Phase I/II, Open-Label Study of R-ICE (Rituximab-Ifosfamide-Carboplatin-Etoposide) With Lenalidomide (R2-ICE) in Patients With First-Relapse/Primary Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Phase: PHASE1
Conditions: Recurrent B-Cell Non-Hodgkin Lymphoma, Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Recurrent Transformed Non-Hodgkin Lymphoma, Refractory B-Cell Non-Hodgkin Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Refractory Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Refractory Transformed Non-Hodgkin Lymphoma
Sponsor: Academic and Community Cancer Research United

 
                                                       1 
 
 
 
 
RU051417I 
Academic and Community Cancer Research United (ACCRU) 
 
Phase I/II, Open-Label Study of R-ICE (Rituximab-Ifosfamide-Carboplatin-Etoposide) with 
Lenalidomide (R2-ICE) in Patients with First-Relapse/Primary Refractory 
Diffuse Large B-Cell Lymphoma (DLBCL) 
 
For any communications regarding this protocol, 
please contact the protocol resource person on the following page. 
 
Study Chairs 
 
ACCRU: 
 
 
 
 
  
 
  
 
Study Cochairs: 
 
 
 
 
 
 
 
 
 
  Statistician: 
  
 
 
Drug Availability  
 
 
 
 
Commercial Agents: Rituximab, Ifosfamide, Carboplatin, Etoposide   
Drug Company Supplied: Lenalidomide (IND #060100) 
 
√ Study contributor(s) not responsible for patient care. 
 
 
Research Coordinating Center 
 
 
 
 
 
Document History 
 
Effective Date 
 
Pre-activation ACCRU 
 
November 20, 2015 
 
Activation ACCRU 
(Addendum 1) 
May 20, 2016 
Addendum 2 
July 29, 2016 
 

Addendum 2 
2  
RU051417I 
 
Protocol Resource 
 
Questions: 
Contact Name: 
Patient eligibility*, test schedule,  
treatment delays/interruptions/adjustments,  
dose modifications, adverse events, forms 
completion and submission 
 
 
 
   
  
Drug administration, infusion pumps,  
nursing guidelines 
 
  
 
Protocol document, consent form, 
regulatory issues 
 
   
  
Paraffin Embedded Tissue Pathology  
 
 
  
Non-paraffin Biospecimens  
 
 
 
 
   
 
 
Adverse 
Events 
(MedWatch, 
Non-AER, 
AML/MDS) 
 
  
 
 
*No waivers of eligibility per ACCRU 
 

Addendum 2 
3  
RU051417I 
 
Index 
 
Schema 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Grouping Factors  
  6.0 
Registration/ Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
 
Appendix I – Consent Form 
 
Appendix II - Image Submission Process 
 
 
Appendix III – Patient Medication Diary 
 

Addendum 2 
                                                 
 
4 
 
 
 
 
RU051417I 
 
Schema  
 
Prior to discussing protocol entry with the patient, call the ACCRU Registration Office (507-284-4130)  
for dose level and to insure that a place on the protocol is open to the patient. 
 
 
 
1See section 7.0 for drug administration and schedule 
2Cycle length = 21 days 
3 See section 18.0.  Patients may receive stem cell transplant (SCT) at physician discretion. If patient goes to SCT, it should be recorded on 
the event monitoring form.  
 
 
R2ICE x 2 cycles1,2 
 
Lenalidomide  
Rituximab 
Ifosfamide 
Carboplatin 
Etoposide  
Evaluation 
of overall 
response 
after 2 
cycles of 
therapy 
 
 
 
Option of another 1-2 
cycles1,2 of R2ICE at 
physician  discretion  
 
Event 
Monitoring3 
PMD at any time 
Unacceptable Adverse Event 
 
 
 
Event Monitoring3 
Patient Refusal  
Registration 

Addendum 2 
                                                 
 
5 
 
 
 
 
RU051417I 
 
 
Generic name: Lenalidomide 
 
Brand name(s): REVLIMID® 
ACCRU Abbreviation: REVLIMID    
  
Availability:   Investigational 
Generic name:  Carboplatin  
  
 
Brand name(s): Paraplatin 
ACCRU Abbreviation:   CBDCA 
  
Availability:   Commercial 
Generic name: Rituximab 
 
Brand name(s): Rituxan® 
ACCRU Abbreviation:   RITUX  
Availability:   Commercial 
Generic name: Etoposide or VP-16 
 
Brand name(s): Toposar® 
ACCRU Abbreviation:   VP16   
Availability:   Commercial 
Generic name:  Ifosfamide 
Brand name(s): Ifex® 
ACCRU Abbreviation:   IFOS   
Availability:   Commercial 
 
 
 
 

Addendum 2 
6  
RU051417I 
 
1.0 
Background   
 
1.1 
Diffuse Large B-Cell Lymphoma: First-Relapse/Primary-Refractory 
 
The first-relapse/primary-refractory diffuse large B-cell lymphomas (DLBCL) constitute at least a quarter 
of all patients with DLBCL. The majority of these are patients who relapse within the first 1.5 years of 
treatment. For patients with primary-refractory and first-relapse DLBCL, the response rate achieved prior 
to proceeding with a stem cell transplant (SCT) is a key variable. Usually this is an autologous stem cell 
transplant (ASCT).  ASCT can be potentially curative for these patients who tend to show 
chemosensitivity by achieving either a complete response (CR) or partial response (PR) with their salvage 
chemotherapy prior to the transplant (Kewalramani et al., 2004; Vacirca et al., 2014). Patients with CR 
tend to do better than patients who achieved PR after salvage chemotherapy. 
 
 
 
1.11 
Current Treatment Regimens for DLBCL: First-Relapse/Primary Refractory 
Treatment for relapsed/refractory disease has lacked a standard of care with a broad range of 
chemoimmunotherapy options (Witzig et al., 2015). The initial addition of rituximab to the 
ifosfamide-carboplatin-etoposide (ICE) regimen for patients with diffuse large B-cell lymphoma 
(DLBCL) lead to a significant improvement in the complete response (CR) and partial response 
(PR) rates (Kewalramani et al.,  2004). The overall response rate (ORR = CR + PR) to ICE alone 
is estimated to be around 70% (25-30% CR). The CR rate in the earlier study almost doubled to 
53% with R-ICE compared to 27% in historic controls who received ICE alone. R-ICE therefore 
became one of the most commonly used salvage treatment regimens for patients with primary-
refractory/first-relapse DLBCL (Table 1). Specifically with patients with first-relapse, the CR 
rates with R-ICE compared to ICE in historic cohorts are noted to be 65% versus 34%. The ORR 
was noted to be 96% versus 79% respectively (Kewalramani et al., 2004). 
Overall, the R-ICE salvage chemotherapy regimen is very well tolerated. Grade 3 and/or 4 
adverse events are infrequent (Kewalramani et al., 2004). Varied numbers of cycles of 
chemotherapy have been tried and proposed (Table 1). In some studies, 1 cycle of R-ICE was 
followed by conditioning with high dose chemotherapy and auto stem cell transplant (ASCT) 
(Stewart et al., 2011). The response rates in those settings, post 1 cycle of R-ICE, have been low 
(4 (6%) complete responses and 40 (63%) partial responses). Additionally, R-ICE chemotherapy 
does not lead to problems with stem cell mobilizations for patients needing an ASCT (Stewart et 
al., 2011). 
Furthermore, when designing future studies and looking at response rates of prior studies, it is 
important to note if the study focused on primary-refractory DLBCL, first-relapse DLBCL or 
both, since the response rates and biology of the two tend to be different (Kewalramani et al., 
2004). First-relapse DLBCL overall tend to do better as compared to patients with primary-
refractory DLBCL. In the CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma) 
study, the overall response rates in patients with relapsed versus refractory disease was 88% 
versus 46%; P < 0.001 (Gisselbrecht et al., 2010).   
 
 
 
 
 
 
 

Addendum 2 
7  
RU051417I 
 
Table 1: Response rates to different regimens in patients with primary refractory/relapse diffuse large B-cell 
lymphoma 
 
Regimen 
N 
CR 
PR 
ORR 
Study 
CORAL study 
R-ICE versus  
R-DHAP;  
3 cycles 
396 
202 vs. 
194 
 
-- 
-- 
62.8% 
vs. 
63.5% 
(Thieblemont  et al., 2011) 
 
R-ICE 
3 cycles 
  
75 
 
40% 
22% 
62% 
(Hernandez-Ilizaliturri et al., 2011) 
R-ICE  
3 cycles 
 
36 
53% 
25% 
78% 
(Kewalramani et al., 2004) 
 
R-ICE 
3 cycles 
32 
50% 
28.1% 
78.1% 
(Guo et al., 2014) Chinese Study 
R2-ICE 
Lenalidomide 
25 
mg-RICE  
(7 out of 14 days) – 
2 cycles 
 
15 
60% 
13% 
73% 
(Feldman et al., 2014) 
 
R-NIMP 
GOELAMS study1 
3 cycles 
 
50 
 
(20 
non-GCB 
versus  
9 GCB) 
44%
 
 
 
(40%  
vs.  
30%)  
22% 
 
(10%  
vs. 
56%) 
66% 
 
(50%  
vs. 
89%) 
 
(Gyan et al., 2013) 
R-Benda 
Every 28 days 
2 cycles 
  
61 
 
15.3% 
30.5% 
45.8% 
(Vacirca et al., 2014) 
GDP versus  
DHAP  
2 
cycles; 
Rituximab 
if 
B-
Cell lymphoma 
310 vs. 
309 
13.8 
vs. 
14.6 
32.3 vs. 
30.1 
 
46.1% 
vs. 
44.7% 
(Crump, 2014) 
ICE  
Nordic study  
3 cycles 
39 
17.9% 
41% 
59% 
(Jerkeman et al., 2004) 
Lenalidomide 
25 
mg  
(21 out of 28 days) 
2 cycles 
40 
 
(17 
non-GCB 
versus  
23 GCB) 
15% 
 
(29.4% 
vs. 
4.3%) 
12.5% 
 
(23.5% 
vs. 
4.3%) 
27.5% 
 
(53%  
vs.  
9%) 
 
(Hernandez-Ilizaliturri et al., 2011) 
 
 
 
 
1 Rituximab, vinorelbine, ifosfamide, mitoxantrone and prednisone; every 28 days 
   
 
 

Addendum 2 
8  
RU051417I 
 
The other point of interest in patients with DLBCL is the heterogeneity within this group of tumors (Gyan 
et al., 2013; Bellas et al., 2014) Based on gene expression profiling (GEP), DLBCL can be broadly 
divided into germinal center B-cell-like (GCB) and activated B-cell like (ABC) subtypes. The latter often 
referred to as the non-GCB subtype, tends to have a worse outcome (34% overall survival versus 76%; P 
< .001).(Hans et al., 2004) This is because some of the known prognostic variables (BCL2, BCL6 and 
MYC rearrangements) are present in the 2 different subtypes to varying degrees. (Thieblemont et al., 
2011) 
 
1.2 
Lenalidomide in Hematologic Malignancies and DLBCL 
 
Lenalidomide (REVLIMID, Celgene Corp., NJ, USA) is a proprietary IMiD™ compound. The 
mechanism of action of lenalidomide is complex and involves immune modulation (Haslett et al., 2003), 
antiangiogenic activity (Zhang et al., 2005) and impacts both the microenvironment and the tumor itself 
(Pellagatti et al., 2007). Lenalidomide is marketed in the United States for the treatment of subjects with 
transfusion dependent anemia due to low- or intermediate-1 risk myelodysplastic syndrome (MDS) 
associated with a deletion 5-q cytogenetic abnormality with or without additional cytogenetic 
abnormalities based on the improvement of anemia (List et al., 2005). It is also used in combination with 
dexamethasone for subjects with previously treated multiple myeloma based on significant antitumor 
activity (Richardson et al., 2002; Rajkumar et al., 2005). 
Recently there has been increased interest in the response to the lenalidomide in patients with the non-
GCB poor prognostic variety. Retrospective analysis of the outcomes of patients with GCB vs non-GCB 
DLBCL treated with salvage lenalidomide at 4 academic institutions showed a significant difference in 
clinical response to this immunomodulatory agent. (Hernandez-Ilizaliturri et al., 2011) ORR was 52.9% 
versus 8.7% (P = .006); CR rate was 23.5% versus 4.3%. Median PFS was 6.2 versus 1.7 months (P = 
.004), although no difference in overall survival (OS) was observed.  
 
Feldman and colleagues in a phase I/II trial also were able to show that the addition of lenalidomide to the 
R-ICE regimen did not result in any serious adverse events with nine out of fifteen patients (60%) 
achieving a complete response with 2 (13%) achieving a partial response. (Feldman et al., 2014) 
Additionally 1 patient in this study failed stem cell collection for an ASCT. 
 
The addition of lenalidomide to the R-ICE regimen could potentially improve the overall response rates 
(ORR) as well as the complete response (CR) rates for DLBCL without compromising the aspect of stem 
cell collection and mobilization; thereby improving the overall survival in these subset of patients. Our 
hypothesis is that the magnitude of benefit is likely to be more in the non-GCB subtype, however, it 
would likely have a positive impact on both GCB and non-GCB subtypes of DLBCL.  
 
Dosing of Lenalidomide: 
 
As noted above, patients tolerated the addition of 25 mg dose daily of lenalidomide from days 1-7 of a 14-
day cycle of R-ICE chemotherapy without need for any dose modifications. For eight of the fifteen 
patients, the cycle was every 21 days (Feldman et al., 2014).  
 
Previously, our group was able to show that lenalidomide could be safely added to the R-CHOP regimen 
(R2CHOP). There were no dose limiting toxicities with the 25 mg daily dose for days 1 through 10 
(Nowakowski et al., 2011).  
 
Other examples of dosing and schedules of regimens where lenalidomide is added to other chemotherapy 
regimens include: 
 
• 
Bendamustine/Dexamethasone; every 28days; Lenalidomide 15 mg 1 through 21 days 
• 
Bortezomib/Dexamethasone; every 21 days; Lenalidomide 25 mg Days 1 through 14 
• 
BiRD (Biaxin [clarithromycin] / Revlimid [lenalidomide] / dexamethasone) every 28 days; 
Lenalidomide 25 mg Days 1 through 21 

Addendum 2 
9  
RU051417I 
 
There is also evidence to suggest that it is not only the dose but the duration of exposure to lenalidomide 
that is important in its role as an immunomodulatory agent.  
 
Based on this and consensus between our experts we plan on dosing lenalidomide days 1 through 14 in a 
21 day treatment cycle of R-ICE as noted in Table 7.1.  We will start with 15 mg daily and escalate to 20 
mg daily as noted by Feldman and colleagues but with a longer duration for 14 days instead of 7 days. 
There are adjustment to doses based on renal function outlined by the manufacturer and other studies, 
however, for the purposes of the study, patients would need a creatinine ≤ 2.0 mg/dL or calculated 
creatinine clearance must be ≥ 30 ml/min using the Cockcroft-Gault formula to be eligible for the study.   
 
A cycle of R2ICE versus RICE chemoimmunotherapy would be 21 days. For the first stage of the study 
to determine the MTD, building upon the work published on the ‘RICER’ regimen of Feldman and 
colleagues, a 3 x 3 dose-escalation design would be used, in which a cohort of three consecutive patients 
would be assigned initially to the lowest dose of lenalidomide in combination with RICE (Feldman et al., 
2014). If no patient developed a dose-limiting toxicity (DLT) during cycle 1 (one cycle being 21 d), the 
subsequent cohort of three patients would be assigned to the next dose. If any patient in any cohort 
developed a DLT, that cohort would be expanded by another three patients. In the absence of a DLT 
being identified, the 20 mg cohort would be expanded to a total of six patients in the current study.  
 
In the original study of the RICER, lenalidomide was dosed for7 days and the following 4 cohorts were 
used (Feldman, Mato et al. 2014): 
- 
Cohort 1:  RICE + Lenalidomide 10mg days 1-7 
- 
Cohort 2:  RICE + Lenalidomide 15mg days 1-7 
- 
Cohort 3:  RICE + Lenalidomide 20mg days 1-7 
- 
Cohort 4:  RICE + Lenalidomide 25mg days 1-7 
 
For the purposes of this study, the same cohorts would be expanded to have lenalidomide given 14 days 
per 21 days cycle instead of the 7 days as noted above.  
For the second phase of the study, patients will be treated with the MTD determined by Lenalidomide 
plus R-ICE (R2ICE regimen) from stage I (Figure 3).  
1.3 
Rationale for the Current Study 
 
Despite various effective salvage chemotherapy regimens available in the primary-refractory/first-relapse 
setting, the overall response rate achieved for patients with DLBCL could still be improved upon to 
increase the proportion of patients going for a SCT. The goal of our study, therefore, would be to 
determine if the addition of lenalidomide to the R-ICE chemoimmunotherapy regimen (R2-ICE) would 
lead to a clinically meaningful improvement in the overall response rates (ORR) for patients with 
primary-refractory/first-relapse DLBCL. As a secondary end point, we would also look at the complete 
metabolic response (CMR) rates.  
 
As a secondary objective at the time of analysis, following the algorithm developed by Hans et al, we 
would analyze patient outcomes based on their subtypes (GCB versus non-GCB subtypes), international 
prognostic index (IPI) and the timing of their recurrence (≤ 12 months versus > 12 months). (Hans, 
Weisenburger et al. 2004; Thieblemont, Briere et al. 2011) . In particular our focus would be to see if it 
leads to improvement in the non-GCB subtype given the overall adverse outcome in this subgroup of 
patients. We would use nanostring technology here in addition to the traditional Hans algorithm to 
classify patients into GCB and non-GCB subtypes. Additionally, we would also evaluate and compare the 
rates the stem cell mobilization achieved in patients receiving R2ICE chemoimmunotherapy compared to 
historical controls.  
 
 
 

Addendum 2 
10  
RU051417I 
 
1.4 
Phases of the Study 
 
1.41 
Phase I 
 
Building upon work done by Feldman and colleagues, we would determine the maximum 
tolerable dose (MTD) of Lenalidomide in combination with R-ICE prior to ASCT. The planned 
number of cycles would be 2 followed by evaluation with a PET/CT scan. Patients would be 
allowed to get 1 or 2 more cycles of the treatment regimen based on the arms randomized to prior 
to proceeding to stem cell collection and transplant as noted in the study schema, after which they 
would proceed to the event monitoring phase. 
  
In the first phase of the study, since the main objective is to determine the MTD, all kinds of B-
cell lymphomas would be allowed. For the second phase, only patients with DLBCL would be 
eligible to participate. Patients with primary mediastinal lymphoma as well as transformed 
lymphoma would be allowed to participate in both phases of the study.  
 
1.42 
Phase II 
 
Based on the MTD determined by the phase I part of the study, lenalidomide would be combined 
with R-ICE to form the R2-ICE regimen as outlined by the study schema. This would be a Phase 
II open-label single arm study.  
 
1.5 
Correlative Research 
 
1.51 
Impact of DLBCL molecular subtype on efficacy of R2-ICE: DLBCL is a heterogeneous disorder 
with different subtypes based on Hans algorithm: germinal center B-cell type (GCB) and 
activated B-cell type (ABC). The latter group is often included in non-GCB type in 
immunohistochemistry (IHC) based classification algorithms. This classification is based on the 
so called cell-of-origin (COO) grouping system (Scott, 2014). The ABC (non-GCB subtype) has 
been associated with worse outcome both in the pre- and post- rituximab era. Retrospective 
analysis of the outcomes of patients with GCB vs non-GCB DLBCL treated with salvage 
lenalidomide at 4 academic institutions was recently performed (Hernandez-Ilizaliturri et. al., 
2011). Forty patients with relapsed/refractory DLBCL were included (24 men; 16 women; 
median age, 66 years; median of 4 prior treatments, including rituximab chemotherapy). Patients 
were classified as GCB (n = 23) or non-GCB (n = 17) DLBCL according to the Hans algorithm. 
The subgroups were similar in terms of stage, IPI score, prior number of treatments, and 
rituximab resistance. A significant difference in clinical response to lenalidomide was observed in 
non-GCB versus GCB patients. ORR was 52.9% versus 8.7% (P = .006); CR rate was 23.5% 
versus 4.3%. Median PFS was 6.2 versus 1.7 months (P = .004), although no difference in OS 
was observed between non-GCB and GCB DLBCL patients. There is also evidence to suggest 
that the DLBCL subtype may have an impact on lenalidomide efficacy in the upfront therapy on 
work done by our group earlier (Nowakowski et. al, 2011, and Nowakowski, 2014) ; however, its 
impact in the relapsed and primary-refractory setting still remains to be determined. 
 
In the current study as part of the correlative studies, we will assess impact of DLBCL subtype on 
the overall response rates achieved for patients with primary-refractory/first-relapse lymphoma. 
In addition to using immunohistochemistry as proposed by the Hans algorithm, we would further 
employ gene expression profiling using nanostring technology for classification of these subtypes 
(Scott, 2014).    
 
 

Addendum 2 
11  
RU051417I 
 
2.0 
Goals    
 
2.1 
Primary 
 
2.11  
Phase I: To assess the safety and maximum tolerated dose (MTD) of the addition of lenalidomide 
to the R-ICE chemoimmunotherapy regimen (R2ICE) for the treatment of primary-
refractory/first-relapse B-cell lymphoma  
 
2.12 
Phase II: To determine if the addition of lenalidomide (based on dose determination from phase I) 
to the R-ICE chemoimmunotherapy regimen (R2-ICE) would lead to clinically meaningful 
improvement in the overall response rates (ORR) for patients with first-relapse/refractory 
DLBCL. 
 
2.2 
Secondary 
 
2.21 
To evaluate the effect of the addition of lenalidomide to RICE on the number (percentage) of 
patients proceeding to SCT.  
 
2.22      To evaluate the effect of the addition of lenalidomide to RICE on other surrogate outcome 
measures including complete metabolic response (CMR) rate and overall survival  
 
 
2.23 
To describe the toxicities associated with the addition of lenalidomide to the R-ICE 
chemoimmunotherapy regimen (R2ICE).    
 
2.3 
Correlative Research 
 
2.31 
To evaluate ORR based on GCB versus non-GCB subtypes.  Hans algorithm by 
immunohistochemistry and gene expression profiling using nanostring technology for 
classification of these subtypes will be used (Scott, 2014). Outcomes will also be compared based 
on patients’ IPI scores and time of recurrence of lymphoma.     
  
2.32 
To evaluate ORR based on percent SUV reduction and percent anatomic size reduction on interim 
PET/CT scans.   
 
 
 
2.33 
To evaluate ORR based on Minimal Residual Disease (MRD) detection (positive vs. negative) 
and quantification after 2 cycles of treatment.  
 
2.34 
Future tissue and blood based studies: Additionally, samples collected during this study would be 
stored for future and ongoing research. (see details below).  
 
 

Addendum 2 
12  
RU051417I 
 
3.0 
Patient Eligibility    
 
Prior to discussing protocol entry with the patient, call the ACCRU Registration Office (507-284-2753) for 
dose level and to insure that a place on the protocol is open to the patient.  
 
3.1 
Inclusion Criteria  
 
3.11 
Age ≥18 years. 
 
3.12 
Histological confirmation of expressing CD20 antigen (Cheson et al.,1999) as determined by 
pathology at the respective institution  and central pathology review at Mayo Clinic Rochester.  
 
NOTES: 
• 
For Phase I, all types of B-cell lymphomas are allowed to participate.  
• 
For phase II, only DLBCL patients are allowed to participate.    
• 
For Phase I only, patients with primary mediastinal large B-cell (PMLBCL) or 
transformed lymphoma are allowed to participate.  
 
ADDITIONAL NOTES REGARDING SLIDE SUBMISSION:  
 
• 
Central pathology review is mandatory, but is retrospective in nature. Slides must be 
submitted ≤30 days after registration to allow for confirmation of DLBCL diagnosis and 
to have sufficient material for GCB/ABC assessment by a gene-expression profiling 
method (see Section 17).  
• 
Patients can be enrolled prior to submission of slides.  
• 
For Phase II, if central review of pathology shows that the patient does NOT have 
DLBCL or the amount of FFPE material is not considered sufficient for COO analysis, 
the patient may remain on the study but the patient should be replaced. 
 
3.13 
Measurable disease (at least 1 lesion ≥ 1.5 cm in diameter) as detected by PET/CT and as defined 
in Section 11.0.    
 
3.15 
Only 1 line of previous anti-lymphoma therapy is allowed and not currently receiving any other 
agent that would be considered as a treatment for the lymphoma. Patients must be ≥ 2 weeks from 
prior anti-lymphoma therapy. The use of steroids and/or rituximab up to 1 week prior to 
registration for management of symptoms is allowed.   
 
3.16 
ECOG Performance Status (PS) 0-2.  (Form available on the ACCRU web site: 
 
  
3.17 
Adequate organ function as defined by the following laboratory values obtained ≤7 days prior to 
registration.:  
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count ≥75,000/mm3 
• 
Total bilirubin ≤ 2 × ULN (unless related to lymphoma or Gilbert’s disease) OR ≤ 5 × ULN 
for subjects with documented or suspected Gilbert’s disease, or related to involvement of the 
liver by the lymphoma.  
• 
Aspartate transaminase (AST) and ALT (SGPT) ≤3 x ULN unless evidence of the direct liver 
and/or bone involvement by lymphoma, then ≤ 5 x ULN 
• 
Renal function assessed by calculated creatinine clearance as follows (see Appendix: 
Cockcroft-Gault estimation of CrCl): 
 Phase I subjects must have calculated creatinine clearance ≥ 60ml/min by Cockcroft-
Gault formula.  

