Conditions: Refractory Peripheral T-Cell Lymphoma Relapsed T-Cell Lymphoma
Keywords: FOT12-CN-301 PTCL (peripheral T-cell lymphoma) pralatrexate vitamin B12 folic acid
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 85
Healthy volunteers: no

Brief summary:
This is a single arm, open-label, multi-center study designed to demonstrate the efficacy and safety of pralatrexate when administered concurrently with vitamin B12 and folic acid supplementation to patients with relapsed or refractory peripheral T-cell lymphoma(PTCL).

Detailed description:
The primary objective of this study is to confirm the objective response rate (ORR) among Chinese subjects with relapsed or refractory PTCL treated with pralatrexate together with concurrent vitamin B12 and folic acid supplementation

Primary endpoint is objective Response Rate by International Working Group Criteria

This study includes 3 phases: Screening, Treatment (pralatrexate) and Follow-up phases.

Screening Phase:

The screening phase will be up to 28 days duration (depending on availability of lab results).

Treatment (pralatrexate) Phase:

The start of study treatment (pralatrexate) is defined as the initiation of pralatrexate. Patients will attend the clinic weekly for 6 weeks of a 7-week cycle to receive pralatrexate, and will be examined by the treating physician. One cycle of pralatrexate therapy is 7 weeks in duration and consists of 6 weekly doses of pralatrexate administered via intravenous (IV) push over 3-5 minutes, followed by 1 week of rest.

Evaluation of response must be performed within 7 days prior to the projected first dose of cycle 2-4 and then within 7 days prior to the projected first dose of every even-numbered subsequent cycle (ie, prior to cycles 6, 8, etc.). Although radiological response assessments have been scheduled every 14 weeks, unscheduled radiological response assessments will be performed earlier if clinical progression is suspected.

Treatment with pralatrexate will continue until 24 months of administration, or until documented disease progression; unacceptable adverse event(s) indicating intolerance of the lowest study dose allowed (20 mg/m2/week); omission of 3 sequential doses of pralatrexate due to a treatment-related AE; 3-week lapse between pralatrexate doses; development of an AE, intercurrent illness, condition, or procedural complication that may interfere with the subject's participation; investigator's decision to withdraw the subject; subject withdraws consent; pregnancy of the subject; noncompliance with trial treatment or procedure requirements; or administrative reasons.

Follow-up phase:

All patients who received at least 1 dose of pralatrexate are to attend the Safety Follow-up Visit \[30 (± 5) days after the last dose of pralatrexate\] and the protocol defined procedures and evaluations will be performed.

After the Safety Follow-up Visit, Routine Follow-up Visits will be based on standard clinical care. All patients who received at least 1 dose of pralatrexate are to attend Routine Follow-up Visits, which will occur every 3 months (± 2 weeks) for determination of progression of disease, subsequent treatment initiation for T-cell lymphoma and survival after the Safety Follow-up Visit for a total duration of 24 months after the last dose of pralatrexate. The protocol-defined procedures/evaluations should be performed at each Routine Follow-up Visit.

Arms:
arm 1: Vitamin B12 and folic acid will be taken concurrently with pralatrexate

Interventions: intervention 1: pralatrexate intervention 2: Vitamin B12 and folic acid
Intervention descriptions: intervention 1: Pralatrexate will be administered at a dose of 30 mg/m2/week for 6 weeks followed by 1 week of rest in a 7-week cycle. Pralatrexate administration occurs once a week during week 1 through week 6 of each cycle. intervention 2: The eligible subjects will receive vitamin supplementation at screening phase, at least 10 days prior to pralatrexate administration on cycle 1, dose 1. Vitamin supplementation will consist of vitamin B12 1 mg intramuscular (IM) q 8-10 weeks and folic acid 1.2mg by mouth (PO) once a day (QD). Once pralatrexate is permanently discontinued, vitamin supplementation should continue at least 1 month after the last pralatrexate dose, or longer at the discretion of the investigator.

Protocol document:
Prot_000.pdf: 
 
 
Protocol <FOT12-CN-301>  Version <1.0>, 18-Mar-2015 
 
 
 
Page 1 of 89 
 
TITLE PAGE 
 
Protocol Number: 
 FOT12-CN-301 
 
 
 
Title: 
A Multi-center, Single Arm, Safety and Efficacy Study of Pralatrexate 
with Vitamin B12 and Folic Acid Supplementation in Subjects with 
Relapsed or Refractory Peripheral T-cell Lymphoma 
 
 
 
 
 
Sponsor: 
Mundipharma (China) Pharmaceutical Co. LTD 
18F, Tower D, Central International Trade Center, 6A Jianguomenwai 
Avenue, Chaoyang District. 
Beijing, China  100022 
 
 
 
Test Drug: 
Pralatrexate injection (Abbreviated as Pralatrexate) 
 
 
 
Indication: 
Relapsed or Refractory Peripheral T-cell Lymphoma 
 
 
 
Phase: 
Phase III 
 
 
 
Release Date: 
03-Apr-2015 
 
 
 
GCP Statement: 
This study is to be performed in full compliance with ICH and all applicable 
local Good Clinical Practices (GCP) and regulations.  All required study 
documentation will be archived as required by competent authorities. 
 
 
 
Confidentiality: 
This document is confidential.  It contains proprietary information of 
Mundipharma (China) Pharmaceutical Co. LTD.  Any viewing or disclosure 
of such information that is not authorised in writing by the Sponsor is strictly 
prohibited.  Such information may be used solely for the purpose of 
reviewing or performing this study. 
 
 
 


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SIGNATURE PAGE FOR PROTOCOL FOT12-CN-301 
Protocol Number: 
FOT12-CN-301 
 
 
Title: 
 
 
 
A Multi-center, Single Arm, Safety and Efficacy Study of Pralatrexate with 
Vitamin B12 and Folic Acid Supplementation in Subjects with Relapsed or 
Refractory Peripheral T-cell Lymphoma. 
Test Drug: 
Pralatrexate 
 
 
Clinical Lead 
Dongsheng Wang 
Group Clinical Lead  
Mundipharma(China) Co., Ltd Beijing, China 
Signature 
 
 
Date 
 
Drug Safety 
Rachel Gao  
Drug Safety Manager 
Mundipharma(China) Co., Ltd  Beijing, China 
Signature 
 
 
Date 
 
Clinical Pharmacologist 
Kevin Smith 
Director of Clinical Pharmacology 
Mundipharma Research GmbH & Co. KG 
Cambridge, UK 
Signature 
 
 
Date 
Statistician 
Stefan Liebscher 
Senior Oncology Statistician, Medical Science 
Mundipharma Research GmbH & Co. KG 
Limburg, Germany 
Signature: 
 
 
Date 
Medical Science  
Zorn, Dr Juergen 
Executive Director of Medical Science 
Mundipharma Research GmbH & Co. KG 
Limburg, Germany 
Signature 
 
 
Date 
Regulatory Affairs 
Yanan Wang 
Regulatory Affairs Manager 
Mundipharma(China) Co., Ltd  Beijing, China 
Signature 
 
 
Date 
 
Research & Development China 
Jane Zhang 
Medical Director, Greater China 
Mundipharma(China) Co., Ltd  Beijing, China  
Signature 
 
 
Date 
 
 


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SIGNATURE PAGE FOR INVESTIGATORS 
Protocol Number: 
FOT12-CN-301 
 
 
Title: 
 
 
 
A Multi-center, Single Arm, Safety and Efficacy Study of Pralatrexate with 
Vitamin B12 and Folic Acid Supplementation in Subjects with Relapsed or 
Refractory Peripheral T-cell Lymphoma. 
Test Drug: 
Pralatrexate 
 
 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol and in accordance with ICH and China Good Clinical Practice guidelines, including the 
Declaration of Helsinki and all its accepted amendments to date. 
 
 
 
 
 
 
 
Investigator 
 
Signature 
 
Date 
 
 
 
 


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1 CLINICAL PROTOCOL SUMMARY 
Name of Sponsor  
Mundipharma (China) Pharmaceutical Co. LTD 
   
Name of Finished Product: 
Folotyn®(pralatrexate injection) 
Name of Active Ingredient: 
pralatrexate 
Protocol No.: FOT12-CN-301 
EUDRACT No.: not applicable 
Short Title of the Study: A single arm study evaluating the efficacy and safety of pralatrexate in 
subjects with relapsed or refractory peripheral T-cell lymphoma 
Full Title of the Study: A multi-center, single arm, safety and efficacy study of pralatrexate with 
Vitamin B12 and Folic Acid supplementation in subjects with relapsed or refractory peripheral T-cell 
lymphoma. 
Investigator(s)/Centre(s): Multi-center in China 
Study Indication:  
Relapsed or Refractory Peripheral T-cell Lymphoma 
Phase of Development: 
Phase 3 
Objectives and Endpoints: 
Objectives 
The primary objective of this study is to confirm the objective response rate (ORR) among Chinese 
subjects with relapsed or refractory peripheral T-cell lymphoma (PTCL) treated with pralatrexate together 
with concurrent vitamin B12 and folic acid supplementation  
The secondary objective includes: 
 
To evaluate further efficacy parameters (Duration of Response; Time to Response; Progression-
Free Survival; Overall Survival) 
 
To evaluate the safety of pralatrexate with concurrent vitamin B12 and folic acid supplementation 
when administered to subjects with relapsed or refractory PTCL  
 
To determine the pharmacokinetic (PK) profile of pralatrexate when administered with vitamin B12 
and folic acid supplementation in subjects with relapsed or refractory PTCL 
Endpoints 
Primary endpoint  
 
Objective Response Rate by International Working Group Criteria 
Secondary endpoints : 
 
Duration of Response (DOR) 
 
Time to Response (TTR) 
 
Progression-Free Survival (PFS)  
 
Overall Survival (OS) 
 
Safety measurements (physical examinations, clinical laboratory values, and treatment emergent 
AEs.) 
 
 PK parameters 
 


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Study Design (Methodology): 
This is a single arm, open-label, multi-center study designed to demonstrate the efficacy and safety of 
pralatrexate when administered concurrently with vitamin B12 and folic acid supplementation to patients 
with relapsed or refractory PTCL.  
This study includes 3 phases: Screening, Treatment (pralatrexate) and Follow-up phases.  
Screening Phase: 
The screening phase will be up to 28 days duration (depending on availability of lab results). All potential 
study patients will be screened and eligibility determined prior to enrollment. The eligible subjects will 
begin to receive vitamin supplementation at screening phase. 
Unless otherwise specified, the protocol defined procedures and evaluations (See Table 1.  Schedule of 
Visits and Procedures) will be performed within 28 days prior to the projected start of pralatrexate 
administration (cycle 1, dose 1). 
Treatment (pralatrexate) Phase: 
The start of study treatment (pralatrexate) is defined as the initiation of pralatrexate. Patients will attend 
the clinic weekly for 6 weeks of a 7-week cycle to receive pralatrexate, and will be examined by the 
treating physician. One cycle of pralatrexate therapy is 7 weeks in duration and consists of 6 weekly 
doses of pralatrexate administered via intravenous (IV) push over 3-5 minutes, followed by 1 week of 
rest.  
Evaluation of response must be performed within 7 days prior to the projected first dose of cycle 2-4 and 
then within 7 days prior to the projected first dose of every even-numbered subsequent cycle (ie, prior to 
cycles 6, 8, etc.). Although radiological response assessments have been scheduled every 14 weeks, 
unscheduled radiological response assessments will be performed earlier if clinical progression is 
suspected. 
Treatment with pralatrexate will continue until 24 months of administration, or until documented disease 
progression; unacceptable adverse event(s) indicating intolerance of the lowest study dose allowed (20 
mg/m2/week); omission of 3 sequential doses of pralatrexate due to a treatment-related AE; 3-week lapse 
between pralatrexate doses; development of an AE, intercurrent illness, condition, or procedural 
complication that may interfere with the subject’s participation; investigator’s decision to withdraw the 
subject; subject withdraws consent; pregnancy of the subject; noncompliance with trial treatment or 
procedure requirements; or administrative reasons.  
Follow-up phase: 
All patients who received at least 1 dose of pralatrexate are to attend the Safety Follow-up Visit [30 (± 5) 
days after the last dose of pralatrexate] and the protocol defined procedures and evaluations will be 
performed.  
After the Safety Follow-up Visit, Routine Follow-up Visits will be based on standard clinical care. All 
patients who received at least 1 dose of pralatrexate are to attend Routine Follow-up Visits, which will 
occur every 3 months (± 2 weeks)   for determination of progression of disease, subsequent treatment 
initiation for T-cell lymphoma and survival after the Safety Follow-up Visit for a total duration of 24 months 
after the last dose of pralatrexate. The protocol-defined procedures/evaluations should be performed at 
each Routine Follow-up Visit. 
 


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Study Design Graphic: 
 
 
 
Number of Subjects: 68 subjects will be treated  
Criteria for Inclusion/Exclusion:  
Inclusion Criteria: 
1. Subject has histologically/cytologically confirmed PTCL, using the World Health Organization (WHO) 
disease classification:  
a. PTCL not otherwise specified (NOS) 
b. Angioimmunoblastic T-cell lymphoma 
c. Anaplastic large cell lymphoma, ALK+ 
d. Anaplastic large cell lymphoma, ALK- 
e. Extranodal NK/T-cell lymphoma – nasal type 
f. Enteropathy-associated T cell lymphoma 
g. Hepatosplenic T-cell lymphoma 
h. Subcutaneous panniculitis-like T-cell lymphoma 
i. Adult T-cell lymphoma/leukemia (human T-cell leukemia virus [HTLV] 1+)  
j. Aggressive NK-cell leukemia 
k. Transformed mycosis fungoides 
2. Subject has to have documented progressive disease (PD) after at least 1 prior systemic treatment.  
3. Subject may not have received an experimental drug or biologic as their only prior therapy. Subject 
must have clear PD after the last treatment received. Subject should have at least 1 biopsy from 
initial diagnosis or in the relapsed setting to confirm the diagnosis of PTCL. Subject must have 
recovered from the toxic effects of prior therapy.  
4. Subjects with an enlarged lymph node or extranodal mass lesion clearly measurable in two 
perpendicular directions and greater than 1.5 cm maximum diameter on computed tomography 
performed within 14 days prior to study enrollment.  
5. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.  
6. At least 18 years of age.  
7. Expected life expectancy ≥ 3 months. 
8. Adequate hematological, hepatic, and renal function as defined by:  
• Absolute neutrophil count (ANC) ≥ 1000/uL (or 1  109/L), platelet count  ≥ 100,000/uL (or 100  
109/L) (at both screening and within 3 days prior to dosing on cycle 1, day 1) 
• Total bilirubin ≤ 1.5 mg/dL, aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ 2.5 X upper limit of normal (ULN) (AST/ALT < 5 X ULN if documented hepatic 
involvement with lymphoma)  
• Creatinine ≤ 1.5 mg/dL (or 132.6 µmol/L) or a calculated creatinine clearance ≥ 50 mL/min  
9. Women of childbearing potential must have agreed to practice a medically acceptable contraceptive 
regimen from study treatment initiation until at least 30 days after the last administration of 
pralatrexate and must have a negative serum pregnancy test within 14 days prior to the first day of 
study treatment. Subjects who are postmenopausal for at least 1 year (> 12 months since last 
<28 
days 
 
Safety and 
Routine 
follow up 
24 
months 
after 
last 
dose 


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menses) or are surgically sterilized did not require this test. 
10. Men who are not surgically sterile must agree to practice a medically acceptable contraceptive 
regimen from study treatment initiation until at least 90 days after the last administration of 
pralatrexate.  
11. Subject gives written informed consent (IC).  
 
Exclusion Criteria: 
1. Subject has: 
a. Precursor T-cell lymphoma or leukemia  
b. T-cell prolymphocytic leukemia (T-PLL) 
c. 
T-cell large granular lymphocytic leukemia 
d. Mycosis fungoides, other than transformed mycosis fungoides 
e. Sézary syndrome 
f. 
Primary cutaneous CD30+ T-cell disorders: Lymphoid papulosis and primary cutaneous 
anaplastic large cell lymphoma 
2. Active concurrent malignancy (except non-melanoma skin cancer or carcinoma in situ of the cervix). 
If there is a history of prior malignancy, the patient must be disease-free for ≥ 5 years. 
3. Congestive heart failure Class III/IV according to the New York Heart Association’s Heart Failure 
guidelines. 
4. Human immunodeficiency virus (HIV)-positive diagnosis. 
5. Has, or history of, brain metastases or central nervous system (CNS) disease. 
6. Active uncontrolled infection, underlying medical condition including unstable cardiac disease, or 
other serious illness that would impair the ability of the subject to receive protocol treatment.  
7. Has major surgery within 2 weeks of study entry. 
8. Receipt of any conventional chemotherapy or radiation therapy (RT) within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to study treatment or planned use during the course of the study. 
9. Receipt of corticosteroids within 7 days of study treatment, unless subject has been taking a 
continuous systemic dose of no more than 10 mg/day or equivalent dose of prednisone, or a local or 
inhaled or intranasal administration at fixed doses for at least 1 month prior to study treatment and 
tumor shrinkage was not observed. 
10. Use of any investigational drugs, biologics, or devices within 4 weeks prior to study treatment or 
planned use during the course of the study. 
11. Receipt of anti-tumor antibody therapy within 100 days prior to study treatment. 
12. History of allogeneic hematopoietic stem cell transplantation. Or subjects with a history of autologous 
hematopoietic stem cell transplantation within 100 days prior to study treatment.  
13. Previous exposure to pralatrexate. 
14. Subject is pregnant or breast-feeding. 
 


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Treatment, Dose, and Mode of Administration: 
Vitamin Administration 
The eligible subjects will receive vitamin supplementation at screening phase, at least 10 days prior to 
pralatrexate administration on cycle 1, dose 1. Vitamin supplementation will consist of vitamin B12 1 mg 
intramuscular (IM) q 8-10 weeks and folic acid 1.2mg by mouth (PO) once a day (QD). Once the subject 
is on-study, the dosing of vitamin supplementation must adhere to the schedule defined by the protocol. 
Once pralatrexate is permanently discontinued, vitamin supplementation should continue at least 1 
month after the last pralatrexate dose, or longer at the discretion of the investigator. 
Pralatrexate Administration 
Pralatrexate will be administered via IV push over 3-5 minutes into a subject IV line containing normal 
saline (0.9% sodium chloride [NaCl]). 
Pralatrexate will be administered at a dose of 30 mg/m2/week for 6 weeks followed by 1 week of rest in a 
7-week cycle. Pralatrexate administration occurs once a week during week 1 through week 6 of each 
cycle. 
Dose omissions and/or reductions will be allowed according to the criteria outlined.  
If an AE occurs that prevents the administration of pralatrexate on the scheduled dosing day (± 2 days), 
the dose will be omitted that week and the subject will be reassessed the following week to proceed to 
the next dose of the cycle. Omitted doses will not be made up at the end of the cycle. 
The pralatrexate dose may be reduced to 20 mg/m2/week if a subject experiences treatment related AEs 
as in Table 3. and Table 4 . No further dose reductions are allowed. If the subject develops an AE 
indicating intolerance of this lowest dose of 20 mg/m2/week, the subject will be discontinued from study 
treatment. There will not be re-escalation of the pralatrexate dose once a dose reduction has occurred. 
 
Prior and Concomitant Therapy 
Permitted Therapies 
In addition to protocol treatment, palliative and supportive care will be provided during this study, as 
clinically indicated, and in accordance with the standard practices of the institution.  
All medications administered from signing the informed consent form through the Safety Follow-up Visit 
are to be recorded on the CRF. Additions, deletions, or changes of dosage of medications are also to be 
noted.  
Prophylaxis and treatment of nausea and vomiting can be administered according to the standard of care 
within the institution, however administration is not recommended prior to the first dose of pralatrexate 
because of its low emetogenic potential. 
Erythropoietin will be allowed if it is judged by the investigator to be in the best interest of the subject (eg, 
for patients with underlying anemia or unacceptable hematological toxicity). 
Other hematopoietic growth factors (eg, granulocyte colony-stimulating factor [G-CSF], granulocyte-
macrophage colony-stimulating factor [GM-CSF]), with the exception of pegfilgrastim (Neulasta®), can be 
administered in accordance with the instructions for treatment modification for hematological toxicities as 
specified in the protocol. 
The administration of appetite stimulating hormones (eg, megestrol acetate) will be allowed to control 
anorexia and cachexia. Use of prophylactic antibiotics will be allowed at the discretion of the investigator.  
Transfusions will be allowed per the discretion of the investigator. 
Therapies Not Permitted 
The prior therapies that are not allowed are described in the Exclusion Criteria. 
Any form of additional therapy for T-cell lymphoma will not be permitted during treatment with 
pralatrexate, including radiation therapy, other cytotoxic agents, biologic, immune response modifiers, 
and herbal products. 
While on treatment with pralatrexate, steroids will not be allowed for prophylaxis or treatment except: 
• 
As continuation of prior systemic steroid treatment at stable of no more than 10 mg/day or 
equivalent dose of prednisone; 
• 
As continuation of local or Inhaled or intranasal steroids at fixed doses as used prior to study 
entry; 
• 
For treatment of possible Addison’s crisis in patients with prior history of steroid use.  
 
 


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Duration of Treatment and Study Duration: 
Pralatrexate administration will continue until a patient experiences any of the following: 
 
Development of PD 
 
Initiation of radiotherapy or systemic chemo/biologic therapy for T-cell lymphoma 
 
Development of an unacceptable AE indicating intolerance of the lowest study dose allowed (20 
mg/m2/week) 
 
Omission of 3 sequential doses of pralatrexate due to a treatment-related AE 
 
3-week lapse between pralatrexate doses 
 
Development of an AE, intercurrent illness, condition, or procedural complication that may interfere 
with the subject’s participation 
 
investigator’s decision to withdraw the subject 
 
Subject withdraws consent 
 
Pregnancy of the subject 
 
Noncompliance with trial treatment or procedure requirements 
 
Administrative reasons 
 
All subjects will be followed for at least 30 days after their last dose of pralatrexate for safety. Subjects 
who discontinue pralatrexate and have received at least 1 dose of pralatrexate are to attend the Safety 
Follow-up Visit and complete the Safety Follow-up Visit procedures. All patients will be followed for 
response, PFS, and survival for a duration of 24 months post last dose of pralatrexate. 
 


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Criteria for Evaluation: 
Analysis Populations 
The primary and secondary efficacy endpoints will be analyzed using the safety population. A subject will 
be considered evaluable for safety population if he/she receives at least 1 dose of pralatrexate. 
The PK endpoints will be analysed using the PK population. The overall PK population is defined as all 
subjects who receive at least one dose of Investigational Medicinal Product (IMP) and have at least one 
primary PK parameter.  Subjects with non-zero baseline concentrations of >5% of Cmax for either 
analyte (R-pralatrexate or S-pralatrexate) will be removed from the PK population. 
Efficacy Evaluation  
The primary analysis will be conducted once all subjects have completed cycle 5 treatment or 
discontinued before. Study treatment may continue per investigator judgment for a maximum of 24 
months.  
Response will be assessed on the basis of clinical, radiological, and pathological criteria. Response will 
be assessed by independent central review and by the treating investigator. Central review assessors will 
be blinded to the response assessments by the treating investigator. The primary analysis will be based 
on response assessed by central review.  
Response rate by International Working Criteria : 
Response rate is defined as number of responders divided by number of subjects, where a subject is 
considered a responder if she/he has obtained a CR, CRu or a PR. 
The following procedures/tests will be included in the evaluation of response: 
1. Radiographic imaging (use same imaging techniques as screening). 
 
CT of chest, neck, abdomen, and pelvis 
 
Other imaging documenting disease site other than chest, neck, abdomen, or pelvis, if applicable 
2. Physical examination to assess liver, spleen, lymph nodes, and skin. Include medical photography 
and ruler measurements of any skin lesions. A sum of the longest diameter (LD) for all skin lesions 
will be calculated. 
3. LDH level determination. 
4. Bone marrow biopsy and aspirate should be performed and assessed by flow cytometry if the subject 
had bone marrow involvement with lymphoma prior to treatment and the subject has a confirmed CR 
by imaging and physical examination. 
5. A tumor biopsy could be performed if needed to confirm a response evaluation. 
6. Results of peripheral blood flow cytometry if applicable.  
Response and progression of disease will be evaluated by using: 
1. 
The IWC proposed by the NCI sponsored International Working Group 
2. 
Bone marrow biopsies should be scored as follows: 
 
Negative = no aggregates or only a few well circumscribed lymphoid aggregates and ≤ 3% 
blasts. 
 
Positive = unequivocally cytologic or architectural evidence of malignancy (percentage of 
invasion and the lymphoma subtype should be indicated). 
 
Indeterminate = increased number or size of aggregates without cytologic or architectural atypia. 
3. 
Measurements of each cutaneous lesions utilizing medical photography and ruler: 
 
A sum of the LD for all cutaneous lesions will be calculated and reported as the baseline sum LD 
and will be used as reference for tumor response 
 
Response and progression of cutaneous disease will be evaluated using the following 
definitions: 
- 
CR = disappearance of all evidence of disease for at least 4 weeks. 
- 
PR = 50% or greater decrease in the sum of the LD of each lesion for at least 4 weeks. 
- 
PD = increase of ≥ 25% of the LD of any lesion or appearance of new lesions. 
- 
SD = less than a PR but does not meet criteria for PD. 
 


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If it is difficult to distinguish residual disease from normal tissue and confirmation of CR depends on this 
determination, it is recommended that the residual lesion be investigated (biopsy or fine needle aspirate) 
before confirming CR status. 
If progression is determined at a time point or by a method not defined in the protocol, those data will be 
sent to central review. 
Duration of Response: 
Duration of response will be measured from first day of documented response to disease progression or 
death, whatever comes first. Subjects receiving subsequent therapy, including transplant before PD is 
documented, will be censored at that time, with a note indicating censoring occurrence, along with 
reason. 
Time to Response: Time to response will be measured from first day of treatment to the first date of 
documented response. 
Progression Free Survival: 
PFS will be measured from treatment day 1 until event or censoring. An event is defined as the earliest of 
the following: death from any cause or disease progression. Subjects undergoing transplant or any other 
subsequent therapy prior to documentation of PD will be censored at that time. 
Overall Survival: 
OS will be measured from treatment day 1 until death or censoring. 
 
Safety evaluation 
Safety will be evaluated by assessment of physical examinations, clinical laboratory values, and 
treatment emergent AEs. 
 
Pharmacokinetics evaluation 
The PK profile of R-pralatrexate and S-pralatrexate will be determined in a subset of this subject 
population. 
Standard PK parameters will be determined for both enantiomers in plasma (area under the curve [AUC], 
steady state volume of distribution [Vdss], steady state clearance [CLss], maximum observed plasma 
concentration [Cmax], trough observed plasma concentration [Ctrough], time of Cmax observation [tmax] 
and terminal phase half-life [t1/2Z]). Collection of plasma to determine the full PK profile will be performed 
in 15 subjects at pre-selected sites. 
 


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Statistical Methods: 
Efficacy Analyses  
The primary endpoint is the objective response rate (ORR) defined as the proportion of subjects 
with CR, CRu or PR as Best Overall Response (BOR). The objective response rate will be tested 
using the exact test for single proportion at two-sided significance level of 5%. The hypotheses 
under test will be H0: ORR<15% vs. H1: ORR≥15%. 
The primary analysis will be based on the independent review data using the safety population. An 
additional analysis based on the investigator assessment data will be performed. All analyses will 
be repeated using the per-protocol population. 
Secondary time-to-event endpoints (e.g. duration of response, PFS, and OS) will be presented 
using Kaplan-Meier curves (product limit estimates) together with a summary of associated statistics 
(e.g. median survival time, first and third quartiles, survival rates including the corresponding two-
sided confidence intervals [CIs]). Censoring rules will be detailed in the SAP. 
Secondary endpoints based on tumor assessments (e.g. duration of response and PFS) will be 
analyzed twice, once using the independent review data and once using the investigator 
assessment data. 
The secondary analyses will be performed using the safety population and repeated using the per-
protocol population.  
Safety Assessments: 
The analysis of the safety parameter will be based on the safety population. The safety endpoints for this 
study are as follows: 
 
Incidence and severity of AEs 
 
Clinically significant changes in vital signs and physical examination findings 
 
Clinically significant changes in laboratory parameters. 
 
