REAL WORLD DATA COLLECTION AMONG PEDIATRIC NEUROBLASTOMA PATIENTS TREATED WITH LORLATINIB THROUGH EXPANDED ACCESS PROGRAM
Conditions: Neuroblastoma
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
Studyinformation 
Title 
Real World Data Collection Among 
Pediatric Neuroblastoma Patients Treated 
with Lorlatinib Through Expanded Access 
Program 
Protocol number 
B7461036 
Protocol version identifier 
Version 1.0 
Date 
23 February 2021  
Active substance 
Lorlatinib (L01XE44) 
Medicinal product 
Lorlatinib  
Research question and objectives 
The overall goal of this real-world data 
collection is to assess demographic, clinical 
characteristics and real-world effectiveness 
of pediatric neuroblastoma patients who 
initiated treatment with lorlatinib through 
expanded access programs.  
 
Author 
, PhD 
 
 
Phone: 
 
Email: 
 
 
, MD 
 
 
 
Phone: 
 
Email: 
  
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In 
the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified. 

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1. TABLE OF CONTENTS 
1. TABLE OF CONTENTS .......................................................................................................3 
2. LIST OF ABBREVIATIONS ................................................................................................5 
3. RESPONSIBLE PARTIES ....................................................................................................6 
4. AMENDMENTS AND UPDATES .......................................................................................7 
5. MILESTONES .......................................................................................................................8 
6. RATIONALE AND BACKGROUND ..................................................................................8 
7. RESEARCH QUESTIONS AND OBJECTIVES ...............................................................10 
8. METHODOLOGY FOR REAL WORLD DATA COLLECTION ....................................10 
8.1. Design of data collection .........................................................................................11 
8.2. Setting ......................................................................................................................11 
8.2.1. Inclusion criteria .........................................................................................12 
8.2.2. Exclusion criteria ........................................................................................12 
8.3. Variables ..................................................................................................................12 
8.4. Data sources ............................................................................................................12 
8.5. Study size ................................................................................................................13 
8.6. Data management ....................................................................................................13 
8.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic 
data record ........................................................................................................13 
8.6.2. Record retention ..........................................................................................14 
8.7. Data analysis ...........................................................................................................15 
8.8. Quality control .........................................................................................................20 
8.9. Limitations of the research methods .......................................................................20 
8.10. Other aspects .........................................................................................................21 
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................21 
9.1. Patient information ..................................................................................................21 
9.2. Patient consent .........................................................................................................21 
9.3. Patient withdrawal ...................................................................................................22 
9.4. Institutional review board (IRB)/Independent ethics committee (IEC) ..................23 
9.5. Ethical conduct of the study ....................................................................................23 

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10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................23 
10.1. Single reference safety document .........................................................................32 
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........33 
12. REFERENCES ..................................................................................................................33 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................35 
ANNEX 2. ADDITIONAL INFORMATION .........................................................................35 
 

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2. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
BSA 
body surface area 
DCT 
data collection tool 
DSU 
drug safety unit 
EDC 
electronic data capture 
HCP 
healthcare professional 
IEC 
independent ethics committee 
IRB 
institutional review board 
MedDRA 
Medical Dictionary for Regulatory Activities 
NANT 
New Agents in Neuroblastoma Therapy consortium 
NB 
neuroblastoma 
OS 
overall survival 
RWD  
real world data 
SAE 
serious adverse event 
SD 
standard deviation 
SIOPEN 
European SIOP Neuroblastoma Group 
SQN 
Syne Qua Non Limited 
TKI 
tyrosine kinase inhibitor 
US 
United States 

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3. RESPONSIBLE PARTIES 
Principal Investigator(s) of the Protocol    
Name, degree(s) 
Job Title 
Affiliation 
Address 
, PhD 
 
Pfizer Inc 
 
 
, MD 
 
Pfizer Inc 
 
 
 
, 
PhD 
 
Pfizer Inc 
 
 
, MD, 
MSc 
 
Pfizer Inc 
 
 
, MD 
 
Pfizer Inc 
 
 
 
 
 
Pfizer Inc 
 
 
, MD, MMSc 
 
 
Pfizer Inc 
 
 
, MD, 
MPH 
 
Pfizer Inc 
 
 
, MD 
FRCP 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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4. AMENDMENTS AND UPDATES 
None 

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5. MILESTONES 
Milestone 
Planned date 
Start of data collection  
25 February 2021 
Treatment completed population – data collection completion 
date 
25 March 2021 
Progress report – Treatment completed population 
28 April 2021 
Interim report 1 – Year 1 
31 December 2021 
Interim report 2 – Year 2 
31 December 2022 
End of data collection (Last patient added to real world data 
collection) 
31 December 2023 
Database lock 
15 February 2024 
Final study report 
31 March 2024 
 
6. RATIONALE AND BACKGROUND 
Neuroblastoma (NB) is an aggressive solid tumor of childhood. Neuroblastoma is the third 
most common childhood cancer in the United States and accounts for 7-10% of pediatric 
cancers.1 Estimated incidence of neuroblastoma is approximately 10-11 cases per million 
children under 15 years of age United States (US) and Europe.2,3 Incidence in children <1 
year is as high has 44.7 per million in Europe and 53 per million in US.2 Neuroblastoma is 
most commonly diagnosed during the first year of life.1,2 While 90% of cases are diagnosed 
before the age of 5, 30% of those are within the first year. The median age of diagnosis is 22 
months. Rarely does it present in adolescence and adulthood, but outcomes are much poorer 
in this age group.4 In addition, neuroblastoma accounts for approximately 12% of all cancer-
related deaths in pediatric population.5,6  
Five-year survival rates for infants with neuroblastoma range from 65% to 88% and overall 
survival has improved over time, likely due to therapeutic improvements.1,3,5,7 However, 
improvements are attributable to improvement in patients with more low or intermediate-risk 
disease, mortality rates among children with high-risk neuroblastoma have shown modest 
improvement.8 
Neuroblastoma is a complex disease but often results in treatment-resistant progression, 
metastasis and death.8 Long-term survival rates for children with high-risk neuroblastoma are 
currently 40-50%.8 Many patients (50-60%) with high-risk neuroblastoma will have either 