Addendum 2 
13  
RU051417I 
 
 Phase II subjects must have calculated creatinine clearance ≥ 30ml/min by Cockcroft-
Gault formula.  See section below, “Dosing Regimen”, regarding lenalidomide dose 
adjustment for calculated creatinine clearance ≥ 30ml/min and < 60ml/min. 
 
 
 
 
 
 
 
 
 
 
 
 
3.18 
For women of childbearing potential only:  Negative pregnancy test ≤10-14 days prior to 
registration. NOTE: the patient must have an additional negative pregnancy test ≤24 hours prior 
to receiving the initial prescription of lenalidomide, per requirements of the REVLIMID 
REMS™ program.   
 
3.19a 
Provide informed written consent. 
 
3.19b Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the 
study (i.e.active treatment and observation)). 
 
3.19c 
Willing to provide blood samples for correlative research purposes (see Sections 4, 6.22, 14.0 ).  
 
3.19d Considered transplant-eligible, as determined by the opinion of the investigator at the 
participating institution. The participating institution does not need to be a transplant center but 
patients can be referred to a transplant center if needed.  
 
3.19e 
Willing and able to register into and comply with the mandatory requirements of Celgene’s 
REVLIMID REMS™ program. 
 
3.19f 
Females of reproductive potential are willing and able to adhere to the scheduled pregnancy 
testing as required by Celgene’s REVLIMID REMS™ program.  
 
3.19g Willing and able to take aspirin (81mg) daily as prophylactic anticoagulation (patients intolerant 
to ASA may use warfarin or low molecular weight heparin). 
 
3.2 
Exclusion Criteria  
 
3.21 
Any of the following because this study involves an agent that has known genotoxic, mutagenic 
and teratogenic effects: 
 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ adequate contraception  
 
NOTE: Patients unwilling or unable to do any of the following are also excluded:  
 
• Men must agree to use a latex condom during sexual contact with a female of child-
bearing potential even if they have had a successful vasectomy. 
• Women of child bearing potential must agree to use 2 methods of reliable contraception 
simultaneously as indicated in Appendix II. 
• All patients must be counseled at a minimum of every 21 days about pregnancy 
precautions and risks of fetal exposure. 
Cockcroft-Gault Equation: 
 
Creatinine clearance for males =   
(140 - age)(weight in kg) 
  
 
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females =   
(140 - age)(weight in kg)(0.85) 
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 

Addendum 2 
14  
RU051417I 
 
 
 
3.22 
Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the 
investigator, would make the patient inappropriate for entry into this study or interfere 
significantly with the proper assessment of safety and toxicity of the prescribed regimens  
including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements. 
 
3.23 
Immunocompromised patients and patients known to be HIV positive and currently receiving 
antiretroviral therapy.  NOTE:  Patients known to be HIV positive, but without clinical evidence 
of an immunocompromised state, are eligible for this trial. Patients with HIV on antiretroviral 
therapy other than AZT and/or stavudine and without prior AIDS defining conditions and 
adequate CD4 count (>400) are eligible. The safety of lenalidomide-RICE (R2ICE) in patients  
with HIV infection and advanced immunosuppression and in patients with organ transplants 
requiring immunosuppression has not been established. 
 
3.24 
History of myocardial infarction ≤180 days prior to registration or congestive heart failure 
requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias. 
 
3.26 
Receiving any other investigational agent which would be considered as a treatment for the 
primary neoplasm. As noted in section 3.15, patients must be ≥ 2 weeks from prior anti-
lymphoma therapy. The use of steroids and/or rituximab up to 1 week prior to registration for 
management of symptoms is allowed.  
 
 
3.27 
Other active malignancy ≤3 years prior to registration.  EXCEPTIONS:  Non-melanotic skin 
cancer, carcinoma-in-situ of the cervix, or any cancer that, in the judgment of the investigator, has 
been treated with curative intent and will not interfere with the study treatment plan and response 
assessment. NOTE:  If there is a history of prior malignancy, they must not be receiving other 
specific treatment such as radiation, chemotherapy, or immunotherapy for their cancer.  
 
3.28 
Unable or unwilling to take any prophylaxis. NOTE: Lenalidomide therapy is associated with 
increased risk of thrombosis. Patients with history of or new/active deep vein 
thrombosis/embolism/thrombophilia are allowed to participate if they are on appropriate 
therapeutic anticoagulation during the treatment on the trial. These patients would not need 
the aspirin with the lenalidomide unless clinically indicated. Therefore, patients must be able and 
willing to receive anticoagulation (prophylaxis versus therapeutic as clinically indicated). 
 
3.29 
History of radiation therapy to ≥ 25% of the bone marrow for other diseases. 
 
3.29a 
Receiving erythroid stimulating agents (EPO: Procrit, Aranesp). 
 
3.29b Patients with active or prior CNS lymphoma or cerebrospinal fluid involvement with malignant 
lymphoma cells. NOTE: These patients are usually treated with CNS directed therapy. Screening 
for CSF/CNS involvement is NOT required but can be performed per treating MD discretion. 
 
 
 
3.29c  Active hepatitis B as defined by seropositivity for hepatitis B surface antigen (HBsAg). Subjects 
with positive hepatitis B core antibody titers and normal liver transaminases are allowed provided 
that antiviral prophylaxis is administered per institutional guidelines. NOTE: Subjects with 
hepatitis C antibody will be eligible provided that they do not have elevated liver transaminases 
or other evidence of active hepatitis. 
 

Addendum 2 
15 
RU051417I 
4.0 
Test Schedule 
 
NOTE: Variation of ≤3 days of scheduled visit is permitted. 
Tests and procedures 
Screening 
≤21 days 
prior to 
registration  
Screening 
≤10-14 
days prior 
to 
registration 
Screening 
≤7 days 
prior to 
registration  
Cycle 1 
Day 1 
Cycle 1 
Day 2 
Active Monitoring Phase 
 
Cycle 1 
Day 3 
 
Cycle 2 
Day 1 
 
Response 
Evaluation 
after 2 cycles 
(Cycle 2 Day 
21)  
Optional 
Cycles:    
3 and 4    
Day 1 
End of 
Treatment 
History and exam, wt, ECOG PS  
 
 
X 
X1 
 
 
X 
X 
X 
X11 
Height 
 
 
X 
 
 
 
 
 
 
 
Adverse event assessment 
 
 
X 
 
 
 
X 
X 
X 
X 
Hematology: CBC with differential 
 
 
X 
X2 
 
 
X2 
X2 
X2 
 
X 
Chemistry:  SGOT (AST), alk phos, T. bili,3 creatinine, 
calcium, phos, glucose, Na, K, glucose 
 
 
X 
X 
 
 
X 
X 
X 
X 
Lactate Dehydrogenase (LDH) 
 
 
X 
 
 
 
 
 
 
 
Thyroid stimulating hormone (TSH) 4 
 
 
X 
 
 
 
 
 
 
 
HIV screen 
X 
 
 
 
 
 
 
 
 
 
Hepatitis B screen8 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test7 
 
X 
 
X 
 
 
X 
X 
X 
X 
PET CT scans5 (see Appendix III) 
X 
 
 
 
 
 
 
X5 
 
 
Central pathology review (see Section 17.2)R, 9  
 
 
 
X 
 
 
 
 
 
 
 
PET/CT scan image submission (See Appendix III) 
X 
 
 
 
 
 
 
X 
 
 
CT Scan6 
X 
 
 
 
 
 
 
 
 
 
Mandatory blood sample (see Section 14.0)R, 10 
 
 
X 
X 
X 
X 
 
X 
 
 
 
1 
If physical examination, vital signs, weight and ECOG performance status were done ≤ 7 days of registration, they do not need to be repeated on Day 1. 
2 
CBC with differential is required twice weekly until hematologic recovery or as clinically indicated.  
3 
Only if Total Bilirubin > upper normal limit. 
4 
TSH levels following baseline may be assessed as clinically indicated. 
5 
≤ 21 days prior to registration. PET/CT scans should be performed to assess for response in patients as defined by the revised Cheson’s criteria (Cheson, 
2014). This response assessment would be performed by the treating institution. However, images would be required to be submitted for future central review  
 

Addendum 2 
16  
RU051417I 
 
per the guidelines in Appendix III for the purpose of study analysis. Patients who are CMR, PMR, or NMR will continue treatment per protocol for 2 cycles. 
Per physician discretion patients may receive a 3rd and 4th cycle of treatment. 
6 
Measurements can be done using the CT part of the PET scan. CT scans of the chest, neck, abdomen & pelvis are mandatory if CT portion of PET scan is not 
available. 
7 
For women of childbearing potential only.  Must be done ≤10-14 days prior to registration and ≤24 hours prior to the start of lenalidomide, per requirements of 
the REVLIMID REMS™ program. NOTE: The subject may not receive lenalidomide until the study doctor has verified that the results of these pregnancy 
tests are negative. A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).  
FCBP with regular or no menstruation must have a postmenopausal pregnancy test done weekly during the first cycle, then every 21 days while on therapy 
(including breaks in therapy); at discontinuation of Lenalidomide and at Day 21 post the last dose of Lenalidomide.  Females with irregular menstruation must 
have a pregnancy test done weekly for the first cycle, then every 14 days while on therapy (including breaks in therapy), at discontinuation of Lenalidomide 
and at Day 14 and Day 21 post the last dose of Lenalidomide.   
8 
Persons at high risk of hepatitis B virus infection should be screened before initiation of rituximab. Carriers of hepatitis B should be closely monitored (see 
Section 9.5). 
9 
Slides should be submitted ≤30 days of enrollment, as instructed in Section 17. Central pathology review is required, but is retrospective and will not prohibit 
enrollment into the study. 
10 Correlative research blood collected prior to treatment Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 3 and Cycle 2 Day 21 (see Section 14.0).  
11 Follow-up period is every 3 months for years 1 to 3, then yearly in years 4 and 5. 
 
 
 
 
 
 
 
 
 
 
R Research funded (see Section 19.0; patients must be willing to submit mandatory blood samples as outlined in Section 14.0). 
 
 

Addendum 2 
17  
RU051417I 
 
5.0 
Grouping Factors 
5.1   
Phase I vs. Phase II 
6.0  
Registration Procedures 
 
NOTE: There is no randomization involved for this Phase I/II study. The form online is titled 
Registration/Randomization, but, for this trial, is meant for registration purposes only.  
 
6.1 Phase I 
 
Prior to discussing protocol entry with the patient, call the ACCRU Registration 
Office (
) for dose level and to insure that a place on the protocol is 
open to the patient.  
 
6.11 
Registration Procedures 
 
6.111 To register a patient, fax (
) a completed eligibility checklist 
to the Academic and Community Cancer Research United (ACCRU) 
Registration Office between 8 a.m. and 4:30 p.m. central time Monday 
through Friday.   
 
6.2 
Phase II 
 
6.21 
Registration Procedures 
 
6.212 
To register a patient, access the ACCRU web page at 
 on “Training Page” and 
enter the registration/randomization application.  The 
registration/randomization application is available 24 hours a day, 7 days a 
week.  Back up and/or system support contact information is available on 
the Web site.  If unable to access the Web site, call the Academic and 
Community Cancer Research United (ACCRU) Registration Office at (
 
between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday 
through Friday). 
 
The instructions for the registration/randomization application are available 
by using the Help button.  Prior to initiation of protocol study intervention, 
this process must be completed in its entirety and a ACCRU subject ID 
number must be available as noted in the instructions.  It is the 
responsibility of the individual and institution registering the patient to 
confirm the process has been successfully completed prior to release of the 
study agent.  Patient registration via the registration/randomization 
application can be confirmed in any of the following ways: 
 
• 
Contact the ACCRU Registration Office 
.  If the 
patient was fully registered, the ACCRU Registration Office staff 
can access the information from the centralized database and 
confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 

Addendum 2 
18  
RU051417I 
 
6.3 
Phase I and II 
 
6.31 
Correlative Research 
 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.19c, 14.1 and/or 
17.11). 
 
As part of ongoing research for ACCRU lymphoma studies, paraffin-embedded 
tissue blocks/slides and blood products will be banked for future studies 
 
6.32 
Prior to accepting the registration, registration/randomization application will 
verify the following: 
 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
6.33 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients.  
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
  If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 
 
6.34 
At the time of registration, the following will be recorded: 
 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn about, prevent, or treat cancer. 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn, prevent, or treat other health problems (for example:  
diabetes, Alzheimer’s disease, or heart disease). 
• 
Patient has/has not given permission for ACCRU to give his/her sample(s) to 
outside researchers. 
 
6.35 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of a medical oncologist or hematologist. 
 
 
 
 
 
 
 
6.36 
Treatment cannot begin prior to registration and must begin ≤14 days after 
registration. 
 
6.37 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 

Addendum 2 
19  
RU051417I 
 
6.38 
All required baseline symptoms (see Section 10.3) must be documented and 
graded. 
 
6.39a 
Blood draw kits must be ordered per instructions in section 14.21.  
   
7.0 
Protocol Treatment 
 
7.1 
Dosing of lenalidomide: 
 
7.11 
Phase I 
 
 
 
 
R2-ICE Treatment Schedule:  Cycle length is 21 days.  
 
Agent 
Dose1 
Route 
Day 
Lenalidomide2 
As assigned by 
Randomization 
Center 
PO 
As assigned by 
Randomization 
Center 
Aspirin2 
81 mg 
PO 
Days 1-14 
Rituximab3 
375 mg/m2 
IV 
Day 1 
Ifosfamide 
5000 mg/m2 
IV 
Day 2 
Mesna 
5000 mg/m2 
IV 
Day 2 
Carboplatin 
AUC 5 
IV 
Day 2 
Etoposide 
100 mg/m2 
IV 
Days 1-3 
Pegfilgrastim4 
6 mg 
SubQ4 
Day 4 
Dexamethasone5 
20 mg 
IV5 
Day 1-2 
Tumor lysis prophylaxis6 
 
 
 
 
1 
Body surface area based on actual body weight  
2 
For patients on the R2-ICE arm taking Lenalidomide, low dose Aspirin 81 
mg daily will continue until the platelet counts fall below 50,000. Patients 
who cannot take aspirin will be placed on prophylactic warfarin or low 
molecular weight heparin (Lovenox 40 mg daily) until the platelet counts fall 
below 50,000.  
3 
Rituximab may be rounded to nearest 50 mg.  Patients will get 
acetaminophen 1000 mg/dose 30 minutes prior to infusion and every 4 hours 
as needed for infusion related reactions (not to exceed 4000 mg/24 hours 
from all sources).  In addition, diphenhydramine 50 mg/dose 30 minutes 
prior and then 25 mg/dose IV every 4 hours as needed for infusion related 
reactions with rituximab. This may be repeated once if symptoms are not 
relieved within 15 minutes of initial dose. Meperidine 25 mg/dose IV push 
prn rigors, may repeat once if first dose ineffective.   
4 
Pegfilgrastim should be given 18 hours after chemotherapy on Day 4-5. G-
CSF (filgrastim) or other growth factors can be used (instead of 
Pegfilgrastim) based on institutional practice.  
5 
Dexamethasone 20 mg IV Day 1 and 2; 30 minutes prior to Rituximab and 
Carboplatin to prevent reactions.  
6 
Tumor lysis prophylaxis per institutional practice. For patients with AKI, 
large tumor burden and/or uric acid > 8 mg/dl, consideration should be given 
to giving rasburicase 6 mg IV once and repeated as needed.  

Addendum 2 
20  
RU051417I 
 
Ifosfamide, carboplatin, and etoposide are commercially available 
chemotherapies that are approved by the U.S. Food and Drug Administration and 
other regulatory agencies for use in patients with multiple types of cancer and in 
various combinations. Use of these drugs to treat patients with DLBCL is 
considered a standard regimen in the United States.  
 
Etoposide 100 mg/m2 will be administered by IV infusion over approximately 1 
hour on Days 1–3 of each cycle. 
 
Carboplatin dose will be calculated using the Calvert formula (below) to achieve 
an area under the curve (AUC) of 5 mg/mL * min (maximum dose = 800 mg) 
and will be administered by IV infusion on Day 2 of each cycle, over 
approximately 1-2 hours: 
 
Carboplatin dose in mg = 5 mg/mL*min x [GFR (mL/min) + 25 (mL/min)] 
Glomerular filtration rate (GFR) will be estimated using the modified Cockcroft-
Gault formula: 
 
GFR = (140 – age [yrs]) x actual weight (kg) 
               72 x serum creatinine (mg/dL) 
 
Note: Multiply by another factor of 0.85 if patient is female. 
 
Ifosfamide 5 g/m2 will be administered beginning Day 2 of each cycle by 
continuous IV infusion over 24 hours +/- 2 hours. Mesna 5 g/m2 should be mixed 
in the same bag and administered in conjunction with ifosfamide. Patients may 
be hospitalized during this 24-hour infusion period.  
 
Post-infusion mesna should be given in accordance with institutional guidelines 
(e.g. oral or IV for 6-12 hours following infusion). 
 
Rituximab at 375 mg/m2 will be administered via IV infusion per institutional 
guidelines. Subjects will receive 2 cycles of RICE or R2ICE before response 
assessment after cycle 2, or significant/serious drug related toxicity occurs. Per 
investigator discretion, patients can receive up to 2 more cycles of therapy before 
they proceed with a transplant.  
 
ICE will be administered via IV infusion as follows: ifosfamide 5 g/m2 
continuously for 24 hours with mesna on Day 2; carboplatin area under the curve 
(AUC) = 5 mg/mL × min [800 mg maximum) on Day 2; etoposide 100 mg/m2 
on Days 1, 2, and 3 in 21-day cycles. 
 
 
 
 

Addendum 2 
21  
RU051417I 
 
7.12 
Phase II 
 
R2ICE Treatment Schedule:  Cycle length is 21 days.  
 
 
 
Agent 
Dose1 
Route 
Day 
Lenalidomide2  
As determined by 
phase I  
PO 
As determined 
by phase I 
Aspirin2 
81 mg 
PO 
Days 1-14 
Rituximab3  
375 mg/m2 
IV 
Day 1 
Ifosfamide   
5000 mg/m2 
IV 
Day 2 
Mesna  
5000 mg/m2 
IV 
Day 2 
Carboplatin 
AUC 5 
IV 
Day 2 
Etoposide 
100 mg/m2 
IV 
Days 1-3 
Pegfilgrastim4  
6 mg  
SubQ4 
Day 4 
Dexamethasone5  
20 mg 
IV5 
Day 1-2 
Tumor lysis prophylaxis 6   
 
 
 
1 Body surface area based on actual body weight  
2 For patients on the R2-ICE arm taking Lenalidomide, low dose Aspirin 81 
mg daily will continued till the platelet counts fall below 50,000. Patients 
who cannot take aspirin will be placed on prophylactic warfarin or low 
molecular weight heparin (Lovenox 40 mg daily) until the platelet counts 
fall below 50,000. Lenalidomide is provided at no charge to patients by 
Celgene Corporation for patients on the R2ICE arm.  
3 Rituximab may be rounded to nearest 50 mg. Patients will get 
acetaminophen 1000 mg/dose 30 minutes prior to infusion and every 4 
hours as needed for infusion related reactions.  In addition, 
diphenhydramine 50 mg/dose 30 minutes prior and then 25 mg/dose IV 
every 4 hours as needed for infusion related reactions with rituximab. This 
may be repeated once if symptoms are not relieved within 15 minutes of 
initial dose. Meperidine 25 mg/dose IV push prn rigors, may repeat once if 
first dose ineffective. 
4 Pegfilgrastim should be given 18 hours after chemotherapy on Day 4-5. G-
CSF (filgrastim) or other growth factors can be used (instead of 
Pegfilgrastim) based on institutional practice.  
5 Dexamethasone 20 mg IV Day 1 and 2; 30 minutes prior to Rituximab and 
Carboplatin to prevent reactions.  
6 Tumor lysis prophylaxis per institutional practice. For patients with AKI, 
large tumor burden and/or uric acid > 8 mg/dl, consideration should be 
given to giving rasburicase 6 mg IV once and repeated as needed.  
 
7.2 
Length of Treatment:  Patients will receive treatment per protocol for 2 cycles.   At the 
end of 2 cycles, patients who are CMR, PMR, or NMR may receive a 3rd and 4th cycle 
of treatment per physician discretion. 
 
7.3 
Stem Cell Transplant (SCT):   After the completion of 2 cycles of R2ICE treatment, 
patients who have achieved  an objective status of CMR, PMR or NMR may proceed to 
SCT during the event monitoring phase.  The SCT should be recorded on the event  
 

Addendum 2 
22  
RU051417I 
 
monitoring form. Depending on the timing of the transplant, patients per physician 
discretion can continue treatment for a 3rd and 4th cycle prior to transplant.   
 
7.4 
For this protocol, the patient must return to the consenting ACCRU institution for 
evaluation at least every 21 days during treatment as specified in the test schedule (see 
Section 4.0).  
 
 
7.5 
Local Medical Doctor (LMD) treatment: 
 
 
Patients must receive treatment with R2ICE per protocol at the participating ACCRU 
institution. However, patients are allowed to receive the transplant at a non-ACCRU 
institution. 
 
7.6 
Phase I – Determination of Maximum Tolerated Dose (MTD)  
 
7.61 
Dose Escalation 
 
Lenalidomide 
Dose Level 
Dose 
Day 
Route 
-2 
10 mg  
Daily for 10 
days 
Orally 
-1 
10 mg  
Daily for 14 
days  
Orally 
*1 
15 mg  
Daily for 14 
days  
Orally 
2 
20 mg  
Daily for 14 
days 
Orally 
 
 
*starting dose level  
 
 
 
7.612  Three patients will be treated at each dose level and observed for a 
 
minimum of 21 days (1 cycle), to assess toxicities, before new patients 
are treated.  Doses will not be escalated in any individual patient. 
 
 
 
 
7.613 Investigators are to contact the ACCRU Operations Office (507-266-
0800) as soon as any dose-limiting toxicity (DLT) occurs. 
 
7.62 
Definitions of DLT 
 
7.621 For this protocol, DLT will be defined as an adverse event attributed 
(definitely, probably, or possibly related) to the study treatment and 
meeting the following criteria with the first cycle: 
 
• 
Any grade ≥ 3 non-hematologic adverse event. The following are 
some of the exceptions noted: 
o Alopecia, anorexia, or fatigue. 
o Grade 3 nausea and/or vomiting if not requiring tube feeding or 
total parenteral nutrition TPN, or diarrhea if not requiring or 
prolonging hospitalization that can be managed to Grade ≤ 2 
with antiemetic or antidiarrheal medications   

Addendum 2 
23  
RU051417I 
 
o Grade 3 fever with neutropenia, with or without infection. 
o Grade 3 infection. 
o Grade 3 tumor lysis syndrome that resolves within 72 hours after 
initiation of treatment.  
o Any grade electrolyte alteration that resolves to grade ≤ 1 within 
72 hours after it occurs.  
 
• 
Hematological adverse events include the following: 
o Failure of platelet recovery to 50,000/mm³ by day 29 
o Failure of absolute neutrophil recovery to 1000/mm³ by Day 29 
  
8.0 
Dosage Modification Based on Adverse Events  
 
Dose adjustments of ICE chemotherapy are to be performed per institutional standards. All 
patients will receive prophylactic hematopoietic growth factors (e.g., granulocyte-colony 
stimulating factor [G-CSF]) to shorten the period of neutropenia and transfusions of blood 
products should be provided during the course of treatment per institutional guidelines.  
 
Standard practice and local prescribing information will be followed for rituximab and 
background chemotherapy. Omitting or discontinuing background therapy must lead to omitting 
or discontinuing of lenalidomide as well. 
 
Dose Modifications at the start of next treatment cycles:  
Dose modifications of Lenalidomide will be based on the dose levels as noted in Table 8.1 and on 
adverse events noted during preceding cycles (see Table 8.2 for guidance regarding dose 
reductions based on adverse events).  
 
Dose modifications during a treatment cycle: 
Please note, while patient is actively on Lenalidomide, modifications are not allowed during the 
particular treatment cycle and are only allowed Day 1 of any particular cycle.  Decreasing by one 
dose level would be for the next cycle of treatment. During active treatment cycle, treatment can 
be held for up to 7 days if needed. 
 
If multiple adverse events are seen, administer dose based on greatest reduction required for any 
single adverse event observed.  Reductions apply to treatment given in the preceding cycle and 
are based on adverse events observed since the prior dose. 
 
 
 
 

Addendum 2 
24  
RU051417I 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
8.1 
Dose Levels (Based on Adverse Events in Table 8.2) 
 
 
Lenalidomide* 
 
Starting Dose 
20 mg days 1-14 
Starting Dose 
15 mg days 1-14 
Starting Dose 10 
mg days 1-14 
Starting Dose 10 
mg days 1-10 
1st dose reduction 
15 mg days 1-14 
10 mg days 1-14 
10 mg days 1-10 
10 mg Daily for 
days 1-7 
2nd dose 
reduction 
10 mg days 1-14 
10 mg days 1-10 
10 mg Daily for 
days 1-7 
Discontinue 
3rd dose reduction 
10 mg days 1-10 
10 mg Daily for 
days 1-7 
Discontinue 
 
4th dose reduction 
10 mg Daily for 
days 1-7 
Discontinue 
 
 
5th dose reduction 
Discontinue 
 
 
 
* Cycle length is 21 days for all treatment cycles 
 
 
 

Addendum 2 
25  
RU051417I 
 
8.2 
Dose modifications for Lenalidomide    
 
Use the following definitions to determine actions in the Action columns of the following 
tables: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. 
The patient does not make up the omitted dose(s) at a later time  
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The 
patient does make up the delayed dose(s) when the patient meets the protocol 
criteria to restart drugs.  
 Discontinue = The specified drug(s) are totally stopped.  
 