Incidence and type of adverse events will be summarized. Laboratory values will be evaluated using 
mean values, the number of subjects who have clinically relevant values outside normal values, and shift 
tables.  
All other safety variables will be analyzed descriptively. In general missing safety data will not be 
replaced. A more detailed description will be presented in the statistical analysis plan. 
 
Pharmacokinetic Assessments: 
Plasma concentration data will be listed by analyte (R-pralatrexate and S-pralatrexate) for subjects in the 
PK population.  Plasma concentration data will be summarised by nominal time-point and treatment as 
continuous data (i.e. n, mean, standard deviation, standard error, median, minimum, and maximum) for 
subjects in the PK population. Additionally, the plasma concentration data will be presented graphically in 
the following way using both a linear and log linear scale: 
 
 
The mean plasma concentration data will be plotted over time 
 
For each subject, the individual plasma concentration data will be plotted over time 
Pharmacokinetic parameters (AUCt, AUCINF, Cmax, Ctrough, tmax, LambdaZ, t1/2Z, CLss, Vdss) will 
be listed by analyte for subjects in the PK population.  Data excluded from the PK analysis will be flagged 
with an asterisk. 
Pharmacokinetic parameters (AUCt, AUCINF, Cmax, Ctrough, tmax, LambdaZ, t1/2Z, CLss, Vdss) for 
each analyte will be summarised descriptively for subjects in the PK population, adjusting for dose where 
necessary. 


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Bioanalytical Methods: 
Plasma will be frozen for subsequent PK analysis. The concentration of R-pralatrexate and S-
pralatrexate at each time-point will be determined by liquid chromatography-tandem mass spectrometry 
(LC/MS/MS). The collection times for full pralatrexate PK are as follows: 
Cycle 1, dose 1: Pre-injection, end-injection, 30 and 60 minutes, and 3, 5, 8, 12, 18, 24, 48, and 72 hours 
post-end injection. 
Cycle 1, doses 2 – 5: Pre-injection  
Cycle 1, dose 6: Pre-injection, end-injection, 30 and 60 minutes, and 3, 5, 8, 12, 18, 24, 48, and 72 hours 
post-end injection. 
Interim Analyses: None planned. 
 
Primary Data Analysis and Cut-off date:  
Based on the PROPEL study 29 out of 32 responses (91%) occurred within the first five cycles of 
treatment. Consequently the data cut-off date for the primary analysis will be defined once all subjects 
have been treated for 5 cycles. 
Sample Size Rationale:  
The primary objective is to demonstrate that the response rate in the Chinese population is greater than 
≥15%. Assuming a true response rate of 29%, a sample size of 68 will provide 80% power to 
demonstrate a response rate of greater than 15% using a two-sided test at 5% significance level. 


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2 TABLE OF CONTENTS 
 
Page 
TITLE PAGE ......................................................................................................................... 1 
SIGNATURE PAGE FOR PROTOCOL FOT12-CN-301 ....................................................... 2 
1 CLINICAL PROTOCOL SUMMARY................................................................................ 4 
2 TABLE OF CONTENTS ................................................................................................ 14 
3 LIST OF ABBREVIATIONS .......................................................................................... 20 
4 STUDY CONDUCT AND OVERSIGHT ......................................................................... 23 
4.1 Sponsor ....................................................................................................................... 23 
4.2 Declaration of Ethical Conduct .................................................................................. 23 
4.3 Investigators and Study Personnel ............................................................................ 23 
4.4 Randomisation ............................................................................................................ 23 
4.5 Data Management ....................................................................................................... 23 
4.6 Monitoring ................................................................................................................... 23 
4.7 Medical Monitoring ..................................................................................................... 24 
4.8 Central Review/Central Laboratory ............................................................................ 24 
4.8.1 Independent Data Monitoring Committee ................................................................... 24 
4.8.2 Central Pathology Review .......................................................................................... 24 
4.8.3 Independent Central Response Review ..................................................................... 25 
4.8.4 Central Laboratory ..................................................................................................... 25 
5 INTRODUCTION ........................................................................................................... 25 
5.1 Therapeutic Area/Background ................................................................................... 25 
5.2 Investigational Drug .................................................................................................... 26 
5.3 Study Rationale ........................................................................................................... 27 
5.4 Risk / Benefit Assessment ......................................................................................... 27 
6 STUDY OBJECTIVES ................................................................................................... 29 
6.1 Aim of the study .......................................................................................................... 29 
6.2 Primary Objective ........................................................................................................ 29 


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6.3 Secondary Objectives ................................................................................................. 29 
7 STUDY SUMMARY AND GRAPHIC ............................................................................. 29 
7.1 Overall Study Design and Plan .................................................................................. 29 
7.2 Study Diagram ............................................................................................................. 31 
7.3 Efficacy Parameters .................................................................................................... 31 
7.3.1 Primary Efficacy Variable ........................................................................................... 31 
7.3.2 Secondary Efficacy Variables ..................................................................................... 31 
7.4 Safety Variables .......................................................................................................... 31 
7.5 Pharmacokinetic Measurements ................................................................................ 31 
8 SELECTION OF SUBJECTS ........................................................................................ 32 
8.1 Number of Subjects .................................................................................................... 32 
8.2 Inclusion Criteria ......................................................................................................... 32 
8.3 Exclusion Criteria ........................................................................................................ 33 
8.4 Removal of Patients from Therapy ............................................................................ 34 
9 ASSESSMENTS AND PROCEDURES ......................................................................... 34 
9.1 Schedule Overview ..................................................................................................... 34 
9.2 STUDY PROCEDURES ................................................................................................ 37 
9.2.1 Screening ................................................................................................................... 37 
9.2.2 Patient Assignment .................................................................................................... 38 
9.2.3 Vitamin Administration ................................................................................................ 38 
9.2.4 Pralatrexate Administration Cycle 1 ............................................................................ 39 
9.2.5 Procedures for Subsequent Cycles ............................................................................ 40 
9.2.6 Early Study Termination Visit ..................................................................................... 43 
9.2.7 Safety Follow-up Visit ................................................................................................. 43 
9.2.8 Routine Follow-up Visit ............................................................................................... 44 
10 STUDY TREATMENTS AND CONCOMITANT THERAPIES ...................................... 44 
10.1 Study Treatments ...................................................................................................... 44 
10.1.1 Vitamin Administration [(Non-Investigational Medicinal Product (NIMP)] .................. 44 
10.1.2 Pralatrexate Administration [Investigational Medicinal Product (IMP)] ...................... 45 
10.2 Identity of Investigational Medicinal Product(s) ..................................................... 45 
10.2.1 Pralatrexate Formulation .......................................................................................... 45 


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10.2.2 Storage and Handling ............................................................................................... 45 
10.2.3 Packaging/Labeling .................................................................................................. 45 
10.3 Dosage and Administration ...................................................................................... 46 
10.3.1 Preparation and Dose Calculation ............................................................................ 46 
10.3.2 Administration of Study Drug .................................................................................... 46 
10.4 Treatment Duration ................................................................................................... 46 
10.5 Treatment Modifications of Pralatrexate ................................................................. 47 
10.5.1 Hematological Toxicities ........................................................................................... 48 
10.5.2 Non-Hematological Toxicities ................................................................................... 49 
10.6 Response Evaluation ................................................................................................ 49 
10.6.1 Timing of Response Evaluations .............................................................................. 49 
10.6.2 Required Procedures/Scans/Tests ........................................................................... 50 
10.6.3 Review of Response ................................................................................................ 51 
10.6.4 Disease Progression ................................................................................................ 52 
10.7 Treatment Compliance/Drug Accountability ........................................................... 52 
10.8 Concomitant Medications ......................................................................................... 52 
10.8.1 Antiemetic Therapy .................................................................................................. 52 
10.8.2 Hematopoietic Growth Factors ................................................................................. 52 
10.8.3 Other Supportive Care Medications .......................................................................... 53 
10.8.4 Radiotherapy, Cytotoxic Therapy, and Biologic or Immune Response Modifiers ...... 53 
10.8.5 Subsequent Treatment ............................................................................................. 53 
10.8.6 Therapies Not Permitted .......................................................................................... 53 
11 PLASMA PHARMACOKINETICS ............................................................................... 53 
12 REFERENCE VALUES ............................................................................................... 54 
12.1 Physical/Vital Sign Assessments............................................................................. 54 
12.2 Laboratory Assessments ......................................................................................... 54 
12.3 Additional Assessments Reference Ranges ........................................................... 55 
13 SAFETY ASSESSMENTS ........................................................................................... 55 
13.1 Adverse Events (AEs) and Serious Adverse Events (SAEs) .................................. 55 
13.2 Reporting of Adverse Events ................................................................................... 57 
13.3 Causality Assessment .............................................................................................. 58 
13.4 Severity Assessment ................................................................................................ 59 


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13.5 Pregnancy .................................................................................................................. 60 
13.6 Laboratory Abnormalities ......................................................................................... 60 
13.7 Vital Signs and Physical Examinations ................................................................... 60 
13.8 ECG Adverse Events................................................................................................. 61 
13.9 Other Safety Considerations/Risk Management ..................................................... 61 
14 STATISTICAL ANALYSES ......................................................................................... 61 
14.1 Statistical Methodology and Analytical Plans ......................................................... 61 
14.2 Statistical Considerations ........................................................................................ 62 
14.3 Analysis Populations ................................................................................................ 62 
14.4 Protocol Violations and Deviations ......................................................................... 62 
14.5 Sample Size and Power Considerations .................................................................. 63 
14.6 Primary Efficacy Variable(s) ..................................................................................... 63 
14.7 Secondary Efficacy Variable(s) ................................................................................ 64 
14.8 Exploratory Efficacy Variables ................................................................................. 65 
14.9 Subject Disposition ................................................................................................... 65 
14.10 Demographic/Baseline Analyses ........................................................................... 66 
14.11 IMP Analyses ........................................................................................................... 66 
14.12 Concomitant Medications Analyses ...................................................................... 66 
14.13 Safety Analyses/Adverse Outcomes ..................................................................... 67 
14.14 Analysis of Adverse Events ................................................................................... 67 
14.15 Laboratory Values ................................................................................................... 67 
14.16 Vital Signs ................................................................................................................ 68 
14.17 ECG .......................................................................................................................... 68 
14.18 Other Special Tests ................................................................................................. 68 
14.19 Pharmacokinetic Measurements and Analysis ..................................................... 69 
14.19.1 Drug Concentration Measurements and Analysis ................................................... 69 
14.19.2 Pharmacokinetic Measurements and Analysis ....................................................... 69 
14.20 Interim Analysis ...................................................................................................... 70 


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15 ETHICS & REGULATORY .......................................................................................... 70 
15.1 Declaration of Ethical Conduct ................................................................................ 70 
15.2 Ethical and Regulatory Review ................................................................................ 70 
15.3 Subject Information and Consent ............................................................................ 71 
15.4 Data Protection and Human Tissue Sampling ........................................................ 72 
15.5 Quality Assurance & Inspection Requirements ...................................................... 72 
16 STUDY MANAGEMENT RECORDS & PUBLICATION .............................................. 72 
16.1 Protocol Amendments .............................................................................................. 72 
16.2 Record Maintenance and Retention ......................................................................... 73 
16.3 Adherence to the Protocol........................................................................................ 74 
16.4 Discontinuation of Study .......................................................................................... 74 
16.5 Registration and Publication of Study Summary and Results ............................... 75 
17 REFERENCE LIST ...................................................................................................... 76 
18 APPENDICES ............................................................................................................. 81 
18.1 Adverse Event Reporting Process ........................................................................... 81 
18.2 REFERENCE VALUES ............................................................................................... 82 
18.2.1 Physical/Vital Sign Assessments .............................................................................. 82 
18.2.2 Laboratory Assessments .......................................................................................... 83 
18.3 ECOG Performance Scale ........................................................................................ 85 
18.4 The International Workshop Criteria (IWC) ............................................................. 86 
18.5 BSA Calculation Formula ......................................................................................... 89 
 
 
 


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LIST OF TABLES 
Table 1 Schedule of Visits and Procedures/CRF Modules .................................................. 35 
Table 2 Pralatrexate Treatment Modifications for Hematological Toxicities ......................... 48 
Table 3 Pralatrexate Treatment Modifications for Mucositis ................................................ 49 
Table 4 Pralatrexate Treatment Modifications for All Other Non-hematological Treatment-
related Toxicities ................................................................................................... 49 
Table 5 Criteria Used to Identify Clinically Notable Vital Sign Abnormalities ........................ 82 
Table 6 Clinical Laboratory Tests ........................................................................................ 83 
Table 7 Laboratory Ranges Used to Identify Markedly Abnormal Laboratory Values .......... 84 
 
LIST OF FIGURES 
Figure 1 Study diagram ....................................................................................................... 31 
Figure 2 Flow diagram for AE reporting ............................................................................... 81 
 


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3 LIST OF ABBREVIATIONS 
β-hCG 
beta-human chorionic gonadotropin 
μL 
Microliter 
μmol 
Micromole 
AE 
adverse event 
AILD 
angioimmunoblastic lymphoma 
ALCL 
anaplastic large cell lymphoma 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMB 
bone marrow biopsy 
BSA 
body surface area 
°C  
degrees centigrade 
CHOP 
cyclophosphamide, doxorubicin, vincristine, prednisone 
CI 
confidence interval 
CLnonren 
nonrenal clearance 
CLren 
renal clearance 
CLtot 
total clearance 
cm 
centimetre 
Cmax 
maximum observed concentration 
CNAP 
Chest, neck, abdomen, pelvis 
CNS 
central nervous system 
CRA 
clinical research associate 
CR 
complete response 
CRF 
case report form 
CRu 
complete response unconfirmed 
CT 
computed tomography 
CTA 
Clinical Trial Agreement 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTCL 
cutaneous T-cell lymphoma 
DHFR 
dihydrofolate reductase 
dL 
decilitre 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
EBV 
Epstein-Barr virus 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EPOCH 
etoposide, doxorubicin, vincristine, prednisone, 
°F  
degrees Fahrenheit 
FDA 
Food and Drug Administration 
fe 
fractional excretion 
FPGS 
folylpolyglutamate synthetase 
g 
gram 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GFR 
Glomerular filtration rate 
GGH 
gamma-glutamyl hydrolase 
GI 
gastrointestinal 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
Hct 
hematocrit 
Hcy 
homocysteine 


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Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
HTLV 
human T-cell leukemia virus 
IB 
Investigator’s Brochure 
IC 
informed consent 
ICE 
ifosfamide, carboplatin and etoposide 
ICH 
International Conference on Harmonization 
IM 
intramuscular 
IMP                                Investigational Medicinal Product 
NIMP                             Non-Investigational Medicinal Product 
IND 
investigational new drug 
IRB 
Institutional Review Board 
IV 
intravenous 
IWC 
International Workshop Criteria 
kg 
kilogram 
Ki 
inhibitory constant 
Km 
binding constant 
L 
litre 
LC/MS/MS 
liquid chromatography/ mass spectrometry/ mass spectrometry 
LD 
longest diameter 
LDH 
lactic dehydrogenase 
m2 
square meter 
mg 
milligram 
min 
minute 
mL 
milliliter 
mm 
millimeter 
mOsmol 
milliosmole 
MRI 
magnetic resonance imaging 
MTX 
methotrexate 
N 
number 
NaCl 
sodium chloride 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphomas 
NK 
natural killer 
No. 
number 
NOS 
not otherwise specified 
NSCLC 
non-small cell lung cancer 
OS 
overall survival 
PBS 
phosphate buffered saline 
PBSCT 
peripheral blood stem cell transplant 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PDX 
pralatrexate 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
pM 
picomolar 
pmol 
picomole 
PO 
by mouth 
PR 
partial response 
pralatrexate 
(RS)-10-propargyl-10-deazaaminopterin 
PT 
prothrombin time 
PTCL 
peripheral T-cell lymphoma 
PTT 
partial thromboplastin time 
q 
every 
QD 
once a day 
RD 
relapsed disease 


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RFC 
reduced folate carrier 
RR 
respiratory rate 
RT 
radiation therapy 
SAE 
serious adverse event 
SAER 
serious adverse event report 
SD 
stable disease 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SPD 
sum of the products of the greatest diameters 
t½ 
half life 
t1/2Z 
terminal phase half-life 
tmax 
time of Cmax observation 
T/NK 
T/natural killer 
T-PLL 
T-cell prolymphocytic leukemia 
TTP 
time to progression 
ULN 
upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
Vdss 
steady state volume of distribution 
Vmax 
maximum rate constant 
WBC 
white blood cells 
WHO 
World Health Organization 
 
 
 


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4 STUDY CONDUCT AND OVERSIGHT 
4.1 Sponsor 
This study will be conducted by qualified Investigators under the Sponsorship of Mundipharma 
(China) Pharmaceutical Co. LTD. 
4.2 Declaration of Ethical Conduct 
This study will be conducted in accordance with the standard operating practices of the 
Sponsor and Contract Research Organisation (CRO), which are designed to ensure 
adherence to Good Clinical Practice (GCP) guidelines as described in Section 15 of this 
protocol. 
4.3 Investigators and Study Personnel 
The study will be conducted at approximately 15 sites in China. 
4.4 Randomisation 
This is a non-randomised study.   
4.5 Data Management 
Data management and statistical analyses will be the responsibility of the Data Management 
and Statistics department at the CRO’s site.  Data from Case Report Forms (CRFs) including 
subject diaries, questionnaires and other external data, e.g. laboratory data, will be entered 
into a clinical database as specified in the CRO’s data management plan.  Quality control and 
data validation procedures will be applied to ensure the validity and accuracy of the clinical 
database.  The Monitoring Plan and Data Management Plan will detail the data entry, cleaning, 
clarification, and validation procedures to be followed by all relevant study staff. 
Data collection will be done by EDC.  Data will be transferred to the CRO database and an 
electronic copy supplied to the site.  Laboratory data collection will be specified in the Data 
Management Plan. 
4.6 Monitoring 
The study will be monitored by qualified personnel from the CRO.  The Monitoring Plan for the 
study will detail this process.  The Investigator will allow monitoring, audit and inspection of the 
clinical, laboratory, and pharmacy facilities as required, to assure compliance with Good 
Clinical Practice and Good Laboratory Practice.  The EDC system and subject’s corresponding 
original medical records (source documents) are to be fully available for review by the CRO 
representatives at regular intervals.  These reviews verify adherence to study protocol and 
data accuracy in accordance with local regulations and Good Clinical Practice.  All records at 


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the site are subject to inspection by the local competent authorities as well as by Sponsor’s 
QA department. 
4.7 Medical Monitoring 
The name of the Study Physician along with the telephone and fax numbers of the other 
contact persons are listed in the study site file. 
4.8 Central Review/Central Laboratory  
4.8.1 Independent Data Monitoring Committee 
The sponsor or designee will coordinate an Independent Data Monitoring Committee (IDMC), 
consisting of 3 members who are not directly involved with the conduct of this study. The 
IDMC will review the safety data periodically and provide recommendations whether to stop or 
continue the trial based on their safety findings. The pralatrexate dose reduction to 20 
mg/m2/week for the remaining study period may also be recommended by IDMC if there are 
significant safety concerns on the treatment dose of 30 mg/m2/week. 
The IDMC will meet at least 2 times to review clinical data: after the first 15 subjects complete 
cycle 1 and after 50% of the subjects to be recruited complete cycle 1. The working 
procedures of the Committee will be outlined in an IDMC Charter.  
4.8.2 Central Pathology Review 
The diagnosis of eligible PTCL histopathological subtype will be confirmed by Central 
Pathology Review.  
The Central Pathology Review will be provided with tissue slides to confirm histopathology, 
and bone marrow aspirate and core biopsy slides to confirm presence or absence of bone 
marrow involvement, along with any supporting documentation. 
For confirmation of treatment response, the following pathology tissue slides should be 
submitted to Central Pathology Review: 
 
If a subject is reported by the investigator to have a complete response (CR), and the 
subject’s screening core bone marrow biopsy is positive or indeterminate for involvement 
of lymphoma, a repeat core bone marrow biopsy is required and the slides should be 
submitted 
 
If bone marrow aspirate or peripheral blood flow cytometry are performed, the result 
reports should be submitted  
 
If a tumor biopsy is performed to confirm a response evaluation, the slides should be 
submitted 
The details for Central Pathology Review will be described in the Study Manual.  


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4.8.3 Independent Central Response Review 
All treatment responses will be eventually evaluated by the Independent Central Review 
Committees as described in the Study Charters.   
All radiographic images and digital photographs for subjects with cutaneous disease will be 
sent to the Independent Central Imaging Laboratory for the independent Central Radiology 
Review. The details will be described in the Site Imaging Manual and Independent Radiology 
Review Charter. 
If applicable, all slides of tumor biopsies, core bone marrow biopsies or bone marrow aspirate, 
and results of peripheral blood flow cytometry will be collected for Central Pathology Review 
as  confirmation as described in Site Pathology manual and Independent Pathology Review 
Charter.  
Independent Central Oncology Review will be conducted by utilizing International Working 
Group Criteria (IWC, see appendix 18.4). The final response review will be performed by 
combining relevant clinical evidences (e.g., physical examination findings of liver and spleen 
etc.), Laboratory results (e.g., LDH), central radiology review results and central pathology 
review results. The details will be described in the Central Oncology Reviewer Charter. 
Detailed description and measurement of tumor burden and eventual evaluation of the 
treatment response, will be reported through the Independent Response Central Review. 
However, the investigators will also assess response according to the IWC but will only report 
their overall response evaluation on the CRF.  
4.8.4 Central Laboratory 
A central laboratory will be used for pharmacokinetic (PK) analyses.  
At each site, the local laboratory will be used for the hematology, chemistry, and pregnancy 
testing to assess study eligibility and safety. All laboratory data locally collected by study sites 
will be employed to analyze in corresponding study sites. 
5 INTRODUCTION 
5.1 Therapeutic Area/Background  
T-cell lymphomas represent a very heterogenous array of aggressive non-Hodgkin’s 
lymphomas (NHLs) and typically account for approximately 5-10% of all  NHL cases in western 
countries and about 10-20% in Asian countries (Vose J et al., 2008). According to the most 
recent World Health Organization (WHO) classification schema published in 2008, mature T-
cell lymphomas are divided into four different subcategories, including nodal, extranodal, 
cutaneous, and leukemic, each based on the predominant clinical behavior of that disease 
entity. There are considered to be at least 22 distinct sub-types of T-cell lymphoma distributed 


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among the four different subcategories. Most PTCL subtypes are, considered highly 
aggressive diseases that respond poorly to conventional chemotherapy. 
The most common varieties are the nodal types, which include PTCL not otherwise specified, 
anaplastic large cell lymphomas, and angioimmunoblastic T-cell lymphomas.  
For most subtypes of PTCL, the frontline treatment regimen is typically a combination 
chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or 
EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, prednisone) or other multi-
drug regimens. Because most PTCL patients will relapse, some oncologists recommend giving 
high-dose chemotherapy followed by an autologous stem cell transplant to some patients who 
had a good response to their initial chemotherapy program. While promising, there is no firm 
clinical data to support that undergoing a transplant in this setting is better than not undergoing 
a transplant. 
Few studies that specifically investigated optimal treatment options for patients with relapsed 
or refractory PTCL have been conducted. High-dose therapy followed by an autologous stem 
cell transplant (SCT), or less commonly, an allogeneic SCT, is a common treatment goal for 
patients with relapsed and refractory T-cell lymphomas. However, peripheral blood SCT 
(PBSCT) has been successful only in patients with disease responsive to chemotherapy. The 
remainder of patients who have either refractory disease or are not candidates for PBSCT 
have historically been destined to succumb to their disease.  
As PTCL is usually aggressive with low survival rate and the disappointing outcomes of the 
available therapies for PTCL, it is in need of additional new treatment options. This is 
especially true for subjects with relapsed or refractory disease who typically have a limited 
response to salvage therapy and an extremely poor overall survival (Campo et al., 1998).  
PTCL has been thought to occur more frequently in Asia. It was reported that frequencies of 
PTCL in Vancouver to be 1.6% of all NHL compared to 18.3% in Hong Kong (Tang. et al., 
2010). The frequencies of PTCL subtypes vary by geographic region. For example, NK-cell 
lymphomas (NKTCL) were reported more common in Asia and are associated with Epstein-
Barr virus (Dearden et al., 2011). FDA has approved new emerging drugs for PTCL in most 
recent years, however, they are still need to be investigated systematically to prove the 
efficacy and safety in patients in Asia.  
5.2 Investigational Drug 
Pralatrexate is an antineoplastic folate analog designed to preferentially accumulate in cancer 
cells. Pralatrexate is an analog of the widely used antifolate, methotrexate. In comparison to 
methotrexate, pralatrexate has demonstrated superior in vitro and in vivo activity in leukemia, 
lymphoma, and breast and lung cancer models (DeGraw et al., 1993; Sirotnak et al., 1998; 
Toner et al., 2006; Wang et al., 2003). Furthermore, compared to methotrexate, pralatrexate is 
more effectively taken up by cancer cells through increased affinity for the reduced folate 


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carrier 1 (RFC-1) and more efficiently polyglutamylated by folylpolyglutamyl synthetase (FPGS) 
(Sirotnak et al., 1998).  
Up to June 2013, twelve Phase 1 or 2 clinical studies with pralatrexate have been completed, 
and 7 Phase 1, 2 or 3 clinical studies with pralatrexate are ongoing. These studies with 
pralatrexate alone or in treatment combination were conducted in several tumour types 
including non-small cell lung cancer (NSCLC), malignant pleural mesothelioma (MPM), 
relapsed or refractory aggressive lymphomas, relapsed or refractory cutaneous T-cell 
lymphomas, advanced or metastatic relapsed transitional cell carcinoma of the urinary bladder, 
and relapsed or refractory PTCL.  
A clinical trial (PDX-008) has been conducted with pralatrexate as a registration study for the 
treatment of patients with relapsed or refractory PTCL. This was a Phase 2, single arm, non-
randomised, open-label, multi-center, international study designed to evaluate the safety and 
efficacy of pralatrexate when administered concurrently with vitamin B12 and folic acid 
supplementation to subjects with relapsed or refractory PTCL.  Based on the study of PDX-
008, the United States (US) Food and Drug Administration (FDA) granted accelerated 
approval in September 2009, for the use of pralatrexate in the treatment of patients with 
relapsed or refractory PTCL at a dose of 30 mg/m2/week for 6 weeks in a 7-week cycle.  
5.3 Study Rationale 
The study is designed to confirm the safety and efficacy of pralatrexate in a Chinese patient 
population to support registration approval in China.  
As T-cell malignancies are very uncommon and are made up of multiple varied sub-types, 
there are few studies that have specifically investigated optimal treatment options for subjects 
with relapsed or refractory disease. Since the primary endpoint of response rate can be 
directly attributed to the antitumor activity of the drug administered, a single-arm study with 
further secondary endpoints of duration of response, time to response, PFS and OS is 
considered appropriate to assess efficacy in heavily pre-treated PTCL subjects with relapsed 
or refractory tumors. 
5.4 Risk / Benefit Assessment 
Approximately 944 patients have been enrolled in the pralatrexate clinical development 
program and approximately 797 subjects have received pralatrexate. In addition, 638 patients 
have received pralatrexate in Investigator Sponsored Studies (ISS) and 38 patients have 
received pralatrexate in Named Patient Programmes (NPP). (Pralatrexate DSUR August 2014) 
As per the current IB for praletraxate (October 2013), the most frequently occurring treatment-
related AEs in the 767 patients were stomatitis (n = 473, 62%), fatigue (n = 305, 40%), nausea 
(n = 275, 36%), and epistaxis (n = 166, 22%). The most frequently occurring treatment-related 
Grade 3 or higher AEs in patients who received pralatrexate across all studies were stomatitis 


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(n = 154, 20%), thrombocytopenia (n = 95, 12%), neutropenia (n = 93, 12%), anemia (n = 64, 
8%), lymphopenia (n = 36, 5%), and fatigue (n = 36, 5%). 
In the PDX-008 study of pralatrexate in patients with relapsed or refractory PTCL, 109 patients 
were considered evaluable for efficacy. Twenty-nine percent (n = 32) of evaluable patients 
experienced either a CR, a CRu, or a PR, as assessed by central independent review. Thirty-
nine percent of patients (n = 43) experienced either a CR/CRu or PR, as assessed by the 
study investigators. 
Sixty-nine patients (63%) in the efficacy analysis set did not have evidence of response to their 
most recent prior therapy. Of these 69 patients, 17 patients (25%) responded to pralatrexate 
as assessed by central review per IWC. For the overall efficacy analysis set, 26 patients (24%) 
did not have evidence of response to any prior therapy. Of these 26 patients, 5 patients (19%) 
responded to pralatrexate per IWC. 
The Kaplan-Meier estimate for the median duration of response assessed by central review 
using IWC for the 32 responding patients, was 306 days (95% confidence interval [CI], 103-not 
estimable) or 10.1 months, with a range of 1-673 days. The median duration of response 
based on response assessed by local investigator, based on 43 responding patients, was 246 
days (95% CI, 154-379) or 8.1 months, with a range of 1-677 days. 
The demonstrated efficacy of pralatrexate in relapsed/refractory PTCL from the PDX-008 study 
led to accelerated approval on 24 Sep 2009 allowing marketing of the drug in the US as 
FOLOTYN (pralatrexate injection) for use in this patient population. Pralatrexate has been 
available for commercial distribution in the US since October 2009. 
Responses have also been observed and reported in patients who received pralatrexate with 
T-cell and B-cell lymphoma (studies PDX-02-078 and PDX-009), CTCL (PDX-010), HL (PDX-
009), NSCLC (PDX-97-006 and PDX-007), and advanced solid tumors (PDX-99-083). In 
addition, efficacy data from a study in NSCLC (PDX-012) showed an estimated difference in 
OS favoring pralatrexate over erlotinib in the full analysis set, the primary efficacy set, and 
certain subsets. 
Patients with lymphoproliferative malignancies, including HL and NHL, particularly T-cell and 
B-cell lymphomas, are in need of additional treatment options. This is especially true for 
patients with recurrent or refractory disease who typically have a limited response to salvage 
therapy and an extremely poor overall survival. Nearly all of the patients were heavily 
pretreated and had failure with or became refractory to prior therapies. Results of PDX-008, 
PDX-02-078, PDX-009, and PDX-010 provide evidence that patients with lymphoproliferative 
malignancies have shown significant response to pralatrexate therapy. 
Given the poor prognosis for patients with advanced, relapsed, or refractory solid tumors in 
general, there is a significant need for new effective agents in this patient population as well. In 
those patient populations (both lymphoproliferative malignancies and solid tumors) for which 


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responses to pralatrexate have been observed, the efficacy of pralatrexate may be studied 
further. 
6 STUDY OBJECTIVES 
6.1 Aim of the study 
The aim of the study is to confirm the efficacy and safety of pralatrexate for the treatment of 
Relapsed or Refractory PTCL in Chinese population.  
 