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refractory disease (responding poorly to therapy) or will relapse (experience disease 
recurrence). To date there are no well-established curative treatment regimens for these 
patients.8,9 Median time to relapse is estimated to be approximately 13 months, and patients 
who relapsed between 6 and 18 months after diagnosis have the highest risk of death.10 
Current treatment approach for high-risk patients include induction chemotherapy (reduce 
tumor burden by shrinking tumor), local control (delayed surgery to remove tumor), 
consolidation (myeloablative therapy with stem cell rescue performed in tandem) and 
maintenance therapy (GD2-directed therapy, which is painful and toxic).11 A published meta-
analysis of three European SIOP Neuroblastoma Group (SIOPEN) trials on standard 
backbone chemotherapy regimens showed poor outcomes in both relapsed and refractory 
neuroblastoma patients.12 It is important to note that, unlike childhood leukemias, there is no 
standard approach for high-risk neuroblastoma patients who suffer a relapse and there is no 
known curative therapy. Response rates in clinical trials of relapsed/refractory neuroblastoma 
ranged from 20-64%.12 After treatment, progression occurred in 54% of patients with 
refractory disease versus 87% of patients with relapsed disease.12 Overall median OS was 
16.1 months, with longer median OS for patients with refractory disease compared to 
relapsed disease.12 Neuroblastoma has significant heterogeneity, therefore risk stratification 
has become an important factor in identifying novel biomarkers to inform treatment 
decisions.9 
Initial reports of anaplastic lymphoma kinase (ALK) gene amplification and overexpression 
suggested a role of ALK in neuroblastoma.13,14 Notably, ALK activating mutations were first 
discovered in the germline of families where the disease is inherited, and subsequently found 
to be present in somatic tissue in ~10% of patients at diagnosis.15-18 The majority of patients 
with familial neuroblastoma have germline mutations in ALK.18 Sporadic neuroblastoma 
tumors also occasionally harbor ALK abnormalities, including 4% of tumors with genomic 
amplification and approximately 10% with missense mutations.14,17-19 Furthermore, the 
presence of ALK mutation correlates with worse prognosis in high and intermediate risk 
patients.20 The detection of ALK mutations and/or amplifications in primary neuroblastomas, 
provides a molecular rational for targeted therapy of neuroblastoma.16 It has been 
demonstrated that downregulation of ALK suppressed proliferation of neuroblastoma cells 
harboring mutated ALK.15 
The identification of ALK as a critical factor in the development of neuroblastoma make it an 
attractive therapeutic target. Lorlatinib is a potent, brain-penetrant, third generation inhibitor 
of ALK.21 Lorlatinib overcomes almost all known ALK resistance mutations observed with 
other ALK TKIs.22 In preclinical models lorlatinib has exhibited superior potency towards 
ALK neuroblastoma tumor models.23,24 In addition, lorlatinib shows strong activity toward 
all tested ALK neuroblastoma mutations.23,24  
New Agents in Neuroblastoma Therapy (NANT) consortium has several ongoing clinical 
trials to identify best therapies and combination of therapies for treatment of pediatric 
patients with neuroblastoma. An on-going Phase 1 dose escalation clinical trial is assessing 

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the use of lorlatinib as a single agent in combination with chemotherapy in patients aged 1 to 
90 years with relapsed/refractory neuroblastoma.25 Recently presented results of this Phase 1 
study showed inhibition of ALK driven neuroblastoma with lorlatinib occurred with 
manageable toxicity and objective anti-tumor activity was observed.26 
Pediatric high-risk neuroblastoma remains an area of high unmet need and poor outcomes in 
young children. Along with the promising early clinical data from the NANT study, we have 
noted several pediatric neuroblastoma patients being treated through Pfizer’s expanded 
access program.  This protocol details the real world data collection of data to evaluate the 
real world effectiveness of lorlatinib in pediatric neuroblastoma patients. Generating real 
world evidence from expanded access programs is becoming increasingly valuable, as this 
data has the potential to supplement regulatory submissions.27 
7.  RESEARCH QUESTIONS AND OBJECTIVES 
The primary goal of the Pfizer expanded access program is to provide access to lorlatinib to 
patients with a serious or immediately life-threatening disease/condition who have exhausted 
all other standards of care and are not eligible for a clinical trial. Treatment is delivered by the 
healthcare professional (HCP) as sponsor of the expanded access request and according to a 
treatment plan approved institutional review board/independent ethics committee as required 
by local laws and regulations or institutional requirements.  
The overall goal of this real-world data collection is to assess demographic, clinical 
characteristics and real-world effectiveness of pediatric neuroblastoma patients who initiated 
treatment with lorlatinib through an expanded access program. Data will be collected to 
address the following specific objectives: 
1. Describe the demographic and clinical characteristics of pediatric neuroblastoma 
patients who initiated treatment with lorlatinib through an expanded access program 
2. Evaluate the effectiveness of treatment with lorlatinib in pediatric neuroblastoma 
patients in terms of duration of treatment, HCP reported response, and duration of 
response 
3. Estimate progression free survival and overall survival 
4. Collection of safety data  
8. METHODOLOGY FOR REAL WORLD DATA COLLECTION 
The real world data (RWD) evaluation will involve supplemental collection of de-identified 
data collected on patients treated with lorlatinib for pediatric neuroblastoma who initiated 
treatment through Pfizer’s expanded access program. Pediatric patients with ALK-aberrant 
neuroblastoma who are prescribed lorlatinib by their healthcare professionals (HCPs) and 
have met Pfizer expanded access program criteria will be eligible for inclusion in data 
collection. Supplementary data will be collected in partnership with Bionical Emas. 

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Prior to initiation of data collection activities, Bionical Emas, in collaboration with Pfizer, 
will develop a customized data collection tool (DCT) to capture data on demographics, 
clinical characteristics and outcomes. The length of the DCT will be kept to a minimum to 
avoid burden on participating institutions. The DCT will be made available to participating 
institutions through a web-based, electronic data capture (EDC) system. 
During data collection, Bionical Emas will review the data on an ongoing basis, with HCPs 
contacted for clarification as required.  Bionical Emas in conjunction with their statistical 
partner Syne Qua Non Limited (SQN) will summarize and report the data at timepoints 
detailed in Section 5. Finally, a data collection report will be developed. 
8.1. Design of data collection  
Up to 50 pediatric patients with ALK-aberrant neuroblastoma who initiated treatment with 
lorlatinib as part of expanded access program will be included. 
 
The real world data collection will be initiated after the patient has been approved for 
expanded access to lorlatinib per Pfizer’s expanded access program and the treating HCP has 
agreed to participate in data collection. All assessments described in this protocol are 
performed as part of normal clinical practice or standard practice guidelines for the patient 
population and healthcare provider specialty in the countries where this data collection is 
being conducted.  Data from patients who have completed treatment, patients receiving 
ongoing treatment and new patients will be captured.  A progress report will be developed for 
the patients who have completed treatment, with a more comprehensive final report 
descriptive in nature produced for the total population.  
 
