The Asymptomatic Follicular Lymphoma (AFL) Trial: A Phase III Study of Single-Agent Rituximab Immunotherapy Versus Zevalin Radioimmunotherapy for Patients With New, Untreated Follicular Lymphoma Who Are Candidates for Observation
Phase: PHASE3
Conditions: Ann Arbor Stage I Grade 1 Follicular Lymphoma, Ann Arbor Stage I Grade 2 Follicular Lymphoma, Ann Arbor Stage II Grade 1 Contiguous Follicular Lymphoma, Ann Arbor Stage II Grade 1 Non-Contiguous Follicular Lymphoma, Ann Arbor Stage II Grade 2 Contiguous Follicular Lymphoma, Ann Arbor Stage II Grade 2 Non-Contiguous Follicular Lymphoma, Ann Arbor Stage III Grade 1 Follicular Lymphoma, Ann Arbor Stage III Grade 2 Follicular Lymphoma, Ann Arbor Stage IV Grade 1 Follicular Lymphoma, Ann Arbor Stage IV Grade 2 Follicular Lymphoma
Sponsor: Mayo Clinic

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LS Addendum 5 
 
 
Protocol Version:   November 09, 2020 
 
 
 
 
 
 
 
The Asymptomatic Follicular Lymphoma (AFL) Trial: A Phase III Study Of Single-Agent 
Rituximab Immunotherapy Versus Zevalin Radioimmunotherapy For Patients with New, 
Untreated Follicular Lymphoma Who Are Candidates for Observation 
 
 
Study Chair*: 
 
 
 
Study Co-Chairs: 
 
 
Pathologist: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
 
 
 
 
 
Lymphoma SPORE Coordinating Center: 
 
 
 
 
 
Study Activation Date:  
February 11, 2015                                                     
                                                                                  
                                                                                  
                                                    
Document History (Effective Date) 
LS Addendum 1 May 13, 2016 
LS Addendum 2_December 21, 2017 
LS Addendum 3_June 12, 2018 
LS Addendum 4  October 8, 2019 
LS Addendum 5  December 15, 2020 
 
Drug Availability 
Commercial Agents:  Rituximab and Zevalin 
 
† Study contributor(s) not responsible for patient care. 
 
Lymphoma SPORE 
University of Iowa/Mayo Clinic 

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Protocol Version:   November 09, 2020 
Protocol Resources 
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 
 
 
  
 
Forms completion and submission 
 
 
 
 
Protocol document, consent form, 
regulatory issues 
 
  
 
Biospecimens  
  
 
Adverse Events (AdEERS, MedWatch, 
Non-AER 
 
 
 
*No waivers of eligibility per NCI 

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Protocol Version:   November 09, 2020 
 Index 
 
Schema 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification 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   
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: ECOG Performance Status 
Appendix II: Patient Information Sheet and FACT-Lym 
Appendix III: Lymphoma Blood Collection Kit – Specimen Checklist and Shipping Instructions  
Appendix IV: Percent Bone Marrow in the Adult Skeleton 
 

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Protocol Version:   November 09, 2020 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Cycle length = 3 months for Cycle 1 (assessment at 3 months) 
2. Cycle length = 3 months for Cycles 2-4 (assessments at 6, 9, and 12 months) 
3. Cycle length = 6 months for Cycles 5-8 (assessments at 18, 24, 30, and 36 months) 
4. Cycle length = 12 months for Cycles 9-10 (assessments at 48 and 60 months) 
5. 10 years after registering no further follow-up is necessary. 
 
Generic name:   90 Yttrium Ibritumomab 
tiuxetan 
Brand name: Zevalin®  
 
 
Lymphoma SPORE abbreviation: Y2B8  
Generic name: Rituximab   
 
 
Brand name: Rituxan®  
 
 
Lymphoma SPORE abbreviation: RITUX 
Randomization 
Arm A1: 
Rituximab x 1 cycle 
Arm B1: 
Rituximab & Zevalin x 1 cycle 
Observation2,3,4 
Observation2,3,4 
Event Monitoring5 
 
PD at any time 
Subsequent treatment for lymphoma 
                Event 
Patient refusal 
                Monitoring 
Failure to return for evaluation  
    during observation 

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Protocol Version:   November 09, 2020 
1.0 
Background   
 
Non-Hodgkin lymphoma (NHL) is the 7th most common cancer in both men and women. Within 
NHL, follicular lymphoma (FL) is the second most common (diffuse large B-cell lymphoma is 
the most common).  Typical teaching regarding FL incites the usual mantra of “treatable but not 
curable”. However, a number of studies with very long-term follow-up demonstrate 20% of 
patients are cured.(1) We acknowledge that in these studies patients were not routinely scanned 
and biopsied throughout the many years of follow-up; however, the point is that they never 
manifested obvious recurrence and lived out their life and died without FL.  Thus, they were 
“effectively cured”.  
 
The treatment of FL continues to evolve. For patients with new, untreated FL the standardized 
approach is to perform a history and physical, obtain basic laboratory tests, staging with a CT or 
PET/CT and a bone marrow aspiration and biopsy. A treatment plan is then formulated based 
initially on whether or not the patient requires chemotherapy. The commonly used criteria to start 
chemotherapy are the GELF criteria (2, 3) or the Follicular Lymphoma International Prognostic 
Index Score (FLIPI score).  Patients who achieve a complete remission (CR) with initial therapy 
have a better outcome than those who merely achieve a partial remission (PR).(1) 
 
1.1 
Patients who Need Chemotherapy:  Patients who have the need for chemotherapy are 
typically treated with rituximab/chemotherapy followed by either observation, two years 
of rituximab maintenance,(4) or a single dose of radioimmunotherapy (RIT).(5, 6)  
Rituximab and RIT both prolong time to progression (TTP) but their effects on overall 
survival (compared to observation followed by repeat treatment at time of relapse) are 
unknown. Bendamustine/rituximab (BR) produces higher overall response rates (ORR) 
and longer progression-free survival (PFS) with less toxicity than RCHOP.(7)There is 
currently no overall survival (OS) benefit from BR.  
 
There are many clinical trials being performed for FL patients who meet the criteria for 
chemotherapy. ECOG 2408 is the current national trial in the cooperative groups. It is 
BR based with 2 years of rituximab maintenance. One arm contains BR + Velcade and 
one arm has Revlimid/Rituximab as maintenance. This study is predicted to reach 
accrual in 2014.  It will not interfere with this proposal since patients must meet 
chemotherapy requirements. There also is an upfront Revlimid/rituximab trial. 
 
1.2 
Patients Not Requiring Chemotherapy: There is no movement yet to treat these 
patients with chemotherapy – thus the main approaches used are observation, 
rituximab immunotherapy, or RIT.  The hypothesis is that patients with advanced but 
asymptomatic FL (AFL) are not reliably curable and since they may do well for years to 
wait for treatment. This approach of treatment nihilism dates back to the pre-rituximab 
days when the options were chemotherapy vs. observation. Since observation was shown 
to not reduce survival and since chemotherapy was toxic the choice was much simpler in 
favor of observation.  The advent of immunotherapy and RIT changed the equation in 
that these treatments were mild, short in duration and effective.  Thus, in 2014 the real 
key issues in this group of AFL patients are preventing chemotherapy (with its inherent 
toxicity and risk of myelodysplastic syndrome), preserving QOL, preventing 
transformation to large cell lymphoma, and aiming to effectively cure a group of patients 
with initial therapy.   

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Why some patients choose observation over rituximab or RIT is not clear.  This is likely 
due in part by patient and physician input.  The number of AFL patients in the United 
States being observed has dropped to about 18% since the institution of rituximab but 
this figure was derived from all new FL patients.(8) It is clear that observation remains a 
recognized standard (a standard not necessarily the standard) for these patients. 
Immunotherapy with rituximab has eroded support for observation, although to date, no 
OS benefit exists for early treatment. In this patient population, studies have shown that 
four doses of rituximab (no maintenance) can produce approximately a 75% ORR with 6 
- 33% CR and in some patients a very long time to next chemotherapy (TTNT).(9, 10)  
Preliminary results from the RESORT ECOG trial in this same patient population 
showed an ORR of 71% after 4 doses of rituximab with approximately a 15% CR. 
Scheduled maintenance after induction is not better than rituximab when needed as far as 
prolonging survival.(11)  Ardeshna et al(12) studied 379 patients with AFL by 
randomizing them between observation versus rituximab induction or rituximab 
induction followed by maintenance every two months for two years. They subsequently 
closed the rituximab induction only group beginning a new treatment rather than 
progression free survival. The primary endpoint was so that it became a two arm study – 
observation versus rituximab maintenance. There were 84 patients who received 
rituximab induction alone. 46% of patients in the observation group were still free of 
treatment at three years compared to 88% in the maintenance rituximab group being free 
of retreatment at three years. 78% of those in the rituximab induction group retreatment 
free at three years. Thus, at the three-year mark, rituximab induction only and rituximab 
maintenance were similar and both were superior to observation as far as preventing 
treatment at three years. Quality-of-life scores with regard to mental adjustment and 
coping were improved in those who receive maintenance rituximab. This study supports 
the use of rituximab monotherapy for patients with AFL. It still does not completely 
settle the issue of whether these patients should receive rituximab maintenance after 
rituximab induction. There was no difference in overall survival nor time to 
transformation. With respect to maintenance rituximab versus rituximab induction 
without maintenance, again there was no difference in overall survival or histologic 
transformation or time to start a new therapy. There was however an improvement in 
progression free survival with rituximab maintenance compared to rituximab induction 
only. 
 
An additional finding of the study was an improvement in quality of life in patients who 
were treated with rituximab compared to those who are simply observed. It is likely that 
this study will continue to support the use of treatment in the AFL population although it 
does not mandate treatment sense survival was not impacted. The improvement in quality 
of life will again be tested in LS138D. 
 
RIT with Zevalin or Bexxar is also a well-tolerated option for this patient population. As 
of February, 2014 Bexxar will no longer be marketed commercially; thus, Zevalin 
(Spectrum Pharmaceuticals) is the only RIT agent commercially available in the US.  
Kaminski et al(13) demonstrated a 95% response rate using a single dose of Bexxar with 
60% of patients being disease-free at 10 years in a group of patients that likely contained 
these types of patients.  A recent publication by Scholz et al (14) found a similar result 
with Zevalin.   It is particularly reassuring that there were no cases of MDS in either of 

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Protocol Version:   November 09, 2020 
these two studies. Kaminski et al. did report one additional case of MDS in their original 
cohort that occurred at eight years from RIT and this patient did have additional 
chemotherapy after RIT(15) (and personal communication October 2012). Therefore, the 
risk of MDS in patients who have never had any chemotherapy appears to be negligible. 
In contrast, the CR rate is very high with RIT, the treatment is very well tolerated, and 
RIT offers a well-tolerated, non-chemotherapy option for these patients. 
 
Illidge et al(16) recently reported a study of Zevalin radioimmunotherapy in patients with 
new, untreated follicular lymphoma who met GELF criteria. This patient population thus 
differs from the AFL trial in that the patient's did have GELF criteria. It is similar to the 
AFL trial in that patients were previously untreated and received radioimmunotherapy 
only. The other difference is that the Illidge study also used two sequential doses of 
Zevalin. The study treated 72 patients and 94% responded with a CR rate of 58% 
(42/72). Nine patients improved with subsequent follow-up achieving an ORR of 96% 
and a CR rate of 69%. The estimated three-year PFS is 58% and OS 95%. The median 
PFS is 40.2 months. Thirty of the 72 patients have progressed and 24 of the 72 have 
required further treatment. 
 
A second recently reported study by Ibatici  et al.(17) treated 50 patients with stage II 
“bulky” stage III or IV FL with a single treatment course of Zevalin. The median age was 
60 years and 14% had elevated LDH. The ORR was 94% and the CR rate was 86% with 
a median follow-up of 38.8 months. The median PFS has not yet been reached. The 
three-year estimated PFS was 63% and the 3-year OS was 90%. No cases of secondary 
hematological malignancies have been observed.  
 
It is important to note that this study included patients who met GELF criteria and those 
that did not meet GELF criteria. The median PFS and OS for the 19 patients (40%) who 
fulfilled GELF criteria was 21.9 months and 50 months, respectively. In the other 29 
patients who did not meet GELF criteria the median PFS and OS has not yet been 
reached. The estimated 3-year OS and PFS in patients without GELF criteria were 97% 
and 75%, respectively. These data support the premise of this study that patients who do 
not meet GELF criteria should have a very high CR rate and a long TTP. It is also likely 
that patients with these characteristics you receive rituximab will also do better; 
therefore, it is still not clear which approach is best. 
 