TREATMENT MODIFICATIONS FOR LENALIDOMIDE 
Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0*  
unless otherwise specified 
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
ACTION 
BASED ON INTERVAL ADVERSE EVENT DURING TREATMENT (DAYS 2-21) 
Any grade ≥ 3 non-
hematologic adverse 
event 
Non-hematologic 
No dose reductions allowed while patient is actively 
getting treatment. Can omit lenalidomide for up to 7 
days if needed.  
Any grade 
hematologic adverse 
event 
 
Does not require dose reduction or omission of 
Lenalidomide. 
AT TIME OF RETREATMENT (DAY 1) 
Investigations/ 
Neutrophil count 
decreased 
Grade ≥ 3 
Hold treatment until ANC ≥ 1000:  
• Days 22-28: if ANC ≥ 1000 proceed with 
treatment without dose reductions.  
• Days 29-35: If ANC recovers to ≥ 1000, reduce 
Lenalidomide by one dose level (see Table 8.1).  
• Days ≥36: discontinue treatment and go to event 
monitoring.  
Investigations/ 
Platelet count decrease 
Grade ≥ 3 
Hold treatment until platelets ≥ 50,000:  
• Days 22-28, if platelets  ≥ 50,000 proceed with 
treatment without dose reductions.  
• Days 29-35: If platelets ≥ 50,000, reduce 
Lenalidomide by one dose level (see Table 8.1).  
• Days ≥36, discontinue treatment and go to event 
monitoring.  
Any grade ≥ 3 non-
hematologic adverse 
event 
Non-hematologic 
Need to recover to grade 2 or lower before 
proceeding. Dose reductions of lenalidomide for the 
next cycle would be based on Table 8.1 
* Located at 
    
 
NOTE:  If the patient experiences a significant adverse event requiring a dose 
reduction at the start of the next cycle, then the dose will remain lowered for that 
entire subsequent cycle.  Dose increments would not be allowed once the reductions 
are made for subsequent cycles.   

Addendum 2 
26  
RU051417I 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Blood products should be utilized as clinically warranted and following institutional 
policies and recommendations.   
 
 
9.3 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such 
as antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the 
medical records. 
 
9.4 
Diarrhea:  This could be managed conservatively with loperamide.  The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea 
free (maximum 16 mg/day). 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed:  
hydration, octreotide, and antidiarrheals.   
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed.  
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
 
9.5 
Carriers of hepatitis B virus (HBV) should be closely monitored for clinical and 
laboratory signs of active HBV infection and for signs of hepatitis during and for up to 
several months following Rituxan therapy.  In patients who develop viral hepatitis, 
Rituxan and any concomitant chemotherapy should be discontinued and appropriate 
treatment, including antiviral therapy, initiated.  There are insufficient data regarding the 
safety of resuming Rituxan therapy in patients who develop hepatitis subsequent to HBV 
reactivation. 
 
9.6  
All patients would receive growth factor support in the form of Pegfilgrastim or 
filgrastim (G-CSF) as per institutional guidelines and availability and coverage. 
Pegfilgrastim can be given 24 hours after chemotherapy on Day 4-5 but before 72 hours 
prior to finishing of chemotherapy. G-CSF (filgrastim) could be used starting the day 
after chemotherapy based on institutional practice. 
 
9.7  
Steroids in the form of Dexamethasone 20 mg IV Day 1 and 2 is to be given 30 minutes 
prior to Rituximab and Carboplatin to prevent reactions.  
 
9.8 
To prevent ifosfamide related bladder toxicity, mesna should be given in accordance with 
institutional guidelines (e.g. oral or IV for 6-12 hours following infusion).  
 
9.9 
Tumor lysis prophylaxis should be done per institutional practice.  Typically, 300 mg of 
Allopurinol can be given daily for tumor lysis prophylaxis before cycle 1 of therapy. For 
patients with acute kidney injury (AKI), large tumor burden and/or uric acid > 8 mg/dl, 
consideration should be given to giving rasburicase 6 mg IV once and repeated as needed. 
 

Addendum 2 
27  
RU051417I 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
web site: 
     
 
a. Adverse event monitoring and reporting is a routine part of every clinical trial.   
 
b. Identify the grade and severity of the event using the CTCAE version 4.0.   
 
c. Determine whether the event is expected or unexpected (see Section 10.2).  
 
d. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
 
e. Determine whether the event must be reported as an expedited report. If yes, determine the 
timeframe/mechanism (see Section 10.4).  
 
f. Determine if other reporting is required (see Section 10.5). 
 
g. Note: All AEs reported via expedited mechanisms must also be reported via the routine 
data reporting mechanisms defined by the protocol (see Sections 10.6 and 18.0). 
 
10.1 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT). 
 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same as 
serious AE which is defined in the table in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, 
(if an investigator brochure is not required, otherwise described in the general 
investigational plan).  
 
Unexpected adverse events or suspected adverse reactions are those not listed in 
Section 15.0 of the protocol, the study specific consent form, package insert (if 
applicable), or in the investigator brochure (or are not listed at the specificity or 
severity that has been observed); if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general 
investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
 
 

Addendum 2 
28  
RU051417I 
 
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational 
plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, 
safety, or welfare of subjects  
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event.  
 
10.31 AEs Experienced Utilizing Investigational Agent(s) and Commercial Agent(s) on 
SEPARATE Arms 
 
• An AE that occurs on an arm using an investigational agent /intervention 
under an IND/IDE must be assessed in accordance with the guidelines in the 
appropriate IND/IDE Reporting Table in Section 10.4.   
 
• An AE that occurs on an arm using a commercial agent on a separate treatment arm 
must be assessed as specified in the protocol.  Refer to Commercial Reporting 
Table in Section 10.4.   
 
10.32 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME Arm 
 
When a commercial agent(s) is (are) used on the same treatment arm as the 
investigational agent/intervention (also, investigational drug, biologic, cellular 
product, or other investigational therapy under an IND), the entire 
combination (arm) is then considered an investigational intervention for 
reporting. These AEs should be assessed as specified in the appropriate 
IND/IDE reporting guidelines in Section 10.4 
 
 

Addendum 2 
29  
RU051417I 
 
10.33 Special Situations for Expedited Reporting  
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events 
 
For this protocol only, the following Adverse Events/Grades are expected to 
occur within this population and do not require Expedited Reporting. These 
events must still be reported via Routine Reporting (see Section 10.6).* 
  
 
System Organ Class 
(SOC) 
 
Adverse event/ Symptoms1 
 
CTCAE Grade at which the 
event will not be 
expeditedly reported 
Blood and lymphatic 
system disorders 
Anemia 
Grade 3 or 4 
Gastrointestinal 
disorders 
Nausea 
Grade 3 or 4 
Vomiting 
Grade 3 or 4 
General disorders and 
administration site 
conditions 
Fatigue 
Grade 3 
Investigations 
White blood cell decreased  
Grade 3 or 4  
Lymphocyte count decreased  
Grade 3 or 4  
Neutrophil count decreased  
Grade 3 or 4  
Platelet count decreased  
Grade 3 or 4  
1These exceptions only apply if the adverse event does not result in 
hospitalization. If the adverse event results in hospitalization, then the standard 
expedited adverse events reporting requirements must be followed. 
 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study) site over that which is listed in the protocol or 
investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event  
*An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent.  Therefore, if an expected AE (for the commercial agent) 
occurs with a higher degree of severity or specificity, expedited reporting is 
required.   
A list of known/expected AEs is reported in the investigator brochure, package 
insert or the literature, including AEs resulting from a drug overdose. 
 
10.331 Death 
 
• 
Any death occurring within 30 days of the last dose, 
regardless of attribution to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 

Addendum 2 
30  
RU051417I 
 
• 
Any death occurring greater than 30 days with an attribution 
of possible, probable, or definite to an agent/intervention 
under an IND/IDE requires expedited reporting within 24-
hours. 
 
• 
Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 
 
• 
Death Neonatal:  A disorder characterized by 
cessation of life during the first 28 days of life. 
 
• 
Death NOS:  A cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
 
• 
Sudden death NOS:  A sudden (defined as instant or 
within one hour of the onset of symptoms) or an 
unobserved cessation of life that cannot be attributed 
to a CTCAE term associated with Grade 5. 
 
• 
Death due to progressive disease should be reported 
as Grade 5 “Neoplasms benign, malignant and 
unspecified (including cysts and polyps) – Other 
(Progressive Disease)” under the system organ class 
(SOC) of the same name.  Evidence that the death 
was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
10.332 Secondary Malignancy 
 
• 
A secondary malignancy is a cancer caused by treatment for a 
previous 
malignancy 
(e.g., 
treatment 
with 
investigational 
agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
• 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE to be reported. Three options are available to 
describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
 

Addendum 2 
31  
RU051417I 
 
 
• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
10.333 Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  
Second malignancies require ONLY routine reporting. 
 
10.335 Pregnancy 
 
• 
Pregnancies and suspected pregnancies (including a positive 
pregnancy test regardless of age or disease state) of a female subject 
occurring while the subject is on lenalidomide, or within  28 days of 
the subject’s last dose of lenalidomide, are considered immediately 
reportable events. Lenalidomide  is to be discontinued immediately. 
The pregnancy, suspected pregnancy, or positive pregnancy test must 
be reported to Celgene Drug Safety immediately by facsimile or 
email using the Pregnancy Initial Report Form, or approved 
equivalent form. The female subject may be referred to an 
obstetrician-gynecologist, (not necessarily one with reproductive 
toxicity experience) or other appropriate healthcare professional for 
further evaluation. 
 
The Investigator will follow the female subject until completion of 
the pregnancy, and must notify Celgene Drug Safety immediately 
about the outcome of the pregnancy (either normal or abnormal 
outcome) using the Pregnancy Follow-up Report Form, or approved 
equivalent form.   
 
IF THE OUTCOME OF THE PREGNANCY WAS 
ABNORMAL (E.G., SPONTANEOUS OR THERAPEUTIC 
ABORTION), THE INVESTIGATOR SHOULD REPORT THE 
ABNORMAL OUTCOME AS AN AE. IF THE ABNORMAL 
OUTCOME MEETS ANY OF THE SERIOUS CRITERIA, IT 
MUST BE REPORTED AS AN SAE TO CELGENE DRUG 
SAFETY IMMEDIATELY BY FACSIMILE, OR OTHER 
APPROPRIATE METHOD, WITHIN 24 HOURS OF THE 
INVESTIGATOR’S KNOWLEDGE OF THE EVENT USING 
THE SAE REPORT FORM OR APPROVED EQUIVALENT 
FORM. 
 
All neonatal deaths that occur within 28 days of birth should be 
reported, without regard to causality, as SAEs. In addition, any infant 
death after 28 days that the Investigator suspects is related to the in 
utero exposure to the IP should also be reported to Celgene Drug 
Safety immediately by facsimile, or other appropriate method, within 
24 hours of the Investigator’s knowledge of the event using the SAE 
Report Form, or approved equivalent form.  

Addendum 2 
32  
RU051417I 
 
Male Subjects 
 
If a female partner of a male subject taking investigational product 
becomes pregnant, the male subject taking lenalidomide should 
notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately. 
 
10.336 Overdose 
 
Overdose, as defined for this protocol, refers to Lenalidomide 
(Revlimid®) in pill form with R-ICE (Rituximab-Ifosfamide-Carboplatin-
Etoposide)IV chemotherapy dosing only.   
 
On a per dose basis, an overdose is defined as the following amount over 
the protocol-specified dose of Lenalidomide (Revlimid®) in pill form 
with R-ICE (Rituximab-Ifosfamide-Carboplatin-Etoposide assigned to a 
given patient, regardless of any associated adverse events or sequelae. 
 
PO any amount over the protocol-specified dose 
IV 10% over the protocol-specified dose   
SC 10% over the protocol-specified dose 
 
On a schedule or frequency basis, an overdose is defined as anything 
more frequent than the protocol required schedule or frequency.   
 
On an infusion rate basis, an overdose is defined as any rate faster than 
the protocol-specified rate.  Complete data about drug administration, 
including any overdose, regardless of whether the overdose was 
accidental or intentional, should be reported in the case report form.    
 
Celgene Drug Safety Contact Information: 
 
      
    
      
     
        
 
 
 

Addendum 2 
33  
RU051417I 
 
10.4 
Expedited Adverse Event Reporting Requirements for IND/IDE Agents   
 
10.41  Expedited Reporting via the ACCRU Adverse Event Expedited Report Form for 
Adverse Events That Occur Within 30 Days1 of the Last Dose of the Investigational 
Agent 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in Section 10.33 
of the protocol.  
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
Additional Instructions: 
1. Any event that results in persistent or significant disability/incapacity, congenital anomaly, or 
birth defect must be reported via expedited mechanisms if the event occurs following 
treatment on a trial under an IND. 

Addendum 2 
34  
RU051417I 
 
2. Use the ACCRU protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
3.  ACCRU Sites: Provide copies by fax 
to the ACCRU SAE Coordinator.  
The ACCRU SAE Coordinator will then electronically send the report to Celgene:  
 
      
    
      
     
        
  
 
The above expedited reports (24-hour and 3 or 7 day) must be submitted via the ACCRU Adverse  
Event Expedited Report Form.   
 
Submit reports to the ACCRU SAE Coordinator via fax 
   
 
4. Once the ACCRU SAE Coordinator receives the report via fax, the ACCRU SAE 
Coordinator will forward a copy of the above expedited reports to: 
 
• 
The ACCRU IND Coordinator, who will notify the FDA as warranted by the event and 
stipulated in the U.S. Code of Federal Regulations. 
 
• 
Celgene:  
 
 
Expedited Reporting by Investigator to Celgene: 
 
For the purpose of regulatory reporting, Celgene Drug Safety will determine the 
expectedness of events of being related to lenalidomide based on the Investigator 
Brochure.  In the United States, all suspected unexpected serious adverse reactions 
(SUSARs) will be reported in an expedited manner in accordance with 21 CFR 312.32. 
 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene 
in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 
24 hours of being aware of the event.  The written report must be completed and supplied 
to Celgene by facsimile within 24 hours of being aware of the event.  The initial report 
must be as complete as possible, including an assessment of the causal relationship 
between the event and the investigational product(s).  Information not available at the 
time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report.  A final report to 
document resolution of the SAE is required.  The Celgene tracking number (RV-CL-
DLBCL-ACCRU-004373) and the institutional protocol number should be included on  
 
 

Addendum 2 
35  
RU051417I 
 
SAE reports (or on the fax cover letter) sent to Celgene.  A copy of the fax transmission 
confirmation of the SAE report to Celgene should be attached to the SAE and retained 
with the patient records. 
 
 
    
    
        
 
 
10.5 
Other Required Reporting 
 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in general, 
include any incident, experience, or outcome that meets all of the following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures involved in the 
research); and 
 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
Some unanticipated problems involve social or economic harm instead of the physical or 
psychological harm associated with adverse events.  In other cases, unanticipated 
problems place subjects or others at increased risk of harm, but no harm occurs. 
 
Note: If there is no language in the protocol indicating that pregnancy is not considered 
an adverse experience for this trial, and if the consent form does not indicate that subjects 
should not get pregnant/impregnate others, then any pregnancy in a subject/patient or a 
male patient’s partner (spontaneously reported) which occurs during the study or within 
120 days of completing the study should be reported as a UPIRTSO. 
 
If the event meets the criteria for an UPIRTSO, submit to your IRB as required by your 
institutional policies.   
 
 

Addendum 2 
36  
RU051417I 
 
10.52 Pre-treatment symptoms/conditions to be graded at baseline and adverse events to be 
graded at each evaluation per the CTCAE v4.0 grading unless otherwise stated in the 
table below: 
 
 
System Organ 
Class (SOC) 
 
Adverse event/Symptoms 
 
Baseline 
Each  
evaluation 
Infections and 
Infestations  
Hepatitis viral* 
X 
X 
Vascular 
Disorders 
Thromboembolic Event 
X 
X 
Blood and 
lymphatic system 
disorders 
Febrile neutropenia 
X 
X 
Gastrointestinal 
disorders 
Upper gastrointestinal 
hemorrhage 
X 
X 
Skin and 
subcutaneous 
tissue disorders 
Rash Maculopapular  
X 
X 
*See Drug Information Section 15.27. 
 
10.53 Case Report Forms - Academic and Community Cancer Research United 
(ACCRU) 
 
 
Submit the following AEs not specified in Section 10.5 (paper or electronic, as 
applicable): 
 
10.531 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.532 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.533  Grade 5 AEs (Deaths) 
 
10.5331 Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the 
study treatment or procedure. 
 
10.5332 Any death more than 30 days after the patient’s last 
study treatment or procedure that is felt to be at least 
possibly treatment related must also be submitted as a 
Grade 5 AE, with a CTCAE type and attribution 
assigned. 
 
10.54   Late-Occurring Adverse Events - Refer to the instructions in the Forms Packet 
(or electronic data entry screens, as applicable) regarding the submission of late 
occurring AEs following completion of the Active Monitoring Phase (i.e., 
compliance with Test Schedule in Section 4.0). 
 
 

Addendum 2 
37  
RU051417I 
 
11.0 
Treatment Evaluation Using PET/CT Cheson’s response criteria for malignant lymphoma 
 
11.1 
Response Considerations (Lymphoma) 
 
 
Schedule of Evaluations:  For the purposes of this study, patients should be evaluated for 
response at cycle 2 day 21. 
 
 
Definitions for clinical response for patients with lymphoma are from the recently revised 
Cheson’s et al criteria published in 2014, derived from the original criteria published in 
2007 (Cheson, 2014 and Cheson, et al 2007). Lymph node measurements should be taken 
from the CT portion of the PET/CT, or other dedicated CT scans where applicable.  
Measurement of lymphadenopathy will be determined by adding the sum of the products 
of the maximal perpendicular diameters of measured lesions (SPD).  Measurable extra 
nodal disease should be assessed in a manner similar to that for nodal disease. For these 
recommendations, the spleen is considered nodal disease. Disease that is only assessable 
(e.g., pleural effusions, bone lesions) will be recorded as present or absent only, unless, 
while an abnormality is still noted by imaging studies or physical examination, it is found 
to be histologically and pathologically negative. 
 
Response is based on PET/CT based on the revised 2014 Cheson’s criteria (Cheson 
2014). 
 
PET/CT scans are required at baseline and after 2 cycles of treatment for all 
patients and should be submitted per instructions in Appendix III. 
 
 

Addendum 2 
38  
RU051417I 
 
Response criteria (Cheson, 2014)  
 
PET-CT Based Response 
CT-Based Response 
Complete 
Response 
Complete metabolic response (CMR) 
 
Complete radiologic response (CR) 
(all of the following) 
 Lymph 
nodes 
and 
extralymphatic 
sites   
Score 1, 2, or 3*  with or without a residual mass 
on 5PS† 
It is recognized that in Waldeyer’s ring or 
extranodal sites with high physiologic uptake or 
with activation within spleen or marrow (eg, with 
chemotherapy or myeloid colony-stimulating 
factors), uptake may be greater than normal 
mediastinum and/or liver. In this circumstance, 
complete metabolic response may be inferred if 
uptake at sites of initial involvement is no greater 
than surrounding normal tissue even if the tissue 
has high physiologic uptake 
Target nodes/nodal masses must regress 
to ≤ 1.5 cm in LDi 
No extralymphatic sites of disease 
Nonmeasured 
lesion 
Not applicable 
Absent 
Organ 
enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if indeterminate, 
IHC negative 
Partial 
Response 
Partial metabolic response (PMR) 
Partial remission (PR) 
(all of the following) 
 Lymph 
nodes 
and 
extralymphatic 
sites   
Score 4 or 5† with reduced uptake compared with 
baseline and residual mass(es) of any size 
At interim, these findings suggest responding 
disease 
At end of treatment, these findings indicate 
residual disease 
≥ 50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites 
When a lesion is too small to measure on 
CT, assign 5 mm X 5 mm as the default 
value 
When no longer visible, 0 X 0 mm 
For a node > 5 mm X 5 mm, but smaller 
than normal, use actual measurement for 
calculation 
 
Nonmeasured 
lesions 
Not applicable 
Absent/normal, 
regressed, 
but 
no 
increase 
Organ 
enlargement 
Not applicable 
Spleen must have regressed by > 50% in 
length beyond normal 
New lesions 
None 
None 
Bone marrow  
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive changes 
from chemotherapy allowed). If there are 
persistent focal changes in the marrow in the 
context of a nodal response, consideration should 
be given to further evaluation with MRI or biopsy 
or an interval scan 
 
Not Applicable  

Addendum 2 
39  
RU051417I 
 
No Response or 
Stable Disease 
No metabolic response (NMR) 
Stable disease (SD) 
Target 
nodes/nodal 
masses, 
extranodal 
lesions 
Score 4 or 5 with no significant change in FDG 
uptake from baseline at interim or end of 
treatment 
< 50% decrease from baseline in SPD of 
up to 6 dominant, measurable nodes and 
extranodal 
sites; 
no 
criteria 
for 
progressive disease are met 
Nonmeasured 
lesions 
Not applicable 
No increase consistent with progression  
Organ 
enlargement 
Not applicable 
No increase consistent with progression  
New lesions 
None 
None 
Bone marrow  
No change from baseline 
Not Applicable 
Progressive 
disease 
Progressive metabolic disease (PMD) 
Progressive disease (PD) 
requires at least 1 of the following 
Individual target 
nodes/nodal 
masses 
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or 
 
New FDG-avid foci consistent with lymphoma at 
interim or end-of-treatment assessment 
PPD progression: 
 
An individual node/lesion must be 
abnormal with:  
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the 
splenic length must increase by > 50% of 
the extent of its prior increase beyond 
baseline (eg, a 15-cm spleen must 
increase to 
> 16 cm). If no prior splenomegaly, must 
increase by at least 2 cm from baseline 
New or recurrent splenomegaly 
Extranodal 
lesions 
Non-measured 
lesions 
None 
New or clear progression of preexisting 
non-measured lesions 
New lesions 
New FDG-avid foci consistent with lymphoma 
rather than another etiology (eg, infection, 
inflammation). If uncertain regarding etiology of 
new lesions, biopsy or interval scan may be 
considered 
Regrowth of previously resolved lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in any 
axis; if < 1.0 cm in any axis, its presence 
must be unequivocal and must be 
attributable to lymphoma 
Assessable 
disease 
of 
any 
size 
unequivocally attributable to lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, 
positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis 
perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions. 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to 

Addendum 2 
40  
RU051417I 
 
consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to six of 
the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two 
diameters. Nodes should preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, liver, spleen, kidneys, 
lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not 
selected as measured, dominant disease and truly assessable disease should be considered not measured. These 
sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not 
meet the requirements for measurability but are still considered abnormal, as well as truly assessable disease, 
which is any site of suspected disease that would be difficult  to follow  quantitatively with  measurement, 
including pleural effusions,  ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions 
that cannot be confirmed  and followed  by imaging. In Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, 
bone marrow), FDG uptake may be greater than in the mediastinum with  complete metabolic response, but  
should be no higher than surrounding normal physiologic uptake (eg, with  marrow  activation as a result  of  
chemotherapy or myeloid growth factors). 
†PET 5PS: 1, no uptake above background; 2, uptake ≤mediastinum; 3, uptake > mediastinum but ≤ liver; 4, 
uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma. 
 
 
12.0 
Descriptive Factors   
 
12.1   Phase I only:  Dose level (as assigned by registration office):     -2 vs. -1 vs. 1 vs. 2  
 
12.2   International Prognostic Index (IPI) [Shipp et al, 1993]:  low risk (0 or 1 risk factors) vs. 
low intermediate (2 risk factors) vs. high intermediate (3 risk factors) vs. high (4 or 5 risk 
factors) 
 
Risk Factors 
0 points 
1 point 
Age 
≤ 60 yrs. 
> 60 yrs. 
Serum LDH 
≤ 1 x normal 
> 1 x normal 
ECOG PS 
0 or 1 
≥2 
Stage  
I or II 
III or IV 
Extranodal involvement 
≤1 site 
>1 site 
 
 
Total number of risk factors = sum of the number of points for each prognostic factor. 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
 
13.1 
Patients who are CMR, PMR, or NMR will continue treatment per protocol for 2 cycles.  
The patient may receive a 3rd and 4th cycle of treatment per MD discretion. 
 
13.2 
Patients who develop PMD while receiving therapy will go to the event-monitoring 
phase. 
 
13.3 
Patients who go off protocol treatment for reasons other than PMD will go to the event-
monitoring phase per Section 18.0. 
 

Addendum 2 
41  
RU051417I 
 
13.4 
Phase I Only:   If a patient fails to complete the first cycle of treatment for reasons other 
than toxicity, the patient will be regarded as not evaluable and will be replaced.    
 
 
13.5 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 
of the protocol.  
• 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted.  No further data submission 
is necessary. 
  
13.6 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event-monitoring phase of the study.  The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered.  Event monitoring 
will be required per Section 18.0 of the protocol. 
13.7 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  No further data submission is necessary. 
 
