Clinical trial NCT00712582
Conditions: Non-Hodgkin's Lymphoma
Keywords: Non-Hodgkin Lymphoma Rituximab Cyclophosphamide Doxorubicin Vincristine ifosfamide etoposide carboplatin stem cell transplant 08-026
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2008-07-01; Completion date: 2021-03-12
Enrollment: 96 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
About 60% of patients with DLBCL can be cured with a chemotherapy program. It is called RCHOP-21 (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone). It is given once every 3 weeks, for 18 weeks. Each three weeks is a cycle. Some factors predict that you may not be cured with R-CHOP-21. The most common ones are:

* Stage - how much DLBCL, PMBL, or FL3B you have
* LDH - a blood chemistry marker; and
* Whether you can do your normal daily activities. (performance status) We think that the best way to cure more patients with poor risk factors is to add new treatment to R-CHOP. You will get different chemotherapy after 4 cycles. This type of treatment is called risk-adapted therapy.

Detailed description:

Arms: arm 1: Induction: RR-CHOP-14 Chemotherapy for Three Cycles Each cycle lasts approximately 14 days. A total of 3 cycles of RR-CHOP-14 will be given. One cycle of CHOP will follow.

Patients whose disease is FDG-PET negative or patients whose FDG-PET scan is positive but repeat biopsy is negative and whose initial Ki-67 expression is \< 80% will receive 3 cycles of standard dose ICE Chemotherapy. arm 2: Induction: RR-CHOP-14 Chemotherapy for Three Cycles Each cycle lasts approximately 14 days. A total of 3 cycles of RR-CHOP-14 will be given. One cycle of CHOP will follow.

Patients whose disease is FDG-PET negative or patients whose FDG-PET scan is positive but repeat biopsy is negative and whose initial Ki-67 expression is ≥80% will receive 2 cycles of augmented RICE Chemotherapy (as per MSKCC protocol 03-075). arm 3: Induction: RR-CHOP-14 Chemotherapy for Three Cycles Each cycle lasts approximately 14 days. A total of 3 cycles of RR-CHOP-14 will be given. One cycle of CHOP will follow.

Consolidation C: Patients with biopsy proven disease after induction therapy. Patients whose bone marrow remain positive at interim restaging will have the option of getting an allogeneic\[m3\] stem cell transplant, in lieu of an ASCT, if they have an acceptable HLA match donor. The allogeneic\[m4\] stem cell transplant regimen will be decided by the MSK Bone Marrow Transplant Service.
Interventions: intervention 1: Etoposide, carboplatin, ifosfamide intervention 2: Rituximab, Ifosfamide, Etoposide, Carboplatin intervention 3: Rituximab, Ifosfamide, Etoposide, Carboplatin, Stem Cell Collection, Mitoxantrone, Cyclophosphamide and etoposide, Carmustine
Intervention descriptions: intervention 1: Patients in consolidation A will receive three drugs in a regimen called ICE. You will have 3 cycles. Each new cycle begins 2 to 3 weeks after the last one. intervention 2: It consists of four drugs in a regimen called augmented RICE (augRICE). It is given every 3 weeks for 2 cycles. intervention 3: It consists of four drugs in a regimen called augRICE. It is given every 3 weeks for 2 cycles. After the rituximab on day 3, you will then be admitted to the hospital for 2 to 3 nights.

Part 2: Stem Cell Collection, Part 3: High dose chemoradiotherapy and stem cell transplant. Your doctor may want you to get radiation therapy. If so, it will start 2 weeks before the highdose chemotherapy. This regimen is called CBV-N chemotherapy. It is given by vein in the hospital.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
 
 
 
 
 
Risk-Adapted Therapy For Patients With Untreated Age-Adjusted International 
Prognostic Index Low-Intermediate  Risk, High-Intermediate  Risk, Or High Risk 
Diffuse Large B Cell Lymphoma 
 
MSKCC THERAPEUTIC/DIAGNOSTIC  PROTOCOL 
 
 
 
Principal 
Investigator/Department: 
Andrew D. Zelenetz,  M.D., Ph.D 
Medicine:  Lymphoma 
Co-Principal 
Investigator(s)/Department: 
Heiko Schöder, M.D. 
Radiology 
Investigator(s)/Department: 
Kurt Bantilan,  M.P.H. 
Reiko Nakajima, M.D. 
Laure Michaud, M.D. 
Jazmin Schwartz, M.D. 
John Humm,  Ph.D 
Medicine:  Lymphoma 
Radiology: SKI 
Medical Physics 
Consenting 
Professional(s)/Department 
Andrew D. Zelenetz,  M.D., Ph.D. 
Medicine:  Lymphoma 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, NY 10021 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND 
SCHEMA 
1 
2.0 
OBJECTIVES AND SCIENTIFIC 
AIMS  1 
3.0 
BACKGROUND AND 
RATIONALE 
2 
4.0 
OVERVIEW OF STUDY DESIGN / 
INTERVENTION 
7 
5.0 
THERAPEUTIC/DIAGNOSTIC 
AGENTS 
12 
6.1 
CRITERIA FOR SUBJECT 
ELIGIBILITY 
18 
6.2 
Subject Inclusion 
Criteria 
 
18 
6.3 
Subject Exclusion 
Criteria 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
 
 
 
 
 
19 
7.0 
RECRUITMENT 
PLAN 19 
8.0 
PRETREATMENT 
EVALUATION 
19 
9.0 
TREATMENT 
INTERVENTION/PLAN 
21 
10.0 
EVALUATION  DURING 
TREATMENT/INTERVENTION 
24 
11.0 
TOXICITIES/SIDE 
EFFECTS 
26 
13.0 
CRITERIA FOR REMOVAL FROM 
STUDY 
29 
14.0  
BIOSTATISTICS 
30 
15.0 
RESEARCH PARTICIPANT REGISTRATION  AND RANDOMIZATION 
PROCEDURES 
32 
16.0 
DATA MANAGEMENT 
ISSUES 
33 
17.0 
PROTECTION OF HUMAN 
SUBJECTS 
34 
18.0 
INFORMED CONSENT 
PROCEDURES 
39 
19.0 
 
REFERENCES 
39 
20.0 
APPENDIX 
1 
42 
21.1 APPENDIX 
2 
43 
21.2 Treatment  Timeline: Screening 
Period 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
 
 
 
 
 
43 
21.3 Treatment  Timeline  for Induction and Interim 
Restaging 
 
44 
21.4 Treatment  Timeline  for Consolidation 
A 
 
45 
21.5 Treatment  Timeline  for Consolidation 
B 
 
46 
21.6 Treatment  Timeline  for Consolidation 
C 
 
47 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
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1.0 
PROTOCOL SUMMARY AND 
SCHEMA 
 
 
The goal of this study is to assess 2 year PFS rates of patients with intermediate and high 
risk diffuse large B cell lymphoma who are treated according to an accelerated treatment 
program that incorporates chemotherapy and rituximab  and uses risk stratification  to one 
of three consolidation programs based upon results of interim restaging FDG-PET 
evaluation;  positive  FDG-PET is confirmed  by biopsy. 
 
Schema is depicted below: 
 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.2 Primary 
objective 
 
 
To determine the 2-year PFS and overall survival from the start of induction therapy 
conditional on attaining either a negative FDG-PET or a negative biopsy at the 
interim evaluation. The probability of this outcome will be evaluated separately in 
the Ki-67 <80 (Consolidation A) and the Ki-67 ≥80 (Consolidation B) cohorts. 
   FDG-PET agent   


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 2 - 
 
 
 
 
2.3 Secondary Objectives 
 
 
a. To obtain preliminary data on biodistribution, dosimetry and potential clinica l 
usefulness of the proliferation marker [18F] fluorothymidine (FLT) in patients with 
diffuse 
large 
cell 
lymphoma, 
using 
combined 
positron 
emissio 
n 
tomography/computed  tomography (FLT-PET/CT).  These scans will  be obtained 
at baseline, and prior to the start of cycle 3; the earliest the second scan can be 
obtained is the day after prednisone completion. FLT-PET scans will be done for 
the first 60 patients. 
 
b. To determine the role of CT volumetric analysis compared to standard 
unidimensional CT in this patient population. These scans will be obtained at 
baseline  (when possible), after cycle 4 of therapy and at the conclusion of treatment. 
 
 
3.1 
BACKGROUND AND RATIONALE 
 
3.2 Introduction 
 
Diffuse large B cell lymphoma (DLBCL) is the most common lympho id 
malignancy in the United States and Europe accounting for one third  of cases. In the past 
5 years, several phase III random assignment trials have demonstrated an improvement in 
PFS with the addition of the chimeric anti-CD20 monoclonal antibody rituximab to CHOP 
or CHOP-like chemotherapy regimens. (Coiffier, Lepage et al. 2002; Feugier, Van Hoof et 
al. 2005; Habermann, Weller et al. 2006; Pfreundschuh, Trumper et al. 2006) However, 
patients < 60 years of age with unfavorable prognostic features have not been included in 
these randomized trials; in this cohort of patients the PFS is < 50%. The standard of care 
remains controversial for these patients.  These patients are the subject of the current study. 
 
 
 
3.3 Pre-Treatment Prognostic Factors 
 
 
The most widely used clinical models for prognosis are the International Prognostic 
Index (IPI) and the more commonly used, age-adjusted IPI (aaIPI). The aaIPI consists of 
three factors (adverse factors include: Eastern Cooperative Oncology Group Performance 
Status [ECOG PS]  2; LDH > normal; Ann Arbor clinical stage III or IV) and is applied 
independently to groups of patients either uniformly  60 years of age or > 60 years of age; 
the four risk groups are determined by the number of adverse factors: Low (L), 0; Low- 
Intermediate (LI), 1; High-Intermediate (HI) 2; and High (H) 3. For example,  the aaIPI 
has been particularly useful in the analysis of the results of trials in a restricted age group 
such as those involving high dose therapy (HDT) and ASCT (Hamlin, Zelenetz et al. 2003) 
or uniform  treatment  of the older patient.  (Feugier,  Van Hoof et al. 2005)  As useful  as 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
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clinical   models  have  been  in  identifying   risk  groups,  they  do  not  identify   specific 
abnormalities  that could lead to therapy tailored  to molecular  lesions. 
The work of the Lymphoma, Leukemia, Myeloma Profiling Project (LLMPP) has 
identified two subtypes of DLBCL: germinal center (GC); and activated B cell (ABC). 
(Alizadeh, Eisen et al. 1999; Rosenwald, Wright et al. 2002) Subsequent work has 
associated the ABC tumors with constitutive activation of the NFB signaling pathway. 
(Rosenwald, Wright et al. 2002; Feuerhake, Kutok et al. 2005) In patients treated with 
doxorubicin-based chemotherapy programs without rituximab the  ABC  subtype  of 
DLBCL has an inferior outcome compared to the GC subtype (Rosenwald, Wright et al. 
2002); however, this difference may be overcome by the addition of rituximab. (Farinha, 
Sehn et al. 2006) Furthermore, molecular studies have validated the clinical findings 
(Hamlin, Portlock et al. 2004) that primary mediastinal large B cell lymphoma  (PMLBCL) 
is a distinct subtype of DLBCL; the molecular features are more closely related to Hodgkin 
Lymphoma (HL) than either the GC or ABC subtypes of DLBCL.(Rosenwald, Wright  et 
al. 2003; Savage, Monti et al. 2003) In addition outcome of some of the more unusual 
subtypes of aggressive lymphoma are yet to be defined in the era of rituximab-based 
chemotherapy. Though gene signatures predictive of outcome have been developed, they 
remain impractical as they depend on gene expression array analysis which is still some 
years away from routine clinical use.  However, the predictive  models have been adapted 
to quantitative polymerase  chain reaction (PCR) using only 6 genes  (Lossos, Czerwinski 
et al. 2004) and immunohistochemistry using only 3 antibodies (Hans, Weisenburger et al. 
2004); both of these models have been able to predict outcome in patients treated with 
conventional chemotherapy, but remain to be validated in patients treated with immuno - 
chemotherapy. 
 
3.4 Interim Evaluation 
 
Though pre-treatment factors influence outcomes of patients with DLBCL, none 
provides a definitive prediction of outcome.  Thus, early identification of patients who may 
or may not respond to standard therapy may provide the opportunity to adapt therapy.  This 
is an important area of ongoing investigation by the Lymphoma Service at MSKCC. 
Ideally,  patients with a negative  interim result would be destined to do well and those with 
a positive results fair poorly. We and others have used early restaging FDG-PET in this 
setting. The published literature suggests that those patients with a negative  interim 
restaging FDG-PET scan have ≥ 80% chance of being progression-free at 3 years; however 
patients with a positive test have PFS that ranges from 10-50%. Hence, the positive 
predictive value of an interim restaging FDG-PET scan is suspect. Despite these data, 
many major centers change therapy to a more aggressive approach, an autologous stem cell 
transplant, if the interim FDG-PET scan is positive, nearly always without biopsy 
confirmation of active disease. 
 
 
3.5 MSKCC Protocol 01-142 
 
As stated above in patients < 60 yrs. old, therapy for poor risk (aaIPI HIR or HR) 
DLBCL remains controversial. The standard of care in the United States is treatment with 
R-CHOP-21 (every  3 weeks).    However,  in  many  centers  in  the  United  States  and 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
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PET 
 
 
internationally, patients with aaIPI HIR or HR disease receive consolidation therapy with 
high dose therapy (HDT) and ASCT despite the lack of a clear overall survival 
improvement compared to the use of HDT and ASCT in the relapsed setting. We recently 
completed a risk-adapted, phase II study for patients with stage IIX, III, and IV DLBCL 
with 1-3 risk factors defined by the age-adjusted IPI (MSKCC protocol 01-142). Induction 
therapy consisted of 4 cycles of R-CHOP-14 (doses of cyclophosphamide-1000 mg/m2 , 
doxorubicin-50 mg/m2 and un-capped vincristine at 1.4 mg/m2).  After interim  restaging 
with FDG-PET, patients with a negative FDG-PET scan received non-cross resistant 
chemotherapy with 3 cycles of ICE. If the PET scan was positive, a repeat biopsy was 
performed, and if negative, ICE was administered;  if positive,  therapy consisted of ICE x 
3, followed  by HDT and ASCT. 
 