6.2 Primary Objective 
The primary objective of this study is to confirm the objective response rate (ORR) among 
Chinese subjects with relapsed or refractory PTCL treated with pralatrexate together with 
concurrent vitamin B12 and folic acid supplementation. 
6.3 Secondary Objectives 
The secondary objectives include: 
 
To evaluate further efficacy parameters (Duration of Response; Time to Response; 
Progression-Free Survival; Overall Survival) among Chinese subjects with relapsed or 
refractory PTCL treated with pralatrexate together with concurrent vitamin B12 and folic 
acid supplementation 
 
To evaluate the safety of pralatrexate with concurrent vitamin B12 and folic acid 
supplementation when administered to Chinese subjects with relapsed or refractory PTCL  
 
To determine the pharmacokinetic (PK) profile of pralatrexate among Chinese subjects 
with PTCL when administered with vitamin B12 and folic acid supplementation 
7 STUDY SUMMARY AND GRAPHIC 
7.1 Overall Study Design and Plan 
This is a single arm, open-label, multi-center study designed to evaluate the efficacy and 
safety of pralatrexate in Chinese subjects when administered concurrently with vitamin B12 
and folic acid supplementation to subjects with relapsed or refractory PTCL.  
This study includes 3 phases: Screening, Treatment (pralatrexate) and Follow-up phases.  
Screening Phase: 
The screening phase will be of up to 28 days duration (depending on availability of lab results). 
All potential study subjects will be screened and determine the eligibility prior to enrolment. 
The eligible subjects will begin to receive vitamin supplementation at screening phase. 


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Unless otherwise specified, the protocol defined procedures and evaluations (See Table 1.  
Schedule of Visits and Procedures) will be performed within 28 days prior to the projected start 
of pralatrexate administration (cycle 1, dose 1). 
Treatment (pralatrexate) Phase: 
The start of study treatment is defined as the initiation of pralatrexate treatment. Vitamin 
supplementation will be initiated at least 10 days prior to pralatrexate administration on cycle 1, 
dose 1. Once the patient is on-study, the dosing of vitamin supplementation must adhere to 
the schedule defined by the protocol. 
Evaluation of response must be performed within 7 days prior to the projected first dose of 
cycle 2-4 and then within 7 days prior to the projected first dose of every even-numbered 
subsequent cycle (i.e. prior to cycles 6, 8, etc). Although radiological response assessments 
have been scheduled every 14 weeks, unscheduled radiological response assessments will be 
performed earlier if clinical progression is suspected. 
Treatment with pralatrexate will continue until 24 months of administration, or until documented 
disease progression; unacceptable adverse event(s) indicating intolerance of the lowest study 
dose allowed (20 mg/m2/week); omission of 3 sequential doses of pralatrexate due to a 
treatment-related AE; 3-week lapse between pralatrexate doses; development of an AE, 
intercurrent illness, condition, or procedural complication that may interfere with the subject’s 
participation; investigator’s decision to withdraw the subject; subject withdraws consent; 
pregnancy of the subject; noncompliance with trial treatment or procedure requirements; or 
administrative reasons.  
Follow-up phase: 
All patients who received at least 1 dose of pralatrexate are to attend the Safety Follow-up 
Visit [30 (± 5) days after the last dose of pralatrexate] and the protocol defined procedures and 
evaluations will be performed.  
After the Safety Follow-up Visit, Routine Follow-up Visits will be based on standard clinical 
care. All patients who received at least 1 dose of pralatrexate are to attend Routine Follow-up 
Visits, which will occur every 3 months (± 2 weeks) for determination of progression of disease, 
subsequent treatment initiation for T-cell lymphoma and survival after the Safety Follow-up 
Visit for a total duration of 24 months after the last dose of pralatrexate. The protocol-defined 
procedures/evaluations should be performed at each Routine Follow-up Visit. 
 


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7.2 Study Diagram 
Figure 1 Study diagram 
 
7.3 Efficacy Parameters 
7.3.1 Primary Efficacy Variable 
  Objective response rate by International Working Criteria and per central review 
7.3.2 Secondary Efficacy Variables 
  Duration of Response (DOR) 
  Time to Response (TTR) 
  Progression-Free Survival (PFS)  
  Overall Survival (OS) 
7.4 Safety Variables 
  Treatment emergent AEs  
  Physical examinations  
  Clinical laboratory values 
7.5 Pharmacokinetic Measurements 
Pharmacokinetic evaluations will be performed. The PK profile of R-pralatrexate and S-
pralatrexate will be determined in 15 subjects at pre-selected sites. 
<28 
days 
 
Safety and 
Routine 
follow up 
24 
months 
after last 
dose 


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Standard PK parameters will be determined for both enantiomers in plasma (area under the 
curve [AUC], steady state volume of distribution [Vdss], steady state clearance [CLss], 
maximum observed concentration [Cmax], trough observed plasma concentration [Ctrough], 
time of Cmax observation [tmax] and terminal phase half-life [t1/2Z]). Collection of plasma to 
determine the full PK profile will be performed in 15 subjects at pre-selected sites. 
8 SELECTION OF SUBJECTS 
8.1 Number of Subjects 
 Eligible patients will be enrolled to the study to achieve 68 evaluable subjects.  
 
8.2 Inclusion Criteria 
Subjects to be included in the study are those who meet all of the following criteria: 
1. Has histologically/cytologically confirmed PTCL, using the World Health Organization 
(WHO) disease classification:  
a. PTCL not otherwise specified (NOS) 
b. Angioimmunoblastic T-cell lymphoma 
c. 
Anaplastic large cell lymphoma, ALK+ 
d. Anaplastic large cell lymphoma, ALK- 
e. Extranodal NK/T-cell lymphoma – nasal type 
f. 
Enteropathy-associated T cell lymphoma 
g. Hepatosplenic T-cell lymphoma 
h. Subcutaneous panniculitis-like T-cell lymphoma 
i. 
Adult T-cell lymphoma/leukemia (human T-cell leukemia virus [HTLV] 1+)   
j. 
Aggressive NK-cell leukemia  
k. 
Transformed mycosis fungoides 
2. Has documented progressive disease (PD) after at least 1 prior systemic treatment.  
3. May not have received an experimental drug or biologic as their only prior therapy. Patient 
must have clear PD after the last treatment received. Patient should have at least 1 biopsy 
from initial diagnosis or in the relapsed setting to confirm the diagnosis of PTCL. Patient 
must have recovered from the toxic effects of prior therapy.   
4. Subjects with an enlarged lymph node or extranodal mass lesion clearly measurable in two 
perpendicular directions and greater than 1.5 cm maximum diameter on computed 
tomography performed within 14 days prior to study enrollment.  
5. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.  
6. At least 18 years of age.  
7. Expected life expectancy ≥ 3 months. 
8. Adequate hematological, hepatic, and renal function as defined by:  


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a. Absolute neutrophil count (ANC) ≥ 1000/uL (or 1  109/L), platelet count ≥ 
100,000/uL (or 100  109/L) (at both screening and within 3 days prior to dosing on 
cycle 1, day 1); 
b. Total bilirubin ≤1.5 mg/dL, aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 2.5 X upper limit of normal (ULN) (AST/ALT < 5 X ULN 
if documented hepatic involvement with lymphoma); 
c. Creatinine ≤ 1.5 mg/dL(or 132.6 µmol/L) or a calculated creatinine clearance ≥ 50 
mL/min. 
9. Women of childbearing potential must have agreed to practice a medically acceptable 
contraceptive regimen from study treatment initiation until at least 30 days after the last 
administration of pralatrexate and must have a negative serum pregnancy test within 14 
days prior to the first day of study treatment. Subjects who are postmenopausal for at least 
1 year (> 12 months since last menses) or are surgically sterilized did not require this test. 
10. Men who are not surgically sterile must agree to practice a medically acceptable 
contraceptive regimen from study treatment initiation until at least 90 days after the last 
administration of pralatrexate.  
11. Patient gave written informed consent (IC).  
 
8.3 Exclusion Criteria 
Subjects to be excluded from the study are those who meet any of the following criteria: 
1. Subject has: 
a. Precursor T-cell lymphoma or leukemia  
b. T-cell prolymphocytic leukemia (T-PLL) 
c. T-cell large granular lymphocytic leukemia 
d. Mycosis fungoides, other than transformed mycosis fungoides 
e. Sézary syndrome 
f. Primary cutaneous CD30+ T-cell disorders: Lymphoid papulosis and primary 
cutaneous anaplastic large cell lymphoma 
2. Active concurrent malignancy (except non-melanoma skin cancer or carcinoma in situ of 
the cervix). If there is a history of prior malignancy, the patient must be disease-free for ≥ 
5 years. 
3. Congestive heart failure Class III/IV according to the New York Heart Association’s Heart 
Failure guidelines. 
4. Human immunodeficiency virus (HIV)-positive diagnosis. 
5. Has, or history of, brain metastases or central nervous system (CNS) disease. 
6. Active uncontrolled infection, underlying medical condition including unstable / uncontrolled 
chronic diseases or other serious illness that would impair the ability of the patient to 
receive protocol treatment. 
7. Has major surgery within 2 weeks of study entry. 


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8. Receipt of any conventional chemotherapy or radiation therapy (RT) within 4 weeks (6 
weeks for nitrosoureas or mitomycin C) prior to study treatment or planned use during the 
course of the study. 
9. Receipt of corticosteroids within 7 days of study treatment, unless patient has been taking 
a continuous systemic dose of no more than 10 mg/day or equivalent dose of prednisone, 
or a local or inhale or intranasal administration at fixed doses for at least 1 month prior to 
study treatment and tumor shrinkage is not observed. 
10. Use of any investigational drugs, biologics, or devices within 4 weeks prior to study 
treatment or planned use during the course of the study. 
11. Receipt of anti-tumor antibody therapy within 100 days prior to study treatment. 
12. History of allogeneic hematopoietic stem cell transplantation. Or subjects with a history of 
autologous hematopoietic stem cell transplantation within 100 days prior to study treatment.  
13. Previous exposure to pralatrexate. 
14. Patient is pregnant or breast-feeding. 
 
 
8.4 Removal of Patients from Therapy 
Study treatment discontinuation is defined as stopping administration of pralatrexate. Once 
pralatrexate is permanently discontinued, vitamin supplementation should continue at least 1 
month after the last pralatrexate dose, or longer at the discretion of the investigator. Study 
treatment will be discontinued for the following reason(s): 
 
 
Development of PD 
 
Initiation of radiotherapy or systemic chemo/biologic therapy for T-cell lymphoma 
 
Development of an unacceptable AE indicating intolerance of the lowest study dose 
allowed (20 mg/m2/week) 
 
Omission of 3 sequential doses of pralatrexate due to a treatment-related AE 
 
3-week lapse between pralatrexate doses 
 
Development of an AE, intercurrent illness, condition, or procedural complication that 
may interfere with the subject’s participation 
 
investigator’s decision to withdraw the subject 
 
Subject withdraws consent 
 
Pregnancy of the subject 
 
Noncompliance with trial treatment or procedure requirements 
 
Administrative reasons 
 
 
9 ASSESSMENTS AND PROCEDURES 
9.1 Schedule Overview 


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Table 1 Schedule of Visits and Procedures/CRF Modules  
CYCLE 1 
SUBSEQUENT CYCLES 
FOLLOW-UP 
Visit 
28 days Prior to 
Pralatrexate 
Dose 1 
10 Days Prior to 
Pralatrexate 
Dose 1 through 
Cycle 1, Dose 1 
 
Cycle 1, 
Dose 1 
24, 48, 72 
Hours 
 post-end 
pralatrexate 
Weeks 
2-6 
Within 7 Days 
Prior to 
Projected 
Dose 1 
Dose 1 
Weeks 2-6
Early Study 
Termination 
Visit 
Safety FU Visit 
Routine FU 
Eligibility Criteria/Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
Document Histopathology 
X1 
 
 
 
 
 
 
 
 
 
 
Central pathology review2 
            X 
 
 
 
 
 
 
 
 
 
 
Unilateral bone marrow biopsy and 
aspirate 
X3 
 
 
 
 
X5 
 
 
X5,6 
X7 
      X5 
CT of Chest, Neck, Abdomen, Pelvis 
(CNAP) 
X 
 
 
 
 
X5 
 
 
X5,6 
X7 
X5 
Other imaging of disease site other than 
CNAP3 
X4 
 
 
 
 
X4,5 
 
 
X4, 5, 6 
X4,7 
X4,5 
Medical photography with ruler 
measurement of cutaneous lesions4 
X4 
 
 
 
 
X4,5 
 
 
X4, 5, 6 
X4,7 
X4,5 
Record Prior Treatment and 
Response for PTCL 
X 
 
 
 
 
 
 
 
 
 
 
Record Medications 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
Record Baseline Symptoms 
 
X 
 
 
 
 
 
 
 
 
 
Record AEs/Attribution 
 
X 
 
X 
X 
 
X 
X 
X 
X8 
      X8 
Record ECOG Performance Status 
X 
 
 
 
X9 
X 
 
 
X 
X 
 
Physical Examination 
X 
 
 
 
X9 
X 
 
 
X 
X 
 
Record Height in cm 
 
X10 
 
 
 
 
 
 
 
 
 
Record Weight in kg 
 
X10 
 
 
 
X 
 
 
 
 
 
Calculate BSA 
 
X10 
 
 
 
X 
 
 
 
 
 
Vitamin B12 Administration  
 
X11 
 
 
X11 
 
X11 
X11 
 
 
 
Folic Acid Administration  
 
X12 
 
 
 
 
 
 
 
 
 
Folic Acid Patient Diary Review 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Pralatrexate administration13 
 
 
X 
 
X 
 
X 
X 
 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 


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CYCLE 1 
SUBSEQUENT CYCLES 
FOLLOW-UP 
Visit 
28 days Prior to 
Pralatrexate 
Dose 1 
10 Days Prior to 
Pralatrexate 
Dose 1 through 
Cycle 1, Dose 1 
 
Cycle 1, 
Dose 1 
24, 48, 72 
Hours 
 post-end 
pralatrexate 
Weeks 
2-6 
Within 7 Days 
Prior to 
Projected 
Dose 1 
Dose 1 
Weeks 2-6
Early Study 
Termination 
Visit 
Safety FU Visit 
Routine FU 
Hematology14 
X 
X15 
 
 
X 
 
X 
X 
X 
X 
 
Chemistry14 
X 
X15 
 
 
X 
X16 
X 
X17 
X 
X 
 
Pregnancy Test (Urine or serum β-HCG) 
18
X 
X 
 
 
 
X 
 
 
 
 
 
Blood for pralatrexate PK19 
 
 
X 
X 
X 
 
 
 
 
 
 
Record Subsequent Treatment for T-cell 
Lymphoma 
 
 
 
 
 
 
 
 
X
X 
X 
Record Date of Death 
 
 
 
 
 
 
 
 
 
 
X 
Foot notes: 
1) 
Include histopathology from original diagnosis of T-cell lymphoma and/or from tumor biopsy in relapse setting.  
2) 
EBV will be tested by the central pathology review laboratory with the submitted slides. 
3) 
Within 28 days of pralatrexate dose 1.  
4) 
Perform if applicable to patient.  
5) 
Evaluation of response must be performed within 7 days prior to the projected first dose of the cycle 2-4 and then within 7 days prior to the projected first dose of every even-
numbered subsequent cycle (ie, prior to cycles 6, 8, etc).  
6) 
The procedures outlined will be conducted, if a patient withdraws informed consent and refuses to attend the Safety Follow-up Visit and Routine Follow-up Visits. If possible, the 
procedures will be performed at the time the patient withdraws consent.  
7) 
All subjects who received at least 1 dose of pralatrexate are to attend the safety follow-up visit 30 (± 5) days after the last dose of pralatrexate. 
8) 
Only until subsequent therapy has started.  
9) 
Cycle 1, week 3 only.  
10) May be done up to 3 days prior to cycle 1, dose 1.  
11) Vitamin B12, 1 mg IM q 8-10 weeks, initiated as described.  
12) Folic acid, 1.2 mg, by mouth daily, initiated as described. 
13) Administer pralatrexate IV push over 3-5 minutes.   
14) Laboratory tests will be conducted in local laboratory, central laboratory, and laboratory for PK test respectively.  
15) Chemistry labs (including LDH) must be completed within 3 days prior to cycle 1, dose 1. Hematology must be completed within 1 day prior to dosing on cycle 1, dose 1 and platelet 
count must have remained ≥100,000/µL (or 100  109/L) to proceed with pralatrexate dosing). 
16) Collect LDH prior to first dose of cycle 2-4 and then prior to every even-numbered subsequent cycles (ie, prior to cycles 6, 8, etc.). 
17) Collect blood for chemistry panel prior to the fourth dose of each cycle. 
18) Serum β-human chorionic gonadotropin [β-hCG] pregnancy test for women who are not postmenopausal or surgically sterile will be performed within 14 days prior to cycle 1, dose 1. 
A urine pregnancy test should also be performed within 72 hours prior to first dose of each treatment cycles. 
19) Collection of plasma to determine the full PK profile will be performed in 15 subjects at pre-selected sites. Cycle 1, week 1, 6: Pre-injection, end-injection, 30 and 60 minutes, and 3, 
5, 8, 12, 18, 24, 48, and 72 hours post-end injection. Cycle 1, week 2-5: Pre-injection.


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9.2 STUDY PROCEDURES 
9.2.1 Screening 
The procedures and evaluations required for enrolment into the study are summarized below. 
All potential study subjects will be screened and eligibility determined prior to enrolment.  
Unless otherwise specified, the following procedures and evaluations will be performed within 
28 days prior to the projected start of pralatrexate administration (cycle 1, dose 1): 
 
1. Obtain written IC. 
2. Review eligibility criteria. 
3. Review medical chart for past medical/surgical history. 
4. Record medications and prior treatment for PTCL. 
5. Record response to prior treatment(s) for PTCL. 
6. Document histopathology from: 
• Original diagnosis of PTCL, and/or 
• Tumor biopsy in the relapsed setting 
Send the pathology specimen(s) to central pathology review (see Study Manuals provided 
by the sponsor for detailed guidance regarding sample requirements and the preparation 
and shipment of slides).  
7. 
Documentation of known measurable disease parameters by the following radiographic 
imaging procedures (the imaging exam do not need to be repeated if it is performed within 
14 days prior to pralatrexate dose 1): 
• Contrast-enhanced CT of chest, neck, abdomen, and pelvis. Please refer to the site 
imaging manual issued by central imaging lab for detailed technical requirements 
• Other imaging techniques documenting disease site other than chest, neck, abdomen, 
and pelvis, if applicable  
8. Documentation of any cutaneous lesions using medical photography and ruler 
measurements of each lesion, if applicable (refer to Study Manuals). 
9. Unilateral bone marrow aspirate and biopsy assessment within 28 days of pralatrexate 
dose 1.  If bone marrow aspirate flow cytometry has been performed, send result reports 
to the central pathology reviewer. 
10. Obtain a 12-lead electrocardiogram (ECG). Repeat ECG during study only if clinically 
indicated. 
11. Perform a comprehensive physical examination. 
12. Assess and record ECOG Performance Status.  
13. Local laboratory:  Collect blood for hematology, chemistry (including serum β-human 
chorionic gonadotropin [β-hCG] pregnancy test for women who are not postmenopausal 
or surgically sterile [within 14 days prior to cycle 1, dose 1]). 


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14. Collect blood for serum creatinine, calculate creatinine clearance using the glomerular 
filtration rate (GFR) according to the Cockroft and Gault Equation: 
GFR* = (140 – age [years]) x actual body weight (kg) 
72 x serum creatinine 
*For female subjects, multiply by 0.85 
15. If peripheral blood flow cytometry has been performed, send result reports to the central 
pathology reviewer.  . 
9.2.2 Patient Assignment 
Patient enrollment will be competitive among participating sites. Each patient who is evaluated 
for participation in this study will be assigned a unique screening number.  
Once it has been determined that a patient meets inclusion and exclusion criteria, the site 
must fax an enrollment form to the sponsor or designee to confirm the eligibility.  The patient 
will be assigned a unique patient enrollment number and will be entered into the study. 
Confirmation of enrollment status and patient number will be faxed back to the site. 
9.2.3 Vitamin Administration 
Vitamin supplementation will be initiated at least 10 days prior to pralatrexate administration on 
cycle 1, dose 1. Vitamin supplementation will consist of vitamin B12 1 mg intramuscular (IM) q 
8-10 weeks and folic acid 1.2 mg by mouth (PO) once a day (QD). Once the patient is on-
study, the dosing of vitamin supplementation must adhere to the schedule defined by the 
protocol. 
 
1. Administer or ensure vitamin B12 supplementation at 1 mg IM q 8-10 weeks: 
• If patient has not received vitamin B12 1 mg IM within the previous 8-10 weeks, 
administer at this time. This schedule should be maintained throughout the course of the 
study. 
• If patient has received vitamin B12 1 mg IM within the previous 8-10 weeks, review date 
of previous vitamin B12 dosing and continue administration q 8-10 weeks. 
  
2. Administer or ensure folic acid supplementation at 1.2 mg, PO QD: 
• If patient has not initiated folic acid 1.2mg PO QD, begin at this time. 
• If patient has initiated folic acid, ensure that the dosing regimen conforms to the protocol 
schedule. 
• Provide the patient with a prescription for folic acid, instructions for administration, and a 
patient diary for documentation of self-administration. 
 
Once pralatrexate is permanently discontinued, vitamin supplementation will continue for at 
least 1 month after the last pralatrexate dose, or longer at the discretion of the investigator. 
 


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9.2.4 Pralatrexate Administration Cycle 1 
9.2.4.1.  Pralatrexate Cycle 1, Dose 1 
The following baseline evaluations and procedures must take place upon treatment initiation 
(pralatrexate cycle 1, dose 1), unless otherwise noted below: 
1. Record current medications. 
2. Review the patient’s diary of folic acid administration to ensure protocol compliance. 
3. Assess and record baseline symptoms. 
4. Record study procedure-related AEs and attribution. 
5. Record weight in kilograms (kg), height in centimeters (cm) and calculate body surface area 
(BSA).  The patient’s weight and BSA (refer to Section 18.5), to calculate the pralatrexate 
dose, may be assessed up to 3 days prior to cycle 1, dose 1.  
7. Local laboratory: Collect pre-injection blood for hematology within 1 day and chemistries 
(including LDH) within 3 days prior to cycle 1, dose 1. Platelet count must remain ≥
100,000/μL and ANC ≥1000/μL to proceed with pralatrexate dosing.  
8. Local laboratory: Collect urine for β-hCG pregnancy test for women who are not 
postmenopausal or surgically sterile (within 72 hours prior to cycle 1, dose 1). The result 
must be negative.   
9. Central laboratory: Collect pre-injection blood sample for pralatrexate PK analysis (only in 
pre-selected sites, see Section 11).  
10. Administer pralatrexate IV push over 3-5 minutes. 
11. Central laboratory: Collect blood samples for post-pralatrexate PK analysis at the 
scheduled time points (see Section 11). 
9.2.4.2.  Cycle 1: 24, 48, and 72 Hours Post-end Dose 1 Pralatrexate Injection (For 
applicable time-points for each patient, see Section 11) 
1. Central laboratory: Collect blood samples for pralatrexate PK analysis at 24, 48, and 72 
hours post-end cycle 1, dose 1 pralatrexate injection (only in pre-selected sites, see Section 
11). 
2. Record study procedure-related AEs and attribution. 
9.2.4.3.  Cycle 1, Weeks 2-6 
1. Record AEs and attribution. 
2. Record concomitant medications. 
3. Review the patient’s diary of folic acid administration to ensure protocol compliance. 
Review dosing procedures with patient and re-supply if needed. 


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4. Review date of previous vitamin B12 injection.  Administer vitamin B12 1 mg IM q 8-10 
weeks. 
5. Local laboratory: Collect blood for hematology and chemistries within 1 day prior to each 
pralatrexate dose. 
6. Central laboratory: Collect pre-injection blood sample for pralatrexate PK analysis (only in 
pre-selected sites, see Section 11). 
7. If the patient is not experiencing any AEs that warrant treatment discontinuation, administer 
pralatrexate IV push over 3-5 minutes. 
9.2.4.4.  Cycle 1, Week 3 
In addition to the above weekly evaluations and procedures, the following should be performed 
or obtained during cycle 1, week 3: 
1. Perform a physical examination. 
2. Assess and record ECOG Performance Status. 
9.2.4.5.  Cycle 1, Week 6 
1. Central laboratory: Collect post-injection blood samples for pralatrexate PK analysis (only in 
pre-selected sites, see Section 11). 
9.2.5 Procedures for Subsequent Cycles 
Subjects may continue to receive pralatrexate unless the patient experiences any of the 
criteria noted in protocol Section 8.4. 
9.2.5.1.  Response Evaluation, Prior to Cycle 2-4 and the Following Even Cycles  
Evaluation of response must be performed within 7 days prior to the projected first dose of the 
cycle 2-4 and then within 7 days prior to the projected first dose of every even-numbered 
subsequent cycle (ie, prior to cycles 6, 8, etc). 
The following procedures/tests are to be performed for evaluation of response: 
1. Radiographic imaging (use same imaging technique as screening): 
• 
Contrast-enhanced CT of chest, neck, abdomen, and pelvis. For detailed technical 
requirements, please refer to the Study Manual issued by central imaging lab. 
• 
Other imaging techniques documenting disease site other than chest, neck, abdomen, 
or pelvis, if applicable. 
• 
Unscheduled imaging exams which may impact the response evaluation. 
2. Physical examination to assess liver, spleen, lymph nodes, and skin. Include medical 
photography with ruler measurements for documentation of any skin lesions. 