Ongoing Clinical Studies: It has been felt by many investigators to be impossible to do a 
randomized study in this AFL patient population; thus, there are no current trials open in 
the US at this time.  
 
It is been demonstrated that patients with FL who achieve CR have a chance at very 
long-term survival and likely approximately 20% are effectively cured.(1) Whether FL is 
“curable” is a contentious subject as discussed above. Because of the long survival of 
these patients and the development of novel agents it is reasonable to try and take 
advantage of the discovery of an early stage asymptomatic patient, achieve CR with a 
non-chemotherapy regimen, and then observe. Avoiding chemotherapy for ≥5 years with 
a non-toxic, non-chemotherapy regimen would be considered meaningful to patients, 
physicians, and health care providers. 
 

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Protocol Version:   November 09, 2020 
1.3 
Hypothesis: Treatment of patients with asymptomatic FL with Zevalin RIT will produce 
a higher CR rate than rituximab alone, and a higher % of patients progression-free at 3 
and 5 years. The rationale for these parameters is that this treatment is low toxicity, brief, 
and will produce valuable remission time and effectively cure a percentage of these 
patients.  
 
An additional important parameter is the time to chemotherapy (TTC).  This parameter is 
important but can be years to measure. Patients who achieve a CR are in turn less likely 
to need chemotherapy. In addition, if the patient enters CR then transformation is less 
likely. Indeed, patients treated with rituximab have a lower chance of transformation 
than those observed;(18) thus supporting the view that less tumor, less chance of 
transformation. 
 
1.4        Translational research:  
 
Beta-2 microglobulin and LDH: this combination of factors has recently been shown to 
be prognostic in follicular lymphoma.(19) Patients with a normal beta-2 microglobulin 
had improved response to chemotherapy given with RIT consolidation in that study. We 
will evaluate this combination as prognostic factors in this prospective trial. 
 
Bcl-2 mutations: Our group (Correia, Nowakowski, Kaufmann, Feldman) have recently 
described the functional and adverse prognosis of FL patients whose tumors have exon 2 
bcl-2 mutations (Correia C et al submitted for publication). The rate of single nucleotide 
variants (SNV) was 53% (20/38). This was confirmed in an additional sample of 11 
cases where 73% (8/11) also had SNV’s. It is unknown what the incidence of these 
mutations are in AFL patients. We would anticipate that it would perhaps be lower and 
we postulate that if present, these patients may have a worse prognosis. This trial 
provides an opportunity to test this hypothesis in a group with lower risk disease. 
 
Serum Cytokine Levels-IL-12:  We measured IL-12 levels in patients with follicular 
lymphoma and found that those patients with higher pretreatment IL 12 (>0.56 ng/mL) 
had a shorter progression free survival.(20) This will be evaluated in this prospective 
study. 
 
Tumor microenvironment: Malignant B cells from biopsies of tumors in patients with 
lymphoma do not play a passive role but instead clearly drive the differentiation and 
function of intratumoral T cells (Figure 1 from (21). Malignant B cells have been found 
to express multiple ligands responsible for inducing regulatory T cells (Treg cells) and 
suppressing other intratumoral effector cells. Lymphoma B cells have been found to 
express CD70, and CD70/CD27 signaling promotes the induction of FoxP3- positive 
Treg cells. (22) Malignant cells also express PD-L1, and interactions with PD1 expressed 
on intratumoral immune cells results in immune suppression.(23, 24) B cells from 
lymphoma biopsies have been found to secrete chemokines and cytokines responsible for 
further immune suppression. CCL22 secreted by lymphoma B cells is involved in 
chemotaxis and migration of intratumoral Treg cells that express the receptor CCR4, 
which results in recruitment of Treg cells to the tumor microenvironment.(22) Treg cells 
recruited to sites of lymphoma have been shown to suppress both effector CD8+ T cells 
and intratumoral CD4+ cells.(22, 25)  Cytokines and chemokines such as IL12 and 

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Protocol Version:   November 09, 2020 
CXCL10 produced by the malignant B cells also have a role in regulating effector T-cell 
function.(20, 26) However, IL-12 has been shown to induce T-cell exhaustion, resulting 
in ineffective T cells that are unable to proliferate or lyse target B cells.(20) Overall, 
malignant B cells skew the T-cell balance within lymph nodes promoting Treg cells and 
inhibiting effector T cells or TH17 cells.(27) 
 
 
2.0 
Goals 
 
2.1 
Primary 
 
2.11 
Test the hypothesis that a single dose of Zevalin RIT will increase the CR rate 
over that achieved with standard rituximab in patients with untreated 
asymptomatic FL.  
 
2.2 
Secondary 
 
2.21  
Test the hypothesis that Zevalin RIT will improve progression-free survival. 
 
 
2.22 
Test the hypothesis that Zevalin RIT will improve time to next (any) therapy and 
time to next chemotherapy.  
 
2.3 
Correlative Research 
 
2.31  
Study the incidence of exon 2 bcl2 mutations in patients with AFL. 
 
2.32 
Measure Tregs and tissue monocytes in on-study FL tumor tissue 

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Protocol Version:   November 09, 2020 
 
2.33     Measure serum cytokines and vitamin D at on study and month 6. 
 
2.34 
Evaluate beta-2 microglobulin plus LDH score as a prognostic factor. 
 
2.35 
Measure ALC, AMC, and ALC/AMC ratio at on study and after treatment. 
 
2.36 
Compare quality of life as measured by the FACT-Lym between arms. 
 
3.0 
Patient Eligibility   
 
3.1 
Inclusion Criteria  
 
3.11 
Age ≥18 years. 
 
3.12 
Histological confirmation of follicular lymphoma grades I, II diagnosed within 
12 months (365 days) prior to registration.  NOTE: The day of biopsy should be 
used as Day 1 of diagnosis for this calculation. 
 
3.13 
Stage I, II, III, or IV disease. NOTE: Stage I disease are eligible only if the 
disease is not amenable to external beam radiation therapy. 
 
3.14 
No indication for chemotherapy; candidate for observation. 
  
3.15 
Measureable disease by tumor imaging with at least one lesion ≥1.5 cm in at 
least one dimension. 
 
3.16 
Previously untreated. NOTE: This includes any chemotherapy or immunotherapy 
or RIT. Patients who received corticosteroids for diseases other than lymphoma 
are eligible as long as prednisone dose is ≤10 mg/day.  
 
3.17 
Low tumor burden as defined by GELF criteria (2): 
• 
No tumor mass (nodal or extranodal) ≥7 cm in one dimension on CT 
• 
Fewer than 3 (2 or less) nodal masses >3 cm 
• 
No systemic or B symptoms 
• 
No splenomegaly greater than 16 cm by CT scan 
• 
No risk of organ compression – ureteral, orbital, neurological, 
gastrointestinal 
• 
No leukemic phase (>5.0  x  109/L circulating FL cells in the blood as 
detected by CBC with differential and smear) 
• 
No cytopenias – ANC <1000 or platelets <100,000 
 
3.18 
Meet standard criteria for RIT:  
• 
<25% marrow involvement with FL 
• 
No evidence of myelodysplasia 
 
3.19a 
ECOG Performance Status (PS) 0, 1, or 2 (Appendix I). 
 

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Protocol Version:   November 09, 2020 
3.19b The following laboratory values obtained ≤ 28 days prior to registration: 
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Hemoglobin >10.0 g/dL 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN) or if total bilirubin is 
>1.5 x ULN, the direct bilirubin must be ≤ ULN 
• 
Alkaline phosphatase ≤3 x ULN 
• 
Aspartate transaminase (AST) ≤3 x ULN 
• 
Creatinine ≤2 x ULN 
 
3.19c 
Negative pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
 
3.19d Provide informed written consent. 
 
3.19e    Willing to travel to a radioimmunotherapy site for Zevalin, if necessary.  
 
3.19f   Willing to return to the enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
Note:  During the Active Monitoring Phase of a study (i.e., active treatment and 
observation), participants must be willing to return to the consenting institution 
for follow-up. 
 
3.19g Willing to provide blood samples at baseline for correlative research purposes 
and tissue for central pathology review (see Sections 6.2, 14.0, and 17.0). 
 
3.19h <25% bone marrow involvement of cellular marrow with lymphoma as 
determined by bilateral bone marrow aspirate and biopsy.  NOTE: The percent 
involvement should be estimated by the hematopathologist using all of the 
biopsy material.   
  
3.19i    Has insurance coverage or is willing to pay for protocol therapy (rituximab x 4 
or Zevalin x 1) 
 
3.2 
Exclusion Criteria  
 
3.21 
Any of the following because this study involves an agent whose genotoxic, 
mutagenic and teratogenic effects on the developing fetus and newborn are 
unknown: 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception for at least three months after completing study 
treatment. 
 
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 

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Protocol Version:   November 09, 2020 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 
3.23 
Patients known to be HIV positive and currently receiving antiretroviral therapy. 
  
 
3.24 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, 
uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
3.25 
Receiving any other investigational agent that would be considered as a 
treatment for the lymphoma. 
 
3.26 
Active other malignancy requiring treatment that would interfere with the 
assessments of response of the lymphoma to protocol treatment and would 
interfere with follow-up assessments through year 5.  
 
3.27 
Presence of CNS lymphoma. 
 
3.28 
Known to have lymphoma related to HIV or AIDS.  NOTE: These patients are 
excluded because it is unknown what effects prolonged B-cell depletion will 
have on these patient’s immune system.  
 
3.29a 
Abnormal renal function (serum creatinine >2 x ULN). 
 
3.29b Received prior external beam radiation therapy for another reason to >25% of 
active bone marrow (see form in Appendix IV). 
 
3.29c 
Serious non-malignant disease such as active infection or other condition which 
in the opinion of the investigator would compromise other protocol objectives. 
 
3.29d Major surgery other than diagnostic surgery ≤4 weeks prior to registration. 
 
3.29e 
Any evidence of myelodysplastic syndrome or marrow chromosomal changes 
suggesting myelodysplasia (-7, -5 etc). 
 
3.29f 
Corticosteroid therapy at the time the patient enters the protocol. NOTE: Patients 
using prednisone or its equivalent for adrenal failure or using ≤10mg of 
prednisone/day for other benign causes are accepted. 
 
3.29g Follicular grades IIIA or IIIB are not eligible. 
 
3.29h Marrow cellularity ≤15% (as determined on all bone marrow samples). 
 
 
3.29i 
Seropositive for or active viral infection with hepatitis B virus (HBV): 
• 
HBsAg positive 

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• 
HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable 
viral DNA 
Notes: 
• 
Subjects who are HBsAg negative, anti-HBs positive, and/or anti-HBc 
positive, but viral DNA negative are eligible. 
• 
Subjects who are seropositive because of HBV vaccination are eligible 
(HBV surface antibody positive, HBV core antibody negative, and HBV 
surface antigen negative). 
 
3.29j 
Active infection with hepatitis C virus (HCV). 
 

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Protocol Version:   November 09, 2020 
  
4.0 
Test Schedule  
 
Tests and procedures 
Baseline 
(Prior to 
Registration) 
Active Monitoring* 
 
 
 
≤28 days 
prior to reg. 
 
Cycle 1 
 
 
 
Observation 
 
 
 
Week 5,6, 
7 post 
Zevalin for 
Arm B pts 
only 
Month 3 post 
Day 1 of 
treatment11,12 
Month 6 post 
Day 1 of 
treatment11,12 
Months 9, 12, 
18, 24, 30, 36, 
48, 60 post 
Day 1 of 
treatment11,12 
History and exam, weight, PS 
X 
 
 
X 
 
Height 
X 
 
 
 
 
Tissue confirmation of FL grade I or II 
from routine diagnostic tissue ≤365 
days prior to registration8 
X 
 
 
 
 
Adverse event assessment 
X 
 
X 
X 
 
Hematology: 
WBC, ANC, ALC, AMC,  Hgb, PLT 
X 
X9 
X 
X 
X 
Lactate dehydrogenase (LDH) -
include ULN 
X 
 
 
X 
X 
Chemistry:  
Creatinine, Glucose, SGOT (AST), 
Alk phos, Ca,  T. Bili, uric acid 
X 
 
 
X 
 
Beta-2 microglobulin (B2M) 
X 
 
 
X 
 
Direct bilirubin3 
X 
 
 
 
X 
Serum pregnancy test1 
X 
 
 
 
 
Bone marrow biopsy – unilateral or 
bilateral 
X5 
 
 
X6 
 
Tumor Measurement/Evaluation of 
indicator lesion (CT, MRI, etc.) 
CT Scan chest, abdomen and pelvis or 
PET/CT; measurements should be by 
CT or the CT portion of a PET/CT.  
May use MRI in situations that 
identify lesion more clearly than CT2 
X 
 
 
X 
X  
(months 12, 
24, 36, 48, 60) 
Research tissue R 
X4 
 
 
 
 
Research bloods7, R 
X 
 
 
X 
 
Hepatitis B and C screen10 
X 
 
 
 
 
Quantitative serum immunoglobulins: 
IgG, IgA, IgM 
X5 
 
 
 
 
QOL (FACT-Lym) 
X13 
 
X13 
X13 
X13 
1. For women of childbearing potential only. Must be done ≤7 days prior to registration. 
2. Use the same method throughout the study.  See Section 11.0 for response criteria. 
3.   To be done only if the total bilirubin is abnormal. 