14.0 
Body Fluid Biospecimens   
 
14.1  Body Fluid Biospecimen Submission 
 
14.11  Summary Table of Body Fluid Biospecimens for This Protocol 
Type of 
biospecimen to 
submit 
Mandatory 
or optional 
When to submit 
Reason for submission 
(background/ 
methodology section) 
Where to 
find specific 
details for 
specimen 
submission 
Blood/blood 
products 
Mandatory 
Serial Draws 
Correlative Studies (Section 
14.31) 
Section 14.2 
 
14.2 
Blood/Blood Products Handling 
 
14.21 Kits are required for this study. 
 
14.211 The kit contains supplies and instructions for collecting, processing, and 
shipping specimens. 
 
 

Addendum 2 
42  
RU051417I 
 
14.212 Participating institutions may obtain kits by completing and faxing the 
Supply Order Form (found in the Forms Packet) to the number listed on 
the form.  Fill out the site address to where the kits will be shipped on the 
fax supply form.  Because we are now being charged for all outgoing 
kits, a small, but sufficient, supply of the specimen collection kits should 
be ordered prior to patient entry. Do not send unused kits back to BAP. 
 
14.213 Kits will be sent via FedEx® Ground at no additional cost to the 
participating institutions.  Allow at least two weeks to receive the kits. 
 
14.214 Kits will not be sent via rush delivery service unless the participating 
institution provides their own FedEx® account number or alternate 
billing number for express service.  ACCRU will not cover the cost for 
rush delivery of kits. 
 
14.22 All samples must be collected Monday-Thursday ONLY. 
 
14.23 Label specimen tubes with protocol number, ACCRU patient ID number, and 
time and date blood drawn. 

Addendum 2 
43  
RU051417I 
 
 
14.24 Collect and process all blood/blood products according to specific kit instructions and table below. 
 
Mandatory  
Collection 
tube 
description 
and/or 
additive 
(color of 
tube top) 
Volume to 
collect per 
tube 
(number 
of tubes to 
be 
collected) 
Blood product 
being 
processed and 
submitted by 
participating 
site 
After  
registration, 
but prior to 
treatment 
Cycle 1 
Day 1 
Cycle 1 
Day 2 
Cycle 1 
Day3 
At 
restaging 
after cycle 
2, i.e. at 
time of 
PET 
scan/end of 
treatment 
Additional 
processing 
required at 
site after 
blood 
draw? 
Storage/ 
shipping 
conditions1 
Mandatory 
ACD 
(yellow) 
10 ml (1) 
Whole Blood 
X 
 
 
X 
No 
Refrigerate/c
old pack (DO 
NOT 
FREEZE) 
Mandatory 
EDTA* 
(purple) 
10 ml (1) 
Whole Blood 
X 
 
 
X 
No 
Refrigerate/c
old pack (DO 
NOT 
FREEZE) 
Mandatory 
EDTA* 
(purple) 
10 ml (1) 
Whole Blood 
X 
X 
X 
X 
No 
Refrigerate/c
old pack (DO 
NOT 
FREEZE) 
Mandatory 
None 
(red) 
10mL(1) 
 
Whole Blood 
X 
 
 
X 
No 
Refrigerate/c
old pack (DO 
NOT 
FREEZE) 
Total      
(100 cc) 
 
 
 
40 cc 
10 cc 
10 cc 
40 cc 
 
 
 
1 After all samples have been collected according to kit instructions, ship all specimens according to shipping instructions (see Section 14.25 for detailed 
shipping instructions.) 
 
14.25 Shipping 
 
14.251 Verify ALL sections of the Blood Specimen Submission Form (see Forms Packet), Mayo Medical Laboratories 
(BAP) Requisition Form (provided in kit), and specimen collection labels are completed and filled in correctly.  
Enter information from the Blood Specimen Submission 

Addendum 2 
44  
RU051417I 
 
  
14.252 Specimens must be shipped the same day they are drawn. 
 
14.253 Ship ACD, EDTA, and no additive (red top) whole blood tubes with a properly prepared cold pack.  See kit 
instructions for specific details for cold pack preparation (i.e., frozen or refrigerated) and proper packing of blood 
and cold pack to avoid freezing of specimen. 
 
14.254 Ship specimens via Priority Overnight service, Monday – Thursday ONLY, to Mayo Foundation, 
 
Do not collect or send samples the day before, the day of, or the observed day of a national 
holiday. Friday Shipments are allowed as long as the shipment is marked for Saturday delivery.    
 
14.255  The BAP  kits will contain a smart shipper label (white barcoded label) affixed to the white colored shipping 
boxes.  The smart shipper label is a pre-addressed return label, which replaces the need for an airbill.  Shipping 
costs will be covered by ACCRU if this brown colored box is used for shipping specimens to Mayo Foundation 
 
 
 
 
 

Addendum 2 
45  
RU051417I 
 
14.3 
Study Methodology and Storage Information 
 
Collection 
tube 
description 
and/or 
additive 
(color of 
tube top) 
Component 
Available 
Minimal 
Residual 
Disease 
assessment 
(MRD) 
Cell Surface 
Markers 
(Flow 
Cytometry) 
DNA 
(SNPs) 
RNA 
Western 
blotting 
Cytokines 
ACD 
(yellow) 
Mononuclear 
cells 
(from 
Ficoll) 
 
X 
(preferred) 
X 
X 
X 
 
EDTA 
(purple) 
Plasma 
X 
 
 
 
 
X 
EDTA 
(purple) 
Buffy coat  
 
X 
X 
(preferred) 
 
X 
 
None 
(red) 
Serum 
 
 
 
 
 
X 
EDTA 
Whole Blood 
X 
 
 
 
 
 
 
14.31 Blood/blood product samples will be collected for protocol specific research.  The following paragraphs offer descriptions 
of current assays being run on lymphoma trials.  These may vary by protocol.  
 
14.311 Serum free light chains: Serum will be processed from the red top tube and will be frozen, batched, and analyzed 
for serum free light chains in 
research laboratory, 
  In 
a recent publication by Martin at all (Translational Research 149(4): 231 - 235, 2007) 36% of patients with mantle 
cell lymphoma had positive serology for serum free light chains.  In this study we will assay for serum free light 
chains at on study and after two cycles of treatment. All samples will be evaluated with the Freelite serum free 
light chain assay (The Binding Site, Birmingham, UK).  This is a commercial assay run routinely in 
 
laboratory.  
 
14.312 Single nucleotide polymorphisms (SNPs) in host immune genes: Buffy coat will be isolated in the Laboratory 
of 
 
 
for future genomic DNA. We have previously demonstrated our 

Addendum 2 
46  
RU051417I 
 
 
ability to analyze SNPs in patients with lymphoma.  For example, 
Cerhan et al. (Blood 109: 5439 - 46) demonstrated that host gene SNP 
profiles could predict prognosis in follicular lymphoma.  This 
information is not yet available for mantle cell lymphoma; therefore we 
will study that in this protocol.  Genomic DNA samples will be batched 
and analyzed in the Mayo Clinic Cancer Center Genotyping Shared 
Resource. 
 
14.313 Vitamin D metabolites: Serum from the red top tube will be 
cryopreserved and batched for 25 hydroxy vitamin D levels.  These will 
be studied in the laboratory of Matthew T. E. Drake, M.D., Ph.D., Mayo 
Clinic Rochester, by liquid chromatography/tandem mass spectrometry.  
The rationale to study vitamin D in lymphoma comes from the finding 
that lymphoma is more common in climates with less sunshine.  A recent 
study in the Journal of Clinical Oncology (26:2984 - 2991, 2008) 
demonstrated a significant improvement in overall survival in colon 
cancer patients with a higher level of vitamin D. 
 
14.314 Serum Cytokines: Thirty cytokines, including pro-inflammatory, Th1 
and Th2 associated cytokines, will be analyzed for each time point. The 
cytokines to be analyzed are IL-1β, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-
6, IL-7, IL-8, IL-10, IL-12p40/p70, IL-13, IL-15, IL-17, TNF-α, IFN-α, 
IFN-γ, GM-CSF, MIP-1α, MIP-1β, IP-10, MIG, Eotaxin, RANTES, 
MCP-1, VEGF, G-CSF, EGF, FGF-basic, and HGF.  Assays will be run 
in triplicate according to the manufacturers’ protocol. Data will be 
collected using the Luminex-100 system Version 1.7 (Luminex, Austin, 
TX) available in our lab at the research base. Data analysis will be 
performed using the MasterPlex QT 1.0 system (MiraiBio, Alameda, 
CA). A five-parameter regression formula will be used to calculate the 
sample concentrations from the standard curves and a change of 50% 
from the baseline value will be considered significant. 
 
14.315 Flow cytometry: 1x106 cells will be washed in phosphate-buffered saline 
(PBS) containing 0.5% bovine serum albumin (BSA), incubated with 
specific antibodies to the marker in question and analyzed on a 
FACSCalibur flow cytometry (Becton-Dickinson).  Isotype controls will 
be done for each sample.  
 
14.4 
Return of Genetic Testing Research Results 
 
 
Because the results generated by the genetic testing included in this section are not 
currently anticipated to have clinical relevance to the patient or their family members, the 
genetic results will not be disclosed to the patients or their physicians. 
 
 
If at any time, genetic results are obtained that may have clinical relevance, IRB review 
and approval will be sought regarding the most appropriate manner of disclosure and 
whether or not validation in a CLIA-certified setting will be required.  Sharing of 
research data with individual patients should only occur when data have been validated 
by multiple studies and testing has been done in CLIA-approved laboratories. 
 
 

Addendum 2 
47  
RU051417I 
 
 
15.0 
Drug Information 
 
15.1 
Lenalidomide (Revlimid, CC-5013, CDC-501) – IND number 060100 
 
The most current version of the Investigator Brochure will be maintained in the 
study folder on the ACCRU website. Updated Investigator’s Brochures should 
be obtained from the study folder as they become available. 
 
Each investigator should obtain a copy of the Investigator’s Brochure prior to 
initiation of the study. 
 
Please consult the most current Investigator’s Brochure and package insert for 
complete drug information. 
 
15.11 Background: Lenalidomide has a wide range of effects, including the inhibition 
of hematopoietic tumor cell proliferation, the enhancement of T cells and natural 
killer (NK) cell activity, the modulation of stem cell differentiation, the inhibition 
of angiogenesis, and the inhibition of inflammation. 
 
15.12 Formulation: For clinical study, lenalidomide is provided as 1.25-, 2.5-, 5-, 10-, 
15-, 20-, and 25-mg capsules for oral administration. Each capsule contains 
lenalidomide as the active ingredient and the following inactive ingredients: 
anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate. 
 
The lenalidomide capsules are supplied in push-through blister foil or tamper-
evident, child-resistant, opaque, high-density polyethylene (HDPE) containers 
with HDPE caps. 
 
15.13 Preparation and storage: Lenalidomide should be stored at room 
temperature, between 59 and 86ºF (15-30ºC).  Store drug away from direct 
sunlight.   
 
15.14 Administration:  Capsules are administered by mouth daily with water. Patients 
should not break, chew or open the capsules. 
 
 
15.15 Pharmacokinetic information: 
a)  Absorption – Lenalidomide is rapidly absorbed following oral administration 
to subjects with multiple myeloma or MDS, with maximum plasma 
concentrations 
occurring 
between 
0.5 
and 
 
1.5 
hours 
post-dose. 
Co-administration with a high-fat and high-calorie meal in healthy subjects 
reduced the extent of absorption, resulting in an approximately 20% decrease in 
AUC and 50% decrease in Cmax in plasma.   
 
In the pivotal MM and MDS registration trials where the efficacy and safety were 
established for lenalidomide, the drug was administered without regard to food 
intake. Thus, lenalidomide can be administered with or without food. 
 
Multiple dosing (up to 100 mg BID) did not cause marked drug accumulation.   
 
 

Addendum 2 
48  
RU051417I 
 
 
b)  Distribution – In vitro (14C)-lenalidomide binding to plasma proteins is 
approximately 30%. 
 
c)  Metabolism – Lenalidomide undergoes limited metabolism. Unchanged 
lenalidomide is the predominant circulating component in humans. Two 
identified metabolites are hydroxy-lenalidomide and N-acetyl-lenalidomide; each 
constitutes less than 5% of parent levels in circulation. 
 
d)  Excretion – Elimination is primarily renal.  Approximately 65% to 85% of 
lenalidomide is eliminated unchanged through urinary excretion in subjects with 
normal renal function. The half-life of elimination is approximately 3 to 4 hours 
(2 to 3 hours in patients 5 to 21 years) at the clinically relevant doses (5 to 50 
mg/day). Steady-state levels are achieved within 4 days. 
 
15.16 Potential Drug Interactions:  In vitro studies demonstrate that lenalidomide is 
not a substrate of CYP enzymes. In addition, lenalidomide shows little inhibitory 
or induction potential towards the CYP enzymes in vitro. Hence, 
coadministration of CYP substrates, inhibitors, or inducers with lenalidomide is 
not likely to result in clinically relevant drug-drug interactions in humans.  
 
In vitro, lenalidomide is not a substrate of BCRP, MRP1, MRP2, MRP3, OAT1, 
OAT3, OATP1B1, OCT1, OCT2, MATE1, OCTN1, or OCTN2. Thus, it is 
unlikely that substrates or inhibitors of these transporters would affect 
lenalidomide disposition in humans. 
 
Lenalidomide is not an inhibitor of BSEP, BCRP, MRP2, OAT1, OAT3, 
OATP1B1, OATP1B3, or OCT2. Thus, lenalidomide is not anticipated to cause 
any significant drug-drug interactions due to inhibition of these transporters. 
 
Lenalidomide is not an inhibitor of UGT1A1 and is not anticipated to cause any 
significant drug-drug interactions due to UGT1A1 inhibition. 
 
In vitro, lenalidomide is a weak substrate, but not an inhibitor of P-glycoprotein 
(P-gp). 
 
Erythropoietic agents or other agents that may increase the risk of thrombosis, 
such as hormone replacement therapy and oral contraceptives, should be used 
with caution in patients with multiple myeloma receiving lenalidomide with 
dexamethasone. 
 
 
Periodic monitoring of digoxin plasma levels is recommended due to increased 
Cmax and AUC with concomitant lenalidomide therapy.  Close monitoring of PT 
and INR is recommended in multiple myeloma patients taking concomitant 
warfarin. 
 
15.17 Known potential toxicities:   
 
Pregnancy Warning: Lenalidomide, a thalidomide analogue, caused limb 
abnormalities in a developmental monkey study similar to birth defects caused by 
thalidomide in humans. If lenalidomide is used during pregnancy, it may cause 
birth defects or embryo-fetal death.  Pregnancy must be excluded before start of 

Addendum 2 
49  
RU051417I 
 
 
treatment. Prevent pregnancy during treatment by the use of two reliable methods 
of contraception. 
 
Very 
Common 
AEs 
(≥ 
10%): 
anemia, 
leukopenia, 
neutropenia, 
thrombocytopenia, cataracts, blurred vision, abdominal pain, constipation, 
diarrhea, dyspepsia, nausea, vomiting, asthenia, chills, edema including 
peripheral, fatigue, pyrexia, abnormal liver function tests, bronchitis, 
nasopharyngitis, pneumonia, rhinitis, upper respiratory tract infection, urinary 
tract 
infection 
weight 
decreased, 
decreased 
appetite, 
hyperglycemia, 
hypocalcemia, hypokalemia, arthralgia, back pain, bone pain, muscle spasms, 
musculoskeletal pain, myalgia, pain in extremity, dizziness, dysgeusia, headache, 
hypoesthesia, neuropathy peripheral, neuropathy, tremor, depression, insomnia, 
cough, dyspnea, epistaxis, pharyngitis, pulmonary embolism, dry skin, pruritus, 
rash, and deep vein thrombosis. 
 
Common (≥ 1% and < 10%): febrile neutropenia, granulocytopenia, hemolytic 
anemia, lymphopenia, pancytopenia, acute myocardial infarction, atrial 
fibrillation, cardiac failure, congestive heart failure, myocardial ischemia, 
palpitations, tachycardia, vertigo, upper abdominal pain, dry mouth,  toothache, 
chest pain, fall,  cholestasis, bacteremia, erysipelas, gastroenteritis, herpes 
simplex, herpes zoster, influenza, lower respiratory infection, respiratory 
infection, sinusitis, sepsis, contusion, alanine aminotransferase increased, c-
reactive protein increased, gamma-glutamyltransferase increased, dehydration, 
diabetes mellitus, gout, hyperuricemia, hypophosphatemia, hypomagnesemia, 
hyponatremia, iron overload, muscular weakness, acute myeloid leukemia, basal 
cell carcinoma, Myelodysplastic syndrome, squamous cell carcinoma of skin, 
tumor flare, tumor lysis syndrome, cerebrovascular accident, lethargy, 
paresthesia, peripheral sensory neuropathy, syncope, mood altered, renal failure, 
respiratory distress, erythema, hyperhidrosis, night sweats, hematoma, 
hypertension, hypotension, peripheral ischemia, thrombosis, and vasculitis. 
 
Uncommon, limited to important or life-threatening (< 1%): hypersensitivity, 
Graft vs. Host Disease 
 
The following additional adverse reactions have been reported in Celgene-
sponsored clinical studies and are considered by the company to be at least 
possibly related to the administration of lenalidomide: pneumonitis, transient 
abnormal liver laboratory tests, hyperthyroidism,  TLS, TFR, rhabdomyolysis, 
and allergic conditions, including angioedema, SJS, and toxic epidermal 
necrolysis.  These reactions are reported voluntarily from a population of 
uncertain size, so it is not possible to reliably estimate their frequency. 
 
Lenalidomide may have minor or moderate influence on the ability to drive and 
use machines. Fatigue, dizziness, somnolence, vertigo and blurred vision have 
been reported with the use of lenalidomide. Therefore, caution is recommended 
when driving or operating machines. 
  
Please refer to the Investigator’s Brochure for a more comprehensive list of 
treatment-emergent adverse events. 
 
 

Addendum 2 
50  
RU051417I 
 
 
15.18 Drug procurement:  Lenalidomide (Revlimid®) will be provided directly to 
research subjects for the duration of their participation in this trial at no charge to 
them or their insurance providers in accordance with the REVLIMID 
REMS™program.  Per standard requirements all physicians who prescribe 
lenalidomide for research subjects enrolled into this trial, and all research 
subjects enrolled into this trial, must be registered in and must comply with all 
requirements of the Celgene  REVLIMID REMS™ program.  Prescriptions must 
be filled within 7 days.  Consideration should be given to prescribing 
lenalidomide 5 to 7 days in advance of Day 1 of each cycle to allow time for 
required patient and prescriber surveys, and drug shipment to patient.  Only 
enough lenalidomide for one cycle of therapy will be supplied to the patient 
each cycle. 
 
Further information about the Revlimid REMS™ program is available at 
 
 
 
 
 Outdated or remaining drug is to be destroyed on-site as per procedures in 
place at each institution. 
 
 
15.19 Nursing Guidelines:  
 
15.191 Myelosuppression is dose-dependent and reversible with treatment 
interruption and/or dose reduction. Monitor CBC w/diff regularly. 
Instruct patient to report any unusual bruising or bleeding 
(thrombocytopenia); signs and symptoms of infection (neutropenia); and 
energy conserving lifestyle (anemia). 
15.192 Lenalidomide can have thrombotic adverse events (i.e DVT and PE). 
Instruct patient to report any limb swelling or pain, and to seek medical 
attention for shortness of breath or chest pain. 
15.193 Because of the potential for birth defects patients should be instructed in 
effective methods of birth control. Female patients should use 2 forms of 
birth control during treatment and for 4 weeks after discontinuing 
therapy. Males must be instructed to use a latex condom during any 
sexual contact with a woman of child bearing potential (even if they have 
had a vasectomy), because it is unknown if lenalidomide is present in 
semen. 
15.194 Patents may experience pruritus, rash and dry skin. Because of the rare 
risk of Steven’s Johnson Syndrome, patients should immediately report 
any rash to their provider. 
15.195 Drug may cause hyperglycemia. Patients with diabetes or impaired 
fasting glucose may need to have their glucose levels monitored more 
closely. 
15.196 Gastrointestinal side effects (diarrhea, constipation, nausea, dyspepsia, 
anorexia, etc) are commonly seen. Manage patent symptomatically and 
monitor for effectiveness. 
15.197 Patients may experience myalgias, arthralgias, and other generalized 
pain. Administer analgesics as ordered and monitor for their 
effectiveness. 
15.198 Upper respiratory symptoms (nasopharyngitis, cough, epistaxis, etc.) can 
be seen. Manage symptomatically and monitor for effectiveness. 

Addendum 2 
51  
RU051417I 
 
 
15.199 Agent may cause fatigue, dizziness, vertigo or blurred vision. Instruct 
patients to use caution when driving or operating machines.  
 
15.2 
Rituximab (Rituxan®, C2B8) 
 
 
 
Refer to the package insert for complete prescribing information. 
 
15.21 Background: Rituximab is a monoclonal antibody directed against the CD20 
antigen on B-lymphocytes. CD20 regulates cell cycle initiation; and, possibly, 
functions as a calcium channel. Rituximab binds to the antigen on the cell 
surface, activating complement-dependent cytotoxicity; and to human Fc 
receptors, mediating cell killing through an antibody-dependent cellular toxicity.  
 
15.22 Formulation: Commercially available for injection, solution [preservative free]: 
10 mg/mL (10 mL, 50 mL) [contains Polysorbate 80]. 
 
15.23 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store vials at refrigeration 
temperature, do not freeze or shake. Protect vials from direct sunlight. 
Withdraw the necessary amount of rituximab and dilute to a final 
concentration of 1-4 mg/mL with 0.9% NaCL or D5W. Gently invert the 
bag to mix the solution; do not shake. Solutions for infusion are stable at 
2ºC to 8ºC for 24 hours and at room temperature for an additional 24 
hours. 
 
15.24 Administration:  Do not administer I.V. push or bolus. Refer to treatment 
section for specific infusion instructions. Suggested administration guidelines 
are: 
Initial infusion: Start rate of 50 mg/hour; if there is no reaction, increase the rate 
by 50 mg/hr every 30 minutes, to a maximum of 400 mg/hour. 
Subsequent infusions: If patient did not tolerate initial infusion follow initial 
infusion guidelines. If patient tolerated initial infusion, start at 100 mg/hour; if 
there is no reaction; increase the rate by 100 mg/hour every 30 minutes, to a 
maximum of 400 mg/hour.  
Note: If a reaction occurs, slow or stop the infusion. If the reaction abates, restart 
infusion at 50% of the previous rate. 
 
Accelerated infusion rate (90 minutes): For patients with previously untreated 
follicular NHL and diffuse large B-cell NHL who are receiving a corticosteroid 
as part of their combination chemotherapy regimen, have a circulating 
lymphocyte count <5000/mm3, or have no significant cardiovascular disease. 
After tolerance has been established (no grade 3 or 4 infusion-related event) at 
the recommended infusion rate in cycle 1, a rapid infusion rate may be used 
beginning with cycle 2. The daily corticosteroid, acetaminophen, and 
diphenhydramine are administered prior to treatment, then the rituximab dose is 
administered over 90 minutes, with 20% of the dose administered over the first 
30 minutes and the remaining 80% is given over 60 minutes. If the 90-minute 
infusion in cycle 2 is tolerated, the same rate may be used for the remainder of 
the treatment regimen (through cycles 6 or 8). 
 
 

Addendum 2 
52  
RU051417I 
 
 
15.25 Pharmacokinetic information: 
Duration: Detectable in serum 3-6 months after completion of treatment; 
B-cell recover begins ~6 months following completion of treatment;  
 
median B-cell levels return to normal by 12 months following completion 
of treatment 
Distribution: RA:  3.1 L; GPA/MPA:  4.5 L 
Absorption:  Immediate and results in a rapid and sustained depletion of 
circulating and tissue-based B cells 
Half-life elimination: Proportional to dose; wide ranges reflect variable 
tumor burden and changes in CD20 positive B-cell populations with 
repeated doses: 
Following first dose: Mean half-life: 3.2 days  
Following fourth dose: Mean half-life: 8.6 days 
CLL: Median terminal half-life: 32 days 
NHL: Median terminal half-life: 22 days 
RA: Mean terminal half-life: 18 days 
GPA/MPA:  23 days 
Excretion: Uncertain; may undergo phagocytosis and catabolism in the 
reticuloendothelial system  
 
 
15.26 Potential Drug Interactions:   
Increased Effect/Toxicity: Monoclonal antibodies may increase the risk 
for allergic reactions to rituximab due to the presence of HAC antibody. 
Antihypertensive medications may exacerbate hypotension. 
Decreased Effect: Currently recommended not to administer live vaccines 
during rituximab treatment. 
 
Herb/Nutraceutical Interactions: Avoid hypoglycemic herbs, including 
alfalfa, bilberry, bitter melon, burdock, celery, domain, fenugreek, 
grainier, garlic, ginger, ginseng, gymnema, marshmallow, and stinging 
nettle (may enhance the hypoglycemic effect of rituximab). Monitor. 
 
 
 

Addendum 2 
53  
RU051417I 
 
 
Immunosuppressants:  Rituximab may enhance the adverse/toxic effects 
of pimecrolimus, tacrolimus and to a lesser extent of denosumab. 
 
Rituximab may enhance the adverse/toxic effects of abatacept, belimumab, 
clozapine, dipyrone and tofacitinib. 
 
