Conditions: Recurrent Childhood Anaplastic Large Cell Lymphoma Recurrent Malignant Solid Neoplasm Recurrent Neuroblastoma Refractory Anaplastic Large Cell Lymphoma Refractory Malignant Solid Neoplasm Refractory Neuroblastoma
Allocation:  | Intervention model: SEQUENTIAL
Enrollment: 122
Healthy volunteers: no

Brief summary:
This phase 1/2 trial the studies side effects and best dose of crizotinib and to see how well it works in treating young patients with solid tumors or anaplastic large cell lymphoma that has returned after a period of improvement or does not respond to treatment. Crizotinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. (Phase 1 completed 2/15/13)

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and recommend a Phase 2 dose of Crizotinib administered orally twice daily to children with relapsed/refractory solid tumors and anaplastic large cell lymphoma (ALCL). (completed 2/15/13) II. To define and describe the toxicities of Crizotinib administered on this schedule.

III. To characterize the pharmacokinetics of Crizotinib in children with refractory cancer.

SECONDARY OBJECTIVES:

I. To preliminarily define the anti-tumor activity of Crizotinib within the confines of a Phase 1 study. (completed 2/15/13) II. To obtain initial Phase 2 data on the anti-tumor activity of Crizotinib in children with relapsed/refractory neuroblastoma and ALCL.

III. To preliminarily examine the relationship between anaplastic lymphoma kinase (ALK) status (e.g, the presence of a mutation, duplication, amplification, and/or translocation) in patients with neuroblastoma (NB) or ALCL and response to Crizotinib.

IV. To preliminarily examine the relationship between minimal residual disease (MRD) status and clinical response to Crizotinib in patients with ALCL.

V. To use a questionnaire to gather preliminary information on the palatability of the oral solution formulation of Crizotinib.

VI. To evaluate for potential alterations in bone growth in pediatric patients.

OUTLINE: This is a phase 1 dose-escalation study (completed 2/15/13) followed by a phase 2 study.

Patients receive crizotinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Arms:
arm 1: Patients receive crizotinib PO BID on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Crizotinib intervention 2: Laboratory Biomarker Analysis intervention 3: Pharmacological Study intervention 4: Questionnaire Administration
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Correlative studies intervention 4: Ancillary studies

Protocol document:
Prot_SAP_ICF_001.pdf: 
 
 
ADVL0912 
 
 
07/27/17 
 
 
 
Activated: 
September 21, 2009 
Version Date: 
07/27/17 
Closed: 
October 23, 2015 
Amendment #: 
12 
 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
ADVL0912 
 
A PHASE 1/2 STUDY OF PF-02341066, AN ORAL SMALL MOLECULE INHIBITOR OF 
ANAPLASTIC LYMPHOMA KINASE (ALK) AND C-MET, IN CHILDREN WITH 
RELAPSED/REFRACTORY SOLID TUMORS AND ANAPLASTIC LARGE CELL LYMPHOMA 
 
Participation Limited to member COG Phase 1 Consortium Institutions and the following non-
member collaborator (NMC) institutions: 
 
CTEP ID/Participating Institution 
 
 
 
 
MA036/ Dana-Farber Cancer Institute 
 
         
 
OH006/ Nationwide Children’s Hospital                                
/
 
CO011/ Children’s Hospital Colorado                                    
 
TX011/ UT Southwestern/Simmons Cancer Center-Dallas  
 
TN008/ Vanderbilt University/Ingram Cancer Center         
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR 
USED FOR ANY OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS 
PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY 
PERSON OR ENTITY.  RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH 
DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO 
GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY 
SUBJECT.  THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL 
ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE 
THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH 
HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR 
HEALTHCARE INSTITUTION. 
 
 
 
 
 
 
 
 
 
 
 
 
For Group Operations and Statistics & Data Center Contacts See: http://members.childrensoncologygroup.org 


 
 
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TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
5 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
9 
1.1 
Primary Aims 
9 
1.2 
Secondary Aims 
9 
2.0 
BACKGROUND 
9 
2.1 
Introduction/Rationale for Development 
9 
2.2 
Preclinical Studies 
11 
2.3 
Adult Studies 
16 
2.4 
Pediatric Studies 
18 
2.5 
Overview of Proposed Pediatric Study 
18 
2.6 
Preliminary Results of the Current Pediatric Study (May 2011) 
18 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
19 
3.1 
Current Study Status 
19 
3.2 
IRB Approval 
19 
3.3 
Patient Registration 
20 
3.4 
Reservation and Contact Requirements 
20 
3.5 
Informed Consent/Assent 
20 
3.6 
Screening Procedures 
20 
3.7 
Eligibility Checklist 
20 
3.8 
Institutional Pathology Report 
20 
3.9 
Study Enrollment 
21 
3.10 
Dose Assignment 
21 
4.0 
PATIENT ELIGIBILITY 
21 
4.1 
Inclusion Criteria 
21 
4.2 
Exclusion Criteria 
26 
5.0 
TREATMENT PROGRAM 
27 
5.1 
Treatment Overview 
27 
5.2 
Criteria for Starting Subsequent Cycles 
27 
5.3 
Dose Escalation Schema 
28 
5.4 
Grading of Adverse Events 
29 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
29 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
29 
6.1 
Dose Modifications for Hematological Toxicity 
29 
6.2 
Dose Modifications for Non-Hematological Toxicity 
30 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
31 
7.1 
Concurrent Anticancer Therapy 
31 
7.2 
Investigational Agents 
31 
7.3 
Supportive Care 
31 
7.4 
Growth Factors 
31 
7.5 
Concomitant Medications 
31 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
32 


 
 
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8.1 
Required Clinical, Laboratory and Disease Evaluation 
32 
8.2 
Pharmacokinetic Studies (for Parts A, B or C) 
33 
8.3 
Correlative Studies 
34 
8.4 
Radiology Studies 
36 
8.5 
Monitoring for Specific Toxicities 
36 
9.0 
AGENT INFORMATION 
37 
9.1 
PF-02341066 
37 
9.2 
Agent Accountability 
41 
9.3 
Agent Ordering 
42 
9.4 
Agent Inventory Records 
42 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA43 
10.1 
Criteria for Removal from Protocol Therapy 
43 
10.2 
Off Study Criteria 
43 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
43 
11.1 
Sample Size and Study Duration 
43 
11.2 
Definitions 
45 
11.3 
Dose Escalation and Determination of MTD 
46 
11.4 
Phase 2 Evaluation in ALK+ Neuroblastoma (Part B) and ALK+ ALCL (Part C) 
48 
11.5 
Inclusion of Children, Women and Minorities 
49 
11.6 
Pharmacokinetic and Correlative Studies 
49 
12.0  
EVALUATION CRITERIA 
49 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
49 
12.2 
Response Criteria 
49 
12.3 
Response Criteria for Patients with Solid Tumors and Measurable Disease 
50 
12.4 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
51 
12.5  
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
51 
12.6 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
53 
12.7 
Response Criteria for Patients with ALCL 
54 
12.8 
Best Response 
54 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
56 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
56 
13.2 
When to Report an Event in an Expedited Manner 
58 
13.3 
Expedited Reporting Methods 
58 
13.4 
Definition of Onset and Resolution of Adverse Events 
58 
13.5 
Other Recipients of Adverse Event Reports 
59 
13.6 
Reporting Secondary AML/MDS 
59 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
60 
14.1 
Categories of Research Records 
60 
14.2 
CDUS 
60 
14.3 
Data and Safety Monitoring Plan 
60 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
61 
APPENDIX II: COMMON SUBSTRATES, INHIBITORS AND INDUCERS OF CYP3A4 
62 
APPENDIX IIIA: PF-02341066 DOSING TABLES 
64 
APPENDIX IIIB:  PF-02341066 DOSING TABLES 
69 
APPENDIX IV: PF-02341066 PEDIATRIC ORAL SOLUTION CALCULATION 
70 


 
 
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APPENDIX V: PHARMACOKINETIC STUDY FORM 
71 
APPENDIX V-A: GUIDELINES FOR SHIPPING SAMPLES TO COVANCE 
72 
APPENDIX VI: PHARMACOGENOMIC STUDY FORM 
74 
APPENDIX VII: NEUROBLASTOMA CORRELATIVE BIOLOGY STUDIES 
75 
APPENDIX VIII:BONE MARROW STUDIES FORM 
76 
APPENDIX IX: TISSUE STUDIES FORM 
77 
APPENDIX X: BONE MARROW AND PERIPHERAL BLOOD STUDIES FORM 
78 
APPENDIX XII: PF-02341066 PATIENT DIARY (CAPSULES) 
80 
APPENDIX XIII: PF-02341066 PATIENT DIARY (ORAL SOLUTION) 
82 
APPENDIX XIV: ORAL SOLUTION ADMINISTRATION INSTRUCTIONS 
84 
APPENDIX XV: POTENTIAL DRUG INTERACTIONS 
86 
APPENDIX XVI: NON-MEMBER COLLABORATOR (NMC) INSTITUTIONS 
87 
REFERENCES 
89 
 


 
 
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For Group Operations (GOC) and 
 
Statistics & Data Center (SDC) contacts see: 
 
https://members.childrensoncologygroup.org/ 
 
 
 
AGENT NSC# and IND#’s  
 
PF-02341066-004, PF-02341066  
(NSC# 749005, IND # 105573) 
 
SEE APPENDICES V-A, VI, VIII, IX AND X FOR SPECIMEN SHIPPING ADDRESSES 
SEE APPENDIX XVI FOR NON-MEMBER COLLABORATOR (NMC) PARTICIPATION


 
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ADVL0912   
 
 
 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about subjects collected during the course of our covered studies.  The 
researchers involved in the studies cannot be forced to disclose the identity or any information collected in 
the study in any legal proceedings at the federal, state, or local level, regardless of whether they are criminal, 
administrative, or legislative proceedings.  However, the subject or the researcher may choose to voluntarily 
disclose the protected information under certain circumstances.  For example, if the subject or his/her 
guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure.  Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. 
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
 
ABSTRACT 
 
There is an emerging paradigm in oncology that clinical efficacy can be obtained with inhibitors directed 
toward oncogenic receptor tyrosine kinases (RTKs) that are mutated or otherwise dysregulated in certain 
tumor types.  Examples of such successful intervention include imatinib in GIST with mutant c-Kit, 
erlotinib in NSCLC with mutant and/or amplified EGFR, trastuzumab in breast cancers with amplified 
HER-2, and sunitinib targeting the VHL-dependent VEGF pathway in RCC. The c-Met RTK is frequently 
altered or dysregulated in advanced cancers and has been implicated in tumor progression,1 and therefore 
represents an attractive novel therapeutic target.  It has been shown that the Met receptor has a role in 
PAX3-FKHR-mediated transformation in rhabdomyosarcomas, and that MET can serve as a therapeutic 
target in this disease.2  The anaplastic lymphoma kinase gene (ALK), which has significant homology to the 
Met oncogene, plays a role in the pathogenesis of anaplastic large-cell lymphomas (ALCL), due to a 
chromosomal translocation that results in expression of an oncogenic kinase fusion protein known as NPM-
ALK.  ALK is an orphan tyrosine kinase transmembrane receptor with homology to neurotrophin receptors 
and the MET oncogene.  Expression is restricted to the developing nervous system with a postulated role in 
the regulation of neuronal differentiation.3  It has recently become clear that many human cancers activate 
ALK signaling by creating unique oncogenic fusions of the ALK gene at 2p23 with a variety of partners 
through chromosomal translocation events,4 resulting in the generation of oncogenic ALK fusion genes and 
their encoded proteins.  Recently, the interest in ALK biology has increased considerably, following the 
discovery of ALK translocations in a fraction of non-small-cell lung cancers5 and in other solid tumors.4  It 
is now clear that many human cancers activate ALK signaling by creating unique oncogenic fusions of ALK 
with a variety of partners through chromosomal translocation events.  Previous work had shown that a 
substantial percentage of human-derived neuroblastoma cell lines express ALK transcripts and ALK protein, 
but no definitive role for this oncogene had been proven.  We have recently discovered that activating 
mutations in the tyrosine kinase domain of the anaplastic lymphoma kinase (ALK) oncogene are the cause 
of hereditary neuroblastoma, and that these mutations can also be somatically acquired.6 ALK was also 
recently identified as a molecular target in neuroblastoma by a screen of human cancer cell lines with 
pharmacologic antagonists of the ALK kinase domain.7 We hypothesize that ALK is a critical neuroblastoma 
oncogene and that activation of this cell surface kinase is a tractable therapeutic target.  
 
 


 
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PF-02341066 is an orally bioavailable small molecule inhibitor of the catalytic activity of c-Met kinase and 
the NPM-ALK fusion protein.  In biochemical and cellular screens, PF-02341066 was shown to be selective 
for c-Met and ALK at pharmacologically relevant concentrations across a panel of >120 diverse kinases.8,9  
PF-02341066 potently inhibited cell proliferation, which was associated with G1S-phase cell cycle arrest 
and induction of apoptosis in ALK-positive ALCL cells but not ALK-negative lymphoma cells.  In addition, 
inhibition of key NPM-ALK signaling mediators was observed at concentrations that required for inhibition 
of NPM-ALK phosphorylation and function.  More recently, the in vitro activity of PF-02341066 was 
examined in a panel of ALCL and neuroblastoma cell lines. PF-02341066 was able to inhibit proliferation 
and ALK-mediated signaling in these cell lines at clinically achievable doses, with potent suppression of 
downstream effectors seen in the neuroblastoma cells.7 
 
 
 
EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
*Twice daily treatment with PF-02341066 will be discontinued if there is evidence of progressive disease 
or drug-related dose-limiting toxicity that requires removal from therapy. Patients with stable disease or 
better who are having clinical benefit from PF-02341066 may continue receiving protocol therapy 
provided that the patient meets the criteria for starting subsequent cycles (Section 5.2) and does not meet 
any of the criteria for removal from protocol therapy or off study criteria (Section 10.0). 
 
 
Baseline 
Cycle 1 
Day 28 
Disease evaluation 
Disease evaluation 
Disease evaluations 
Cycle 2+ 
See Table 8.1 
for timing of 
disease 
evaluations 
PF-02341066 PO twice daily 
 
 
 
Continue if no PD or DLT* 


 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To estimate the maximum tolerated dose (MTD) and recommend a Phase 2 dose of 
PF-02341066 administered orally twice daily to children with relapsed/refractory 
solid tumors and anaplastic large cell lymphoma (ALCL). 
 
1.1.2 
To define and describe the toxicities of PF-02341066 administered on this schedule. 
 
1.1.3 
To characterize the pharmacokinetics of PF-02341066 in children with refractory 
cancer. 
 
1.2 
Secondary Aims 
 
1.2.1 
To preliminarily define the anti-tumor activity of PF-02341066 within the confines 
of a Phase 1 study. 
 
1.2.2 
To obtain initial Phase 2 data on the anti-tumor activity of PF-02341066 in children 
with relapsed/refractory neuroblastoma and ALCL. 
 
1.2.3 
To preliminarily examine the relationship between ALK status (e.g, the presence of 
a mutation, duplication, amplification, and/or translocation) in patients with NB or 
ALCL and response to PF-02341066. 
 
1.2.4 
To preliminarily examine the relationship between MRD status and clinical response 
to PF-02341066 in patients with ALCL. 
 
1.2.5 
To use a questionnaire to gather preliminary information on the palatability of the 
oral solution formulation of PF-02341066. 
 
1.2.6 
To evaluate for potential alterations in bone growth in pediatric patients. 
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
PF-02341066 is a small-molecule inhibitor of the c-Met/HGFR and ALK receptor tyrosine 
kinase.  The rationale for use of this mechanism to treat cancer is supported by an emerging 
paradigm in oncology that robust clinical efficacy can be obtained with well-tolerated 
inhibitors directed toward oncogenic tyrosine kinases that are genetically altered through 
activating mutations, gene translocations, or gene amplification.  Recent examples include 
Gleevec® in gastrointestinal stromal tumors with mutant c-Kit or chronic myelogenous 
leukemia with BCR-Abl gene translocations, Tarceva® in non-small cell lung cancer with 
mutant EGFR, Herceptin® in breast cancers with amplified HER-2/neu, and SU11248 
targeting the VHL-dependent VEGF pathway in renal cell carcinoma. An extensive body of 
literature indicates that c-Met/HGFR is one of the most frequently mutated or otherwise 
abnormally activated RTKs in various human cancers.1 The c-Met/Hepatocyte growth factor 
receptor (HGFR) has been well characterized for its role in regulation of cell growth, 
migration, and invasion of both tumor cells and endothelial cells.1  An extensive body of 
literature indicates that c-Met/HGFR is one of the receptor tyrosine kinases (RTKs) most 


 
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frequently mutated or otherwise abnormally activated in late-stage human cancer.  When 
activated, c-Met/HGFR plays a critical role in regulation of tumor oncogenic processes such 
as mitogenesis, survival, invasive growth, metastasis and tumor angiogenesis.  Activating 
mutations in c-Met/HGFR have been identified in multiple adult solid tumors.1 Recent data 
shows that ALK is overexpressed in glioblastoma compared to normal brain, and that 
ribozyme-mediated targeting of ALK leads to reduced tumor growth of glioblastoma 
xenografts and increased apoptosis in the tumors.10 
 
ALK was first described in anaplastic large cell lymphoma,11 where a chromosomal 
translocation leads to production of an oncogenic fusion protein with the ALK intracellular 
region fused to the nucleophosmin (NPM) N-terminus. Similarly, ALK fusion transcripts, 
most commonly with EML4, are potent oncogenic drivers in a subset of non-small cell lung 
cancers (NSCLC),5 and additional ALK fusions drive inflammatory myofibroblastic tumors 
(IMTs) and other cancers.12 Among selective kinase inhibitors tested in a panel of 602 cell 
lines derived from a variety of human cancers, it was found that a selective inhibitor of ALK 
potently suppressed growth of lines derived from anaplastic large cell lymphomas and 
neuroblastomas.7 Anaplastic lymphoma kinase (ALK) and its mutant translocation with the 
nucleophosmin gene (NPM-ALK) results in a constitutively active ALK receptor tyrosine 
kinase expressed in the majority (~80%) of anaplastic large cell lymphomas (ALCL).13 
PF-02341066 demonstrated potent activity against NPM-ALK, an oncogenic fusion protein 
variant of the ALK, which results from a chromosomal translocation which is implicated in 
the pathogenesis of human anaplastic large cell lymphoma.13 In addition, recent data indicates 
that mutations in ALK are responsible for the majority of heritable neuroblastoma cases, and 
also are present in a substantial subset of high-risk neuroblastomas due to somatic 
mutation.6,14 Preclinical data in neuroblastoma confirm the oncogenic potential of mutated 
ALK, and RNA inhibition of ALK message validates the feasibility of a targeted approach 
in this tumor type.6 Consistent with its predicted mechanism of action, PF-02341066 
inhibited target-dependent tumor cell proliferation or invasion, induced tumor cell apoptosis, 
and inhibited angiogenesis in nonclinical tumor models.  Oral administration of PF-02341066 
also demonstrated efficacy, including marked cytoreductive antitumor activity, in several 
tumor models that expressed activated c-Met/HGFR or NPM-ALK. The collective rationale 
for investigation of PF-02341066 in clinical studies is built on genetic alteration of its 
molecular targets, its predicted ability to target multiple processes that are common to cancer 
progression, and preclinical efficacy data.  
 