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Protocol Version:   November 09, 2020 
4.   Patients will be requested to submit paraffin embedded tumor for research purposes.  This is optional 
and the patient can participate in the study without providing this sample.  Patients at Mayo Clinic 
will be requested to provide an optional fresh research biopsy.  
5.   Bone marrow and immunoglobulins acceptable within 180 days prior to registration. 
6.  Repeat bone marrow only in patients with an initial positive bone marrow 
7. Research bloods at baseline (visit 1/screening) and end of six months (visit 2/End of Cycle 2) only.  
The baseline samples can be collected after the patient consents but prior to starting treatment. 
8.   Patient can be registered with local pathology review; central review will be done on all cases (see 
Section 17.0). 
9.  CBCs should be drawn weekly or until ANC ≥ 1000 and platelets ≥ 50,000 at physician discretion. 
10. Hepatitis B surface antigen (HbsAg) and antibody to Hepatitis B core (anti-HBc); Hepatitis C 
antibody. All patients must be screened prior to registration. Those patients who have evidence of 
chronic or acute infection with either hepatitis B or C may not be treated on this protocol. 
11. ± 1 week. 
12. Data at the Month 3 visit is entered as Cycle 1.  Data at the Month 6, 9, and 12 visits are entered as 
Cycle 2, 3, and 4, respectively.  Data at the Month 18, 24, 30, and 36 visits are entered as Cycle 5, 6, 
7, and 8, respectively.  Data at the Month 48 and 60 visits are entered as Cycle 9 and 10, respectively. 
13. Patient questionnaire booklet must be used; copies are not acceptable for this submission.  Booklet 
for baseline visit should be completed prior to starting treatment.  Patient should be given a booklet 
to complete in clinic prior to review of the patient’s treatment response and discussions of patient’s 
general health since last treatment evaluation. 
R. Research funded (see Section 19.0). 
 
 

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Protocol Version:   November 09, 2020 
 
5.0 
Stratification Factors  
 
5.1 
Diagnosis: < 3 months vs. 3-12 months. 
 
5.2 
Beta-2 Microglobulin (using institutional values): normal vs. abnormal.  
 
5.3 
Lactate Dehydrongenase (using institutional values): normal vs. abnormal. 
 
6.0  
Registration Procedures  
 
 6.1 
To register a patient, access the Lymphoma SPORE web page and enter the remote 
registration/randomization application.  The registration/randomization application is 
available 24 hours a day, 7 days a week.  Back up is available between 8 a.m. and 4:30 
p.m. Central Time (Monday through Friday) by phone at 
 
  
 
The instructions for registration/randomization application are available on the 
Lymphoma SPORE secured web page and detail the process for completing and 
confirming patient registration.  Prior to initiation of protocol treatment, this process 
must be completed in its entirety and a Lymphoma SPORE 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 that 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 Lymphoma SPORE Registration Office 
If the patient 
was fully registered, the Lymphoma SPORE Registration Office staff can access the 
information from the centralized database and confirm the registration.  
• 
In the registration/randomization application, select the Show Subject button to 
verify that the patient registration data is retrievable. 
• 
Enter the registration/randomization application and, using the Lymphoma SPORE 
subject ID, confirm the patient appears in the registration/randomization application. 
 
6.2 
Correlative Research 
A mandatory correlative research component is part of this study, the patient will be 
automatically registered onto this component (see Sections 3.19g and 14.0). 
 
An optional correlative research component is part of this study, there will be an option 
to select if the patient is to be registered onto this component (see Section 17.0). 
 
• 
Patient has/has not given permission to have additional tissues collected from their 
diagnostics biopsy submitted for research. 
• 
Patient has/has not given permission to obtain the optional fresh research tissue 
biopsy prior to starting treatment.  (Mayo patients only) 
 
6.3 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients. 
 

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Protocol Version:   November 09, 2020 
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. 
 
6.4 
Prior to accepting the registration, registration 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 
 
6.5 
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 of lymphoma by the Lymphoma SPORE. 
• 
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. 
• 
Patient has/has not given permission for Lymphoma SPORE to give his/her 
sample(s) to researchers at other institutions. 
 
6.6 
Treatment cannot begin prior to registration and must begin ≤ 21 days after registration. 
 
6.7 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.8 
All required baseline symptoms (see Section 10.6) must be documented and graded. 
 
6.9a 
Treatment on this protocol must commence at the University of Iowa Holden 
Comprehensive Cancer Center or the Mayo Clinic Cancer Center under the supervision 
of a physician investigator registered with NCI Pharmaceutical Management Branch 
(PMB) and the Lymphoma SPORE Operations Office.  
 
6.9b 
Blood draw kit is available on site.  
 
6.9c 
Patient questionnaire booklet is available on site. 
 

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Protocol Version:   November 09, 2020 
7.0 
Protocol Treatment 
 
7.1 
Treatment Schedule – Arm A: Rituximab 
 
Agent 
Dose 
Route 
Day 
Cycle Length 
Rituximab1 
375 mg/m2/day 
IV 
1, 8, 15, 
22 
3 months 
1. 
Substitution of a rituximab biosimilar covered by patients’ insurance plan is acceptable 
for Arm A. 
 
The following pre-medications are suggested prior to rituximab:  acetaminophen 650-1000 
mg PO 30 minutes prior to rituximab and every 4 hours as needed for infusion related 
reactions, diphenhydramine 50 mg PO 30 minutes prior to rituximab, diphenhydramine 25 
mg IV every 4 hours as needed for infusion related reactions, meperidine 25 mg IV push as 
needed for rigors, may repeat x 1 dose if first dose is ineffective 
 
7.2 
Treatment Schedule – Arm B: Zevalin 
 
Agent 
Dose 
Route 
Day 
Cycle Length 
Rituximab1 
250 mg/m2/day 
IV 
1, 8 
3 months 
Zevalin 
0.3 mCi/kg or 0.4 
mCi/kg** 
IV 
8* 
*  Administer within 4 hours of completion of rituximab infusion. 
**  Maximum dose = 32 mCi.  Dose at 0.4 mCi/kg for patients with platelet counts greater 
than or equal to 150,000/mm3 and at 0.3 mCi/kg for patients with platelet counts 100,000 
to 149,000/mm3 
1. Substitution of a rituximab biosimilar covered by patients’ insurance plan is not allowed 
for Arm B. 
 
The following pre-medications are suggested prior to rituximab:  acetaminophen 650-1000 
mg PO 30 minutes prior to rituximab and every 4 hours as needed for infusion related 
reactions (maximum of 4000 mg in 24 hours), diphenhydramine 50 mg PO 30 minutes prior 
to rituximab, diphenhydramine 25 mg IV every 4 hours as needed for infusion related 
reactions, meperidine 25 mg IV push as needed for rigors, may repeat x 1 dose if first dose is 
ineffective. 
 
7.3 
For this protocol, patients randomized to Zevalin can be treated either at the enrolling 
site or referred to Mayo Clinic Rochester, Arizona, or Florida for the Day 1, 8 rituximab 
and Zevalin on Day 8. The enrolling site is also permitted to provide Day 1 rituximab if 
this is prearranged and coordinated with the Zevalin site. This can be arranged by calling 
the study 
after the patient has been registered. 
 
8.0 
Dosage Modification Based on Adverse Events  
 
8.1 
There are no dose modifications in this study. 

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Protocol Version:   November 09, 2020 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Patients may receive allopurinol at the discretion of the treating physician. 
 
9.3 
It is very unlikely that the patient would require blood products or growth factors. 
However, the patient may be administered hematopoietic growth factors (erythropoietin, 
GM-CSF, G-CSF, pegfilgrastim, oprelvekin) at the discretion of the treating physician.  
These should not be used prophylactically.  The use of these agents should be recorded. 
 
9.4 
Rituximab reactions: Patients who experience rituximab reactions may receive oral or 
IV corticosteroids in order to enable completion of rituximab therapy. Suggested 
doses are 100 mg of hydrocortisone IV or 50-100 mg methylprednisolone (Solu-
Medrol) IV pre-rituximab or to treat a rituximab reaction that does not respond to 
diphenhydramine and acetaminophen. Patients who experience a reaction that 
requires IV steroids may be pretreated with corticosteroids at the next dose. 
 
9.5 
Patients found to have immunoglobulin deficiency on pre-treatment testing may 
receive IVIG at physician discretion and per recommended guidelines. 
 

LS138D 
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Protocol Version:   November 09, 2020 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Adverse Event Characteristics 
 
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: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)     
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE version 4.0.  
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.3).  With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4).  Important: Expedited adverse 
event reporting requires submission of a MedWatch report(s). Expedited reports 
are to be completed within the timeframes and via the mechanisms specified in 
Sections 10.4. All AEs reported via expedited mechanisms must also be reported 
via the routine data reporting mechanisms defined by the protocol (see Sections 
10.52 and 18.0). 
 
10.12 
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).  Grade is an essential element of the 
Guidelines and, in general, relates to severity for the purposes of regulatory reporting 
to NCI. 
 
 
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 
 
• 
The determination of whether an AE is expected is based on the agent-
specific information provided in Section 15.0 of this protocol. 
 
• 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.0 of this protocol. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is 
neither identified in nature, severity, or frequency of risk in the information 
provided for IRB review nor mentioned in the consent form.  
 

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LS Addendum 5 
 
 
Protocol Version:   November 09, 2020 
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.  
 

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Protocol Version:   November 09, 2020 
10.4  
Expedited Reporting Requirements for CIP Studies using Commercial Agent(s) 
ONLY: 
 
Expedited Reporting Requirements for Adverse Events that Occur in a Non-
IND/IDE trial within 30 Days of the Last Administration of a Commercial Agent 1, 2  
 
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 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in section 
10.41 of the protocol.  
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported via MedWatch 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 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
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 
 

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LS Addendum 5 
 
 
Protocol Version:   November 09, 2020 
 
Additional Instructions: 
1. An increased incidence of an expected adverse event (AE) is based on the patients 
treated for this study at their site.  A list of known/expected AEs is reported in the 
package insert or the literature, including AEs resulting from a drug overdose. 
2. Submit form to the FDA, 
 
   
 
 
 
 
 
  
 
 
 
Reporting Serious Adverse Events to Acrotech Biopharma:  The Investigator must notify 
Acrotech Biopharma of any event that meets one of the criteria for an SAE within 24 
hours of first knowledge.  For the initial report, please complete a standard MedWatch 
form and email to 
with all relevant documentation 
(laboratory tests, hospital admission/discharge summary, etc.).  Please assure that patient 
identifiers are redacted from all documentation, except for patient initials and date of 
birth.  
 
Acrotech Biopharma: 
 
  
 
SAE Email:
 
 
 

LS138D 
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LS Addendum 5 
 
 
Protocol Version:   November 09, 2020 
10.41 Special Situations for Expedited Reporting  
 
EXPECTED Serious Adverse Events 
 
An expedited report may not be required for specific Grade 1, 2, 3 and 4 Serious 
Adverse Events where the AE is EXPECTED. Any protocol specific reporting 
procedures MUST BE SPECIFIED BELOW and will supercede the standard 
Expedited Adverse Event Reporting Requirements.  Note:  These adverse events 
must still be reported through the routine reporting mechanism [i.e. 
Nadir/Adverse Events Form]; see footnote 1. 
 
 
System Organ Class (SOC) 
 
Adverse event/ Symptoms 
 
CTCAE Grade at which the 
event will not be 
expeditedly reported.1 
Blood and lymphatic system 
disorders 
Anemia 
≤ Grade  4 
Investigations 
White blood cell decreased 
≤ Grade 4 
Lymphocyte count decreased  
≤ Grade 4 
Neutrophil count decreased 
≤ Grade 4 
Platelet count decreased 
≤ Grade 4 
1  These 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. 
 
