Conditions: Large B-cell Diffuse Lymphoma of Testis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 54
Healthy volunteers: no

Brief summary:
This trial is a phase II non-comparative study aimed to determine the feasibility and toxicity of the R-CHOP regimen in combination with intrathecal liposomal cytarabine and systemic intermediate-dose methotrexate followed by loco-regional radiotherapy.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone, liposomal cytarabine, methotrexate
Intervention descriptions: intervention 1: Weeks 1-15:

* 6 cycles of CHOP on Days 1 to 5, to be repeated q21 Days
* Rituximab 375 mg/m2 on Day 0 or Day 1 of every CHOP cycle
* IT chemoth:Depocyte 50 mg on Day 0 of cycles 2,3,4\&5 of R-CHOP

Weeks 18-22:

• Methotrexate 1.5 g/m2 q14 Days x 2

From Week 24:

• Scrotal prophylactic radiotherapy or involved field radiotherapy(but can be planned concomitantly to R-CHOP in pts with bilateral disease)

Protocol document:
Prot_SAP_000.pdf: 


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TABLE OF CONTENTS 
 
 
INVESTIGATOR AGREEMENT (STUDY ACKNOWLEDGEMENT) ......................................................................  4 
PROTOCOL SYNOPSIS .................................................................................................................................  5 
1. INTRODUCTION .....................................................................................................................................  6 
1.1. Background ....................................................................................................................................  6 
1.1.1. Primary testicular lymphoma background ..............................................................................  6 
1.1.2. Liposomal cytarabine (depocyte) background ........................................................................  7 
1.1.3. Rituximab background ..........................................................................................................  7 
1.2. Overall rationale for the study .........................................................................................................  8 
2. OBJECTIVES ...........................................................................................................................................  8 
2.1. Primary objective ............................................................................................................................  8 
2.2. Secondary objectives .......................................................................................................................  8 
3. OVERVIEW OF STUDY DESIGN ...............................................................................................................  9 
3.1. Statistical plan and rationale ...........................................................................................................  9 
3.2. Study design ...................................................................................................................................  9 
4. STUDY POPULATION ...........................................................................................................................  10 
4.1. General considerations ..................................................................................................................  10 
4.2. Inclusion criteria ...........................................................................................................................  11 
4.3. Exclusion criteria ...........................................................................................................................  11 
5. REGISTRATION AND STUDY DRUG SUPPLY ..........................................................................................  12 
6. DOSAGE AND ADMINISTRATION .........................................................................................................  13 
6.1. Drug administration ......................................................................................................................  13 
6.1.1. Treatment schedule and doses ............................................................................................  13 
6.2. Dose modification and delay .........................................................................................................  14 
6.2.1. CHOP dose modification .....................................................................................................  14 
6.2.2. Rituximab dose modification ...............................................................................................  14 
7. RADIOTHERAPY PORTS ........................................................................................................................  15 
8. CONCOMITANT THERAPY ....................................................................................................................  15 
8.1. Permitted therapy .........................................................................................................................  16 
8.2. Prohibited therapy ........................................................................................................................  16 
9. STUDY EVALUATIONS ..........................................................................................................................  16 
9.1. Study Procedures ..........................................................................................................................  16 
9.1.1.  Overview ...........................................................................................................................  16 
9.1.2. Pretreatment (screening) phase ..........................................................................................  17 
9.1.3. Treatment phase ................................................................................................................  17 
9.1.4. Intermediate evaluations (after third course of R-CHOP) ......................................................  18 
9.1.5. Consolidation phase ...........................................................................................................  18 
9.1.6. End of treatment restaging .................................................................................................  18 
9.1.7. Follow-up phase .................................................................................................................  19 
9.2. Pathology review ..........................................................................................................................  20 
9.3. Endpoint definitions ......................................................................................................................  20 
9.3.1. Criteria for evaluation .........................................................................................................  20 
9.4. Safety evaluations .........................................................................................................................  22 
10. SUBJECT COMPLETION / WITHDRAWAL ..............................................................................................  23 
10.1. Completion .................................................................................................................................  23 
10.2. Discontinuation of Treatment ......................................................................................................  23 
10.3. Withdrawal From the Study .........................................................................................................  23 


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11. ADVERSE EVENT(AE) AND SERIOUS ADVERSE EVENT (SAE) REPORTING .............................................  24 
11.1. Definitions ..................................................................................................................................  24 
11.1.1. Adverse Events definition and classification ......................................................................  24 
11.1.2. Attribution definitions ......................................................................................................  25 
11.2. Procedures ..................................................................................................................................  25 
11.2.1. All Adverse Events ............................................................................................................  25 
11.2.2. Serious Adverse Events and SUSAR ...................................................................................  26 
12. STUDY DRUG INFORMATION ..............................................................................................................  27 
12.1. Physical description of study drug(s) ............................................................................................  27 
12.2. Packaging ...................................................................................................................................  27 
12.3. Labeling .....................................................................................................................................  27 
12.4. Preparation and handling ............................................................................................................  28 
12.4.1. DepoCyte .........................................................................................................................  28 
12.4.2. Rituximab ........................................................................................................................  28 
12.5. Drug accountability .....................................................................................................................  28 
13. ETHICAL ASPECTS ..............................................................................................................................  28 
13.1. Regulatory Ethics Compliance .....................................................................................................  28 
13.1.1. Investigator responsibilities ...........................................................................................................  28 
13.2. Independent Ethics Committee or Institutional Review Board (IEC/IRB) .........................................  28 
13.3. Informed Consent .......................................................................................................................  29 
13.4. Privacy of personal data ..............................................................................................................  30 
14. ADMINISTRATIVE REQUIREMENTS ......................................................................................................  31 
14.1. Data Quality Assurance ...............................................................................................................  31 
14.2. Record retention .........................................................................................................................  31 
14.3. On-site audits .............................................................................................................................  31 
15. REFERENCES ......................................................................................................................................  32 
 
 
ATTACHMENT 1 - Performance Status scales .............................................................................................  33 
ATTACHMENT 2 - WHO classification for lymphoma ..................................................................................  34 
ATTACHMENT 3 - Instructions for the preparation and handling of DEPOCYTE injections ...........................  37 
ATTACHMENT 4 - Dispensing information for Rituximab ............................................................................  38 
ATTACHMENT 5 – Methotrexate schedule .................................................................................................. 40 
ATTACHMENT 6 - Creatinine clearance calculation ....................................................................................  42 
ATTACHMENT 7 - New York Heart Association Classification of Cardiac Disease ........................................  43 
ATTACHMENT 8 - Suggested Body Surface Area Calculation ......................................................................  44 
ATTACHMENT 9 - Timing of treatment and investigations .........................................................................  45 
 
 
 
 
 
 
 
 
 
 
 
 
 


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INVESTIGATOR AGREEMENT (STUDY ACKNOWLEDGEMENT) 
 
 
PROTOCOL IELSG 30  
 
A PHASE II STUDY OF R-CHOP WITH INTENSIVE CNS PROPHYLAXIS AND SCROTAL IRRADIATION IN 
PATIENTS WITH PRIMARY TESTICULAR DIFFUSE LARGE B-CELL LYMPHOMA 
 
 
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed 
regarding the study drug and the conduct of the study. 
 
 
 
 
 
 
.................................................................... ...................................................... ......................................  
Investigator (printed name) 
Signature 
Date 
 
 
Institution, Address, Phone Number * ............................................................................................................  
 
......................................................................................................................................................................  
 
 
 
 
 
On behalf of the IELSG: 
December 2, 2008 
Prof. Dr. med. Franco Cavalli 
.................................................................... ...................................................... ......................................  
Sponsor representative 
Signature 
Date 
 
 
 
 
 
 
* If the address or phone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor and will not require protocol amendment(s). 
 
 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
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PROTOCOL SYNOPSIS 
 
TITLE: A PHASE II STUDY OF R-CHOP WITH INTENSIVE CNS PROPHYLAXIS AND SCROTAL IRRADIATION IN 
PATIENTS WITH PRIMARY TESTICULAR DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) 
 
AIM 
To assess the feasibility, activity and safety of a therapeutic program in which patients with testicular large cell 
lymphoma receive state-of-the-art chemo-immunotherapy plus both intrathecal (with liposomal cytarabine) 
and systemic CNS prophylaxis (with intermediate-dose methotrexate), followed by locoregional radiotherapy. 
 
PATIENT POPULATION 
 Primary testicular DLBCL 
 Ann Arbor stage I-II at presentation (including bilateral testis involvement)  
 untreated disease 
 bidimensionally measurable, evaluable or no evidence of disease 
 age 18-80 years 
 ECOG performance status ≤2 
 
STUDY DESIGN AND STATISTICAL RATIONALE 
Phase II non comparative study aimed to determine the feasibility and toxicity of the R-CHOP regimen in 
combination with intrathecal liposomal cytarabine and systemic intermediate-dose methotrexate followed by 
loco-regional radiotherapy. The previous IELSG 5 retrospective analysis on 373 patients with testis lymphoma, 
showed a PFS of 48% at 5 years in the entire population, regardless of the type of treatment. The IELSG 10 
prospective clinical study was designed with a sample size of 50 patients defined to reject the null hypothesis 
of a PFS of 50% under the alternative hypothesis that the true PFS is 70% with a 5% significance level (two-
sided) and 80% power. 
The early results of IELSG 10 study seem to suggest that Rituximab-CHOP regimen plus intrathecal prophylaxis 
with methotrexate may reduce the incidence of CNS relapses and, therefore, improve the outcome. However, 
the follow up is not yet adequate to allow any sound conclusion and, at present, it is unclear on which 
estimation of PFS should a sample size be calculated. According to the recruitment rate of the previous IELSG 
10, assuming a similar number of participating centers, we may expect to enroll approximately 35 cases in 4 
years. At that point, the feasibility of the design should be adequately evaluated and the follow up data from 
the previous IELSG 10 study should be mature enough for a careful calculation of the sample size in order to 
transform this pilot study in a formal phase II trial.  
 
TREATMENT PROGRAM 
 
WEEKS 1-15 
- 6 cycles of CHOP on days 1 to 5, to be repeated q 21 days 
 
- Rituximab on day 0 or day 1 
 
- IT chemotherapy: Depocyte®, 50 mg on day 0 of cycles 2, 3, 4, 5 of CHOP 
WEEKS 18-22 
- Methotrexate 1.5 g/m2  q 14 days x 2 
FROM WEEKS 24 
- Scrotal prophylactic radiotherapy or involved field radiotherapy 
 
  (but can be planned concomitantly to R-CHOP in patients with bilateral disease) 
 
SAFETY PARAMETERS 
Clinical laboratory data, physical exams, observations for adverse events 
 
TIME PERIOD AND NUMBER OF PATIENTS 
Starting Date of Study 
March 2009 
Completion Date 
March 2013 
Trial sample 
35 patients will be enrolled over 36 months 