PF-02341066 is an orally bioavailable, selective c-Met/HGFR aminopyridine tyrosine kinase 
inhibitor and a potent ATP-competitive inhibitor of recombinant, human c-Met/HGFR kinase 
activity with a mean Ki of 4 nM.  In preliminary biochemical screens, PF-02341066 inhibited 
HGF-stimulated or constitutive total tyrosine phosphorylation of wild type c-Met/HGFR with 
a mean IC50 value of 11 nM across a panel of human tumor cell lines.  In addition, PF-
02341066 demonstrated potent activity against NPM-ALK in a human lymphoma cell line 
(IC50 ~ 24 nM). PF-02341066 has also shown potent activity in preclinical in vivo xenograft 
models of GTL-16 gastric carcinoma (mean 60% regression) and the NCI-H441 non-small 
cell lung carcinoma (mean 48% regression) models.  PF-02341066 also demonstrated near 
complete tumor growth inhibition in both the U87MG glioblastoma (97% growth inhibition) 
and PC-3 prostate carcinoma models (87% growth inhibition) at 50 mg/kg/day. In the Karpas 
299 NPM-ALK positive human ALCL lymphoma tumor model, administration of PF-
02341066 at 100 mg/kg/day resulted in complete regression of tumors of all mice in this 
dosing cohort within 15 days of the initial compound administration. After 17 days, PF-
02341066 treatment was stopped, resulting in tumor regrowth. When tumors grew to a larger 
size (>600 mm3), PF-02341066 treatment was reinitiated for an additional 13 days and 


 
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complete regression of tumors was once again demonstrated. PF-02341066 exhibits 
convincing antitumor activity in several xenograft models.  Importantly, it delivers antitumor 
efficacy in xenograft models with a large safety window, providing increased confidence that 
mechanism-based toxicity will not be limiting in the clinic. 
 
These data, coupled with preclinical in vitro data in high-risk neuroblastoma, provide a 
compelling rationale for investigating PF-02341066 in pediatric solid tumors, including CNS 
tumors, neuroblastoma and ALCL. 
 
There is robust preclinical rationale to maximize the recommended phase 2 dose based upon 
laboratory data that mutated ALK is more difficult to inhibit relative to translocated ALK (as 
seen in ALCL and lung cancer), and the fact that certain mutations (F1174L) are 
hyperactivated and thus are relatively resistant to ALK inhibition (Figure 1), but this 
resistance can be overcome in a dose-dependent manner.  
 
 
 
 
 
 
 
 
2.2 
Preclinical Studies 
 
2.2.1 
Antitumor Activity 
Preclinical in vitro and in vivo data demonstrated that PF-02341066 is a potent and 
selective inhibitor of the c-Met/HGFR and ALK receptor tyrosine kinases, as well as 
several of their oncogenic variants (ATP binding site mutations in c-Met and the 
NPM-ALK fusion protein). In a series of cell-based functional assays, PF-02341066 
potently inhibited human GTL-16 gastric carcinoma cell growth, HGF-stimulated 
human NCI-H441 lung carcinoma cell migration and invasion through a matrigel 
matrix and HGF-stimulated MDCK cell motility/scattering, with IC50 values 
ranging from 6.1 to 16 nM.  Additionally, PF-02341066 inhibited proliferation of 
Karpas 299 ALCL cells that express an NPM-ALK fusion protein due to a t(2;5) 
chromosomal translocation (IC50 = 60 nM).  Growth inhibition by PF-02341066 in 
these NPM-ALK positive lymphoma cells was associated with G0/G1 cell cycle 
arrest and induction of apoptosis. When investigated for potential antiangiogenic 
Figure 1. Dose-response curves in vitro to PF-02341066 in 4 NB cell lines 
harboring different ALK mutations showing differential sensitivity.  


 
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activity, PF-02341066 inhibited HGF-mediated HUVEC endothelial cell survival 
(IC50 = 11 nM) and matrigel invasion (IC50 = 35 nM) as well as HMVEC 
endothelial cell tubulogenesis in fibrin gels, with IC50’s of 11 nM to approximately 
80 nM.  These studies suggest that PF-02341066 is active against tumors of diverse 
tissue types, and may also harbor anti-angiogenic effects. 
 
 
The antitumor activity of PF-02341066 has also been evaluated in a variety of human 
tumor xenograft models representative of cancer indications in which dysregulation 
of c-Met/HGFR is implicated. PF-02341066 demonstrated potent cytoreductive 
activity in both the GTL-16 gastric carcinoma (mean 60% regression) and the NCI-
H441 non-small cell lung carcinoma (mean 48% regression) models, suggesting the 
potential to monitor patient objective response as a means of assessing clinical 
efficacy. PF-02341066 also demonstrated near complete tumor growth inhibition in 
both the U87MG glioblastoma (97% growth inhibition) and PC-3 prostate carcinoma 
models (87% growth inhibition) at 50 mg/kg/day. In models in which multiple dose 
levels were evaluated (GTL-16, U87MG, and NCI-H441), dose-dependent inhibition 
of tumor growth correlated with inhibition of c-Met/HGFR phosphorylation. In these 
studies it was observed that complete inhibition of c-Met/HGFR was achieved for 
the full dosing interval at 50 mg/kg/day.  In the Karpas 299 NPM-ALK positive 
human ALCL lymphoma tumor model, administration of PF-02341066 at 100 
mg/kg/day resulted in complete regression of tumors of all mice in this dosing cohort 
within 15 days of the initial compound administration. After 17 days, PF-02341066 
treatment was stopped, resulting in tumor regrowth. When tumors grew to a larger 
size (>600 mm3), PF-02341066 treatment was reinitiated for an additional 13 days 
and complete regression of tumors was once again demonstrated. 
 
2.2.2 
Preliminary Activity of PF-02341066 in Neuroblastoma  
Mutations in the ALK proto-oncogene are the major cause of hereditary 
neuroblastoma (NB)6 and are somatically acquired in sporadic primary tumors.14-16 
We resequenced the ALK tyrosine kinase domain in 449 primary NB DNAs, and 
stained a tissue microarray (TMA) of 160 NBs with anti-ALK and anti-pALK 
antibodies. We evaluated the anti-tumor activity of PF-02341066, an orally 
bioavailable small molecule inhibitor of ALK, against a panel of patient derived cell 
lines in vitro and in vivo. Mutations were discovered in at least 15% of NBs, and 
across the spectrum of NB phenotypes. R1275Q substitutions were most common 
(45%), followed by F1174L (15%), both located in key regulatory regions of the 
receptor’s tyrosine kinase domain. Evaluation of matched constitutional DNAs 
demonstrated 10% of mutations were occult germline mutations.  ALK was highly 
expressed in 50 % of TMA cores and pALK in 30%.  Integration of primary tumor 
microarrays showed a correlation between ALK copy number and mRNA expression. 
PF-02341066 showed differential sensitivity dependent on ALK status in a panel of 
18 neuroblastoma cell lines in vitro. A wild type (WT) amplified line and 2 lines 
harboring the R1275Q mutation were sensitive with IC50s in the 145 – 301 nM range, 
while four cell lines with the F1174Lwere more resistant (IC50s >950 nM).  Cell lines 
with normal copy number WT ALK were also more resistant. Inhibition of 
proliferation was correlated with abolishing phosphorylation of ALK, STAT3 and 
AKT. These in vitro observations were recapitulated in xenograft studies of PF-
02341066 sensitivity. PF-02341066 caused complete regression of R1275Q 
xenografts, but caused only minimal growth delay in F1174L and WT xenografts 
(N=10/arm). PF-02341066 is a potent inhibitor of the most common ALK mutation 
in neuroblastoma.   


 
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The pharmacokinetics of a single oral dose of PF-02341066 was studied in mice at 
the dose that produced the optimal therapeutic effect in neuroblastoma xenografts 
(200 mg/kg ≈ 80 mg/m2). A one-compartment model was fit to the plasma 
concentration-time data (sampled over 28 h) and the parameters are shown below: 
 
Parameter 
Value 
Units 
Absorption rate constant (ka) 
2.2 
h-1 
Apparent volume of distribution (Vd/F) 
10 
L/m2 
Elimination rate constant (kel) 
0.056 
h-1 
AUC0-28h 
116 
mcg•h/mL 
AUC0-∞ 
147 
mcg•h/mL 
Steady state trough concentration (C12h) 
8.8 
mcg/mL 
Half-life (t1/2) 
12 
h 
 
Biochemical analyses linked the reduced susceptibility of F1174L-mutated ALK to 
PF-02341066 inhibition (compared with R1275Q) to increased ATP-binding 
affinity, as seen with development of resistance to EGFR inhibitors in non-small cell 
lung cancer (NSCLC). The activating R1275Q ALK mutation increases Km for ATP, 
mirroring the common L858R EGFR mutation. By contrast, the activating F1174L 
ALK mutation slightly reduces Km for ATP, so that its kinetic parameters resemble 
those of the gefitinib/erlotinib-resistant L858R/T790M EGFR mutant in NSCLC. 
Despite the resistance seen in the studies described here, our results indicate that 
patients harboring the F1174L mutation may benefit from treatment with ATP-
competitive ALK inhibitors in some circumstances. Our biochemical results indicate 
that the reduced sensitivity of F1174L-expressing cell lines can be explained, at least 
in part, by an increased ATP-binding affinity compared with R1275Q – as manifest 
by Km, ATP values – which reduces the potency of ATP-competitive inhibitors (Table 
1). For PF-02341066 itself, an increase in dosage to overcome the relative difference 
in Km, ATP compared with R1275Q-mutated ALK may be possible (Table 2, 
manuscript submitted). 
 
 
Table 1. 
Kinetic parameters of ALK-TKD. Data are shown as mean ± SEM of at least 3 independent 
experiments. 
 
kinase 
kcat 
(min-1) 
Km, peptide 
(mM) 
kcat/Km, peptide 
(min-1·mM-1) 
Km, ATP* 
(mM) 
kcat/Km, ATP (min-
1·mM-1) 
Wild-type 
9.32 ± 0.85 
2.88 ± 0.42 
3.41 ± 0.44 
0.134 ± 0.007 
69.7 
R1275Q 
119 ± 13 
2.56 ± 0.32 
46.8 ± 1.9 
0.326 ± 0.033 
364 
F1174L 
365 ± 61 
9.18 ± 1.43 
39.7 ± 2.8 
0.127 ± 0.011 
2870 
 
 
 
 
 
 
pWild-type 
424 ± 63 
1.80 ± 0.17 
237 ± 35 
0.159 ± 0.012 
2660 
pR1275Q 
347 ± 15 
1.39 ± 0.10 
252 ± 24 
0.248 ± 0.015 
1400 
pF1174L 
436 ± 51 
1.25 ± 0.20 
357 ± 25 
0.109 ± 0.001 
3980 
* Determined at 1 mM peptide. 
 
 


 
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Table 2. ALK-TKD inhibition by PF-02341066 in vitro at two different ATP concentrations. 
Data are shown as mean ± SEM for at least 3 independent experiments. 
 
 
kinase 
IC50, 2 mM ATP 
(nM) 
IC50, 0.2 mM ATP 
(nM) 
Wild-type  
147 ± 6 
-- 
R1275Q 
84.6 ± 8.0 
80.4 ± 4.8 
F1174L 
130 ± 10 
88.5 ± 6.4 
 
2.2.3 
Animal Toxicology 
The primary PF-02341066 toxicities in nonclinical studies were observed in the 
gastrointestinal tract (rat, dog, monkey), hematopoietic system (rat, dog, monkey), 
kidneys (rat), reproductive organs (rat), and actively growing long bones (rat). 
Emesis and diarrhea were dose-limiting toxicities observed during the single-dose 
escalation range-finding study in dogs. Microscopic evidence of minimal to mild 
renal cortical tubule vacuolation was observed following 28 days of dosing in male 
rats treated with ≥50 mg/kg/day. Bone marrow hypocellularity was observed in 
toxicity studies in rats and monkeys treated for 28 days at doses of 150 mg/kg/day 
(rats, males only) and 50 mg/kg/day (monkeys). Bone marrow hypocellularity was 
not observed in dogs; however, a decrease in white blood cells was identified 
following 3 single doses up to 40 mg/kg and 7 days of PF-02341066 at 20 mg/kg/day. 
Repeated administration of PF-02341066 for 28 days caused minimally decreased 
bone formation at the primary spongiosa of growing long bones at a dose of 150 
mg/kg/day in male rats. PF-02341066 administration was associated with decreased 
heart rate, increased LVEDP, and decreased myocardial contractility. Increases in 
sPR interval, QRS, and QT interval were believed to be secondary to the reduction 
in heart rate. Additional effects related to PF-02341066 administration involved 
genetic toxicity findings, and other findings of uncertain risk to humans including 
decreased cellularity in lymphoid organs, elevated liver enzymes, potential for 
phototoxicity, and effects on the salivary glands. 
 
2.2.4 
Non-clinical Pharmacokinetic Studies 
Single-dose pharmacokinetics of PF-02341066 in the male Sprague-Dawley rat, 
Beagle dog, and cynomolgus monkey following intravenous administration 
demonstrated moderate systemic plasma clearance in all preclinical species (9 to 47 
mL/min/kg). Volume of distribution at steady state ranged from 2.9 to 24 L/kg in the 
rat, 11 to 13 L/kg in the dog, and 13 L/kg in the monkey, which all greatly exceeded 
the volume of total body water and indicated extensive distribution of PF-02341066 
into body tissues. The terminal half-life ranged from 2.3 to 17 hours. Linear 
pharmacokinetics were observed in all preclinical species at doses of 1 and 5 mg/kg. 
Oral bioavailability from the solution and suspension formulations at 12.5 to 50 
mg/kg in rats ranged from 26% to 63%, and in dogs and monkeys ranged from 38% 
to 66%.  
 
In vitro studies with pooled human liver microsomes and specific CYP probe 
substrates indicated the highest potency for crizotinib-mediated CYP inhibition was 
for CYP3A, with IC50 values of 8.2 µM and 7.3 µM for felodipine oxidase and 
testosterone 6β-hydroxylase activities, respectively. The inhibitor potency of 
crizotinib was less for CYP2B6 and CYP2C9, with IC50 values of 22 µM and 23 
µM, respectively. Low inhibitor potency was observed for CYP1A2, CYP2C8, 
CYP2C19, and CYP2D6 (IC50 values >30 µM). Clinical interactions with substrates 


 
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of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 are unlikely. 
Crizotinib demonstrated time-dependent inhibition of CYP3A in human liver 
microsomes with a kinact of 0.11 min-1 and KI of 3.0 µM (midazolam as the substrate). 
Crizotinib caused marked induction of CYP3A4 based on mRNA levels in human 
cryopreserved hepatocytes at concentrations up to 7 µM; however, a corresponding 
induction of CYP3A4 enzyme activity was not observed. This finding is likely due 
to the crizotinib-mediated time-dependent inhibition of CYP3A4.  
 
The potential of crizotinib to inhibit P-gp was evaluated in an in vitro study in Caco-
2 cells. Crizotinib demonstrated a concentration-dependent inhibitory effect on P-
gp-mediated digoxin efflux, with an IC50 value of 5.8 µM. Therefore, 
coadministration of crizotinib could potentially increase the plasma concentration of 
P-gp substrates such as digoxin in vivo via inhibition of intestinal P-gp-mediated 
efflux.  
 
Pfizer has developed PF-02341066, as an oral solution, for patients who are unable 
to swallow capsules. Based on the physiochemical properties of this agent, the 
bioavailability of the oral suspension (PIB - powder in bottle) should be comparable 
to the powder-in-capsule (PIC). In vitro dissolution tests showed that the dissolution 
rate was fast, dose-independent and formulation-independent when pH=1.0 (fasted 
state) or pH=4.5 (fed state). The only exception was that the 100-mg PIC had slightly 
slower dissolution rate than 50-mg PIC and an immediate release tablet (IRT) when 
pH=4.5 (fed state) with Paddle motion. Moreover, results from a recent 
bioavailability study in normal healthy subjects demonstrated bioequivalence 
between PIC and IRT in term of AUC and Cmax, suggesting that dissolution may 
not be a limiting step of absorption. The oral clearance (CL/F) of PF-02341066 was 
observed to be 80-100 L/hr administered as the PIC in adult patients (Study 
A8081001), indicating PF-02341066 is a drug with either high clearance (CL), low 
bioavailability (F), or both. The likely low bioavailability may be due to low 
permeability and/or extensive GI/hepatic metabolism rather than poor dissolution of 
the PIC formulation. Therefore, it is believed that the oral suspension (PIB) will have 
a similar bioavailability compared to the PIC, which is currently used in adult patient 
trials.   
 
Pfizer has more recently developed PF-02341066 as an oral solution (OS), which 
along with their Formulated Capsule (FC), is moving forward for commercial 
development. The OS is a sweetened and flavored aqueous solution, containing PF-
02341066 (25 mg/mL) and excipients. PF-02341066 is 100% dissolved in the OS. 
Results from study A8081019 demonstrated that OS of PF-02341066 was 
bioequivalent to the FC.  In vitro dissolution tests showed that the dissolution rates 
of the solid formulations were fast and similar, suggesting that dissolution may be 
not limiting in PF-02341066 absorption. Based on these data, the OS is considered 
to be bioequivalent to the PIC formulation currently used in this trial. 
 
 


 
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2.3 
Adult Studies 
 
2.3.1 
Phase 1 Studies 
 
An ongoing Phase 1 trial (A8081001) evaluating PF-02341066 as an oral single 
agent is being conducted to investigate the safety, pharmacokinetics and 
pharmacodynamics of PF-02341066 in adult patients with advanced cancer 
(excluding leukemias).  This trial includes a dose escalation component followed by 
a dose expansion component in a selected cohort of molecularly-defined patients 
referred to as the enriched population.  During the dose escalation phase, PF-
02341066 was administered under fasting conditions QD or BID on a continuous 
schedule.  The objectives of the dose escalation component of the trial were to 
establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and 
pharmacokinetics 
(PK) 
of 
PF-02341066 
in 
patients 
with 
advanced 
cancer.  Enrollment for the dose escalation part of the trial is complete and 37 
patients have been dosed.  Three DLTs have been observed including Grade 3 ALT 
increase in 1 patient at 200 mg QD and Grade 3 fatigue in 2 patients at 300 mg 
BID.  The MTD was determined to be 250 mg BID administered in a continuous 
daily dosing regimen.  The MTD for QD administration is currently being 
determined. 
 
ALK gene rearrangement-positive patients were identified for the expansion cohort 
of the ongoing Phase 1 trial using a diagnostic test with a break apart ALK FISH 
probe.  One hundred and thirteen ALK+ NSCLC patients have entered the enriched 
population cohort as of 7 August 2010.  Clinical activity data is reported for these 
113 patients as of data cut-off date.  Over 50% of the patients had at least 3 prior 
treatments for NSCLC and 15 patients had an ECOG performance status of 2 at 
baseline for this study. 
 
The objective response rate (ORR) was: 56% (95%CI: 46%, 66%).  The median 
duration of response for those patients who responded was 6.0 months.  The median 
Progression Free Survival (PFS) was 9.2 months (95% CI: 7.6, 10.3 months). 
 
The most common treatment-related adverse events in the evaluable subset is 
gastrointestinal toxicity consisting of nausea, diarrhea and vomiting.  These adverse 
events were primarily Grade 1-2 in severity.  Nausea and emesis were independent 
of dose or duration of treatment and were effectively managed using I.V. or oral anti-
emetics.  Diarrhea can be effectively controlled by anti-diarrheals.  The percentage 
of patients having visual changes which consisted mainly of seeing shadows or 
streaks during changes in light has occurred in ~45% of patients.  All of these visual 
events were Grade 1 in severity.  These adverse events did not affect patient 
management as no patients temporarily stopped treatment, had their dose reduced or 
were permanently discontinued from treatment. Five patients have experienced 
Grade 3 (n=4) or Grade 4 (n=1) increases in ALT.  These events occurred within the 
first cycle treatment, i.e. first 28 days of treatment.   Patients were asymptomatic and 
the ALT increases were reversible upon discontinuation of study medication.  Only 
one patient discontinued treatment due to an increase in ALT levels. 
 
In a recent review of safety for PF-02341066, Pfizer has determined that there are 4 
potential cases of pneumonitis in patients with non-small cell lung cancer (NSCLC), 
which may be related to PF-02341066. One additional case was a radiation recall 


 
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pneumonitis. Based on the 4 cases that were not linked to radiation treatment and 
relative to all enrolled adult patients (N=255) who have been treated with PF-
02341066, as of September 15, 2010, the current frequency of non-radiation recall 
pneumonitis is 1.6%.  One of the 4 cases was fatal. The 3 other patients were 
permanently discontinued from the study and recovered from the event. The one 
patient who experienced radiation recall pneumonitis, was appropriately treated and 
was able to restart PF-02341066. Interpretation of the 4 non-radiation recall cases 
was complicated by the underlying non-small cell lung cancer for which the patients 
were being treated. In addition these 3 cases were complicated by the co-
administration of other drugs known to potentially cause pneumonitis and/or other 
pulmonary complications. 
 
