A Randomised Phase II Trial of Inotuzumab Ozogamicin Plus Rituximab & CVP (IO-R-CVP) vs Gemcitabine Plus Rituximab & CVP (Gem-R-CVP) for the First Line Treatment of Patients With DLBCL Who Are Not Suitable for Anthracycline Containing Chemotherapy
Phase: PHASE2
Conditions: Diffuse Large B Cell Lymphoma
Sponsor: University College, London

INCA protocol v7.0 18th November 2019 
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         INCA TRIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A multicentre randomised phase II clinical trial of 
Inotuzumab Ozogamicin plus Rituximab and CVP (IO-R-
CVP) versus Gemcitabine plus Rituximab and CVP (Gem-
R-CVP) for the first line treatment of patients with diffuse 
large B cell lymphoma who are not suitable for 
anthracycline containing chemotherapy.  
 
 
 
 
Trial Sponsor: 
University College London 
Trial Sponsor reference:
11/0475
 
Trial funders:
Pfizer Limited & CTAAC
Trial funder references: 
WS1993028 (Pfizer) 
A14898 (CTAAC) 
Clinicaltrials.gov no: 
NCT01679119 
EUDRACT no:
2012-001900-39
CTA no:
20363/0312/001
REC no: 
12/YH/0452
 
 
Protocol version no:
V7.0
Protocol version date: 
 
18 Nov 2019
 
 

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Protocol v7.0, 18-11-2019 authorisation signatures 
 
 
 
*Please note: This trial protocol must not be applied to patients treated outside the INCA trial.  
Cancer Research UK & UCL Cancer Trials Centre (UCL CTC) can only ensure that approved 
trial investigators are provided with amendments to the protocol. 

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Coordinating Centre: 
For general queries, supply of trial documentation and central data management please 
contact: 
INCA Trial Coordinator 
Cancer Research UK & UCL Cancer Trials Centre 
90 Tottenham Court Road 
London 
W1T 4TJ 
United Kingdom 
Tel:  
+44 (0) 20 7679 9860 
Fax: 
+44 (0) 20 7679 9861 
09:00 to 17:00 Monday to Friday (UK time) excluding bank holidays 
Email: 
ctc.inca@ucl.ac.uk   
Other trial contacts: 
Chief Investigator: 
Dr Andrew McMillian 
 
Address: 
 
Nottingham City Hospital 
Hucknall Road 
Nottingham 
NG5 1PB 
 
Trial Management Group (TMG): 
 
Andrew McMillan      
Consultant Haematologist 
Nottingham University Hospitals NHS 
Trust 
 
Kim Linton      
Consultant Medical Oncologist 
The Christie NHS Foundation Trust 
 
Andrew Davies    
Consultant Medical Oncologist 
University Hospital Southampton NHS 
Foundation Trust 
 
Paul Fields      
Consultant Haematologist 
Guy’s and St Thomas’ NHS Foundation 
Trust 
 
Graham Collins
Consultant Haematologist
Oxford University Hospitals NHS Trust
 
Sharon Barrans 
 
 
Elizabeth Phillips 
 
 
Laura Clifton-Hadley 
 
 
Pip Patrick 
 
 
Amy Kirkwood 
 
 
Lindsey Stevens 
 
Clinical Scientist 
 
 
Haematology SpR 
 
 
Trials Group Lead 
 
 
Senior Trial Coordinator 
 
 
Statistician 
 
 
Trial Coordinator 
 
Haematological Malignancy Diagnostic 
Service (HMDS), Leeds 
 
University College London Hospitals 
NHS Foundation Trust 
 
Cancer Research UK & UCL Cancer 
Trials Centre 
 
Cancer Research UK & UCL Cancer 
Trials Centre 
 
Cancer Research UK & UCL Cancer 
Trials Centre 
 
Cancer Research UK & UCL Cancer 
Trials Centre 

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Table of Contents 
 
Section
Title
Page number
1
Protocol Summary
5
1.1 
Summary of Trial Design 
5 
1.2 
Trial Schema 
8 
2
Introduction
9
2.1 
Background 
9 
3 
3.1 
3.2 
Trial design 
Trial objectives 
Trial endpoints 
10 
12 
13
3.3 
Trial activation 
13 
4
Selection of Sites/Site Investigators
13
4.1 
Site selection 
13 
4.1.1 
Selection of Principal Investigator and other investigators at sites 
14 
4.1.2 
Training requirements for site staff 
14 
4.2 
Site initiation and activation 
14 
4.2.1 
Site initiation 
14 
4.2.2 
Required documentation 
14 
4.2.3 
Site activation letter 
15 
5
Informed consent
15
6
Selection of patients
16
6.1 
Screening log 
16 
6.2 
Patient eligibility 
16 
6.2.1 
Inclusion & exclusion criteria for randomisation 
16 
6.3
Pregnancy and Birth Control
18
6.3.1 
Pregnancy and birth control 
18 
6.3.2 
Risk of exposure of trial treatment during Pregnancy 
18 
6.3.3 
Pregnancy testing 
18 
6.3.4 
Contraceptive advice 
18 
6.3.5 
Action to be taken in the event of a Pregnancy 
19 
6.3.6 
Long term fertility 
20 
6.3.7 
Lactation 
20 
7
Randomisation Procedures
20
7.1 
Randomisation 
20 
7.2 
Initial trial drug supply 
21 
8
Trial Treatment
21
8.1 
Treatment summary 
21 
8.2 
Summary Treatment Schedule 
21 
8.3 
Trial Treatment Details 
24 
8.4 
Dose modifications 
25 
8.5 
Managements of Overdoses, Trial treatment error or Occupational 
exposure 
27 
8.6 
Supportive Care 
28 
8.7 
Concomitant medication 
28 
8.8 
Pharmacy Responsibilities 
29 
8.8.1 
Temperature Excursions 
29 
8.8.2 
IMP accountability 
30 
8.9 
24 hour/Out-of-office hours emergency drug-specific advice 
30 
8.10 
Other trial treatments/interventions 
30 
8.11 
Clinical management after treatment discontinuation 
30 
9
Assessments
30
9.1 
Pre-randomisation assessments 
31 
9.2 
Assessments during treatment 
32 
9.3 
Assessments on completion of trial treatment 
33 
9.4 
Assessments during trial follow-up 
33 
Table 1 
Schedule of Assessments 
35 
10 
11
Exploratory Biological Studies 
Data Management Guidelines
37 
39

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11.1 
Completing Case Report Forms 
39 
11.2 
Missing Data 
39 
11.3 
Timelines for data return 
39 
11.4 
Data Queries 
40 
12
Pharmacovigilance
40
12.1 
Definitions  
40 
12.2 
Reporting Procedures 
41 
12.2.1 
Reporting of Adverse Events (AEs) 
42 
12.2.2 
Reporting of Serious Adverse Events (SAEs) 
42 
 
Adverse Event Reporting Flowchart 
44 
12.3 
SUSARs 
45 
12.4 
Safety Monitoring 
45 
12.5 
Pregnancy 
45 
12.6 
Development Safety Update Reports (DSURs) 
46 
13
Incident Reporting and Serious Breaches
47
13.1  
Incident Reporting 
47 
13.2 
Serious Breaches 
47 
14
Trial Monitoring and Oversight
47
14.1 
On-Site Monitoring 
47 
14.2 
Central Monitoring 
48 
14.3 
‘For Cause’ On-Site Monitoring 
48 
14.4 
Oversight Committees 
49 
14.4.1 
Trial Management Group (TMG) 
49 
14.4.2 
Trial Steering Committee (TSC) 
49 
14.4.3 
Independent Data Monitoring Committee (IDMC) 
49 
14.4.4 
Role of UCL CTC 
49 
15
Withdrawal of Patients
50
15.1 
Discontinuation of Treatment 
50 
15.2 
Future Data Collection 
50 
15.3 
Losses to Follow-Up 
50 
16
Trial Closure
51
16.1 
End of Trial 
51 
16.2 
Archiving of Trial Documentation 
51 
16.3 
Early discontinuation of trial 
51 
16.4 
Withdrawal from trial participation by a site 
51 
17
Statistics
52
17.1 
Sample Size Calculation 
52 
17.2 
Population for analysis 
52 
17.3 
Analysis of the primary endpoint 
52 
17.4 
Analysis of secondary endpoints 
52 
17.4.1 
Efficacy (secondary) 
52 
17.4.2 
Heath related Quality of Life and functional assessments 
53 
17.5 
Interim analyses 
53 
18
Ethical and Regulatory Approvals
54
18.1 
Ethical Approval 
54 
18.2 
Regulatory Approval 
54 
18.3 
Site Approvals 
54 
18.4 
Protocol Amendments 
55 
18.5 
Patient Confidentiality & Data Protection 
55 
19
Sponsorship and Indemnity
56
19.1 
Sponsor Details 
56 
19.2 
Indemnity 
56 
20
Funding
57
21
Publication Policy
57
22
References
58
 
Appendix 1:  Abbreviations  
 
 
 
 
 
         60 
Appendix 2:  Revised Cheson criteria for response assessment 
         62 
Appendix 3:  ECOG Performance Scale 
 
 
 
 
         66 
Appendix 4:  International Prognostic Index 
 
 
 
         67 
Appendix 5:  Protocol Version History 
 
 
 
 
         68

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1 PROTOCOL SUMMARY 
1.1 
Summary of Trial Design  
Title: 
A multicentre randomised phase II clinical trial of 
Inotuzumab Ozogamicin (IO) plus Rituximab and CVP 
(IO-R-CVP) versus Gemcitabine plus Rituximab and 
CVP (Gem-R-CVP) for the first line treatment of patients 
with Diffuse Large B Cell Lymphoma (DLBCL) who are 
not suitable for anthracycline containing chemotherapy. 
Short Title/acronym:
INCA
EUDRACT no:
2012-001900-39
Sponsor name:
University College London 
Sponsor reference:
11/0475
Funders name:
Pfizer Limited  
Funders reference:
WS1993028 (Pfizer) and A14898 (CTAAC)
Clinicaltrials.gov no:
 NCT01679119 
Design: 
A multicentre, randomised, phase II trial comparing IO-R-
CVP with Gem-R-CVP in the first line treatment of 
patients with DLBCL who are not fit for anthracycline-
containing chemotherapy. If international sites participate 
they will have the option of using R-CEOP as the control 
arm.
Overall aim: 
To determine the efficacy and safety of IO-R-CVP in 
patients with previously untreated DLBCL who are not-fit 
for R-CHOP. 
Primary endpoint: 
Progression free survival at 2 years from date of 
randomisation 
Secondary endpoints: 
Overall response rate 
Overall survival 
Treatment toxicity according to CTCAE v4.03 
Quality of life measured by EORTC QLQ-C30 
Performance status post treatment 
Co-morbidities of patients measured by the Cumulative 
Illness Rating Scale (CIRS)  
Exploratory Biological 
Studies: 
Translational studies will investigate the frequency of 
different sub-groups of DLBCL (ABC vs GCB), and 
assess the frequency of NFκB mutations in elderly 
patients. In addition, the frequency and prognostic 
significance of EBV tumoural status, assess CD22 
expression levels in tumour samples by RQ-PCR and the 
role of FLT-3 ligand in predicting neutropenic fever will be 
investigated. A single 7ml EDTA blood sample will be 
sent to HMDS, Leeds, for future germline DNA extraction 
as part of future ethically approved translational studies
Target accrual: 
66 per arm (132 total) 
Inclusion & exclusion criteria: 
Inclusion criteria include: 
a) Age 18 years 
b) Histologically proven DLBCL with demonstration of 
CD20 positivity (concurrent or previous diagnosis of 
low grade lymphoma is permitted only if no systemic 
therapy has been given). Bulky Stage Ia-IV 
c) Unsuitable 
for 
anthracycline-containing 
chemotherapy due to impaired cardiac function or 

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presence of significant co-morbidities 
d) ECOG PS 0-2 
e) Adequate bone marrow, liver and renal function 
f) Life expectancy >3 months 
 
Exclusion criteria include: 
a) Stage Ia (non-bulky) 
b) ECOG PS >2 
c) CNS involvement 
d) Previous low grade lymphoma treated with 
systemic therapy 
e) HIV, Serological evidence of active Hepatitis B or 
Hepatitis C infection whether acute or chronic 
f) Previous 
treatment 
for 
lymphoma 
(prior 
corticosteroids permitted) 
 
For full inclusion/exclusion criteria see section 6 
(Selection of patients)
Number of sites:
15-25 UK sites
Countries:
UK  
Treatment summary: 
All 
patients 
should 
receive 
steroids prior 
to 
randomisation into the trial 
Patients may receive up to the equivalent of 1mg/kg per 
day of Prednisolone for up to 14 days prior to 
randomisation.   For cases where logistical issues have 
delayed treatment start, up to 28 days’ worth of steroids 
is permissible after approval from the CTC and a TMG 
member. Patients receiving a longer duration of steroids 
are not eligible if there is symptomatic disease 
progression after the initial 14 days of steroid treatment. 
See section 8 of the protocol for further details.   
 
Inotuzumab Ozogamicin-R-CVP arm: 
D1        Cyclophosphamide 750mg/m2 IV 
D1        Vincristine 1.4mg/m2  (max 2mg) IV 
D1-5     Prednisolone 100mg OD Oral 
D1        Rituximab 375mg/m2 IV 
D2        Inotuzumab Ozogamicin 0.8mg/m2 IV* 
D4-12   Primary GCSF prophylaxis 
 
*Prednisolone should be given in the morning of day 2 
(prior to administration of Inotuzumab Ozogamicin) and 
patients should be pre-medicated with paracetamol 1g 
(PO) and chlorpheniramine 4mg (PO) according to local 
policies 
 
Gem-R-CVP arm:  
D1, D8 Gemcitabine up to 1g/m2 IV** 
D1        Cyclophosphamide 750mg/m2 IV 
D1        Vincristine 1.4mg/m2  (max 2mg) IV 
D1-5     Prednisolone 100mg OD Oral 
D1        Rituximab 375mg/m2 IV 
D9-17   Primary GCSF prophylaxis 
 
 

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** Patients with ECOG PS 0-1: The starting dose for 
Gemcitabine is 875mg/m2 (during cycle 1).  If tolerated 
this can be escalated in cycle 2 and subsequent cycles to 
1g/m2.   
 
Patients with ECOG PS 2: The starting dose for 
Gemcitabine is 750mg/m2 (during cycle 1).  If tolerated 
this can be escalated in cycle 2 to 875mg/m2.  If tolerated 
this can be escalated in cycle 3 and subsequent cycles to 
1g/m2.  See section 8 of the protocol for further details. 
 
In both treatment arms, cycles repeated every 21 days 
to a maximum of 6 cycles and followed in both arms by 2 
further doses of intravenous rituximab 375mg/m2 at 21-
day intervals - day 1 of cycles 7 and 8. (i.e. 8 doses of 
rituximab in total). 
 
International sites would have the opportunity to choose 
an alternative control arm (R-CEOP) see section 8 (Trial 
treatment) for details.
Duration of recruitment: 
5 Years 
Duration of follow up: 
For a minimum of two years or until death whichever 
occurs first 
Definition of end of trial: 
When all patients have completed at least two years of 
follow-up post last trial treatment 
Other related research: 
Detailed 
assessment 
of 
co-morbidities 
using 
the 
Cumulative Illness Rating Scale (CIRS) tool prior to 
treatment and assessment of quality of life (EORTC 
QLQ-C30) and functional assessments (ADL and IADL 
scores) before, during and after treatment.
 

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1.2 
Trial Schema 
 
 
 
 
Histologically proven DLBCL with contraindications to anthracycline  
All patients:
Pre randomisation Steroids 
ECOG PS 0-2
ECOG PS > 2 after 
steroids: Not eligible for 
randomisation 
Baseline co-morbidity score, 
QoL and functional assessments 
Randomisation
Arm A: Standard Arm
Gem-R-CVP 
3 cycles – 21 day interval 
Arm B: Experimental Arm
Inotuzumab Ozogamicin + R-CVP 
3 cycles – 21 day interval 
After 3 cycles:
Interim CT scan 
QoL & functional 
assessments 
Further 3 cycles of Gem-R-
CVP 
Total 6 cycles 
Further 3 cycles of Inotuzumab 
Ozogamicin + R-CVP 
Total 6 cycles 
2 cycles of Rituximab
2 cycles of Rituximab
End of treatment 
assessments: 
CT scan 
QoL & functional assessments 
Follow up:
CT scans at 3 months and 1 year after end of treatment 
QoL & functional assessments at 6 months and 24 months after end of treatment 
Patients approached with PIS and consent obtained

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2 INTRODUCTION 
2.1 
Background 
The incidence of diffuse large B cell lymphoma (DLBCL) is increasing and with an expanding 
elderly population, the incidence will continue to rise [1]. Given that about 40% of cases of 
DLBCL occur in patients aged over 70 years [2] and the number of co-morbidities increases 
with age [3], research to investigate the optimal treatment of DLBCL in this group of patients is 
needed.  
 
The 
optimal 
treatment 
of 
DLBCL 
is 
combination 
chemotherapy 
incorporating 
cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) in combination with the 
chimeric anti-CD20 monoclonal antibody rituximab. The addition of rituximab to CHOP led to 
significant improvements in outcome compared to CHOP alone and the initial trial 
demonstrating this was conducted in elderly patients aged 60-80 years [4, 5]. These results 
have been reproduced in other trials, confirming R-CHOP as the standard of care in DLBCL [6]. 
In most trials to date, 8 doses of rituximab have been added to 6-8 cycles of chemotherapy and 
for this reason in this trial, a total of 8 doses of rituximab will be given in both treatment arms[4, 
6, 7]. 
 
Whilst R-CHOP remains the standard of care for the majority of patients with DLBCL, 
anthracycline use is precluded in a proportion of patients at high risk of developing 
cardiotoxicity, especially congestive cardiac failure. The risk of developing congestive cardiac 
failure is dose dependent, and increases with age and in the presence of co-morbidities (pre-
existing cardiac disease, hypertension and diabetes) [8].   
 
Alternatives to R-CHOP in patients unable to receive anthracyclines: 
There is no standard of care for patients who are unfit for anthracycline treatment. It has been 
routine to omit the doxorubicin from R-CHOP, giving R-CVP instead. However anecdotally the 
outcome for patients treated with R-CVP is poor and attempts have been made to replace the 
doxorubicin with alternative agents.  
 
A recent UK phase II trial investigated the safety and efficacy of adding gemcitabine to R-CVP 
in the first line treatment of DLBCL in a cohort of patients with significant cardiac co-morbidities 
precluding anthracycline use (either left ventricular ejection fraction (LVEF) ≤50% or LVEF 
>50% in the presence of ischaemic cardiac disease, hypertension or diabetes). This gave an 
overall response rate of 60% and 1 year PFS and OS of 53% and 63% respectively in a cohort 
of patients in whom treatment is very difficult [9].  
 
Etoposide has been substituted for doxorubicin in the R-CEOP regimen [10]. In a retrospective 
study this has been reported to lead to 5 year overall survival of 49% with 57% progression free 
survival at 5 years. Liposomal doxorubicin  has also been substituted for doxorubicin in elderly 
patients with DLBCL with high overall response rates and overall survival, but importantly, 
patients with cardiac co-morbidities were excluded from this trial [11]. Similarly, reduced doses 
of doxorubicin (R-mini-CHOP) were assessed in patients over 80 years old in a recent GELA 
study but it is not clear whether patients with cardiac co-morbidities were included in this study 
[12].  
 
