity 
Myelosuppression is the dose limiting toxicity in non marrow supported regimens.  With 
marrow support liver, kidney, and lung are likely to be the dose limiting organs for 
toxicity.  Infusional toxicity of chills and rigors are common with the first administration 
but rarely with subsequent doses.  Decreasing the rate of infusion and the administration 
of antihistamines can control these toxicities. 
c. 
Drug Storage, Reconstitution and Stability 
All antibodies will be stored in the investigational pharmacy at 4ºC until the day of use.  


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Once diluted the unlabeled antibody is to be used within 24 hours if held at 4ºC and at 
room temperature for an additional 12 hours.  The radiolabeled solutions should be used 
within 6 hrs and should be held at 2-8ºC until administered.   
4.2 
VP-16 (epipodophyllotoxin, etoposide, 4'-demethyl-9(4,6-o-ß) d-
ethylideneglycopyranoside). 
a. 
Drug Formulation and Procurement 
VP-16 is supplied by Bristol Laboratories in a 100 mg ampule in 5 cc of a solution 
containing citric acid, 10 mg; benzyl alcohol, 150 mg; polysorbate 80, purified, 250 mg; 
polyethylene glycol 300, 3.75 gm; absolute alcohol q s., 5 cc. 
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 ampoule 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 60 mg/kg/4 hours. 
4.3 
Cyclophosphamide (Neosar, Cytoxan), NSC-26271 
a. 
Drug Formulation and Procurement 
Cyclophosphamide is an alkylating agent dispensed in 100, 200 and 500 mg vials 
containing a dry powder.  Cyclophosphamide will be purchased from Adria Laboratories. 
b. 
Drug Toxicity 
Patients must be well hydrated before and for several hours following administration of 
cyclophosphamide to reduce the potential for hemorrhagic cystitis.  The more common 
side effects include nausea and vomiting, and alopecia.  Acute toxicity includes 
principally leukopenia, with the nadir occurring 7-14 days after a single IV dose.  At high 
doses, occasional pulmonary toxicity has been reported.  Rare cardiac toxicity (congestive 
heart failure) has occurred in patients previously treated with anthracyclines. 
c. 
Drug Storage, Reconstitution and Stability 
Cyclophosphamide is reconstituted with either sterile water for injection, USP or 
bacteriostatic water for injection, USP (Paraben preserved only), using 5 ml for the 100 
mg vial, 10 ml for the 200 mg vial or 25 ml for the 500 mg vial.  Each ml of reconstituted 
solution contains 20 mg cyclophosphamide per ml.  The drug is diluted in 5% dextrose 
and water or physiological saline and given by IV infusion. 


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4.4 
Mesna (Sodium 2-Mercaptoethane sulfonate) 
a. 
Drug Formulation and Procurement 
Mesna is provided by Bristol Laboratories as a 10% (100 mg/ml) solution in water with 
0.25 mg EDTA as excipient in 4 ml ampules. 
b. 
Drug Storage, Reconstitution and Stability 
Mesna solutions have been shown to be stable on extended storage at room temperature 
in ampules.  No change in composition of the ampules was noted at one year's storage in 
these conditions. 
On exposure to air Mesna is known to undergo oxidation to disulfide.  Since the Mesna 
concentration of opened ampules may decrease with time, the ampule should be opened 
just before use and the unused part discarded. 
c. 
Administration 
Each dose of Mesna will be diluted in 50 cc of 5% dextrose/water or 0.9% normal saline 
and infused intravenously over 15 minutes. 
06/05/00 
4.5 
DTPA (Diethyltriaminepenatacetic acid) 
a. 
Drug Formulation and Procurement 
DTPA will be purchased from Heyl Pharmaceuticals, Berlin, Germany.  It is supplied as a 
1 gram ampule in 5 mls.  
b. 
Drug toxicity 
DTPA has been known to cause headaches, fever, chills, flu-like symptoms, nasal 
stuffiness, nausea, vomiting, abdominal cramping, and diarrhea.  Other side effects that 
are less common include pain at the injection site, dehydration, decreased blood pressure, 
irregularities of heart rhythm, decreased blood counts, increased calcium, numbness and 
tingling, sneezing, excessive tearing, kidney damage, and zinc deficiency (which can 
result in a facial and perianal rash and tongue and mouth sores).  In addition, there is 
always a risk of a very uncommon or previously unknown side effect occurring.  Stopping 
the infusion normally reverses the side effects.  Headaches and tingling have been 
observed at the City of Hope but were reversible.  Trace metals will be administered at 
the end of infusion to replace any depleted heavy metals. 
c. 
Drug Storage, Reconstitution and Stability 
The DTPA solution will be diluted with 250 mls normal saline and administered over 24 
hours.  Additional IV fluids will be administered to maintain a minimum of 125 mls/hour 
of fluid.  No other heavy metals should be administered during the 24 hour infusion.  
Potassium may be administered as needed.  DTPA has a long aqueous stability but should 


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be used within 48 hours of being drawn up by the pharmacy.  Patients will receive 250 
mgs/m2 to a maximum of a total dose of 500 mgs. 
5.0 
STAGING CRITERIA 
Staging of disease must be evaluated at least 21 days after the end of the last chemotherapy and 
within 42 days prior to transplant. 
5.1 
The Ann Arbor staging criteria will be used.  Stage is determined based on extent of 
disease at the time of diagnosis. 
5.2 
Ann Arbor Classification (AJCC Manual for Staging of Cancer, 4th ed. 1992) 
STAGE I 
Involvement of a single lymph node region (1) or a single extralymphatic organ or 
site (1E). 
STAGE II 
Involvement of two or more lymph node regions on the same side of the diaphragm 
(II) or localized involvement of an extralymphatic organ or site and its associated 
regional lymph nodes (11E). 
STAGE III 
Involvement of lymph node regions on both sides of the diaphragm (111) which may 
be accompanied by localized involvement of an associated extralymphatic organ or 
site (111E) or spleen (111S) or both (II(1SE). 
STAGE IV 
Diffuse or disseminated involvement of one or more extralymphatic organs with or 
without associated lymph node involvement, or isolated extralymphatic organ 
involvement with distant (non-regional) nodal involvement. 
A = Asymptomatic  
B = Fever, sweats, weight loss > 10% of body weight 
5.3 
Definitions of Sensitivity of Disease: 
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. 
05/10/00 
5.4 
Definitions of Poor Risk Disease 
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 aggressive NHL including mantle cell lymphoma who required 2 
different induction chemotherapy regimens to achieve a partial/complete 
remission. 


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05/03/01 
3. 
Patients with B-Cell NHL who fail to achieve a complete remission after adequate 
induction chemotherapy regimen(s). 
05/10/00 
6.0 
ELIGIBILITY CRITERIA 
05/10/00 
6.1 
Favorable biodistribution on imaging dose 
08/07/01 
6.2 
age  18 and  60 years  
10/29/03 
6.3 
All patients must have biopsy proven diagnosis of low- and intermediate-grade NHL 
including follicular small cleaved, follicular mixed, follicular large cell, diffuse small 
cleaved, diffuse mixed, diffuse large cell, and immunoblastic lymphoma (working 
formulation B, C, D, E, F, G and H) including mantle cell lymphoma. Transformed low-
grade lymphomas are eligible 
6.4 
Demonstrated monoclonal CD20 + B-cell population in lymph nodes and/or bone marrow 
05/10/00 
6.5 
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 
05/10/00,05/30/02 
10/29/03 
6.6 
Patients must have bone marrow aspiration and biopsy within 42 days before salvage 
chemotherapy or stem cell collection which show  10% lymphomatous involvement of 
total cellularity 
09/08/00, 05/30/02 6.7  
Platelet count should be normal before initiation of chemotherapy for salvage purposes or 
stem cell mobilization.  If the patient collected his/her stem cells at an outside facility, 
then the platelet count must be normal before the imaging dose of antibody 
6.8  
Normal renal function test with serum creatinine of  1.5 mg/dl, or a creatinine clearance 
of  60 ml/min 
6.9 
Adequate pulmonary function as measured by FEV1 > 65% of predicted measured, or a 
DLCO  50% of predicted measured 
04/06/04 
6.10 
Cardiac Ejection fraction of > 50% by echocardiogram or multiple gated acquisition scan 
6.11 
Adequate liver function tests with a bilirubin of  1.5 x normal and SGOT or SGPT  2 x 
normal 
6.12 
Negative human immunodeficiency virus antibody 
05/03/01 
6.13 
ECOG performance status 0 or 1; or KPS  80 
6.14 
No active CNS disease or prior history of CNS disease 
07/13/00 
6.15 
Patients who have received involved field external beam therapy to area excluding lung, 
heart, liver and kidney are allowed, but will be evaluated on a case by case basis 
6.16 
Patients must have recovered from last therapy and should be at least four weeks from 
prior radiation or chemotherapy 


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08/07/01 
6.17 
The patient should have a baseline CT scan and Ga 67 scan and/or FDG-PET scan after 
the last chemotherapy prior to initiation of treatment 
10/29/03 
6.18 
Normal cytogenetic study on bone marrow (prior to salvage chemotherapy or stem cell 
collection).  However, cytogenetic study on peripheral blood is acceptable if bone marrow 
biopsy has already been done and shows no sign of MDS or lymphoma and a repeat bone 
marrow is deemed unnecessary by attending physician 
7.0 
EXCLUSION CRITERIA 
7.1 
Presence of human anti-mouse antibody (HAMA) or human anti-chimeric antibody 
7.2 
Prior radioimmunotherapy 
7.3 
Failure to collect adequate number of CD34 + cells  3x106 /kg 
7.4 
Abnormal cytogenetic study on the bone marrow aspirate sample prior to stem cell 
collection 
7.5 
Prior bone marrow transplantation 
07/13/00 
7.6 
Prior malignancy except for adequately treated basal cell or squamous cell skin cancer, 
adequately treated noninvasive carcinomas, or other cancer from which the patient has 
been disease-free for at least five years 
7.7 
Active evidence of Hepatitis B and C infection; Hepatitis B surface antigen positive 
02/08/01 
7.8 
History of alcohol abuse 
10/29/03 
7.9 
Patient weighs more than 250 pounds 
8.0 
TREATMENT PLAN 
8.1 
Outline of the preparative regimen 
Day -21 
Dosimetry with 5 mCi IDEC-In2B8 following 250 mg/M2 Rituxan 
Day -14 
IDEC-Y2B8 with 5 mCi IDEC-In2B8 following 250 mg/M2 Rituxan  
05/30/02 
Day -7 
Bone marrow biopsy and dose estimation 
05/30/02, 10/29/03 
Day -4  
Etoposide 40 mg/kg adjusted ideal body weight (Cohort 1) or 60 mg/kg 
adjusted ideal body weight for other cohorts 
10/29/03 
Day -2  
Cyclophosphamide 100 mg/kg ideal body weight 
06/05/00 
Day 0  
DTPA infusion 
Day +1 
Peripheral Stem Cell reinfusion 
Day +1 
Start G-CSF 5 g/kg/d IV 


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07/13/00 
8.2 
Pre-Transplant Therapy 
10/29/03 
a. 
Autologous Stem Cell Collection and Cryopreservation 
All patients should have bone marrow aspiration and biopsy which show no microscopic 
evidence of lymphomatous involvement, or  10% involvement at the time of stem cell 
collection.  In addition, cytogenetic studies, immunophenotyping, gene rearrangement 
should be done.  Peripheral blood stem cells (PBSCs) will be collected via leukapheresis 
procedures that have been previously described.  Patients will receive PBSCs collected 
after mobilization by: 1) growth factors, ie. G-CSF 10 µg/kg/d or 2) chemotherapy with 
growth factors.  A minimum of CD34+ cells, 3.0 x 106/kg should be collected. 
b. 
Trimethoprim Sulfa 
All patients should receive trimethoprim sulfa (one double-strength tablet PO bid) 
beginning day -8 through day -2 prior to PBSCT as prophylaxis against PCP.  (The choice 
of trimethoprim sulfa as a prophylactic agent may be altered based on a history of 
sensitivity to this agent.)  Dosing should be discontinued 48 hours prior to PBSC infusion 
because of potential myelosuppression. 
10/29/03 
c. 
CNS Prophylaxis 
CNS prophylaxis is recommended for patients with mantle cell lymphoma or diffuse 
large cell lymphoma who had bone marrow involvement at diagnosis or at time of 
relapse.  For patients with mantle cell lymphoma who have never received high-dose 
MTX, CNS prophylaxis with intrathecal chemotherapy should be given. 
8.3 
Radioimmunotherapy 
08/07/01 
a. 
Rituxan 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.  If hypersensitivity or infusion-related events do not occur, escalate the 
infusion rate in 50 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. 
b. 
IDEC-In2B8 Administration - Two mg of IDEC-In2B8 (5.0 mCi of 111In) will be 
administered for the dosimetry portion of the protocol.  The imaging dose will be 
administered over 10 minutes by slow IV injection immediately following the 
infusion of Rituxan.  A .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. 
c. 
IDEC-Y2B8 Administration – IDEC-Y2B8 (40-100 mCi of 90Y with 3.2 – 6.4 mg 
of antibody) will be administered for the therapy portion of the protocol.  The 
yttrium will be combined with a dose of IDEC-In2B8 (5.0 mCi of 111In) identical 
to the dosimetry dose.  The combined radiopharmaceuticals will be administered 


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by controlled infusion pump over 20 minutes.  A .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-In/Y2B8 has been infused. 
d. 
Bone marrow biopsy. 
8.4 
Chemotherapy 
10/25/00, 12/20/00 
a. 
VP-16 is to be administered as a single infusion on day -4.  The dose is 40 or 60 
mg/kg and is calculated on adjusted ideal body weight to be consistent with 
standard VP-16 dosing for transplant protocols.  The drug is infused undiluted 
directly into a port of a double or triple lumen indwelling intravenous catheter, 
with a total infusion time of 4 hours.  The drug is to be drawn into one or more 
plastic syringes and infused with a syringe infusion pump, placed in an evacuated 
bottle and infused through a pediatric infusion pump, or infused by gravity 
without a pump.  Thus the total dose for a 70 kg patient would be 4,200 mg.  At 
20 mg/ml, the volume of VP-16 would be 210 ml.  The rate of infusion would 
thus be 210 ml/240 minutes or 0.875 ml/minute.  Appropriate anti-emetics and 
sedatives should be given before the infusion begins.  Before, and 2 hours into, 
the infusion the patient is to receive 25 mg of diphenhydramine, and 100 mg of 
hydrocortisone to prevent allergic reactions.  If necessary, diuretics may be given. 
 The intravenous hydration should be continued before, during and after the VP-
16.  Since in rare cases metabolic acidosis has been observed after high dose VP-
16, additional NaHCO3 may be needed. 
10/29/03 
b. 
Cyclophosphamide is administered at a total dose of 100 mg/kg given in one dose 
on day -2 and is calculated on ideal body weight.  Adjustments to the ideal body 
weight calculation for overweight patients are permitted.  For patients who are 
weigh less than 95% of ideal body weight, cyclophosphamide will be dosed 
according to actual body weight.  The drug should be dissolved in about 250 cc of 
D5W and infused IV over two hours.  Appropriate anti-emetics and sedatives 
should be given.  To prevent hemorrhagic cystitis, all patients should receive 
hydration with intravenous fluids, according to institutional standards, at the rate 
of 3.0 l/m2/day beginning four hours prior to cyclophosphamide and continuing 
until 24 hours after cyclophosphamide.  In addition, mesna at 40 mg/kg (based on 
ideal body weight) will be given immediately before cyclophosphamide (hr 0) and 
at 3, 6, 9, 12, 15, 18 and 21 hrs later for a total of 8 doses.  Each dose of mesna 
will be given IV over 15 minutes. 
06/05/00, 10/29/03, 06/16/04 
c. 
DTPA is to be administered by continuous intravenous infusion through a port of 
a double or triple lumen indwelling intravenous catheter.  The dose should be ≥ 
250 mgs/m2, but ≤ 500 mgs.  The DTPA should be made up in normal saline and 
infused over 24 hours by infusion pump.  No magnesium or other heavy metal 
should be given during the same time period.  Two hours after the end of the 
DTPA infusion 1 ml of trace metal solution should be infused every eight hours 
for five days.  This should be given by slow intravenous delivery or else as part of 
standard hyperalimentation.  Urine samples will be collected every 12 hours for 


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72 hours beginning 24 hours prior to DTPA infusion. 
07/13/00, 05/03/01 8.5 
Peripheral Stem Cell Reinfusion 
PBSCs will be thawed and infused according to standard guideline at approximately 72 hours 
after completion of cyclophosphamide. 
8.6 
Growth Factor Therapy 
All patients will receive rh-G-CSF, 5 mcg/kg/day IV beginning on day +1, after PBSC infusion 
and continue daily until ANC >500 for 3 consecutive days. 
07/13/00 
8.7 
Supportive Care: 
All patients will be housed in private rooms during the period of granulocytopenia.  
Nonabsorbable antibiotics for gastrointestinal decontamination should be used according to 
institutional guideline.  Trimethoprim-sulfamethoxazole will be administered from day -8 to day 
-2 and prophylaxis should be re-instituted when white blood cells are > 3000 and continued until 
6 months post-transplant.  Empiric broad spectrum antibiotics and parenteral nutrition should be 
used as clinically indicated.  Low-dose amphotericin-B (0.1 to 0.2 mg/kg) should be administered 
on day +1 and continued daily until granulocytopenia resolves.  All blood components should be 
irradiated to 1,500 cGy. 
a. 
Access to Vessels 
Prior to admission, during pre-transplant evaluation, all patients should have a permanent 
central catheter placed. 
b. 
Hyperalimentation 
All patients will receive appropriate Hyperalimentation as soon as necessary after 
admission.  The goal will be to prevent even a short duration of negative nitrogen 
balance. 
c. 
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. 
d. 
Management of Fever/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 


IRB PROTOCOL #98153 
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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 antifungal therapy with Amphotericin-B. 
8.8 
Criteria for Removal from Protocol Treatment 
a. 
Progression of disease. 
b. 
Patients may withdraw from study at any time for any reason. 
8.9 
All reasons for discontinuation of treatment must be documented in the Flow Sheets. 
8.10 
All patients will be followed for survival until death.  Secondary malignancy monitoring 
on this protocol will be done through 5 years post HCT.  After such time, secondary 
malignancy monitoring will be done by the Long Term Follow Up office.   
9.0 
STUDY DESIGN AND RULES FOR DOSE ESCALATION 
This is a phase I/II trial.  For the phase I portion of the study, the rules for dose escalation, dose 
expansion, and termination of escalation are given in section 9.2.  Prior to treatment with Y2B8, 
patients are required to undergo an imaging scan to verify that they have a favorable 
biodistribution.  While waiting to assess toxicities in the initial cohort of 3 to 6 patients, 
additional patients who are determined to be eligible may be accrued at the unescalated dose 
level.  The rationale for this is twofold.  First, patients must be evaluated for distribution as soon 
as possible in order to have patients ready for timely accrual to the next dose level.  If the dose 
escalation decision is delayed, the investigators want to treat the patients at the unescalated dose 
level so that their disease does not progress.  Second, patients will be accrued to unescalated dose 
levels to avoid a loss of momentum in patient accrual.  Modifications to the standard phase I 
design involving accrual of cohorts of 3-6 patients per dose level have been incorporated to 
appropriately handle the varying number of patients accrued to each dose level (see section 9.2).  
Study design considerations and targeted response rates for the phase II portion of the trial are 
given in section 9.3.  Because the eligibility criteria are the same for both the phase I and the 
phase II portions of the trial, the patients treated at the dose level defined as the MTD from the 
phase I portion of the trial will count towards the accrual for the phase II portion of the trial. 
9.1 
Dose Limiting Toxicity (DLT) 
05/03/01  
Dose limiting toxicity (DLT) in a given patient is defined as any grade III non-hematologic 
toxicity not reversible to grade II or less within 96 hours, or any grade IV non-hematologic 
toxicity.  Toxicity will be graded according to the NCI Common Toxicity Criteria (CTC) version 
2.0 and toxicity Module (Appendices I and II, http://ctep.info.nih.gov/ctc3/ctc.htm) with the 
addition of BMT Complex/Multi-Component Events (Appendix VI, http://ctep.info.nih.gov/ctc3/ 
ctc.htm).  To be evaluable for toxicity, a patient must receive a complete course of treatment and 
be observed for 6 weeks after the administration of Y2B8 or have experienced a DLT.  All 
patients who are not evaluable for toxicity will be replaced. 


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9.2 
Definition of Maximum Tolerated Dose (MTD) and DLT-Level and Rules for Dose 
Escalation 
This trial differs from the standard phase I design in that additional patients beyond the standard 
3 or 6 patients per dose level may be accrued to the current dose level while waiting to assess 
toxicities in the initial 3 or 6 patients.  To this end, a decision rule has been added that 
incorporates toxicity information from the additional patients accrued to a dose level.  As toxicity 
information on each additional patient accrued to the trial becomes available, the decision to 
escalate, de-escalate and expand the previous dose level, expand the current cohort or stop the 
trial will be evaluated.  The decision rule (R) will be as follows:  Let x = number of DLTs in n 
patients.  Escalate to the next dose level if R = (x + 0.5) / (n + 2) is ≤ 0.20.  Stop accrual to a dose 
level if R > 0.30.  Continue accrual to a dose level if 0.20 < R ≤ 0.30.  A minimum of three 
patients must be accrued to a dose level.  As soon as 3 patients have been accrued to a dose level 
and toxicity has been assessed, escalation to the next level is allowed, provided that acceptable 
toxicity has been observed.  If accrual to a dose level must be expanded due to toxicity, a 
minimum of 6 patients must be accrued to the expanded dose level. 
Operationally, the rule is to close a dose level and de-escalate if 2 DLTs are observed among 6 or 
fewer patients, or if 3 DLTs are observed among any number of patients.  The dose will be 
escalated if 0 DLTs are observed in 3 or more evaluated patients, if 1 DLT is observed in 6 or 
more evaluated patients, or if 2 DLTs are observed in 11 patients.  At most, 11 patients will be 
accrued to a dose level.  However, if a dose is escalated while toxicity follow-up is still 
outstanding for some patients, the accumulating results from the two dose levels may be pooled 
for the purpose of justifying the continued accrual to the higher dose. 
Table 1 shows values for R based on different combinations of DLTs and numbers of patients.  
Values indicating continued accrual to the current dose are shown in bold. 
Table 1 
 
Number of DLTs (x) 
Number of  
Patients (n) 
 
0 
 
1 
 
2 
 
3 
0.10 
0.30 
0.50 
 
4 
0.08 
0.25 
0.42 
 
5 
0.07 
0.21 
0.36 
 
6 
0.06 
0.19 
0.31 
 
7 
0.06 
0.17 
0.28 
 
8 
0.05 
0.15 
0.25 
 
9 
0.05 
0.14 
0.23 
 
10 
0.04 
0.13 
0.21 
 
11 
0.04 
0.12 
0.19 
This criterion is the posterior mean with a beta (0.5, 1.5) prior, which has a smaller mean, but is 
no more informative than a flat prior.  The criterion is consistent with the conventional rule of 
expanding a dose level to six patients if 1 out of 3 patients experience DLT and stopping if 2 or 


IRB PROTOCOL #98153 
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more patients out of 6 treated at the same dose level experience DLT.  The proposed criterion 
rationalizes the conventional design in order to rationally extend if to larger numbers of patients 
per dose level.  The rationalization is that a dose level is opened with a weak prior expectation of 
a 25% DLT rate, and the dose is escalated or de-escalated as the accumulating data indicate a rate 
below 20% or above 30%. 
The phase I portion of the trial will be closed when 6 patients have been accrued to the highest 
dose level below the DLT level with at most 1 patient experiencing DLT or when 11 patients 
have been accrued with at most 2 patients experiencing DLT.  This dose level will be defined as 
the MTD. 
To demonstrate an application of the escalation rule, consider the following examples: 
Example 1:  Three patients are accrued to dose level 1.  A fourth patient is accrued to the trial 
prior to assessment of toxicity for the third patient and is therefore also treated at dose level 1.  
No DLTs are observed in the first 3 patients such that the fifth patient is accrued to dose level 2 
and subsequent to this the fourth patient accrued to dose level 1 experiences a DLT.  With 1 DLT 
in four patients, from Table 1 the value for R is 0.25 therefore accrual to dose level 2 must be 
halted such that accrual to dose level 1 can be expanded.  Six patients will need to be accrued 
with at most 1 out of 6 patients experiencing DLT in order for accrual to dose level 2 to resume.  
The patient treated at dose level 2 may be counted among the required 6 patients if no DLT is 
encountered. 
Example 2:  Dose level 3 is expanded such that 6 patients are accrued.  A seventh patient is 
accrued to the trial prior to assessment of toxicity for the sixth patient and is therefore also 
treated at dose level 3.  Only one DLT is observed in the first 6 patients such that the eighth 
patient is accrued to dose level 4 and subsequent to this the seventh patient accrued to dose level 
3 experiences a DLT.  With 2 DLTs in seven patients, from Table 1 the value for R is 0.28 
therefore accrual to dose level 4 must be halted so that accrual to dose level 3 can be expanded.  
Eleven patients (including the patient treated at dose level 4) will need to be accrued to dose level 
3 (or above) with at most 2 patients experiencing DLTs in order for accrual to dose level 4 to 
resume.  Two DLTs among 11 patients corresponds to R = 0.19 which is consistent with 1 DLT 
among 6 patients.  A maximum of 11 patients can be accrued to a single dose level. 
9.3 
Design Considerations for the Phase II Trial 
All patients accrued to the dose level established to be the MTD will be included in the 
assessment of response for the phase II portion of the trial.  The primary goal of this portion of the 
trial is to obtain estimates of the efficacy of IDEC-Y2B8 in combination with high-dose etoposide 
and cyclophosphamide followed by ASCT for treatment of patients with relapsed and refractory 
NHL.  A minimum of 17 and a maximum of 37 patients will be accrued to this portion of the trial.  
Justification for the sample size as well as a description of the study design for the phase II portion 
of the trial is provided in section 12.0. 


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10.0 STUDY CALENDAR - PREPARATIVE REGIMEN AND PBSCT 
REQUIRED STUDIES 
Pre 
Study 
DAY 
-21 
DAY 
-14 
DAY 
-7 
DAY 
-4 
DAY 
-2 
DAY 
0 
DAY 
7 
DAY 
14 
DAY 
30 
DAY 
60 
DAY 
100 
DAY 
180 
YR 
1 
YR 
2 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H & PE 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X$ 
10/29/03 
Weight and KPS 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X$ 
Tumor Assessment 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X$ 
Toxicity Notation 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X$ 
X$ 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10/29/03 
CBC/Platelets 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X$ 
10/29/03 
Differential¥ 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X$ 
08/07/01, 10/29/03 
HAMA/HACA 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X« 
X 
 
10/29/03 
Comp Metabolic Panel + LDH 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X$ 
10/29/03 
Magnesium 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
PT/PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoglobulin Levels 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
08/07/01 
Peripheral Blood Mononuclear 
Immunophenotyping 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
CMV Titer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis Profile 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10/29/03 
Herpes Simplex 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
08/07/01, 05/30/02 
BM%, # 
X 
 
 
X^ 
 
 
 
 
 
 
 
X 
 
X 
X 
05/03/01 
Creatinine Clearance 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
05/30/02 
Chest X-ray or CT Chest 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
X 
X& 
05/30/02 
CT scans*, + 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X& 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
MUGA or ECHO 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
DLCO/FEV1 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
08/07/01, 10/29/03, 
04/06/04 
Ga 67 Scan and/or FDG-PET 
Scan 
X¢ 
 
 
 
 
 
 
 
 
X  
 
 
X 
X 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stem Collections 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IDEC-In2B8 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IDEC-Y2B8 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Rituxan 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
VP-16 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
06/16/04 
PBSCT 
 
 
 
 
 
 
X§ 
 
 
 
 
 
 
 
 
06/16/04 
G-CSF 
 
 
 
 
 
 
X§ 
 
 
 
 
 
 
 
 
06/05/00 
DTPA 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
10/29/03 (delete @,06/20/07) &  restaging at Day 100, at 6 months then follow-up evaluation every six months for three years, and then yearly up to 5 yrs post BMT 
$  All late complications such as cataracts formation and occurrence of second malignancies must be documented and reported. 
*  CT scans of chest, abdomen and pelvis as indicated 
08/07/01 (delete #, add^) 
^  biopsy core for determination of radioactivity 
05/03/01 
%  bone marrow aspiration and biopsy, cytogenetic study, immunophenotyping and gene rearrangement 
05/30/02, 06/20/07 
#  Follow-up bone marrow is required at day 180, yr 1 up to 5 yrs post BMT. 
05/30/02, 10/29/03 
+  For pts in CR at time of transplant, CT scans to be done between days 30 and 100. 
10/29/03 
«  Day 180 HAMA/HACA acceptable between days 150 and 210 
10/29/03 
¢  Pre-study PET scan should be done 14 days after stem cell collection to avoid GCSF enhancement effect 
10/29/03  
¥  ANC is acceptable in lieu of differential 
04/06/04 
  If PET scan positive at baseline, day +30 PET scan required 
06/16/04 
§  Day +1 


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11.0 
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 .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. 
05/30/02 
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 Status, 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. 
11.1 
Complete Response (CR) 
Complete disappearance of all measurable evidence of non-evaluable disease.  No new lesions.  
No disease related symptoms.  No evidence of non-evaluable disease, including normalization of 
markers and other abnormal lab values.  All measurable, evaluable and non-evaluable lesions and 
sites must be assessed using the same techniques as baseline.  Refers to clinical CR-when 
restaging surgery is required, a separate pathologic response variable is defined. 
11.2 
Partial Response (PR) 
Applies only to patients with at least one measurable lesion.  Greater than or equal to 50% 
decrease under baseline in the sum of products of perpendicular diameters of all measurable 
lesions.  No progression of evaluable disease. No new lesions.  All measurable and evaluable 
lesions and sites must be assessed using the same techniques as baseline. 
11.3 
Stable Disease (SD) 
Does not qualify for CR, PR or Progression.  All measurable and evaluable sites and lesions must 
be assessed using the same techniques as baseline. 
11.4 
Progressive Disease (PD)  
50% increase or an increase of 10 cm2 (whichever is smaller) in the sum of products of all 
measurable lesions over smallest sum observed (over baseline if no decrease) using the same 


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techniques as baseline, OR clear worsening of any evaluable disease, OR reappearance of any 
lesion which had disappeared, OR appearance of any new lesion/site, OR failure to return for 
evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). For 
“scan only” bone disease, increased uptake does not constitute clear worsening.  Worsening of 
existing non-evaluable disease not constitute progression. 
11.5 
Relapse 
08/07/01 
Relapse is defined as the re-appearance of any clinical evidence of lymphoma in a patient who 
has had a CR.  Relapse for partial responders are defined as progressive disease relative to 
disease status during the partial remission. 
11.6 
Duration of Response 
This is measured from the documented beginning of response (CR or PR) 
11.7 
Performance Status  
Patients will be graded according to the current Performance Status Scales/Scores (Appendix 
IV). 
11.8 
Time to Progression 
From date of registration to date of first observation of progressive disease or death due to any 
cause. 
11.9 
Time to Death 
From date of registration to date of death due to any cause. 
12.0 
STATISTICAL CONSIDERATIONS 
12.1 
Study Design and Justification of Sample Size 
The definition of dose limiting toxicity is given in section 6.1.  The maximum tolerated dose is 
defined in section 6.2.  The number of patients to be treated at each dose level examined in the 
phase I trial as well as the rules for dose escalation is given in section 6.2. 
The phase II portion of the study will follow a two-stage minimax design suggested by Simon (1).  
It is assumed that a true response rate less than 20% would not warrant further study of this agent.  
It is also assumed that a response rate of 40% would be considered promising for further studies in 
these patients.  In the first stage, seventeen evaluable patients will be entered.  If less than four 
responses are observed, the accrual will stop with the conclusion that the regimen is not promising 
for further study.  If four or more responses are observed in the first 17 patients, additional 20 
patients will be accrued during the second stage of the study.  Eleven or more responses out of 37 
patients will be considered as evidence warranting further study of the regimen providing other 
factors, such as toxicity and survival, also appear favorable.  If less than 11 responses out of 37 
patients are observed, further study of the regimen would not be warranted. 
The probability of falsely declaring an agent with a 20% response probability as  warranting further 


IRB PROTOCOL #98153 
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study is 0.10 (alpha) and the probability of correctly declaring an agent with a 40% response 
probability as warranting further study is 0.90 (power). With 37 patients the true probability of 
response can be estimated with a maximum standard error equal to 0.08. 
The phase I portion study is expected to accrue a minimum of 15-18 evaluable patients and a 
maximum of 30.  The phase II portion of the study will accrue a minimum of 17 patients and a 
maximum of 37 patients, of which at least six of these patients will have been included in the 
phase I portion of the study.  It should take approximately 24-36 months to complete both the 
phase I and phase II portions of this trial. 
12.2 
Analysis of Clinical Endpoints 
Patients will be considered evaluable for response and evaluable for toxicity as outlined in section 
11.0.  The toxicities observed at each dose level will be summarized in terms of type (organ 
affected or laboratory determination such as absolute neutrophil count), severity (by NCI 
Common Toxicity Criteria and nadir or maximum values for the laboratory measures), time of 
onset (i.e. course number), duration, and reversibility or outcome.  Tables will be created to 
summarize these toxicities and side effects by dose and by course.  Baseline information (e.g. the 
extent of prior therapy) and demographic information will be presented, as well, to describe the 
patients treated in the phase I portion of the study.  All responses will be reported from the phase 
I portion of the study 
Response rates and duration of response will be estimated for the phase II portion of survival.  
Confidence intervals for the response rate will be established by calculating exact 95% 
confidence limits for a binomial parameter.  The duration of overall and disease-free survival of 
the patient will be estimated using the product-limit method of Kaplan and Meier. 
13.0 
REGISTRATION GUIDELINES 
08/07/01 
Once a signed, written informed consent has been obtained and all pretreatment evaluations have 
been performed, patients will be entered on study, after review of patient eligibility criteria by the 
assigned Data Manager from the City of Hope Department of Biostatistics.  Patients may be 
screened for registration by calling the Department of Biostatistics, ext. 62468. 
14.0 
RECORDS TO BE KEPT AND DATA SUBMISSION SCHEDULE 
14.1 
Confidentiality of Records 
The original data collection forms will be stored in secure cabinets in the Department of 
Biostatistics.  All radioimmunotherapy associated data will be kept in the Department of 
Radioimmunotherapy. 
14.2 
Patient Consent Form 
At the time of registration, signed and dated copies of the patient Informed Consent form with 
the Human Rights must be available (for patient, chart, and Biostatistics Office). 