2.3.2 
Phase 2 Studies 
There have been no Phase 2 studies in adults. 
 
2.3.3 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
Preliminary pharmacokinetic (PK) data are available for the first 145 patients 
enrolled in the adult Phase 1 trial 17. After oral administration of PF 02341066 on an 
empty stomach, peak plasma concentrations were reached at ~ 4 hours post dose and 
followed by a multi-exponential declining pattern with an average terminal half-life 
of 43 to 51 hours.  Following multiple oral dosing for 15 days or longer, crizotinib 
AUCtau increased with median accumulation ratios ranging from 1.7 to 3.4 after QD 
dosing and from 4.0 to 5.9 after BID dosing, respectively.  No evidence of 
nonlinearity in PK was observed at doses ranging from 100 mg to 200 mg QD and 
200 mg to 300 mg BID, as evidenced by generally proportional increases in mean 
AUCtau and Cmax after single or multiple doses. There was moderate variability in 
AUCtau (coefficient of variation [CV], 12–60%) and Cmax (CV, 21–71%) across all 
doses studied. Crizotinib concentrations reached steady state within 15 days after 
repeated administration at 250 mg BID. Median trough plasma concentration at 
steady state (274 ng/mL total or 57 nM free drug) exceeded the target efficacious 
levels predicted for inhibition of c-MET (13 nM) and ALK (~26 nM) based on 
preclinical mouse tumor models. Co-administration with a standard high-fat meal 
did not appear to change the geometric mean of AUC24 and Cmax of crizotinib 
following single 250-mg crizotinib doses in cancer patients. 
PF-02341066 showed time-dependent inhibition of CYP3A isozymes in human liver 
microsomes.  In order to assess the effect of PF-02341066 on CYP3A activity in the 
GI tract and the liver, PK of midazolam (a CYP3A substrate probe) following a 
single oral 2 mg dose was evaluated before (Day -7) and after (Cycle 2 Day 1) 
repeated administration of PF-02341066 at 250 mg BID in 13 patients.17  A 3.6-fold 
(90% CI: 2.7-4.9) increase in the oral midazolam AUC was observed following 28 
days of PF-02341066 dosing at 250 mg BID, suggesting that PF-02341066 is a 
moderate inhibitor of CYP3A.  
 
 


 
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2.4 
Pediatric Studies 
 
2.4.1 
Prior Experience in Children  
There have been no previous clinical trials of PF-02341066 in children.  
 
2.5 
Overview of Proposed Pediatric Study 
This will be a Phase 1 dose-finding study of PF-02341066 to determine the maximum dose 
that is safe and tolerable. Children with relapsed or refractory solid tumors and children with 
relapsed/refractory ALCL will be treated with PF-02341066 orally, on a continuous 
schedule.  The starting dose will be 100 mg/m2 (70% of the adult MTD of 250 mg twice daily 
or approximately 140 mg/m2) administered orally twice daily continuously. Eligibility will 
include all relapsed/refractory solid tumors and patients with ALCL for the Phase 1 portion 
of this study (Part A1).  Patients with recurrent/refractory malignancies that have confirmed 
ALK fusion proteins, ALK mutations or evidence for MET mutation or amplification, will 
be able to enroll at any time during the phase 1 portion of the protocol (Part A2). Except for 
the initial dose level, their accrual will lag one dose level behind the phase 1 trial. Patients 
with recurrent/refractory neuroblastoma not eligible for Part A1 will also be able to enroll on 
a separate stratum (Part A3) at one dose level below the dose level at which patients on Part 
A1 are actively enrolling.  Due to the prevalence of ALK translocations in systemic ALCL, 
and with promising preclinical data on the activity of PF-02341066 in neuroblastoma, this 
study includes a Phase 2 expansion at the maximum tolerated dose in two separate parts of 
the study, to obtain preliminary efficacy data in patients with ALK+ relapsed/refractory 
neuroblastoma or ALCL (Part B or Part C), as well as patients with any ALK or MET 
activated tumor (Part A2).  
 
To assess biological correlates of efficacy, we will access (when available) banked tumor 
DNA as well as tissue blocks from diagnosis or relapse in participating subjects with 
neuroblastoma and ALCL, for correlative biology studies.  We will also obtain bone marrow 
prior to and while on treatment from patients with neuroblastoma, as well as bone marrow 
and peripheral blood from patients with ALCL. The study will include pharmacokinetic as 
well as correlative studies. A multi-strata Phase 2 study will open group-wide, and stage 1 
data from the neuroblastoma and ALCL cohorts, as well as data for subjects enrolled at the 
MTD in this study, will be utilized as part of the COG-wide Phase 2 trial. 
 
2.6 
Preliminary Results of the Current Pediatric Study (May 2011) 
A total of 39 subjects have been enrolled on the pediatric phase 1 study of PF-02341066. 
Twenty-five subjects were enrolled on Part A1, 9 subjects on Part A2, and 5 subjects on Part 
A3. On Part A1, no hematologic DLTs were observed during the first cycle; at dose level 4 
(215 mg/m2/dose BID), 1 subject experienced grade 3 dizziness, probably related to study 
drug, and 1 subject experienced grade 5 intra-tumoral hemorrhage, possibly related to study 
drug. One subject at dose level 2 (130 mg/m2/dose BID) experienced a grade 4 intra-tumoral 
hemorrhage, with an attribution of unlikely related to study drug in Cycle 2 of therapy. There 
are no laboratory data or data from the adult trial with PF-02341066 to suggest that this drug 
leads to intra-tumoral hemorrhage. In >300 adult patients, including patients with NSCLC 
and brain metastases, there has not been any intra-tumoral hemorrhage observed. On Part 
A2, 1 subject experienced a grade 4 hematologic DLT (grade 4 neutropenia) at dose level 3 
(165 mg/m2/dose BID). On Part A3, no DLTs were seen. Therefore, dose level 4 will be 
expanded to enroll one additional non-CNS patient in Part A1 according to the rolling-six 
design and dose-escalation will proceed if criteria for DLT are not met. The current 
amendment will exclude potential participants with known primary and/or metastatic CNS 
involvement due to the occurrence of 2 CNS adverse events reported to date on this trial.  


 
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Nineteen children enrolled on the pediatric phase 1 trial had adequate pharmacokinetic 
sampling completed after the first dose of PF-02341066. The disposition of PF-02341066 in 
children was highly variable (apparent clearance [CL/F] ranged from 9 to 276 L/m2/h). The 
relationship between dose and AUC of PF-02341066 was difficult to assess because of the 
variability (the AUC0-∞ at the 130 mg/m2 dose level ranged from 1.2 to 14 mcg•h/mL).  The 
AUC0-∞ at the 215 mg/m2 dose level was 2.6 and 7.4 mcg•h/mL in 2 patients.  The mean t1/2 
was 6.7 h, but it ranged from 2.9 to 21 h.  The half-life was considerably shorter in children 
than adults, but may be underestimated because of sampling period after the first dose was 
22-24 h.  Therefore the AUC0-∞ may also be underestimated.  Mean steady state trough 
concentrations were 112, 224, 286 and 441 at the 100, 130, 165 and 215 mg/m2 dose levels, 
respectively. As a result of this artificially short half-life, it is likely that the AUC 
extrapolated to infinity is substantially underestimated and the AUCinf of a single dose may 
not be equal to the AUCtau at steady state.  In addition, auto-induction of metabolism may 
also impact the steady-state AUC.  To address this, we will perform steady state PK, which 
can be compared to the exposures in preclinical models. Given the importance placed on the 
PK in children on this trial as a way to relate to the preclinical studies and the primary driver 
for deciding to dose-escalate, PKs will be required for patients on Part A, Part B or Part C. 
 
 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
3.1 
Current Study Status 
Investigators should refer to the COG website to determine if the study is currently open for 
accrual.  If the study is listed as active, investigators should then access the Studies Requiring 
Reservations page to ensure that a reservation for the study is available. To access the Studies 
Requiring Reservations page:  
1. Log in to https://members.childrensoncologygroup.org.  
2. From the menu bar, click eRDES. The eRDES sub-menu appears.  
3. Click Reservation. The Studies requiring Reservations page appears. 
 
3.2 
IRB Approval 
Local IRB/REB approval of this study must be obtained by a site prior to enrolling patients. 
Sites must submit IRB/REB approvals to the NCI’s Cancer Trials Support Unit (CTSU) 
Regulatory Office and allow 3 business days for processing. The submission must include a 
fax coversheet (or optional CTSU IRB Transmittal Sheet) and the IRB approval document(s). 
The CTSU IRB Certification Form may be submitted in lieu of the signed IRB approval 
letter.  All CTSU forms can be located on the CTSU web page (www.ctsu.org). Any other 
regulatory documents needed for access to the study enrollment screens will be listed for the 
study on the CTSU Member’s Website under the RSS Tab.   
 
IRB/REB approval documents may be faxed (1-215-569-0206),  
Emailed (CTSURegulatory@ctsu.coccg.org) or mailed to the CTSU Regulatory office.   
 
 


 
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When a site has a pending patient enrollment within the next 24 hours, this is considered a 
“Time of Need” registration. For Time of Need registrations, in addition to marking your 
submissions as ‘URGENT’ and faxing the regulatory documents, call the CTSU Regulatory 
Helpdesk at: 1-866-651-CTSU. For general (non-regulatory) questions, call the CTSU 
General Helpdesk at: 1-888-823-5923. 
 
3.3 
Patient Registration 
Prior to enrollment on study, all patients must have been registered via the RDE system into 
the COG Cancer Registry (Diagnosis/Registry).  The patient registration application is 
available 24 hours a day, 7 days a week.  The assigned COG patient identification number 
will be used to identify the patient in all future interactions with the COG. If you have 
problems with registration, please refer to the online help in the eRDE area of the COG 
website. 
 
3.4 
Reservation and Contact Requirements 
Before enrolling a patient on study, a reservation must be made at the Statistics & Data Center 
and the Study Chair or Vice Chair should be notified. (The patient will need a COG patient 
identification number in order to obtain a reservation). Patients must be enrolled within 7 
calendar days of making a reservation.  
 
Reservations may be obtained 24-hours a day through the COG website. Please refer to the  
Reservation System eRDES User Guide that can be downloaded at: 
https://members.childrensoncologygroup.org/_files/Help/UserGuides/eRDES_ReservationSystem_UserGuide.pdf 
 
3.5 
Informed Consent/Assent 
The investigational nature and objectives of the trial, the procedures and treatments involved 
and their attendant risks and discomforts, and potential alternative therapies will be carefully 
explained to the patient or the patient’s parents or guardian if the patient is a child, and a 
signed informed consent and assent will be obtained according to institutional guidelines. 
 
3.6 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent.  This can be accomplished 
through one of the following mechanisms: a) the COG screening protocol, b) an IRB-
approved institutional screening protocol or c) the study-specific protocol.  Documentation 
of the informed consent for screening will be maintained in the patient’s research chart. 
Studies or procedures that were performed for clinical indications (not exclusively to 
determine eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
3.7 
Eligibility Checklist 
Before the patient can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist.  A signed copy of the checklist will be faxed 
immediately following enrollment, using eRDES Document Imaging Program, to the 
Operations Center at (626) 447-2204. For more information on eRDES Document Imaging, 
please refer to the eRDES Document Imaging User Guide – Institutional, which can be 
downloaded at: 
https://members.childrensoncologygroup.org/_files/Help/UserGuides/eRDES_DocumentIm
aging_UserGuide_Institutional.pdf 
 
3.8 
Institutional Pathology Report 


 
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Immediately following enrollment, the institutional pathology report for the diagnosis under 
which the patient is being enrolled must be faxed, with the corresponding shuttle sheet, to 
the Operations Center at (626) 447-2204. The fax must include the associated study number 
and COG patient registration and accession numbers. Personal identifiers, including the 
patient’s name and initials must be removed from the institutional pathology report prior to 
submission to COG. 
 
3.9 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have 
been met. Patients who give informed consent for the protocol in order to undergo screening 
for eligibility are not considered enrolled and should not be enrolled until the screening is 
completed and they are determined to meet all eligibility criteria. Study enrollment is 
accomplished by going to the Enrollment application in the RDE system.  If you have 
problems with enrollment, refer to online help in the Applications area of the COG website. 
Patients must be enrolled before treatment begins.  The date protocol therapy is projected to 
start must be no later than five (5) calendar days after the date of study enrollment. Patients 
must not receive any protocol therapy prior to enrollment. 
 
3.10 
Dose Assignment 
The dose level will be assigned via RDE at the time of study enrollment. 
 
 
4.0 
PATIENT ELIGIBILITY 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated.  If more than 7 calendar days elapse between the date 
eligibility studies outlined in Section 4.1.7 were obtained and the start date of treatment, then the 
following studies must be repeated prior to treatment: CBC with differential, bilirubin, ALT (SGPT) 
and serum creatinine.  If any of these repeat laboratory studies are outside the parameters required 
for eligibility (labs may again be repeated within 48-72 hours), then the patient is off protocol therapy.  
Imaging studies, bone marrow aspirates and biopsies are required within 14 days prior to start of 
protocol therapy. If more than 14 days have elapsed between the date imaging studies to determine 
eligibility were obtained (i.e., for patients with neuroblastoma on Part A or Part B per Section 4.1.4.2) 
and the start date of treatment, then repeat imaging studies must be obtained prior to initiating 
protocol therapy. 
 
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived (per COG policy posted 5/11/01).  All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient’s 
medical or research record which will serve as the source document for verification at the time 
of audit. 
 
4.1 
Inclusion Criteria 
 
4.1.1 
Age:  Patients must be > than 12 months and ≤ 21 years of age at the time of study 
enrollment. 
 
4.1.2 
BSA (Phase 2): Patients receiving the formulated capsules must have a BSA ≥ 0.63 m2 
at the time of study enrollment. 
 
4.1.3 
Diagnosis: Patients must have had histologic verification of malignancy at original 


 
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diagnosis or relapse. 
 
4.1.3.1 
a.  Phase 1 (Part A1) - COMPLETE: Patients with relapsed or 
refractory solid tumors or anaplastic large cell lymphoma (excluding 
patients with primary or metastatic CNS tumors or patients with 
primary cutaneous ALCL).  
 
b. Phase 1 (Part A2) - COMPLETE: Patients with confirmed ALK 
fusion proteins, ALK mutations, ALK amplification (defined as 
greater than 4-fold increase in the ALK signal number as compared to 
reference signal number on chromosome 2q arm) or MET mutation or 
amplification. Testing to confirm the presence of ALK fusion proteins, 
ALK mutations, ALK amplification or evidence of MET mutation or 
amplification for eligibility purposes must be performed as a CLIA-
certified assay. ALK immunohistochemistry can be used as a 
surrogate for FISH for patients with IMT or ALCL. 
 
Note: Evidence for MET mutation or amplification is defined as: 
• 
positive for c-Met amplification by FISH; or 
• 
positive for known c-Met kinase domain activating mutations 
including V1110L, H1112L, H1112Y, H1124D, M1149T, 
T1191I, V1206L, L1213V, V1238I, M1268T, P1009S, T1010I, 
R988C, V941L, but excluding Y1248C, Y1248H, Y1248D, and 
Y1253D; or 
• 
Chromosomal translocations that lead to altered transcriptional 
regulation of c-Met and/or HGF including metastatic alveolar 
soft part sarcoma, clear cell sarcoma, rhabdomyosarcoma, or 
translocation associated renal cell carcinoma).  
 
c. Phase 1 (Part A3)- COMPLETE: Patients with relapsed or refractory 
neuroblastoma, with or without bone marrow involvement, who are 
not eligible for Part A1 or A2 or cannot enroll on Part A1 because of 
stratum suspension or lack of available slots. (These patients will be 
enrolled at one dose level below the dose level at which patients on 
Part A1 are actively enrolling.) 
 
4.1.3.2 Phase 2 (Part B):  Patients with ALK+ relapsed or refractory neuroblastoma. 
 
4.1.3.3 Phase 2 (Part C): Patients with ALK+ relapsed or refractory anaplastic large 
cell lymphoma (excluding patients with primary cutaneous ALCL).  
 
4.1.3.4 Phase 2 (Part A2): Patients with diagnoses other than neuroblastoma or 
ALCL with confirmed ALK fusion proteins, ALK mutations, ALK 
amplification (defined as greater than 4-fold increase in the ALK signal 
number as compared to reference signal number on chromosome 2q arm) or 
MET mutation or amplification. Testing to confirm the presence of ALK 
fusion proteins, ALK mutations, ALK amplification or evidence of MET 
mutation or amplification for eligibility purposes must be performed as a 
CLIA-certified assay. ALK immunohistochemistry can be used as a 
surrogate for FISH for patients with IMT. 
 


 
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Note: Evidence for MET mutation or amplification is defined as: 
• 
Positive for c-Met amplification by FISH; or 
• 
Positive for known c-Met kinase domain activating mutations 
including V1110L, H1112L, H1112Y, H1124D, M1149T, 
T1191I, V1206L, L1213V, V1238I, M1268T, P1009S, T1010I, 
R988C, V941L, but excluding Y1248C, Y1248H, Y1248D, and 
Y1253D; or 
• 
Chromosomal translocations that lead to altered transcriptional 
regulation of c-Met and/or HGF including metastatic alveolar 
soft part sarcoma, clear cell sarcoma, rhabdomyosarcoma, or 
translocation associated renal cell carcinoma).  
 
4.1.4 
Disease Status:  
 
4.1.4.1 Phase 1 (Part A) 
Patients must have either measurable and/or evaluable disease (see Sections 
12.3, 12.4, 12.5, 12.6, and 12.7 for definitions). 
 
4.1.4.2  Phase 2 (Part B) 
Patients with neuroblastoma must have proven ALK+ disease with either 
measurable and/or evaluable disease as indicated below: 
B1. Measurable tumor on MRI, CT scan or X-ray obtained within 2 
weeks prior to study enrollment (see Section 12.3.1) 
B2. Evaluable tumor by MIBG scan (See Section 12.5.1) and/or bone 
marrow involvement with tumor cells seen on routine morphology 
(see Section 12.6.1). 
 
4.1.4.3 Phase 2 (Part C) 
Patients must have proven ALK+ disease with either measurable or 
evaluable disease (see Sections 12.3.1, 12.4.1, and 12.7). 
 
4.1.5 
Performance Level:  Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥50 
for patients ≤ 16 years of age (See Appendix I).  Note: Patients who are unable to 
walk because of paralysis, but who are up in a wheelchair, will be considered 
ambulatory for the purpose of assessing the performance score. 
 
4.1.6 
Prior Therapy 
 
4.1.6.1 Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer therapy. 
 
a. Myelosuppressive chemotherapy:   
• 
Solid Tumors: Patients with solid tumors must not have received 
within 3 weeks of enrollment onto this study (6 weeks if prior 
nitrosourea).   
• 
Lymphoma: Patients with lymphoma who relapse during standard 
maintenance therapy are eligible at time of relapse. For patients with 
ALCL who relapse while they are receiving cytotoxic therapy, at 
least 14 days must have elapsed since the completion of cytotoxic 
therapy. Note: Cytoreduction with hydroxyurea can be initiated and 


 
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continued for up to 24 hours prior to the start of PF-02341066.   
 
b. Hematopoietic growth factors: At least 7 days since the completion of 
therapy with a growth factor. 
 
c. Biologic (anti-neoplastic agent):  At least 7 days since the completion of 
therapy with a biologic agent. For agents that have known adverse 
events occurring beyond 7 days after administration, this period must be 
extended beyond the time during which adverse events are known to 
occur.  The duration of this interval must be discussed with the Study 
Chair. 
 
d. Monoclonal antibodies:  At least 7 days or 3 half-lives, whichever is 
longer, must have elapsed since prior treatment with a monoclonal 
antibody.   
 
e. XRT:  ≥ 2 wks for local palliative XRT (small port); ≥ 6 weeks must 
have elapsed since treatment with therapeutic doses of MIBG; ≥ 6 
months must have elapsed if prior TBI, craniospinal XRT or ≥ 50% 
radiation of pelvis; ≥ 6 wks must have elapsed if other substantial BM 
radiation. 
 
f. 
Bone Marrow/Stem Cell Transplant or Infusion without TBI: 
 
i. 
(Part A1 or Part C): No evidence of active graft vs. host disease 
and ≥ 3 months must have elapsed since stem cell transplant or 
infusion. 
 
ii. 
(Part A2, Part A3, or Part B): No evidence of active graft vs. 
host disease and ≥ 6 weeks must have elapsed since stem cell 
transplant or infusion. 
 
g. Immunotherapy: At least 42 days after the completion of any type of 
immunotherapy, e.g. tumor vaccines. 
 