8.2. Setting 
Clinical practice and treatment of each patient will follow as determined by each treating 
HCP individually. There will be no interference from Pfizer with the HCP’s diagnostic and 
treatment decisions. The decision to treat a patient with lorlatinib will be prior to and 
independent of participation in the real world data collection and according to the clinical 
judgement of their HCP. Therefore, the data collection will in no way influence prescribing 
patterns or treatment decisions. If eligible, the patient will receive treatment through Pfizer’s 
expanded access program independent of involvement in the collection of real world data.  
HCPs treating a patient approved to receive lorlatinib via Pfizer’s expanded access program 
will be invited to take part in the real world data collection. Upon HCP agreement, they will 
receive access to the EDC, where they can enter data into the DCT. 
The first pediatric neuroblastoma patient received lorlatinib in March 2017 as part of 
expanded access programs and the program is ongoing. Data collection is anticipated to 
initiate in January 2021 and is estimated to have last patient entered into real world dataset at 

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the end in December 2023. Database lock would occur in February 2024, as outlined in 
Section 5. 
Data will be collected via DCT at multiple time points for patients who are receiving ongoing 
treatment. These timepoints will be determined by HCP standard practice for treatment and 
follow-up of their patients. Visits are anticipated to occur every 3-4 months, corresponding 
with re-supply of lorlatinib. Data will be collected on a continual basis until discontinuation 
of treatment with lorlatinib, death, loss to follow-up or end of study, whichever comes first. 
8.2.1. Inclusion criteria 
Patients must meet all the following inclusion criteria to be eligible for inclusion in the study:  
1. Patient treatment with lorlatinib is initiated through Pfizer’s expanded access program for 
treatment of ALK+ neuroblastoma. 
2. HCP documentation of at least one tumor assessment of response after patient has had at 
least one dose of lorlatinib 
3. Evidence of a personally signed and dated informed consent document indicating that the 
patient (or a legally acceptable representative, or a waiver of informed consent has been 
granted by the IRB/IEC) has been informed of all pertinent aspects of the study. 
8.2.2. Exclusion criteria 
Patients meeting any of the following criteria will not be included in the study: 
1, Any patient who does not meet any of the inclusion criteria defined in the previous section. 
8.3. Variables 
Variables will include demographics at the start of lorlatinib treatment (age, gender, race, 
body surface area (BSA)), clinical characteristics (date of initial diagnosis, high risk at 
diagnosis,  ALK aberration date of sample collection and testing, testing platform, ALK and 
other genetic mutations, ALK amplification, translocation or over-expression, and MYCN 
amplification, prior anti-cancer treatment, ALK inhibitor use, disease status), treatment start 
date, starting dose, resupply date(s), BSA, response assessment (date, disease status, HCP 
reported response, International Neuroblastoma Response Criteria (INRC) response 
assessment criteria28 and assessment modality), last date of lorlatinib, patient alive, date of 
death, date of discontinuation of lorlatinib and reason for discontinuation of lorlatinib. Safety 
data will be collected in DCT as outlined in Section 10. 
8.4. Data sources  
The primary data source will be data collected through a DCT. Bionical Emas is the vendor 
responsible for facilitating capture of HCP responses in DCT via EDC. Bionical Emas is also 
responsible for de-identification of patient level information. Anonymized pathology reports 

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submitted as part of the initial lorlatinib request will be summarized and entered into the 
DCT by Pfizer to confirm information such as ALK aberration testing and status. 
As part of Pfizer’s expanded access program, HCPs report a full description of Adverse 
Events (AEs) to the local Pfizer Drug Safety Unit (DSU) using the expanded access adverse 
event report.  AEs captured by the local Pfizer Drug Safety Unit (DSU)will be compared and 
reconciled to the AEs captured in the DCT and used to summarize the reported AEs. Upon 
resupply request the requesting HCP certifies that safety reporting has been done per Pfizer 
expanded access program requirements. Safety information will also be collected in the DCT 
as the HCP reviews the patient chart as outlined in Section 10. 
8.5. Study size 
With primary goal of the Pfizer expanded access program is to provide treatment access to 
patients with an unmet clinical need, no formal power calculations were conducted to 
determine sample size. Furthermore, the data collection does not involve hypotheses testing 
(via statistical testing) and it is primarily being conducted to understand treatment outcomes. 
Target sample size will comprise every patient fulfilling eligibility criteria above and 
providing informed consent for real world data collection. 
8.6. Data management  
Bionical Emas will implement Data Management practices for collating and managing the 
data.  These include (1) HCP access management and training, (2) data review, and (3) 
database storage and retention. 
 
HCP Access Management and Training: 
Bionical Emas will add HCPs to the EDC using details obtained from Pfizer after 
confirmation of patient eligibility and HCP agreement. HCP information will include: HCP 
name, country, location.  
Data Review: 
Data review is iterative process to ensure integrity and quality of data. Bionical Emas will 
ensure data are complete, reliable and processed correctly. 
8.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic data record 
As used in this protocol, the term DCT should be understood to refer to either a paper form 
or an electronic data record or both, depending on the data collection method used in this 
study. 
A DCT is required and should be completed for each included patient.  The completed 
original DCT are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. The HCP shall ensure that the DCTs 

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securely stored in encrypted electronic form and will be password protected to prevent access 
by unauthorized third parties. 
The HCP has ultimate responsibility for the collection and reporting of all clinical, safety, 
and laboratory data entered on the DCT and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
DCT must be electronically signed by the HCP or by an authorized staff member to attest 
that the data contained on the DCT are true.  Any corrections to entries made in the DCT or 
source documents must be dated, initialed, and explained (if necessary) and should not 
obscure the original entry. 
In most cases the source documents are the hospital or the HCP's chart.  In these cases, data 
collected on the DCT must match those charts.  
In some cases, the DCT may also serve as the source document.  In these cases, a document 
should be available at the HCP site and at Pfizer that clearly identifies those data that will be 
recorded on the DCT, and for which the DCT will stand as the source document. 
8.6.2. Record retention     
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
HCP agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, e.g., DCT and hospital records), all original signed informed 
consent/assent documents, copies of all DCT, safety reporting forms, source documents, 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (e.g., letters, meeting minutes, and telephone call reports).  The records 
should be retained by the HCP according to local regulations or as specified in the clinical 
study agreement (CSA), whichever is longer.  The HCP must ensure that the records continue 
to be stored securely for so long as they are retained. 
If the HCP becomes unable for any reason to continue to retain study records for the required 
period (e.g., retirement, relocation), Pfizer should be prospectively notified.  The study 
records must be transferred to a designee acceptable to Pfizer, such as another HCP, another 
institution, or to an independent third party arranged by Pfizer.  
HCP records must be kept for a minimum of 15 years after completion or discontinuation of 
the study or for longer if required by applicable local regulations.  
The HCP must obtain Pfizer's written permission before disposing of any records, even if 
retention requirements have been met. 

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8.7. Data analysis  
Bionical Emas in collaboration with Syne Qua Non Limited (SQN) will perform the data 
analyses described in this protocol using SAS statistical software. Statistical summaries, 
figures and listings will be produced using SAS (version 9.4 or later). 
All development of data summaries and analyses will be documented and retained for 
traceability including dataset specifications and derivations, name of the programmed outputs 
and assigned program authors and reviewers.   
 
All data outputs will be fully quality controlled including review of the logs and associated 
outputs.   
 