IRB PROTOCOL #98153 
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15.0 
GENDER AND MINORITIES 
15.1 
Planned Gender and Minority Inclusion for Transplant Patients with Intermediate 
Grade Lymphoma at City of Hope 
 
American 
Indian or 
Alaskan 
Native 
Asian or 
Pacific 
Islander 
Black, 
not of 
Hispanic 
Origin 
Hispanic 
White, 
not of 
Hispanic 
Origin  
White, 
Hispanic 
or not-
Hispanic 
Unknown 
Other or 
Unknown 
Total 
Female 
 
0% 
 
9% 
 
4% 
 16% 
 
54% 
 
17% 
 
0% 
 100% 
Male 
 
0% 
 
5% 
 
2% 
 20% 
 
60% 
 
12% 
 
1% 
 100% 
Unknown 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
15.2 
Actual Gender and Minority Inclusion for Transplant Patients with Intermediate 
Grade Lymphoma at City of Hope 
 
American 
Indian or 
Alaskan 
Native 
Asian or 
Pacific 
Islander 
Black, 
not of 
Hispanic 
Origin 
Hispanic 
White, 
not of 
Hispanic 
Origin  
White, 
Hispanic 
or not-
Hispanic 
Unknown 
Other or 
Unknown 
Total 
Female 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
Male 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
Unknown 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
16.0 
DATA MANAGEMENT 
Clinical Statistics maintains a patient database at City of Hope Medical Center, Department of 
Biostatistics to allow 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 unique patient number to assure 
patient confidentiality. Any publications or presentations refer to patient by unique patient 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.  They are maintained by the COHMC data collection staff.  
Access is restricted to personnel authorized by the Division of Clinical Research. 
17.0 
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, 


IRB PROTOCOL #98153 
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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, or IDEC 
Pharmaceuticals Corporation. 
18.0 
REFERENCES 
 1. Parker SL, Tong T, Bolden S, Wingo PA: Cancer Statistics, 1997 [published erratum 
appears in CA Cancer J Clin 1997 Mar-Apr;47(2):68].  CA.Cancer J.Clin. 47:5, 1997 
 2. Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman 
CAJ, Miller TP: Comparison of a Standard Regimen (CHOP) with Three Intensive 
Chemotherapy Regimens for Advanced Non-Hodgkin's Lymphoma [see comments].  
N.Engl.J.Med. 328:1002, 1993 
 3. Vose JM, Anderson JR, Kessinger A, Bierman PJ, Coccia P, Reed EC, Gordon B, 
Armitage JO: High-Dose Chemotherapy and Autologous Hematopoietic Stem-Cell 
Transplantation for Aggressive Non-Hodgkin's Lymphoma [see comments].  J.Clin.Oncol. 
11:1846, 1993 
 4. Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, Sonneveld P, 
Gisselbrecht C, Cahn JY, Harousseau JL: Autologous Bone Marrow Transplantation as 
Compared with Salvage Chemotherapy in Relapses of Chemotherapy-Sensitive Non-
Hodgkin's Lymphoma [see comments].  N.Engl.J.Med. 333:1540, 1995 
 5. Bierman PJ, Vose JM, Anderson JR, Bishop MR, Kessinger A, Armitage JO: High-Dose 
Therapy with Autologous Hematopoietic Rescue for Follicular Low-Grade Non-Hodgkin's 
Lymphoma.  J.Clin.Oncol. 15:445, 1997 
 6. Nademanee A, Schmidt GM, O'Donnell MR, Snyder DS, Parker PM, Stein A, Smith E, 
Molina A, Wong KK, Stepan DE, Margolin KA, Somlo G, Raschko J, Sniecinski I, Lipsett 
JA, Dagis A, Niland JC, Forman SJ: Fractionated Total Body Irradiation (FTBI), High-
Dose Etoposide (VP-16) and Cyclophosphamide (CY) Followed by Autologous Bone 
Marrow Transplantation (ABMT):  The Results in 110 Patients with Non-Hodgkin's 
Lymphoma (NHL).  Blood 82:143a (559), 1993 (abstr.) 
 7. Horning SJ, Negrin RS, Chao JC, Long GD, Hoppe RT, Blume KG: Fractionated Total-
Body Irradiation, Etoposide, and Cyclophosphamide Plus Autografting in Hodgkin's 
Disease and Non-Hodgkin's Lymphoma.  J.Clin.Oncol. 12:2552, 1994 
 8. Weaver CH, Petersen FB, Appelbaum FR, Bensinger WI, Press O, Martin P, Sandmaier B, 
Deeg HJ, Hansen JA, Brunvand M: High-Dose Fractionated Total-Body Irradiation, 
Etoposide, and Cyclophosphamide Followed by Autologous Stem-Cell Support in Patients 
with Malignant Lymphoma.  J.Clin.Oncol. 12:2559, 1994 
 9. Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, 
Janakiraman N, Foon KA, Liles TM, Dallaire BK, Wey K, Royston I, Davis T, Levy R: 
IDEC-C2B8 (Rituximab) Anti-CD20 Monoclonal Antibody Therapy in Patients With 
Relapsed Low-Grade Non-Hodgkin's Lymphoma.  Blood 90:2188, 1997 
 10. McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman 
MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, 
Dallaire BK: Rituximab Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed 
Indolent Lymphoma:  Half of Patients Respond to a Four-Dose Treatment Program.  
Journal of Clinical Oncology 16:2825, 1998 
 11. Czuczman M, Grillo-López AJ, White CA, Saleh M, Gordon L, LoBuglio AF, Jonas C, 
Dallaire B, Varns C: IDEC-C2B8/CHOP Chemoimmunotherapy in Patients With Low-


IRB PROTOCOL #98153 
PAGE 27 
VERSION 17 
03/28/14 
 
Grade Lymphoma:  Clinical and BCL-2 (PCR) Final Results.  Blood 88:453a (1799), 1996 
(abstr.) 
 12. Kaminski MS, Zasadny KR, Francis IR, Milik AW, Ross CW, Moon SD, Crawford SM, 
Burgess JM, Petry NA, Butchko GM: Radioimmunotherapy of B-Cell Lymphoma with 
[131I]Anti-B1 (Anti-CD20) Antibody.  N.Engl.J.Med. 329:459, 1993 
 13. Stagg R, Wahl RL, Estes J, Tidmarsh G, Kroll S, Shochat D, Zasadny K, Kaminski MS: 
Phase I/II Study of Iodine-131 Anti-B1 Antibody for Non-Hodgkin's Lymphoma (NHL):  
Final Results.  Proceedings of ASCO 17:39a (150), 1998 (abstr.) 
 14. Vose J, Saleh M, Lister A, Rohatiner A, Knox S, Radford J, Zelenetz AD, Stagg R, 
Tidmarsh G, Wahl R, Kaminski MS: Iodine-131 Anti-B1 Antibody for Non-Hodgkin's 
Lymphoma (NHL):  Overall Clinical Trial Experience.  Proceedings of ASCO 17:10a (38), 
1998 (abstr.) 
 15. Press OW, Eary JF, Appelbaum FR, Martin PJ, Badger CC, Nelp WB, Glenn S, Butchko G, 
Fisher D, Porter B: Radiolabeled-Antibody Therapy of B-Cell Lymphoma With Autologous 
Bone Marrow Support [see comments].  N.Engl.J.Med. 329:1219, 1993 
 16. Press O, Eary J, Liu S, Petersdorf S, Bush S, Durack L, Martin P, Maloney D, Matthews D, 
Fisher D, Gooley T, Appelbaum F, Bernstein I: A Phase I/II Trial of High Dose Iodine-131-
Anti-B1 (Anti-CD20) Monoclonal Antibody, Etoposide, Cyclophosphamide, and 
Autologous Stem Cell Transplantation for Patients With Relapsed B Cell Lymphomas.  
Proceedings of ASCO 17:3a (9), 1998 (abstr.) 
 17. Knox SJ, Goris ML, Trisler K, Negrin R, Davis T, Liles TM, Grillo-Lopez A, Chinn P, 
Varns C, Ning S, Fowler S, Deb N, Becker M, Marquez C, Levy R: Yttrium-90-Labeled 
Anti-CD20 Monoclonal Antibody Therapy of Recurrent B-Cell Lymphoma.  Clin.Cancer 
Res. 2:457, 1996 
 18. Witzig T, Wiseman G, White CA, Solinger A, Gordon L, Raubitschek A, Emmanoulides C, 
Royston I, Parker E, Chinn P, Grillo-López A: IDEC-Y2B8 90Yttrium Anti-CD20 
Radioimmunotherapy of Relapsed Non-Hodgkin's Lymphoma (NHL):  Interim Results of a 
Phase I/II Trial.  Blood 90:586a (2606), 1997 (abstr.) 
 19. Wiseman GA, Solinger AM, Grillo-López A, Stabin M, Dunn WL, Witzig TE, Spies S, 
Gordon L, Raubitschek A, Margolin K, Karvelis K, Janakiraman N, Silverman DH, 
Emmanoulides C, Royston I, Chinn P, Parker E, Carter W, White CA: IDEC-Y2B8 (90Y 
Conjugated Anti-CD20) Dosimetry Calculated From 111In Anti-CD20 in Patients With Low 
and Intermediate Grade B-Cell Non-Hodgkin's Lymphoma (NHL) Emphasis on Bone 
Marrow (BM).  Blood 90:510a (2273), 1997 (abstr.) 
20. Witzig TE, White CA, Wiseman GA, Gordon LI, Emmanoulides C, Raubitschek A, 
Janakiraman N, Gutheil J, Schilder RJ, Spies S, Silverman DH, Parker E, and Grillo-López 
A:  Phase I/II Trial of Yttrium 90 Ibritumomab Tiuxetan (IDEC-Y2B8) 
Radioimmunotherapy for Treatment of Relapsed or Refractory CD20 Positive B-Cell Mon-
Hodgkin’s Lymphoma.  Submitted 1999. 
 


IRB PROTOCOL #98153 
PAGE A1 
VERSION 17 
03/28/14 
 
1 
Appendix I 
Common Toxicity Criteria (CTC) 
 
FINAL 1/30/98 
CTC Version 2.0 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
ALLERGY/IMMUNOLOGY 
Allergic reaction/ 
hypersensitivity  
(including drug 
fever) 
none 
transient rash, 
drug fever < 
38°C (<100.4°F) 
urticaria, drug 
fever  38°C 
( 100.4°F), 
and/or 
asymptomatic 
bronchospasm 
symptomatic 
bronchospasm, 
requiring 
parenteral 
medication(s), 
with or without 
urticaria; allergy-
related 
edema/angioede
ma 
anaphylaxis 
Note: Isolated urticaria, in the absence of other manifestations of an allergic or hypersensitivity reaction, is graded in the 
DERMATOLOGY/SKIN category. 
Allergic rhinitis  
(including sneezing, 
nasal stuffiness, 
postnasal drip) 
none 
mild, not 
requiring 
treatment 
moderate, 
requiring 
treatment 
- 
- 
Autoimmune 
reaction 
none 
serologic or other 
evidence of 
autoimmune 
reaction but 
patient is 
asymptomatic 
(e.g., vitiligo), all 
organ function is 
normal and no 
treatment is 
required 
evidence of 
autoimmune 
reaction 
involving a non-
essential organ or 
function (e.g., 
hypothyroidism), 
requiring 
treatment other 
than 
immunosuppressi
ve drugs 
reversible 
autoimmune 
reaction 
involving 
function of a 
major organ or 
other toxicity 
(e.g., transient 
colitis or anemia), 
requiring short-
term 
immunosuppressi
ve treatment 
autoimmune 
reaction causing 
major grade 4 
organ 
dysfunction; 
progressive and 
irreversible 
reaction; long-
term 
administration of 
high-dose 
immuno-
suppressive 
therapy required 
Also consider Hypothyroidism, Colitis, Hemoglobin, Hemolysis. 
Serum sickness 
none 
- 
- 
present 
- 
Urticaria is graded in the DERMATOLOGY/SKIN category if it occurs as an isolated symptom. If it occurs with other 
manifestations of allergic or hypersensitivity reaction, grade as Allergic reaction/hypersensitivity above. 
Vasculitis 
none 
mild, not 
requiring 
treatment 
symptomatic, 
requiring 
medication 
requiring steroids 
ischemic changes 
or requiring 
amputation 
Allergy/Immunology
-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 


IRB PROTOCOL #98153 
PAGE A2 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
AUDITORY/HEARING 
Conductive hearing loss is graded as Middle ear/hearing in the AUDITORY/HEARING category. 
Earache is graded in the PAIN category. 
External auditory 
canal 
normal 
external otitis 
with erythema or 
dry desquamation 
external otitis 
with moist 
desquamation 
external otitis 
with discharge, 
mastoiditis 
necrosis of the 
canal soft tissue 
or bone 
Note: Changes associated with radiation to external ear (pinnae) are graded under Radiation dermatitis in the 
DERMATOLOGY/SKIN category. 
Inner ear/hearing 
normal 
hearing loss on 
audiometry only 
tinnitus or 
hearing loss, not 
requiring hearing 
aid or treatment 
tinnitus or 
hearing loss, 
correctable with 
hearing aid or 
treatment 
severe unilateral 
or bilateral 
hearing loss 
(deafness), not 
correctable 
Middle ear/hearing 
normal 
serous otitis 
without 
subjective 
decrease in 
hearing 
serous otitis or 
infection 
requiring medical 
intervention; 
subjective 
decrease in 
hearing; rupture 
of tympanic 
membrane with 
discharge 
otitis with 
discharge, 
mastoiditis or 
conductive 
hearing loss 
necrosis of the 
canal soft tissue 
or bone 
Auditory/Hearing-
Other 
(Specify, 
) 
normal 
mild 
moderate 
severe 
life-threatening or 
disabling 
BLOOD/BONE MARROW 
Bone marrow 
cellularity 
normal for 
age 
mildly 
hypocellular or 
25% reduction 
from normal 
cellularity for age 
moderately 
hypocellular or 
>25 -  50% 
reduction from 
normal cellularity 
for age or >2 but 
<4 weeks to 
recovery of 
normal bone 
marrow 
cellularity 
severely 
hypocellular or 
>50 -  75% 
reduction in 
cellularity for age 
or 4 - 6 weeks to 
recovery of 
normal bone 
marrow 
cellularity 
aplasia or >6 
weeks to recovery 
of normal bone 
marrow 
cellularity 
Normal ranges: 
 
 
 
 
 
children (  18 years) 
90% 
cellularity 
average 
 
 
 
 
younger adults (19-
59) 
60-70% 
cellularity 
average 
 
 
 
 
older adults (  60 
years) 
50% 
cellularity 
average 
 
 
 
 
Note: Grade Bone marrow cellularity only for changes related to treatment not disease. 


IRB PROTOCOL #98153 
PAGE A3 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
CD4 count 
WNL 
< LLN - 
500/mm3 
200 - < 500/mm3 
50 - < 200/mm3 
< 50/mm3 
Haptoglobin 
normal 
decreased 
- 
absent 
- 
Hemoglobin (Hgb) 
WNL 
< LLN - 10.0 g/dl 
< LLN - 100 g/L 
< LLN - 6.2 
mmol/L 
8.0 - < 10.0 g/dl 
80 - < 100 g/L 
4.9 - < 6.2 
mmol/L 
6.5 - < 8.0 g/dl 
65 - 80 g/L 
4.0 - < 4.9 
mmol/L 
< 6.5 g/dl 
< 65 g/L 
< 4.0 mmol/L 
Note: The following criteria may be used for leukemia studies or bone marrow infiltrative/myelophthisic process if the 
protocol so specifies. 
For leukemia studies 
or bone marrow 
infiltrative/ 
myelophthisic 
processes 
WNL 
10 - <25% 
decrease from 
pretreatment 
25 - <50% 
decrease from 
pretreatment 
50 - <75% 
decrease from 
pretreatment 
75% decrease 
from pretreatment 
Hemolysis (e.g., 
immune hemolytic 
anemia, drug-related 
hemolysis, other) 
none 
only laboratory 
evidence of 
hemolysis [e.g., 
direct 
antiglobulin test 
(DAT, Coombs’) 
schistocytes] 
evidence of red 
cell destruction 
and  2gm 
decrease in 
hemoglobin, no 
transfusion 
requiring 
transfusion 
and/or medical 
intervention (e.g., 
steroids) 
catastrophic 
consequences of 
hemolysis (e.g., 
renal failure, 
hypotension, 
bronchospasm, 
emergency 
splenectomy) 
Also consider Haptoglobin, Hgb. 
Leukocytes (total 
WBC) 
WNL 
< LLN - 3.0 x 109 
/L 
< LLN - 
3000/mm3 
2.0 - < 3.0 x 109 
/L 
2000 - < 
3000/mm3 
1.0 - < 2.0 x 109 
/L 
1000 - < 
2000/mm3 
< 1.0 x 109 /L 
< 1000/mm3 
For BMT studies: 
WNL 
2.0 - <3.0 X 
109/L 
2000 - 
<3000/mm3 
1.0 - <2.0 x 109 
/L 1000 - 
<2000/mm3 
0.5 - <1.0 x 109 
/L 500 - 
<1000/mm3 
<0.5 x 109 /L 
<500/mm3 
Note: The following criteria using age, race and sex normal values may be used for pediatric studies if the protocol so 
specifies. 
 
75 - <100% 
LLN 
50 - <75% LLN 
25 - 50% LLN 
<25% LLN 
Lymphopenia 
WNL 
<LLN - 1.0 x 109 
/L 
<LLN - 
1000/mm3 
0.5 - <1.0 x 109 
/L 
500 - 
<1000/mm3 
<0.5 x 109 /L 
<500/mm3 
- 
Note: The following criteria using age, race, and sex normal values may be used for pediatric studies if the protocol so 
specifies. 
 
75-<100%LLN 
50-<75%LLN 
25-<50%LLN 
<25%LLN 
Neutrophils/granuloc
ytes 
(ANC/AGC) 
WNL 
1.5 - <2.0 x 109 
/L 
1500 - 
<2000/mm3 
1.0 - <1.5 x 109 
/L 
1000 - 
<1500/mm3 
0.5 - <1.0 x 109 
/L 
500 - 
<1000/mm3 
< 0.5 x 109 /L 
< 500/mm3 
For BMT: 
WNL 
1.0 - <1.5 x 109 
/L 
1000 - 
<1500/mm3 
0.5 - <1.0 x 109 
/L 
500 - 
<1000/mm3 
0.1 - <0.5 x 109 
/L 
100 - <500/mm3 
<0.1 x 109 /L 
<100/mm3 


IRB PROTOCOL #98153 
PAGE A4 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Note: The following criteria may be used for leukemia studies or bone marrow infiltrative/myelophthisic process if the 
protocol so specifies. 
For leukemia studies 
or bone marrow 
infiltrative/ 
myelophthisic 
process 
WNL 
10 - <25% 
decrease from 
baseline 
25 - <50% 
decrease from 
baseline 
50 - <75% 
decrease from 
baseline 
75% decrease 
from baseline 
Platelets 
WNL 
< LLN - <75.0 x 
109 /L 
< LLN - 
75000/mm3 
50.0 - < 75.0 x 
109 /L 
50000 - < 
75000/mm3 
10.0 - < 50.0 x 
109 /L 
10000 - < 
50000/mm3 
< 10.0 x 109 /L 
< 10000/mm3 
For BMT: 
WNL 
50.0 - <75.0 x 
109 /L 
50000 - 
<75000/mm3  
20.0 - <50.0 x 
109 /L 
20000 - 
<50000/mm3 
10.0 - <20.0 x 
109 /L 
10000 - 
<20000/mm3 
<10.0 x 109 /L 
<10000/mm3 
Note: The following criteria may be used for leukemia studies or bone marrow infiltrative/myelophthisic process if the 
protocol so specifies. 
For leukemia studies 
or bone marrow 
infiltrative/ 
myelophthisic 
process 
WNL 
10 - <25% 
decrease from 
baseline 
25 - <50% 
decrease from 
baseline 
50 - <75% 
decrease from 
baseline 
75% decrease 
from baseline 
Transfusion: 
Platelets 
none 
- 
- 
yes 
platelet 
transfusions and 
other measures 
required to 
improve platelet 
increment; 
platelet 
transfusion 
refractoriness 
associated with 
life-threatening 
bleeding. (e.g., 
HLA or cross 
matched platelet 
transfusions) 


IRB PROTOCOL #98153 
PAGE A5 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
For BMT: 
none 
1 platelet 
transfusion in 24 
hours 
2 platelet 
transfusions in 24 
hours 
3 platelet 
transfusions in 24 
hours 
platelet 
transfusions and 
other measures 
required to 
improve platelet 
increment; 
platelet 
transfusion 
refractoriness 
associated with 
life-threatening 
bleeding. (e.g., 
HLA or cross 
matched platelet 
transfusions) 
Also consider Platelets. 
Transfusion: pRBCs 
none 
- 
- 
Yes 
- 
For BMT: 
none 
2 u pRBC 
( 15cc/kg) in 24 
hours elective or 
planned 
 
 
3 u pRBC (>15 
30cc/kg) in 24 
hours elective or 
planned 
4 u pRBC 
(>30cc/kg) in 24 
hours 
hemorrhage or 
hemolysis 
associated with 
life-threatening 
anemia; medical 
intervention 
required to 
improve 
hemoglobin 
Also consider Hemoglobin. 
Blood/Bone 
Marrow-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
CARDIOVASCULAR (ARRHYTHMIA) 
Conduction 
abnormality/ 
Atrioventricular 
heart block 
none 
asymptomatic, 
not requiring 
treatment (e.g., 
Mobitz type I 
second-degree 
AV block, 
Wenckebach) 
symptomatic, but 
not requiring 
treatment 
symptomatic and 
requiring 
treatment (e.g., 
Mobitz type II 
second-degree 
AV block, third-
degree AV block) 
life-threatening 
(e.g., arrhythmia 
associated with 
CHF, 
hypotension, 
syncope, shock) 
Nodal/junctional 
arrhythmia/dysrhyth
mia 
none 
asymptomatic, 
not requiring 
treatment 
symptomatic, but 
not requiring 
treatment 
symptomatic and 
requiring 
treatment 
life-threatening 
(e.g., arrhythmia 
associated with 
CHF, 
hypotension, 
syncope, shock) 
Palpitations 
none 
present 
- 
- 
- 
Note: Grade palpitations only in the absence of a documented arrhythmia. 


IRB PROTOCOL #98153 
PAGE A6 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Prolonged QTc 
interval (QTc > 0.48 
seconds) 
none 
asymptomatic, 
not requiring 
treatment 
symptomatic, but 
not requiring 
treatment 
symptomatic and 
requiring 
treatment 
life-threatening 
(e.g., arrhythmia 
associated with 
CHF, 
hypotension, 
syncope, shock) 
Sinus bradycardia 
none 
asymptomatic, 
not requiring 
treatment 
symptomatic, but 
not requiring 
treatment 
symptomatic and 
requiring 
treatment 
life-threatening 
(e.g., arrhythmia 
associated with 
CHF, 
hypotension, 
syncope, shock) 
Sinus tachycardia 
none 
asymptomatic, 
not requiring 
treatment 
symptomatic, but 
not requiring 
treatment 
symptomatic and 
requiring 
treatment of 
underlying cause 
- 
Supraventricular 
arrhythmias 
(SVT/atrial 
fibrillation/ flutter) 
none 
asymptomatic, 
not requiring 
treatment 
symptomatic, but 
not requiring 
treatment 
symptomatic and 
requiring 
treatment 
life-threatening 
(e.g., arrhythmia 
associated with 
CHF, 
hypotension, 
syncope, shock) 
Syncope (fainting) is graded in the NEUROLOGY category. 
Vasovagal episode 
none 
- 
present without 
loss of 
consciousness 
present with loss 
of consciousness 
- 
Ventricular 
arrhythmia 
(PVCs/bigeminy/trig
eminy/ 
ventricular 
tachycardia) 
none 
asymptomatic, 
not requiring 
treatment 
symptomatic, but 
not requiring 
treatment 
symptomatic and 
requiring 
treatment 
life-threatening 
(e.g., arrhythmia 
associated with 
CHF, 
hypotension, 
syncope, shock) 
Cardiovascular/ 
Arrhythmia-Other  
(Specify, 
___________) 
none 
asymptomatic, 
not requiring 
treatment 
symptomatic, but 
not requiring 
treatment 
symptomatic, and 
requiring 
treatment of 
underlying cause 
life-threatening 
(e.g., arrhythmia 
associated with 
CHF, 
hypotension, 
syncope, shock) 
CARDIOVASCULAR (GENERAL) 
Acute vascular leak 
syndrome 
absent 
- 
symptomatic, but 
not requiring 
fluid support 
respiratory 
compromise or 
requiring fluids 
life-threatening; 
requiring pressor 
support and/or 
ventilatory 
support 
Cardiac- 
ischemia/infarction 
none 
non-specific T-
wave flattening 
or changes 
asymptomatic, 
ST- and T- wave 
changes 
suggesting 
ischemia 
angina without 
evidence of 
infarction 
acute myocardial 
infarction 


IRB PROTOCOL #98153 
PAGE A7 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Cardiac left 
ventricular function 
normal 
asymptomatic 
decline of resting 
ejection fraction 
of  10% but < 
20% of baseline 
value; shortening 
fraction  24% 
but < 30% 
asymptomatic but 
resting ejection 
fraction below 
LLN for 
laboratory or 
decline of resting 
ejection fraction 
j
 20% of 
baseline value; < 
24% shortening 
fraction 
CHF responsive 
to treatment 
severe or 
refractory CHF or 
requiring 
intubation 
CNS cerebrovascular ischemia is graded in the NEUROLOGY category. 
Cardiac troponin I 
(cTnI) 
normal 
- 
- 
levels consistent 
with unstable 
angina as defined 
by the 
manufacturer 
levels consistent 
with myocardial 
infarction as 
defined by the 
manufacturer 
Cardiac troponin T 
(cTnT) 
normal 
 0.03 - < 0.05 
ng/ml 
 0.05 - < 0.1 
ng/ml 
 0.1 - < 0.2 
ng/ml 
 0.2 ng/ml 
Edema 
none 
asymptomatic, 
not requiring 
therapy 
symptomatic, 
requiring therapy 
symptomatic 
edema limiting 
function and 
unresponsive to 
therapy or 
requiring drug 
discontinuation 
anasarca (severe 
generalized 
edema) 
Hypertension 
none 
asymptomatic, 
transient increase 
by >20 mmHg 
(diastolic) or to > 
150/100* if 
previously WNL; 
not requiring 
treatment 
recurrent or 
persistent or 
symptomatic 
increase by > 20 
mmHg (diastolic) 
or to > 150/100* 
if previously 
WNL; not 
requiring 
treatment 
requiring therapy 
or more intensive 
therapy than 
previously 
hypertensive 
crisis 
*Note: For pediatric patients, use age and sex appropriate normal values > 95th percentile ULN. 
Hypotension 
none 
changes, but not 
requiring therapy 
(including 
transient 
orthostatic 
hypotension) 
requiring brief 
fluid replacement 
or other therapy 
but not 
hospitalization; 
no physiologic 
consequences 
requiring therapy 
and sustained 
medical attention, 
but resolves 
without persisting 
physiologic 
consequences 
shock (associated 
with acidemia 
and impairing 
vital organ 
function due to 
tissue 
hypoperfusion) 
Also consider Syncope (fainting). 
Note: 
Angina or MI is graded as Cardiac- ischemia/infarction in the CARDIOVASCULAR (GENERAL) category. 
For pediatric patients, systolic BP 65 mmHg or less in infants up to 1 year old and 70 mmHg or less in children older 
than 1 year of age, use two successive or three measurements in 24 hours. 
Myocarditis 
none 
- 
- 
CHF responsive 
to treatment 
severe or 
refractory CHF 


IRB PROTOCOL #98153 
PAGE A8 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Operative injury of 
vein/artery 
none 
primary suture 
repair for injury, 
but not requiring 
transfusion 
primary suture 
repair for injury, 
requiring 
transfusion 
vascular 
occlusion 
requiring surgery 
or bypass for 
injury 
myocardial 
infarction; 
resection of organ 
(e.g., bowel, 
limb) 
Pericardial effusion/ 
pericarditis 
none 
asymptomatic 
effusion, not 
requiring 
treatment 
pericarditis (rub, 
ECG changes, 
and/or chest pain) 
physiologic 
consequences 
resulting from 
symptoms 
tamponade 
(drainage or 
pericardial 
window required) 
Peripheral arterial 
ischemia 
none 
- 
brief episode of 
ischemia 
managed non-
surgically and 
without 
permanent deficit 
requiring surgical 
intervention 
life-threatening or 
with permanent 
functional deficit 
(e.g., amputation) 
Phlebitis 
(superficial) 
none 
- 
present 
- 
- 
Note: 
Injection site reaction is graded in the DERMATOLOGY/SKIN category. 
Thrombosis/embolism is graded in the CARDIOVASCULAR (GENERAL) category. 
Syncope (fainting) is graded in the NEUROLOGY category. 
Thrombosis/embolis
m 
none 
- 
deep vein 
thrombosis, not 
requiring 
anticoagulant 
deep vein 
thrombosis, 
requiring 
anticoagulant 
therapy 
embolic event 
including 
pulmonary 
embolism 
Vein/artery operative injury is graded as Operative injury of vein/artery in the CARDIOVASCULAR (GENERAL) 
category. 
Visceral arterial 
ischemia (non-
myocardial) 
none 
- 
brief episode of 
ischemia 
managed non-
surgically and 
without 
permanent deficit 
requiring surgical 
intervention 
life-threatening or 
with permanent 
functional deficit 
(e.g., resection of 
ileum) 
Cardiovascular/ 
General-Other  
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
COAGULATION 
Note: See the HEMORRHAGE category for grading the severity of bleeding events. 
DIC  
(disseminated 
intravascular 
coagulation) 
absent 
- 
- 
laboratory 
findings present 
with no bleeding 
laboratory 
findings and 
bleeding 
Also grade Platelets. 
Note: Must have increased fibrin split products or D-dimer in order to grade as DIC. 
Fibrinogen 
WNL 
0.75 - <1.0 x 
LLN 
0.5 - <0.75 x 
LLN 
0.25 - <0.5 x 
LLN 
<0.25 x LLN 
Note: The following criteria may be used for leukemia studies or bone marrow infiltrative/myelophthisic process if the 
protocol so specifies. 


IRB PROTOCOL #98153 
PAGE A9 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
For leukemia studies: WNL 
<20% decrease 
from pretreatment 
value or LLN 
20 - <40% 
decrease from 
pretreatment 
value or LLN 
40 - <70% 
decrease from 
pretreatment 
value or LLN 
<50 mg% 
Partial 
thromboplastin time 
(PTT) 
WNL 
> ULN -  1.5 x 
ULN 
> 1.5 -  2 x 
ULN 
>2 x ULN 
- 
Phelbitis is graded in the CARDIOVASCULAR (GENERAL) category. 
Prothrombin time 
(PT) 
WNL 
> ULN -  1.5 x 
ULN 
> 1.5 -  2 x 
ULN 
>2 x ULN 
- 
Thrombosis/embolism is graded in the CARDIOVASCULAR (GENERAL) category. 
Thrombotic 
microangiopathy 
(e.g., thrombotic 
thrombocytopenic 
purpura/TTP or 
hemolytic uremic 
syndrome/HUS) 
absent 
- 
- 
laboratory 
findings present 
without clinical 
consequences 
laboratory 
findings and 
clinical 
consequences, 
(e.g., CNS 
hemorrhage/ 
bleeding or 
thrombosis/ 
embolism or 
renal failure) 
requiring 
therapeutic 
intervention 
For BMT: 
- 
evidence of RBC 
destruction 
(schistocytosis) 
without clinical 
consequences 
evidence of RBC 
destruction with 
elevated 
creatinine ( 3 x 
ULN) 
evidence of RBC 
destruction with 
creatinine (>3 x 
ULN) not 
requiring dialysis 
evidence of RBC 
destruction with 
renal failure 
requiring dialysis 
and/or 
encephalopathy 
Also consider Hemoglobin (Hgb), Platelets, Creatinine. 
Note: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments). 
Coagulation-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
CONSTITUTIONAL SYMPTOMS 
Fatigue 
(lethargy, malaise, 
asthenia) 
none 
increased fatigue 
over baseline, but 
not altering 
normal activities 
moderate (e.g., 
decrease in 
performance 
status by 1 
ECOG level or 
20% Karnofsky 
or Lansky) or 
causing difficulty 
performing some 
activities 
severe (e.g., 
decrease in 
performance 
status by 2 
ECOG levels or 
40% Karnofsky 
or Lansky) or loss 
of ability to 
perform some 
activities 
bedridden or 
disabling 
Note: See Appendix IV (http://ctep.info.nih.gov/ctc3/ctc.htm) for performance status scales. 


IRB PROTOCOL #98153 
PAGE A10 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Fever (in the absence 
of neutropenia, 
where neutropenia is 
defined as AGC < 
1.0 x 109/L) 
none 
38.0 - 39.0°C 
(100.4 - 102.2°F) 
39.1 - 40.0°C 
(102.3 - 104.0°F 
) 
> 40.0°C 
(>104.0°F ) for < 
24hrs 
> 40.0°C 
(>104.0°F ) for > 
24hrs 
Also consider Allergic reaction/hypersensitivity. 
Note: The temperature measurements listed above are oral or tympanic. 
Hot flashes/flushes are graded in the ENDOCRINE category. 
Rigors, chills 
none 
mild, requiring 
symptomatic 
treatment (e.g., 
blanket) or non-
narcotic 
medication 
severe and/or 
prolonged, 
requiring narcotic 
medication 
not responsive to 
narcotic 
medication 
- 
Sweating  
(diaphoresis) 
normal 
mild and 
occasional 
frequent or 
drenching 
- 
- 
Weight gain 
< 5% 
5 - <10% 
10 - <20% 
 20% 
- 
Also consider Ascites, Edema, Pleural effusion. 
Weight gain - veno-
occlusive disease 
(VOD) 
 
 
 
 
 
Note: The following criteria is to be used ONLY for weight gain associated with Veno-Occlusive Disease. 
<2% 
2 - <5% 
5 - <10%  
10% or as 
ascities 
10% or fluid 
retention 
resulting in 
pulmonary failure 
Weight loss 
< 5% 
5 - <10% 
10 - <20% 
20% 
- 
Also consider Vomiting, Dehydration, Diarrhea. 
Constitutional 
Symptoms-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
DERMATOLOGY/SKIN 
Alopecia 
normal 
mild hair loss 
pronounced hair 
loss 
- 
- 
Bruising  
(in absence of grade 
3 or 4 
thrombocytopenia) 
none 
localized or in 
dependent area 
generalized 
- 
- 
Note: 
Bruising resulting from grade 3 or 4 thrombocytopenia is graded as Petechiae/purpura and 
Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia in the HEMORRHAGE category, not in the 
DERMATOLOGY/SKIN category. 


IRB PROTOCOL #98153 
PAGE A11 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Dermatitis, focal 
(associated with 
high-dose 
chemotherapy and 
bone marrow 
transplant) 
none 
faint erythema or 
dry desquamation 
moderate to brisk 
erythema or a 
patchy moist 
desquamation, 
mostly confined 
to skin folds and 
creases; moderate 
edema 
confluent moist 
desquamation, 
1.5 cm 
diameter, not 
confined to skin 
folds; pitting 
edema 
skin necrosis or 
ulceration of full 
thickness dermis; 
may include 
spontaneous 
bleeding not 
induced by minor 
trauma or 
abrasion 
Dry skin 
normal 
controlled with 
emollients 
not controlled 
with emollients 
- 
- 
Erythema multiforme 
(e.g., Stevens-
Johnson syndrome, 
toxic epidermal 
necrolysis) 
absent 
- 
scattered, but not 
generalized 
eruption 
severe or 
requiring IV 
fluids (e.g., 
generalized rash 
or painful 
stomatitis) 
life-threatening 
(e.g., exfoliative 
or ulcerating 
dermatitis or 
requiring enteral 
or parenteral 
nutritional 
support) 
Flushing 
absent 
present 
- 
- 
- 
Hand-foot skin 
reaction 
none 
skin changes or 
dermatitis 
without pain 
(e.g., erythema, 
peeling) 
skin changes with 
pain, not 
interfering with 
function 
skin changes with 
pain, interfering 
with function 
- 
Injection site 
reaction 
none 
pain or itching or 
erythema 
pain or swelling, 
with 
inflammation or 
phlebitis 
ulceration or 
necrosis that is 
severe or 
prolonged, or 
requiring surgery 
- 
Nail changes 
normal 
discoloration or 
ridging 
(koilonychia) or 
pitting 
partial or 
complete loss of 
nail(s) or pain in 
nailbeds 
- 
- 
Petechiae is graded in the HEMORRHAGE category. 
Photosensitivity 
none 
painless erythema 
painful erythema 
erythema with 
desquamation 
- 
Pigmentation 
changes (e.g., 
vitiligo) 
none 
localized 
pigmentation 
changes 
generalized 
pigmentation 
changes 
- 
- 
Pruritus 
none 
mild or localized, 
relieved 
spontaneously or 
by local measures 
intense or 
widespread, 
relieved 
spontaneously or 
by systemic 
measures 
intense or 
widespread and 
poorly controlled 
despite treatment 
- 
Purpura is graded in the HEMORRHAGE category. 


IRB PROTOCOL #98153 
PAGE A12 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Radiation dermatitis 
none 
faint erythema or 
dry desquamation 
moderate to brisk 
erythema or a 
patchy moist 
desquamation, 
mostly confined 
to skin folds and 
creases; moderate 
edema 
confluent moist 
desquamation, 
1.5 cm 
diameter, not 
confined to skin 
folds; pitting 
edema 
skin necrosis or 
ulceration of full 
thickness dermis; 
may include 
bleeding not 
induced by minor 
trauma or 
abrasion 
Note: Pain associated with radiation dermatitis is graded separately in the PAIN category as Pain due to radiation. 
Radiation recall 
reaction (reaction 
following 
chemotherapy in the 
absence of additional 
radiation therapy that 
occurs in a previous 
radiation port) 
none 
faint erythema or 
dry desquamation 
moderate to brisk 
erythema or a 
patchy moist 
desquamation, 
mostly confined 
to skin folds and 
creases; moderate 
edema 
confluent moist 
desquamation, 
1.5 cm 
diameter, not 
confined to skin 
folds; pitting 
edema 
skin necrosis or 
ulceration of full 
thickness dermis; 
may include 
bleeding not 
induced by minor 
trauma or 
abrasion 
Rash/desquamation 
none 
macular or 
papular eruption 
or erythema 
without 
associated 
symptoms 
macular or 
papular eruption 
or erythema with 
pruritis or other 
associated 
symptoms 
covering <50% 
of body surface 
or localized 
desquamation or 
other lesions 
covering <50% 
of body surface 
area 
symptomatic 
generalized 
erythroderma or 
macular, papular 
or vesicular 
eruption or 
desquamation 
covering 50% of 
body surface area 
generalized 
exfoliative 
dermatitis or 
ulcerative 
dermatitis 
For BMT: 
none 
macular or 
papular eruption 
or erythema 
covering <25% 
of body surface 
area without 
associated 
symptoms 
macular or 
papular eruption 
or erythema with 
pruritis or other 
associated 
symptoms 
covering 25 - 
<50% of body 
surface or 
localized 
desquamation or 
other lesions 
covering 25 - 
<50% of body 
surface area 
symptomatic 
generalized 
erythroderma or 
symptomatic 
macular, papular 
or vesicular 
eruption, with 
bullous 
formation, or 
desquamation 
covering 50% of 
body surface area  
generalized 
exfoliative 
dermatitis or 
ulcerative 
dermatitis or 
bullous formation 
Also consider Allergic reaction/hypersensitivity. 
Note: Erythema multiforme (Stevens-Johnson syndrome) is graded separately as Erythema multiforme. 