Specific protocol exceptions to expedited reporting should be reported 
expeditiously by investigators ONLY if they exceed the expected grade of the 
event. 
 
10.5 
Other Required Reporting 
 
10.51 Persistent or Significant Disabilities/Incapacities 
 
Any AE that results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions (formerly referred to as disabilities), congenital 
abnormities or birth defects, must be reported immediately if they occur at any time 
following treatment with an agent under an IND/IDE since they are considered to be a 
serious AE and must be reported to the sponsor as specified in 21 CFR 312.64(b). 
 
10.52   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. 
 
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. 

LS138D 
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LS Addendum 5 
 
 
Protocol Version:   November 09, 2020 
 
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 benigh, malignant and unspecified (incl 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. 
 
10.53 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 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 
 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
10.54 Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior malignancy 

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LS Addendum 5 
 
 
Protocol Version:   November 09, 2020 
(and is NOT a metastasis from the initial malignancy).  Second malignancies 
require ONLY routine reporting. 
 
10.6 
Required Routine Reporting 
 
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
 
 
System Organ 
Class (SOC)  
 
Adverse event/Symptoms 
 
Baseline 
Each  
evaluation 
Investigations 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
White blood cell decreased 
X 
X 
Skin and 
subcutaneous 
tissue disorders 
Rash maculo-papular 
X 
X 
 
10.61 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6 
 
10.611 Grade 2 AEs deemed possibly, probably, or definitely related to the 
study treatment or procedure. 
 
10.612 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.613   Grade 5 AEs (Deaths) 
 
10.6131 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
 
10.6132 
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. 
 
10.62    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). 
 

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Protocol Version:   November 09, 2020 
11.0 
Treatment Evaluation  
 
11.1 
Response Considerations  
 
 
Definitions for clinical response for patients with lymphoma are from the Cheson et al. 
Revised Response Criteria for Malignant Lymphoma .(28) Lymph node measurements 
should be taken from the CT portion of the PET/CT, or MRI scans, or 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 extranodal 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 (eg, 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 CT alone or the CT component of PET/CT or MRI where 
applicable. 
 
 
 

LS138D 
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LS Addendum 5 
 
 
Protocol Version:   November 09, 2020 
Response criteria, modified from Cheson et al. 2007.  
Response 
Category 
Definition 
Nodal Masses 
Spleen, liver 
Bone Marrow 
CR 
Disappearance of all 
evidence of disease. 
Regression to normal size on 
CT 
 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared 
on repeat biopsy; 
if indeterminate by 
morphology, 
immunohistochemi
stry should be 
negative 
PR 
Regression of 
measurable disease 
and no new sites 
≥50% decrease in SPD of up to 
6 largest dominant masses; no 
increase in size of other nodes 
and  
regression on CT 
≥50% decrease 
in SPD of 
nodules (for 
single nodule in 
greatest 
transverse 
diameter); no 
increase in size 
of liver or 
spleen 
Irrelevant if 
positive prior to 
therapy; cell type 
should be 
specified 
SD 
Failure to attain 
CR/PR or PD 
No change in size of previous 
lesions on CT 
 
 
PD (Relapse/ 
Progressive 
disease) 
Any new lesion or 
increase by ≥50% of 
previously involved 
sites from nadir 
Appearance of a new lesion(s) 
> 1.5 cm in any axis, ≥50% 
increase from nadir in SPD of 
more than one node, or ≥50% 
increase in longest diameter of 
a previously identified node > 
1 cm in short axis. 
> 50% increase 
from nadir in 
the SPD of any 
previous lesions 
New or recurrent 
involvement 
Abbreviations: CR, complete response; FDG, [18F]fluorodeoxyglucose; PET, positron emission 
tomography; CT, computed tomography; PR, partial response; SPD, sum of the product of the diameters; 
SD, stable disease; PD, progressive disease. 
 
 

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Protocol Version:   November 09, 2020 
11.11 Complete Response (CR).  The designation of CR requires all of the following: 
 
11.111 Complete disappearance of all detectable clinical evidence of disease 
and definitely disease-related symptoms if present before therapy.  
 
11.112 All lymph nodes and nodal masses must have regressed on CT to normal 
size (≤1.5 cm in their greatest transverse diameter for nodes > 1.5 cm 
before therapy). Previously involved nodes that were 1.1 to 1.5 cm in 
their long axis and more than 1.0 cm in their short axis before treatment 
must have decreased to ≤1.0 cm in their short axis after treatment.  . 
 
11.113 The spleen and/or liver, if considered enlarged before therapy on the 
basis of a physical examination or CT scan, should not be palpable on 
physical examination and should be considered normal size by imaging 
studies, and nodules related to lymphoma should disappear. However, 
determination of splenic involvement is not always reliable because a 
spleen considered normal in size may still contain lymphoma, whereas 
an enlarged spleen may reflect variations in anatomy, blood volume, the 
use of hematopoietic growth factors, or causes other than lymphoma.  
Similarly, other organs considered to be enlarged before therapy due to 
involvement by lymphoma, such as liver and kidneys, must have 
decreased in size. 
 
11.114 If the bone marrow was involved by lymphoma before treatment, the 
infiltrate must have cleared on repeat bone marrow biopsy. The biopsy 
sample on which this determination is made must be adequate (with a 
goal of > 20 mm unilateral core). If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry. A sample 
that is negative by immunohistochemistry but that demonstrates a small 
population of clonal lymphocytes by flow cytometry will be considered a 
CR until data become available demonstrating a clear difference in 
patient outcome.  
 
11.12 Criteria for Partial Response (PR). The designation of PR requires all of the 
following: 
 
11.121 At least a 50% decrease in sum of the product of the diameters (SPD) of 
up to six of the largest dominant nodes or nodal masses. These nodes or 
masses should be selected according to all of the following:  
• 
they should be clearly measurable in at least 2 perpendicular 
dimensions 
• 
if possible they should be from disparate regions of the body 
• 
they should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved 
 
11.122 No increase should be observed in the size of other nodes, liver, or 
spleen. 
 

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Protocol Version:   November 09, 2020 
11.123 Splenic and hepatic nodules must regress by 50% in their SPD or, for 
single nodules, in the greatest transverse diameter.  
 
11.124 With the exception of splenic and hepatic nodules, involvement of other 
organs is usually assessable and no measurable disease should be 
present. 
 
11.125 Bone marrow assessment is irrelevant for determination of a PR if the 
sample was positive before treatment. However, if positive, the cell type 
should be specified (eg, large-cell lymphoma or small neoplastic B cells). 
Patients who achieve a CR by the above criteria, but who have persistent 
morphologic bone marrow involvement will be considered partial 
responders.  
When the bone marrow was involved before therapy and a clinical CR 
was achieved, but with no bone marrow assessment after treatment, 
patients should be considered partial responders. 
 
11.126 No new sites of disease should be observed. 
 
11.127 CT criteria should be used  
 
 
 
 
 
 
11.13 Criteria for Stable Disease (SD) 
 
11.131  A patient is considered to have SD when he or she fails to attain the 
criteria needed for a CR or PR (see above), but does not fulfill those for 
progressive disease (see below).  
 
11.132  There must be no change in the size of the previous lesions on the post-
treatment CT scan. 
 
11.14 Relapsed Disease (after CR)/Progressive Disease (PD) (after PR, SD): 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm 
regardless of the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it 
should only be considered abnormal if its short axis is more than 1.0. Lymph 
nodes ≤1.0 x ≤1.0 cm will not be considered as abnormal for relapse or 
progressive disease.  
 
11.141 Appearance of any new lesion more than 1.5 cm in any axis during or at 
the end of therapy, even if other lesions are decreasing in size. Increased 
FDG uptake in a previously unaffected site should only be considered 
relapsed or progressive disease after confirmation with other modalities. 
In patients with no prior history of pulmonary lymphoma, new lung 
nodules identified by CT are mostly benign. Thus, a therapeutic decision 
should not be made solely on the basis of the PET without histologic 
confirmation. 
 

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Protocol Version:   November 09, 2020 
11.142 At least a 50% increase from nadir in the SPD of any previously involved 
nodes, or in a single involved node, or the size of other lesions (eg, 
splenic or hepatic nodules). To be considered progressive disease, a 
lymph node with a diameter of the short axis of less than 1.0 cm must 
increase by 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the 
long axis. 
 
11.143  At least a 50% increase in the longest diameter of any single previously 
identified node more than 1 cm in its short axis.  
 
 
 
12.0 
Descriptive Factors  
 
12.1 
Follicular Lymphoma International Prognostic Index 2 (FLIPI2) (29)  low risk (0 risk 
factors) vs. intermediate risk (1 or 2 risk factors) vs. high risk (3-5 risk factors)  
 
Risk Factors 
0 points 
1 point 
β2-microglobulin 
≤ ULN 
> ULN 
Longest diameter of the 
largest involved node 
≤ 6 cm 
> 6 cm 
Bone marrow involvement 
No 
Yes 
Hemoglobin Level 
≥12 g/dL 
<12 g/dL 
Age 
≤60 years 
>60 years 
 
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 will be evaluated per the test schedule during cycle 1 of treatment. 
 
13.2 
After treatment, patients will be observed at 3, 6, 9, 12, 18, 24, 30, 36, 48, and 60 months 
from day 1 of treatment. 
 
13.3 
Criteria for removing patients from treatment and initiating observation. 
 
13.31 Requested withdrawal or patient non-compliance. 
 
13.4 
Patients who have progressive or relapsed disease, receive subsequent treatment for 
lymphoma, refuse further observation, or fail to return for evaluation during observation 
will go to event monitoring. 
 
13.5 
At 5 years from day 1 of treatment, all patients still on observation will go to event 
monitoring every 12 months until 10 years from time of registration per Section 18.0. 
 
13.6 
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.  

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Protocol Version:   November 09, 2020 
The patient may continue protocol treatment at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. The patient will 
continue treatment (if no safety concerns), observation, and event monitoring as 
specified for all patients (or will be taken off study, if applicable).  
• 
If the patient received treatment, the patient will continue treatment (if no safety 
concerns), observation, and event monitoring as specified for all patients.  
• 
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. 
 
13.7 
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.  The patient may continue protocol treatment at the discretion of the 
physician as long as there are no safety concerns, and the patient was properly registered. 
The patient will continue treatment (if no safety concerns), observation, and event 
monitoring as specified for all patients.  
 
13.8 
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. 

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Protocol Version:   November 09, 2020 
 
14.0 
Body Fluid Biospecimens    
 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
 
 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or 
Body 
Fluid 
being 
Collected 
Type of 
Collection 
Tube 
(color of 
tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Visit 1 
(Screenin
g/Baseline
)  
Visit 2 
(End of 
6 
months/
End of 
Cycle 2) 
Process 
at site? 
(Yes or 
No) 
Temperature 
 Conditions 
for Storage 
/Shipping1  
Plasma cytokines, 
Tumor Treg and 
Monocyte content, 
Vitamin D, and 
Blood molecular 
markers  
(Section 14.3) 
 
Mandatory 
Whole 
Blood 
ACD 
(yellow) 
8.5 mL 
(2)2 
X 
X 
No 
Ambient 
temperature 
NO cold pack 
required 
Mandatory 
Whole 
Blood 
EDTA 
(purple) 
10 mL 
(1) 
X 
X 
No 
Mandatory 
Whole 
Blood 
None 
(red) 
10 mL 
(1) 
X 
X 
No 
1After all samples have collected according to kit instructions, ship all specimens according to shipping instructions (see Section 
14.24 for detailed shipping instructions). 
2Mayo Clinic Rochester only: Samples will be collected in three 6 mL tubes. 
 
 
 
 
 
 
 
 

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Protocol Version:   November 09, 2020 
14.2 
Blood/Blood Products Handling 
 
14.21 Kits are required for this study for non-Mayo Rochester sites. 
 
The kit contains supplies and instructions for collecting, processing, and 
shipping specimens. 
 
Participating institutions may obtain kits by e-mailing 
  E-mail requests should include the site 
address, contact information and number of kits being requested. 
 
Kits will be sent via FedEx® Ground at no additional cost to the participating 
institutions.  Allow 3 to 4 business days to receive the kits. 
 
14.22 Label specimen tubes with the protocol number, the patient’s initials (last, first, 
middle), study patient ID number (if available) and date of blood collection. 
 
14.23 Collect all peripheral blood according to specific kit instructions (see Appendix 
III) and table above. 
 
14.24 Shipping 
 
Specimens must be shipped the same day they are drawn. 
 
Ship ACD, EDTA, and no additive (red top) whole blood tubes in their 
respective Styrofoam boxes; no cold pack is required but may be used. Avoid 
freezing of specimen. The Fed Ex airbills is pre-addressed. 
 