15.27 Known potential adverse events: Consult the package insert for the most 
current and complete information. Refer to the package insert pertaining to 
the following boxed warnings: Severe infusion reactions; Progressive 
multifocal leukoencephalopathy (PML); Tumor lysis syndrome leading to 
acute renal failure; and severe and sometimes fatal mucocutaneous 
reactions (lichenoid dermatitis, paraneoplastic pemphigus, Stevens-
Johnson syndrome, toxic epidermal necrolysis and vesiculobullous 
dermatitis).  
Common known potential toxicities, > 10%:   
Cardiovascular: Peripheral edema, hypertension 
Central nervous system: Fever, fatigue, chills, headache, insomnia, pain 
Dermatologic: Rash, pruritus, angioedema 
Gastrointestinal: Nausea, diarrhea, abdominal pain, weight gain 
Hematologic: Lymphopenia, anemia, leukopenia, neutropenia, neutropenic 
fever, thrombocytopenia 
Hepatic: ALT increased 
Neuromuscular & skeletal: Neuropathy, weakness, muscle spasm, 
arthralgia 
Respiratory: Cough, rhinitis, epistaxis 
Miscellaneous: Infection, night sweats, mild-to-moderate infusion-related 
reactions: Chills, fever, rigors, dizziness, hypertension, myalgia, nausea, 
pruritus, rash, and vomiting. 
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Hypotension, peripheral edema, hypertension, flushing, 
edema 
Central nervous system: Dizziness, anxiety, agitation, migraine 
Dermatologic: Urticaria 
Endocrine & metabolic: Hyperglycemia 
Gastrointestinal: Vomiting, dyspepsia,  
Neuromuscular & skeletal: Back pain, myalgia, paresthesia 
Ocular: Conjunctivitis, lacrimation disorder 
Respiratory: Dyspnea, throat irritation, bronchospasm, upper respiratory 
tract infection, sinusitis 
Miscellaneous: LDH increased 
 
Rare known potential toxicities, <1% (Postmarketing and/or case 
reports):  
Acute renal failure (associated with tumor lysis syndrome), anaphylactoid 
reaction/anaphylaxis, angina, aplastic anemia, ARDS, arrhythmia, bowel 
obstruction, bronchiolitis obliterans, cardiac failure, cardiogenic shock, 
disease progression (Kaposi’s sarcoma), fatal infusion-related reactions, 
gastrointestinal perforation, hemolytic anemia, hepatic failure, hepatitis, 
hepatitis B reactivation, hyperviscosity syndrome (in Waldenstrom’s 
macroglobulinemia), 
hypoxia, 
interstitial 
pneumonitis, 
lichenoid 

Addendum 2 
54  
RU051417I 
 
 
dermatitis, lupus-like syndrome, marrow hypoplasia, MI, neutropenia, 
optic 
neuritis, 
pancytopenia, 
paraneoplastic 
pemphigus, 
pleuritis, 
pneumonia, pneumonitis, polyarticular arthritis, pure red cell aplasia, renal 
toxicity, serum sickness, Stevens-Johnson syndrome, supraventricular 
arrhythmia, systemic vasculitis, toxic epidermal necrolysis, urticaria, 
uveitis, 
vasculitis 
with 
rash, 
ventricular 
fibrillation, 
ventricular 
tachycardia, vesiculobullous dermatitis, viral reactivation (includes JC 
virus [PML], cytomegalovirus, herpes simplex virus, parvovirus B19, 
varicella zoster virus, West Nile virus, and hepatitis C), wheezing 
 
15.28 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
 
15.29 Nursing Guidelines:  
 
15.291 Do not administer as an IV push or bolus since it increases the risk of a 
hypersensitivity reaction. 
 
15.292 Hypotension, bronchospasms, and angioedema have occurred in 
association with Rituxan infusion.  Because of this it is recommended 
that patients be pre-medicated with acetaminophen and diphenhydramine 
before infusion.  Stop infusion for severe reaction.  Infusion may be 
restarted at 50% rate after resolution of symptoms.  It is recommended 
that diphenhydramine, acetaminophen, epinephrine, bronchodilators, IV 
saline, and corticosteroids are available for immediate use in the event of 
a hypersensitivity reaction during administration. 
 
15.293 Patients should be cautioned to withhold their anti-hypertensive 
medication for 12 hours prior to drug administration. 
 
15.294 Patients with preexisting cardiac conditions including arrhythmias and 
angina have had recurrences of these events during Rituxan therapy and 
should be monitored throughout the infusion and immediate post-
infusion period. 
 
15.295 It has been found that patients with bulky disease (lesion >10 cm in 
diameter) have an increased incidence of adverse events. Monitor for 
signs and symptoms of tumor lysis syndrome, and acute renal failure. 
 
15.296 An infusion-related symptom complex consisting of fever and 
chills/rigors occurs in the majority of patients during the first infusion.  
These reactions generally occur within 30 minutes to 2 hours of 
beginning the first infusion and resolve with slowing or stopping the 
infusion and giving supportive care.  The incidence of adverse reactions 
decreased from 80% to 40% with subsequent infusions. 
 
15.297 Cytopenias are common and can be long term.  Monitor CBC.  Instruct 
patient to report signs and symptoms of infection, excessive bruising 
and/or bleeding to the health care team. 
 
 

Addendum 2 
55  
RU051417I 
 
 
15.298 GI disturbances (nausea, abdominal pain and, less commonly, diarrhea, 
vomiting, dyspepsia) headache, and weakness are common side effects.  
Treat as necessary.  Monitor for effectiveness. 
 
15.299 Adequate birth control measures should be used during therapy and for 
12 months following therapy.  Women should not breastfeed while drug 
is detectable in serum. 
 
15.299a Endocrine and metabolic disturbances can be seen 
(hyper/hypoglycemia, hypocalcemia, hypocholesterolemia, 
hyperphosphatemia, hyperuricemia). Monitor labs and for signs or 
symptoms of these conditions. Treat accordingly. 
 
15.299b There is the possibility of reactivation of Hepatitis B (HBV). Patients 
who are at high risk of hepatitis B virus should be screened prior to 
initiation of therapy. Carriers of hepatitis B should be closely 
monitored. 
 
15.3 
Ifosfamide 
 
 
 
Refer to the package insert for complete prescribing information. 
 
15.31 Background: Ifosfamide is an alkylating agent that prevents cell division by 
cross-linking DNA strands.  It inhibits protein synthesis and DNA synthesis. 
Ifosfamide is a cell cycle phase nonspecific agent.  
 
15.32 Formulation: Commercially available for injection as:  
 
Injection, solution: 1 gram/20 mL (20 mL), 3 gram/60 mL (60 mL) 
 
Injection, solution reconstituted, 1 gram, 3 gram 
 
15.33 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store intact vials at room temperature 
(either 20 to 25 ºC or 68 to 77 ºF). Injections are prepared by adding Sterile 
Water for Injection, USP or Bacteriostatic Water for Injection, USP (benzyl 
alcohol or parabens preserved), to the vial and shake to dissolve. 
 
Dosage 
Strength 
Quantity of 
Diluent 
Final 
Concentration 
1 gram 
20 mL 
50 mg/mL 
3 grams 
60 mL 
50 mg/mL 
 
 
Solutions of ifosfamide may be diluted further to achieve concentrations of 0.6 to 
20 mg/mL in the following fluids:  5% Dextrose Injection, USP; 0.9% Sodium 
Chloride Injection, USP; Lactated Ringer’s Injection, USP; Sterile Water for 
Injection, USP 
 
 
Reconstituted solutions should be refrigerated and used within 24 hours. Further 
dilutions are stable for 24 hours refrigerated. 
  
 
 

Addendum 2 
56  
RU051417I 
 
 
15.34 Administration:  Refer to the treatment section for specific administration 
instructions. Administer IV over at least 30 minutes (infusion times vary by 
protocol; refer to specific protocol for infusion duration). 
 
 
15.35 Pharmacokinetic information: 
Distribution: Vd: approximates total body water; penetrates the CNS, but not in 
therapeutic levels 
Protein binding: negligible 
Metabolism: Hepatic to active metabolites ifosforamide mustard, 4-hydroxy-
ifosfamide, acrolein, and inactive dichlorethylated and carboxy metabolites 
Half-life elimination: High dose (5000 mg/m2) ~ 15 hours; lower dose (1600-
2400 mg/m2) ~ 7 hours 
Excretion: High dose (5000 mg/m2) – urine (70-86%; 61% as unchanged drug); 
lower dose (1600-2400 mg/m2) – urine (12-18% as unchanged drug) 
 
 
15.36 Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of  CYP2B6 (major), 2C8 (minor), 2C9 
(minor), 3A4 (minor); Inhibits CYP3A4 (weak); Induces CYP2C9 
(weak/moderate)  
Increased Effect/Toxicity: Ifosfamide may increase the levels/effects of:  
Aripiprazole, clozapine, dofetilide, lefunomide, lomitapide, natalizumab, 
pimozide, tofacitinib, vaccines (live), vitamin K antagonists; levels of ifosfamide 
may be increased by:  Busulfan, CYP2B6 inhibitors (strong/moderate), CYP3A4 
inhibitors (strong/moderate), dabrafenib, denosumab, dofetilide, trastuzumab 
Decreased Effect: Ifosfamide may decrease the levels/effects of:  BCG, 
Coccidiodin skin test, sipuleucel-T, vaccines (inactivated), vaccines (live); levels 
of ifosfamide may be decreased by CY2B6 inducers, CYP3A4 inducers, 
echinacea 
 
15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
 
Common known potential toxicities, > 10%:   
Central nervous system:  CNS toxicity or encephalopathy 
Dermatologic:  Alopecia 
Endocrine & metabolic: Metabolic acidosis 
Gastrointestinal: Nausea and vomiting 
Hematologic: Leukopenia (nadir 8-14 days), anemia, thrombocytopenia 
Renal:  Hematuria 
 
Less common known potential toxicities, 1% - 10%:  
Central nervous system: Fever 
Gastrointestinal:  Anorexia 
Hematologic:  Neutropenic fever 
Hepatic:  Bilirubin increased, liver dysfunction, transaminases increased 
Local:  Phlebitis 
Renal: Renal impairment 
Miscellaneous:  Infection 
 
 
 

Addendum 2 
57  
RU051417I 
 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Acute respiratory distress syndrome, acute tubular necrosis, agranulocytosis, 
alkaline 
phosphatase 
increased, 
allergic 
reaction, 
alveolitis 
(allergic), 
amenorrhea, aminoaciduria, amnesia, anaphylactic reaction, angina, angioedema, 
anuria, arrhythmia, arthralgia, asterixis, atrial ectopy, atrial fibrillation/flutter, 
azoospermia, bladder irritation, bleeding, blurred vision, bone marrow failure, 
bradycardia, bradyphrenia, bronchospasm, bundle branch block, BUN increased, 
capillary leak syndrome, cardiac arrest, cardiogenic shock, cardiomyopathy, 
cardiotoxicity, catatonia, cecitis, chest pain, cholestasis, coagulopathy, colitis, 
conjunctivitis, creatinine clearance decreased/increased, creatinine increased, 
cylindruria, cytolytic hepatitis, delirium, delusion, dermatitis, diarrhea, DIC, 
DVT, dysesthesia, dyspnea, dysuria, echolalia, edema, ejection fraction 
decreased, enterocolitis, enuresis, enzymuria, erythema, extrapyramidal disorder, 
facial swelling, Fanconi syndrome, fatigue, gait disturbance, GGT increased, GI 
hemorrhage, glycosuria, gonadotropin increased, granulocytopenia, growth 
retardation (children), hemolytic anemia, hemolytic uremic syndrome, 
hemorrhagic cystitis, hepatic failure, hepatic sinusoidal obstruction syndrome 
(SOS; formerly veno-occlusive disease [VOD]), hepatitis fulminant, hepatitis 
(viral), hepatorenal syndrome, herpes zoster, hyperglycemia, hyper-/hypotension, 
hypersensitivity 
reactions, 
hypocalcemia, 
hypokalemia, 
hyponatremia, 
hypophosphatemia, hypoxia, ileus, immunosuppression, infertility, infusion site 
reactions (erythema, inflammation, pain, pruritus, swelling, tenderness), 
interstitial lung disease, jaundice, LDH increased, leukoencephalopathy, 
lymphopenia, malaise, mania, mental status change, methemoglobinemia, MI, 
mucosal inflammation/ulceration, multiorgan failure, mutism, myocardial 
hemorrhage, myocarditis, nephrogenic diabetes insipidus, neuralgia, neutropenia, 
oligospermia, oliguria, osteomalacia (adults), ovarian failure, ovulation disorder, 
palmar-plantar erythrodysesthesia syndrome, pancreatitis, pancytopenia, panic 
attack, paranoia, paresthesia, pericardial effusion, pericarditis, peripheral 
neuropathy, petechiae, phosphaturia, pleural effusion, Pneumocystis jiroveci 
pneumonia, pneumonia, pneumonitis, pollakiuria, polydipsia, polyneuropathy, 
polyuria, portal vein thrombosis, premature atrial contractions, premature 
menopause, progressive multifocal leukoencephalopathy, proteinuria, pruritus, 
pulmonary edema, pulmonary embolism, pulmonary fibrosis, pulmonary 
hypertension, QRS complex abnormal, radiation recall dermatitis, rash (including 
macular and papular), renal failure, renal parenchymal damage, renal tubular 
acidosis, respiratory failure, reversible posterior leukoencephalopathy syndrome 
(RPLS), rhabdomyolysis, rickets, salivation, secondary malignancy, seizure, 
sepsis, septic shock, SIADH, skin necrosis, spermatogenesis impaired, status 
epilepticus, sterility, Stevens-Johnson syndrome, stomatitis, ST segment 
abnormal, supraventricular extrasystoles, tachycardia, tinnitus, toxic epidermal 
necrolysis, tubulointerstitial nephritis, tumor lysis syndrome, T-wave inversion, 
uremia, urticaria, vasculitis, ventricular extrasystoles/fibrillation/tachycardia, 
ventricular failure, vertigo, visual impairment, wound healing impairment 
 
15.38 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
 
 

Addendum 2 
58  
RU051417I 
 
 
15.39 Nursing Guidelines: 
 
15.391 Monitor CBC. Myelosupression is dose limiting. Instruct patient to 
report any signs/symptoms of infection, unusual bruising or bleeding to 
the health care team. 
 
15.392 Nausea and vomiting are common. Premedicate with antiemetics as 
ordered and monitor for their effectivness. Provide for post 
administration antiemetics as ordered. Antiemetics with sedationg side 
effects should be avoided as these may mask potential CNS toxicities. 
 
15.393 Inform patient about alopecia. 
 
15.394 CNS toxicities are common.  Document patients baseline neurological 
status. Re-assess neurological status throughout treatment. Instruct 
patient or family member to report any of the following, somnolence, 
lethagy, 
ataxia, 
disorientation, 
confusion, 
dizziness, 
depressive 
symptoms, or coma to the health care team immediately. 
 
15.395 Ifosfamide can induce hemorrhagic cystitis, which is dose-limiting. 
Instruct patient to report any hematuria, dysuria or urinary frequency to 
the health care team immediately. It is important that Mesna always be 
used in conjunction with IFOS administration. Doses of Mesna should 
always be given on time. Oral mesna can be very nauseating. Provide for 
antiemetics when oral mesna is sent home with patient. Instruct patient 
that all doses must be taken in their entirety, and on time. If this is not 
possible due to nausea, patient must return to the clinic or the ER to have 
the missed dose and all subsequent doses administered IV. 
 
15.396 Monitor renal function tests. 
 
15.4 
Carboplatin (Paraplatin®, CBDCA) 
 
 
Refer to the package insert for complete prescribing information. 
 
15.41 Background: Carboplatin is an alkylating agent which covalently binds to DNA; 
interferes with the function of DNA by producing intrerstrand DNA cross-links. 
 
15.42 Formulation: Commercially available for injection as:  
Solution Reconstituted: 150 mg. 
Solution: 10 mg/mL (5 mL, 15 mL, 45 mL, 60 mL) 
 
15.43 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store intact vials at room 
temperature at 25ºC (77F); excursions permitted to 15ºC to 30ºC (59ºF to 
86ºF).  Protect from light. Further dilution to a concentration as low as 0.5 
mg/mL is stable at room temperature (25ºC) for 8 hours in 0.9% NaCl or 
D5W.Stability has also been demonstrated for dilutions in D5W in PVC 
bags at room temperature for 8 days; , however, the manufacturer states to 
use within 8 hours due to lack of preservative.  

Addendum 2 
59  
RU051417I 
 
 
 
15.44 Administration:  Refer to the treatment section for specific administration 
instructions. When administered as a part of a combination chemotherapy 
regimen, sequence of administration may vary by regimen; refer to specific 
protocol for sequence recommendation.  Needles or IV administration sets that  
contain aluminum should not be used in the preparation or administration of 
carboplatin; aluminum can react with carboplatin resulting in precipitate 
formation and loss of potency. 
 
 
15.45 Pharmacokinetic information: 
Distribution: Vd: 16 L/kg; into liver, kidney, skin, and tumor tissue. 
Protein binding: 0%; however the platinum from carboplatin becomes 
irreversibly bound to plasma proteins. 
Metabolism: Minimally hepatic to aquated and hydroxylated compounds. 
Half-life elimination: 
CrCl > 60 mL/min:  Carboplatin:  2.6-5.9 hours (based on dose of 300-500 
mg/m2); Platinum (from carboplatin): > 5 days. 
Excretion: Urine (~70% as carboplatin within 24 hours; 3% to 5% as 
platinum within 1-4 days). 
 
 
15.46 Potential Drug Interactions:   
Increased Effect/Toxicity: Aminoglycosides increase risk of ototoxicity 
and/or nephrotoxicity. When administered as sequential infusions, 
observational studies indicate a potential for increased toxicity when 
platinum derivatives (carboplatin, cisplatin) are administered before taxane 
derivatives (docetaxel, paclitaxel). 
Herb/Nutraceutical Interactions: Avoid black cohosh, dong quai in 
estrogen-dependent tumors.  
 
15.47 Known potential adverse events: Consult the package insert for the most 
current and complete information. Percentages reported with single-agent 
therapy. Note: Myelosuppression is dose related, schedule related, and 
infusion-rate dependent (increased incidences with higher doses, more 
frequent doses, and longer infusion times) and, in general, rapidly 
reversible upon discontinuation. 
 
Common known potential toxicities, > 10%:   
Central nervous system: Pain 
Endocrine & metabolic: Hyponatremia, hypomagnesemia, hypocalcemia, 
hypokalemia 
Gastrointestinal:Vomiting, abdominal pain, nausea   
Hematologic: Myelosuppression (dose related and dose limiting; nadir at 
~21 days; recovery by ~28 days), leukopenia, anemia, neutropenia, 
thrombocytopenia 
Hepatic: Alkaline phosphatase increased, AST increasedHypersensitivity:  
Hypersensitivity 
Neuromuscular & skeletal: Weakness 
Renal: Creatinine clearance decreased, BUN increased 
 
Less common known potential toxicities, 1% - 10%:  
Central nervous system: Peripheral neuropathy, neurotoxicity 

Addendum 2 
60  
RU051417I 
 
 
Dermatologic: Alopecia 
Gastrointestinal: 
Constipation, 
diarrhea, 
stomatitis/mucositis, 
taste 
dysgeusia 
Hematologic: Hemorrhagic/bleeding complications 
Hepatic: Bilirubin increased 
Infection: Infection 
Local: Pain at the injection site 
Neuromuscular & skeletal: Peripheral neuropathy 
Ocular: Visual disturbance 
Otic: Ototoxicity 
Renal: Creatinine increased 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Anaphylaxis, anorexia, bronchospasm, cardiac failure, cerebrovascular 
accident, dehydration, embolism, erythema, febrile neutropenia, hemolytic 
anemia (acute), hemolytic uremic syndrome, hyper-/hypotension, injection 
site reaction (pain, redness, swelling), limb ischemia (acute), malaise, 
metastases, pruritus, skin rash, tissue necrosis (associated with 
extravasation), urticaria, vision loss 
 
15.48 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
15.49 Nursing guidelines: 
 
15.491 Monitor CBC and PLTs.  Watch for profound neutropenia and give low 
count precautions and instructions as necessary.  Nadir occurs at 
approximately day 21 with recovery at day 28-30.  Thrombo-neutro-
leukopenia may be cumulative.  Thrombocytopenia can be dose-limiting 
and is more pronounced than with cisplatin.  It can be more severe in 
patients with previous chemotherapy, concurrent radiation therapy, or 
patients with impaired renal function.  Instruct patient to immediately 
report any unusual bruising or bleeding.  Anemia (70-90% of patients) 
may be symptomatic with asthenia being the most common complaint.  
Instruct patient in energy saving lifestyle. 
 
15.492 Assess baseline renal function (creatinine clearance).  Reduced renal 
function can contribute to an increased risk of thrombocytopenia.  
 
15.493 Monitor fluid status - encourage hydration. 
 
15.494 Advise patient of probable taste alterations.  Frequent oral hygiene is 
helpful.  Instruct patient in appropriate interventions to achieve and 
maintain optimal nutritional status. 
 
15.495 Older patients (>65) may experience some peripheral neuropathy with 
paresthesias.  Instruct patients to report any tingling, burning, loss of 
sensation. 
 
 

Addendum 2 
61  
RU051417I 
 
 
15.496 Mild nausea and vomiting occur in up to 94% of patients, 6-12 hours 
after 
treatment 
and 
may 
persist 
for 
24 
hours 
or 
longer.  
Diarrhea/cramping/constipation has been experienced by approximately 
17%. 
 
Premedicate 
with 
antiemetics/antidiarrheals—evaluate 
effectiveness. 
 
15.497 Administer following Taxol (in regimens that contain both drugs) to 
 
maximize cell kill. 
 
15.498  Patients have experienced allergic reactions while receiving carboplatin. 
Watch for signs and symptoms of hypersensitivity reactions. If these 
occur, stop drug immediately, notify MD, and treat appropriately. 
 
15.5 
Etoposide (VePesid®, Toposar®, VP16) 
 
Refer to the package insert for complete prescribing information. 
 
15.51 Background: Etoposide has been shown to delay transit of cells through the S 
phase and arrest cells in late S or early G2 phase. The drug may inhibit 
mitochondrial transport at the NADH dehydrogenase level or inhibit uptake of 
nucleosides into HeLa cells. It is a topoisomerase II inhibitor and appears to 
cause DNA strand breaks. Etoposide does not inhibit microtubular assembly. 
 
15.52 Formulation: Commercially available for injection as:  
 
Injection, solution: 20 mg/mL (5 mL, 25 mL, 50 mL)  
 
15.53 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store intact vials at room 
temperature of 25ºC (77ºF); do not freeze. Protect from light. Etoposide 
should be diluted to a concentration of 0.2-0.4 mg/mL in D5W or NS for 
administration. Diluted solutions have concentration-dependent stability; 
more concentrated solutions have shorter stability times. Precipitation may 
occur with concentrations > 0.4 mg/mL. Following dilution 0.9% Sodium 
Chloride or D5W to concentrations of 0.2-0.4 mg/mL, then drug is 
chemically stable for 96 and 24 hours at room temperature respectively.  
 
15.54 Administration:  Refer to the treatment section for specific administration 
instructions. Administer standard doses over at least 30-60 minutes to minimize 
the risk of hypotension. 
 
 
15.55 Pharmacokinetic information: 
Distribution: Vd: 7-171 L/m2; poor penetration across the blood-brain 
barrier; CSF concentrations <5% of plasma concentrations 
Protein binding: 94% to 98% 
Metabolism: Hepatic via CYP3A4 and 3A5, to various metabolites. 
Half-life elimination: Terminal 4-11 hours 
Excretion: Urine (56%; 45% as unchanged drug) within 120 hours; feces 
(44%) within 120 hours 
 
 
15.56 Potential Drug Interactions: 
Metabolism/Transport Effects: Substrate of  CYP1A2 (minor), 

Addendum 2 
62  
RU051417I 
 
 
CYP2E1 (minor), CYP3A4 (major), P-glycoprotein; Inhibits CYP2C9 
(weak), 3A4 (weak)  
Ethanol/Herb/Nutraceutical Interactions: Avoid ethanol (may increase 
GI irritation). Avoid concurrent St John’s wort; may decrease etoposide 
levels. 
 
15.57 Known potential adverse events: Consult the package insert for the most 
current and complete information. U.S. boxed warning: Severe dose-
limiting and dose-related myelosuppression with resulting infection or 
bleeding may occur. 
 
Common known potential toxicities, > 10%:   
Dermatologic: Alopecia 
Gastrointestinal: Nausea/vomiting, anorexia, diarrhea 
Hematologic:  Leukopenia, thrombocytopenia, anemia 
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Hypotension 
Gastrointestinal: Stomatitis, abdominal pain 
Hepatic: Hepatic toxicity 
Neuromuscular & skeletal: Peripheral neuropathy 
Miscellaneous: Anaphylactic-like reaction 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Amenorrhea, blindness (transient/cortical), cyanosis, extravasation, facial 
swelling, hypersensitivity, hypersensitivity-associated apnea, interstitial 
pneumonitis, laryngospasm, maculopapular rash, metabolic acidosis, MI, 
mucositis, myocardial ischemia, optic neuritis, perivasculitis, pruritus, 
pulmonary fibrosis, radiation-recall dermatitis, rash, reversible posterior  
leukoencephalopathy syndrome (RPLS), seizure, Stevens-Johnson  
syndrome, tongue swelling, toxic epidermal necrolysis, toxic megacolon, 
vasospasm 
 
15.58 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
 
 
15.59 Nursing Guidelines:  
 
15.591 Monitor CBC.  Neutropenia may be severe.  Instruct patients to report 
any sign/symptoms of infection to the health care team. 
 
 
 
 
15.592 Rare myocardial infarctions have been reported in patients who have 
received prior mediastinal XRT.  Instruct patient to report any chest pain, 
or racing of the pulse to the health care team immediately.  
 
 
 
 
15.593 Advise patient of possible mild, reversible alopecia. 
 
 
 

Addendum 2 
63  
RU051417I 
 
 
 
 
 
15.594 A rapid infusion may cause hypotension and/or allergic reaction; 
administer medication over 30-60 minutes and monitor VS during 
administration. 
 