IRB PROTOCOL #98153 
PAGE A13 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Urticaria  
(hives, welts, 
wheals) 
none 
requiring no 
medication 
requiring PO or 
topical treatment 
or IV medication 
or steroids for 
<24 hours 
requiring IV 
medication or 
steroids for 24 
hours 
- 
Wound- infectious 
none 
cellulitis 
superficial 
infection 
infection 
requiring IV 
antibiotics 
necrotizing 
fascitis 
Wound- non-
infectious 
none 
incisional 
separation 
incisional hernia 
fascial disruption 
without 
evisceration 
fascial disruption 
with evisceration 
Dermatology/Skin-
Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
ENDOCRINE 
Cushingoid 
appearance (e.g., 
moon face with or 
without buffalo 
hump, centripetal 
obesity, cutaneous 
striae) 
absent 
- 
present 
- 
- 
Also consider Hyperglycemia, Hypokalemia. 
Feminization of male 
absent 
- 
- 
present 
- 
Gynecomastia 
none 
mild 
pronounced or 
painful 
pronounced or 
painful and 
requiring surgery 
- 
Hot flashes/flushes 
none 
mild or no more 
than 1 per day 
moderate and 
greater than 1 per 
day 
- 
- 
Hypothyroidism 
absent 
asymptomatic,TS
H elevated, no 
therapy given 
symptomatic or 
thyroid 
replacement 
treatment given 
patient 
hospitalized for 
manifestations of 
hypothyroidism 
myxedema coma 
Masculinization of 
female 
absent 
- 
- 
present 
- 
SIADH (syndrome 
of inappropriate 
antidiuretic 
hormone) 
absent 
- 
- 
present 
- 
Endocrine-Other  
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
GASTROINTESTINAL 
Amylase is graded in the METABOLIC/LABORATORY category. 
Anorexia 
none 
loss of appetite 
oral intake 
significantly 
decreased 
requiring IV 
fluids 
requiring feeding 
tube or parenteral 
nutrition 


IRB PROTOCOL #98153 
PAGE A14 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Ascites (non-
malignant) 
none 
asymptomatic 
symptomatic, 
requiring 
diuretics 
symptomatic, 
requiring 
therapeutic 
paracentesis 
life-threatening 
physiologic 
consequences 
Colitis 
none 
- 
abdominal pain 
with mucus 
and/or blood in 
stool 
abdominal pain, 
fever, change in 
bowel habits with 
ileus or peritoneal 
signs, and 
radiographic or 
biopsy 
documentation 
perforation or 
requiring surgery 
or toxic 
megacolon 
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 
thrombocytopenia, Melena/GI bleeding, Rectal bleeding/hematochezia, Hypotension. 
Constipation 
none 
requiring stool 
softener or 
dietary 
modification 
requiring 
laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
obstruction or 
toxic megacolon 
Dehydration 
none 
dry mucous 
membranes 
and/or 
diminished skin 
turgor 
requiring IV fluid 
replacement 
(brief) 
requiring IV fluid 
replacement 
(sustained) 
physiologic 
consequences 
requiring 
intensive care; 
hemodynamic 
collapse 
Also consider Hypotension, Diarrhea, Vomiting, Stomatitis/pharyngitis (oral/pharyngeal mucositis). 
Diarrhea 
Patients without 
colostomy: 
none 
increase of < 4 
stools/day over 
pre-treatment 
increase of 4-6 
stools/day, or 
nocturnal stools 
increase of 7 
stools/day or 
incontinence; or 
need for 
parenteral 
support for 
dehydration 
physiologic 
consequences 
requiring 
intensive care; or 
hemodynamic 
collapse 
Patients with a 
colostomy: 
none 
mild increase in 
loose, watery 
colostomy output 
compared with 
pretreatment 
moderate increase 
in loose, watery 
colostomy output 
compared with 
pretreatment, but 
not interfering 
with normal 
activity 
severe increase in 
loose, watery 
colostomy output 
compared with 
pretreatment, 
interfering with 
normal activity 
physiologic 
consequences, 
requiring 
intensive care; or 
hemodynamic 
collapse 
For BMT 
none 
>500 - 1000ml 
of diarrhea/day 
>1000 - 1500ml 
of diarrhea/day 
>1500ml of 
diarrhea/day 
severe abdominal 
pain with or 
without ileus 
For Pediatric BMT: 
 
>5 - 10 ml/kg of 
diarrhea/day 
>10 - 15 ml/kg 
of diarrhea/day 
>15 ml/kg of 
diarrhea/day 
- 
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 
thrombocytopenia, Pain, Dehydration, Hypotension. 


IRB PROTOCOL #98153 
PAGE A15 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Duodenal ulcer 
(requires 
radiographic or 
endoscopic 
documentation) 
none 
- 
requiring medical 
management or 
non-surgical 
treatment 
uncontrolled by 
outpatient 
medical 
management; 
requiring 
hospitalization 
perforation or 
bleeding, 
requiring 
emergency 
surgery 
Dyspepsia/heartburn 
none 
mild 
moderate 
severe 
- 
Dysphagia, 
esophagitis, 
odynophagia (painful 
swallowing) 
none 
mild dysphagia, 
but can eat 
regular diet 
dysphagia, 
requiring 
predominantly 
pureed, soft, or 
liquid diet 
dysphagia, 
requiring IV 
hydration 
complete 
obstruction 
(cannot swallow 
saliva) requiring 
enteral or 
parenteral 
nutritional 
support, or 
perforation 
Note: If toxicity is radiation-related, grade either under Dysphagia- esophageal related to radiation or Dysphagia- 
pharyngeal related to radiation. 
Dysphagia- 
esophageal related to 
radiation 
none 
mild dysphagia, 
but can eat 
regular diet 
dysphagia, 
requiring 
predominantly 
liquid, pureed or 
soft diet 
dysphagia 
requiring feeding 
tube, IV 
hydration or 
hyperalimentatio
n 
complete 
obstruction 
(cannot swallow 
saliva); ulceration 
with bleeding not 
induced by minor 
trauma or 
abrasion or 
perforation 
Also consider Pain due to radiation, Mucositis due to radiation. 
Note: Fistula is graded separately as Fistula- esophageal. 
Dysphagia - 
pharyngeal related to 
radiation 
none 
mild dysphagia, 
but can eat 
regular diet 
dysphagia, 
requiring 
predominantly 
pureed, soft, or 
liquid diet 
dysphagia, 
requiring feeding 
tube, IV 
hydration or 
hyperalimentatio
n 
complete 
obstruction 
(cannot swallow 
saliva); ulceration 
with bleeding not 
induced by minor 
trauma or 
abrasion or 
perforation 
Also consider Pain due to radiation, Mucositis due to radiation. 
Note: Fistula is graded separately as Fistula- pharyngeal. 
Fistula- esophageal 
none 
- 
- 
present 
requiring surgery 
Fistula- intestinal 
none 
- 
- 
present 
requiring surgery 
Fistula- pharyngeal 
none 
- 
- 
present 
requiring surgery 
Fistula- rectal/anal 
none 
- 
- 
present 
requiring surgery 
Flatulence 
none 
mild 
moderate 
- 
- 


IRB PROTOCOL #98153 
PAGE A16 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Gastric ulcer  
(requires 
radiographic or 
endoscopic 
documentation) 
none 
- 
requiring medical 
management or 
non-surgical 
treatment 
bleeding without 
perforation, 
uncontrolled by 
outpatient 
medical 
management; 
requiring 
hospitalization or 
surgery 
perforation or 
bleeding, 
requiring 
emergency 
surgery 
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 
thrombocytopenia. 
Gastritis 
none 
- 
requiring medical 
management or 
non-surgical 
treatment 
uncontrolled by 
out-patient 
medical 
management; 
requiring 
hospitalization or 
surgery 
life-threatening 
bleeding, 
requiring 
emergency 
surgery 
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 
thrombocytopenia. 
Hematemesis is graded in the HEMORRHAGE category. 
Hematochezia is graded in the HEMORRHAGE category as Rectal bleeding/hematochezia. 
Ileus (or 
neuroconstipation) 
none 
- 
intermittent, not 
requiring 
intervention 
requiring non-
surgical 
intervention 
requiring surgery 
Mouth dryness 
normal 
mild 
moderate 
- 
- 
Mucositis 
 
 
 
 
 
Note: 
Mucositis not due to radiation is graded in the GASTROINTESTINAL category for specific sites: Colitis, 
Esophagitis, Gastritis, Stomatitis/pharyngitis (oral/pharyngeal mucositis), and Typhlitis; or the 
RENAL/GENITOURINARY category for Vaginititis. 
Radiation-related mucositis is graded as Mucositis due to radiation. 
Mucositis due to 
radiation 
none 
erythema of the 
mucosa 
patchy 
pseudomembrano
us reaction 
(patches 
generally  1.5 
cm in diameter 
and non-
contiguous) 
confluent 
pseudomembrano
us reaction 
(contiguous 
patches generally 
> 1.5 cm in 
diameter) 
necrosis or deep 
ulceration; may 
include bleeding 
not induced by 
minor trauma or 
abrasion 
Also consider Pain due to radiation. 
Note: 
Grade radiation mucositis of the larynx here. 
Dysphagia related to radiation is also graded as either Dysphagia- esophageal related to radiation or Dysphagia- 
pharyngeal related to radiation, depending on the site of treatment. 
Nausea 
none 
able to eat 
oral intake 
significantly 
decreased 
no significant 
intake, requiring 
IV fluids 
- 
Pancreatitis 
none 
- 
- 
abdominal pain 
with pancreatic 
enzyme elevation 
complicated by 
shock (acute 
circulatory 
failure) 
Also consider Hypotension. 


IRB PROTOCOL #98153 
PAGE A17 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Note: Asymptomatic amylase and Amylase are graded in the METABOLIC/LABORATORY category. 
Pharyngitis is graded in the GASTROINTESTINAL category as Stomatitis/pharyngitis (oral/pharyngeal mucositis). 
Proctitis 
none 
increased stool 
frequency, 
occasional blood-
streaked stools, or 
rectal discomfort 
(including 
hemorrhoids), not 
requiring 
medication 
increased stool 
frequency, 
bleeding, mucus 
discharge, or 
rectal discomfort 
requiring 
medication; anal 
fissure 
increased stool 
frequency/diarrhe
a, requiring 
parenteral 
support; rectal 
bleeding, 
requiring 
transfusion; or 
persistent mucus 
discharge, 
necessitating 
pads 
perforation, 
bleeding or 
necrosis or other 
life-threatening 
complication 
requiring surgical 
intervention (e.g., 
colostomy) 
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 
thrombocytopenia, and Pain due to radiation. 
Note: 
Fistula is graded separately as Fistula- rectal/anal. 
Proctitis occurring more than 90 days after the start of radiation therapy is graded in the RTOG/EORTC Late Radiation 
Morbidity Scoring Scheme. (See Appendix V, http://ctep.info.nih.gov/ctc3/ctc.htm) 
Salivary gland 
changes 
none 
slightly thickened 
saliva/may have 
slightly altered 
taste (e.g., 
metallic); 
additional fluids 
may be required 
thick, ropy, sticky 
saliva; markedly 
altered taste; 
alteration in diet 
required 
- 
acute salivary 
gland necrosis 
Sense of smell 
normal 
slightly altered 
markedly altered 
- 
- 
Stomatitis/pharyngiti
s (oral/pharyngeal 
mucositis) 
none 
painless ulcers, 
erythema, or mild 
soreness in the 
absence of 
lesions 
painful erythema, 
edema, or ulcers, 
but can eat or 
swallow 
painful erythema, 
edema, or ulcers 
requiring IV 
hydration 
severe ulceration 
or requires 
parenteral or 
enteral nutritional 
support or 
prophylatic 
intubation 
For BMT: 
none 
painless ulcers, 
erythema, or mild 
soreness in the 
absence of 
lesions 
painful erythema, 
edema or ulcers 
but can swallow 
painful erythema, 
edema, or ulcers 
preventing 
swallowing or 
requiring 
hydration or 
parenteral (or 
enteral) 
nutritional 
support 
severe ulceration 
requiring 
prophylactic 
intubation or 
resulting in 
documented 
aspiration 
pneumonia 
Note: Radiation-related mucositis is graded as Mucositis due to radiation. 
Taste disturbance 
(dysgeusia) 
normal 
slightly altered 
markedly altered 
- 
- 


IRB PROTOCOL #98153 
PAGE A18 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Typhlitis  
(inflammation of the 
cecum) 
none 
- 
- 
abdominal pain, 
diarrhea, fever, or 
radiographic 
documentation 
perforation, 
bleeding or 
necrosis or other 
life-threatening 
complication 
requiring surgical 
intervention (e.g., 
colostomy) 
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 
thrombocytopenia, Hypotension, Febrile/neutropenia. 
Vomiting 
none 
1 episode in 24 
hours over 
pretreatment 
2-5 episodes in 
24 hours over 
pretreatment 
6 episodes in 24 
hours over 
pretreatment; or 
need for IV fluids 
Requiring 
parenteral 
nutrition; or 
physiologic 
consequences 
requiring 
intensive care; 
hemodynamic 
collapse 
Also consider Dehydration. 
Weight gain is graded in the CONSTITUTIONAL SYMPTOMS category. 
Weight loss is graded in the CONSTITUTIONAL SYMPTOMS category. 
Gastrointestinal-
Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
HEMORRHAGE 
Note: 
Transfusion in this section refers to pRBC infusion. 
For any bleeding with grade 3 or 4 platelets (< 50,000), always grade Hemorrhage/bleeding with grade 3 or 4 
thrombocytopenia. Also consider platelets, transfusion- pRBCS, and transfusion-platelets in addition to the grade 
that incorporates the site or type of bleeding. 
If the site or type of hemorrhage/bleeding is listed, also use the grading that incorporates the site of bleeding: CNS 
hemorrhage/bleeding, Hematuria, Hematemesis, Hemoptysis, Hemorrhage/bleeding with surgery, Melena/lower GI 
bleeding, Petechiae/purpura (Hemorrhage/bleeding into skin), Rectal bleeding/hematochezia, Vaginal bleeding. 
If the platelet count is 50,000 and the site or type of bleeding is listed, grade the specific site. If the site or type is 
not listed and the platelet count is 50,000, grade Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia 
and specify the site or type in the OTHER category. 
Hemorrhage/ble
eding with 
grade 3 or 4 
thrombocytopen
ia 
none 
mild without 
transfusion 
 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
Also consider Platelets, Hemoglobin, Transfusion-platelet, Transfusion-pRBCs. 
Note: 
This toxicity must be graded for any bleeding with grade 3 or 4 thrombocytopenia. Also grade the site or type of 
hemorrhage/bleeding. If the site is not listed, grade as Other in the HEMORRHAGE category. 


IRB PROTOCOL #98153 
PAGE A19 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Hemorrhage/ble
eding without 
grade 3 or 4 
thrombocytopen
ia 
none 
mild without 
transfusion 
 
requiring 
transfusion 
catastrophic 
bleeding 
requiring 
major non-
elective 
intervention 
Also consider Platelets, Hemoglobin, Transfusion-platelet, Transfusion-pRBCs. 
Note: 
Bleeding in the absence of grade 3 or 4 thrombocytopenia is graded here only if the specific site or type of 
bleeding is not listed elsewhere in the HEMORRHAGE category. Also grade as Other in the HEMORRHAGE 
category. 
CNS 
hemorrhage/ble
eding 
none 
- 
- 
bleeding 
noted on CT 
or other scan 
with no 
clinical 
consequence
s 
hemorrhagic 
stroke or 
hemorrhagic 
vascular 
event 
(CVA) with 
neurologic 
signs and 
symptoms 
Epistaxis 
none 
mild without 
transfusion 
- 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
Hematemesis 
none 
mild without 
transfusion 
- 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
Hematuria  
(in the absence 
of vaginal 
bleeding) 
none 
microscopic 
only 
intermittent 
gross 
bleeding, no 
clots 
persistent 
gross 
bleeding or 
clots; may 
require 
catheterizati
on or 
instrumentat
ion, or 
transfusion 
open surgery 
or necrosis 
or deep 
bladder 
ulceration 
Hemoptysis 
none 
mild without 
transfusion 
- 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 


IRB PROTOCOL #98153 
PAGE A20 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Hemorrhage/ble
eding 
associated with 
surgery 
none 
mild without 
transfusion 
- 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
Note: Expected blood loss at the time of surgery is not graded as a toxicity. 
Melena/GI 
bleeding 
none 
mild without 
transfusion 
- 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
Petechiae/purpu
ra 
(hemorrhage/bl
eeding into skin 
or mucosa) 
none 
rare 
petechiae of 
skin 
petechiae or 
purpura in 
dependent 
areas of skin 
generalized 
petechiae or 
purpura of 
skin or 
petechiae of 
any mucosal 
site 
- 
Rectal bleeding/ 
hematochezia 
none 
mild without 
transfusion 
or 
medication 
persistent, 
requiring 
medication 
(e.g., steroid 
suppositorie
s) and/or 
break from 
radiation 
treatment 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
Vaginal 
bleeding 
none 
spotting, 
requiring < 
2 pads per 
day 
requiring  
2 pads per 
day, but not 
requiring 
transfusion 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
Hemorrhage-
Other  
(Specify site, 
___________) 
none 
mild without 
transfusion 
- 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
HEPATIC 
Alkaline 
phosphatase 
WNL 
> ULN - 2.5 
x ULN 
> 2.5 - 5.0 x 
ULN 
> 5.0 - 20.0 
x ULN 
> 20.0 x 
ULN 
Bilirubin 
WNL 
> ULN - 1.5 
x ULN 
> 1.5 - 3.0 x 
ULN 
> 3.0 - 10.0 
x ULN 
> 10.0 x 
ULN 
Bilirubin- graft versus host disease (GVHD) 
Note: The following criteria are used only for bilirubin associated with graft versus host disease. 
 
normal 
2 - <3 
mg/100 ml 
3 - <6 
mg/100 ml 
6 - <15 
mg/100 ml 
15 mg/100 
ml 


IRB PROTOCOL #98153 
PAGE A21 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
GGT 
(  - Glutamyl 
transpeptidase) 
WNL 
> ULN - 2.5 
x ULN 
> 2.5 - 5.0 x 
ULN 
> 5.0 - 20.0 
x ULN 
> 20.0 x 
ULN 
Hepatic 
enlargement 
absent 
- 
- 
present 
- 
Note: Grade Hepatic enlargement only for changes related to VOD or other treatment related toxicity. 
Hypoalbumine
mia 
WNL 
<LLN - 3 
g/dl 
2 - <3 g/dl 
<2 g/dl 
- 
Liver 
dysfunction/fail
ure (clinical) 
normal 
- 
- 
asterixis 
encephalopa
thy or coma 
Note: Documented viral hepatitis is graded in the INFECTION category. 
Portal vein flow 
normal 
- 
decreased 
portal vein 
flow 
reversal/retr
ograde 
portal vein 
flow 
- 
SGOT (AST)  
(serum glutamic 
oxaloacetic 
transaminase) 
WNL 
> ULN - 2.5 
x ULN 
> 2.5 - 5.0 x 
ULN 
> 5.0 - 20.0 
x ULN 
> 20.0 x 
ULN 
SGPT (ALT)  
(serum glutamic 
pyruvic 
transaminase) 
WNL 
> ULN - 2.5 
x ULN 
> 2.5 - 5.0 x 
ULN 
> 5.0 - 20.0 
x ULN 
> 20.0 x 
ULN 
Hepatic-Other  
(Specify, 
) 
none 
mild 
moderate 
severe 
life-
threatening 
or disabling 
INFECTION/FEBRILE NEUTROPENIA 
Catheter-related 
infection 
none 
mild, no 
active 
treatment 
moderate, 
localized 
infection, 
requiring 
local or oral 
treatment 
severe, 
systemic 
infection, 
requiring IV 
antibiotic or 
antifungal 
treatment or 
hospitalizati
on 
life-
threatening 
sepsis (e.g., 
septic 
shock) 
Febrile 
neutropenia  
(fever of 
unknown origin 
without 
clinically or 
microbiological
ly documented 
infection) 
none 
- 
- 
Present 
Life-
threatening 
sepsis (e.g., 
septic 
shock) 
(ANC < 1.0 x 
109/L, fever 
38.5°C) 
 
 
 
 
 
Note: Hypothermia instead of fever may be associated with neutropenia and is graded here. 


IRB PROTOCOL #98153 
PAGE A22 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Infection 
(documented 
clinically or 
microbiological
ly) with grade 3 
or 4 
neutropenia 
none 
- 
- 
present 
life-
threatening 
sepsis (e.g., 
septic 
shock) 
(ANC < 1.0 x 
109/L) 
 
 
 
 
 
Note: 
Hypothermia instead of fever may be associated with neutropenia and is graded here. In the absence of 
documented infection with grade 3 or 4 neutropenia, grade as Febrile neutropenia. 
Infection with 
unknown ANC 
none 
- 
- 
present 
life-
threatening 
sepsis (e.g., 
septic 
shock) 
Note: This toxicity criterion is used in the rare case when ANC is unknown. 
Infection 
without 
neutropenia 
none 
mild, no 
active 
treatment 
moderate, 
localized 
infection, 
requiring 
local or oral 
treatment 
severe, 
systemic 
infection, 
requiring IV 
antibiotic or 
antifungal 
treatment, or 
hospitalizati
on 
life-
threatening 
sepsis (e.g., 
septic 
shock) 
Infection/Febril
e Neutropenia-
Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-
threatening 
or disabling 
Wound-infectious is graded in the DERMATOLOGY/SKIN category. 
LYMPHATICS 
Lymphatics 
normal 
mild 
lymphedema 
moderate 
lymphedema 
requiring 
compression
; lymphocyst 
severe 
lymphedema 
limiting 
function; 
lymphocyst 
requiring 
surgery 
severe 
lymphedema 
limiting 
function 
with 
ulceration 
Lymphatics-
Other  
(Specify, 
) 
none 
mild 
moderate 
severe 
life-
threatening 
or disabling 
METABOLIC/LABORATORY 


IRB PROTOCOL #98153 
PAGE A23 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Acidosis  
(metabolic or 
respiratory) 
normal 
pH < 
normal, but 
7.3 
- 
pH < 7.3 
pH < 7.3 
with life-
threatening 
physiologic 
consequence
s 
Alkalosis  
(metabolic or 
respiratory) 
normal 
pH > 
normal, but 
7.5 
- 
pH > 7.5 
pH > 7.5 
with life-
threatening 
physiologic 
consequence
s 
Amylase 
WNL 
> ULN - 1.5 
x ULN 
> 1.5 - 2.0 x 
ULN 
> 2.0 - 5.0 x 
ULN 
>5.0 x ULN 
Bicarbonate 
WNL 
< LLN - 16 
mEq/dl 
11 - 15 
mEq/dl 
8 - 10 
mEq/dl 
< 8 mEq/dl 
CPK 
(creatine 
phosphokinase) 
WNL 
> ULN - 2.5 
x ULN 
> 2.5 - 5 x 
ULN 
> 5 - 10 x 
ULN 
> 10 x ULN 
Hypercalcemia 
WNL 
> ULN - 
11.5 mg/dl 
> ULN - 2.9 
mmol/L 
>11.5 - 12.5 
mg/dl 
> 2.9 - 3.1 
mmol/L 
>12.5 - 13.5 
mg/dl 
> 3.1 - 3.4 
mmol/L 
> 13.5 mg/dl 
> 3.4 
mmol/L 
Hypercholester
olemia 
WNL 
> ULN - 
300 mg/dl 
> ULN - 
7.75 
mmol/L 
> 300 - 400 
mg/dl 
> 7.75 - 
10.34 
mmol/L 
> 400 - 500 
mg/dl 
>10.34 - 
12.92 
mmol/L 
> 500 mg/dl 
> 12.92 
mmol/L 
Hyperglycemia 
WNL 
> ULN - 
160 mg/dl 
> ULN - 8.9 
mmol/L 
> 160 - 250 
mg/dl 
> 8.9 - 13.9 
mmol/L 
> 250 - 500 
mg/dl 
> 13.9 - 
27.8 
mmol/L 
> 500 mg/dl 
> 27.8 
mmol/L or 
ketoacidosis 
Hyperkalemia 
WNL 
> ULN - 5.5 
mmol/L 
> 5.5 - 6.0 
mmol/L 
> 6.0 - 7.0 
mmol/L 
> 7.0 
mmol/L 
Hypermagnese
mia 
WNL 
> ULN - 3.0 
mg/dl 
> ULN - 
1.23 
mmol/L 
- 
> 3.0 - 8.0 
mg/dl 
> 1.23 - 
3.30 
mmol/L 
> 8.0 mg/dl 
> 3.30 
mmol/L 
Hypernatremia 
WNL 
> ULN - 
150 mmol/L 
>150 - 155 
mmol/L 
>155 - 160 
mmol/L 
>160 
mmol/L 
Hypertriglyceri
demia 
WNL 
> ULN - 2.5 
x ULN 
> 2.5 - 5.0 x 
ULN 
> 5.0 - 10 x 
ULN 
> 10 x ULN 


IRB PROTOCOL #98153 
PAGE A24 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Hyperuricemia 
WNL 
> ULN -  
10 mg/dl 
 0.59 
mmol/L 
without 
physiologic 
consequence
s 
- 
> ULN -  
10 mg/dl 
 0.59 
mmol/L 
with 
physiologic 
consequence
s 
> 10 mg/dl 
> 0.59 
mmol/L 
Also consider Tumor lysis syndrome, Renal failure, Creatinine, Potassium. 
Hypocalcemia 
WNL 
<LLN - 8.0 
mg/dl 
<LLN - 2.0 
mmol/L 
7.0 - < 8.0 
mg/dl 
1.75 - < 2.0 
mmol/L 
6.0 - < 7.0 
mg/dl 
1.5 - < 1.75 
mmol/L 
<6.0 mg/dl 
< 1.5 
mmol/L 
Hypoglycemia 
WNL 
<LLN - 55 
mg/dl 
<LLN - 3.0 
mmol/L 
40 - < 55 
mg/dl 
2.2 - < 3.0 
mmol/L 
30 - < 40 
mg/dl 
1.7 - < 2.2 
mmol/L 
< 30 mg/dl 
< 1.7 
mmol/L 
Hypokalemia 
WNL 
<LLN - 3.0 
mmol/L 
- 
2.5 - <3.0 
mmol/L 
<2.5 
mmol/L 
Hypomagnesem
ia 
WNL 
<LLN - 1.2 
mg/dl 
<LLN - 0.5 
mmol/L 
0.9 - <1.2 
mg/dl 
0.4 - < 0.5 
mmol/L 
0.7 - < 0.9 
mg/dl 
0.3 - < 0.4 
mmol/L 
< 0.7 mg/dl 
< 0.3 
mmol/L 
Hyponatremia 
WNL 
<LLN - 130 
mmol/L 
- 
120 - <130 
mmol/L 
<120 
mmol/L 
Hypophosphate
mia 
WNL 
<LLN -2.5 
mg/dl 
<LLN - 0.8 
mmol/L 
2.0 - <2.5 
mg/dl 
g
0.6 - <0.8 
mmol/L 
1.0 - <2.0 
mg/dl 
g
0.3 - <0.6 
mmol/L 
< 1.0 mg/dl 
<0.3 
mmol/L 
Hypothyroidism is graded in the ENDOCRINE category. 
Lipase 
WNL 
> ULN - 1.5 
x ULN 
> 1.5 - 2.0 x 
ULN 
> 2.0 - 5.0 x 
ULN 
> 5.0 x ULN 
Metabolic/Labo
ratory-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-
threatening 
or disabling 
MUSCULOSKELETAL 
Arthralgia is graded in the PAIN category. 
Arthritis 
none 
mild pain with 
inflammation, 
erythema or joint 
swelling but not 
interfering with 
function 
moderate pain 
with 
inflammation, 
erythema, or joint 
swelling 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain with 
inflammation, 
erythema, or joint 
swelling and 
interfering with 
activities of daily 
living 
disabling 


IRB PROTOCOL #98153 
PAGE A25 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Muscle weakness 
(not due to 
neuropathy) 
normal 
asymptomatic 
with weakness on 
physical exam 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
bedridden or 
disabling 
Myalgia is graded in the PAIN category. 
Myositis 
(inflammation/dama
ge of muscle) 
none 
mild pain, not 
interfering with 
function 
pain interfering 
with function, but 
not interfering 
with activities of 
daily living 
pain interfering 
with function and 
interfering with 
activities of daily 
living 
bedridden or 
disabling 
Also consider CPK. 
Note: Myositis implies muscle damage (i.e., elevated CPK). 
Osteonecrosis  
(avascular necrosis) 
none 
asymptomatic 
and detected by 
imaging only 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
symptomatic; or 
disabling 
Musculoskeletal-
Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
NEUROLOGY 
Aphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category. 
Arachnoiditis/menin
gismus/ 
radiculitis 
absent 
mild pain not 
interfering with 
function 
moderate pain 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain 
interfering with 
activities of daily 
living 
unable to 
function or 
perform activities 
of daily living; 
bedridden; 
paraplegia 
Also consider Headache, Vomiting, Fever. 
Ataxia 
(incoordination) 
normal 
asymptomatic but 
abnormal on 
physical exam, 
and not 
interfering with 
function 
mild symptoms 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
moderate 
symptoms 
interfering with 
activities of daily 
living 
bedridden or 
disabling 
CNS cerebrovascular 
ischemia 
none 
- 
- 
transient 
ischemic event or 
attack (TIA) 
permanent event 
(e.g., cerebral 
vascular 
accident) 
CNS hemorrhage/bleeding is graded in the HEMORRHAGE category. 


IRB PROTOCOL #98153 
PAGE A26 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Cognitive 
disturbance/ 
learning problems 
none 
cognitive 
disability; not 
interfering with 
work/school 
performance; 
preservation of 
intelligence 
cognitive 
disability; 
interfering with 
work/school 
performance; 
decline of 1 SD 
(Standard 
Deviation) or 
loss of 
developmental 
milestones 
cognitive 
disability; 
resulting in 
significant 
impairment of 
work/school 
performance; 
cognitive decline 
> 2 SD 
inability to 
work/frank 
mental 
retardation 
Confusion 
normal 
confusion or 
disorientation or 
attention deficit 
of brief duration; 
resolves 
spontaneously 
with no sequelae 
confusion or 
disorientation or 
attention deficit 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
confusion or 
delirium 
interfering with 
activities of daily 
living 
harmful to others 
or self; requiring 
hospitalization 
Cranial neuropathy is graded in the NEUROLOGY category as Neuropathy-cranial. 
Delusions 
normal 
- 
- 
present 
toxic psychosis 
Depressed level of 
consciousness 
normal 
somnolence or 
sedation not 
interfering with 
function 
somnolence or 
sedation 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
obtundation or 
stupor; difficult 
to arouse; 
interfering with 
activities of daily 
living 
coma 
Note: Syncope (fainting) is graded in the NEUROLOGY category. 
Dizziness/lightheade
dness 
none 
not interfering 
with function 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
interfering with 
activities of daily 
living 
bedridden or 
disabling 
Dysphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category. 
Extrapyramidal/  
involuntary 
movement/ 
restlessness 
none 
mild involuntary 
movements not 
interfering with 
function 
moderate 
involuntary 
movements 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe 
involuntary 
movements or 
torticollis 
interfering with 
activities of daily 
living 
bedridden or 
disabling 
Hallucinations 
normal 
- 
- 
present 
toxic psychosis 
Headache is graded in the PAIN category. 


IRB PROTOCOL #98153 
PAGE A27 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Insomnia 
normal 
occasional 
difficulty 
sleeping not 
interfering with 
function 
difficulty 
sleeping 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
frequent 
difficulty 
sleeping, 
interfering with 
activities of daily 
living 
- 
Note: This toxicity is graded when insomnia is related to treatment. If pain or other symptoms interfere with sleep do 
NOT grade as insomnia. 
Irrit
ability 
(children <3 years of 
age) 
normal 
mild; easily 
consolable 
moderate; 
requiring 
increased 
attention 
severe; 
inconsolable 
- 
Leukoencephalopath
y associated 
radiological findings 
none 
mild increase in 
SAS 
(subarachnoid 
space) and/or 
mild 
ventriculomegaly
; and/or small 
(+/- multiple) 
focal T2 
hyperintensities, 
involving 
periventricular 
white matter or < 
1/3 of susceptible 
areas of 
cerebrum 
moderate 
increase in SAS; 
and/or moderate 
ventriculomegaly
; and/or focal T2 
hyperintensities 
extending into 
centrum ovale; or 
involving 1/3 to 
2/3 of susceptible 
areas of 
cerebrum 
severe increase in 
SAS; severe 
ventriculomegaly
; near total white 
matter T2 
hyperintensities 
or diffuse low 
attenuation (CT); 
focal white 
matter necrosis 
(cystic) 
severe increase in 
SAS; severe 
ventriculomegaly
; diffuse low 
attenuation with 
calcification 
(CT); diffuse 
white matter 
necrosis (MRI) 
Memory loss 
normal 
memory loss not 
interfering with 
function 
memory loss 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
memory loss 
interfering with 
activities of daily 
living 
amnesia 
Mood alteration- 
anxiety agitation 
normal 
mild mood 
alteration not 
interfering with 
function 
moderate mood 
alteration 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe mood 
alteration 
interfering with 
activities of daily 
living 
suicidal ideation 
or danger to self 
Mood alteration- 
depression 
normal 
mild mood 
alteration not 
interfering with 
function 
moderate mood 
alteration 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe mood 
alteration 
interfering with 
activities of daily 
living 
suicidal ideation 
or danger to self 


IRB PROTOCOL #98153 
PAGE A28 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Mood alteration- 
euphoria 
normal 
mild mood 
alteration not 
interfering with 
function 
moderate mood 
alteration 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe mood 
alteration 
interfering with 
activities of daily 
living 
danger to self 
Neuropathic pain is graded in the PAIN category. 
Neuropathy- cranial 
absent 
- 
present, not 
interfering with 
activities of daily 
living 
present, 
interfering with 
activities of daily 
living 
life-threatening, 
disabling 
Neuropathy- motor 
normal 
subjective 
weakness but no 
objective findings 
mild objective 
weakness 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
objective 
weakness 
interfering with 
activities of daily 
living 
paralysis 
Neuropathy-sensory 
normal 
loss of deep 
tendon reflexes or 
paresthesia 
(including 
tingling) but not 
interfering with 
function 
objective sensory 
loss or 
paresthesia 
(including 
tingling), 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
sensory loss or 
paresthesia 
interfering with 
activities of daily 
living 
permanent 
sensory loss that 
interferes with 
function 
Nystagmus 
absent 
present 
- 
- 
- 
Also consider Vision-double vision. 
Personality/behavior
al 
normal 
change, but not 
disruptive to 
patient or family 
disruptive to 
patient or family 
disruptive to 
patient and 
family; requiring 
mental health 
intervention 
harmful to others 
or self; requiring 
hospitalization 
Pyramidal tract 
dysfunction (e.g.,  
tone, hyperreflexia, 
positive Babinski, 
,
 
fine motor 
coordination) 
normal 
asymptomatic 
with abnormality 
on physical 
examination 
symptomatic or 
interfering with 
function but not 
interfering with 
activities of daily 
living 
interfering with 
activities of daily 
living 
bedridden or 
disabling; 
paralysis 
Seizure(s) 
none 
- 
seizure(s) self-
limited and 
consciousness is 
preserved 
seizure(s) in 
which 
consciousness is 
altered 
seizures of any 
type which are 
prolonged, 
repetitive, or 
difficult to 
control (e.g., 
status epilepticus, 
intractable 
epilepsy) 


IRB PROTOCOL #98153 
PAGE A29 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Speech impairment  
(e.g., dysphasia or 
aphasia) 
normal 
- 
awareness of 
receptive or 
expressive 
dysphasia, not 
impairing ability 
to communicate 
receptive or 
expressive 
dysphasia, 
impairing ability 
to communicate 
inability to 
communicate 
Syncope (fainting) 
absent 
- 
- 
present 
- 
Also consider CARDIOVASCULAR (ARRHYTHMIA), Vasovagal episode, CNS cerebrovascular ischemia. 
Tremor 
none 
mild and brief or 
intermittent but 
not interfering 
with function 
moderate tremor 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe tremor 
interfering with 
activities of daily 
living 
- 
Vertigo 
none 
not interfering 
with function 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
interfering with 
activities of daily 
living 
bedridden or 
disabling 
Neurology-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
OCULAR/VISUAL 
Cataract 
none 
asymptomatic 
symptomatic, 
partial visual loss 
symptomatic, 
visual loss 
requiring 
treatment or 
interfering with 
function 
- 
Conjunctivitis 
none 
abnormal 
ophthalmologic 
changes, but 
asymptomatic or 
symptomatic 
without visual 
impairment (i.e., 
pain and 
irritation) 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
- 
Dry eye 
normal 
mild, not 
requiring 
treatment 
moderate or 
requiring 
artificial tears 
- 
- 
Glaucoma 
none 
increase in 
intraocular 
pressure but no 
visual loss 
increase in 
intraocular 
pressure with 
retinal changes 
visual 
impairment 
unilateral or 
bilateral loss of 
vision (blindness) 