4.1.6.2 Patients must not have received prior therapy with PF-02341066. 
 
4.1.7 
Organ Function Requirements 
 
4.1.7.1 Adequate Bone Marrow Function Defined as: 
 
 
Patients on Part A1 or Part C of the study: 
a. For patients with solid tumors or ALCL without bone marrow 
involvement: 
- 
Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 
- 
Platelet count ≥ 75,000/mm3 (transfusion independent, defined as 
not receiving platelet transfusions within a 7 day period prior to 
enrollment) 
- 
Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions) 
 
 
b. Patients with known bone marrow metastatic disease:  


 
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- 
Peripheral absolute neutrophil count (ANC) ≥ 750/mm3 
- 
Platelet count ≥ 25,000/mm3 (may receive platelet transfusions) 
- 
Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions) 
- 
Not known to be refractory to red cell or platelet transfusions 
 
Transfusions are permitted to meet both the platelet and hemoglobin 
criteria. Note:  Patients with known bone marrow metastatic disease are 
not evaluable for hematological toxicity for the purposes of dose 
escalation. 
 
Patients on Part A2, Part A3 or Part B of the study: 
Patients eligible for Part A2, Part A3, or Part B of the study must meet the 
hematologic criteria below for enrollment: 
- 
Peripheral absolute neutrophil count (ANC) ≥ 750/mm3 
- 
Platelet count ≥ 25,000/mm3 (may receive platelet transfusions) 
- 
Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions) 
- 
Not known to be refractory to red cell or platelet transfusions 
 
Transfusions are permitted to meet both the platelet and hemoglobin 
criteria. 
 
4.1.7.2 Adequate Renal Function Defined as: 
- 
Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
 
 
Age 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the 
Schwartz formula for estimating GFR18 utilizing child length and stature 
data published by the CDC. 
 
4.1.7.3 Adequate Liver Function Defined as: 
- 
Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of 
normal (ULN) for age  
- 
SGPT (ALT) ≤ 110 U/L.  For the purpose of this study, the ULN for 
SGPT is 45 U/L.  
- 
Serum albumin ≥ 2 g/dL. 
 
4.1.7.4 Adequate Cardiac Function defined as: 
- 
QTc ≤ 480 msec 
 
4.1.8 
Informed Consent: All patients and/or their parents or legal guardians must sign a 
written informed consent. Assent, when appropriate, will be obtained according to 
institutional guidelines.  
 


 
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4.1.9 
Drug Administration: Patients taking the capsule formulation must be able to 
swallow capsules. Feeding tube administration is allowed for patients receiving the 
oral solution (OS). 
 
4.2 
Exclusion Criteria 
 
4.2.1 
Pregnancy or Breast-Feeding 
Pregnant or breast-feeding women will not be entered on this study, as there is no 
available information regarding human fetal or teratogenic toxicities. Pregnancy tests 
must be obtained in girls who are post-menarchal. Males or females of reproductive 
potential may not participate unless they have agreed to use an effective 
contraceptive method. 
 
4.2.2 
Concomitant Medications 
 
4.2.2.1 Corticosteroids:  Patients receiving corticosteroids who have not been on a 
stable or decreasing dose of corticosteroid for the prior 7 days are not 
eligible. 
 
4.2.2.2 Investigational Drugs:  Patients who are currently receiving another 
investigational drug are not eligible. 
 
4.2.2.3 Anti-cancer Agents:  Patients who are currently receiving other anti-cancer 
agents, with the exception of hydroxyurea for patients with ALCL, are not 
eligible. 
 
 
4.2.2.4 CYP3A4 Substrates with Narrow Therapeutic Indices:  As PF-02341066 is 
an inhibitor of CYP3A4, patients chronically receiving medications known 
to be metabolized by CYP3A4 and with narrow therapeutic indices including 
pimozide, aripiprazole, triazolam, ergotamine and halofantrine are not 
eligible. The topical use of these medications (if applicable) is allowed. See 
Appendix II. 
 
4.2.2.5 CYP3A4 Inhibitors: Patients chronically receiving drugs that are known 
potent CYP3A4 inhibitors within 7 days prior to study enrollment, including 
but not limited to ketoconazole, itraconazole, miconazole, clarithromycin, 
erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, 
delavirdine, nefazodone, diltiazem, verapamil, and grapefruit juice are not 
eligible. The topical use of these medications (if applicable), e.g. 2% 
ketoconazole cream, is allowed. See Appendix II. 
 
4.2.2.6 CYP3A4 Inducers: Patients chronically receiving drugs that are known 
potent CYP3A4 inducers within 12 days prior to study enrollment, including 
but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, 
rifampin, tipranavir, ritonavir, and St. John’s wort are not eligible. The 
topical use of these medications (if applicable) is allowed. See Appendix II. 
 
4.2.3 
Patients with known interstitial fibrosis or interstitial lung disease are not eligible. 
 
4.2.4 
Patients with a known history of myocardial infarction or cerebrovascular accident 
are not eligible. 


 
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4.2.5 
Patients with CNS tumors or known CNS metastases are not eligible. Patients with 
a history of CNS metastases that have been surgically resected are eligible only if 
the baseline evaluation (see Section 8.1 footnote 18) shows no evidence of current 
CNS metastases. Patients with any evidence of CNS metastases on baseline 
evaluation are not eligible, regardless of whether the lesions have been previously 
treated and/or appear stable. 
 
4.2.6 
Infection:  Patients who have an uncontrolled infection are not eligible. 
 
4.2.7 
Patients who in the opinion of the investigator may not be able to comply with the 
safety monitoring requirements of the study are not eligible. 
 
 
5.0 
TREATMENT PROGRAM 
 
5.1 
Treatment Overview 
 
5.1.1 
Drug Administration 
 
Treatment Schedule Table 
Days 1-28 
PF-02341066 orally twice daily 
Day 28 
End of Cycle 
 
For patients receiving PF-02341066 capsule formulation, the capsules must be swallowed 
whole. For patients receiving PF-02341066 oral solution (OS), see the guidelines for 
preparation and administration in Appendix XIV. Feeding tube administration is allowed for 
patients receiving the OS.  If a patient vomits after a dose of PF-02341066 (capsule or OS), 
it will not be repeated. See also Section 9.1.7 regarding administration instructions. Refer to 
the dosing nomogram in Appendix IIIB for the formulated capsules (FC) and see the formula 
and calculation in Appendix IV for the OS.  After Cycle 1, patients may, for convenience, 
change formulations from FC to OS or vice versa.  
 
Patients that enrolled on Parts A1, A2 & A3 prior to Amendment#6 must continue to 
receive their current formulation PIC or OS. Refer to the dosing nomogram Appendix 
IIIA for the PIC formulation and Appendix IV for the formula and calculation for the 
OS. Newly enrolled patients on Parts A2, B & C should receive therapy with either the 
FC or the OS.  
 
A cycle of therapy is considered to be 28 days.  
 
Drug doses should be adjusted based on the BSA determined based on height and weight 
obtained within one week prior to the beginning of each cycle.  
 
 
5.2 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient has at least stable disease, an ANC ≥ 
250/mm3 (for patients with known bone marrow involvement) or ≥ 500/mm3 (for patients 
without known bone marrow involvement), and has again met other laboratory parameters 
for hematologic, renal, and liver function as defined in the eligibility section (Sections 


 
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4.1.7.1, 4.1.7.2, and 4.1.7.3).  Patients with stable disease or better who are having clinical 
benefit from PF-02341066 may continue receiving protocol therapy provided that the patient 
meets the criteria for starting subsequent cycles (Section 5.2) and does not meet any of the 
criteria for removal from protocol therapy or off study criteria (Section 10.0). 
 
 
 
5.3 
Dose Escalation Schema 
 
5.3.1 
Inter-Patient Escalation [Phase 1 (Part A) only] - COMPLETE 
The starting dose will be 100 mg/m2/dose BID with dose levels for subsequent groups 
of patients as follows: 
Dose Level 
Dose (mg/m2/dose BID) 
0 
70   
1 
100  
2 
130  
3 
165  
4 
215  
5 
280 
6 
365 
 
5.3.2 
Patients with recurrent/refractory malignancies that have confirmed ALK fusion 
proteins, ALK mutations or ALK amplification (defined as greater than 4-fold 
increase in the ALK signal number as compared to reference signal number on 
chromosome 2q arm) or evidence for MET mutation or amplification who have 
exhausted all standard treatment options can be accrued to a separate stratum (Part 
A2) if they are not eligible for enrollment on the phase 1 dose escalation component 
of the trial (Part A1).  These patients will be enrolled at one dose level below that of 
patients in part A1, or at the starting dose level (dose level 1) if dose escalation has 
not yet occurred. For patients enrolled with a confirmed ALK or MET aberration 
(Part A1 or A2), intra-patient dose escalation will be permitted for up to one dose 
level in cycles of therapy subsequent to cycle 1 if the patient is tolerating the dose at 
which they began therapy and if the next higher dose level has been established as 
tolerable. Part A2 will remain open during the Phase 2 portion of the study. 
 
 
Patients with recurrent/refractory neuroblastoma, with or without bone marrow 
involvement, who are not eligible for Part A1 or A2 or cannot enroll on Part A1 
because of stratum suspension or lack of available slots, can be accrued to a separate 
stratum (Part A3). These patients will be enrolled at one dose level below the dose 
level at which patients on Part A1 are actively enrolling. For these patients, intra-
patient dose escalation will be permitted for up to one dose level if the patient is 
tolerating the dose at which they began therapy and if the next higher dose level has 
been established as tolerable. 
 
5.3.3 
Dosing for the Phase 2 expansion, Part A2 (patients with ALK or MET+ 
tumors), Part B (patients with ALK+ neuroblastoma) and Part C (patients with 
ALK+ ALCL): Patients in the initial Phase 2 expansion will be treated at the 
recommended dose from the Phase 1 component of this trial, which is 280 
mg/m2/dose BID. 
 
5.3.4 
Intra-Patient Escalation 
Intra-patient dose escalation is not allowed with the exception of dosing for patients 
in Part A1 (patients with ALK or MET+ tumors), A2 or Part A3 of the study, in 


 
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cycles of therapy subsequent to cycle 1 (See Section 5.3.2). Sites will be notified by 
the COG Phase I Operations office if their patient may proceed with an intrapatient 
dose escalation following the completion of Cycle 1 or subsequent cycles.   
 
5.4 
Grading of Adverse Events 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting beginning October 
1, 2011. All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov). Any suspected or confirmed dose-limiting toxicity should be 
reported immediately (within 24 hours) to the Study Chair. 
 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are possibly, probably or definitely 
attributable to PF-02341066.  The DLT observation period for the purposes of dose-
escalation will be the first cycle of therapy. 
 
Dose limiting hematological and non-hematological toxicities are defined differently.   
 
5.5.1 
Non-hematological dose-limiting toxicity: 
• 
Any Grade 4 non-hematological toxicity 
• 
Any Grade 3 non-hematological toxicity with the specific exclusion of: 
- 
Grade 3 nausea and vomiting of less < 3 days duration 
- 
Grade 3 ALT/AST that return to levels that meet initial eligibility criteria 
within 7 days of study drug interruption and that do not recur upon study 
drug re-challenge. Note: For the purposes of this study the ULN for ALT is 
defined as 45 U/L. 
- 
Grade 3 fever or infection < 5 days duration. 
- 
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia responsive to oral supplementation 
• 
Grade 2 allergic reactions that necessitate discontinuation of study drug will not 
be considered a dose-limiting toxicity. 
• 
Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is 
considered sufficiently medically significant or sufficiently intolerable by 
patients that it requires treatment interruption. 
• 
Any adverse event requiring interruption of study drug for ≥ 7 days or which 
recurs upon drug challenge. 
 
5.5.2 
Hematological dose limiting toxicity 
For patients evaluable for hematological toxicity (See Section 4.1.7.1), DLT will be 
defined as: 
• 
Grade 4 thrombocytopenia or Grade 4 neutropenia (see also Section 6.1) 
 
 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dosage modification or use of Filgrastim. 
 
6.1 
Dose Modifications for Hematological Toxicity 
 


 
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6.1.1 
If a patient on Part A1 or without known bone marrow involvement on part A2, A3, 
B or C experiences Grade 4 neutropenia or thrombocytopenia, the treatment will be 
withheld.  If a patient with known bone marrow involvement on part A2, A3, B or C 
experiences an ANC < 250/mm3, the treatment will be withheld. Counts should be 
checked every other day during Cycle 1 or twice weekly if during Cycle 2 or 
subsequent cycles until Grade 3 or less.  
 
6.1.1.1 If the toxicity resolves to meet on study parameters within 14 days of drug 
discontinuation, the patient may resume treatment at the next lower dose 
level.  Doses reduced for toxicity will not be re-escalated, even if there is 
minimal or no toxicity with the reduced dose.  
 
6.1.1.2 If toxicity does not resolve to meet on study parameters within 14 days of 
drug discontinuation, the patient must be removed from protocol therapy. 
 
6.1.2 
If hematological dose-limiting toxicity recurs in a patient who has resumed treatment 
at a dose level that is one below that assigned at study enrollment, the patient must 
be removed from protocol therapy. 
 
6.2 
Dose Modifications for Non-Hematological Toxicity 
 
6.2.1 
If a patient experiences non-hematological dose-limiting toxicity as defined in 
Section 5.5.1, the treatment will be withheld.  
 
6.2.1.1 When the toxicity resolves to meet on study parameters within 14 days of 
drug discontinuation, the patient may resume treatment at the next lower 
dose level.  Doses reduced for toxicity will not be re-escalated, even if there 
is minimal or no toxicity with the reduced dose. 
 
6.2.1.2 If toxicity does not resolve to meet on study parameters within 14 days of 
drug discontinuation, the patient must be removed from protocol therapy. 
 
6.2.2 
If non-hematological dose-limiting toxicity recurs in a patient who has resumed 
treatment at the reduced dose level, at a dose level that is one below that assigned at 
study enrollment, the patient must be removed from protocol therapy. 
  
 


 
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7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
Concurrent Anticancer Therapy 
 
7.1.1 
Concurrent 
cancer 
therapy, 
including 
chemotherapy, 
radiation 
therapy, 
immunotherapy, or biologic therapy may NOT be administered to patients receiving 
study drug with the exceptions noted below. If these treatments are administered the 
patient will be removed from protocol therapy. 
 
7.1.2 
Part C: Patients with ALCL who benefit from treatment (SD, PR or CR) with PF-
02341066 during Cycle 1 may at the treating investigator’s discretion receive 
intrathecal methotrexate in subsequent cycles of therapy.   
 
7.2 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
7.3 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general supportive 
care are to be used as necessary (see Section 6.0). 
 
7.4 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered in accordance with Section 6.1 or for culture proven bacteremia or invasive 
fungal infection. The Study Chair should be notified before growth factors are initiated. 
 
7.5 
Concomitant Medications 
The metabolism of PF-02341066 is predominantly mediated by the CYP3A isozymes in 
human liver microsomes and hepatocytes.  Co-administration with drugs that are CYP3A 
inhibitors and inducers may change the plasma concentrations of PF-02341066 in humans. 
The chronic concurrent use of potent CYP3A inhibitors and potent CYP3A inducers must be 
avoided from 7 days and 12 days, respectively, prior to the first dose of PF-02341066 until 
treatment discontinuation (See Sections 4.2.2.5 and 4.2.2.6).  The list of potent CYP3A4 
inhibitors and inducers in Sections 4.2.2.5 and 4.2.2.6 are also not permitted while the patient 
is on study therapy. The topical use of these medications (if applicable) is allowed. CYP3A4 
inhibitors/inducers NOT listed in Sections 4.2.2.5 and 4.2.2.6 should be avoided whenever 
possible, and therapeutic alternatives to these agents are recommended.  However, if no 
therapeutic alternatives are available, patients may continue to receive PF-02341066. Please 
see Appendix II for a list of common substrates, inhibitors, and inducers of CYP3A4. 
 
PF-02341066 showed time-dependent inhibition of CYP3A isozymes in human liver 
microsomes. In the adult Phase 1 trial, the oral midazolam AUC was increased by 3.6-fold 
(90% CI: 2.7-4.9, n=13) after 28-day PF-02341066 administration at 250 mg BID, suggesting 
that PF-02341066 is a moderate inhibitor of CYP3A. Therefore, caution must be exercised 
in subjects receiving PF-02341066 in combination with drugs that are predominantly 
metabolized by CYP3A.  In particular, chronic coadministration of PF-02341066 with 
CYP3A4 substrates with narrow therapeutic indices must be avoided from the time of the 
first dose of PF-02341066 until treatment discontinuation. See Section 4.2.2.5 for the list of 
CYP3A4 substrates with narrow therapeutic indices. PF-02341066 has minimal potential to 
inhibit other human CYP isoforms such as CYP1A2, 2C8, 2C9, 2C19 and 2D6.  
 
Additionally, the concurrent use of non-prescription drugs (excluding vitamins) or herbal 
supplements is not recommended. 
 
 
 
 


 
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8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
All enrollment/eligibility studies must be performed within 1 week prior to study enrollment 
(unless otherwise specified). If more than 7 calendar days elapse between the date eligibility 
studies outlined in Section 4.1.7 were obtained and the start date of treatment, then the 
following studies must be repeated prior to treatment: CBC with differential, bilirubin, ALT 
(SGPT) and serum creatinine.  If any of these repeat laboratory studies are outside the 
parameters required for eligibility (labs may again be repeated within 48-72 hours), then the 
patient is off protocol therapy.  Imaging studies, bone marrow aspirates and biopsies are 
required within 14 days prior to start of protocol therapy (repeat the tumor imaging if 
necessary).  
 