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1. 
INTRODUCTION 
 
 
1.1. Background 
 
1.1.1. Primary testicular lymphoma background 
 
PTL is a rare disease that represents 1% to 2% of all non-Hodgkin’s lymphomas, with an estimated incidence 
of 0.26/100,000 per year. 1 PTLs account for no more than 5% of all testicular malignancies, however they 
represent the most frequent testicular cancer in men older than 50 years of age. 2 PTL is a typically disease of 
elderly, 85% of PTLs are diagnosed  in men over 60 years of age. 3 Histologically, 90% or more of PTLs are of 
diffuse large-cell type (DLBCL) with B cell phenotype. 
PTL has a propensity to disseminate systematically to several extranodal sites including the contralateral testis, 
central nervous system (CNS 6% - 16%), skin (0% - 35%), Waldeyer’s ring (5%), lung, pleura and soft tissue. 
Mainly, the portion of patients showing CNS involvement at diagnosis, 2% to 16%, is higher than in nodal 
lymphomas.3,6,7 
Primary testicular lymphomas (PTL) are very aggressive malignancies with poor prognosis. Five year survival 
ranged from 16% to 50% and median survival has been reported of only 12-24 months according to the 
different series of patients.2,8,7 The use of anthracycline-based chemotherapy has been associated with a 5-
yr survival of 30-60% in different series, nevertheless there is a continuous relapse pattern with no evidence 
of plateau in the survival curve.9,10,11,12,7 Doxorubicin-containing regimens has allowed an improvement in 
the relapse-free survival comparing orchiectomy ± radiotherapy, however the advantage on survival time 
varied a lot among the different series published so far.13,11,7 In the largest series of patients reported so far 
by the IELSG (373 patents), the outcome of patients was extremely poor with an actuarial 5- and 10-years OS 
of 48% and 27% and an actuarial 5- and 10-years progression free survival of 48% and 33% respectively. 
The survival and PFS curves showed no clear evidence of a plateau, suggesting no cure for patients affecting 
by primary testicular lymphoma, even for those presenting with stage I/II (5 and 10 yrs OS in stage I 58% and 
29%, stage II 46% and 29%7, respectively). The majority of patients with PTL relapse despite complete 
response to initial treatment. When radiation is given to the retroperitoneal lymph nodes, failures are 
systemic. Very few cases of in-field relapses have been reported. After chemotherapy both systemic and 
regional relapses are seen. Most relapses occurred in the first two years, but late relapses have also been 
described.14,7 One of the peculiar feature of PTL is a contralateral testis relapse occurring in 5-35% of the 
patients.5 In the retrospective series of 373 patients reported by IELSG, the commonest sites of relapse were: 
CNS (5 and 10-years risk of CNS relapse 20% and 35%) and contralateral testis (15% at 3 years, 40% at 15 
years) occurring in patients not receiving prophylactic scrotal radiotherapy.7 Prophylactic irradiation of the 
contralateral testis has been proved to successfully prevent testicular recurrences in some studies.13,7 In the 
IELSG study prophylactic radiotherapy to contralateral testis  was also associated with better PFS (5-year PFS 
36% vs 70%) and OS (5-year OS 38% vs 66%). Moreover, CNS relapses are definitely more common than in 
other aggressive lymphomas and they have been reported up to 30% of the patients within 1-2 years from 
diagnosis. However, late relapse have also been described, sometimes as CNS relapse alone.12,11 The high 
rate of CNS recurrence is troublesome and has led to a recommendation for routine CNS prophylaxis. 
Although the use of prophylactic intrathecal chemotherapy has been advocated, its value is controversial 
because CNS relapses occur more frequently in brain parenchyma than in meninges and also in patients who 
had received intrathecal chemotherapy.6,7  The best strategy to prevent CNS relapse is still a matter of 
debate. 
As well demonstrated in nodal diffuse large B-cell lymphoma (DLBCL) , the addition of Rituximab to CHOP 
chemotherapy may be useful in PTL as suggested by preliminary data of IELSG10 study recently reported.16 In 
this study 45 patients with stage I-II PTL were treated with CHOP - Rituximab and  CNS prophylaxis with 4 
administrations of intrathecal methotrexate and scrotal radiotherapy ± loco-regional radiotherapy for stage II. 
The preliminary results suggest an improvement in the outcome with a 3-year OS and EFS of 88% and 78%, 
no contralateral testis relapse and 2.5% actuarial risk of CNS relapse at three years. However the median 
follow-up is still short and systemic and CNS recurrence rate might increase with a longer follow-up. Perhaps 
the incorporation of chemotherapy agents that have a better penetration into the CNS, as intermediate/high-


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
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dose methotrexate and/or intrathecal liposomal cytarabine, would allow a more effective control of the 
disease and may prevent CNS recurrence. A new prospective phase II study has been outlined aimed to further 
reduce systemic and CNS recurrence and, possibly, better define the standard treatment for PTL. Patients will 
receive state-of-the-art chemoimmunotherapy plus both intrathecal and systemic CNS prophylaxis. 
 
1.1.2. Liposomal cytarabine (Depocyte) background 
 
Potential risks of depocyte. 
The following adverse event occurring in two or more patients receiving DepoCyte in the phase III/IV clinical 
studies were associated with patient outcomes categorized as serious. The events are listed by descending 
order of frequency within body system. 
Body as a Whole: headache, fever, asthenia, back pain, hydrocephalus, pain, sepsis, neoplasm, 
 injection site reaction, infection, mucous membrane disorder, abdominal pain, chills, accidental injury 
Nervous system: seizure, psychosis (hallucinations/delusions), confusion, arachnoiditis, intracranial 
hypertension, somnolence, meningitis, agitation, neuropathy, hypoesthesia, liquor alterations, dizziness, gait 
disorders, coma, subdural haematoma, meningism, facial paralysis. 
Digestive system: nausea, vomiting, gastrointestinal haemorrhage, intestinal occlusion, diarrhoea, anorexia 
Cardiovascular system: cardiac arrest, pulmonary embolus, hypotension, syncope, deep thrombophlebitis. 
Hemic and Lymphatic system: neutropenia, thrombopenia, anaemia. 
Metabolic and Nutritional Disorder: dehydration, hyperglycaemia, hyponatremia, alkalosis 
Respiratory system: pneumonia, apnoea, dyspnoea, bronchitis 
Special senses: deafness 
Urogenital system: urinary tract infection 
Skin and Appendages: sweating 
 
1.1.3. Rituximab background 
 
Potential risks of rituximab. 
The most serious adverse reactions with rituximab include: infusion reactions, tumor lysis syndrome, 
mucocutaneous reactions, hypersensitivity reactions, cardiac arrhythmias, angina, and renal failure. The 
incidence of clinically significant abdominal pain, anemia, dyspnea, hypotension and neutropenia was higher 
in subjects with bulky disease (lesions > 10 cm) vs subjects with lesions < 10 cm. During retreatment with 
rituximab the incidence of grade 3 and 4 adverse events was similar to the experience of patients receiving 
the first treatment (58% and 57% respectively). 
Mild to moderate infusion reactions consisting of fever and chill/rigors occurred in the majority of patients 
during the first infusion. Other frequent infusion reaction symptoms included nausea, pruritus, angioedema, 
asthenia, hypotension, headache, bronchospasm, throat irritation, rhinitis, urticaria, rash, vomiting, myalgia, 
dizziness and hypertension. These reactions generally occurred within 30 to 120 minutes of beginning the first 
infusion and resolved with slowing or interruption of the rituximab infusion and with supportive care. 
Rituximab induced B-cell depletion in 70-80%of patients and was associated with decrease serum 
immunoglobulins in a minority of subjects, infections events occurred in 31% of patients. Grade 3 and 4 
infectious events including sepsis occurred in 25 of patients. Grade 3 and 4 cytopenia were reported in 485 of 
subjects, a single occurrence of transient aplastic anemia and 2 occurrence of hemolytic anemia were 
reported. In addition, there have been a limited number of postmarketing reports of pancytopenia, marrow 
hypoplasia and late onset neutropenia (defined as occurring 40 days after the last dose of rituximab) in 
patients with hematological malignancies. Grade 3 and 4 cardiac events including hypotension and rare fatal 
cardiac failure with symptomatic onset after rituximab administration have been reported. Pulmonary events 
were experienced by 38% of patients. The most common respiratory adverse events were increased cough, 
rhinitis, bronchospasm, dyspnea and sinusitis. In addition, immune/autoimmune events have been reported 
including uveitis, optic neuritis (in a subject with systemic vasculitis), pleuritis in a subject with lupus-like 
syndrome, serum sickness with with polyarticular arthritis and vasculitis with rash.  
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure and death has been reported in 
some patients with hematological malignancies treated with rituximab. The majority of patients received 
rituximab in combination with chemotherapy. The median time to the diagnosis of hepatitis was 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
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approximately 4 months after the beginning of rituximab and approximately 1 month after the last dose. 
Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection and 
for signs of hepatitis during and for up to several months following rituximab therapy. In patients who develop 
viral hepatitis, rituximab and any concomitant chemotherapy should be discontinued and appropriate 
treatment including antiviral drugs should be initiated. 
Two patients have died after being treated with rituxan for systemic lupus erythematosus (SLE). The cause of 
death was a viral infection of the brain called progressive multifocal leukoencephalopathy (PML) that is caused 
by reactivated JC virus. Latent JC virus is present in about 80 percent of adults. Rituxan is prescribed off-label 
for other serious disease and conditions such as SLE. The sponsor estimates that approximately 10,000 
patients with SLE have been treated with Rituxan. Reactivation or exacerbation of viral infections including JC 
virus leading to PML may occur when patients receive Rituxan for any reason.  Patients who have been 
treated with Rituxan and present or develop new neurological signs or symptoms should be evaluated for 
PML.  
Less common adverse events (>1% and <5%) reported from clinical studies included agitation anorexia, 
hypokinesia, hyperstesia, hypoglicemia, injection site pain, insomnia, lacrimation disorder, malaise, 
nervousness, neuritis, neuropathy, paresthesia, somnolence, vertigo and weight decrease.    
 
 
1.2. Overall rationale for the study 
 
A previous IELSG large retrospective analysis on 373 patients with testis lymphoma, showed a PFS of 48% at 
5 years in the entire population, regardless of the type of treatment. A more recent IELSG prospective study 
has suggested that systemic doxorubicin regimens with rituximab and intrathecal prophylaxis with short acting 
methotrexate may improve the outcome but long term results are available only for a few patients and this 
approach reduces but does not eliminate CNS relapses. The incorporation of chemotherapy agents that have a 
better penetration into the CNS, as intermediate-dose methotrexate and intrathecal liposomal cytarabine 
which maintains cytotoxic concentrations of ara-C in the CSF for at least 14 days, would allow a more 
effective control of the disease and may prevent CNS recurrence. 
 
 
 
 
2. 
OBJECTIVES 
 
 
2.1. Primary objective 
 
To demonstrate safety and feasibility of the R-CHOP regimen in combination with intrathecal liposomal 
cytarabine and systemic intermediate-dose methotrexate followed by loco-regional radiotherapy in untreated 
patient with stage I and II Primary Testicular Lymphoma  
 
 
2.2. Secondary objectives 
 
To evaluate the efficacy of the R-CHOP regimen in combination with intrathecal liposomal cytarabine and 
systemic intermediate-dose methotrexate followed by loco-regional radiotherapy in prolonging 3-year 
Progression-Free Survival (PFS) and 3-year Event-Free-Survival (EFS) rate compared to historical standard 
treatment.   
To evaluate 3-year overall survival of the patients treated with R-CHOP in combination with intrathecal 
liposomal cytarabine and systemic intermediate-dose methotrexate followed by loco-regional radiotherapy. 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
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3. 
OVERVIEW OF STUDY DESIGN 
 
This is an open label, non randomized, phase II, multicenter, prospective trial to evaluate the safety and 
feasibility of the R-CHOP regimen in combination with intrathecal liposomal cytarabine and systemic 
intermediate-dose methotrexate followed by loco-regional radiotherapy in patients with  stage I and II  PTL. 
 
 
3.1. Statistical plan and rationale 
 
The previous IELSG 5 retrospective analysis on 373 patients with testis lymphoma, showed a PFS of 48% at 5 
years in the entire population, regardless of the type of treatment.  
The IELSG 10 prospective clinical study was designed with a sample size of 50 patients defined to reject the 
null hypothesis of a PFS of 50% under the alternative hypothesis that the true PFS is 70% with a 5% 
significance level (two-sided) and 80% power. 
The early results of IELSG 10 study seem to suggest that Rituximab-CHOP regimen plus intrathecal prophylaxis 
with methotrexate may reduce the incidence of CNS relapses and, therefore, improve the outcome. However, 
the follow up is not yet adequate to allow any sound conclusion and, at present, it is unclear on which 
estimation of PFS should a sample size be calculated. According to the recruitment rate of the previous IELSG 
10, assuming a similar number of participating centers, we may expect to enroll approximately 35 cases in 3 
years. At that point, the feasibility of the design should be adequately evaluated and the follow up data from 
the previous IELSG 10 study should be mature enough for a careful calculation of the sample size in order to 
transform this pilot study in a formal phase II trial.  
 
 
3.2. Study design 
 
The study is divided in 4 phases. 
 
1. 
Pretreatment (screening) phase of approximately 28 days. Patients will be evaluated, according to the 
protocol, before to be enrolled in the study by means of the conventional procedures. 
 
2. 
Open label non randomized multicenter treatment phase. The investigator will assess patient response 
to therapy using efficacy measurements and disease response criteria. Patients will be evaluated 
through this phase for possible toxicities and delays in dosing. Dose modifications will be made as 
required according to dose modification rules. Patients will be treated with six courses of R-CHOP 
chemotherapy with a twenty-one day rest period between them. Courses 2,3,4 and 5 will be scheduled 
with the association of intrathecal chemotherapy with Depocyte®. 
 
Patients with progressive disease at any time will be withdrawn from the study. 
 
3. 
Consolidation phase. Three weeks after the 6th course of  R-CHOP chemotherapy, patients will receive 
two courses of intermediate-dose Methotrexate therapy every two weeks followed, two weeks later, by 
scrotal prophylactic radiotherapy or involved field radiotherapy (but can be planned concomitantly to R-
CHOP in patients with bilateral disease). 
 
4. 
Follow-up phase. Patients will be followed for disease progression and survival until the end of the 
study which is expected to be 36 months after the last patients enrolled into the study completed the 
treatment. For OS determination information will be required up to 5 years. 
 
The study design is presented in the figure below. 
 


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4. 
STUDY POPULATION 
 
 
4.1. General considerations 
 
Patients 18-80 years old are eligible for this clinical trial if they have stage I and II Primary Testicular 
Lymphoma at diagnosis untreated. 
Specific inclusion and exclusion criteria for enrolling subjects in this study are described in the following 
sections.  
 
 


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4.2. Inclusion criteria 
 
Patients must satisfy the following criteria to be enrolled in the study. 
 