IRB PROTOCOL #98153 
PAGE A30 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Keratitis  
(corneal 
inflammation/ 
corneal ulceration) 
none 
abnormal 
ophthalmologic 
changes but 
asymptomatic or 
symptomatic 
without visual 
impairment (i.e., 
pain and 
irritation) 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
unilateral or 
bilateral loss of 
vision (blindness) 
Tearing (watery 
eyes) 
none 
mild: not 
interfering with 
function 
moderate: 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
interfering with 
activities of daily 
living 
- 
Vision- blurred 
vision 
normal 
- 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
- 
Vision- double 
vision (diplopia) 
normal 
- 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
- 
Vision- flashing 
lights/floaters 
normal 
mild, not 
interfering with 
function 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
- 
Vision- night 
blindness 
(nyctalopia) 
normal 
abnormal electro-
retinography but 
asymptomatic 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
- 
Vision- photophobia 
normal 
- 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
- 
Ocular/Visual-Other  
(Specify, 
) 
normal 
mild 
moderate 
severe 
unilateral or 
bilateral loss of 
vision (blindness) 
PAIN 


IRB PROTOCOL #98153 
PAGE A31 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Abdominal pain or 
cramping 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Arthralgia  
(joint pain) 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Arthritis (joint pain with clinical signs of inflammation) is graded in the MUSCULOSKELETAL category. 
Bone pain 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Chest pain  
(non-cardiac and 
non-pleuritic) 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Dysmenorrhea 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Dyspareunia 
none 
mild pain not 
interfering with 
function 
moderate pain 
interfering with 
sexual activity 
severe pain 
preventing sexual 
activity 
- 
Dysuria is graded in the RENAL/GENITOURINARY category. 
Earache (otalgia) 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 


IRB PROTOCOL #98153 
PAGE A32 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Headache 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Hepatic pain 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Myalgia  
(muscle pain) 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Neuropathic pain  
(e.g., jaw pain, 
neurologic pain, 
phantom limb pain, 
post-infectious 
neuralgia, or painful 
neuropathies) 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Pain due to radiation 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Pelvic pain 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Pleuritic pain 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 


IRB PROTOCOL #98153 
PAGE A33 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Rectal or perirectal 
pain (proctalgia) 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Tumor pain  
(onset or 
exacerbation of 
tumor pain due to 
treatment) 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Tumor flair is graded in the SYNDROME category. 
Pain-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
disabling 
PULMONARY 
Adult Respiratory 
Distress Syndrome 
(ARDS) 
absent 
- 
- 
- 
present 
Apnea 
none 
- 
- 
present 
requiring 
intubation 
Carbon monoxide 
diffusion capacity 
(DLCO) 
 90% of 
pretreatment 
or normal 
value 
75 - <90% of 
pretreatment or 
normal value 
50 - <75% of 
pretreatment or 
normal value 
25 - <50% of 
pretreatment or 
normal value 
< 25% of 
pretreatment or 
normal value 
Cough 
absent 
mild, relieved by 
non-prescription 
medication 
requiring narcotic 
antitussive 
severe cough or 
coughing spasms, 
poorly controlled 
or unresponsive 
to treatment 
- 
Dyspnea  
(shortness of breath) 
normal 
- 
dyspnea on 
exertion 
dyspnea at 
normal level of 
activity 
dyspnea at rest or 
requiring 
ventilator support 
FEV1 
 90% of 
pretreatment 
or normal 
value 
75 - <90% of 
pretreatment or 
normal value 
50 - <75% of 
pretreatment or 
normal value 
25 - <50% of 
pretreatment or 
normal value 
< 25% of 
pretreatment or 
normal value 
Hiccoughs (hiccups, 
singultus) 
none 
mild, not 
requiring 
treatment 
moderate, 
requiring 
treatment 
severe, 
prolonged, and 
refractory to 
treatment 
- 


IRB PROTOCOL #98153 
PAGE A34 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Hypoxia 
normal 
- 
decreased O2 
saturation with 
exercise 
decreased O2 
saturation at rest, 
requiring 
supplemental 
oxygen 
decreased O2 
saturation, 
requiring 
pressure support 
(CPAP) or 
assisted 
ventilation 
Pleural effusion  
(non-malignant) 
none 
asymptomatic 
and not requiring 
treatment 
symptomatic, 
requiring 
diuretics 
symptomatic, 
requiring O2 or 
therapeutic 
thoracentesis 
life-threatening 
(e.g., requiring 
intubation) 
Pleuritic pain is graded in the PAIN category. 
Pneumonitis/pulmon
ary infiltrates 
none 
radiographic 
changes but 
asymptomatic or 
symptoms not 
requiring steroids 
radiographic 
changes and 
requiring steroids 
or diuretics 
radiographic 
changes and 
requiring oxygen 
radiographic 
changes and 
requiring assisted 
ventilation 
Pneumothorax 
none 
no intervention 
required 
chest tube 
required 
sclerosis or 
surgery required 
life-threatening 
Pulmonary embolism is graded as Thrombosis/embolism in the CARDIOVASCULAR (GENERAL) category. 
Pulmonary fibrosis 
none 
radiographic 
changes, but 
asymptomatic or 
symptoms not 
requiring steroids 
requiring steroids 
or diuretics 
requiring oxygen 
requiring assisted 
ventilation 
Note: Radiation-related pulmonary fibrosis is graded in the RTOG/EORTC Late Radiation Morbidity Scoring Scheme- 
Lung. (See Appendix V, http://ctep.info.nih.gov/ctc3/ctc.htm) 
Voice 
changes/stridor/laryn
x (e.g., hoarseness, 
loss of voice, 
laryngitis) 
normal 
mild or 
intermittent 
hoarseness 
persistent 
hoarseness, but 
able to vocalize; 
may have mild to 
moderate edema 
whispered 
speech, not able 
to vocalize; may 
have marked 
edema 
marked 
dyspnea/stridor 
requiring 
tracheostomy or 
intubation 
Note: 
Cough from radiation is graded as cough in the PULMONARY category. 
Radiation-related hemoptysis from larynx/pharynx is graded as Grade 4 Mucositis due to radiation in the 
GASTROINTESTINAL category.  Radiation-related hemoptysis from the thoracic cavity is graded as Grade 4 
Hemoptysis in the HEMORRHAGE category. 
Pulmonary-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
RENAL/GENITOURINARY 
Bladder spasms 
absent 
mild symptoms, 
not requiring 
intervention 
symptoms 
requiring 
antispasmotic 
severe symptoms 
requiring narcotic 
- 
Creatinine 
WNL 
> ULN - 1.5 x 
ULN 
> 1.5 - 3.0 x 
ULN 
> 3.0 - 6.0 x 
ULN 
> 6.0 x ULN 
Note: Adjust to age-appropriate levels for pediatric patients. 
Dysuria  
(painful urination) 
none 
mild symptoms 
requiring no 
intervention 
symptoms 
relieved with 
therapy 
symptoms not 
relieved despite 
therapy 
- 


IRB PROTOCOL #98153 
PAGE A35 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Fistula or GU fistula  
(e.g., vaginal, 
vesicovaginal) 
none 
- 
- 
requiring 
intervention 
requiring surgery 
Hemoglobinuria 
- 
present 
- 
- 
- 
Hematuria (in the absence of vaginal bleeding) is graded in the HEMORRHAGE category. 
Incontinence 
none 
with coughing, 
sneezing, etc. 
spontaneous, 
some control 
no control (in the 
absence of 
fistula) 
- 
Operative injury to 
bladder and/or ureter 
none 
- 
injury of bladder 
with primary 
repair 
sepsis, fistula, or 
obstruction 
requiring 
secondary 
surgery; loss of 
one kidney; 
injury requiring 
anastomosis or 
re-implantation 
septic obstruction 
of both kidneys 
or vesicovaginal 
fistula requiring 
diversion 
Proteinuria 
normal or < 
0.15 g/24 
hours 
1+ or 0.15 - 1.0 
g/24 hours 
2+ to 3+ or 1.0 - 
3.5 g/24 hours 
4+ or > 3.5 g/24 
hours 
nephrotic 
syndrome 
Note: If there is an inconsistency between absolute value and uristix reading, use the absolute value for grading. 
Renal failure 
none 
- 
- 
requiring dialysis, 
but reversible 
requiring dialysis 
and irreversible 
Ureteral obstruction 
none 
unilateral, not 
requiring surgery 
- 
bilateral, not 
requiring surgery 
stent, 
nephrostomy 
tube, or surgery 
Urinary electrolyte 
wasting (e.g., 
Fanconi’s syndrome, 
renal tubular 
acidosis) 
none 
asymptomatic, 
not requiring 
treatment 
mild, reversible 
and manageable 
with oral 
replacement 
reversible but 
requiring IV 
replacement 
irreversible, 
requiring 
continued 
replacement 
Also consider Acidosis, Bicarbonate, Hypocalcemia, Hypophosphatemia. 
Urinary 
frequency/urgency 
normal 
increase in 
frequency or 
nocturia up to 2 x 
normal 
increase > 2 x 
normal but < 
hourly 
hourly or more 
with urgency, or 
requiring catheter 
- 
Urinary retention 
normal 
hesitancy or 
dribbling, but no 
significant 
residual urine; 
retention 
occurring during 
the immediate 
postoperative 
period 
hesitancy 
requiring 
medication or 
occasional in/out 
catheterization 
(<4 x per week), 
or operative 
bladder atony 
requiring 
indwelling 
catheter beyond 
immediate 
postoperative 
period but for < 6 
weeks 
requiring 
frequent in/out 
catheterization  
(  4 x per week) 
or urological 
intervention (e.g., 
TURP, 
suprapubic tube, 
urethrotomy) 
bladder rupture 


IRB PROTOCOL #98153 
PAGE A36 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Urine color change  
(not related to other 
dietary or 
physiologic cause 
e.g., bilirubin, 
concentrated urine, 
hematuria) 
normal 
asymptomatic, 
change in urine 
color 
- 
- 
- 
Vaginal bleeding is graded in the HEMORRHAGE category. 
Vaginitis  
(not due to infection) 
none 
mild, not 
requiring 
treatment 
moderate, 
relieved with 
treatment 
severe, not 
relieved with 
treatment, or 
ulceration not 
requiring surgery 
ulceration 
requiring surgery 
Renal/Genitourinary-
Other (Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
SECONDARY MALIGNANCY 
Secondary 
Malignancy-Other  
(Specify type, 
__________) 
excludes metastastic 
tumors 
none 
- 
- 
- 
present 
SEXUAL/REPRODUCTIVE FUNCTION 
Dyspareunia is graded in the PAIN category. 
Dysmenorrhea is graded in the PAIN category. 
Erectile impotence 
normal 
mild (erections 
impaired but 
satisfactory) 
moderate 
(erections 
impaired, 
unsatisfactory for 
intercourse) 
no erections 
- 
Female sterility 
normal 
- 
- 
sterile 
- 
Femininization of male is graded in the ENDOCRINE category. 
Irregular menses  
(change from 
baseline) 
normal 
occasionally 
irregular or 
lengthened 
interval, but 
continuing 
menstrual cycles 
very irregular, but 
continuing 
menstrual cycles 
persistent 
amenorrhea 
- 
Libido 
normal 
decrease in 
interest 
severe loss of 
interest 
- 
- 
Male infertility 
- 
- 
Oligospermia  
(low sperm 
count) 
Azoospermia  
(no sperm) 
- 
Masculinization of female is graded in the ENDOCRINE category. 


IRB PROTOCOL #98153 
PAGE A37 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Vaginal dryness 
normal 
mild 
requiring 
treatment and/or 
interfering with 
sexual function, 
dyspareunia 
- 
- 
Sexual/Reproductive 
Function-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
disabling 
SYNDROMES (not included in previous categories) 
Acute vascular leak syndrome is graded in the CARDIOVASCULAR (GENERAL) category. 
ARDS (Adult Respiratory Distress Syndrome) is graded in the PULMONARY category. 
Autoimmune reactions are graded in the ALLERGY/IMMUNOLOGY category. 
DIC (disseminated intravascular coagulation) is graded in the COAGULATION category. 
Fanconi’s syndrome is graded as Urinary electrolyte wasting in the RENAL/GENITOURINARY category. 
Renal tubular acidosis is graded as Urinary electrolyte wasting in the RENAL/GENITOURINARY category. 
Stevens-Johnson syndrome (erythema multiforme) is graded in the DERMATOLOGY/SKIN category. 
SIADH (syndrome of inappropriate antidiuretic hormone) is graded in the ENDOCRINE category. 
Thrombotic microangiopathy (e.g., thromboitic thrombocytopenic purpura/TTP or hemolytic uremic syndrom/HUS) is 
graded in the COAGULATION category. 
Tumor flare 
none 
mild pain not 
interfering with 
function 
moderate pain; 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain; pain 
or analgesics 
interfering with 
function and 
interfering with 
activities of daily 
living 
Disabling 
Also consider Hypercalcemia. 
Note: 
Tumor flare is characterized by a constellation of symptoms and signs in direct relation to initiation of therapy 
(e.g., anti-estrogens/androgens or additional hormones). The symptoms/signs include tumor pain, inflammation of 
visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte disturbances. 
Tumor lysis 
syndrome 
absent 
- 
- 
present 
- 
Also consider Hyperkalemia, Creatinine. 
Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) is graded under the 
RENAL/GENITOURINARY category. 
Syndromes-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 


IRB PROTOCOL #98153 
PAGE A38 
VERSION 17 
03/28/14 
 
Appendix II 
Toxicity Module 
To be implemented at the request of the study sponsor or principal investigator in the protocol or by 
protocol amendment when more detailed information is considered pertinent. 
Toxicity: 
Date of Treatment: 
Course Number: 
Date of onset: 
 
Grade at onset: 
Date of first change in grade:  
 
Grade: 
Date of next change in grade: 
 
Grade: 
Date of next change in grade: 
 
Grade: 
Date of next change in grade: 
 
Grade: 
Date of next change in grade: 
 
Grade: 
Date of next change in grade: 
 
Grade: 
Did toxicity resolve? 
Yes______ 
No______ 
 
If so, date of resolution of toxicity: 
 
 
Date of last observation (if prior to 
recovery): 
 
 
Reason(s) observations stopped (if 
prior to recovery): 
 
 
Was patient retreated? 
Yes______ 
No______ 
 
If yes, was treatment delayed for 
recovery? 
Yes______ 
No______ 
 
Date of next treatment? 
 
 
Dose reduced for next treatment? 
Yes______ 
No______ 
 
Additional Comments: 
________________________________________________________________________________________  
________________________________________________________________________________________  
If module is being activated for new toxicity, not currently in CTC, please provide definitions for 
toxicity grading: 
Grade 0 = 
____________________________________________________________________ 
Grade 1 = 
____________________________________________________________________ 
Grade 2 = 
____________________________________________________________________ 
Grade 3 = 
____________________________________________________________________ 
Grade 4 = 
____________________________________________________________________ 


IRB PROTOCOL #98153 
PAGE A39 
VERSION 17 
03/28/14 
 
Appendix III 
Infection Module 
To be implemented at the request of the study sponsor or principal investigator in the protocol or by 
protocol amendment when more detailed information is considered pertinent. 
1. Use the Common Toxicity Criteria definitions to grade the severity of the infection. 
2. Specify type of infection from the following (CHOOSE ONE): 
BACTERIAL 
FUNGAL 
PROTOZOAL 
VIRAL 
UNKNOWN 
3. Specify site of infection from the following (CHOOSE ALL THAT APPLY): 
BLOOD CULTURE POSITIVE 
BONE INFECTION 
CATHETER (intravenous) 
CATHETER (intravenous), tunnel infection 
CENTRAL NERVOUS SYSTEM INFECTION 
EAR INFECTION 
EYE INFECTION 
GASTROINTESTINAL INFECTION 
ORAL INFECTION 
PNEUMONIA 
SKIN INFECTION 
UPPER RESPIRATORY INFECTION 
URINARY TRACT INFECTION 
VAGINAL INFECTION 
INFECTION, not otherwise specified (Specify site, __________) 
4. Specify organism, if known: _______________. 
5. Prophylactic antibiotic, antifungal, or antiviral therapy administration 
Yes_______ 
No_______ 
If prophylaxis was given prior to infection, please specify below: 
Antibiotic prophylaxis  _____________________________________________________ 
Antifungal prophylaxis  ____________________________________________________ 
Antiviral prophylaxis  ______________________________________________________ 
Other prophylaxis  _________________________________________________________ 


IRB PROTOCOL #98153 
PAGE A40 
VERSION 17 
03/28/14 
 
Appendix IV 
Performance Status Scales/Scores 
ECOG or Zubrod Scale  
Karnofsky Score 
0 
Asymptomatic and fully active 
 
100% 
1 
Symptomatic; fully ambulatory; restricted in physically 
strenuous activity 
 
80-90% 
2 
Symptomatic; ambulatory; capable of self-care; more than 
50% of waking hours are spent out of bed 
 
60-70% 
3 
Symptomatic; limited self-care; spends more than 50% of 
time in bed, but not bedridden 
 
40-50% 
4 
Completely disabled; no self-care; bedridden 
 
20-30% 


IRB PROTOCOL #98153 
PAGE A41 
VERSION 17 
03/28/14 
 
Appendix V 
RTOG/EORTC Late Radiation Morbidity Scoring Scheme 
Use for toxicities occurring greater than 90 days after radiation therapy. 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Bladder-  
Late RT Morbidity 
Scoring 
No change 
from baseline 
Slight epithelial 
atrophy/minor 
telangiectasia 
(microscopic 
hematuria) 
Moderate 
frequency/ 
generalized 
telangiectasia/ 
intermittent 
macroscopic 
hematuria 
Severe frequency 
and 
dysuria/severe 
generalized 
telangiectasia 
(often with 
petechiae); 
frequent 
hematuria; 
reduction in 
bladder capacity 
(< 150 cc) 
Necrosis/contract
ed bladder 
(capacity < 100 
cc)/severe 
hemorrhagic 
cystitis 
Bone- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Asymptomatic; 
no growth 
retardation; 
reduced bone 
density 
Moderate pain or 
tenderness; 
growth 
retardation; 
irregular bone 
sclerosis 
Severe pain or 
tenderness; 
complete arrest of 
bone growth; 
dense bone 
sclerosis 
Necrosis/ 
spontaneous 
fracture 
Brain- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Mild headache; 
slight lethargy 
Moderate 
headache; great 
lethargy 
Severe 
headaches; severe 
CNS dysfunction 
(partial loss of 
power or 
dyskinesia) 
Seizures or 
paralysis; coma 
Esophagus- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Mild fibrosis; 
slight difficulty in 
swallowing 
solids; no pain on 
swallowing 
Unable to take 
solid food 
normally; 
swallowing semi-
solid food; 
dilatation may be 
indicated 
Severe fibrosis; 
able to swallow 
only liquids; may 
have pain on 
swallowing; 
dilation required 
Necrosis/ 
perforation; 
fistula 
Heart- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Asymptomatic or 
mild symptoms; 
transient T wave 
inversion and ST 
changes; sinus 
tachycardia > 110 
(at rest) 
Moderate angina 
on effort; mild 
pericarditis; 
normal heart size; 
persistent 
abnormal T wave 
and ST changes; 
low QRS 
Severe angina; 
pericardial 
effusion; 
constrictive 
pericarditis; 
moderate heart 
failure; cardiac 
enlargement; 
EKG 
abnormalities 
Tamponade/sever
e heart 
failure/severe 
constrictive 
pericarditis 
Joint- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Mild joint 
stiffness; slight 
limitation of 
movement 
Moderate 
stiffness; 
intermittent or 
moderate joint 
pain; moderate 
Severe joint 
stiffness; pain 
with severe 
limitation of 
movement 
Necrosis/complet
e fixation 


IRB PROTOCOL #98153 
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VERSION 17 
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Grade 
Toxicity 
0 
1 
2 
3 
4 
limitation of 
movement 
Kidney- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Transient 
albuminuria; no 
hypertension; 
mild impairment 
of renal function; 
urea 25 - 35 
mg%; creatinine 
1.5 - 2.0 mg%; 
creatinine 
clearance > 75% 
Persistent 
moderate 
albuminuria (2+); 
mild 
hypertension; no 
related anemia; 
moderate 
impairment of 
renal function; 
urea > 36 - 60 
mg%; creatinine 
clearance > 50 - 
74% 
Severe 
albuminuria; 
severe 
hypertension; 
persistent anemia 
(< 10 g%); severe 
renal failure; urea 
> 60 mg%; 
creatinine > 4 
mg%; creatinine 
clearance  
< 50% 
Malignant 
hypertension; 
uremic coma/urea 
> 100% 
Larynx- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Hoarseness; 
slight arytenoid 
edema 
Moderate 
arytenoid edema; 
chondritis 
Severe edema; 
severe chondritis 
Necrosis 
Liver- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Mild lassitude; 
nausea; 
dyspepsia; 
slightly abnormal 
liver function 
Moderate 
symptoms; some 
abnormal liver 
function tests; 
serum albumin 
normal 
Disabling hepatic 
insufficiency; 
liver function 
tests grossly 
abnormal; low 
albumin; edema 
or ascites 
Necrosis/hepatic 
coma or 
encephalopathy 
Lung- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Asymptomatic or 
mild symptoms 
(dry cough); 
slight 
radiographic 
appearances 
Moderate 
symptomatic 
fibrosis or 
pneumonitis 
(severe cough); 
low grade fever; 
patchy 
radiographic 
appearances 
Severe 
symptomatic 
fibrosis or 
pneumonitis; 
dense 
radiographic 
changes 
Severe 
respiratory 
insufficiency/ 
continuous 
O2/assisted 
ventilation 
Mucous membrane- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Slight atrophy 
and dryness 
Moderate atrophy 
and 
telangiectasia; 
little mucus 
Marked atrophy 
with complete 
dryness; severe 
telangiectasia 
Ulceration 
Salivary glands- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Slight dryness of 
mouth; good 
response on 
stimulation 
Moderate dryness 
of mouth; poor 
response on 
stimulation 
Complete dryness 
of mouth; no 
response on 
stimulation 
Fibrosis 
Skin- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Slight atrophy; 
pigmentation 
change; some 
hair loss 
Patchy atrophy; 
moderate 
telangiectasia; 
total hair loss 
Marked atrophy; 
gross 
telangiectasia 
Ulceration 
Small/Large 
intestine- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Mild diarrhea; 
mild cramping; 
bowel movement 
5 x daily slight 
rectal discharge 
Moderate 
diarrhea and 
colic; bowel 
movement > 5 x 
daily; excessive 
Obstruction or 
bleeding, 
requiring surgery 
Necrosis/ 
perforation fistula 


IRB PROTOCOL #98153 
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Grade 
Toxicity 
0 
1 
2 
3 
4 
or bleeding 
rectal mucus or 
intermittent 
bleeding 
Spinal cord- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Mild Lhermitte’s 
syndrome 
Severe 
Lhermitte’s 
syndrome 
Objective 
neurological 
findings at or 
below cord level 
treatment 
Mono-, para-, 
quadriplegia 
Subcutaneous tissue- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Slight induration 
(fibrosis) and loss 
of subcutaneous 
fat 
Moderate fibrosis 
but 
asymptomatic; 
slight field 
contracture; < 
10% linear 
reduction 
Severe induration 
and loss of 
subcutaneous 
tissue; field 
contracture > 
10% linear 
measurement 
Necrosis 
Eye- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Asymptomatic 
cataract; minor 
corneal ulceration 
or keratitis 
Symptomatic 
cataract; 
moderate corneal 
ulceration; minor 
retinopathy or 
glaucoma 
Severe keratitis; 
severe 
retinopathy or 
detachment; 
severe glaucoma 
Panophthalmitis; 
blindness 
Radiation-Other 
(Specify, 
) 
None 
Mild 
Moderate 
Severe 
Life-threatening 
or disabling 


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Appendix VI 
BMT Complex/Multi-Component Events 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Note: 
The grading of Complex/Multi-Component Events in bone marrow transplant will be defined in the protocol. 
The grading scale must use the CTC criteria for grading the specific component events (toxicities). 
Failure to engraft 
absent 
mild 
moderate 
severe 
life-threatening 
Also consider Hemoglobin (Hgb), Neutrophils/granulocytes (ANC/AGC), Platelets 
Graft versus host 
disease 
absent 
mild 
moderate 
severe 
life-threatening 
Also consider Fatigue, Rash/desquamation, Diarrhea, Bilirubin-GVHD 
Stem cell infusion 
complications 
absent 
mild 
moderate 
severe 
life-threatening 
Also consider Allergic reaction/hypersensitivity, Arrhythmia, Hypertension, Hypotension, Fever, Rigors/chills, 
Sweating, Rash/desquamation, Urticaria, Diarrhea, Nausea, Vomiting, Hemorrhage/bleeding with grade 3 or 4 
thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Hemoptysis, Alkaline phosphatase, 
Bilirubin, GGT, SGOT, SGPT, Infection, Hyperkalemia, Hypernatremia, Hypokalemia, Depressed level of 
consciousness, Seizures, Abdominal pain, Headache, Creatinine, Hemoglobinuria 
Veno-Occlusive 
Disease (VOD) 
absent 
mild 
moderate 
severe 
life-threatening 
Also consider Weight gain-VOD, Bilirubin, Depressed level of consciousness, Hepatic pain, Renal failure, Hepatic 
enlargement. 
 


 
06/20/07 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 EAST DUARTE ROAD 
DUARTE, CA 91010 
DEPARTMENT OF HEMATOLOGY / BONE MARROW TRANSPLANTATION 
05/10/00 
TITLE: 
A PHASE I/II TRIAL OF ESCALATING DOSE OF YTTRIUM-90-LABELED ANTI-CD20 
MONOCLONAL ANTIBODY IN COMBINATION WITH HIGH-DOSE ETOPOSIDE AND 
CYCLOPHOSPHAMIDE FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION FOR 
PATIENTS WITH POOR RISK/RELAPSED B-CELL NON-HODGKIN’S LYMPHOMA 
CITY OF HOPE PROTOCOL NUMBER/VERSION NUMBER: 
IRB# 98153 
VERSION 17 
10/29/03, 04/06/04,  DATE(S) OF AMENDMENT(S)/REVISION(S): 
06/16/04 
Amendment 
1 – 01/31/00 – Version 01 
Amendment 
8 – 02/08/01 – Version 08 
Amendment 
2 – 05/10/00 – Version 02 
Amendment 
9 – 05/03/01 – Version 09 
Amendment 
3 – 06/05/00 – Version 03 
Amendment 10 – 08/07/01 – Version 10 
Amendment 
4 – 07/13/00 – Version 04 
Amendment 11 – 05/30/02 – Version 11 
Amendment 
5 – 09/08/00 – Version 05 
Amendment 12 – 10/29/03 – Version 12 
Amendment 
6 – 10/25/00 – Version 06 
Amendment 13 – 04/06/04 – Version 13 
Amendment 
7 – 12/20/00 – Version 07 
Amendment 14 – 06/16/04 – Version 14 
Amendment    15  –   06/20/07  –   Version 15 
Amendment    16  –   04/18/12  –   Version 16 
(title page only change) 
Amendment   17  –   03/28/14   --  Version 17  
 
 
 
 
 
 
 
          
SITE: 
Lymphoma 
HISTOLOGY: 
Low and Intermediate Grade CD20 (+) 
STAGE (IF APPLICABLE): 
II, III, IV 
MODALITY: 
Chemotherapy/Radioimmunotherapy 
TYPE: 
Phase I/II 
PRINCIPAL INVESTIGATOR: 
06/16/04 
Auayporn Nademanee, M.D. 
Department of Hematology/Hematopoietic Cell Transplantation 
COLLABORATING INVESTIGATOR: 
Andrew Raubitschek, M.D. 
Department of Radioimmunotherapy 
PARTICIPATING CLINICIANS: 
06/16/04 
Stephen J. Forman, M.D. 
Department of Hematology/Hematopoietic Cell Transplantation 
10/29/03 
Joycelynne Palmer, Ph.D. 
Department of Biostatistics 
PARTICIPATING INSTITUTIONS: 
City of Hope National Medical Center 
INVESTIGATIONAL NEW DRUG (IND) NUMBER: 
BB-IND 8836 
 


IRB PROTOCOL #98153 
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i 
05/10/00, 06/05/00, 09/08/00, 10/29/03, 06/16/04 
TABLE OF CONTENTS 
 1.0 
BACKGROUND RATIONALE 
1 
 2.0 
OBJECTIVES 
8 
 3.0 
STUDY DESIGN 
8 
 4.0 
DRUG FORMULATION 
9 
 5.0 
STAGING CRITERIA 
12 
 6.0 
ELIGIBILITY CRITERIA 
13 
 7.0 
EXCLUSION CRITERIA 
14 
 8.0 
TREATMENT PLAN 
14 
 9.0 
STUDY DESIGN AND RULES FOR DOSE ESCALATION 
18 
10.0 
STUDY CALENDAR - PREPARATIVE REGIMEN AND PBSCT 
21 
11.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
22 
12.0 
STATISTICAL CONSIDERATIONS 
23 
13.0 
REGISTRATION GUIDELINES 
24 
14.0 
RECORDS TO BE KEPT AND DATA SUBMISSION SCHEDULE 
24 
15.0 
GENDER AND MINORITIES 
25 
16.0 
DATA MANAGEMENT 
25 
17.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
25 
18.0 
REFERENCES 
26 
Appendix I  
Common Toxicity Criteria (CTC) 
A1 
Appendix II 
Toxicity Module 
A38 
Appendix III 
Infection Module 
A39 
Appendix IV 
Performance Status Scales/Scores 
A40 
Appendix V 
RTOG/EORTC Late Radiation Morbidity Scoring Scheme A41 
Appendix VI 
BMT Complex/Multi-Component Events 
A44 
 


IRB PROTOCOL #98153 
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1 
10/29/03 
1.0 
BACKGROUND RATIONALE 
Non-Hodgkin’s lymphomas (NHLs) 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 old.1  Despite the use of 
aggressive combination chemotherapy regimens, approximately 30-40% of patients with 
intermediate- and high-grade NHL does not achieve complete remission (CR) or suffers relapse 
after attaining 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  Recently, the benefit of high-dose therapy and ASCT proved to be 
superior to conventional salvage chemotherapy in a randomized Parma study of 215 patients with 
chemotherapy-sensitive NHL in relapse.4  The 5-year event-free survival (EFS) was 46% for the 
ASCT group as 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 patients derive long-term benefits from this 
treatment and recurrent disease remains the single most common cause of treatment failure post-
high-dose therapy and ASCT.  Therefore, new therapeutic approaches are needed. 
Patients with low-grade NHL have indolent clinical courses 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.  Relapsed low-grade 
lymphoma may still respond to salvage therapy.  But the duration of subsequent remissions 
progressively decreases.  High-dose therapy and ASCT has been shown to improve survival and 
to 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. 
Recently, the role of radioimmunotherapy for treatment of NHL has emerged.  Radioisotope-
labeled monoclonal antibodies provide a mechanism by which radioactivity can be directly 
targeted to tumors sites while sparing normal tissues.  B-cell lymphomas are attractive targets for 
radioimmunotherapy because of their radiosensitivity, their well-defined surface antigens and the 
availability of multiple monoclonal antibodies to those antigens. 


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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.  But so far, 
none of these regimens have emerged as the best regimen.  However, since NHL is radio-
sensitive and based on experience with acute leukemia, the combination of total body irradiation 
(TBI) and cyclophosphamide (Cy) has been widely used as a preparative regimen for some 
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 Hope6, Stanford University7 and Fred Hutchinson Cancer Research Center (FHCRC)8 
demonstrate the activity of this regimen in patients with lymphoid malignancies.  The transplant-
related mortality within 100 days was 7-8%, with the common causes of death being 
venoocclusive disease (VOD), diffuse alveolar hemorrhage and infection.  The major transplant-
related morbidities were mucositis and skin toxicities, which were fully reversible.  The 5-year 
EFS and overall survival (OS) were 52% [95% Confidence interval (CI) 42-62%] and 61% (95% 
CI 50-73%), respectively for 134 patients with NHL who underwent ASCT utilizing this regimen 
at Stanford.  These results have been confirmed in the Southwestern Oncology Group 
cooperative trial.  Despite its effectiveness, the relapse rate of 34-53 % remains considerably 
high.  Thus, new preparative regimens need to be explored. 
1.2 
Radionuclides for Radioimmunotherapy 
Iodine-131 (131I) has been the gold standard for radioimmunotherapy due to its long track record 
in treating thyroid carcinomas, its well-defined radiochemistry, its clinical availability, and its 
potential for both radioimmunoscintigraphy and radioimmunotherapy.  131I has been employed in 
the majority of reported clinical trials of radioimmunotherapy.  However, there are disadvantages 
to 131I, including its long 8-day half life, the risks of radiation exposure to health care providers 
and the non-specific irradiation to normal organs from gamma components of 131I. 
Yttrium-90 (90Y) 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.  In addition, the short half-life of 90Y facilitates 
its use in combination with other agents, i.e. chemotherapy or total body radiation, and allows for 
high dose rates at localized sites.  Unfortunately, 90Y cannot be used for 
radioimmunoscintigraphy due to its absence of gamma emissions.  Indium-111 (111In) has been 
substituted as an imaging reagent to show tumor localization in patients scheduled for 90Y 
therapy, based on its biodistribution which is close to that of 90Y.  111In-labeled murine 
monoclonals have been used successfully in clinical imaging trials for cutaneous T-cell 
lymphoma, chronic lymphocytic leukemia, melanoma, and colon cancer. 
1.3 
Anti-CD 20 
Anti-CD20 (anti-B1) is a murine monoclonal antibody of isotype IgG2a, raised against 
cryopreserved Burkitt’s 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’s lymphomas 
and B-cell chronic lymphocytic leukemias tested, but not on T-cells, plasma cells, uncommitted 


IRB PROTOCOL #98153 
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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. 
1.4 
IDEC-C2B8 
IDEC-C2B8 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.  IDEC-C2B8 shows specificity for the CD 20 antigen and binds 
with an apparent affinity of 4.3 x 10-9M.  IDEC-C2B8 has also been reported to induce apoptosis 
and to sensitize drug-resistant human B-cell lymphoma cell lines to cytotoxic chemotherapy. 
A phase I dose escalation pharmacokinetic trial of IDEC-C2B8 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.9  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 abdomen. 
A phase III trial to assess the safety and efficacy of IDEC-C2B8 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.10  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.  IDEC-
C2B8 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. 
IDEC-C2B8 has also been studied in combination with chemotherapy.  Czuczman et al11 


IRB PROTOCOL #98153 
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conducted a phase II multi-center study evaluating the safety and anti-tumor activity of IDEC-
C2B8 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.  
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.  This combined therapy is being 
investigated in previously untreated patients with intermediate- and high-grade NHL. 
1.5 
Results of Radiolabeled Antibodies in the Treatment of Non-Hodgkin’s Lymphoma  
Most recent radioimmunotherapy trials for lymphoma have utilized 131I-labeled anti-B1 (anti-
CD20) antibody.  Kaminski et al12 first reported on a trial utilizing multiple treatments with low 
dose 131I-labeled anti-B1 antibody in ten patients who had a CD20 positive B-cell lymphoma in 
whom primary therapy had failed.  Six of the nine treated patients had tumor responses, including 
patients with bulky or chemotherapy-resistant diseases.  Four patients had complete remissions 
(CR), and two had partial responses.  The follow-up time was relatively short, but no disease 
progression was observed in the four patients who achieved a CR at 8-11 months.  Toxicity was 
minimal with mild or no myelosuppression. 
Based on these results, a phase I/II study of 131I-labeled anti-B1 was conducted in 58 heavily pre-
treated patients with NHL (28 low-grade, 14 transformed low-grade, 15 intermediate-grade, and 
2 high-grade).13  The median number of prior therapy was 4, 88% had stage III or IV disease, 
36% had bulky disease, 51% had an elevated LDH level and 14 had failed BMT.  Patients 
received 1-3 dosimetric doses followed by a therapeutic dose.  The dosimetric dose involved the 
IV administration of 5 mCi of 131I anti-B1 antibody to determine the rate of whole body clearance 
so that a whole body radiation dose could be calculated.  Each dosimetric dose was preceded by 
0, 95, or 475 mg of unlabeled antibody.  Therapeutic dose escalation was initiated at 25 cGy and 
adjusted in 10 cGy increment until the MTD.  The MTD was 75 cGy for patients who had not 
undergone BMT.  The overall response rate in these heavily pre-treated patients was 71% with a 
CR rate of 34%.  The median duration of response was 271 days (95% CI; 40-394 days) and the 
median duration of CR was 566 days.  Response was observed in both low-grade and 
transformed low-grade NHL as well as in patients with bulky disease and patients who had 
relapsed post-BMT. 
Further trials of 131I-labeled anti-B1 antibody at non-myeloablative doses has been studied in 4 
separate clinical trials (phase I and II, single and multi-center) in 113 patients with low-grade 
NHL including 25 with transformed low-grade NHL.14  Patients received a single dosimetric 
dose of 450 mg of unlabeled anti-B1 infusion over one hour followed by 35 mg radiolabeled with 
5 mCi 131I over ½ hour.  The therapeutic dose was administered 7 to 14 days after the dosimetric 
dose and consisted of the same unlabeled and labeled antibody doses.  The overall response rate 
was 77% with a CR rate of 45% and 67% of the complete responders were in continuous 
remission for > 4 years.  Reversible hematologic toxicity was the dose- limiting toxicity. ANC < 
100/mm3 was observed in 2.6% of patients and platelets < 10,000/mm3 in 5.3%.  The nadir 