No formal statistical testing is planned, and all data analyses will be descriptive and 
explorative.   
8.7.1 Data Reporting Milestones 
Data on patients who have completed treatment, patients receiving ongoing treatment and 
new patients will be captured. The plan is to report the data collectively and cumulatively 
with the first data reporting to provide an initial assessment of a group of patients having 
completed treatment.  Patients who completed treatment by the time data collection is 
initiated (completed treatment prior to January 2021) will be those included in the initial 
progress report. Data reporting will be provided annually thereafter with a final report as 
outlined in Section 5. 
8.7.2 Analysis Set 
Data summaries and listings will be produced on all the data collected, regardless of patients 
fulfilling the inclusion and exclusion criteria detailed in Section 8.2.1 and Section 8.2.2.  
 
8.7.3 Patient Disposition and Demography  
Patient disposition will account for the number of patients receiving treatment, continued 
treatment and discontinued treatment at a specific milestone.  Potential reasons for 
discontinuing treatment will include disease progression, adverse event excluding death, 
death, lost to follow up, and other. 
Demographic and patient characteristics will include variables as noted in Section 8.3. 
Additional variables will be statistically derived and reported including time since initial 
diagnosis. Time since initial diagnosis, in months, will be derived as: 12*((Date of initial 
diagnosis) – (First Date of lorlatinib Treatment)+1)/365.25. 
8.7.4 Safety endpoints 

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All adverse events collected on the DCT will be listed and summarized for all data reporting 
milestones.  Adverse Events will be coded using the latest Medical Dictionary for Regulatory 
Activities (MedDRA) version. The version used will be indicated in the data summaries and 
listings. 
 
All patients who discontinue treatment due to safety reasons such as AEs, will be captured 
and reported as a reason for discontinuation in the patient disposition summaries and listings. 
All Adverse Event data captured will be listed.  In addition a separate listing will be 
presented for Serious Adverse Events. 
The number and percentage of patients reporting at least one Adverse Event will be 
summarized within the following categories: 
• Adverse Events 
• Treatment-related 
• Serious  
• Serious treatment-related   
 
The following summary tables will also be presented: 
• Number and percentage of patients and number of Adverse Events by MedDRA  
System Organ Class (SOC) and Preferred Term (PT);  
• Serious Adverse Events by SOC and PT. 
 
SOC and PT will be presented in decreasing frequency of the total number of patients with 
Adverse Events.  If a patient experienced more than one Adverse Event, the patient will be 
counted once for each SOC and once for each PT.   
 
8.7.5  Effectiveness endpoints 
To assess the effectiveness of lorlatinib, the following endpoints will be collected via the 
DCT or derived: 
Endpoint 
Source Variable (if 
endpoint derived) 
Description/Derivation 
Objective tumor 
response of primary 
tumor (soft tissue), soft 
 
Collected by the DCT at each visit. Outcomes 
include complete response (CR), partial response 

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tissue metastasis, and 
bone metastasis  
(PR), stable disease (SD) and progressive 
disease (PD). 
Bone marrow response 
 
Collected by the DCT at each visit. Outcomes 
include CR, PD, minimal disease (MD) and SD. 
HCP Reported 
Objective Response 
 
Collected by the DCT at each visit. Outcomes 
include CR, PR, minor response (MR), SD and 
PD. 
Derived Objective 
Response 
Objective Tumor 
response components 
Derived and compared for robustness to the HCP 
Reported Objective Response applying the 
following rules: 
RESPONSE 
CRITERIA 
Complete Response 
(CR) 
All components meet 
criteria for CR 
Partial Response (PR) 
PR in at least one 
component and all 
other components are 
either CR, MD (Bone 
marrow), PR (Soft 
tissue or Bone) or 
Not involved (NI); no 
component with PD.   
Minor Response 
(MR) 
PR or CR in at least 
one component but at 
least one other 
component with SD; 
no component with 
PD. 
Stable Disease (SD) 
SD in one component 
with no better than 
SD or NI in any other 
component; no 
component with PD. 
Progressive Disease 
(PD) 
Any component with 
PD 
Best Overall response 
HCP Reported Response Derived as the best overall response taking the 
HCP Reported Response observed up to the data 
cut-off date for a specific milestone. (The 

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Repeated using Derived 
Objective Response 
sequence order from best to worst is CR, PR, 
MR, SD, PD.) 
Overall Response Rate 
(ORR) 
Best Overall Response  
Derived as Best overall response of CR+PR of 
the total population observed up to the data cut-
off date for a specific milestone.  
Duration of response 
Treatment Start and 
HCP Reported Response 
Date 
 Derived as (Date of PD or death, whichever 
occurs first) – (Date of PR or CR, whichever 
occurs first) + 1  
Progression free 
survival (PFS) 
Treatment Start and 
HCP Reported 
PD/Death Date 
Derived as (Date of PD or death (by any cause in 
the absence of PD)) – (Treatment start date) + 1 
Duration of treatment 
Treatment Start and 
Stop Dates 
Derived as (Treatment stop date) – (Treatment 
start date) + 1 
Overall survival (OS) 
Treatment Start and 
Death Dates  
Derived as (Date of death) – (Treatment start 
date) + 1 
 
8.7.6 Statistical summaries 
Demographic and clinical characteristics 
The number and percentage of patients will be presented within each categorized variable.  In 
addition, descriptive statistics for continuous variables will include the mean, standard 
deviation, median, interquartile range, minimum and maximum.   
The demographics will also be presented by subgroups for any subgroups with more than 5 
patients. 
 
HCP’s reported objective response 
For each response component (with the exception of best response), the responses will be 
listed along with the date of the assessment.   A derived objective response will be produced 
and compared to the HCP overall reported response for confirmation of robustness.     
Best Overall Response (BOR) and Overall Response Rate (ORR) 
For the BOR, the number and percentage of patients in each ordered category will be 
presented and summarized by baseline disease status.  In addition, the ORR will be presented 
including the Clopper Pearson 95% Confidence interval. 

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Duration of response 
The number and percentage of patients will be presented within each of the following 
categories for duration of response: 0 to <3 months; 3 months to <6 months; 6 months to <1 
year; 1 to <2 years; 2 to <3 years >3 years; lost to follow-up.  Kaplan-Meier (KM) estimates 
will be used to give the median, Q1 and Q3 duration of response, with 95% confidence 
limits.  If a patient does not show symptoms of progressive disease, their duration of 
response will be censored at their last visit date prior to the data cut-off date.  
Time to event 
KM estimates will be presented, where possible, for duration of treatment, progression free 
survival and overall survival (i.e., time to death).  The following censoring rules will be 
applied: 
• Duration of treatment 
Patients who have not discontinued treatment at the data cut-off date will be censored 
based on the last recorded date when the patient was known to be continuing 
treatment prior to the data cut-off date. 
• Progression free survival 
Patients who have not experienced PD or died at the data cut-off date will be 
censored at the date of last contact prior to the data cut-off date. 
• Overall survival 
Any patient not known to have died at the data cut-off date will be censored based on 
the last recorded date on which the patient was known to be alive prior to the data 
cut-off date.  
The KM curves will be used to estimate the median, Q1 and Q3 survival times, with 95% 
confidence limits.  The proportion of patients with an event will also be estimated from the 
corresponding Kaplan-Meier curves with 95% confidence limits.  
 