1. 
Patients with primary testicular lymphoma at diagnosis. Histological subtype included into the study is 
only Diffuse Large B Cell Lymphoma (Attachment 2: WHO classification of lymphoma). 
2. 
Orchiectomy is mandatory, before enrolment of the patient into the study.  
3. 
Orchiectomy should be performed within 2 months before study entry.  
4. 
Age 18-80 
5. 
Untreated patients 
6. 
Ann Arbor Stage IE and IIE. Bilateral testicular involvement at presentation will not be considered Stage 
IV. These patients may be included into the study and the final Ann Arbor stage (I or II)  will be 
determined by the extent of nodal disease.  
7. 
Bidimensionally measurable or evaluable disease. Patients who have had all disease removed by surgery 
are eligible. 
8. 
Adequate haematological counts: ANC > 1.0 x 109/L and PLTs count > 75 x 109/L  
9. 
Cardiac ejection fraction ≥ 45% by MUGA scan or echocardiography 
10. 
Non peripheral neuropathy or any active non-neoplastic CNS disease. 
11. 
No other major life-threatening illnesses that may preclude chemotherapy 
12. 
Conjugated bilirubin ≤ 2 x ULN. 
13. 
Alkaline phosphatase and transaminases ≤ 2 x ULN. 
14. 
Creatinine clearance ≥ 45 ml/min. 
15. 
HIV negativity 
16. 
HBV negativity or patients with HBcAb +, HbsAg -, HBsAb+/- with HBV-DNA negative 
17. 
HCV negativity with the exception of patients with no signs of active chronic hepatitis histologically 
confirmed 
18. 
Life expectancy > 6 months. 
19. 
Performance status < 2 according to ECOG scale. 
20. 
No psychiatric illness that precludes understanding concepts of the trial or signing informed consent 
21. 
Written informed Consent 
 
 
4.3. Exclusion criteria 
 
Potential patients who meet any of the following criteria will be excluded from participating in the study. 
 
1. 
Has known or suspected hypersensitivity or intolerance to rituximab 
2. 
History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, 
gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic 
disturbances 
3. 
Uncontrolled diabetes (if receiving antidiabetic agents, subjects must be on a stable dose for at least 3 
months before first dose of study drug) 
4. 
Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of 
enrollment, New York Heart Association (NYHA) Class III or IV heart failure (Attachment 5, NYHA 
Classification of Cardiac Disease), uncontrolled angina, clinically significant pericardial disease, or 
cardiac amyloidosis 
5. 
History of clinically relevant hypotension 


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6. 
CNS involvement (meningeal and/or brain involvement by lymphoma) 
7. 
Evolving  malignancy within 3 years with the exception of localized non-melanomatous skin cancer 
8. 
HIV positivity 
9. 
HBV positivity with the exception of patients with HBcAb +, HbsAg -, HBs Ab+/-  with HBV-DNA 
negative 
10. 
HCV positivity with the exception of patients with no signs of active chronic hepatitis histologically 
confirmed 
11. 
Active opportunistic infection 
12. 
Receipt of extensive radiation therapy, systemic chemotherapy, or other antineoplastic therapy 
13. 
Exposure to Rituximab prior study entry 
14. 
Have received an experimental drug or used an experimental medical device within 4 weeks before the 
planned start of treatment. Concurrent participation in non-treatment studies is allowed, if it will not 
interfere with participation in this study. 
15. 
Any other co-existing medical or psychological condition that would preclude  participation in the study 
or compromise ability to give informed consent 
 
 
 
 
5. 
REGISTRATION AND STUDY DRUG SUPPLY 
 
 
Prior to registration the following steps have to be performed: 
 check inclusion and exclusion criteria 
 obtain informed consent 
 complete pre-treatment screening procedures (see study evaluation 9.1.2) 
 fill the registration form 
Registration is done by faxing the completed Registration Form, dated and signed to the IELSG 
central office: 
 
 
IELSG - Oncology Institute of Southern Switzerland - Ospedale San Giovanni - CH-6500 
Bellinzona 
 
The office is open from Monday to Friday 08:00 - 17:00 CET 
 
 
A confirmation of registration (Confirmed Registration / Drug Order Form) will be faxed by the IELSG to 
the investigator, and if needed to the coordination office of any national group / intergroup participating to 
the study.  
The same form, which contains the investigator address, to whom Depocyte® must be sent, is also faxed to 
Mundipharma International Limited, Cambridge, England. 
 
Mundipharma will then supply the labelled study drug directly to the investigator.  
 
 
 
 


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6. 
DOSAGE AND ADMINISTRATION 
 
 
6.1. Drug administration 
 
The amount (in mg) of RITUXIMAB and of chemotherapeutic agent (CHOP) to be administered will be 
determined based on body surface area (BSA) using a standard formula provided in Attachment 8, (Suggested 
Body Surface Area Calculation). 
Instructions including calculation of the subject’s dose, preparation and handling of the RITUXIMAB infusion 
are provided in Attachment 4, (Instructions for the Preparation and Handling of RITUXIMAB Injections). 
Instructions including preparation and handling of the DEPOCYTE administration, discarding of used study 
drug supplies, and precautions and care are provided in Attachment 3, (Instructions for the Preparation and 
Handling of DEPOCYTE Injections).   
Study drug will be administered only to eligible subjects under the supervision of the investigator or identified 
sub-investigator(s). 
 
6.1.1. Treatment schedule and doses 
 
Treatment phase 
 
R-CHOP 
Rituximab 
375 mg/m2 
day 0 or day 1 
Cyclophosphamide 
750 mg/m2 
day 1 
Doxorubicin 
50 mg/m2 
day 1  
Vincristine 
1.4 mg/m2 (2 mg dose max) 
day 1 
Prednisone 
40 mg/m2 
day 1-5 
 
IT CHEMOTHERAPY  
Depocyte® 
50 mg 
on day 0 of cycles 2, 3, 4 and 5 of R-CHOP  
R-CHOP courses will be repeated every 3 weeks. The prophylactic intrathecal Depocyte will be given for a total 
of 4 times, during R-CHOP cycles. 
 
Consolidation phase 
 
Begins three weeks after the R-CHOP/IT therapy completion.  
 
INTERMEDIATE-DOSE MTX 
Methotrexate 
1.5 g/m2 
It will be administrated diluted in 500 ml of normal saline solution (NaCl 0.9%). A urine flow ≥ 125 ml/hr has 
to be recorded in the 12 hrs before the MTX administration. 
For MTX handling and administration see Attachement 5. 
Intermediate-dose Methotrexate courses will be repeated every 14 days for 2 cycles. 
 
All patients will undergo interim restaging procedures after the 3rd course (and before the 4th) of R-CHOP. 
Clinical response will be re-assessed at the end of planned treatment, one-two month after the completion of 
the whole therapy, including radiotherapy. Additional imaging studies during the treatment phase will be 
done only if clinically indicated. 
Patients with progressive disease at any time will be withdrawn from the study. 
 
 


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6.2. Dose modification and delay 
 
Dose modifications may be made according to any observed toxicity during the previous cycle, as outlined 
below. Toxicities are to be assessed according to the National Cancer Institute Common Toxicity Criteria for 
Adverse Events (NCI CTCAE) 
version 3.0, 12/12/2003, National Institute of Health (NIH) http://ctep.cancer.gov/reporting/ctc.html 
 
6.2.1. CHOP dose modification 
 
Patients will start R-CHOP every 21 days if neutrophils  > 1.0 x 109/L and platelets > 75 x 109/L. 
 If neutrophils are < 1.5 x 109/L and/or platelets < 75 x 109/L: R-CHOP must be delayed  (after 7 days, on 
day +28) 
 If  Neutrophils ≥ 1.5 x 109/L and Platelets ≥ 75 x 109/L on Day +28 R-CHOP will be performed with no 
change in dose 
In case of neutropenia Filgrastim or Peg-Filgastrim should be added in the following course of chemotherapy 
according to “2006 update of recommendations for the use of white blood cell growth factors: an evidence-
based clinical practice guideline”(Journal Clinical Oncology 2006 24:3187-3205), and to primary physician 
judgment in order to avoid delay. Primary prophylaxis of neutropenia with filgastrim or peg-Figastrim is 
allowed in patients over 65 years of age according to the same guidelines. 
 Dose modification for sensory neuropathy. No modification as long as neuropathy does not affect function. 
Any decrease of function (grade 3/4) would lead to dose reduction of vincristine by 50%. If grade 4 toxicity 
persists after reduction of vincristine by 50%, vincristine may be eliminated from subsequent cycles. 
 Prednisone dose may be decreased by 50% or discontinued if patients have increase in serum glucose to > 
300 mg/dl, or other psychological disturbances such as psychosis or anxiety attacks. 
 
Just patients who have achieved PR/CR after three cycles of CHOP will continue therapy. All other patients will 
be removed from the study and will be considered for other possible therapies according to the local policy. 
 
6.2.2. Rituximab dose modification 
 
Rituximab administration and dose modification must follow labeling instructions and guidelines. Please refer 
to the approved product label for instructions. 
Patients who develop severe infusion reactions should have rituximab infusion discontinued and supportive 
care measures as medically indicated (e.g. fluids, vasopressors, oxygen, bronchodilators, acetaminophen, etc.). 
In most cases, the infusion can be resumed at 50% reduction rate (e.g. from 100 mg/hr to 50 mg/hr) when 
symptoms have completely resolved. Patients requiring close monitoring during first and all subsequent 
infusions include those with pre-existing cardiac and pulmonary conditions, those with prior clinically 
significant cardiopulmonary adverse events, and those with high numbers of circulating malignant cells (>25 x 
109/l) with or without evidence of high tumor burden. 
 
 
 
 


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7. 
RADIOTHERAPY PORTS 
 
 
Scrotal radiation therapy will be given to all patients. 
 
Timing 
Radiation therapy will begin three weeks after the completion of chemotherapy, provided that WBC is 
>3000/µl and platelets >100,000/µl. 
 
Portal and treatment definition 
PROPHYLACTIC SCROTAL RT 
The clinical target volume (CTV) includes the contralateral testis. 
 
Localization and simulation 
Patients must be simulated in the treatment position on a dedicated treatment simulator or CT simulator. 
 
Treatment technique 
Patients should be treated in supine position. 
Scrotal radiotherapy - CTV should be defined clinically by palpation. The contralateral testis should be treated 
with the direct anterior beam with electron beam 9 to 12 MeV or 6MV field bolus should be placed for 
patients who are treated with 6MV linear accelerator. Care should be taken to avoid unnecessary radiation to 
the perineum or the legs. 
 
Dose definition and schedule 
For prophylactic scrotal RT, the following dose fractionations schedules are acceptable: 
 
25 Gy in 10-15 fractions 
 
30 Gy in 10-20 daily fractions 
 
 
 
 
8. 
CONCOMITANT THERAPY 
 
 
During treatment are recommended as concomitant therapy: 
 
Pre-phase therapy is recommended in older patients (>65 years) with PDN 100 mg/die for 10 days and 
VCR 1.5 mg total dose 
 
G-CSF or Peg-Filgrastim as primary prophylaxis for the prevention of febrile neutropenia in older (>65 
years) patients in according to 2006 Update of Recommendations for the use of white blood cell 
growth factors (SmithTJ, Khatcheressian J, Lyman GH, et al. 2006 Update of Recommendation for use 
of white blood cell growth factors: an evidenced-based clinical practice guideline. J Clin Oncol 2006; 
24: 3187-3205) 
 
Cotrimoxazole BACTRIM 3 tablets/week (or 1 x 2/day for two days/week) or Pentamidine aerosol every 
15 days in patients with Bactrim allergy or in patients with G6PD deficiency throughout the treatment 
and consolidation phase 
 
In patients with Ab antiHBcAg +, Ab antiHBsAg +/- prophylaxis against hepatitis B reactivation with 
Lamivudine 100 mg/die from the start of the treatment to one year after the end of the treatment 
All concomitant medications for medical conditions other than B-NHL are permitted, as clinically indicated. 
All supportive therapies other than anti-cancer treatment needed for the management of patients enrolled in 
this study are permitted. 


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8.1. Permitted therapy 
 
The following medications and support therapies that may be used if needed during this study:  
 
Antiviral prophylaxis with acyclovir 800-1200 mg at day since the beginning of therapy is strongly 
recommended  in patients with herpes virus infection reactivation  Additional prophylaxis with 
levofloxacin or ciprofloxacin will be administered in case of neutropenia <1.0 x 109/l. 
 
G-CSF or Peg-Filgastrim is allowed and will be given according to primary physician decision in 
presence of neutropenia < 1.0 x 109/L. 
 
Platelets and red blood cell transfusion are allowed, if needed with filtered and irradiated products in 
case of Hb < 8 g/dL or Plts < 10 x 109/L. 
 
Erythropoietin therapy is allowed according to ASH/ASCO guidelines 
 
Immunoglobulin assay is advisable once a month during the therapy with immunoglobulin replacement 
in case of IgG level < 0.3-0.5 gr/dl and frequent infectious events.  
 
Laxatives and other prebiotics and probiotics are recommended to prevent constipation and should be 
administered according to standard practice 
 
Antiemetic agents 
 
Premedication for rituximab infusion with paracetamol and diphenhydramine is mandatory before each 
infusion of rituximab, because it may reduce infusion reactions. 
 