STUDIES TO BE OBTAINED 
Pre-
Study 
During Cycle 1 
Subsequent Cycles^ 
History 
X 
X 
X 
Physical Exam with vital signs  
X 
Weekly 
X 
Height, weight, BSA 
X 
 
X 
Performance Status 
X 
 
X 
CBC, differential, platelets 
X 
Weekly1 
Weekly in Cycle 2 and then 
once every cycle thereafter2 
Urinalysis 
X 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
X 
Creatinine, ALT, AST, bilirubin 
X 
Weekly 
X 
Total protein/albumin 
X 
 
X 
Tumor Disease Evaluation  
(Phase 1: Parts A1, A2 & A3)4, 15 
X3 
End of Cycle 1 
End of Cycles 3, 5, 7 and then 
every 3 cycles21 
Tumor Disease Evaluation  
(Phase 2: Part A2)4 
X 
End of Cycle 1 
End of Cycles 3, 5, 7 and then 
every 3 cycles21 
Tumor Disease Evaluation Part B4, 15 
X 
 End of Cycle 1   
End of Cycles 3, 5, 7, and then 
every 3 cycles 
Tumor Disease Evaluation  Part C4 
X3 
End of Cycle 1  
End of Cycle 3, 7, 11, 17, 23, 
and then yearly thereafter 
PET scan 5 
X 
End of Cycle 1 
With Tumor Disease 
Evaluation 
Bone marrow evaluation  
(Phase 1: Parts A1, A2 & A3)6, 7, 16 
X 
End of Cycle 1 
End of Cycles 3, 5, 7 and then 
every 3 cycles21 
Bone marrow evaluation  
(Phase 2: Part A2) 16 
X 
End of Cycle 1 
End of Cycles 3, 5, 7 and then 
every 3 cycles21 
Bone marrow evaluation Parts B 6, 16 
X 
End of Cycle 1 
End of Cycles 3, 5, 7 and then 
every 3 cycles 
Bone Marrow Evaluation Part C 7. 16 
X 
End of Cycle 1 
End of Cycle 3, 7, 11, 17, 23, 
and then yearly thereafter 
CSF cytology8. 17 
X 
End of Cycle 1 
As clinically indicated 
Urinary HVA/VMA9 
X 
 
X 
Pregnancy test10 
X 
 
 
Snellen Eye chart11 
X 
End of Cycle 1 
End of Cycles 3, 5, 7 and then 
every 3 cycles 
Patient diary12 
 
X 
X 
Pharmacokinetics13 
 
X 
 
Correlative biology studies14 
X 
X 
X 
EKG 
X 
 
 


 
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CNS Imaging (CT or MRI) 18 
X 
 
 
Taste Questionnaire19 
 
Weekly 
X 
Plain radiograph tibial growth plates20 
X 
 
See Section 8.5.1 
^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 
If patients develop Grade 4 neutropenia or thrombocytopenia to < 20,000/mm3 then CBCs should be checked at 
least every other day until recovery to Grade 3 (See also Section 6.0). 
2 
If patients develop Grade 4 neutropenia or thrombocytopenia to < 20,000/mm3 then CBCs should be checked 
twice weekly until recovery to Grade 3 (See also Section 6.0). 
3 
Patients with ALCL must have CT neck/chest/abdomen/pelvis at study enrollment.  
4 
Tumor Disease Evaluation should be obtained at the end of the next consecutive cycle after initial documentation 
of either a PR or CR. Study drug should not be interrupted unless required by Section 6.1 or 6.2.   
5 
Patients with ALCL are required to have PET scans within 2 weeks prior to start of therapy and should also be 
followed with PET scans if positive at diagnosis. Patients with NB are required to have PET scans within 2 weeks 
prior to the start of therapy only if their disease is MIBG non-avid and should be followed with PET scans if 
baseline scans are positive.  
6 
Patients with neuroblastoma must have bilateral bone marrow aspirates and biopsies. These do not need to be 
repeated if negative at study enrollment and patient is responding to therapy.  
7 
Patients with ALCL must have bilateral bone marrow aspirates and biopsies. These do not need to be repeated if 
negative at study enrollment and patient is responding to therapy. 
8 
Phase 1: Part A – all ALCL patients, if clinically indicated; Part C – all ALCL patients 
9 
Phase 1: Part A – Neuroblastoma patients only; Part B – all neuroblastoma patients 
10 
Patients of childbearing potential require a negative pregnancy test prior to starting treatment and must use an 
acceptable method of birth control.  Abstinence is an acceptable method of birth control. 
11 
Snellen Eye Chart should be used to evaluate visual acuity. If a decline in visual acuity occurs or other visual 
symptoms occur, the patient should be referred for an ophthalmologic exam.   
12 
Review patient diary after completion of each treatment cycle and fax a copy, with the corresponding shuttle 
sheet, to the COG Statistics and Data Center (626) 447-2204.  See Appendix XII and XIII. 
13 
See Section 8.2 and Appendix V for timing of PK studies. 
14 
See Section 8.3 and Appendix VI, VII, VIII, IX, and X for the nature and timing of correlative biology studies. 
15 
Patients with neuroblastoma must have both CT/MRI and MIBG scintigraphy performed prior to enrollment if 
the patient was enrolled with or has a history of MIBG avid tumor. Otherwise, the patient must have both CT/MRI 
and bone scan prior to enrollment. For patients with neuroblastoma and measurable disease by CT or MRI, lesions 
should be measured and followed using the same modality (CT or MRI) in addition to MIBG or bone scan. For 
patients with neuroblastoma with evaluable disease by MIBG scintigraphy or bone scan, use the same modality 
(MIBG scintigraphy or bone scan) to image patients; CT/MRI are not required but may be performed as clinically 
indicated. 
16 
For patients with positive bone marrow involvement at time of study enrollment, evaluate until negative per the 
schedule described in the table above.   
17 
For patients with ALCL and positive CSF involvement at time of study enrollment, evaluate until negative per 
the schedule described in the table above.   
18 
Baseline CNS imaging is required in patients with a prior history of CNS disease to ensure that the patient does 
not currently have CNS disease. 
19  
For consenting patients who are receiving the oral solution (OS). See Patient Taste Questionnaire on ADVL0912 
Case Report Form. 
20  
Plain radiographs of at least one tibial growth plate should be obtained in all patients prior to the first dose of 
protocol therapy.  In patients with open growth plates, follow-up plain radiographs of the same growth plate(s) 
should be obtained according to Section 8.5.1. 
21 
Patients with ALCL currently enrolled on Part A of the study should follow the same evaluation schedule provided 
for patients on Part C (i.e. End of Cycle 3, 7, 11, 17, 23, and then yearly thereafter). 
 
 
 
 
 
8.2 
Pharmacokinetic Studies (for Parts A, B or C) 
 


 
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8.2.1 
Description of Studies and Assay 
Plasma will be collected for the purpose of determining PF-02341066 concentrations 
for pharmacokinetic analysis. 
 
8.2.2 
Sampling Schedule  
Sampling schedule is based on adult PK data and the experience seen in children on 
this pediatric trial.  For all patients, plasma samples will be obtained prior to the first 
dose on Day 1 of Cycle 1 and at steady state, defined as being between days 15 and 
28 of BID dosing in Cycle 1 at the following time points: pre-dose (12 h after the 
last dose), 1 hr, 2 hr, 4 hrs, and 6-8 hrs.  
  
8.2.3 
Sample Collection and Handling Instructions 
Blood samples (2 mL each) will be collected in K2EDTA tubes. Record the exact 
date and time that the sample is drawn and the last dose of drug is administered on 
the Pharmacokinetic Study Form (see Appendix V). Once collected, samples should 
be processed immediately and kept out of direct sunlight due to the light sensitive 
nature of PF-02341066.  Blood samples will be placed immediately on ice-bath and 
centrifuged at approximately 1700 g for 10 minutes at 4º C.  Plasma samples will be 
stored at approximately -20°C within 1 hour of collection.  Further details regarding 
pharmacokinetic sample processing, labeling, and shipping can be found in 
Appendix V. 
 
8.3 
Correlative Studies 
 
8.3.1 
Description of Studies 
 
8.3.1.1 Pharmacogenomic Studies (for patients on Parts A, B or C): 
Whole blood samples for pharmacogenomics will be obtained for the 
purpose of genotyping the alleles of cytochrome P450 enzymes and drug 
transport proteins.  Instructions regarding sample collection, handling and 
shipping can be found in Sections 8.3.2.1, 8.3.3.1, and Appendix VI. 
 
8.3.1.2 Tissue and Bone Marrow Studies for Neuroblastoma: 
Tumor tissue from patients with neuroblastoma, if available, and bone 
marrow will be evaluated for correlative biology studies. Archival tumor 
tissue should be submitted for all patients with neuroblastoma, and extra 
effort should be expended to obtain consent for this tissue. If a patient with 
neuroblastoma does not have tissue available, the study chair must be 
notified. Details of this work are outlined in Appendix VII. 
 
8.3.1.3 Bone Marrow and Peripheral Blood Studies for ALCL: 
Minimal disease studies will be performed in children with ALCL.  These 
correlative studies are required and the study chair must be notified if 
these samples are not available.  RT-PCR will be performed on total RNA 
extracted from bone marrow and/or serial peripheral blood specimens, for 
detection of the t(2;5) NPM/ALK fusion transcript.  
 
8.3.2 
Sampling Schedule  
8.3.2.1 Pharmacogenomic Studies (for patients on Parts A, B or C): 
One peripheral blood sample (3 mL) will be collected at baseline prior to the 
first dose of PF-02341066.  
 


 
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8.3.2.2 Tissue and Bone Marrow Studies for Neuroblastoma: 
Tissue (paraffin-embedded, or fresh frozen tissue) and bone marrow will be 
collected from original diagnosis, relapse, or any subsequent resection or 
biopsy prior to treatment with PF-02341066 from patients with 
neuroblastoma. If marrow is positive for tumor cells at time of study 
enrollment, a marrow will also be repeated at times of disease evaluations as 
described in Section 8.1 and sent to the laboratory in Appendix VIII for these 
correlative studies.  
 
8.3.2.3 Bone Marrow and Peripheral Blood Studies for ALCL: 
A single bone marrow sample will be obtained prior to starting Cycle 1 in 
patients with ALCL.  In addition, peripheral blood samples will be obtained 
prior to starting Cycle 1, on day 15 of Cycle 1, at the beginning of Cycle 2, 
then once every cycle thereafter through cycle 11 and then every 3 cycles.  
The timing of collection of all specimens should coincide with routine 
laboratory evaluations and should be submitted to Dr. Megan Lim at the 
address listed in Appendix X. 
 
8.3.3 
Sample Collection and Handling Instructions 
 
8.3.3.1 Pharmacogenomic Studies (for patients on Parts A, B or C): 
Blood samples (3 mL) will be collected into one plastic K2EDTA collection 
tube and stored at -70º C. Record the exact time that the sample is drawn on 
the Pharmacogenomic Study Form (see Appendix VI). Detailed instructions 
regarding pharmacogenomic sample processing, labeling, and shipping can 
be found in Appendix VI. 
 
8.3.3.2 Tissue and Bone Marrow Studies for Neuroblastoma: 
Tumor material should be sent to Dr. Yaël Mossé at room temperature by 
regular mail or using the institution’s courier account at the address listed in 
Appendix IX.  
 
Bone marrow should be sent to Dr. Yaël Mossé at room temperature by 
overnight Federal Express mail at the address listed in Appendix VIII. In 
patients with neuroblastoma, a bone marrow aspirate will be obtained (3-5 
mL if ≤10 kg and 5 mL in children > 10 kg). Detailed instructions regarding 
sample processing, labeling, and shipping can be found in Appendix VIII. 
 
8.3.3.3 Bone Marrow and Peripheral Blood Studies for ALCL: 
Peripheral blood (15 mL if >10 kg and 10 mL in children ≤10 kg) and bone 
marrow (5 mL if > 10 kg and 3-5 mL in children ≤10 kg) will be collected 
in patients with ALCL. Record the exact time and date that the sample is 
drawn. Samples should be shipped room temperature, the same day as 
drawn. If the samples cannot be shipped immediately (i.e. is collected in the 
evening and will be shipped out the next morning via FedEx), they should 
be stored in a refrigerator until shipment. Note: Samples should be sent 
within 24 hours from time drawn. 
 
Each tube must be labeled with the patient’s study registration number, the 
study I.D., and the date and time the sample was drawn. Data should be 
recorded on the study form in Appendix X, which must accompany the 


 
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sample(s). Detailed instructions regarding sample processing, labeling, and 
shipping can be found in Appendix X. Samples will be sent at room 
temperature to Dr. Megan S. Lim at the address listed in Appendix X. 
 
8.4 
Radiology Studies 
 
8.4.1 
Central Radiology Review for Response:  
Patients who respond to therapy (PR, CR) or have long term stable disease (SD) on 
protocol therapy (≥ 6 cycles) will be centrally reviewed. COG Operations Center will 
notify the Imaging Center of any patient requiring central review. The Imaging 
Center will then request that the treating institution forward the requested images for 
central review. The central image evaluation results will be entered into eRDE for 
review by the COG Operations Center.  
 
The images are to be forwarded electronically to Imaging Research Center at 
Children’s Hospital Los Angeles via the grid.  
 
COG institutions that are not connected to the grid can send the images on hard copy 
film, CD ROM, or by FTP. Submitted imaging studies should be clearly marked with 
the COG patient ID, study number (ADVL0912) and date and shipped to Syed 
Aamer at the address below: 
 
Syed Aamer 
Imaging Research Center 
Data Administrator  
Children’s Hospital Los Angeles  
4650 Sunset Boulevard, MS # 81 
Los Angeles, CA 90027 
Phone: (323) 361-3898 
Fax: 
(323) 361-3054 
E-mail: saamer@chla.usc.edu  
 
8.4.2 
Bone Age/Knee MRI 
All tibial radiographs and knee MRIs (if obtained) should be submitted for review to 
the address listed above in Section 8.4.1. 
 
8.5 
Monitoring for Specific Toxicities 
 
8.5.1 
Growth Plate Toxicity 
Patients will have a plain AP radiograph of a single proximal tibial growth plate 
obtained prior to the first dose of protocol therapy.  
a. If patients are found to have a closed tibial growth plate, no further radiographs 
will be required.  
b. If patients are found to have an open tibial growth plate, then repeat plain AP 
radiographs of the same tibial growth plate will be obtained at the end of Cycle 
3 and then approximately every 6 months thereafter (timed with the nearest 
disease evaluation). 
• 
Patients with evidence of growth plate thickening or other changes should 
have a knee MRI performed to further assess the degree of physeal pathology 
and undergo more frequent x-ray follow up. MRI should be performed 
without contrast. 


 
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• 
Patients with knee MRI changes should be managed in an individualized 
manner. Decisions regarding continuation of PF-02341066 should be made 
after discussion with the Study Chair or Study Vice-Chair and DVL 
Leadership, taking into account the presence of any symptoms referable to 
the knee as well as the patient’s response to PF-02341066. Consultation with 
an orthopedic surgeon may also be indicated. Plans for follow-up imaging 
will also be made on an individualized basis, taking into account the 
presence of symptoms at the knee or other joints as well as the decision to 
continue PF-02341066 or not. 
 
 
9.0 
AGENT INFORMATION 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
O 
Cl 
Cl 
F 
N 
NH2 
N 
N 
NH 


 
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•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
10.1 
Criteria for Removal from Protocol Therapy 
 
a) 
Clinical (including physical examination), laboratory (e.g., serum tumor markers) or 
radiographic evidence of progressive disease (See Section 12.0). 
b) 
Adverse Events requiring removal from study (See Section 6.0). 
c) 
Refusal of further protocol therapy by patient/parent/guardian. 
d) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e) 
Physician determines it is not in the patient’s best interest. 
f) 
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) and 
serum creatinine) are outside the parameters required for eligibility prior to the start of 
PF-02341066 (See Section 8.1). 
g)  Patients who develop a second malignant neoplasm. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below).  Ongoing adverse events, or adverse events that emerge after the patient 
is removed from protocol therapy, but within 30 days of the last dose of investigational agent, 
must be followed and reported via RDE and CTEP-AERS (if applicable).  Follow-up data 
will be required unless consent is withdrawn. 
 
10.2 
Off Study Criteria 
 
a) 
Thirty days after the last dose of the investigational agent. 
b) 
Death 
c) 
Lost to follow-up 
d) 
Withdrawal of consent for any further data submission. 
e) 
Enrollment onto another COG therapeutic (anti-cancer) study. 
 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
 
Parts of the Study: 
Part A1: Patients with relapsed/refractory solid tumors or anaplastic large cell lymphoma 
(ALCL) – Phase 1 
COMPLETE 
Part A2: Patients with recurrent/refractory malignancies who have confirmed ALK fusion 
proteins, ALK mutations, ALK amplification or evidence for MET mutation or 
amplification.  Once Parts B and C are open to accrual, patients who are not eligible 
for either Part should enroll on Part A2, provided that they meet all other eligibility 
criteria for Part A2 (see Section 4.0). 
Part A3: Patients with recurrent/refractory neuroblastoma, who are not eligible for Part A1 
or A2 or who cannot enroll on Part A1 because of stratum suspension or lack of 
available slots. 
COMPLETE  
Part B:  Patients with ALK+ relapsed/refractory neuroblastoma – Phase 2 
Part C: 
Patients with ALK+ relapsed/refractory ALCL – Phase 2 
 
 
 


 
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There will be three parts of the study during the phase 1 component.  Part A1 will be a 
standard phase 1 trial using the rolling 6 design for patients with relapsed/refractory solid 
tumors and ALCL.  Part A2 will be patients with recurrent/refractory malignancies that have 
confirmed ALK fusion proteins, ALK mutations or amplification, or evidence for MET 
mutation or amplification who have exhausted all standard treatment options. Patients with 
confirmed ALK fusion proteins, ALK mutations or amplification or MET mutation or 
amplification will preferentially enroll in Part A1 when possible, and then Part A2 if not 
eligible for Part A1.  Part A3 will be for patients with recurrent/refractory neuroblastoma, 
that do not have a confirmed ALK fusion protein, ALK mutation or ALK amplification, and 
are either not eligible for Part A1 or cannot enroll on Part A1 because of stratum suspension 
or lack of available slots.  Accrual to Part A3 will begin at dose level 1, once initial accrual 
of Part A1 patients to dose level 1 has proceeded to dose level 2.  
 
Patients in Parts A2 and A3 will be enrolled at one dose level below that of patients enrolled 
in Part A1.  If dose escalation has not yet occurred, patients in Part A2 will be enrolled at 
the starting dose level (dose level 1).  Intra-patient dose escalation of up to one dose level 
will be permitted in Part A1 (for patients with confirmed ALK or MET+ tumors), A2 and A3 
in cycles of therapy subsequent to cycle 1 if the patient is tolerating the dose at which they 
began therapy and if the next higher dose level has been established as tolerable in Part A1.   
 
Two to six evaluable patients with relapsed/refractory solid tumors and ALCL (Part A1) will 
be entered at each dose level for determination of maximum tolerated dose (see Section 11.3).   
The minimum sample size required to identify the MTD (Part A1) is 9 patients, which assumes 
the starting dose is the MTD and 2 of 3 patients in the next higher dose level experience a 
DLT.  As of May 2011, 25 subjects have enrolled on Part A1. One additional non-CNS patient 
will be enrolled at dose level 4 for a total of 6 evaluable non-CNS patients at this dose level. 
If no DLT is experienced, we will dose-escalate to dose level 5.  Assuming we will require 
only 1 more patient in dose level 4, and that we proceed with dose escalation and require 6 
more evaluable patients in each of dose levels 5 and 6 before the MTD is reached, up to 17 
additional patients will be required to complete this part of the study, assuming an 
inevaluability rate of 20%. In the unlikely event that all three of these dose levels will require 
expansion to 12 evaluable patients (see Section 11.2.2), a total of 39 additional patients will 
be required, assuming an inevaluability rate of 20%. With an observed accrual rate of 2-3 
patients per month, we expect this part of the study to be complete within an additional 5-9 
months. 
 
Up to twenty patients may enroll onto Part A2 at each lagging dose level behind Part A1. In 
the case that an MTD is not achieved in Part A1, up to twenty patients may be enrolled onto 
Part A2 at the recommended phase 2 dose.  If the dose is not tolerated in Part A2 at a given 
dose level (greater than 1/3 of patients in the dose level experience DLTs), the stratum will 
be closed to further accrual.   
 
Once the MTD or recommended Phase 2 dose has been determined in Part A1, Part A2 will 
remain open at this dose for the duration of the Phase 2 part of the study.  When Parts B and 
C are open to accrual, patients who are not eligible for either Part should enroll on Part A2, 
provided that they meet all other eligibility criteria for Part A2 (see Section 4.0). A total of 
30 evaluable patients may enroll in Part A2 at the MTD or recommended Phase 2 dose. If 20 
evaluable patients are accrued during this time with less than 3 observed responses, 
enrollment to this stratum will be discontinued. Additionally, if 0 responses are observed out 
of 10 evaluable patients with the same histologic tumor type treated at the recommended 
phase 2 dose, enrollment of that tumor type will be discontinued. A maximum of 45 patients 


 
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is anticipated in this stratum, given the current number of enrollments.  If greater than 1/3 of 
patients experience DLTs at this dose level, the stratum will be closed to further accrual.  All 
patients enrolled on Part A2 who meet the eligibility criteria for Parts B or C of the study 
who are evaluable for response as described in Section 11.2.3 of this protocol will be included 
in the evaluation rule.   
 
Up to three patients may enroll onto Part A3 at one dose level below the dose level that Part 
A1 patients are actively enrolling.  If two out of three patients in Part A3 experience a DLT 
at a given dose level, the stratum will be closed to further accrual.  A maximum of 15 patients 
is anticipated in this part. 
 
Accrual to Parts B and C will only open once the MTD or recommended phase 2 dose has 
been determined for Part A1. Review of patient accrual onto recent Phase 2 solid tumor 
studies and ALK+ accruals to this study indicates the following entry rates for the various 
tumors under study can be achieved: 
 
Disease Group/Part 
 
Patients/Year 
Neuroblastoma 
  
15 
ALCL 
 
3-5 
 
Assuming an inevaluability rate of 10%, a minimum of 11 patients and a maximum of 45 
patients are expected to enroll in Parts B and C.  We anticipate that the duration of the study 
(enrollment and evaluation) will require between 48 to 54 months.  
 