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3. Local laboratory: Collect blood for LDH. 
4. If the patient’s screening bone marrow biopsy/aspirate results are positive or indeterminate 
and the patient has a confirmed CR by imaging, the repeat core bone marrow biopsy slides 
need to be submitted to Central Pathology Review for confirmation of response. If bone 
marrow aspirate flow cytometry has been performed, send result reports to the central 
pathology reviewer. Once a patient’s bone marrow is negative for lymphoma, the bone 
marrow biopsy will be repeated only when clinically indicated unless it is the patient’s only 
site of disease. 
5. A tumor biopsy may be performed and the slides should be sent to central pathology 
reviewer to confirm a response evaluation.  
6. If peripheral blood flow cytometry has been performed, send result reports to the central 
pathology reviewer. 
All treatment responses will be eventually evaluated by the Independent Central Review 
Committees as described in the Study Charters.   
All radiographic images and digital photographs for subjects with cutaneous disease will be 
sent to the Independent Central Imaging Laboratory for the independent Central Radiology 
Review. The details will be described in the Site Imaging Manual and Independent Radiology 
Review Charter. 
If applicable, all slides of tumor biopsies, core bone marrow biopsies or bone marrow aspirate, 
and results of peripheral blood flow cytometry will be collected for Central Pathology Review 
as  confirmation as described in Site Pathology manual and Independent Pathology Review 
Charter.  
Independent Central Oncology Review will be conducted by utilizing International Working 
Group Criteria (IWC, see appendix 18.4). The final response review will be performed by 
combining relevant clinical evidences (e.g., physical examination findings of liver and spleen 
etc.), Laboratory results (e.g., LDH), central radiology review results and central pathology 
review results. The details will be described in the Central Oncology Reviewer Charter. 
Detailed description and measurement of tumor burden and eventual evaluation of the 
treatment response, will be reported through the Independent Response Central Review. 
However, the investigators will also assess response according to the IWC but will only report 
their overall response evaluation on the CRF. 
9.2.5.2.  Subsequent Cycles, Dose 1 
Dose 1 of subsequent cycles can be delayed due to an AE for no more than 3 weeks after the 
last dose of pralatrexate.  If > 3 weeks lapse between pralatrexate doses, the patient must 
discontinue study treatment. 


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9.2.5.2.1.  Within 7 Days Prior to the Projected Dose 1 
1. Perform a physical examination. 
2. Record weight in kg and calculate BSA. 
3. Assess and record ECOG Performance Status. 
4. Local laboratory: Collect urine for β-hCG pregnancy test for women who are not 
postmenopausal or surgically sterile (within 72 hours prior to cycle 1, dose 1). The result 
must be negative.   
9.2.5.2.2.  Dose 1 
The following evaluations or procedures should be completed within 1 day prior to dose 1 of 
subsequent cycles: 
1. Record concomitant medications. 
2. Record AEs and attribution. 
3. Review the patient’s diary of folic acid administration. Review dosing procedures with 
patient and re-supply if needed. 
4. Review date of previous vitamin B12 injection.  Administer vitamin B12 1 mg IM q 8-10 
weeks. 
5. Local laboratory: Collect blood for hematology and chemistry (including LDH) within1 day 
prior to pralatrexate dose. 
6. If the patient is not experiencing any AEs that warrant treatment modification, administer 
pralatrexate IV push over 3-5 minutes. 
9.2.5.2.3.  Subsequent Cycles, Weeks 2–6 
The following evaluations or procedures should be completed within 1 day prior to day of 
dosing: 
1. Record AEs and attribution. 
2. Record concomitant medications. 
3. Review the patient’s diary of folic acid administration to ensure protocol compliance. 
4. Review date of previous vitamin B12 injection.  Administer vitamin B12 1 mg IM q 8-10 
weeks. 
5. Local laboratory: Collect blood for hematology within1 day prior to each pralatrexate dose.  
Within 1 day prior to the fourth dose of each subsequent cycle, collect blood for hematology 
and chemistry. 


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6. If the patient is not experiencing any AEs that warrant treatment modification, administer 
pralatrexate IV push over 3-5 minutes. 
9.2.6 Early Study Termination Visit 
The procedures outlined below will be conducted, if a patient withdraws informed consent and 
refuses to attend the Safety Follow-up Visit and Routine Follow-up Visits. If possible, the 
procedures will be performed at the time the patient withdraws consent. 
1. Complete the response evaluation procedures in Section 9.2.5.1 if the following occurs: 
• The patient terminates in cycle 1 and has received at least 1 dose of pralatrexate. 
• The patient terminates during any cycle of pralatrexate and it has been ≥ 10 weeks 
since protocol-required response assessments are obtained (prior to cycle 2-4 and every 
even cycle thereafter during the treatment phase or every 3 months in the follow-up 
phase), and subsequent treatment for T-cell lymphoma has not been initiated. 
2. Record concomitant medications. 
3. Record AEs and attribution. 
4. Review and collect the patient’s diary of folic acid administration. 
5. Perform a physical examination. 
6. Assess and record ECOG Performance Status. 
7. Local laboratory: Collect blood for hematology and chemistry (including LDH). 
9.2.7 Safety Follow-up Visit 
All subjects who received at least 1 dose of pralatrexate are to attend the safety follow-up visit 
30 (± 5) days after the last dose of pralatrexate. The following procedures and evaluations 
should be performed: 
1. Record concomitant medications. 
2. Record AEs and attribution. 
3. Review and collect the patient’s diary of folic acid administration. 
4. Instruct patient to discontinue folic acid. 
5. Perform a physical examination. 
6. Assess and record ECOG Performance Status. 
7. Local laboratory: Collect blood for hematology and chemistry. 
8. If disease progression has not been previously documented, and subsequent treatment for 
T-cell lymphoma has not been initiated, complete the response evaluation procedures (see 
Section 10.2.5.1) if: 


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• The patient terminates in cycle 1 and has received at least 1 dose of pralatrexate. 
• It has been ≥ 10 weeks since protocol-required response assessments are obtained 
(prior to every even cycle during the treatment phase). 
9. Record subsequent treatment for T-cell lymphoma, if applicable. 
9.2.8 Routine Follow-up Visit 
After the Safety Follow-up Visit, routine follow-up visits will be based on standard clinical care. 
All subjects who received at least 1 dose of pralatrexate are to attend routine follow-up visits, 
which will occur every 3 months (+/-2 weeks) after the safety follow-up visit till two years after 
the last dose of  pralatrexate to collect the information of progression of disease or subsequent 
treatment for T-cell lymphoma initiation, as well as survival.  
The frequency of response assessments for those subjects who sustain a CR for at least 1 
year will be based on the institution’s standard of care and will no longer be required every 3 
months. 
Once progression of disease has been documented or subsequent treatment for T-cell 
lymphoma has been initiated, routine follow-up visits contacted by telephone for information of 
survival will be required.  Subjects who achieve a CR and proceed to stem cell transplant will 
continue 
to 
be 
followed 
for 
subsequent 
therapy, 
and 
survival. 
The 
following 
procedures/evaluations should be performed at each routine follow-up visit. 
1. Record study treatment related AEs. 
2. Evaluation of response (see Section 9.2.5.1, item 1 for tests and procedures). 
3. Record all subsequent treatment for T-cell lymphoma. 
4. If applicable, record date of death. 
10 Study treatments and concomitant therapies 
10.1 Study Treatments  
The start of study treatment is defined as the initiation of pralatrexate. The eligible subjects 
begin to administrate vitamin supplementation at screening phase.  
 
10.1.1 Vitamin Administration [(Non-Investigational Medicinal Product (NIMP)] 
Vitamin supplementation should be initiated at least 10 days prior to the study treatment. 
Vitamin supplementation will consist of vitamin B12 1 mg intramuscular (IM) q 8-10 weeks and 
folic acid 1.2mg by mouth (PO) once a day (QD). Once the patient is on-study, the dosing of 
vitamin supplementation must adhere to the schedule defined by the protocol. If a patient 
vomits within 15 minutes of taking the folic acid tablet, another dose should be taken the same 
day. 


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Once pralatrexate is permanently discontinued, vitamin supplementation will continue for at 
least 1 month after the last pralatrexate dose, or longer at the discretion of the investigator. 
Vitamin B12 and folic acid will be supplied by the study sponsor. Treatment administration will 
be documented and records maintained by the study staff. Patients will be asked to record 
self-administration of folic acid in a diary to be reviewed by study staff during the course of the 
study. 
 
10.1.2 Pralatrexate Administration [Investigational Medicinal Product (IMP)] 
Pralatrexate will be administered via IV push over 3-5 minutes into a patient IV line containing 
normal saline (0.9% sodium chloride [NaCl]). 
Pralatrexate will be administered at a dose of 30 mg/m2/week for 6 weeks followed by 1 week 
of rest in a 7-week cycle. Pralatrexate administration occurs once a week during week 1 
through week 6 of each cycle. 
Dose omissions and/or reductions will be allowed according to the criteria described in Section 
10.5.  
 
10.2 Identity of Investigational Medicinal Product(s) 
10.2.1 Pralatrexate Formulation 
The pralatrexate drug product will be supplied by the sponsor and will have been tested and 
released according to established specifications. Pralatrexate is formulated as a sterile 
solution for injection and will be supplied in single-use glass vials containing an isotonic 
parenteral solution at a concentration of 20 mg/mL of pralatrexate. The osmolality of 
pralatrexate injection is 280~300 mOsmol/kg.  The formulation is a clear yellow solution. 
 
10.2.2 Storage and Handling 
Pralatrexate is a cytotoxic agent. The institutional, local, and all applicable policies and 
procedures should be followed for proper handling and disposal of chemotherapy drugs. 
 
Pralatrexate should be stored refrigerated at 2-8°C (36-46°F) and protected from light. 
Pralatrexate contains no bacteriostatic agent; each vial is for single-use only. Vials of 
pralatrexate should be stored under secured conditions with access limited to authorized study 
personnel only. 
 
10.2.3 Packaging/Labeling 
The contents of the label will be in accordance with all applicable regulatory requirements.  
Each vial of pralatrexate used in this study will have a label with the following information: 
generic name, strength of test drug, storage requirements, caution statement regarding new 
drug for investigational use only, statement specifying vial is for single-use only, lot number, 
and the name and address of the sponsor and its manufacturer. 


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10.3 Dosage and Administration 
10.3.1 Preparation and Dose Calculation 
Caution should be exercised in the handling, preparing, and administering of the solution.  The 
use of gloves and other protective clothing is recommended.  If pralatrexate comes in contact 
with the skin, immediately and thoroughly wash with soap and water.  If pralatrexate comes in 
contact with mucous membranes, flush thoroughly with water. 
 
The stock pralatrexate solution should be infused at the original concentration of 20 mg/mL. 
 
The BSA will be calculated based on the patient’s weight obtained within 3 days prior to the 
first pralatrexate dose of each cycle (refer to Section 18.5).  The patient will receive the same 
pralatrexate dose throughout the 6 weeks of treatment within a cycle unless the patient 
experiences a ≥10% change in weight. The volume to be infused will be based on the 
following calculation: 
  
Volume (mL)  =  (Patient BSA [m2]) x (pralatrexate dose [mg/m2]) 
20 mg/mL (pralatrexate concentration) 
 
Subjects with a BSA > 2 m2 can be treated either at actual BSA or at BSA = 2 m2, at the 
discretion of the investigator. 
 
10.3.2 Administration of Study Drug 
Pralatrexate is supplied as a preservative free, sterile, isotonic, nonpyrogenic clear yellow 
aqueous solution contained in a single-use clear glass vial for IV administration. Before 
administration, pralatrexate vials should be inspected for abnormalities such as cracks, 
sediments, crystals, turbidity, articulate matter or discoloration etc. If any abnormalities are 
noted, the sponsor should be notified and the vial should not be used. Appropriate procedures 
for cytotoxic agents should be followed for administration of pralatrexate. 
Pralatrexate will be administered as an intravenous push over 3-5 minutes via the side port of 
a free-flowing 0.9% Sodium Chloride Injection, intravenous line. The calculated dose of 
Pralatrexate should be aseptically withdrawn into a syringe for immediate use. If the 
pralatrexate injection is interrupted or delayed, the administration should be restarted as soon 
as possible. When available, the 2-part, lot-number sticker should be removed from the 
pralatrexate vial and placed on the patient’s source documents for each vial of pralatrexate 
used. 
 
10.4 Treatment Duration 
Pralatrexate administration will continue until 24 months of pralatrexate have been 
administrated, or the patient experiences any of the following: 
 
Development of disease progression 


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 
Initiation of radiotherapy or systemic therapy for T-cell lymphoma 
 
Development of an AE indicating intolerance of the lowest study dose allowed (20 
mg/m2/week) 
 
Omission of 3 sequential doses of pralatrexate due to a treatment-related AE 
 
3-week lapse between pralatrexate doses 
 
Development of an AE, intercurrent illness, condition, or procedural complication that 
may interfere with the patient’s participation 
 
Investigator decision to withdraw the subject 
 
Subject withdraws consent 
 
Pregnancy of the subject 
 
Noncompliance with trial treatment or procedure requirements 
 
Administrative reasons 
All subjects will be followed for at least 30 days after their last dose of pralatrexate for safety. 
Subjects who discontinue pralatrexate and have received at least 1 dose of pralatrexate are to 
attend the Safety Follow-up Visit and complete the Routine Follow-up Visit procedures. 
10.5 Treatment Modifications of Pralatrexate 
Management of severe or intolerable adverse reactions may require dose omission, reduction, 
or interruption of pralatrexate administration. Dose omissions and/or reductions will be allowed 
according to the criteria outlined below in Table 2, Table 3, and Table 4. 
Complete blood cell counts and severity of mucositis should be monitored weekly. Serum 
chemistry tests including renal and hepatic function, should be performed prior to the start of 
the first and fourth dose of a given cycle. 
The following conditions must to meet prior to administering any dose of pralatrexate:  
 
Mucositis should be ≤ Grade 1 
 
Platelet count should be ≥ 100,000/μL (or 100  109/L) for first dose and ≥ 50,000/μL 
(or 50  109/L) for all subsequent doses 
 
Absolute neutrophil count (ANC) should be ≥ 1,000/μL (or 1  109/L) 
The dose of pralatrexate will be 30 mg/m2/week, which can be reduced to 20 mg/m2/week in 
the event of a treatment-related AE. No further dose reductions are allowed. If the patient 
develops an AE indicating intolerance of this lowest dose of 20 mg/m2/week, the patient will be 
discontinued from study treatment.  There will not be re-escalation of the pralatrexate dose 
once a dose reduction has occurred. 
Pralatrexate administration occurs once a week during week 1 through week 6 of each cycle. If 
an AE occurs that prevents the administration of pralatrexate on the scheduled dosing day (+/-
2 days), the dose will be omitted that week and the patient will be reassessed the following 


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week to proceed to the next dose of the cycle.  Omitted doses will not be made up at the end 
of the cycle. 
If pralatrexate administration is delayed for more than 2 days within a week (eg, administration 
on a Thursday instead of Monday) due to administrative reasons (eg, vacation, holiday, etc.) 
the dosing schedule for the subsequent weeks should be adapted to continue on the new 
administration day within the week (eg, on Thursdays rather than on Mondays). 
Once pralatrexate is permanently discontinued, vitamin supplementation will continue for at 
least 1 month after the last pralatrexate dose, or longer at the discretion of the investigator. 
All treatment-emergent AEs will be managed per the investigator’s judgment or the site’s 
clinical standard of care. 
Subjects will be monitored for safety throughout the study and at specific time points. If safety 
concerns arise, the pralatrexate dose administered to subjects will be revisited. 
10.5.1 Hematological Toxicities 
Treatment modification for hematological toxicities is as follows: 
Table 2 Pralatrexate Treatment Modifications for Hematological Toxicities 
 
Hematological 
Parameter 
Duration of 
Toxicity 
Action 
Dose upon Restart 
Platelets < 50,000/μL 
(or 50  109/L) on day 
of treatment 
1 week 
Omit dose 
Continue prior dose 
2 weeks 
Omit dose 
20 mg/m2 
3 weeks 
Treatment 
discontinuation 
 
ANC 500~1,000 /μL 
(or 0.5-1  109/L) and 
no fever
1 week 
Omit dose 
Continue prior dose 
ANC 500~1,000 /μL 
(or 0.5-1  109/L) with 
fever or  
ANC < 500/μL (or 0.5 
 109/L) 
1 week 
Omit dose, give G-
CSF or GM-CSF 
support 
Continue prior dose 
with G-CSF or GM-
CSF support 
2 weeks or 
recurrence  
Omit dose, give G-
CSF or GM-CSF 
support 
20 mg/m2 with G-
CSF or GM-CSF 
support 
3 weeks or 2nd 
recurrence 
Treatment 
discontinuation 
 
   ANC: absolute neutrophil count 
 


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10.5.2 Non-Hematological Toxicities 
For all instances of mucositis, dose adjustments will be made as follows: 
Table 3 Pralatrexate Treatment Modifications for Mucositis 
 
Mucositis Gradea on Day 
of Treatment 
Action 
Dose upon Recovery to  
≤ Grade 1 
Grade 2 
Omit dose  
Continue prior dose 
Grade 2 recurrence  
Omit dose 
20 mg/m2 
Grade 3 
Omit dose 
20 mg/m2 
Grade 4 
Treatment 
discontinuation 
 
a: Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, 
Version 4.03) 
 
For all other non-hematological toxicities excluding nausea/vomiting, dose adjustments will be 
made as follows: 
Table 4 Pralatrexate Treatment Modifications for All Other Non-hematological Treatment-related 
Toxicities 
Toxicity Gradea on Day of 
Treatment 
Action 
Dose upon Recovery to  
≤ Grade 2 
Grade 0-2 
No change in 
pralatrexate dose 
— 
Grade 3 
Omit dose  
20 mg/m2 
Grade 4 
Treatment 
discontinuation  
— 
a: Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, 
Version 4.03) 
10.6 Response Evaluation 
10.6.1 Timing of Response Evaluations 
All assessment techniques documenting disease status at screening must be repeated at 
every protocol-required time point for response evaluation. 
Response evaluation will occur at the following study time points: 


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 
Treatment Phase: Within 7 days prior to the projected first dose of the cycle 2-4 and then 
within 7 days prior to the projected first dose of every even-numbered subsequent cycle (ie, 
prior to cycles 6, 8, etc). 
 
Safety Follow-up Visit (collect under the following conditions provided that subsequent 
treatment for T-cell lymphoma has not been initiated): 
- 
The patient discontinues in cycle 1 and has received at least 1 dose of pralatrexate. 
- 
The patient discontinues during any subsequent cycle of pralatrexate and it has been 
≥10 weeks since protocol-required response assessments are obtained. 
 
Routine Follow-up Visit: Every 3 months (+/-2 weeks) after the safety follow-up visit until 
progression of disease has been determined or subsequent treatment for T-cell lymphoma 
has been initiated.  
 
Early Termination Visit: 
- 
The patient terminates the study in cycle 1 and has received at least 1 dose of 
pralatrexate. 
- 
The patient terminates the study during any subsequent cycle of pralatrexate or during 
routine follow-up visits, and it has been ≥10 weeks since protocol-required response 
assessments are obtained, and subsequent treatment for T-cell lymphoma has not 
been initiated. 
10.6.2 Required Procedures/Scans/Tests 
The following procedures/tests are to be performed for evaluation of response: 
1. 
Radiographic imaging: 
a. Contrasted-enhangced CT of chest, neck, abdomen, and pelvis. For detailed technical 
requirements, please refer to the site imaging manual issued by central imaging lab.  
b. Other imaging techniques documenting disease site other than chest, neck, abdomen, or 
pelvis, if applicable. 
c Unscheduled imaging exams at the discretion of physician, which may impact the 
response evaluation. 
2. 
Physical examination to assess liver, spleen, lymph nodes, and skin. Include medical 
photography with ruler measurements for documentation of any skin lesions. 
3. 
Local laboratory: Collect blood for LDH. 


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4. 
If the patient’s screening bone marrow biopsy/aspirate results were positive or 
indeterminate and the patient has a confirmed CR by imaging, a repeat bone marrow 
biopsy and aspirate assessment must be performed and the slides should be submitted 
for central pathology review. If bone marrow aspirate flow cytometry has been performed, 
send result reports for central pathology review. Once a patient’s bone marrow is negative 
for lymphoma, the bone marrow biopsy will be repeated only when clinically indicated 
unless it is the patient’s only site of disease. 
5. 
A tumor biopsy may be performed if needed to confirm a response evaluation. 
6. 
If peripheral blood flow cytometry has been performed, send result reports to the central 
pathology review. 
10.6.3 Review of Response 
Response will be assessed according to the IWC (Appendix 18.4).  
All treatment responses will be eventually evaluated by the Independent Central Review 
Committees as described in the Study Charters.   
All radiographic images and digital photographs for subjects with cutaneous disease will be 
sent to the Independent Central Imaging Laboratory for the independent Central Radiology 
Review. The details will be described in the Site Imaging Manual and Independent Radiology 
Review Charter. 
If applicable, all slides of tumor biopsies, core bone marrow biopsies or bone marrow aspirate, 
and results of peripheral blood flow cytometry will be collected for Central Pathology Review 
as  confirmation as described in Site Pathology manual and Independent Pathology Review 
Charter.  
Independent Central Oncology Review will be conducted by utilizing International Working 
Group Criteria (IWC, see appendix 18.4). The final response review will be performed by 
combining relevant clinical evidences (e.g., physical examination findings of liver and spleen 
etc.), Laboratory results (e.g., LDH), central radiology review results and central pathology 
review results. The details will be described in the Central Oncology Reviewer Charter. 
Detailed description and measurement of tumor burden and eventual evaluation of the 
treatment response, will be reported through the Independent Response Central Review. 
However, the investigators will also assess response according to the IWC but will only report 
their overall response evaluation on the CRF. 


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10.6.4 Disease Progression 
PD should be documented according to the site’s standard procedures. If objective PD has 
been clearly documented, a confirmatory assessment is not required. 
Once PD has been documented or subsequent treatment for T-cell lymphoma has been 
initiated, response assessments will no longer be collected. 
10.7 Treatment Compliance/Drug Accountability 
The Investigator and study staff will be responsible for the accountability and record 
maintenance of all clinical supplies (dispensing, inventory, and returns) following Sponsor 
instructions and will adhere to GCP guidelines as well as applicable China specific regulations.  
At each visit the Investigator must check and document subjects’ compliance with taking study 
treatment(s). 
Under no circumstances will the Investigator allow the study treatment(s) to be used other than 
as directed by this protocol.  Clinical supplies will not be dispensed to any individual who is not 
enrolled and currently participating in the study.   
10.8 Concomitant Medications 
All medications administered from signing the informed consent form through the Safety 
Follow-up Visit will be recorded on the CRF. Additions, deletions, or changes of dosage of 
medications will also be noted. 
 
10.8.1 Antiemetic Therapy 
There is no data evidence to expect drug-drug interactions between pralatrexate and standard 
antiemetic therapy and no specific antiemetic therapy has yet been proven to be superior over 
others in the setting of pralatrexate administration. Therefore, prophylaxis and treatment of 
nausea and vomiting can be administered according to the standard of care within the 
institution, however administration is not recommended prior to first dose because of the low 
emetogenity of pralatrexate. Steroids are not allowed for prophylaxis or treatment. 
 
10.8.2 Hematopoietic Growth Factors 
Erythropoietin will be allowed if it is judged by the investigator to be in the best interest of the 
patient (e.g, for subjects with underlying anemia or unacceptable hematologic toxicity).  Other 
hematopoietic growth factors (eg, granulocyte colony-stimulating factor [G-CSF], granulocyte-
macrophage colony-stimulating factor [GM-CSF]), with the exception of pegfilgrastim 
(Neulasta®), are to be administered in accordance with the instructions for treatment 
modification for hematological toxicities in Section 10.5.1. 
 


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10.8.3 Other Supportive Care Medications 
The administration of appetite stimulating hormones (eg, megestrol acetate) is allowed to 
control anorexia and cachexia. 
 
Use of prophylactic antibiotics is allowed and may be administered at the discretion of the 
investigator. 
 
Transfusions are allowed per the discretion of the investigator. 
 
10.8.4 Radiotherapy, Cytotoxic Therapy, and Biologic or Immune Response 
Modifiers 
No radiotherapy, other cytotoxic agents, biologic, or immune response modifiers (especially 
thymosin) are to be administered to subjects until study treatment has been discontinued. 
 
10.8.5 Subsequent Treatment 
All subsequent treatment data for T-cell lymphoma will be collected until completion of the 
study. Additional treatment for T-cell lymphoma should not be administered during treatment 
with pralatrexate. 
 
10.8.6 Therapies Not Permitted 
The prior therapies that are not allowed are described in the Exclusion Criteria. 
 
Any form of additional therapy for T-cell lymphoma will not be permitted during treatment with 
pralatrexate, including radiation therapy, other cytotoxic agents, biologic, immune response 
modifiers, and herbal products. 
 
While on treatment with pralatrexate, steroids are not allowed for prophylaxis or treatment 
except: 
 
As continuation of prior systemic steroid treatment at stable of no more than 10 
mg/day or equivalent dose of prednisone  
 
As continuation of local or Inhaled or intranasal steroids as used prior to study entry 
 
For treatment of possible Addison’s crisis in patients with prior history of steroid use 
11 Plasma Pharmacokinetics 
Collection of plasma to determine the full PK profile of R-pralatrexate and S-pralatrexate will 
be performed in 15 subjects at pre-selected sites. Participation in the pharmacokinetic 
assessment portion of the protocol will be limited to sites with appropriately trained staff and 
adequate equipment for procuring and processing the specimens. 
 


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Plasma will be frozen for subsequent PK analysis. The concentration of R-pralatrexate and S-
pralatrexate at each time-point will be determined by liquid chromatography/mass 
spectrometry/mass spectrometry (LC/MS/MS) methodology using a previous validated assay.   
See Study Manuals provided by the sponsor for detailed guidance regarding the collection, 
processing, and shipment of samples. 
 
The collection times for full pralatrexate PK (15 subjects) are as follows: 
 
Cycle 1, Dose 1: Pre-injection, end-injection, 30 and 60 minutes, and 3, 5, 8, 12, 18, 24, 48, 
and 72 hours post-end injection. 
 
Cycle 1, Doses 2 – 5: Pre-injection 
 
Cycle 1, Dose 6: Pre-injection, end-injection, 30 and 60 minutes, and 3, 5, 8, 12, 18, 24, 48, 
and 72 hours post-end injection. 
12 REFERENCE VALUES 
12.1 Physical/Vital Sign Assessments 
Vital signs (e.g. blood pressure [systolic blood pressure, diastolic blood pressure], pulse rate, 
respiration rate and temperature (axillary) will be obtained at the visits designated on the 
Schedule of Visits and Procedures (Table 1). Blood pressure and pulse rate will be measured 
after the subject has been sitting for 3 minutes. 
Each clinically notable vital sign abnormality has to be recorded on the AE section of the EDC.  
Table 5 in Appendix 18.2.1 describes parameters for clinically notable vital signs.  Additionally, 
if the change in vital signs qualifies as a SAE it has to be reported to the CRO/Sponsor using 
the SAE data form (Section 13.2). 
12.2 Laboratory Assessments 
All scheduled clinical laboratory tests will be performed by local laboratories. Local laboratories 
will perform tests to qualify subjects for entry into the study and relative safety assessment. 
Laboratory certification will be included in the clinical study report for this protocol as appendix. 
The Schedule of Visits and Procedures (Section 9.1) shows the time points at which blood and 
urine samples will be collected for clinical laboratory tests.  Table 6 in Appendix 18.2.2 
presents the clinical laboratory tests to be performed. 
A laboratory abnormality may qualify as an AE or SAE as described in Section 13.1.  
Additionally, if the abnormality qualifies as a SAE it must be reported to the Sponsor using the 
SAE data form (Section 13.2). Table 7 in Appendix 18.2.2 presents the criteria (i.e. upper limit, 
lower limit criteria for each laboratory parameter) that will be used to identify subjects with 
markedly abnormal laboratory values. 