Use of corticosteroids is allowed in emergency or as pre-medication for rituximab infusion  
 
 
8.2. Prohibited therapy 
 
The following medications and supportive therapies are prohibited at all times: 
 
Any antineoplastic agent other than those planned by the study program.  
 
Any experimental agent  
 
 
 
 
9. 
STUDY EVALUATIONS 
 
 
9.1. Study Procedures 
 
9.1.1. Overview 
 
Patients participation will include: 
1. 
The pretreatment (screening) phase will be 30 days for all laboratory tests and radiographic imaging 
phase and up to 60 days for orchiectomy and bone marrow evaluation.  
2. 
The open label treatment phase will extend from the first day of the first course of R-CHOP to a 
maximum of 6 courses. 
3. 
The consolidation phase will extend from the first day of the first course of Intermediate-dose MTX to 
the end of radiotherapy. 
4. 
The follow-up phase will begin after the completion of the consolidation phase. Follow-up will continue 
until disease progression (PD), patient withdrawal, death or the study completion (expected to be 36 
months from the date of the last patient’s end of therapy). 
 


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Hematology results must be available and reviewed by the investigator to evaluate for possible hematological 
toxicity.  
All subjects will be monitored for adverse events throughout the study and for 30 days after the end of 
treatment.  
 
9.1.2. Pretreatment (screening) phase  
 
All patients must satisfy all the inclusion criteria and none of exclusion criteria listed in section 4.2 and 4.3  
and sign informed consent before the first dose of study drug can be administered. Results of procedures 
performed as part of standard medical care before signing the informed consent may be used as part of the 
screening evaluation if performed within 30 days of beginning of therapy for laboratory tests and imaging 
studies, within 60 days for orchiectomy and bone marrow biopsy and aspirate. 
 
Complete medical history 
 
Concomitant diseases and treatment 
 
Recent clinical history (B symptoms) 
 
Physical examination (size of lymph nodes, sign of organ involvement) 
 
ECOG performance status 
 
ECG and echocardiogram or blood pool cardioscintigraphy 
 
Bone marrow biopsy and aspirate 
 
Orchiectomy 
 
Chest and abdomen computer tomography; CT of the head and neck at the discretion of the treating 
physician 
 
Testicular ultrasound 
 
CT-PET scan (if possible, recommended but not mandatory) 
 
Hematology (hemoglobin, WBC and differential, Platelets) 
 
Blood chemistry (AST, ALT, ALP, total bilirubin, creatinine, albumin, serum LDH) 
 
Clearance creatinine 
 
Beta-2-microglobulin 
 
IgA, IgG, IgM 
 
HIV  
 
HBsAg, HBsAb, HBcAb and HBV-DNA, HBV-DNA in case of HBcAb+  
 
HCVAb, HCV-RNA in case of HCVAb+ 
 
Lumbar puncture for determination of cell count, differential, cytologic and flow cytometry examination 
in patients with neurologic symptoms and/or clinical suspicion of meningeal lymphoma involvement 
 
Additional assessments if necessary according to the local standards and if clinically indicated at the 
discretion of the treating physician. 
 
Written informed consent. 
 
9.1.3. Treatment phase 
 
Before each course the following parameters will be evaluated: 
 
Physical examination  
 
Hematology (Whole blood cell counts and differential) 
 
Blood chemistry (AST, ALT, ALP, LDH, total bilirubin, creatinine, albumin). 
 
determination of cell count, differential, cytologic and flow cytometry examination of CNS fluid (during 
the planned 4 IT therapies) 
 


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9.1.4. Intermediate evaluations (after third course of R-CHOP) 
 
 
Physical examination (size of lymph nodes, signs of organ involvement)  
 
ECOG performance status 
 
Hematology (hemoglobin, WBC and differential, Platelets) 
 
Blood chemistry (AST, ALT, ALP, total bilirubin, creatinine, albumin, serum LDH) 
 
Chest and abdomen computer tomography; CT of the head and neck at the discretion of the treating 
physician 
 
Testicular ultrasound 
 
Additional assessments if necessary according to the local standards and if clinically indicated at the 
discretion of the treating physician. 
 
Interim CT-PET scan is advisable, if previously positive, according to local policy but it is not mandatory.  
 
All patients with disease in CR, PR will continue the trial. 
All patients in SD/PD will be withdrawn from the study and evaluated as treatment failure 
 
9.1.5. Consolidation phase 
 
Before each course the following parameters will be evaluated: 
 
Physical examination  
 
Hematology  (Whole blood cell counts and differential) 
 
Blood chemistry (AST, ALT, ALP, LDH, total bilirubin, creatinine, albumin) 
 
Clearance creatinine 
 
9.1.6. End of treatment restaging 
 
Response to the treatment will be evaluated 1-2 months after the end of the whole treatment and includes 
the following tests and evaluation: 
 
Recent clinical history  
 
Physical examination (size of lymph nodes, sign of organ involvement) 
 
ECOG performance status 
 
Chest and abdomen computer tomography; CT of the head and neck at the discretion of the treating 
physician 
 
Testicular ultrasound  
 
CT-PET scan (to be performed three months after radiotherapy) is mandatory according to recent 
international criteria of response (Cheson et al 2007) 
 
Hematology (hemoglobin, WBC and differential, Platelets) 
 
 
Blood chemistry (AST, ALT, ALP, total bilirubin, creatinine, albumin, serum LDH) 
 
Clearance creatinine 
 
Beta-2-microglobulin 
 
IgA, IgG, IgM 
 
Additional assessments if necessary according to the local standards and if clinically indicated at the 
discretion of the treating physician. 
 
9.1.7. Follow-up phase 
 


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After the completion of the end of treatment evaluation all patients will enter in the follow up phase. 
The follow up phase will end in case of dead or progressive disease. 
During the follow-up phase the following parameters will be evaluated: 
 
Minimal evaluations at months 3, 9, 15, 21 and 30 
 
Physical examination  
 
Recent clinical history  
 
ECOG performance status 
 
Hematology (hemoglobin, WBC and differential, Platelets) 
 
Blood chemistry (AST, ALT, ALP, creatinine, serum LDH, total bilirubin, albumin) 
 
Additional assessments if clinically indicated 
 
Extensive evaluations at months 6, 12, 18, 24 and 36 
 
Recent clinical history  
 
Physical examination (size of lymph nodes, sign of organ involvement) 
 
ECOG performance status 
 
Chest and abdomen computer tomography; CT of the head and neck at the discretion of the treating 
physician 
 
Testicular ultrasound 
 
Hematology (hemoglobin, WBC and differential, Platelets) 
 
Blood chemistry (AST, ALT, ALP, total bilirubin, creatinine, albumin) 
 
Clearance creatinine 
 
Serum LDH 
 
Beta-2-microglobulin 
 
IgA, IgG, IgM 
 
Additional assessments if necessary according to the local standards and if clinically indicated at the 
discretion of the treating physician 
 
 


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9.2. Pathology review 
 
The work of the pathologist is essential for the success of this study and includes diagnosis and classification 
of the lymphoma according to the WHO classification criteria. 
The local pathlogist of each center participating in this trial has to be informed by the local investigator about 
the trial protocol, particularly about data and sample processing. The IESLG Lymphoma Review Center will 
review all cases. 
After examination by the local pathologist, paraffin block shold be sent for central pathology review and 
additional pathological studies to the IELSG Lymphoma Review Center (LRC) at the IELSG Coordinating 
Center. 
In addition, a copy of original report(s) including diagnosis, classification and immunophenotyping by the local 
pathologist will be sent by fax or e-mail to the IELSG coordinating center. If possible, diagnostically relevant 
clinical data (i.e., peripheral blood examination, bone marrow aspiration cytology, immunoelectrophoresis) 
should be added. In case of doubt the LRC may request paraffin embedded material to complement the 
analysis. 
 
 
9.3. Endpoint definitions 
 
Overall Response Rate (ORR): Complete Remission, Complete Remission Unconfirmed, Partial Remission. 
A patient is defined as a responder if he has a complete or partial response. Patients without response 
assessment (due to whatever reason) will be considered as non-responder.  
 
9.3.1. Criteria for evaluation 
 
The recently published recommendations of an International Workshop to Standardise Response Criteria for 
Non-Hodgkin´s Lymphomas [Cheson et al., 2007 Journal Clinical Oncology 25: 579-586] will be applied. 
 
Response criteria will be determined as follows: 
 
Complete response (CR) is required: 
1. 
Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if 
present before therapy. 
2. 
(a) Typically FDG-avid lymphoma: in patients with no pre-treatment  PET scan or when the PET scan is 
positive before therapy, a post-treatment residual mass of any size is  permitted as long as it is  PET 
negative. 
(b) Variably FDG-avid lymphomas /FDG avidity unknown: in patients without a pre-treatment PET scan, 
or if a pre-treatment  PET scan was negative, 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. 
3. 
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 
involvements 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. 
4. 
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 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
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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. 
 
Partial Remission (PR) is required: 
1. 
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 least2 perpendicular dimensions; if possible they 
should be from disparate regions of the body; and they should include mediastinal and retroperitoneal 
areas of disease whenever these sites are involved. 
2. 
No increase should be observed in the size of other nodes, liver, or spleen. 
3. 
Splenic and hepatic nodules must regress by 50% in their SPD or, for single nodules, in the greatest 
transverse diameter. 
4. 
With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable 
and no measurable disease should be present. 
5. 
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 (e.g. 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. 
6. 
No new sites of disease should be observed. 
7. 
Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the PET scan was 
positive before therapy, the post-treatment PET should be positive in at least one previously involved 
site. 
8. 
Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment PET scan, or if 
a pretreatment PET scan was negative, CT criteria should be used. 
 
Stable Disease (SD) is required:  
1. 
A patient is considered to have SD when he or she fails to attain the criteria needed for a CR or PR, but 
does not fulfil those for progressive disease (see Relapsed Disease [after CR]/Progressive Disease[after 
PR, SD]). 
2. 
Typically FGD-avid lymphomas: the PET should be positive at prior sites of disease with no new areas of 
involvement on the post-treatment CT or PET. 
3. 
Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment PET scan or if 
the pretreatment PET was negative, there must be no change in the size of the previous lesions on the 
post-treatment CT scan. 
 
Relapsed Disease (after CR) / Progressive Disease (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 cm. Lymph nodes 1.0x 1.0 cm will not be considered as abnormal for relapse or progressive 
disease.  
1. 
Appearance of any new lesion more than1.5 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. 
2. 
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 (e.g. splenic or hepatic nodules). To be considered progressive 
disease, a lymphnode 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 than1.5 cm in the long axis. 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
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3. 
At least a 50% increase in the longest diameter of any single previously identified node more than1 cm 
in its short axis. 
4. 
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET 
positive before therapy unless the lesion is too small to be detected with current PET systems(< 1.5 cm 
in its long axis by CT). 
5. 
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 (e.g. 
pleural effusions, bone lesions) will be recorded as present or absent only, unless, while an abnormality 
is still noted by imaging studies or physical examination, it is found to be histologically negative. 
6. 
In clinical trials where PET is unavailable to the vast majority of participants, or where PET is not 
deemed necessary or appropriate for use (e.g. a trial in patients with MALT lymphoma), response 
should be assessed as above, but only using CT scans. However, residual masses should not be 
assigned CRu status, but should be considered partial responses. 
 
Overall survival will be determined from the date of enrollment into the study to the date of death from any 
cause. Patients who have not died at the time of the final analysis will be censored at the date of the last 
contact.  
 
Event-free survival (time to treatment failure) is measured from the time from study entry to any 
treatment failure including disease progression, or discontinuation of treatment for any reason (e.g. disease 
progression, toxicity, patient preference, initiation of new treatment without documented progression, or 
death). It may be useful in the evaluation of some therapies such as those that are highly toxic. 
 
Progression-free survival PFS is defined as the time from entry onto a study until lymphoma progression 
or death as a result of any cause. PFS is the preferred end point in lymphoma involving incurable histologic 
subtypes clinical trials (e.g. follicular, other low-grade lymphoma, or mantle cell lymphoma). In studies in 
which failure to respond without progression is considered an indication for another therapy, such patients 
should be censored at that point for the progression analysis. 
 
Disease-Free Survival is measured from the time of occurrence of disease-free state or attainment of a CR 
to disease recurrence or death as a result of lymphoma or acute toxicity of treatment. This definition may be 
complicated by deaths that occur during the follow-up period that are unrelated to the lymphoma, and there 
is controversy about whether such deaths should be considered as events or censored at the time of 
occurrence. Although it is often possible to identify those deaths related to the lymphoma, there is the 
potential for bias in the attribution of deaths. 
 
Lymphoma-Specific Survival is defined as time from study entry to death as a result of lymphoma. This 
end point is potentially subject to bias because the exact cause of death is not always easy to ascertain. To 
minimize the risk of bias, the event should be recorded as death as a result of lymphoma, or as a result of 
toxicity from the drug. Death as a result of unknown causes should be attributed to the therapy. 
 