MSKCC 01-142: DLBCL: Risk Adapted for Therapy 
CS IIX, III or IV disease, age-adjusted IPI 1, 2, or 3 Risk Factors, 
Transplant Eligible 
 
 
 
R-C1000HOuncappedP-14 x 4 
 
+ 
FDG-PET agent 
- 
 
 
⚫ Prospective, biopsy 
 
determination of 
“positive PET” 
⚫ Therapy interval 2 
Repeat Bx 
 
 
 
 
 
ICE X 3 
followed by 
Observation 
weeks 
⚫ PET 10-14 days post 
cycle 4 
⚫ Treatment is adapted 
by biopsy, not PET 
⚫ No radiation therapy 
permitted except for 
testicular disease 
⚫ IT methotrexate for 
aaHR, paranasal 
sinus, testis, BM 
 
 
Eighty-seven patients have received therapy on study. Baseline characterist ics 
include: At a median follow-up of 30 months the event-free survival (EFS) is 88%. Only 
one patient had progressive disease on R-CHOP-14. At interim restaging, 31/86 pts had 
FDG-PET avid disease of which only 4 had a positive biopsy. There was no difference in 
PFS for pts with an interim restaging negative FDG-PET scan (50/55) vs. positive FDG- 
PET positive (27/31), p=0.36; hence the false positive rate of the interim restaging FDG- 
PET scan was 87%. Pts with PMLBL had the same outcome as patients with standard 
DLBCL, p=0.41. In univariate analysis, the only factor that had a negative prognostic 
impact was Ki-67 ≥ 80, p=0.0006. Our-dose dense approach overcame the poor prognostic 
features of the standard prognostic models used for DLBCL, and obviates the need for an 
upfront ASCT in nearly all patients.  (Moskowitz CH 2006) 
We were unable to risk-adapt therapy based upon imaging modalities and 
surprisingly Ki-67 expression has prognostic import in this patient population. This 
followup  study focuses on these 2 issues. 
Bx - 
Bx + 
ICE X 2 
RICE x 1 
followed by 
HDT/ASCT 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
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3.6 Nuclear Medicine Imaging 
The International Working Group response criteria did not provide striking 
discrimination in outcomes of patients between those categorized as a partial response (PR) 
and those categorized as a complete response (CR). Recently, it has been shown that 
inclusion of FDG-PET at the conclusion of therapy can dramatically enhance the 
discrimination between CR and PR in patients with DLBCL; thus, FDG-PET has been 
incorporated in to a modified  version of the International Working Group response criteria. 
In MSKCC 01-142, the role of interim re-staging evaluation with FDG-PET was 
limited  by the very poor positive predictive  value;  based upon biopsy evaluation of the 
abnormal site of activity. However, we confirmed  others findings  that the negative 
predictive  value was high.  The false positive  FDG-PET appears to be influenced  by a 
number of variables  including:  intralesional inflammation;  time between therapy and 
scan; and influence  of the immunotherapy.   The study design of MSKCC 01-142 clearly 
did not permit optimal use of FDG-PET.  In the current study we have modified  several 
treatment parameters  we hope will improve  the positive  predictive  value of FDG-PET. 
 
18F Fluorothymidine  PET 
3'-deox y-3'-[(18)F] fluorothymidine ([(18)F]FLT) is a new PET radiotracer that 
can be used to assess tumor cell proliferation  (Mier, Haberkorn et al. 2002). Imaging with 
FLT takes advantage of the fact that pyrimidine  nucleosides  and several of their 
analogues  are phosphorylated  to the respective monophosphate  (MP) by thymidine  kinase 
1 (TK-1) and are incorporated into DNA. FLT is also substrate for thymidine  kinase-1 
(TK-1), which has been demonstrated both in vitro (Rasey, Grierson et al. 2002) and in 
vivo (Buck, Halter et al. 2003; Vesselle,  Grierson et al. 2003; Wagner, Seitz et al. 2003). 
TK-1 activity is up-regulated  in cells entering the S-phase, whereas the protein is nearly 
undetectable  in growth arrested cells.  TK-1 catalyzes  the phosphorylation of FLT to 
FLT-monophosphate.  Because it lacks a 3'-hydroxyl group, very little  FLT is 
incorporated into DNA. Thus, FLT measures an early event in DNA synthesis, rather than 
DNA incorporation.  Nevertheless,  many reports have shown a positive correlation 
between FLT uptake and S-phase fraction of cells in vitro (Seitz, Wagner et al. 2001; 
Rasey, Grierson et al. 2002; Schwartz, Tamura et al. 2003) and the fraction of 
proliferating cells in vivo (MIB-1; Ki-67) (Vesselle,  Grierson et al. 2002). Accordingly, 
FLT might  be a useful imaging agent to monitor the early response to therapy in cancer 
patients. While there are no convincing clinical  data at this time, some studies  (Dittmann, 
Dohmen et al. 2002; Apisarnthanarax,  Alauddin et al. 2006) showed a close correlation 
between FLT uptake in tumor cell cultures  or xenografts  and growth arrest. Since there is 
limited  clinical experience  with this new radiotracer in patients undergoing 
chemotherapy,  we will obtain data to a) assess biodistribution,  b) verify published 
dosimetry data, and c) address the potential clinical  usefulness  of this new imaging agent 
in patients with lymphoma  treated on this new study and correlate the results with other 
clinical and biologic  prognostic factors.  The data derived from this study will tell us if 
and how (time point of imaging,  details of image acquisition)  PET with FLT will be 
meaningful  in lymphoma  patients.   It is expected that FLT will be the next PET tracer to 
be approved for broad clinical  use by the FDA.  However, it is essential to establish the 
utility of this tracer in the evaluation of lymphoma.   In this study, we will examine  the 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
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biodistribution of FLT in patients with DLBCL and determine  what impact therapy has 
on that distribution.   It is hoped that FLT imaging may provide an early read out on 
treatment response.  Therefore,  we will obtain scans at baseline  and after the first  or 
second cycle of chemotherapy. 
 
3.7 Volumetric Segmentation and Response Assessment in Lymphoma 
 
Traditionally, tumors have been measured with a single diameter (uni-dimens ion) 
on computed tomography (CT) before, during, and after therapy, and the changes of the 
measurement are used to assess tumor response to therapy. However, these conventional 
measurement techniques may not accurately reflect true tumor size change since most 
tumors and lymph nodes, in particular, are not perfectly spherical and they do not change 
symmetrically. Continuous advances in CT imaging technology have afforded  the 
capability of acquiring “isotropic” images, alllowing tumor volumes to be measured with 
higher degrees of accuracy. A question facing us is whether change in tumor volume can 
serve as a better marker for response assessment than the single or two diameters used by 
conventional methods. Our hypotheses are that volume change of a lymphomatous mass 
measured on longitudinal CT images may serve as a more accurate surrogate for therapy 
response compared to unidimensional size changes. Residual masses after therapy, 
especially in lymphoma patients, often contain fibrosis or necrosis that cannot be 
differentiated from viable tumor with anatomic CT imaging. However even functio nal 
FDG-PET imaging has a modest false negative rate and as indicated above potential for 
false positives. Therefore, the two may play a complementary role. Accurate anatomic 
localization and size measurement using CT will continue playing an important role in the 
detection, diagnosis,  staging,  and response assessment  in lymphoma. 
An automated lymph node segmentation algorithm has been developed which will 
greatly improve the efficiency of routine radiological/oncological image interpretation, as 
well as provide a methodology of objective and reproducible tumor  size determinat io n. 
This is essential to the evaluation of volumetric techniques to be used in response 
assessment and to the acceptance of such techniques in clinical practice, and  may 
ultimately play the same important role in the detection of other solid tumors that 
metastasize  to the lymph nodes. 
 
3.8 Proposed Treatment and Rationale 
 
Our dose-dense R-CHOP-14/ICE program used in MSKCC 01-142 was highly 
efficacious. However, we identified two major limitations. First, as designed, the interim 
FDG-PET (without a confirmatory biopsy) was not able to identify patients destined to 
relapse.  Second, patients with high tumor growth fractions  indicated  by Ki-67 staining of 
≥ 80% had a significant poorer outcome. The current phase II study attempts to address 
these limitations by selecting alternative therapy for patients with high growth fractions 
and by incorporating new multiple imaging modalities to predict which patient may benefit 
from a consolidative upfront ASCT. Risk stratification willl   continue to be based upon 
biopsy confirmation of abnormal interim restaging. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
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4.1 
OVERVIEW OF STUDY DESIGN / INTERVENTION 
 
4.2 Design 
 
 
 
 
Patient accrual 
 
Transplant  eligible  patients between the ages of 18 and 65 with CD20+ diffuse  large B 
cell lymphoma.   Patients must meet eligibility criteria outlined  in section 6.0. 
 
End of Study (for each patient) 
 
End of study will be defined as either death, loss to follow-up,  early withdrawal,  or 
removal from study, failure  to achieve a CR, 2-year relapse-free survival  and 5-year 
overall survival.   Patients will be followed  until the end of study. 
 
Number of centers: Single institution 
Number of patients: 90 
Estimated  study duration: 44-48 months 
   FDG-PET agent  


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
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4.3 Intervention 
 
All induction  and consolidation treatment visits have a +/- 3 day window (excluding 
the interim restaging scans). 
 
Antimicrobial  Prophylaxis: Throughout  induction  and all consolidation  chemotherapy 
(excluding transplant),  the following antimicrobial prophylaxis  will be given: 
Trimethoprim/Sulfamethoxazole  160/800 (DS) oral twice daily TIW (patients with 
known allergy to Trimethoprim/Sulfamethoxazole  can receive alternative  pneumocystis 
carinii prophylaxis),  Acyclovir  400 mg oral bid, and Fluconazole  100 mg oral qd.  For 
prophylaxis  during Consolidation C transplant,  see below. 
 
INDUCTION: RR-CHOP-14 Chemotherapy  for Three Cycles 
 
Each cycle lasts approximately  14 days. 
A total of 3 cycles of RR-CHOP-14 will be given.   One cycle of CHOP will follow. 
 
There are no dose reductions of the Rituximab, cyclophosphamide, or doxorubicin. If 
patients develop grade III/IV neurotoxicity from vincristine, the dose can be reduced at the 
discretion of the primary attending. Treatment is delayed  until  the absolute  neutrophil 
count is > 1000/ul and the platelet count is > 50,000/ul. 
 
Cycle s 1-3: RR-CHOP-14 
 
Day -2 or Day 2: 
Rituximab  375 mg/m2  IVPB 
 
Day 0: 
Rituximab  375mg/m2  IVPB 
Cyclophosphamide  1000 mg/m2  IVPB 
Doxorubicin  50mg/m2   IVP 
Vincristine  1.4 mg/m2   (no cap) IVP 
Prednisone 100mg PO daily for five days 
Alternatively,  Prednisone  may be started on Day 1 and continue  through Day 5. 
 
Growth factor support: 
G-CSF SQ Days 6-10 at either 300ug or 480 ug /day OR Pegfilgrastim  6mg once 24-48 
hrs post completion of intravenous  chemotherapy. 
 
Day 0 of next cycle is day 14 as long as ANC ≥ 1000 and platelets ≥50 k (this requireme nt 
is not applicable for patients with bone marrow involvement); RCHOP in cycle 3 and 
CHOP in cycle 4 should be two weeks apart also. 
 
 
Cycle 4: CHOP, no rituximab  will be administe re d 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
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This cycle will last 21 days 
 
Day 0: 
Cyclophosphamide  1000 mg/m2  IVPB 
Doxorubicin  50mg/m2   IVP 
Vincristine  1.4 mg/m2   (no cap) IVP 
Prednisone 100mg PO daily for five days. 
Alternatively,  Prednisone  may be started on Day 1 and continue  through Day 5. 
 
Growth factor support: 
G-C SF SQ Days 6-10 at either 300ug or 480 ug/day OR Pegfilgrastim 6mg once 24-48 hrs 
post completion of intravenous  chemotherapy. 
 
Inte rim re staging CT (with volume tric analysis) and FDG-PET scanning will be done 
on days 17-20 of cycle 4 of induction  che mothe rapy. 
 
 
CONSOLIDATION 
 
Risk-Adapted based on Biopsy and Pre-treatment Ki-67. If the interim FDG-PET 
scan is positive in a site of measurable disease and correlates to disease shown on the CT 
scan, the patient will undergo a repeat biopsy. 
If the biopsy is negative, the patient will receive consolidation A or B depending 
upon pre-treatment Ki-67 expression; if positive the patient will receive consolidation C. 
Patients whose bone marrow was initially positive and remains positive post-induction will 
receive consolidation  C. 
 
Consolidation A: Patients whose disease is FDG-PET negative or patients whose 
FDG-PET scan is positive but repeat biopsy is negative and whose initial Ki-67 
expression is < 80% will receive 3 cycles of standard dose ICE Chemotherapy. 
 
Each cycle of ICE lasts 14 days. Patients must have a platelet count of 50,000/ul and an 
ANC of at least 1000/ul to proceed to subsequent cycles of ICE. For delays of greater than 
2 weeks, the PI must be notified and it the delay must be reported the IRB/PB. Creatinine 
clearance is estimated from 12 hour urine collections  obtained on admission. 
 
Days 1-3: 
Etoposide 100 mg/ m2  IVPB Days 1, 2, 3 
Carboplatin AUC 5 (maximum  dose 800 mg [equivalent  to CrCl of 135 ml/min)  IVPB 
AUC dosing is calculated  by the Calvert Formula: 
AUC 5 = 5 x (CrCl+25) 
 
 
Day 2: 
Ifosfamide  5 g/m2  admixed  with MESNA 5 g/m2  IVCI over 24 hours beginning  on Day 2. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
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Growth factor support: 
Pegfilgrastim 6mg 24-48 hrs post completion of chemotherapy or G-CSF SQ Days 5-12 at 
either 300ug or 480 ug/day 
 
 
Consolidation B: Patients whose disease is FDG-PET negative or patients whose 
FDG-PET scan is positive but repeat biopsy is negative and whose initial Ki-67 
expression is ≥80% will receive 2 cycles of augmented RICE Chemotherapy (as per 
MSKCC protocol 03-075). 
 
Days 1 and 3: 
Rituximab  375 mg/m2  IVPB 
 
Admit for RICEaug chemotherapy.   Each cycle of RICEaug lasts 21 days.  Patients must 
have a platelet count of 50,000/ul and an ANC of at least 1000/ul to proceed to 
subsequent cycles of RICEaug (this requirement  is not applicable  for patients with bone 
marrow involvement).  For delays of greater than 2 weeks, the PI must be notified  and it 
the delay must be reported the IRB/PB. 
Creatinine  clearance is estimated from 12 hour 
urine collections  obtained on admission. 
 
Days 4-6: 
Etoposide 200 mg/m2   IVPB q12 hrs x 3 
Ifosfamide  5 g/m2/day administered  with MESNA 5 g/m2/day mixed  IVCI over 24 hours 
x 2 starting on Day 4 (Total dose of both Ifosfamide  and MESNA is 10 gm/m2) 
Carboplatin AUC 5 (maximum  dose 800 mg equivalent  to CrCl of 135 ml/min)  IVPB on 
Day 6 
AUC dosing is calculated  by the Calvert Formula: 
AUC 5 = 5 x (CrCl+25) 
 
Growth factor support: 
Pegfilgrastim 6mg 24-48 hrs post completion of chemotherapy or G-CSF SQ Days 5-12 at 
either 300ug or 480 ug/day. 
 
 
Consolidation C: Patients with biopsy proven disease after induction  therapy 
Patients whose bone marrow remain positive at interim restaging will have the option 
of getting an allogeneic stem cell transplant,  in lieu of an ASCT,  if they have an 
acceptable HLA match  donor.   The allogeneic stem cell transplant  regimen will be 
decided by the MSK Bone Marrow Transplant Service. 
 
 
Part 1: RICEaug Chemotherapy  for 2 cycles (as above) 
However, after Cycle 2 patients will  receive  G-CSF at 10 ug/kg instead of pegfilgrast im, 
continuing until the completion of leukapheresis. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 11 - 
 
 
 
 
Part 2: Stem Cell Collection 
The  target  yield  for leukapheresis  will  be 5x106  CD34+ cells/kg. 
Leukapheresis  will 
continue  for up to 5 days until the target yield is reached. 
 