Inotuzumab Ozogamicin: 
Inotuzumab Ozogamicin is a humanised anti-CD22 antibody conjugated to calicheamicin, a 
potent antitumor antibiotic. CD22 is expressed on the majority of B-cell non-Hodgkin 
lymphomas (NHL). As of May 2011, approximately 408 subjects have received inotuzumab 
ozogamicin in clinical trials, either as a single agent (3 completed or ongoing studies) in 
combination with rituximab (4 completed or ongoing studies), or in combination with 
chemotherapy. A phase I/II study evaluating the safety of inotuzumab ozogamicin in 

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combination with R-CVP regimen in patients with relapsed or refractory CD22+ B-cell NHL is 
nearing completion. The maximum tolerated dose of inotuzumab ozogamicin is 1.8 mg/m2 
based on grade 4 haematologic toxicity (thrombocytopenia and neutropenia lasting more than 7 
days) reported following 2.4 mg/m2, the highest dose tested [13]. 
 
Preliminary safety and efficacy data demonstrates that inotuzumab ozogamicin 0.8 mg/m2 is 
safe and tolerable when given in combination with full dose R-CVP chemotherapy.  Response 
rate data are highly encouraging [14]. Inotuzumab Ozogamicin cannot be added to the Gem-R-
CVP regimen due to a predicted excess of severe grade III/IV haematological toxicity, 
especially thrombocytopenia. 
 
Trial design: 
In this randomised phase II clinical trial, patients with previously untreated DLBCL who are 
unable to receive anthracyclines due to co-morbidities will be randomised to either Inotuzumab 
Ozogamicin in combination with R-CVP, or gemcitabine in combination with R-CVP.  
 
If international sites participate they will have the option of choosing to use R-CEOP as an 
alternative to Gem-R-CVP in the control arm. 
 
Translational research questions: 
A number of exploratory endpoints will investigate potentially useful clinical biomarkers in this 
trial.  
 
The principal translational research questions will investigate: 
 
 
The frequency of molecularly defined subgroups of DLBCL (ABC vs. GCB) in an 
elderly patient population 
 
 
The frequency of somatic mutations in the NF-кB signalling pathway in DLBCL in 
elderly patients 
 
 
The frequency and potential predictive and prognostic value of EBV tumoural status 
in elderly patients with DLBCL 
 
 
Whether FLT3 ligand can be used to predict neutropenic fever. This component will 
be optional depending on site facilities for collection and storage of serum samples 
and patients’ consent  
 
For further details of translational research see section 10 (Exploratory Biological Studies). 
 
Summary: 
In summary, as the population ages there will be more patients with DLBCL who are assessed 
as being unsuitable to receive R-CHOP. Given that there is no internationally accepted 
standard of care for this group of patients there is a need to assess new regimens. The addition 
of the novel immunoconjugate Inotuzumab Ozogamicin to R-CVP will be assessed in this trial. 
 
3.0  TRIAL DESIGN 
 
Trial design: 
This is a randomised phase 2 trial with an experimental arm consisting of Inotuzumab 
Ozogamicin 
added 
to 
the 
standard 
immunochemotherapy 
regimen 
of 
rituximab, 
cyclophosphamide, vincristine and prednisolone (R-CVP). The control arm will consist of 
gemcitabine added to the same combination (Gem-R-CVP). If international sites participate 
they will be permitted to use an alternative control arm of R-CEOP.  

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6 cycles of either of the randomised schedules will be administered at 3 weekly intervals and 
will be followed by 2 further doses of rituximab at 21-day intervals in both treatment arms (i.e. 8 
doses of rituximab will be given in total in both the experimental and control arms).  
 
Primary G-CSF prophylaxis please see section 8.6.  
 
Dose reductions according to haematological toxicity are specified in the protocol (see section 
8.4 (Dose modifications)). 
 
The main inclusion criteria will be patients of any age with biopsy proven CD20 positive diffuse 
large 
B 
cell 
lymphoma 
whom 
the 
investigator 
deems 
unsuitable 
for 
R-CHOP 
immunochemotherapy. This will include patients with cardiac impairment (LVEF≤ 50%) or co-
morbidities and a LVEF of >50% as used in the Gem-R-CVP trial.  
 
Over 90% of DLBCL cases are positive for CD22 [15]). CD22 status will be confirmed 
retrospectively but will not be an entry requirement as Immuno-histochemical staining of 
diagnostic biopsy specimens is not routinely available in all participating centres.  
 
All patients will receive steroids prior to randomisation into the study (see section 8 for full 
details).  All patients with a performance status of ≤2 after the steroids will be randomised 
between the experimental and control arm. The use of steroids has been reported to improve 
performance status by the DSHNHL group and therefore there is recommendation in section 8 
of the protocol regarding the optimal steroid schedule [6, 15].  
 
Cumulative Illness Rating Scale (CIRS) score will be recorded for the pre-chemotherapy 
assessment of co-morbidities. Quality of life assessment (EORTC QLQ-C30) will be carried out 
at baseline (after steroids), after 3 cycles, after 6 cycles, and at both 6 and 12 months from end 
of therapy. In addition, an assessment of functionality (ADL and IADL) will be made at the same 
time points. 
 
Treatment arms: 
All patients will receive steroids prior to randomisation unless clinically contraindicated (see 
section 8.2 for full details (Summary Treatment Schedule).   
 
Patients with an ECOG performance status of 2 after steroids will be randomised in a 1:1 
randomisation to: 
 
Intervention arm (Inotuzumab Ozogamicin-R-CVP): 
 
D1 
Cyclophosphamide 
750mg/m2 
IV 
D1
Vincristine
1.4mg/m2 (max 2mg)
IV
D1-5
Prednisolone*
100mg OD
Oral
D1 
Rituximab 
375mg/m2 
IV 
D2
Inotuzumab Ozogamicin*
0.8mg/m2
IV
* 
Prednisolone should be given in the morning of day 2 (prior to the 
administration of Inotuzumab Ozogamicin) and patients should be pre-
medicated with paracetamol 1g (PO) and chlorpheniramine 4mg (PO) 
according to local policies.  Inotuzumab ozogamicin is light sensitive and 
must be protected from light during preparation and administration of the 
infusion using a UV protective covering (see section 8.3 for full details). The 
Inotuzumab ozogamicin should be infused within 1 hour at room temperature 
at a rate of 50 mL/hour (see section 8.3 for full details). 
D4-12 
G-CSF primary prophylaxis for all patients e.g. filgrastim 300mcg sc od. Peg-
filgrastim permitted as an alternative to daily G-CSF and dose as per local 
policy. G-CSF should be stopped if Neutrophils are >1.0 x 10.9/l after 
neutrophil nadir

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Control arm (Gem-R-CVP): 
 
D1, D8 
*Gemcitabine 
Up to 1g/m2* 
IV 
D1
Cyclophosphamide
750mg/m2
IV
D1 
Vincristine 
1.4mg/m2 (max 2mg) 
IV 
D1-5
Prednisolone
100mg OD
Oral
D1
Rituximab
375mg/m2
IV
D9-17 
G-CSF primary prophylaxis for all patients e.g. filgrastim 300mcg sc od. Peg-
filgrastim permitted as an alternative to daily G-CSF and dose as per local 
policy. G-CSF should be stopped if Neutrophils are >1.0 x 10.9/l after 
neutrophil nadir 
 
*Patients with ECOG Performance Status 0-1: The starting dose for Gemcitabine is 
875mg/m2 (during cycle 1).  If tolerated this can be escalated in cycle 2 and subsequent 
cycles to 1g/m2.  See section 8.2 of the protocol for further details. 
 
Patients with ECOG Performance Status 2: The starting dose for Gemcitabine is 
750mg/m2 (during cycle 1).  If tolerated this can be escalated in cycle 2 to 875mg/m2.  If 
tolerated this can be escalated in cycle 3 and subsequent cycles to 1g/m2.  See section 
8.2 of the protocol for further details. 
 
If grade III/IV haematological toxicity is observed, dose of gemcitabine to be reduced. 
See section 8.4 (Dose modifications) for further details on dose reductions. 
 
Cycles for both arms repeated every 21 days for 6 cycles, and followed 21 days after day 1 of 
cycle 6 by 2 additional doses of intravenous rituximab 375mg/m2 at 21-day intervals (i.e. 
patients will receive 8 doses of rituximab in total – day 1 of cycle 1 to cycle 8). 
 
Alternative Control arm (R-CEOP): ALTERNATIVE FOR USE IN INTERNATIONAL 
CENTRES ONLY, NOT FOR UK SITES 
 
D1 
Rituximab 
375mg/m2 
IV 
D1
Cyclophosphamide
750mg/m2
IV
D1 
Vincristine 
1.4mg/m2 (max 2mg) 
IV 
D1-5
Prednisolone
100mg OD
Oral
D1
Etoposide
50mg/m2
IV
D2, D3 
Etoposide 
100mg/m2 
Oral 
D6-14 
G-CSF primary prophylaxis for all patients e.g. filgrastim 300mcg sc od. Peg-
filgrastim permitted as an alternative to daily G-CSF. 
 
Cycles repeated every 21 days for 6 cycles, and followed 21 days after day 1, cycle 6 by 2 
additional doses of intravenous rituximab 375mg/m2 at 21-day intervals (i.e. patients will receive 
8 doses of rituximab in total – day 1 of cycle 1 to cycle 8). 
 
3.1 
Trial Objectives 
 
The primary objective is to determine whether adding inotuzumab ozogamicin to R-CVP 
improves progression free survival when compared to Gem-R-CVP, in the first line treatment of 
DLBCL in patients who are not able to receive anthracycline-containing immunochemotherapy. 
 
The secondary objectives include measuring the safety/tolerability of the regimen and to 
measure impact of this regimen on overall survival, response, quality of life and functionality.  
 
 
 

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3.2 
Trial Endpoints 
 
The primary endpoint is progression free survival (PFS) at 2 years from date of randomisation. 
 
 
Secondary endpoints:  
o 
Overall response rate (ORR) 
o 
Overall survival (OS) 
o 
Treatment toxicity according to CTCAE v4.03 
o 
Quality of life measured by EORTC QLQ-C30 
o 
Performance status post treatment 
o 
To gather information on the co-morbidities of patients unsuitable for 
anthracycline-containing chemotherapy by the Cumulative Illness Rating 
Scale (CIRS)  
 
 
Translational Endpoints: 
 
o 
To 
determine 
the 
frequency 
of 
different 
molecular 
subtypes 
(ABC/GCB/unclassifiable), as determined by gene expression profiling in 
the study population and to assess the impact of this on clinical outcomes 
o 
Assess the frequency of NFκB mutations in study population 
o 
To assess the frequency and prognostic significance of EBV tumoural 
status 
o 
To assess CD22 expression levels in tumour samples by RQ-PCR 
o 
To assess the role of FLT-3 ligand serum measurement in predicting 
neutropenic fever 
3.3 
Trial activation 
UCL CTC will ensure that all trial documentation has been reviewed and approved by all 
relevant bodies and that the following have been obtained prior to activating the trial: 
 
 
Health Research Authority (HRA) approval including Research Ethics Committee 
approval 
 
Clinical Trial Authorisation from the Medicines and Healthcare products Regulatory 
Agency (MHRA)  
 
‘Adoption’ into NIHR portfolio  
 
Adequate funding for central coordination 
 
Confirmation of sponsorship 
 
Adequate insurance provision 
 
4 
SELECTION OF SITES/SITE INVESTIGATORS 
4.1 
Site Selection 
In this protocol trial ‘site’ refers to the hospital where trial-related activities are conducted. 
Sites must be able to comply with: 
 
 
Trial treatment(s), imaging, clinical care, follow up schedules and all requirements of the 
trial protocol 
 
Requirements of the UK Policy Framework for Health and Social Care Research issued 
by the Health Research Authority and the Medicines for Human Use (Clinical Trials) 
Regulation (SI 2004/1031), and all amendments 

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 
Data collection requirements, including adherence to CRF submission timelines as per 
section 11.3 (Timelines for Data Return) 
 
Biological sample collection, processing and storage requirements  
 
Monitoring requirements, as outline in the protocol section 14  (Trial Monitoring and 
Oversight and trial monitoring plan) 
4.1.1 Selection of Principal Investigator and other investigators at sites 
Each sites must appoint an appropriate Principal Investigator (PI), i.e. a health care 
professional authorised by the site to lead and coordinate the work of the trial on behalf of a 
site.  Co-investigators must be trained and approved by the PI.  All PIs and co-investigators 
must be medical doctors and have experience of treating diffuse large B-cell lymphoma.  The 
PI is responsible for the conduct of the trial at their site and for ensuring that any amendments 
are implemented in a timely fashion.  If a PI plans to take a leave of absence, UCL CTC must 
be informed promptly.  For absences greater than three months of where the PI is no longer 
able to perform his/her duties at the site, UCL CTC may terminate recruitment at site.  A new 
suitable replacement must be identified by the site and UCL CTC notified.   
UCL CTC may terminate recruitment at a site where a suitable replacement PI has not been 
identified within three months. 
4.1.2 Training requirements for site staff 
All site staff must be appropriately qualified by education, training and experience to perform 
the trial related duties allocated to them, which must be recorded on the site delegation log. 
CVs for all staff must be kept up-to-date, signed and dated and copies held in the Investigator 
Site File (ISF).  A current, signed copy of the CV with evidence of GCP training (or copy of GCP 
certificate) for the PI must be forwarded to UCL CTC upon request. 
GCP training is required for all staff responsible for trial activities.  The frequency of repeat 
training may be dictated by the requirements of their employing institution, or 2 yearly where 
the institution has no policy, and more frequently when there have been updates to the legal or 
regulatory requirements for the conduct of clinical trials. 
4.2 
Site initiation and Activation 
4.2.1 Site initiation 
Before a site is activated, the UCL CTC trial team will arrange a site initiation with the site which 
the PI, the pharmacy lead and site research team must attend. The site will be trained in the 
day-to-day management of the trial and essential documentation required for the trial will be 
checked. 
Site initiation will be performed for each site during a site visit or teleconference.  Re-initiating 
sites may be required where there has been a significant delay between initiation and enrolling 
the first patient as per monitoring plan. 
4.2.2 Required documentation 
The following documentation must be submitted by the site to UCL CTC prior to a site being 
activated by UCL CTC trial team: 
 
 
Trial specific Site Registration Form (identifying relevant local staff)   
 
Relevant institutional approvals 

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 
A completed site delegation log that is initialled and dated by the PI (with all tasks and 
responsibilities delegated appropriately) 
 
Completed Site Contacts form (with contact information for all members of local staff) 
 
A signed and dated copy of the PI’s current CV (with documented up-to-date GCP 
training, or copy of GCP training certificate) 
 
Trial specific prescriptions 
 
In addition, the following agreements must be in place: 
 
 
A signed Clinical Trial Site Agreement (CTSA) between the Sponsor and the relevant 
institution (usually a NHS Trust) 
4.2.3 Site activation letter 
Once the UCL CTC trial team has received all required documentation and the site has been 
initiated, a site activation letter will be issued to the PI, at which point the site may start to 
approach patients. 
Once the site has been activated by UCL CTC, the PI is responsible for ensuring:  
 
adherence to the most recent version of the protocol; 
 
all relevant site staff are trained in the protocol requirements; 
 
appropriate recruitment and medical care of patients in the trial; 
 
timely completion and return of CRFs (including assessment of all adverse events); 
 
prompt notification and assessment of all serious adverse events; 
 
that the site has facilities to provide 24 hour medical advice for trial patients. 
 
5 
INFORMED CONSENT 
 
Sites are responsible for assessing a patient’s capacity to give informed consent. 
Sites must ensure that all patients have been given the current approved version of the patient 
information sheets, are fully informed about the trial and have confirmed their willingness to 
take part in the trial by signing the current approved consent form. 
Sites must assess a patient’s ability to understand verbal and written information in English and 
whether or not an interpreter would be required to ensure fully informed consent. If a patient 
requires an interpreter and none is available, the patient should not be considered for the trial. 
The PI, or, where delegated by the PI, other appropriately trained site staff, are required to 
provide a full explanation of the trial and all relevant treatment options to each patient prior to 
trial entry.  During these discussions, the current approved patient information sheets for the 
trial should be discussed with the patient.   
A minimum of twenty four (24) hours must be allowed for the patient to consider and discuss 
participation in the trial.  
Written informed consent on the current approved version of the consent form for the trial must 
be obtained before any trial-specific procedures are conducted.  The discussion and consent 
process must be documented in the patient notes. 
Site staff are responsible for: 
 
checking that the current approved version of the patient information sheet and consent 
form are used; 

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 
checking that information on the consent form is complete and legible; 
 
checking that the patient has completed/initialled all relevant sections and signed and 
dated the form; 
 
checking that an appropriate member of staff has countersigned and dated the consent 
form to confirm that they provided information to the patient; 
 
checking that an appropriate member of staff has made dated entries in the patient’s 
medical notes relating to the informed consent process (i.e. information given, consent 
signed etc.); 
 
following randomisation: adding the patients’ trial number to all copies of the consent 
form, which should be filed in the patient’s medical notes and investigator site file; 
 
following randomisation giving the patient a copy of their signed consent form, patient 
information sheet and patient contact card. 
 
The right of the patient to refuse to participate in the trial without giving reasons must be 
respected.  All patients are free to withdraw at any time.  Patient withdrawal of consent from the 
trial must be explicitly documented in the source documents. Also refer to section 15.0 
(Withdrawal of patients). 
6 
SELECTION OF PATIENTS 
6.1 
Screening Log 
A screening log must be maintained and appropriately filed at site.  Sites should record each 
patient screened for the trial/all patients identified with DLCBL and the reasons why they were 
not randomised in the trial if this is the case. The log must be sent to UCL CTC when 
requested.  
6.2 
Patient Eligibility 
There will be no exception to the eligibility requirements at the time of randomisation. Queries 
in relation to the eligibility criteria must be addressed prior to randomisation. Patients are 
eligible for the trial if all the inclusion criteria are met and none of the exclusion criteria applies.  
Patient eligibility must be confirmed by an investigator who is suitably qualified and who has 
been allocated this duty, as documented on the site staff delegation log, prior to randomising 
the patient.  Confirmation of eligibility must be documented in the patients’ notes and on the 
randomisation CRF. 
Patients must give written informed consent before any trial specific screening investigations 
may be carried out.  Refer to section 9.1 (Pre-randomisation Assessments) for the list of 
assessments and procedures required to evaluate the suitability of patients prior to entry. 
6.2.1 Inclusion Criteria for randomisation 
 
Informed written consent for the trial 
 
Histologically proven diffuse large B cell lymphoma (DLBCL) according to the current 
World Health Organisation (WHO) classification including all morphological variants. 
The B cell nature of the proliferation must be verified by demonstration of CD20 
positivity. A concurrent (synchronous) diagnosis of low grade lymphoma (e.g. on bone 
marrow trephine or presence of both low grade and DLBCL in a lymph node biopsy) or 
previous diagnosis of low grade lymphoma which hasn’t been treated with a systemic 
therapy is permitted.  
 
Bulky Stage IA (lymph node or lymph node mass ≥10cm in maximum diameter), stage 
IB, stage II, stage III and stage IV disease 

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 
ECOG performance status 0-2  
 
Measurable disease 
 
Age 18 years 
 
Adequate contraceptive precautions for all patients of childbearing potential 
 
History of malignant disease diagnosed at any time in the past with completed radical 
treatment and the risk of relapsing within the next 5 years is <10%.  Patients previously 
treated should be free of sequelae of treatment which would compromise the delivery of 
study drugs as compared with other eligible patients.   Cases with second malignancy 
where eligibility is uncertain should be discussed in the first instance with the CTC. 
 