Ship specimens via Priority Overnight service on Monday – Thursday 
Preferred (Friday only if you must) directly to: 
 
Predolin Biobank 
   
 
 
 
Please send email message to 
  The message should 
include the study name, sample type, Fed Ex airbill tracking number, contact 
name and telephone number.  Phone calls if necessary to 
 
 
Shipping costs will be covered by the study if these kits and Fed Ex airbills are 
used for shipping specimens. Each kit contains the required tubes.  
 
14.3 
Background and Methodology 
 
14.31  Plasma cytokines: Plasma cytokine levels will be measured using a standard 30-
plex ELISA (Invitrogen, Camarillo, CA) as previously described.(26) Thirty 

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Protocol Version:   November 09, 2020 
cytokines will be analyzed using the Luminex- 200 system. Data will be acquired 
using STarStation software (Applied Cytometry, Dinnington, Sheffield, UK). 
 
14.32 Tumor Treg and Monocyte content: This will be measured using standard IHC 
methods and subsets enumerated by the study pathologist. 
 
14.33 Vitamin D: 25(OH)D and 1,25(OH)D concentrations will be performed using 
the on-study, pretreatment research serum sample in the 
 
 under the direction of 
 The normal range and that 
laboratory is 25-80 ng/ML. Patients will be classified as “insufficient” if the 
level is less than 25 ng/ML. 
 
14.34 Blood molecular markers:  Serum, plasma, and blood mononuclear cells will 
be cryopreserved and used by the SPORE investigators for markers of prognosis 
and markers to predict response.  Specific assays and sample calculations will be 
determined using the approval system in the SPORE and will follow standard 
Mayo and Iowa procedures for sample request and approval. 
 
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. 
 
15.0 
Drug Information  
 
15.1 
Rituximab (Rituxan®, C2B8) 
 
15.11 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.  
 
15.12 Formulation: Commercially available for injection, solution [preservative free]: 
10 mg/mL (10 mL, 50 mL) [contains Polysorbate 80]. 
 
15.13 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 

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LS Addendum 5 
 
 
Protocol Version:   November 09, 2020 
2ºC to 8ºC for 24 hours and at room temperature for an additional 24 
hours. 
 
15.14 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). 
 
 
15.15 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: 4.5L 
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: Median terminal half-life: 18 days 
GPA/MPA: 23 days 
Excretion: Uncertain; may undergo phagocytosis and catabolism in the 
reticuloendothelial system  
 
 

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Protocol Version:   November 09, 2020 
15.16 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. 
 
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. 
 
15.17 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: Fatigue, chills, neuropathy, headache, insomnia, 
pain 
Dermatologic: Skin rash, pruritus, night sweats 
Endocrine & Metabolic: Weight gain 
Gastrointestinal: Nausea, diarrhea, abdominal pain 
Hematologic: Lymphocytopenia, anemia, leukopenia, neutropenia, 
thrombocytopenia, cytopenia, febrile neutropenia 
Hepatic: ALT increased 
Hypersensitivity: Angioedema 
Immunologic: Antibody development 
Infection: Infection, bacterial infection 
Neuromuscular & skeletal: Weakness, muscle spasm, arthralgia 
Respiratory: Cough, rhinitis, epistaxis 
Miscellaneous: Infusion related reaction  
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Hypotension, flushing 
Central nervous system: Dizziness, anxiety, migraine, paresthesia 
Dermatologic: Urticaria 
Endocrine & metabolic: Hyperglycemia, increased lactate dehydrogenase  

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LS Addendum 5 
 
 
Protocol Version:   November 09, 2020 
Gastrointestinal: Vomiting, dyspepsia 
Infection: Viral infection, fungal infection 
Neuromuscular & skeletal: Back pain, myalgia 
Respiratory: Dyspnea, throat irritation, bronchospasm, upper respiratory 
tract infection, sinusitis 
 
Rare known potential toxicities, <1% (Postmarketing and/or case 
reports):  
Acute mucocutaneous toxicity, acute renal failure (associated with tumor 
lysis syndrome), acute respiratory distress, anaphylactoid 
reaction/anaphylaxis, angina, pectoris, aplastic anemia, arthritis 
(polyarticular), bone marrow depression, bronchiolitis obliterans, cardiac 
arrhythmia, cardiac failure, cardiogenic shock, encephalitis, fulminant 
hepatitis, gastrointestinal perforation, hemolytic anemia, hepatic failure, 
hepatitis, hypogammaglobulinemia (prolonged) hypoxia, increased serum 
immunoglobulins (hyperviscosity syndrome in Waldenstrom’s 
macroglobulinemia), interstitial pneumonitis, intestinal obstruction, 
Kaposi’s sarcoma (progression), laryngeal edema, lichenoid dermatitis, 
lupus-like syndrome, mucositis, myelitis, MI, nephrotoxicity, optic 
neuritis, pancytopenia, paraneoplastic pemphigus, pleurisy, pneumonia, 
pneumonitis, polymyositis, progressive multifocal leukoencephalopathy,  
pure red cell aplasia, reactivated pure red cell aplasia, reactivated 
tuberculosis, reactivation of HBV, reversible posterior 
leukoencephalopathy syndrome, serum sickness, Stevens-Johnson 
syndrome, supraventricular arrhythmia, toxic epidermal necrolysis, 
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 
 
15.18 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
 
15.19 Nursing Guidelines:  
 
1. Do not administer as an IV push or bolus since it increases the risk of a 
hypersensitivity reaction. 
 
2. 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. 
 
3. Patients should be cautioned to withhold their anti-hypertensive medication 
for 12 hours prior to drug administration. 

LS138D 
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LS Addendum 5 
 
 
Protocol Version:   November 09, 2020 
 
4. 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. 
 
5. 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. 
 
6. 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. 
 
7. 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. 
 
8. GI disturbances (Nausea, abdominal pain and less commonly diarrhea, 
vomiting, dyspepsia) headache, and weakness are common side effects.  
Treat as necessary.  Monitor for effectiveness. 
 
9. 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. 
 
10. 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.  
 
11. 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. 
 
15.2 
Ibritumomab (Zevalin) 
 
15.21 Background: Ibritumomab is a monoclonal antibody directed against the CD20 
antigen on B-lymphocytes. Ibritumomab binding induces apoptosis in B 
lymphocytes in vitro. It is combined with the chelator tiuxetan, which acts as a 
specific chelation site for either Indium-111 or Yttrium-90. The monoclonal 
antibody acts as a delivery system to direct the radioactive isotope to the targeted 
cells, however, binding has been observed in lymphoid cells throughout the body 
and in lymphoid nodules in organs such as the large and small intestines. Y-90 
emits beta particles. Beta-emission induces cellular damage through the 
formation of free radicals (in both target cells and surrounding cells).  

LS138D 
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LS Addendum 5 
 
 
Protocol Version:   November 09, 2020 
 
15.22 Formulation: Commercially available for injection, Kit, Intravenous 
[preservative free]: 3.2 mg/2 mL 
 
15.23 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Do not exceed the Y-90 
ibritumomab maximum allowable dose of 32 mCi; do not administer to 
patients with altered biodistribution (determined by imaging with In-111 
ibritumomab). Use should be reserved to physicians and other 
professionals qualified and experienced in the safe handling of 
radiopharmaceuticals, and in monitoring and emergency treatment of 
infusion reactions. The contents of the kit are not radioactive until 
radiolabeling occurs. During and after radiolabeling, adequate shielding 
should be used with this product, in accordance with institutional radiation 
safety procedures. Radiolabeling of ibritumomab with Yttrium-90 must be 
performed by appropriate personnel in a specialized facility. 
 
15.24 Administration:  Inject slowly, over 10 minutes through a 0.22 micron low 
protein binding in-line filter. After injection, flush line with at least 10 mL 
normal saline. Y-90 ibritumomab: Establish free-flowing I.V. line prior to 
administration. Avoid extravasation; if signs or symptoms of extravasation 
occur, stop infusion and restart in another limb.  
 
 
15.25 Pharmacokinetic information: 
Duration: Beta cell recovery begins in ~12 weeks; generally in normal 
range with 9 months. 
Distribution: To lymphoid cells throughout the body and in lymphoid 
nodules in organs such as the large and small intestines, spleen, testes, and 
liver 
Metabolism: Has not been characterized; the product of yttrium-90 
radioactive decay is zirconium-90 (nonradioactive); Indium-111 decays to 
cadmium-111 (nonradioactive). 
Half-life elimination: Y-90 ibritumomab: 30 hours; Indium-111 decays 
with a physical half-life of 67 hours; Yttrium-90 decays with a physical 
half-life of 64 hours. 
Excretion: A median of 7.2% of the radiolabeled activity was excreted in 
urine over 7 days.  
 
 
15.26 Potential Drug Interactions:   
Increased Effect/Toxicity: Ibritumomab may increase the  levels of: 
Leflunomide; Natalizumab; Vaccines (Live); Vitamin K Antagonists 
 
The levels/effects of Ibritumomab may be increased by: Anticoagulants; 
Antiplatelet Agents; Denosumab; Pimecrolimus: Tacrolimus (Topical); 
Trastuzumab 
 
Decreased Effect: Ibritumomab may decrease the levels/effects of: BCG; 
Cardiac Glycosides; Sipuleucel-T; Vaccines; Vitamin K Antagonists. 
 

LS138D 
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LS Addendum 5 
 
 
Protocol Version:   November 09, 2020 
Herb/Nutraceutical Interactions: Avoid Echinacea (may diminish 
therapeutic effect). Avoid cat’s claw, dong quai, evening primrose, 
feverfew, garlic, ginger, ginkgo, red clover, horse chestnut, green tea, 
ginseng (all have antiplatelet activity). 
 
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: Do not exceed the Y-90 ibritumomab 
maximum allowable dose of 32 mCi; do not administer to patients 
with altered biodistribution (determine by imaging with In-111 
ibritumomab). Serious fatal infusion reactions may occur with the 
rituximab component of the therapeutic regimen. Delayed, prolonged, 
and severe cytopenias are common. Do not administer to patients with 
greater than or equal to 25% lymphoma marrow involvement, 
patients with impaired marrow reserve. 
 
Common known potential toxicities, > 10%:   
Central nervous system: Fatigue 
Gastrointestinal: Nausea, abdominal pain, diarrhea 
Hematologic: Thrombocytopenia, neutropenia, anemia, leukopenia, 
lymphocytopenia, metastases, including acute myelogenous leukemia and 
Myelodysplastic syndrome 
Neuromuscular & skeletal: Weakness 
Respiratory: Nasopharyngitis, cough 
Miscellaneous: Infection 
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Hypertension 
Central nervous system: Dizziness 
Dermatologic: Night sweats, pruritus, skin rash 
Gastrointestinal: Anorexia 
Genitourinary: Urinary tract infection 
Hematologic & oncologic: Petechia, bruise, severe cytopenia 
Neuromuscular & skeletal: myalgia  
Respiratory: Bronchitis, flu-like symptoms, rhinitis, pharyngolaryngeal 
pain, sinusitis, epistaxis 
Miscellaneous: fever 
 
Rare known potential toxicities, <1% (Postmarketing and/or case 
reports):  
Anaphylactic reactions, arthritis, cerebral hemorrhage, cytogenetic 
abnormalities, encephalopathy, hematemesis, hemorrhage, 
hypersensitivity; infusion site erythema/ulceration, radiation 
injury/complications, meningioma, pulmonary edema, pulmonary 
embolism, radiation necrosis, stroke, subdural hematoma, tachycardia, 
vaginal hemorrhage 
 
15.28 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 

LS138D 
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LS Addendum 5 
 
 
Protocol Version:   November 09, 2020 
 
 
15.29 Nursing Guidelines:  
 
1. Drug does not emit gamma radiation, just Beta emissions that have only 
moderate penetrating power of a few millimeters.  Therefore, radiation 
exposure to hospital personnel is minimal.  The isotope can be administered in 
the outpatient setting.  However, it is recommended that the treatment room be 
prepared for possible contamination in the event of spillage. 
 
• 
Absorbent pads should be placed under the infusion site and over the 
bed tables. 
• 
Direct the patient to wash their hands thoroughly after using the toilet. 
• 
Direct the patient to use condoms during sexual relations for one week 
following administration. 
 
2. Administer through a free flowing IV line within 4 hours following 
completion of rituximab. After injection, flush line with at least 10 mL of 
normal saline.  
 
3. Monitor patients closely for signs of extravasation. If extravasation is 
suspected, stop infusion immediately and restart in another limb. 
 