Part 3: High dose chemoradiotherapy  and ASCT 
Patients will be eligible  to receive IFRT if clinically indicated  beginning 2 weeks prior to 
initiation of high dose chemotherapy. 
 
High dose cytoreduction will be with CBV-N chemotherapy. 
 
Day 0 is the day of stem cell reinfusion;  CBV-N will be administered  as follows: 
 
• Mitoxantrone  (45 mg/m2)  IVPB x 1 on day – 8 
• Carmustine  (300 mg/m2)  IVPB x 1 on day – 4 
• Cyclophosphamide  (1500 mg/m2)  IVPB daily x 4 days on day – 7, - 6, - 5, - 4 
• Etoposide (250 mg/m2)  IVPB daily x 4 days on day – 7, - 6, - 5, - 4 
 
PBPC will be infused  approximately  24-48 hours after completion of chemotherapy  (day 
0). 
 
Post Stem Cell Rescue Rituximab Maintenance 
No later than Day +35 post ASCT patients will receive rituximab  bimonthly for 6 doses. 
 
 
Radiation Therapy 
Radiation therapy is not permitted for patient treated on this study other than as stipulated 
above in Consolidation  C and for scrotal radiation in patients with testicular  lymphoma. 
Intrathecal Prophylaxis 
Patients willl      receive 6 doses of intrathecal methotrexate  or cytarabine during the course of 
induction and consolidation therapy in the following circumstances: 
Testicular  involvement 
Paranasal sinus or nasopharynx  involvement 
Bone marrow involvement  by large celll      lymphoma 
Patients with aaIPI HR disease 
Patients with more than 2 extra-nodal sites of disease 
 
Antimicrobial  Prophylaxis 
Antimicrobial prophylaxis for Augmented RICEx2 is the  same  as  specified  in 
Consolidation B. Antimicrobial prophylaxis for transplant phase: On admissio n: 
Ciprofloxacin 500 mg PO b.i.d. (continue until the patient requires broad spectrum 
antibiotics for neutropenic fever) Fluconazole 100 mg PO or IV b.i.d. (continue until the 
ANC is > 1000/mm3 X 3 days or until amphotericin B therapy is initiated). Nystatin 
powder applied to the groin and the axilla BID Vitamin K 10 mg PO or sc. one to three 
times per week unless added to TPN. Day +5 : G-CSF 480 ug sc. QD ( continue  until ANC 
> 1000/mm3 x 3 days.) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 12 - 
 
 
 
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC  AGENTS 
 
Doxorubicin 
Mechanism of action: is an anthracycline  antibiotic  derived as a fermentation product of 
Streptomyces peucetius  (caesius).  The drug is tightly  bound to DNA, preventing  DNA- 
directed DNA and RNA synthesis.  The drug may also act via a free radical mechanism.  It 
appears to be active in all phases of the cell cycle. 
Formulatio n:  The drug is supplied reconstituted  in 10, 50 and 200 mg vials. 
Storage: Reconstituted  solutions  are stable at room temperature  for 24 hours and under 
refrigeration for 48 hours. 
Administratio n: The drug is administered  via a freely-flowing intravenous  line over 15 
minutes.   Care must be taken to avoid extravasation. 
Toxicity:   include  nausea, vomiting,  itching,  hives or red rash at the injection site. Urine 
can be pink or red in color for as long as 48 hours after the treatment.  Alopecia, 
stomatitis,  and reversible  myelosuppression can occur. 
Extravasation may occur if leakage around the intravenous  site occurs. 
Cardiomyopathy has been reported with this compound,  usually  in patients who have 
received total doses in excess of 500 mg/m2. 
 
Cyclophosphamide 
Mechanism of action: a nitrogen mustard derivative,  is converted to polyfunctional 
alkylating metabolites  by hepatic microsomal  enzymes.   It interferes  with DNA 
replication and RNA transcription,  and possesses potent immunosuppressive  activity. 
Formulatio n:  The drug is supplied as a lyophilized  powder in 100 mg, 200 mg, 500 mg, l 
g, and 2 g vials. 
Preparation/Stora ge :  It is reconstituted  to result in a concentration of 20 mg/mL.   It is 
stable for 24 hours at room temperature or for 6 days refrigerated  (2°-8° C). 
Toxicity:  include  nausea, vomiting,  anorexia, edema, cardiomyopathy,  skin rash, 
alopecia, reversible  myelosuppression,  hemolytic  anemia, possible  sterility,  hemorrhagic 
cystitis,  and syndrome  of inappropriate  antidiuretic  hormone production. 
 
Vincristine 
Mechanism of action: is a member of the vinca alkaloid  class of natural product anti- 
tumor agents. It exerts its antineoplastic  effects by binding to tubulin,  resulting in 
inhibition of microtubule  assembly.  This, in turn, blocks formation of the mitotic  spindle 
resulting in the accumulation of cells in mitosis. 
Formulatio n:  The drug is supplied reconstituted  to a concentration of 1 mg/ Ml 
Preparation/Stora ge :  The drug is administered  via a freely-flowing intravenous  line over 
1-2 minutes,  with care taken to avoid extravasation. 
Toxicity:  include  peripheral neuropathy,  constipation,  alopecia, metallic  taste in the 
mouth, mild nausea, paraesthesia and paresis.  Extravasation may result in soft tissue 
necrosis. 
 
Rituximab (Rituxan®, C2B8) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 13 - 
 
 
 
 
Mechanism of action: Rituximab  binds to the CD20 antigen expressed on B-cells and 
causes cell death by complement  mediated lysis  and ADCC. 
Formulatio n:  Rituximab  is a genetically engineered,  chimeric,  murine/human monoclonal 
antibody directed against the CD20 antigen found on the surface of normal and malignant 
pre-B and mature B cells.  The antibody is an IgG1  κ immunoglobulin  containing murine 
light-and  heavy-chain variable  region sequences and human constant region sequences. 
Rituximab  is composed of two heavy chains of 451 amino acids and two light  chains of 
213 amino acids (based on cDNA analysis)  and has an approximate  molecular  mass of 
145 kD.  Rituximab  has a binding affinity for the CD20 antigen of ~8.0 nM.  Rituximab 
is supplied as 100 mg and 500 mg sterile, preservative-free,  single-use  vials. 
Preparation: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.  Do 
not infuse  rituximab  concomitantly with another IV solution or other IV medications. 
The appropriate dose is withdrawn and diluted  to a final concentration of 1-4 mg/ml in 
either 0.9% sodium chloride  or 5% dextrose solution.  The solution is then stable at 2° to 
8°C for 24 hours and at room temperature for an additional 12 hours. 
Storage: Vials can be stored at 2o to 8oC. They should  be protected from sunlight. 
Administratio n: The first infusion should be administered  at an initial rate of 50 mg/hr.   If 
hypersensitivity or infusion-related  events do not occur, the rate may be increased by 50 
mg/hr every 30 minutes  up to a maximum of 400 mg/hr.  Subsequent infusions  may be 
started at 100 mg/hr and the rate increased by 100 mg/hr at every 30 minutes  to a 
maximum  of 400 mg/hr,  as tolerated. Patients will be premedicated with acetaminophen 
650-mg po, diphenhydramine  50 mg IV, and lorazepam 0.5 mg IV 30 minutes  prior to 
beginning the rituximab  infusion.  For severe reactions, the infusion will be stopped and 
can be resumed at 50% of the prior rate once the reactions are treated and symptoms 
resolved. 
Toxicity:  common: Fever, chills,  fatigue,  headache; less common: nausea, vomiting, 
rhinitis,  pruritus,  hypotension;  rare: neutropenia,  thrombocytopenia,  asthenia,  arthritis, 
vasculitis,  lupus-like  syndrome,  pleuritis,  bronchiolitis  obliterans,  uveitis,  optic neuritis, 
and skin reactions such as toxic epidermal necrolysis  and pemphigus. 
 
Fatal Infusion Reactions: Severe and fatal cardiopulmonary events, including 
angioedema,  hypoxia,  pulmonary infiltrates,  acute respiratory distress syndrome, 
myocardial infarction,  and cardiogenic  shock, have been reported.  These severe reactions 
typically occurred during the first infusion with time to onset of 30-120 minutes. 
 
Cardiac Events:  Patients with preexisting cardiac conditions,  including arrhythmia  and 
angina,  have had recurrences of these cardiac events during rituximab  infusions. 
 
Tumor Lysis Syndrome:  Tumor lysis syndrome has been reported and is characterized 
in patients with a high number of circulating malignant  cellls (≥25,000 ul) by rapid 
reduction in tumor volume,  renal insufficiency,  hyperkalemia,  hypocalcemia, 
hyperuricemia,  and hyperphosphatemia. 
 
Renal Events:  Rituximab  has been associated with severe renal toxicity including acute 
renal failure  requiring dialysis,  and in some cases has lead to death.  Renal toxicity has 
occurred in patients with high numbers of circulating malignant  cellls (≥25,000/mm2  ) or 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 14 - 
 
 
 
 
high tumor burden who experience tumor lysis  syndrome and in patients administered 
concomitant  cisplatin. 
 
Mucocutaneous Reactions: Severe bullous  skin reactions, including fatal cases of toxic 
epidermal necrolysis  and paraneoplastic  pemphigus,  have been reported in patients 
treated with rituximab.   The onset of reaction has varied from 1 to 13 weeks following 
rituximab  exposure. 
 
Hematologic Events: In clinical trials, Grade 3 and 4 cytopenias were reported in 48% of 
patients treated with RITUXIMAB;  these include: lymphopenia  (40%), neutropenia 
(6%), leukopenia  (4%), anemia (3%), and thrombocytopenia  (2%).  The median duration 
of lymphopenia  was 14 days (range, 1 to 588 days) and of neutropenia  was 13 days 
(range, 2 to 116 days).  A single  occurrence of transient  aplastic anemia  (pure red cell 
aplasia) and two occurrences of hemolytic  anemia following  RITUXIMAB  therapy were 
reported. 
In addition,  there have been a limited  number of post-marketing  reports of 
prolonged pancytopenia,  marrow hypoplasia,  and late onset neutropenia  (defined as 
occurring 40 days after the last dose of RITUXIMAB)  in patients with hematologic 
malignancies.   In reported cases of late onset neutropenia  (NCI-CTC Grade 3 and 4), the 
median duration of neutropenia  was 10 days (range 3 to 148 days).  Documented 
resolution of the neutropenia  was described in approximately one-half of the reported 
cases; of those with documented recovery, approximately  half received growth factor 
support.  In the remaining cases, information on resolution was not provided.  More than 
half of the reported cases of delayed onset neutropenia  occurred in patients who had 
undergone  prior autologous  bone marrow transplantation.   In an adequately designed, 
controlled,  clinical trial, the reported incidence  of NCI-CTC, Grade 3 and 4 neutropenia 
was higher  in patients receiving RITUXIMAB in combination with fludarabine  as 
compared to those receiving fludarabine  alone (76% [39/51] vs. 39% [21/53]). 
 
Infectious Events: Rituxan induced B-cell depletion in 70% to 80% of patients with 
NHL and was associated with decreased serum immunoglobulins  in a minority of 
patients; the lymphopenia  lasted a median of 14 days (range, 1-588 days).  Infectious 
events occurred in 31% of patients: 19% of patients had bacterial infections,  10% had 
viral infections,  1% had fungal infections,  and 6% were unknown infections.   Serious 
infectious  events (Grade 3 or 4), includ ing sepsis, occurred in 2% of patients. 
 
Other Serious Viral Infections:  The following additional serious viral infections,  either 
new, reactivated or exacerbated, have been identified  in clinical studies or postmarketing 
reports. The majority of patients  received Rituxan in combination with chemotherapy or 
as part of a hematopoietic  stem cell transplant.  These viral infections  included  JC virus 
(progressive  multifocal  leukoencephalopathy [PML]), cytomegalovirus,  herpes simplex 
virus, parvovirus  B19, varicella  zoster virus,  West Nile virus, and hepatitis  C. In some 
cases, the viral infections  occurred up to one year following discontinuation of Rituxan 
and have resulted in death. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 15 - 
 
 
 
 
Hepatitis  B virus (HBV) reactivation with fulminant  hepatitis,  hepatic failure,  and death 
has been reported in some patients with hematologic  malignancies  treated with rituximab. 
The majority of patients received rituximab  in combination with chemotherapy.   The 
median time to the diagnosis  of hepatitis  was approximately 4 months after the initiation 
of rituximab  and approximately one month after the last dose. 
 
PML is a rare demyelinating disease of the brain caused by infection with the JC virus 
that usually leads to death or severe disability. 
JC virus infection resulting in PML and 
death has been reported rarely in patients with hematologic  malignancies  receiving 
rituximab.  The majority of these patients had received rituximab  in combination with 
chemotherapy or as part of a hematopoietic  stem cell transplant. 
Cases of PML resulting 
in death have also been reported in patients with systemic  lupus erythematosus  (SLE) 
treated with rituximab.   These patients with SLE had longstanding disease, history of 
prior immunosuppressant  therapy, and were diagnosed with PML within 12 months  of 
their last infusion of rituximab. 
Physicians  should consider PML in any patient presenting with new onset neurologic 
manifestations.  Consultation with a neurologist,  brain MRI, and lumbar puncture should 
be considered as clinically indicated.   In patients who develop PML, rituximab  should be 
discontinued  and reductions  or discontinuation of any concomitant  chemotherapy or 
immunosuppressive  therapy should be considered. 
 
Bowel Obstruction  and Perforation:   Abdominal pain, bowel obstruction and 
perforation,  in some cases leading to death, were observed in patients receiving Rituxan 
in combination with chemotherapy for DLBCL. In post-marketing reports, which include 
both patients with low-grade or follicular  NHL and DLBCL, the mean time to onset of 
symptoms  was 6 days (range 1−77) in patients with documented gastro-intestinal 
perforation.  Complaints  of abdominal pain, especially early in the course of treatment, 
should prompt a thorough diagnostic  evaluation and appropriate treatment. 
 
Additional  Safety Signals:  The following serious adverse events have been reported to 
occur in patients following completion of rituximab  infusions:  arthritis,  disorders of 
blood vessels (vasculitis,  serum sickness and lupus-like  syndrome),  eye disorders (uveitis 
and optic neuritis),  lung disorders including pleuritis  and scarring of the lung 
(bronchiolitis  obliterans),  that may result in fatal outcomes, and fatal cardiac failure. 
 
Supplier: Genentech, Inc., IDEC Pharmaceuticals  Corp. 
 
