A Phase 2 Open Label Study to Investigate the Safety and Clinical Activity of Autologous EBV-specific T Cells (CMD-003) for the Treatment of Patients With EBV Positive Lymphomas
Phase: PHASE2
Conditions: Hodgkin Lymphoma, Lymphoma, Large B-Cell, Diffuse, Post-transplant Lymphoproliferative Disorder
Sponsor: Cell Medica Ltd

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PROTOCOL SYNOPSIS 
PROTOCOL No: 
CM-2015-01 
STUDY TITLE: 
A Phase 2 open label study to investigate the safety and clinical activity of autologous EBV-
specific T cells (CMD-003) for the treatment of patients with EBV positive lymphomas  
STUDY ACRONYM:   
CIVIC (Cellular Immunotherapy for Viral-Induced Cancer) 
INVESTIGATIONAL PRODUCT (CMD-003): 
Autologous LMP1, LMP2, EBNA1 and BARF1 EBV-specific T cells.  Treatment consists of up to 5 
doses administered over a 2-month period.  Each dose is comprised of 2 x 107 cells/m2 given 
every 2 weeks intravenously via a peripheral or central line over a 1 to 10-minute period for a 
maximum of 5 doses. 
PHASE OF DEVELOPMENT: 
Phase 2 
NUMBER OF SITES: 
NUMBER OF PATIENTS 
Approximately 12-15 US sites. 
Up to 70 patients 
LENGTH OF STUDY: 
Each patient will be monitored for safety and efficacy for 1 year after the first CMD-003 dose 
administration.  This study is expected to complete patient enrollment in 24 months, for a total 
study duration of 3 years from the first patient in to the last patient study visit.  Long-term 
survival information will be collected for an additional 12 months following the Final Study Visit. 
STUDY OBJECTIVES: 
To evaluate the safety and efficacy of EBV-specific autologous T cells (CMD-003) in the 
treatment of EBV+ DLBCL, HL and PTLD after failing first-line treatment. 
STUDY DESIGN: 
This is an open label, Phase 2 multicenter trial. Up to 70 patients with 3 types of EBV positive 
tumors will be enrolled and treated with autologous EBV-specific T cell infusion (CMD-003).   
The study is composed of 2 phases: Screening and Treatment.  In the Screening Phase, patients 
with history of EBV positive lymphoma or active post-transplant lymphoproliferative disease 
(PTLD) will be screened for this trial.  Patients must have documentation of Epstein-Barr early 

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RNA (EBER) positive tumor based on a report from a certified laboratory to be considered for 
screening in this study. Informed consent and if applicable, assent will be obtained before any 
study procedures are performed. A 200 mL whole blood sample will be obtained as starting 
material for the GMP manufacture of CMD-003. The manufacturing and product release time 
for CMD-003 is approximately 40 days from the initial blood procurement.   
The Treatment Phase of the study will commence with the initiation of lymphodepleting therapy 
in the HL and DLBCL cohorts, followed by the infusion of CMD-003. Baseline assessments will 
include, but not be limited to: PET-CT imaging to document disease status, documentation of 
medications and interim medical history changes, plus the evaluation of clinical status and 
standard safety laboratory tests. Lymphodepleting therapy consisting of cyclophosphamide and 
fludarabine, will be administered during the week prior to the first CMD-003 infusion, unless in 
the judgment of the Investigator, patients are unable to tolerate lymphodepletion.  
Modification or omission of the lymphodepletion regimen requires prior approval of the 
Medical Monitor. The investigational cell product, CMD-003 will be administered every 2 weeks 
for a maximum of 5 doses.   
During the study, there will be an assessment of adverse events (AEs) and concomitant 
medications at every study visit.  Patients will be assessed at periodic study visits for 1 year from 
their first CMD-003 administration.  Patients receiving ≤ 2 doses of CMD-003 will undergo their 
first disease response assessment at Week 8. Patients receiving ≥ 3 doses of CMD-003 will 
undergo their first disease response assessment at Month 3. Additional response assessments 
will be repeated every 3 months beginning at Month 6 through the Final Study Visit (Month 12). 
Tumor response will be evaluated based on Lugano 2014 Criteria by an independent radiological 
review committee.  Individual sites will be allowed to use other imaging techniques for medical 
management in addition to the Lugano mandated procedures.   
The patients’ plasma and whole blood EBV DNA viral load and EBV-specific T cell activity will be 
assessed at Screening, Baseline (prior to lymphodepletion) and all study visits from Day 1 
through the Final Study Visit (Month 12).  Survival status and disease status will be captured 
using telephone and/or medical record based data capture out to Month 24. 
A central pathology laboratory provided by the Sponsor will perform EBER (ISH) and test for 
other relevant biomarkers on tumor tissue samples obtained in this study.  Pre-treatment and 
post-treatment tumor tissue will be batched and tested under a separate laboratory protocol.  
The testing is being performed centrally to reduce testing variability, to investigate the CMD-
003 mechanism of action and support the development of a companion diagnostic. 
SELECTION CRITERIA FOR SCREENING PHASE: 
FOR INCLUSION  
1. The study will include 3 primary cohorts, with any of the following EBV+ diseases:  