IRB PROTOCOL #98153 
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typically occurred at week 5-6 with recovery by week 8-9.  The most common non-hematologic 
toxicities were transient mild to moderate fever, nausea, asthenia, and chills.  None of the 
patients developed HAMA.  These results suggest that 131I-labeled anti-B1 is safe and effective 
and may induce prolonged CR in heavily pre-treated low-grade and transformed low-grade NHL. 
1.6 
Results of 131I anti-B1 Monoclonal Antibody with Autologous Bone Marrow Support 
Although promising results have been reported with radiolabeled MAb for NHL, these results 
may be improved by using higher dose or myeloablative radiation dose.  The use of radiolabeled 
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 al15 conducted a 
trial utilizing 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 al16 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 a cohorts of 4 patients each with doses of 131I-anti-B1 antibody (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 death; 3 from progressive NHL and 1 from 
disseminated Varicella.  These results suggest that 131I- anti-B1 antibody can be given at doses 
delivering  25 Gy to critical normal organs, with pulmonary and gastrointestinal toxicities being 
dose-limiting.  Although additional studies are needed, 131I-anti-B1 antibody can be safely given 
in combination with high-dose chemotherapy in an autologous stem cell transplant setting for 
NHL. 
1.7 
90Y -Anti-CD20 Radioimmunotherapy for Relapsed NHL 
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.17  The primary objectives 


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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's 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 
nonhematological 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. 
Results of a phase I/II study utilizing chimeric antibody Rituximab as the unlabeled clearing 
antibody and 90Y conjugated anti-CD20 (IDEC-Y2B8, conjugated to the parent murine 
monoclonal 2B8) was recently reported.  In the study reported by Witzig et al18, the first portion 
of the study compared 100 mg/m 2 with 250 mg/m 2of Rituximab as the clearing dose and 
compared dosimetry imaging capabilities.  It was determined that 250 mg/m2 of Rituximab was 
the optimal dose to be used.  In the second portion of the phase I study, the dose of IDEC-Y2B8 
was escalated from 0.2 mCi/kg to 0.4 mCi/kg. No bone marrow or stem cell harvest was 
required.  None of the patients treated at 0.2, 0.3 and 0.4 mCi/kg whose baseline platelet count > 
150,000/mm3 developed grade 4 hematologic toxicity, whereas 3 of 6 patients treated at 0.2 or 
0.3 mCi/kg with baseline platelet counts between 100,000 to 150,000/mm3 developed transient 
grade 4 hematologic toxicity. 
The dosimetry from this phase I/II trial of IDEC-Y2B8 was reported by Wiseman et al.19  Forty-
two patients with low- and intermediate-grade NHL received IDEC-Y2B8 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 111I.  
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 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. 
Outcomes from this trial have been compiled in a submitted publication.19  The overall response 
rate (ORR) for the intent-to-treat population (n = 51) was 67% (26% CR, 41% PR); for the low-
grade group (n = 34) 82% (27% CR, 56% PR); 43% for intermediate grade (n = 4); and 0% for 
mantle cell (n = 3).  Responses were seen in patients with bulky (> 7 cm) disease (41%) and 


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splenomegaly (50%).  Kaplan-Meier estimate of time-to-progression in responders and duration 
of response is 12.9+ months and 11.7+ months, respectively.  Adverse events were primarily 
hematologic and correlated with baseline extent of marrow involvement with NHL and baseline 
platelet count.  Only one patient developed an anti-antibody response (HACA/HAMA). 
1.8 
Study Proposal 
The high-dose therapy regimen of FTBI 1200 cGy, etoposide 60 mg/kg and Cy 100 mg/kg has 
been used extensively at City of Hope as a preparative regimen for patients with hematological 
malignancies.  Given the relatively high relapse rate associated with this regimen, the effective 
anti-lymphoma therapy of IDEC-C2B8, and the safety and feasibility of IDEC-Y2B8 with the 
ability to directly deliver radiation to tumors sites, we propose to study a new preparative 
regimen in patients with relapsed NHL which will utilize 90Y-labeled anti-CD20 antibody 
(IDEC-Y2B8) instead of TBI in combination with high-dose etoposide and cyclophosphamide.  
We plan to conduct a phase I/II trial to define the maximum tolerated dose (MTD) of IDEC-
Y2B8 that can be given with high-dose etoposide and cyclophosphamide followed by ASCT, and 
to define the response rate and toxicities associated with this regimen.  To avoid liver toxicity, 
etoposide dose will be started at 40 mg/kg and escalated to 60 mg/kg and the dose of Cy will be 
fixed at 100 mg/kg. 
05/03/01, 06/16/04 The patient will undergo a dosimetry study with IDEC-In2B8 to confirm favorable localization of 
isotope one week prior to administration of therapeutic dose IDEC-Y2B8.  Serial gamma camera 
images will be obtained at the end of the infusion, 24 hours, 48 hours, 72 - 96 hours, 120 hours 
and 144 hours post-infusion.  At each time point, one whole body and 4 spot planar scans will be 
acquired with the Toshiba dual head camera.  In addition, two SPECT images will be obtained at 
48 and 72 -96 hour time points.  Nuclear Medicine images will be used to estimate the 
distribution of activity in various organs, especially liver, lungs, kidney, heart and spleen.  Blood 
samples will be drawn prior to IDEC-C2B8 and at approximately 0 hours (immediately prior to 
IDEC-In2B8), 2 hours, 4 - 6 hours, 24 hours, 48 hours, 72 - 96 hours, 120 hours and 144 hours 
following antibody infusion.  These samples will be used to analyze antibody clearance and bone 
marrow dose estimates.  Urine samples will be collected daily for six days to analyze 
radioisotope clearance. 
05/03/01, 08/07/01, 
06/16/04 
Favorable biodistribution will be defined as tumor dose greater than any normal organ, except 
spleen and bone marrow, ie. liver, lung, kidney.  For patients in CR at time of transplantation, no 
specific tumor localization is required as long as Ga 67 scan and/or FDG-PET scan is negative.  
Tumor dose will be calculated from multiple gamma camera images and blood/urine 
pharmacokinetics.  If the patient shows favorable biodistribution, the therapeutic dose will be 
administered on day -14.  Serial gamma camera images will be obtained at the end of the 
infusion, 24 hours, 48 hours, 72 - 96 hours, 120 hours and 144 hours post-infusion.  At each time 
point, one whole body and 4 spot planar scans will be acquired with the Toshiba dual head 
camera.  Nuclear Medicine images will be used to confirm estimates of the distribution of 
activity in various organs, especially liver, lungs, kidney, heart and spleen.  Blood samples will 
be drawn prior to IDEC-C2B8 and at approximately 0 hours (immediately prior to IDEC-In2B8 / 
IDEC-Y2B8), 2 hours, 4 - 6 hours, 24 hours, 48 hours, 72 - 96 hours, 120 hours and 144 hours 
following antibody infusion.  These samples will be used to analyze antibody clearance and bone 


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marrow dose estimation.  Urine samples will be collected daily for six days to analyze 
radioisotope clearance.  The therapeutic dose will be administered to deliver a target dose of 
1000 cGy to the organ projected to receive the highest dose from the imaging study.  After the 
first two dose levels the dose will be increased in increments of 250 cGy until a maximum of 
2500 cGy is attained or dose limiting toxicity is encountered. 
10/29/03 
2.0 
OBJECTIVES 
05/10/00 
2.1 
To evaluate the safety and efficacy of a new preparative regimen of 90Y-labeled anti-
CD20 MAb (IDEC-Y2B8) in combination with high-dose etoposide and 
cyclophosphamide followed by ASCT for treatment of patients with relapsed/refractory 
and poor risk NHL. 
2.2 
To determine the MTD of 90Y-anti-CD20 MAb which can be given with high-dose 
etoposide 60 mg/kg and high-dose cyclophosphamide 100 mg/kg followed by ASCT in 
patients with NHL. 
2.3 
To perform dosimetry study to estimate the radiation dose delivered to the tumor and 
normal organs. 
2.4 
To evaluate the short-term and long-term complication of this new preparative regimen. 
3.0 
STUDY DESIGN 
This is an open-label phase I-II clinical and efficacy study of a new preparative regimen followed 
by autologous stem cell support in patients with relapsed and refractory NHL.  Patients with  
low-, and intermediate-grade NHL who have relapsed followed conventional chemotherapy or 
have failed to achieve remission, and who are candidates for high-dose therapy and ASCT will be 
eligible for this study. All patients will receive IDEC-Y2B8 in combination with high-dose 
etoposide and cyclophosphamide followed by ASCT.  The dose of Cy will be fixed at 100 mg/kg. 
There will be two doses escalating schema for etoposide and IDEC-Y2B8.  Etoposide will be 
started at 40 mg/kg (cohort 1) and escalate to 60 mg/kg (cohort 2).  The dose of Y2B8 will be the 
same for cohort 1 and 2, to deliver 1000 cGy to the normal organ receiving the greatest 
accumulation.  If no dose limiting toxicity is observed, while the etoposide dose remains at 60 
mg/kg, the dose of Y2B8 will be escalated to 1250 cGy, and then to a maximum of 2500 cGy, or 
until the MTD has been reached.  Therefore, there will be cohorts with 3 patients per cohort as 
follows (an additional 2 patients per cohort will be accrued if there are eligible patients available 
prior to the determination of toxicity on the current dose level): 
Cohort 1: 
Y2B8 to deliver 1000 cGy to highest normal 
organ excluding spleen and bone marrow 
 
etoposide 40 mg/kg  
 
cyclophosphamide 100 mg/kg 
Cohort 2: 
Y2B8 to deliver 1000 cGy to highest normal 
organ excluding spleen and bone marrow 
 
etoposide 60 mg/kg 
 
cyclophosphamide 100 mg/kg 


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Cohort 3: 
Y2B8 to deliver 1250 cGy to highest normal 
organ excluding spleen and bone marrow 
 
etoposide 60 mg/kg 
 
cyclophosphamide 100 mg/kg 
Cohort 4: 
Y2B8 to deliver 1500 cGy to highest normal 
organ excluding spleen and bone marrow 
 
etoposide 60 mg/kg 
 
cyclophosphamide 100 mg/kg 
Cohort 5: 
Y2B8 to deliver 1750 cGy to highest normal 
organ excluding spleen and bone marrow 
 
etoposide 60 mg/kg 
 
cyclophosphamide 100 mg/kg 
Cohort 6 to 8: 
Y2B8 to deliver 2000-2500 cGy to highest normal 
organ excluding spleen and bone marrow 
 
etoposide 60 mg/kg  
 
cyclophosphamide 100 mg/kg 
05/03/01 
All patients will have peripheral blood stem cell collected with the target CD34+ of 3.0x106/kg.  
Patients will undergo dosimetry studies on day –21 and therapy on day -14.  Etoposide will be 
given on day -4, followed by a day rest and cyclophosphamide on day -2. PBSC will be infused 
on day +1 when the radiation dose to the reinfused stem cells is estimated to be < 5 cGy. 
4.0 
DRUG FORMULATION 
4.1 
IDEC-Y2B8 
a. 
Drug Formulation and Procurement 
IDEC-2B8-MX-DTPA 
Two ml glass septum vial containing 2 ml (3.2 mg) IDEC-
2B8-MX-DTPA in low metal normal saline at 1.6 mg/ml. 
RITUXAN (IDEC-C2B8) 
Ten ml (100 mg) and/or 50 ml (500 mg) pharmaceutical 
grade glass vials at a concentration of 10 mg of protein per ml. 
111In-chloride 
5 mCi of Indium-111 chloride supplied in .05M HCl. 
90Y-chloride 
40-100 mCi Yttrium-90 chloride supplied in .05M HCl.  
10/29/03 
b. 
Drug Toxicity 
Myelosuppression is the dose limiting toxicity in non marrow supported regimens.  With 
marrow support liver, kidney, and lung are likely to be the dose limiting organs for 
toxicity.  Infusional toxicity of chills and rigors are common with the first administration 
but rarely with subsequent doses.  Decreasing the rate of infusion and the administration 
of antihistamines can control these toxicities. 
c. 
Drug Storage, Reconstitution and Stability 
All antibodies will be stored in the investigational pharmacy at 4ºC until the day of use.  


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Once diluted the unlabeled antibody is to be used within 24 hours if held at 4ºC and at 
room temperature for an additional 12 hours.  The radiolabeled solutions should be used 
within 6 hrs and should be held at 2-8ºC until administered.   
4.2 
VP-16 (epipodophyllotoxin, etoposide, 4'-demethyl-9(4,6-o-ß) d-
ethylideneglycopyranoside). 
a. 
Drug Formulation and Procurement 
VP-16 is supplied by Bristol Laboratories in a 100 mg ampule in 5 cc of a solution 
containing citric acid, 10 mg; benzyl alcohol, 150 mg; polysorbate 80, purified, 250 mg; 
polyethylene glycol 300, 3.75 gm; absolute alcohol q s., 5 cc. 
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 ampoule 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 60 mg/kg/4 hours. 
4.3 
Cyclophosphamide (Neosar, Cytoxan), NSC-26271 
a. 
Drug Formulation and Procurement 
Cyclophosphamide is an alkylating agent dispensed in 100, 200 and 500 mg vials 
containing a dry powder.  Cyclophosphamide will be purchased from Adria Laboratories. 
b. 
Drug Toxicity 
Patients must be well hydrated before and for several hours following administration of 
cyclophosphamide to reduce the potential for hemorrhagic cystitis.  The more common 
side effects include nausea and vomiting, and alopecia.  Acute toxicity includes 
principally leukopenia, with the nadir occurring 7-14 days after a single IV dose.  At high 
doses, occasional pulmonary toxicity has been reported.  Rare cardiac toxicity (congestive 
heart failure) has occurred in patients previously treated with anthracyclines. 
c. 
Drug Storage, Reconstitution and Stability 
Cyclophosphamide is reconstituted with either sterile water for injection, USP or 
bacteriostatic water for injection, USP (Paraben preserved only), using 5 ml for the 100 
mg vial, 10 ml for the 200 mg vial or 25 ml for the 500 mg vial.  Each ml of reconstituted 
solution contains 20 mg cyclophosphamide per ml.  The drug is diluted in 5% dextrose 
and water or physiological saline and given by IV infusion. 


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4.4 
Mesna (Sodium 2-Mercaptoethane sulfonate) 
a. 
Drug Formulation and Procurement 
Mesna is provided by Bristol Laboratories as a 10% (100 mg/ml) solution in water with 
0.25 mg EDTA as excipient in 4 ml ampules. 
b. 
Drug Storage, Reconstitution and Stability 
Mesna solutions have been shown to be stable on extended storage at room temperature 
in ampules.  No change in composition of the ampules was noted at one year's storage in 
these conditions. 
On exposure to air Mesna is known to undergo oxidation to disulfide.  Since the Mesna 
concentration of opened ampules may decrease with time, the ampule should be opened 
just before use and the unused part discarded. 
c. 
Administration 
Each dose of Mesna will be diluted in 50 cc of 5% dextrose/water or 0.9% normal saline 
and infused intravenously over 15 minutes. 
06/05/00 
4.5 
DTPA (Diethyltriaminepenatacetic acid) 
a. 
Drug Formulation and Procurement 
DTPA will be purchased from Heyl Pharmaceuticals, Berlin, Germany.  It is supplied as a 
1 gram ampule in 5 mls.  
b. 
Drug toxicity 
DTPA has been known to cause headaches, fever, chills, flu-like symptoms, nasal 
stuffiness, nausea, vomiting, abdominal cramping, and diarrhea.  Other side effects that 
are less common include pain at the injection site, dehydration, decreased blood pressure, 
irregularities of heart rhythm, decreased blood counts, increased calcium, numbness and 
tingling, sneezing, excessive tearing, kidney damage, and zinc deficiency (which can 
result in a facial and perianal rash and tongue and mouth sores).  In addition, there is 
always a risk of a very uncommon or previously unknown side effect occurring.  Stopping 
the infusion normally reverses the side effects.  Headaches and tingling have been 
observed at the City of Hope but were reversible.  Trace metals will be administered at 
the end of infusion to replace any depleted heavy metals. 
c. 
Drug Storage, Reconstitution and Stability 
The DTPA solution will be diluted with 250 mls normal saline and administered over 24 
hours.  Additional IV fluids will be administered to maintain a minimum of 125 mls/hour 
of fluid.  No other heavy metals should be administered during the 24 hour infusion.  
Potassium may be administered as needed.  DTPA has a long aqueous stability but should 


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be used within 48 hours of being drawn up by the pharmacy.  Patients will receive 250 
mgs/m2 to a maximum of a total dose of 500 mgs. 
5.0 
STAGING CRITERIA 
Staging of disease must be evaluated at least 21 days after the end of the last chemotherapy and 
within 42 days prior to transplant. 
5.1 
The Ann Arbor staging criteria will be used.  Stage is determined based on extent of 
disease at the time of diagnosis. 
5.2 
Ann Arbor Classification (AJCC Manual for Staging of Cancer, 4th ed. 1992) 
STAGE I 
Involvement of a single lymph node region (1) or a single extralymphatic organ or 
site (1E). 
STAGE II 
Involvement of two or more lymph node regions on the same side of the diaphragm 
(II) or localized involvement of an extralymphatic organ or site and its associated 
regional lymph nodes (11E). 
STAGE III 
Involvement of lymph node regions on both sides of the diaphragm (111) which may 
be accompanied by localized involvement of an associated extralymphatic organ or 
site (111E) or spleen (111S) or both (II(1SE). 
STAGE IV 
Diffuse or disseminated involvement of one or more extralymphatic organs with or 
without associated lymph node involvement, or isolated extralymphatic organ 
involvement with distant (non-regional) nodal involvement. 
A = Asymptomatic  
B = Fever, sweats, weight loss > 10% of body weight 
5.3 
Definitions of Sensitivity of Disease: 
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. 
05/10/00 
5.4 
Definitions of Poor Risk Disease 
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 aggressive NHL including mantle cell lymphoma who required 2 
different induction chemotherapy regimens to achieve a partial/complete 
remission. 


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05/03/01 
3. 
Patients with B-Cell NHL who fail to achieve a complete remission after adequate 
induction chemotherapy regimen(s). 
05/10/00 
6.0 
ELIGIBILITY CRITERIA 
05/10/00 
6.1 
Favorable biodistribution on imaging dose 
08/07/01 
6.2 
age  18 and  60 years  
10/29/03 
6.3 
All patients must have biopsy proven diagnosis of low- and intermediate-grade NHL 
including follicular small cleaved, follicular mixed, follicular large cell, diffuse small 
cleaved, diffuse mixed, diffuse large cell, and immunoblastic lymphoma (working 
formulation B, C, D, E, F, G and H) including mantle cell lymphoma. Transformed low-
grade lymphomas are eligible 
6.4 
Demonstrated monoclonal CD20 + B-cell population in lymph nodes and/or bone marrow 
05/10/00 
6.5 
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 
05/10/00,05/30/02 
10/29/03 
6.6 
Patients must have bone marrow aspiration and biopsy within 42 days before salvage 
chemotherapy or stem cell collection which show  10% lymphomatous involvement of 
total cellularity 
09/08/00, 05/30/02 6.7  
Platelet count should be normal before initiation of chemotherapy for salvage purposes or 
stem cell mobilization.  If the patient collected his/her stem cells at an outside facility, 
then the platelet count must be normal before the imaging dose of antibody 
6.8  
Normal renal function test with serum creatinine of  1.5 mg/dl, or a creatinine clearance 
of  60 ml/min 
6.9 
Adequate pulmonary function as measured by FEV1 > 65% of predicted measured, or a 
DLCO  50% of predicted measured 
04/06/04 
6.10 
Cardiac Ejection fraction of > 50% by echocardiogram or multiple gated acquisition scan 
6.11 
Adequate liver function tests with a bilirubin of  1.5 x normal and SGOT or SGPT  2 x 
normal 
6.12 
Negative human immunodeficiency virus antibody 
05/03/01 
6.13 
ECOG performance status 0 or 1; or KPS  80 
6.14 
No active CNS disease or prior history of CNS disease 
07/13/00 
6.15 
Patients who have received involved field external beam therapy to area excluding lung, 
heart, liver and kidney are allowed, but will be evaluated on a case by case basis 
6.16 
Patients must have recovered from last therapy and should be at least four weeks from 
prior radiation or chemotherapy 


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08/07/01 
6.17 
The patient should have a baseline CT scan and Ga 67 scan and/or FDG-PET scan after 
the last chemotherapy prior to initiation of treatment 
10/29/03 
6.18 
Normal cytogenetic study on bone marrow (prior to salvage chemotherapy or stem cell 
collection).  However, cytogenetic study on peripheral blood is acceptable if bone marrow 
biopsy has already been done and shows no sign of MDS or lymphoma and a repeat bone 
marrow is deemed unnecessary by attending physician 
7.0 
EXCLUSION CRITERIA 
7.1 
Presence of human anti-mouse antibody (HAMA) or human anti-chimeric antibody 
7.2 
Prior radioimmunotherapy 
7.3 
Failure to collect adequate number of CD34 + cells  3x106 /kg 
7.4 
Abnormal cytogenetic study on the bone marrow aspirate sample prior to stem cell 
collection 
7.5 
Prior bone marrow transplantation 
07/13/00 
7.6 
Prior malignancy except for adequately treated basal cell or squamous cell skin cancer, 
adequately treated noninvasive carcinomas, or other cancer from which the patient has 
been disease-free for at least five years 
7.7 
Active evidence of Hepatitis B and C infection; Hepatitis B surface antigen positive 
02/08/01 
7.8 
History of alcohol abuse 
10/29/03 
7.9 
Patient weighs more than 250 pounds 
8.0 
TREATMENT PLAN 
8.1 
Outline of the preparative regimen 
Day -21 
Dosimetry with 5 mCi IDEC-In2B8 following 250 mg/M2 Rituxan 
Day -14 
IDEC-Y2B8 with 5 mCi IDEC-In2B8 following 250 mg/M2 Rituxan  
05/30/02 
Day -7 
Bone marrow biopsy and dose estimation 
05/30/02, 10/29/03 
Day -4  
Etoposide 40 mg/kg adjusted ideal body weight (Cohort 1) or 60 mg/kg 
adjusted ideal body weight for other cohorts 
10/29/03 
Day -2  
Cyclophosphamide 100 mg/kg ideal body weight 
06/05/00 
Day 0  
DTPA infusion 
Day +1 
Peripheral Stem Cell reinfusion 
Day +1 
Start G-CSF 5 g/kg/d IV 


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07/13/00 
8.2 
Pre-Transplant Therapy 
10/29/03 
a. 
Autologous Stem Cell Collection and Cryopreservation 
All patients should have bone marrow aspiration and biopsy which show no microscopic 
evidence of lymphomatous involvement, or  10% involvement at the time of stem cell 
collection.  In addition, cytogenetic studies, immunophenotyping, gene rearrangement 
should be done.  Peripheral blood stem cells (PBSCs) will be collected via leukapheresis 
procedures that have been previously described.  Patients will receive PBSCs collected 
after mobilization by: 1) growth factors, ie. G-CSF 10 µg/kg/d or 2) chemotherapy with 
growth factors.  A minimum of CD34+ cells, 3.0 x 106/kg should be collected. 
b. 
Trimethoprim Sulfa 
All patients should receive trimethoprim sulfa (one double-strength tablet PO bid) 
beginning day -8 through day -2 prior to PBSCT as prophylaxis against PCP.  (The choice 
of trimethoprim sulfa as a prophylactic agent may be altered based on a history of 
sensitivity to this agent.)  Dosing should be discontinued 48 hours prior to PBSC infusion 
because of potential myelosuppression. 
10/29/03 
c. 
CNS Prophylaxis 
CNS prophylaxis is recommended for patients with mantle cell lymphoma or diffuse 
large cell lymphoma who had bone marrow involvement at diagnosis or at time of 
relapse.  For patients with mantle cell lymphoma who have never received high-dose 
MTX, CNS prophylaxis with intrathecal chemotherapy should be given. 
8.3 
Radioimmunotherapy 
08/07/01 
a. 
Rituxan 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.  If hypersensitivity or infusion-related events do not occur, escalate the 
infusion rate in 50 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. 
b. 
IDEC-In2B8 Administration - Two mg of IDEC-In2B8 (5.0 mCi of 111In) will be 
administered for the dosimetry portion of the protocol.  The imaging dose will be 
administered over 10 minutes by slow IV injection immediately following the 
infusion of Rituxan.  A .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. 
c. 
IDEC-Y2B8 Administration – IDEC-Y2B8 (40-100 mCi of 90Y with 3.2 – 6.4 mg 
of antibody) will be administered for the therapy portion of the protocol.  The 
yttrium will be combined with a dose of IDEC-In2B8 (5.0 mCi of 111In) identical 
to the dosimetry dose.  The combined radiopharmaceuticals will be administered 


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by controlled infusion pump over 20 minutes.  A .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-In/Y2B8 has been infused. 
d. 
Bone marrow biopsy. 
8.4 
Chemotherapy 
10/25/00, 12/20/00 
a. 
VP-16 is to be administered as a single infusion on day -4.  The dose is 40 or 60 
mg/kg and is calculated on adjusted ideal body weight to be consistent with 
standard VP-16 dosing for transplant protocols.  The drug is infused undiluted 
directly into a port of a double or triple lumen indwelling intravenous catheter, 
with a total infusion time of 4 hours.  The drug is to be drawn into one or more 
plastic syringes and infused with a syringe infusion pump, placed in an evacuated 
bottle and infused through a pediatric infusion pump, or infused by gravity 
without a pump.  Thus the total dose for a 70 kg patient would be 4,200 mg.  At 
20 mg/ml, the volume of VP-16 would be 210 ml.  The rate of infusion would 
thus be 210 ml/240 minutes or 0.875 ml/minute.  Appropriate anti-emetics and 
sedatives should be given before the infusion begins.  Before, and 2 hours into, 
the infusion the patient is to receive 25 mg of diphenhydramine, and 100 mg of 
hydrocortisone to prevent allergic reactions.  If necessary, diuretics may be given. 
 The intravenous hydration should be continued before, during and after the VP-
16.  Since in rare cases metabolic acidosis has been observed after high dose VP-
16, additional NaHCO3 may be needed. 
10/29/03 
b. 
Cyclophosphamide is administered at a total dose of 100 mg/kg given in one dose 
on day -2 and is calculated on ideal body weight.  Adjustments to the ideal body 
weight calculation for overweight patients are permitted.  For patients who are 
weigh less than 95% of ideal body weight, cyclophosphamide will be dosed 
according to actual body weight.  The drug should be dissolved in about 250 cc of 
D5W and infused IV over two hours.  Appropriate anti-emetics and sedatives 
should be given.  To prevent hemorrhagic cystitis, all patients should receive 
hydration with intravenous fluids, according to institutional standards, at the rate 
of 3.0 l/m2/day beginning four hours prior to cyclophosphamide and continuing 
until 24 hours after cyclophosphamide.  In addition, mesna at 40 mg/kg (based on 
ideal body weight) will be given immediately before cyclophosphamide (hr 0) and 
at 3, 6, 9, 12, 15, 18 and 21 hrs later for a total of 8 doses.  Each dose of mesna 
will be given IV over 15 minutes. 
06/05/00, 10/29/03, 06/16/04 
c. 
DTPA is to be administered by continuous intravenous infusion through a port of 
a double or triple lumen indwelling intravenous catheter.  The dose should be ≥ 
250 mgs/m2, but ≤ 500 mgs.  The DTPA should be made up in normal saline and 
infused over 24 hours by infusion pump.  No magnesium or other heavy metal 
should be given during the same time period.  Two hours after the end of the 
DTPA infusion 1 ml of trace metal solution should be infused every eight hours 
for five days.  This should be given by slow intravenous delivery or else as part of 
standard hyperalimentation.  Urine samples will be collected every 12 hours for 


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72 hours beginning 24 hours prior to DTPA infusion. 
07/13/00, 05/03/01 8.5 
Peripheral Stem Cell Reinfusion 
PBSCs will be thawed and infused according to standard guideline at approximately 72 hours 
after completion of cyclophosphamide. 
8.6 
Growth Factor Therapy 
All patients will receive rh-G-CSF, 5 mcg/kg/day IV beginning on day +1, after PBSC infusion 
and continue daily until ANC >500 for 3 consecutive days. 
07/13/00 
8.7 
Supportive Care: 
All patients will be housed in private rooms during the period of granulocytopenia.  
Nonabsorbable antibiotics for gastrointestinal decontamination should be used according to 
institutional guideline.  Trimethoprim-sulfamethoxazole will be administered from day -8 to day 
-2 and prophylaxis should be re-instituted when white blood cells are > 3000 and continued until 
6 months post-transplant.  Empiric broad spectrum antibiotics and parenteral nutrition should be 
used as clinically indicated.  Low-dose amphotericin-B (0.1 to 0.2 mg/kg) should be administered 
on day +1 and continued daily until granulocytopenia resolves.  All blood components should be 
irradiated to 1,500 cGy. 
a. 
Access to Vessels 
Prior to admission, during pre-transplant evaluation, all patients should have a permanent 
central catheter placed. 
b. 
Hyperalimentation 
All patients will receive appropriate Hyperalimentation as soon as necessary after 
admission.  The goal will be to prevent even a short duration of negative nitrogen 
balance. 
c. 
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. 
d. 
Management of Fever/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 


IRB PROTOCOL #98153 
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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 antifungal therapy with Amphotericin-B. 
8.8 
Criteria for Removal from Protocol Treatment 
a. 
Progression of disease. 
b. 
Patients may withdraw from study at any time for any reason. 
8.9 
All reasons for discontinuation of treatment must be documented in the Flow Sheets. 
8.10 
All patients will be followed for survival until death.  Secondary malignancy monitoring 
on this protocol will be done through 5 years post HCT.  After such time, secondary 
malignancy monitoring will be done by the Long Term Follow Up office.   
9.0 
STUDY DESIGN AND RULES FOR DOSE ESCALATION 
This is a phase I/II trial.  For the phase I portion of the study, the rules for dose escalation, dose 
expansion, and termination of escalation are given in section 9.2.  Prior to treatment with Y2B8, 
patients are required to undergo an imaging scan to verify that they have a favorable 
biodistribution.  While waiting to assess toxicities in the initial cohort of 3 to 6 patients, 
additional patients who are determined to be eligible may be accrued at the unescalated dose 
level.  The rationale for this is twofold.  First, patients must be evaluated for distribution as soon 
as possible in order to have patients ready for timely accrual to the next dose level.  If the dose 
escalation decision is delayed, the investigators want to treat the patients at the unescalated dose 
level so that their disease does not progress.  Second, patients will be accrued to unescalated dose 
levels to avoid a loss of momentum in patient accrual.  Modifications to the standard phase I 
design involving accrual of cohorts of 3-6 patients per dose level have been incorporated to 
appropriately handle the varying number of patients accrued to each dose level (see section 9.2).  
Study design considerations and targeted response rates for the phase II portion of the trial are 
given in section 9.3.  Because the eligibility criteria are the same for both the phase I and the 
phase II portions of the trial, the patients treated at the dose level defined as the MTD from the 
phase I portion of the trial will count towards the accrual for the phase II portion of the trial. 
9.1 
Dose Limiting Toxicity (DLT) 
05/03/01  
Dose limiting toxicity (DLT) in a given patient is defined as any grade III non-hematologic 
toxicity not reversible to grade II or less within 96 hours, or any grade IV non-hematologic 
toxicity.  Toxicity will be graded according to the NCI Common Toxicity Criteria (CTC) version 
2.0 and toxicity Module (Appendices I and II, http://ctep.info.nih.gov/ctc3/ctc.htm) with the 
addition of BMT Complex/Multi-Component Events (Appendix VI, http://ctep.info.nih.gov/ctc3/ 
ctc.htm).  To be evaluable for toxicity, a patient must receive a complete course of treatment and 
be observed for 6 weeks after the administration of Y2B8 or have experienced a DLT.  All 
patients who are not evaluable for toxicity will be replaced. 


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9.2 
Definition of Maximum Tolerated Dose (MTD) and DLT-Level and Rules for Dose 
Escalation 
This trial differs from the standard phase I design in that additional patients beyond the standard 
3 or 6 patients per dose level may be accrued to the current dose level while waiting to assess 
toxicities in the initial 3 or 6 patients.  To this end, a decision rule has been added that 
incorporates toxicity information from the additional patients accrued to a dose level.  As toxicity 
information on each additional patient accrued to the trial becomes available, the decision to 
escalate, de-escalate and expand the previous dose level, expand the current cohort or stop the 
trial will be evaluated.  The decision rule (R) will be as follows:  Let x = number of DLTs in n 
patients.  Escalate to the next dose level if R = (x + 0.5) / (n + 2) is ≤ 0.20.  Stop accrual to a dose 
level if R > 0.30.  Continue accrual to a dose level if 0.20 < R ≤ 0.30.  A minimum of three 
patients must be accrued to a dose level.  As soon as 3 patients have been accrued to a dose level 
and toxicity has been assessed, escalation to the next level is allowed, provided that acceptable 
toxicity has been observed.  If accrual to a dose level must be expanded due to toxicity, a 
minimum of 6 patients must be accrued to the expanded dose level. 
Operationally, the rule is to close a dose level and de-escalate if 2 DLTs are observed among 6 or 
fewer patients, or if 3 DLTs are observed among any number of patients.  The dose will be 
escalated if 0 DLTs are observed in 3 or more evaluated patients, if 1 DLT is observed in 6 or 
more evaluated patients, or if 2 DLTs are observed in 11 patients.  At most, 11 patients will be 
accrued to a dose level.  However, if a dose is escalated while toxicity follow-up is still 
outstanding for some patients, the accumulating results from the two dose levels may be pooled 
for the purpose of justifying the continued accrual to the higher dose. 
Table 1 shows values for R based on different combinations of DLTs and numbers of patients.  
Values indicating continued accrual to the current dose are shown in bold. 
Table 1 
 
Number of DLTs (x) 
Number of  
Patients (n) 
 
0 
 
1 
 
2 
 
3 
0.10 
0.30 
0.50 
 
4 
0.08 
0.25 
0.42 
 
5 
0.07 
0.21 
0.36 
 
6 
0.06 
0.19 
0.31 
 
7 
0.06 
0.17 
0.28 
 
8 
0.05 
0.15 
0.25 
 
9 
0.05 
0.14 
0.23 
 
10 
0.04 
0.13 
0.21 
 
11 
0.04 
0.12 
0.19 
This criterion is the posterior mean with a beta (0.5, 1.5) prior, which has a smaller mean, but is 
no more informative than a flat prior.  The criterion is consistent with the conventional rule of 
expanding a dose level to six patients if 1 out of 3 patients experience DLT and stopping if 2 or 


IRB PROTOCOL #98153 
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more patients out of 6 treated at the same dose level experience DLT.  The proposed criterion 
rationalizes the conventional design in order to rationally extend if to larger numbers of patients 
per dose level.  The rationalization is that a dose level is opened with a weak prior expectation of 
a 25% DLT rate, and the dose is escalated or de-escalated as the accumulating data indicate a rate 
below 20% or above 30%. 
The phase I portion of the trial will be closed when 6 patients have been accrued to the highest 
dose level below the DLT level with at most 1 patient experiencing DLT or when 11 patients 
have been accrued with at most 2 patients experiencing DLT.  This dose level will be defined as 
the MTD. 
To demonstrate an application of the escalation rule, consider the following examples: 
Example 1:  Three patients are accrued to dose level 1.  A fourth patient is accrued to the trial 
prior to assessment of toxicity for the third patient and is therefore also treated at dose level 1.  
No DLTs are observed in the first 3 patients such that the fifth patient is accrued to dose level 2 
and subsequent to this the fourth patient accrued to dose level 1 experiences a DLT.  With 1 DLT 
in four patients, from Table 1 the value for R is 0.25 therefore accrual to dose level 2 must be 
halted such that accrual to dose level 1 can be expanded.  Six patients will need to be accrued 
with at most 1 out of 6 patients experiencing DLT in order for accrual to dose level 2 to resume.  
The patient treated at dose level 2 may be counted among the required 6 patients if no DLT is 
encountered. 
Example 2:  Dose level 3 is expanded such that 6 patients are accrued.  A seventh patient is 
accrued to the trial prior to assessment of toxicity for the sixth patient and is therefore also 
treated at dose level 3.  Only one DLT is observed in the first 6 patients such that the eighth 
patient is accrued to dose level 4 and subsequent to this the seventh patient accrued to dose level 
3 experiences a DLT.  With 2 DLTs in seven patients, from Table 1 the value for R is 0.28 
therefore accrual to dose level 4 must be halted so that accrual to dose level 3 can be expanded.  
Eleven patients (including the patient treated at dose level 4) will need to be accrued to dose level 
3 (or above) with at most 2 patients experiencing DLTs in order for accrual to dose level 4 to 
resume.  Two DLTs among 11 patients corresponds to R = 0.19 which is consistent with 1 DLT 
among 6 patients.  A maximum of 11 patients can be accrued to a single dose level. 
9.3 
Design Considerations for the Phase II Trial 
All patients accrued to the dose level established to be the MTD will be included in the 
assessment of response for the phase II portion of the trial.  The primary goal of this portion of the 
trial is to obtain estimates of the efficacy of IDEC-Y2B8 in combination with high-dose etoposide 
and cyclophosphamide followed by ASCT for treatment of patients with relapsed and refractory 
NHL.  A minimum of 17 and a maximum of 37 patients will be accrued to this portion of the trial.  
Justification for the sample size as well as a description of the study design for the phase II portion 
of the trial is provided in section 12.0. 