Ifosfamide (Ifex®) 
Mechanism of action: Ifosfamide  is activated in the liver  by microsomal enzymes  and the 
subsequent ifosfamide  mustard causes direct alkylation of DNA. 
Formulatio n:  Ifosfamide  is supplied in single  dose vials for constitution and 
administration by IV infusion.   Each contains 1 gram or 3 grams of sterile ifosfamide. 
Preparation: Injections  are prepared by adding sterile  water to the vial.  The 1-gram dose 
is mixed with 20 mL and the 3-gram dose with 60 mL for a final concentration of 50 
mg/mL. 
Storage: The dry powder may be stored at room temperature. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 16 - 
 
 
 
 
Toxicity:  Alopecia, nausea and vomiting,  hematuria,  gross hematuria,  CNS toxicity, 
infection,  renal dysfunction,  allergic  reactions and at high doses, cardiotoxicity. 
Supplier: Bristol-Myers  Squibb 
 
Carboplatin  (Paraplatin®) 
Mechanis m of action: Carboplatin binds to DNA and causes cross-linking with a non-cell 
cycle dependent tumor cell lysis.   It inhibits  DNA synthesis  by altering the template  via 
the formation of intrastrand  cross-links. 
Formulatio n:  Paraplatin®  is supplied  as a sterile lyophilized  powder available  in single- 
dose vial containing 50 mg, 150 mg, and 450 mg of carboplatin for administration by IV 
infusion.   Each vial contains  equal parts of carboplatin and mannitol. 
Preparation: Immediately before use the content of each vial must be reconstituted  with 
sterile solution: 50 mg strength with 5 mL, 150 mg with 15 mL and 450 mg with 45 mL. 
These solutions  produce a concentration of 10 mg/mL.  The solution is stable for 8 hours 
at room temperature. 
Storage: Unopened vials are stable for the life  indicated on the insert if protected from 
light. 
Toxicity:  Myelosuppression,  nausea, vomiting,  peripheral neuropathy,  ototoxicity, 
hepatic toxicity,  electrolyte  abnormalities,  hypomagnesemia,  hypocalcemia,  and allergic 
reactions. 
Supplier: Bristol-Myers  Squibb 
 
VP-16 (etoposide, Vepesid®) 
Mechanism of action: Induction of an irreversible  blockade of cells in the premitotic 
phases of the cell cycle leading to accumulation of cells in late S or G2 phases. This 
mechanism  is secondary to interference  of the scissors-reunion reaction of the enzyme 
topoisomerase II. 
Formulatio n:  VP-16 injection is available  in 100-mg (5-mL) sterile multiple-dose vials. 
The pH is 3-4. Each mL contains 20-mg etoposide, 2-mg citric acid, 30-mg benzyl 
alcohol, 80-mg polysorbate 80, 650-mg polyethylene  glycol 300 and 30.5% alcohol. 
Preparation: The computed dose is diluted  in 500 mL of normal saline and given by 
intravenous  infusion over 1 hour. 
 
Storage: Unopened vials of VP-16 are stable for 24 months at room temperature.  Vials 
are diluted as recommended  to a concentration of 0.2 or 0.4 mg/mL  and are stable for 96 
and 48 hours respectively,  at room temperature  under normal light  in both plastic and 
glass containers. 
Toxicity:  Leukopenia, thrombocytopenia,  alopecia, nausea, vomiting,  headache, fever, 
hypotension,  anorexia, and allergic  reactions. 
Supplier: Bristol-Myers  Squibb 
 
Mesna (Mesnex®) 
Mechanism of action: Mesna was developed as a prophylactic  agent to inhibit 
hemorrhagic  cystitis  induced by ifosfamide  and is analogous  to the cysteine-cystine 
system; mesna is rapidly metabolized  to mesna disulfide  and acts as a free radical 
scavenger. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 17 - 
 
 
 
 
Formulatio n:  Mesna is a sterile preservative  free aqueous solution of clear, colorless 
appearance in clear glass vials for IV administration.   Mesna injection contains 100 
mg/ml Mesna, 0.25 mg/ml acetate disodium,  and sodium hydroxide to maintain pH 6.5- 
8.5. 
Preparation: For IV administration the drug is diluted  in sterile solution to make a final 
concentration of 20 mg/ml. 
Storage: Diluted  solutions  are chemically and physically stable for 24 hours at room 
temperature. It is recommended  that solutions  be refrigerated  and used within 6 hours. 
Toxicity:  Nausea, vomiting,  diarrhea 
Supplier: Bristol-Myers  Squibb 
 
Neupogen® (Filgrastim,  G-CSF) 
Mechanism of action: NEUPOGEN® is a human protein, which is involved  in the 
promotion of the growth and maturation of granulocytic  progenitors  and the stimulation 
of functional activity. 
Formulatio n:  Available  as a recombinant  DNA product supplied as 1 or 2 ml vials 
containing clear colorless sterile protein solution. 
Storage: It can be stored at 2-6°C and is stable for at least 30 months. 
Toxicity:  Bone pain, exacerbation of preexisting autoimmune  disorders, transient  and 
reversible  changes in alkaline  phosphatase, uric acid and LDH. 
Supplier: Amgen, Inc. 
 
Neulasta® (Pegfilgrastim, G-CSF) 
Mechanism of action: NEULASTA® is a human protein, which is involved  in the 
promotion of the growth and maturation of granulocytic  progenitors  and the stimulation 
of functional activity.  It is a covalent conjugate of recombinant  methionyl  human G-CSF 
(Filgrastim)  and monomethoxypolyethylene  glycol 
Formulatio n:  Available  as a pegalated recombinant  DNA product supplied as .6mL 
prefilled  syringe  containing clear colorless sterile protein solution. 
Storage: It can be stored at 2-8°C and is stable for at least 30 months. 
Toxicity:  Bone pain, exacerbation of preexisting autoimmune  disorders, transient  and 
reversible  changes in alkaline  phosphatase, uric acid and LDH, nausea, fatigue,  alopecia, 
diarrhea, vomiting,  constipation,  fever, anorexia, skeletal pain, headache, taste 
perversion,  dyspepsia, myalgia,  insomnia,  abdominal pain, arthralgia,  generalized 
weakness, peripheral edema, dizziness,  granulocytopenia,  stomatitis,  mucositis,  and 
neutropenic  fever 
Supplier: Amgen, Inc. 
 
18F Fluorothymidine 
Please see section 3.5 Background and Rationale. 
FLT will be synthesized  by the MSKCC cyclotron facility.   FLT has been synthesized  by 
the MSKCC cyclotron facility for about 2 years and has been used in patients with gastric 
cancer at MSKCC, and in patients with a variety of diseases (e.g., lung, esophageal and 
colorectal cancer) in several institutions  in this country and Europe.  No side effects have 
been reported from any of the institutions.   The primary source of the FLT will be the 
MSKCC cyclotron  facility;  however, alternative  commercial  sources are available  to ensure 
consistent  supply  of FLT. If a commercial  supplier  of FLT is used for a particular  study, the 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 18 - 
 
 
 
 
supplier  will  be required  to meet all of the acceptance criteria outlined  in the FDA-approved 
MSKCC FLT IND (#104742)  prior to administration.   Here at MSKCC, we have 
extensively tested the FLT for toxicity and pyrogenicity,  and the product has met all 
requirements.  The radiochemical purity is > 95%. For each scan, we will inject 8mCi of 
FLT. By doing so, the effective  dose equivalent  from these 2 scans will be 3.87 rem. 
Although FLT will be administered  as part of an FDA-approved IND application,  based 
on published  dosimetry data, the dose from FLT is indeed within the (more conservative) 
dose restrictions  set forth for radiopharmaceutical  studies done under the aegis of the 
radioactive  drug research committee  (see Appendix table 1). 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
• 
Histologic  diagnosis  of diffuse  large B cell lymphoma,  PMLBL, or follicular 
lymphoma  grade 3B confirmed  by the department of hematopathology at MSKCC. 
Patients with discordant bone marrow involvement  (i.e. involvement  by small 
cleaved cells or small lymphocytic  lymphoma)  are eligible 
• 
Tumors express CD20 as determined  by immunohistochemistry. 
o 
Ki-67 evaluation of tumor tissue 
• 
Patients must have stage III, or IV disease.  Patients with IIX disease must have at 
least one other age-adjusted IPI risk factor. 
o 
KPS ≤ 70 
o 
LDH > upper limit  of normal 
• 
All patients must have FDG-PET avid (minimum  SUV 2.5) measurable  disease. 
• 
Patients must have normal baseline  cardiac function based upon echocardiogram or 
gated blood pool scan (MUGA) with an ejection fraction  ≥ 50% 
• 
Patients must have a serum creatinine  of ≤ 1.5 mg/dl; if creatinine  >1.5 mg/dl 
creatinine  clearance must be >60 ml/minute. 
• 
Patients must have ANC>1000/mcl and Platelets>50,000/mcl.  If patient has 
cytopenias due to bone marrow involvement,  these requirements  are not applicable. 
• 
Patients must have a bilirubin level of < 2.0 mg/dl in the absence of a history of 
Gilbert's disease (or pattern consistent  with Gilbert’s). 
• 
Patients must be Hepatitis  B surface antigen negative,  Hepatitis  B core antibody 
negative,  and Hepatitis  C negative. 
• 
All patients of childbearing and child-creating age must be using an acceptable 
form of birth control from the initiation of treatment on study until 1 year after 
completion of chemotherapy and/or transplant. 
• 
Women who are pre-menopausal must have a negative  pregnancy test 
• 
Age between 18 and 65 
• 
Patients must be HIV negative.  This test may be pending in a patient without  risk 
factors, as determined  by the patient’s  physician. 
• 
If patients have a history of malignancy other than cutaneous basal cell or squamous 
cell carcinoma,  they must be disease-free for ≥ 5 years at the time of enrollment. 
• 
Patients or their guardians  must be capable of providing informed  consent. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 19 - 
 
 
 
 
• 
Patients must be suitable  to undergo stem cell transplant 
 
6.3 
Subject Exclusion Criteria 
 
• 
Any lymphoma  subtype other than DLBCL, PMLBL, follicular  lymphoma  grade 
3B. 
• 
Patients with either parenchymal brain or lepto-meningeal  involvement. 
• 
No more than 14 days of prednisone therapy between the diagnostic  biopsy of either 
DLBCL, PMLBL, or follicular  lymphoma  grade 3B and the initiation of treatment 
on study. 
• 
Known pregnancy or breast-feeding. 
• 
Medical illness  unrelated  to NHL which in the opinion of the attending physician 
and principal investigator  will preclude administration of chemotherapy safely. 
This includes  patients with uncontrolled  infection,  chronic renal insufficiency, 
myocardial infarction within the past 6 months,  unstable angina,  cardiac 
arrhythmias  other than chronic atrial fibrillation and chronic  active or persistent 
hepatitis,  or New York Heart Associatio n Classification III or IV heart disease. 
• 
History of any malignancy for which the disease-free interval is <5 years, excluding 
curatively treated cutaneous basal cell or squamous cell carcinoma  and carcinoma 
in-situ of the cervix. 
 
7.0 
RECRUITMENT PLAN 
 
Patients seen in the inpatient  or outpatient  setting who meet eligibility criteria will be 
recruited to this study.  A Lymphoma  disease management  team physician will evaluate 
all patients.  Participation is voluntary.  The patient will be made aware of their diagnosis, 
current nature of this treatment program.  All patients will be required to sign a statement 
of informed  consent that conforms to FDA and IRB/PB guidelines. 
8.1 
PRETREATMENT EVALUATION 
All patients will have the following baseline  studies: 
Within 2 weeks prior to treatment initia tio n 
• Complete history and physical 
• CBC with differential 
• Electrolytes  (Na, K, Cl, CO2), BUN, Cr, bilirubin,  total protein, albumin,  alkaline 
phosphatase, uric acid, phosphorus, AST, ALT, LDH, urinalysis,  and pregnancy 
test in pre-menopausal women 
• EKG 
 
Within 4 weeks prior to treatment initia tio n: 
• Documentation of ejection fraction by echocardiogram  or MUGA scan 
• Documentation of HIV seronegativity at MSKCC 
• Hepatitis  B surface antigen & core antibody, Hepatitis  C antibody 
• CT scans of the chest, abdomen, and pelvis  (with volumetric  analysis  when 
possible) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 20 - 
 
 
 
 
• FDG-PET/CT scan 
• Bilateral Bone marrow biopsy 
o Note: Bilateral bone marrow biopsy not required if unilateral bone 
marrow biopsy within 4 weeks prior to treatment  initiation shows 
involvement  by lymphoma 
• Creatinine  clearance if serum Cr>1.5 mg/dl 
• FLT PET/CT (only the first 60 patients  will receive the FLT-PET scan): 
o FLT PET/CT can be waived  for the following patients: 
▪ Patients who have aggressive  disease that requires immediate 
treatment;  these patients may enroll on the protocol without  an 
FLT PET scan. 
▪ Patients with other extenuating circumstances,  as determined 
by the principle  investigators  of the study. 
▪ Patients who enroll on study after 60 patients have already 
been imaged with an FLT-PET scan 
 
o Patients should be fasted for 6 hours, but liberal intake of water is allowed 
o Two Intravenous  lines will be established:   one line for FLT administration 
(Mediport or forearm) and the other line for obtaining one blood sample 
(forearm). 
o An area of interest will be determined  based on prior CT scan and/or FDG 
PET, for instance,  the largest nodal mass identified  on CT and/or lesion with 
them most intense FDG uptake 
o Patient will be placed in the FDG-PET/CT scanner.  A low dose scout view 
and CT of the selected body region (1 field  of view = 15 cm) will be obtained. 
o Approximately 8mCi (296 MBq) FLT will be injected intravenously and 
dynamic  images will be acquired for up to 40 min over this lesion. During that 
time the patient will rest comfortably in the PET scanner. 
o Following dynamic  image acquisition,  the patient will be removed from the 
scanner and will have an opportunity to stretch, use the rest room etc. 
o Then a PET/CT scan of the body, extending from skull base to approximately 
the upper thighs,  will be obtained.  Again, during this scan the patient will rest 
comfortably on the scanner bed, but this time the table will move  
consecutively through the scanner. One three (3) ml blood sample will be 
obtained for metabolite  analysis  at the end of the scan. 
o The IV lines will be removed at the end of the study 
o The radiopharmacy will keep a log of all activities  administered  under this 
protocol. 
 
FLT PET is considered investigational,  and thus these scans will be performed under an 
FDA-approved Investigational New Drug (IND) application.   The results of the FLT 
scans will have no impact on patient management. 
 
Prior to ICE administratio n: 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
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• Tissue blocks or 10 unstained  slides, if original biopsy done at outside 
institutions,  to further characterize  the underlying lymphoma 
• Ki-67 staining of tumor 
 
9.0 
TREATMENT INTERVENTION/PLAN 
 
All induction  and consolidation treatment visits have a +/- 3 day window (excluding 
the interim restaging scans). 
 
Antimicrobial  Prophylaxis: Throughout  induction  and all consolidation  chemotherapy 
(excluding transplant),  the following antimicrobial prophylaxis  will be given: 
Trimethoprim/Sulfamethoxazole  160/800 (DS) oral twice daily TIW (patients with 
known allergy to Trimethoprim/Sulfamethoxazole  can receive alternative  pneumocystis 
carinii prophylaxis),  Acyclovir  400 mg oral bid, and Fluconazole  100 mg oral qd.  For 
prophylaxis  during Consolidation C transplant,  see below. 
 
INDUCTION: RR-CHOP-14 Chemotherapy for Three Cycles 
Each cycle lasts approximately 14 days. 
A total of 3 cycles of RR-CHOP-14 will be given.  One cycle of CHOP will follow. 
 
There are no dose reductions of the Rituximab, cyclophosphamide, or doxorubicin. If 
patients develop grade III/IV neurotoxicity from vincristine, the dose can be reduced at the 
discretion of the primary attending. Treatment is delayed until the absolute  neutrophil 
count is > 1000/ul and the platelet count is > 50,000/ul. 
Cycle s 1-3: RR-CHOP-14 
Day -2 or Day 2: 
Rituximab  375 mg/m2  IVPB 
 
Day 0: 
Rituximab  375mg/m2  IVPB 
Cyclophosphamide  1000 mg/m2  IVPB 
Doxorubicin  50mg/m2   IVP 
Vincristine  1.4 mg/m2   (no cap) IVP 
Prednisone 100mg PO daily for five days 
Alternatively,  Prednisone  may be started on Day 1 and continue  through Day 5. 
 