11.2 
Definitions 
 
11.2.1 Evaluable For Adverse Effects 
Any patient who receives the study drug will be evaluable for Adverse Effects. 
However, for the consideration of dose escalation, patients must be fully evaluable 
for toxicity. Any patient who experiences DLT at any time during protocol therapy 
is considered fully evaluable for Adverse Effects. Patients without DLT who receive 
at least 85% of the prescribed dose per protocol guidelines are also considered fully 
evaluable for Adverse Effects. Patients who are not fully evaluable for Adverse 
Effects at a given dose level will be replaced. 
 
11.2.2 Maximum Tolerated Dose 
The MTD will be the maximum dose at which fewer than one-third of patients 
experience DLT (See Section 5.5) during Cycle 1 of therapy. In the event that two 
DLTs observed out of 6 evaluable patients are different classes of Adverse Effects 
(e.g. hepatotoxicity and myelosuppression), expansion of the cohort to 12 patients 
will be considered if all of the following conditions are met:  
 
•  One of the DLTs does not appear to be related to dose 
•  The Adverse Effects are readily reversible 
•  The study chair, DVL statistician, DVL committee chair or vice chair, and 
IND sponsor all agree that expansion of the cohort is acceptable 
 
If fewer than 1/3 of patients in the expanded cohort experience dose-limiting 
toxicities, the dose escalation can proceed. 
 
 


 
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11.2.3 Evaluability for Response 
Any patient who is enrolled and receives at least one dose of PF-02341066 will be 
considered evaluable for response provided: (1) the patient demonstrates progressive 
disease or death while on protocol therapy; or (2) the patient is observed on protocol 
therapy for at least one cycle and the tumor is not removed surgically prior to the 
time complete response or partial response is confirmed, or (3) the patient 
demonstrates a complete or partial response as confirmed according to protocol 
criteria. Patients who demonstrate a complete or partial response confirmed by 
central review will be considered to have experienced a response for the application 
of the rule given in Section 11.4. Two objective status determinations are required 
to confirm best response (Section 12.8). All other patients will be considered non-
responders. All patients considered to have a response (CR or PR) must have imaging 
studies reviewed centrally at the COG. Centers will be notified by the COG about 
requests for scans of patients with stable disease. See Section 8.4 regarding shipping 
instructions. Preliminary assessment of activity using institutionally provided tumor 
measurements will be entered into CDUS quarterly. The central review by COG will 
be provided as the final reviewed assessment of response when such becomes 
available. 
 
11.3 
Dose Escalation and Determination of MTD 
The rolling six phase 1 trial design will be used for the conduct of Part A1 of this study.19 
Two to six patients can be concurrently enrolled onto a dose level, dependent upon (1) the 
number of patients enrolled at the current dose level, (2) the number of patients who have 
experienced DLT at the current dose level, and (3) the number of patients entered but with 
tolerability data pending at the current dose level.  Accrual is suspended when a cohort of six 
has enrolled or when the study endpoints have been met.  
 
Dose level assignment is based on the number of participants currently enrolled in the cohort, 
the number of DLTs observed, and the number of participants at risk for developing a DLT 
(i.e., participants enrolled but who are not yet assessable for toxicity). For example, when 
three participants are enrolled onto a dose cohort, if toxicity data is available for all three 
when the fourth participant entered and there are no DLTs, the dose is escalated and the 
fourth participant is enrolled to the subsequent dose level. If data is not yet available for one 
or more of the first three participants and no DLT has been observed, or if one DLT has been 
observed, the new participant is entered at the same dose level. Lastly, if two or more DLTs 
have been observed, the dose level is de-escalated. This process is repeated for participants 
five and six. In place of suspending accrual after every three participants, accrual is only 
suspended when a cohort of six is filled. When participants are inevaluable for toxicity, they 
are replaced with the next available participant if escalation or de-escalation rules have not 
been fulfilled at the time the next available participant is enrolled onto the study. 
 
The following table provides the decision rules for enrolling a patient at (i) the current dose 
level (ii) at an escalated dose level, (iii) at a de-escalated dose level, or whether the study is 
suspended to accrual: 
 
 
# Pts 
Enrolled 
# Pts 
with 
DLT 
# Pts without 
DLT 
# Pts with 
Data Pending 
Decision 
 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 


 
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# Pts 
Enrolled 
# Pts 
with 
DLT 
# Pts without 
DLT 
# Pts with 
Data Pending 
Decision 
 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
 
3 
0 
3 
0 
Escalate** 
 
3 
≥ 2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
 
4 
0 
4 
0 
Escalate** 
 
4 
≥ 2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 
 
5 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Same dose level 
 
5 
0 
5 
0 
Escalate** 
 
5 
≥ 2 
0, 1, 2 or 3 
0, 1, 2 or 3 
De-escalate* 
 
 
 
 
 
 
 
6 
0 
0, 1, 2, 3, or 4 
2, 3, 4, 5 or 6 
Suspend 
 
6 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Suspend 
 
6 
0 or 1 
5 or 6 
0 or 1 
Escalate** 
 
6 
≥ 2 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
De-escalate* 
* If six patients already entered at next lower dose level, the MTD has been defined. 
**If final dose level has been reached, the recommended dose has been reached. 
 
 
If two or more of a cohort of up to six patients experience DLT at a given dose level, then 
the MTD has been exceeded and dose escalation will be stopped. 
 
Since this agent is not expected to be associated with dose-limiting myelosuppression, at least 
2 of every cohort of 3 or 5 of every cohort of 6 patients must be evaluable for hematologic 
toxicity. If hematologic dose limiting toxicity is observed, all subsequent patients who are 
enrolled in Part A1 must be evaluable for hematologic toxicity. Patients in Part A2 or A3 
may be enrolled irrespective of whether or not they have bone marrow involvement. 
 
In addition to determination of the MTD, a descriptive summary of all toxicities will be 
reported. 
 
Results of pharmacokinetic testing will also be reported, including clearance, Cmax, Tmax, Css, 
and terminal half-life. Single-dose AUC, trough estimation, and estimate a t½ of 
accumulation will be obtained.  
 
While the primary aim of this study is to evaluate the toxicity of PF-02341066, patients will 
have disease evaluations performed as indicated in Section 8.1.  Disease response will be 
assessed according to RECIST criteria for patients with solid tumors, and will be reported 
descriptively.   
 
 


 
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11.4 
Phase 2 Evaluation in ALK+ Neuroblastoma (Part B) and ALK+ ALCL (Part C) 
 
11.4.1 Study Design 
 
The best response of disease to PF-02341066 will be examined separately in each of 
these two parts. In Parts B and C, the following Simon’s optimal two stage design20 
will be used. 
 
 
Cumulative Number 
of Responses 
Decision 
Stage 1: Enter 10 patients 
0 
Terminate the trial: agent ineffective 
1 or more 
Inconclusive result, continue 
trial(proceed to stage 2) 
 
Stage 2: Enter 10 additional 
patients 
2 or less      
Terminate the trial: agent ineffective 
3 or more 
Terminate the trial: agent effective 
 
PF-02341066 will not be considered of sufficient interest for further evaluation in a 
disease category if the true response rate is 5% and of sufficient activity if the true 
response rate is 25%. If PF-02341066 has a true response rate of 5%, the rule 
described above will identify it of sufficient activity for further study with probability 
0.07 (type I error), and the trial will have an expected sample size of 14 with 60% 
probability of early termination.  If PF-02341066 has a true response rate of 25%, 
the rule described above will identify it of sufficient activity for further study with 
probability 0.88 (power against the alternative hypothesis P = 0.25). 
 
Once the trial has terminated in Part B, enrollment onto Part C will be evaluated for 
closure.   
 
Response in all patients with solid tumors will be determined according to RECIST 
as defined in the protocol as either complete response (CR), partial response (PR), 
stable disease (SD) or progressive disease (PD), or as described in Section 12.0 for 
other categories of responses assessment, and reported as final results.  A report on 
the efficacy assessment will be posted on the completed disease stratum as part of 
the semi-annual study committee meeting book report. 
 
It is anticipated that a multi-strata Phase 2 study will open group wide upon 
completion of stage 1 enrollment in Part B.  Data collected from any patients enrolled 
at the MTD or recommended phase 2 dose or enrolled onto Parts B or C will be 
utilized in the Phase 2 study. 
 
11.4.2 Method of Analysis 
Response criteria are described in Section 12.0. Response rates will be calculated as 
the percent of patients whose best response is a CR or PR and confidence intervals 
will be constructed according to the method of Chang.21 A responder is defined as a 
patient who achieves a best confirmed response (as defined in Section 12.8) of PR 
or CR on the study.  
 
 
 


 
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11.5 
Inclusion of Children, Women and Minorities 
The study is open to all participants regardless of gender or ethnicity.  Review of accrual to 
past COG studies of new agents demonstrates the accrual of both genders and all NIH-
identified ethnicities to such studies.  Efforts will be made to extend the accrual to a 
representative population, but in a Phase I/II trial which will accrue a limited number of 
patients in the Phase I portion, a balance must be struck between patient safety considerations 
and limitations on the number of individuals exposed to potentially toxic or ineffective 
treatments on the one hand and the need to explore gender, racial, and ethnic aspects of 
clinical research on the other. If differences in outcome that correlate to gender, racial, or 
ethnic identity are noted, accrual may be expanded or additional studies may be performed 
to investigate those differences more fully. 
 
11.6 
Pharmacokinetic and Correlative Studies 
A descriptive analysis of pharmacokinetic (PK) parameters of PF-02341066 will be 
performed to define systemic exposure, drug clearance, and other pharmacokinetic 
parameters. The PK parameters will be summarized with simple summary statistics, 
including means, medians, ranges, and standard deviations (if numbers and distribution 
permit).   
 
Due to small patient numbers, the correlative studies are expected to be descriptive and 
exploratory in nature.  The results of these studies are expected to generate hypotheses for 
testing in future studies.   
 
Pharmacogenomic data, ALK status, and MRD status will be reported descriptively.  Where 
possible, we will attempt to preliminarily assess correlation between ALK status and 
response to PF-02341066, and MRD status and response to PF-02341066.  
 
 
 
 
12.0  
EVALUATION CRITERIA 
 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting beginning October 
1, 2011.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov). 
 
12.2 
Response Criteria  
As outlined, patients will be assigned to one of the following categories for assessment of 
response:  a) solid tumor and measurable disease (Section 12.3); b) solid tumor and evaluable 
disease (Section 12.4); c) neuroblastoma with MIBG positive lesions (Section 12.5); d) 
neuroblastoma with bone marrow involvement (Section 12.6); or e) ALCL (Section 12.7).  
Note:  Neuroblastoma patients who do not have MIBG positive lesions or bone marrow 
involvement should be assessed for response as solid tumor patients with measurable or 
evaluable disease.  
 
 


 
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12.3 
Response Criteria for Patients with Solid Tumors and Measurable Disease 
This study will use a minor modification of the (RECIST) Response Evaluation Criteria in 
Solid Tumors from the NCI for assessment of radiographic response. 
 
12.3.1 Measurable Disease 
The presence of at least one lesion that can be accurately measured in at least one 
dimension with the longest diameter at least 10 mm. The investigator will identify 
up to 10 measurable lesions to be followed for response. Previously irradiated lesions 
that have not demonstrated clear progression post radiation do not qualify as being 
measurable or evaluable. 
 
Serial measurements of lesions are to be done with appropriate imaging modalities.  
Bone scans or MIBG scans cannot be used to measure lesions (see Section 12.5 for 
response criteria for MIBG).  The same method of assessment is to be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
 
12.3.2 Quantification of Disease Burden 
The sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the disease measurement. 
 
12.3.3 End-of-Cycle Response 
 
a) 
Complete Response (CR) 
Disappearance of all target and non-target lesions.  If immunocytology is 
available, no disease must be detected by that methodology. 
 
b) 
Partial Response (PR) 
At least a 30% decrease in the disease measurement, taking as reference the 
disease measurement done to confirm measurable disease at study enrollment. 
 
c) 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest disease measurement since the 
treatment started. 
 
d) 
Progressive Disease (PD) 
At least a 20% increase in the disease measurement, taking as reference the 
smallest disease measurement recorded since the start of treatment, or the 
appearance of one or more new lesions, or evidence of laboratory or clinical 
progression. 
 
12.3.4 Overall Best Response Assessment 
Each patient will be classified according to their “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
objective statutes described in Section 12.8.  
 
 


 
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12.4 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
 
12.4.1 Evaluable Disease 
The presence of at least one lesion that cannot be accurately measured in at least one 
dimension.  Such lesions may be evaluable by nuclear medicine techniques, 
immunocytochemistry techniques, tumor markers or other reliable measures.  
 
12.4.2 Complete Response (CR) 
Disappearance of all evaluable disease. 
 
12.4.3 Partial response 
Partial responses cannot be determined in patients with evaluable disease.  
 
 
 
12.4.4 Stable Disease (SD) 
That which does not qualify as Complete Response (CR), Partial Response (PR), or 
Progressive Disease. 
 
12.4.5 Progressive Disease (PD) 
The appearance of one or more new lesions or evidence of laboratory, clinical, or 
radiographic progression. 
 
12.4.6 Overall Best Response Assessment 
Each patient will be classified according to their “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
objective statutes described in Section 12.8. 
 
 
12.5  
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
 
12.5.1  MIBG Positive Lesions 
Patients who have a positive MIBG scan at the start of therapy will be evaluable for 
MIBG response. The use of 123I for MIBG imaging is recommended for all scans. If 
the patient has only one MIBG positive lesion and that lesion was radiated, a biopsy 
must be done at least 4 weeks after radiation was completed and must show viable 
neuroblastoma. 
 
 
 
12.5.2  The following criteria will be used to report MIBG response by the treating 
institution: 
 
 
 
Complete response (CR) 
 
Complete resolution of all MIBG positive lesions 
 
Partial Response (PR) 
Resolution of at least one MIBG positive lesion, with persistence of other MIBG 
positive lesions 
 
 
Stable disease (SD) 
 
No change in MIBG scan in number of positive lesions 
 
 
 
Progressive disease (PD) 
 
Development of new MIBG positive lesions 
 
 


 
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12.5.3 The response of MIBG lesions will be assessed on central review using the Curie 
scale as outlined below. Central review responses will be used to assess efficacy for 
study endpoint. See Section 8.4 for details on transferring images to the Imaging 
Research Center. 
 
NOTE: This scoring should also be done by the treating institution for end of course 
response assessments. 
 
The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th 
general sector allocated for any extra-osseous lesion visible on MIBG scan. In each 
region, the lesions are scored as follows. The absolute extension score is graded as:  
0 = no site per segment,  
1 = 1 site per segment,  
2 = more than one site per segment,  
3 = massive involvement (>50% of the segment).  
 
The absolute score is obtained by adding the score of all the segments. See diagram 
of sectors below: 
 
 
The relative score is calculated by dividing the absolute score at each time point by 
the corresponding pre-treatment absolute score. The relative score of each patient is 
calculated at each response assessment compared to baseline and classified as below: 
1. Complete response: all areas of uptake on MIBG scan completely resolved. If 
morphological evidence of tumor cells in bone marrow biopsy or aspiration is 
present at enrollment, no tumor cells can be detected by routine morphology on 
two subsequent bilateral bone marrow aspirates and biopsies done at least 3 weeks 
apart to be considered a Complete Response. 


 
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2. Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 
(lesions strongly reduced). 
3. Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) 
to 1.0 (lesions not reduced). 
4. Progressive disease: New lesions on MIBG scan. 
 
12.5.4 Overall Best Response Assessment 
Each patient will be classified according to their “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
objective statutes described in Table 3 in Section 12.8. 
 
 
12.6 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
12.6.1 Bone Marrow Involvement 
Bone marrow obtained within 2 weeks prior to study enrollment with tumor cells 
seen on routine morphology (not by NSE staining only) of bilateral aspirate or biopsy 
on at least one of the bone marrow samples. 
 
Bone Marrow responses determined by H&E Staining of bilateral bone marrow 
biopsies and aspirates are defined as follows: 
 
• 
Complete Response (CR) 
No tumor cells detectable by routine morphology on 2 consecutive bilateral bone 
marrow aspirates and biopsies performed at least 4 weeks (± 5 days) apart.  
 
• 
Progressive Disease (PD) 
o In patients who enroll with neuroblastoma in bone marrow by morphology 
have progressive disease if there is a doubling in the amount of tumor in the 
marrow AND a minimum of 25% tumor in bone marrow by morphology. 
(For example, a patient entering with 5% tumor in marrow by morphology 
must increase to ≥ 25% tumor to have progressive disease; a patient entering 
with 30% tumor must increase to > 60%). 
o In patients who enroll without evidence of neuroblastoma in bone marrow 
will be defined as progressive disease if tumor is detected in 2 consecutive 
bone marrow biopsies or aspirations done at least 4 weeks (± 5 days) apart. 
 
• 
Stable Disease 
Persistence of tumor in bone marrow that does not meet the criteria for either 
complete response or progressive disease. 
 
 
 


 
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12.7 
Response Criteria for Patients with ALCL 
 
12.7.1 Complete Response 
Disappearance of all evidence of disease from all sites for at least 4 weeks. This will 
be determined by PE and imaging. Bone marrow aspirate/biopsy must be normal and 
any macroscopic nodules in any organs detectable on imaging techniques should no 
longer be present. PET scans must be negative if initially positive. 
 
12.7.2 Complete Response Unconfirmed 
A residual lymph node mass > 1.5 cm in greatest transverse diameter that has 
regressed by >75% in sum of the products of the greatest perpendicular diameters 
(SPD), or any residual lesions in organs that have decreased by >75% and with a 
negative PET scan and SUV <3. Patients with only residual positive bone lesions on 
PET scans will be considered in CRu. Patients with bone involvement may have 
positive lesions on PET scans for some time; therefore, these patients will be 
considered in CRu if the other residual lesions have disappeared, or of the residual 
lymph node mass or masses >1.5 cm in greatest transverse diameter have regressed 
by >75% in sum of the products of the greatest perpendicular diameters (SPD).  
 
12.7.3 Partial Response 
≥50% decrease in the SPD of the lesions. No new lesions. 
 
12.7.4 No Response (Stable Disease) 
Failure to qualify for a PR. No new lesions. 
 
12.7.5 Progressive disease 
≥25% increase in the size of any lesions or appearance of new lesions. 
 
 
12.8 
Best Response 
Two objective status determinations of disease status, by CT or MRI, obtained on two 
consecutive determinations, separated by at least a 3 week time period, are required to 
determine the patient’s overall best response.  Two objective status determinations of CR 
before progression are required for best response of CR.  Two determinations of PR or better 
before progression, but not qualifying for a CR, are required for a best response of PR.  Two 
determinations of stable/no response or better before progression, but not qualifying as CR 
or PR, are required for a best response of stable/no response; if the first objective status is 
unknown, only one such determination is required.  Patients with an objective status of 
progression on or before the second evaluations (the first evaluation is the first radiographic 
evaluation after treatment has been administered) will have a best response of progressive 
disease.  Best response is unknown if the patient does not qualify for a best response of 
progressive disease and if all objective statuses after the first determination and before 
progression are unknown. 
 


 
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Table 1.  Sequences of objective statuses with corresponding best response. 
1st Status 
2nd Status 
3rd Status 
Best Response 
Progression 
 
 
Progressive disease 
Stable, PR, CR 
Progression 
 
Progressive disease 
Unknown 
Progression 
 
Progressive disease 
Stable 
Stable 
Progression 
Stable 
Stable, Unknown 
PR, CR 
Progression 
Stable 
Stable, Unknown 
Unknown 
Progression 
Unknown 
PR 
PR 
Progression 
PR 
PR 
CR 
Progression 
PR 
PR, CR 
Unknown 
Progression 
Unknown 
CR 
CR 
Progression 
CR 
Unknown 
Stable 
Progression 
Stable 
 
Table 2: Overall Response for Patients with Neuroblastoma and Measurable Disease 
CT/MRI 
MIBG 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
CR/PR/SD 
Non-PD 
Non-PD 
Any 
SD 
PR 
CR/PR 
Non-PD 
Non-PD 
Any 
PR 
CR/PR 
PR 
Non-PD 
Non-PD 
Any 
PR 
CR 
CR 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
CR 
CR 
CR 
Normal 
CR 
 
Table 3: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease Only 
For those patients in Part A or Part B that are enrolled without disease measurable by CT/MRI, any new or 
newly identified lesion by CT/MRI that occurs during therapy would be considered progressive disease. 
MIBG 
CT/MRI 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
New Lesion 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
No New Lesion 
Non-PD 
Non-PD 
Any 
SD 
PR 
No New Lesion 
Non-PD 
Non-PD 
Any 
PR 
CR 
No New Lesion 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
 
 
 


 
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13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event data collection and reporting which are required as part of every clinical trial, are done 
to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies 
using similar agents.  Adverse events are reported in a routine manner at scheduled times during a 
trial.  (Please follow directions for routine reporting provided in the data collection packet for this 
protocol).  Additionally, certain adverse events must be reported in an expedited manner to allow for 
optimal monitoring of patient safety and care.  The following sections provide information about 
expedited reporting. 
 