 
9.4. Safety evaluations 
 
The study will include the following evaluations of safety and tolerability: 
 
Adverse Events 
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject’s legally acceptable representative) for the duration of the study.  
 
Clinical Laboratory Tests 
All laboratory tests should be performed at the laboratory of the investigational site: laboratory certificates or 
accreditation and normal ranges must be submitted before the patient’s enrollment. 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
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Electrocardiogram 
Vital Signs (pulse, temperature, blood pressure, respiration rate) 
 
Physical Examination 
Any clinically significant abnormalities persisting at the end of the study will be followed by the investigator 
until resolution or until reaching a clinically stable endpoint. 
 
Safety and feasibility of treatment: severe hematological toxicities (grade 3-4) expected. 
Grading of toxicity will be defined according to the International Common Toxicity Criteria, version 3.0 
(12/12/2003) 
 
 
 
 
10. 
SUBJECT COMPLETION / WITHDRAWAL 
 
 
10.1. Completion 
 
 
A subject will be considered as having completed the study if he/she has completed all assessments at week 
30 of the [open label] treatment phase.] [Subjects who discontinue study treatment due to lack of efficacy are 
also considered to have completed the study.]  
 
 
10.2. Discontinuation of Treatment  
 
A patient should be discontinued from study treatment based on:  
 
Investigator discretion based on safety issues  
 
Progressive disease 
 
No response after the third course of therapy 
 
Any ≥ grade 3 toxicity for > 2 weeks 
 
 
10.3. Withdrawal From the Study 
 
A subject will be withdrawn from the study for any of the following reasons: 
 
Lost at follow-up 
 
Consent withdrawal  
 
Discontinuation of study treatment (final assessments will be obtained) if applicable 
When a subject withdraws before completing the study, the reason for withdrawal is to be documented on the 
CRF and in the source document. Study drug assigned to the withdrawn subject may not be assigned to 
another subject.  
 
 
 
 


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11. 
ADVERSE EVENT(AE) AND SERIOUS ADVERSE EVENT (SAE) 
REPORTING 
 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies are crucial for 
the protection of subjects and are mandated by regulatory agencies worldwide.  
 
 
11.1. Definitions 
 
11.1.1. Adverse Events definition and classification 
 
Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
pharmaceutical product. An adverse event does not necessarily have a causal relationship with the treatment. 
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. (Definition per International Conference on 
Harmonization [ICH]). 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the baseline 
condition, or abnormal results of diagnostic procedures, including laboratory test abnormalities. 
 
Serious Adverse Event (SAE) 
A serious adverse event as defined by ICH is any untoward medical occurrence that at any dose meets any of 
the following conditions: 
 
Results in death 
 
Is life-threatening (The subject was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe.) 
 
Requires hospitalization or prolongation of existing hospitalization  
 
Results in persistent or significant disability / incapacity 
 
Is a congenital anomaly / birth defect 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is also 
appropriate in situations other than those listed above. For example, important medical events may not be 
immediately life threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the outcomes listed in the definition above. Any adverse event is 
considered a serious adverse event if it is associated with clinical signs or symptoms judged by the investigator 
to have a significant clinical impact. 
 
Unlisted (unexpected) Adverse Event 
The nature or severity of the adverse event is not consistent with the applicable product information. For an 
investigational product, the expectedness of an adverse event will be determined by whether or not it is listed 
in the Investigator's Brochure.  
 
Associated with the use of the drug 
An adverse event is considered associated with the use of the drug if the attribution is possible, probable, or 
very likely by the definitions listed in Section 11.1.2. 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is a serious adverse drug reaction (SADR), the nature or severity of which is not consistent with the 
applicable product information. 
A serious event or drug reaction is not defined as a SUSAR when: 
 
it is serious but expected 
 
it does not fit the definition of a SAE o SADR, whether expected or not 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
25 / 45 
 
11.1.2. Attribution definitions 
 
Intensity (severity) reporting and attribution 
 
For both serious and non-serious adverse events, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. 
 
Intensity for each adverse event will be determined by using Version 3.0 of the National Cancer Institute 
Common Toxicity Criteria (NCI CTC) as a guideline, wherever possible. The criteria will be provided to the 
investigator as a separate document. In those cases where the NCI CTC do not apply, intensity should be 
defined according to the following criteria: 
- mild 
awareness of sign or symptom, but easily tolerated 
- moderate 
discomfort enough to cause interference with normal daily activities 
- severe 
inability to perform normal daily activities 
- life threatening immediate risk of death from the reaction as it occurred 
- death 
 
Relationship to study drug administration will be determined as follows 
 
Not related 
An adverse event which is not related to the use of the drug. 
Unlikely/doubtful An adverse event for which an alternative explanation is more likely, e.g., concomitant 
drug(s), concomitant disease(s), or the relationship in time suggests that a causal 
relationship is unlikely. 
Possible 
An adverse event which might be due to the use of the drug. An alternative explanation, 
e.g., concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time 
is reasonable; therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event which might be due to the use of the drug. The relationship in time is 
suggestive (e.g., confirmed by dechallenge). An alternative explanation is less likely, e.g. 
concomitant drug(s), concomitant disease(s). 
Definite/very likely An adverse event which is listed as a possible adverse reaction and cannot be reasonably 
explained by an alternative explanation, e.g., concomitant drug(s), concomitant disease(s). 
The relationship in time is very suggestive (e.g. it is confirmed by dechallenge and 
rechallenge). 
 
 
11.2. Procedures 
 
11.2.1. All Adverse Events 
 
All adverse events other than disease progression will be reported from the time a signed and dated informed 
consent form is obtained until 30 days after the lst dose of study drug. All events that meet the definition of a 
serious adverse event will be reported as serious adverse events, regardless of whether they are protocol-
specific assessments. 
All adverse events, regardless of seriousness, severity, or presumed relationship to study therapy, must be 
recorded using medical terminology in the source document and the CRF. Whenever possible, diagnoses 
should be given when signs and symptoms are due to a common etiology (e.g. cough, runny nose, sneezing, 
sore throat, and head congestion should be reported as “upper respiratory infection”). Investigators must 
record in the CRF their opinion concerning the relationship of the adverse event to study therapy. All measures 
required for adverse event management must be recorded in the source document and reported according to 
sponsor instructions.  


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
26 / 45 
 
All grade 3 and 4 adverse events, considered related, must be followed until resolution of the event, or the 
event improves to a grade 2 or better. The events of interest in the table above of grade 2 or higher will be 
followed until grade 1 or better. The unresolved aforementioned events will be followed for a maximum of 6 
months.  
Sections of the CRFs containing adverse event information will be submitted by the investigator to a 
representative of the sponsor. Serious adverse event reports will be submitted as described in Section 11.2.2, 
Serious Adverse Events. 
The investigator-Sponsor must report adverse events to the appropriate Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise required and 
documented by the IEC/IRB. The Investigator-Sponsor assumes responsibility for appropriate reporting of 
adverse events to regulatory authorities. The Investigator-Sponsor shall also report all serious adverse events 
to the pharmaceutical companies providing the study medication.   
 
11.2.2. Serious Adverse Events and SUSAR 
 
Reporting of SAE 
 
All serious adverse events occurring during clinical studies must be reported by fax to the sponsor IELSG 
(IELSG Coordinating Center, CH-6500 Bellinzona – Switzerland; Phone: ++41 91 811 90 40 – Fax: ++41 91 
811 91 82;  E-mail: ielsg@ticino.com) by investigational staff within 24 hours of their knowledge of the 
event, using the SAE Report Forms, which must be signed by a member of the investigational staff. 
 
The SAE outcome must be reported within 14 days, using the SAE Follow up Form. In case the SAE is still 
ongoing after 14 days, additional SAE Follow up Forms must be sent again to report the final outcome. 
 
The cause of death of a subject in a clinical study, whether or not the event is expected or associated with 
the investigational agent, is considered a serious adverse event. Any event requiring hospitalization (or 
prolongation of hospitalization) that occurs during the course of a subject’s participation in the clinical study 
must be reported as a serious adverse event, except hospitalizations for: 
 
a standard procedure for protocol therapy administration 
 
social reasons in absence of an adverse event 
 
surgery or procedure planned before entry into the study (must be documented in the CRF) 
 
study drug administration 
 
study related procedures defined in the protocol 
 
Reporting of SUSAR 
  
All relevant information about suspected unexpected serious adverse reactions (SUSAR's) are recorded and 
reported in an expedited fashion. 
Events that fall into this category must be reported within 24 hours of occurrence using the SAE Report 
Form (see above).  
It is the legal requirement of the sponsor to report SUSARs to the Competent Authorities and Ethics 
Committees (fatal or life-threatening within 7 days, nonfatal and non life-threatening within 15 days) 
 
 
 
 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
27 / 45 
 
12. 
STUDY DRUG INFORMATION 
 
 
12.1. Physical description of study drug(s) 
 
DepoCyte® (Cytarabine Liposomal Injection) is a sterile sustained –release formulation of cytarabine that is 
manufactured by encapsulating an aqueous solution of cytarabine (ARA-C) in spherical multivesicular lipid- 
based particles (DepoFoam drug delivery system).  
DepoCyte®injection contains cytarabine (also called cytosine arabinoside, ara-C, 4-amino-1-1-β-D-
arabinofuranosynol-2(1H)-pyrimidine (C9H13N3O5, molecular weight 243.22).), which is an analogue of the 
nucleosides cytidine and deoxycytidine, but contains arabinose in place of the usual ribose or deoxyribose. 
Cytarabine is an odourless white powder that is freely soluble in water and slightly soluble in alcohol.  
Cytarabine enters cells by a facilitated diffusion mechanism. Once inside the cell, cytarabine must be 
metabolised to a nucleotide, ara-CTP, before it can exert its effects. 
Ara-CTP inhibits DNA polymerase and terminates DNA chain elongation. The cytotoxic effects are therefore 
specific to the S-phase of the cell cycle. This means that the cytotoxic effects are a function of concentration 
and duration of exposure, and prolonged exposure of cells to the drug is vital to achieve maximum activity. 
The half-life of free cytarabine in the CSF is only 3.4 hours, so cytotoxic levels are maintained for less than 24 
hours. Because the drug is cleared rapidly relative to flow rates within the CSF, it often does not spread well 
throughout the neuraxis. In contrast, DepoCyte®injection distributes well throughout the neuraxis and 
increases the half-life of cytarabine in the CSF over 40-fold, as shown in the pharmacokinetic study by 
Chamberlain et al. The concentration of cytarabine after administration of DepoCyte®injection is maintained 
for at least 14 days. 
 
DepoCyte® is formulated as a sterile non- pyrogenic white to off- white suspension of cytarabine in sodium 
chloride 0, 9% w/v in Water for Injection. DepoCyte® is preservative free. Inactive ingredient at the respective 
approximate concentrations are cholesterol, 4.1 mg/mL; triolein, 1.2 mg/mL; 1,2-dioleoyl-sn-glycero-3-
phosphocholine (DOPC), 5.7 mg/mL; and 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG), 1.0 
mg/mL. The pH of the product falls within the range from 5.5 to 8.5.  
The lipid-encapsulated aqueous chambers form spherical particles of approximately 20 µm in diameter. The 
particles are suspended in 5 mL of sterile NaCl, 0 9% at a concentration of 10mg/mL and stored ready to use 
without further dilution. DepoCyte®    has the consistency and appearance of skim milk. When stored in 
sterile normal saline at 2° - 8° C the particles are stable for 12 months.  When the particles are injected into 
the CSF they spread throughout the neuraxis and slowly release the cytarabine. The particles gradually 
degrade and disappear from the CSF, and the lipids enter the normal lipid metabolic pathways for 
triglycerides, phospholipids and cholesterol in the body. .As a single injection of 50 mg, DepoCyte® maintains 
cytotoxic concentration of cytarabine in the CSF for ≥14 days in most patients, thus, IT administration of 
DepoCyte® is required just once every two weeks  
 
 
12.2. Packaging 
 
DepoCyte® suspension is provided in a 5 mL  ready-to-use single-use glass vials containing 50 mg (10mg/mL) 
of cytarabine. 
 
 
12.3. Labeling 
 
The study drug label contains information to meet the applicable regulatory requirements. The label text in 
English/Italian is provided in Attachment 11. 
 
 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
28 / 45 
 
12.4. Preparation and handling 
 
12.4.1. DepoCyte 
 
For additional information refer to the package insert for liposomal cytarabine (DepoCyte®). See also 
Attachment 3. 
 
12.4.2. Rituximab 
 
For additional information refer to the package insert for rituximab. See also Attachment 4. 
 
 
12.5. Drug accountability 
 
After patient’s registration, the study drug will directly be supplied to the clinical investigator by Mundipharma 
(see 5. Registration) 
The clinical investigator is responsible for ensuring that all study drug (i.e., Deppocyte®) received at the site is 
inventoried and accounted for throughout the study. Study drug must be handled strictly in accordance with 
the protocol and the container label and will be stored in a limited access area and under locked conditions. 
Study drug should be dispensed under the supervision of investigator, a qualified member of the 
investigational staff, or by a hospital/clinic pharmacist. Study drug will be supplied only to subjects 
participating in the study. Returned study drug must not be dispensed again, even to the same subject. Study 
drug may not be relabeled or reassigned for use by other subjects. The investigator agrees neither to dispense 
the study drug form, nor store it at any site other than study sites agreed upon the sponsor. 
 