Growth factor support: 
G-CSF SQ Days 6-10 at either 300ug or 480 ug /day OR Pegfilgrastim  6mg once 24-48 
hrs post completion of intravenous  chemotherapy. 
 
Day 0 of next cycle is day 14 as long as ANC ≥ 1000 and platelets ≥50 k (this requireme nt 
is not applicable for patients with bone marrow involvement) ; RCHOP in cycle 3 and 
CHOP in cycle 4 should be two weeks apart also. 
 
Cycle 4: CHOP, no rituximab  will be administe re d 
This cycle will last 21 days 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 22 - 
 
 
 
 
 
 
Day 0: 
Cyclophosphamide  1000 mg/m2  IVPB 
Doxorubicin  50mg/m2   IVP 
Vincristine  1.4 mg/m2   (no cap) IVP 
Prednisone 100mg PO daily for five days. 
Alternatively,  Prednisone  may be started on Day 1 and continue  through Day 5. 
 
Growth factor support: 
G-C SF SQ Days 6-10 at either 300ug or 480 ug/day OR Pegfilgrastim 6mg once 24-48 hrs 
post completion of intravenous  chemotherapy. 
 
Inte rim re staging CT (with volume tric analysis) and FDG-PET scanning will be done 
on days 17-20 of cycle 4 of induction  che mothe rapy. 
 
CONSOLIDATION 
Risk-Adapted based on Biopsy and Pre-treatment Ki-67. If the interim FDG-PET scan is 
positive in a site of measurable disease and correlates to disease shown on the CT scan, the 
patient will undergo a repeat biopsy. If the biopsy is negative, the patient will receive 
consolidation A or B depending upon pre-treatment Ki-67 expression; if positive the 
patient will receive consolidation C. Patients  whose bone marrow was initially  positive 
and remains  positive post-induction will receive consolidation  C. 
 
Consolidation A: Patients whose disease is FDG-PET negative (any residual lesion 
seen on companion CT with FDG uptake < blood pool activity in large vessels in the 
same field of view ) or patients whose FDG-PET scan is positive but repeat biopsy is 
negative and whose initial Ki-67 expression is < 80% will receive 3 cycles of standard 
dose ICE Chemotherapy. 
 
Each cycle of ICE lasts 14 days. Patients must have a platelet count of 50,000/ul and an 
ANC of at least 1000/ul to proceed to subsequent cycles of ICE. For delays of greater than 
2 weeks, the PI must be notified and it the delay must be reported the IRB/PB. Creatinine 
clearance is estimated from 12 hour urine collections  obtained on admission. 
 
Days 1-3: 
Etoposide 100 mg/ m2  IVPB Days 1, 2, 3 
Carboplatin AUC 5 (maximum  dose 800 mg [equivalent  to CrCl of 135 ml/min)  IVPB 
AUC dosing is calculated  by the Calvert Formula: 
AUC 5 = 5 x (CrCl+25) 
 
Day 2: 
Ifosfamide  5 g/m2  admixed with MESNA 5 g/m2  IVCI over 24 hours beginning  on Day 2. 
 
Growth factor support: 
Pegfilgrastim 6mg 24-48 hours post completion of chemotherapy or G-CSF SQ Days 5-12 
at either 300ug or 480 ug/day. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
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Consolidation B: Patients whose disease is FDG-PET negative or patients whose 
FDG-PET scan is positive but repeat biopsy is negative and whose initial Ki-67 
expression is ≥80% will receive 2 cycles of augmented RICE Chemotherapy (as per 
MSKCC protocol 03-075). 
 
Days 1 and 3: 
Rituximab  375 mg/m2  IVPB 
 
Admit for RICEaug chemotherapy. Each cycle of RICEaug lasts 21 days. Patients must 
have a platelet count of 50,000/ul and an ANC of at least 1000/ul to proceed to subsequent 
cycles of RICEaug. For delays of greater than 2 weeks, the PI must be notified and it the 
delay must be reported the IRB/PB. Creatinine clearance is estimated from 12 hour urine 
collections  obtained on admission. 
 
Days 4-6: 
Etoposide 200 mg/m2   IVPB q12 hours x 3 
Ifosfamide  5 g/m2/day administered  with MESNA 5 g/m2/day mixed  IVCI over 24 hours 
x 2 starting on Day 4 (Total dose of both Ifosfamide  and MESNA is 10 gm/m2) 
Carboplatin AUC 5 (maximum  dose 800 mg equivalent  to CrCl of 135 ml/min)  IVPB on 
Day 6 
AUC dosing is calculated  by the Calvert Formula: 
AUC 5 = 5 x (CrCl+25) 
 
Growth factor support: 
Pegfilgrastim 6mg 24-48 hours post completion of chemotherapy  or G-CSF SQ Days 5-12 
at either 300ug or 480 ug/day. 
 
 
Consolidation C: Patients with biopsy proven disease after induction  therapy 
Patients whose bone marrow remain positive at interim restaging will have the option 
of getting an allogeneic stem cell transplant,  in lieu of an ASCT,  if they have an 
acceptable HLA match  donor.   The allogeneic stem cell transplant  regimen will be 
decided by the MSK Bone Marrow Transplant Service. 
 
Part 1: RICEaug Chemotherapy  for 2 cycles (as above) 
However, after Cycle 2 patients will  receive G-CSF at 10 ug/kg instead of pegfilgrast im, 
continuing until the completion of leukapheresis. 
 
Part 2: Stem Cell Collection 
The target  yield  for leukapheresis  will  be 5x106  CD34+ cells/kg. 
Leukaphereses  will 
continue  for up to 5 days until the target yield is reached. 
 
Part 3: High dose chemoradiotherapy  and ASCT 
Patients will be eligible  to receive IFRT if clinically indicated  beginning 2 weeks prior to 
initiation of high  dose chemotherapy. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
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High dose cytoreduction will be with CBV-N chemotherapy. 
 
Day 0 is the day of stem cell reinfusion;  CBV-N will be administered  as follows: 
 
• Mitoxantrone  (45 mg/m2)  IVPB x 1 on day – 8 
• Carmustine  (300 mg/m2)  IVPB x 1 on day – 4 
• Cyclophosphamide  (1500 mg/m2)  IVPB daily x 4 days on day – 7, - 6, - 5, - 4 
• Etoposide (250 mg/m2)  IVPB daily x 4 days on day – 7, - 6, - 5, - 4 
 
PBPC will be infused  approximately 24-48 hours after completion of chemotherapy (day 
0). 
 
Post Stem Cell Rescue Rituximab Maintenance 
No later than Day +35 post ASCT patients will receive rituximab  bimonthly for 6 doses. 
 
Radiation Therapy 
Radiation therapy is not permitted for patient treated on this study other than as stipulated 
above in Consolidation  C and for scrotal radiation in patients with testicular  lymphoma. 
Intrathecal Prophylaxis 
Patients willl      receive 6 doses of intrathecal methotrexate  or cytarabine during the course of 
induction and consolidation therapy in the following circumstances: 
Testicular  involvement 
Paranasal sinus or nasopharynx involvement 
Bone marrow involvement  by large celll      lymphoma 
Patients with aaIPI HR disease 
Patients with more than 2 extra-nodal sites of disease 
 
Antimicrobial  Prophylaxis 
Antimicrobial prophylaxis for Augmented RICEx2 is the same  as  specified  in 
Consolidation B. Antimicrobial prophylaxis for transplant phase: On admissio n: 
Ciprofloxacin 500 mg PO b.i.d. (continue until the patient requires broad spectrum 
antibiotics for neutropenic fever) Fluconazole 100 mg PO or IV b.i.d. (continue until the 
ANC is > 1000/mm3 X 3 days or until amphotericin B therapy is initiated). Nystatin 
powder applied to the groin and the axilla BID Vitamin K 10 mg PO or sc. one to three 
times per week unless added to TPN. Day +5 : G-CSF 480 ug sc. QD ( continue  until ANC 
> 1000/mm3 x 3 days.) 
 
10.1 
EVALUATION  DURING TREATMENT/INTERVENTION 
 
10.2 Pre-Treatment Evaluation 
 
Prior to treatment  as per institutional guidelines,  patients will have a repeat 
Echocardiogram  or MUGA scan and PFT’s (PFTs for Consolidation C only). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 25 - 
 
 
 
 
10.3 Evaluation During Treatment 
 
• Physical exam, CBC prior to each cycle of therapy, and assessment of toxicity 
prior to each chemotherapy. 
 
• Interim restaging (including all previously positive  imaging studies and bone 
marrow examinations)  2-3 weeks after fourth cycle of induction;  patients with 
FDG-PET negative  disease will receive consolidation A/B and those with FDG 
PET avid disease will undergo repeat biopsy.  A positive  FDG PET scan is 
defined as follows:  any uptake equal to or greater than surrounding background 
activity.   This is dependent upon the location of the lesion;  therefore the SUV 
value itself cannot be used as a criteria  for a positive  or negative  scan. 
 
• FLT PET 
One FLT PET/CT scan will be obtained prior to the start of cycle 2 (first 30 
patients on study) or prior to the start of cycle 3 (the next thirty patients to receive 
FLT PET scans); the earliest the scan can be obtained is the day after prednisone 
completion  in that cycle.  If the FLT PET scan was waived at baseline, a follow- 
up FLT PET scan after cycle 1 or 2 is not required. 
The first 30 consecutive  patients who enroll to the study will undergo FLT PET 
scanning at baseline  and prior to the start of cycle 2; an additional 30 patients (not 
necessarily consecutive)  will receive FLT PET scans at baseline  and prior to cycle 
3.  Scans will be obtained as described above under 8.0.  FLT imaging is 
exploratory,  therefore no therapeutic  decisions will be based on FLT scan findings 
in this trial.  Interim analyses  of our first set of patient’s shows that dynamic 
images may have to be acquired for up to 60 minutes  in order to capture significant  
data points for kinetic  analysis.  Therefore, we will obtain dynamic  images over a 
selected body region/lesion for up to 60 min, followed  by a scan of the torso from 
skull base to upper thigh. 
One three (3) ml blood sample will be 
taken at the end of the scan for metabolite  analysis. 
 
Funding for FLT studies was initially  intended for 60 patients.   Now that 60 
patients have undergone  the FLT-PET scan at baseline  and either after cycle 1 
(Cohort 1) or cycle 2 (Cohort 2), the FLT-PET scan will now be replaced by an 
FDG-PET scan that will be done after cycle 2 for the remaining 30 patients to 
enroll on study (Cohort 3). The results of this FDG-PET scan after cycle 2 will be 
for research purposes only and will have no impact on patient management. 
10.4 Post-Treatment Evaluation 
Consolidation A/B: 
4-6 weeks post completion of ICE-based chemotherapy,  CT scans (with volumetric 
analysis)  and FDG PET scans will be repeated. Patients will be seen on a three to four 
month basis for the first two years post-therapy.  Imaging  studies, either a CT or a FDG 
PET scan will be done at 5-7 month intervals  post-therapy for the first two years and then 
at the discretion of the attending physician thereafter. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 26 - 
 
 
 
 
Consolidation C: 
Patients will be seen every one to three weeks post transplant  until the restaging 
evaluation,  a CT scan (with volumetric  analysis)  and a FDG PET scan, at 90-120 days 
post-treatment.  Thereafter,  patients will be seen on a one to three month basis for the 
first two years post-transplant.   Imaging studies, either a CT or a FDG PET scan will be 
done at 5-7 months after the initial imaging studies for the first two years and then at the 
discretion of the attending physician thereafter. 
 
11.1 
TOXICITIES/SIDE  EFFECTS 
 
Toxicity will be graded according to NCI toxicity criteria  version 3.0.  The side effects 
and expected toxicities  associated with the various  agents are listed in section 5.0 and in 
the Investigator’s  Brochure; any toxicity that is not listed is considered unexpected.  In 
addition, placement  of a leukapheresis  catheter can be associated with pneumothorax, 
deep venous thrombosis,  infection and bleeding. 
 
 
11.2 Collecting and Reporting 
Non-he matologic toxicitie s : 
CHOP chemotherapy  has been standard of care for lymphoma  management  since 1975, 
and ICE chemotherapy is standard management  for relapsed aggressive  lymphoma  based 
upon randomized  data and has been administered  to >1500 pts at MSKCC since 1993, 
when we were the first institution to do a phase 2 clinical  trial with combination therapy. 
Therefore,  we will not be reporting the data of expected grade I-II non-hematologic 
toxicities to the IRB/PB.  The following are the most common non-hematologic 
toxicities  that have occurred and are expected in most patients: 
 
• Febrile Neutropenia 
• Diarrhea 
• Peripheral Neuropathy 
• Constipation 
• Fever 
• Nausea 
• Fatigue 
• Headache 
• Mucositis 
• Vomiting 
 
We will be recording and reporting unexpected grade I-II and all grade III-V non- 
hematologic toxicities to the IRB/PB as Serious Adverse Events.  Neutropenic  fever is 
expected and will not be reported to the IRB/PB.  Any patient who has neutropenic  sepsis 
and positive  blood cultures  will be reported to the IRB/PB. 
 
He matologic toxicitie s (Comple te Blood Count Abnormalitie s): 
All patients on study will have laboratory data collected, both in their medical records 
and in MSK’s database, CRDB.  This includes  all grades I-V hematologic  toxicities.   All 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 27 - 
 
 
 
 
grade I-III hematologic toxicities are expected and will not be reported to the 
IRB/PB.  The following are the most common expected hematologic  toxicities  in most 
patients who enroll on study: 
 
• Low hemoglobin 
• Low lymphocytes 
• Low platelets 
• Low leukocytes 
• Low neutrophil/granulocyte  count 
Grade IV/V hematologic  toxicities  willl      be captured in the patient’s  medical record, as 
welll      as MSK’s database, CRDB.  The only grade IV hematologic toxicity that will be 
reported to the IRB/PB is thrombocytopenia  with evidence of bleeding.  Grade IV 
thrombocytopenia  without  evidence of bleeding and requiring  a blood transfusion 
will not be reported to the IRB/PB.  All grade V hematologic toxicities will be 
reported to the IRB/PB. 
Ele ctrolyte and Live r Function Te st Abnormalitie s (Compre he nsive M e tabolic 
Pane l Abnorma litie s) 
All electrolyte  and liver function test abnormalities  will be captured in CRDB. 
Grade I-III abnormalities  in glucose, albumin,  alkaline  phosphatase,  potassium,  sodium, 
magnesium,  phosphorus,  bilirubin,  and calcium are expected with this course of treatment 
and will not be reported to the IRB/PB; grade IV/V abnormalities  will be reported to the 
IRB/PB.  Grade II-V liver  function test abnormalities  in AST and ALT and grade III-V 
abnormalities  in creatinine,  amylase, and lipase will be reported to the IRB/PB. 
 
ALL grade V events will be reported to the IRB/PB if a participant  is enrolled and 
actively participating  in the trial OR when event occurs within 30 days of the last 
protocol treatment intervention. 
 