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Values out of the lower normal range do not automatically lead to an exclusion of the subject 
from the study. The decision to discontinue a subject from the study due to bilirubin or 
creatinine levels below the lower limit of normal should be based on the medical judgement of 
the Investigator. Microscopic urinalysis will only be performed when certain parameters of the 
macroscopic urinalysis show abnormal results. 
12.3 Additional Assessments Reference Ranges 
Not applicable. 
13 SAFETY ASSESSMENTS 
Safety assessments will be recorded from the point at which the Informed Consent is signed. 
These will consist of: 
 
Monitoring and recording all adverse events (AEs) and serious adverse events (SAEs), 
observed or volunteered, regardless of suspected causal relationship to the IMP.  This 
includes reactions, interactions, accidents, illnesses, misuse and abuse. Please refer 
to table 1 section 10.1 for schedule visit arrangement including AE collection. 
 
Events will be graded for severity according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 2010.  
The obligations and responsibilities with regards to collection, distribution and onward 
reporting of adverse events and reactions to the appropriate regulatory bodies, committees 
and other investigators will be carried out in accordance with local and international 
regulations and are documented in a separate Safety Management Plan.   
13.1 Adverse Events (AEs) and Serious Adverse Events (SAEs) 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical trial 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.   
An AE can be:   
 
Any unfavourable and unintended sign (including reactions from overdose, abuse, 
incorrect use of any treatment, or interaction) 
 
Any new disease or exacerbation of an existing disease (e.g. increase in frequency or 
worsening in nature) 
 
Any deterioration in measurements of laboratory values or other clinical tests (e.g. ECG, 
vital signs or X-ray) that results in symptoms, a change in treatment, or discontinuation 
from the IMP 
 
Recurrence of an intermittent medical condition (e.g. headache) not present at baseline 
 
Other medical events regardless of their relationship to the IMP, such as accidents, 
falls and any injuries resulting from them. 


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A Serious Adverse Event (SAE) is any AE that: 
 
results in death 
 
is life-threatening (i.e. the subject is at immediate risk of death from the AE as it 
occurred) 
 
requires inpatient hospitalisation or prolongation of existing hospitalisation  
 
results in persistent or significant disability/incapacity 
 
is a congenital anomaly/birth defect (in the child of a subject who is exposed to the IMP) 
 
is a medically important event or reaction. 
Assessment of medically important events: 
The Investigator must check the list of Important Medical Events (supplied in the Investigator 
Site File) to determine whether criteria for a SAE is met.  Additionally, any event not on this list, 
but that the Investigator determines is medically important (e.g. if it jeopardises the patient or 
requires intervention to prevent a serious outcome) should be reported as an SAE. 
Grade 4 events from the investigations system organ class, or from another system organ 
class (SOC) if used synonymously to an investigation result where grading is based mainly on 
the numerical result of a laboratory test without immediate serious threat to the patient (e.g. 
SOC Investigation: Neutrophil count decreased or SOC Blood and lympathic system organ 
class: Neutropenia) should only be reported as a SAE if they fulfil the seriousness criteria per 
definition given above or the investigator considers the event serious (medically significant). All 
clinical diagnosis or symptom grade 4 toxicity should normally result in seriousness 
classification and be reported as an SAE.  
 Events specific to this protocol that may not require immediate reporting include: 
Disease Progression – Natural progression or deterioration of the malignancy under study will 
be recorded as part of the efficacy evaluation and should not be recorded as an AE/SAE.  
Signs and symptoms should not be reported as AEs/SAEs if they are clearly related to a 
relapse or an expected change or progression of the baseline malignant disease. 
A SAE must be reported immediately (within 24 hours), independent of the circumstances or 
suspected cause, if it occurs or comes to the attention of the Investigator at any time during 
the study period.  Any SAE with a suspected causal relationship to the IMP occurring at any 
time after completion of the study must be promptly reported. 
The following mandatory information must be provided to the Sponsor pharmacovigilance 
contact within 24 hours for each SAE: 
- Protocol number 


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- Site number 
- Subject number 
- AE 
- IMP(s) 
- Investigator's name and contact details 
Causality assessment should be completed as soon as possible. 
A succinct medical summary narrative should be provided as soon as possible. 
Follow-up information should be actively sought until the SAE has resolved or sequelae have 
stabilised.  Additional information e.g. hospital reports or death certificates, may be requested 
by the Sponsor and should be anonymised/pseudonymised before transmission and 
subsequently filed in the Investigator Site File.  
The medical safety of the subject is of paramount importance when discussing study 
continuation.  Not all SAEs will require the subject to be discontinued from the study. 
13.2 Reporting of Adverse Events   
See also Figure 2, Appendix Section 18.1. 
Reporting period – Events will be recorded from the point at which the Informed Consent is 
signed until 30 (± 5) days after the last dose of pralatrexate. This includes new AEs that are 
reported in the 30 (± 5) days following the subject’s last dose of pralatrexate. Any AE that is 
still on-going after 30 (± 5) days after the completion / discontinuation visit will have an 
outcome of ‘on-going’ in the CRF, however the Investigator will continue to follow up on-going 
AEs and record information in the source documents.  SAEs will be followed until the event 
resolves or the event or sequelae stabilise and this information will be reported to the Sponsor 
using the SAE Data Form.  
Medical conditions that are diagnosed at the screening visit will only be documented as 
adverse events if they are known to have started or are suspected to have started after the 
subject has signed the informed consent form. All other medical findings at the medical 
examination at the screening visit will be documented as medical history.  Medical judgement 
should be exercised to estimate if a condition is likely to have started between the signing of 
the informed consent and the date/time of the physical examination. 
If the Investigator becomes aware of a SAE after the completion of the study, which may have 
been caused by an IMP or NIMP used in the study, they should report it to the Sponsor by 
phone, fax or e-mail. 
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For subjects who receive at least one dose of study medication - All AEs will be collected on 
the AE section of the EDC.  In addition, a note should be made in the source documentation of 
the subject.   
SAEs - All SAEs will be collected on the AE section of the EDC and flagged as serious. A 
separate paper SAE Data Form should be completed and reported to sponsor within 24 hours 
since getting SAE information by investigator. 
Reporting term - A cluster of signs and symptoms that results from a single cause or that could 
form a diagnosis should be reported as a single AE (e.g. fever, elevated WBC, cough, 
abnormal chest x-ray, etc. can all be reported as “pneumonia.”). 
Contact - The sponsor drug safety contact phone number/fax number and email address will 
be stored in the Investigator Site File.  Questions relating to Drug Safety and 
Pharmacovigilance should be addressed to this number or e-mailed.  
13.3 Causality Assessment  
The question of the relationship of an AE to the IMP should be determined by the Investigator 
after thorough consideration of all facts that are available. 
Assessment of causality is based on considering associative connections (time or place), 
pharmacological explanations, previous knowledge of the drug, presence of characteristic 
clinical or pathological phenomena, underlying conditions in the study population, exclusion of 
other causes, and/or absence of alternative explanations. 
The Investigator will be asked if a reasonable possibility of a causal relationship to the IMP 
is suspected.  
 
“Yes” should be selected if there are facts (evidence) or arguments to suggest a causal 
relationship.  
 
“No” should be selected if there are no facts (evidence) or arguments to suggest a 
causal relationship. 
Please note that causality assessment of adverse events in the CRF only relates to the IMP(s) 
named in Section 13.3. 
If an AE is related to a non-investigational medicinal product e.g. concomitant therapy only, 
and not an interaction or effect of the IMP, or to a study procedure, the causality assessment 
will be “No” (no reasonable possibility of a causal relationship to IMP). The suspected drug or 
procedure should be indicated in the narrative in such cases. 


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13.4 Severity Assessment  
The Investigator (or medically qualified designee) will evaluate the comments of the subject 
and the response to treatment to judge the severity of the AE. All adverse events will be 
graded according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) Version [4.03] criteria.  Where a specific definition of the severity of an event 
is not given in the CTCAE grading criteria, the following definitions will be used: 
CTCAE 
Grade 
Severity 
Description 
Grade 1 
Mild 
▫ Minor 
▫ Mild symptoms and intervention not indicated 
▫ Non-prescription intervention indicated 
▫ No specific medical intervention 
▫ Asymptomatic laboratory finding only 
▫ Radiographic finding only 
▫ Marginal clinical relevance 
Grade 2 
Moderate 
▫ Intervention indicated 
▫ Minimal, local, non-invasive intervention (e.g. packing, cautery) 
▫ Limiting instrumental activities of daily living (e.g. shopping; 
laundry; transportation; conduct finances) 
Grade 3 
Severe 
▫ Medically significant but not life-threatening 
▫ Inpatient or prolongation of hospitalisation indicated 
▫ Important medical event that does not result in hospitalisation 
but may jeopardise the patient or may require intervention either: 
 
to prevent hospitalisation or 
 
to prevent the AE from becoming life-threatening or 
potentially resulting in death 
▫ Disabling - results in persistent or significant disability or 
incapacity 
▫ Limiting self-care activities of daily living (e.g. getting in and out 
of bed; dressing; eating; getting around inside; bathing; using the 
toilet) 
Grade 4 
Life 
threatening  
 
▫ Life-threatening consequences 
▫ Urgent intervention indicated 
▫ Urgent operative intervention indicated 
▫ Patient is at risk of death at the time of the event if immediate 
intervention is not undertaken 
Grade 5 
Death related to AE 


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Source: http://evs.nci.nih.gov/ftp1/CTCAE/Documentation/CTCAE_Governance_2010-03-11.pdf 
AEs with CTCAE grade 5 are always serious, and must be reported according to Section 13.1.  
Special attention should be given to Grade 3 and 4 events and seriousness on numeric values 
considered as per the guidance in section 13.1.  
Any medication necessary for the treatment of an adverse event must be recorded on the 
Concomitant Therapy Section of the EDC and, if applicable, on the SAE Data Form.   
13.5 Pregnancy 
Pregnancy occurring in a subject or a male subject’s female partner during a clinical study 
must be reported to the Sponsor using the Pregnancy Notification Form.  The CRO/Sponsor 
will contact the investigator to confirm significant pregnancy information i.e. AEs during 
pregnancy, the pregnancy outcome, and any events to 3 months post-partum. Female subject 
will be terminated from the study if pregnancy is confirmed and continues. If the subject or the 
spouse of a male subject get pregnant, they need to be followed up until at least 3-months 
post-partum.  
 
13.6 Laboratory Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply: 
 
They result in a change in IMP schedule of administration (change in dosage, 
delay in administration, IMP discontinuation, or other medical or treatment 
intervention (e.g. anaemia requiring transfusions or hyperglycaemia requiring 
potassium supplement)) 
 
They are considered as clinically significant by the Investigator. 
Where possible, the AE description should be the diagnosis rather than the abnormal 
laboratory value.  The same is true if abnormal values reflect a worsening of an underlying 
condition. Abnormal laboratory values that are present at Screening are not AEs (unless they 
are a consequence of a Screening procedure).  Where an Investigator does not deem an 
abnormal (or markedly abnormal, see Table 7 in section 18.2.2) laboratory value to be 
clinically significant, the reason must be clearly document in the source notes (e.g. normal 
fluctuation of the disease). 
 
13.7 Vital Signs and Physical Examinations 
AEs from vital sign or physical examination assessments include any changes, values or 
findings (abnormalities): 
 
which result in medical intervention  
 
and/or is deemed by the Investigator as clinically significant  
 
and/or meets the clinically notable abnormal criteria (see Table 5 in section 18.2.1). 


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13.8 ECG Adverse Events 
A simultaneous 12-lead resting ECG will be obtained at screening and will be performed 
during study only if clinically indicated.  For consistency, the same physician should read all 
ECGs from one subject whenever possible.  Abnormal test findings as judged by the 
Investigator as clinically significant should be recorded as AEs. 
13.9 Other Safety Considerations/Risk Management 
Preventable medication administration errors with an IMP are a potential safety issue and 
must be reported immediately to the Sponsor/CRO as a protocol deviation.  Examples of 
these include: 
• Overdose - This must always be reported, and may additionally (but not always) meet the 
criteria for an AE/SAE. No specific information is available on the treatment of overdosage 
of pralatrexate. If an overdose occurs, general supportive measures should be instituted 
as deemed necessary by the treating physician. Based on pralatrexate’s mechanism of 
action, consider the prompt administration of leucovorin. 
• Drug Abuse - Defined as intentional excessive and persistent or sporadic use of a 
medicinal product which is accompanied by harmful physical or psychological effects.  
Drug abuse is always a medically important event and subject to immediate SAE reporting.   
• Drug Diversion - Defined as study treatment that is sold or given to other persons either 
deliberately or accidentally.  This may include accidental misdirection of study supply into 
mainstream hospital supplies.  Adverse events in persons other than the subject after drug 
diversion will be processed in the Sponsor’s drug safety database. 
Any packaging or labelling that has been identified as causing potential risk (e.g. due to 
similarity with other products or unclear instruction) must be immediately reported to the 
Sponsor. 
14 Statistical Analyses 
All data analyses will be performed by the Sponsor or a designated CRO after the study is 
completed and the database is locked. Statistical programming and analyses will be performed 
using SAS and/or other validated statistical software as required. 
14.1 Statistical Methodology and Analytical Plans 
The statistical analyses described in this section will be performed as further outlined in the 
Statistical Analysis Plan (SAP), which will be finalised prior to database lock and will be 
included in the clinical study report for this protocol.  The final SAP will take into account any 
amendment to the protocol. 


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14.2 Statistical Considerations 
In general, continuous data will be summarised using the following descriptive statistics: n, 
mean, standard deviation, median, minimum and maximum.  Categorical data will be 
summarised as the number and percentage of subjects in each category. 
 
Further details of statistical methods and analyses will be documented in the SAP. 
14.3 Analysis Populations 
Enrolled Population 
The enrolled population is defined as all subjects who signed informed consent. 
 
Safety Population 
The safety population is defined as all subjects who receive at least one dose of IMP. 
 
Per Protocol Population (PPP) 
The Per Protocol Population is defined as all subjects in the safety population who fulfil the 
following criteria: 
 
•       The absence of any major protocol violations 
•       The completion of a minimal 3 doses of exposure to the treatment regimen of one 
treatment cycle   
Major protocol violations will be agreed at the data review meeting prior to database lock. 
 
Pharmacokinetic Population  
The overall PK population is defined as all subjects who receive at least one dose of IMP and 
have at least one primary PK parameter. Subjects with non-zero baseline concentrations of >5% 
of Cmax for either analyte (R-pralatrexate or S-pralatrexate) will be removed from the PK 
population. 
14.4 Protocol Violations and Deviations 
The following protocol violations may exclude a subject from the PPP: 
 
1) Failure to comply with the major inclusion/exclusion criteria. 
2) Being non-compliant with study treatments. 
3) Taking any prohibited concomitant therapies. 
 
Additional factors excluding subjects from inclusion in the PPP may be included in the SAP for 
the study.  Major protocol violations will be agreed at the data review meeting prior to 
database lock. Further details will be documented in the SAP. 


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14.5 Sample Size and Power Considerations 
Based on the PROPEL study 29 out of 32 responses (91%) occurred within the first five cycles 
of treatment. Consequently the data cut-off date for the primary analysis will be defined once 
all subjects have been treated for 5 cycles. 
 
The primary objective is to demonstrate that the response rate in the Chinese population is 
greater than ≥15%. Assuming a true response rate of 29%, a sample size of 68 will provide 
80% power to demonstrate a response rate of greater than 15% using a two-sided test at 5% 
significance level.  
14.6 Primary Efficacy Variable(s)  
The primary endpoint is the objective response rate (ORR) by International Working Criteria 
defined as the proportion of subjects with CR, CRu or PR as Best Overall Response (BOR). 
The objective response rate will be tested using the exact test for single proportion at two-
sided significance level of 5%. The hypotheses under test will be H0: ORR<15% vs. H1: ORR
≥15%. 
 
The primary analysis will be based on the independent review data using the safety population. 
An additional analysis based on the investigator assessment data will be performed. All 
analyses will be repeated using the per-protocol population. 
 
Response rate by International Working Criteria : 
 
Response rate is defined as number of responders divided by number of subjects, where a 
subject is considered a responder if she/he has obtained a CR, CRu or a PR. 
 
The following procedures/tests will be included in the evaluation of response: 
 
1. Radiographic imaging (use same imaging techniques as screening). 
• 
CT of chest, neck, abdomen, and pelvis 
• 
Other imaging documenting disease site other than chest, neck, abdomen, or pelvis, if 
applicable 
2. Physical examination to assess liver, spleen, lymph nodes, and skin. Include medical 
photography and ruler measurements of any skin lesions. A sum of the longest diameter (LD) 
for all skin lesions will be calculated. 
3. LDH level determination. 
4. Bone marrow biopsy and aspirate should be performed and assessed by flow cytometry if 
the subject had bone marrow involvement with lymphoma prior to treatment and the subject 
has a confirmed CR by imaging and physical examination. 


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5. A tumor biopsy could be performed if needed to confirm a response evaluation. 
6. Results of peripheral blood flow cytometry if applicable. 
 
Response and progression of disease will be evaluated by using: 
 
1. The IWC proposed by the NCI sponsored International Working Group 
2. Bone marrow biopsies should be scored as follows: 
• 
Negative = no aggregates or only a few well circumscribed lymphoid aggregates and ≤ 3% 
blasts. 
• 
Positive = unequivocally cytologic or architectural evidence of malignancy (percentage of 
invasion and the lymphoma subtype should be indicated). 
• 
Indeterminate = increased number or size of aggregates without cytologic or architectural 
atypia. 
3. Measurements of each cutaneous lesions utilizing medical photography and ruler: 
• 
A sum of the LD for all cutaneous lesions will be calculated and reported as the baseline sum LD 
and will be used as reference for tumor response 
• 
Response and progression of cutaneous disease will be evaluated using the following 
definitions: 
- 
CR = disappearance of all evidence of disease for at least 4 weeks. 
- 
PR = 50% or greater decrease in the sum of the LD of each lesion for at least 4 weeks. 
- 
PD = increase of ≥ 25% of the LD of any lesion or appearance of new lesions. 
- 
SD = less than a PR but does not meet criteria for PD. 
 
If it is difficult to distinguish residual disease from normal tissue and confirmation of CR 
depends on this determination, it is recommended that the residual lesion be investigated 
(biopsy or fine needle aspirate) before confirming CR status. 
 
If progression is determined at a time point or by a method not defined in the protocol, those 
data will be sent to central review. 
14.7 Secondary Efficacy Variable(s) 
Secondary efficacy endpoints are 
 
 
Duration of Response (DOR) 
 
Time to Response (TTR) 
 
Progression-Free Survival (PFS)  
 
Overall Survival (OS) 
 
Duration of Response: 
 


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Duration of response will be measured from first day of documented response to disease 
progression or death, whatever comes first. Subjects receiving subsequent therapy, including 
transplant before PD is documented, will be censored at that time, with a note indicating 
censoring occurrence, along with reason. 
 
Time to Response: 
 
Time to response will be measured from first day of treatment to the first date of documented 
response. 
 
Progression Free Survival: 
 
PFS will be measured from treatment day 1 until event or censoring. An event is defined as 
the earliest of the following: death from any cause or disease progression. Subjects 
undergoing transplant or any other subsequent therapy prior to documentation of PD will be 
censored at that time. 
 
Overall Survival: 
 
OS will be measured from treatment day 1 until death or censoring. 
 
It is recognized that the product-limit estimate for PFS may, in fact, lie above that for OS due to 
censoring PFS at transplant and not censoring OS at transplant. This will be understood as a 
consequence of the way in which transplant is handled in the statistical analysis of these data. 
 
Secondary time-to-event endpoints (e.g. duration of response, time to response, PFS, and OS) 
will be presented using Kaplan-Meier curves (product limit estimates) together with a summary 
of associated statistics (e.g. median survival time, first and third quartiles, survival rates 
including the corresponding two-sided confidence intervals [CIs]). Censoring rules will be 
detailed in the SAP. 
 
Secondary endpoints based on tumor assessments (e.g. duration of response, time to 
response and PFS) will be analysed twice, once using the independent review data and once 
using the investigator assessment data.  
 
The secondary analyses will be performed using the safety population and repeated using the 
per-protocol population. 
14.8 Exploratory Efficacy Variables 
Not applicable. 
14.9 Subject Disposition 
The number and percentage of subjects enrolled and the primary reason for screen failure will 
be summarised for subjects in the enrolled population. 


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The number and percentage of subjects in each population and the reasons for exclusion from 
the PPP will be summarised for subjects in the safety population. 
 
The number and percentage of subjects that discontinue the study and the primary reason for 
discontinuation will be summarised for subjects in the safety population. 
 
The number and percentage of subjects enrolled from each site will be summarised for 
subjects in the safety population. 
 
14.10 Demographic/Baseline Analyses 
Demographic and baseline variables will be summarised for subjects in the safety population. 
 
Age, weight, height, and body mass index will be summarised as continuous data. Gender and 
race will be summarised as categorical data. 
 
Current medical conditions will be summarised by System Organ Class and Preferred Term. 
14.11 IMP Analyses 
The following variables will be defined to assess exposure to study treatment: 
 
 
Number of infusions 
 
Duration of treatment (weeks) = [(Date of last dose  date of first dose) + 7] ÷ 7 
 
Cumulative dose (mg/m2) = Sum of all total doses administered (mg/m2) 
 
Dose intensity (mg/m2/week) = Cumulative dose (mg/m2) ÷ Duration of treatment (week) 
 
Relative dose intensity (%) = Dose intensity ÷ Planned weekly dose intensity x 100, 
whereas planned weekly dose intensity (mg/m2/week) = 30 mg/m2/week 
For subjects who did not receive any amount of a compound, the dose exposure parameters 
for that treatment (number of infusions, duration of treatment, cumulative dose, dose intensity, 
relative dose intensity) will be set to 0. 
 
All these variables will be summarised as continuous data. Additionally, the relative dose 
intensity will be summarised categorised (ie, number and percentage of subjects with relative 
dose intensity of <60%, 60-<80%, 80-<90%, 90-<110%, ≥110%). Moreover, the number and 
percentage of subjects with any dose delay and with any dose reduction will be presented. 
 
The number and percentage of subjects treated by cycle as well as the number of cycles 
received by patient will be presented. 
14.12 Concomitant Medications Analyses 
Concomitant medications will be assigned an 11-digit code using the World Health 
Organisation Drug Dictionary (WHO-DD) drug codes.  Concomitant medications will be further 


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coded to the appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating therapeutic 
classification.  
The number and percentage of subjects taking concomitant medications will be summarised 
by ATC anatomical class, pharmacological class, pharmacological sub-class and treatment 
group for subjects in the safety population. 
14.13 Safety Analyses/Adverse Outcomes 
Safety data that will be evaluated includes adverse events (AEs), laboratory values, and vital 
signs.  Safety data will be summarised for subjects in the safety population.  All safety data will 
be listed. 
14.14 Analysis of Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
system to give a System Organ Class (SOC) and preferred term for each event. 
Only treatment emergent AEs will be summarised. A treatment emergent AE is defined as any 
AE with an onset date on or after the first dose of IMP if the AE is absent before the first dose 
of IMP, or worsened after the first dose of IMP. This will also include AEs with an onset date 
up to and including 30 days after the last dose of IMP. In addition, this will include AEs with an 
onset date after 30 days considered as related to IMP by the investigator. 
The number and percentage of subjects reporting any AE will be summarised by the ‘preferred 
term’ nested within the SOC.  In addition, the number of reported AEs will be summarised.  
 
AEs will be summarised by worst severity and relationship to IMP.  In addition, severe AEs, 
AEs leading to death, serious AEs, AEs leading to discontinuation from study, AEs requiring 
additional therapy, AEs leading to dose reduction, and AEs leading to dose interruption will be 
summarised.  
14.15 Laboratory Values 
Clinical laboratory data to be summarised includes haematology, blood chemistry, and 
urinalysis.  Appendix Section 18.2.2 Table 7 lists the ranges applied for this study. 
Clinical laboratory results recorded at each visit and change from baseline to each visit will be 
summarised as continuous data for each parameter.  Each parameter will be assigned an LNH 
classification according to whether the value is lower than (L), within (N) or higher than (H) the 
reference range for that parameter.  Results will be summarised using shift tables to evaluate 
categorical changes from baseline to end of study with respect to reference range values 
(lower than, within, higher than). 
Clinical laboratory values after first dose of IMP will be evaluated for markedly abnormal 
values. The number and percentage of subjects reporting markedly abnormal values will be 


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summarised for each parameter.  Each subject can be counted once in the parameter high 
and the parameter low categories, as applicable.  Scatter plots will be produced for each 
laboratory parameter comparing baseline and end of study values. In addition, clinically 
laboratory parameters will be plotted over time using a box and whisker plot. 
14.16 Vital Signs 
Vital sign parameters to be summarised include systolic blood pressure, diastolic blood 
pressure, pulse rate, respiration rate, and axillary temperature.   
Vital sign results recorded at each visit and change from baseline to each visit will be 
summarised as continuous data for each parameter. Appendix Section 18.2.1 Table 5 lists the 
abnormal ranges applied for this study. 
Vital sign results for each parameter will be assigned an LNH classification according to 
whether the value is lower than (L), within (N) or higher than (H) the reference range for that 
parameter. Vital sign results will be summarised using shift tables to evaluate categorical 
changes from baseline to end of study with respect to reference range values (lower than, 
within, higher than). 
Vital sign values after first dose of IMP will be evaluated for clinically notable abnormalities. 
The number and percentage of subjects reporting clinically notable abnormalities will be 
summarised for each parameter by treatment group. Each subject can be counted once in the 
parameter high and the parameter low categories, as applicable.  
Scatter plots will be produced for each vital sign parameter comparing baseline and end of 
study values. In addition, vital signs will be plotted over time using a box and whisker plot. 
14.17 ECG 
If applicable, ECG results recorded at each visit and change from baseline to each visit will be 
summarised as continuous data for each parameter. 
Clinically significant ECG findings as determined by the Investigator will be reported.  
14.18 Other Special Tests  
None planned.  All analyses, including any further analyses not yet described in this study 
protocol, will be pre-specified and described in the SAP. 