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• Cohort A: Diffuse large B-cell lymphoma (DLBCL), 1) in first or subsequent relapse, 
not eligible for autologous transplantation following salvage therapy OR  2) relapse 
following autologous transplantation. 
• Cohort B: Hodgkin lymphoma (HL), post brentuximab vedotin (BV) treatment, with 
progressive disease, relapse, partial response, stable disease or unable to tolerate 
BV.   
• Cohort C: Solid organ transplant patients with post-transplant lymphoproliferative 
disorder (PTLD) with progressive disease, relapse, partial response or stable disease 
following rituximab and chemotherapy treatment or following rituximab therapy 
alone if not able to tolerate chemotherapy.  
2. Presence of active lymphoma or active PTLD, based on imaging performed within the 
previous 3 months. 
3. Tumor positive for EBER based on report from certified laboratory. 
4. Absolute lymphocyte count (ALC) > 500/µL. 
5. Male or female ≥ 12 years of age. 
6. Weight ≥ 35 kg. 
7. ECOG performance score 0-2, inclusively or Lansky score ≥ 60, as age appropriate. 
8. Able to understand and comply with the requirements of the study and to provide 
written informed consent or age appropriate assent for pediatric patients. 
FOR EXCLUSION 
1. Known CNS lymphoma. 
2. Primary refractory HL or DLBC, defined either by progression at any time during first-line 
chemotherapy and up to 3 months after end of first-line chemotherapy, or by failure to 
achieve at least PR with first-line therapy. 
3. Bulky disease, defined as, any site of disease > 5 cm diameter. 
4. Relapse or progression following previous autologous EBV-specific T cell treatment. 
5. Use of systemic corticosteroids > 0.5 mg/kg/day prednisolone or equivalent dose of 
alternative corticosteroid within 10 days prior to obtaining 200 mL starting material. 
6. Known hypersensitivity to the investigational cell product or any components in the final 
formulation (e.g. DMSO and/or HSA). 
7. Positive laboratory test for anti-HIV 1, 2; HBsAg, anti-HTLV-I; anti-HCV, or syphilis 
(Patients with anti-hepatitis B core antibody are eligible if negative for HBsAg; patients 
positive for anti-HCV may be enrolled if negative by nucleic acid amplification test).        
8. Positive -hCG test in females of childbearing potential.  
9. Patient is pregnant or lactating.   

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10. Female patients of childbearing potential and male patients with partners of 
childbearing potential unwilling to use a highly effective method of birth control during 
the study and for 6 months after the study treatment is concluded. 
11. Systemic fungal, bacterial, viral or other infection that is not controlled. 
12. History of any of the following cardiovascular conditions within the past 3 months:  
a. Class III or IV heart failure as defined by the New York Heart Association,  
b. Cardiac angioplasty or stenting, 
c. Documented myocardial infarction, or  
d. Unstable angina. 
13. Cardiac ejection fraction < 35%. 
14. Prior allogeneic hematopoietic stem cell transplantation (allo HSCT). 
15. Known history of primary immunodeficiency. 
16. Active second malignancy, except for basal cell carcinoma of skin, squamous cell 
carcinoma of the skin or cervical carcinoma in situ. 
17. Previous non-hematologic malignancy, unless the tumor was treated with curative intent 
more than 5 years prior to study entry.  
18. Clinically significant medical condition e.g. pulmonary, neurologic, cardiovascular, 
metabolic, hepatic or hematologic that could jeopardize patient safety, interfere with 
the objectives of the protocol, or limit patient compliance with study requirements, as 
determined by the Investigator. 
SELECTION CRITERIA FOR TREATMENT PHASE:   
FOR INCLUSION 
1. Presence of active lymphoma or PTLD, based on baseline imaging. 
2. Recovery from acute hematologic, hepatic and renal chemotherapy-related toxicities as 
defined by ≤ Grade 1 according to NCI CTCAE v4.0. (Transfusion to achieve the 
hematologic criteria is acceptable.) 
3. Estimated life expectancy ≥ 14 weeks. 
4. ECOG performance score 0-2, inclusively or Lansky score ≥ 60, as age appropriate. 
5. Able to understand and comply with the requirements of the study and to provide 
written informed consent or age appropriate assent for pediatric patients. 
FOR EXCLUSION 
1. Systemic corticosteroids within 24 hours prior to study product administration. 
2. Use of any chemotherapy agent (apart from the lymphodepletion regimen required by 
this protocol) within 2 weeks prior to first study product dose. 
3. Major surgery within prior 2 weeks. 
4. Radiotherapy within prior 3 weeks. 