For detailed information regarding SAE reporting,  see section 17.2. 
 
11.3 Expected Toxicities: 
 
The expected side effects and toxicities  associated with the various agents are listed 
below, in section 5.0 and in the Investigator’s  Brochure; any toxicity that is not listed is 
considered unexpected. 
 
Etoposide: Myelosuppression,  alopecia, nausea, vomiting,  headache, fever, hypotension, 
anorexia, and alllergic  reactions. 
 
Doxorubicin: Nausea, vomiting,  itching,  hives or red rash, alopecia, stomatitis,  reversible 
myelosuppression,  extravasation,  and cardiomyopathy. 
 
Cyclophosphamide: Nausea, vomiting,  anorexia, edema, cardiomyopathy,  skin rash, 
alopecia, reversible  myelosuppression,  hemolytic  anemia, possible sterility,  hemorrhagic 
cystitis,  and syndrome  of inappropriate  antidiuretic  hormone production. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 28 - 
 
 
 
 
 
 
Vincristine:  peripheral neuropathy,  constipation,  alopecia, metallic  taste in the mouth, 
mild nausea, paraesthesia and paresis.  Extravasation may result in soft tissue necrosis. 
 
Ifosfamide:  Alopecia, nausea and vomiting,  hematuria,  gross hematuria,  CNS toxicity, 
infection,  renal dysfunction,  allergic  reactions and at high doses, cardiotoxicity. 
 
 
Carboplatin: Myelosuppression,  nausea, vomiting,  peripheral neuropathy,  ototoxicity, 
hepatic toxicity,  electrolyte  abnormalities,  hypomagnesemia,  hypocalcemia,  and allergic 
reactions. 
 
Neupogen: Bone pain, exacerbation of preexisting autoimmune  disorders, transient  and 
reversible  changes in alkaline  phosphatase, uric acid and LDH. 
 
 
Mesna: Nausea, vomiting,  diarrhea. 
 
Rituximab: Fever, chilll   s,  nausea, asthenia,  hypotension,  angioedema,  respiratory distress, 
tumor lysis  syndrome, neutropenia.  A very rare side effect is progressive  multifocal 
leukoencephalopathy (PML); it is almost always fatal. 
 
[18F]FLT: 
 
Placement  of a catheter for infusion of [18F] FLT and blood samples may cause pain, 
bruising,  infection and venous scarring.   Standard medical care will be used to minimize 
these risks. 
 
When FLT was given to HIV patients in higher  concentrations  liver failure  was seen, but 
in this study less than 1000 fold of FLT will be used.  (Flexner et. al. 1994)  In many 
patients where FLT has been studied in the U.S. and Europe, none of this was 
documented. 
 
 
 
 
12.0 
Criteria for Therapeutic Response/Outcome Assessment 
 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance of 
all evidence of 
disease 
(a) FDG-avid or PET 
positive prior to therapy; 
mass of any size permitted 
if FDG-PET negative (b) 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared on repeat 
biopsy; if indeterminate by 
morphology, 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
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Variably FDG-avid or PET 
negative; regression to 
normal size on CT 
immunohistochemistry 
should be negative 
PR 
Regression of 
measurable 
disease and no 
new sites 
50% decrease in SPD of 
up to 6 largest dominant 
masses; no increase in size 
of other nodes (a) FDG- 
avid or PET positive prior 
to therapy; one or more 
PET positive at previously 
involved site (b) Variably 
FDG-avid or PET negative; 
regression on CT 
50% decrease in 
SPD of nodules 
(for single nodule 
in greatest 
transverse 
diameter); no 
increase in size of 
liver or spleen 
Irrelevant if positive prior to 
therapy; cell type should be 
specified 
SD 
Failure to attain 
CR/PR or PD 
(a) FDG-avid or PET 
positive prior to therapy; 
FDG-PET positive at prior 
sites of disease and no new 
sites on CT or PET 
(b) Variably FDG-avid or 
PET negative; no change in 
size of previous lesions on 
CT 
Relapsed 
disease or 
PD 
Any new lesion or 
increase by 50% 
of previously 
involved sites 
from nadir 
Appearance of a new 
lesion(s) > 1.5 cm in any 
axis, 
50% increase in 
SPD of more than one 
node, or 50% increase in 
longest diameter of a 
previously identified node 
> 1 cm in short axis 
> 50% increase 
from nadir in the 
SPD of any 
previous lesions 
New or recurrent 
involvement 
Lesions FDG-PET positive 
if FDG-avid lymphoma or 
FDG-PET positive prior to 
therapy 
 
Abbreviations: CR, complete remission;  FDG, [18F]fluorodeoxyglucose;  PET, positron 
emission tomography;  CT, computed tomography;  PR, partial remission;  SPD, sum of the 
product of the diameters; SD, stable disease; PD, progressive  disease. 
 
 
 
Determining Overall Best Response: Since this is a combination therapy protocol, 
remission status and best response is determined  one-month post completion of 
treatment.   The interim  scan is not used to determine  a patient’s remission status or 
overall best response; rather, the interim scan is used only to determine  whether a patient 
needs to have a biopsy and the outcome of this biopsy determines  the type of 
consolidation treatment  a patient receives on protocol. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
The following patients will be removed from study: 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
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• Patients who have progression of disease while on treatment.  These patients may 
be offered alternate treatments. 
• Patients who develop unacceptable toxicity. 
• Patients who develop active HBV infection or hepatitis. 
• Patients who request that they be removed from study.  This will not compromise 
the care they receive at this institution. 
• Patients who are non-compliant  with treatment or follow- up. 
 
 
14.0 
BIOSTATISTICS 
 
This protocol implements  a risk adaptive therapeutic  approach for patients with 
untreated diffuse  large B cell lymphoma.  All patients will receive RR-CHOP-14 
induction chemotherapy.  If their Ki-67 pretreatment  evaluation is <80, then the patient 
will be assigned to ICE consolidation therapy (Consolidation A), otherwise they will 
receive augmented  RICE consolidation therapy (Consolidation B). An additional 
component of this study is that patients will receive a FDG-PET scan and biopsy interim 
evaluation.  Patients that are biopsy positive will not receive Consolidation A or B. 
Instead they will receive consolidation C, which is augmented  RICE followed  by a 
HDT/ASCT consolidation therapy, or alllogeneic  stem celll      transplant  if a patient’s bone 
marrow remains positive  after induction therapy and they have an acceptable HLA match 
donor. 
 
The primary outcome of this study is remaining alive  and progression free for two years 
from the start of induction therapy conditional on attaining either a negative  FDG-PET or 
a negative  biopsy at the interim evaluation.  The probability of this outcome will be 
evaluated separately in the Ki-67 <80 cohort (Consolidation A) and the Ki-67 ≥80 cohort 
(Consolidation B). All patients that do not experience the progression free survival 
endpoint and have a negative  biopsy at the interim  evaluation will attempt to be followed 
for a minimum of 2 years from initiation of therapy on protocol.  Patients who have a 
negative  biopsy and are lost to follow  up prior to 2 years who are alive  will be counted as 
failures  for the primary endpoint. 
 
 
For Ki-67 <80 and either a negative  FDG-PET or a negative  biopsy at the interim 
evaluation,  the therapy will not be considered sufficiently active if the two year 
progression free survival probability is less than 0.80.  Fifty patients will be accrued to 
this cohort.  If at the end of the trial, 45 patients are alive and progression free at 24 
months (+/-2 months),  then this combination therapy will be considered promising in this 
patient population.   This design has a type 1 error equal to 0.05 and has power greater 
than 0.95 when the two-year progression free survival  probability is 0.95. 
 
 
For Ki-67 ≥80 and either a negative  FDG-PET or a negative  biopsy at the interim 
evaluation,  the therapy will not be considered sufficiently active if the two-year 
progression free survival probability is less than 0.50.  Twenty six patients will be 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 31 - 
 
 
 
 
accrued to this cohort.  If at the end of the trial, 17 patients are alive and progression free 
at 24 months (+/-2 months), then this combination therapy will be considered promising 
in this patient population.   This design has a type 1 error equal to 0.10 and has power 
greater than 0.90 when the two-year progression free survival probability is 0.75. 
 
At the conclusion of the study, within each study cohort, the probability of progression 
over time will be computed using the cumulative  incidence  function (competing risks 
methodology)  to account for patients removed from the follow-up  due to a positive 
biopsy at the interim evaluation.   In addition,  a competing risks regression model will be 
employed to explore the factors that are associated with the time to progression. 
 
Based on our experience in MSKCC 01-142, we expect an accrual of approximately 2 
patients per month; thus, the study will take approximately 44-48 months to complete. 
Enrollment will continue until 26 patients with high Ki-67 are enrolled, not necessarily 
stopping when 90 patients are accrued overall. 
 
Secondary endpoints: 
The reference radiologists  will evaluate all sites of disease on sequential imaging studies 
(pre-treatment,  after cycle 4, and at conclusion of therapy) in this research study.  The 
secondary endpoints will be evaluated in as many patients as possible (all consolidations, 
A, B and C, will be included). 
 
Functional  imaging: 
Patients will undergo FDG PET/CT at baseline, after cycle 4 of chemotherapy and after 
the end of treatment.   Diagnostic  CT will also be obtained at these time points.  In 
contrast, FLT PET/CT will be done at baseline  and after cycle 1 or cycle 2 of 
chemotherapy,  for the first 60 patients who undergo the FLT-PET scan.  The remaining 
30 patients to enroll on study will receive an additional FDG PET scan after cycle 2. 
In this protocol, we will obtain preliminary data on biodistribution,  and potential clinical 
usefulness  of the proliferation marker [18F] fluorothymidine  (FLT) in patients with 
diffuse  large cell lymphoma,  using combined positron emission tomography/computed 
tomography (FLT-PET/CT).   For the first 30 consecutive  patients, the FLT PET scans 
will be obtained at baseline (prior to therapy) and after cycle 1. After the first 30 patients 
are accrued to the study, an additional 30 patients (not necessarily consecutive)  will 
receive FLT PET scans at baseline  and after cycle 2 of chemotherapy.  We will study the 
biodistribution of FLT in large cell lymphoma  and changes in FLT distribution in 
response to chemotherapy.  The latter may provide first insights  into the potential clinical 
usefulness  of FLT in monitoring the response to chemotherapy in lymphoma.  Note, 
however, that FLT PET is exploratory only; that is, FLT findings  will not affect treatment 
decisions. 
FLT PET will be obtained as a dynamic  study, with image acquisition  for up to 40 min 
over one 15 cm field of view (for one ion more than one lesion(s)  identified  on previous 
CT scan and/or FDG PET). This will be followed  by a whole body scan from the skull 
base to at least the upper thigh (further  extending if disease more distally was found 
clinically or on the prior FDG PET study). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 32 - 
 
 
 
 
In the analysis,  we will correlate FLT findings  with CT and FDG PET findings  (e.g., does 
uptake occur in all lesions seen on CT and/or FDG PET, and what is the intensity of such 
uptake in a given organ (e.g., liver versus lung)  and in comparison to FDG uptake). A  
two sample non-parametric  test will be used to assess whether  there is a difference  in  
FLT SUV after the first or second cycle of chemotherapy,  or in the degree of decline in 
FLT uptake (baseline  → post cycle 1 or post cycle 2), between groups of patients with 
response on CT and/or FDG PET after cycle 4 of chemotherapy.  The correlation between 
FLT and FDG SUV uptake will be assessed via Spearman rank correlation coefficient. 
We will correlate the degree of Ki-67 staining at baseline  with FLT uptake in the baseline 
scan and the improvement  on FLT scan done between baseline and cycle 1 or between 
the baseline scan and cycle 2 . We will also investigate  if changes in FLT uptake  
(baseline  → post cycle 1 or 2) correlate with ultimate  patient outcome (DFS; binary 
outcome). 
 
The data analysis  equipment  and software for nuclear medicine  imaging is continuously 
changing and evolving.  As new imaging analysis  methods are developed, we will apply 
those that are optimal to the imaging purpose, including automated and semi-automated 
determination of quantitative  measures such as standardized  uptake values (SUV), 
location and extent of lesion, site within the body, gating lesion motion to 
respiration/pulse,  and all other kinetic approaches to determine  uptake. 
 
CT Volumetric  Analysis: 
To determine  the role of CT volumetric  analysis  compared to standard CT in this patient 
population.   We will explore the relative  tumor burden determined  following means: 
unidimensional  measurements  of the largest cross-sectional dimension;  sum of the 
products of the maximal perpendicular  cross-sectional measurements;  volumetric  sum of 
lymph node masses.  These measurements  will be determined  at baseline  whenever 
possible, after 4 cycles of therapy and at the end of therapy.  The three CT volumetric 
measurements  will be compared via the ranked based Friedman's test for paired data. 
 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
Patients wishing to enroll will be registered after signing an informed  consent. 
 
 
15.2 Research Participant  Registration 
 
Confirm eligibility as defined in the section entitled  Criteria for Patient/Subject 
Eligibility. 
 
Obtain informed  consent, by following procedures defined in section entitled  Informed 
Consent Procedures. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 33 - 
 
 
 
 
During the registration process registering individuals  will be required to complete a 
protocol specific  Eligibility  Checklist. 
 
All participants  must be registered through the Protocol Participant  Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available  Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. The PPR fax numbers are (646) 735- 
0008 and (646) 735-0003. Registrations  can be phoned in or faxed. The completed 
signature  page of the written consent/verbal script and a completed Eligibility Checklist 
must be faxed to PPR. 
 
16.1 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study.  The 
responsibilities  of the RSA include  project compliance,  data collection,  abstraction and 
entry, data reporting, regulatory monitoring,  problem resolution and prioritization and to 
coordinate the activities  of the protocol study team. 
The data collected for this study will be entered into a secure database.  Source 
documentation will be available  to support the computerized  patient record. 
Data to be collected will include:  FDG-PET scan results, CR, PR and failure  rates, 
CD34+ cell yields,  toxicities  of treatment, and duration of treatment. 
 
16.2 Quality Assurance 
 
Weekly registration reports will be generated to monitor  patient accruals and 
completeness  of registration data.  Routine  data quality reports will be generated to assess 
missing data and inconsistencies.   Accrual rates, extent,  and accuracy of evaluations  and 
follow-up  will be monitored  periodically throughout  the study period and potential 
problems will be brought to the attention of the study team for discussion and action. 
Random-sample  data quality and protocol compliance  audits will be conducted by the 
study team, at a minimum  of two times per year, more frequently if indicated. 
 
Retention of Records: All documentation of adverse events, records of study drug receipt 
and dispensation,  and all IRB/PB correspondence will be retained for at least 2 years after 
the investigation is completed. 
 
16.3 Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering 
Cancer Center were approved by the National Cancer Institute  in September 2001. The 
plans address the new policies  set forth by the NCI in the document entitled  “Policy of 
the National Cancer Institute  for Data and Safety Monitoring of Clinical Trials” which 
can be found at:  http://cance rtria ls. nc i. nih. go v/researc hers/dsm/inde x. html.   The DSM 
Plans at MSKCC were established  and are monitored  by the Office of Clinical Research. 
The MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at:  
http://msk web2.msk cc.org/irb/index .htm 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 34 - 
 
 
 
 
There are several different  mechanisms  by which clinical  trials are monitored  for data, 
safety and quality.   There are institutional processes in place for quality assurance (e.g., 
protocol monitoring,  compliance  and data verification audits, therapeutic  response, and 
staff education on clinical  research QA) and departmental procedures for quality control, 
and there are two institutional committees  that are responsible  for monitoring the 
activities  of our clinical  trials programs.  The committees:  Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical  trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board. 
 