 
 
 
13. 
ETHICAL ASPECTS 
 
 
13.1. Regulatory Ethics Compliance 
 
13.1.1. Investigator responsibilities 
 
The investigator is responsible for ensuring that the clinical study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory requirements. 
GCP is an international ethical and scientific quality standard for designing, conducting, recording, and 
reporting studies that involve the participation of human subjects. Compliance with this standard provides 
public assurance that the rights, safety, and well being of study subjects are protected, consistent with the 
principles that originated in the Declaration of Helsinki, and that the clinical study data are credible. 
 
 
13.2. Independent Ethics Committee or Institutional Review 
Board (IEC/IRB)  
 
Before the start of the study, the investigator will provide the IEC/IRB with current and complete copies of the 
following documents: 
 
final protocol and, if applicable, amendments 
 
informed consent form (and any other written materials to be provided to the subjects) 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
29 / 45 
 
 
Investigator’s Brochure (or equivalent information) and amendments 
 
information on compensation for study-related injuries or payment to subjects for participation in the 
study, if applicable 
 
investigator’s curriculum vitae or equivalent information (unless not required, as documented by 
IEC/IRB) 
 
information regarding funding, institutional affiliations, other potential conflicts of interest, and 
incentives for subjects 
 
any other documents that the IEC/IRB requests to fulfil its obligation 
 
If study drug is being provided, it will not be shipped until after IEC/IRB has given full approval of the final 
protocol, amendments (if any), the informed consent form, applicable recruiting materials, and subject 
compensation programs, and the Investigator-sponsor has received a copy of this approval. This approval 
letter must be dated and must clearly identify the documents being approved. 
 
During the study the investigator will send the following documents to the IEC/IRB for their review and 
approval, where appropriate: 
 
protocol amendments 
 
revision(s) to informed consent form and any other written materials to be provided to subjects 
 
if applicable, new or revised subject recruiting materials approved by the sponsor 
 
revisions to compensation for study-related injuries or payment to subjects for participation in the study, 
if applicable 
 
Investigator’s Brochure amendments or new edition(s) 
 
summaries of the status of the study (at least annually or at intervals stipulated in guidelines of the 
IEC/IRB) 
 
reports of adverse events that are serious, unlisted, and associated with the investigational drug 
 
new information that may affect adversely the safety of the subjects or the conduct of the study 
 
deviations from or changes to the protocol to eliminate immediate hazards to the subjects 
 
report of deaths of subjects under the investigator's care 
 
notification if a new investigator is responsible for the study at the site 
 
any other requirements of the IEC/IRB 
 
For protocol amendments that increase subject risk, the amendment and applicable informed consent form 
revisions must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s). 
At least once a year, the IEC/IRB will be informed about  the clinical ongoing of this clinical study. This request 
should be documented in writing. 
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about the study 
completion. 
 
 
13.3. Informed Consent 
 
Each subject (or a legally acceptable representative) must give written consent according to local requirements 
after the nature of the study has been fully explained. The consent form must be signed before performance of 
any study-related activity. The consent form that is used must be approved by IELSG and by the reviewing 
IEC/IRB. The informed consent should be in accordance with principles that originated in the Declaration of 
Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy. 
Before entry into the study, the investigator or an authorized member of the investigational staff must explain 
to potential subjects or their legally acceptable representatives the aims, methods, reasonably anticipated 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
30 / 45 
 
benefits, and potential hazards of the study, and any discomfort it may entail. Subjects will be informed that 
their participation is voluntary and that they may withdraw consent to participate at any time. They will be 
informed that choosing not to participate will not affect the care the subject will receive for the treatment of 
his/her disease. Subjects will be told that alternative treatments are available if they refuse to take part and 
that such refusal will not prejudice future treatment.  
The subject or legally acceptable representative will be given sufficient time to read the informed consent form 
and the opportunity to ask questions. After this explanation and before entry to the study, consent should be 
appropriately recorded by means of either the subject's or his/her legally acceptable representative's dated 
signature. After having obtained the consent, a copy of the informed consent form must be given to the 
subject. 
Subjects will also be asked to consent to participate in a genetic research component of the study. Refusal to 
participate will not result in ineligibility for the rest of the clinical study unless participation in genetic testing is 
required as an inclusion criterion. After informed consent is appropriately obtained, the subject or his/her 
legally acceptable representative will sign and personally date a separate DNA informed consent form 
indicating agreement or refusal to participate in the genetic testing. A copy of this informed consent form will 
be given to the subject. 
If the subject or legally acceptable representative is unable to read or write, an impartial witness should be 
present for the entire informed consent process (which includes reading and explaining all written information) 
and personally date and sign the informed consent form after the oral consent of the subject or legally 
acceptable representative is obtained. 
 
 
13.4. Privacy of personal data 
 
The collection and processing of personal data from subjects enrolled in this study will be limited to those data 
that are necessary to investigate the efficacy, safety, quality, and utility of the investigational product(s) used 
in this study. 
These data must be collected and processed with adequate precautions to ensure confidentiality and 
compliance with applicable data privacy protection laws and regulations. 
 
The investigator-sponsor ensures that the personal data will be 
 
processed fairly and lawfully 
 
collected for specified, explicit, and legitimate purposes and not further processed in a way 
incompatible with these purposes 
 
adequate, relevant, and not excessive in relation to said purposes 
 
accurate and, where necessary, kept current 
 
Explicit consent for the processing of personal data will be obtained from the participating subject (or his/her 
legally acceptable representative) before collection of data. Such consent should also address the transfer of 
the data to other entities and to other countries. 
The subject has the right to request through the investigator access to his/her personal data and the right to 
request rectification of any data that are not correct or complete. Reasonable steps should be taken to 
respond to such a request, taking into consideration the nature of the request, the conditions of the study, 
and the applicable laws and regulations. 
 
 
 
 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
31 / 45 
 
14. 
ADMINISTRATIVE REQUIREMENTS 
 
 
14.1. Data Quality Assurance 
 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study centers, review of protocol procedures with the investigator and associated personnel 
before the study. Written instructions will be provided for collection, preparation, and shipment of blood, 
plasma, and urine samples. CRF completion guidelines will be provided and reviewed with study personnel 
before the start of the study. The sponsor will review CRFs for accuracy and completeness during on-site 
monitoring visits and after their return to the sponsor; any discrepancies will be resolved with the investigator 
or designee, as appropriate 
Investigator will permit trial-related monitoring, providing direct access to source documents/data  
 
 
14.2. Record retention 
 
Once controlled for accuracy and completeness, copy of all CRFs will be kept at the IELSG coordination office, 
where the contained data will be transferred into an electronic study database. 
The results of the study will be reported in a Clinical study Report generated by the investigator-sponsor and 
will contain all data from all investigational sites. 
 
 
14.3. On-site audits 
 
Investigator / institution will permit trial-related audits, providing direct access to source documents / data 
 
 
 
 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
32 / 45 
 
15. REFERENCES 
 
Duncan PR, Checa F, Gowing NF, McElwain TJ, Peckham MJ. Extranodal non-Hodgkin's lymphoma presenting 
in the testicle: a clinical and pathologic study of 24 cases. Cancer 1980; 45: 1578-1584. 
Zucca E, Roggero E, Bertoni F and Cavalli F. Primary extranodal non-Hodgkin's lymphomas. Part 1: 
gastrointestinal, cutaneous and genitourinary lymphomas. Ann Oncol. 1997; 8:727-737. 
Doll DC, Weiss RB. Malignant lymphoma of the testis. American Journal of Medicine 1986; 81: 515-524. 
Ferry JA, Harris NL, Young RH, Coen J, Zietman A, Scully RE. Malignant lymphoma of the testis, epididymis, 
and spermatic cord. A clinicopathologic study of 69 cases with immunophenotypic analysis. Am J Surg Pathol 
1994; 18: 376-390.   
Shahab N, Doll DC. Testicular Lymphoma. Semin Oncol, 1999; 26:259-269 
Fonseca R, Habermann TM, Colgan JP, et al. Testicular lymphoma is associated with a high incidence of 
extranodal recurrence. Cancer 2000; 88: 154-161.  
Zucca E, Conconi A, Mughal TI, et al: Patterns of outcome nd prognostic factors in primary larg-cell lymphoma 
of the testis in a survey by the International Extranodal Lymphoma Study Group. J Clin Oncol 2003; 21:20-27.  
Moller MB, D'Amore F, Christensen BE. Testicular lymphoma: A population-based study of incidence, clinico-
pathological correlations and prognosis. Eur J Cancer 1994; 30A: 1760-1764. 
Crellin AM, Hudson BV, Bennett MH, Harland S, Hudson GV. Non-Hodgkin's lymphoma of the testis. 
Radiotherapy & Oncology 1993May; 27: 99-106. 
Liang R, Chiu E, Loke SL. An analysis of 12 cases of non-Hodgkin's lymphomas involving the testis [letter]. 
Annals of Oncology 1990Sep; 1: 383-383. 
Tondini C, Ferreri AJ, Siracusano L, Valagussa P, Giardini R, Rampinelli I, et al. Diffuse large-cell lymphoma of 
the testis. J Clin Oncol 1999; 17: 2854-2858. 
Touroutoglou N, Dimopoulos MA, Younes A, Hess M, Pugh W, Cox J, et al. Testicular lymphoma: late relapses 
and poor outcome despite doxorubicin- based therapy. J Clin Oncol 1995; 13: 1361-1367.   
Connors JM, Klimo P, Voss N, Fairey RN, Jackson S. Testicular lymphoma: improved outcome with early brief 
chemotherapy. J Clin Oncol 1988; 6: 776-781.   
Ikeda Y, Nakazawa S, Kudo M. Intracranial malignant lymphoma developing 20 years after total removal of 
testicular malignant lymphoma--case report. Neurol Med Chir (Tokyo ) 1986; 26: 68-70. 
Zietman AL, Coen JJ, Ferry JA, et al. The management and outcome of stage IAE non Hodgkin’s lymphoma of 
the testis. J Urol 1996; 155: 943-946. 
Vitolo U, Zucca E, Martelli M, et al. Primary Diffuse Large B-Cell Lymphoma Of The Testis (PTL): A Prospective 
Study Of Rituximab (R)-CHOP With CNS And Contralateral Testis Prophylaxis. Results Of The IELSG 10 Study. 
Blood 2006; 108 (11): 208 (Abs).  
P. McLaughlin, F.B. Hagemeister and A. J. Grillo-Lopez “ Rituximab in indolent lymphoma: the single agent 
Pivotal trial “ Seminars in Oncology vol 26, n5 suppl 14, 79-87, 1999 
Mor V, Laliberte L, Morris JN, et al. The Karnofsky Performance Status Scale: an examination of its reliability 
and validity in a research setting. Cancer 1984;53:2002-2007.  
Calhoun EA, Welshman EE, Chang CH, et al. Psychometric evaluation of the Functional Assessment of Cancer 
Therapy/Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving 
systemic chemotherapy. Int J Gynecol Cancer 2003;13:7416  
The Criteria Committee of the New York Heart Association, Inc.: Diseases of the heart and blood vessels; 
Nomenclature and criteria for diagnosis, 6th Ed. Boston: Little, Brown; 1964. 
Cheson, Pfistner, et al. Revised Response Criteria for Malignant Lymphoma. Journal of Clinical Oncology 
2007; 25:579-586 
Smith, Khatcheressian et al. 2006 Update of Recommendation for the Use of White Blood Cell Growth 
Factors: An Evidence-Based Clinical Practice Guideline 2006 ; 24:3187-3205 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
33 / 45 
 
ATTACHMENT 1 
 
Performance Status scales 
 
The following table presents the Karnofsky performance status scale. 
Which of the following descriptions best describes the subject’s level of performance at this time: 
 
Eastern Cooperative Oncology Group 
(Zubrod-ECOG)1,2 
KARNOFSKY SCORE 
Description 
Grade 
Scale 
Description 
Fully active, able to carry on all pre-
disease activities without restriction. 
0 
100 
 
90 
Normal, no complaints, no 
evidence of disease. 
Able to carry on normal activity, 
minor symptoms or signs of 
disease. 
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g. light house work, office 
work) 
1 
80 
 
70 
Normal activity with effort, some 
signs or symptoms of disease. 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
Ambulatory and capable of all self 
care but unable to carry out any work 
activities. 
Up and about more than 50% of 
waking hours. 
2 
60 
 
50 
Requires occasional assistance, but 
is able to care for most of his 
needs. 
Requires considerable assistance 
and frequent medical care. 
Capable of only limited self care, 
confirmed to bed or chair more than 
50% of waking hours. 
3 
40 
 