8.7.7 Subgroups 
Subgroups of interest will be explored when a sufficient amount of data are available (n≥5)  
Examples of subgroups that may be investigated include, but not limited, to age, disease 
status at baseline, and prior anti-cancer treatment. The categories associated with these 
subgroups are tabulated below. 

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Subgroup 
Categories 
Age 
Categorized based on the distribution of age 
in the study population, for example: ≤1 
year; >1 to ≤12 years; >12 years 
Disease status at baseline 
Recurrent/Progressive; 
Refractory/Resistant; 
Prior anti-cancer treatment 
ALK Inhibitor; Chemotherapy; 
Immunotherapy; Transplant; Surgery; 
MIBG therapy; Radiation;  
 
8.7.8 Missing data 
Statistical summaries, figures and listings will be based on all available data, as observed.  
Missing data will not be imputed with the exception of partial dates as per below.  However, 
the amount of missing data will be reported. 
For the endpoints requiring date derivations such as duration of response, time to event, the 
following imputation for partial dates will be applied: 
- 
Missing year: no imputation with date remaining as missing 
- 
Missing month: impute as month 6 (June, mid-year approximately) 
- 
Missing day: impute as 15 (mid month approximately)  
8.8. Quality control 
Programmed validation checks will be available in the EDC system.  These will be triggered 
when the data is saved in the electronic DCT.  Data Management will perform an aggregate 
review of the data, to look for outliers, patterns of inconsistent or missing data and any other 
identified key risk to the integrity of the data. During data collection, Bionical Emas will 
review the data on an ongoing basis, with sites contacted for clarification as required.  Any 
issues identified from this review shall be flagged to Pfizer by Bionical Emas. 
8.9. Limitations of the research methods 
Patients included in this program represent a convenience sample such that supplemental data 
will be collected on patients of HCPs who are willing to participate in the data collection 
component and initiated treatment with lorlatinib through Pfizer’s expanded access program. 

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All data captured in the DCT will be limited to information available to the HCP 
participating in the program. Information on health care services received outside the HCP’s 
care setting will be unavailable. 
Data will be entered directly by the participating HCP and therefore may be subject to entry 
errors and resulting inaccuracies in reporting. Although there will be data checks in place to 
improve internal consistency of the data, responses will not be validated against the patients’ 
medical records by an independent reviewer. 
8.10. Other aspects 
Not applicable 
9. PROTECTION OF HUMAN SUBJECTS 
9.1. Patient information  
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws.  
 
The personal data will be stored at the study site in encrypted electronic form and will be 
password protected to ensure that only authorized study staff have access.  The study site will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster.  In the event of a potential personal data breach, the 
study site shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law. 
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, patient-specific code.  
The HCP site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the clinical study agreement and applicable privacy laws. 
9.2. Patient consent 
The informed consent/assent documents and any patient recruitment materials must be in 
compliance with local regulatory requirements and legal requirements, including applicable 
privacy laws. 

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The informed consent/assent documents used during the informed consent process and any 
patient recruitment materials must be reviewed and approved by Pfizer, approved by the 
institutional review board (IRB)/independent ethics committee (IEC) before use, and 
available for inspection. 
The HCP must ensure that each study patient or legal guardian, is fully informed about the 
nature and objectives of the study, the sharing of data relating to the study and possible risks 
associated with participation, including the risks associated with the processing of the 
patient’s personal data.  The HCP further must ensure that each study patient or legal 
guardian is fully informed about his or her right to access and correct his or her personal data 
and to withdraw consent for the processing of his or her personal data. 
Whenever consent is obtained from a patient’s legal guardian, the patient’s assent 
(affirmative agreement) must subsequently be obtained when the patient has the capacity to 
provide assent, as determined by the IRB/IEC.  If the HCP determines that a patient’s 
decisional capacity is so limited that he or she cannot reasonably be consulted, then, as 
permitted by the IRB/IEC and consistent with local regulatory and legal requirements, the 
patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his or her own consent, the source documents 
must record why the patient did not provide consent (e.g., minor, decisionally impaired 
adult), how the HCP determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (e.g., parent, 
spouse), and that the patient’s assent was obtained or waived.  If assent is obtained verbally, 
it must be documented in the source documents. 
If the study includes minor patients who reach the age of majority during the study, as 
recognized under local law, they must re-consent as adults to remain in the study.  If the 
enrollment of emancipated minors is permitted by the study age criteria, the IRB/IEC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian. 
The HCP, or a person designated by the HCP, will obtain written informed consent from 
each patient or the patient’s legally acceptable representative, parent(s), or legal guardian and 
the patient’s assent, when applicable, before any study-specific activity is performed unless a 
waiver of informed consent has been granted by an IRB/IEC.  The HCP will retain the 
original of each patient's signed consent/assent document. 
9.3. Patient withdrawal 
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the HCP or sponsor for safety, behavioral, or 
administrative reasons.  In any circumstance, every effort should be made to document 
patient outcome, if applicable.  The HCP would inquire about the reason for withdrawal and 
follow-up with the patient regarding any unresolved adverse events.   

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If the patient withdraws from the data collection, and also withdraws consent for disclosure 
of future information, no further evaluations should be performed, and no additional data 
should be collected.  The sponsor may retain and continue to use any data collected before 
such withdrawal of consent. 
Treatment discontinuation or loss to follow-up do not constitute patient withdrawal, date of 
discontinuation or loss to follow-up will be considered last visit date for that patient. 
9.4. Institutional review board (IRB)/Independent ethics committee (IEC) 
It is the responsibility of the HCP to have prospective approval of the study protocol, 
protocol amendments, and informed consent forms, and other relevant documents, 
(e.g., recruitment advertisements), if applicable, from the IRB/IEC.  All correspondence with 
the IRB/IEC should be retained by the HCP. Copies of IRB/IEC approvals should be 
forwarded to Pfizer. 
9.5. Ethical conduct of the study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in the Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the 
International Society for Pharmacoepidemiology (ISPE), Good Practices for Outcomes 
Research issued by the International Society for Pharmacoeconomics and Outcomes 
Research (ISPOR), International Ethical Guidelines for Epidemiological Studies issued by 
the Council for International Organizations of Medical Sciences (CIOMS), European 
Medicines Agency (EMA) European Network of Centers for Pharmacoepidemiology and 
Pharmacovigilance (ENCePP) Guide on Methodological Standards in 
Pharmacoepidemiology, The ENCePP Code of Conduct for scientific independence and 
transparency in the conduct of pharmacoepidemiologic and pharmacovigilance studies, and 
the Food and Drug Administration (FDA) Guidance for Industry: Good Pharmacovigilance 
Practices and Pharmacoepidemiologic Assessment. 
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS  
REQUIREMENTS 
The table below summarizes the requirements for recording safety events on the data 
collection tool and for reporting safety events on the non-interventional study (NIS) adverse 
event monitoring (AEM) Report Form to Pfizer Safety.  These requirements are delineated 
for three types of events: (1) serious adverse events (SAEs); (2) non-serious AEs (as 
applicable); and (3) scenarios involving drug exposure, including exposure during pregnancy, 
exposure during breast feeding, medication error, overdose, misuse, extravasation, lack of 
efficacy, and occupational exposure.  These events are defined in the section “Definitions of 
safety events.”   
 