 
 
 
15.595  Drug is a radiosensitizer and irritant.  Assess IV patency before and 
throughout infusion.  Patients who have receive prior radiation  may 
experience radiation recall.  Assess skin in these areas and monitor  
 
 
 
 
closely.  Instruct patient to report any rash or skin changes to the health 
care team immediately. 
 
 
 
 
15.596 
Anaphylaxis is rare but has been observed.  Symptoms may include 
hypotension, bronchospasm, fever, or chills.  Have the anaphylaxis tray 
available. 
 
 
 
 
15.597 
Nausea and vomiting are usually mild.  However the incidence is 
increased with oral administration.  Premedicate with antiemetics as 
ordered and monitor for their effectiveness.  
 
 
 
 
15.598 
Instruct patient in importance of maintaining adequate hydration to 
avoid hyperuricemia. 
 
 
 
 
15.599a Monitor liver function tests. 
 
 
 
 
15.599b VP16 solution is oil based and settles to bottom of bag or drip 
chamber.  Be sure to agitate bag to avoid reaction to concentrated 
solution.  Reaction would include flushing, shortness of breath, back 
pain, and anxiety. 
 
 
 
 
15.599c Advise patient that facial flushing is common and may occur even after 
administration. 
 
 
 
15.599d Monitor INR closely in patients on warfarin therapy, as VP-16 may 
increase PT time. 
 
 
 
15.599e May increase the toxicity of methotrexate or cyclosporine 
(cytotoxicity) when given concurrently. 
 
16.0  
Statistical Considerations and Methodology  
 
16.1 
Overview:  This is a phase I/II study designed to evaluate the safety and efficacy of the 
addition of lenalidomide to R-ICE (R2-ICE) for patients with first relapse or primary 
refractory diffuse large B-cell lymphoma.  The phase I portion is designed to determine 
the maximally tolerated dose (MTD) and toxicity profile of lenalidomide in combination 
with R-ICE using the standard cohort 3+3 design. The phase II portion will utilize a one-
stage design with an interim analysis to evaluate the overall response rate of R2-ICE. 
 
16.11  Primary Endpoint:  
 
The primary endpoint of the phase I portion of this trial is to assess the maximum 
tolerated dose (MTD) of the addition of lenalidomide to R-ICE.  The primary 
endpoint in the phase II portion of this trial is the overall response rate after two 
cycles of treatment. A response will be defined as a CMR or PMR noted as the 

Addendum 2 
64  
RU051417I 
 
 
objective status after two cycles of treatment.  Throughout Section 16.0, response 
will be considered synonymous with “success”, unless specified otherwise.  All 
patients meeting the eligibility criteria who have signed a consent form and have 
begun treatment will be evaluable for overall response, with the exception of 
patients who are determined to be a major treatment violation. 
 
16.12  Sample Size:  
 
The phase I portion of this study is expected to require a minimum of 9 and a 
maximum of 12 evaluable patients. DLBCL patients treated at the MTD in the 
phase I portion will also be included in the phase II portion. Additional evaluable 
patients will be accrued at the MTD dose level for a total of 45 evaluable patients 
in the phase II portion of this study.  If a patient is found to be ineligible after 
enrollment due to central pathology review, they will be replaced.  We anticipate 
accruing an additional 6 patients (2 phase I, 4 phase II) to account for 
ineligibility, cancellation, major treatment violation, or other reasons.  Maximum 
projected accrual is 63 patients. 
 
16.13  Accrual Rate and Study Duration:  
 
The anticipated accrual rate is 4-5 evaluable patients per month.  It is anticipated 
that it will likely take about 2 months to enroll, treat, and evaluate each set of 3 
patients in the phase I portion of this study.   The phase I portion is expected to 
take between 6 and 8 months. Once the phase II portion of the trial begins, we 
can expect to accrue the required patients in about 10-12 months. We can expect 
to begin final analysis approximately 1.25 years after beginning the phase II 
portion, i.e. as soon as the last patient accrued has completed the response 
evaluation after two cycles of treatment and data entry has been completed. The 
overall study duration is expected to be a maximum of 2 years.   
 
 
Phase I Portion  
 
16.2 
Study Design:  The phase I study is designed to determine the maximally tolerated dose 
(MTD) and toxicity profile of the addition of lenalidomide to R-ICE in patients with first-
relapse or primary refractory diffuse large B-cell lymphoma using the standard cohort 
3+3 design. Three patients will be treated at each dose level and observed for a minimum 
of three weeks (i.e. one full cycle) before new patients are treated.  Doses will not be 
escalated in any individual patient. 
 
16.21  MTD Definition: MTD is defined as the dose level below the lowest dose that 
induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of 
a maximum of 6 new patients). A total of 6 patients treated at the MTD will be 
sufficient to identify common toxicities at the MTD. For instance, those toxicities 
with an incidence of at least 25% will be observed with a probability of at least 
82% (1-(1-0.25)6). 
 
Refer to Section 7.62 for definition of dose-limiting toxicity (DLT). 
 
16.22 MTD Determination: 
 
Dose Escalation:  The phase I portion of this study will utilize a standard cohort 
of three design.   The dose levels to which patients will be assigned in sequential 

Addendum 2 
65  
RU051417I 
 
 
cohorts are described in Section 7.61.   The first cohort of three patients will be 
treated at dose level 1.  Decisions on when and how to dose escalate are 
described below. 
 
16.221  Three patients will be treated at a given dose level combination and 
observed for one cycle (3 weeks) to assess toxicity.  
 
16.222  If DLT is not seen in any of the 3 patients, 3 new patients will be accrued 
and treated at the next higher dose level. If DLT is seen in 2 or 3 of 3 
patients treated at a given dose level, then the next 3 patients will be 
treated at the next lower dose level, if only 3 patients were enrolled and 
treated at this lower dose level.  
 
16.223  If DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 
additional patients will be enrolled and treated at the same dose level. If 
DLT is seen in at least one of these additional three patients (≥2 of 6), the 
MTD will have been exceeded and further accrual will cease to this 
cohort. If dose-limiting toxicity (DLT) is not seen in any of the three 
additional patients, 3 new patients will be accrued and treated at the next 
higher dose level.  
 
16.224  After enrolling 6 patients on a specific dose level, if DLT is observed in 
at least 2 of 6 patients, then the MTD will have been exceeded and 
defined as the previous dose unless only 3 patients were treated at the 
lower dose level. In that case, 3 additional patients will be treated at this  
 
lower dose level such that a total of 6 patients are treated at the MTD to 
more fully assess the toxicities associated with the MTD. 
 
16.225  Dose de-escalation: If dose-limiting toxicity meets the stopping 
boundaries set by the above dose escalation algorithm at dose level 1 (for 
example, more than 1 out of 3 patients or more than 1 out of 6 patients), 
the next cohort of three patients will be entered at a dose level of -1. If 
dose level -1 meets the stopping boundaries, the next cohort of three 
patients will be entered at dose level -2.  Further dose re-escalation will 
depend on the toxicity profile observed at these dose levels, and re-
evaluation of the regimen by the study team may be done. 
 
16.226  If a patient fails to complete the first cycle of treatment for reasons other 
than toxicity, the patient will be regarded as inevaluable and will be 
replaced.    
 
 

Addendum 2 
66  
RU051417I 
 
 
16.227  Operating Characteristics for standard cohort of 3 design: The following 
table gives the probability of dose escalation at a single dose level as a 
function of the true probability of DLT at that level using the cohorts of 3 
design described above. 
 
True Rate 
of DLT (%) 
Probability of Dose Escalation 
10 
0.91 
20 
0.71 
30 
0.49 
40 
0.31 
50 
0.17 
 
16.23 Analysis Plans: All the relevant results pertaining to toxicity, MTD, response, 
timed endpoints and laboratory correlates will be examined in an exploratory and 
hypothesis-generating fashion. The small sample size and the heterogeneous 
patient population associated with phase I studies restricts the generalizability of 
the results. Any notable statistical result should only be viewed as preliminary 
evidence for further study in Phase II trials rather than a definitive finding in and 
of itself. 
 
16.231  Adverse Events Profile 
 
The number and severity of all adverse events (overall and by dose-
level) will be tabulated and summarized in this patient population. The 
Grade 3+ adverse events will also be described and summarized in a 
similar fashion. This will provide an indication of the level of tolerance 
for this treatment combination in this patient group.  
 
16.232  Toxicity Profile 
 
The term toxicity is defined as adverse events that are classified as 
either possibly, probably, or definitely related to study treatment.  Non-
hematologic toxicities will be evaluated via the ordinal CTC standard 
toxicity grading. Hematologic toxicity measures of thrombocytopenia, 
neutropenia, and leukopenia will be assessed using continuous variables 
as the outcome measures (primarily nadir) as well as categorization via 
CTC standard toxicity grading. 
  
Overall toxicity incidence as well as toxicity profiles by dose level and 
patient will be explored and summarized. Frequency distributions, 
graphical techniques and other descriptive measures will form the basis 
of these analyses.  
 
16.233  Response Profile   
 
A response is defined to be a CMR or PMR noted as the objective status 
after 2 cycles of treatment.  All patients meeting the eligibility criteria  
who have signed a consent form and have begun treatment will be 
evaluable for response.  

Addendum 2 
67  
RU051417I 
 
 
 
Responses will be summarized by simple descriptive summary statistics 
delineating complete and partial responses as well as no response and 
progressive disease in this patient population.  
 
 
Phase II Portion  
 
16.3  
Statistical Design: 
 
16.31 Decision Rule:  
 
Based on recent data and prior randomized controlled trials in the salvage setting 
for this patient population, the estimated overall response rate for two cycles of 
R-ICE based on similar salvage chemotherapy is around 45% (Gisselbrecht, 
Glass et al. 2010; Kewalramani, Zelenetz et al. 2004; Gyan, Damotte et al. 2013; 
Stewart, Duan et al. 2011; Thieblemont, Briere et al. 2011; Vacirca, Acs et al. 
2014; Crump et al., 2014). For the addition of lenalidomide to be clinically 
meaningful, our hypothesis is that the addition of lenalidomide in the relapse 
setting would increase the overall response rate by approximately 20%. 
 
The largest success proportion where the proposed treatment strategy would be 
considered ineffective in this population is 45%.  The smallest success proportion 
that would warrant subsequent studies with the proposed treatment strategy in 
this patient population is 65%.  The following one-stage design with an interim 
analysis based on a Simon optimum design(Simon 1989) uses 20 or 45 patients 
to test the null hypothesis that the true success proportion in a given patient 
population is at most 45%. 
 
16.311 Interim Analysis Decision Rule:  Enter 20 patients into the study. If 9 or 
fewer successes are observed in the first 20 evaluable patients, we will 
consider this regimen ineffective in this patient population and terminate 
this study. Otherwise, if the number of successes is at least 10, we will 
proceed with accrual. 
 
16.312 Final Decision Rule: Enter an additional 25 patients into the study. If 24 
or fewer successes are observed in the first 45 evaluable patients, we will 
consider this regimen ineffective in this patient population. If 25 or more 
successes are observed in the first 45 evaluable patients, we may 
recommend further testing of this regimen in subsequent studies in this 
population. 
 
16.313 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making process.  Analyses involving over accrued 
patients are discussed in Section 16.44. 
 
16.314 NOTE:  The trial will not be halted while the first 20 patients are 
evaluated for the interim analysis.  However, if the accrual is especially 
rapid, we may temporarily suspend accrual to prevent missing important 
acute toxicity patterns. 

Addendum 2 
68  
RU051417I 
 
 
 
16.32 Power and Significance Level: Assuming that the number of responses is 
binomially distributed, with a significance level of 9%, the probability of 
declaring that the regimen warrants further studies (i.e., statistical power) and the 
probability of stopping after the interim analysis under various response 
proportions can be tabulated as a function of the true response proportion as 
shown in the table below. 
 
If the true success proportion is… 
0.45 
0.50 
0.55 
0.60 
0.65 
Then the probability of declaring that 
the regimen is promising and warrants 
further study is… 
0.090 
0.249 
0.491 
0.735 
0.900 
And the probability of stopping after the 
interim analysis is… 
0.591 
0.412 
0.249 
0.128 
0.053 
 
16.33 Other Considerations: Toxicity, quality/duration of response, and patterns of 
treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study. 
 
16.4 
Analysis Plan:  The analysis for this trial will commence at planned time points (see 16.3) 
and at the time the patients have become evaluable for the primary endpoint. Such a 
decision will be made by the Statistician and Study Chair, in accord with CCS Standard 
Operating Procedures, availability of data for secondary endpoints (eg, laboratory 
correlates), and the level of data maturity. It is anticipated that the earliest date in which 
the results will be made available via manuscript, abstract, or presentation format is when 
the last patient has been followed for at least 2 months. 
 
16.41 Primary Endpoint:   
 
16.411  Definition: The primary endpoint of this trial is the overall response rate 
after two cycles of treatment. A response will be defined as a CMR or 
PMR noted as the objective status after two cycles of treatment.  All 
patients meeting the eligibility criteria who have signed a consent form 
and have begun treatment will be evaluable for overall response, with the 
exception of patients who are determined to be a major treatment 
violation. 
 
16.412  Estimation:  The proportion of successes will be estimated by the number 
of successes divided by the total number of evaluable patients.  
 
Confidence intervals for the true success proportion will be calculated 
according to the approach of Duffy and Santner (Duffy and Santner 
1987). 
 
16.42 Secondary Endpoints:    
 
16.421 Overall proportion of patients (%) proceeding to stem cell 
transplant. Definition: The percentage of patients proceeding to stem 
cell transplant will be estimated by the number of patients who proceed 
to transplant divided by  the total number of evaluable patients.  Exact 

Addendum 2 
69  
RU051417I 
 
 
binomial 95% confidence intervals for the true success proportion will be 
calculated.   
 
16.422 Complete metabolic response (CMR) rate: The CMR rate will be 
estimated by the number of patients with an objective status of CMR 
divided by the total number of evaluable patients. All evaluable patients 
will be used for this analysis. Exact binomial 95% confidence intervals 
for the true CMR rate will be calculated. 
 
16.423 Overall survival (OS): Survival time is defined as the time from 
registration to death due to any cause. The distribution of survival time 
will be estimated using the method of Kaplan-Meier. 
 
16.424 Percentage of Adverse Events (%) categorized based on severity 
using CTCAE system/organ/class criteria 4.0. Definition: All eligible 
patients that have initiated treatment will be considered evaluable for 
assessing adverse event rate(s). The maximum grade for each type of 
adverse event will be recorded for each patient, and frequency tables will 
be reviewed to determine patterns. Additionally, the relationship of the 
adverse event(s) to the study treatment will be taken into consideration.  
The frequency and percentage of patients experiencing a particular 
grade/severity of adverse event would be aggregated and combined data 
reported.   
 
16.43 Correlative Analyses: 
 
16.431  Association of histologic subtype as assessed by pathology and its 
association with the primary endpoint of the study. Definition: 
Histologic subtype (GCB vs.ABC vs. unclassified) from tumor tissue at 
the start of the study will be evaluated by 2 methods:  Hans algorithm by 
IHC and gene expression profiling using nanostring technology.  For 
each method, the relationship between overall response (responder vs. 
non-responder) CR rate and subtype will be evaluated using Chi-square 
tests (or Fisher’s exact test if the data in the contingency table is sparse). 
16.432 Association of SUV reduction (%) noted on interim PET/CT scan 
with the primary endpoint of the study. Definition: This will be 
evaluated by calculating the percentage (%) SUV reduction noted on 
interim PET/CT scan and correlated with the overall response (responder 
vs. non-responder) by using a two sample t-test .    
 
16.433 Association of anatomic size reduction (%) noted on interim 
PET/CT scan with the primary endpoint of the study. Definition: 
This would be evaluated by calculating the percentage (%) anatomic size 
reduction noted on interim PET/CT scan and correlated with the overall 
response (responder vs. non-responder) by using a two sample t-test. 
 
16.434  Association of Minimum Residual Disease (MRD) detection in blood 
with the primary endpoint of the study. Definition: Minimum residual 
disease (MRD) detection (positive versus negative as per Sequenta, Inc 
® technology) in blood will be evaluated in all patients at baseline and 
after 2 cycles of treatment.  The correlation of MRD detection (positive 

Addendum 2 
70  
RU051417I 
 
 
vs. negative) with overall response will be evaluated using Chi-square 
tests (or Fisher’s exact test if the data in the contingency table is sparse).  
 
16.435 Association of Minimum Residual Disease (MRD) blood level with 
the primary endpoint of the study. Definition: Minimum residual 
disease (MRD) blood level (measured as per million leucocytes as per 
Sequenta, Inc.® technology) will be evaluated in all patients at baseline 
and after 2 cycles of treatment.  The correlation of MRD quantification 
(per million leucocytes as per Sequenta, Inc.® )  with overall response 
(responder vs. non-responder) will be evaluated using two sample t-tests. 
 
16.436  Storage of serum samples for future research. Description: Serum 
samples will be collected and stored for future and ongoing research. 
Some of the initial work for which this would be utilized would include 
but not limited to studying the serum free light chains (FLC), serum free 
DNA and the minimal residual disease (MRD).  These measures will be 
summarized descriptively using medians and ranges (continuous 
measures) or frequencies (categorical measures).   
 
16.44   Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any  
 
decision making processes; however, they will be included in final point 
estimates and confidence intervals. 
 
16.45 Data & Safety Monitoring 
 
16.451 The principal investigator(s) and the study statistician will review the 
study at least every quarter to identify accrual, adverse event, and any 
endpoint problems that might be developing. The Mayo Clinic Cancer 
Center (MCCC) Data Safety Monitoring Board (DSMB) is responsible 
for reviewing accrual and safety data for this trial at least twice a year, 
based on reports provided by the MCCC Statistical Office. 
 
16.452 Adverse Event Stopping Rule: The stopping rules specified below are 
based on the knowledge available at study development.  We note that 
the rule may be adjusted in the event of either (1) the study re-opening to 
accrual or (2) at any time during the conduct of the trial and in 
consideration of newly acquired information regarding the adverse event 
profile of the treatments under investigation.  The study team may 
choose to suspend accrual because of unexpected adverse event profiles 
that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended if at any time we observe events 
considered at least possibly related to study treatment (i.e. an adverse 
event with attribute specified as “possible,” “probable,” or “definite”) 
that satisfy any of the following: 
  
Phase I (Includes all dose levels in phase I):   By the nature of the 
“cohorts of three” phase I study design, toxicity (i.e., adverse events that 
are possibly, probably or definitely related to study treatment) stopping 

Addendum 2 
71  
RU051417I 
 
 
rules are in place for each dose level. Specifically, if 2 or more dose-
limiting toxicities (DLTs) are observed during cycle 1 at any given dose 
level, accrual to that dose level will be stopped, and patients will be 
accrued to the next lower dose level until a maximum of 6 patients are 
treated at the lower level. Note that a DLT that affects dose escalation is 
only that which is observed in the first cycle of treatment. However, all 
cycles will be reviewed and the study team will determine whether the 
dose level needs to be adjusted for future patients if ≥1 in the first 3 
patients OR ≥ 2 in the first 6 patients experience a grade 4 or higher non-
hematologic adverse event at least possibly related to treatment over all 
cycles at any given dose level 
 
 
Phase II (includes all phase II patients, including Phase I patients 
treated at the MTD): 
 
• 
if 5 or more patients in the first 15 treated patients experience a grade 
4 or higher non-hematologic adverse event at least possibly related to 
treatment, excluding febrile neutropenia and dehydration. 
 
• 
if after the first 15 patients have been treated, 30% of all patients 
experience a grade 4 or higher non-hematologic adverse event at 
least possibly related to treatment, excluding febrile neutropenia and 
dehydration. 
 
We note that we will review grade 4 and 5 adverse events deemed 
“unrelated” or “unlikely to be related”, to verify their attribution and to 
monitor the emergence of a previously unrecognized treatment-related 
adverse event. 
 
16.5   Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrails.gov” website. The Primary and Secondary Endpoints 
along with other required information for this study will be reported on 
ClinicalTrials.gov. For purposes of timing of the Results Reporting, the initial estimated 
completion date for the Primary Endpoint of this study is 2 years after the study opens to 
accrual. The definition of “Primary Endpoint Completion Date” (PECD) for this study is 
at the time the last patient registered has completed the response evaluation after two 
cycles of treatment. 
 
16.6 
Inclusion of Women and Minorities 
 
16.61 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.62 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race or gender, and there is no reason to expect 
such differences to exist.  Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 
 
 

Addendum 2 
72  
RU051417I 
 
 
16.63 The geographical region served by ACCRU, has a population which includes 
approximately 5-7% minorities. Based on prior ACCRU studies involving similar 
disease sites, we expect about 5-7% of patients will be classified as minorities by 
race and about 40% of patients will be women.  Expected sizes of racial by 
gender subsets are shown in the following table: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
 0 
 1 
 1 
Not Hispanic or Latino 
 25 
 37 
 62 
Ethnic Category: Total of all subjects 
 25 
38 
63 
Racial Category 
American Indian or Alaskan Native 
 0 
 0  
 0 
Asian 
 0 
 1 
 1 
Black or African American 
 1 
 1 
 2 
Native Hawaiian or other Pacific Islander 
 0 
 0 
 0 
White 
 24 
36 
60 
Racial Category: Total of all subjects 
25 
38 
63 
 
Ethnic 
Categories: 
 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, 
South or Central American, or other Spanish culture or origin, 
regardless of race. The term “Spanish origin” can also be used in 
addition to “Hispanic or Latino.” 
 
Not Hispanic or Latino 
 
Racial 
Categories: 
 
American Indian or Alaskan Native – a person having origins in 
any of the original peoples of North, Central, or South America, 
and who maintains tribal affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of 
the Far East, Southeast Asia, or the Indian subcontinent including, 
for example, Cambodia, China, India, Japan, Korea, Malaysia, 
Pakistan, the Philippine Islands, Thailand, and Vietnam. (Note: 
Individuals from the Philippine Islands have been recorded as 
Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of 
the black racial groups of Africa. Terms such as “Haitian” or 
“Negro” can be used in addition to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having 
origins in any of the original peoples of Hawaii, Guam, Samoa, or 
other Pacific Islands. 
White – a person having origins in any of the original peoples of 
Europe, the Middle East, or North Africa. 

Addendum 2 
73  
RU051417I 
 
 
17.0  
Pathology Considerations/Tissue Biospecimens  
 
17.1 
Tissue Biospecimen Submission  
 
17.11 Summary Table of Tissue Biospecimens for This Protocol 
 
 
Type 
of 
tissue 
biospecimen 
to submit 
 
 
 
Mandatory 
or 
optional 
 
 
 
When 
to 
submit 
 
 
Reason 
for 
submission 
(background/methodology 
section) 
Where 
to 
find 
specific details for  
biospecimen 
submission 
All H&E 
diagnostic 
slides 
Mandatory 
Within 30 
days after 
registration 
Pathology Central review 
See Section 17.2 
CD20 stained 
slide 
Mandatory 
 
Pathology Central review 
See Section 17.2 
Formalin-
fixed paraffin-
embedded 
(FFPE) tissue 
block or (15) 
4µm 
unstained 
slides with (1) 
corresponding 
H&E stained 
slide  
Mandatory 
Within 30 
days after 
registration 
Correlative Studies (Section 
17.5) 
Section See 
section 17.3 
If an institution is not able to provide the optional FFPE tissue, it does not cause the patient to be ineligible; 
however, the collection of these tissues is strongly recommended.  
 
17.2 
All Diagnostic Slides for Confirmation of Diagnosis (Mandatory) 
 
17.21 The following materials below are mandatory (unless indicated otherwise) and required for 
shipment: 
 
• 
Diagnostic H&E Stained Slides from Most Recent Tumor Tissue Biopsy 
• 
CD20 stained slide 
• 
Lymphoma Pathology Reporting Form 
• 
Surgical Pathology Report 
• 
Tumor Tissue Immunochemistry or Immunophenotyping by Flow Cytometry Report 
(if available) 
• 
Pre-study Bone Marrow Biopsy Report (if available) 
• 
Pre-study Peripheral Blood Immunophenotyping by Flow Cytometry Report (if 
available) 
 
Note: Include the ACCRU patient ID number on all materials listed above. 
 
17.22 The diagnostic slide(s) must be appropriately packed to prevent damage (e.g., slides should 
be placed in appropriate slide container) and placed in an individual plastic bag.  Label the 
bag with the protocol number, ACCRU patient ID number, and patient initials.  
 
17.23 Verify that Section 1 of the Lymphoma Pathology Reporting Form is completed and filled 
in correctly. 
 

Addendum 2 
74  
RU051417I 
 
 
17.24 Review is being performed at the ACCRU Research Base at Mayo Clinic Rochester.  Ship 
all diagnostic slides and accompanying materials as follows: 
 
17.251 Mayo Clinic Rochester (MCR) patients only: please forward pathology 
material to
 
or review. 
 
17.252 For all memberships, including MCJ and MCA, ship all specimens and 
accompanying materials to the ACCRU Research Base: 
 
 
 
 
 
17.253 The ACCRU Operations Office will forward the diagnostic slides to Dr. 
 
for central review to confirm diagnosis of MCL.  
 
17.3 
Paraffin Embedded Tissue Blocks/Slides (Mandatory research tissue) 
 
17.31 Submit one formalin fixed paraffin-embedded (FFPE) tumor tissue block from the most 
recent tumor tissue biopsy. A corresponding H&E slide from the submitted block must 
be provided to permit quality assessment (QA) of the tissue block.  Once the QA is 
completed, the H&E slide will be returned, unless specified otherwise in section 17.29.      
 