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10.0 STUDY CALENDAR - PREPARATIVE REGIMEN AND PBSCT 
REQUIRED STUDIES 
Pre 
Study 
DAY 
-21 
DAY 
-14 
DAY 
-7 
DAY 
-4 
DAY 
-2 
DAY 
0 
DAY 
7 
DAY 
14 
DAY 
30 
DAY 
60 
DAY 
100 
DAY 
180 
YR 
1 
YR 
2 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H & PE 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X$ 
10/29/03 
Weight and KPS 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X$ 
Tumor Assessment 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X$ 
Toxicity Notation 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X$ 
X$ 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10/29/03 
CBC/Platelets 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X$ 
10/29/03 
Differential¥ 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X$ 
08/07/01, 10/29/03 
HAMA/HACA 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X« 
X 
 
10/29/03 
Comp Metabolic Panel + LDH 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X$ 
10/29/03 
Magnesium 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
PT/PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoglobulin Levels 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
08/07/01 
Peripheral Blood Mononuclear 
Immunophenotyping 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
CMV Titer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis Profile 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10/29/03 
Herpes Simplex 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
08/07/01, 05/30/02 
BM%, # 
X 
 
 
X^ 
 
 
 
 
 
 
 
X 
 
X 
X 
05/03/01 
Creatinine Clearance 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
05/30/02 
Chest X-ray or CT Chest 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
X 
X& 
05/30/02 
CT scans*, + 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X& 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
MUGA or ECHO 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
DLCO/FEV1 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
08/07/01, 10/29/03, 
04/06/04 
Ga 67 Scan and/or FDG-PET 
Scan 
X¢ 
 
 
 
 
 
 
 
 
X  
 
 
X 
X 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stem Collections 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IDEC-In2B8 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IDEC-Y2B8 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Rituxan 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
VP-16 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
06/16/04 
PBSCT 
 
 
 
 
 
 
X§ 
 
 
 
 
 
 
 
 
06/16/04 
G-CSF 
 
 
 
 
 
 
X§ 
 
 
 
 
 
 
 
 
06/05/00 
DTPA 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
10/29/03 (delete @,06/20/07) &  restaging at Day 100, at 6 months then follow-up evaluation every six months for three years, and then yearly up to 5 yrs post BMT 
$  All late complications such as cataracts formation and occurrence of second malignancies must be documented and reported. 
*  CT scans of chest, abdomen and pelvis as indicated 
08/07/01 (delete #, add^) 
^  biopsy core for determination of radioactivity 
05/03/01 
%  bone marrow aspiration and biopsy, cytogenetic study, immunophenotyping and gene rearrangement 
05/30/02, 06/20/07 
#  Follow-up bone marrow is required at day 180, yr 1 up to 5 yrs post BMT. 
05/30/02, 10/29/03 
+  For pts in CR at time of transplant, CT scans to be done between days 30 and 100. 
10/29/03 
«  Day 180 HAMA/HACA acceptable between days 150 and 210 
10/29/03 
¢  Pre-study PET scan should be done 14 days after stem cell collection to avoid GCSF enhancement effect 
10/29/03  
¥  ANC is acceptable in lieu of differential 
04/06/04 
  If PET scan positive at baseline, day +30 PET scan required 
06/16/04 
§  Day +1 


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11.0 
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 .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. 
05/30/02 
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 Status, 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. 
11.1 
Complete Response (CR) 
Complete disappearance of all measurable evidence of non-evaluable disease.  No new lesions.  
No disease related symptoms.  No evidence of non-evaluable disease, including normalization of 
markers and other abnormal lab values.  All measurable, evaluable and non-evaluable lesions and 
sites must be assessed using the same techniques as baseline.  Refers to clinical CR-when 
restaging surgery is required, a separate pathologic response variable is defined. 
11.2 
Partial Response (PR) 
Applies only to patients with at least one measurable lesion.  Greater than or equal to 50% 
decrease under baseline in the sum of products of perpendicular diameters of all measurable 
lesions.  No progression of evaluable disease. No new lesions.  All measurable and evaluable 
lesions and sites must be assessed using the same techniques as baseline. 
11.3 
Stable Disease (SD) 
Does not qualify for CR, PR or Progression.  All measurable and evaluable sites and lesions must 
be assessed using the same techniques as baseline. 
11.4 
Progressive Disease (PD)  
50% increase or an increase of 10 cm2 (whichever is smaller) in the sum of products of all 
measurable lesions over smallest sum observed (over baseline if no decrease) using the same 


IRB PROTOCOL #98153 
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techniques as baseline, OR clear worsening of any evaluable disease, OR reappearance of any 
lesion which had disappeared, OR appearance of any new lesion/site, OR failure to return for 
evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). For 
“scan only” bone disease, increased uptake does not constitute clear worsening.  Worsening of 
existing non-evaluable disease not constitute progression. 
11.5 
Relapse 
08/07/01 
Relapse is defined as the re-appearance of any clinical evidence of lymphoma in a patient who 
has had a CR.  Relapse for partial responders are defined as progressive disease relative to 
disease status during the partial remission. 
11.6 
Duration of Response 
This is measured from the documented beginning of response (CR or PR) 
11.7 
Performance Status  
Patients will be graded according to the current Performance Status Scales/Scores (Appendix 
IV). 
11.8 
Time to Progression 
From date of registration to date of first observation of progressive disease or death due to any 
cause. 
11.9 
Time to Death 
From date of registration to date of death due to any cause. 
12.0 
STATISTICAL CONSIDERATIONS 
12.1 
Study Design and Justification of Sample Size 
The definition of dose limiting toxicity is given in section 6.1.  The maximum tolerated dose is 
defined in section 6.2.  The number of patients to be treated at each dose level examined in the 
phase I trial as well as the rules for dose escalation is given in section 6.2. 
The phase II portion of the study will follow a two-stage minimax design suggested by Simon (1).  
It is assumed that a true response rate less than 20% would not warrant further study of this agent.  
It is also assumed that a response rate of 40% would be considered promising for further studies in 
these patients.  In the first stage, seventeen evaluable patients will be entered.  If less than four 
responses are observed, the accrual will stop with the conclusion that the regimen is not promising 
for further study.  If four or more responses are observed in the first 17 patients, additional 20 
patients will be accrued during the second stage of the study.  Eleven or more responses out of 37 
patients will be considered as evidence warranting further study of the regimen providing other 
factors, such as toxicity and survival, also appear favorable.  If less than 11 responses out of 37 
patients are observed, further study of the regimen would not be warranted. 
The probability of falsely declaring an agent with a 20% response probability as  warranting further 


IRB PROTOCOL #98153 
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study is 0.10 (alpha) and the probability of correctly declaring an agent with a 40% response 
probability as warranting further study is 0.90 (power). With 37 patients the true probability of 
response can be estimated with a maximum standard error equal to 0.08. 
The phase I portion study is expected to accrue a minimum of 15-18 evaluable patients and a 
maximum of 30.  The phase II portion of the study will accrue a minimum of 17 patients and a 
maximum of 37 patients, of which at least six of these patients will have been included in the 
phase I portion of the study.  It should take approximately 24-36 months to complete both the 
phase I and phase II portions of this trial. 
12.2 
Analysis of Clinical Endpoints 
Patients will be considered evaluable for response and evaluable for toxicity as outlined in section 
11.0.  The toxicities observed at each dose level will be summarized in terms of type (organ 
affected or laboratory determination such as absolute neutrophil count), severity (by NCI 
Common Toxicity Criteria and nadir or maximum values for the laboratory measures), time of 
onset (i.e. course number), duration, and reversibility or outcome.  Tables will be created to 
summarize these toxicities and side effects by dose and by course.  Baseline information (e.g. the 
extent of prior therapy) and demographic information will be presented, as well, to describe the 
patients treated in the phase I portion of the study.  All responses will be reported from the phase 
I portion of the study 
Response rates and duration of response will be estimated for the phase II portion of survival.  
Confidence intervals for the response rate will be established by calculating exact 95% 
confidence limits for a binomial parameter.  The duration of overall and disease-free survival of 
the patient will be estimated using the product-limit method of Kaplan and Meier. 
13.0 
REGISTRATION GUIDELINES 
08/07/01 
Once a signed, written informed consent has been obtained and all pretreatment evaluations have 
been performed, patients will be entered on study, after review of patient eligibility criteria by the 
assigned Data Manager from the City of Hope Department of Biostatistics.  Patients may be 
screened for registration by calling the Department of Biostatistics, ext. 62468. 
14.0 
RECORDS TO BE KEPT AND DATA SUBMISSION SCHEDULE 
14.1 
Confidentiality of Records 
The original data collection forms will be stored in secure cabinets in the Department of 
Biostatistics.  All radioimmunotherapy associated data will be kept in the Department of 
Radioimmunotherapy. 
14.2 
Patient Consent Form 
At the time of registration, signed and dated copies of the patient Informed Consent form with 
the Human Rights must be available (for patient, chart, and Biostatistics Office). 


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15.0 
GENDER AND MINORITIES 
15.1 
Planned Gender and Minority Inclusion for Transplant Patients with Intermediate 
Grade Lymphoma at City of Hope 
 
American 
Indian or 
Alaskan 
Native 
Asian or 
Pacific 
Islander 
Black, 
not of 
Hispanic 
Origin 
Hispanic 
White, 
not of 
Hispanic 
Origin  
White, 
Hispanic 
or not-
Hispanic 
Unknown 
Other or 
Unknown 
Total 
Female 
 
0% 
 
9% 
 
4% 
 16% 
 
54% 
 
17% 
 
0% 
 100% 
Male 
 
0% 
 
5% 
 
2% 
 20% 
 
60% 
 
12% 
 
1% 
 100% 
Unknown 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
15.2 
Actual Gender and Minority Inclusion for Transplant Patients with Intermediate 
Grade Lymphoma at City of Hope 
 
American 
Indian or 
Alaskan 
Native 
Asian or 
Pacific 
Islander 
Black, 
not of 
Hispanic 
Origin 
Hispanic 
White, 
not of 
Hispanic 
Origin  
White, 
Hispanic 
or not-
Hispanic 
Unknown 
Other or 
Unknown 
Total 
Female 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
Male 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
Unknown 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
 
0% 
16.0 
DATA MANAGEMENT 
Clinical Statistics maintains a patient database at City of Hope Medical Center, Department of 
Biostatistics to allow 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 unique patient number to assure 
patient confidentiality. Any publications or presentations refer to patient by unique patient 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.  They are maintained by the COHMC data collection staff.  
Access is restricted to personnel authorized by the Division of Clinical Research. 
17.0 
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, 


IRB PROTOCOL #98153 
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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, or IDEC 
Pharmaceuticals Corporation. 
18.0 
REFERENCES 
 1. Parker SL, Tong T, Bolden S, Wingo PA: Cancer Statistics, 1997 [published erratum 
appears in CA Cancer J Clin 1997 Mar-Apr;47(2):68].  CA.Cancer J.Clin. 47:5, 1997 
 2. Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman 
CAJ, Miller TP: Comparison of a Standard Regimen (CHOP) with Three Intensive 
Chemotherapy Regimens for Advanced Non-Hodgkin's Lymphoma [see comments].  
N.Engl.J.Med. 328:1002, 1993 
 3. Vose JM, Anderson JR, Kessinger A, Bierman PJ, Coccia P, Reed EC, Gordon B, 
Armitage JO: High-Dose Chemotherapy and Autologous Hematopoietic Stem-Cell 
Transplantation for Aggressive Non-Hodgkin's Lymphoma [see comments].  J.Clin.Oncol. 
11:1846, 1993 
 4. Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, Sonneveld P, 
Gisselbrecht C, Cahn JY, Harousseau JL: Autologous Bone Marrow Transplantation as 
Compared with Salvage Chemotherapy in Relapses of Chemotherapy-Sensitive Non-
Hodgkin's Lymphoma [see comments].  N.Engl.J.Med. 333:1540, 1995 
 5. Bierman PJ, Vose JM, Anderson JR, Bishop MR, Kessinger A, Armitage JO: High-Dose 
Therapy with Autologous Hematopoietic Rescue for Follicular Low-Grade Non-Hodgkin's 
Lymphoma.  J.Clin.Oncol. 15:445, 1997 
 6. Nademanee A, Schmidt GM, O'Donnell MR, Snyder DS, Parker PM, Stein A, Smith E, 
Molina A, Wong KK, Stepan DE, Margolin KA, Somlo G, Raschko J, Sniecinski I, Lipsett 
JA, Dagis A, Niland JC, Forman SJ: Fractionated Total Body Irradiation (FTBI), High-
Dose Etoposide (VP-16) and Cyclophosphamide (CY) Followed by Autologous Bone 
Marrow Transplantation (ABMT):  The Results in 110 Patients with Non-Hodgkin's 
Lymphoma (NHL).  Blood 82:143a (559), 1993 (abstr.) 
 7. Horning SJ, Negrin RS, Chao JC, Long GD, Hoppe RT, Blume KG: Fractionated Total-
Body Irradiation, Etoposide, and Cyclophosphamide Plus Autografting in Hodgkin's 
Disease and Non-Hodgkin's Lymphoma.  J.Clin.Oncol. 12:2552, 1994 
 8. Weaver CH, Petersen FB, Appelbaum FR, Bensinger WI, Press O, Martin P, Sandmaier B, 
Deeg HJ, Hansen JA, Brunvand M: High-Dose Fractionated Total-Body Irradiation, 
Etoposide, and Cyclophosphamide Followed by Autologous Stem-Cell Support in Patients 
with Malignant Lymphoma.  J.Clin.Oncol. 12:2559, 1994 
 9. Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, 
Janakiraman N, Foon KA, Liles TM, Dallaire BK, Wey K, Royston I, Davis T, Levy R: 
IDEC-C2B8 (Rituximab) Anti-CD20 Monoclonal Antibody Therapy in Patients With 
Relapsed Low-Grade Non-Hodgkin's Lymphoma.  Blood 90:2188, 1997 
 10. McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman 
MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, 
Dallaire BK: Rituximab Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed 
Indolent Lymphoma:  Half of Patients Respond to a Four-Dose Treatment Program.  
Journal of Clinical Oncology 16:2825, 1998 
 11. Czuczman M, Grillo-López AJ, White CA, Saleh M, Gordon L, LoBuglio AF, Jonas C, 
Dallaire B, Varns C: IDEC-C2B8/CHOP Chemoimmunotherapy in Patients With Low-


IRB PROTOCOL #98153 
PAGE 27 
VERSION 17 
03/28/14 
 
Grade Lymphoma:  Clinical and BCL-2 (PCR) Final Results.  Blood 88:453a (1799), 1996 
(abstr.) 
 12. Kaminski MS, Zasadny KR, Francis IR, Milik AW, Ross CW, Moon SD, Crawford SM, 
Burgess JM, Petry NA, Butchko GM: Radioimmunotherapy of B-Cell Lymphoma with 
[131I]Anti-B1 (Anti-CD20) Antibody.  N.Engl.J.Med. 329:459, 1993 
 13. Stagg R, Wahl RL, Estes J, Tidmarsh G, Kroll S, Shochat D, Zasadny K, Kaminski MS: 
Phase I/II Study of Iodine-131 Anti-B1 Antibody for Non-Hodgkin's Lymphoma (NHL):  
Final Results.  Proceedings of ASCO 17:39a (150), 1998 (abstr.) 
 14. Vose J, Saleh M, Lister A, Rohatiner A, Knox S, Radford J, Zelenetz AD, Stagg R, 
Tidmarsh G, Wahl R, Kaminski MS: Iodine-131 Anti-B1 Antibody for Non-Hodgkin's 
Lymphoma (NHL):  Overall Clinical Trial Experience.  Proceedings of ASCO 17:10a (38), 
1998 (abstr.) 
 15. Press OW, Eary JF, Appelbaum FR, Martin PJ, Badger CC, Nelp WB, Glenn S, Butchko G, 
Fisher D, Porter B: Radiolabeled-Antibody Therapy of B-Cell Lymphoma With Autologous 
Bone Marrow Support [see comments].  N.Engl.J.Med. 329:1219, 1993 
 16. Press O, Eary J, Liu S, Petersdorf S, Bush S, Durack L, Martin P, Maloney D, Matthews D, 
Fisher D, Gooley T, Appelbaum F, Bernstein I: A Phase I/II Trial of High Dose Iodine-131-
Anti-B1 (Anti-CD20) Monoclonal Antibody, Etoposide, Cyclophosphamide, and 
Autologous Stem Cell Transplantation for Patients With Relapsed B Cell Lymphomas.  
Proceedings of ASCO 17:3a (9), 1998 (abstr.) 
 17. Knox SJ, Goris ML, Trisler K, Negrin R, Davis T, Liles TM, Grillo-Lopez A, Chinn P, 
Varns C, Ning S, Fowler S, Deb N, Becker M, Marquez C, Levy R: Yttrium-90-Labeled 
Anti-CD20 Monoclonal Antibody Therapy of Recurrent B-Cell Lymphoma.  Clin.Cancer 
Res. 2:457, 1996 
 18. Witzig T, Wiseman G, White CA, Solinger A, Gordon L, Raubitschek A, Emmanoulides C, 
Royston I, Parker E, Chinn P, Grillo-López A: IDEC-Y2B8 90Yttrium Anti-CD20 
Radioimmunotherapy of Relapsed Non-Hodgkin's Lymphoma (NHL):  Interim Results of a 
Phase I/II Trial.  Blood 90:586a (2606), 1997 (abstr.) 
 19. Wiseman GA, Solinger AM, Grillo-López A, Stabin M, Dunn WL, Witzig TE, Spies S, 
Gordon L, Raubitschek A, Margolin K, Karvelis K, Janakiraman N, Silverman DH, 
Emmanoulides C, Royston I, Chinn P, Parker E, Carter W, White CA: IDEC-Y2B8 (90Y 
Conjugated Anti-CD20) Dosimetry Calculated From 111In Anti-CD20 in Patients With Low 
and Intermediate Grade B-Cell Non-Hodgkin's Lymphoma (NHL) Emphasis on Bone 
Marrow (BM).  Blood 90:510a (2273), 1997 (abstr.) 
20. Witzig TE, White CA, Wiseman GA, Gordon LI, Emmanoulides C, Raubitschek A, 
Janakiraman N, Gutheil J, Schilder RJ, Spies S, Silverman DH, Parker E, and Grillo-López 
A:  Phase I/II Trial of Yttrium 90 Ibritumomab Tiuxetan (IDEC-Y2B8) 
Radioimmunotherapy for Treatment of Relapsed or Refractory CD20 Positive B-Cell Mon-
Hodgkin’s Lymphoma.  Submitted 1999. 
 


IRB PROTOCOL #98153 
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1 
Appendix I 
Common Toxicity Criteria (CTC) 
 
FINAL 1/30/98 
CTC Version 2.0 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
ALLERGY/IMMUNOLOGY 
Allergic reaction/ 
hypersensitivity  
(including drug 
fever) 
none 
transient rash, 
drug fever < 
38°C (<100.4°F) 
urticaria, drug 
fever  38°C 
( 100.4°F), 
and/or 
asymptomatic 
bronchospasm 
symptomatic 
bronchospasm, 
requiring 
parenteral 
medication(s), 
with or without 
urticaria; allergy-
related 
edema/angioede
ma 
anaphylaxis 
Note: Isolated urticaria, in the absence of other manifestations of an allergic or hypersensitivity reaction, is graded in the 
DERMATOLOGY/SKIN category. 
Allergic rhinitis  
(including sneezing, 
nasal stuffiness, 
postnasal drip) 
none 
mild, not 
requiring 
treatment 
moderate, 
requiring 
treatment 
- 
- 
Autoimmune 
reaction 
none 
serologic or other 
evidence of 
autoimmune 
reaction but 
patient is 
asymptomatic 
(e.g., vitiligo), all 
organ function is 
normal and no 
treatment is 
required 
evidence of 
autoimmune 
reaction 
involving a non-
essential organ or 
function (e.g., 
hypothyroidism), 
requiring 
treatment other 
than 
immunosuppressi
ve drugs 
reversible 
autoimmune 
reaction 
involving 
function of a 
major organ or 
other toxicity 
(e.g., transient 
colitis or anemia), 
requiring short-
term 
immunosuppressi
ve treatment 
autoimmune 
reaction causing 
major grade 4 
organ 
dysfunction; 
progressive and 
irreversible 
reaction; long-
term 
administration of 
high-dose 
immuno-
suppressive 
therapy required 
Also consider Hypothyroidism, Colitis, Hemoglobin, Hemolysis. 
Serum sickness 
none 
- 
- 
present 
- 
Urticaria is graded in the DERMATOLOGY/SKIN category if it occurs as an isolated symptom. If it occurs with other 
manifestations of allergic or hypersensitivity reaction, grade as Allergic reaction/hypersensitivity above. 
Vasculitis 
none 
mild, not 
requiring 
treatment 
symptomatic, 
requiring 
medication 
requiring steroids 
ischemic changes 
or requiring 
amputation 
Allergy/Immunology
-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 


IRB PROTOCOL #98153 
PAGE A2 
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Grade 
Toxicity 
0 
1 
2 
3 
4 
AUDITORY/HEARING 
Conductive hearing loss is graded as Middle ear/hearing in the AUDITORY/HEARING category. 
Earache is graded in the PAIN category. 
External auditory 
canal 
normal 
external otitis 
with erythema or 
dry desquamation 
external otitis 
with moist 
desquamation 
external otitis 
with discharge, 
mastoiditis 
necrosis of the 
canal soft tissue 
or bone 
Note: Changes associated with radiation to external ear (pinnae) are graded under Radiation dermatitis in the 
DERMATOLOGY/SKIN category. 
Inner ear/hearing 
normal 
hearing loss on 
audiometry only 
tinnitus or 
hearing loss, not 
requiring hearing 
aid or treatment 
tinnitus or 
hearing loss, 
correctable with 
hearing aid or 
treatment 
severe unilateral 
or bilateral 
hearing loss 
(deafness), not 
correctable 
Middle ear/hearing 
normal 
serous otitis 
without 
subjective 
decrease in 
hearing 
serous otitis or 
infection 
requiring medical 
intervention; 
subjective 
decrease in 
hearing; rupture 
of tympanic 
membrane with 
discharge 
otitis with 
discharge, 
mastoiditis or 
conductive 
hearing loss 
necrosis of the 
canal soft tissue 
or bone 
Auditory/Hearing-
Other 
(Specify, 
) 
normal 
mild 
moderate 
severe 
life-threatening or 
disabling 
BLOOD/BONE MARROW 
Bone marrow 
cellularity 
normal for 
age 
mildly 
hypocellular or 
25% reduction 
from normal 
cellularity for age 
moderately 
hypocellular or 
>25 -  50% 
reduction from 
normal cellularity 
for age or >2 but 
<4 weeks to 
recovery of 
normal bone 
marrow 
cellularity 
severely 
hypocellular or 
>50 -  75% 
reduction in 
cellularity for age 
or 4 - 6 weeks to 
recovery of 
normal bone 
marrow 
cellularity 
aplasia or >6 
weeks to recovery 
of normal bone 
marrow 
cellularity 
Normal ranges: 
 
 
 
 
 
children (  18 years) 
90% 
cellularity 
average 
 
 
 
 
younger adults (19-
59) 
60-70% 
cellularity 
average 
 
 
 
 
older adults (  60 
years) 
50% 
cellularity 
average 
 
 
 
 
Note: Grade Bone marrow cellularity only for changes related to treatment not disease. 


IRB PROTOCOL #98153 
PAGE A3 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
CD4 count 
WNL 
< LLN - 
500/mm3 
200 - < 500/mm3 
50 - < 200/mm3 
< 50/mm3 
Haptoglobin 
normal 
decreased 
- 
absent 
- 
Hemoglobin (Hgb) 
WNL 
< LLN - 10.0 g/dl 
< LLN - 100 g/L 
< LLN - 6.2 
mmol/L 
8.0 - < 10.0 g/dl 
80 - < 100 g/L 
4.9 - < 6.2 
mmol/L 
6.5 - < 8.0 g/dl 
65 - 80 g/L 
4.0 - < 4.9 
mmol/L 
< 6.5 g/dl 
< 65 g/L 
< 4.0 mmol/L 
Note: The following criteria may be used for leukemia studies or bone marrow infiltrative/myelophthisic process if the 
protocol so specifies. 
For leukemia studies 
or bone marrow 
infiltrative/ 
myelophthisic 
processes 
WNL 
10 - <25% 
decrease from 
pretreatment 
25 - <50% 
decrease from 
pretreatment 
50 - <75% 
decrease from 
pretreatment 
75% decrease 
from pretreatment 
Hemolysis (e.g., 
immune hemolytic 
anemia, drug-related 
hemolysis, other) 
none 
only laboratory 
evidence of 
hemolysis [e.g., 
direct 
antiglobulin test 
(DAT, Coombs’) 
schistocytes] 
evidence of red 
cell destruction 
and  2gm 
decrease in 
hemoglobin, no 
transfusion 
requiring 
transfusion 
and/or medical 
intervention (e.g., 
steroids) 
catastrophic 
consequences of 
hemolysis (e.g., 
renal failure, 
hypotension, 
bronchospasm, 
emergency 
splenectomy) 
Also consider Haptoglobin, Hgb. 
Leukocytes (total 
WBC) 
WNL 
< LLN - 3.0 x 109 
/L 
< LLN - 
3000/mm3 
2.0 - < 3.0 x 109 
/L 
2000 - < 
3000/mm3 
1.0 - < 2.0 x 109 
/L 
1000 - < 
2000/mm3 
< 1.0 x 109 /L 
< 1000/mm3 
For BMT studies: 
WNL 
2.0 - <3.0 X 
109/L 
2000 - 
<3000/mm3 
1.0 - <2.0 x 109 
/L 1000 - 
<2000/mm3 
0.5 - <1.0 x 109 
/L 500 - 
<1000/mm3 
<0.5 x 109 /L 
<500/mm3 
Note: The following criteria using age, race and sex normal values may be used for pediatric studies if the protocol so 
specifies. 
 
75 - <100% 
LLN 
50 - <75% LLN 
25 - 50% LLN 
<25% LLN 
Lymphopenia 
WNL 
<LLN - 1.0 x 109 
/L 
<LLN - 
1000/mm3 
0.5 - <1.0 x 109 
/L 
500 - 
<1000/mm3 
<0.5 x 109 /L 
<500/mm3 
- 
Note: The following criteria using age, race, and sex normal values may be used for pediatric studies if the protocol so 
specifies. 
 
75-<100%LLN 
50-<75%LLN 
25-<50%LLN 
<25%LLN 
Neutrophils/granuloc
ytes 
(ANC/AGC) 
WNL 
1.5 - <2.0 x 109 
/L 
1500 - 
<2000/mm3 
1.0 - <1.5 x 109 
/L 
1000 - 
<1500/mm3 
0.5 - <1.0 x 109 
/L 
500 - 
<1000/mm3 
< 0.5 x 109 /L 
< 500/mm3 
For BMT: 
WNL 
1.0 - <1.5 x 109 
/L 
1000 - 
<1500/mm3 
0.5 - <1.0 x 109 
/L 
500 - 
<1000/mm3 
0.1 - <0.5 x 109 
/L 
100 - <500/mm3 
<0.1 x 109 /L 
<100/mm3 


IRB PROTOCOL #98153 
PAGE A4 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Note: The following criteria may be used for leukemia studies or bone marrow infiltrative/myelophthisic process if the 
protocol so specifies. 
For leukemia studies 
or bone marrow 
infiltrative/ 
myelophthisic 
process 
WNL 
10 - <25% 
decrease from 
baseline 
25 - <50% 
decrease from 
baseline 
50 - <75% 
decrease from 
baseline 
75% decrease 
from baseline 
Platelets 
WNL 
< LLN - <75.0 x 
109 /L 
< LLN - 
75000/mm3 
50.0 - < 75.0 x 
109 /L 
50000 - < 
75000/mm3 
10.0 - < 50.0 x 
109 /L 
10000 - < 
50000/mm3 
< 10.0 x 109 /L 
< 10000/mm3 
For BMT: 
WNL 
50.0 - <75.0 x 
109 /L 
50000 - 
<75000/mm3  
20.0 - <50.0 x 
109 /L 
20000 - 
<50000/mm3 
10.0 - <20.0 x 
109 /L 
10000 - 
<20000/mm3 
<10.0 x 109 /L 
<10000/mm3 
Note: The following criteria may be used for leukemia studies or bone marrow infiltrative/myelophthisic process if the 
protocol so specifies. 
For leukemia studies 
or bone marrow 
infiltrative/ 
myelophthisic 
process 
WNL 
10 - <25% 
decrease from 
baseline 
25 - <50% 
decrease from 
baseline 
50 - <75% 
decrease from 
baseline 
75% decrease 
from baseline 
Transfusion: 
Platelets 
none 
- 
- 
yes 
platelet 
transfusions and 
other measures 
required to 
improve platelet 
increment; 
platelet 
transfusion 
refractoriness 
associated with 
life-threatening 
bleeding. (e.g., 
HLA or cross 
matched platelet 
transfusions) 


IRB PROTOCOL #98153 
PAGE A5 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
For BMT: 
none 
1 platelet 
transfusion in 24 
hours 
2 platelet 
transfusions in 24 
hours 
3 platelet 
transfusions in 24 
hours 
platelet 
transfusions and 
other measures 
required to 
improve platelet 
increment; 
platelet 
transfusion 
refractoriness 
associated with 
life-threatening 
bleeding. (e.g., 
HLA or cross 
matched platelet 
transfusions) 
Also consider Platelets. 
Transfusion: pRBCs 
none 
- 
- 
Yes 
- 
For BMT: 
none 
2 u pRBC 
( 15cc/kg) in 24 
hours elective or 
planned 
 
 
3 u pRBC (>15 
30cc/kg) in 24 
hours elective or 
planned 
4 u pRBC 
(>30cc/kg) in 24 
hours 
hemorrhage or 
hemolysis 
associated with 
life-threatening 
anemia; medical 
intervention 
required to 
improve 
hemoglobin 
Also consider Hemoglobin. 
Blood/Bone 
Marrow-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
CARDIOVASCULAR (ARRHYTHMIA) 
Conduction 
abnormality/ 
Atrioventricular 
heart block 
none 
asymptomatic, 
not requiring 
treatment (e.g., 
Mobitz type I 
second-degree 
AV block, 
Wenckebach) 
symptomatic, but 
not requiring 
treatment 
symptomatic and 
requiring 
treatment (e.g., 
Mobitz type II 
second-degree 
AV block, third-
degree AV block) 
life-threatening 
(e.g., arrhythmia 
associated with 
CHF, 
hypotension, 
syncope, shock) 
Nodal/junctional 
arrhythmia/dysrhyth
mia 
none 
asymptomatic, 
not requiring 
treatment 
symptomatic, but 
not requiring 
treatment 
symptomatic and 
requiring 
treatment 
life-threatening 
(e.g., arrhythmia 
associated with 
CHF, 
hypotension, 
syncope, shock) 
Palpitations 
none 
present 
- 
- 
- 
Note: Grade palpitations only in the absence of a documented arrhythmia. 


IRB PROTOCOL #98153 
PAGE A6 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Prolonged QTc 
interval (QTc > 0.48 
seconds) 
none 
asymptomatic, 
not requiring 
treatment 
symptomatic, but 
not requiring 
treatment 
symptomatic and 
requiring 
treatment 
life-threatening 
(e.g., arrhythmia 
associated with 
CHF, 
hypotension, 
syncope, shock) 
Sinus bradycardia 
none 
asymptomatic, 
not requiring 
treatment 
symptomatic, but 
not requiring 
treatment 
symptomatic and 
requiring 
treatment 
life-threatening 
(e.g., arrhythmia 
associated with 
CHF, 
hypotension, 
syncope, shock) 
Sinus tachycardia 
none 
asymptomatic, 
not requiring 
treatment 
symptomatic, but 
not requiring 
treatment 
symptomatic and 
requiring 
treatment of 
underlying cause 
- 
Supraventricular 
arrhythmias 
(SVT/atrial 
fibrillation/ flutter) 
none 
asymptomatic, 
not requiring 
treatment 
symptomatic, but 
not requiring 
treatment 
symptomatic and 
requiring 
treatment 
life-threatening 
(e.g., arrhythmia 
associated with 
CHF, 
hypotension, 
syncope, shock) 
Syncope (fainting) is graded in the NEUROLOGY category. 
Vasovagal episode 
none 
- 
present without 
loss of 
consciousness 
present with loss 
of consciousness 
- 
Ventricular 
arrhythmia 
(PVCs/bigeminy/trig
eminy/ 
ventricular 
tachycardia) 
none 
asymptomatic, 
not requiring 
treatment 
symptomatic, but 
not requiring 
treatment 
symptomatic and 
requiring 
treatment 
life-threatening 
(e.g., arrhythmia 
associated with 
CHF, 
hypotension, 
syncope, shock) 
Cardiovascular/ 
Arrhythmia-Other  
(Specify, 
___________) 
none 
asymptomatic, 
not requiring 
treatment 
symptomatic, but 
not requiring 
treatment 
symptomatic, and 
requiring 
treatment of 
underlying cause 
life-threatening 
(e.g., arrhythmia 
associated with 
CHF, 
hypotension, 
syncope, shock) 
CARDIOVASCULAR (GENERAL) 
Acute vascular leak 
syndrome 
absent 
- 
symptomatic, but 
not requiring 
fluid support 
respiratory 
compromise or 
requiring fluids 
life-threatening; 
requiring pressor 
support and/or 
ventilatory 
support 
Cardiac- 
ischemia/infarction 
none 
non-specific T-
wave flattening 
or changes 
asymptomatic, 
ST- and T- wave 
changes 
suggesting 
ischemia 
angina without 
evidence of 
infarction 
acute myocardial 
infarction 


IRB PROTOCOL #98153 
PAGE A7 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Cardiac left 
ventricular function 
normal 
asymptomatic 
decline of resting 
ejection fraction 
of  10% but < 
20% of baseline 
value; shortening 
fraction  24% 
but < 30% 
asymptomatic but 
resting ejection 
fraction below 
LLN for 
laboratory or 
decline of resting 
ejection fraction 
j
 20% of 
baseline value; < 
24% shortening 
fraction 
CHF responsive 
to treatment 
severe or 
refractory CHF or 
requiring 
intubation 
CNS cerebrovascular ischemia is graded in the NEUROLOGY category. 
Cardiac troponin I 
(cTnI) 
normal 
- 
- 
levels consistent 
with unstable 
angina as defined 
by the 
manufacturer 
levels consistent 
with myocardial 
infarction as 
defined by the 
manufacturer 
Cardiac troponin T 
(cTnT) 
normal 
 0.03 - < 0.05 
ng/ml 
 0.05 - < 0.1 
ng/ml 
 0.1 - < 0.2 
ng/ml 
 0.2 ng/ml 
Edema 
none 
asymptomatic, 
not requiring 
therapy 
symptomatic, 
requiring therapy 
symptomatic 
edema limiting 
function and 
unresponsive to 
therapy or 
requiring drug 
discontinuation 
anasarca (severe 
generalized 
edema) 
Hypertension 
none 
asymptomatic, 
transient increase 
by >20 mmHg 
(diastolic) or to > 
150/100* if 
previously WNL; 
not requiring 
treatment 
recurrent or 
persistent or 
symptomatic 
increase by > 20 
mmHg (diastolic) 
or to > 150/100* 
if previously 
WNL; not 
requiring 
treatment 
requiring therapy 
or more intensive 
therapy than 
previously 
hypertensive 
crisis 
*Note: For pediatric patients, use age and sex appropriate normal values > 95th percentile ULN. 
Hypotension 
none 
changes, but not 
requiring therapy 
(including 
transient 
orthostatic 
hypotension) 
requiring brief 
fluid replacement 
or other therapy 
but not 
hospitalization; 
no physiologic 
consequences 
requiring therapy 
and sustained 
medical attention, 
but resolves 
without persisting 
physiologic 
consequences 
shock (associated 
with acidemia 
and impairing 
vital organ 
function due to 
tissue 
hypoperfusion) 
Also consider Syncope (fainting). 
Note: 
Angina or MI is graded as Cardiac- ischemia/infarction in the CARDIOVASCULAR (GENERAL) category. 
For pediatric patients, systolic BP 65 mmHg or less in infants up to 1 year old and 70 mmHg or less in children older 
than 1 year of age, use two successive or three measurements in 24 hours. 
Myocarditis 
none 
- 
- 
CHF responsive 
to treatment 
severe or 
refractory CHF 


IRB PROTOCOL #98153 
PAGE A8 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Operative injury of 
vein/artery 
none 
primary suture 
repair for injury, 
but not requiring 
transfusion 
primary suture 
repair for injury, 
requiring 
transfusion 
vascular 
occlusion 
requiring surgery 
or bypass for 
injury 
myocardial 
infarction; 
resection of organ 
(e.g., bowel, 
limb) 
Pericardial effusion/ 
pericarditis 
none 
asymptomatic 
effusion, not 
requiring 
treatment 
pericarditis (rub, 
ECG changes, 
and/or chest pain) 
physiologic 
consequences 
resulting from 
symptoms 
tamponade 
(drainage or 
pericardial 
window required) 
Peripheral arterial 
ischemia 
none 
- 
brief episode of 
ischemia 
managed non-
surgically and 
without 
permanent deficit 
requiring surgical 
intervention 
life-threatening or 
with permanent 
functional deficit 
(e.g., amputation) 
Phlebitis 
(superficial) 
none 
- 
present 
- 
- 
Note: 
Injection site reaction is graded in the DERMATOLOGY/SKIN category. 
Thrombosis/embolism is graded in the CARDIOVASCULAR (GENERAL) category. 
Syncope (fainting) is graded in the NEUROLOGY category. 
Thrombosis/embolis
m 
none 
- 
deep vein 
thrombosis, not 
requiring 
anticoagulant 
deep vein 
thrombosis, 
requiring 
anticoagulant 
therapy 
embolic event 
including 
pulmonary 
embolism 
Vein/artery operative injury is graded as Operative injury of vein/artery in the CARDIOVASCULAR (GENERAL) 
category. 
Visceral arterial 
ischemia (non-
myocardial) 
none 
- 
brief episode of 
ischemia 
managed non-
surgically and 
without 
permanent deficit 
requiring surgical 
intervention 
life-threatening or 
with permanent 
functional deficit 
(e.g., resection of 
ileum) 
Cardiovascular/ 
General-Other  
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
COAGULATION 
Note: See the HEMORRHAGE category for grading the severity of bleeding events. 
DIC  
(disseminated 
intravascular 
coagulation) 
absent 
- 
- 
laboratory 
findings present 
with no bleeding 
laboratory 
findings and 
bleeding 
Also grade Platelets. 
Note: Must have increased fibrin split products or D-dimer in order to grade as DIC. 
Fibrinogen 
WNL 
0.75 - <1.0 x 
LLN 
0.5 - <0.75 x 
LLN 
0.25 - <0.5 x 
LLN 
<0.25 x LLN 
Note: The following criteria may be used for leukemia studies or bone marrow infiltrative/myelophthisic process if the 
protocol so specifies. 