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14.19 Pharmacokinetic Measurements and Analysis 
14.19.1 Drug Concentration Measurements and Analysis 
Plasma concentrations of R-pralatrexate and S-pralatrexate will be quantified by liquid 
chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) methodology using a 
previously validated assay.  
14.19.2 Pharmacokinetic Measurements and Analysis 
Plasma concentrations will be listed by analyte (R-pralatrexate and S-pralatrexate) for the 
subjects in the PK population. 
Plasma concentrations for each analyte will be summarised descriptively by nominal time-point 
and treatment as continuous data (i.e. n, mean, standard deviation, standard error, median, 
minimum and maximum) for subjects in the PK population. 
The plasma concentration data for each analyte for subjects in the PK population will be 
presented graphically in a number of ways using both a linear and a log-linear scale: 
 
The mean plasma concentration data will be plotted over time 
 
For each subject, the individual plasma concentration data will be plotted over time 
Pharmacokinetic parameters (AUCt, AUCINF, Cmax, Ctrough, tmax, LambdaZ, t1/2Z, CLss, 
Vdss) will be listed by analyte for subjects in the PK population, if data permit.  Data excluded 
from the PK analysis will be flagged with an asterisk.  
Pharmacokinetic parameters (AUCt, AUCINF, Cmax, Ctrough, tmax, LambdaZ, t1/2Z, CLss, 
Vdss) for R-pralatrexate and S-pralatrexate will be derived using noncompartmental analysis 
(NCA) method (WinNonlin® Version 6.3, Pharsight Corporation, St. Louis, MO, USA).  
Concentration values below the lower limit of quantitation (LLOQ) will be set to zero prior to 
the first quantifiable concentration and as missing thereafter. The log linear trapezoid rule will 
be used in AUC calculations. To derive the extrapolated AUC (%AUCextra), the last observed 
concentration value above the LLOQ will be used for the calculation. If the %AUCextra is 
greater than 20% of AUCINF, the value of AUCINF will be reported as “Not Available” (NA). 
LambdaZ, t1/2 as well as any PK parameters derived from LambdaZ will not be reported if the 
adjusted R2 in LambdaZ estimation is less than 0.8.  Accumulation in exposure at steady state 
will also be reported. 
Pharmacokinetic parameters (AUCt, AUCINF, Cmax, Ctrough, tmax, LambdaZ, t1/2Z, CLss, 
Vdss) for each analyte will be summarised descriptively for subjects in the PK population, 
adjusting for dose where necessary. Descriptive statistics including mean, SD, coefficient of 
variation (CV), SE, number (N), minimum, maximum, and median will be calculated for all 
pharmacokinetic parameters except tmax by analyte, study day, and the actual administered 


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dose.  Additionally, geometric means and geometric CV will be calculated for AUCt, AUCINF 
and Cmax. tmax will be summarized by minimum, maximum and median. 
14.20 Interim Analysis 
There will be no formal interim analysis.  
The primary analysis will be performed based on a data cut-off date defined after all subjects 
have been treated for 5 cycles. The study report based on the cut-off data will be prepared and 
used for NDA submission. However, the study will continue till the protocol defined termination 
criteria.  
15 Ethics & Regulatory 
15.1 Declaration of Ethical Conduct 
This study will be conducted in accordance with the standard operating practices of the 
Sponsor and CRO, which are designed to ensure adherence to Good Clinical Practice (GCP) 
guidelines as required by the following: 
1. Declaration of Helsinki, 1964 (“Recommendations Guiding Physicians in Biomedical 
Research Involving Human Subjects”), and all its accepted amendments to date 
concerning medical research in humans. 
2. ICH E6 Guideline for GCP and subsequent notes for guidance (CPMP/ICH/135/95)  
European Agency for the Evaluation of Medicinal Products, Committee for Proprietary 
Medicinal Products, International Conference on Harmonisation of Pharmaceuticals for 
Human Use. (Note for Guidance on Good Clinical Practice, 2002). 
3. European Union (EU) Clinical Trials Directive 2001/20/EC on the regulation of clinical 
trials in the EU and the implementation of GCP. 
4. GCP Directive 2005/28/EC 
This study will be conducted in accordance with national and local laws of the countries where 
study sites are located. 
The Investigator agrees, when signing the protocol, to adhere to the instructions and 
procedures described in the protocol and to adhere to the principles of ICH Good Clinical 
Practice to which the protocol conforms as well as all governing local regulations and 
principles for medical research. 
15.2 Ethical and Regulatory Review 
The protocol, any protocol amendments, the patient information sheet (PIS), informed consent 
form (ICF) and any study related information or documents issued to subjects for recruitment, 
data recording etc., will be reviewed and approved along with other required documents by the 
Ethics Committee (EC) and each study site’s local EC before subjects are screened for entry.  


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The ECs should be constituted and functioning in accordance with ICH E6, Section 3.2, and 
any local regulations.  A list of the EC(s) that provided a positive opinion for this study will be 
included in the clinical study report for this protocol. 
A signed letter of positive opinion regarding the study from the EC Chairman must be sent to 
the Investigator. The Sponsor/CRO must be provided with a copy prior to study start and the 
release of any study treatment to the site by the Sponsor or its designee (ICH E6).  The 
Investigators or Sponsor will submit, depending on local regulations, periodic reports and 
inform the EC of any reportable adverse events (AEs) per ICH guidelines and local EC 
standards of practice. 
SAEs should be reported to the EC in accordance with local regulatory requirements. 
In the case of early termination/temporary halt of the study, the Investigator should notify the 
EC and CA within 15 days and a detailed written explanation of the reasons for the 
termination/halt should be given.  If the EC decides to suspend or terminate the study, the 
Investigator will immediately send the notice of study suspension or termination by the EC to 
the Sponsor/CRO. 
At the end of the study, the Sponsor should notify the EC and CA within 90 days.  The end of 
the study will be the date of the last scheduled study visit for the last subject in the study.  The 
Sponsor will always also provide the EC/CA with a summary of the study’s outcome. 
15.3 Subject Information and Consent 
Informed consent should be obtained by means of a PIS and Informed Consent Form (ICF), 
prepared in accordance with ICH E6 Section 4.8.10 and applicable local regulations, written in 
non-technical language.  All subjects and/or their guardians/legally authorised representatives 
will be provided with oral and written information describing the nature and duration of the 
study and the procedures to be performed.  The subject will be asked to sign and date an ICF 
prior to any study-specific procedures being performed.  No subject can enter the study before 
his/her informed consent has been obtained.  A sample subject ICF used in the study will be 
included in the clinical study report for this protocol. 
As part of administering the informed consent document, the Investigator must explain to each 
subject and/or their guardian/legally authorised representative the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, and any potential discomfort.  Each subject must be informed that participation in the 
study is voluntary and that he/she may withdraw from the study at any time and that 
withdrawal of consent will not affect his/her subsequent medical treatment or relationship with 
the treating physician.  The subject should understand the PIS and ICF before signing and 
dating the ICF.  The Investigator or person obtaining consent must also sign and date the form.  
Each subject will be given a copy of the signed informed consent and written information.   


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The original signed ICF for each subject will be verified by the Sponsor/CRO monitors and 
kept in the study centre investigational site files.   
15.4 Data Protection and Human Tissue Sampling 
Data protection will be carried out in accordance with the Principles of the Data Protection Act 
(1998) 95/46/EC.  This will apply to all study data in whatever format it is collected and 
recorded.   
Any scan data, imaging, ECGs etc., collected for the trial will be retained in the subject’s 
medical notes held with the Investigator.   
Samples collected for the purpose of safety analysis will not be retained after analysis.    
15.5 Quality Assurance & Inspection Requirements 
This study will be organised, performed, and reported in compliance with the protocol, 
Standard Operating Procedures (SOPs) of the Sponsor and CRO.   ICH E6 defines Quality 
Assurance (QA) as ‘all those planned and systemic actions that are established to ensure that 
the trial is performed and the data are generated, documented (recorded) and reported in 
compliance with Good Clinical Practice (GCP) and the applicable regulatory requirements’.  
Sponsor QA activity will be undertaken as outlined in the study audit plan.  Section 5.19.3(b) of 
ICH E6 states that the audit plan and procedures for a trial audit should be guided by the 
importance of the trial to submissions to competent authorities, the number of subjects in the 
trial, the type and complexity of the trial, the level of risks to the trial subjects and any identified 
problem(s).  QA activities may be outsourced to CROs or independent consultants.  The 
investigator is required to support audit activities, to be available to the auditors upon request 
and to permit the auditor direct access to source data/documents. 
A competent authority (CA) /authorised third party may also wish to conduct an inspection 
(during the study or after its completion).  If an inspection is requested by a CA, the 
Investigator must inform the Sponsor immediately that this request has been made. 
16 Study management Records & Publication 
16.1 Protocol Amendments 
The Investigator should not implement any deviation from, or changes to the protocol without 
agreement by the Sponsor and prior review and documented approval from the EC (ICH E6 
4.5.2). 
Any change to the protocol requires a written substantial or non-substantial protocol 
amendment.  Substantial protocol amendments specifically affecting the safety of subjects, the 
scope of the investigation, or the scientific quality of the study require approval by the 


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applicable ECs of all sites.  These requirements should in no way prevent any immediate 
action from being taken by the Investigator, or by the Sponsor, in the interest of preserving the 
safety of all subjects included in the study.  If an immediate change to the protocol is felt by the 
Investigator to be necessary for safety reasons, the Sponsor designee must be notified 
promptly and the EC for the site must be informed in accordance with the policy of the EC 
approving the study, local regulations and policies.  Changes affecting only administrative 
aspects of the study do not require substantial protocol amendments or EC approval, but the 
EC must be kept informed of such changes.  In these cases, the Sponsor will send a letter to 
the EC detailing such changes. 
16.2 Record Maintenance and Retention 
In order to provide the Sponsor with accurate, complete, and legible case reports, the following 
criteria are to be maintained in all study related and source documentation: 
 
All entries are to be typed or printed using a ballpoint pen. 
 
There are to be no erasures, write-overs, use of correction fluid or tape, and the 
original entry must remain legible. 
    Errors are to be corrected by placing one line through the error.  The correct entry 
should appear next to the error, dated, and initialled by the responsible person making 
the change.  The name of anyone making corrections must appear on the Site 
Signature Log collected at the beginning of the study and as study assignments 
change throughout the conduct of the study.  Each error is to be corrected separately. 
 
The Investigator (Principal Investigator or Sub Investigator) must sign and date the 
CRF where noted.  A signature stamp may not be used. 
 
Changes to any study document that has been previously signed by the Investigator 
must be initialled and dated by the Investigator after the change is made.  Changes 
made to CRFs via data clarification forms issued by the Sponsor must likewise be 
signed by the Investigator. 
Neither a subject’s name nor initials are to appear on documents transmitted to the Sponsor in 
order to maintain confidentiality.  Additional anonymisation/pseudonymisation laws as 
applicable by country will also be adhered to. 
In order to provide the Sponsor/CRO with accurate, complete, and legible data, the following 
criteria are to be maintained: 
 
Source documents will be completed according to a source document agreement 
outlining all the data that is to be collected in the source documents throughout the 
study. 
 
EDC entries should be made as close to the visit of the subject as possible. 
The circumstances of completion or termination of the study notwithstanding, the Investigator 
has the responsibility to retain all study documents, including but not limited to the protocol, 


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copies of EDC, Investigator's Brochure, regulatory agency registration documents, ICFs, and 
EC correspondence. 
The site should plan on retaining study documents for approximately 15 years after completion 
of the study. This will include copies of the EDC. 
It is requested that at the completion of the required retention period, or should the Investigator 
retire or relocate, the Investigator contact the Sponsor, allowing the Sponsor the option of 
permanently retaining the study records.  Records retained will be stored independently of the 
Sponsor, and the Sponsor will not be permitted direct access to this data. 
16.3 Adherence to the Protocol 
The Investigator will conduct the study in strict accordance with the protocol, which has been 
written to enable the Investigator’s compliance with ICH E6, Section 4. 
There are to be no waivers to the Inclusion/Exclusion criteria and no Investigator-led 
deviations from the schedules and procedures set out within this protocol.  Any subject whose 
treatment deviates from the protocol or who is not qualified for study participation may be 
ineligible for analysis and may compromise the study. 
Any unintentional deviation or violation that is discovered should be reported to the 
Sponsor/CRO immediately.  Any deviation of violation that may have an impact upon subject’s 
safety or suitability for the study should be reported to, and discussed with the Medical Monitor. 
Subjects who have not signed an IRB/EC approved ICF cannot receive study medication. 
The Investigator and research team must comply with the 13 principles of ICH GCP and all 
applicable local regulatory laws and regulations. 
16.4 Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical or administrative reasons 
at any time, however not without good cause.  Reimbursement for expenses covering subjects, 
use of live-in facilities, laboratory tests, and other professional fees will be made.  The 
Investigator will refund the excess of payments made in advance. 
The Investigator reserves the right to discontinue the study should his/her judgement so 
dictate.  In such an event, final settlement of the grant-in-aid will be adjusted pro rata, and the 
Investigator will refund the excess of payments made in advance.  The Investigator will notify 
the EC in case of study discontinuation.  Study records must be retained as noted above. 


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16.5 Registration and Publication of Study Summary and Results 
If a study design is of the type required for registration in a public database as detailed in the 
guidance on www.clinicaltrial.gov or www.ClinicalTrialResults.org the study will be registered 
on a public database according to the Sponsor’s SOPs.  If required by local legislation the 
study will also be registered in other public databases. 
Following the end of the study the results should be published within a year of product 
approval for newly registered products, or within a year of completion of the clinical study 
report (CSR) if the product is already approved.  If results are intended for publication in a peer 
review scientific journal, no detailed results will be published on a public database beforehand. 
 
The site may publish or present the results of this protocol subject to the protection of any 
patentable rights of the Sponsor or its nominee(s) and subject to the protection of the 
Sponsor’s confidential information.  The Sponsor will be furnished with a copy of any proposed 
publication or presentation at least 60 days prior to submission for review of confidential or 
patentable information.  Upon notice by the Sponsor, however, that the Sponsor reasonably 
believes that a patent application claiming an invention relating to the IMP(s) made during the 
performance of the study will be filed prior to such publication, such publication may be 
delayed for an additional 30 days or until any patent application or applications have been filed, 
whichever will first occur. 
For multi-site studies, it is mandatory that the first publication be based on data obtained from 
all analysed subjects; therefore Investigators participating in multi-site studies must agree not 
to present data gathered individually or by a subgroup of sites prior to the full, initial publication, 
unless this has been agreed to by all other Investigators and the Sponsor.  Publication of 
clinical trial results may include the presentation of such work at national and international 
congresses, symposia, professional meetings, peer-reviewed journals, and via other 
appropriate channels.  Named authors and contributors to such publications shall be 
determined by the Sponsor in accordance with both the Company Publication Policy and the 
criteria as outlined by standard authorship guidelines.  Selected Investigators, Consultants and 
Scientific Advisors may be invited to be named authors on such publications by the Sponsor.  
If the Investigator/Consultant/Scientific Advisor agrees to participate in the publication as an 
author, they will be asked to participate in the creation of all versions of the document(s) in 
question prior to submission or public dissemination.  The Sponsor will ensure that any 
reasonable comments made by the invited author will be incorporated into the publication and 
that the named author will consent to the publication of the final version of the document.  The 
copyright associated with any publication will be and shall remain the sole property of the 
Sponsor, unless or until the copyright of the document is transferred to the scientific peer-
reviewed journal prior to and as part of the publication process. 
 
 


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17 REFERENCE LIST  
Copies of all references will be held in the trial master file. 
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17. Gisselbrecht C, Gaulard P, Lepage E, et al. Prognostic significance of T-cell phenotype in 
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methotrexate in ascitic and solid murine tumor models. Cancer Chemother Pharmacol 
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38. Lee JS, Libshitz HI, Murphy WK, et al. Phase II study of 10-ethyl-10-deaza- aminopterin 
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39. Souhami RL, Rudd RM, Spiro SG, et al. Phase II study of Edatrexate in stage III and IV 
non-small-cell lung cancer. Cancer Chemother Pharmacol 1992;30(6):465- 8. 
40. Schornagel JH, van der Vegt S, Verweij J, et al. Phase II study of edatrexate in 
chemotherapy-naive subjects with metastatic breast cancer. Ann Oncol 1992;3(7):549-52. 
41. Vandenberg TA, Pritchard KI, Eisenhauer EA, et al. Phase II study of weekly edatrexate as 
first-line chemotherapy for metastatic breast cancer: a National Cancer Institute of Canada 
Clinical Trials Group study. J Clin Oncol 1993;11(7):1241-4. 
42. Casper ES, Christman KL, Schwartz GK, et al. Edatrexate in subjects with soft tissue 
sarcoma. Activity in malignant fibrous histiocytoma. Cancer 1993;72(3):766-70. 
43. DeGraw JI, Colwell WT, Piper JR, et al. Synthesis and antitumor activity of 10- propargyl-
10-deazaaminopterin. J Med Chem 1993;36(15):2228-31. 
44. Sirotnak FM, DeGraw JI, Colwell WT, et al. A new analogue of 10- deazaaminopterin with 
markedly enhanced curative effects against human tumor xenografts in mice. Cancer 
Chemother Pharmacol 1998;42(4):313-8. 
45. Wang ES, O'Connor O, She Y, et al. Activity of a novel anti-folate (PDX, 10- propargyl 10-
deazaaminopterin) against human lymphoma is superior to methotrexate and correlates with 
tumor RFC-1 Gene Expression. Leukemia & Lymphoma 2003;44(6):1027-35. 
46. Hoovis ML, Chu MY. Enhancement of the antiproliferative action of 1- -D- 
arabinofuranosylcytosine by methotrexate in murine leukemic cells (L5178Y). Cancer Res 
1973;33(3):521-5. 
47. Cadman E, Eiferman F. Mechanism of synergistic cell killing when methotrexate precedes 
cytosine arabinoside: study of L1210 and human leukemic cells. J Clin Invest 1979;64(3):788-
97. 


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48. Toner LE, Vrhovac R, Smith EA, et al. The schedule-dependent effects of the novel 
antifolate pralatrexate and gemcitabine are superior to methotrexate and cytarabine in models 
of human non-Hodgkin's lymphoma. Clin Cancer Res 2006;12(3):924-932. 
49. Krug LM, Ng KK, Kris MG, et al. Phase I and pharmacokinetic study of 10- propargyl-10-
deazaaminopterin, a new antifolate. Clin Cancer Res 2000;6(9):3493-8. 
50. Krug LM, Azzoli CG, Kris MG, et al. 10-propargyl-10-deazaaminopterin: an antifolate with 
activity in subjects with previously treated non-small cell lung cancer. Clin Cancer Res 
2003;9(6):2072-8. 
51. O'Connor O, Hamlin PA, Neylon E, et al. Pralatrexate (10-propargyl-10- deazaaminopterin 
(PDX)), a novel antifolate, effects durable complete remissions (CR) in subjects with a diversity 
of drug resistant T-cell lymphomas with minimal toxicity. (Abstract 2678). Blood 2005;106(11). 
52. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 
1989;10(1):1-10. 
53. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to 
standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International 
Working Group. J Clin Oncol 1999;17(4):1244-53. 
54. Savage DG, Lindenbaum J, Stabler SP, et al. Sensitivity of serum methylmalonic acid and 
total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med 
1994;96(3):239-46. 
55. Niyikiza C, Walling J, Thornton D, et al. LY231514 (MTA): relationship of vitamin 
metabolite profile to toxicity (abstract 2139). 34th Proceedings of American Society of Clinical 
Oncology (ASCO) 1998;17:558a. 
56. Juweid ME, Wiseman GA, Vose JM, et al. Response assessment of aggressive non-
Hodgkin's lymphoma by integrated International Workshop Criteria and fluorine-18-
fluorodeoxyglucose positron emission tomography. J Clin Oncol 2005;23(21):4652-61. 
57. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer Stat 
Assoc 1958;53:457-81. 
58. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649-55. 
 


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18 APPENDICES 
 
18.1 Adverse Event Reporting Process 
Figure 2 Flow diagram for AE reporting  
 
Adverse Event 
Complete CRF/EDC 
considering the 
following:
Assign severity grade
Does the 
event meet any of the 
following criteria?

Results in death

Is life threatening

Results in persistent or significant disability/incapacity

Requires in-patient hospitalisation or prolongs existing hospitalisation

Results in a congenital anomaly or birth defect

Is an important medical event that may not result in the above
Record outcome
Yes
No
Assess causality
Is the 
event listed in the protocol 
as not requiring immediate 
SAE reporting?
No
Yes
Submit report immediately 
(within 24 hours) with 
outcome/status information 
and follow up until sequalae 
resolved or stabilised


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18.2 REFERENCE VALUES 
18.2.1 Physical/Vital Sign Assessments 
Table 5 describes parameters for clinically notable vital signs. 
Table 5 Criteria Used to Identify Clinically Notable Vital Sign Abnormalities 
Vital Sign Parameter 
Value 
Change From Baselinea 
Systolic blood pressure 
 180 mmHg 
Increase of  20 mmHg 
 
 90 mmHg 
Decrease of  20 mmHg 
Diastolic blood pressure 
 105 mmHg 
Increase of  15 mmHg 
 
 50 mmHg 
Decrease of  15 mmHg 
Pulse rate 
 120 bpm 
Increase of  15 bpm 
 
 50 bpm 
Decrease of  15 bpm 
Respiration rate 
< 8 breaths/minute 
- 
 
> 24 breaths/minute 
- 
aBoth value and change from baseline criteria must be met to qualify as a clinically notable vital sign abnormality. 
 
 
 


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18.2.2 Laboratory Assessments 
Table 6 presents the clinical laboratory tests to be performed. 
Table 6 Clinical Laboratory Tests  
Category 
Parameters 
Haematology 
RBC, haemoglobin, haematocrit, platelets, and WBC with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils) 
Chemistry 
 
Electrolytes 
sodium, potassium, chloride, bicarbonate (HCO3-) 
Liver function tests 
alkaline phosphatase, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), gamma-glutamyl-transferase (GGT), 
total bilirubin, direct bilirubin 
Renal function parameters 
blood urea, creatinine 
Other 
glucose, calcium, albumin, cholesterol, triglycerides, phosphorus 
(inorganic phosphate), lactate dehydrogenase (LDH), total 
protein, globulin, uric acid 
Table 7 presents the criteria (i.e. upper limit, lower limit criteria for each laboratory parameter) 
that will be used to identify subjects with markedly abnormal laboratory values.  Identification 
of markedly abnormal lab values not covered by table 7 are subject to the clinical judgement of 
the investigator. 


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Table 7 Laboratory Ranges Used to Identify Markedly Abnormal Laboratory Values 
 
Units 
Laboratory Parameter 
Lower Limit 
Upper Limit 
Haematology 
 
 
Haemoglobin 
10 g/dL (100 g/L) or 6.2 
mmol/L 
—–– 
Platelets 
75.0  109/L or 75000/mm3 
—–– 
Leukocytes 
3.0  109/L or 3000/mm3 
—–– 
Lymphocytes 
1.0  109/L or 1000/mm3 
—–– 
Neutrophils 
1.5  109/L or 1500/mm3 
—–– 
Clinical Chemistry 
Electrolytes 
 
 
Sodium 
 LLN 
150 mmol/L 
Potassium 
 LLN 
5.5 mmol/L 
Bicarbonate (HCO3-) 
15 mEq/dL or 15 mmol/L 
—–– 
Liver Function Tests  
 
 
Alkaline phosphatase 
—–– 
3  ULN  
AST 
—–– 
3  ULN 
ALT 
—–– 
3  ULN 
GGT (GGTP) 
—–– 
3  ULN 
Total bilirubin 
—–– 
1.5  ULN 
Renal Function Tests 
 
 
Creatinine 
—–– 
1.5  ULN 
Other Chemistry 
 
 
Calcium 
8 mg/dL or 2.0 mmol/L 
11.5 mg/dL or 2.9 mmol/L 
Phosphorous (inorganic phosphate) 
2.5 mg/dL or 0.8 mmol/L 
— 
Glucose 
55 mg/dL or 3.0 mmol/L 
160 mg/dL or 8.9 mmol/L 
Uric acid 
—–– 
 ULN 
Cholesterol 
—–– 
300 mg/dL or 7.75 mmol/L 
Triglycerides 
—–– 
2.5  ULN 
Albumin 
3 g/dL 
—–– 
 
 
 


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18.3 ECOG Performance Scale 
ECOG Grade 
Performance 
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 cable of all self-care, but unable to carry out any 
work activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead 
 
 
 


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18.4 The International Workshop Criteria (IWC)  
The following criteria are considered anatomic definitions (Table 8).  In the future, as 
additional radiographic, laboratory, and functional studies become more widely available and 
clearly demonstrate predictive value, they may be recommended as well. 
 
CR requires the following: 
1. Complete disappearance of all detectable clinical and radiographic evidence of 
disease and disappearance of all disease-related symptoms if present before 
therapy, and normalization of those biochemical abnormalities (e.g., lactate 
dehydrogenase [LDH]) definitely assignable to NHL. 
2. All lymph nodes and nodal masses must have regressed 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 greatest transverse diameter before 
treatment must have decreased to ≤1 cm in their greatest transverse diameter after 
treatment, or by more than 75% in the sum of the products of the greatest diameters 
(SPD). 
3. The spleen, if considered to be enlarged before therapy on the basis of a CT scan, 
must have regressed in size and must not be palpable on physical examination. 
However, no normal size can be specified because of the difficulties in accurately 
evaluating splenic and hepatic size. For instance, spleens thought to be of normal 
size may contain lymphoma, whereas an enlarged spleen may not necessarily reflect 
the presence of lymphoma but variations in anatomy, blood volume, the use of 
hematopoietic growth factors, or other causes. The determination of splenic volume 
or splenic index by CT scan are cumbersome and not widely used. Any macroscopic 
nodules in any organs detectable on imaging techniques should no longer be 
present. Similarly, other organs considered to be enlarged before therapy due to 
involvement by lymphoma, such as liver and kidneys, must have decreased in size. 
4. If the bone marrow was involved by lymphoma before treatment, the infiltrate must 
be cleared on repeat bone marrow aspirate and biopsy of the same site. The sample 
on which this determination is made must be adequate (≥20 mm biopsy core). Flow 
cytometric, molecular, or cytogenetic studies are not considered part of routine 
assessment to document persistent disease at the present time. These studies 
should only be incorporated into trials examining important research questions. 
 
 
Copyright © 2005 by the American Society of Clinical Oncology. All rights reserved. Reprinted with 
permission from the American Society of Clinical Oncology. 
Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response 
criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 
1999;17(4): 1244. 
 
 
 


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Table 8.  Response Criteria for Non-Hodgkin's Lymphoma 
 
CR/unconfirmed (CRu) includes those subjects who fulfill criteria 1 and 3 above, but with one 
or more of the following features: 
1. A residual lymph node mass greater than 1.5 cm in greatest transverse diameter that 
has regressed by more than 75% in the SPD. Individual nodes that were previously 
confluent must have regressed by more than 75% in their SPD compared with the 
size of the original mass. 
2. Indeterminate bone marrow (increased number or size of aggregates without 
cytologic or architectural atypia). 
 
 
PR requires the following: 
1. 50% decrease in SPD of the six largest dominant nodes or nodal masses. These 
nodes or masses should be selected according to the following features: (a) they 
should be clearly measurable in at least two perpendicular dimensions, (b) they 
should be from as disparate regions of the body as possible, and (c) they should 
include mediastinal and retroperitoneal areas of disease whenever these sites are 
involved. 
2. No increase in the size of the other nodes, liver, or spleen. 
3. Splenic and hepatic nodules must regress by at least 50% in the SPD. 
4. With the exception of splenic and hepatic nodules, involvement of other organs 
is considered assessable and not measurable disease. 
5. Bone marrow assessment is irrelevant for determination of a PR because it is 
assessable and not measurable disease; however, if positive, the cell type should 
be specified in the report, e.g., large-cell lymphoma or low-grade lymphoma (ie, 
small, lymphocytic small cleaved, or mixed small and large cells). 
6. No new sites of disease. 
 
 
 
 
Copyright © 2005 by the American Society of Clinical Oncology. All rights reserved. Reprinted withpermission 
from the American Society of Clinical Oncology.Cheson BD, Horning SJ, Coiffier B, et al. Report of an 
international workshop to standardize responsecriteria for non-Hodgkin’s lymphomas. NCI Sponsored 
International Working Group. J Clin Oncol1999;17(4): 1244.l 2005;23(21):4652-61. 
 


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Stable disease is defined as less than a PR (see above) but is not progressive disease (see 
below). 
 
Relapsed disease (CR, CRu) requires the following: 
1. Appearance of any new lesion or increase by 50% in the size of previously involved 
sites. 
2. 50% increase in greatest diameter of any previously identified node greater than 
1 cm in its short axis or in the SPD of more than one node. 
 
 
Progressive disease (PR, nonresponders) requires the following: 
 
1. 50% increase from nadir in the SPD of any previously identified abnormal node for 
PRs or nonresponders. 
2. Appearance of any new lesion during or at the end of therapy. 
 
Response Assessment 
Response is currently assessed on the basis of clinical, radiologic, and pathologic (ie, bone 
marrow) criteria. 
 