4. Cytopenias are common, especially thrombocytopenia. Monitor CBC. 
Instruct patient to report any sign of infection, unusual bruising or bleeding 
to the health care team. 
 
5. Monitor for cutaneous reactions.  
 
6. Patients may experience fatigue. 
 
7. Gastrointestinal side effects including nausea, abdominal pain, and diarrhea 
have been seen. Treat symptomatically and monitor for effectiveness. 
 
16.0  
Statistical Considerations and Methodology  
 
16.1 
Overview:  This is a randomized phase III study designed to compare the complete 
response rate at 6 months between Rituximab (Arm A) and Zevalin (Arm B) for 
treatment of asymptomatic follicular lymphoma. 
 
16.11 
Primary Endpoint:   The primary endpoint of this study is the complete response 
rate at the 6-month disease assessment which will be compared between the two 
arms.  A patient is considered to be a complete responder if the objective status 
at the 6-month disease assessment is a complete response.  Any patient not 
meeting the definition of a complete response will be considered as a non-
responder for the primary endpoint.  A modified intent-to-treat approach will be 
employed for the primary analysis such that all randomized subjects meeting the 
eligibility criteria who do not cancel participation prior to treatment initiation 
and did not experience a major treatment violation (during the first cycle of 
treatment) will be included in the primary analysis.  Sensitivity analysis will be 
conducted including all patients who did not cancel participation prior to 

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LS Addendum 5 
 
 
Protocol Version:   November 09, 2020 
treatment initiation.  The percentage of patients in each response category (e.g., 
CR, PR, STAB, Relapse/PD) will also be tabulated by arm. 
 
16.2   Statistical Considerations:   
 
16.21     Statistical Design: 
 
 
Previous studies of treatment with four doses of single agent Rituximab in this 
patient population have shown CR rates of 6-33% (9 and 10).  In addition, 
preliminary results of an additional study, the RESORT ECOG trial, show a CR 
rate of 15% in this same population (11).  This study is designed to detect an 
improvement in complete response rate from 20% with Rituximab (Arm A) to 
50% with Zevalin (Arm B).  The proportion of patients who have a CR at 6 
months will be evaluated and compared between the two treatment regimens 
using a two-sided α=0.05 continuity corrected Cochran–Mantel–Haenszel 
(CMH) test with stratification factors as defined in Section 5.0. 
 
The primary goal of this trial is to compare the CR rate at 6 months between 
Rituximab and Zevalin. We will randomize 116 evaluable patients in a 1:1 ratio 
to Rituximab or Zevalin. This final analysis will take place after all patients have 
completed the disease assessment at 6 months. A sample size of 58 evaluable 
patients per arm (116 total evaluable) provides 90% power to detect an 
improvement in complete response rate from 20% to 50%, using a two-sided chi-
square test at a significance level of 0.05.  To ensure that 116 evaluable patients 
are randomized, we will enroll/randomize 128 total patients.  
 
The CR rate in each arm will be estimated by the number of evaluable patients 
who achieve a CR as the objective status on the disease assessment at 6 months 
divided by the total number of randomized evaluable patients in that arm.  The 
CR rates will be compared between the two arms.  If the CR rate is higher in the 
Zevalin arm, where the p-value is less than 0.05, this will be considered 
sufficient evidence that the Zevalin arm may be recommended for further testing 
in subsequent studies. 
 
This study will use a dynamic allocation procedure to allocate an equal number 
of patients to each of the two treatment regimens.(30) This procedure will 
balance the marginal distributions of the stratification factors between these two 
treatment arms. The stratification factors that will be used are listed in Section 
5.0. 
 
This study will be based on a modified intent-to-treat approach including all 
randomized patients meeting the eligibility criteria who do not cancel 
participation prior to treatment initiation and did not experience a major 
treatment violation (during the first cycle of treatment) based on the randomized 
treatment assignment.  
 
The study will be permitted to be published after all patients have undergone the 
6-month disease assessment to establish the CR rate between each arm. This 
essentially fulfills the first goal of the study.  See Section 16.3 for further 
analysis plans.  

LS138D 
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LS Addendum 5 
 
 
Protocol Version:   November 09, 2020 
 
16.23 
Other considerations: Adverse events, 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. 
 
16.24 
Sample Size:  This study is expected to accrue a maximum of 128 patients unless 
undue toxicity is encountered. 
 
16.25 
Accrual Rate and Study Duration:  The anticipated accrual rate is 4 patients per 
month.  This study is expected to accrue in ~2.75 years.  The total study duration 
is expected to be approximately ~3.25 years, or until the last patient accrued has 
been observed for at least 6 months.   
 
16.3    Secondary Outcome Analyses:  The secondary endpoints listed below will be evaluated in 
each arm independently and will also be compared between the two arms.  Analysis of all 
endpoints will occur at the time of the primary analysis (after all patients have completed 
the 6-month disease assessment), after all patients have been followed for 3 years, and 
after all patients have been followed for 5 years.  For all secondary endpoints, p-values 
<0.001 will be considered statistically significant at either of the first two analyses.  At 
the 5-year analysis, p-values <0.05 will be considered as statistically significant.  P-value 
boundaries are based on the Haybittle-Peto rule.(31, 32) A final analysis for the purpose 
of providing updated descriptive estimates may be undertaken after all patients have been 
followed for 10 years.   
 
16.31  Progression-free survival (PFS) is defined as the time from registration to the 
earliest date documentation of disease progression or death due to any cause. The 
distribution of progression-free survival time will be estimated using the method 
of Kaplan-Meier within each arm and compared between the arms using a log-
rank test.  The progression-free survival rates at 3 years and 5 years will be 
estimated in each arm. 
 
16.32  Time to any therapy (TTNT)  is defined as the time from registration to the date 
of initiation of any treatment for follicular lymphoma. The distribution of time to 
any therapy will be estimated using the method of Kaplan-Meier within each arm 
and compared between the arms using a log-rank test.  The percentage of patients 
free of any therapy at 3 years and 5 years will be estimated in each arm. 
 
16.33 Time to chemotherapy (TTC)  is defined as the time from registration to the date 
of initiation of chemotherapy for follicular lymphoma. The distribution of time 
to chemotherapy will be estimated using the method of Kaplan-Meier within 
each arm and compared between the arms using a log-rank test.  The percentage 
of patients free of chemotherapy at 3 years and 5 years will be estimated in each 
arm.  
 
16.34  Adverse Events: 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 

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Protocol Version:   November 09, 2020 
will be reviewed to determine patterns. Additionally, the relationship of the 
adverse event(s) to the study treatment will be taken into consideration.  Rates of 
individual adverse events (grade 3 and higher) will be compared between arms 
using a Fisher’s exact test. 
 
16.4 
Correlative Research:  The correlative endpoints listed below will be evaluated in each 
arm independently and may also be compared between the two arms.  For each measure, 
values may be investigated with respect to response (CR vs. less than CR) using two-
sample t-tests (continuous measures) or chi-square tests (categorical measures).  
Relationship with time to event measures (PFS, TTNT, TTC) will be evaluated using 
Kaplan-Meier methods and log-rank statistics (categorical measures) or Cox 
proportional hazards models (continuous measures).  For values collected at more than 
one time point, changes over time will be evaluated using paired-t-tests (continuous 
measures) or McNemar’s or Bhapkar’s tests (categoical measures).  Endpoints and 
additional analyses are described below.  Analysis involving quality of life are 
described in Section 16.47. 
 
16.41 The incidence of exon 2 bcl2 mutations will evaluated at baseline.   
 
16.42 Tissue Tregs and tissue monoctyes will be quantified for the on study tumor 
biopsies.  These values will be reported as percentages. 
 
16.43 Serum cytokines will be analyzed for each time point (pre-treatment and 6 
months).   Each cytokine will be evaluated in reference to normal controls and 
levels will be categorized as normal, elevated, or suppressed. 
 
16.44 Vitamin D levels will be evaluated at on study.  At each time point, Vitamin D 
level will be categorized as normal (sufficient) vs. abnormal (insufficient).  
Vitamin D insuffiency will be defined as a 25 hydroxy-vitamin D (D2 + D3) 
level <25 ng/mL in the central (Mayo) laboratory.    
 
16.45 Beta-2 microglobulin (B2m) plus LDH score will be evaluted in relation to the 
institutional upper limit of normal (IULN).  Patients will be categorized at 
baseline as low risk (both factors ≤ 150% ULN), intermediate risk (one factor ≤ 
150% IULN and the other factor > 150% ULN), or high risk (both factors > 
150% IULN).  The prognostic value of B2m plus LDH score in relation to PFS 
will be evaluated using Kaplan-Meier methods and log-rank statistics. Use of 
B2m plus LDH was previously reported. (18) 
 
16.46 ALC, AMC, and ALC/AMC ratio will be measured at baseline and after 
treatment.  Both the absolute and relative change will be summarized for each 
measure. 
 
16.47 Quality of life will be assessed prior to review of treatment response and 
discussions of patient’s general health since last treatment evaluation.  QOL will 
be measured using the FACT-Lym.  The FACT-Lym consists of the FACT-

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Protocol Version:   November 09, 2020 
General (FACT-G) with 27 items and a lymphoma-specific concerns scale with 
15 items, each item measured on a 0-4 scale (0=not at all; 4=very much).  The 
FACT-G is a general measure of quality of life of cancer patients containing four 
subscales: physical well-being, social/family well-being, emotional well-being, 
and functional well-being.  It is widely used in cancer clinical trials and is 
reliable and valid for general research purposes (33) The additional items of the 
lymphoma-specific concerns scale were developed to capture items relevant to 
the QOL of lymphoma patients.  The FACT-Lym has been shown in a cohort of 
non-Hodgkin’s lymphoma patients to be easy to administer, reliable, valid, and 
sensitive to change.(34) The recall period for the FACT-Lym is 7 days.  The 
FACT-Lym will be administered to all willing patients via a paper booklet in 
clinic at baseline and at 3, 6, 9, 12, 18, 24, 30, 36, 48, and 60 months while the 
patient remains in the active monitoring phase of the study (on treatment or in 
observation).  The FACT-Lym will be scored according to the published scoring 
algorithm with the following scale scores computed at each time point:  physical 
well-being (PWB, 7 items, score range 0-28), social/family well-being (SWB, 7 
items, score range 0-28), emotional well-being (EWB, 6 items, score range 0-24), 
functional well-being (FWB, 7 items, score range 0-28), FACT-G total score 
(PWB+ SWB+ EWB+ FWB, score range 0-108), FACT-LymS score 
(lymphoma-specific concerns, 15 items, score range 0-60), FACT-Lym total 
score (FACT-G+ FACT-LymS, score range 0-168), and the Trial Outcome Index 
(PWB+ FWB+ FACT-LymS, score range 0-116).  A clinically meaningful 
change is defined as 2-3 points in the PWB and FWB (35) 3-7 points in the 
FACT-G total (35) and 3-5 points in the FACT-LymS (36). 
 
 
The primary QOL analysis will be conducted at the time of the primary clinical 
analysis and will include the baseline, month 3 and month 6 QOL data.  
Additional analyses will be conducted after patients have been followed for 3 
years and for 5 years.   The primary analysis will compare the FACT-TOI 
between arms at the 3 month and the 6 month time points using analysis of 
covariance adjusting for the baseline FACT-TOI score.  Mean FACT-TOI will 
be graphically presented by arm using a mean plot with standard deviation error 
bars including all available data with pateints according to the randomized 
treatment assignment.  Baseline characteristics will be comapred between arms 
within the subject of patients who provide QOL data at one or more time points 
using t-tests for continuous variables and chi-squared tests for categorical 
variables.  To assess for selection bias, baseline characteristics for patients who 
provide QOL data at one or more time points will be compared to patients who 
do not provide any QOL data using t-tests for continuous variables and chi-
squared tests for categorical variables. Subseqent analysis will include comarison 
of FACT-TOI area-under-the-curve from baseline to 6 months between arms 
using analysis of covariance adjusting for the baseline FACT-TOI score.  
Responder-type analysis will also be performed in which the percentage of 
patients who report a 6-point worsening from baseline at either 3 or 6 months 
will be compared between arms using a chi-square test .  The “responder” 
definition will be investigated using cumulative distribution curves.  Lastly, a 

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Protocol Version:   November 09, 2020 
linear mixed-effects model will be used to compare the FACT-TOI over time 
between arms with the post-baseline FACT-TOI score as the modeled outcome 
and predictors are baseline FACT-TOI, arm, time (treated as a continuous 
variable and measured at the planned month of assessment), and treatment-by-
time interaction.  Similar analyses described for the FACT-TOI will be repeated 
for the other scale scores, and for all scales after 3 and 5 years of follow-up. 
 