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Safety event 
Recorded on the data 
collection tool 
Reported on the NIS AEM 
Report Form to Pfizer 
Safety within 24 hours of 
awareness 
SAE 
All 
All 
Non-serious AE 
All 
All 
Scenarios involving exposure 
to a drug under study, 
including exposure during 
pregnancy, exposure during 
breast feeding, medication 
error, overdose, misuse, 
extravasation, lack of efficacy, 
and occupational exposure 
All (regardless of whether 
associated with an AE), 
except occupational 
exposure  
All (regardless of whether 
associated with an AE) 
Note: Any associated AE is 
reported together with the 
exposure scenario. 
 
For each AE, the HCP must pursue and obtain information adequate both to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as a SAE 
(refer to section "Serious Adverse Events” below).  
Safety events listed in the table above must be reported to Pfizer within 24 hours of 
awareness of the event by the HCP regardless of whether the event is determined by the 
HCP to be related to lorlatinib.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer must be made immediately, irrespective of the extent of available event 
information.  This timeframe also applies to additional new (follow-up) information on 
previously forwarded safety event reports.  In the rare situation that the HCP does not 
become immediately aware of the occurrence of a safety event, the HCP must report the 
event within 24 hours after learning of it and document the time of his/her first awareness of 
the events. 
 
For safety events that are considered serious or that are identified in the far right column of 
the table above that are reportable to Pfizer within 24 hours of awareness, the HCP is 
obligated to pursue and to provide any additional information to Pfizer in accordance with 
this 24-hour timeframe.  In addition, an HCP may be requested by Pfizer to obtain specific 
follow-up information in an expedited fashion.  This information is more detailed than that 
recorded on the data collection tool.  In general, this will include a description of the AE in 
sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality.  Any information relevant to the event, such as 
concomitant medications and illnesses, must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative.  
 
Reporting period  

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For each patient, the safety event reporting period begins at the time of  the patient’s first 
dose of lorlatinib or the time of the patient’s informed consent if s/he is being treated with 
lorlatinib at the start of the study, and lasts through the end of the observation period of the 
study, which must include at least 28 calendar days following the last administration of a 
drug under study; a report must be submitted to Pfizer Safety (or its designated 
representative) for any of the types of safety events listed in the table above occurring during 
this period.  If a patient was administered a drug under study on the last day of the 
observation period, then the reporting period should be extended for 28 calendar days 
following the end of observation.  Most often, the date of informed consent is the same as the 
date of enrollment.  In some situations, there may be a lag between the dates of informed 
consent and enrollment.  In these instances, if a patient provides informed consent but is 
never enrolled in the study (e.g., patient changes his/her mind about participation), the 
reporting period ends on the date of the decision to not enroll the patient.  
 
If the HCP becomes aware of a SAE occurring at any time after completion of the study and 
s/he considers the SAE to be related to lorlatinib, the SAE also must be reported to Pfizer 
Safety.  
 
Causality assessment 
The HCP is required to assess and record the causal relationship.  For all AEs, sufficient 
information should be obtained by the HCP to determine the causality of each AE.  For AEs 
with a causal relationship to lorlatinib, follow-up by the HCP is required until the event 
and/or its sequelae resolve or stabilize at a level acceptable to the HCP, and Pfizer concurs 
with that assessment.   
An HCP’s causality assessment is the determination of whether there exists a reasonable 
possibility that lorlatinib caused or contributed to an AE.  If the HCP’s final determination of 
causality is “unknown” and s/he cannot determine whether lorlatinib caused the event, the 
safety event must be reported within 24 hours.   
If the HCP cannot determine the etiology of the event but s/he determines that lorlatinib did 
not cause the event, this should be clearly documented on the data collection tool and the NIS 
AEM Report Form.  
DEFINITIONS OF SAFETY EVENTS 
Adverse events 
An AE is any untoward medical occurrence in a patient administered a medicinal product.  
The event need not necessarily have a causal relationship with the product treatment or 
usage. Examples of AEs include but are not limited to:   

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• Abnormal test findings (see below for circumstances in which an abnormal test finding 
constitutes an AE); 
• Clinically significant signs and symptoms; 
• Changes in physical examination findings; 
• Hypersensitivity; 
• Lack of efficacy;  
• Drug abuse;  
• Drug dependency. 
Additionally, for medicinal products, they may include the signs or symptoms resulting from: 
• Drug overdose; 
• Drug withdrawal; 
• Drug misuse;  
• Off-label use;  
• Drug interactions; 
• Extravasation; 
• Exposure during pregnancy; 
• Exposure during breast feeding; 
• Medication error; 
• Occupational exposure. 
Abnormal test findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows:  
• Test result is associated with accompanying symptoms, and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention, and/or 

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• Test result leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment, or other therapy, and/or 
• Test result is considered to be an AE by the HCP or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 
Serious adverse events 
A SAE is any untoward medical occurrence in a patient administered a medicinal or 
nutritional product (including pediatric formulas) at any dose that: 
• Results in death; 
• Is life-threatening; 
• Requires inpatient hospitalization or prolongation of hospitalization (see below for 
circumstances that do not constitute AEs); 
• Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
• Results in congenital anomaly/birth defect. 
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as a SAE unless the outcome is fatal within the safety reporting 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as a SAE.  If the malignancy has a fatal outcome during the study or within the 
safety reporting period, then the event leading to death must be recorded as an AE and as a 
SAE with severity Grade 5. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above, the important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
Additionally, any suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic, is considered serious.  The event may be suspected from 

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clinical symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product.  The terms “suspected transmission” and “transmission” are considered 
synonymous.  These cases are considered unexpected and handled as serious expedited cases 
by pharmacovigilance (PV) personnel.  Such cases are also considered for reporting as 
product defects, if appropriate. 
 