 
During the protocol development  and review process, each protocol will be assessed for 
its level of risk and degree of monitoring required.  Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be 
addressed and the monitoring procedures will be established  at the time of protocol 
activation. 
 
17.1 
PROTECTION  OF HUMAN SUBJECTS 
Potential Risks 
Potential risks and adverse events associated with this trial include:  fever, chills,  asthenia, 
hypotension,  anaphylaxis,  tumor lysis syndrome, death, CNS toxicity,  microscopic  and 
gross hematuria,  nausea, vomiting,  alopecia, cardiotoxicity,  neutropenia,  febrile 
neutropenia,  thrombocytopenia,  anemia, peripheral neuropathy,  ototoxicity,  hepatic 
toxicity,  renal insufficiency,  electrolyte  abnormalities,  allergic  reactions, teratogenicity, 
pneumothorax,  deep venous thrombosis,  and catheter-related  sepsis. 
 
 
Mild to moderate medullary bone pain is the most common side effect associated with G- 
CSF therapy and occurs in approximately 20-25% of patients. It is effectively treated 
with non-narcotic  analgesics.   Other side effects include  transient  and reversible  changes 
in alkaline  phosphatase, uric acid, and LDH. Exacerbation of pre-existing autoimmune 
disorders, subclinical splenomegaly,  alopecia, and cutaneous vasculitis  are rarely 
reported. 
 
Potential Benefits 
 
Patients who achieve a CR with CHOP chemotherapy do significantly better than those 
patients who fail upfront therapy.  Patients on this trial may have a higher  probability of 
achieving a CR than they would with standard CHOP and therefore may have a longer 
relapse-free and overall survival. 
 
Provisions for preventing and treating adverse events 
 
Treatment  of febrile  neutropenia,  cytopenias,  ifosfamide-related  gross and microscopic 
hematuria,  and catheter related sepsis, thrombosis,  and pneumothorax will be in 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 35 - 
 
 
 
 
accordance with standard medical practices employed at MSKCC. Rituximab 
administration will be premedicated  with acetaminophen,  Diphenhydramine,  and Ativan 
in order to prevent infusion-related  adverse effects.   Infusion will be titrated as tolerated 
as described in section 5.0. In the event of an adverse reaction,  the infusion will be 
stopped, the patient will be assessed and treatment  will be administered  in accordance 
with standard medical practice. 
Patients will receive standard anti-emetics  as prophylaxis  against  nausea and vomiting. 
 
Alternatives/Options  for treatment 
 
For patients eligible,  alternative  therapy would consist of CHOP in standard dosing, in an 
accelerated fashion,  or R-CHOP 
 
Costs 
 
The patient will be responsible  for all costs related to treatment  and complications  of 
treatment, including G-CSF, pegfilgrastim,  and all hospitalizations. FLT is 
investigational and the patients will not pay for the FLT scans. 
 
Privacy and confidentiality 
 
Confidentiality will be maintained  within the limits  of the law.  Only qualified 
individuals  from MSKCC; the National Cancer Institute;  the FDA; Genentech;  will be 
able to review patients' medical records.  Neither the patients' names nor other identifying 
information will be used in reports or publications  arising from this study. 
17.2 Privacy 
 
MSKCC’s Privacy Office may a lllow the use and disclosure of protected 
health information pursuant to a completed and signed Research Authorization form. 
The use and disclosure of protected health information will be limited to the individuals 
described in the Research Authorization form. A Research Authorization form must be 
completed by the Principal Investigator  and approved by the IRB and Privacy Board. 
17.3 Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be 
submitted  electronically to the SAE Office at sae@mskcc.org containing the following 
information: 
Fields populated from the CRDB: 
• 
Subject’s name (generate the report with only initia ls  if it will be sent outside 
of MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 36 - 
 
 
 
 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship  of the adverse event to the treatment  (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes  the following information: 
o An explanation of how the AE was handled  
o A description of the subject's condition 
o Indication  if the subject remains on the study 
o If an amendment  will need to be made to the protocol and/or consent form 
 
The PI’s signature  and the date it was signed are required on the completed report.  
For IND/IDE protocols: 
The CRDB AE report should be completed  as above and the FDA assigned IND/IDE 
number written at the top of the report. If appropriate, the report will be forwarded to the 
FDA by the SAE staff through the IND Office 
 
In the event of an adverse event, the first concern will be for the safety of the subject. 
Investigators  are required to report all serious adverse events, regardless of causality to 
rituximab,  whether expected or unexpected, to Genentech Drug Safety and the IRB/PB. 
 
All serious adverse events meeting these criteria will be reported for the time period 
beginning with any amount of exposure to rituximab  through the protocol-defined 
follow-up  period (i.e., 30 days since last treatment  on protocol).  Serious criteria, 
definitions,  and guidance for reporting follow. 
 
An adverse event (AE) is any untoward medical occurrence in a subject participating in 
an investigational trial or protocol regardless of causality assessment.  An adverse event 
can be an unfavorable  and unintended  sign (including an abnormal laboratory finding), 
symptom,  syndrome or disease associated with or occurring during the use of an 
investigational product whether or not considered related to the investigational  product. 
 
Serious adverse events (SAE) are adverse events occurring at any dose which meet one 
or more of the following  serious criteria: 
 
• Results in death (i.e. the AE caused or lead to death) 
 
• Is life-threatening (i.e. the AE placed the subject at immediate risk of death; it does 
not apply to an AE which hypothetically might have caused the death if it were more 
severe) 
 
• Requires or prolongs inpatient  hospitalization  (i.e. the AE required at least a 24-hour 
inpatient  hospitalization or prolonged a hospitalization beyond the expected length of 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 37 - 
 
 
 
 
stay; hospitalizations  for elective  medical/surgical  procedures, scheduled treatments, 
or routine  check-ups are not SAEs by this criterion).   Hospitalizations  for 
uncomplicated  febrile  neutropenia  do not need to be reported as SAEs. 
 
• Is disabling (i.e. the AE resulted in a substantial disruption of the subject’s ability to 
carry out normal life functions) 
 
• Is a congenital anomaly/birth  defect (i.e., an adverse outcome in a child or fetus of a 
subject exposed to the trial drug prior to conception or during pregnancy) 
 
• It does not meet any of the above serious criteria  but may jeopardize  the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed 
above 
 
SAEs include  any sign, symptom or medical condition that meets any of the above 
criteria and emerges during rituximab  treatment or during a post-treatment  follow-up 
period that (1) was not present at the start of treatment  and is not a chronic  condition that 
is part of the patient’s  medical history,  OR (2) was present at the start of treatment or as 
part of the patient’s medical history but worsened in severity and/or frequency during 
therapy. 
 
Expected adverse events are those adverse events that are listed in section 5.0, section 
11.1 or characterized  in the current Investigator  Brochure. 
 
Unexpected adverse events are those not listed in section 5.0, section 11.0, the current 
Investigator  Brochure or not identified.   This includes  adverse events for which the 
specificity or severity is not consistent  with the description in the Investigator  Brochure. 
For example, under this definition,  hepatic necrosis would be unexpected if the 
Investigator  Brochure only referred to elevated hepatic enzymes  or hepatitis. 
 
Attribution:  All serious adverse events will be graded according to CTCAE version 3.0 
and willl      be recorded in MSKCC’s CRDB database and reported to the IRB/PB.  The 
following categories and definitions  of causal relationship  to treatment  intervention as 
determined  by the physician will be used: 
• Definite:  The SAE is clearly related to treatment intervention 
• Probable: The SAE is likely related to treatment intervention 
• Possible: The SAE may be related to treatment intervention 
• Unlikely: The SAE is doubtfully related to treatment intervention 
• Unrelated: The SAE is clearly NOT related to treatment intervention 
 
Reportable events are those which occur within 30 days from the last day of treatment on 
protocol. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 38 - 
 
 
 
 
Reporting of Serious Adverse Events Associated with Rituximab 
 
All serious adverse events (SAEs) outlined above that we will be reporting, regardless of 
causality to rituximab should be recorded on the institution’s own Serious Adverse Event 
report form (with patient identifying information removed with the exception of D.O.B., 
initials,  subject number) and faxed to: 
 
Genentech Drug Safety 
Tel: 
(888) 835-2555 
Fax: 
(650) 225-4682 or (650) 225-4683 
 
(Please use the safety reporting fax cover sheet attached to this document for your fax 
transmission.) 
 
Follow-up  information: 
 
Additional information may be added to a previously submitted  report by any of the 
following methods: 
 
• Adding to the original  report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow- up  with the 
original  form 
• Summarizing new information  and faxing it with a cover letter including subject 
identifiers  (i.e. D.O.B. initial,  subject number),  protocol description and number, if 
assigned, suspect drug, brief adverse event description,  and notation that additional or 
follow-up  information is being submitted   (The patient identifiers  are important  so 
that the new information is added to the correct initial  report) 
 
Occasionally Genentech may contact the reporter for additional information,  clarification, 
or current status of the subject for whom and adverse event was reported.  For questions 
regarding SAE reporting, you may contact the Genentech Drug Safety representative 
noted above. 
 
Study Drug Relationship: 
 
The investigator  will determine  which events are associated with the use of the study 
drugs.  For reporting purposes, an AE should be regarded as possibly related to the use of 
the investigational  product if the investigato r  believes: 
 
• There is a clinically plausible  time sequence between onset of the AE and rituximab 
administration;  and/or 
• There is a biologically plausible  mechanism for rituximab  causing or contributing to 
the AE; and 
• The AE cannot be attributed solely to concurrent/underlying illness,  other drugs, or 
procedures. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 39 - 
 
 
 
 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified  procedures are carried out, consenting  professionals  will 
explain full details of the protocol and study procedures as well as the risks involved  to 
participants  prior to their inclusion in the study. Participants  will also be informed  that 
they are free to withdraw  from the study at any time. All participants  must sign an 
IRB/PB-approved consent form indicating their consent to participate.  This consent form 
meets the requirements  of the Code of Federal Regulations  and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include  the following: 
 
1. 
The nature and objectives, potential risks and benefits  of the intended study. 
2. 
The length of study and the likely follow-up  required. 
3. 
Alternatives  to the proposed study. (This will include  available  standard and 
investigational therapies. In addition,  patients will be offered an option of 
supportive  care for therapeutic  studies.) 
4. 
The name of the investigator(s)  responsible  for the protocol. 
5. 
The right of the participant  to accept or refuse study interventions/interactions  and 
to withdraw  from participation at any time. 
Before any protocol-specific  procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific  information. 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed  consent form. 
 
Each participant  and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed  consent form. 
 
19.1 
REFERENCES 
 
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Apisarnthanarax,  S., M. M. Alauddin,  et al. (2006). "Early detection of 
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IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 40 - 
 
 
 
 
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Barditch-Crovo PA, Petty BG, Baron PA, Armstrong D, et al. (1994) "Relationship 
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Habermann, T. M., E. A. Weller, et al. (2006). "Rituximab-CHOP versus CHOP alone or 
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Hamlin,  P. A., C. S. Portlock, et al. (2004). "Primary Mediastinal  Large B Cell 
Lymphoma: Elucidating Optimal Therapy and Prognostic Factors; an Analysis  in 141 
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Hamlin,  P. A., A. D. Zelenetz,  et al. (2003). "Age-adjusted International Prognostic  Index 
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Hans, C. P., D. D. Weisenburger,  et al. (2004). "Confirmation of the molecular 
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IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 41 - 
 
 
 
 
 
 
Moskowitz CH, H. P., Horwitz SA et al ( 2006 ). "Phase II Trial of Dose-Dense R-CHOP 
Followed by Risk-Adapted Consolidation with Either ICE or ICE and ASCT, Based upon 
the Results of Biopsy Confirmed  Abnormal Interim Restaging PET Scan, Improves 
Outcome in Patients with Advanced Stage DLBCL." Blood 108: 532. 
 
Pfreundschuh,  M., L. Trumper, et al. (2006). "CHOP-like chemotherapy plus rituximab 
versus CHOP-like chemotherapy alone in young patients with good-prognosis  diffuse 
large-B-cell lymphoma: a randomised  controlled  trial by the MabThera International 
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Rasey, J. S., J. R. Grierson, et al. (2002). "Validation of FLT uptake as a measure of 
thymidine  kinase-1 activity in A549 carcinoma  cells." J Nucl Med 43(9): 1210-7. 
 
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survival  after chemotherapy for diffuse  large-B-cell lymphoma." N Engl J Med 346(25): 
1937-47. 
 
Rosenwald, A., G. Wright,  et al. (2003). "Molecular  diagnosis  of primary mediastinal B 
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Savage, K. J., S. Monti, et al. (2003). "The molecular  signature  of mediastinal large B- 
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features with classical Hodgkin lymphoma."  Blood 102(12): 3871-9. 
 
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Seitz, U., M. Wagner, et al. (2001). "In vivo evaluation of 5-[(18)F]fluoro-2'- 
deoxyuridine  as tracer for positron emission tomography in a murine  pancreatic cancer 
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Vesselle, H., J. Grierson, et al. (2002). "In vivo validation of 3'deoxy-3'- 
[(18)F]fluorothymidine  ([(18)F]FLT) as a proliferation imaging tracer in humans: 
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immunohistochemistry and flow cytometry in human lung tumors."  Clin Cancer Res 
8(11): 3315-23. 
 
Vesselle,  H., J. Grierson, et al. (2003). "18F-Fluorothymidine  radiation dosimetry in 
human PET imaging studies."  J Nucl Med 44(9): 1482-8. 
 