No previous chemotherapy, radiotherapy or other investigational drug for this indication 
– previous corticosteroids up to a dose equivalent to prednisolone 1mg/kg/day for up to 
14 days are permitted prior to randomisation.  For cases where logistical issues have 
delayed treatment start, up to 28 days’ worth of steroids is permissible after approval 
from the CTC and a TMG member. Patients receiving a longer duration of steroids are 
not eligible if there is symptomatic disease progression after the initial 14 days of steroid 
treatment 
 
EITHER 
Unsuitable for anthracycline-containing chemotherapy due to impaired cardiac function 
defined by an ejection fraction of ≤50%  
 
OR 
 Left ventricle ejection fraction >50% but in the presence of significant co- morbidities 
(diabetes mellitus, hypertension or ischaemic heart disease) precluding anthracycline-
containing chemotherapy as determined by treating physician.  
Co-morbidities must be documented on the randomisation form and CIRS score 
recorded using the Cumulative Illness Rating Scale 
 
Adequate bone marrow function (Platelets >100x109/l, WBC >3.0 x109/l, Neutrophils 
>1.5x109/l) at time of study entry unless attributed to bone marrow infiltration by DLBCL 
 
Life expectancy >3 months 
 
 
6.2.2 Exclusion Criteria for randomisation 
 
Symptomatic central nervous system or meningeal involvement by DLBCL 
 
Previous diagnosis of low grade lymphoma which has been treated with a systemic 
therapy 
 
Non-bulky stage IA disease 
 
ECOG performance status 3-4  
 
History of chronic liver disease or suspected alcohol abuse 
 
Serum bilirubin greater than upper limit of normal unless attributable to Gilbert’s 
syndrome or haemolysis. 
 
Alanine and/or aspartate aminotransferase levels (ALT and/or AST) and alkaline 
phosphatase (ALP) greater than 2.5 times the upper limit of normal  
 
Glomerular filtration rate (GFR) <30ml/min. GFR calculated by Cockroft-Gault (not 
eGFR)  
 
Serological evidence of active hepatitis B or C infection whether acute or chronic 
(defined as positive anti-HCV serology; positive HBsAg). All positive HBcAb results 
should also be excluded on safety grounds regardless of HBsAg or HBV DNA status.   
Antibodies to Hepatitis B surface antigen (anti-HBs) due to a history of past vaccination 
is acceptable   
 
Known history of HIV seropositive status 
 
Patients with a history of Venoocclusive Disease (VOD) and Sinusoidal Obstructive 
Syndrome (SOS) 
 
Patients with a screening of QTcF interval >470msec 
 
Medical or psychiatric conditions compromising the patient’s ability to give informed 
consent 
 
Women who are pregnant or lactating 
 
LVEF >50% in the absence of significant co-morbidities that preclude anthracycline use  

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 
Patients with a history of severe allergic/anaphylactic reaction to any humanised 
monoclonal antibody 
 
Patients with serious active infection 
 
6.3 Pregnancy and birth control  
 
6.3.1 Pregnancy and birth control  
 
A woman of childbearing potential (WOCBP) is a sexually mature woman (i.e. any female who 
has experienced menstrual bleeding) who has not: 
 
undergone a hysterectomy or bilateral oophorectomy/salpingectomy 
 
been postmenopausal for 12 consecutive months (i.e. who has had menses at any time 
in the preceding 12 consecutive months without an alternative medical cause) 
 
had premature ovarian failure confirmed by a specialist gynaecologist 
 
XY genotype, Turner syndrome, uterine agenesis 
 
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
 
6.3.2 Risk of exposure to trial treatment during pregnancy 
 
The risk to the human embryo or foetus from exposure to Inotuzumab Ozogamicin are currently 
unknown.  When Inotuzumab Ozogamicin was given daily to pregnant rats and rabbits, 
maternal toxicity occurred in both species, but foetal toxicity occurred only in rats at a 
maternally toxic dosage. Gemcitabine has also shown reproductive toxicity in animal studies.    
 
Cyclophosphamide and Vincristine are known to cause foetal harm, with a particular risk for 
women taking Vincristine in the first trimester of pregnancy. The manufacturers of these drugs 
state that they should not be used during pregnancy. The risks to the human embryo or foetus 
from exposure to Gemcitabine, Rituximab and Inotuzumab Ozogamicin are currently unknown. 
Administration of Prednisolone to pregnant animals can cause abnormalities of foetal 
development including cleft palate, intra-uterine growth retardation and effects on brain growth 
and development. There is currently no evidence in human studies that Prednisolone does 
result in an increased incidence of congenital abnormalities.  However, when administered for 
prolonged periods or repeatedly during pregnancy, Prednisolone may increase the risk of 
intrauterine growth retardation. There are no adequate and well-controlled data from studies in 
pregnant women exposed to Rituximab. However IgG immunoglobulins are known to cross the 
placental barrier and transient B-cell depletion and lymphocytopenia have been reported in 
some infants born to mothers exposed to Rituximab during pregnancy.  
  
6.3.3 Pregnancy testing 
 
All women of childbearing potential who are at risk of becoming pregnant must undergo a 
serum pregnancy test at baseline. 
 
6.3.4 Contraceptive advice  
 
Due to the insufficient data on the effects of trial treatment during pregnancy and lactation, 
female patients of childbearing potential must consent to use one of the following highly 
effective methods of contraception until 12 months post last trial treatment. Methods with low 
user dependency are preferable, particularly where introduced as a result of participation in the 
trial. 
 

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Highly effective methods of effective contraception for this trial are: 
 
combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1: 
 
oral 
 
intravaginal 
 
transdermal 
 
progestogen-only 
hormonal 
contraception 
associated 
with 
inhibition 
of 
ovulation1: 
o oral (e.g. desogestrel) 
o injectable 
o implantable2 
 
intrauterine device (IUD)2 
 
intrauterine hormone-releasing system ( IUS)2 
 
bilateral tubal occlusion2 
 
vasectomised partner2,3 
 
sexual abstinence4 
1. Hormonal contraception may be susceptible to interaction with the IMP/NIMP, which may reduce the efficacy of the 
contraception method. 
2. Contraception methods that are considered to have low user dependency. 
3. Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical 
success. 
4. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 
 
Due to the potential risk of genotoxicity and/or risk to the foetus from exposure to seminal fluid: 
• 
Male patients (including male patients who have had vasectomies) must consent to use 
condoms with female partners who are WOCBP or partners who are pregnant, during 
treatment and until 12 months post last trial treatment.  
• 
Male patients must also advise their female partners who are WOCBP regarding 
contraceptive requirements as listed for female patients who are WOCBP. 
The method(s) of contraception used must be stated in the patient medical notes. The medical 
notes of male participants should include a statement that the female partner has been 
informed about contraception advice. 
 
6.3.5 Action to be taken in the event of a Pregnancy 
 
Female patients: 
If a female patient becomes pregnant  
• prior to initiating treatment, the patient will not receive trial treatment unless they elect to 
have a termination (please note, in such instances, termination must be the patient’s 
own choice) 
• during treatment, the patient will be withdrawn from treatment and, if they consent to 
pregnancy monitoring, followed up until pregnancy outcome  
• after the end of the treatment (and for 12 months after discontinuing treatment), the 
patient will be followed up until pregnancy outcome if they consent to pregnancy 
monitoring. 
 

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Male patients:  
If a female partner of a male patient becomes pregnant between the patient’s informed consent 
and 12 months of the last trial treatment, the male participant can continue with the study whilst 
their female partner will be followed up if they have given consent to pregnancy monitoring.  
 
Notification to UCL CTC – refer to section 12.5 for further details.  
6.3.6 Long term infertility 
The effect on human fertility is unknown for some of the trial drugs, although some have been 
shown to cause azoospermia and amenorrhoea, which may be irreversible. Infertility in patients 
might be temporary or permanent. Female patients also might experience an earlier 
menopause. Any requirement for egg and sperm preservation by individual patients should be 
considered as per local site policy prior to entry to the trial, and collection undertaken prior to 
commencing chemotherapy. 
 
6.3.7 Lactation 
 
It is unknown whether Cyclophosphamide, Vincristine, Gemcitabine, Rituximab and Inotuzumab 
Ozogamicin are excreted in human breast milk. Prednisolone is excreted in small amounts in 
breast milk. Infants of women receiving doses high than 40mg a day may have a degree of 
adrenal suppression. 
 
Therefore, women must not breast feed during and for 12 months post last treatment 
administration. 
  
7 RANDOMISATION PROCEDURES 
Patient randomisation will be performed centrally at UCL CTC and this must be performed prior 
to commencement of any trial treatment.  Patients will be allocated to a treatment arm stratified 
by IPI (0-2 vs. 3-5), left ventricular ejection fraction (<50% vs. > 50%), control treatment (the 
control treatment offered within the patient’s centre i.e. R-GCVP or R-CEOP)* and centre, using 
minimisation. 
 
*Stratification by control arm will only be used in the event of international participation. 
 
Pre-randomisation evaluations should be carried out at sites as detailed in section 9.1 (Pre-
randomisation Assessments). 
7.1 
Randomisation 
Following pre-randomisation evaluations, confirmation of eligibility and consent of a patient at a 
site, the randomisation form must be fully completed and faxed to UCL CTC.  These will be 
used to confirm patient eligibility.  If further information is required UCL CTC will contact the 
person requesting randomisation to discuss the patient and request updated forms to be faxed. 
 
N.B. If the site is unable to fax, randomisation forms may be sent by email. If emailing forms, 
patient identifiable information from the form (e.g. NHS number, day and month of birth) must 
be redacted before it is emailed to ctc.inca@ucl.ac.uk. The identifiable information must be 
provided to UCL CTC via telephone so that UCL CTC can transcribe this information on to the 
form. The un-redacted form must then be posted to UCL CTC, and a copy kept in the patient 
file at site. 
 
Once eligibility has been confirmed a trial number and treatment allocation will be assigned for 
the patient and details should be added to the form by the site. 

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UCL CTC will fax/email confirmation of the patient’s inclusion in the trial, their trial number and 
treatment allocation to the main site contact and pharmacy. 
 
 
  
 
Randomisation telephone number:
+44 (0)20 7679 9860
Randomisation fax number: 
Randomisation email address:
+44 (0)20 7679 9861 
ctc.inca@ucl.ac.uk
UCL CTC Office hours: 
09:00 to 17:00 Monday to Friday 
(UK Time)  
Once a patient has been randomised onto the trial they must be provided with the following: 
 
A copy of their signed consent form and patient information sheet 
 
A patient contact card.  Site contact details for 24 hour medical care must be added to 
this card and patients advised to carry this with them at all times while participating in 
the trial 
7.2 
Initial Trial Drug Supply 
Inotuzumab Ozogamicin will be provided by Pfizer Limited and distributed by Almac Clinical 
Services. 
 
Cyclophosphamide, Gemcitabine, Prednisolone, Rituximab, Vincristine and G-CSF will be 
provided by site from hospital commercial stocks as details in the Summary of Drug 
Arrangements (SoDA). 
 
Please see the current version of the SoDA for further details of drug supply and re-supply for 
the trial. 
8 TRIAL TREATMENT 
8.1 
Treatment summary  
For the purpose of this protocol for UK sites, the IMPs are Inotuzumab Ozogamicin and 
Gemcitabine. The NIMPs are the steroids, Rituximab, Cyclophosphamide, Vincristine and 
Prednisolone. 
8.2 
Summary Treatment Schedule   
Both trial arms: Steroids pre-randomisation 
 
All patients should receive steroids prior to randomisation into the trial*.  Patients may receive 
up to the equivalent of 1mg/kg per day prednisolone for up to 14 days prior to randomisation.  
For cases where logistical issues have delayed treatment start, up to 28 days worth of steroids 
is permissible after approval from the CTC and a TMG member. Patients receiving a longer 
duration of steroids are not eligible if there is symptomatic disease progression after the initial 
14 days of steroid treatment**. 
 

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The use of steroids prior to starting the randomisation treatment must be recorded in the 
patients’ medical records and in the trial case report forms. 
 
Ideally, there should no break between completing steroids and starting the randomised 
treatment, i.e. the prednisolone should continue until chemotherapy is commenced. However a 
gap of up to 72 hours will be permissible if logistic considerations prevent chemotherapy being 
started directly at the cessation of the steroids.  Steroids can also be temporarily stopped for 
clinical reasons – e.g. in patients with diabetes who need to undergo CT scanning. 
*Steroids can be omitted if patients have a clinical contraindication to steroids (e.g. a co-
morbidity such as unstable diabetes/acute gastric ulceration or bleeding) as long as the ECOG 
is <2. 
 
**Patients on long-term low dose steroids (e.g. 10mg prednisolone daily or equivalent) for 
other medical conditions will be permitted to be entered into the study.   
 
The following serves as guidance for the investigator for instances where patients have yet to 
have steroids when consulting the protocol: 
 
It is recommended that patients may receive 60mg prednisolone for 7 days prior to starting the 
randomised treatment, however it may be administered for a minimum of 5 days and maximum 
of 28 days (see section above).  The dose may be split if not tolerated as a single dose (e.g. 
taken 8am and 12pm daily). 
 
Drug
Dose 
D1
D2
D3
D4
D5
D6
D7
Prednisolone (po) 
60mg 
X 
X 
X 
X 
X 
X 
X 
 
Randomised treatment 
 
Patients with an ECOG performance status of 2 after steroids* will be randomised in a 1:1 
randomisation to Gem-R-CVP or IO-R-CVP. 
 
*Steroids may be omitted due to patient having a clinical contraindication to steroids see above for 
further details 
 
UK control arm (Gem-R-CVP)  
 
Cycles repeated every 21 days for 6 cycles 
 
Drug 
Dose 
Route 
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Gemcitabine* 
Up to 1g 
/m2*
IV 
X 
 
 
 
 
 
 
X 
Cyclophosphamide 
750mg/m2 
IV 
X 
 
 
 
 
 
 
 
Vincristine** 
1.4mg/m2 
IV 
X 
 
 
 
 
 
 
 
Prednisolone 
100mg 
PO 
X 
X 
X 
X 
X 
 
 
 
Rituximab 
375mg /m2 
IV 
X 
 
 
 
 
 
 
 
G-CSF*** 
D9-17 
 
Intravenous rituximab is then given alone for 2 further doses at 21 day intervals after cycle 6, 
i.e. day 1 of cycles 7 and 8. 
 
* Patients with ECOG Performance Status 0-1: The starting dose for Gemcitabine is 
875mg/m2 (during cycle 1).  If tolerated this can be escalated in cycle 2 and subsequent cycles 
to 1g/m2.   
 

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Patients with ECOG Performance Status 2: The starting dose for Gemcitabine is 750mg/m2 
(during cycle 1).  If tolerated this can be escalated in cycle 2 to 875mg/m2.  If tolerated this can 
be escalated in cycle 3 and subsequent cycles to 1g/m2.   
 
**Vincristine maximum dose 2mg 
 
*** G-CSF should be stopped if Neutrophils are >1.0 x 10.9/l after neutrophil nadir. Pegylated 
G-CSF may be given as an alternative to daily G-CSF. Dose and timing of pegylated G-CSF 
according to local policies.  
Alternative control arm for international sites only (R-CEOP). 
Cycles repeated every 21 days for 6 cycles 
If international sites participate they will be required to choose one control regimen for all 
patients, it cannot be selected on a patient by patient basis. 
 
Drug 
Dose 
Route 
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Etoposide 
50mg/m2 
IV 
X 
 
 
 
 
Etoposide 
100mg/m2 
PO 
 
X 
X 
 
 
Cyclosphosphamide 
750 mg/m2 
IV 
X 
 
 
 
 
Vincristine* 
1.4mg/m2 
IV 
X 
 
 
 
 
Prednisolone 
100mg 
PO 
X 
X 
X 
X 
X 
Rituximab 
375mg/m2 
IV 
X 
 
 
 
 
G-CSF** 
D6-14 
 
Intravenous rituximab is then given alone for 2 further doses at 21 day intervals after cycle 6, 
i.e. day 1 of cycles 7 and 8. 
 
*Vincristine maximum dose 2mg 
 
 
**Pegylated G-CSF may be given as an alternative to daily G-CSF. Dose and timing of 
pegylated G-CSF according to local policies.  
 
Intervention arm (IO-R-CVP) 
Cycles repeated every 21 days for 6 cycles 
 
Drug 
Dose 
Route 
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Inotuzumab Ozogamicin  
0.8mg/m2
IV 
 
X**
* 
 
 
 
Cyclophosphamide 
750 mg/m2
IV 
X 
 
 
 
 
Vincristine* 
1.4mg/m2 
IV 
X 
 
 
 
 
Prednisolone 
100mg 
PO 
X 
X**
* 
X 
X 
X 
Rituximab 
375mg/m2 
IV 
X 
 
 
 
 
G-CSF** 
D4-12 
 
Intravenous rituximab is then given alone for 2 further doses at 21 day intervals after cycle 6, 
i.e. day 1 of cycles 7 and 8. 
 
*Vincristine maximum dose 2mg 
 

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** G-CSF should be stopped if Neutrophils are >1.0 x 10.9/l after neutrophil nadir.  Pegylated 
G-CSF may be given as an alternative to daily G-CSF. Dose and timing of pegylated G-CSF 
according to local policies.  
 
*** Prednisolone should be given in the morning of day 2 and premed with paracetamol 1g (PO) 
and chlorpheniramine 4mg (PO) according to local policies. Inotuzumab ozogamicin is light 
sensitive and must be protected from light during preparation and administration of the infusion 
using a UV protective covering (see section 8.3 for full details). The Inotuzumab ozogamicin 
should be infused within 1 hour at room temperature at a rate of 50 mL/hour (see section 8.3 
for full details). 
8.3 
Trial Treatment Details  
Body Surface Area (BSA) should be calculated as per local practice. BSA should be 
recalculated in case of weight variation of greater than 10%.  
 
Dose capping should not be performed for either IO-R-CVP or Gem-R-CVP but in cases of 
concern contact the UCL CTC for advice.  Dose banding is allowed but must not 
reduce/increase total dose by more than 10% (rounded to nearest whole percentage point from 
the original calculated dose). 
 
Inotuzumab Ozogamicin: 
Inotuzumab ozogamicin (CMC-544) is an antibody-targeted IV chemotherapy agent composed 
of a CD22-targeted antibody linked to calicheamicin, a potent cytotoxic antitumor antibiotic. It is 
currently unlicensed in the UK. CD22 is expressed on mature B cells. On binding to CD22, 
inotuzumab ozogamicin is rapidly internalised so delivering the cytotoxic agent calicheamicin 
into the cell resulting in cell death.  
 
Inotuzumab ozogamicin will be given intravenously on day 2 of each cycle at 0.8mg/m2 on the 
IO-R-CVP arm.  
 
Inotuzumab ozogamicin is supplied in amber glass vials as a white, unpreserved, lyophilized 
cake. The vials must be stored refrigerated (2-8°C). Prior to reconstitution, allow drug vials to 
warm to room temperature for approximately 15 minutes.  
 
Inotuzumab ozogamicin is light sensitive and must be protected from light during preparation 
and administration of the infusion using a UV protective covering. The reconstituted 
Inotuzumab ozogamicin solution in the syringe barrel(s) must be covered with foil if not 
immediately injected into the IV bag. The diluted solution of Inotuzumab ozogamicin in the IV 
bag must be covered (with an amber bag or covered with foil). It is recommended that all 
preparations are done in the pharmacy aseptic unit according to local procedures.  Vials and IV 
bags containing reconstituted and diluted Inotuzumab ozogamicin should be gently mixed, 
avoiding vigorous agitation. 
 