17.32 The FFPE tissue block is preferred; however, if an institution is unable to provide a 
tissue block, cut (15) 4-micron sections and mount sections on charged glass slides. Label 
the slides with ACCRU patient ID number, accession number, and order of sections 
(i.e., 1-11).  (1) four micron slide for the H&E stain the first cut slide (i.e., slide labeled 
1).  This slide will be reviewed centrally under the research base’s protocol for assessing 
tissue quality.  Do not bake or place covers slips on the slides.  
 
17.33 The following materials below are required (unless indicated otherwise) for shipment: 
 
• 
Paraffin Embedded Tissue Blocks with Corresponding H&E Slide (or 15 Unstained 
Slides with Corresponding H&E Slide) 
• 
Research Tissue Submission Form 
• 
Surgical Pathology Report 
• 
Operative Report (optional) 
 
Note: Please include the ACCRU patient ID number on all materials listed above. 
 
17.34 The block/slides/cores must be appropriately packed to prevent damage (e.g., slides should 
be placed in appropriate slide container) and placed in an individual plastic bag.  Label the 
bag with the protocol number, ACCRU patient ID number, and patient initials. 
 
17.35 Tissue specimens must be shipped ≤30 days after registration. 
 
17.36 Verify that the appropriate sections of the Tissue Specimen Submission Form are 
completed and filled in correctly. Enter information from the Tissue Specimen Submission 
Form into the remote data entry system on the same day the specimen is submitted (see 
Forms Packet). 

Addendum 2 
75  
RU051417I 
 
 
 
17.37 Ship all block/slide tissue specimens and accompanying materials to the ACCRU Research 
Base: 
 
 
 
 
 
17.38 If corresponding H&E slide was not submitted with the tissue specimen, the ACCRU 
Operations Office will request a slide to be processed (i.e., cut and H&E stained) from the 
tumor tissue block.  Processing will be performed in the Pathology Research Core (PRC), 
Mayo Clinic Rochester. 
 
17.39a The ACCRU Operations Office will forward the blocks and/or H&E slide(s) to 
 
and colleagues to be reviewed under the research base’s protocol for 
assessing tissue quality for the proposed correlative studies. 
 
17.39b After the pathologist assesses the tissue quality, the block and appropriate paperwork will 
be returned to the ACCRU Operations Office. 
 
17.4 
Frozen Tumor Tissue (None) 
 
17.5 
Study Methodology and Storage Information 
 
Submitted tissue samples will be handled as follows in the appropriate laboratories in the 
Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, at the direction of 
 
  
 
17.51 Fluorescence in situ hybridization (FISH):  Probes for protocol-specific markers will be 
analyzed on the tissue block or tissue microarray. 
 
17.52 Immunohistochemical stains: Samples will be stained for protocol-specific markers.  
 
17.53 Proliferation rate: The primary tumor tissue will be stained with Ki-67 or Mib-1 to assess 
the proliferative rate where applicable. 
 
17.54 Remaining tumor tissue will be banked for future research according to the patient consent 
permission.  Tissue blocks and/or slides will be stored in the ACCRU Central Operations 
Office (Attn: Pathology Coordinator).  Potential future research may include 
immunohistochemistry (IHC) analyses, DNA extraction, and/or tissue microarray (TMA) 
construction to analyze predictive biomarkers, changes in expression pattern with therapy, 
and correlation with response and/or adverse events.  For TMAs, the donor block remains 
intact except for 6 small (0.6mm) holes where the cores were taken.  This process has 
minimal impact on the utility of the block for future clinical diagnostic needs. As protocols 
are developed, they will be presented for ACCRU and IRB review and approval.  (This 
collection is part of a general strategy of investigation for ACCRU hematology studies.) 
 
 

Addendum 2 
76  
RU051417I 
 
 
 
17.55 The institutional pathologist will be notified by the ACCRU Operations Office (Pathology 
Coordinator) if the block may be depleted. 
 
17.56 Blocks requested to accommodate individual patient management will be returned 
promptly upon request after slides or cores are cut. 
 
17.6 
Return of Genetic Testing Research Results 
 
Because the results generated by the genetic testing included in this section are not currently 
anticipated to have clinical relevance to the patient or their family members, the genetic results will 
not be disclosed to the patients or their physicians. 
 
If, at any time, genetic results are obtained that may have clinical relevance, IRB review and 
approval will be sought regarding the most appropriate manner of disclosure and whether or not 
validation in a CLIA-certified setting will be required.  Sharing of research data with individual 
patients should only occur when data have been validated by multiple studies and testing has been 
done in CLIA-approved laboratories. 
 
18.0 
Records and Data Collection Procedures 
 
 
18.1 Submission Timetables 
 
Initial Material(s)  
 
1.  Submit copy to the ACCRU Ops Office, Attn. QAS for RU051417I.   
 
 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
On-Study  
 
 
 
 
 
 
 
≤2 weeks  after registration 
Adverse Event – Baseline 
Measurement - Baseline  
CT/PET/MRI Scan Report1 
Pathology Reporting Lymphoma  
(see Section 17.2) 
Research Blood Submission- Baseline  
(see Section 14.0) 
Research Tissue Submission  
(see Section 17.3) 
PET/CT Scan CD Submission  
(see Appendix III) 
≤ 30 days after registration 
End of Active Treatment/Cancel Notification 
Form 
Submit ≤2 weeks  after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 

Addendum 2 
77  
RU051417I 
 
 
Central Pathology Review Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
Pathology Materials (this is for central 
review, eligibility, etc.)1 
Submit ≤30 days after registration (see Section 17.2) 
1.  After the central review has been completed, forward a copy of the completed Pathology Reporting Form 
to the QAS for documentation. Send to: ACCRU Ops Office, Attn. QAS for RU051417I.   
 
Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation during 
treatment 
At end of treatment 
 
Evaluation/Treatment  
X 
X 
Nadir/Adverse Event  
X 
X 
Measurement  
X1 
X1 
Research Blood Submission  
X (see Section 14.0) 
 
CT/PET/ Scan Report1 
X (see Appendix III) 
 
PET/CT Scan CD Submission3 
X (see Appendix III) 
 
End of Active Treatment/Cancel Notification  
 
X 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
Deviation Form2 
X 
X 
 
1. Submit copy of documentation of response or progression to the 
 
 
2. Submit only if applicable. 
3. Cycle 2, Day 21 
  
Follow-up Material(s)  
CRF 
Event Monitoring Phase1 
q. 3 
months 
until 
PMD2 
 
 
 
At 
PMD2 
After 
PMD 
q. 6 
mos. 
 
 
 
Death 
 
 
 
New Primary 
Event Monitoring  
X 
X 
X 
X 
At each occurrence 
Transplant and Engraftment Data Form3 
Collect when applicable 
 
1. If a patient is still alive 5 years after registration, no further follow-up is required. 
2. Submit copy of documentation of response or progression to the 
 
3. Complete this form one time after the treating physician has decided whether or not the patient will receive 
transplant. 

Addendum 2 
78  
RU051417I 
 
 
19.0  
Budget 
 
19.1 
Each site should review the test schedule (Section 4.0), taking into account local and regional 
coverage policies, to determine which items are standard of care and which are research at their 
site.  Refer to the payment synopsis for funding provided per accrual for covering study costs, as 
well as any additional invoiceables that may be allowed. 
 
 
19.2 
Tests to be research funded: 
 
 
 
19.21 Mandatory blood samples for research. 
 
19.3 
Celgene will provide Lenalidomide (Revlimid®) directly to research subjects for the duration of 
their participation in this trial at no charge to them or their insurance providers in accordance with 
the REVLIMID REMSprogram. 
 
20.0 
References 
 
Bellas, C., D. Garcia, et al. (2014). "Immunohistochemical and molecular characteristics with prognostic 
significance in diffuse large B-cell lymphoma." PloS one 9(6): e98169. 
 
Cheson BD, Horning SJ, Coiffier B, et al. Report of an International Workshop to Standardize Response 
Criteria for Non-Hodgkin’s Lymphomas. J Clin Oncol 1999;17:1244-53. 
 
 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 
2014;32:3059-68. 
 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier  B, Fisher RI, 
Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, 
Connors JM, Federico M, Diehl V; International Harmonization Project on Lymphoma. Revised response 
criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86.  
 
Crump M, Kuruvilla J, Couban S, et al. Randomized comparison of gemcitabine, dexamethasone, and 
cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell 
transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014 
Nov 1;32(31):3490-6.  Epub 2014 Sep 29. PubMed PMID: 25267740. 
 
Duffy D, Santner T. Confidence intervals for a binomial parameter based on multistage tests.  Biometrics 
1987;43: 81-93. 
 
Feldman, T., A. R. Mato, et al. (2014). "Addition of lenalidomide to rituximab, ifosfamide, carboplatin, 
etoposide (RICER) in first-relapse/primary refractory diffuse large B-cell lymphoma." British journal of 
haematology 166(1): 77-83. 
 
Gisselbrecht, C., B. Glass, et al. (2010). "Salvage regimens with autologous transplantation for relapsed 
large B-cell lymphoma in the rituximab era." Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 28(27): 4184-4190. 
 
Gyan, E., D. Damotte, et al. (2013). "High response rate and acceptable toxicity of a combination of 
rituximab, vinorelbine, ifosfamide, mitoxantrone and prednisone for the treatment of diffuse large B-cell 
lymphoma in first relapse: results of the R-NIMP GOELAMS study." British journal of haematology 
162(2): 240-249. 
 
 

Addendum 2 
79  
RU051417I 
 
 
Hans, C. P., D. D. Weisenburger, et al. (2004). "Confirmation of the molecular classification of diffuse 
large B-cell lymphoma by immunohistochemistry using a tissue microarray." Blood 103(1): 275-282. 
 
Haslett, P. A., W. A. Hanekom, et al. (2003). "Thalidomide and a thalidomide analogue drug costimulate 
virus-specific CD8+ T cells in vitro." The Journal of infectious diseases 187(6): 946-955. 
 
Hernandez-Ilizaliturri, F. J., G. Deeb, et al. (2011). "Higher response to lenalidomide in  
relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center 
B-cell-like phenotype." Cancer 117(22): 5058-5066. 
 
Kewalramani, T., A. D. Zelenetz, et al. (2004). "Rituximab and ICE as second-line therapy before 
autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma." 
Blood 103(10): 3684-3688. 
 
List, A., S. Kurtin, et al. (2005). "Efficacy of lenalidomide in myelodysplastic syndromes." The New 
England journal of medicine 352(6): 549-557. 
 
Lund JL, Ostgard LS, Prandoni P, et al. Incidence, determinants and the transient impact of cancer 
treatments on venous thromboembolism risk among lymphoma patients in Denmark. Thrombosis research 
2015;136(5):917-23. 
 
Nowakowski, G. S., B. LaPlant, et al. (2011). "Lenalidomide can be safely combined with R-CHOP 
(R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study." Leukemia 25(12): 
1877-1881. 
 
Nowakowski GS, LaPlant B, Macon WR, et al. Lenalidomide combined with R-CHOP overcomes negative 
prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell 
lymphoma: a phase II study. J Clin Oncol 2015;33(3):251-7. 
 
Pellagatti, A., M. Jadersten, et al. (2007). "Lenalidomide inhibits the malignant clone and up-regulates the 
SPARC gene mapping to the commonly deleted region in 5q- syndrome patients." Proceedings of the 
National Academy of Sciences of the United States of America 104(27): 11406-11411. 
 
Petterson TM, Marks RS, Ashrani AA, et al. Risk of site-specific cancer in incident venous 
thromboembolism: a population-based study. Thrombosis research 2015;135(3):472-8. 
 
Pocock S, Simon J. Sequential treatment assignment with balancing for prognostic factors in the controlled 
clinical trial. . Biometrics 1975;31:103-115. 
 
Rajkumar, S. V., S. R. Hayman, et al. (2005). "Combination therapy with lenalidomide plus dexamethasone 
(Rev/Dex) for newly diagnosed myeloma." Blood 106(13): 4050-4053. 
 
Richardson, P. G., R. L. Schlossman, et al. (2002). "Immunomodulatory drug CC-5013 overcomes drug 
resistance and is well tolerated in patients with relapsed multiple myeloma." Blood 100(9): 3063-3067. 
 
Rubinstein LV, Korn EL, Freidlin B, Hunsberger S, Ivy SP, Smith MA. Design issues of randomized phase 
II trials and a proposal for phase II screening trials. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2005;23(28):7199-7206. Prepublished on 2005/09/30 as DOI 
10.1200/JCO.2005.01.149. 
 
Simon, R. Optimal two-stage designs for phase II clinical trials.  Controlled clinical trials 1989;10(1): 1-10. 
 
 

Addendum 2 
80  
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Stewart, D. A., Q. Duan, et al. (2011). "A prospective phase II study of RICE re-induction, then high-dose 
fludarabine and busulfan, followed by autologous or allogeneic blood stem cell transplantation for indolent 
b-cell lymphoma." Clinical lymphoma, myeloma & leukemia 11(6): 475-482. 
 
Thieblemont, C., J. Briere, et al. (2011). "The germinal center/activated B-cell subclassification has a 
prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a 
bio-CORAL study." Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 29(31): 4079-4087. 
 
Vacirca, J. L., P. I. Acs, et al. (2014). "Bendamustine combined with rituximab for patients with relapsed or 
refractory diffuse large B cell lymphoma." Annals of hematology 93(3): 403-409. 
 
Zhang, H., V. Vakil, et al. (2005). "Circulating endothelial progenitor cells in multiple myeloma: 
implications and significance." Blood 105(8): 3286-3294. 
 

RU051417I  
Appendix I 
Addendum 2 
 
 
Page 1 of 17 
 
 
 
ACCRU Informed Consent Template for Cancer  
Treatment Trials 
(English Language) 
 
 
*NOTES FOR LOCAL INVESTIGATORS: [NOTE: Retain this section and asterisk item below for ACCRU 
model consents] 
• 
The goal of the informed consent process is to provide people with sufficient information for 
making informed choices.   The informed consent form provides a summary of the clinical study 
and the individual's rights as a research participant.  It serves as a starting point for the necessary 
exchange of information between the investigator and potential research participant.  This 
template for the informed consent form is only one part of the larger process of informed consent. 
For more information about informed consent, review the "Recommendations for the 
Development of Informed Consent Documents for Cancer Clinical Trials" prepared by the 
Comprehensive Working Group on Informed Consent in Cancer Clinical Trials for the National 
Cancer 
Institute. 
 
The 
Web 
site 
address 
for 
this 
document 
is 
 
• A blank line, __________, indicates that the local investigator should provide the appropriate 
information before the document is reviewed with the prospective research participant.  
• Suggestion for Local Investigators:  An NCI pamphlet explaining clinical trials is available for 
your patients.  The pamphlet is entitled: "If You Have Cancer…What You Should Know about 
Clinical 
Trials". 
 
This 
pamphlet 
may 
be 
ordered 
on 
the 
NCI 
Web 
site 
at 
to request a free 
copy.  
• Optional feature for Local Investigators: Reference and attach drug sheets, pharmaceutical 
information for the public, or other material on risks.  Check with your local IRB regarding review 
of additional materials. 
*These notes for {authors and} investigators are instructional and should not be included in the informed 
consent form given to the prospective research participant.  
 
 

RU051417I  
Appendix I 
Addendum 2 
 
 
Page 2 of 17 
 
 
 
Phase I/II, Open-Label Study of R-ICE (Rituximab-Ifosfamide-Carboplatin-Etoposide)  
with Lenalidomide (R2-ICE) in Patients with First-Relapse/Primary Refractory 
Diffuse Large B-Cell Lymphoma (DLBCL) 
 
This is an important form.  Please read it carefully.  It tells you what you need to know about this research study.  
If you agree to take part in this study, you need to sign this form.  Your signature means that you have been told 
about the study and what the risks are.  Your signature on this form also means that you want to take part in this 
study. 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial to you.   Clinical 
trials include only people who choose to take part. Please take your time to make your decision about taking part.  
You may discuss your decision with your friends and family.  You can also discuss it with your health care team.  If 
you have any questions, you can ask your study doctor for more explanation.  
 
You are being asked to take part in this research study because you have diffuse large B-cell lymphoma that has 
come back even though you have already received treatment.  
 
Why is this research study being done? 
 
The purpose of this study is to find out what effects, good and/or bad, the addition of lenalidomide to standard 
chemotherapy (R-ICE) has on you and your cancer. The combination of Lenalidomide with standard chemotherapy 
is also referred to as R2-ICE. 
 
How many people will take part in the research study? 
 
At the beginning of the study, up to 12 patients will be treated with standard chemotherapy (R-ICE) plus increasing 
doses of Lenalidomide, to find the highest dose that does not cause unacceptable side effects.  This is referred to as 
the Maximum Tolerated Dose (or MTD). Once that dose is found, up to 51 additional patients will be enrolled in 
the study.  A total of 63 patients are the most that would be able to enter the study.  
 
What will happen if I take part in this research study? 
 
Before you begin the study …  
 
In order to participate in this study you must register into and follow the requirements of the REVLIMID REMS™ 
program of Celgene Corporation.  This program provides education and counseling on the risks of fetal exposure, 
blood clots and reduced blood counts.  You will be required to receive counseling every 28 days during treatment 
with lenalidomide, follow the pregnancy testing (as required by your risk category) and birth control requirements 
of the program that are appropriate for you and take telephone surveys regarding your compliance with the 
program.    
[Note to Informed Consent Authors: the above paragraph must be included verbatim in all informed consent 
documents. The text in this paragraph cannot be revised.] 
 
In addition, you will need to have the following exams, tests or procedures to find out if you can be in the study.  
These exams, tests or procedures are part of regular cancer care and may be done even if you do not join the study.  
If you have had some of them recently, they may not need to be repeated.  This will be up to your study doctor. 
 
 
 

RU051417I  
Appendix I 
Addendum 2 
 
 
Page 3 of 17 
 
 
 
Within 1 to 3 weeks before study registration 
 
• 
Physical exam (including height and weight) 
• 
Performance status: Your doctor will ask you a series of questions to measure how well you are 
able to perform ordinary tasks and carry out activities in your daily life. 
• 
Routine blood tests 
• 
Research blood tests – when you have the routine blood test done, we will also take between 2 
teaspoons and 4 tablespoons of additional blood for research and banking for future research.  Giving 
this extra blood is required if you participate in this study. 
• 
PET-CT scan to see where the cancer is located and measure any palpable lymph nodes. 
• 
Pregnancy test (only for women able to have children)  
 
During the study…  
 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, then you 
will need the following tests and procedures.  They are part of regular cancer care.  
 
• 
Routine blood tests and physical exam  
• 
PET-CT scan to see where the cancer is located. 
 
You will need these tests and procedures that are part of regular cancer care.   They are being done more 
often because you are in this study.   
 
• 
Routine blood tests and physical exams (including height and weight) 
• 
Pregnancy test (only for women able to have children) 
 
You will need these tests and procedures that are either being tested in this study or being done to see how 
the study is affecting your body. 
 
• 
Research blood sample (between 2 teaspoons and 4 tablespoons). This is required if you decide to 
participate in this study. 
• 
Review of your previously done tumor biopsy to confirm tumor type and perform research tests on 
the tumor tissue 
 
Some of the research blood sample will be used for genetic testing. Because the genetic tests in this study are not 
used for regular medical care, you will not be told the results of the test(s).  The test results will not be put in your 
medical record either. 
 
If it is not known if you have Human Immunodeficiency Virus (HIV) or hepatitis B, you will need to have a blood 
test done.  If your HIV or hepatitis B test result is positive, you will need to have a second test done to make sure 
the findings are the same.  The researcher will tell you how to find medical help and counseling as needed, and you 
may not be able to take part in the study.  Your health insurer or you will have to pay for the cost of the repeat test, 
any follow-up medical care, or counseling.  
 
If the HIV or hepatitis B test result is positive, it is the state law that they be reported to the State Department of 
Health.  The tests results will also be put in your medical record. 
Female patients should not donate blood during treatment and for at least 28 days after taking lenalidomide.  
Male patients should not donate blood, semen or sperm during treatment or for at least 28 days after taking 

RU051417I  
Appendix I 
Addendum 2 
 
 
Page 4 of 17 
 
 
lenalidomide.  
When you are finished taking R2-ICE, the following tests are required: 
 
 
• 
Physical exam (including height and weight) 
• 
Performance status: Your doctor will ask you a series of questions to measure how well you are 
able to perform ordinary tasks and carry out activities in your daily life. 
• 
Routine blood tests 
• 
Research blood tests – when you have the routine blood test done, we will also take between 2 
teaspoons and 4 tablespoons of additional blood for research and banking for future research.  Giving 
this extra blood is required if you participate in this study. 
• 
PET-CT scan to see where the cancer is located and measure any palpable lymph nodes. 
• 
Pregnancy test (only for women able to have children)  
 
 
Study Plan 
 
You will receive R2-ICE every 21 days in this study. This 21-day period of time is called a cycle.  This cycle will 
be repeated once, for a total of 2 cycles. Four of the medications (R-ICE) are given in the vein (IV) usually in the 
hospital (inpatient). The second “R” (Revlimid ® or Lenalidomide) is a pill that is taken along with the other 
chemotherapy for 1-2 weeks.  Scans will be obtained before considering the possibility of a transplant.  If your 
doctor determines that you are benefitting from the treatment (that your disease is not getting worse and you are not 
having bad side effects), you may receive an additional 1 or 2 cycles of treatment. The chart below gives a simple 
picture of how the study will proceed.  Start reading at the top and read down the list, following the lines and 
arrows.  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
R2-ICE given every 21 days for at least 2 cycles and up to 4 cycles  
Follow-up visits are usually every 3 months 
for the first 3 years, then every 6 months for 
approximately 2 more years.  (Tests and 
imaging on these visits is at the treating 
physician’s discretion/institutional 
guidelines.) 
 
Pre-screening and Registration 
• Every cycle: Study doctor visit, blood tests, study and 
pregnancy test (females only) 
 
• Prior to Cycle 3, end of Cycle 4, or end of treatment 
if stopping the study early: PET-CT scan. 
 
• Follow-up visits and procedures will be determined 
by your physician. 

RU051417I  
Appendix I 
Addendum 2 
 
 
Page 5 of 17 
 
 
How long will I be in the research study? 
 
You will be asked to take R2-ICE for 2 cycles, and possibly 1-2 additional cycles.  After you are finished taking 
R2-ICE, the study doctor will ask you to visit the office for follow-up exams every 3 months for about 3 years or 
until your disease gets worse, then every 6 months until your disease gets worse. The total length of time for the 
study, including follow-up visits, is approximately 5 years from the day you are enrolled.  
 
 
Can I stop being in the research study? 
 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping or decide to 
stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the R2-ICE can be 
evaluated by your doctor.  Another reason to tell your doctor that you are thinking about stopping is to discuss what 
follow-up care and testing could be most helpful for you. 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in your best interest; 
if you do not follow the study rules; or if the study is stopped. 
 
What side effects or risks can I expect from being in the research study? 
 
You may have side effects while on the study.  Everyone taking part in the study will be watched carefully for 
any side effects.  However, doctors don’t know all the side effects that may happen.  Side effects may be mild or 
very serious.  Your health care team may give you medicines to help lessen side effects.  Many side effects go away 
soon after you stop taking the study treatment.   In some cases, side effects can be serious, long lasting, or may 
never go away.  There also is a risk of death. 
 
You should talk to your study doctor about any side effects that you have while taking part in the study.    
 
Risks and side effects related to Lenalidomide include those which are:  
 
Likely (greater than 20% chance that any of these may happen): 
 
*Side effects considered serious are in bold. 
 