Wagner, M., U. Seitz, et al. (2003). "3'-[18F]fluoro-3'-deoxythymidine  ([18F]-FLT) as 
positron emission tomography tracer for imaging proliferation in a murine  B-Cell 
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Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 42 - 
 
 
 
 
 
 
Haioun et al (2001) Tandem autotransplant  as first-line  consolidative  treatment in poor- 
risk aggressive  lymphoma:  A pilot study of 36 patients.  Annals of Oncology 12: 1749- 
1755. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20.0 
APPENDIX 1 
Absorbed Doses 
(1) 
1 FLT PET-CT 
2 FLT PET- 
CT 
3 FLT PET- 
CT 
1 * 8 m Ci 
0.9 rad (2) + 
2 * 0.9 rad + 
3 * 0.90 rad + 
3 * 8 m Ci 
F18-FLT1 
FLT 
8 m Ci FLT 
2 * 8 m Ci FLT 
FLT 
Target Organ 
rad/m Ci 
rad 
rad 
rad 
rad 
Adrenals 
0.08 
0.61 
1.51 
3.03 
4.54 
Bone Surfaces 
0.06 
0.47 
1.37 
2.74 
4.10 
Brain 
0.01 
0.10 
1.00 
. 
2.00 
3.00 
Breasts 
0.03 
0.25 
1.15 
2.30 
3.45 
Gall Bladder Wall 
0.06 
0.50 
1.40 
2.80 
4.20 
Heart Wall 
0.06 
0.49 
1.39 
2.79 
4.18 
Kidneys 
0.13 
1.05 
1.95 
3.91 
5.86 
Large Intestine - Lower Wall 
0.02 
0.13 
1.03 
2.07 
3.10 
Large Intestine - Upper Wall 
0.05 
0.37 
1.27 
2.53 
3.80 
Lens of Eye 
0.04 
0.31 
1.21 
2.42 
3.63 
Liver 
0.17 
1.34 
2.24 
4.49 
6.73 
Lungs 
0.04 
0.30 
1.20 
2.40 
3.60 
Muscle / Other tissue 
0.06 
0.50 
1.40 
2.79 
4.19 
Pancreas 
0.09 
0.68 
1.58 
3.16 
4.74 
Red Marrow 
0.09 
0.71 
1.61 
3.22 
4.83 
Skin 
0.02 
0.13 
1.03 
2.06 
3.09 
Small Intestine 
0.05 
0.42 
1.32 
2.64 
3.96 
Stomach Wall 
0.05 
0.42 
1.32 
2.63 
3.95 
Testes 
0.05 
0.39 
1.29 
2.58 
3.87 
Thyroid 
0.04 
0.31 
1.21 
2.42 
3.62 
Total Body 
0.05 
0.37 
1.27 
2.55 
3.82 
Urinary Bladder Wall 
0.00 
45-min Voiding Interval 
0.03 
0.24 
1.14 
2.27 
3.41 
1-hr Voiding Interval 
0.04 
0.32 
1.22 
2.43 
3.65 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 43 - 
 
 
 
 
 
1.5-hr Voiding Interval 
0.06 
0.47 
1.37 
2.75 
4.12 
2-hr Voiding Interval 
0.08 
0.63 
1.53 
3.07 
4.60 
Effective Dose Equivalent 
("rem") 
0.10 
1.04 
1.94 
3.87 
5.81 
REFERENCES 
1. Vesselle et al. J Nucl Med 44: 1482-1488, 2003. 
2. Wu et al. Eur J Nucl Med Mol Imaging 31:38-43, 2004. 
21.1 APPENDIX 2 
 
21.2 Treatment Timeline: Screening Period 
 
a. 
FLT-PET/CT   scans will be performed  under an IND 
b. 
Creatinine clearance only if serum Cr> 1.5 mg/dl 
c. 
Documentation of HIV seronegativity mus t be performed  at MSKCC. 
d. 
A tissue biopsy confirming  the Diffuse Large  B Cell Lymphoma  diagnosis. Results must be 
 
Treatment 
Screening 
Visit 
Prior to ICE 
administration 
Within one month 
of treatment 
initiation 
Within 2 weeks 
treatment of 
initiation 
Hepatitis  B surface antigen & core antibody 
X 
Hepatitis  C antibody 
X 
Echocardiogram  or MUGA 
X 
Ki-67 Staining of tumor 
X 
Tissue blocks or 10 unstained  slides 
X 
HIV testc 
X 
CT Scan of Chest/Abdomen/Pelvisf 
X 
FDG-PET/CT scan 
X 
FLT-PET/CT scang 
Xa 
Bilateral Bone Marrow Biopsyh 
X 
Creatinine  Clearance 
Xb 
Complete history 
X 
Physical Exam 
X 
CBC w/ differential 
X 
Comprehensive  Metabolic Panel 
X 
Urinalysis 
X 
Pregnancy  Teste 
X 
EKG 
X 
confirmed  by MSKCC 
e. 
Pregnancy test in pre-menopausal women only 
f. 
The CT scan should be done with volumetric  analysis when possible 
g. 
Unless not required per protocol 
h. 
Bilateral  bone marrow biopsy not required if unilateral bone marrow  biopsy don e within 4 weeks 
prior to treatment initiation shows involvement by lymphoma 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
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21.3 Treatment Timeline for Induction  and Interim Restaging 
 
 
 
Treatment 
Induction 
Interim 
Restaging 
Visit 
Cycles 1- 
3, Day -2d 
Cycles 1- 
3, Day 0 
Cycles 1- 
3, Day 2 
Cycles 1- 
3, Days 
6-10 
PO ST 
cycle 1 or 
Cycle 2 
Cycle 
4f Day 
0 
Cycle 4 
Days 0- 
4 
Cycle 4 
Days 6- 
10 
Cycle 4 Days 
17-20 
CT Scan of 
Chest/Abdomen/ 
Pelvisi 
X 
FDG-PET/CT   scan 
X 
FLT-PET/CT 
Xa, b, c 
Bilateral  Bone 
Marrow Biopsy 
Xg 
Physical Exam 
X 
X 
CBC w/ differential 
X 
X 
Rituximab   375 
mg/m2   IVPB 
Xj 
X 
Xj 
Cyclophosphamide 
1000  mg/m2  IVPB 
X 
X 
Doxorubicin  50 
mg/m2  IVPB 
X 
X 
Vincristine  1.4 
mg/m2  IVP (no cap) 
X 
X 
Prednisone 100 mg 
PO daily for 5 days 
X 
X 
Growth  Factor 
Supporte 
X 
X 
Antimicrobial 
Prophylaxish 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a. 
FLT-PET/CT  scans will be performed  under an  FDA IND. 
b. 
The FLT-PET  scan should be performed  after completion of prednisone in cycle 1 or cycle 2 and 
before the first dose of Rituximab   in cycle 2 of induction therapy.  The first 30 consecutive 
patients on study had the FLT PET scan after cycle 1; the next 30 who have an FLT PET  scan will 
have  their FLT PET scan after cycle 2. 
c. 
Only 60 patients will  receive FLT-PET   scan. For the subsequent 30 patients who enroll on study, 
FLT-PET  scan at baseline and after cycle 2 will not be done and will be replaced with an FDG- 
PET scan after cycle 2. 
d. 
Day 0 of next cycle is Day 14 as long as ANC > 1000 and platelets > 50,000. 
e. 
SQ at either 300ug/day or 480 ug/day OR Pegfilgrastim 6 mg  once 24-48  hrs post completion of 
intravenous  chemotherapy. 
f. 
Cycle 4 will  last 21 days. 
g. 
Bilateral  Bone Biopsy for patients with a positive scan only, can be done at any point post-therapy 
in cycle 4. Only unilateral biopsy required at interim if unilateral biopsy at baseline showed 
involvement by lymphoma. 
h. 
Trimethoprim/Sulfametho xa zole   160/800  (DS)  oral twice daily TIW (patients with known allergy 
to Trimethoprim/Sulfamethoxa zole   can receive alternative pneumocystis carinii prophylaxis), 
Acyclovir 400 mg oral bid, and Fluconazole 100  mg oral qd 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 45 - 
 
 
 
 
 
i. 
The CT scan must be done with volumetric  analysis 
j. 
Rituximab   is to be given EITHER  on Day -2 or Day 2, not on both days. 
 
21.4 Treatment Timeline for Consolidation A 
 
 
Treatment 
Consolidation A1, 2 
Visit 
Cycles 1-3, 
Day 1 
Cycles 1-3, 
Day 2 
Cycles 1-3, 
Day 3 
Cycles 1-3, 
Day 4 
Cycles 1-3, 24- 
48 hours post 
completion of 
chemotherapy 
4-6 weeks 
post 
completion 
of cycle 3 
Physical 
Exam 
X 
CBC 
X 
Etoposide 
100 mg/m2 
IVPB 
X 
X 
X 
Carboplatin 
AUC 5 
IVPB3 
X 
Ifosfamide  5 
g/m2  with 
MESNA 5 
g/m2  IVCI4 
X 
Pegfilgrastim 
6 mg 
X 
CT scan6 
X 
FDG PET 
scan 
X 
Antimicrobial 
Prophylaxis5 
X 
X 
X 
X 
X 
X 
1. 
Consolidation A: Patients whose disease is FDG-PET negative or patients whose FDG-PET scan is 
positive but repeat biopsy is negative and whose initial Ki-67 expression is ≥80% will receive 3 
cycles of standard dose ICE Chemotherapy. 
2. 
Patients must  have a platelet  count of 50,000/ul  and an ANC  of at least 1000/ul  to proceed to 
subsequent cycles of ICE. 
3. 
Maximum  dose 800 mg (equivalent to CrCl  of 135 ml/min).  AUC dosing is calculated by the Calvert 
Formula: AUC 5 = 5 x (CrCl+25) 
4. 
Ifosfamide 5 g/m2  admixed  with MESNA  5 g/m2 IVCI  over 24 hours beginning on Day 2. 
5. 
Trimethoprim/Sulfametho xa zole   160/800  (DS)  oral twice daily TIW (patients with known allergy 
to Trimethoprim/Sulfamethoxa zole   can receive alternative pneumocystis carinii prophylaxis), 
Acyclovir 400 mg oral bid, and Fluconazole 100  mg oral qd 
6. 
The CT scan must be done with volumetric  analysis 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 46 - 
 
 
 
 
21.5 Treatment Timeline for Consolidation B 
 
 
 
1. 
Consolidation B: Patients whose disease is FDG-PET negative or patients whose FDG-PET scan is 
positive but repeat biopsy is negative and whose initial Ki-67  expression is ≥80 will receive 2 cycles 
of augmented RICE  Chemotherapy (as per MSKCC  protocol 03-075) 
2. 
Patients must  have a platelet  count of 50,000/ul  and an ANC  of at least 1000/ul  to proceed to 
subsequent cycles of ICE. 
3. 
Etoposide is administered every 12 hours starting on day 4. 
4. 
Maximum  dose 800 mg (equivalent to CrCl  of 135 ml/min).  AUC dosing is calculated by the Calvert 
Formula: AUC 5 = 5 x (CrCl+25) 
5. 
Ifosfamide 5 g/m2  admixed  with MESNA  5 g/m2 IVCI  over 24 hours beginning on Day 4. 
6. 
Trimethoprim/Sulfametho xa zole   160/800  (DS)  oral twice daily TIW (patients with known allergy 
to Trimethoprim/Sulfamethoxa zole   can receive alternative pneumocystis carinii prophylaxis), 
Acyclovir 400 mg oral bid, and Fluconazole 100  mg oral qd 
7. 
The CT scan must be done with volumetric  analysis 
Treatment 
Consolidation B1, 2 
Visit 
Cycles 1-2, 
Day 1 
Cycles 1- 
2, 
Day 3 
Cycles 1- 
2, Day 4 
Cycles 1- 
2, Day 6 
Cycles 1-2, 
24-48  hours 
post 
completion of 
cycle 
4-6 weeks 
post 
completion 
of cycle 2 
Physical 
Exam 
X 
CBC 
X 
Etoposide 
100 mg/m2 
IVPB 
X 
Carboplatin 
AUC 5 
IVPB4 
X 
Ifosfamide  5 
g/m2  with 
MESNA 5 
g/m2  IVCI5 
X 
Pegfilgrastim 
6 mg 
X 
Rituximab 
375 mg/m2 
IVPB 
X 
X 
CT scan7 
X 
FDG-PET 
scan 
X 
Antimicrobial 
Prophylaxis6 
X 
X 
X 
X 
X 
X 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 47 - 
 
 
 
 
21.6 Treatment Timeline for Consolidation C 
 
 
Treatment 
Consolidation  C1, 2  Part I 
Part II 
Part III 
Visit 
Cycles 
1-2, 
Day 1 
Cycles 
1-2, 
Day 3 
Cycles 
1-2, 
Day 4 
Cycles 
1-2, 
Day 6 
Cycles 1- 
2, 24-48 
hours post 
completion 
of cycle 
Stem cell 
collection, 
post cycle 
213 
Stem  Cell 
Transplant 
& 
Post 
transplant 
Physical Exam 
X 
CBC 
X 
Etoposide 100 
mg/m2  IVPB3 
X 
Carboplatin AUC 
5 IVPB4 
X 
Ifosfamide  5 g/m2 
with MESNA 5 
g/m2  IVCI5 
X 
Pegfilgrastim 6 mg 
X 
Rituximab  375 
mg/m2   IVPB 
X 
X 
X10 
FDG-PET Scan 
X8 
CT scan11 
X8 
Leukapheresis 
X6 
High dose 
chemoradiotherapy 
and ASCT7 
X 
Bone Marrow 
Biopsy 
X9 
Antimicrobial 
Prophylaxis12 
X 
X 
X 
X 
X 
X 
X 
1. 
Consolidation B: Patients whose disease is FDG-PET negative or patients whose FDG-PET scan is 
positive but repeat biopsy is negative and whose initial Ki-67  expression is ≥80 will receive 2 cycles 
of augmented RICE  Chemotherapy (as per MSKCC  protocol 03-075) 
2. 
Patients must  have a platelet  count of 50,000/ul  and an ANC  of at least 1000/ul  to proceed to 
subsequent cycles of ICE. 
3. 
Etoposide is administered every 12 hours starting on day 4. 
4. 
Maximum  dose 800 mg (equivalent to CrCl  of 135 ml/min).  AUC dosing is calculated by the Calvert 
Formula: AUC 5 = 5 x (CrCl+25) 
5. 
Ifosfamide 5 g/m2  admixed  with MESNA  5 g/m2 IVCI  over 24 hours beginning on Day 4. 
6. 
The target yield for leukapheresis will  be 5x106    CD34+  cells/kg.   Leukaphereses will  continue for 
up to 5 days until the target yield is reached. 
7. Patients will  be eligible to receive IFRT  if clinically  indicated beginning 2 weeks prior to initiation 
of high  dose chemotherapy. (CBV-N)   it will  be administered  as follows: 
Mitoxantrone (45 mg/m2)  IVPB x 1 on day – 8 
Carmustine (300 mg/m2) IVPB  x 1 on day – 4 
Cyclophosphamide (1500  mg/m2)  IVPB  daily x 4 days on day – 7, - 6, - 5, - 4 
Etoposide (250 mg/m2)  IVPB  daily x 4 days on day – 7, - 6, - 5, - 4 
PBPC  will  be infused approximately  24-48  hours after completion  of chemotherapy (day 0). 
8. 90-120  Days after high dose therapy. 
9. Only necessary if patient had a positive bone marrow  biopsy at restaging. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-026 A(15) 
Approval date: 06-Nov-2019 
- 48 - 
 
 
 
 
 
10. No later than Day +35 post ASCT patients will receive rituximab   bimonthly for 6 doses. 
11. The CT scan must be done with volumetric  analysis 
12. Antimicrobial  prophylaxis for Augmented RICEx2  is the same as specified in Consolidation B. 
Antimicrobial  prophylaxis for transplant phase: On admission: Ciprofloxacin  500 mg  PO b.i.d. 
(continue until the patient requires broad spectrum antibiotics for neutropenic fever) Fluconazole 
100 mg PO or IV b.i.d. (continue until the ANC is > 1000/mm3  X 3 days or until amphotericin B 
therapy is initiated). Nystatin powder applied to the groin and the axilla  BID Vitamin  K 10 mg PO 
or sc. one to three times per week unless added to TPN.  Day +5 : G-CSF  480 ug sc. QD ( 
continue until ANC > 1000/mm3   x 3 days.) 
13. Patients whose bone marrow  remain  positive at interim restaging will  also have the option of 
getting an allogeneic stem cell transplant, in lieu of an ASCT, if they have an acceptable HLA 
match donor.  The allogeneic stem cell transplant regimen  will  be decided by the MSK Bone 
Marrow Transplant Service