Refer to the Summary of Drug Arrangements for further information on the preparation of 
Inotuzumab ozogamicin. 
 
When infusing the product, prime the infusion line and infuse the entire contents of the bag at 
the rate of 50 mL/hour.   IV lines may only be exposed to light for the approximate 1 hour stated 
for infusion; if delays in start of administration occur, or if infusions may take longer than the 
suggested 1 hour, lines must be protected from light.  
 
Flush the line with 22 mL sodium chloride 0.9% injection after the contents of the bag have 
been infused. 
 
Gemcitabine: 

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Gemcitabine is a nucleoside analogue which has shown efficacy as single agent and also in 
combination with other drugs in the treatment of B cell lymphomas as well as T cell lymphoma 
and Hodgkin Lymphoma. Gemcitabine has been added to the R-CVP regimen in the first-line 
setting, delivering excellent response rates in a group of patients with cardiac co-morbidities 
precluding anthracycline therapy in a phase II trial [9].  
 
Gemcitabine will be given as an i.v. infusion on day 1 and day 8 of each cycle on the Gem-R-
CVP arm.   
 
For patients with ECOG PS 0-1: The starting dose for Gemcitabine is 875mg/m2 (during cycle 
1).  If tolerated this can be escalated in cycle 2 and subsequent cycles to 1g/m2.  
 
For patients with an ECOG PS 2: The starting dose for Gemcitabine is 750mg/m2 (during 
cycle 1).  If tolerated this can be escalated in cycle 2 to 875mg/m2.  If tolerated this can be 
escalated in cycle 3 and subsequent cycles to 1g/m2.   
 
Administration of Gemcitabine should be given according to local guidelines and policies.  
Prolonged infusion times should be avoided to minimise toxicity.  
 
R-CVP and G-CSF administration in both treatment arms 
Rituximab 375mg/m2 is given as an intravenous infusion. Administration of rituximab including 
pre-medications and rate of administration according to local guidelines and policies. 
Cyclophosphamide and Vincristine should be given intravenously according to local policy. 
Prednisolone should be given orally in tablet form once daily as per local policy. For details of 
G-CSF administration please see section 8.6. 
8.4 
Dose Modifications 
 
Gem-R-CVP 
 
Haematological toxicity: 
No dose adjustments or modifications based on haematological toxicity will be made for the 
following drugs: prednisolone, rituximab, cyclophosphamide or vincristine.   
 
Haematological toxicity with Gemcitabine is common and dose modification should be carried 
out as follows: 
 
Neutrophils  
 
day 1 of cycles 2-6: neutrophils ≥ 1x109/l, 100% dose; neutrophils < 1x109/l, defer 
treatment 1 week and initiate at next lower dose level upon neutrophil recovery to ≥ 
1x109/l 
 
 
day 8 of cycles 1-6: neutrophils ≥ 1x109/l, 100% dose; neutrophils < 1x109/l, omit 
gemcitabine and restart subsequent cycles at next lower dose level 
 
Platelets  
 
day 1 of cycles 2-6: ≥ 75x109/l, 100% dose; platelets < 75x109/l, defer treatment 1 week 
and initiate gemcitabine at next lower dose level upon platelet recovery to ≥ 75x109/l 
 
 
day 8 of cycles 1-6: ≥ 75x109/l, 100% dose; platelets < 75x109/l, omit and restart  
subsequent cycles at next lower dose level  
 
Dose reduction schema: 
 
Current dose
Dose reduction Dose reduction 

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on Day 1
on Day 8
1g/m2 
875mg/m2
875mg/m2
875mg/m2 
750mg/m2 
750mg/m2 
750mg/m2 
500mg/m2
500mg/m2
 
If a patient is unable to tolerate 500mg/m2 gemcitabine should be omitted permanently and 
continue with R-CVP only. 
 
In subsequent cycles, dose of gemcitabine may be re-escalated to 750mg/m2, then to 
875mg/m2, and subsequently to 1g/m2 at the discretion of the local investigator provided that no 
grade 3 or 4 haematological toxicity was observed at the lower dose. 
 
Non-haematological toxicity: 
 
Neuropathy  
If grade ≥2 motor or ≥3 sensory neuropathy, reduce vincristine dose to 1mg (flat dose) per 
cycle. If neurotoxicity increases despite this dose reduction, stop vincristine for future cycles. 
 
Constipation 
If grade 2 constipation occurs, reduce vincristine dose to 1mg (flat dose) per cycle. If greater 
than grade 2 omit vincristine. Investigator can reintroduce vincristine at 1mg if constipation 
resolves to grade 1 or better. 
 
Hepatic impairment 
In this study for elevated alanine and/or aspartate aminotransferase levels (ALT and/or AST) 
where the value is ≤2.5 x ULN with a normal total bilirubin there should be no dose 
modifications for gemcitabine, prednisolone, rituximab, cyclophosphamide or vincristine.  Sites 
should adhere to the SPC and manufacturer’s recommendation to dose reduce vincristine by 
50% for patients with a bilirubin >2.5 x ULN.    
 
IO-R-CVP 
 
Haematological toxicity: 
 
No dose adjustments or modifications based on haematological toxicity will be made for the 
following drugs: prednisolone, rituximab, cyclophosphamide or vincristine. 
 
Haematological toxicity with Inotuzumab Ozogamicin is common and dose modification should 
be carried out as follows: 
 
Neutrophils  
 
day 1 of cycles 2-6: neutrophils ≥ 1x109/l, 100% dose; neutrophils < 1x109/l, defer 
treatment for up to 2 weeks and initiate at next lower dose level in subsequent cycles.   
 
Platelets  
 
day 1 of cycles 2-6: ≥ 75x109/l, 100% dose; platelets < 75x109/l, defer treatment for up 
to 2 weeks and initiate at next lower dose level in subsequent cycles.   
 
Dose reduction levels from 0.8mg/m2 starting dose: 
 
Day 1
Starting dose 
0.8mg/m2 
Level 1
0.5mg/ m2
 

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There will be no more than 1 dose level reduction of inotuzumab ozogamicin permitted. If a 
patient requires a 2nd dose level reduction, inotuzumab ozogamicin should be omitted 
permanently and continue with R-CVP only. 
 
In subsequent cycles, dose of inotuzumab ozogamicin may be re-escalated to 0.8mg/m2 at the 
discretion of the local investigator provided that no grade 3 or 4 haematological toxicity was 
observed at the lower dose. 
 
Non-haematological toxicity: 
 
Neuropathy  
If grade ≥2 motor or ≥3 sensory neuropathy, reduce vincristine dose to 1mg (flat dose) per 
cycle. If neurotoxicity increases despite this dose reduction, stop vincristine for future cycles. 
 
Hepatic impairment 
Inotuzumab ozogamicin is known to cause hepatotoxicity, with low grade aminotransferase 
elevations being the most commonly reported hepatic adverse events in previous studies. 
Serious hepatic events of veno-occlusive disease, hepatic cirrhosis, hepatic fibrosis, nodular 
regenerative hyperplasia, hepatic failure, ascites, hyperbilirubinemia, and hepatitis/acute 
hepatitis have also been reported in <2% of cases, with some fatal events. 
 
In this study alanine and/or aspartate aminotransferase levels (ALT and/or AST) and alkaline 
phosphatase (ALP) must be less than or equal to 2.5 times the upper limit of normal for both 
study eligibility and study drug dosing, bilirubin must not be greater than upper limit of normal 
for study eligibility and study drug dosing (unless attributable to Gilbert’s syndrome or 
haemolysis).  
 
If grade 4 alanine and/or aspartate aminotransferase levels (ALT and/or AST) occurs 
(irrespective of duration) or Grade 2 hyperbilirubinemia (>1.5 x ULN) ≥7 days, defer treatment 
for up to 2 weeks or until resolved to grade 1 or less and initiate Inotuzumab ozogamicin at the 
next lower dose in subsequent cycles.  
 
In this study for elevated alanine and/or aspartate aminotransferase levels (ALT and/or AST) 
where the value is ≤2.5 x ULN with a normal total bilirubin there should be no dose 
modifications for prednisolone, rituximab, cyclophosphamide or vincristine.  Sites should 
adhere to the SPC and manufacturer’s recommendation to dose reduce vincristine by 50% for 
patients with a bilirubin >2.5 x ULN. 
 
QTc Changes 
If QTcF is between 471 msec and 499 msec (average of 3 ECGs), defer treatment for up to 2 
weeks.  If it resolves back to ≤470 msec within the 2 weeks then continue inotuzumab 
ozogamicin at original dose.  If QTcF doesn’t resolve initiate at next lower dose. If QTcF 
resolves continue at lower dose do not increase dose. If QTcF is >500 msec at any point 
inotuzumab ozogamicin should be omitted permanently and the patient should continue with R-
CVP only.  
 
Potassium/Sodium abnormalities 
If any potassium or sodium abnormalities are detected these should be corrected prior to 
administering inotuzumab ozogamicin, and if it is thought that any concomitant medication is 
contributing to QTc prolongation the use of such concomitant medication should be stopped if 
necessary. 
 
Constipation 
If grade 2 constipation occurs, reduce vincristine dose to 1mg (flat dose) per cycle. If greater 
than grade 2 omit vincristine. Investigator can reintroduce vincristine at 1mg if constipation 
resolves to grade 1 or better. 
 

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There will be no more than 1 dose level reduction of inotuzumab ozogamicin permitted. If a 
patient requires a 2nd dose level reduction, inotuzumab ozogamicin should be omitted 
permanently and continue with R-CVP only. 
8.5 
Management of Overdoses, Trial treatment error or 
Occupational Exposure 
Overdose 
 
Administration of a quantity of a trial treatment, either per administration or cumulatively, which 
is in excess of the protocol specified dose.  The dose can either be evaluated as overdose by 
the trial team at site or by the Sponsor upon review. 
 
Overdoses should be reported on an incident report (see section 13.0).  Any adverse events 
resulting from an overdose should be reported as an SAE (see section 12.2.2 for reporting 
procedures). 
 
Trial Treatment error 
 
Any unintentional error in prescribing, dispensing, or administration of a trial treatment while in 
the control of a healthcare professional or consumer.  The error can be identified either by the 
trial team at site or by the Sponsor upon review. 
 
Trial treatment errors should be reported on an incident report (see section 13.0).  Any adverse 
events resulting from a medication error should be reported as an SAE (see section 12.2.2 for 
reporting procedures). 
Occupational exposure 
 
Exposure to a trial treatment as a result of one’s professional or non-professional occupation.  
Occupational exposure should be reported on an incident report form (see section 13.0). 
8.6 
Supportive Care 
Supportive medications to prevent or treat nausea, vomiting, tumour lysis syndrome, and anti-
microbial prophylaxis to be given according to local policies. 
 
Ondansetron can be given to patients as a supportive medication but the dose must not exceed 
8mg bd.    
 
Primary G-CSF prophylaxis to be given to all patients in both treatment arms, as once daily 
sub-cutaneous injections on: 
 
 days 9-17 of each Gem-R-CVP cycle 
 days 4-12 of each IO-R-CVP cycle 
 
or, if using pegylated G-CSF, to be scheduled according to local policy.  
 
G-CSF should be stopped if Neutrophils are >1.0 x 10.9/l after neutrophil nadir. 
8.7 
Concomitant medication 
Patients may receive concomitant therapy deemed to provide adequate supportive care at the 
investigator’s discretion. All medications or other treatments taken by the patient during the trial 
(including those initiated prior to the start of the trial) must be recorded in the patient’s clinical 

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notes and appropriate CRFs. Yellow fever and other live attenuated vaccines (including H 
zoster) are not recommended due to the risk of systemic, possibly fatal, disease, particularly in 
immunosuppressed patients. Refer to the latest version of the SmPC for rituximab, 
cyclophosphamide, vincristine, prednisolone and gemcitabine when giving concomitant 
medications to avoid cross interactions with the metabolism of these drugs and toxicity. 
 
Other medications 
 
The following medications should be avoided for patients in the IO-R-CVP arm as they 
significantly prolong QTc. 
 
Amiodarone 
Arsenic trioxide  
Astemizole  
Bepridil                                         
Chloroquine  
Chlorpromazine  
Cisapride  
Clarithromycin  
Disopyramide  
Dofetilide  
Domperidone  
Droperidol  
Erythromycin  
Halofantrine 
Haloperidol 
Ibutilide  
Levomethadyl 
Mesoridazine  
Methadone  
Moxifloxacin  
Pentamidine  
Pimozide 
Probucol  
Procainamide 
Quinidine  
Sotalol  
Terfenadine  
Thioridazine  
Vandetanib  
Inotuzumab Ozogamicin 
It is unlikely that inotuzumab ozogamicin will inhibit the metabolic clearance of concomitant 
drugs that are substrates of CYP enzymes via reversible inhibition or mechanism-based 
inhibition. It is unlikely that inotuzumab ozogamicin will be involved in clinical induction-
mediated interactions with concomitant drugs that are substrates for cytochrome P450. 
8.8 
Pharmacy Responsibilities 
All pharmacy aspects of the trial at participating sites are the responsibility of the PI, who may 
delegate this responsibility to the local pharmacist or other appropriately qualified personnel, 
who will be the Pharmacy Lead.  The delegation of duties must be recorded on the site staff 
delegation log. 
Inotuzumab Ozogamicin supplied for the INCA trial is for INCA patients only and must not be 
used outside the context of this protocol. 
Pharmacists should refer to the Summary of Drug Arrangements for further details on suppliers, 
ordering, labelling, storage, preparation and handling and destruction. 
8.8.1 Temperature Excursions 
  
All temperature excursions outside the storage conditions specified in the IB for inotuzumab 
ozogamicin (and the SPC for Gemcitabine if stock is ring fenced for the trial)/Summary of Drug 
Arrangements must be reported to UCL CTC as per the ‘Pharmacy Procedure for Reporting 
Temperature Excursions’ (see Pharmacy Site File). 
 
Upon identifying an excursion: 
 
all affected trial stock must be quarantined IMMEDIATELY  

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 
the ‘Notification of Temperature Excursion’ form must be completed and e-mailed to 
ctc.excursions@ucl.ac.uk or faxed to +44 (0)20 7679 9871. 
 
 
Please note that UCL CTC must be informed immediately if a patient has been 
administered drug affected by a temperature excursion. 
 
8.8.2 IMP accountability 
 
The Pharmacy Lead must ensure that appropriate records are maintained. 
 
These records must include accountability for each drug including receipt (inotuzumab 
ozogamicin only), dispensing, returned medication and destruction of returned/unused 
medication. Accountability forms will be supplied and must be used unless there is prior 
agreement from UCL CTC to use in-house records. 
Copies of completed drug accountability logs must be submitted to UCL CTC for all trial 
patients upon request.  Also refer to section 14.2 (Central Monitoring). 
8.9  24 Hour/Out-of-Office Hours Emergency Drug-Specific Advice  
Inotuzumab 
Ozogamicin 
24 hours 
01304 616161 or 
Eumedinfo@pfizer.com 
All other IMPs 
and NIMPs used 
in this protocol 
Office hours 
09:00 to 17:00 Monday to 
Friday, excluding Bank 
Holidays 
(UK Time)
Contact UCL CTC on +44 (0) 20 7679 
9868 or ctc.inca@ucl.ac.uk  
 
8.10  Other Trial Treatments/Interventions 
Central Nervous System Prophylaxis: 
High risk of CNS involvement is defined as per BCSH Guidance on CNS prophylaxis in NHL 
and should be followed [31].  High risk is raised (>ULN) and more than 1 extranodal localisation 
or involvement of testicular, breast and paraspinal sites. 
 
They should receive treatment according to local practice. Systemic methotrexate for CNS 
prophylaxis should not normally be used in this cohort of patients.  All prophylactic intrathecal 
methotrexate injection must be given after the systemic immunochemotherapy and must be 
given in accordance with DOH regulations on Intrathecal chemotherapy. 
 
Radiotherapy: 
Radiotherapy to sites of residual disease or original sites of bulky disease may be given at local 
investigator’s discretion but should not be administered within 38 days of day 1 of the last cycle 
of immunochemotherapy in either treatment arm.  
8.11  Clinical Management after Treatment Discontinuation 
If the patient is withdrawn from treatment for any reason, they should receive appropriate 
management at the discretion of the treating clinician. Also refer to section 15 (Withdrawal of 
Patients) for further details regarding treatment discontinuation, patient withdrawal from trial 
treatment and withdrawal of consent to data collection. 

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9 ASSESSMENTS 
9.1 
Pre-randomisation Assessments  
Patients must give written informed consent before any trial specific screening investigations 
may be carried out.  The following assessments or procedures are required to evaluate the 
suitability of patients for the trial. These must be performed 14 days prior to randomisation 
except the CT scan, bone marrow biopsy, ECG and LVEF assessments which can be 
performed within 35 days prior to randomisation. The diagnostic biopsy (excision or core 
biopsy) can be performed at any time prior to randomisation. 
 
Any time prior to randomisation 
 
Diagnostic biopsy with histological confirmation of DLBCL according to the current WHO 
classification including all morphological variants with demonstration of CD20 positivity.  
 
Within 35 days prior to patient trial randomisation 
 
Contrast enhanced CT scan of the neck, thorax, abdomen and pelvis.  The CT scan of 
the neck should be done but for those cases where it has been omitted, it does not 
need to be repeated as long as a full clinical examination has been performed (ideally to 
also include an ultrasound/MRI) and this has been documented in the patients notes.  
Note: If it is not possible to use contrast (i.e. contrast is contraindicated in the patient or 
a CT was previously conducted outside of the 35 day window and a repeat CT with 
contrast is contraindicated) then a PET-CT should be performed with other imaging e.g. 
MRI as clinically indicated. The method of disease assessment used should be 
consistent through the duration of the trial. 
 
Bone marrow trephine biopsy   
 
Electrocardiogram (ECG) including QTcF interval (average of 3 ECGs)* 
 
Assessment of left ventricular ejection fraction (LVEF)* 
 
Virology screening to include: 
o Hepatitis B virus (HBV): hepatitis B surface antigen (HBsAg), hepatitis B core 
antibody (HBcAb)  
o Hepatitis C virus (HCV): antibody serology  
 
Human Immunodeficiency virus (HIV) screening suggested as standard of care, but not 
mandated 
 
Optional: PET-CT can also be used for staging (ideally the CT component should be 
contrast enhanced unless contraindicated as described above)  
*To be performed within 35 days unless any clinical suspicion of a change in cardiac status warranting 
repeated investigation. 
 
Within 14 days prior to patient trial randomisation 
 
Medical history including concomitant diseases and treatment 
 
Physical examination 
 
Vital sign monitoring 
 
Height and weight 
 
Full blood count (FBC) to include haemoglobin, white blood cell count, absolute 
neutrophil count and platelet count 
 
Serum biochemistry (sodium, potassium, urea, creatinine, bilirubin, liver transaminases 
(ALT or AST), prothrombin time, alkaline phosphatase, lactate dehydrogenase (LDH), 
albumin, total protein, and β2 microglobulin (β2MCG)) 
 
Glomerular filtration rate (GFR) calculated by Cockroft-Gault (not by eGFR)  
 
Cerebrospinal fluid (CSF) examination if clinically indicated or high risk of CNS 
involvement.  BCSH guidance on CNS prophylaxis in NHL should be followed.  High 
risk is raised serum LDH (>ULN) and more than 1 extranodal localization or involvement 
of testicular, breast and paraspinal sites.  CNS directed therapy may be added if in the 
opinion of the local PI there is a significant risk of CNS involvement. 