Hospitalization 
Hospitalization is defined as any initial admission (even if less than 24 hours) to a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (e.g., from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, an event leading to an emergency room visit should be assessed for medical 
importance.  
Hospitalization in the absence of a medical AE is not in itself an AE and is not reportable.  
For example, the following reports of hospitalization without a medical AE are not to be 
reported.  
• Social admission (e.g., patient has no place to sleep) 
• Administrative admission (e.g., for yearly exam) 
• Optional admission not associated with a precipitating medical AE (e.g., for elective 
cosmetic surgery) 
• Hospitalization for observation without a medical AE 
• Admission for treatment of a pre-existing condition not associated with the development 
of a new AE or with a worsening of the pre-existing condition (e.g., for work-up of 
persistent pre-treatment lab abnormality) 
• Protocol-specified admission during clinical study (e.g., for a procedure required by the 
study protocol) 
Scenarios necessitating reporting to Pfizer Safety within 24 hours  
Scenarios involving exposure during pregnancy, exposure during breastfeeding, medication 
error, overdose, misuse, extravasation, lack of efficacy, and occupational exposure are 
described below. 
Exposure during pregnancy 

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An exposure during pregnancy (EDP) occurs if: 
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed to (e.g., environmental) lorlatinib, or the female becomes, or is found to be, 
pregnant after discontinuing and/or being exposed to lorlatinib (maternal exposure). 
An example of environmental exposure would be a case involving direct contact with a 
Pfizer product in a pregnant woman (e.g., a nurse reports that she is pregnant and has been 
exposed to chemotherapeutic products). 
2. A male has been exposed, either due to treatment or environmental exposure to lorlatinib 
prior to or around the time of conception and/or is exposed during the partner pregnancy 
(paternal exposure). 
As a general rule, prospective and retrospective exposure during pregnancy reports from any 
source are reportable irrespective of the presence of an associated AE and the procedures for 
SAE reporting should be followed. 
If a study participant or study participant’s partner becomes, or is found to be, pregnant 
during the study participant’s treatment with lorlatinib, this information must be submitted to 
Pfizer, irrespective of whether an AE has occurred using the NIS AEM Report Form and the 
EDP Supplemental Form.  
In addition, the information regarding environmental exposure to lorlatinib in a pregnant 
woman (e.g., a patient reports that she is pregnant and has been exposed to a cytotoxic 
product by inhalation or spillage) must be submitted using the NIS AEM Report Form and 
the EDP Supplemental Form.  This must be done irrespective of whether an AE has occurred.   
Information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy; in addition, follow-
up is conducted to obtain information on EDP outcome for all EDP reports with pregnancy 
outcome unknown.  A pregnancy is followed until completion or until pregnancy termination 
(e.g., induced abortion) and Pfizer is notified of the outcome.  This information is provided 
as a follow up to the initial EDP report.  In the case of a live birth, the structural integrity of 
the neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) 
for termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (e.g., ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 

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live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
procedures for reporting SAEs should be followed. 
Additional information about pregnancy outcomes that are reported as SAEs follows:  
• Spontaneous abortion includes miscarriage and missed abortion; 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs.  In addition, infant deaths after 1 month should be reported as SAEs 
when the HCP assesses the infant death as related or possibly related to exposure to 
investigational product. 
Additional information regarding the exposure during pregnancy may be requested.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (e.g., follow-up on 
preterm infants to identify developmental delays).   
In the case of paternal exposure, the study participant will be provided with the Pregnant 
Partner Release of Information Form to deliver to his partner.  It must be documented that the 
study participant was given this letter to provide to his partner. 
 
Exposure during breastfeeding 
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated AE.  An exposure during breastfeeding report is not created when a Pfizer drug 
specifically approved for use in breastfeeding women (e.g., vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an AE associated with such a 
drug’s administration, the AE is reported together with the exposure during breastfeeding. 
 
Medication error 
A medication error is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product that may cause or lead to inappropriate medication use or patient harm 
while in the control of the health care professional, patient, or consumer.  Such events may 
be related to professional practice, health care products, procedures, and systems including: 
prescribing; order communication; product labeling, packaging, and nomenclature; 
compounding; dispensing; distribution; administration; education; monitoring; and use.   
Medication errors include: 
• Near misses, involving or not involving a patient directly (e.g., inadvertent/erroneous 
administration, which is the accidental use of a product outside of labeling or prescription 
on the part of the healthcare provider or the patient/consumer); 

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• Confusion with regard to invented name (e.g., trade name, brand name). 
The HCP must submit the following medication errors to Pfizer, irrespective of the presence 
of an associated AE/SAE: 
• Medication errors involving patient exposure to the product, whether or not the 
medication error is accompanied by an AE. 
• Medication errors that do not involve a patient directly (e.g., potential medication errors 
or near misses).  When a medication error does not involve patient exposure to the 
product the following minimum criteria constitute a medication error report: 
• An identifiable reporter; 
• A suspect product; 
• The event medication error. 
Overdose, Misuse, Extravasation 
Reports of overdose, misuse, and extravasation associated with the use of a Pfizer product are 
reported to Pfizer by the HCP, irrespective of the presence of an associated AE/SAE.  
Lack of Efficacy 
Reports of lack of efficacy to a Pfizer product are reported to Pfizer by the HCP, irrespective 
of the presence of an associated AE/SAE or the indication for use of the Pfizer product. 
Occupational Exposure 
Reports of occupational exposure to a Pfizer product are reported to Pfizer by the HCP, 
irrespective of the presence of an associated AE/SAE. 
 
REQUIREMENTS – BIONICAL EMAS 
This study protocol requires human review of patient-level unstructured data; unstructured 
data refer to verbatim medical data, including text-based descriptions and visual depictions of 
medical information, such as medical records, images of physician notes, neurological scans, 
X-rays, or narrative fields in a database.  The reviewer is obligated to report adverse events 
(AEs) with explicit attribution to any Pfizer drug that appear in the reviewed information 
(defined per the patient population and study period specified in the protocol).  Explicit 
attribution is not inferred by a temporal relationship between drug administration and an AE, 

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but must be based on a definite statement of causality by a healthcare provider linking drug 
administration to the AE. 
The requirements for reporting safety events on the non-interventional study (NIS) adverse 
event monitoring (AEM) Report Form to Pfizer Safety are as follows: 
• All serious and non-serious AEs with explicit attribution to any Pfizer drug that 
appear in the reviewed information must be recorded on the DCT and reported, within 
24 hours of awareness, to Pfizer Safety using the NIS AEM Report Form. 
• Scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, lack of 
efficacy, and occupational exposure associated with the use of a Pfizer product must 
be reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM 
Report Form. 
For these AEs with an explicit attribution or scenarios involving exposure to a Pfizer product, 
the safety information identified in the unstructured data reviewed is captured in the Event 
Narrative section of the report form, and constitutes all clinical information known regarding 
these AEs.  No follow-up on related AEs will be conducted. 
 
All research staff members must complete the following Pfizer training requirements:    
•  “YRR Training for Vendors Working on Pfizer Studies (excluding interventional 
clinical studies and non-interventional primary data collection studies with 
sites/investigators)”.  
These trainings must be completed by research staff members prior to the start of data 
collection.  All trainings include a “Confirmation of Training Certificate” (for signature by 
the trainee) as a record of completion of the training, which must be kept in a retrievable 
format.  Copies of all signed training certificates must be provided to Pfizer.  
 