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5. Investigational agents within prior 4 weeks. 
6. Use of any antibody therapy within prior 6 weeks. 
7. Systemic fungal, bacterial, viral or other infection that is not controlled. 
8. History of any of the following cardiovascular conditions within the past 3 months:  
a. Class III or IV heart failure as defined by the New York Heart Association,  
b. Cardiac angioplasty or stenting, 
c. Documented myocardial infarction, or  
d. Unstable angina. 
9. Prior allogeneic hematopoietic stem cell transplantation (allo HSCT). 
10. Active second malignancy, except for basal cell carcinoma of skin, squamous cell 
carcinoma of the skin or cervical carcinoma in situ. 
11. Clinically significant medical condition e.g. pulmonary, neurologic, cardiovascular, 
metabolic, hepatic or hematologic that could jeopardize patient safety, interfere with 
the objectives of the protocol, or limit patient compliance with study requirements, as 
determined by the Investigator. 
STUDY TREATMENTS: 
For patients with HL or DLBCL, a lymphodepletion regimen consisting of a single dose of 
cyclophosphamide 900 mg/m2, administered IV on Day -4 and fludarabine 25 mg/m2, 
administered in 3 separate IV doses on Days -3, -2 and -1, will be given prior to the first CMD-
003 infusion on Day 1.  The lymphodepletion regimen should be omitted or modified if: 
• the patient has ≥ Grade 2 hematologic and/or renal toxicities, or  
• in the Investigator’s judgment, the patient is already lymphodepleted, or 
• the patient is unlikely to tolerate lymphodepletion.   
Modification or omission of this lymphodepletion regimen requires prior approval of the 
Medical Monitor. 
For patients with PTLD receiving immune suppression, the immune suppression regimen will be 
based on the Investigator’s choice.  Reduction of immune suppression beginning before whole 
blood collection and before the first CMD-003 infusion is recommended if in the Investigator’s 
judgment such reduction in immune suppression will not jeopardize the function of the solid 
organ graft or medical condition of the patient. 
CMD-003 treatment will consist of up to 5 doses given over a 2-month period.  Each dose is 
comprised of 2 x 107 CD3+ cells/m2 administered intravenously over a 1 to 10-minute period via 
a peripheral or existing central line.  
STUDY ENDPOINTS:  
PRIMARY 
• Overall response rate (ORR), defined as best single observed response (CR or PR) 

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SECONDARY  
• Complete response rate (CR)  
• Duration of response (DoR)  
• Disease control (CR+PR+SD)  
• Time to response (TTR) 
• Progression free survival (PFS)  
• Disease free survival (DFS) 
• Overall survival (OS) 
• Adverse events (AEs) 
EXPLORATORY 
• Virological response based on reduction in EBV DNA levels as measured by PCR. 
• Peripheral blood EBV-antigen-specific T cell activity based on ELISpot activity. 
• ORR based on LYRIC criteria as assessed centrally by independent radiology committee. 
 CRITERIA FOR EVALUATION: 
EFFICACY 
Disease response will be assessed per Lugano 2014 Criteria at Baseline, Week 8 or Month 3 (as 
determined by the number of administered CMD-003 doses), and then every 3 months 
beginning at Month 6 through the Final Study Visit (Month 12). Patient response to treatment 
will be determined by an independent review committee.    
SAFETY 
Safety assessments will include: 
• Adverse event assessments (NCI CTCAE v4.0). AEs will be recorded from the 
time of the first investigational cell product dose until 30 days after the last 
investigational cell product dose.  SAEs will be recorded for up to 1 year 
following first CMD-003 infusion. 
• Physical examination, vital signs, weight and pulse oximetry. (Vital signs and 
pulse oximetry obtained before and up to 1 hour following CMD-003 infusion.) 
• Serum chemistry, hematology, coagulation and urinalysis laboratory evaluations. 
MECHANISM OF ACTION/IMMUNE FUNCTION 
• Immunological assessment of EBV-specific T cell activity and phenotyping. 
• Levels of plasma and whole blood EBV DNA (viral load). Tumor and peri-tumor 
biomarker analysis 
 