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 
If female and of childbearing potential, a negative serum pregnancy test (β-human 
chorionic gonadotropin (β-HCG) see section 6.3.3 (Pregnancy testing) for further details 
 
 
 
 
After patient has had some steroids but before randomisation (ideally should be done as 
close to randomisation as possible so that the best ECOG performance status is 
recorded) 
 
Documentation of baseline ECOG performance status 
 
Quality of life questionnaire: EORTC QLQ-C30 
 
Functionality assessments: ADL and IADL 
 
Co-morbidity score: Cumulative Illness Rating Scale (CIRS) 
 
Exploratory Biological Studies:  
 
Forward diagnostic tissue block to HMDS Leeds 
 
A single 7ml EDTA blood sample will be sent to HMDS, Leeds, for future germline DNA 
extraction as part of future ethically approved translational studies 
 
Optional 
 
4.9 ml blood serum sample sent to ‘The Paterson Institute For Cancer Research’ 
Manchester for FLT-3 analysis. See the latest version of the Laboratory Handbook for 
further details and section 9.2 (Assessments during treatment)  
9.2 
Assessments during Treatment  
During treatment, patients should be seen on day 1 and day 8 of every treatment cycle 
(regardless of treatment arm) and the following assessments/investigations performed:  
 
 
Physical examination 
 
Vital sign monitoring 
 
ECOG performance status 
 
Toxicity and adverse event assessment 
 
FBC to include haemoglobin, white blood cell count, absolute neutrophil count 
and platelet count – can be done up to 3 days before treatment 
 
Serum biochemistry (sodium, potassium, urea, creatinine, bilirubin, liver 
transaminases (ALT or AST), prothrombin time, alkaline phosphatase, lactate 
dehydrogenase (LDH), albumin and total protein) – can be done up to 3 days 
before treatment - must be done at day 1 and day 8 of each cycle 
 
LFT results to be known before starting each cycle of IO-R-CVP 
 
ECG with QTcF should be done before starting each cycle of IO-R-CVP 
(average of 3 ECGs) 
 
FLT-3 ligand analysis (optional translational research component (see section 10 (Exploratory 
Biological Studies)).  
 
Serum samples for this are required at the following time points: 
 
Baseline (between day 14 pre-randomisation and day 1 pre-treatment) 
 
Cycle 1 day 3 (+/- 1 day) 
 
Cycle 1 day 8 (+/- 1 day) 
 
Cycle 2 day 1 (- 1 day) 
 
Before the 4th cycle: 
In addition to the usual assessments required before starting a cycle, patients will also require 
the following performed before beginning cycle 4: 

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 
Repeat quality of life questionnaire: EORTC QLQ-C30  
 
Repeat functionality assessment: IADL and ADL 
 
Contrast enhanced CT scan of chest, abdomen and pelvis (and neck if involved 
at baseline). PET-CT can be also be used (ideally the CT component should be 
contrast enhanced). The same PET-CT scanner should be used that was used at 
baseline if possible.  
Note: If it is not possible to use contrast (i.e. contrast is contraindicated in the 
patient then a PET-CT should be performed with other imaging e.g. MRI as 
clinically indicated.  
9.3 
Assessments on Completion of Trial Treatment  
The following should be performed at end-of-treatment i.e. after 6 cycles of combined 
immunochemotherapy and 2 subsequent doses of intravenous rituximab or, if treatment 
stopped before this time, after last treatment received. 
 
 
Physical examination 
 
ECOG performance status 
 
Toxicity and adverse event assessment 
 
FBC to include haemoglobin, white blood cell count, absolute neutrophil count 
and platelet count 
 
Serum biochemistry (sodium, potassium, urea, creatinine, bilirubin, liver 
transaminases (ALT or AST), prothrombin time, alkaline phosphatase, lactate 
dehydrogenase (LDH), albumin and total protein) 
 
Repeat functionality assessment: IADL and ADL 
 
Repeat quality of life questionnaire: EORTC QLQ-C30  
 
Repeat assessment of left ventricular ejection fraction within 3 months of 
completing treatment 
 
Contrast enhanced CT scan of chest, abdomen and pelvis (and neck if involved 
at baseline). PET-CT can be also be used (ideally the CT component should be 
contrast enhanced). The same PET-CT scanner should be used that was used at 
baseline if possible.  
Note: If it is not possible to use contrast (i.e. contrast is contraindicated in the 
patient) then a PET-CT should be performed with other imaging e.g. MRI as 
clinically indicated  
The scan should be performed at end of treatment wherever possible even if 6 
cycles of treatment (+ 2 additional rituximab infusions) have not been completed   
 
Repeat bone marrow biopsy if bone marrow was initially involved and the CT 
shows CR or CRu.  If the end of treatment PET-CT scan is clear then a repeat 
bone marrow biopsy is optional. 
 
Assessment of disease response will be according to the revised International Working Group 
response criteria for non-Hodgkin’s lymphoma  – revised Cheson criteria [17], see Appendix 2 
for details. 
9.4 
Assessments During Follow-Up 
Follow-up 3 monthly during first year, 4 monthly in the second year, 6 monthly during 3rd year, 
and annually thereafter with the following assessments performed: 
 
 
Physical examination 
 
ECOG performance status 

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 
Contrast enhanced CT scan of chest, abdomen and pelvis (and neck if involved 
at baseline) at 3 months and 1 year after completion of treatment. PET-CT can 
be also be used (ideally the CT component should be contrast enhanced). The 
same PET-CT scanner should be used that was used at baseline if possible.  
Note: If it is not possible to use contrast (i.e. contrast is contraindicated in the 
patient) then a PET-CT should be performed with other imaging e.g. MRI as 
clinically indicated.  
 
Repeat functionality assessment: IADL and ADL at 6 & 24 months after end of 
treatment 
 
Repeat quality of life questionnaire: EORTC QLQ-C30 at 6 & 24 months after 
end of treatment 
 
All efforts should be made by the Site to contact the patient’s GP to assess their condition, if a 
patient fails to attend a clinic or cannot be followed up at site. Patients will be flagged through 
the Health and Social Care Information Centre or alternative registries (including in devolved 
nations) to ensure long term follow-up is achieved. 

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Table 1, Schedule of Assessments  
 
Pre-randomisation7
Day 1 & 8 
every 
cycle 
Before 4th 
cycle 
End of 
treatment 
Follow-
up12 
Medical History 
x 
 
 
 
 
Physical Examination 
x 
x 
x 
x 
x 
Vital sign monitoring 
x 
x 
x 
 
 
Height & weight 
x 
 
 
 
 
ECOG PS 
x 
x 
x 
x 
x 
CIRS co-morbidity score 
x 
 
 
 
 
QOL: EORTC QLQ-C30 
x 
 
x 
x 
x13 
Functional assessments: 
ADL & IADL 
x 
 
x 
x 
x13 
ECG including QTcF 
interval 
x8 
x14 
 
 
 
Measurement of LVEF  
x8 
 
 
x 
 
CT scan/PET-CT 
x8 
 
x10 
x10 
x10 
Bone marrow trephine 
biopsy 
x8 
 
 
x11 
 
Serum biochemistry1 
x 
x 
x 
x 
 
β2 microglobulin 
(β2MCG) 
x 
 
 
 
 
FBC2 
x 
x 
x 
x 
 
Virology screening3 
x8 
 
 
 
 
β –HCG for pregnancy4 
x 
 
 
 
 
CSF5 
x 
 
 
 
 
Glomerular filtration rate 
(GFR) 
x 
 
 
 
 
Toxicity  
assessment 
 
x 
x 
x 
x 
Adverse events 
 
x 
 
x 
 
Exploratory Biological Studies 
Diagnostic tissue block & 
7ml EDTA blood sample6  
x 
 
 
 
 
FLT-3 ligand analysis 
(optional) 
x 
x9  
 
 
 
 
1 Serum biochemistry (sodium, potassium, urea, creatinine, bilirubin, liver transaminases (ALT or AST), prothrombin 
time, alkaline phosphatase, lactate dehydrogenase (LDH), albumin and total protein).  If any potassium or sodium 
abnormalities are detected these should be corrected before administering inotuzumab ozogamicin.  Can be done up 
to 3 days before treatment. Must be done on day 1 and day 8 during treatment in both arms 
2 Full blood count to include haemoglobin, white blood cell count, absolute neutrophil count and platelet count.  Can 
be done up to 3 days before treatment 
3 Virology screening to include HbsAg, HbcAb and HCV antibody serology. HIV screening suggested as standard of 
care, but not mandated. 
4If female and of childbearing potential. 
5 CSF = Cerebrospinal fluid examination. Only if clinically indicated or lymphomatous involvement of bone marrow, 
orbit, nasal/paranasal sinuses, paraspinal region, testis, peripheral blood and bone. 
6 Samples sent to HMDS, Leeds. 
7  All to be performed within 14 days to date of trial randomisation with the exception of CT scan and bone marrow 
biopsy. 

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8 Contrast enhanced CT of the neck, thorax, abdomen and pelvis, bone marrow trephine biopsy and serology to be 
performed within 35 days to date of trial randomisation. PET-CT can also be used (ideally the CT component should 
be contrast enhanced).  If it is not possible to use contrast (i.e. contrast is contraindicated in the patient) then a PET-
CT should be performed with other imaging e.g. MRI as clinically indicated.   ECG (average of 3 ECGs) and 
assessment of LVEF to be performed within 35 days unless any clinical suspicion of a change in cardiac status 
warranting repeated investigation. 
9 Serum samples taken at cycle 1 day 3, cycle 1 day 8 and cycle 2 day 1 if patient is participating in this sub-study 
and provided written informed consent. 
10 Contrast enhanced CT scan of thorax, abdomen and pelvis (neck if involved at baseline) should be carried out at 
the end of treatment, at 3 months and at 1 year after finishing treatment. PET-CT can also be used (ideally the CT 
component should be contrast enhanced).  The same PET-CT scanner should be used that was used at baseline if 
possible.  Note: If it is not possible to use contrast (i.e. contrast is contraindicated in the patient) then a PET-CT 
should be performed with other imaging e.g. MRI as clinically indicated.   
11 Bone marrow biopsy to be repeated at the end of treatment if marrow was involved at baseline and the CT shows 
CR or CRu for accurate response assessment. 
12 Follow-up: 3 monthly clinic visit during the first year, 4-monthly during the second year, 6-monthly for the third year 
and annually thereafter.  
13 IADL, ADL and EORTC QLQ C-30 at 6 & 24 months after end of treatment. 
14 ECG with QTcF should be done before every cycle of IO-R-CVP (average of 3 ECGs). 

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10 EXPLORATORY BIOLOGICAL STUDIES 
A number of exploratory endpoints will be investigated in this trial exploring the use of 
biomarkers in clinical outcomes  
 
Gene expression profiling of fresh frozen material has provided new insights into the biology of 
DLBCL. In patients treated with CHOP or CHOP like chemotherapy, unsupervised hierarchical 
clustering identified two distinct subgroups of the disease; one with a phenotype similar to 
germinal centre derived B-cells (GCB like) and one with a phenotype similar to activated 
peripheral B-cells (ABC like) [18]. These molecular subgroups had distinct clinical outcomes. 
The initial observations were extended to a larger series of tumours by the Leukaemia and 
Lymphoma Molecular Profiling Project  [19] and the molecular model subsequently refined to a 
discriminator based upon the expression of just 27 genes (Rimsza, Wright et al. 2009). With the 
advent of R-CHOP chemotherapy, this molecular classification was found to be robust, and the 
inferior prognosis of the ABC-like lymphomas remained inferior with 3 year progression free 
survival of the ABC group 40% compared to 75% in the GCB group [20]. The frequency of 
molecularly defined subgroups in elderly DLBCL is unknown and the prognostic value of 
molecular class uncertain. Using RNA extracted from formalin fixed paraffin embedded tumour 
blocks, the Illumina DASL system will be used to provide whole transcriptome information from 
the patients tumour material for ABC/GCB classification and for exploration of additional 
candidate biomarkers associated with response to regimens under investigation. This system in 
being successfully employed for patient stratification in the NCRN REMoDL-B for younger 
patients with DLBCL with the procedure being performed at the Haematological Malignancies 
Diagnostic Service in Leeds. 
 
Several oncogenic mechanisms distinguish the two DLBCL sub-groups [21], in particular the 
observation that constitutive activation of the nuclear factor-кB (NF-кB) signalling pathway 
appears central to cell survival in ABC-like lymphomas [22]. These tumours rely upon the 
CARD11/MALT1/BCL10 signalling complex to activate the central kinase in the NF-кB pathway, 
IкB kinase [23, 24]. More than half of ABC-DLBCL carry somatic mutations in multiple genes, 
including negative (A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7 and TNFRSF11A) 
regulators of NF-kB [25].  Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme 
involved in termination of NF-kB responses, is most commonly affected, with one third of 
patients 
displaying 
biallelic 
inactivation 
by 
mutations 
and/or 
deletions. 
Functional 
characterisation of GCB-like DLBCL cell lines has suggested that the NF-кB pathway may also 
be activated in a small subset of this group [26].  The induction of the NF-кB pathway appears 
to suppress the apoptotic effect of cytotoxic chemotherapy [27] and this may contribute to the 
observed differences in outcome between the biological subtypes of DLBCL. DNA extracted 
from FFPE blocks will be used for analysis of somatic mutations of 70 genes that are 
recurrently mutated in aggressive B-cell lymphoma.  The mutation analysis will be carried out 
by HaloPlexHS target enrichment and Illumina HiSeq4000 sequencing, together with an in-
house validated variant calling algorithm as described in our recent study (Cucco et al, Lab 
Invest. 2018;98(8): 1084-1092). Mutations identified in this elderly population will be fully 
annotated and  their clinical relevance carefully considered (Ming Du, University of Cambridge). 
 
FLT3 ligand is a cytokine involved in maintaining the stem cell compartment and levels rise in 
response to bone marrow stress. Circulating levels are easily measurable and inversely 
proportional to the levels of colony forming cells. In a small population of diffuse large B-cell 
lymphoma patients receiving standard chemotherapy, without primary GCSF prophylaxis, 
changes in FLT3 ligand at day 3 were found to be more sensitive than neutrophil counts in 
predicting febrile neutropenia (FN) at any time during chemotherapy – sensitivity 83%, 
specificity 53% [28]. In this trial, the population will consist of a majority of elderly patients with 
multiple comorbidities. It is expected that grade ¾ neutropenia rates will exceed 20% despite 
mandated primary GCSF prophylaxis and that this will result in a high risk of FN. Toxicity is an 

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important secondary endpoint of this study. This exploratory analysis, measuring ELISA 
quantified FLT3 ligand at baseline (within 14 days of trial entry), cycle 1 day 3 & day 8 (+/- 1 
day) and cycle 2 day 1, will determine if changes are predictive of neutropenia/sepsis events in 
this ‘real world’ scenario and of potential value in guiding individualised treatment modification 
in the future. An elevated signal at day 2/8 may inform the need for additional measures 
beyond GCSF alone to reduce sepsis risk (e.g. antibiotics, early review, dose reduction from 
cycle 2 etc.). Serum will be collected at the above time points and analysed in a GCLP 
accredited laboratory (Professor Caroline Dive, Paterson Institute for Cancer Research, The 
University of Manchester). See laboratory handbook. This component of the translational 
research will be optional depending on sites’ facilities for serum sample collection and storage 
and specific patient consent. 
 
Epstein-Barr virus-positive (EBV-positive) diffuse large B-cell lymphoma (DLBCL) of the elderly 
is a newly described lymphoproliferative disorder recently included as a “provisional” entity in 
the most current WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 
The frequency and potential predictive and prognostic value of EBV tumoral status in patients 
with DLBCL is poorly understood. Immunohistochemistry from diagnostic material will be 
performed for a number of lymphoma markers along with EBV-LMP1 and in situ hybridisation 
for EBER (performed at HMDS).  
 
Patient material will be centrally collated to allow for further immunohistochemical analysis. 
Section from the formalin fixed paraffin embedded tumour blocks will be taken for RNA and 
DNA extraction for transciptome and genomic analysis respectively. Material will be stored in 
an HTA accredited tumour bank. A translational research committee will be formed and 
applications welcomed for additional studies.  
 
A single 7ml EDTA blood sample will be sent to HMDS, Leeds, for future germline DNA 
extraction as part of future ethically approved translational studies. 
 
Please refer to the INCA Laboratory Manual for detailed information for processing and 
shipping the samples. 

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11 DATA MANAGEMENT AND DATA HANDLING GUIDELINES 
Data will be collected from sites on version controlled case report forms (CRFs) designed for 
the trial and supplied by UCL CTC.  Data must be accurately transcribed onto trial CRFs and 
must be verifiable from source data at site.  Examples of source documents are hospital 
records which include patient’s notes, laboratory and other clinical reports etc. 
Where copies of supporting source documentation (e.g. autopsy reports, pathology reports, CT 
scan images etc.) are being submitted to UCL CTC, the patient’s trial number must be clearly 
indicated on all material and any patient identifiers removed/blacked out prior to sending to 
maintain confidentiality. 
Please note that, for this trial, patients must consent to their initials, date of birth, gender and 
NHS number being supplied to UCL CTC.  This information will be used to collect long-term 
follow-up of patients through the Health and Social Care Information Centre (NHS IC) Medical 
Research Information Service (MRIS) and to assist with follow-up via GPs. 
11.1 Completing Case Report Forms  
All CRFs must be completed and signed by staff who are listed on the site staff delegation log 
and authorised by the PI to perform this duty.  The PI is responsible for the accuracy of all data 
reported in the CRF. 
All entries must be clear, legible and written in ball point pen. Any corrections made to a CRF at 
site must be made by drawing a single line through the incorrect item ensuring that the previous 
entry is not obscured.  Each correction must be dated and initialled.  Correction fluid must not 
be used.   
The use of abbreviations and acronyms should be avoided.  
Once completed the original CRFs must be sent to UCL CTC and a copy kept at site.   
Pfizer Limited will be notified of any disease related deaths occurring in any patients that have 
been exposed to Inotuzumab Ozogamicin from treatment to 30 days post treatment. 
11.2 Missing Data 
To avoid the need for unnecessary data queries CRFs must be checked at site to ensure there 
are no blank fields before sending to UCL CTC (unless it is specifically stated that a field may 
be left blank).  When data are unavailable because a measure has not been taken or test not 
performed, enter “ND” for not done.  If an item was not required at the particular time the form 
relates to, enter “NA” for not applicable.  When data are unknown enter the value “NK” (only 
use if every effort has been made to obtain the data). 
11.3 Timelines for Data Return 
CRFs must be completed at site and returned to UCL CTC as soon as possible after the 
relevant visit and within 1 month of the patient being seen. Sites who persistently do not return 
data within the required timelines may be suspended from recruiting further patients into the 
trial by UCL CTC and subjected to a ‘for cause’ monitoring visit. See section 14.3 (’For cause’ 
on-site monitoring) for details. 

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11.4 Data Queries 
Data arriving at UCL CTC will be checked for legibility, completeness, accuracy and 
consistency, including checks for missing or unusual values.  Data clarification requests will be 
sent to the data contact at site.  Further guidance on how data contacts should respond to data 
queries can be found on the Data Clarification Request forms. 
12  PHARMACOVIGILANCE  
12.1  Definitions 
The following definitions have been adapted from Directive 2001/20/EC, ICH E2A “Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting” and ICH GCP 
E6: 
 
Adverse Event (AE) 
Any untoward medical occurrence or effect in a patient treated on a trial protocol, which does 
not necessarily have a causal relationship with an IMP.  An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom or 
disease temporally associated with the use of an IMP, whether or not related to that IMP.  See 
section 12.2.1 for AE reporting procedures. 
 