Reporting requirements may include the following considerations: 1) whether the patient has received 
an investigational or commercial agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the prior experience (expectedness) 
of the adverse event; and 3) whether or not hospitalization or prolongation of hospitalization was 
associated with the event. 
 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND).  In some instances, the investigational agent may be available commercially, but 
is actually being tested for indications not included in the approved package label. 
 
Commercial agents are those agents not provided under an IND but obtained instead from a 
commercial source.  The NCI, rather than a commercial distributor, may on some occasions distribute 
commercial agents for a trial. 
 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
 
Step 1: Identify the type of adverse event using the NCI CTCAE version 4.0. The 
descriptions and grading scales found in the revised CTCAE version 4.0 will be used 
for AE reporting beginning October 1, 2011. All appropriate treatment locations 
should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP website (http://ctep.cancer.gov). 
 
Step 2:  Grade the adverse event using the NCI CTCAE. 
 
Step 3:  Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
Unrelated, Unlikely, Possible, Probable, and Definite. 
Note:  This includes all events that occur within 30 days of the last dose of protocol 
treatment.  Any event that occurs more than 30 days after the last dose of treatment 
and is attributed (possibly, probably, or definitely) to the agent(s) must also be 
reported according to the instructions above. 
 
Step 4:  Determine the prior experience of the adverse event.  Expected events are those that 
have been previously identified as resulting from administration of the agent.  An 
adverse event is considered unexpected, for expedited reporting purposes only, 
when either the type of event or the severity of the event is not listed in bold font 
in the table of toxicities listed in the drug information section (Section 9.1.9) of 
the protocol. 
 
Step 5:  Review Table A in this section to determine if: 
• there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• there are any protocol-specific exceptions to the reporting requirements. 
 


 
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Table A: Phase 1 Trials Utilizing an Agent under a CTEP IND or Non-CTEP IND:  CTEP-AERS 
Expedited Reporting Requirements for Adverse Events That Occur Within 30 Days1 of the Last Dose 
of the Investigational Agent 
 
 
 
Grade 1 
 
Grade 23 
 
Grade 2 
 
Grade 33 
 
Grade 33 
Grades 
4 & 52, 3 
Unexpected 
and 
Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected 
and 
Expected 
with 
Hospitali-
zation 
without 
Hospitali- 
zation 
with 
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
5 Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
24-Hour; 
5 
Calendar 
Days 
5 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the 
last dose of treatment with an agent under a CTEP IND or non-CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification (via CTEP-AERS for CTEP IND agents; via e-mail to COG AE Coordinator for 
agents in non-CTEP IND studies) followed by complete report within 5 calendar days for: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• Grade 4 unexpected events  
• Grade 5 expected events and unexpected events 
 
2 Although a CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full 
report is required as outlined in the table. 
 
3    Please see exceptions below under section entitled “Additional Instructions or Exceptions.” 
March 2005 
 
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  Attribution 
to treatment or other cause should be provided. 
 
• 
Expedited AE reporting timelines defined: 
 “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-AERS (via 
e-mail to COG AE Coordinator for agents in non-CTEP IND studies) within 24 hours of learning 
of the event followed by a complete CTEP-AERS report within 5 calendar days of the initial 24-
hour report. 
 “5 calendar days” - A complete CTEP-AERS report on the AE must be submitted within 5 
calendar days of the investigator learning of the event.  
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and designation 
as expected or unexpected with the exception of any events identified as protocol-specific expedited 
adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or 
birth defects must be reported via CTEP-AERS if the event occurs following treatment with an agent 
under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial registration 
on all reports. 
 


 
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Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for Phase 1 Trials 
Utilizing an Agent under a CTEP-IND or Non-CTEP IND: 
 
• Any death that occurs more than 30 days after the last dose of treatment with an investigational agent 
which can be attributed (possibly, probably, or definitely) to the agent and is not due to cancer 
recurrence/progression must be reported via CTEP-AERS for an agent under a CTEP or non-CTEP 
IND agent per the timelines outlined in the table above. 
 
• Myelosuppression, including Grade 4 lymphopenia, does not require expedited reporting whether it 
is expected or unexpected, unless it is associated with hospitalization. 
 
As referenced in the CTEP Adverse Event Reporting Requirements, an AE that resolves and then recurs 
during a subsequent cycle does not require CTEP-AERS reporting unless (1) the Grade increases; or (2) 
hospitalization is associated with the recurring AE. 
 
13.2 
When to Report an Event in an Expedited Manner 
 
• 
Some adverse events require notification within 24 hours (refer to Table A) to NCI via 
the web at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/CTEP-AERS.htm  
(Telephone the COG AE Coordinator at: 626-241-1545 within 24 hours of becoming aware 
of the event if the CTEP-AERS 24-Hour Notification web-based application is unavailable) 
and by telephone call to the Study Chair. Once internet connectivity is restored, a 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original 
submitter at the site. 
 
• 
When the adverse event requires expedited reporting, submit the report within 5 
calendar days of learning of the event. 
 
 
13.3 
Expedited Reporting Methods 
 
13.3.1 CTEP-AERS Reporting 
To report adverse events in an expedited fashion use the NCI’s Adverse Event 
Expedited 
Reporting 
System 
(CTEP-AERS) 
that 
can 
be 
found 
at 
http://ctep.cancer.gov. 
 
An CTEP-AERS report must be submitted electronically via the CTEP-AERS 
Web-based application located at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_event
s.htm.  If prompted to enter a sponsor e-mail address, please type in: 
COGCAdEERS@childrensoncologygroup.org. 
 
Fax supporting documentation to COG (fax # 626-241-1795; attention: COG AE 
Coordinator).  ALWAYS include the ticket number on all faxed documents. 
 
13.4 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG data submission 
forms and do not alter the guidelines for CTEP-AERS reporting. 
 
13.4.1 If an adverse event occurs more than once in a cycle of therapy only the most severe 


 
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grade of the event should be reported. 
 
13.4.2 If an adverse event progresses through several grades during one cycle of therapy, 
only the most severe grade should be reported. 
 
13.4.3 The duration of the AE is defined as the duration of the highest (most severe) grade 
of the Adverse Effects.  
 
13.4.4 The resolution date of the AE is defined as the date at which the AE returns to 
eligibility criteria level or ≤ Grade 1 level, whichever level is greater (note that the 
resolution date may therefore be different from the date at which the grade of the AE 
decreased from its highest grade).  If the AE does not return to baseline the resolution 
date should be recorded as "ongoing."   
 
13.4.5 An adverse event that persists from one cycle to another should only be reported 
once unless the grade becomes more severe in a subsequent cycle. An adverse event 
which resolves and then recurs during a different cycle, must be reported each cycle 
it recurs.  
 
13.5 
Other Recipients of Adverse Event Reports 
 
13.5.1 Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) should 
be reported at the end of each cycle using the forms provided in the data form packet 
(See Section 14.1). 
 
13.5.2 COG will forward reports and supporting documentation to the Study Chair, to the 
FDA (when COG holds the IND) and to the pharmaceutical company (for industry 
sponsored trials). 
 
13.5.3 Adverse events determined to be reportable must also be reported according to the 
local policy and procedures to the Institutional Review Board responsible for 
oversight of the patient. 
 
13.6 
Reporting Secondary AML/MDS 
All cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that 
occur in patients on NCI-sponsored trials following their chemotherapy for cancer must be 
reported to the Investigational Drug Branch (IDB) of the NCI Cancer Therapy Evaluation 
Program (CTEP) and included as part of the second malignant neoplasm reporting 
requirements for this protocol (see data submission packet).  Submit the following 
information within two weeks of an AML/MDS diagnosis occurring after treatment for 
cancer on NCI-sponsored trials: 
 
• 
a completed CTEP-AERS report; 
• 
Non-treatment related cases of AML/MDS for CTCAE v4.0 should be reported 
using “Neoplasms benign, malignant and unspecified (incl cysts and polyps) - 
Other, specify.” 
• 
To grade a non life-threatening event for “Myelodysplastic syndrome”, use 
“Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, 
specify” where the specified term is MDS. 
 
Note:  If a patient has been enrolled in more than one NCI-sponsored study, the 


 
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ADVL0912   
 
 
 
07/27/17 
CTEP-AERS report must be submitted for the most recent trial. 
 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
14.1 
Categories of Research Records 
Research records for this study can be divided into three categories: 
 
1. 
Non-computerized Information:  Roadmaps, Pathology Reports, Surgical Reports 
and Patient Taste Questionnaire. These forms are faxed, with the corresponding 
shuttle sheet, to the Statistics & Data Center at (626) 447-2204. 
 
2. 
Reference Labs, Biopathology Reviews, and QARC data:  These data accompany 
submissions to these centers, which forward their data electronically to the COG 
Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other data will be entered 
in the COG Remote Data Entry System with the aid of schedules and worksheets 
(essentially paper copies of the RDE screens) provided in the data form packet. 
 
See separate Data Form Packet, which includes submission schedule. 
 
14.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are 
due January 31, April 30, July 31 and October 31.  This is not a responsibility of institutions 
participating in this trial. 
 
14.3 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
14.3.1 Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG Data and Safety Monitoring Committee is to protect the interests of patients 
and the scientific integrity for all Phase 1 and 2 studies. The DSMC consists of a 
chair; a statistician external to COG; one external member; one consumer 
representative; the lead statistician of the developmental therapy scientific 
committee; and a member from the NCI. The DSMC meets at least every 6 months 
to review current study results, as well as data available to the DSMC from other 
related studies. Approximately 6 weeks before each meeting of the Phase 1 and 2 
DSMC, study chairs will be responsible for working with the study statistician to 
prepare study reports for review by the DSMC. The DSMC will provide 
recommendations to the COG Developmental Therapeutics Chair and the Group 
Chair for each study reviewed to change the study or to continue the study 
unchanged. Data and Safety Committee reports for institutional review boards can 
be prepared using the public data monitoring report as posted on the COG Web site. 
 
14.3.2 Monitoring by the Study Chair and Developmental Therapeutics Leadership 
The study chair will monitor the study regularly and enter evaluations of patients’ 
eligibility, evaluability, and dose limiting toxicities into the study database. In 
addition, study data and the study chair’s evaluations will be reviewed by the 
Developmental Therapeutics Chair, Vice Chair and Statistician on a weekly 
conference call. 


 
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APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
Karnofsky 
Lansky 
Score 
Description 
Score Description 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on normal 
activity or do active work. 
70 
Both greater restriction of and less time spent 
in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of the day; 
no active play, able to participate in all quiet 
play and activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet activities. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to very 
passive activities. 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed. 
 
 


 
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APPENDIX II: COMMON SUBSTRATES, INHIBITORS AND INDUCERS OF CYP3A4 
 
The following lists describe medications which are common CYP3A4 substrates, inhibitors and inducers.  
This list should not be considered all inclusive; please refer to other resources such as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx for additional information.  Consult individual drug 
labels for specific information on metabolism by CYP3A4. Note: The topical use of these medications (if 
applicable), e.g. 2% ketoconazole cream, is allowed. 
 
Substrates 
Macrolide Antibiotics 
clarithromycin 
erythromycin 
NOT azithromycin 
 
Anti-arrhythmics 
quinidine 
 
Benzodiazepines 
alprazolam 
diazepam 
midazolam 
triazolam 
 
Immune Modulators 
cyclosporine 
tacrolimus (FK506) 
sirolimus 
 
HIV Antivirals 
indinavir 
nelfinavir 
ritonavir 
saquinavir 
 
Antihistamines 
astemizole 
chlorpheniramine 
terfenidine 
 
Calcium Channel Blockers 
amlodipine 
diltiazem 
felodipine 
lercanidipine 
nifedipine 
nisoldipine 
nitrendipine 
verapamil 
HMG CoA Reductase Inhibitors 
atorvastatin 
cerivastatin 
lovastatin 
NOT pravastatin 
simvastatin 
 
Steroid 6beta-OH 
estradiol 
hydrocortisone 
progesterone 
testosterone 
 
Other 
alfentanyl 
buspirone 
cafergot 
caffeine=>TMU 
cocaine 
dapsone 
codeine-N-demethyl 
dextromethorphan 
eplerenone 
fentanyl 
finasteride 
imatinib 
lidocaine 
methadone 
ondansetron 
pimozide 
propranolol 
quinine 
salmetrerol 
sildenafil 
tamoxifen 
paclitaxel 
trazodone 
vincristine 


 
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haloperidol (in part) 
irinotecan 
zaleplon 
zolpidem 
Inhibitors 
HIV Antivirals 
delaviridine 
indinavir 
nelfinavir 
ritonavir 
saquinavir 
 
Other 
amiodarone NOT azithromycin 
cimetidine 
ciprofloxacin 
clarithromycin 
diethyl-dithiocarbamate 
diltiazem 
erythromycin 
fluconazole 
fluvoxamine 
gestodene 
grapefruit juice 
itraconazole 
ketoconazole 
mifepristone 
nefazodone 
norfloxacin 
norfluoxetine 
mibefradil 
verapamil 
voriconazole 
Inducers 
HIV Antivirals 
efavirenz 
nevirapine 
 
Other 
barbiturates 
carbamazepine 
glucocorticoids 
modafinil 
phenobarbital 
phenytoin 
rifampin 
St. John’s wort 
troglitazone 
pioglitazone 
rifabutin 
 


 
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APPENDIX IIIA: PF-02341066 DOSING TABLES 
(FOR PATIENTS RECEIVING THE POWDER IN CAPSULE (PIC) FORMULATION) 
 
Note: Patients enrolled on Phase 1 portion of the study that are receiving the Powder in Capsule (PIC) 
formulation must continue to follow the dosing nomograms below. For patients using the pediatric Oral 
Solution (OS), refer to Appendix IV. 
 
 
PF-02341066 Dose Assignment: 100 mg/m2/dose BID (DOSE LEVEL 1) 
 
PF-02341066 
(mg/day) 
PF-02341066 
(mg PO BID) 
BSA (m2) 
Total Daily Dose 
mg q am 
mg q hs 
0.40-0.43 
80 
40 
40 
0.44-0.55 
100 
50 
50 
0.56-0.65 
120 
60 
60 
0.66-0.75 
140 
70 
70 
0.76-0.85 
160 
80 
80 
0.86-0.94 
180 
90 
90 
0.95-1.06 
200 
100 
100 
1.07-1.16 
220 
110 
110 
1.17-1.26 
240 
120 
120 
1.27-1.36 
260 
130 
130 
1.37-1.44 
280 
140 
140 
1.45-1.56 
300 
150 
150 
1.57-1.66 
320 
160 
160 
1.67-1.76 
340 
170 
170 
1.77-1.87 
360 
180 
180 
≥ 1.88 
400 
200 
200 
 
 


 
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PF-02341066 Dose Assignment: 130 mg/m2/dose BID (DOSE LEVEL 2) 
 
PF-02341066 
(mg/day) 
PF-02341066 
(mg PO BID) 
BSA (m2) 
Total Daily Dose 
mg q am 
mg q hs 
0.30-0.33 
80 
40 
40 
0.34-0.42 
100 
50 
50 
0.43-0.50 
120 
60 
60 
0.51-0.58 
140 
70 
70 
0.59-0.66 
160 
80 
80 
0.67-0.72 
180 
90 
90 
0.73-0.81 
200 
100 
100 
0.82-0.89 
220 
110 
110 
0.90-0.97 
240 
120 
120 
0.98-1.04 
260 
130 
130 
1.05-1.10 
280 
140 
140 
1.11-1.20 
300 
150 
150 
1.21-1.28 
320 
160 
160 
1.29-1.35 
340 
170 
170 
1.36-1.44 
360 
180 
180 
1.45-1.58 
400 
200 
200 
1.59-1.67 
420 
210 
210 
1.68-1.74 
440 
220 
220 
1.75-1.83 
460 
230 
230 
1.84-1.97 
500 
250 
250 
≥ 1.98 
520 
260 
260 
 
 


 
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PF-02341066 Dose Assignment: 165 mg/m2/dose BID (DOSE LEVEL 3) 
 
PF-02341066 
(mg/day) 
PF-02341066 
(mg PO BID) 
BSA (m2) 
Total Daily Dose 
mg q am 
mg q hs 
0.30-0.33 
100 
50 
50 
0.34-0.39 
120 
60 
60 
0.40-0.46 
140 
70 
70 
0.47-0.52 
160 
80 
80 
0.53-0.56 
180 
90 
90 
0.57-0.64 
200 
100 
100 
0.65-0.70 
220 
110 
110 
0.71-0.76 
240 
120 
120 
0.77-0.82 
260 
130 
130 
0.83-0.87 
280 
140 
140 
0.88-0.95 
300 
150 
150 
0.96-1.00 
320 
160 
160 
1.01-1.06 
340 
170 
170 
1.07-1.13 
360 
180 
180 
1.14-1.25 
400 
200 
200 
1.26-1.31 
420 
210 
210 
1.32-1.37 
440 
220 
220 
1.38-1.45 
460 
230 
230 
1.46-1.55 
500 
250 
250 
1.56-1.61 
520 
260 
260 
1.62-1.71 
540 
270 
270 
1.72-1.85 
600 
300 
300 
1.86-1.92 
620 
310 
310 
≥1.93 
640 
320 
320 
 
 


 
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PF-02341066 Dose Assignment: 215 mg/m2/dose BID (DOSE LEVEL 4) 
 
PF-02341066 
(mg/day) 
PF-02341066 
(mg PO BID) 
BSA (m2) 
Total Daily Dose 
mg q am 
mg q hs 
0.30-0.35 
140 
70 
70 
0.36-0.39 
160 
80 
80 
0.40-0.44 
180 
90 
90 
0.45-0.49 
200 
100 
100 
0.50-0.54 
220 
110 
110 
0.55-0.58 
240 
120 
120 
0.59-0.63 
260 
130 
130 
0.64-0.67 
280 
140 
140 
0.68-0.72 
300 
150 
150 
0.73-0.77 
320 
160 
160 
0.78-0.82 
340 
170 
170 
0.83-0.86 
360 
180 
180 
0.87-0.95 
400 
200 
200 
0.96-1.00 
420 
210 
210 
1.01-1.05 
440 
220 
220 
1.06-1.11 
460 
230 
230 
1.12-1.19 
500 
250 
250 
1.20-1.23 
520 
260 
260 
1.24-1.32 
540 
270 
270 
1.33-1.42 
600 
300 
300 
1.43-1.47 
620 
310 
310 
1.48-1.55 
640 
320 
320 
1.56-1.65 
700 
350 
350 
1.66-1.76 
720 
360 
360 
1.77-1.89 
800 
400 
400 
≥ 1.90 
820 
410 
410 
 
 
 
 


 
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PF-02341066 Dose Assignment: 280 mg/m2/dose BID (DOSE LEVEL 5) 
 
PF-02341066 
(mg/day) 
PF-02341066 
(mg PO BID) 
BSA (m2) 
Total Daily Dose 
mg q am 
mg q hs 
0.30-0.33 
180 
90 
90 
0.34-0.37 
200 
100 
100 
0.38-0.41 
220 
110 
110 
0.42-0.45 
240 
120 
120 
0.46-0.48 
260 
130 
130 
0.49-0.51 
280 
140 
140 
0.52-0.55 
300 
150 
150 
0.56-0.58 
320 
160 
160 
0.59-0.62 
340 
170 
170 
0.63-0.66 
360 
180 
180 
0.67-0.69 
380 
190 
190 
0.70-0.73 
400 
200 
200 
0.74-0.76 
420 
210 
210 
0.77-0.80 
440 
220 
220 
0.81-0.83 
460 
230 
230 
0.84-0.87 
480 
240 
240 
0.88-0.91 
500 
250 
250 
0.92-0.94 
520 
260 
260 
0.95-0.98 
540 
270 
270 
0.99-1.03 
560 
280 
280 
1.04-1.09 
600 
300 
300 
1.10-1.12 
620 
310 
310 
1.13-1.16 
640 
320 
320 
1.17-1.21 
660 
330 
330 
1.22-1.26 
700 
350 
350 
1.27-1.30 
720 
360 
360 
1.31-1.37 
740 
370 
370 
1.38-1.44 
800 
400 
400 
1.45-1.48 
820 
410 
410 
1.49-1.55 
840 
420 
420 
1.56-1.62 
900 
450 
450 
1.63-1.71 
920 
460 
460 
1.72-1.80 
1000 
500 
500 
1.81-1.89 
1020 
510 
510 
≥ 1.90 
1100 
550 
550 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX IIIB:  PF-02341066 DOSING TABLES 
(FOR PATIENTS RECEIVING THE FORMULATED CAPSULES) 
 
Note: The dosing tables in Appendix IIIB are for patients enrolled on Parts A2, B & C 
as of Amendment #6 who are receiving the Formulated Capsules (FC). For patients 
using the pediatric Oral Solution (OS), refer to Appendix IV. 
 