30 
Disabled, requires special care and 
assistance. 
Severely disabled, hospitalization is 
indicated although death is not 
imminent. 
Completely disabled. Cannot carry on 
any self care.  
Totally confined to bed or chair. 
4 
20 
 
10 
 
 0 
Hospitalization necessary, very sick, 
active supportive treatment  
necessary. 
Moribund, fatal processes 
progressing rapidly. 
Dead 
 
1 Zubrod, C.G., et al. Appraisal of Methods for the Study of Chemotherapy of Cancer in Man.  
 
Journal of Chronic Diseases, 11:7-33, 1960. 
2 Oken, M.M., et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol (CCT) 5: 649-655, 1982 
3 Karnofsky, D.A., Abelmann, W.H., Craver, L.F., and Burchenal, J.H., The use of the nitrogen 
mustards in the palliative treatment of carcinoma. Cancer (Philad.) 1:634, 1948. 
4 Schag, C.C., Heinrich, R.L., Ganz, P.A., Karnofsky Performance Status Revisited : Reliability, 
Validity, and Guidelines, Clinical Oncology. 2:187-193, 1984. 
5 Mor V, Laliberte L, Morris JN, et al. The Karnofsky Performance Status Scale: an examination 
of its reliability and validity in a research setting. Cancer 1984;53:2002-2007. 
 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
34 / 45 
 
ATTACHMENT 2 
 
WHO classification for lymphoma 
 
Swerdlow SH, Campo E, Harris NL et al (Eds.). WHO Classification of Tumours of Haematopoietic and 
Lymphoid Tissues. 4th Ed. IARC Lyon 2008 
 
MYELOPROLIFERATIVE NEOPLASMS 
 
Chronic myelogenous leukaemia, 
 
BCR-ABL1 positive 
9875/3 
Chronic neutrophilic leukaemia 
9963/3 
Polycythaemia vera 
9950/3 
Primary myelofibrosis 
9961/3 
Essential thrombocythaemia 
9962/3 
Chronic eosinophilic leukaemia, NOS 
9964/3 
Mastocytosis 
 
Cutaneous mastocytosis 
9740/1 
 
Systemic mastocytosis 
9741/3 
 
Mast cell Leukaemia 
9742/3 
 
Mast cell sarcoma 
9740/3 
 
Extracutaneous mastocytoma 
9740/1 
Myeloproliferative neoplasm, unclassifiable  
9975/3 
 
MYELOID 
AND 
LYMPHOID 
NEOPOLASMS 
WITH 
EOSINOPHILIA AND ABNORMALITIES OF PDGFRA, 
PDGRFB OR FGFR1 
 
Myeloid and lymphoid neoplasms  
 
with PDGFRA rearrangement 
9965/3 
Myeloid neoplasms  
  
with PDGFRB rearrangement  
9966/3 
Myeloid and lymphoid neoplasms  
  
with FGFR1 abnormalities 
9967/3 
 
MYELODYSPLASTIC/MYELOPROLIFERATIVE 
NEOPLASMS 
 
Chronic myelomonocytic leukaemia 
9945/3 
Atypical chronic myeloid leukaemia,  
  
BCR-ABL1 negative  
9876/3 
Juvenile myelomonocytic leukaemia 
9946/3 
Myelodysplastic/Myeloproliferative neoplasm, 
   Unclassifiable  
9975/3 
Refractory anaemia with ring sideroblasts   
 
associated with marked thombocytosis 
9982/3 
 
MYELODISPLASTIC SYNDROMES 
 
Refractory cytopenia with unilineage dysplasia 
 
Refractory anaemia 
9980/3 
 
Refractory neutropenia 
9991/3 
 
Refractory thrombocytopenia 
9992/3 
Refractory anaemia with ring sideroblasts 
9982/3 
Refractory cytopenia with  
 
multilineage dysplasia 
9985/3 
Refractory anaemia with excess blasts 
9983/3 
Myelodysplastic syndrome  
 
associated with isolated  del(5q) 
9986/3 
Myelodysplastic syndrome, unclassifiable 
9989/3 
Childhood myelodisplastic syndrome 
 
Refractory cytopenia of childhood 
9985/3 
 
ACUTE MYELOID LEUKAEMIA (AML)  AND RELATED 
PRECURSOR NEOPLASMS 
 
AML with recurrent genetic abnormalities 
 
AML with t(8;21)(q22 ;q22); 
  
RUNX1-RUNX1T1  
9896/3 
AML with inv(16)(p13.1q22) 
  
or t(16 ;16)(p13.1 ;q22) ; CBFB-MYH11 
9871/3 
Acute promyelocytic leukaemia  
 
with t(15 ;17)(q22 ;q12) ;  PML-RARA  
9866/3 
AML with t(9 ;11)(p22 ;q23) ; MLLT3-MLL  
9897/3 
AML with t(6 ;9)(p23 ;q34) ; DEK-NUP214  
9865/3 
AML with inv(3)(q21q26.2) 
  
or t(3 ;3)(q21 ;q26.2) ; RPN1-EVI1  
9869/3 
AML (megakaryoblastic) 
  
with t(1 ;22)(p13 ;q13) ; RMB15-MKL1  
9911/3 
AML with mutated NPM1 
9861/3 
AML with mutated CEBPA  
9861/3 
 
AML with myelodysplasia-rel. changes 
9895/3 
 
Therapy-related myeoloid neoplasms 
9920/3 
 
Acute myeloid leukaemia, NOS  
9861/3 
 
 
AML with minimal differentiation 
9872/3 
 
AML without maturation 
9873/3 
 
AML with maturation 
9874/3 
 
Acute myelomonocytic leukaemia 
9867/3 
 
Acute monoblastic and monocytic leuk. 
9891/3 
 
Acute erythroid  leukaemia 
9840/3 
 
Acute megakaryoblastic leukaemia 
9910/3 
 
Acute basophilic leukaemia 
9870/3 
 
Acute panmyelosis with myelofibrosis  
9931/3 
 
Myeloid sarcoma 
9930/3 
 
Myeloid proliferations related to Down syndrome  
 
Transient abnormal myelopoiesis 
9898/1 
 
Myeloid leukaemia  
 
associated with Down syndrome 
9898/3 
 
Blastic plasmacytoid dendritic cell neoplasm 
9727/3 
 
ACUTE LEUKAEMIAS OF AMBIGUOUS LINEAGE  
 
Acute undifferentiated leukaemia 
9801/3 
Mixed phenotype acute leukaemia 
 
with t(9 ;22)(q34 ;q11.2) ; BCT-ABL1 
9806/3 
Mixed phenotype acute leukaemia 
  
with t(v ;11q23) ; MLL rearranged  
9807/3 
Mixed phenotype acute leukaemia, 
 
B/myeloid, NOS 
9808/3 
Mixed phenotype acute leukaemia, 
 
T/myeloid, NOS 
9809/3 
Natural killer (NK) cell lymphoblastic  
 
Leukaemia/lymphoma 
PRECURSOR LYMPHOID NEOPLASMS  
 
B lymphoblastic leukaemia/lymphoma 
 
B lymphoblastic leukaemia/lymphoma, NOS 
9811/3 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
35 / 45 
 
B lymphoblastic leukaemia/lymphoma 
 
with recurrent genetic abnormalities  
 
 
B lymphoblastic leukaemia/lymphoma 
  
with t(9 ;22)(q34 ;q11.2) ; BCR-ABL1  
9812/3 
 
B lymphoblastic leukaemia/lymphoma  
  
with t(v ;11q23) ; MLL rearranged  
9813/3 
 
B lymphoblastic leukaemia/lymphoma 
  
with t(12 ;21)(p13 ;q22) ; TEL-AML1 
  
(ETV6-RUNX1)  
9814/3 
 
B lymphoblastic leukaemia/lymphoma 
  
 with hyperdiploidy 
9815/3 
 
B lymphoblastic leukaemia/lymphoma 
  
with hypodiploidy (hypodiploid ALL)  
9816/3 
 
B lymphoblastic leukaemia/lymphoma 
  
with t(5 ;14)(q31 ;q32) ; IL3-IGH  
9817/3 
 
B lymphoblastic leukaemia/lymphoma with  
  
T(1 ;19)(q23 ;p13.3) ; E2AA-PBX1  
  
(TCF3-PBX1)  
9818/3 
 
T lymphoblastic leukaemia/lymphoma  
9837/3 
 
MATURE B-CELL NEOPLASMS 
 
Chronic lymphocytic leukaemia/ 
 
Small lymphocytic lymphoma 
9823/3 
B-cell prolymphocytic leukaemia 
9833/3 
Splenic B-cell marginal zone lymphoma 
9689/3 
Hairy cell leukaemia  
9940/3 
Splenic B-cell lymphoma/leukaemia, unclass 
9591/3 
 
Splenic diffuse red pulp small B-cell lym 
9591/3 
 
Hairy cell leukaemia-variant  
9591/3 
Lymphoplasmacytic lymphoma 
9671/3 
 
Waldenström macroglobulinemia 
9761/3 
Heavy chain diseases 
9762/3 
 
Alpha heavy chain disease 
9762/3 
 
Gamma heavy chain disease 
9762/3 
 
Mu heavy chain disease 
9762/3 
Plasma cell myeloma 
9732/3 
Solitary plasmacytoma of bone 
9731/3 
Extraosseous plasmacytoma 
9734/3 
Extranodal marginal zone lymphoma 
 
of mucosa-associated lymphoid tissue 
 
(MALT lymphoma) 
9699/3 
Nodal marginal zone lymphoma 
9699/3 
 
Paediatric nodal marginal zone lymph  
9699/3 
Follicular lymphoma  
9690/3 
 
Paediatric follicular lymphoma  
9690/3 
Primary cutaneous follicle centre lymphoma 
9597/3 
Mantle cell lymphoma 
9673/3 
Diffuse large B-cell lymphoma  (DLBCL), NOS 
9680/3 
 
T-cell/histiocyte rich large B-cell lymph 
9688/3 
 
Primary DLBCL of the CNS 
9680/3 
 
Primary cutaneous DLBCL, leg type 
9680/3 
 
EBV positive DLBCL of the elderly  
9680/3 
DLBCL associated with chronic inflammation 
9680/3 
Lymphomatoid granulomatosis 
9766/1 
Primary mediastinal (thymic) large  
 
 
B-cell lymphoma  
9679/3 
Intravascular large B-cell lymphoma 
9712/3 
ALK positive large B-cell lymphoma 
9737/3 
Plasmablastic lymphoma 
9735/3 
Large B-cell lymphoma arising in HHV8- 
 
associated multicentric Castleman dis. 
9738/3 
Primary effusion lymphoma 
9678/3 
Burkitt lymphoma 
9687/3 
B-cell lymphoma, unclassifiable, with features    
 
intermediate between diffuse large B-cell  
 
lymphoma and Burkitt lymphoma  
9680/3 
B-cell lymphoma, unclassifiable, with features  
 
intermediate between diffuse large B-cell 
 
Lymphoma and classical Hodgkin lymph. 
9596/3 
 
MATURE T-CELL AND NK-CELL NEOPLASMS  
 
T-cell prolymphocytic leukaemia 
9834/3 
T-cell large granular lymphocytic leukaemia 
9831/3 
Chronic lymphoprolifer. disorder of NK-cells 
9831/3 
Aggressive NK cell leukaemia 
9948/3 
Systemic EBV positive T-cell lymphoproliferative  
 
disease of childhood 
9724/3 
Hydroa vacciniforme-like lymphoma 
9725/3 
Adult T-cell leukaemia/lymphoma 
9827/3 
Extranodal NK/T cell lymphoma, nasal type 
9719/3 
Enteropathy-associated T-cell lymphoma 
9717/3 
Hepatosplenic T-cell lymphoma 
9716/3 
Subcutaneous panniculitis-like  
 
T-cell lymphoma 
9708/3 
Mycosis fungoides 
9700/3 
Sézary syndrome 
9701/3 
Primary cutaneous CD30 positive T-cell 
 
lymphoproliferative disorders 
 
 
Lymphomatoid papulosis 
9718/1 
 
Primary cutaneous anaplastic large cell  
 
lymphoma  
9718/3 
Primary cutaneous gamma-delta  
 
T-cell lymphoma 
9762/3 
Primary cutaneous CD8 positive aggressive  
 
Epidermotropic cytotoxic T-cell lymph. 
9709/3 
Primary cutaneous CD4 positive small/medium 
 
T-cell lymphoma 
9709/3 
Peripheral T-cell lymphoma, NOS 
9702/3 
Angioimmunoblastic T-cell lymphoma 
9705/3 
Anaplastic large cell lymphoma, ALK positive 
9714/3 
Anaplastic large cell lymph., ALK negative  
9702/3 
 
HODGKIN LYMPHOMA 
 
Nodular lymphocyte predominant 
 
Hodgkin lymphoma  
9659/3 
Classical Hodgkin lymphoma 
9650/3 
 
Nodular sclerosis classical  
 
 
Hodgkin lymphoma 
9663/3 
 
Lymphocyte-rich classical  
 
  
Hodgkin lymphoma 
9651/3 
 
Mixed cellularity classical  
 
 
Hodgkin lymphoma 
9652/3 
 
Lymphocyte-depleted classical  
 
 
Hodgkin lymphoma 
9653/3 
 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
36 / 45 
 
HISTIOCYTIC AND DENDRITIC CELL NEOPLASMS  
 
Histiocytic sarcoma 
9755/3 
Langerhans cell histiocytosis 
9751/3 
Langerhans cell sarcoma 
9756/3 
Interdigitating dendritic cell sarcoma 
9757/3 
Follicular dendritic cell sarcoma  
9758/3 
Fibroblastic reticular cell tumour 
9759/3 
Indeterminate dendritic cell tumour 
9757/3 
Disseminated juvenile xanthogranuloma 
 
 
POST-TRANSPLANT 
LYMPHOPROLIFERATIVE 
DISORDERS (PTLD)  
 
Early lesions 
 
Plasmacytic hyperplasia 
9971/1 
 
Infectious mononucleosis-like PTLD 
9971/1 
Polymorphic PTLD 
9971/3 
Monomorphic PTLD (B- andT/NK-cell types)*  
Classical Hodgkin lymphoma type PTLD* 
 
 
 
 
NOS, not otherwise specified.  
 