Adverse Reaction (AR) 
 
All untoward and unintended responses to an IMP related to any dose administered. A causal 
relationship between an IMP and an adverse event is at least a reasonable possibility, i.e. the 
relationship cannot be ruled out. 
 
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) 
 
An adverse event or adverse reaction that at any dose:  
• 
Results in death 
• 
Is life threatening (the term “life-threatening” refers to an event in which the patient 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 in-patient hospitalisation or prolongs existing hospitalisation 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Any other medical event that, in the medical judgment of the Principal Investigator, may 
jeopardise the subject or may require medical or surgical intervention to prevent one of 
the outcomes listed above is also considered an SAE   
 
See section 12.2.2 for SAE reporting procedures. 
 
 
 

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Suspected Unexpected Serious Adverse Reaction (SUSAR)  
A serious adverse reaction, the nature or severity of which is not consistent with the applicable 
reference safety information. 
i.e. an adverse event that meets all the following criteria: 
 
Serious – meets one or more of serious criteria, listed under the definition of SAE above 
 
Related – assessed by the local PI or designee, or Sponsor as causally related to one 
or more elements of the trial treatment 
 
Unexpected – the event is not consistent with the applicable reference safety 
information 
See section 12.3 for reporting procedures for these events. 
Overdose, Trial treatment error or Occupational exposure 
 
Refer to section 8.5 for details on reporting of these events 
 
12.2  Reporting Procedures 
 
Adverse Event Term 
 
An adverse event term must be provided for each adverse event. Wherever possible a valid 
term listed in the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 should be 
used.  This is available online at: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html  
 
Severity grade 
 
Severity grade of each adverse event must be determined by CTCAE v4.03 (use version listed 
above). 
 
Causality 
 
The relationship between the treatment and an adverse event will be assessed. 
For AEs, (including SAEs) the local PI or designee will assess whether the event is causally 
related to each IMP. 
For SAEs, a review will also be carried out by the Sponsor’s delegate. 
Causal relationship to each IMP must be determined as follows: 
• 
None 
There is no evidence of any causal relationship. 
• 
Unlikely 
There is little evidence to suggest a causal relationship (e.g. because the event did not 
occur within a reasonable time after administration of an IMP).  There is another 
reasonable explanation of the event (e.g. the patient’s clinical condition, other 
concomitant treatments). 
• 
Possibly 

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There is some evidence to suggest a causal relationship (e.g. because the event occurs 
within a reasonable time after administration of an IMP).  However, the influence of 
other factors may have contributed to the event (e.g. the patient’s clinical condition, 
other concomitant treatments). 
• 
Probably 
There is evidence to suggest a causal relationship and the influence of other factors is 
unlikely. 
• 
Definitely 
There is clear evidence to suggest a causal relationship and other possible contributing 
factors can be ruled out. 
 
UCL CTC will consider events evaluated as possible, probably and definitely related to 
be adverse reactions. 
12.2.1 Reporting of Adverse Events (AEs) 
All adverse events that occur between informed consent and 30 calendar days post last IMP 
administration must be recorded in the patient notes and the trial CRFs. Those meeting the 
definition of a Serious Adverse Event (SAE) must also be reported to UCL CTC using the trial 
specific SAE Report.  Also see section 12.2.2 (Reporting of Serious Adverse Events (SAEs)). 
Pre-existing conditions (i.e. conditions present at informed consent) do not qualify as adverse 
events unless they worsen or recur (i.e. improves/resolves and then worsens/reappears again).  
E.g. an AE could be an exacerbation of a chronic or intermittent pre-existing condition including 
either an increase in frequency and/or intensity of the condition (worsening or the event).  
Another example of an AE is when a pre-existing condition improves during the trial (e.g. from 
grade 3 to grade 1) and then it worsens again (e.g. from grade 1 to grade 2), even if the event 
is of severity equal or lower to the original condition (improvement and recurrence of the event). 
NB the disease under study and it anticipated day-to-day fluctuations would not be an AE. 
12.2.2 Reporting of Serious Adverse Events (SAEs) 
All SAEs that occur between the signing of informed consent and 30 calendar days post last 
IMP administration (or after this date if the site investigator feels the event is related to an 
IMP) must be submitted to UCL CTC by fax or email within 24 hours of observing or learning of 
the event, using the trial specific SAE Report.  All sections on the SAE Report must be 
completed.  If the event is not being reported to UCL CTC within 24 hours, the 
circumstances that led to this must be detailed in the SAE Report to avoid unnecessary 
queries. 
Exemptions from SAE Report submission 
For this trial, the following events are exempt from requiring submission on an SAE Report, but 
must be recorded in the relevant section(s) of the trial CRFs: 
 
events that occur more than 30 calendar days post last IMP administration that 
are not considered unless: 
 
considered to be a late effect of the trial treatment 
 
it is a pregnancy related event (see section 12.5) 
 
Disease-related events (this does not apply to disease-related deaths on the IO-
R-CVP treatment arm which are reportable according to SAE reporting 
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Please note that hospitalisation for elective treatment, palliative care or prolongation of 
hospitalisation due to social/logistical reasons do not qualify as an SAE. 
 
 
Completed SAE Reports must be faxed or emailed within 24 hours of 
becoming aware of the event to UCL CTC 
Fax: +44 (0)20 7679 9861 
Email: ctc.inca@ucl.ac.uk 
 

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SAE Follow-Up Reports 
UCL CTC will follow up all SAEs/SARs  until resolution and until there are no further queries.  
Sites must ensure any new and relevant information is provided to UCL CTC promptly.  If an 
event term changes or a new event is added, the causality must be re-assessed by an 
investigator.  If the event is not being reported  to UCL CTC within 24 hours, the circumstances 
that led to the delay must be detailed in the SAE/SAR Report to avoid unnecessary queries. 

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SAE and AE Reporting Flowchart 
 
 

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SAE Processing at UCL CTC 
On receipt of the SAE Report, UCL CTC will check for legibility, completeness, accuracy and 
consistency.  Expectedness will be evaluated, to determine whether or not the case qualifies for 
expedited reporting, using the RSI (the current IB for inotuzumab ozogamicin and SPC for 
gemcitabine). 
The CI, or their delegate (e.g. a clinical member of the TMG), will review the SAE and perform 
an evaluation of causality on behalf of UCL CTC.  If UCL CTC has considered expectedness 
difficult to determine, the reviewer, will be consulted for their opinion at this time.   
UCL CTC will submit all SAE Reports concerning patients who have received Inotuzumab 
Ozogamicin to Pfizer Limited according to the timelines outlined in the agreement between UCL 
and Pfizer Limited.  
12.3  SUSARs 
If the event is evaluated as a Suspected Unexpected Serious Adverse Reaction (SUSAR), UCL 
CTC will submit a report to the MHRA and REC within the required timelines.   
Wherever possible evaluations of causal relationship by both the site and the Sponsor’s clinical 
reviewer will be reported. 
Informing Sites of SUSARs 
UCL CTC will inform all PIs of any SUSARs that occur on the trial.  PIs will receive a quarterly 
line listing which must be processed according to local requirements.   
UCL CTC will forward reports received from Pfizer Limited regarding SUSARs that have 
occurred on other trials using Inotuzumab Ozogamicin to all PI’s. These must be processed 
according to local requirements and filed with the applicable IB. 
12.4  Safety Monitoring 
UCL CTC will provide safety information to the Trial Management Group (TMG) and the 
Independent Data Monitoring Committee (IDMC) on a periodic basis for review.   
Trial safety data will be monitored to identify: 
 
Whether disease-related events (exempt from SAE reporting as per section 12.2.2) 
appear to be enhanced by the IMP 
 
new adverse reactions to the combination therapy or individual IMP; 
 
a higher incidence in rare adverse events than is stated in the IB/SPC for an IMP;  
 
trial related events that are not considered related to the IMP but may lead to changes 
to the trial documents.  These would include events related to NIMPs 
If UCL CTC identifies or suspects any issues concerning patient safety at any point during the 
trial, the CI or TMG will be consulted for their opinion and if necessary the issue will be referred 
to the IDMC.   

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12.5  Pregnancy 
If a female trial patient or the female partner of a male trial patient becomes pregnant at any 
point during the trial, the site must submit a trial specific Pregnancy Report to UCL CTC by fax 
or email within 24 hours of learning of its occurrence.   
The site must request consent from a pregnant trial patient or female partner of a male patient 
to report information regarding a pregnancy using: 
 
For female patients: the trial specific Pregnancy Monitoring Information Sheet and 
Informed Consent Form for trial patients. 
 
For female partners of male patients: the trial specific Pregnancy Monitoring Information 
Sheet and Informed Consent Form for partners of study patients 
If consent is not given, the notification that a pregnancy has occurred will be retained by UCL 
CTC however no further action will be taken on the information detailed in the report. 
 
All pregnancies must be reported by faxing or emailing a completed 
Pregnancy Report within 24 hours of becoming aware of the pregnancy to 
UCL CTC 
Fax: +44 (0)20 7679 9861 
Email: ctc.inca@ucl.ac.uk 
Pregnancy Follow-Up Reports 
For pregnant patients or partners who consent, their pregnancies must be followed-up until an 
outcome is determined.  Follow-up Pregnancy Reports must be submitted to UCL CTC by fax 
or email within 24 hours of learning of the outcome.  Reports must include an evaluation of the 
possible relationship of each trial treatment to the pregnancy outcome.   
SAEs during pregnancy 
Any SAE occurring in a pregnant patient must be reported using the trial specific SAE Report, 
according to SAE reporting procedures.  Refer to section 12.2.2 (Reporting of Serious Adverse 
Events (SAEs)) for details. 
Pregnancy Report processing at UCL CTC 
UCL CTC will submit a report to the MHRA and the REC if the pregnancy outcome meets the 
definition of a SUSAR.  Refer to section 12.3 (SUSARs) for details. 
UCL CTC will submit all Pregnancy Reports concerning exposure to Inotuzumab Ozogamicin to 
Pfizer Limited according to the timelines outlined in the agreement between UCL and Pfizer 
Limited. 
12.6  Development Safety Update Reports (DSURs)  
Safety data obtained from the trial will be included in DSURs that UCL CTC will submit to the 
MHRA and the REC.   
UCL CTC will provide Pfizer Limited with DSURs that include information regarding Inotuzumab 
Ozogamicin. 

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13  INCIDENT REPORTING AND SERIOUS BREACHES  
13.1  Incident Reporting 
Organisations must notify UCL CTC of all deviations from the protocol or GCP immediately.  An 
incident report may be requested and will be provided, but an equivalent document (e.g. Trust 
Incident form) is acceptable where already completed. 
If site staff are unsure whether a certain occurrence constitutes a deviation from the protocol or 
GCP, the UCL CTC trial team can be contacted immediately to discuss. 
UCL CTC will use an organisation’s history of non-compliance to make decisions on future 
collaborations. 
UCL CTC will assess all incidents to see if they meet the definition of a serious breach.  
13.2   Serious Breaches  
A “serious breach” is defined as a breach of the protocol or of the conditions or principles of 
Good Clinical Practice (or equivalent standards for conduct of non-CTIMPs) which is likely to 
affect to a significant degree the safety or physical or mental integrity of the trial subjects, or the 
scientific value of the research. 
Systematic or persistent non-compliance by a site with GCP and/or the protocol, including 
failure to report SAEs occurring on trial within the specified timeframe, may be deemed a 
serious breach. 
In cases where a serious breach has been identified, UCL CTC will inform the MHRA and REC 
within 7 calendar days of becoming aware of the breach. 
UK sites must have written procedures for notifying the Sponsor of serious breaches (MHRA 
Guidance on the Notification of Serious Breaches). 
14  TRIAL MONITORING AND OVERSIGHT 
UK participating sites and PIs must agree to allow trial-related on-site monitoring, Sponsor 
audits and regulatory inspections by providing direct access to source data/documents as 
required.  Patients are informed of this in the patient information sheet and are asked to 
consent to their medical notes being reviewed by appropriate individuals on the consent form. 
UCL CTC will determine the appropriate level and nature of monitoring required for the trial.  
Risk will be assessed on an ongoing basis and adjustments made accordingly. 
14.1  On-Site Monitoring  
The degree of on-site monitoring will be proportionate to the objective, purpose, phase, design, 
size, complexity, endpoints and risks associated with the trial. 

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Details of monitoring activities will be included in the trial monitoring plan. The monitoring plan 
will be under review throughout the trial and updates provided as necessary. 
Sites will be sent a letter in advance confirming when a routine monitoring visit is scheduled to 
take place.  The letter will include a list of the documents to be reviewed, interviews that will be 
conducted, planned inspections of the facilities and who will be performing the visit. 
Monitoring Follow Up 
Following a monitoring visit, the Trial Monitor/Trial Coordinator will provide a follow up email to 
the site, which will summarise the documents reviewed and a statement of findings, incidents, 
deficiencies, conclusions, actions taken and/or actions required. The PI at each site will be 
responsible for ensuring that monitoring findings are addressed in a timely manner, and by the 
deadline specified. 
14.2  Central Monitoring 
Sites will be requested to submit screening logs and staff delegation logs to UCL CTC at the 
frequency detailed in the trial monitoring plan or on request and these will be checked for 
consistency and completeness.  Also refer to sections 4.2.2 (Required documentation) and 6.1 
(Screening log). 
Ensuring patient eligibility is the responsibility of the PI or other delegated Investigator(s). 
Checks of the criteria listed on the randomisation form will be undertaken by an appropriately 
trained UCL CTC staff member prior to randomisation. Also refer to section 7.1 
(Randomisation). 
Details relating to the informed consent process will be collected on the randomisation form and 
are subject to review by CTC as part of patient eligibility.  
Sites will be required to submit accountability logs in accordance with the trial monitoring plan. 
Data received at UCL CTC will be subject to review in accordance with section 11.4 (Data 
Queries).  
Sites will be requested to conduct quality control checks of documentation held within the 
Investigator Site File and Pharmacy Site File at the frequency detailed in the trial monitoring 
plan. Checklists detailing the current version/date of version controlled documents will be 
provided for this purpose. 
Patients will be flagged with the Health and Social Care Information Centre to enable long-term 
follow-up of these patients. 
Where central monitoring of data and/or documentation submitted by sites indicates that a 
patient may have been placed at risk (e.g. evidence of an overdose having been administered, 
indication that stopping rules for an IMP were not observed following an adverse reaction, etc.), 
the matter will be raised urgently with site staff and escalated as appropriate (refer to section 13 
(Incident Reporting and Serious Breaches) and 14.3 (‘For cause’ on-site monitoring) for further 
details). 
14.3  ’For Cause’ On-Site Monitoring 
Additional on-site monitoring visits may be scheduled where there is evidence or suspicion of 
non-compliance at a site with important aspect(s) of the trial protocol/GCP requirements.  Sites 
will be sent a letter in advance outlining the reason(s) for the visit and confirming when it will 

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take place.  The letter will include a list of the documents that are to be reviewed, interviews 
that will be conducted, planned inspections of the facilities and who will be performing the visit. 
UCL CTC will assess whether it is appropriate for the site to continue participation in the trial 
and whether the incident(s) constitute a serious breach. Refer to section 13 (Incident Reporting 
and Serious Breaches) for details. 
14.4  Oversight Committees 
14.4.1 Trial Management Group (TMG) 
The TMG will include the Chief Investigator, clinicians and experts from relevant specialties and 
INCA trial staff from UCL CTC (see page 1).  The TMG will be responsible for overseeing the 
trial.  The group will meet regularly approximately twice a year or as necessary and will send 
updates to PIs (via newsletters or at Investigator meetings) and to the NCRI Haematological 
Oncology Clinical Studies Group.  
The TMG will review substantial amendments to the protocol prior to submission to the REC 
and MHRA. All PIs will be kept informed of substantial amendments through their nominated 
responsible individual and are responsible for their prompt implementation. 
Members of the TMG will be required to sign a TMG charter outlining their duties and 
responsibilities.  
14.4.2 Trial Steering Committee (TSC) 
The role of the TSC is to provide overall supervision of the trial.  The TSC will review the 
recommendations of the Independent Data Monitoring Committee and, on consideration of this 
information, recommend any appropriate amendments/actions for the trial as necessary.  The 
TSC acts on behalf of the funders and Sponsor. 
Members of the TSC will be required to sign a TSC charter outlining their duties and 
responsibilities.  
14.4.3 Independent Data Monitoring Committee (IDMC) 
The role of the IDMC is to provide independent advice on data and safety aspects of the trial.  
Meetings of the Committee will be held annually to review interim analyses or as necessary to 
address any issues.  The IDMC is advisory to the TSC and can recommend premature closure 
of the trial to the TSC. 
Members of the IDMC will be required to sign an IDMC charter outlining their duties and 
responsibilities.  
14.4.4 Role of UCL CTC 
UCL CTC will be responsible for the day to day coordination and management of the trial and 
will act as custodian of the data generated in the trial (on behalf of UCL).  UCL CTC is 
responsible for all duties relating to pharmacovigilance which are conducted in accordance with 
section 12.0 (Pharmacovigilance).  

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15  WITHDRAWAL OF PATIENTS 
In consenting to the trial, patients are consenting to trial treatment, assessments, collection of 
biological samples, follow-up and data collection.  
15.1 Discontinuation of Trial Treatment  
A patient may be withdrawn from trial treatment whenever such treatment is no longer in the 
patient’s best interests, but the reasons for doing so must be recorded in the patient’s notes 
and on the relevant Case Report Form(s).  Reasons for discontinuing treatment may include: 
• 
Disease progression whilst on therapy 
• 
Unacceptable toxicity 
• 
Intercurrent illness which prevents further treatment 
• 
Patient decision not to continue with trial treatment 
• 
Any alterations in the patient’s condition which justifies the discontinuation of treatment 
in the site investigator’s opinion 
• 
Non-compliance with the trial treatment and/or procedures 
• 
If a female patient becomes pregnant or male/female fails to use adequate birth control 
(for patients of childbearing potential) 
 
In these cases patients will remain within the trial for the purposes of follow-up and data 
analysis according to the treatment option to which they have been allocated unless they 
explicitly withdraw consent.  
If a patient expresses their wish to withdraw from trial treatment, sites should explain the 
importance of remaining on trial follow-up, or failing this of allowing routine follow-up data to be 
used for trial purposes and for allowing existing collected data to be used.  If the patient gives a 
reason for their withdrawal, this should be recorded. 
15.2 Future Data Collection   
If a patient explicitly states they do not wish to contribute further data to the trial their decision 
must be respected, with the exception of essential safety data, and recorded on the relevant 
CRF. In this event data due up to the date of withdrawal must be submitted but no further data, 
other than essential safety data sent to UCL CTC. The patient will also be removed from 
flagging with the Health and Social Care Information Centre. 
15.3 Losses to Follow-Up 
If a patient moves from the area, every effort should be made for the patient to be followed up 
at another participating trial site and for this new site to take over the responsibility for the 
patient, or for follow-up via GP.  Details of participating trial sites can be obtained from the UCL 
CTC trial team who must be informed of the transfer of care and follow up arrangements.  If it is 
not possible to transfer to a participating site, the registering site remains responsible for 
submission of forms. 
If a patient is lost to follow-up at a site every effort should be made to contact the patient’s GP 
to obtain information on the patient’s status.  
Patients lost to follow up will be tracked by UCL CTC via the Health and Social Care 
Information Centre.  