IRB PROTOCOL #98153 
PAGE A9 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
For leukemia studies: WNL 
<20% decrease 
from pretreatment 
value or LLN 
20 - <40% 
decrease from 
pretreatment 
value or LLN 
40 - <70% 
decrease from 
pretreatment 
value or LLN 
<50 mg% 
Partial 
thromboplastin time 
(PTT) 
WNL 
> ULN -  1.5 x 
ULN 
> 1.5 -  2 x 
ULN 
>2 x ULN 
- 
Phelbitis is graded in the CARDIOVASCULAR (GENERAL) category. 
Prothrombin time 
(PT) 
WNL 
> ULN -  1.5 x 
ULN 
> 1.5 -  2 x 
ULN 
>2 x ULN 
- 
Thrombosis/embolism is graded in the CARDIOVASCULAR (GENERAL) category. 
Thrombotic 
microangiopathy 
(e.g., thrombotic 
thrombocytopenic 
purpura/TTP or 
hemolytic uremic 
syndrome/HUS) 
absent 
- 
- 
laboratory 
findings present 
without clinical 
consequences 
laboratory 
findings and 
clinical 
consequences, 
(e.g., CNS 
hemorrhage/ 
bleeding or 
thrombosis/ 
embolism or 
renal failure) 
requiring 
therapeutic 
intervention 
For BMT: 
- 
evidence of RBC 
destruction 
(schistocytosis) 
without clinical 
consequences 
evidence of RBC 
destruction with 
elevated 
creatinine ( 3 x 
ULN) 
evidence of RBC 
destruction with 
creatinine (>3 x 
ULN) not 
requiring dialysis 
evidence of RBC 
destruction with 
renal failure 
requiring dialysis 
and/or 
encephalopathy 
Also consider Hemoglobin (Hgb), Platelets, Creatinine. 
Note: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments). 
Coagulation-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
CONSTITUTIONAL SYMPTOMS 
Fatigue 
(lethargy, malaise, 
asthenia) 
none 
increased fatigue 
over baseline, but 
not altering 
normal activities 
moderate (e.g., 
decrease in 
performance 
status by 1 
ECOG level or 
20% Karnofsky 
or Lansky) or 
causing difficulty 
performing some 
activities 
severe (e.g., 
decrease in 
performance 
status by 2 
ECOG levels or 
40% Karnofsky 
or Lansky) or loss 
of ability to 
perform some 
activities 
bedridden or 
disabling 
Note: See Appendix IV (http://ctep.info.nih.gov/ctc3/ctc.htm) for performance status scales. 


IRB PROTOCOL #98153 
PAGE A10 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Fever (in the absence 
of neutropenia, 
where neutropenia is 
defined as AGC < 
1.0 x 109/L) 
none 
38.0 - 39.0°C 
(100.4 - 102.2°F) 
39.1 - 40.0°C 
(102.3 - 104.0°F 
) 
> 40.0°C 
(>104.0°F ) for < 
24hrs 
> 40.0°C 
(>104.0°F ) for > 
24hrs 
Also consider Allergic reaction/hypersensitivity. 
Note: The temperature measurements listed above are oral or tympanic. 
Hot flashes/flushes are graded in the ENDOCRINE category. 
Rigors, chills 
none 
mild, requiring 
symptomatic 
treatment (e.g., 
blanket) or non-
narcotic 
medication 
severe and/or 
prolonged, 
requiring narcotic 
medication 
not responsive to 
narcotic 
medication 
- 
Sweating  
(diaphoresis) 
normal 
mild and 
occasional 
frequent or 
drenching 
- 
- 
Weight gain 
< 5% 
5 - <10% 
10 - <20% 
 20% 
- 
Also consider Ascites, Edema, Pleural effusion. 
Weight gain - veno-
occlusive disease 
(VOD) 
 
 
 
 
 
Note: The following criteria is to be used ONLY for weight gain associated with Veno-Occlusive Disease. 
<2% 
2 - <5% 
5 - <10%  
10% or as 
ascities 
10% or fluid 
retention 
resulting in 
pulmonary failure 
Weight loss 
< 5% 
5 - <10% 
10 - <20% 
20% 
- 
Also consider Vomiting, Dehydration, Diarrhea. 
Constitutional 
Symptoms-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
DERMATOLOGY/SKIN 
Alopecia 
normal 
mild hair loss 
pronounced hair 
loss 
- 
- 
Bruising  
(in absence of grade 
3 or 4 
thrombocytopenia) 
none 
localized or in 
dependent area 
generalized 
- 
- 
Note: 
Bruising resulting from grade 3 or 4 thrombocytopenia is graded as Petechiae/purpura and 
Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia in the HEMORRHAGE category, not in the 
DERMATOLOGY/SKIN category. 


IRB PROTOCOL #98153 
PAGE A11 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Dermatitis, focal 
(associated with 
high-dose 
chemotherapy and 
bone marrow 
transplant) 
none 
faint erythema or 
dry desquamation 
moderate to brisk 
erythema or a 
patchy moist 
desquamation, 
mostly confined 
to skin folds and 
creases; moderate 
edema 
confluent moist 
desquamation, 
1.5 cm 
diameter, not 
confined to skin 
folds; pitting 
edema 
skin necrosis or 
ulceration of full 
thickness dermis; 
may include 
spontaneous 
bleeding not 
induced by minor 
trauma or 
abrasion 
Dry skin 
normal 
controlled with 
emollients 
not controlled 
with emollients 
- 
- 
Erythema multiforme 
(e.g., Stevens-
Johnson syndrome, 
toxic epidermal 
necrolysis) 
absent 
- 
scattered, but not 
generalized 
eruption 
severe or 
requiring IV 
fluids (e.g., 
generalized rash 
or painful 
stomatitis) 
life-threatening 
(e.g., exfoliative 
or ulcerating 
dermatitis or 
requiring enteral 
or parenteral 
nutritional 
support) 
Flushing 
absent 
present 
- 
- 
- 
Hand-foot skin 
reaction 
none 
skin changes or 
dermatitis 
without pain 
(e.g., erythema, 
peeling) 
skin changes with 
pain, not 
interfering with 
function 
skin changes with 
pain, interfering 
with function 
- 
Injection site 
reaction 
none 
pain or itching or 
erythema 
pain or swelling, 
with 
inflammation or 
phlebitis 
ulceration or 
necrosis that is 
severe or 
prolonged, or 
requiring surgery 
- 
Nail changes 
normal 
discoloration or 
ridging 
(koilonychia) or 
pitting 
partial or 
complete loss of 
nail(s) or pain in 
nailbeds 
- 
- 
Petechiae is graded in the HEMORRHAGE category. 
Photosensitivity 
none 
painless erythema 
painful erythema 
erythema with 
desquamation 
- 
Pigmentation 
changes (e.g., 
vitiligo) 
none 
localized 
pigmentation 
changes 
generalized 
pigmentation 
changes 
- 
- 
Pruritus 
none 
mild or localized, 
relieved 
spontaneously or 
by local measures 
intense or 
widespread, 
relieved 
spontaneously or 
by systemic 
measures 
intense or 
widespread and 
poorly controlled 
despite treatment 
- 
Purpura is graded in the HEMORRHAGE category. 


IRB PROTOCOL #98153 
PAGE A12 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Radiation dermatitis 
none 
faint erythema or 
dry desquamation 
moderate to brisk 
erythema or a 
patchy moist 
desquamation, 
mostly confined 
to skin folds and 
creases; moderate 
edema 
confluent moist 
desquamation, 
1.5 cm 
diameter, not 
confined to skin 
folds; pitting 
edema 
skin necrosis or 
ulceration of full 
thickness dermis; 
may include 
bleeding not 
induced by minor 
trauma or 
abrasion 
Note: Pain associated with radiation dermatitis is graded separately in the PAIN category as Pain due to radiation. 
Radiation recall 
reaction (reaction 
following 
chemotherapy in the 
absence of additional 
radiation therapy that 
occurs in a previous 
radiation port) 
none 
faint erythema or 
dry desquamation 
moderate to brisk 
erythema or a 
patchy moist 
desquamation, 
mostly confined 
to skin folds and 
creases; moderate 
edema 
confluent moist 
desquamation, 
1.5 cm 
diameter, not 
confined to skin 
folds; pitting 
edema 
skin necrosis or 
ulceration of full 
thickness dermis; 
may include 
bleeding not 
induced by minor 
trauma or 
abrasion 
Rash/desquamation 
none 
macular or 
papular eruption 
or erythema 
without 
associated 
symptoms 
macular or 
papular eruption 
or erythema with 
pruritis or other 
associated 
symptoms 
covering <50% 
of body surface 
or localized 
desquamation or 
other lesions 
covering <50% 
of body surface 
area 
symptomatic 
generalized 
erythroderma or 
macular, papular 
or vesicular 
eruption or 
desquamation 
covering 50% of 
body surface area 
generalized 
exfoliative 
dermatitis or 
ulcerative 
dermatitis 
For BMT: 
none 
macular or 
papular eruption 
or erythema 
covering <25% 
of body surface 
area without 
associated 
symptoms 
macular or 
papular eruption 
or erythema with 
pruritis or other 
associated 
symptoms 
covering 25 - 
<50% of body 
surface or 
localized 
desquamation or 
other lesions 
covering 25 - 
<50% of body 
surface area 
symptomatic 
generalized 
erythroderma or 
symptomatic 
macular, papular 
or vesicular 
eruption, with 
bullous 
formation, or 
desquamation 
covering 50% of 
body surface area  
generalized 
exfoliative 
dermatitis or 
ulcerative 
dermatitis or 
bullous formation 
Also consider Allergic reaction/hypersensitivity. 
Note: Erythema multiforme (Stevens-Johnson syndrome) is graded separately as Erythema multiforme. 


IRB PROTOCOL #98153 
PAGE A13 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Urticaria  
(hives, welts, 
wheals) 
none 
requiring no 
medication 
requiring PO or 
topical treatment 
or IV medication 
or steroids for 
<24 hours 
requiring IV 
medication or 
steroids for 24 
hours 
- 
Wound- infectious 
none 
cellulitis 
superficial 
infection 
infection 
requiring IV 
antibiotics 
necrotizing 
fascitis 
Wound- non-
infectious 
none 
incisional 
separation 
incisional hernia 
fascial disruption 
without 
evisceration 
fascial disruption 
with evisceration 
Dermatology/Skin-
Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
ENDOCRINE 
Cushingoid 
appearance (e.g., 
moon face with or 
without buffalo 
hump, centripetal 
obesity, cutaneous 
striae) 
absent 
- 
present 
- 
- 
Also consider Hyperglycemia, Hypokalemia. 
Feminization of male 
absent 
- 
- 
present 
- 
Gynecomastia 
none 
mild 
pronounced or 
painful 
pronounced or 
painful and 
requiring surgery 
- 
Hot flashes/flushes 
none 
mild or no more 
than 1 per day 
moderate and 
greater than 1 per 
day 
- 
- 
Hypothyroidism 
absent 
asymptomatic,TS
H elevated, no 
therapy given 
symptomatic or 
thyroid 
replacement 
treatment given 
patient 
hospitalized for 
manifestations of 
hypothyroidism 
myxedema coma 
Masculinization of 
female 
absent 
- 
- 
present 
- 
SIADH (syndrome 
of inappropriate 
antidiuretic 
hormone) 
absent 
- 
- 
present 
- 
Endocrine-Other  
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
GASTROINTESTINAL 
Amylase is graded in the METABOLIC/LABORATORY category. 
Anorexia 
none 
loss of appetite 
oral intake 
significantly 
decreased 
requiring IV 
fluids 
requiring feeding 
tube or parenteral 
nutrition 


IRB PROTOCOL #98153 
PAGE A14 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Ascites (non-
malignant) 
none 
asymptomatic 
symptomatic, 
requiring 
diuretics 
symptomatic, 
requiring 
therapeutic 
paracentesis 
life-threatening 
physiologic 
consequences 
Colitis 
none 
- 
abdominal pain 
with mucus 
and/or blood in 
stool 
abdominal pain, 
fever, change in 
bowel habits with 
ileus or peritoneal 
signs, and 
radiographic or 
biopsy 
documentation 
perforation or 
requiring surgery 
or toxic 
megacolon 
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 
thrombocytopenia, Melena/GI bleeding, Rectal bleeding/hematochezia, Hypotension. 
Constipation 
none 
requiring stool 
softener or 
dietary 
modification 
requiring 
laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
obstruction or 
toxic megacolon 
Dehydration 
none 
dry mucous 
membranes 
and/or 
diminished skin 
turgor 
requiring IV fluid 
replacement 
(brief) 
requiring IV fluid 
replacement 
(sustained) 
physiologic 
consequences 
requiring 
intensive care; 
hemodynamic 
collapse 
Also consider Hypotension, Diarrhea, Vomiting, Stomatitis/pharyngitis (oral/pharyngeal mucositis). 
Diarrhea 
Patients without 
colostomy: 
none 
increase of < 4 
stools/day over 
pre-treatment 
increase of 4-6 
stools/day, or 
nocturnal stools 
increase of 7 
stools/day or 
incontinence; or 
need for 
parenteral 
support for 
dehydration 
physiologic 
consequences 
requiring 
intensive care; or 
hemodynamic 
collapse 
Patients with a 
colostomy: 
none 
mild increase in 
loose, watery 
colostomy output 
compared with 
pretreatment 
moderate increase 
in loose, watery 
colostomy output 
compared with 
pretreatment, but 
not interfering 
with normal 
activity 
severe increase in 
loose, watery 
colostomy output 
compared with 
pretreatment, 
interfering with 
normal activity 
physiologic 
consequences, 
requiring 
intensive care; or 
hemodynamic 
collapse 
For BMT 
none 
>500 - 1000ml 
of diarrhea/day 
>1000 - 1500ml 
of diarrhea/day 
>1500ml of 
diarrhea/day 
severe abdominal 
pain with or 
without ileus 
For Pediatric BMT: 
 
>5 - 10 ml/kg of 
diarrhea/day 
>10 - 15 ml/kg 
of diarrhea/day 
>15 ml/kg of 
diarrhea/day 
- 
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 
thrombocytopenia, Pain, Dehydration, Hypotension. 


IRB PROTOCOL #98153 
PAGE A15 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Duodenal ulcer 
(requires 
radiographic or 
endoscopic 
documentation) 
none 
- 
requiring medical 
management or 
non-surgical 
treatment 
uncontrolled by 
outpatient 
medical 
management; 
requiring 
hospitalization 
perforation or 
bleeding, 
requiring 
emergency 
surgery 
Dyspepsia/heartburn 
none 
mild 
moderate 
severe 
- 
Dysphagia, 
esophagitis, 
odynophagia (painful 
swallowing) 
none 
mild dysphagia, 
but can eat 
regular diet 
dysphagia, 
requiring 
predominantly 
pureed, soft, or 
liquid diet 
dysphagia, 
requiring IV 
hydration 
complete 
obstruction 
(cannot swallow 
saliva) requiring 
enteral or 
parenteral 
nutritional 
support, or 
perforation 
Note: If toxicity is radiation-related, grade either under Dysphagia- esophageal related to radiation or Dysphagia- 
pharyngeal related to radiation. 
Dysphagia- 
esophageal related to 
radiation 
none 
mild dysphagia, 
but can eat 
regular diet 
dysphagia, 
requiring 
predominantly 
liquid, pureed or 
soft diet 
dysphagia 
requiring feeding 
tube, IV 
hydration or 
hyperalimentatio
n 
complete 
obstruction 
(cannot swallow 
saliva); ulceration 
with bleeding not 
induced by minor 
trauma or 
abrasion or 
perforation 
Also consider Pain due to radiation, Mucositis due to radiation. 
Note: Fistula is graded separately as Fistula- esophageal. 
Dysphagia - 
pharyngeal related to 
radiation 
none 
mild dysphagia, 
but can eat 
regular diet 
dysphagia, 
requiring 
predominantly 
pureed, soft, or 
liquid diet 
dysphagia, 
requiring feeding 
tube, IV 
hydration or 
hyperalimentatio
n 
complete 
obstruction 
(cannot swallow 
saliva); ulceration 
with bleeding not 
induced by minor 
trauma or 
abrasion or 
perforation 
Also consider Pain due to radiation, Mucositis due to radiation. 
Note: Fistula is graded separately as Fistula- pharyngeal. 
Fistula- esophageal 
none 
- 
- 
present 
requiring surgery 
Fistula- intestinal 
none 
- 
- 
present 
requiring surgery 
Fistula- pharyngeal 
none 
- 
- 
present 
requiring surgery 
Fistula- rectal/anal 
none 
- 
- 
present 
requiring surgery 
Flatulence 
none 
mild 
moderate 
- 
- 


IRB PROTOCOL #98153 
PAGE A16 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Gastric ulcer  
(requires 
radiographic or 
endoscopic 
documentation) 
none 
- 
requiring medical 
management or 
non-surgical 
treatment 
bleeding without 
perforation, 
uncontrolled by 
outpatient 
medical 
management; 
requiring 
hospitalization or 
surgery 
perforation or 
bleeding, 
requiring 
emergency 
surgery 
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 
thrombocytopenia. 
Gastritis 
none 
- 
requiring medical 
management or 
non-surgical 
treatment 
uncontrolled by 
out-patient 
medical 
management; 
requiring 
hospitalization or 
surgery 
life-threatening 
bleeding, 
requiring 
emergency 
surgery 
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 
thrombocytopenia. 
Hematemesis is graded in the HEMORRHAGE category. 
Hematochezia is graded in the HEMORRHAGE category as Rectal bleeding/hematochezia. 
Ileus (or 
neuroconstipation) 
none 
- 
intermittent, not 
requiring 
intervention 
requiring non-
surgical 
intervention 
requiring surgery 
Mouth dryness 
normal 
mild 
moderate 
- 
- 
Mucositis 
 
 
 
 
 
Note: 
Mucositis not due to radiation is graded in the GASTROINTESTINAL category for specific sites: Colitis, 
Esophagitis, Gastritis, Stomatitis/pharyngitis (oral/pharyngeal mucositis), and Typhlitis; or the 
RENAL/GENITOURINARY category for Vaginititis. 
Radiation-related mucositis is graded as Mucositis due to radiation. 
Mucositis due to 
radiation 
none 
erythema of the 
mucosa 
patchy 
pseudomembrano
us reaction 
(patches 
generally  1.5 
cm in diameter 
and non-
contiguous) 
confluent 
pseudomembrano
us reaction 
(contiguous 
patches generally 
> 1.5 cm in 
diameter) 
necrosis or deep 
ulceration; may 
include bleeding 
not induced by 
minor trauma or 
abrasion 
Also consider Pain due to radiation. 
Note: 
Grade radiation mucositis of the larynx here. 
Dysphagia related to radiation is also graded as either Dysphagia- esophageal related to radiation or Dysphagia- 
pharyngeal related to radiation, depending on the site of treatment. 
Nausea 
none 
able to eat 
oral intake 
significantly 
decreased 
no significant 
intake, requiring 
IV fluids 
- 
Pancreatitis 
none 
- 
- 
abdominal pain 
with pancreatic 
enzyme elevation 
complicated by 
shock (acute 
circulatory 
failure) 
Also consider Hypotension. 


IRB PROTOCOL #98153 
PAGE A17 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Note: Asymptomatic amylase and Amylase are graded in the METABOLIC/LABORATORY category. 
Pharyngitis is graded in the GASTROINTESTINAL category as Stomatitis/pharyngitis (oral/pharyngeal mucositis). 
Proctitis 
none 
increased stool 
frequency, 
occasional blood-
streaked stools, or 
rectal discomfort 
(including 
hemorrhoids), not 
requiring 
medication 
increased stool 
frequency, 
bleeding, mucus 
discharge, or 
rectal discomfort 
requiring 
medication; anal 
fissure 
increased stool 
frequency/diarrhe
a, requiring 
parenteral 
support; rectal 
bleeding, 
requiring 
transfusion; or 
persistent mucus 
discharge, 
necessitating 
pads 
perforation, 
bleeding or 
necrosis or other 
life-threatening 
complication 
requiring surgical 
intervention (e.g., 
colostomy) 
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 
thrombocytopenia, and Pain due to radiation. 
Note: 
Fistula is graded separately as Fistula- rectal/anal. 
Proctitis occurring more than 90 days after the start of radiation therapy is graded in the RTOG/EORTC Late Radiation 
Morbidity Scoring Scheme. (See Appendix V, http://ctep.info.nih.gov/ctc3/ctc.htm) 
Salivary gland 
changes 
none 
slightly thickened 
saliva/may have 
slightly altered 
taste (e.g., 
metallic); 
additional fluids 
may be required 
thick, ropy, sticky 
saliva; markedly 
altered taste; 
alteration in diet 
required 
- 
acute salivary 
gland necrosis 
Sense of smell 
normal 
slightly altered 
markedly altered 
- 
- 
Stomatitis/pharyngiti
s (oral/pharyngeal 
mucositis) 
none 
painless ulcers, 
erythema, or mild 
soreness in the 
absence of 
lesions 
painful erythema, 
edema, or ulcers, 
but can eat or 
swallow 
painful erythema, 
edema, or ulcers 
requiring IV 
hydration 
severe ulceration 
or requires 
parenteral or 
enteral nutritional 
support or 
prophylatic 
intubation 
For BMT: 
none 
painless ulcers, 
erythema, or mild 
soreness in the 
absence of 
lesions 
painful erythema, 
edema or ulcers 
but can swallow 
painful erythema, 
edema, or ulcers 
preventing 
swallowing or 
requiring 
hydration or 
parenteral (or 
enteral) 
nutritional 
support 
severe ulceration 
requiring 
prophylactic 
intubation or 
resulting in 
documented 
aspiration 
pneumonia 
Note: Radiation-related mucositis is graded as Mucositis due to radiation. 
Taste disturbance 
(dysgeusia) 
normal 
slightly altered 
markedly altered 
- 
- 


IRB PROTOCOL #98153 
PAGE A18 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Typhlitis  
(inflammation of the 
cecum) 
none 
- 
- 
abdominal pain, 
diarrhea, fever, or 
radiographic 
documentation 
perforation, 
bleeding or 
necrosis or other 
life-threatening 
complication 
requiring surgical 
intervention (e.g., 
colostomy) 
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 
thrombocytopenia, Hypotension, Febrile/neutropenia. 
Vomiting 
none 
1 episode in 24 
hours over 
pretreatment 
2-5 episodes in 
24 hours over 
pretreatment 
6 episodes in 24 
hours over 
pretreatment; or 
need for IV fluids 
Requiring 
parenteral 
nutrition; or 
physiologic 
consequences 
requiring 
intensive care; 
hemodynamic 
collapse 
Also consider Dehydration. 
Weight gain is graded in the CONSTITUTIONAL SYMPTOMS category. 
Weight loss is graded in the CONSTITUTIONAL SYMPTOMS category. 
Gastrointestinal-
Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
HEMORRHAGE 
Note: 
Transfusion in this section refers to pRBC infusion. 
For any bleeding with grade 3 or 4 platelets (< 50,000), always grade Hemorrhage/bleeding with grade 3 or 4 
thrombocytopenia. Also consider platelets, transfusion- pRBCS, and transfusion-platelets in addition to the grade 
that incorporates the site or type of bleeding. 
If the site or type of hemorrhage/bleeding is listed, also use the grading that incorporates the site of bleeding: CNS 
hemorrhage/bleeding, Hematuria, Hematemesis, Hemoptysis, Hemorrhage/bleeding with surgery, Melena/lower GI 
bleeding, Petechiae/purpura (Hemorrhage/bleeding into skin), Rectal bleeding/hematochezia, Vaginal bleeding. 
If the platelet count is 50,000 and the site or type of bleeding is listed, grade the specific site. If the site or type is 
not listed and the platelet count is 50,000, grade Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia 
and specify the site or type in the OTHER category. 
Hemorrhage/ble
eding with 
grade 3 or 4 
thrombocytopen
ia 
none 
mild without 
transfusion 
 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
Also consider Platelets, Hemoglobin, Transfusion-platelet, Transfusion-pRBCs. 
Note: 
This toxicity must be graded for any bleeding with grade 3 or 4 thrombocytopenia. Also grade the site or type of 
hemorrhage/bleeding. If the site is not listed, grade as Other in the HEMORRHAGE category. 


IRB PROTOCOL #98153 
PAGE A19 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Hemorrhage/ble
eding without 
grade 3 or 4 
thrombocytopen
ia 
none 
mild without 
transfusion 
 
requiring 
transfusion 
catastrophic 
bleeding 
requiring 
major non-
elective 
intervention 
Also consider Platelets, Hemoglobin, Transfusion-platelet, Transfusion-pRBCs. 
Note: 
Bleeding in the absence of grade 3 or 4 thrombocytopenia is graded here only if the specific site or type of 
bleeding is not listed elsewhere in the HEMORRHAGE category. Also grade as Other in the HEMORRHAGE 
category. 
CNS 
hemorrhage/ble
eding 
none 
- 
- 
bleeding 
noted on CT 
or other scan 
with no 
clinical 
consequence
s 
hemorrhagic 
stroke or 
hemorrhagic 
vascular 
event 
(CVA) with 
neurologic 
signs and 
symptoms 
Epistaxis 
none 
mild without 
transfusion 
- 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
Hematemesis 
none 
mild without 
transfusion 
- 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
Hematuria  
(in the absence 
of vaginal 
bleeding) 
none 
microscopic 
only 
intermittent 
gross 
bleeding, no 
clots 
persistent 
gross 
bleeding or 
clots; may 
require 
catheterizati
on or 
instrumentat
ion, or 
transfusion 
open surgery 
or necrosis 
or deep 
bladder 
ulceration 
Hemoptysis 
none 
mild without 
transfusion 
- 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 


IRB PROTOCOL #98153 
PAGE A20 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Hemorrhage/ble
eding 
associated with 
surgery 
none 
mild without 
transfusion 
- 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
Note: Expected blood loss at the time of surgery is not graded as a toxicity. 
Melena/GI 
bleeding 
none 
mild without 
transfusion 
- 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
Petechiae/purpu
ra 
(hemorrhage/bl
eeding into skin 
or mucosa) 
none 
rare 
petechiae of 
skin 
petechiae or 
purpura in 
dependent 
areas of skin 
generalized 
petechiae or 
purpura of 
skin or 
petechiae of 
any mucosal 
site 
- 
Rectal bleeding/ 
hematochezia 
none 
mild without 
transfusion 
or 
medication 
persistent, 
requiring 
medication 
(e.g., steroid 
suppositorie
s) and/or 
break from 
radiation 
treatment 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
Vaginal 
bleeding 
none 
spotting, 
requiring < 
2 pads per 
day 
requiring  
2 pads per 
day, but not 
requiring 
transfusion 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
Hemorrhage-
Other  
(Specify site, 
___________) 
none 
mild without 
transfusion 
- 
requiring 
transfusion 
catastrophic 
bleeding, 
requiring 
major non-
elective 
intervention 
HEPATIC 
Alkaline 
phosphatase 
WNL 
> ULN - 2.5 
x ULN 
> 2.5 - 5.0 x 
ULN 
> 5.0 - 20.0 
x ULN 
> 20.0 x 
ULN 
Bilirubin 
WNL 
> ULN - 1.5 
x ULN 
> 1.5 - 3.0 x 
ULN 
> 3.0 - 10.0 
x ULN 
> 10.0 x 
ULN 
Bilirubin- graft versus host disease (GVHD) 
Note: The following criteria are used only for bilirubin associated with graft versus host disease. 
 
normal 
2 - <3 
mg/100 ml 
3 - <6 
mg/100 ml 
6 - <15 
mg/100 ml 
15 mg/100 
ml 


IRB PROTOCOL #98153 
PAGE A21 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
GGT 
(  - Glutamyl 
transpeptidase) 
WNL 
> ULN - 2.5 
x ULN 
> 2.5 - 5.0 x 
ULN 
> 5.0 - 20.0 
x ULN 
> 20.0 x 
ULN 
Hepatic 
enlargement 
absent 
- 
- 
present 
- 
Note: Grade Hepatic enlargement only for changes related to VOD or other treatment related toxicity. 
Hypoalbumine
mia 
WNL 
<LLN - 3 
g/dl 
2 - <3 g/dl 
<2 g/dl 
- 
Liver 
dysfunction/fail
ure (clinical) 
normal 
- 
- 
asterixis 
encephalopa
thy or coma 
Note: Documented viral hepatitis is graded in the INFECTION category. 
Portal vein flow 
normal 
- 
decreased 
portal vein 
flow 
reversal/retr
ograde 
portal vein 
flow 
- 
SGOT (AST)  
(serum glutamic 
oxaloacetic 
transaminase) 
WNL 
> ULN - 2.5 
x ULN 
> 2.5 - 5.0 x 
ULN 
> 5.0 - 20.0 
x ULN 
> 20.0 x 
ULN 
SGPT (ALT)  
(serum glutamic 
pyruvic 
transaminase) 
WNL 
> ULN - 2.5 
x ULN 
> 2.5 - 5.0 x 
ULN 
> 5.0 - 20.0 
x ULN 
> 20.0 x 
ULN 
Hepatic-Other  
(Specify, 
) 
none 
mild 
moderate 
severe 
life-
threatening 
or disabling 
INFECTION/FEBRILE NEUTROPENIA 
Catheter-related 
infection 
none 
mild, no 
active 
treatment 
moderate, 
localized 
infection, 
requiring 
local or oral 
treatment 
severe, 
systemic 
infection, 
requiring IV 
antibiotic or 
antifungal 
treatment or 
hospitalizati
on 
life-
threatening 
sepsis (e.g., 
septic 
shock) 
Febrile 
neutropenia  
(fever of 
unknown origin 
without 
clinically or 
microbiological
ly documented 
infection) 
none 
- 
- 
Present 
Life-
threatening 
sepsis (e.g., 
septic 
shock) 
(ANC < 1.0 x 
109/L, fever 
38.5°C) 
 
 
 
 
 
Note: Hypothermia instead of fever may be associated with neutropenia and is graded here. 


IRB PROTOCOL #98153 
PAGE A22 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Infection 
(documented 
clinically or 
microbiological
ly) with grade 3 
or 4 
neutropenia 
none 
- 
- 
present 
life-
threatening 
sepsis (e.g., 
septic 
shock) 
(ANC < 1.0 x 
109/L) 
 
 
 
 
 
Note: 
Hypothermia instead of fever may be associated with neutropenia and is graded here. In the absence of 
documented infection with grade 3 or 4 neutropenia, grade as Febrile neutropenia. 
Infection with 
unknown ANC 
none 
- 
- 
present 
life-
threatening 
sepsis (e.g., 
septic 
shock) 
Note: This toxicity criterion is used in the rare case when ANC is unknown. 
Infection 
without 
neutropenia 
none 
mild, no 
active 
treatment 
moderate, 
localized 
infection, 
requiring 
local or oral 
treatment 
severe, 
systemic 
infection, 
requiring IV 
antibiotic or 
antifungal 
treatment, or 
hospitalizati
on 
life-
threatening 
sepsis (e.g., 
septic 
shock) 
Infection/Febril
e Neutropenia-
Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-
threatening 
or disabling 
Wound-infectious is graded in the DERMATOLOGY/SKIN category. 
LYMPHATICS 
Lymphatics 
normal 
mild 
lymphedema 
moderate 
lymphedema 
requiring 
compression
; lymphocyst 
severe 
lymphedema 
limiting 
function; 
lymphocyst 
requiring 
surgery 
severe 
lymphedema 
limiting 
function 
with 
ulceration 
Lymphatics-
Other  
(Specify, 
) 
none 
mild 
moderate 
severe 
life-
threatening 
or disabling 
METABOLIC/LABORATORY 


IRB PROTOCOL #98153 
PAGE A23 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Acidosis  
(metabolic or 
respiratory) 
normal 
pH < 
normal, but 
7.3 
- 
pH < 7.3 
pH < 7.3 
with life-
threatening 
physiologic 
consequence
s 
Alkalosis  
(metabolic or 
respiratory) 
normal 
pH > 
normal, but 
7.5 
- 
pH > 7.5 
pH > 7.5 
with life-
threatening 
physiologic 
consequence
s 
Amylase 
WNL 
> ULN - 1.5 
x ULN 
> 1.5 - 2.0 x 
ULN 
> 2.0 - 5.0 x 
ULN 
>5.0 x ULN 
Bicarbonate 
WNL 
< LLN - 16 
mEq/dl 
11 - 15 
mEq/dl 
8 - 10 
mEq/dl 
< 8 mEq/dl 
CPK 
(creatine 
phosphokinase) 
WNL 
> ULN - 2.5 
x ULN 
> 2.5 - 5 x 
ULN 
> 5 - 10 x 
ULN 
> 10 x ULN 
Hypercalcemia 
WNL 
> ULN - 
11.5 mg/dl 
> ULN - 2.9 
mmol/L 
>11.5 - 12.5 
mg/dl 
> 2.9 - 3.1 
mmol/L 
>12.5 - 13.5 
mg/dl 
> 3.1 - 3.4 
mmol/L 
> 13.5 mg/dl 
> 3.4 
mmol/L 
Hypercholester
olemia 
WNL 
> ULN - 
300 mg/dl 
> ULN - 
7.75 
mmol/L 
> 300 - 400 
mg/dl 
> 7.75 - 
10.34 
mmol/L 
> 400 - 500 
mg/dl 
>10.34 - 
12.92 
mmol/L 
> 500 mg/dl 
> 12.92 
mmol/L 
Hyperglycemia 
WNL 
> ULN - 
160 mg/dl 
> ULN - 8.9 
mmol/L 
> 160 - 250 
mg/dl 
> 8.9 - 13.9 
mmol/L 
> 250 - 500 
mg/dl 
> 13.9 - 
27.8 
mmol/L 
> 500 mg/dl 
> 27.8 
mmol/L or 
ketoacidosis 
Hyperkalemia 
WNL 
> ULN - 5.5 
mmol/L 
> 5.5 - 6.0 
mmol/L 
> 6.0 - 7.0 
mmol/L 
> 7.0 
mmol/L 
Hypermagnese
mia 
WNL 
> ULN - 3.0 
mg/dl 
> ULN - 
1.23 
mmol/L 
- 
> 3.0 - 8.0 
mg/dl 
> 1.23 - 
3.30 
mmol/L 
> 8.0 mg/dl 
> 3.30 
mmol/L 
Hypernatremia 
WNL 
> ULN - 
150 mmol/L 
>150 - 155 
mmol/L 
>155 - 160 
mmol/L 
>160 
mmol/L 
Hypertriglyceri
demia 
WNL 
> ULN - 2.5 
x ULN 
> 2.5 - 5.0 x 
ULN 
> 5.0 - 10 x 
ULN 
> 10 x ULN 


IRB PROTOCOL #98153 
PAGE A24 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Hyperuricemia 
WNL 
> ULN -  
10 mg/dl 
 0.59 
mmol/L 
without 
physiologic 
consequence
s 
- 
> ULN -  
10 mg/dl 
 0.59 
mmol/L 
with 
physiologic 
consequence
s 
> 10 mg/dl 
> 0.59 
mmol/L 
Also consider Tumor lysis syndrome, Renal failure, Creatinine, Potassium. 
Hypocalcemia 
WNL 
<LLN - 8.0 
mg/dl 
<LLN - 2.0 
mmol/L 
7.0 - < 8.0 
mg/dl 
1.75 - < 2.0 
mmol/L 
6.0 - < 7.0 
mg/dl 
1.5 - < 1.75 
mmol/L 
<6.0 mg/dl 
< 1.5 
mmol/L 
Hypoglycemia 
WNL 
<LLN - 55 
mg/dl 
<LLN - 3.0 
mmol/L 
40 - < 55 
mg/dl 
2.2 - < 3.0 
mmol/L 
30 - < 40 
mg/dl 
1.7 - < 2.2 
mmol/L 
< 30 mg/dl 
< 1.7 
mmol/L 
Hypokalemia 
WNL 
<LLN - 3.0 
mmol/L 
- 
2.5 - <3.0 
mmol/L 
<2.5 
mmol/L 
Hypomagnesem
ia 
WNL 
<LLN - 1.2 
mg/dl 
<LLN - 0.5 
mmol/L 
0.9 - <1.2 
mg/dl 
0.4 - < 0.5 
mmol/L 
0.7 - < 0.9 
mg/dl 
0.3 - < 0.4 
mmol/L 
< 0.7 mg/dl 
< 0.3 
mmol/L 
Hyponatremia 
WNL 
<LLN - 130 
mmol/L 
- 
120 - <130 
mmol/L 
<120 
mmol/L 
Hypophosphate
mia 
WNL 
<LLN -2.5 
mg/dl 
<LLN - 0.8 
mmol/L 
2.0 - <2.5 
mg/dl 
g
0.6 - <0.8 
mmol/L 
1.0 - <2.0 
mg/dl 
g
0.3 - <0.6 
mmol/L 
< 1.0 mg/dl 
<0.3 
mmol/L 
Hypothyroidism is graded in the ENDOCRINE category. 
Lipase 
WNL 
> ULN - 1.5 
x ULN 
> 1.5 - 2.0 x 
ULN 
> 2.0 - 5.0 x 
ULN 
> 5.0 x ULN 
Metabolic/Labo
ratory-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-
threatening 
or disabling 
MUSCULOSKELETAL 
Arthralgia is graded in the PAIN category. 
Arthritis 
none 
mild pain with 
inflammation, 
erythema or joint 
swelling but not 
interfering with 
function 
moderate pain 
with 
inflammation, 
erythema, or joint 
swelling 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain with 
inflammation, 
erythema, or joint 
swelling and 
interfering with 
activities of daily 
living 
disabling 


IRB PROTOCOL #98153 
PAGE A25 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Muscle weakness 
(not due to 
neuropathy) 
normal 
asymptomatic 
with weakness on 
physical exam 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
bedridden or 
disabling 
Myalgia is graded in the PAIN category. 
Myositis 
(inflammation/dama
ge of muscle) 
none 
mild pain, not 
interfering with 
function 
pain interfering 
with function, but 
not interfering 
with activities of 
daily living 
pain interfering 
with function and 
interfering with 
activities of daily 
living 
bedridden or 
disabling 
Also consider CPK. 
Note: Myositis implies muscle damage (i.e., elevated CPK). 
Osteonecrosis  
(avascular necrosis) 
none 
asymptomatic 
and detected by 
imaging only 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
symptomatic; or 
disabling 
Musculoskeletal-
Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
NEUROLOGY 
Aphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category. 
Arachnoiditis/menin
gismus/ 
radiculitis 
absent 
mild pain not 
interfering with 
function 
moderate pain 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain 
interfering with 
activities of daily 
living 
unable to 
function or 
perform activities 
of daily living; 
bedridden; 
paraplegia 
Also consider Headache, Vomiting, Fever. 
Ataxia 
(incoordination) 
normal 
asymptomatic but 
abnormal on 
physical exam, 
and not 
interfering with 
function 
mild symptoms 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
moderate 
symptoms 
interfering with 
activities of daily 
living 
bedridden or 
disabling 
CNS cerebrovascular 
ischemia 
none 
- 
- 
transient 
ischemic event or 
attack (TIA) 
permanent event 
(e.g., cerebral 
vascular 
accident) 
CNS hemorrhage/bleeding is graded in the HEMORRHAGE category. 