• 
Fatigue or feeling tired 
• 
Neutropenia or a decrease in white blood cells that can make you more prone to infections 
• 
Thrombocytopenia or a decrease in platelets which can cause you to bruise or bleed easily and/or may 
require platelet transfusion 
• 
Constipation or difficulty moving your bowels 
• 
Diarrhea or loose/frequent bowel movements 
• 
Abnormalities of liver tests 
 
Less likely (less than 20% chance that any of these may happen): 
 
• 
Anemia or a decrease in red blood cells that can cause tiredness which may require red blood cell 
transfusion 
• 
Nausea 
• 
Loss of appetite 
• 
Back pain 
• 
Joint pain  

RU051417I  
Appendix I 
Addendum 2 
 
 
Page 6 of 17 
 
 
• 
Muscle cramps 
• 
Swelling of the arms and legs 
• 
Problems falling asleep or staying asleep 
• 
Fever 
• 
Cough  
• 
Shortness of breath or difficulty catching your breath  
• 
Upper respiratory infection 
• 
Rash 
• 
Itching and dry skin 
• 
Lack or loss of strength 
• 
Dizziness 
• 
Headache 
• 
Abnormal thyroid function or inflammation of thyroid gland 
• 
Abdominal pain and or distension 
• 
Gastrointestinal bleeding 
• 
Bowel obstruction 
• 
Infections involving various organs 
• 
Allergic reaction to drug 
• 
Abnormalities of mineral levels in blood 
• 
Heartburn 
• 
Muscle pain 
 
Serious (occurring in 1% or more of patients and not listed in bold above): 
 
• 
Neutropenia associated with a fever 
• 
Pulmonary embolism or blood clot in or around the lungs 
• 
Deep vein thrombosis or blood clots in a larger blood vessel 
• 
Atrial fibrillation or irregular heartbeat 
• 
Progression of the disease being studied  
• 
Pneumonia or an infection of the lungs 
• 
Sepsis or an infection of the blood 
• 
Dehydration 
• 
Kidney failure which can cause increases or decreases in the amounts of chemicals in your blood which can 
cause irregular heartbeats, muscle twitching, seizures, and/or death.  
• 
Myocardial infarction (heart attack) 
• 
Stroke (bleeding in the brain or clotting) 
 
Rare cases of the following events have been reported: 
 
• 
Angioedema- an allergic skin disease characterized by patches of swelling involving the skin and/or the 
lining of your nose, mouth, and gastrointestinal tract. 
• 
Anaphylaxis- serious potentially life-threatening type of allergic reaction that may cause breathing 
difficulty, dizziness, low blood pressure, and loss of consciousness. 
• 
Stevens-Johnson syndrome and toxic epidermal necrolysis- serious allergic skin reactions that begin as a 
rash in one area and later cover more of the body leading to detachment of the top layer of skin (could be 
body-wide).  Medical journals have reported patients with allergic skin reaction with thalidomide who also 
developed the same type of reaction with lenalidomide 
• 
Tumor lysis syndrome- metabolic complication that can occur during or without treatment of cancer.  
These complications are caused by the break-down products of dying cancer cells and include 

RU051417I  
Appendix I 
Addendum 2 
 
 
Page 7 of 17 
 
 
hyperkalemia (high potassium), hyperphosphatemia (high phosphorus), hyperuricemia and hyperuricosuria 
(high uric acid in blood and urine), hypocalcemia (low calcium), and consequent acute uric acid 
nephropathy and acute renal failure (kidney damage). 
• 
Tumor Flare reaction- a condition that involves any of the following increase in the size of the cancerous 
lymph nodes, rash and slight fever. 
• 
Rhabdomyolysis- a serious condition involving the destruction of skeletal muscle that can lead to kidney 
failure. Signs and symptoms include dark, red, or cola colored urine and muscle tenderness, stiffness, 
aching (myalgia) or weakness. 
• 
Increase in blood levels of lipase due to inflammation of pancreas gland. 
• 
Abnormalities of blood clotting 
• 
Bone marrow failure 
• 
Decrease in lymphocytes (type of white blood cells) 
• 
Enlarged spleen 
• 
Abnormal heart rhythms 
• 
congestive heart failure (condition where the heart becomes weak and cannot pump enough blood to the 
rest of the body 
• 
Decreased function of adrenal gland 
• 
Decreased hearing 
• 
Vision abnormalities 
• 
Clotting in blood vessels of intestines 
• 
Seizures 
• 
Graft-versus-host disease (when transplanted donor tissue attacks the tissues of the recipient's body   
 
Also Reported on Lenalidomide Trials But with the Relationship to Lenalidomide Still Undetermined:   
 
• 
Tissue swelling  (angioedema)  
• 
Rhabdomyolysis (breakdown of muscle fibers). This occurs when muscle cells die and release cell contents 
into the blood stream. It can cause muscle pain and a number of health problems, including damage to the 
kidneys. If severe, this could be life threatening.  
 
These events have the potential to be fatal. 
 
Your health care team may give you medicines to help lessen side effects. Many side effects go away soon after 
you stop taking study drug.  In some cases, side effects can be serious, long lasting or may never go away. 
 
You should talk to your study doctor about any side effects that you have while taking part in the study.  
 
 
Hematologic Toxicity 
 
Lenalidomide is associated with significant neutropenia (decrease in white blood cells that help fight infection) and 
thrombocytopenia (decrease in platelets that help with blood clotting). You will have your blood counts checked 
frequently when starting treatment with lenalidomide. 
 
Deep Vein Thrombosis and Pulmonary Embolism 
 
Lenalidomide has demonstrated an increased risk of deep vein thrombosis (DVT, blood clot in a larger blood 
vessel) and pulmonary embolism (PE, a blood clot in or around the lungs) in some people with certain medical 
conditions. The study staff will ask you about any risk factors you may have.  [If you have a history of blood clots 
your doctor will prescribe either an injectable blood thinner (low molecular weight heparin )or Coumadin (blood 

RU051417I  
Appendix I 
Addendum 2 
 
 
Page 8 of 17 
 
 
thinner pill) for the first four months of the study treatment.  The doctor may continue to prescribe the medication 
or aspirin for the remainder of your course of study treatment.  All other patients will receive (at the discretion of   
the treating physician) either oral low–dose aspirin or another treatment to prevent blood clotting during study  
participation.]  Patients unable or unwilling to undergo treatment for prevention of blood clots will not be eligible to  
 
participate in this study.  You will be instructed on the signs and symptoms of DVT and PE and if symptoms occur 
you should contact your study doctor promptly. 
 
Second new cancers 
 
 
According to researchers, patients with cancer have a higher risk of developing a second new cancer when 
compared to people without cancer.  In clinical studies of newly diagnosed multiple myeloma, a higher number of 
second cancers were reported in patients treated with induction therapy (treatment as first step to reducing number 
of cancer cells) and/or bone marrow transplant then lenalidomide for a long period of time compared to patients 
treated with induction therapy and/or bone marrow transplant then placebo (a capsule containing no lenalidomide).  
Patients should make their doctors aware of their medical history and any concerns they may have regarding their 
own increased risk of other cancers. 
 
Other Risks 
 
If any physician other than the study doctor prescribes medication for you for another condition or you are taking 
any over-the-counter medications or vitamins, you must inform the study staff.  This is important because the 
interaction of some medications may cause serious side effects. 
 
Lenalidomide has been shown to increase the level of digoxin in the blood in some patients; please tell your doctor 
if you are taking digoxin. 
 
Your condition may not get better or may become worse while you are in this study. 
 
Risks Associated with Pregnancy 
 
Lenalidomide is related to thalidomide.  Thalidomide is a known to cause severe life-threatening human birth 
defects.  Findings from a monkey study indicate that lenalidomide caused birth defects in the offspring of female 
monkeys who received the drug during pregnancy. If lenalidomide is taken during pregnancy, it may cause birth 
defects or death to any unborn baby.  Females must not become pregnant while taking lenalidomide.  You have 
been informed that the risk of birth defects is unknown. If you are female, you agree not to become pregnant while 
taking lenalidomide. 
 
Lenalidomide is detected in very small quantities in human semen according to a study for up to three days after 
stopping the drug. For patients who may not be able to get rid of the drug, such as people with kidney problems, 
lenalidomide may be present for more than three days. The risk to the fetus in females of child bearing potential 
whose male partner is receiving lenalidomide is unknown at this time.  For these reasons male patients receiving 
lenalidomide must use a latex condom while taking lenalidomide, when temporarily stopping lenalidomide, and for 
28 days after permanently stopping lenalidomide treatment during any sexual contact with a pregnant female or a 
female of child bearing potential even if you have undergone a successful vasectomy.  
 
You have been informed of the risk of birth defects.  If you are female, you agree not to become pregnant while 
taking lenalidomide. For this reason, lenalidomide is provided to patients under a special distribution program 
called REVLIMID REMS™. 
[Note to Informed Consent Authors: the above paragraph must be included verbatim in all informed consent 
documents. The text in this paragraph cannot be revised.] 

RU051417I  
Appendix I 
Addendum 2 
 
 
Page 9 of 17 
 
 
You should not donate blood during treatment or for 28 days after the treatment is completed. 
 
You must NEVER share lenalidomide with anyone else. 
 
 
Risks and Side-Effects Associated with Rituximab, Ifosfamide, Carboplatin, and Etoposide (R-ICE): 
 
The components of R-ICE are approved for various types of cancer. R-ICE is commonly used to treat your disease. 
Your study doctor will explain the risks associated with R-ICE therapy, each of its components and any pre-
medication and post-medication given to decrease the risk of side effects.  
 
In addition to the individual side effects of each R-ICE components (included below), your risk of certain side 
effects may be further increased because of the combination.  
 
Particularly with ICE treatment, many people have a temporary drop in the number of blood cells made by the bone 
marrow: 
• 
ICE will reduce the number of white blood cells, which can lead to increased risk of getting an infection or 
feeling ill; 
• 
ICE can decrease the production of red blood cells, which may make you feel tired or breathless; 
• 
ICE can reduce the production of platelets, which helps the blood to clot and stops bleeding. Bruising may 
occur more easily. 
 
Other common side effects of ICE are: 
• 
Nausea, vomiting, stomatitis or irritation of the stomach lining, loss of appetite, altered taste, diarrhea, 
fatigue, weakness, fever, alopecia or hair loss, decreased kidney function, blood in the urine, liver 
dysfunction, phlebitis or inflammation of the vein, back pain, abdominal pain, blue or purple discoloration 
of the skin, increased sweating, voice changes, neuropathy or numbness/tingling in fingers and toes, 
tinnitus (ringing in the ears), and hearing loss. 
• 
A drop in blood pressure can happen if etoposide is given quickly. 
• 
Anaphylactic-like reactions characterized by chills fever, irregular heart rate, difficulty breathing, and 
shortness of breath may be experienced. 
 
• 
This drug may have a harmful effect on a developing baby, it is important that you use adequate birth 
control while participating in this study. 
• 
Short term confusion and somnolence (sleepiness) is an uncommon side effect of ifosfamide. 
 
The potential to increase the severity of side effects or cause new side effects by adding lenalidomide is unknown.  
 
As with any medication, allergic reaction is a possibility. 
 
Risks and Side Effects of Ifosfamide (Ifex®) include those which are: 
 
Likely (events occurring greater than 20% of the time): 
• 
Decrease in blood counts leading to an increased risk of infection 
• 
Hair loss 
• 
Vomiting, nausea  
• 
Anemia which may cause tiredness, or may require blood transfusions  
• 
Bruising, bleeding  
 
 
 

RU051417I  
Appendix I 
Addendum 2 
 
 
Page 10 of 17 
 
 
Less likely (events occurring less than or equal to 20% of the time): 
• 
Loss of energy, confusion and drowsiness  
• 
Drowsiness (sleepiness)  
• 
Weakness, fatigue 
• 
Dizziness, loss of balance 
• 
Bladder irritation resulting in painful urination and blood in urine (hemorrhagic cystitis) 
• 
Decreased kidney function 
• 
Fever 
• 
Diarrhea, constipation 
• 
Mouth sores 
• 
Loss of taste 
• 
Numbness and tingling in fingers and toes  
• 
Electrolyte abnormality, dehydration (low potassium, low sodium, low magnesium, low calcium) 
• 
Skin redness/rash 
 
Rare but serious (events occurring less than 2-3% of the time): 
• 
Life threatening infections, especially when white blood cell count is low  
• 
Damage to the liver (Bilirubin increased, liver dysfunction, transaminases increased) 
• 
Severe damage to lungs (Acute respiratory distress syndrome) 
• 
Allergic reaction 
• 
Heart rhythm abnormalities (atrial ectopy, atrial fibrillation/flutter, bundle branch block) 
• 
Tendency to form blood clots 
• 
Low or high blood pressure 
• 
Heart failure/heart damage (cardiac arrest, cardiogenic shock, cardiomyopathy, cardiotoxicity) 
• 
Vision abnormalities 
• 
Decreased wound healing 
 
 
Risks and Side Effects of Carboplatin (Paraplatin®, CBDCA) include those which are: 
 
Likely (events occurring greater than 20% of the time): 
• 
Hair loss 
• 
Vomiting, nausea 
• 
Decrease in blood counts leading to an increased risk of infection 
• 
Anemia which may cause tiredness, or may require blood transfusions  
• 
Low platelet count – this may make you bruise more easily and bleed longer if injured 
• 
Belly pain  
• 
Weakness, fatigue 
• 
Loss of appetite and weight loss 
 
Less likely (events occurring less than or equal to 20% of the time): 
• 
Diarrhea, constipation, abdominal pain 
• 
Numbness and tingling in fingers and toes  
• 
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of the 
face or throat  
• 
Pain at the injection site 
• 
Skin redness/rash 
• 
Change in kidney function (decreased creatinine clearance)  
• 
Changes in taste 

RU051417I  
Appendix I 
Addendum 2 
 
 
Page 11 of 17 
 
 
• 
Damage to organs which may cause hearing and balance problems 
• 
Dizziness 
 
Rare but serious (events occurring less than 2-3% of the time): 
• 
Allergic reactions  (Red flushed skin and itching on palms and feet, immediate nausea and/or swelling or 
tingling in the mouth or throat) 
• 
Irritation and damage to skin and tissue at injection site if drug leaked from the vein 
• 
Changes in vision 
• 
Mouth sores 
• 
Life threatening infections, especially when white blood cell count is low  
• 
Tendency to form blood clots 
• 
Low or high blood pressure 
• 
Heart failure 
 
 
Risks and Side Effects of Etoposide (VePesid®, Toposar®, VP16) include those which are:  
 
Likely (events occurring greater than 20% of the time): 
• 
Hair loss 
• 
Decrease in blood counts leading to an increased risk of infection 
• 
Anemia which may cause tiredness, or may require blood transfusions  
• 
Bruising, bleeding  
• 
Flushed face 
 
Less likely (events occurring less than or equal to 20% of the time): 
• 
Low blood pressure 
• 
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of the 
face or throat  
• 
Vomiting, nausea  
• 
Loss of appetite  
• 
Mouth sores 
• 
Belly pain 
• 
Numbness and tingling in fingers and toes (neuropathy) 
 
Rare but serious (events occurring less than 2-3% of the time): 
• 
Life threatening infections, especially when white blood cell count is low  
• 
Severe allergic reactions associated with a skin rash (may cause rash, low blood pressure, wheezing, 
shortness of breath, swelling of the face or throat and skin desquamation – Stevens Johnson Syndrome) 
• 
Damage to the heart (Myocardial infarction/ischemia) 
• 
Damage to the lungs (interstitial pneumonitis) 
• 
Blue or purple discoloration of the skin (vasospasm) 
• 
A drop in blood pressure can happen if etoposide is given quickly 
 
For more information about risks and side effects, ask your study doctor. 
 
 
Are there benefits to taking part in the research study? 
 
Taking part in this study may or may not make your health better.  While doctors hope R2-ICE will be more useful 
against cancer compared to the usual treatment, there is no proof of this yet.  We do know that the information from 

RU051417I  
Appendix I 
Addendum 2 
 
 
Page 12 of 17 
 
 
this study will help doctors learn more about R2-ICE as a treatment for cancer.  This information could help future 
cancer patients. 
 
What other choices do I have if I do not take part in this research study? 
 
You do not have to be in this study to receive treatment for your cancer. Your other choices may include: 
 
• 
Getting treatment or care for your cancer without being in a study 
• 
Taking part in another study 
• 
Getting no treatment 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Will my medical information be kept private? 
 
We will do our best to make sure that the personal information in your medical record will be kept private.  
However, we cannot guarantee total privacy.  Your personal information may be given out if required by law.  If 
information from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, and data analysis 
include: 
 
• 
Academic and Community Cancer Research United (ACCRU) 
• 
Celgene (provider of Lenalidomide) 
• 
The local IRB  
• 
Government agencies, like the Food and Drug Administration (FDA), involved in keeping research safe for 
people 
 
In order to obtain lenalidomide free of charge from Celgene, your name, address, phone, date of birth and 
the fact that you are participating in this trial will be disclosed to Celgene and its agents or vendors that 
supply lenalidomide and administer the REVLIMID REMS™ program. By signing this consent form you 
agree to this disclosure. 
 
A description of this clinical trial will be available on 
as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a summary of study 
results.  You can search this Web site at any time. 
 
[Note to Informed Consent Authors: the above paragraph complies with the new FDA regulation found at 21 
CFR 50.25(c) and must be included verbatim in all informed consent documents. The text in this paragraph 
cannot be revised.] 
 
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed by the local 
institution.  The regulations may or may not be included in the informed consent form depending on local 
institutional policy.] 
 
 
What are the costs of taking part in this research study? 
 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of treating your cancer 
in this study.  Some health plans will not pay these costs for people taking part in studies.  Check with your health 

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Addendum 2 
 
 
Page 13 of 17 
 
 
plan or insurance company to find out what they will pay for.  Taking part in this study may or may not cost your 
insurance company more than the cost of getting regular cancer treatment. You may be responsible for co-payments 
and deductibles that are typical for your insurance coverage. 
 
You will NOT have to pay for the following: 
 
• 
Lenalidomide.  
• 
Extra blood work being done (research blood tests), to better understand how R2-ICE is working. 
 
You WILL have to pay for: 
 
• 
All doctor’s visits, including physical exams and medical histories 
• 
Routine blood test to check your health 
• 
All standard imaging done while on the study (CT scans, PET scans, ECG, etc.) 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s Web 
site at 
.    You can print a copy of the “Clinical 
Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free 
copy. 
 
 
What happens if I am injured because I took part in this research study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that you 
have been injured because of taking part in this study.  You can tell the doctor in person or call him/her at 
__________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You and/or your health 
plan will be charged for this treatment.   The study will not pay for medical treatment.   
 
 
What are my rights if I take part in this research study? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in the study.  If you 
decide to take part in this study, you may leave the study at any time.   No matter what decision you make, there 
will be no penalty to you and you will not lose any of your regular benefits.  Leaving the study will not affect your 
medical care.  You can still get your medical care from our institution.    
 
We will tell you about new information or changes in the study that may affect your health or your willingness to 
continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing 
this form.   
 
 
 

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Addendum 2 
 
 
Page 14 of 17 
 
 
Who can answer my questions about the research study? 
 
You can talk to your study doctor about any questions or concerns you have about this study.  Contact your study 
doctor __________________ [name(s)] at __________________ [telephone number]. 
 
For questions about your rights while taking part in this study, call the ________________________ [name of 
center] Institutional Review Board (a group of people who review the research to protect your rights) at 
__________________ (telephone number).  [Note to Local Investigator: Contact information for patient 
representatives or other individuals in a local institution who are not on the IRB or research team but take calls 
regarding clinical trial questions can be listed here.] 
 
About Using Biological Samples for Research 
 
For this study, we will be collecting between 2 teaspoons to 4 tablespoons of blood for future research, at each 
draw. This is a mandatory blood draw. This study also has laboratory tests that will be performed to study small 
samples of blood and biopsy tissue. The blood will be taken after registration, but just before treatment starts on the 
first day of the first cycle, Days 2 and 3 of cycle 1, at the end of cycle 2,  and/or at the end of treatment if 
discontinued early, and/or if your disease gets worse. It will be drawn at the same time as your usual blood work, 
which is needed for treatment. 
 
The biopsy tissue sample will be from your original biopsy.  No additional biopsies will be done to get this tissue.   
 
You are required to provide blood and tissue samples in order to take part in the treatment portion of this study. 
 
The blood and tissue samples will be sent to laboratories at Mayo Clinic in Rochester, MN, associated with 
ACCRU, where the tests will be done.  These tests will be done in order to understand how your cancer responds to 
treatment.  It is hoped that this will help investigators better understand your type of cancer.  The results of these 
tests will not be sent to you or your study doctor and will not be used in planning your care.  These tests are for 
research purposes only and you will not have to pay for them.   
We would like to keep some of the leftover blood and tissue for future research.  If you agree, this blood and/or 
tissue will be kept and may be used in research to learn more about cancer and other diseases.  Please read the 
online booklet called "Providing Your Tissue for Research: What You Need To Know," to learn more about tissue 
research:
  
Your blood and tissue may be helpful for research whether you do or do not have cancer.  The research that may be 
done with your blood and/or tissue is not designed specifically to help you.  It might help people who have cancer 
and other diseases in the future.  
Reports about research done with your blood and/or tissue will not be given to you or your doctor.  These reports 
will not be put in your health record.  The research will not have an effect on your care.  
Things to Think About 
The choice to let us keep the leftover blood and/or tissue for future research is up to you.  No matter what you 
decide to do, it will not affect your care.  
If you decide now that your blood and tissue can be kept for research, you can change your mind at any time.  Just 
contact us and let us know that you do not want us to use your tissue.  Then any blood and tissue that remains will 
no longer be used for research.  

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Addendum 2 
 
 
Page 15 of 17 
 
 
In the future, people who do research may need to know more about your health.  While ACCRU may give them 
reports about your health, it will not give them your name, address, phone number, or any other information that 
will let the researchers know who you are.  
Sometimes blood and tissue is used for genetic research (about diseases that are passed on in families).  Even if 
your blood and tissue is used for this kind of research, the results will not be put in your health records.  
Your blood and/or tissue will be used only for research and will not be sold.  The research done with your blood 
and/or tissue may help to develop new products in the future.  
Benefits  
The benefits of research using blood and/or tissue include learning more about what causes cancer and other 
diseases, how to prevent them, and how to treat them.  
Risks  
The greatest risk to you is the release of information from your health records.  We will do our best to make sure 
that your personal information will be kept private.  The chance that this information will be given to someone else 
is very small.  
 
Making Your Choice 
 
Please read each sentence below and think about your choice.  After reading each sentence, circle "Yes" or "No".  If 
you have any questions, please talk to your doctor or nurse, or call our research review board at the IRB's phone 
number.  
No matter what you decide to do, it will not affect your care. 
 
1. My sample(s) may be kept for use in future research to learn about, prevent, or treat cancer.  
 
 
  Yes 
  No  
Please initial here: ________  
Date: ________ 
 
2. My sample(s) may be kept for use in future research to learn about, prevent or treat other health problems (for 
example: diabetes, Alzheimer's disease, or heart disease).  
 
 
  Yes 
  No  
Please initial here: ________  
Date: ________ 
 
If you want your sample(s) destroyed at any time, write to the Secretary of the ___________________ Institutional 
Review Board ____________________________________________.   
ACCRU has the right to end storage of the sample(s) without telling you.  
 
 
 
 

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Appendix I 
Addendum 2 
 
 
Page 16 of 17 
 
 
Please read the following statements and mark your choice: 
 
I permit ACCRU to give my sample(s) to outside researchers: 
 
  Yes 
 
  No  
Please initial here: 
 
 
Date: 
 
 
 
 
 
 
Where can I get more information? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
 
  
 
 
 
 
 
 
 
 
 
You will get a copy of this form.  If you want more information about this study, ask your study doctor. 
 

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Appendix I 
Addendum 2 
 
 
Page 17 of 17 
 
 
Signature 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I have read it or it 
has been read to me.  I understand the information and have had my questions answered.  
 
I understand I will be registered into the REVLIMID REMS™ program, and agree to receive counseling 
and to comply with the pregnancy precaution requirements of the REVLIMID REMS™ program. 
[Note to Informed Consent Authors: the above paragraph must be included verbatim in all informed consent 
documents. The text in this paragraph cannot be revised.] 
 
I agree to take part in this study. 
 
 
Printed Participant Name: __________________________________________ 
 
 
Participant Signature: ______________________________________________ 
 
 
Date: _____________________________________ 
 
 
Printed name of person obtaining informed consent:  
 
__________________________________________ 
 
 
Signature of person obtaining informed consent: 
 
___________________________________________ 
 
 
Date _____________________________________ 
 
 
 
This model informed consent form has been reviewed by the ACCRU and is the official consent document for this 
study.  Local IRB changes to this document are allowed.  Sections “What are the risks of the research study” or “What 
other choices do I have if I don’t take part in this research study?” should always be used in their entirety if possible.  
Editorial changes to these sections may be made as long as they do not change information or intent.  If the institutional 
IRB insists on making deletions or more substantive modifications to these sections, they may be justified in writing by 
the investigator and approved by the IRB.  Under these circumstances, the revised language and justification must be 
forwarded to the Academic and Community Cancer Research United (ACCRU) Operations Office for approval before 
a patient may be registered to this study. 
 
Consent forms will have to be modified for each institution as it relates to where information may be obtained on the 
conduct of the study or research subject.  This information should be specific for each institution. 

 
RU051417I 
Appendix II 
Addendum 2 
Page 1 of 1 
 
 
 
 
Image Submission Process 
 
PET/CT scans should be performed in accordance with the test schedule in Section 4.0 to assess for 
response.  PET/CT scans done at baseline should be submitted within 30 days of enrollment. Similarly 
PET/CT scans done at the time of response evaluation after 2 cycles should also be submitted within 30 
days of response assessment.  
 
Scans should be submitted on CD, accompanied by a radiographic report and sent to the following:  
 
 
 
 
  
    
 
 
Submit the reports AND radiographic images free of marks that may obscure the lesions or bias the 
evaluation of the independent reviewer(s). Radiographic images must be deidentified and labelled with the 
ACCRU study number of RU051417I and the assigned ACCRU patient identification number. 
Radiographic images must include the date the image was performed and the corresponding time point in 
the study (see Section 4.0). 
 
 
 

Name _________________ 
 
                                                      
                    RU051417I 
 
 
Appendix III - Addendum 2 
 
 
Page 1 of 1 
Area Below Only To Be Completed only by Coordinator 
 
Number of pills returned_____     
 
Study Coordinator Initials________ 
 
Date______________________ 
 
Discrepancy Yes____ No_____ 
PATIENT MEDICATION DIARY 
Instructions 
 
• 
Please indicate on the calendar below every day that you take your study medication by placing the dose taken on 
the line under the date.  
• 
If you miss a dose, place a “0” under the date, but remember to take your prescribed dose at the next regularly 
scheduled time. 
• 
Bring all bottles and any unused study medication along with this diary when you return for your next 
appointment. 
 
 
Medication(s) 
Dose 
Lenalidomide 
TBD 
Aspirin 
81 mg 
 
 
 
 
 
Date:__________________ 
Participant’s Signature___________________________________ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date 
 
 
 
 
 
 
 
Lenalidomide 
 
 
 
 
 
 
 
Aspirin  
 
 
 
 
 
 
 
Comments 
 
 
 
 
 
 
 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date 
 
 
 
 
 
 
 
Lenalidomide  
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
Comments 
 
 
 
 
 
 
 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Date 
 
 
 
 
 
 
 
Lenalidomide  
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
Comments