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16  TRIAL CLOSURE 
16.1  End of Trial 
For regulatory purposes the end of the trial will occur when all patients have completed at least 
two years of follow-up post-treatment. At this point the ‘declaration of end of trial’ form will be 
submitted to the MHRA and Ethics Committee, as required. 
Following this, UCL CTC will advise sites on the procedure for closing the trial at the site. 
Once the end of trial has been declared, no more prospective patient data will be collected but 
sites must co-operate with any data queries regarding existing data to allow for analysis and 
publication of results. 
16.2  Archiving of Trial Documentation 
At the end of the trial, UCL CTC will archive securely all centrally held trial related 
documentation for a minimum of 5 years.  Arrangements for confidential destruction will then be 
made.  It is the responsibility of PIs to ensure data and all essential documents relating to the 
trial held at site are retained securely for a minimum of 5 years after the end of the trial, and in 
accordance with national legislation.. 
Essential documents are those which enable both the conduct of the trial and the quality of the 
data produced to be evaluated and show whether the site complied with the principles of GCP 
and all applicable regulatory requirements.   
UCL CTC will notify sites when trial documentation held at sites may be archived.  All archived 
documents must continue to be available for inspection by appropriate authorities upon 
request. 
16.3  Early Discontinuation of Trial 
The trial may be stopped before completion as an Urgent Safety Measure on the 
recommendation of the TSC or IDMC (see section 14.4.2 Trial Steering Committee (TSC) and 
14.4.3 Independent Data Monitoring Committee (IDMC)).  Sites will be informed in writing by 
UCL CTC of reasons for early closure and the actions to be taken with regards the treatment 
and follow up of patients.  
16.4  Withdrawal from Trial Participation by a Site 
Should a site choose to close to recruitment the PI must inform UCL CTC in writing.  Follow up 
as per protocol must continue for any patients recruited into the trial at that site and other 
responsibilities continue as per the CTSA. 

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17  STATISTICS 
17.1  Sample Size Calculation 
The study is designed as a randomised phase II trial and aims to show an increase in the 2 
year progression free survival (PFS) rate of 15% in the IO-R-CVP arm.  
 
A total of 61 PFS events (progressions or deaths) are required to detect a hazard ratio of 0.62, 
which equates to a 15% improvement in 2-year PFS of IO-R-CVP compared with Gem-R-CVP 
(50% to 65%) with a 15% one sided alpha level and 80% power.  
 
132 patients (66 in each arm) will be recruited over a period of 4 years and it is anticipated that 
we will see the 61 events required 1 year after the last patient has been randomised.. 
 
The sample size was calculated using NQuery.  
 
Patients will be replaced if they are withdrawn from the study prior to receiving any IMP or if 
found to be ineligible due to a misdiagnosis. 
17.2  Population for Analysis 
All patients will be included in the primary analysis, progression free survival. In the analysis of 
response we will consider all patients who received at least one cycle of treatment as well the 
group who completed at least 3 cycles. 
17.3  Analysis of the Primary Endpoint 
The primary endpoint is progression free survival rate and will be analysed using Kaplan-Meier 
survival analysis and Cox regression (or restricted mean survival time (RMST) if the 
assumption of proportionality is violated). PFS time will be measured from date of 
randomisation until progression or death. Patients who are alive without progression will be 
censored at the date last seen. 
 
A subgroup analysis of PFS will be carried out for different levels of the Co-morbidity score 
(Cumulative Illness Rating Scale (CIRS)), IPI, LVEF and ADL/IADL. 
17.4  Analysis of Secondary Endpoints 
17.4.1 Efficacy (secondary) 
 
Kaplan–Meier methods will be used to analyse overall survival. Survival times will be 
calculated from the date of randomisation until death. Patients who are alive will be 
censored at the date last seen. 
 
Rates of response at the end of treatment, according to the revised International 
Working Group response criteria for non-Hodgkin’s lymphoma (Cheson criteria [17]) will 
be compared (see Appendix 2 for details). 
 
Compliance to treatment (number of cycles, dose delays and reductions) will be 
compared. 
 
The impact of the steroids and subsequent treatment on performance status and 
functionality. 

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 
Toxicity will be closely monitored (see below) and the numbers of grade 3 and 4 events 
(according to CTCAE v 4.03) compared between the arms. 
17.4.2 Health related Quality of Life and functional assessments 
 
Co-morbidity score: Cumulative Illness Rating Scale (CIRS) 
 
Quality of life questionnaire: EORTC QLQ-C30  
 
Functionality assessments: ADL and IADL 
 
QOL and functionality will be analysed using methods for repeated measures, such as mixed 
modelling. 
 
Descriptive statistics will be used to investigate the Co-morbidities seen at baseline.  
17.5  Interim Analyses 
There will be no formal interim analyses, however the independent data monitoring committee 
will see the unblinded results at least once a year to monitor the safety and efficacy endpoints. 
 
As Inotuzumab Ozogamicin is an unlicensed drug we will be monitoring the toxicities in this arm 
very closely. The table below outlines the number of events we would need to observe before 
requiring a TMG safety review or to consider stopping the trial. 
 
The number of events needed to consider stopping recruitment early is such that the exact 
lower 95% CI (one-sided) exceeds 15% i.e. the true rate is likely to exceed these limits. 
 
Number of Patients 
(N) 
Number of treatment related 
deaths needed for TMG safety 
review 
(more than 15% of N)
Number of treatment 
related deaths needed 
to consider stopping 
10 
2 
4 
15
3
6
20 
4 
7 
25
4
8
30 
5 
9 
35
6
10
 

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18  ETHICAL AND REGULATORY CONSIDERATIONS  
In conducting the trial, the Sponsor, UCL CTC and sites shall comply with all relevant guidance, 
laws and statutes, as amended from time to time, applicable to the performance of clinical trials 
including, but not limited to: 
• 
the principles of ICH Harmonised Tripartite Guideline for Good Clinical Practice 
(CPMP/ICH/135/95) as set out in Schedule 1 (Conditions and Principles of Good 
Clinical Practice and for the Protection of Clinical Trial Subjects) of the Medicines for 
Human Use (Clinical Trials) Regulations 2004 and the GCP Directive 2005/28/EC, as 
set out in SI 2006/1928 
• 
Human Rights Act 1998 
• 
Data Protection Act 2018 and General Data Protection Regulation (EU)2016/679 
(GDPR) 
• 
Freedom of Information Act 2000 
• 
Human Tissue Act 2004 
• 
Human Tissue Act (Scotland) 2006 
• 
Medicines Act 1968  
• 
Medicines for Human Use (Clinical Trials) UK Regulations SI 2004/1031, and 
subsequent amendments  
• 
Good Manufacturing Practice  
• 
UK Policy Framework for Health and Social Care Research issued by the Health 
Research Authority 
18.1  Ethical Approval 
The trial will be conducted in accordance with the World Medical Association Declaration of 
Helsinki entitled ‘Ethical Principles for Medical Research Involving Human Subjects’ (1996 
version) and in accordance with the terms and conditions of the ethical approval given to the 
trial. 
The trial has received a favourable opinion from the NRES Committee Yorkshire and the 
Humber-Leeds East Research Ethics Committee (REC) and Health Research Authority (HRA) 
approval for conduct in the UK.    
 
UCL CTC will submit Annual Progress Reports to the REC, commencing one year from the 
date of ethical approval for the trial. 
18.2  Regulatory Approval  
A Clinical Trial Authorisation (CTA) has been granted for the trial. 
The trial will be conducted at approved trial sites in accordance with the trial protocol and the 
terms of the CTA granted by the MHRA. 
18.3  Site Approvals 
The Lead Comprehensive Local Research Network (CLRN) Trent has given NHS permission 
following global governance checks.  Local governance checks will be undertaken by local 
CLRNs associated with individual trial sites. 
Evidence of approval from the Trust R&D for a trial site must be provided to UCL CTC.  Sites 
will only be activated when all necessary local permissions for the trial have been obtained.   

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18.4  Protocol Amendments 
UCL CTC will be responsible for gaining ethical and regulatory approval(s), as appropriate, for 
amendments made to the protocol and other trial-related documents.  Once approved, UCL 
CTC will ensure that all amended documents are distributed to sites as appropriate. 
Site staff will be responsible for acknowledging receipt of documents and for implementing all 
amendments promptly. 
18.5  Patient Confidentiality & Data Protection 
Patient identifiable data, including their initials, date of birth and NHS number will be collected 
by UCL CTC.  UCL CTC will preserve patient confidentiality and will not disclose or reproduce 
any information by which patients could be identified.  Data will be stored in a secure manner 
and UCL CTC trials are registered in accordance with the Data Protection Act 2018 and GDPR 
with the Data Protection Officer at UCL. 

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19  SPONSORSHIP AND INDEMNITY 
19.1  Sponsor Details  
Sponsor Name: 
University College London 
Address: 
 
Joint Research Office 
Gower Street 
London 
WC1E 6BT
Contact: 
 
Tel: 
Fax: 
Director of Research Support 
020 3447 9995/2178 (unit admin) 
0207 3447 9937 
19.2  Indemnity  
University College London holds insurance against claims from participants for injury caused by 
their participation in the clinical trial. Participants may be able to claim compensation if they can 
prove that UCL has been negligent. However, as this clinical trial is being carried out in a 
hospital, the hospital continues to have a duty of care to the participant of the clinical trial. 
University College London does not accept liability for any breach in the hospital’s duty of care, 
or any negligence on the part of hospital employees. This applies whether the hospital is an 
NHS Trust or not.   
Participants may also be able to claim compensation for injury caused by participation in this 
clinical trial without the need to prove negligence on the part of University College London or 
another party.  Participants who sustain injury and wish to make a claim for compensation 
should do so in writing in the first instance to the Chief Investigator, who will pass the claim to 
the Sponsor’s Insurers, via the Sponsor’s office. 
Hospitals selected to participate in this clinical trial shall provide clinical negligence insurance 
cover for harm caused by their employees and a copy of the relevant insurance policy or 
summary shall be provided to University College London, upon request. 
 

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20  FUNDING 
Pfizer Limited is supporting the central coordination of the trial through UCL CTC. 
Pfizer Limited will be supplying Inotuzumab Ozogamicin free of charge to sites for this trial. 
CR UK is providing endorsement for the trial through the Clinical Trials Awards and Advisory 
Committee, CTAAC. 
21  PUBLICATION POLICY 
All publications and presentations relating to the trial will be authorised by the Trial 
Management Group. The first publication of the trial results will be in the name of the Trial 
Management Group, if this does not conflict with the journal’s policy. The TMG will form the 
basis of the writing committee and advise on the nature of publications. If there are named 
authors, these should include the Chief Investigator(s), Trial Coordinator(s), Statistician(s) and, 
Central Laboratory Staff involved in the trial. Contributing site investigators in this trial will also 
be acknowledged. Data from all sites will be analysed together and published as soon as 
possible. Participating sites may not publish trial results prior to the first publication by the TMG 
or without prior written consent from the TMG. The trial data is owned by the Sponsor. 
However, drug companies who have provided funding towards the trial will be permitted to see 
the draft manuscripts and make comments at least 45 days prior to submission for publication. 
The Clinicaltrials.gov number and CR UK funding reference number allocated to this trial will be 
quoted in any publications resulting from this trial. 
 

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22  REFERENCES 
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Morton, L.M., et al., Lymphoma incidence patterns by WHO subtype in the United 
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Coiffier, B., et al., Long-term outcome of patients in the LNH-98.5 trial, the first 
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Cunningham, D., et al., R-CHOP14 versus R-CHOP21: Result of a randomized phase 
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Fields, P., et al., First Analysis of a Phase II Study of Rituximab-Gemcitabine, 
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Moccia, A.A., et al., R-CHOP with Etoposide Substituted for Doxorubicin (R-CEOP): 
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Zaja, F., et al., CHOP-rituximab with pegylated liposomal doxorubicin for the treatment 
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Peyrade, F., et al., Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly 
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Investigators brochure. Inotuzumab Ozogamicin (PF-05208773; CMC-544). September 
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Ogura, M., et al., An Open-Label, Phase I Study of R-CVP in Combination with 
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Leonard, J.P., et al., Epratuzumab, a humanized anti-CD22 antibody, in aggressive 
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Pfreundschuh, M., How I treat elderly patients with diffuse large B-cell lymphoma. 
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Alizadeh, A.A., et al., Distinct types of diffuse large B-cell lymphoma identified by gene 
expression profiling. Nature, 2000. 403(6769): p. 503-11. 

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19. 
Rosenwald, A., et al., The use of molecular profiling to predict survival after 
chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med, 2002. 346(25): p. 1937-
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Lenz, G., et al., Stromal gene signatures in large-B-cell lymphomas. N Engl J Med, 
2008. 359(22): p. 2313-23. 
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Lenz, G., et al., Molecular subtypes of diffuse large B-cell lymphoma arise by distinct 
genetic pathways. Proc Natl Acad Sci U S A, 2008. 105(36): p. 13520-5. 
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Davis, R.E., et al., Constitutive nuclear factor kappaB activity is required for survival of 
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1861-74. 
23. 
Ngo, V.N., et al., A loss-of-function RNA interference screen for molecular targets in 
cancer. Nature, 2006. 441(7089): p. 106-10. 
24. 
Lenz, G., et al., Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. 
Science, 2008. 319(5870): p. 1676-9. 
25. 
Compagno, M., et al., Mutations of multiple genes cause deregulation of NF-kappaB in 
diffuse large B-cell lymphoma. Nature, 2009. 459(7247): p. 717-21. 
26. 
Gilmore, T.D., et al., The c-Rel transcription factor and B-cell proliferation: a deal with 
the devil. Oncogene, 2004. 23(13): p. 2275-86. 
27. 
Packham, G., The role of NF-kappaB in lymphoid malignancies. Br J Haematol, 2008. 
143(1): p. 3-15. 
28. 
Greystoke, 
A., 
et 
al., 
Assessment 
of 
circulating 
biomarkers 
for 
potential 
pharmacodynamic utility in patients with lymphoma. Br J Cancer, 2011. 104(4): p. 719-
25. 
29. 
Oken, M., et al., Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am. J. Clin. Oncol, 1982. 5: p. 649-655. 
30. 
The International Non-Hodgkin’s Lymphoma Prognostic Factors Project., A Predictive 
Model for aggressive Non-Hodgkin’s Lymphoma. N. Engl. J. Med, 1993. 329(14): p. 
987-984. 
31. 
McMillan A et al.  Guideline on the prevention of secondary central nervous system 
lymphoma: British Committee for Standards in Haematology. Br J Haem, Oct 2013, 163 
(2) p. 168-181 
 

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APPENDIX 1: ABBREVIATIONS 
ADL
Activities of Daily Living 
AE
Adverse Event
ALT
Alanine transaminase
ALP
Alkaline Phosphatase 
AR
Adverse Reaction
AST
Aspartate aminotransferase 
Β-HCG
β-human chorionic gonadotropin
BSA
Body Surface Area 
CCC
Country Coordinating Centre
CI 
CIRS
Chief Investigator 
Cumulative illness rating score 
CLS 
CNS
Country Lead Site  
Central Nervous System  
CR
Complete Response
CRF 
CSF
Case Report Form 
Cerebrospinal fluid 
CT
Computerised Tomography
CTA
Clinical Trial Authorisation) 
CTAAC
Clinical Trials Award and Advisory Committee
CTCAE
Common Terminology Criteria for Adverse Events
CTSA
Clinical Trial Site Agreement 
DLBCL 
DNA
Diffuse Large B Cell Lymphoma 
Deoxyribonucleic acid 
DSHNHL
Deutsche Studiengruppe Hochmaligne Non-Hodgkin-Lymphome
DSUR 
EBV 
EGFR
Development Safety Update Report  
Epstein Barr Virus 
Estimated Glomerular Filtration Rate
ECG
Electrocardiogram 
ECOG
Eastern Cooperative Oncology Group
EDTA
Ethylene Diamine Tetra Acetate
EEA 
EMA 
EORTC
European Economic Area 
European Medicines Agency 
The European Organisation for Research and Treatment of Cancer 
EudraCT
European Clinical Trials Database
FBC
Full Blood Count 
G
Gram
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor 
GEM
Gemcitabine
GFR 
HMDS
Glomerular Filtration Rate 
Haematological Malignancy Diagnostic Service
HBV 
HCV 
HIV
Hepatitis B Virus 
Hepatitis C Virus 
Human Immunodeficiency Virus
IADL
Instrumental Activities of Daily Living 
IB
Investigator’s Brochure
ICH GCP
International Conference of Harmonisation-Good Clinical Practice
IDMC
Independent Data Monitoring Committee 
IMP
Investigational Medicinal Product
INO
Inotuzumab ozogamicin 
ISF
Investigator Site File
IV
Intravenous

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LCRN
Local Clinical Research Network
LDH 
LFT 
LVEF
Lactate Dehydrogenase 
Liver Function Test 
Left Ventricular Ejection Fraction 
MCG
Microgram
MG
Milligram
MHRA
Medicines and Healthcare products Regulatory Agency  
ml
Millilitre
NCRI
National Cancer Research Institute 
NIHR
National Institute for Health Research
NIMP 
NHL 
NHS 
NHS IC 
od
Non Investigational Medicinal Product 
Non Hodgkins Lymphoma 
National Health Service  
National Health Service Information Centre 
Once Daily
ORR 
OS
Overall Response Rate 
Overall Survival 
PFS
Progression Free Survival
PI
Principal Investigator 
po
By mouth
PR 
PSF 
QOL
Partial Response 
Pharmacy Site File 
Quality of Life
REC
Research Ethics Committee 
RQ-PCR
Real-time quantitative polymerase chain reaction
SAE
Serious Adverse Event 
SAR
Serious Adverse Reaction
SD
Stable Disease
SDV
Source Data Verification 
SPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction  
TMF
Trial Master File 
TMG
Trial Management Group
TSC
Trial Steering Committee 
UCL CTC
CR UK and UCL Cancer Trials Centre
WBC 
WHO
White Blood Cells 
World Health Organisation
 
 

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APPENDIX 2: REVISED CHESON CRITERIA FOR RESPONSE 
ASSESSMENT 
 
Response rates will be classified using revised response criteria for malignant lymphoma 
published by International Harmonization Project on Lymphoma [17]. 
 
The designation of Complete Response (CR) requires the following: 
 
1. Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms if present before therapy. 
 
2a. Typically FDG-avid lymphoma: in patients with no pretreatment PET scan or when the PET 
scan was positive before therapy, a post-treatment residual mass of any size is permitted as 
long as it is PET negative. 
 
2b. Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pretreatment 
PET scan, or if a pretreatment 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 involvement is not always reliable because a 
spleen considered normal in size may still contain lymphoma, whereas an enlarged spleen may 
reflect variations in anatomy, blood volume, the use of hematopoietic growth factors, or causes 
other than lymphoma. 
 
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 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. 
 
Complete Response unconfirmed (CRu): 
The use of the above definition for CR and that below for PR eliminates the category of CRu. 
i.e. a response of CRu will not be permitted. 
 
Partial Response (PR): 
The designation of PR requires all of the following: 
 
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 least 2 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. 

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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 (eg, large cell 
lymphoma or small neoplastic B cells). Patients who achieve a CR by the above criteria, but 
who have persistent morphologic bone marrow involvement will be considered partial 
responders. When the bone marrow was involved before therapy and a clinical CR was 
achieved, but with no bone marrow assessment after treatment, patients should be considered 
partial responders. 
 
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): 
Stable disease (SD) is defined as the following: 
 
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. Lymph nodes ≤1.0 x≤1.0 cm will not be considered 
as abnormal for relapse or progressive disease. 
 
1. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, 
even if other lesions are decreasing in size. Increased FDG uptake in a previously unaffected 
site should only be considered relapsed or progressive disease after confirmation with other 
modalities. In patients with no prior history of pulmonary lymphoma, new lung nodules identified 
by CT are mostly benign. Thus, a therapeutic decision should not be made solely on the basis 
of the PET without histologic confirmation. 
 
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 lymph node with a diameter of the short axis of less than 1.0 
cm must increase by ≥50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis. 
 
3. At least a 50% increase in the longest diameter of any single previously identified node more 
than 1 cm in its short axis. 
 

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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). 
 
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. 
 
In clinical trials where PET is unavailable to the vast majority of participants, or where PET is 
not deemed necessary or appropriate for use, 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. 

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Summary table: 
 
Response
Definition
Nodal masses
Spleen/Liver
Bone Marrow
CR 
Disappearance of 
all evidence of 
disease 
 
(a) FDG- avid or PET 
positive prior to therapy; 
mass of any size permitted if 
PET negative. 
 
(b) Variably FDG-avid or 
PET negative; regression to 
normal size on CT
Not palpable, 
nodules 
disappeared 
 
Infiltrate cleared 
on repeat biopsy; 
if indeterminate 
by morphology, 
immuno-
histochemistry 
should be 
negative
PR 
Regression of 
measurable 
disease and no 
new sites of 
disease 
≥50% decrease in SPD of up 
to 6 largest dominant 
masses; no increase in size 
of other nodes 
 
(a) FDG-avid or PET positive 
prior to therapy; one or more 
PET positive at previously 
involved site 
 
(b) Variably FDG-avid or 
PET negative; regression on 
CT
≥50% 
decrease in 
SPD of 
nodules (for 
single nodule 
in greatest 
transverse 
diameter); no 
increase in 
size of liver 
or spleen 
Irrelevant if 
positive prior to 
therapy; cell type 
should be 
specified 
 
SD 
Failure to attain 
CR/PR or PD 
(a) FDG-avid or PET positive 
prior to therapy; PET Positive 
at prior sites of disease and 
no new sites on CT or PET 
 
(b) Variably FDG-avid or 
PET negative; no change in 
size of previous lesions on 
CT 
 
 
Relapse or 
PD 
Any new lesion or 
increase by ≥50% 
of previously 
involved sites from 
nadir 
 
Appearance of a new 
lesion(s) >1.5 cm in any axis, 
≥50% increase in SPD of 
more than one node, or 
≥50% increase in longest 
diameter of a previously 
identified node >1cm in short 
axis. 
  
Lesions PET positive if FDG-
avid lymphoma or PET 
positive prior to therapy 
>50% 
increase 
from nadir in 
the SPD of 
any 
previous 
lesions 
 
New or recurrent 
involvement 
 
 
Abbreviations: CR, complete remission; FDG, [18F] fluorodeoxyglucose; PET, positron emission 
tomography; CT, computed tomography; PR, partial remission; SPD, sum of the product of the 
diameters; SD, stable disease; PD, progressive disease. 
 

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APPENDIX 3: ECOG PERFORMANCE STATUS SCALE 
ECOG PERFORMANCE STATUS [29] 
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1 
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
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead

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APPENDIX 4: INTERNATIONAL PROGNOSTIC INDEX [30] 
One point is scored for each of the following variables. 
 
 Age >60 years 
 Serum LDH >upper limit of normal 
 Performance status 2-4 
 Ann Arbor Stage III-IV 
 >1 extranodal site of disease 
 
Score 0-1 = low risk 
Score 2 = low-intermediate risk 
Score 3 = high-intermediate risk 
Score 4-5 = high risk 

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APPENDIX 5: PROTOCOL VERSION HISTORY 
Protocol:
Amendments:
Version 
no. 
Date 
Amendment 
no.  
Protocol 
Section 
(no./title)
Summary of main changes 
from previous version. 
1.0 
13th July 2012 
n/a 
n/a 
n/a 
1.1 
4th September 
2012 
n/a 
 
Vital sign monitoring added to:-  
Section 5.1 – Pre registration evaluation 
Section 8.2 – Assessments during 
treatment 
Table 1 – Schedule of assessments 
 
Added >2.5 times normal level of 
AST/ALT and ALP as an exclusion 
criteria in:  
Section 5.3.1 (exclusion criteria) 
 
Added ALP measurement to AST/ALT  
Section 7.3.3 – Dose modifications  
 
Bilirubin levels amended in section 7.3.3 
to match exclusion criteria in:- 
Section 5.3.1 – Inclusion and Exclusion 
criteria for registration 
 
Removed reference to the use of a 
patient diary and documenting the 
return of oral prednisolone in: 
Section 4.0 – Informed consent 
Section 6.1 – Registration 
Section 8.2 – Assessments during 
treatment 
 

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2.0 
 
17.0 
 
 
 
Section 6.1 – 
Pre-
registration 
evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 6.3 – 
Patient 
eligibility 
Updated to latest CTC protocol template 
4.1 23Apr13 
 
Diagnostic biopsy can be done any 
point prior to registration. 
 
ECG must now include QTcF interval 
 
CT scan of the neck should be done but 
for those cases it has been omitted, it 
does not need to be repeated as long as 
a full clinical examination has been 
performed 
(ideally 
to 
include 
an 
ultrasound/MRI) 
 
Bone marrow trephine biopsy can now 
be performed after steroid pre phase 
has started in cases of urgent clinical 
need 
 
Optional – A PET-CT can now be done 
for 
staging 
as 
long 
as 
the 
CT 
component of the PET-CT is contrast 
enhanced 
 
BCSH guidance on CNS prophylaxis in 
NHL should be followed.  High risk – 
serum LDH >ULN and more than 1 
extranodal localisation or involvement of 
testicular, breast and paraspinal sites.  
CNS directed therapy may be added if, 
in the opinion of the PI, there is 
significant risk of CNS involvement 
 
Prothrombin time added to biochemistry 
tests 
 
Superficial bladder cancer added to 
inclusion criteria for no active malignant 
disease 
 
Exclusion criteria – Attributable to 
lymphoma removed for serum bilirubin 
greater than upper limit of normal.  
Haemolysis added. 
 
Exclusion criteria – Attributable to 
lymphoma removed for ALT and/or AST 
and ALP greater than 2.5 times the 
upper limit of normal 
 
Serological evidence for Hepatitis B or 
C amended in exclusion criteria 
 
2 new exclusion criteria added – 
Patients with history of Venoocclusive 
Disease 
(VOD) 
and 
Sinusoidal 
Obstructive 
Syndrome 
(SOS) 
and 
Patients with screening of QTcF interval 
>470msec 
 

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Section 6.3.3 – 
Contraceptive 
advice 
 
Section 6.3.4 – 
Long term 
infertility 
 
Section 8.2 – 
Summary 
treatment 
schedule 
 
 
 
 
 
 
 
 
 
Section 8.3 – 
trial treatment 
details 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4 – 
Dose 
modifications 
 
Section 8.6 – 
Concomitant 
medication 
 
Section 8.9 – 
Other trial 
treatments/ 
interventions 
 
Section 9.2 – 
Assessments 
during 
treatment 
 
 
 
Contraceptive advice changed – single 
barrier method only needed within the 
trial 
 
Recommendation added for sites to 
speak 
to 
patients 
about 
egg 
preservation prior to trial entry 
 
Break between steroid pre-phase and 
randomised treatment changed to no 
break and steroid pre phase changed to 
a maximum of 14 days 
 
Recommendation 
of 
when 
G-CSF 
should be stopped added to the protocol 
 
Details of pre-medications to be given to 
patients on the IO-R-CVP arm added to 
the protocol (paracetamol 1g (PO) and 
chorpheniramine 4mg (PO) 
 
BSA should be recalculated now in case 
of weight variation of 10% 
 
Dose banding is now allowed in the trial 
 
Clarification that diluted IO must be 
covered (with an amber bag or covered 
with foil) 
 
Clarification that IO infusion should be 1 
hour 
 
Clarification 
that 
administration 
of 
gemcitabine should be given according 
to local guidelines and policies 
 
Dose modification section re-formatted 
and additional sections added 
 
 
Details of medications to be avoided for 
patients on the IO-R-CVP arm 
 
 
Clarification on the definition of high risk 
of CNS involvement and treatment of 
CNS disease changed 
 
 
FBC and serum biochemistry can be done 
up to 3 days before treatment. 
 
ECG with QTcF should be done before 
starting each cycle of IO-R-CVP 
 
Prothrombin time added to biochemistry 
tests 
 
Clarification that CT scan before 4 cycle 
must be contrast enhanced 

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Section 9.3 – 
Assessments 
on completion 
of trial 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 9.4 – 
Assessments 
during follow-
up 
 
 
 
Various 
sections 
 
β2 
microglobulin 
removed 
from 
assessments 
during 
treatment 
and 
follow up 
 
BM biopsy only needs to be done now if 
BM was initially involved and the CT 
shows CR or Cru 
 
Prothrombin time added to biochemistry 
tests 
 
Clarification that CT scan should be 
contrast enhanced 
 
Optional: A PET-CT can be used to 
determine response as long as the CT 
component of the PET-CT in contrast 
enhanced. 
 
Removed the requirement to perform 
AE and toxicity assessments during 
follow up 
 
Clarification that CT scan should be 
contrast enhanced 
 
Administrative changes throughout the 
protocol after review from CPAS 
2.1 
11th August 
2014 
N/A – non-
substantial 
amendment 
Section 1,1 
(Summary of 
trial design) 
and 3 (Trial 
design) 
 
6.1 (pre-
registration 
evaluations) 
and 9.2 
(assessments 
during 
treatment) 
 
8.4 (dose 
modification) 
Clarification that the maximum dose of 
Vincristine is 2mg so that it is in line with 
the treatment section of the protocol and 
summary of drug arrangements 
 
 
Clarification that an average of 3 ECG’s 
should be conducted at baseline and 
prior to each cycle of I-O in order to 
calculate the QTcF interval (as indicated 
in the dose modification section of the 
protocol) 
 
 
Clarification that if bilirubin is >2.5x ULN 
dose reduce Vincristine by 50% as per 
the SPC and manufacturers guidance 
 
MHRA and REC will be notified of the 
above mentioned changes when the 
next 
substantial 
amendment 
is 
submitted. 
3.0 
15th October 
2014 
 
1.1 Summary 
of Trial Design 
 
1.2 Trial 
Schema 
 
3.0 Trial 
Design (and 
treatment 
arms) 
Information updated in line with rest of 
protocol changes 
 
Updated in line with rest of protocol 
changes 
 
Clarification that all patients will receive 
steroids and that patients will be treated 
with a lower dose of Gemcitabine 
depending on the ECOG PS 

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6.1 (Pre-
randomisation 
evaluation) 
 
 
 
 
 
 
 
 
 
 
6.3.1 
(Inclusion and 
Exclusion 
criteria for 
randomisation) 
 
 
 
 
 
 
 
7.0 
(Randomisatio
n procedures) 
 
8.2 (Trial 
treatment) 
 
 
 
 
 
 
 
 
 
8.3 (Trial 
treatment 
details) 
 
8.4 (Dose 
modifications) 
 
9.2 
(Assessments 
during 
treatment, on 
completion of 
trial treatment 
(9.3) and 
follow up (9.4)) 
 
Table 1 – 
Schedule of 
Assessments 
 
12.1 
Definitions of 
Adverse 
Events 
All assessments need to be done with 
the 
specified 
time 
frame 
before 
randomisation as registration step has 
been removed from the trial. 
 
Clarification what needs to be done if 
contrast is contraindicated or CT scan 
outside the 35 day window 
 
Assessments which need to be done 
after patient has received some steroids 
made clearer 
 
A concurrent (synchronous) diagnosis of 
low grade lymphoma is allowed and has 
been moved to the inclusion criteria so 
clearer 
 
ECOG performance status 0-2 added to 
inclusion criteria as needs to be done 
before randomisation 
 
ECOG performance status 3-4 added to 
exclusion criteria before randomisation 
 
Registration 
stage 
removed 
from 
protocol as patient’s are now registered 
and randomised at the same time 
 
All patients will receive steroids before 
randomised treatment so pre-phase 
section removed from protocol.     
 
Clarification on when steroids don’t 
need to be given and also when 
randomised treatment should start 
 
New 
dosing 
schedule 
for 
patients 
receiving Gemcitabine added 
 
New 
dosing 
schedule 
for 
patients 
receiving Gemcitabine added 
 
Dose reduction schema amended in line 
with new lower dose of Gemcitabine 
 
 
Clarification what needs to be done if 
contrast is contraindicated or CT scan 
outside the 35 day window 
 
 
 
 
 
Amended in line with rest of protocol – 
pre-registration assessments removed, 
updated CT information added 
 
SUSAR term updated in line with 
current CTC protocol template 
 
 

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12.2.2 Serious 
Adverse Events 
(SAEs) 
 
 
14.2 Central 
Monitoring 
 
 
 
17.1 (Sample 
size 
calculation) 
SAE processing at UCL CTC paragraph 
updated in line with current CTC 
protocol template 
 
 
Informed consent log no longer used in 
the trial as information collected on 
randomisation form.  Paragraph relating 
to this log removed 
 
Sample size reduced to 132 patients (66 
patients per arm) and recruitment period 
increased to 3 years 
4.0 
16th 
November 
2015 
31 
1.1 Summary 
of Trial Design 
 
Throughout 
protocol 
 
 
 
 
6.1 Pre-
randomisation 
evaluation 
 
6.3.1 Inclusion 
and Exclusion 
criteria for 
randomisation 
 
 
 
 
Table 1, 
Schedule of 
Assessments 
 
9.3 
Assessments 
on completion 
of trial 
Updated in line with rest of protocol 
 
 
‘significant 
cardiac 
comorbidities’ 
replaced with ‘significant comorbidities’ 
as 
‘diabetes’, 
‘hypertension’ 
are  
acceptable comorbidities according to 
eligibility criteria 
 
Translational research section updated 
detailing which samples are optional 
within the trial 
 
Patients with a previous diagnosis of 
low grade lymphoma which hasn't been 
treated with systemic therapy are now 
eligible for the trial 
Clarification added whether patients 
with history of malignant disease may 
be eligible for the trial  
 
Sample information updated in line with 
rest of the protocol 
 
Clarification that bone marrow biopsy at 
the end of treatment is optional if the 
end of treatment PET-CT scan is clear  
 

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5.0 
22nd 
December 
2016 
Substantial 
Various 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.1 Summary 
of Trial Design 
 
 
1.2 Trial 
schema 
 
3.0 Trial 
Design 
 
 
 
 
 
 
Updated to latest CTC protocol template 
7.0 
25Jul2016. 
 
Various 
sections 
moved, new information added to the 
following sections:- 4.1.1  Selection of 
Principal 
Investigator 
and 
other 
investigators 
at 
site; 
4.2.1 
Site 
Initiation; 6.2 Patient Eligibility; 6.3 
Pregnancy and birth control; 6.3.4 
Contraceptive Advice; 6.3.5 Action to be 
taken in the event of a Pregnancy; 8.5 
Management 
of 
Overdoses, 
Trial 
Treatment 
error 
or 
Occupational 
Exposure; 11.4 Data Queries; 15.1 
Discontinuation of Trial Treatment 
 
Anticipated 
duration 
of 
recruitment 
changed to 4 years as recruitment 
period extended for a further year 
 
1 year changed to 24 months as per 
rest of protocol 
 
Clarification 
that 
the 
Inotuzumab 
Ozogamicin is light sensitive and must 
be 
protected 
from 
light 
during 
preparation and administration of the 
infusion 
using 
a UV 
protective 
covering.   Infusion time should be 1 
hour at room temperature 

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Page | 76 
 
 
 
6.1 Pre-
randomisation 
evaluation 
 
8.3 Trial 
treatment 
details 
 
 
 
 
 
 
 
 
 
9.2 
Assessments 
during 
Treatment 
 
Table 1 
Schedule of 
Assessments 
 
12.2.2 Serious 
Adverse 
Events 
 
17.1 Sample 
Size 
Calculation 
 
17.3 Analysis 
of the Primary 
Endpoint 
 
Various 
Now in Section 9.0 Assessments – 
clarification that QTcF interval should be 
done as per rest of protocol not QTc 
 
Clarification 
that 
the 
Inotuzumab 
Ozogamicin is light sensitive and must 
be 
protected 
from 
light 
during 
preparation and administration of the 
infusion 
using 
a UV 
protective 
covering.   Infusion time should be 1 
hour at room temperature. 
 
Expiry time of Inotuzumab Ozogamicin 
changed to 4 hours as per new 
information received from Pfizer 
 
Clarification that QTcF interval should 
be done as per rest of protocol not QTc 
 
 
 
Clarification that QTcF interval should 
be done as per rest of protocol not QTc 
 
 
Pfizer have never been sent SAE 
quarterly line listings so this has been 
deleted 
 
Patients will be replaced if found to be 
ineligible due to a misdiagnosis 
 
 
Additional information relating to the 
analysis of the primary end point has 
been added to the protocol 
 
Minor 
administrative 
changes 
throughout the protocol 
6.0 
5th January 
2018 
Substantial 
1.1Summary 
of Trial Design 
 
 
 
 
 
 
6.2.1 Inclusion 
criteria for 
randomisation 
 
7.1 
Randomisation 
 
8.2 Summary 
Treatment 
Schedule 
 
Pre-phase steroids can be up to 28 
days if logistical reasons have delayed 
treatment 
 
Duration of recruitment – recruitment 
phase extended for a further year to 5 
years 
 
Pre-phase steroids can be up to 28 
days if logistical reasons have delayed 
treatment 
 
Randomisation forms can now be sent 
in by email 
 
Pre-phase steroids can be up to 28 
days if logistical reasons have delayed 
treatment 
 
 
 

INCA  
 
INCA Protocol v7.0 18th November 2019 
Protocol Template version 3.1 14Sep11- updated in line with protocol template 8.0 19/Jun/196 
Page | 77 
 
 
 
8.3 Trial 
Treatment 
Details 
 
 
 
 
 
 
9.1 Pre-
randomisation 
Assessments 
 
12.2.1 
Reporting of 
Adverse 
Events 
 
12.2.2 
Reporting of 
Serious 
Adverse 
Events 
 
 
12.5 
Pregnancy 
 
17.1 Sample 
size 
calculation 
 
Various 
 
 
Word ‘increase’ added to dose banding 
paragraph because sites can decrease 
or increase total dose 
 
Information relating to how to prepare 
the Inotuzumab Ozogamicin removed 
from this section and sites asked to 
refer to Summary of Drug Arrangements 
 
Virology screening can now be done 
within 35 days prior to randomisation 
rather than 14 days 
 
AEs 
30 
days 
post 
last 
IMP 
administration need to be reported 
rather 
than 
post 
last 
treatment 
administration 
 
SAEs 
30 
days 
post 
last 
IMP 
administration need to be reported 
rather 
than 
post 
last 
treatment 
administration 
 
SAE forms can now be sent in by email 
 
Pregnancy forms can now be sent in by 
email 
 
Updated 
in 
line 
with 
extended 
recruitment time 
 
 
Minor changes throughout the protocol 
to bring it up to date with the current 
CTC protocol template 
7.0 
18th November 
2019 
Substantial 
10.0 
Exploratory 
Biological 
Studies 
 
21.0 
Publication 
 
Various 
Analysis to be performed by Ming Du, at 
University of Cambridge, updated in line 
with current practices. 
 
 
Central Laboratory Staff added to list of 
people to be included in publications. 
 
Changes throughout the protocol to 
bring it up to date with the current CTC 
protocol template.   
 
List of TMG members updated to 
include all current members.