1. CT scans remain the standard for evaluation of nodal disease. Thoracic, abdominal, 
and pelvic CT scans are recommended even if those areas were not initially involved 
because of the unpredictable pattern of recurrence in NHL. Studies should be 
performed no later than 2 months after treatment has been completed to assess 
response. This interval may vary with the type of treatment, e.g, a longer period may 
be more appropriate for biologic agents where the anticipated time to response may 
be greater. 
2. A bone marrow aspirate and biopsy should only be performed to confirm a CR if they 
were initially positive or if it is clinically indicated by new abnormalities in the 
peripheral blood counts or blood smear. 
 
 
Copyright © 2005 by the American Society of Clinical Oncology. All rights reserved. Reprinted 
withpermission from the American Society of Clinical Oncology.Cheson BD, Horning SJ, Coiffier B, et al. 
Report of an international workshop to standardize responsecriteria for non-Hodgkin’s lymphomas. NCI 
Sponsored International Working Group. J Clin Oncol1999;17(4): 1244.l 2005;23(21):4652-61. 
 


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18.5 BSA Calculation Formula 
Recommend use below formula to calculate the BSA (applicable to male and female)*: 
 
S=0.0061×Height +0.0124×Weight-0.0099 
  (S: BSA, unit: M2; Height, unit: cm; Weight, unit: kg) 
 
*Hu YM, Wu XL, Hu ZH, Ren AH, Wei XQ, Wang XC, et al. Study of formula for calculating body surface 
areas of the Chinese adults. Sheng Li Xue Bao. 1999;51(1):45-48. 

SAP_001.pdf: 
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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
Page 1 of 34 
 
Statistical Analysis Plan 
 
A Multi-center, Single Arm, Safety and Efficacy Study of 
Pralatrexate with Vitamin B12 and Folic Acid 
Supplementation in Subjects with Relapsed or Refractory 
Peripheral T-cell Lymphoma 
 
 
 
 
 
 
   Protocol Number: FOT12-CN-301 
Version: V2.0 
  Date: February07, 2018 
Sponsor: Mundipharma (China) Pharmaceutical 
Co., Ltd 
Sponsor Address: Room 1808 Tower D CITC, 6A 
Jianguomen Wai Avenue, Beijing 100022, 
China 
National Principal 
Investigator: 
Jun Zhu 
    Leading Investigational 
Institute: 
Beijing Cancer Hospital 
            CRO: 
Hangzhou Tigermed Consulting Co., Ltd 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
Page 2 of 34 
 
Confidentiality Statement 
The information contained in this Statistical Analysis Plan (SAP) is confidential and the 
information contained within it may not be reproduced or otherwise disseminated without 
the approval of Mundipharma (China) Pharmaceutical Co., Ltd or its subsidiaries.


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
Page 3 of 34 
 
Prepared by:  
 
 
 
 
 
Pancy Yi 
Senior Statistician 
Hanzhou Tigermed Consulting Co., Ltd 
 
 
Date 
 
 
 
 
Qingqing Xiao  
PK Scientist 
Mosim Co., Ltd 
 
 
Date 
 
 
Approved by:  
 
 
Stefan Liebscher 
Principal Statistician 
Mundipharma Research 
 
 
Date 
 
Reiner Uhl 
Senior Statistician 
Mundipharma Research 
 
 
Date 
 
Cai Chunxiao 
Clinical Lead  
Mundipharma Research 
 
Date 
 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
Page 4 of 34 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................ 8 
2. 
OBJECTIVES AND PARAMETERS ........................................................... 8 
2.1. 
Objectives ....................................................................................... 8 
2.1.1. 
Aim of the study ............................................................... 8 
2.1.2. 
Primary Objective ............................................................ 8 
2.1.3. 
Secondary Objectives ...................................................... 8 
2.2. 
Parameters ..................................................................................... 8 
2.2.1. 
Primary Efficacy Variable ................................................. 8 
2.2.2. 
Secondary Efficacy Variables .......................................... 9 
2.2.3. 
Safety Variables............................................................... 9 
2.2.4. 
Pharmacokinetic Measurements ...................................... 9 
3. 
STUDY DESIGN ........................................................................................ 9 
3.1. 
Summary of Study Design .............................................................. 9 
3.2. 
Sample Size Rationale .................................................................. 11 
3.3. 
Assessment and Procedure .......................................................... 11 
3.3.1. 
Schedule Overview ........................................................ 11 
4. 
ANALYSIS POPULATIONS ..................................................................... 14 
5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING............................................................................................... 14 
5.1. 
General Considerations for Data Analyses ................................... 14 
5.2. 
Missing Data ................................................................................. 15 
5.3. 
Baseline Definition ........................................................................ 15 
5.4. 
Response Assessment Date ......................................................... 16 
5.5. 
Best Response to Prior Treatment of PTCL .................................. 16 
5.6. 
Reference Code............................................................................ 16 
6. 
STATISTICAL METHODS ........................................................................ 17 
6.1. 
Disposition of Subjects .................................................................. 17 
6.2. 
Demographic and Baseline Disease Characteristics ..................... 17 
6.3. 
Protocol Deviations ....................................................................... 18 
6.4. 
Medical/Surgical History (Other than PTCL) ................................. 18 
6.5. 
Concomitant Medication ............................................................... 18 
6.6. 
Exposure ...................................................................................... 18 
6.6.1. 
IMP Analyses ................................................................. 18 
6.6.2. 
Vitamin Supplementation Analyses ................................ 19 
6.7. 
Safety Analyses ............................................................................ 19 
6.7.1. 
Adverse Events (AEs) and Serious Adverse Events 
(SAEs) ........................................................................... 19 
6.7.2. 
Laboratory Assessment ................................................. 20 
6.7.3. 
Vital Signs ...................................................................... 22 
6.7.4. 
ECG ............................................................................... 23 
6.7.5. 
Other Tests .................................................................... 23 
6.8. 
Efficacy Analyses .......................................................................... 23 
6.8.1. 
Primary Efficacy Variable ............................................... 23 
6.8.2. 
Secondary Efficacy Variables ........................................ 23 


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MUNDIPHARMA                                                                                     
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6.8.3. 
Discordance between Independent Central Review and 
Investigator Assessment ................................................ 25 
6.9. 
Subgroup Analyses ....................................................................... 26 
6.10. 
Pharmacokinetic Analyses ............................................................ 26 
6.10.1. 
Plasma Concentration.................................................... 27 
6.10.2. 
Pharmacokinetic Parameters ......................................... 27 
7. 
ATTACHMENTS ...................................................................................... 29 
 
 
 


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MUNDIPHARMA                                                                                     
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LIST OF ABBREVIATIONS 
AE  
adverse event  
ATC 
Anatomical-Therapeutic-Chemical 
AUC 
area under the curve 
BMI  
body mass index  
BOR 
best overall response 
BSA 
body surface area 
CI 
confidence interval 
CLss 
steady state clearance 
Cmax 
maximum observed concentration 
CNAP 
chest, neck, abdomen, pelvis 
CR 
complete response 
CRF 
Case Report Form 
CRu 
complete response unconfirmed 
CSR 
Clinical Study Report 
CT 
computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CV 
coefficient of variation 
DOR 
Duration of Response 
DP 
decimal place 
EBV 
epstein-barr virus 
ECG  
electrocardiogram  
ECOG 
Eastern Cooperative Oncology Group 
EDR 
early discrepancy rate 
IDMC 
Independent Data Monitoring Committee 
IM 
intramuscular 
IMP  
Investigational Medicinal Product  
IV  
intravenous 
LDH  
lactic dehydrogenase 
LDR 
late discrepancy rate 
LLT 
Lowest Level Term 
MedDRA 
Medical Dictionary for Regulatory Activities 
ORR 
objective response rate 
OS 
Overall Survival 
PD 
progressive disease  
PFS 
Progression-Free Survival 
PK 
pharmacokinetic(s)  
PPP 
Per Protocol Population 
PR 
partial response 
PT 
Preferred Term 
PTCL 
peripheral T-cell lymphoma 
SAE  
serious adverse event  
SAP 
Statistical Analysis Plan 
SE 
standard error  
SD 
standard deviation 
SOC 
System Organ Class 


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MUNDIPHARMA                                                                                     
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TEAE 
treatment emergent adverse event 
Tmax 
time of Cmax observation 
t1/2Z 
terminal phase half-life 
TTR 
Time to Response 
Vdss 
steady state volume of distribution 
 


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MUNDIPHARMA                                                                                     
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Page 8 of 34 
 
1. 
INTRODUCTION 
The analyses described in this document will be included in a Clinical Study Report 
(CSR) to support a regulatory submission. This Statistical Analysis Plan (SAP) describes 
all planned analyses that will be conducted and presented for FOT12-CN-301 study and 
is based upon Section 14 (Statistical Analysis) of the protocol version 1.0 dated April 3, 
2015. 
The primary analysis will be performed based on a data cut-off date defined after all 
subjects have been treated for 5 cycles. The final analysis will be performed based on all 
the subjects complete the study. 
2. 
OBJECTIVES AND PARAMETERS 
2.1. 
Objectives 
2.1.1. 
Aim of the study 
The aim of the study is to confirm the efficacy and safety of pralatrexate for the treatment 
of Relapsed or Refractory peripheral T-cell lymphoma (PTCL) in Chinese population.  
2.1.2. 
Primary Objective  
The primary objective of this study is to confirm the objective response rate (ORR) 
among Chinese subjects with relapsed or refractory PTCL treated with pralatrexate 
together with concurrent vitamin B12 and folic acid supplementation.  
2.1.3. 
Secondary Objectives  
 To evaluate further efficacy parameters (Duration of Response; Time to Response; 
Progression-Free Survival; Overall Survival) among Chinese subjects with relapsed 
or refractory PTCL treated with pralatrexate together with concurrent vitamin B12 
and folic acid supplementation  
 To evaluate the safety of pralatrexate with concurrent vitamin B12 and folic acid 
supplementation when administered to Chinese subjects with relapsed or refractory 
PTCL  
 To determine the pharmacokinetic (PK) profile of pralatrexate among Chinese 
subjects with PTCL when administered with vitamin B12 and folic acid 
supplementation  
2.2. 
Parameters 
2.2.1. 
Primary Efficacy Variable 
Objective response rate by International Working Criteria and per central review.   


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MUNDIPHARMA                                                                                     
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2.2.2. 
Secondary Efficacy Variables 
 Duration of Response (DOR) 
 Time to Response (TTR) 
 Progression-Free Survival (PFS) 
 Overall Survival (OS) 
2.2.3. 
Safety Variables 
 Treatment emergent AEs  
 Physical examinations  
 Clinical laboratory values  
 
2.2.4. 
Pharmacokinetic Measurements 
Pharmacokinetic evaluations will be performed. The PK profile of R-pralatrexate and S-
pralatrexate will be determined in 15 subjects at pre-selected sites. 
Standard PK parameters will be determined for both enantiomers in plasma (area under 
the curve [AUC], steady state volume of distribution [Vdss], steady state clearance 
[CLss], maximum observed concentration [Cmax], time of Cmax observation [tmax] and 
terminal phase half-life [t1/2Z]). Accumulation in exposure at steady state will also be 
reported, such as the ratio of AUC [ARAUC] and Cmax [ARCmax]. Collection of 
plasma to determine the full PK profile will be performed in 15 subjects at pre-selected 
sites. 
3. 
STUDY DESIGN 
3.1. 
Summary of Study Design 
This is a single arm, open-label, multi-center study designed to evaluate the efficacy and 
safety of pralatrexate in Chinese subjects when administered concurrently with vitamin 
B12 and folic acid supplementation to subjects with relapsed or refractory PTCL. 
This study includes 3 phases: Screening, Treatment (pralatrexate) and Follow-up phases. 
Screening Phase: 
The screening phase will be of up to 28 days duration (depending on availability of lab 
results). All potential study subjects will be screened and determined of the eligibility 
prior to enrolment. The eligible subjects will begin to receive vitamin supplementation at 
screening phase. 
Unless otherwise specified, the protocol defined procedures and evaluations (See Table 1. 
Schedule of Visits and Procedures) will be performed within 28 days prior to the 
projected start of pralatrexate administration (cycle 1, dose 1). 
Treatment (pralatrexate) Phase: 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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The start of study treatment is defined as the initiation of pralatrexate treatment. Vitamin 
supplementation will be initiated at least 10 days prior to pralatrexate administration on 
cycle 1, dose 1. Once the patient is on-study, the dosing of vitamin supplementation must 
adhere to the schedule defined by the protocol. 
Evaluation of response must be performed within 7 days prior to the projected first dose 
of cycle 2-4 and then within 7 days prior to the projected first dose of every even 
numbered subsequent cycle (i.e. prior to cycles 6, 8, etc). Although radiological response 
assessments have been scheduled every 14 weeks, unscheduled radiological response 
assessments will be performed earlier if clinical progression is suspected.  
Treatment with pralatrexate will continue until 24 months of administration, or until 
documented disease progression; unacceptable adverse event(s) indicating intolerance of 
the lowest study dose allowed (20 mg/m2/week); omission of 3 sequential doses of 
pralatrexate due to a treatment-related AE; 3-week lapse between pralatrexate doses; 
development of an AE, intercurrent illness, condition, or procedural complication that 
may interfere with the subject’s participation; investigator’s decision to withdraw the 
subject; subject withdraws consent; pregnancy of the subject; noncompliance with trial 
treatment or procedure requirements; or administrative reasons. 
Follow-up phase: 
All patients who received at least 1 dose of pralatrexate are to attend the Safety Follow-
up Visit [30 (± 5) days after the last dose of pralatrexate] and the protocol defined 
procedures and evaluations will be performed. 
After the Safety Follow-up Visit, Routine Follow-up Visits will be based on standard 
clinical care. All patients who received at least 1 dose of pralatrexate are to attend 
Routine Follow-up Visits, which will occur every 3 months (± 2 weeks) for determination 
of progression of disease, subsequent treatment initiation for T-cell lymphoma and 
survival after the Safety Follow-up Visit for a total duration of 24 months after the last 
dose of pralatrexate. The protocol-defined procedures/evaluations should be performed at 
each Routine Follow-up Visit. 
Figure 1 Study diagram 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
Page 11 of 34 
 
 
3.2. 
Sample Size Rationale 
The primary objective is to demonstrate that the response rate in the Chinese population 
is greater than ≥15%. Assuming a true response rate of 29%, a sample size of 68 will 
provide 80% power to demonstrate a response rate of greater than 15% using a two-sided 
test at 5% significance level. 
3.3. 
Assessment and Procedure 
3.3.1. 
Schedule Overview 
Table 1 presents the schedule of visits and procedures/CRF module


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MUNDIPHARMA                                                                                        Protocol No. FOT12-CN-301            
SAP final V2.0 
Page 12 of 34 
 
Table 1 Schedule of Visits and Procedures/CRF Modules  
 


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MUNDIPHARMA                                                                                        Protocol No. FOT12-CN-301            
SAP final V2.0 
Page 13 of 34 
 


Confidential 
MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
Page 14 of 34 
 
4. 
ANALYSIS POPULATIONS 
Enrolled Population  
The enrolled population is defined as all subjects who signed informed consent.  
Safety Population  
The safety population is defined as all subjects who receive at least one dose of IMP.  
Per Protocol Population (PPP) 
The Per Protocol Population is defined as all subjects in the safety population who fulfil 
the following criteria:  
1) The absence of any major protocol deviations 
2) The completion of a minimal 3 doses of exposure to the treatment regimen of one 
treatment cycle, except discontinuation due to toxicity and disease progression 
All major protocol deviations will be agreed at the data review meeting prior to database 
lock. 
Pharmacokinetic Population 
The overall PK population is defined as all subjects who receive at least one dose of IMP 
and have at least one primary PK parameter. Subjects with non-zero baseline 
concentrations of >5% of Cmax for either analyte (R-pralatrexate or S-pralatrexate) will 
be removed from the PK population.   
5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
AND HANDLING 
5.1. 
General Considerations for Data Analyses  
In general, continuous data will be summarized using the following descriptive statistics: 
n, mean, standard deviation, median, minimum and maximum. The decimal places will 
be defined as table 2. 
Table 2 decimal places for descriptive statistics 
Label 
No. of decimal places (dp) 
N 
Always present to 0 dp 
Mean 
1 dp more than raw data 
Median 
Same as raw data if the number of data points is odd.  
1 dp more than raw data if the number of data points is even. 
SD 
2 dp more than raw data 
Min 
Same as raw data 
Max 
Same as raw data 
 
Categorical data will be summarized as the number and percentage of subjects in each 
category. 
All unscheduled records will be included in the corresponding listings but not included in 
the summary analyses. 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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All data processing, summarization and analyses will be performed using Version 9.1.3 
(or later) of the SAS statistical software package (Windows OS). 
5.2. 
Missing Data  
In general, all available data will be included in the analyses and will be summarized as 
far as possible. Unless otherwise specified there will be no substitution of missing data, 
i.e. missing data will not be replaced but will be handled as 'missing' in the statistical 
evaluation. 
For plasma concentration data, all values below the quantifiable limit will be set to 0 for 
descriptive summary statistics. 
For partial dates, no imputation rule will be derived for listings. For tables, when 
calculating duration of PTCL, if initial diagnosis date of PTCL does not have complete 
information of day, month, and year, it will be imputed with the criteria as 
Imputation for incomplete start dates: 
    If year, month and day are missing then use the minimum of the subject's first visit 
date or the consent date. 
    If month and day are missing then use January 1. 
    If only day is missing, then use 1 for the first day of the month. 
Imputation for incomplete end dates: 
    If year, month, and day are missing then use the subject's last visit date. 
    If month and day are missing then use December 31. 
    If only day is missing, then use the last day of the month. 
Do not expand the record past the subject's last visit. 
When defining TEAE, if any AEs have partial start date, it will be imputed with the 
criteria as 
    If year, month and day are missing then use the minimum of the subject's first visit 
date or the consent date. 
    If month and day are missing, first compare with year of first dose. If they are same 
then use first dose date else use January 1.  
If only day is missing, first compare with year and month of first dose. If they are 
same then use first dose date else use 1 for the first day of the month. 
No partial dates will be imputed for efficacy endpoint calculation. 
5.3. 
Baseline Definition  
Baseline is defined as the last non missing value before first intake of IMP in cycle 1. 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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5.4. 
Response Assessment Date 
For the efficacy analysis, investigator response assessment date is calculated as 
 If the response is PD, then choose the earliest dates among target, non-target and new 
lesion measurement per cycle. 
 If the response is non PD, then choose the latest dates among target and non-target 
lesion measurement per cycle. 
5.5. 
Best Response to Prior Treatment of PTCL 
 If the subject has any responses of CR, CRu, PR, SD, PD or NA, the best response 
should be CR > CRu > PR > SD > NA > PD. 
5.6. 
Reference Code  
 Exact binomial test: Proportion and CI 
ods output BinomialProp = xx1  BinomialCLs = xx2; 
proc freq data=xxx; 
   tables response / binomial(exact); 
   weight Count; 
run; 
 Kaplan-Meier method: Quartile and corresponding CI, Product-Limit Survival 
Estimates  
proc lifetest data = xxx; 
  time aval*CNSR(1); 
    ods output censoredSummary = xx1  
                   quartiles = xx2 
                   ProductLimitEstimates = xx3; 
    survival out = xx4 confband=ALL bandmin=100 bandmax=500 
maxtime=600; 
run; 
 CI for Geometric Mean  
 
First log-transformed for each value, i.e. logaval = log(aval).    
proc means data = xxx n mean std median max min noprint clm 
alpha=0.05; 
  var logaval; 
  output out = xx1 LCLM=lclm uclm=uclm; 
run;  
Then the transformed back lower limit is exp(lclm) and upper limit is exp(uclm). 
 CI for ratios of AUC and Cmax between visits 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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First log-transformed for each value, i.e. logaval = log(aval).  
ods output conflimits=<out>; 
proc ttest data=<data> alpha=0.10; 
     paired <lnAval_week6> * <lnAval_day1>; 
run; 
 
6. 
STATISTICAL METHODS  
6.1. 
Disposition of Subjects 
The number and percentage of subjects screened, failed screening along with the primary 
reason for screen failure will be summarized for subjects in the enrolled population. The 
enrollment status will also be listed.  
The number and percentage of subjects in each population and the reasons for exclusion 
from the PPP will be summarized for subjects in the enrolled population. The exclusion 
reason will also be listed.  
The number and percentage of subjects enrolled from each site will be summarized and 
listed for subjects in the enrolled, safety and per protocol population.  
The number and percentage of subjects under study treatment, discontinued from study 
treatment and the primary reason for discontinuation from study treatment will be 
summarized in the safety population. The corresponding listing will be provided.  
For the follow up phase (safety and/or routine follow up phases), the number and 
percentage of patients entered the follow-up phase will be summarized. 
6.2. 
Demographic and Baseline Disease Characteristics 
Demographic and baseline variables will be summarized and listed for all subjects in the 
safety population and PK population.  
The duration of PTCL is from the initial diagnosis date or first prior treatment date of 
PTCL, whichever occurs earlier, to the date of inform consent signed off. If initial 
diagnosis date does not have complete information of day, month, and year, it will be 
imputed as the rule defined in section 5.2.  
Continuous variables include age, height, weight, BMI (weight (kg)/height (m)^2), BSA, 
duration of PTCL and number of regimen of prior systemic therapy (including 
Chemotherapy, Autologous stem cell transplant).  
Categorical variables include age group, gender, race, ethnicity, subtype of PTCL both 
from investigator and central review, ECOG performance status, documented progressive 
disease on prior treatment of PTCL, prior treatment of PTCL, best response to any of 
prior treatment of PTCL and last response to all the prior treatments of PTCL. 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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6.3. 
Protocol Deviations 
The following protocol deviations may exclude a subject from the PPP: 
 Failure to comply with the major inclusion/exclusion criteria, e.g., not meeting the 
Inclusion Criterion #1 the histopathological subtype confirmed by central pathology 
review 
 Being non-compliant with study treatments 
 Without completing of a minimal 3 doses of exposure to the treatment regimen of 
one treatment cycle, except discontinuation due to toxicity and disease 
progression 
 Taking any prohibited concomitant therapies 
Major protocol deviations will be agreed at the data review meeting prior to database 
lock. Major protocol deviations will be summarized and all the protocol deviations will 
be listed. 
6.4. 
Medical/Surgical History (Other than PTCL) 
Medical/surgical history (other than PTCL) will be summarized and listed by System 
Organ Class (SOC) and Preferred Term (PT) in the safety population. 
6.5. 
Concomitant Medication 
Concomitant medication will be summarized and listed by coded term using WHO Drug 
Dictionary in the safety population. 
The number and percentage of subjects taking concomitant medications will be 
summarized by ATC anatomical class (ATC level 1), pharmacological class (ATC level 
2), pharmacological sub-class (ATC level 3) and coded term for subjects in the safety 
population.  
6.6. 
Exposure 
6.6.1. 
IMP Analyses 
The following variables will be defined to assess exposure to study treatment: 
 Number of infusions 
 Duration of treatment (weeks): First calculate [(Date of last dose - date of first dose) 
+ 7] ÷ 7 per subject per cycle. Then sum all the cycle durations for each subject. 
 Cumulative dose (mg/m2) = Sum of all total doses administered (mg/m2) 
 Dose intensity (mg/m2/week) = Cumulative dose (mg/m2) ÷ Duration of treatment 
(week) 
 Relative dose intensity (%) = Dose intensity ÷ Planned weekly dose intensity x 100, 
whereas planned weekly dose intensity (mg/m2/week) = 30 mg/m2/week 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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All these variables will be summarized as continuous data. Additionally, the relative dose 
intensity will be categorically summarized (ie, number and percentage of subjects with 
relative dose intensity of <60%, 60-<80%, 80-<90%, 90-<110%, 110-<120%, >=120%).  
Moreover, the number and percentage of subjects with any dose reduction, temporarily 
interrupted, permanently discontinued, not administered and corresponding reason will be 
presented. 
The number and percentage of total cycles subjects received as well as the maximum 
cycle number will be presented. 
Listing of exposure will also be provided. 
6.6.2. 
Vitamin Supplementation Analyses 
Vitamin B12 administration will be listed by subject.  
Compliance of folic acid will be summarized by cycle. The compliance will be calculated 
as (duration per cycle – number of days with dose skipped per cycle)/ duration per cycle. 
Also the listing will be provided. 
6.7. 
Safety Analyses 
Safety data that will be evaluated includes adverse events (AEs), serious adverse events 
(SAEs), laboratory assessment, vital signs, ECG and other tests. Safety data will be 
summarized for subjects in the safety population. 
6.7.1. 
Adverse Events (AEs) and Serious Adverse Events (SAEs)  
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system to give a System Organ Class (SOC) and Preferred Term (PT) for each 
event. Events will also be graded for severity according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 
Only TEAEs (treatment emergent adverse event) will be summarized. A treatment 
emergent AE is defined as any AE with an onset date on or after the first dose of IMP if 
the AE is absent before the first dose of IMP, or worsened after the first dose of IMP. 
This will also include AEs with an onset date up to and including 30 days after the last 
dose of IMP. In addition, this will include AEs with an onset date after 30 days 
considered as related to IMP by the investigator. 
An overview summary table of TEAEs including treatment related TEAEs, CTCAE 
grade>=3 TEAEs, treatment related CTCAE grade>=3 TEAEs, treatment emergent 
SAEs, treatment related and emergent SAEs, significant TEAEs (leading to death, 
requiring treatment given, leading to IMP dose decreased, withheld transiently, 
discontinuation) will be provided. 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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In general, the number and percentage of subjects reporting any TEAEs will be 
summarized by the preferred term nested within the SOCs. Although a MedDRA term 
may be reported more than once for a subject, that subject will be counted only once in 
the incidence count for that MedDRA term.  
A summary of TEAEs by SOC, PT and maximum CTCAE grade will also be provided. 
In addition, the number of reported TEAEs will be summarized. 
Also, a listing of AEs will be prepared, including AE start/end date, CTCAE grade, 
relationship to IMP, serious or not, action taken to IMP and AE outcome. 
TEAE leading to withdrawal and Treatment emergent SAEs would be tabulated. 
Moreover, in order to ensure that the true occurrence rate of AEs is not obscured in cases 
where certain AEs are reported with similar preferred terms, certain AE terms will be 
grouped used the MedDRA version 18.0. For this presentation, certain similar preferred 
terms will be identified, grouped, and coded to a single preferred term, which are deemed 
to represent the same conditions from a medical perspective, in order to present the event 
in a uniform manner. The grouping of AE terms will be as follows: 
 Liver Function Test Abnormal (including Alanine Aminotransferase Increased, 
Alanine Aminotransferase, Aspartate Aminotransferase, Aspartate 
Aminotransferase Increased, and Transaminases Increased)  
 Mucosal Inflammation (including Stomatitis, Stomatitis Haemorrhagic, Anal 
Inflammation, Vaginal Inflammation, Proctitis, Oesophagitis, Mouth Ulceration, 
Oral Mucosal Erythema, Pharyngeal Inflammation, Pharyngitis, Gingivitis, and 
Balanoposthitis,) 
 Thrombocytopenia (including Platelet Count Decreased) 
 Oedema (including Oedema Peripheral) 
 Dry Mouth (including Lip Dry and Dry Throat) 
 Dyspepsia (including Gastritis and Gastrooesophageal Reflux Disease) 
 Odynophagia (including Oesophageal Pain) 
 Pruritus (including Pruritus Generalized) 
 Anemia (including Hemoglobin Decreased) 
 Hypokalemia (including Blood Potassium Decreased) 
 Neutropenia (including Neutrophil Count Decreased) 
 Leukopenia (including White Blood Cell Count Decreased) 
 Lymphopenia (including Lymphocyte count decreased) 
Summary of the incidence of all TEAEs, treatment-related, CTCAE grade>=3 AEs and 
SAEs grouped by the similar preferred terms as above will also be presented.  
6.7.2. 
Laboratory Assessment  
Clinical laboratory data to be summarized includes haematology, blood chemistry, and 
urinalysis.  