Re-training must be completed on an annual basis using the most current Your Reporting 
Responsibilities training materials.  
 
10.1. Single reference safety document 
The Core Data Sheet (CDS) will serve as the single reference safety document during the 
course of the study, which will be used by Pfizer safety to assess any safety events reported 
to Pfizer Safety by the HCP during the course of this study.  
The product label should continue to be used by the HCP for prescribing purposes and 
guidance. 
 

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11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
The results of this data collection will be summarized in a report. This report will then be 
used to inform presentation and reporting of data collection results to regulatory authorities 
as needed. It is further planned to submit publications, at least one conference abstract and at 
least one manuscript based on the results of this data collection to a peer-reviewed journal. 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
competent authority in any area of the world, or if the HCP is aware of any new information 
which might influence the evaluation of the benefits and risks of a Pfizer product, Pfizer 
should be informed immediately.   
In addition, the HCP will inform Pfizer immediately of any urgent safety measures taken by 
the HCP to protect the study patients against any immediate hazard, and of any serious 
breaches of this NI study protocol that the HCP becomes aware of. 
12. REFERENCES 
 
1. 
Ward E, DeSantis C, Robbins A, et al: Childhood and adolescent cancer 
statistics, 2014. CA Cancer J Clin 64:83-103, 2014 
 
2. 
Georgakis MK, Dessypris N, Baka M, et al: Neuroblastoma among children in 
Southern and Eastern European cancer registries: Variations in incidence and temporal trends 
compared to US. Int J Cancer 142:1977-1985, 2018 
 
3. 
Spix C, Pastore G, Sankila R, et al: Neuroblastoma incidence and survival in 
European children (1978-1997): report from the Automated Childhood Cancer Information 
System project. Eur J Cancer 42:2081-91, 2006 
 
4. 
Esiashvili N, Anderson C, Katzenstein HM: Neuroblastoma. Curr Probl 
Cancer 33:333-60, 2009 
 
5. 
Smith MA, Seibel NL, Altekruse SF, et al: Outcomes for children and 
adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28:2625-34, 
2010 
 
6. 
Park JR, Eggert A, Caron H: Neuroblastoma: biology, prognosis, and 
treatment. Hematol Oncol Clin North Am 24:65-86, 2010 
 
7. 
Siegel RL, Miller KD, Jemal A: Cancer statistics, 2019. CA Cancer J Clin 
69:7-34, 2019 
 
8. 
Maris JM: Recent advances in neuroblastoma. N Engl J Med 362:2202-11, 
2010 
 
9. 
Whittle SB, Smith V, Doherty E, et al: Overview and recent advances in the 
treatment of neuroblastoma. Expert Rev Anticancer Ther 17:369-386, 2017 
 
10. 
London WB, Castel V, Monclair T, et al: Clinical and biologic features 
predictive of survival after relapse of neuroblastoma: a report from the International 
Neuroblastoma Risk Group project. J Clin Oncol 29:3286-92, 2011 
 
11. 
Matthay KK, Maris JM, Schleiermacher G, et al: Neuroblastoma. Nat Rev Dis 
Primers 2:16078, 2016 

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Page 34 of 35 
 
12. 
Moreno L, Rubie H, Varo A, et al: Outcome of children with relapsed or 
refractory neuroblastoma: A meta-analysis of ITCC/SIOPEN European phase II clinical 
trials. Pediatr Blood Cancer 64:25-31, 2017 
 
13. 
Osajima-Hakomori Y, Miyake I, Ohira M, et al: Biological role of anaplastic 
lymphoma kinase in neuroblastoma. Am J Pathol 167:213-22, 2005 
 
14. 
Passoni L, Longo L, Collini P, et al: Mutation-independent anaplastic 
lymphoma kinase overexpression in poor prognosis neuroblastoma patients. Cancer Res 
69:7338-46, 2009 
 
15. 
Chen Y, Takita J, Choi YL, et al: Oncogenic mutations of ALK kinase in 
neuroblastoma. Nature 455:971-4, 2008 
 
16. 
George RE, Sanda T, Hanna M, et al: Activating mutations in ALK provide a 
therapeutic target in neuroblastoma. Nature 455:975-8, 2008 
 
17. 
Janoueix-Lerosey I, Lequin D, Brugieres L, et al: Somatic and germline 
activating mutations of the ALK kinase receptor in neuroblastoma. Nature 455:967-70, 2008 
 
18. 
Mosse YP, Laudenslager M, Longo L, et al: Identification of ALK as a major 
familial neuroblastoma predisposition gene. Nature 455:930-5, 2008 
 
19. 
Schulte JH, Bachmann HS, Brockmeyer B, et al: High ALK receptor tyrosine 
kinase expression supersedes ALK mutation as a determining factor of an unfavorable 
phenotype in primary neuroblastoma. Clin Cancer Res 17:5082-92, 2011 
 
20. 
Bresler SC, Weiser DA, Huwe PJ, et al: ALK mutations confer differential 
oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell 
26:682-94, 2014 
 
21. 
Shaw AT, Felip E, Bauer TM, et al: Lorlatinib in non-small-cell lung cancer 
with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-
in-man phase 1 trial. Lancet Oncol 18:1590-1599, 2017 
 
22. 
Gainor JF, Dardaei L, Yoda S, et al: Molecular Mechanisms of Resistance to 
First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer 
Discov 6:1118-1133, 2016 
 
23. 
Infarinato NR, Park JH, Krytska K, et al: The ALK/ROS1 Inhibitor PF-
06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma. 
Cancer Discov 6:96-107, 2016 
 
24. 
Guan J, Tucker ER, Wan H, et al: The ALK inhibitor PF-06463922 is 
effective as a single agent in neuroblastoma driven by expression of ALK and MYCN. Dis 
Model Mech 9:941-52, 2016 
 
25. 
NANT 2015-02: A Phase 1 Study of Lorlatinib (PF-06463922) - Full Text 
View - ClinicalTrials.gov, 2020 
 
26. 
Goldsmith KC, Kayser K, Groshen SG, et al: Phase I trial of lorlatinib in 
patients with ALK-driven refractory or relapsed neuroblastoma: A New Approaches to 
Neuroblastoma Consortium study. Journal of Clinical Oncology 38:10504-10504, 2020 
 
27. 
Report on Leveraging Real-World Treatment Experience from Expanded 
Access Protocols | Expanded Access Navigator, 2020 

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28. 
Park JR, Bagatell R, Cohn SL, et al: Revisions to the International 
Neuroblastoma Response Criteria: A Consensus Statement From the National Cancer 
Institute Clinical Trials Planning Meeting. J Clin Oncol 35:2580-2587, 2017 
 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
None 
ANNEX 2. ADDITIONAL INFORMATION 
Not applicable