The italicized numbers are provisional codes for the 4th edition of ICD-O. While they are expected to be incorporated in the next 
ICD-O edition, they currently remain subject to changes.  
 
The italicized histologic types are provisional entities, for which the WHO Working Group felt there was insufficient evidence to 
recognize as distinct diseases at this time.  
 
* These lesions are classified according to the leukaemia or lymphoma to which they correspond, and are assigned the respective 
ICD-O code.  
 
 
 
 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
37 / 45 
 
ATTACHMENT 3 
 
Instructions for the preparation and handling of DEPOCYTE 
injections 
 
DepoCyte® should be stored in a refrigerator between 2° to 8°C (DO NOT FREEZE). 
 
The principal investigator has to authorize those personnel having access to and the ability to administer the 
investigational medicinal product. This will be documented on a so called “authorised personnel form” 
provided by the monitor. Only qualified personnel who are familiar with procedures which minimize undue 
exposure to themselves and to the environment shall undertake, in a self-contained protective environment, 
the preparation, handling and safe disposal of DepoCyte®. 
 
The vial must be at room temperature prior to performing the following procedures. Immediately prior to 
withdrawing a dose of DepoCyte®, the vial should be gently agitated by rolling the vial between the palms. 
Avoid excessive agitation (DO NOT SHAKE). No filtering, reconstitution or dilution is required prior to 
withdrawing drug. DepoCyte®must be used within 4 hours of withdrawal from the single-dose vial. Since 
DepoCyte®does not contain any preservatives, unused portions of each vial should be properly discarded. Do 
not mix DepoCyte®with any other medications. 
 
Concurrent steroid administration is important for the prevention of drug-related arachnoiditis. 
Therefore the patients should receive dexamethasone 4mg po (or iv) b.i.d. on the day of intrathecal injection. 
Steroid medication should be continued for 5 days after Depocyte® injection as standard part of the R-CHOP 
regimen (i.e., Prednisone 40mg/m2 d 1-5) 
 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
38 / 45 
 
ATTACHMENT 4 
 
Dispensing information for Rituximab 
 
DESCRIPTION 
Rituximab is a mouse/human chimeric antibody. The rituximab antibody is produced by a Chinese hamster 
ovary transfectoma. Rituximab will be provided in l00 mg (l0 mL) and 500 mg (50 mL) pharmaceutical grade 
vials at a concentration of l0.0 mg of protein per mL (actual concentration should be noted on the product 
label). 
 
RECOMMENDED PREPARATION AND ADMINISTRATION 
1. 
Refer to the clinical trial protocol for details about the dose and dose schedule. 
2. 
Rituximab should be stored at 2-8°C. Do not freeze or store at room temperature. The product is a 
protein - HANDLE GENTLY AND AVOID FOAMING. The avoidance of foaming during product handling, 
preparation and administration is important, as foaming may lead to the de-naturing of the product 
proteins. 
3. 
All transfer procedures require strict adherence to aseptic techniques, preferably in a laminar flow hood. 
4. 
Prepare the rituximab infusion solution as follows: 
(a) Refrigerate (2-8°C) all materials and solutions prior to use. 
(b) Use sterile, non-pyrogenic, disposable containers, syringes, needles, stopcocks and transfer tubing, 
etc. 
(c) Transfer of the rituximab from the glass vial should be made by using a suitable sterile graduated 
syringe and large gauge needle. 
(d) Transfer the appropriate amount of rituximab from the graduated syringe, into a partially filled IV 
pack containing sterile pyrogen-free 0.9% sodium chloride solution, USP (saline solution). The 
final concentration of rituximab in saline solution should be a maximum of 1 mg/ml. 
Mix by inverting the bag gently. DO NOT USE A VACUUM APPARATUS to transfer the product 
from the syringe to the plastic bag. 
(e) Place an IV administration into the outflow port of the bag containing the infusion solution. 
(f) NOTE: DO NOT USE evacuated glass containers which require vented administration sets because 
this causes foaming as air bubbles pass through the solution. 
5. 
The administration of rituximab will be accomplished by slow IV infusion.CAUTION: DO NOT 
ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. 
6. 
IV pumps such as the IMED 960 may be used with the rituximab infusion. DO NOT INFUSE 
CONCOMITANTLY with another IV solution or IV medications. Prime the line with the rituximab solution 
such that approximately 30 mL are delivered 
7. 
Administration of rituximab 
 
Pre-administration of allopurinol (or suitable alternative) 
Patients thought to be at risk of tumor lysis syndrome should be well-hydrated and treated with allopurinol 
(300 mg p.o.) or suitable alternative treatment for 12-24 hours before prior to the first dose of therapy with 
rituximab. 
 
Caution: Do not administer rituximab as an intravenous push or bolus 
Rituximab will be administered intravenously in an out- or in-patient setting. Oral premedication (1000 mg of 
paracethamole and 50-100 mg diphenhydramine hydrochloride) needs to be administered 30-60 minutes 
prior to starting each infusion of rituximab. Prednisone/prednisolone as part of the chemotherapy protocol will 
be administered in the prescribed dose before the infusion of rituximab, preferably as oral medication. A 
peripheral or central intravenous (iv) line will be established. Before starting the infusion, there should be a 




IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
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ATTACHMENT 5 
 
Methotrexate schedule (> 500 MG and ≤ 3000 MG)   
 
Day 
Date 
Time 
Treatment 
Nurse 
Signature 
16:00 – 24:00 
1000 ml Gluc / NaCl 2:1 
 
0 
../../…. 
20:00 
2 cp  Hydrochlorothiazide 250 mg p.os.  
 
100 ml Gluc / NaCl 2:1 
 
24:00 – 08:00 
500 ml NaHCO3 1,4% 
 
06:00 
2 cp  Hydrochlorothiazide 250 mg p.os.  
 
08:00 – 12:00 
1000 ml Gluc NaCl 2:1 
 
08:00 – 14:00 
500 ml NaHCO3 1,4% 
 
11:30 – 11:45 
20 mg Metroclopramide in 100 ml  
NaCl 0.9% i.v. 
 
Attention! Before Methotrexate infusion: 
1. Diuresis has to be al least 1500 ml in the last 12 hrs and 500 ml in the last 4 hrs 
2. pH must be 8 in two assessments 
12:00 
2 cp  Hydrochlorothiazide 250 mg p.os.  
 
12:00 – 14:00 
…. mg Methotrexate in 500 ml NaCl 0,9% 
 
14:00 – 22:00 
1000 ml Gluc / Nacl 2:1 
 
14:00 – 02:00 
500 ml NaHCO3 1,4 % 
 
….. 
……. 
 
18:00 
2 cp  Hydrochlorothiazide 250 mg p.os.  
 
22:00 – 06:00 
1000 ml Gluc / NaCl 2:1 
 
1 
../../…. 
24:00 
2 cp  Hydrochlorothiazide 250 mg p.os.  
 
02:00 – 14:00 
500 ml NaHCO3 1,4% 
 
….. 
……. 
 
06:00 
2 cp  Hydrochlorothiazide 250 mg p.os.  
 
06:00-14:00 
1000 ml Gluc / NaCl 2:1 
 
30 mg Calciumfolinate i.v. bolus 
 
12:00 
2 cp  Hydrochlorothiazide 250 mg p.os.  
 
14:00 – 22:00 
1000 ml Gluc NaCl 2:1 
 
14:00 – 02:00 
500 ml NaHCO3 1,4% 
 
….. 
…… 
 
18:00 
1 cp 15 mg Calciumfolinate p.os.  
 
 
2 cp  Hydrochlorothiazide 250 mg p.os.  
 
22:00 – 06:00 
1000 ml Gluc / NaCl 2:1 
 
1 cp 15 mg Calciumfolinate p.os. .  
 
2 
../../…. 
24:00 
2 cp  Hydrochlorothiazide 250 mg p.os.  
 
02:00 – 14:00 
500 ml NaHCO3 1,4% 
 
1 cp 15 mg Calciumfolinate p.os.  
 
06:00 
2 cp  Hydrochlorothiazide 250 mg p.os.  
 
1000 ml Gluc / NaCl 2:1 
 
06:00 – 14:00 
1 cp 15 mg Calciumfolinate p.os.  
 
12:00 
2 cp  Hydrochlorothiazide 250 mg p.os. then stop if MTX level 
is normal. 
 
14:00 - ….. 
Upon clinical judgement:  
1000 ml Glucose 5%  
(according to MTX levels post-48 hours) 
 
14:00 - ….. 
Upon clinical judgement:  
500 ml NaHCO3 1,4% 
(according to MTX levels post-48 hours) 
 
….. 
…… 
 
3 
../../…. 
18:00 
1 cp 15 mg Calciumfolinate p.os.  
 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
41 / 45 
 
 
Day 
Date 
Time 
Treatment 
Nurse 
Signature 
3 
(cont.) 
../../…. 
(continued) 
24:00 
1 cp 15 mg Calciumfolinate p.os.  
 
4 
../../…. 
15 mg Calciumfolinate p.os. must be administered every 6 hours up to 72 hours after 
MTX infusion start time.  
 
 
Hydric balance and wight: D1-3: every 12 hours (06:00 + 18:00) 
After MTX infusion urinary pH must be > 8: 
- 
if pH = 8, must be assessed every 6 hours 
- 
if pH < 8, must be assessed each urine sample 
Never administer Lasix during urine alkalinisation time. 
For 6 hours after MTX diuresis must be > 1000ml. If under this value upon clinical judgement enhance hydric intake or diuresis. 24 
hours diuresis must be at least 3000 ml. 
MTX levels will be assessed 24 and 48 hours after the MTX start infusion time.  
 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
42 / 45 
 
ATTACHMENT 6 
 
Creatinine clearance calculation 
 
Creatinine clearance for men and women will be calculated according to the Cockcroft-Gault formula as 
follows: 
 
In men:  
140 " age
(
) # weight kg
(
)
[
]
72 # creatinine mg/dL
(
)
[
]
 
 
In women: 
140 " age
(
) # weight kg
(
)
[
]
72 # creatinine mg/dL
(
)
[
]
 x 0.85  
 
 
Note: 
Age (in years), weight (in kg), serum-creatinine (in mg/dL) 
72 (normalized to 72 kg body weight and a body surface of 1.72 m2) 
 
 
 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
43 / 45 
 
ATTACHMENT 7 
 
New York Heart Association Classification of Cardiac Disease 
 
The following table presents the NYHA classification of cardiac disease 
 
 Class 
Functional Capacity 
Objective Assessment 
 I 
Patients with cardiac disease but without resulting 
limitations of physical activity. Ordinary physical activity 
does not cause undue fatigue, palpitation, dyspnea, or 
anginal pain. 
No objective evidence
of 
cardiovascular
disease. 
 II 
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
Objective evidence of
minimal cardiovascular
disease. 
 II 
Patients with cardiac disease resulting in marked limitation 
of physical activity. They are comfortable at rest. Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or 
anginal pain. 
Objective evidence of
moderately 
severe
cardiovascular disease. 
 IV 
Patients with cardiac disease resulting in inability to carry 
on any physical activity without discomfort. Symptoms of 
heart failure or the anginal syndrome may be present even 
at rest. If any physical activity is undertaken, discomfort is 
increased. 
Objective evidence of
severe cardiovascular
disease. 
 
Source: The Criteria Committee of the New York Heart Association, Inc.: Diseases of the heart and blood 
vessels; Nomenclature and criteria for diagnosis, 6th Ed. Boston: Little, Brown; 1964 
 


IELSG 30 PROTOCOL – version 1.2 – May 10, 2010 
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ATTACHMENT 8 
 
Suggested Body Surface Area Calculation 
 
 
BSA should be determined using the Mosteller formula as follows: 
 
 
BSA = 
Ht(inches) "Wt(lbs)
3131
 
 
OR 
 
BSA = 
Ht(cm) "Wt(kg)
3600
 
 
 
Source: NEJM 1987; 317: 1098