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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Clinical laboratory results recorded at each visit and change from baseline to each visit 
will be summarized as continuous data for each parameter.  
Normal and abnormalities (with/without clinical significance) in each laboratory 
parameter will be summarized by cycle and listed. 
Shift tables of normal and abnormalities from baseline to the post baseline will be 
generated.  
Scatter plots will be produced for each laboratory parameter comparing baseline and end 
of study values. In addition, clinically laboratory parameters will be plotted over time 
using a box and whisker plot.  
Each parameter will be assigned an LNH classification according to whether the value is 
lower than (L), within (N) or higher than (H) the reference range for that parameter. 
Results will be summarized using shift tables to evaluate categorical changes from 
baseline to end of study with respect to reference range values (lower than, within, higher 
than).  
Clinical laboratory values after first dose of IMP will be evaluated for markedly 
abnormal values. Laboratory ranges used to identify markedly abnormal laboratory 
values will be defined in table 3. The number and percentage of subjects reporting 
markedly abnormal values will be summarized for each parameter. Each subject can be 
counted once in the parameter high and the parameter low categories, as applicable.  
 
Table 3 Laboratory Ranges Used to Identify Markedly Abnormal Laboratory Values  
                                               Units  
Laboratory Parameter  
Lower Limit  
Upper Limit  
Haematology  
Haemoglobin  
<10 g/dL (100 g/L) or <6.2 mmol/L  —––  
Platelets  
<75.0 × 109/L or <75000/mm3  
—––  
Leukocytes  
<3.0 × 109/L or <3000/mm3  
—––  
Lymphocytes  
<1.0 × 109/L or <1000/mm3  
—––  
Neutrophils  
<1.5 × 109/L or <1500/mm3  
—––  
Clinical Chemistry  
Electrolytes  
Sodium  
< LLN  
>150 mmol/L  
Potassium  
< LLN  
>5.5 mmol/L  
Bicarbonate (HCO3-)  
≤15 mEq/dL or ≤15 mmol/L  
—––  
Liver Function Tests  
Alkaline phosphatase  
—––  
>3 × ULN  
AST  
—––  
>3 × ULN  
ALT  
—––  
>3 × ULN  
GGT (GGTP)  
—––  
>3 × ULN  
Total bilirubin  
—––  
>1.5 × ULN  
Renal Function Tests  
Creatinine  
—––  
>1.5 × ULN  
Other Chemistry  


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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Calcium  
<8 mg/dL or <2.0 mmol/L  
>11.5 mg/dL or >2.9 mmol/L  
Phosphorous (inorganic phosphate)  <2.5 mg/dL or <0.8 mmol/L  
—  
Glucose  
<55 mg/dL or <3.0 mmol/L  
>160 mg/dL or >8.9 mmol/L  
Uric acid  
—––  
> ULN  
Cholesterol  
—––  
>300 mg/dL or >7.75 mmol/L  
Triglycerides  
—––  
>2.5 × ULN  
Albumin  
<3 g/dL  
—––  
 
6.7.3. 
Vital Signs  
Vital sign parameters to be summarized include systolic blood pressure, diastolic blood 
pressure, pulse rate, respiration rate, and axillary temperature. 
Vital sign results recorded at each visit and change from baseline to each visit will be 
summarized as continuous data for each parameter.  
Scatter plots will be produced for each vital sign parameter comparing baseline and end 
of study values. In addition, vital signs will be plotted over time using a box and whisker 
plot. 
Vital sign results for each parameter will be assigned an LNH classification according to 
whether the value is lower than (L), within (N) or higher than (H) the reference range for 
that parameter. Vital sign results will be summarized using shift tables to evaluate 
categorical changes from baseline to end of study with respect to reference range values 
(lower than, within, higher than). The range will be defined in table 4. 
Table 4 Reference Range for Vital Sign Parameter 
Vital Sign Parameter  
Reference Range 
Systolic blood pressure  
90-140 mmHg 
Diastolic blood pressure  
60-90 mmHg 
Pulse rate  
60-100 bpm 
12-20 breaths per minute 
Axillary Temperature 
≤ 37 °C 
 
Vital sign values after first dose of IMP will be evaluated for clinically notable 
abnormalities. Criteria used to identify clinically notable vital sign abnormalities will be 
defined in table 5. The number and percentage of subjects reporting clinically notable 
abnormalities will be summarized for each parameter. Each subject can be counted once 
in the parameter high and the parameter low categories, as applicable. 
Table 5 Criteria Used to Identify Clinically Notable Vital Sign Abnormalities  
Vital Sign Parameter  
Value  
Change From Baseline a  
Systolic blood pressure  
≥ 180 mmHg  
Increase of ≥ 20 mmHg  
≤ 90 mmHg 
Decrease of ≥ 20 mmHg  
Diastolic blood pressure  
≥ 105 mmHg  
Increase of ≥ 15 mmHg  
≤ 50 mmHg 
Decrease of ≥ 15 mmHg  
Pulse rate  
≥ 120 bpm  
Increase of ≥ 15 bpm  


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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≤ 50 bpm 
Decrease of ≥ 15 bpm  
Respiration rate  
< 8 breaths/minute  
-  
> 24 breaths/minute 
-  
a Both value and change from baseline criteria must be met to qualify as a clinically notable vital sign 
abnormality.  
 
6.7.4. 
ECG  
Clinically significant ECG findings as determined by the Investigator will be summarized 
and listed.  
6.7.5. 
Other Tests 
Physical examination will be summarized by normal/abnormal and listed by visit. 
PTCL related symptoms and results of bone marrow examination will be listed.  
6.8. 
Efficacy Analyses 
6.8.1. 
Primary Efficacy Variable 
The primary endpoint is the objective response rate (ORR) by International Working 
Criteria defined as the proportion of subjects with CR, CRu or PR as Best Overall 
Response (BOR). The objective response rate will be tested using the exact binomial test 
for single proportion at two-sided significance level of 5%. The hypotheses under test 
will be H0: ORR=15% vs. H1: ORR≠15%.  
The primary analysis will be based on the independent review data using the safety 
population. An additional analysis based on the investigator assessment data will be 
performed. All analyses will be repeated using the per-protocol population.  
Also present number of subjects achieved response by site. 
6.8.2. 
 Secondary Efficacy Variables 
 Duration of Response (DOR) 
Duration of response will be derived based on responders. Duration of response will be 
measured from first response date, i.e. first achieved CR/CRu/PR, to the date of disease 
progression or death, whatever comes first. The subject will be considered as event if the 
response is PD or the subject died after achieving CR/CRu/PR, and the event end date 
will be the PD date or death date, whatever comes first. The duration is calculated as 
(minimum (first PD or death date) – first response date + 1)/30.4375. 
If the subject receives subsequent therapy, including transplant, before PD or death, the 
subject will be censored at that time. The subject who withdraw consent to participate in 
the study prior to progression will be censored at the date of their last evaluable 
assessment of response. The subject who withdraw from treatment prior to progression 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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without withdrawing consent will be followed for disease status whenever possible. 
Otherwise the subject will be censored at the date of last tumor assessment date.  
Duration of complete response will also be calculated. The algorithm is the same of DOR 
but change endpoint from CR/CRu/PR to CR/CRu.  
 Time to Response (TTR) 
Time to first response will be derived based on responders. Time to first response will be 
measured from first treatment date to the first date of documented response. If the 
response is CR, CRu or PR, then the subject will be considered as event and event end 
date will be the earliest date of archived any of CR, CRu or PR. The duration is 
calculated as (minimum (CR date, CRu date, PR date) – first treatment date + 1)/30.4375.  
Time to best response will also be calculated. Time to best response will be measured 
from first treatment date to the date of documented best response (CR is better than CRu, 
CRu is better than PR). The event rule and censor rule is the same as time to first 
response. 
 Progression Free Survival (PFS) 
PFS will be measured from first treatment date until PD or death, whatever comes first. 
The subject will be considered as event if the response is PD or the subject died, and the 
event end date will be the PD date or death date, whatever comes first. The duration is 
calculated as (minimum (first PD or death date) – first treatment date + 1)/30.4375.  
If the subject receives subsequent therapy, including transplant, before PD or death, the 
subject will be censored at that time. The subject who withdraw consent to participate in 
the study prior to progression will be censored at the date of their last evaluable 
assessment of response. The subject who withdraw from treatment prior to progression 
without withdrawing consent will be followed for disease status whenever possible. 
Otherwise the subject will be censored at the date of last tumor assessment date. If the 
subject has no assessment, then the subject will be censored at first treatment date. 
 Overall Survival (OS) 
OS will be measured from first treatment date until death. The subject will be considered 
as event if the subject died, and the event end date will be the death date. The duration is 
calculated as (death date) – first treatment date + 1)/30.4375. 
The subject who withdraw consent to participate in the study, including consent to be 
followed, will be censored on the date of withdrawal. The subject who withdraw from 
treatment without withdrawing consent will be followed for survival status whenever 
possible. Otherwise the subject will be censored at the date of last contact date.  
Time to response endpoints will be summarized as continuous variable using descriptive 
statistics. Also will be categorized by response occurred cycle. 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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Other secondary time-to-event endpoints (e.g. duration of response, PFS, and OS) will be 
presented using Kaplan-Meier curves (product limit estimates) together with a summary 
of associated statistics (e.g. median survival time, first and third quartiles, survival rates 
including the corresponding two-sided confidence intervals [CIs]).  
Response will be assessed by independent central review and by the treating investigator. 
Then for the secondary endpoints based on tumor assessments (e.g. duration of response, 
time to response and PFS)), they will be analysed twice, once using the independent 
review data and once using the investigator assessment data.  
Shift table will be presented to compare response between investigator assessment and 
central review assessment. 
The secondary analyses will be performed using the safety population and repeated using 
the per-protocol population.  
Listing of tumor assessment will be presented with independent review data investigator 
assessment data.  
6.8.3. Discordance between Independent Central Review and Investigator 
Assessment  
The early discrepancy rate and late discrepancy rate as defined below will be 
summarized. The agreement between independent central review and investigator is 
represented in a tabular form (table 6) below. 
Table 6 Independent Central Review versus Investigator Disease Progression Assessment  
 
Independent Central Review 
PD 
No PD 
Investigator PD 
a = a1 + a2 + a3 
b 
No PD 
c 
d 
a1: number of agreements on timing and occurrence of PD. 
a2: number of times investigator declares PD later than independent central review. 
a3: number of times investigator declares PD earlier than independent central review. 
The early discrepancy rate (EDR) is defined as 
EDR = (b + a3)/(a + b) 
The EDR represents the positive predictive value of investigator assessment and 
quantifies the frequency with which the investigator declares progression early relative to 
independent central review as a proportion of the total number of investigator assessed 
PD’s. 
The late discrepancy rate (LDR) is defined as 
LDR = (c + a2)/(b + c + a2 + a3) 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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The LDR quantifies the frequency that investigator declares progression later than 
independent central review as a proportion of the total number of discrepancies. 
6.9. 
Subgroup Analyses 
For the objective response rate, subgroup analyses will be performed. If any category is 
less than 5 subjects, then only generate number of responder and response rate, i.e. no 
need to create CI and p-value. 
The following subgroups will be examined. 
 Age group (<55, 55-<65 or >=65) 
 Gender (male or female) 
 PTCL subtype from Investigator 
  PTCL not otherwise specified (NOS)  
  Angioimmunoblastic T-cell lymphoma                                              
  Anaplastic large cell lymphoma, ALK+                                             
  Anaplastic large cell lymphoma, ALK-                                             
  Extranodal NK/T-cell lymphoma - nasal type                                       
  Enteropathy-associated T cell lymphoma                                           
  Hepatosplenic T-cell lymphoma                                                      
  Subcutaneous panniculitis-like T-cell lymphoma                                   
  Adult T-cell lymphoma/leukemia (human T-cell leukemia virus[HTLV] 1+)           
  Aggressive NK-cell leukemia                                                        
  Transformed mycosis fungoides                                                      
  Other                                                                           
 Best response to any of prior treatment of PTCL (responder (CR + CRu + PR) or non-
responder) 
 Last response to all the prior treatments of PTCL (responder (CR + CRu + PR) or 
non-responder) 
 Number of regimen of Prior Systemic Therapy (1, 2, 3 or >=4) 
 Time from most recent therapy (<3 months or >=3 months) 
 LDH level at baseline (above normal or normal/low) 
6.10. Pharmacokinetic Analyses 
The PK profile of R-pralatrexate and S-pralatrexate will be determined in 15 subjects at 
pre-selected sites. 
The collection times for full pralatrexate PK are as follows:  


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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 Cycle 1, dose 1: Pre-injection, end-injection, 30 and 60 minutes, and 3, 5, 8, 12, 18, 
24, 48, and 72 hours post-end injection.  
 Cycle 1, doses 2 – 5: Pre-injection  
 Cycle 1, dose 6: Pre-injection, end-injection, 30 and 60 minutes, and 3, 5, 8, 12, 18, 
24, 48, and 72 hours post-end injection. 
 
6.10.1. 
Plasma Concentration 
Plasma concentration data will be listed by analyte (R-pralatrexate and S-pralatrexate) for 
subjects in the pharmacokinetic population.  
Plasma concentrations for each analyte will be summarized descriptively by nominal 
time-point for subjects in the pharmacokinetic population as continuous data. All values 
below the quantifiable limit will be set to 0 for descriptive summary statistics. 
Individual and mean (SD) plasma concentration profiles for each analyte for subjects in 
the pharmacokinetic population will be presented graphically in a linear and log linear 
scale.  
6.10.2. 
Pharmacokinetic Parameters 
Noncompartmental method (Phoenix WinNonlin, Version 6.3 or higher version, Certara, 
Princeton, USA) will be used to derive pharmacokinetic parameters. The following 
pharmacokinetic parameters will be reported, AUCINF, AUCt, Cmax, CLss, LamdaZ, 
tmax, t1/2Z, Vdss, %AUCextra, ARAUC and ARCmax. PK parameters and relate CDISC 
standard terminology is listed in Table 7. Main formulas for calculation of PK parameters 
is listed in Table 8. 
Table 7  Relate CDISC standard terminology of PK parameters 
PK parameters  
CDISC standard terminology 
ARAUC 
ARAUC 
ARCmax 
ARCMAX 
AUCINF 
AUCIFO 
AUCt 
AUCLST 
%AUCextra 
AUCPEO 
AUCtau 
AUCTAU 
CL(CLss) 
CLO 
Cmax 
CMAX 
R2ADJ 
R Squared Adjusted 
LamdaZ 
LAMZ 
t1/2Z 
LAMZHL 
tmax 
TMAX 
Vd(Vdss) 
VZO 
 
Table 8 Main formulas for calculation of PK parameters 
PK parameters 
Unit 
Formulas 
ARAUC 
Ratio 
ARAUC=AUCtweek6/AUCtday1 
ARCmax 
Ratio 
ARCmax=Cmaxweek6/Cmaxday1 
AUCINF 
h*ng/mL 
Log linear trapezoid(Linear up log down) AUCINF=AUCt+Clast/ LamdaZ 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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AUCt 
h*ng/mL 
Log linear trapezoid(Linear up log down) 
%AUCextra 
% 
%AUCextra=(AUCINF-AUCt)/AUCINF*100 
AUCtau 
h*ng/mL 
AUC between the dose interval 
CL 
L/h 
CL=DOSE/AUCINF 
Cmax 
ng/mL 
Directly obtained from the observed concentration vs. time curve 
LamdaZ 
h-1 
Estimated terminal slope of the linear regression of log-transformed 
t1/2Z 
h 
t1/2Z=LN2/ LamdaZ 
tmax 
h 
Directly obtained from the observed concentration vs. time curve 
Vd 
L 
Vd=DOSE/(AUCINF* LamdaZ) 
 
Pharmacokinetic parameters will be listed by analyte for subjects in the PK population. 
Data excluded from the PK analysis will be flagged with an asterisk. If the %AUCextra is 
greater than 20% of AUCINF, this will be flagged in the listings. LambdaZ, t1/2 and 
AUCINF will not be included in statistical summaries or analysis if the adjusted R2 in 
LambdaZ estimation is less than 0.8. 
Pharmacokinetic parameters for each analyte will be summarised descriptively for 
subjects in the PK population, adjusting for dose where necessary. Descriptive statistics 
including mean, SD, coefficient of variation (CV), SE, number of subjects with available 
data (n), minimum, maximum, and median will be calculated for all pharmacokinetic 
parameters (except tmax) by analyte, study day, and the actual administered dose. 
Additionally, geometric means and geometric CV will be calculated for AUCt, AUCINF 
and Cmax. The algorithm is  
Geometric means = exp[(log(y1) + …+ log(yn))/n] 
Geometric SD = exp(SD(log(y1),…,log(yn))) 
Geometric CV (%)= (exp((log(Geometric SD)) 2) – 1)1/2 x 100 
Tmax will be summarized by n, mean, minimum, maximum and median.  
Log-transformed AUCt and Cmax at Day 1 and Week 6 will be used to calculate two-
sided 90% confidence intervals for paired observations. Mean values and their associated 
confidence intervals will then be back transformed to provide point estimates and 90% 
confidence intervals for the ratios. Incomplete pairs will be excluded from the 
calculation. Only subjects who provided non-missing values for both periods, so that a 
non-missing day 1 to week 6 difference can be calculated, will be included. 
 
 
 
 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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7. 
ATTACHMENTS 
1. Tables, listings and figures shell will be attached. 
 
 
 
 
 
LIST OF TABLES 
Table 1.1 Screen Failure Enrolled Population 
Table 1.2 Analysis Populations Enrolled Population 
Table 1.3 Disposition Enrolled Population 
Table 1.4 Treatment Discontinuation Safety Population 
Table 1.5 Site Enrolled Population 
Table 2.1 Subject Demography Safety Population 
Table 2.2 Subject Demography Pharmacokinetic Population 
Table 2.3 Baseline Characteristics Safety Population 
Table 2.4 Baseline Characteristics Pharmacokinetic Population 
Table 3 Medical/Surgical History (Other than PTCL) By System Organ Class and 
Preferred Term Safety Population 
Table 4 Concomitant Medication Safety Population 
Table 4.1 Concomitant Medication by ATC Safety Population 
Table 5.1 Study Treatment Exposure Safety Population 
Table 5.2 Cycles Given Safety Population 
Table 5.3 Treatment Adjustment Safety Population 
Table 5.4 Compliance for Folic Acid Administration Safety Population 
Table 6.1 Overview of All Treatment Emergent Adverse Events Safety Population 
Table 6.1.1 Overview of Significant Treatment Emergent Adverse Events Safety 
Population 
Table 6.2 Treatment Emergent Adverse Events By System Organ Class and Preferred 
Term Safety Population 
Table 6.3 Serious Treatment Emergent Adverse Events By System Organ Class and 
Preferred Term Safety Population 
Table 6.4 Treatment Related Treatment Emergent Adverse Events By System Organ 
Class and Preferred Term Safety Population 
Table 6.5 Treatment Related Serious Treatment Emergent Adverse Events By System 
Organ Class and Preferred Term Safety Population 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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Table 6.6 CTCAE Grade >= 3 Treatment Emergent Adverse Events By System Organ 
Class and Preferred Term Safety Population 
Table 6.7 Treatment Related CTCAE Grade >= 3 Treatment Emergent Adverse Events 
By System Organ Class and Preferred Term Safety Population 
Table 6.8 Treatment Emergent Adverse Events Leading to IMP decreased By System 
Organ Class and Preferred Term Safety Population 
Table 6.9 Treatment Emergent Adverse Events Leading to IMP Withheld transiently By 
System Organ Class and Preferred Term Safety Population 
Table 6.10 Treatment Emergent Adverse Events Leading to IMP Withdraw Permanently 
By System Organ Class and Preferred Term Safety Population 
Table 6.11 Treatment Emergent Adverse Events Leading to Death By System Organ 
Class and Preferred Term Safety Population 
Table 6.12 Treatment Emergent Adverse Events by Maximum CTCAE Grade By System 
Organ Class and Preferred Term Safety Population 
Table 6.13 Serious Treatment Emergent Adverse Events by Maximum CTCAE Grade By 
System Organ Class and Preferred Term Safety Population 
Table 6.14 Treatment Related Treatment Emergent Adverse Events by Maximum 
CTCAE Grade By System Organ Class and Preferred Term Safety Population 
Table 6.14.1 Grouped Treatment Emergent Adverse Events by Maximum CTCAE Grade 
By System Organ Class and Preferred Term Safety Population 
Table 6.15 Grouped Treatment Emergent Adverse Events By Similar Preferred Term 
Safety Population 
Table 6.16 Grouped Serious Treatment Emergent Adverse Events By Similar Preferred 
Term Safety Population 
Table 6.17 Treatment Related Grouped Treatment Emergent Adverse Events By Similar 
Preferred Term Safety Population 
Table 6.18 CTCAE Grade >= 3 Grouped Treatment Emergent Adverse Events By 
Similar Preferred Term Safety Population 
Table 7.1 Continuous Laboratory Results Safety Population 
Table 7.2 Categorical Laboratory Evaluations Safety Population 
Table 7.3 Shift of Categorical Laboratory Evaluations by Clinically Significance Safety 
Population 
Table 7.4 Shift of Categorical Laboratory Evaluations by Low/Within/High Classification 
Safety Population 
Table 7.5 Markedly Abnormal Laboratory Evaluations Safety Population 
Table 8.1 Continuous Vital Sign Results Safety Population 
Table 8.2 Shift of Categorical Vital Sign by Low/Within/High Classification Safety 
Population 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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Table 8.3 Clinically Notable Vital Sign Safety Population 
Table 9 Electrocardiogram Safety Population 
Table 10 Physical Examination Safety Population 
Table 11.1 Objective Response Rate Safety Population 
Table 11.2 Objective Response Rate Per Protocol Population 
Table 11.3 Best Overall Response Rate Safety Population 
Table 11.4 Best Overall Response Rate Per Protocol Population 
Table 11.5 Duration of Response Safety Population of Responder 
Table 11.6 Duration of Response Per Protocol Population of Responder 
Table 11.7 Time to First Response Safety Population of Responder 
Table 11.8 Time to First Response Per Protocol Population of Responder 
Table 11.7.1 Time to Best Response Safety Population Population of Responder 
Table 11.8.1 Time to Best Response Per Protocol Population of Responder 
Table 11.9 Progression Free Survival Safety Population 
Table 11.10 Progression Free Survival Per Protocol Population 
Table 11.11 Overall Survival Safety Population 
Table 11.12 Overall Survival Per Protocol Population 
Table 11.13 Duration of Complete Response Safety Population of Complete Responder 
Table 11.14 Duration of Complete Response Per Protocol Population of Complete 
Responder 
Table 11.15 Objective Response Rate by Site Safety Population 
Table 11.16 Subsequent Treatment for PTCL Safety Population 
Table 11.17 Shift of Best Response between Investigator Assessment and Central Review 
Assessment Safety Population 
Table 11.18 Subgroup Analysis of Objective Response Rate by Subtype of PTCL from 
Investigator Safety Population 
Table 11.18.1 Subgroup Analysis of Objective Response Rate by Subtype of PTCL from 
Central review Safety Population 
Table 11.19 Subgroup Analysis of Objective Response Rate by Best Response to Any of 
Prior Treatment of PTCL Safety Population 
Table 11.20 Subgroup Analysis of Objective Response Rate by Number of Regimen of 
Prior Systemic Therapy Safety Population 
Table 11.21 Subgroup Analysis of Objective Response Rate by Age Group Safety 
Population 
Table 11.22 Subgroup Analysis of Objective Response Rate by Gender Safety Population 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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Table 11.22.1 Subgroup Analysis of Objective Response Rate by Last response to all the 
prior treatments of PTCL Safety Population 
Table 11.22.2 Subgroup Analysis of Objective Response Rate by Time from most recent 
therapy Safety Population 
Table 11.22.3 Subgroup Analysis of Objective Response Rate by LDH level at baseline 
Safety Population 
Table 11.23 Discordance between Investigator Assessment and Central Review 
Assessment Safety Population 
Table 12.1 Summary of Plasma Concentration by Analyte and Time Pharmacokinetic 
Population 
Table 12.2 Summary of Plasma Concentration by Analyte and Time Sensitivity Analysis 
Table 12.3 Summary of Pharmacokinetic Parameters (except tmax) by Analyte 
Pharmacokinetic Population 
Table 12.4 Summary of Pharmacokinetic Parameters (except tmax) by Analyte 
Sensitivity Analysis 
Table 12.5 Summary of Pharmacokinetic Parameters (tmax) by Analyte Pharmacokinetic 
Population 
Table 12.6 Summary of Pharmacokinetic Parameters (tmax) by Analyte Sensitivity 
Analysis 
Table 12.7 Summary of Pharmacokinetic Parameters (AUC and Cmax) by Analyte 
Pharmacokinetic Population 
Table 12.8 Summary of Pharmacokinetic Parameters (AUC and Cmax) by Analyte 
Sensitivity Analysis 
Table 12.9 Comparison of Pharmacokinetic Parameters (AUCLST and Cmax) between 
different visits by Analyte Pharmacokinetic Population 
Table 12.10 Comparison of Pharmacokinetic Parameters (AUCLST and Cmax) between 
different visits by Analyte Sensitivity Analysis 
LIST OF LISTINGS 
Listing 1.1 Screen Failure Enrolled Population 
Listing 1.2 Population Enrolled Population 
Listing 1.3 Protocol Deviations Enrolled Population 
Listing 2 Treatment Completion Safety Population 
Listing 3 Subject Demographics and Baseline Characteristics Safety Population 
Listing 4 History and Prior Treatment of PTCL Safety Population 
Listing 5 Medical/Surgical History (Other than PTCL) Safety Population 
Listing 6 Concomitant Medication Safety Population 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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Listing 7.1 Exposure Safety Population 
Listing 7.2 Vitamin B12 Administration Safety Population 
Listing 7.3 Folic Acid Administration Safety Population 
Listing 8 Adverse Event Safety Population 
Listing 8.1 Treatment Emergent Adverse Event Leading to IMP Withdraw Permanently 
Safety Population 
Listing 8.2 Serious Treatment Emergent Adverse Events Safety Population 
Listing 8.3 Significant Treatment Emergent Adverse Events Safety Population 
Listing 8.4 Death Safety Population 
Listing 9.1 Laboratory Evaluations (Other than LDH) Safety Population 
Listing 9.2 Laboratory Evaluations (LDH) Safety Population 
Listing 10 Vital Sign Safety Population 
Listing 11 Electrocardiogram Safety Population 
Listing 12 Physical Examination Safety Population 
Listing 13 PTCL Related Symptoms Safety Population 
Listing 14 Bone Marrow Examination Safety Population 
Listing 15 Cutaneous Lesions Measurement Safety Population 
Listing 16 Target Lesion Safety Population 
Listing 17 Non-target Lesion Safety Population 
Listing 18 New Lesion Safety Population 
Listing 19 Overall Response Assessed by Investigator and Central Review Safety 
Population 
Listing 20 Progress Disease Safety Population 
Listing 21 Component of Response Assessment Safety Population 
Listing 22 Efficacy Time to Event Variables Safety Population 
Listing 23 Listing of Plasma Concentration Pharmacokinetic Population 
Listing 24 Listing of Pharmacokinetic Parameters Pharmacokinetic Population 
LIST OF FIGURES 
Figure 1 Scatter Plot of Laboratory Evaluations in Baseline and End of Study Safety 
Population 
Figure 2 Boxplot of Laboratory Evaluations Safety Population 
Figure 3 Scatter Plot of Vital Sign in Baseline and End of Study Safety Population 
Figure 4 Boxplot of Vital Sign Safety Population 


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MUNDIPHARMA                                                                                     
Protocol No. FOT12-CN-301                                              SAP final V2.0 
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Figure 5 Kaplan-Meier Graph of Duration of Response Safety Population 
Figure 6 Kaplan-Meier Graph of Duration of Complete Response Safety Population 
Figure 7 Kaplan-Meier Graph of Progression Free Survival Safety Population 
Figure 8 Kaplan-Meier Graph of Overall Survival Safety Population 
Figure 9 Individual Plasma Concentration Plot (Linear and Semi-log) Pharmacokinetic 
Population 
Figure 10 Mean (SD) Plasma Concentration Plot (Linear and Semi-log) Pharmacokinetic 
Population 
Figure 11 Mean (SD) Plasma Concentration Plot (Linear and Semi-log) Sensitivity 
Analysis