IRB PROTOCOL #98153 
PAGE A26 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Cognitive 
disturbance/ 
learning problems 
none 
cognitive 
disability; not 
interfering with 
work/school 
performance; 
preservation of 
intelligence 
cognitive 
disability; 
interfering with 
work/school 
performance; 
decline of 1 SD 
(Standard 
Deviation) or 
loss of 
developmental 
milestones 
cognitive 
disability; 
resulting in 
significant 
impairment of 
work/school 
performance; 
cognitive decline 
> 2 SD 
inability to 
work/frank 
mental 
retardation 
Confusion 
normal 
confusion or 
disorientation or 
attention deficit 
of brief duration; 
resolves 
spontaneously 
with no sequelae 
confusion or 
disorientation or 
attention deficit 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
confusion or 
delirium 
interfering with 
activities of daily 
living 
harmful to others 
or self; requiring 
hospitalization 
Cranial neuropathy is graded in the NEUROLOGY category as Neuropathy-cranial. 
Delusions 
normal 
- 
- 
present 
toxic psychosis 
Depressed level of 
consciousness 
normal 
somnolence or 
sedation not 
interfering with 
function 
somnolence or 
sedation 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
obtundation or 
stupor; difficult 
to arouse; 
interfering with 
activities of daily 
living 
coma 
Note: Syncope (fainting) is graded in the NEUROLOGY category. 
Dizziness/lightheade
dness 
none 
not interfering 
with function 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
interfering with 
activities of daily 
living 
bedridden or 
disabling 
Dysphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category. 
Extrapyramidal/  
involuntary 
movement/ 
restlessness 
none 
mild involuntary 
movements not 
interfering with 
function 
moderate 
involuntary 
movements 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe 
involuntary 
movements or 
torticollis 
interfering with 
activities of daily 
living 
bedridden or 
disabling 
Hallucinations 
normal 
- 
- 
present 
toxic psychosis 
Headache is graded in the PAIN category. 


IRB PROTOCOL #98153 
PAGE A27 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Insomnia 
normal 
occasional 
difficulty 
sleeping not 
interfering with 
function 
difficulty 
sleeping 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
frequent 
difficulty 
sleeping, 
interfering with 
activities of daily 
living 
- 
Note: This toxicity is graded when insomnia is related to treatment. If pain or other symptoms interfere with sleep do 
NOT grade as insomnia. 
Irrit
ability 
(children <3 years of 
age) 
normal 
mild; easily 
consolable 
moderate; 
requiring 
increased 
attention 
severe; 
inconsolable 
- 
Leukoencephalopath
y associated 
radiological findings 
none 
mild increase in 
SAS 
(subarachnoid 
space) and/or 
mild 
ventriculomegaly
; and/or small 
(+/- multiple) 
focal T2 
hyperintensities, 
involving 
periventricular 
white matter or < 
1/3 of susceptible 
areas of 
cerebrum 
moderate 
increase in SAS; 
and/or moderate 
ventriculomegaly
; and/or focal T2 
hyperintensities 
extending into 
centrum ovale; or 
involving 1/3 to 
2/3 of susceptible 
areas of 
cerebrum 
severe increase in 
SAS; severe 
ventriculomegaly
; near total white 
matter T2 
hyperintensities 
or diffuse low 
attenuation (CT); 
focal white 
matter necrosis 
(cystic) 
severe increase in 
SAS; severe 
ventriculomegaly
; diffuse low 
attenuation with 
calcification 
(CT); diffuse 
white matter 
necrosis (MRI) 
Memory loss 
normal 
memory loss not 
interfering with 
function 
memory loss 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
memory loss 
interfering with 
activities of daily 
living 
amnesia 
Mood alteration- 
anxiety agitation 
normal 
mild mood 
alteration not 
interfering with 
function 
moderate mood 
alteration 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe mood 
alteration 
interfering with 
activities of daily 
living 
suicidal ideation 
or danger to self 
Mood alteration- 
depression 
normal 
mild mood 
alteration not 
interfering with 
function 
moderate mood 
alteration 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe mood 
alteration 
interfering with 
activities of daily 
living 
suicidal ideation 
or danger to self 


IRB PROTOCOL #98153 
PAGE A28 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Mood alteration- 
euphoria 
normal 
mild mood 
alteration not 
interfering with 
function 
moderate mood 
alteration 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe mood 
alteration 
interfering with 
activities of daily 
living 
danger to self 
Neuropathic pain is graded in the PAIN category. 
Neuropathy- cranial 
absent 
- 
present, not 
interfering with 
activities of daily 
living 
present, 
interfering with 
activities of daily 
living 
life-threatening, 
disabling 
Neuropathy- motor 
normal 
subjective 
weakness but no 
objective findings 
mild objective 
weakness 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
objective 
weakness 
interfering with 
activities of daily 
living 
paralysis 
Neuropathy-sensory 
normal 
loss of deep 
tendon reflexes or 
paresthesia 
(including 
tingling) but not 
interfering with 
function 
objective sensory 
loss or 
paresthesia 
(including 
tingling), 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
sensory loss or 
paresthesia 
interfering with 
activities of daily 
living 
permanent 
sensory loss that 
interferes with 
function 
Nystagmus 
absent 
present 
- 
- 
- 
Also consider Vision-double vision. 
Personality/behavior
al 
normal 
change, but not 
disruptive to 
patient or family 
disruptive to 
patient or family 
disruptive to 
patient and 
family; requiring 
mental health 
intervention 
harmful to others 
or self; requiring 
hospitalization 
Pyramidal tract 
dysfunction (e.g.,  
tone, hyperreflexia, 
positive Babinski, 
,
 
fine motor 
coordination) 
normal 
asymptomatic 
with abnormality 
on physical 
examination 
symptomatic or 
interfering with 
function but not 
interfering with 
activities of daily 
living 
interfering with 
activities of daily 
living 
bedridden or 
disabling; 
paralysis 
Seizure(s) 
none 
- 
seizure(s) self-
limited and 
consciousness is 
preserved 
seizure(s) in 
which 
consciousness is 
altered 
seizures of any 
type which are 
prolonged, 
repetitive, or 
difficult to 
control (e.g., 
status epilepticus, 
intractable 
epilepsy) 


IRB PROTOCOL #98153 
PAGE A29 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Speech impairment  
(e.g., dysphasia or 
aphasia) 
normal 
- 
awareness of 
receptive or 
expressive 
dysphasia, not 
impairing ability 
to communicate 
receptive or 
expressive 
dysphasia, 
impairing ability 
to communicate 
inability to 
communicate 
Syncope (fainting) 
absent 
- 
- 
present 
- 
Also consider CARDIOVASCULAR (ARRHYTHMIA), Vasovagal episode, CNS cerebrovascular ischemia. 
Tremor 
none 
mild and brief or 
intermittent but 
not interfering 
with function 
moderate tremor 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe tremor 
interfering with 
activities of daily 
living 
- 
Vertigo 
none 
not interfering 
with function 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
interfering with 
activities of daily 
living 
bedridden or 
disabling 
Neurology-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
OCULAR/VISUAL 
Cataract 
none 
asymptomatic 
symptomatic, 
partial visual loss 
symptomatic, 
visual loss 
requiring 
treatment or 
interfering with 
function 
- 
Conjunctivitis 
none 
abnormal 
ophthalmologic 
changes, but 
asymptomatic or 
symptomatic 
without visual 
impairment (i.e., 
pain and 
irritation) 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
- 
Dry eye 
normal 
mild, not 
requiring 
treatment 
moderate or 
requiring 
artificial tears 
- 
- 
Glaucoma 
none 
increase in 
intraocular 
pressure but no 
visual loss 
increase in 
intraocular 
pressure with 
retinal changes 
visual 
impairment 
unilateral or 
bilateral loss of 
vision (blindness) 


IRB PROTOCOL #98153 
PAGE A30 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Keratitis  
(corneal 
inflammation/ 
corneal ulceration) 
none 
abnormal 
ophthalmologic 
changes but 
asymptomatic or 
symptomatic 
without visual 
impairment (i.e., 
pain and 
irritation) 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
unilateral or 
bilateral loss of 
vision (blindness) 
Tearing (watery 
eyes) 
none 
mild: not 
interfering with 
function 
moderate: 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
interfering with 
activities of daily 
living 
- 
Vision- blurred 
vision 
normal 
- 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
- 
Vision- double 
vision (diplopia) 
normal 
- 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
- 
Vision- flashing 
lights/floaters 
normal 
mild, not 
interfering with 
function 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
- 
Vision- night 
blindness 
(nyctalopia) 
normal 
abnormal electro-
retinography but 
asymptomatic 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
- 
Vision- photophobia 
normal 
- 
symptomatic and 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
symptomatic and 
interfering with 
activities of daily 
living 
- 
Ocular/Visual-Other  
(Specify, 
) 
normal 
mild 
moderate 
severe 
unilateral or 
bilateral loss of 
vision (blindness) 
PAIN 


IRB PROTOCOL #98153 
PAGE A31 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Abdominal pain or 
cramping 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Arthralgia  
(joint pain) 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Arthritis (joint pain with clinical signs of inflammation) is graded in the MUSCULOSKELETAL category. 
Bone pain 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Chest pain  
(non-cardiac and 
non-pleuritic) 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Dysmenorrhea 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Dyspareunia 
none 
mild pain not 
interfering with 
function 
moderate pain 
interfering with 
sexual activity 
severe pain 
preventing sexual 
activity 
- 
Dysuria is graded in the RENAL/GENITOURINARY category. 
Earache (otalgia) 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 


IRB PROTOCOL #98153 
PAGE A32 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Headache 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Hepatic pain 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Myalgia  
(muscle pain) 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Neuropathic pain  
(e.g., jaw pain, 
neurologic pain, 
phantom limb pain, 
post-infectious 
neuralgia, or painful 
neuropathies) 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Pain due to radiation 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Pelvic pain 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Pleuritic pain 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 


IRB PROTOCOL #98153 
PAGE A33 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Rectal or perirectal 
pain (proctalgia) 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Tumor pain  
(onset or 
exacerbation of 
tumor pain due to 
treatment) 
none 
mild pain not 
interfering with 
function 
moderate pain: 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain: pain 
or analgesics 
severely 
interfering with 
activities of daily 
living 
disabling 
Tumor flair is graded in the SYNDROME category. 
Pain-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
disabling 
PULMONARY 
Adult Respiratory 
Distress Syndrome 
(ARDS) 
absent 
- 
- 
- 
present 
Apnea 
none 
- 
- 
present 
requiring 
intubation 
Carbon monoxide 
diffusion capacity 
(DLCO) 
 90% of 
pretreatment 
or normal 
value 
75 - <90% of 
pretreatment or 
normal value 
50 - <75% of 
pretreatment or 
normal value 
25 - <50% of 
pretreatment or 
normal value 
< 25% of 
pretreatment or 
normal value 
Cough 
absent 
mild, relieved by 
non-prescription 
medication 
requiring narcotic 
antitussive 
severe cough or 
coughing spasms, 
poorly controlled 
or unresponsive 
to treatment 
- 
Dyspnea  
(shortness of breath) 
normal 
- 
dyspnea on 
exertion 
dyspnea at 
normal level of 
activity 
dyspnea at rest or 
requiring 
ventilator support 
FEV1 
 90% of 
pretreatment 
or normal 
value 
75 - <90% of 
pretreatment or 
normal value 
50 - <75% of 
pretreatment or 
normal value 
25 - <50% of 
pretreatment or 
normal value 
< 25% of 
pretreatment or 
normal value 
Hiccoughs (hiccups, 
singultus) 
none 
mild, not 
requiring 
treatment 
moderate, 
requiring 
treatment 
severe, 
prolonged, and 
refractory to 
treatment 
- 


IRB PROTOCOL #98153 
PAGE A34 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Hypoxia 
normal 
- 
decreased O2 
saturation with 
exercise 
decreased O2 
saturation at rest, 
requiring 
supplemental 
oxygen 
decreased O2 
saturation, 
requiring 
pressure support 
(CPAP) or 
assisted 
ventilation 
Pleural effusion  
(non-malignant) 
none 
asymptomatic 
and not requiring 
treatment 
symptomatic, 
requiring 
diuretics 
symptomatic, 
requiring O2 or 
therapeutic 
thoracentesis 
life-threatening 
(e.g., requiring 
intubation) 
Pleuritic pain is graded in the PAIN category. 
Pneumonitis/pulmon
ary infiltrates 
none 
radiographic 
changes but 
asymptomatic or 
symptoms not 
requiring steroids 
radiographic 
changes and 
requiring steroids 
or diuretics 
radiographic 
changes and 
requiring oxygen 
radiographic 
changes and 
requiring assisted 
ventilation 
Pneumothorax 
none 
no intervention 
required 
chest tube 
required 
sclerosis or 
surgery required 
life-threatening 
Pulmonary embolism is graded as Thrombosis/embolism in the CARDIOVASCULAR (GENERAL) category. 
Pulmonary fibrosis 
none 
radiographic 
changes, but 
asymptomatic or 
symptoms not 
requiring steroids 
requiring steroids 
or diuretics 
requiring oxygen 
requiring assisted 
ventilation 
Note: Radiation-related pulmonary fibrosis is graded in the RTOG/EORTC Late Radiation Morbidity Scoring Scheme- 
Lung. (See Appendix V, http://ctep.info.nih.gov/ctc3/ctc.htm) 
Voice 
changes/stridor/laryn
x (e.g., hoarseness, 
loss of voice, 
laryngitis) 
normal 
mild or 
intermittent 
hoarseness 
persistent 
hoarseness, but 
able to vocalize; 
may have mild to 
moderate edema 
whispered 
speech, not able 
to vocalize; may 
have marked 
edema 
marked 
dyspnea/stridor 
requiring 
tracheostomy or 
intubation 
Note: 
Cough from radiation is graded as cough in the PULMONARY category. 
Radiation-related hemoptysis from larynx/pharynx is graded as Grade 4 Mucositis due to radiation in the 
GASTROINTESTINAL category.  Radiation-related hemoptysis from the thoracic cavity is graded as Grade 4 
Hemoptysis in the HEMORRHAGE category. 
Pulmonary-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
RENAL/GENITOURINARY 
Bladder spasms 
absent 
mild symptoms, 
not requiring 
intervention 
symptoms 
requiring 
antispasmotic 
severe symptoms 
requiring narcotic 
- 
Creatinine 
WNL 
> ULN - 1.5 x 
ULN 
> 1.5 - 3.0 x 
ULN 
> 3.0 - 6.0 x 
ULN 
> 6.0 x ULN 
Note: Adjust to age-appropriate levels for pediatric patients. 
Dysuria  
(painful urination) 
none 
mild symptoms 
requiring no 
intervention 
symptoms 
relieved with 
therapy 
symptoms not 
relieved despite 
therapy 
- 


IRB PROTOCOL #98153 
PAGE A35 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Fistula or GU fistula  
(e.g., vaginal, 
vesicovaginal) 
none 
- 
- 
requiring 
intervention 
requiring surgery 
Hemoglobinuria 
- 
present 
- 
- 
- 
Hematuria (in the absence of vaginal bleeding) is graded in the HEMORRHAGE category. 
Incontinence 
none 
with coughing, 
sneezing, etc. 
spontaneous, 
some control 
no control (in the 
absence of 
fistula) 
- 
Operative injury to 
bladder and/or ureter 
none 
- 
injury of bladder 
with primary 
repair 
sepsis, fistula, or 
obstruction 
requiring 
secondary 
surgery; loss of 
one kidney; 
injury requiring 
anastomosis or 
re-implantation 
septic obstruction 
of both kidneys 
or vesicovaginal 
fistula requiring 
diversion 
Proteinuria 
normal or < 
0.15 g/24 
hours 
1+ or 0.15 - 1.0 
g/24 hours 
2+ to 3+ or 1.0 - 
3.5 g/24 hours 
4+ or > 3.5 g/24 
hours 
nephrotic 
syndrome 
Note: If there is an inconsistency between absolute value and uristix reading, use the absolute value for grading. 
Renal failure 
none 
- 
- 
requiring dialysis, 
but reversible 
requiring dialysis 
and irreversible 
Ureteral obstruction 
none 
unilateral, not 
requiring surgery 
- 
bilateral, not 
requiring surgery 
stent, 
nephrostomy 
tube, or surgery 
Urinary electrolyte 
wasting (e.g., 
Fanconi’s syndrome, 
renal tubular 
acidosis) 
none 
asymptomatic, 
not requiring 
treatment 
mild, reversible 
and manageable 
with oral 
replacement 
reversible but 
requiring IV 
replacement 
irreversible, 
requiring 
continued 
replacement 
Also consider Acidosis, Bicarbonate, Hypocalcemia, Hypophosphatemia. 
Urinary 
frequency/urgency 
normal 
increase in 
frequency or 
nocturia up to 2 x 
normal 
increase > 2 x 
normal but < 
hourly 
hourly or more 
with urgency, or 
requiring catheter 
- 
Urinary retention 
normal 
hesitancy or 
dribbling, but no 
significant 
residual urine; 
retention 
occurring during 
the immediate 
postoperative 
period 
hesitancy 
requiring 
medication or 
occasional in/out 
catheterization 
(<4 x per week), 
or operative 
bladder atony 
requiring 
indwelling 
catheter beyond 
immediate 
postoperative 
period but for < 6 
weeks 
requiring 
frequent in/out 
catheterization  
(  4 x per week) 
or urological 
intervention (e.g., 
TURP, 
suprapubic tube, 
urethrotomy) 
bladder rupture 


IRB PROTOCOL #98153 
PAGE A36 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Urine color change  
(not related to other 
dietary or 
physiologic cause 
e.g., bilirubin, 
concentrated urine, 
hematuria) 
normal 
asymptomatic, 
change in urine 
color 
- 
- 
- 
Vaginal bleeding is graded in the HEMORRHAGE category. 
Vaginitis  
(not due to infection) 
none 
mild, not 
requiring 
treatment 
moderate, 
relieved with 
treatment 
severe, not 
relieved with 
treatment, or 
ulceration not 
requiring surgery 
ulceration 
requiring surgery 
Renal/Genitourinary-
Other (Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 
SECONDARY MALIGNANCY 
Secondary 
Malignancy-Other  
(Specify type, 
__________) 
excludes metastastic 
tumors 
none 
- 
- 
- 
present 
SEXUAL/REPRODUCTIVE FUNCTION 
Dyspareunia is graded in the PAIN category. 
Dysmenorrhea is graded in the PAIN category. 
Erectile impotence 
normal 
mild (erections 
impaired but 
satisfactory) 
moderate 
(erections 
impaired, 
unsatisfactory for 
intercourse) 
no erections 
- 
Female sterility 
normal 
- 
- 
sterile 
- 
Femininization of male is graded in the ENDOCRINE category. 
Irregular menses  
(change from 
baseline) 
normal 
occasionally 
irregular or 
lengthened 
interval, but 
continuing 
menstrual cycles 
very irregular, but 
continuing 
menstrual cycles 
persistent 
amenorrhea 
- 
Libido 
normal 
decrease in 
interest 
severe loss of 
interest 
- 
- 
Male infertility 
- 
- 
Oligospermia  
(low sperm 
count) 
Azoospermia  
(no sperm) 
- 
Masculinization of female is graded in the ENDOCRINE category. 


IRB PROTOCOL #98153 
PAGE A37 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Vaginal dryness 
normal 
mild 
requiring 
treatment and/or 
interfering with 
sexual function, 
dyspareunia 
- 
- 
Sexual/Reproductive 
Function-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
disabling 
SYNDROMES (not included in previous categories) 
Acute vascular leak syndrome is graded in the CARDIOVASCULAR (GENERAL) category. 
ARDS (Adult Respiratory Distress Syndrome) is graded in the PULMONARY category. 
Autoimmune reactions are graded in the ALLERGY/IMMUNOLOGY category. 
DIC (disseminated intravascular coagulation) is graded in the COAGULATION category. 
Fanconi’s syndrome is graded as Urinary electrolyte wasting in the RENAL/GENITOURINARY category. 
Renal tubular acidosis is graded as Urinary electrolyte wasting in the RENAL/GENITOURINARY category. 
Stevens-Johnson syndrome (erythema multiforme) is graded in the DERMATOLOGY/SKIN category. 
SIADH (syndrome of inappropriate antidiuretic hormone) is graded in the ENDOCRINE category. 
Thrombotic microangiopathy (e.g., thromboitic thrombocytopenic purpura/TTP or hemolytic uremic syndrom/HUS) is 
graded in the COAGULATION category. 
Tumor flare 
none 
mild pain not 
interfering with 
function 
moderate pain; 
pain or analgesics 
interfering with 
function, but not 
interfering with 
activities of daily 
living 
severe pain; pain 
or analgesics 
interfering with 
function and 
interfering with 
activities of daily 
living 
Disabling 
Also consider Hypercalcemia. 
Note: 
Tumor flare is characterized by a constellation of symptoms and signs in direct relation to initiation of therapy 
(e.g., anti-estrogens/androgens or additional hormones). The symptoms/signs include tumor pain, inflammation of 
visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte disturbances. 
Tumor lysis 
syndrome 
absent 
- 
- 
present 
- 
Also consider Hyperkalemia, Creatinine. 
Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) is graded under the 
RENAL/GENITOURINARY category. 
Syndromes-Other 
(Specify, 
) 
none 
mild 
moderate 
severe 
life-threatening or 
disabling 


IRB PROTOCOL #98153 
PAGE A38 
VERSION 17 
03/28/14 
 
Appendix II 
Toxicity Module 
To be implemented at the request of the study sponsor or principal investigator in the protocol or by 
protocol amendment when more detailed information is considered pertinent. 
Toxicity: 
Date of Treatment: 
Course Number: 
Date of onset: 
 
Grade at onset: 
Date of first change in grade:  
 
Grade: 
Date of next change in grade: 
 
Grade: 
Date of next change in grade: 
 
Grade: 
Date of next change in grade: 
 
Grade: 
Date of next change in grade: 
 
Grade: 
Date of next change in grade: 
 
Grade: 
Did toxicity resolve? 
Yes______ 
No______ 
 
If so, date of resolution of toxicity: 
 
 
Date of last observation (if prior to 
recovery): 
 
 
Reason(s) observations stopped (if 
prior to recovery): 
 
 
Was patient retreated? 
Yes______ 
No______ 
 
If yes, was treatment delayed for 
recovery? 
Yes______ 
No______ 
 
Date of next treatment? 
 
 
Dose reduced for next treatment? 
Yes______ 
No______ 
 
Additional Comments: 
________________________________________________________________________________________  
________________________________________________________________________________________  
If module is being activated for new toxicity, not currently in CTC, please provide definitions for 
toxicity grading: 
Grade 0 = 
____________________________________________________________________ 
Grade 1 = 
____________________________________________________________________ 
Grade 2 = 
____________________________________________________________________ 
Grade 3 = 
____________________________________________________________________ 
Grade 4 = 
____________________________________________________________________ 


IRB PROTOCOL #98153 
PAGE A39 
VERSION 17 
03/28/14 
 
Appendix III 
Infection Module 
To be implemented at the request of the study sponsor or principal investigator in the protocol or by 
protocol amendment when more detailed information is considered pertinent. 
1. Use the Common Toxicity Criteria definitions to grade the severity of the infection. 
2. Specify type of infection from the following (CHOOSE ONE): 
BACTERIAL 
FUNGAL 
PROTOZOAL 
VIRAL 
UNKNOWN 
3. Specify site of infection from the following (CHOOSE ALL THAT APPLY): 
BLOOD CULTURE POSITIVE 
BONE INFECTION 
CATHETER (intravenous) 
CATHETER (intravenous), tunnel infection 
CENTRAL NERVOUS SYSTEM INFECTION 
EAR INFECTION 
EYE INFECTION 
GASTROINTESTINAL INFECTION 
ORAL INFECTION 
PNEUMONIA 
SKIN INFECTION 
UPPER RESPIRATORY INFECTION 
URINARY TRACT INFECTION 
VAGINAL INFECTION 
INFECTION, not otherwise specified (Specify site, __________) 
4. Specify organism, if known: _______________. 
5. Prophylactic antibiotic, antifungal, or antiviral therapy administration 
Yes_______ 
No_______ 
If prophylaxis was given prior to infection, please specify below: 
Antibiotic prophylaxis  _____________________________________________________ 
Antifungal prophylaxis  ____________________________________________________ 
Antiviral prophylaxis  ______________________________________________________ 
Other prophylaxis  _________________________________________________________ 


IRB PROTOCOL #98153 
PAGE A40 
VERSION 17 
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Appendix IV 
Performance Status Scales/Scores 
ECOG or Zubrod Scale  
Karnofsky Score 
0 
Asymptomatic and fully active 
 
100% 
1 
Symptomatic; fully ambulatory; restricted in physically 
strenuous activity 
 
80-90% 
2 
Symptomatic; ambulatory; capable of self-care; more than 
50% of waking hours are spent out of bed 
 
60-70% 
3 
Symptomatic; limited self-care; spends more than 50% of 
time in bed, but not bedridden 
 
40-50% 
4 
Completely disabled; no self-care; bedridden 
 
20-30% 


IRB PROTOCOL #98153 
PAGE A41 
VERSION 17 
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Appendix V 
RTOG/EORTC Late Radiation Morbidity Scoring Scheme 
Use for toxicities occurring greater than 90 days after radiation therapy. 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Bladder-  
Late RT Morbidity 
Scoring 
No change 
from baseline 
Slight epithelial 
atrophy/minor 
telangiectasia 
(microscopic 
hematuria) 
Moderate 
frequency/ 
generalized 
telangiectasia/ 
intermittent 
macroscopic 
hematuria 
Severe frequency 
and 
dysuria/severe 
generalized 
telangiectasia 
(often with 
petechiae); 
frequent 
hematuria; 
reduction in 
bladder capacity 
(< 150 cc) 
Necrosis/contract
ed bladder 
(capacity < 100 
cc)/severe 
hemorrhagic 
cystitis 
Bone- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Asymptomatic; 
no growth 
retardation; 
reduced bone 
density 
Moderate pain or 
tenderness; 
growth 
retardation; 
irregular bone 
sclerosis 
Severe pain or 
tenderness; 
complete arrest of 
bone growth; 
dense bone 
sclerosis 
Necrosis/ 
spontaneous 
fracture 
Brain- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Mild headache; 
slight lethargy 
Moderate 
headache; great 
lethargy 
Severe 
headaches; severe 
CNS dysfunction 
(partial loss of 
power or 
dyskinesia) 
Seizures or 
paralysis; coma 
Esophagus- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Mild fibrosis; 
slight difficulty in 
swallowing 
solids; no pain on 
swallowing 
Unable to take 
solid food 
normally; 
swallowing semi-
solid food; 
dilatation may be 
indicated 
Severe fibrosis; 
able to swallow 
only liquids; may 
have pain on 
swallowing; 
dilation required 
Necrosis/ 
perforation; 
fistula 
Heart- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Asymptomatic or 
mild symptoms; 
transient T wave 
inversion and ST 
changes; sinus 
tachycardia > 110 
(at rest) 
Moderate angina 
on effort; mild 
pericarditis; 
normal heart size; 
persistent 
abnormal T wave 
and ST changes; 
low QRS 
Severe angina; 
pericardial 
effusion; 
constrictive 
pericarditis; 
moderate heart 
failure; cardiac 
enlargement; 
EKG 
abnormalities 
Tamponade/sever
e heart 
failure/severe 
constrictive 
pericarditis 
Joint- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Mild joint 
stiffness; slight 
limitation of 
movement 
Moderate 
stiffness; 
intermittent or 
moderate joint 
pain; moderate 
Severe joint 
stiffness; pain 
with severe 
limitation of 
movement 
Necrosis/complet
e fixation 


IRB PROTOCOL #98153 
PAGE A42 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
limitation of 
movement 
Kidney- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Transient 
albuminuria; no 
hypertension; 
mild impairment 
of renal function; 
urea 25 - 35 
mg%; creatinine 
1.5 - 2.0 mg%; 
creatinine 
clearance > 75% 
Persistent 
moderate 
albuminuria (2+); 
mild 
hypertension; no 
related anemia; 
moderate 
impairment of 
renal function; 
urea > 36 - 60 
mg%; creatinine 
clearance > 50 - 
74% 
Severe 
albuminuria; 
severe 
hypertension; 
persistent anemia 
(< 10 g%); severe 
renal failure; urea 
> 60 mg%; 
creatinine > 4 
mg%; creatinine 
clearance  
< 50% 
Malignant 
hypertension; 
uremic coma/urea 
> 100% 
Larynx- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Hoarseness; 
slight arytenoid 
edema 
Moderate 
arytenoid edema; 
chondritis 
Severe edema; 
severe chondritis 
Necrosis 
Liver- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Mild lassitude; 
nausea; 
dyspepsia; 
slightly abnormal 
liver function 
Moderate 
symptoms; some 
abnormal liver 
function tests; 
serum albumin 
normal 
Disabling hepatic 
insufficiency; 
liver function 
tests grossly 
abnormal; low 
albumin; edema 
or ascites 
Necrosis/hepatic 
coma or 
encephalopathy 
Lung- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Asymptomatic or 
mild symptoms 
(dry cough); 
slight 
radiographic 
appearances 
Moderate 
symptomatic 
fibrosis or 
pneumonitis 
(severe cough); 
low grade fever; 
patchy 
radiographic 
appearances 
Severe 
symptomatic 
fibrosis or 
pneumonitis; 
dense 
radiographic 
changes 
Severe 
respiratory 
insufficiency/ 
continuous 
O2/assisted 
ventilation 
Mucous membrane- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Slight atrophy 
and dryness 
Moderate atrophy 
and 
telangiectasia; 
little mucus 
Marked atrophy 
with complete 
dryness; severe 
telangiectasia 
Ulceration 
Salivary glands- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Slight dryness of 
mouth; good 
response on 
stimulation 
Moderate dryness 
of mouth; poor 
response on 
stimulation 
Complete dryness 
of mouth; no 
response on 
stimulation 
Fibrosis 
Skin- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Slight atrophy; 
pigmentation 
change; some 
hair loss 
Patchy atrophy; 
moderate 
telangiectasia; 
total hair loss 
Marked atrophy; 
gross 
telangiectasia 
Ulceration 
Small/Large 
intestine- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Mild diarrhea; 
mild cramping; 
bowel movement 
5 x daily slight 
rectal discharge 
Moderate 
diarrhea and 
colic; bowel 
movement > 5 x 
daily; excessive 
Obstruction or 
bleeding, 
requiring surgery 
Necrosis/ 
perforation fistula 


IRB PROTOCOL #98153 
PAGE A43 
VERSION 17 
03/28/14 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
or bleeding 
rectal mucus or 
intermittent 
bleeding 
Spinal cord- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Mild Lhermitte’s 
syndrome 
Severe 
Lhermitte’s 
syndrome 
Objective 
neurological 
findings at or 
below cord level 
treatment 
Mono-, para-, 
quadriplegia 
Subcutaneous tissue- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Slight induration 
(fibrosis) and loss 
of subcutaneous 
fat 
Moderate fibrosis 
but 
asymptomatic; 
slight field 
contracture; < 
10% linear 
reduction 
Severe induration 
and loss of 
subcutaneous 
tissue; field 
contracture > 
10% linear 
measurement 
Necrosis 
Eye- 
Late RT Morbidity 
Scoring 
No change 
from baseline 
Asymptomatic 
cataract; minor 
corneal ulceration 
or keratitis 
Symptomatic 
cataract; 
moderate corneal 
ulceration; minor 
retinopathy or 
glaucoma 
Severe keratitis; 
severe 
retinopathy or 
detachment; 
severe glaucoma 
Panophthalmitis; 
blindness 
Radiation-Other 
(Specify, 
) 
None 
Mild 
Moderate 
Severe 
Life-threatening 
or disabling 


 
A Phase I/II Trial of Escalating Dose of Yttrium-90-labeled Anti-CD20 Monoclonal Antibody in 
Combination with High-Dose Etoposide and Cyclophosphamide followed by Autologous Stem 
Cell Transplantation for Patients with Relapsed B-Cell Non-Hodgkin's Lymphoma 
 
NCT00562978 
 
Document Date 03/28/2014 
 


IRB PROTOCOL #98153 
PAGE A44 
VERSION 17 
03/28/14 
 
Appendix VI 
BMT Complex/Multi-Component Events 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Note: 
The grading of Complex/Multi-Component Events in bone marrow transplant will be defined in the protocol. 
The grading scale must use the CTC criteria for grading the specific component events (toxicities). 
Failure to engraft 
absent 
mild 
moderate 
severe 
life-threatening 
Also consider Hemoglobin (Hgb), Neutrophils/granulocytes (ANC/AGC), Platelets 
Graft versus host 
disease 
absent 
mild 
moderate 
severe 
life-threatening 
Also consider Fatigue, Rash/desquamation, Diarrhea, Bilirubin-GVHD 
Stem cell infusion 
complications 
absent 
mild 
moderate 
severe 
life-threatening 
Also consider Allergic reaction/hypersensitivity, Arrhythmia, Hypertension, Hypotension, Fever, Rigors/chills, 
Sweating, Rash/desquamation, Urticaria, Diarrhea, Nausea, Vomiting, Hemorrhage/bleeding with grade 3 or 4 
thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Hemoptysis, Alkaline phosphatase, 
Bilirubin, GGT, SGOT, SGPT, Infection, Hyperkalemia, Hypernatremia, Hypokalemia, Depressed level of 
consciousness, Seizures, Abdominal pain, Headache, Creatinine, Hemoglobinuria 
Veno-Occlusive 
Disease (VOD) 
absent 
mild 
moderate 
severe 
life-threatening 
Also consider Weight gain-VOD, Bilirubin, Depressed level of consciousness, Hepatic pain, Renal failure, Hepatic 
enlargement.