 

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STATISTICAL METHODS: 
SAFETY ANALYSES 
All recorded AEs will be listed and tabulated by system organ class, preferred term, and dose 
and coded according to the most current version of MedDRA. The incidence of AEs will be 
tabulated and reviewed for potential significance and clinical importance. Any significant 
physical examination findings and results of clinical laboratory tests will be listed. All safety data 
will be analysed for the entire safety population as well as by disease cohort. 
EFFICACY ANALYSES 
The primary efficacy endpoint is ORR as defined as the proportion of evaluable patients with a 
best response of CR or PR from a single observation.  Evaluable patients are defined in this 
protocol, as all patients with baseline PET-CT assessable or CT measurable disease (as 
determined by the Independent Radiology Review Committee (IRRC)), who received at least 1 
dose of CMD-003, and whose formal disease response has been determined at a scheduled 
study visit (including early termination visits).  
In addition to ORR, CR, Disease Control, DoR, TTR, PFS, DFS and OS will be analyzed to determine 
clinical benefit durability in evaluable patients. For ORR in each disease cohort, an exact 
binomial 90% confidence interval will be determined by the Clopper-Pearson method. Median 
time to response and DoR will be summarized for those patients with confirmed responses, 
using the Kaplan-Meier method; PFS, DFS and OS will be similarly summarized.  
In each disease cohort after 7 evaluable patients have completed the 8 week or 3 month (as 
applicable) assessment, the IDSMC will review safety and response data.  Within each cohort, if 
0 responses (CR or PR) are observed, the cohort will be closed to further accrual.  If ≥ 1 response 
(CR or PR) is observed, up to 7 additional patients may be enrolled in that cohort, for a total of 
14 patients.   
The final analysis will be conducted when the last enrolled patient has an event or has 
completed at least 12 months of study participation, whichever occurs first. Patients alive at 
data cut-off are censored at the last date the patient is known to be alive.  Long-term patient 
survival will be collected for up to 1 year following the Final Study Visit. 
An ORR at the final analysis in a given disease cohort of 3/14 or higher will support a conclusion 
that a true ORR in that cohort is higher than 5% (alpha=0.05, 1-sided).  Additional patients may 
be added to improve the precision of the estimates of the various endpoint response rates. 

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SAMPLE SIZE JUSTIFICATION: 
The CIVIC study is based on a Simon two-stage (minimax) design for each disease cohort. The 
Futility Boundary is set at 5% (the response threshold below which the treatment would not be 
developed further) and the Success Boundary at 30% (the response threshold at which the 
treatment is considered successful), with power at 80% (20% chance of false negative or type II 
error, within cohort), and the false positive rate or type I error is set at 5% within each cohort.  
Therefore, the total number of patients used for sample size assumption in each cohort is 14 
evaluable patients (7 in the first stage and 7 in the second stage).   
In Stage I, 1 or more responses in a cohort must be seen to continue to Stage II. For Stages I and 
II combined, 3 or more responses in a cohort are required to support the conclusion that the 
true response rate exceeds 5% and a true response rate of 30% cannot be ruled out.  
Assuming there are a minimum of 7 and a maximum of 14 evaluable patients across Cohorts A-
C, the sample size (total evaluable patients) will range from 21-42.   
In addition, it is estimated that up to 50% of the patients enrolled and treated will not fulfil the 
evaluable patient definition for ORR primary efficacy analysis.  Possible reasons include but are 
not limited to, patients with non-measurable/non-assessable disease baseline and/or not 
completing a study specific tumor assessment.   
INDEPENDENT REVIEW OF DATA  
An Independent Radiology Review Committee (IRRC) will assess all study images according to 
international consensus standards (Lugano 2014 Criteria).  An Independent Data and Safety 
Monitoring Committee (IDSMC) will review safety data.  
The IDSMC will have the ability to recommend stopping or modifying the study based on safety 
data.  The IDSMC will also review the assessments of the IRRC to adjudicate the overall response 
status of each patient.  The IDSMC will review each patient disease cohort after 7 evaluable 
patients are enrolled (Stage I), and recommend whether enrolment in that disease cohort 
should be continued (Stage II). The IRRC and IDSMC procedures will be documented in charters.