 
Missing data will be handled in several ways. All analyses will first be 
completed using all available data, followed by analyses completed using 
imputed data using the arm minimum followed by the arm maximum.  Lastly, we 
will employ pattern mixture models for longitudinal analyses.  Output from all 
analyses will be compared to assess the degree to which missing data impacts 
study results. 
 
 
For all statistical analyses, p-values <0.05 will be considered statistically 
significant.  For interpreting the clinical significance of effects will be evaluted 
using the FACT cut-offs described above as well as using Cohen’s cut-offs (37): 
 <0.20=trivial; 0.20-<0.50=small; 0.50-<0.80=moderate; and >/=0.80=large. 
 
16.5  
Data & Safety Monitoring: 
 
16.51     The principal investigator(s) and the study statistician will review the study at 
least twice a year 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. 
16.52 Adverse Event Stopping Rules (these rules apply to Arm A and Arm B 
independently):   Both Arms A (rituximab) and B (Zevalin) are commercial 
agents used at the FDA-approved dose with standard CBC and bone marrow 
criteria. Since the doses are the same, we do not expect any difference in the 
toxicity profile as described in the label.    We note that the Adverse Event 
Stopping 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 
treatment(s) under investigation.  The study team may choose to suspend accrual 
because of unexpected adverse event profiles that have not crossed the specified 
rule below. 
In our previous study of single-agent rituximab for untreated FL(10), we 
observed 14% grade 3,4 AEs. In previous Zevalin studies for untreated FL (14) 
there was, as expected, 15% grade 3 and 17% grade 4 (total 32% grades 3,4) 
neutropenia that was reversible. There was no grades 3,4 non-hematologic 
toxicity.  These toxicities, if they occur, do so within 12 weeks for both Arms A 
and B. Accrual will be temporarily suspended to both arms if at any time we 
observe events considered at least possibly related to study treatment (i.e., an 

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Protocol Version:   November 09, 2020 
adverse event with attribute specified as  “possible”, “probable”, or “definite”) 
that satisfy either of the following: 
 
• 
if 3 or more patients in the first 12 treated patients experience a grade 4 or 
higher non-hematologic adverse event at least possibly related to treatment. 
 
• 
if after the first 12 patients have been treated, 25% of all patients experience 
a grade 4 or higher non-hematologic adverse event at least possibly related to 
treatment. 
 
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. 
 
16.6 
Results Reporting 
 
16.61  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 
 For purposes of timing 
of the Results Reporting, the initial estimated completion date for the 
Primary Endpoint of this study is 3.25 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 been followed for 
at least 6 months. 
 
16.62   Publications:  This study includes endpoints that require various amounts 
of follow-up.  Due to this, primary endpoint results will be reported after 
all patients have completed the 6-month response assessment (6-12 
months after completion of accrual).  Time to event endpoints including 
PFS, TTNT, and TTC will require additional follow-up.  These measures 
may be reported in the initial report with the CR rate, as well as after 3 
years, 5 years, and 10 years after the completion of accrual. 
 
16.7 
Inclusion of Women and Minorities 
 
16.71 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.72 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, 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. 
 

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Protocol Version:   November 09, 2020 
16.83 The geographical region served by MCCC has a population which includes 
approximately 5% minorities. Based on prior MCCC studies involving similar 
disease sites, we expect about 5% of patients will be classified as minorities by 
race and about 45% of patients will be women. Expected sizes of racial by 
gender subsets are shown in the following table: 
 

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Protocol Version:   November 09, 2020 
Accrual Estimates by Gender/Ethnicity/Race for All Phase 2 and 3 Studies 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
1 
1 
0 
2 
Not Hispanic or Latino 
57 
69 
0 
126 
Unknown 
0 
0 
0 
0 
Ethnic Category: Total of all subjects 
58 
70 
0 
128 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
2 
2 
0 
4 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
56 
68 
0 
124 
More than one race 
0 
0 
0 
0 
Unknown 
0 
0 
0 
0 
Racial Category: Total of all subjects 
58 
70 
0 
128 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, 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. 
 

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Protocol Version:   November 09, 2020 
 
17.0  
Pathology Considerations/Tissue Biospecimens   
 
17.1  
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
 
 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Type of 
Tissue to 
Collect 
Block, 
Slides, Core, 
etc. (# of 
each to 
submit) 
Visit 1 
(Screening)  
Process at 
site? (Yes 
or No) 
Temperatu
re 
 Conditions 
for Storage 
/Shipping  
Central Path review 
Mandatory 
H&E 
stained 
slides 
H&E stained 
diagnostic 
slides 
X 
No 
Ambient air 
Tregs, Monocytes 
(Section 17.31) 
Optional 
Paraffin 
embedded 
1 paraffin-
embedded 
block; if 
block not 
available 
then 1 H&E 
slide and 20 
(4µ) 
unstained 
slides  
X 
No 
Ambient air 
Bcl-2 mutations 
(Section 17.31) 
Optional 
Paraffin 
embedded 
X 
No 
Ambient air 
Research Fresh Tissue 
Optional for 
patients 
enrolled at 
Mayo only 
Fresh 
Excisional or 
core needle 
(3-6 cores) 
biopsy 
X 
No 
 
 

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LSAddendum 5 
 
Protocol Version: November 9, 2020 
17.2 
Diagnostic Slides from Original and /or Recurrent Tissue 
 
Central pathology review will be conducted for confirmation of diagnosis by 
 
nd colleagues at Mayo Clinic Rochester.   
 
 
The appropriate representative tumor tissue samples will be forwarded to the Lymphoma 
SPORE Biospecimens Core for central diagnostic review and classification to confirm 
the diagnosis.  This is a retrospective review to determine the evaluability of the patient’s 
data for analysis.  The results of the review are the purposes of the trial only and will not 
be returned to the site. 
 
Required materials 
): 
 
• 
Lymphoma Pathology Reporting Form (Complete Section I only) 
• 
Bone marrow biopsy report  
• 
Tumor tissue pathology report 
• 
Tumor tissue diagnostic H&E stained slide 
• 
Tumor tissue immunochemistry or immunophenotyping by flow cytometry report (if 
available) 
 
17.3 
Correlative Tissue Collection  
 
17.31 Paraffin Embedded Tissue 
 
17.311 Representative diagnostic FFPE tumor tissue block.  If block cannot be 
sent then please send one (1) H&E slide, and twenty (20) 4µm unstained 
air-dried slides.  Do not coverslip the unstained slides. If questions 
please 
 
   
   
 
 

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LSAddendum 5 
 
Protocol Version: November 9, 2020 
18.0 
Records and Data Collection Procedures   
 
18.1 
Submission Timetable 
 
Initial Material(s)  
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
On-Study  
 
 
 
 
≤14 days after registration 
Adverse Event– Baseline  
Measurement – Baseline  
Tumor Tissue Biopsy Pathology Report 
CT/PET/MRI Scan Report 
Research Paraffin Embedded Submission – 
Baseline (All Patients) 
 
≤30 days after registration 
Research Fresh Tissue Submission – 
Baseline (Mayo Patients only) 
Research Blood Submission  
≤ 21 days after registration 
End of Active Treatment/Cancel Notification  
Submit ≤14 days after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
Patient Questionnaire Booklet 
≤14 days after registration - Patient questionnaire booklet 
must be used; copies are not acceptable for this submission. 
Booklet Compliance  
≤14 days after registration - This form must be completed 
only if the patient questionnaire booklet contains absolutely 
NO patient provided assessment information. 
 
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.) 
Submit ≤30 days after registration (see Section 17.0) 
 
Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
At each evaluation 
during treatment 
At end of 
treatment 
Observation 
Evaluation/Treatment  
X2 
X 
 

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LSAddendum 5 
Protocol Version:   November 09, 2020 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
At each evaluation 
during treatment 
At end of 
treatment 
Observation 
Evaluation/Observation  
 
 
X1 
Nadir/Adverse Event (Cycles 1 & 2 Only) 
X 
X 
X3 
Measurement  
X 
X 
X 
Research Blood Submission  
 
 
X (see Section 14.0) 
Patient Questionnaire Booklet 4 
X 
X 
X 
Booklet Compliance 5 
X 
X 
X 
End of Active Treatment/Cancel Notification  
 
X 
 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
At each occurrence 
(see Section 10.0)3 
CT/PET/MRI Scan Report 
X6 
 
X6 
1. Complete at each evaluation during Observation (see Section 4.0). 
2. Complete at each evaluation during Active Treatment (see Section 4.0). 
3. AE form and expedited reports needed for Cycle 1 (treatment – months 0-3) and Cycle 2 (first 
cycle of observation – months 3-6) only. 
4. Patient questionnaire booklet must be used; copies are not acceptable for this submission. 
5. This form must be completed only if the patient questionnaire booklet contains absolutely NO 
patient provided assessment information. 
6. Submit copy of documentation of response or progression to the Lymphoma SPORE Operations 
Office, Attention: QAS for LS138D. 
 
Follow-up Material(s) 
CRF 
Event Monitoring Phase1 
 
 
q. 12 
months 
until PD2 
 
 
 
At PD2 
After 
PD q. 
12 mos. 
 
 
 
Death 
 
 
 
New Primary 
Event Monitoring  
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 10 years after registration, no further follow-up is required. 
2. Submit copy of documentation of response or progression to the MCCC Operations Office, 
Attention: QAS for LS138D.

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Protocol Version:   November 09, 2020 
 
19.0  
Budget 
 
19.1 
Costs charged to patient: rituximab and Zevalin are standard of care and will be 
commercial 
 
19.2 
Tests to be research funded: Lymphoma SPORE will cover the research translational 
costs and kits and mailing. This will involve the clinical trials core B and the 
Biospecimens Core. 
 
 
19.3 
Other budget concerns: Protocol administration, study coordinator time, data 
management, and statistical analysis efforts will be funded by Acrotech Biopharma.

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20.0 
References 
 
1. 
Bachy E, Brice P, Delarue R, Brousse N, Haioun C, Le Gouill S, et al. Long-term follow-up of 
patients with newly diagnosed follicular lymphoma in the prerituximab era: effect of response quality on 
survival--A study from the groupe d'etude des lymphomes de l'adulte. J Clin Oncol. 2010;28(5):822-9. 
Epub 2009/12/23. doi: JCO.2009.22.7819 [pii] 
10.1200/JCO.2009.22.7819. PubMed PMID: 20026809. 
2. 
Brice P, Bastion Y, Lepage E, Brousse N, Haioun C, Moreau P, et al. Comparison in low-tumor-
burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a 
randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des 
Lymphomes de l'Adulte. J Clin Oncol. 1997;15(3):1110-7. PubMed PMID: 9060552. 
3. 
Solal-Celigny P, Lepage E, Brousse N, Tendler CL, Brice P, Haioun C, et al. Doxorubicin-
containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: final analysis 
of survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaires 86 Trial [see comments]. 
Journal of Clinical Oncology. 1998;16(7):2332-8. 
4. 
Salles G, Seymour JF, Offner F, Lopez-Guillermo A, Belada D, Xerri L, et al. Rituximab 
maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to 
rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 
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10.1016/S0140-6736(10)62175-7. PubMed PMID: 21176949. 
5. 
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Ibritumomab Tiuxetan Consolidation of First Remission in Advanced-Stage Follicular Non-Hodgkin 
Lymphoma: Updated Results After a Median Follow-Up of 7.3 Years From the International, 
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10.1200/JCO.2012.45.6400. PubMed PMID: 23547079. 
6. 
Morschhauser F, Radford J, Van Hoof A, Vitolo U, Soubeyran P, Tilly H, et al. Phase III trial of 
consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after 
first remission in advanced follicular lymphoma. J Clin Oncol. 2008;26(32):5156-64. PubMed PMID: 
18854568. 
7. 
Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grunhagen U, Losem C, et al. 
Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with 
indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority 
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PubMed PMID: 23433739. 
8. 
Nastoupil L, Sinha R, Byrtek M, Taylor M, Cerhan JR, Friedberg J, et al. A Comparison of the 
Effectiveness of First-Line Chemoimmunotherapy Regimens for Follicular Lymphoma (FL) Used in the 
United States. ASH Annual Meeting Abstracts. 2011;118(21):97-. 
9. 
Colombat P, Brousse N, Morschhauser F, Franchi-Rezgui P, Soubeyran P, Delwail V, et al. 
Single Treatment with Rituximab Monotherapy for Low-Tumor Burden Follicular Lymphoma (FL): 
Survival Analyses with Extended Follow-Up (F/Up) of 7 Years. ASH Annual Meeting Abstracts. 
2006;108(11):486-. 
10. 
Witzig TE, Vukov AM, Habermann TM, Geyer S, Kurtin PJ, Friedenberg WR, et al. Rituximab 
Therapy for Patients With Newly Diagnosed, Advanced-Stage, Follicular Grade I Non-Hodgkin's 
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2005;23(6):1103-8. 
11. 
Kahl BS, Hong F, Williams ME, Gascoyne RD, Wagner LI, Krauss JC, et al. Results of Eastern 
Cooperative Oncology Group Protocol E4402 (RESORT): A Randomized Phase III Study Comparing 

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Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma. ASH Annual 
Meeting Abstracts. 2011;118(21):LBA-6. 
12. 
Ardeshna KM, Qian W, Smith P, Braganca N, Lowry L, Patrick P, et al. Rituximab versus a 
watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: 
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2045(14)70027-0. PubMed PMID: 24602760. 
13. 
Kaminski MS, Tuck M, Estes J, Kolstad A, Ross CW, Zasadny K, et al. 131I-Tositumomab 
Therapy as Initial Treatment for Follicular Lymphoma. N Engl J Med. 2005;352(5):441-9. 
14. 
Scholz CW, Pinto A, Linkesch W, Linden O, Viardot A, Keller U, et al. 90Yttrium-Ibritumomab-
Tiuxetan as First-Line Treatment for Follicular Lymphoma: 30 Months of Follow-Up Data From an 
International Multicenter Phase II Clinical Trial. J Clin Oncol. 2013;31(3):308-13. Epub 2012/12/13. doi: 
10.1200/JCO.2011.41.1553. PubMed PMID: 23233718. 
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Kaminski MS, Tuck M, Estes J, Kolstad A, Ross CW, Regan D, et al. Tositumomab and Iodine I-
131 Tositumomab for Previously Untreated, Advanced-Stage, Follicular Lymphoma: Median 10 Year 
Follow-up Results. Blood (ASH Annual Meeting Abstracts). 2009;114(22):3759-. 
16. 
Illidge TM, Mayes S, Pettengell R, Bates AT, Bayne M, Radford JA, et al. Fractionated 90Y-
Ibritumomab Tiuxetan Radioimmunotherapy As an Initial Therapy of Follicular Lymphoma: An 
International Phase II Study in Patients Requiring Treatment According to GELF/BNLI Criteria. J Clin 
Oncol. 2014;32(3):212-8. Epub 2013/12/04. doi: 10.1200/JCO.2013.50.3110. PubMed PMID: 24297953. 
17. 
Ibatici A, Pica GM, Nati S, Vitolo U, Botto B, Ciochetto C, et al. Safety and efficacy of Yttrium-
Ibritumomab-Tiuxetan for untreated follicular lymphoma patients. An Italian cooperative study. Br J 
Haematol. 2013. Epub 2013/12/19. doi: 10.1111/bjh.12695. PubMed PMID: 24344981. 
18. 
Link BK, Maurer MJ, Nowakowski GS, Ansell SM, Macon WR, Syrbu SI, et al. Rates and 
Outcomes of Follicular Lymphoma Transformation in the Rituximab Era: A Report From the University 
of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource. ASH Annual Meeting Abstracts. 
2012;120(21):1546-. 
19. 
Press OW, Unger JM, Rimsza LM, Friedberg JW, LeBlanc M, Czuczman MS, et al. A 
comparative analysis of prognostic factor models for follicular lymphoma based on a phase III trial of 
CHOP-rituximab versus CHOP + 131iodine--tositumomab. Clin Cancer Res. 2013;19(23):6624-32. Epub 
2013/10/17. doi: 10.1158/1078-0432.CCR-13-1120. PubMed PMID: 24130072; PubMed Central 
PMCID: PMC3872052. 
20. 
Yang ZZ, Grote DM, Ziesmer SC, Niki T, Hirashima M, Novak AJ, et al. IL-12 upregulates TIM-
3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J 
Clin Invest. 2012;122(4):1271-82. Epub 2012/03/20. doi: 10.1172/JCI59806 
59806 [pii]. PubMed PMID: 22426209; PubMed Central PMCID: PMC3314462. 
21. 
Ansell SM. Malignant B cells at the helm in follicular lymphoma. J Clin Oncol. 
2013;31(21):2641-2. Epub 2013/06/19. doi: 10.1200/JCO.2013.49.2165. PubMed PMID: 23775955. 
22. 
Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM. CD70+ non-Hodgkin lymphoma B 
cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells. Blood. 
2007;110(7):2537-44. PubMed PMID: 17615291. 
23. 
Wilcox RA, Feldman AL, Wada DA, Yang ZZ, Comfere NI, Dong H, et al. B7-H1 (PD-L1, 
CD274) suppresses host immunity in T-cell lymphoproliferative disorders. Blood. 2009;114(10):2149-
58. Epub 2009/07/15. doi: blood-2009-04-216671 [pii] 
10.1182/blood-2009-04-216671. PubMed PMID: 19597183. 
24. 
Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, Timmerman JM. Programmed death 
ligand 1 is expressed by non-hodgkin lymphomas and inhibits the activity of tumor-associated T cells. 
Clin Cancer Res. 2011;17(13):4232-44. Epub 2011/05/05. doi: 10.1158/1078-0432.CCR-10-2660. 
PubMed PMID: 21540239. 

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25. 
Yang ZZ, Novak AJ, Stenson MJ, Witzig TE, Ansell SM. Intratumoral CD4+CD25+ regulatory 
T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood. 
2006;107(9):3639-46. PubMed PMID: 16403912. 
26. 
Ansell SM, Maurer MJ, Ziesmer SC, Slager SL, Habermann TM, Link BK, et al. Elevated 
pretreatment serum levels of interferon-inducible protein-10 (CXCL10) predict disease relapse and 
prognosis in diffuse large B-cell lymphoma patients. Am J Hematol. 2012;87(9):865-9. Epub 2012/06/08. 
doi: 10.1002/ajh.23259. PubMed PMID: 22674570; PubMed Central PMCID: PMC3429646. 
27. 
Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM. Malignant B cells skew the balance of 
regulatory T cells and TH17 cells in B-cell non-Hodgkin's lymphoma. Cancer Res. 2009;69(13):5522-30. 
Epub 2009/06/11. doi: 0008-5472.CAN-09-0266 [pii] 
10.1158/0008-5472.CAN-09-0266. PubMed PMID: 19509224; PubMed Central PMCID: PMC2764404. 
28. 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
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JCO.2006.09.2403 [pii] 
10.1200/JCO.2006.09.2403. PubMed PMID: 17242396. 
29. 
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Epub 2009/08/05. doi: JCO.2008.21.3991 [pii] 
10.1200/JCO.2008.21.3991. PubMed PMID: 19652063. 
30. 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in 
the controlled clinical trial. Biometrics. 1975;31(1):103-15. Epub 1975/03/01. PubMed PMID: 1100130. 
31. 
Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol. 
1971;44(526):793-7. Epub 1971/10/01. PubMed PMID: 4940475. 
32. 
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of 
randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br 
J Cancer. 1976;34(6):585-612. Epub 1976/12/01. PubMed PMID: 795448; PubMed Central PMCID: 
PMC2025229. 
33. 
Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, et al. The Functional Assessment 
of Cancer Therapy scale: development and validation of the general measure. Journal of Clinical 
Oncology. 1993;11(3):570-9. 
34. 
Wagner LI, Berg SR, Gandhi M, Hlubocky FJ, Webster K, Aneja M, et al. The development of a 
Functional Assessment of Cancer Therapy (FACT) questionnaire to assess dermatologic symptoms 
associated with epidermal growth factor receptor inhibitors (FACT-EGFRI-18). Support Care Cancer. 
2013;21(4):1033-41. Epub 2012/11/07. doi: 10.1007/s00520-012-1623-4. PubMed PMID: 23128934. 
35. 
Webster K, Cella D, Yost K. The Functional Assessment of Chronic Illness Therapy (FACIT) 
Measurement System: properties, applications, and interpretation. Health Qual Life Outcomes. 
2003;1:79. Epub 2003/12/18. doi: 10.1186/1477-7525-1-79. PubMed PMID: 14678568; PubMed Central 
PMCID: PMC317391. 
36. 
Hlubocky FJ, Webster K, Beaumont J, Cashy J, Paul D, Abernethy A, et al. A preliminary study 
of a health related quality of life assessment of priority symptoms in advanced lymphoma: the National 
Comprehensive Cancer Network-Functional Assessment of Cancer Therapy - Lymphoma Symptom 
Index. Leuk Lymphoma. 2013;54(9):1942-6. Epub 2013/01/17. doi: 10.3109/10428194.2012.762977. 
PubMed PMID: 23320888. 
37. 
Cohen J. Statistical power analysis for the behavioral sciences. Hillsdale New Jersey: Lawrence 
Erlbaum Associates; 1988. 
 

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Appendix I ECOG Performance Status Scale 
 
 
Appendix I 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
5 
Dead. 

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Appendix II Patient Information Sheet 
 
PATIENT INFORMATION SHEET 
Patient Completed Quality of Life Booklet 
______________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains some 
questions about your ‘quality of life’ as a patient receiving treatment for cancer.  Your 
answers will help us to better understand how the treatment you are receiving is affecting 
the way you feel. 
 
1. 
This booklet contains one set of questions: 
 
• 
FACT-Lym (42 questions) 
 
2. 
Directions on how to complete the set of questions are written on the top of the set. 
 
3. 
Please complete the booklet during your scheduled clinical visit and return it to your 
nurse, physician, or research coordinator. 
 
Thank you for taking the time to help us. 
 

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Appendix III Lymphoma Blood Collection Kit –  
Specimen Checklist and Shipping Instructions 
 
Hematology Malignancies Program/Predolin Biobank 
The Asymptomatic Follicular Lymphoma (AFL) Trial: A Phase III Study of Immunotherapy Versus 
Zevalin For Patients with New, Untreated Follicular Lymphoma Who are Candidates for Observation 
 
** PLEASE AVOID DRAWING OR SENDING SPECIMENS ON FRIDAYS AND HOLIDAYS** 
 
Kit Contents: 
• 
Small Styrofoam box and cardboard mailing sleeve 
• 
Patient Information Form 
• 
FedEx Airbill with pre-printed return address 
• 
8.5ml ACD (yellow top) collection tubes 
• 
10ml EDTA (purple top) collection tube 
• 
10ml Red Top collection tube 
• 
Absorbent tube holder 
• 
Zip lock specimen bag 
 
Packing and Shipping Instructions: 
1. Collect the following Peripheral blood specimens: 
 
• 
17ml into two (2) ACD tubes 
• 
10ml in one (1) EDTA tube 
• 
10ml in one (1) Red Top tube 
2. All specimens are to be clearly labeled with the protocol number LS138D, the patient’s initials (last, 
first, middle) and date of collection. 
3. Place the tubes in the absorbent holder and seal in the zip lock specimen bag. 
4. Place the filled specimen bag in the Styrofoam container. 
5. Loosely pack with paper toweling. 
6. Place the Styrofoam container and the Patient Information Form within the cardboard mailing sleeve. 
7. Prepare the package for shipping, applying packing tape as needed.  Complete the sender portion of 
the return FedEx Air bill and adhere to the exterior lid of the box.  Ship specimens via priority 
overnight delivery (next day delivery by 10am) the same day collected. 
8. Notify Federal Express for pick-up and/or leave package at the designated FedEx drop-off location. 
Please e-mail 
 to notify the 
laboratory when samples are being shipped.  Indicate the protocol number, the Fed Ex tracking number, 
name and phone number of the contact person.  The blood samples in prepared kits should be shipped to 
the following: 
 
 
 
 
 
 

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Patient Information Form 
 
 
Specimen Date:      /        /           
Institution/Affiliate:                 
Physician:                             
Patient Initials (last name, first name):                 
Protocol #: LS138D                                                                                           
                 
Lymphoma SPORE Subject ID #:                                                                                                         
                    
Contact Person:                                                                                                         
                                       
Institution:                                                                                                         
                                               
Address:  
 City                                           State                  Zip 
Phone #:                                                                                                         
                                       
FAX #:  
 
 
 
Please indicate which samples are being shipped at this time: 
1. Visit 1 (Screening /Baseline) 
2. Visit 2 (End of 6 months/End of Cycle 2) 
 
Any questions concerning sample collection for the LS138D study please contact: 
  
  
 
 
 
Affiliates who anticipate participating in this study should please call in advance for kits. 

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Appendix IV Bone Marrow