PF-02341066 Dose Assignment: 280 mg/m2/dose BID  
(DOSE LEVEL 5 and RECOMMENDED PHASE 2 DOSE) 
 
 
PF-02341066 
(mg/day) 
PF-02341066 
(mg PO BID) 
BSA (m2) 
Total Daily Dose 
mg q am 
mg q hs 
0.63-0.80 
400 
200 
200 
0.81-0.98 
500 
250 
250 
0.99-1.16 
600 
300 
300 
1.17-1.33 
700 
350 
350 
1.34-1.51 
800 
400 
400 
1.52-1.69 
900 
450 
450 
1.70-1.87 
1000 
500 
500 
1.88-≥ 2.0 
1100 
550 
550 
 
For 1st dose reduction due to toxicity 
 
PF-02341066 
(mg/day) 
PF-02341066 
(mg PO BID) 
BSA (m2) 
Total Daily Dose 
mg q am 
mg q hs 
0.63-0.80 
300 
150 
150 
0.81-0.98 
350 
200 
150 
0.99-1.16 
400 
200 
200 
1.17-1.33 
500 
250 
250 
1.34-1.51 
600 
300 
300 
1.52-1.69 
650 
350 
300 
1.70-1.87 
700 
350 
350 
1.88-≥ 2.0 
800 
400 
400 
 
For 2nd dose reduction due to toxicity 
 
PF-02341066 
(mg/day) 
PF-02341066 
(mg PO BID) 
BSA (m2) 
Total Daily Dose 
mg q am 
mg q hs 
0.63-0.80* 
* 
* 
* 
0.81-0.98* 
* 
* 
* 
0.99-1.16 
300 
150 
150 
1.17-1.33 
350 
200 
150 
1.34-1.51 
400 
200 
200 
1.52-1.69 
450 
250 
200 
1.70-1.87 
500 
250 
250 
1.88-≥ 2.0 
600 
300 
300 
 
*These patients will receive oral solution if 2nd dose reduction is required 


 
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APPENDIX IV: PF-02341066 PEDIATRIC ORAL SOLUTION CALCULATION 
 
 
To calculate dosing volumes for each patient based on BSA, the following formula should be used: 
 
Dosing Volume (mL) = Prescribed Dose (mg/m2) x BSA (m2) 
       25 (mg/mL) 
 
Calculated dosing volumes should be rounded up to the nearest 0.1 mL for the actual deliverable dose. 
 
Examples: 
• 
Patient BSA 0.75 m2, Dose Level 1 Dosing volume = 3.0 mL BID 
         
Dosing Volume (mL) = (100 mg/m2 x 0.75 m2) / (25 mg/mL) = 3 mL 
 
• 
Patient BSA 0.75 m2, Dose Level 3 Dosing volume = 5.0 mL BID 
               
Calculated Volume (mL) = (165 mg/m2 x 0.75 m2) / (25 mg/mL) = 4.95 mL 
Dosing Volume (mL) =  5 mL (rounded up to nearest 0.1 mL) 
 
 
 
Note: For patients receiving PF-02341066 PIC refer to Appendix IIIA and FC refer to Appendix IIIB. 
 
 
 
 


 
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APPENDIX V: PHARMACOKINETIC STUDY FORM 
 
COG Pt ID # _______________ 
ACC # _______________  
Please do not write patient names on this form or on samples. 
 
Cycle 1, Day 1 Date: |__/__|__/__|__/__|  
   Cycle 1, Date of Steady State Sampling: |__/__|__/__|__/__| 
 
Dose Level: _______mg/m2 
Dose Administered: ______mg/day 
Body Surface Area: ______m2 
 
 
For all patients on Parts A, B or C, plasma samples (2 mL) will be obtained prior to the first dose on Day 1 of Cycle 1 and 
at steady state, defined as being between days 15 and 28 of BID dosing in Cycle 1 at the following time points: pre-dose 
(12 h after the last dose), 1 hr, 2 hr, 4 hrs, and 6-8 hrs. Record the exact date and time each sample is drawn and the last PF-
02341066 dose is administered before the pharmacokinetic sample is drawn. Sample handling and processing instructions 
are described below and in Section 8.2.  
 
Blood 
Sample 
No. 
Time Point 
Cycle 1 
Scheduled Collection Time 
Date Dose 
Given 
Actual Date 
Sample 
Collected 
Actual Time 
Collected or  
Dose Given 
(24-hr clock) 
1 
Pre-Dose 
Prior to the first dose on Day 1 
 
 
|__|__| : |__|__| 
Last dose before Pre-Dose at Steady State Obtained 
 
 
|__|__| : |__|__| 
2 
Pre-Dose at 
Steady State 
12 h after the last dose recorded above 
 
 
|__|__| : |__|__| 
Steady State Dose Given 
 
 
|__|__| : |__|__| 
3 
Steady State  
1 hr. after 
 
 
|__|__| : |__|__| 
4 
Steady State  
2 hrs. after 
 
|__|__| : |__|__| 
5 
Steady State  
4 hrs. after 
 
|__|__| : |__|__| 
6 
Steady State  
6-8 hrs. after 
 
|__|__| : |__|__| 
 
 
Sample Processing Procedures   
1. Label the cryovial tube with the patient’s study registration number, the study I.D. (ADVL0912), and the date and time the 
sample was drawn; please label as “plasma”. Affix storage label to 2 mL cryovial (vertically). 
2. Draw 2 mL of blood into a 4-mL K2EDTA (lavender top) Vacutainer tube. Once collected, samples should be processed 
immediately and kept out of direct sunlight due to the light sensitive nature of PF-02341066. 
3. Mix the blood with the anticoagulant by gently inverting the tube 6 to 8 times.  
4. Place sample on wet ice. 
5. Centrifuge the blood samples at approximately 1700g for 10 minutes at 4oC to harvest the plasma.    
6. Remove the plasma by transfer pipette and transfer ~1 mL of plasma into the 2 mL pre-labeled cryovial. Cap the tubes tightly.   
7. Record the date and time of collection for each sample on this form.  A copy of this form must accompany the sample(s) at 
time of shipment. 
8. Place the cryovial containing the plasma inside the cryovial storage box provided and store the plasma at -20 to -70oC 
within 1 hour of collection until shipment. 
One copy of this Pharmacokinetic Study Form should be faxed to the study research coordinator with the corresponding shuttle 
sheet, to the Operations Center at (626) 447-2204. A second copy should be sent with the samples to Covance at the address listed 
in Appendix V-A.  See Appendix V-A for detailed guidelines for packaging and shipping PK samples to Covance.   
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form below: 
 
Signature: ______________________________________________                    Date:__________________________ 
 
 
(site personnel who collected samples) 


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THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
ADVL0912   
 
 
 
07/27/17 
APPENDIX VI: PHARMACOGENOMIC STUDY FORM 
 
COG Pt ID # _______________ 
ACC # _______________ 
Please do not write patient names on this form or on samples. 
 
Cycle 1, Day 1 Date: |__/__|__/__|__/__|  
Body Surface Area: |__|°|__|__| m2 
 
 
 
 
Dose Level: ________mg/m2 
 
Total Dose: _______mg/day 
 
• 
One peripheral blood sample (3 mL) will be obtained on Day 1 of Cycle 1 prior to the first dose of PF-
02341066 for genotyping the alleles of cytochrome P450 enzymes and drug transport proteins. 
• 
Record the exact time that the sample is drawn along with the exact time that the last dose is administered.  
 
 
Date 
Time 
Sample Obtained: 
|__/__|__/__|__/__| 
|___|___| : |___|___| 
Drug Administered: 
|__/__|__/__|__/__| 
|___|___| : |___|___| 
 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study I.D. (ADVL0912), and the date 
and time the sample was drawn; please label as “pharmacogenomic sample”. 
 
Sample Processing Procedures   
1. Draw 3 mL of blood into a 4-mL K2EDTA (lavender top) Vacutainer tube. 
2. Label the tube with the patient’s study registration number, the study I.D. (ADVL0912), and the date and 
time the sample was drawn. 
3. Gently mix the blood with the anticoagulant by gently inverting the tube (15 times). 
4. Record the date and time of collection for each sample on this form.  
5. After mixing the blood with the anticoagulant, place the blood collection tube inside the cryovial storage box 
provided and store the blood at -20°C. 
 
Data should be recorded on this Pharmacogenomic Study Form, which must accompany the sample(s) at the time 
of shipment. One copy of the Pharmacogenomic Study Form should be faxed to the study Research Coordinator 
with the corresponding shuttle sheet, to the Operations Center at (626) 447-2204. A second copy should be sent 
with the sample to the laboratory at Pfizer, Inc. at the address below.  
 
Sample Shipping 
1. Ship all accumulated samples on dry ice. Shipments should be sent Monday through Wednesday only for 
priority overnight delivery. Do not ship on Thursday or Friday.  
2. Genotype whole blood samples should be shipped to the address below. Please notify the laboratory of a 
pending shipment along with the FedEx tracking number by phone at (860) 686-3203 or by e-mail 
(PGxLab@pfizer.com). 
3. Ship samples to:  
 
 
 
CLIA PGx Lab 
Pfizer, Inc. 
Attn:  Cheryl Tow-Keogh / Linda Wood 
Building 118E, Room 261 
Eastern Point Rd 
Groton, CT 06355 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this 
form below: 
 
Signature: ______________________________________________                    Date:__________________________ 
 
 
(site personnel who collected samples) 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
ADVL0912   
 
 
 
07/27/17 
APPENDIX VII: NEUROBLASTOMA CORRELATIVE BIOLOGY STUDIES 
 
1. COMPREHENSIVE DNA RESEQUENCING OF ALK 
Tumor tissue will be requested for all research subjects. The optimal sample will be tumor at the time 
of study enrollment, but tumor tissue from diagnosis or at any other point during therapy prior to 
treatment with PF-02341066 will be accepted. This can be archived tissue (frozen or paraffin) from 
the institution or from the Biopathology Center (BPC) for those subjects enrolled on ANBL00B1. If 
a tumor block is not available, unstained slides may be shipped instead. DNA extraction and Sanger-
based re-sequencing of the 29 coding exons of ALK and 500bp of the promoter region will be 
performed at CHOP.  
 
2. DEFINE ALK ALLELIC STATUS 
We will define whole genome DNA copy number status as well as ALK allelic using the Illumina 
HH550K Single Nucleotide Polymorphism (SNP) array.6,22,23 The primary goal of this assay is to 
determine if the ALK and/or MYCN loci are amplified. For samples in which allelic gain or 
amplification exist in the context of a mutation, we will also design allele specific quantitative PCR 
probes to determine if the mutated allele is somatically gained. 
 
3. DEFINE ALK TRANSLOCATION STATUS*** 
We will perform FISH for ALK translocations using the LSI ALK Dual Color, Break Apart 
Rearrangement probe (Abbott-Vysis) either on touch preps or paraffin-embedded tumor from all 
available neuroblastoma primary tumors gather for experiments #1 and #2 above. 
***These studies will only be pursued if ongoing investigations show that ALK translocations are a 
significant mechanism for ALK activation in neuroblastoma. 
 
4. DETERMINE THE MALIGNANT TRANSFORMING PROPERTIES OF ALL ALK 
MUTATIONS IDENTIFIED 
To determine the functional consequences of various candidate ALK mutations, we will engineer 
mutant full-length ALK cDNAs using site-directed mutagenesis. We will then over-express these 
constructs in a mammalian neural-crest derived cell line and assay for malignant transformation. We 
will use a lentiviral system for stable integration of alk constructs into retinal pigment epithelial cells 
that express telomerase (RPE1-hTERT) and look for evidence of malignant transformation.24 We will 
then screen for transformation in vitro using standard assays. 
 
5. DETERMINE THE BIOCHEMICAL CONSEQUENCES OF ALK ACTIVATION BY 
SURVEYING DOWNSTREAM SIGNALING PATHWAYS IN ALK-MUTANT SAMPLES 
We will determine which of the major canonical signaling pathways are activated as a consequence 
of mutant ALK. Specifically, we will assess native and phosphorylated ALK, STAT3, AKT, ERK, 
and SHP2 expression on all available tumor tissue from patients enrolled on this trial. We will 
compare the signaling properties of the various mutations and look for differential signaling patterns 
that may predict increased sensitivity to growth inhibition by ALK inhibition. 
 
6. EXPLORE POTENTIAL MECHANISMS OF RESISTANCE TO PF-02341066 AT TIME OF 
DISEASE PROGRESSION ON THIS STUDY  
We will collect bone marrow samples before and during treatment with PF-02341066, flow-sort for 
tumor cells, and establish cell lines in culture. These cell line models will then be used for direct re-
sequencing of ALK as well as for in vitro and in vivo cytotoxicity assays to explore mechanisms of 
potential acquired drug resistance.  


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
ADVL0912   
 
 
 
07/27/17 
APPENDIX VIII:BONE MARROW STUDIES FORM 
 
 
 
(FOR PATIENTS WITH NEUROBLASTOMA ONLY) 
 
Patient ID #: 
 
 
Study ID: ADVL0912 
BSA (m2): 
 
Dose level (mg/m2):  
Accession #:   
Actual Dose:  
 
Time dose taken:  
Date:  
Please do not write patient names on this form or on samples. 
 
• 
In patients with neuroblastoma, a bone marrow aspirate will be obtained (5 mL sample).  In children 
weighing ≤ 10 kg, this sample can be 3-5 mL. 
• 
These samples will be obtained prior to starting Cycle 1 in patients with neuroblastoma. If marrow is positive 
for tumor cells at time of study enrollment, a marrow will also be repeated at times of disease evaluation 
(See Section 8.3.2.2). 
 
Type of sample: 
  bone marrow 
Date Sample Collected: 
 
 
Collection of Bone Marrow  
 
Bone marrow aspiration: 
Collect 5 mL of bone marrow in preservative free heparin (100 units heparin/1 mL of bone marrow) by 
aspiration. 
 
Shipment of Bone Marrow 
 
Place bone marrow in polypropylene screw top tube(s). 
 
Label tube with patient’s registration number, the study ID (ADVL0912), and date and time it was 
drawn. 
 
Place tube(s) in container. 
 
Place the container with the conical tube in a styrofoam box.  
 
Package sample as appropriate for biologic material. 
 
Ship the sample on the same day it was obtained with Federal Express overnight priority delivery 
to: 
Attn: Dr. Yaël Mossé 
The Children’s Hospital of Philadelphia 
The Colket Translational Research Building 
Room 3300 
3501 Civic Center Boulevard 
Philadelphia, PA 19104 
 
 
Do not ship samples for delivery on a weekend or Holiday. 
 
Samples must be received within 24 hours of obtaining the sample. 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and 
date this form below: 
 
Signature: ________________________________________            Date:________________________ 
 
 
(site personnel who collected samples) 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
ADVL0912   
 
 
 
07/27/17 
APPENDIX IX: TISSUE STUDIES FORM 
(FOR PATIENTS WITH NEUROBLASTOMA ONLY) 
 
 
Patient ID #: 
 
 
Study ID: ADVL0912 
BSA (m2): 
 
Dose level (mg/m2):  
Accession #:   
Actual Dose:  
 
Time dose taken:  
Date:  
 
Tumor Sample Labeling: 
Samples should be labeled with the following information: 
 
Protocol number: ADVL0912  
Institution:        _________________ 
Patient ID #:     _________________ 
Accession #:     _________________ 
Sample Date:    _________________ 
Site of Acquired Tissue:  __________________ 
 
Tissue obtained at (check one option below): 
Diagnosis      Relapse 
 
 
Shipment of Tumor Tissue: 
Paraffin embedded tumor specimens must be packaged appropriately and shipped at room temperature to Dr. 
Yaël Mossé (at the address below). If a tumor block is not available, please send as many scrolls from the 
tumor block and/or a minimum of 10 unstained slides may be shipped instead. Please indicate above the date 
of the sample, site of tissue acquisition and whether it was obtained at diagnosis or relapse. Shipments should 
be sent Monday through Thursday only for priority overnight delivery using the COG FedEx account (do 
not ship on Friday). One copy of this form should be faxed to the study Research Coordinator with the 
corresponding shuttle sheet, to the Operations Center at (626) 447-2204.  
A second copy should be sent with the tissue sample to lab address below. 
 
Attn: Dr. Yaël Mossé 
The Children’s Hospital of Philadelphia 
The Colket Translational Research Building 
Room 3300 
3501 Civic Center Boulevard 
Philadelphia, PA 19104 
 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and 
date this form below: 
 
 
Signature: ___________________________________________             Date:______________________ 
 
 
(site personnel who collected samples) 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
ADVL0912   
 
 
 
07/27/17 
APPENDIX X: BONE MARROW AND PERIPHERAL BLOOD STUDIES FORM 
(PATIENTS WITH ANAPLASTIC LARGE CELL LYMPHOMA) 
 
Patient ID #: 
 
 
Study ID: ADVL0912 
BSA (m2): 
 
Dose level (mg/m2):  
Accession #:   
Actual Dose:  
 
Time dose taken:  
Date:  
 
A single bone marrow sample will be obtained prior to starting Cycle 1 in patients with ALCL. In addition, peripheral 
blood samples will be obtained prior to starting Cycle 1, on day 15 of Cycle 1, at the beginning of Cycle 2, then as 
indicated in Section 8.1 for each subsequent cycle through cycle 11, and then every 3 cycles.   
 
Type of sample  
(check one) : 
 bone marrow 
 peripheral blood 
• 
In ALCL patients, a bone marrow aspirate will be 
obtained (5 mL sample).  In children weighing ≤ 10 
kg, this sample can be 3-5 mL. 
 
• 
In ALCL patients, peripheral blood will be collected 
(15 mL if weight > 10 kg, 10 mL if weight ≤10kg). 
Date Sample Collected: 
 
 
Collection of Bone Marrow or Peripheral Blood 
Bone marrow or peripheral blood should be collected in a K+ EDTA (lavender-top) tube. 
 
Shipment of Bone Marrow or Peripheral Blood 
 
Label tube with patient’s registration number, the study ID (ADVL0912), and date and time it was drawn. 
 
Place tube(s) in container. 
 
Place the container with the conical tube in a styrofoam box.  
 
Package sample as appropriate for biologic material. 
 
Ship the sample on the same day it was obtained with Federal Express overnight priority delivery to: 
 
Megan S. Lim, MD, PhD 
109 Zina Pitcher Place 
BSRB 2378, SPC 2200 
Ann Arbor, MI 48109 
Phone: (734) 615-4388 
Fax: (734) 615-9666 
E-mail: meganlim@umich.edu 
 
fuzon@med.umich.edu 
 
 
Do not ship samples for delivery on a weekend or Holiday. 
 
Samples must be sent within 24 hours of time drawn. 
 
Notify Fuzon Chung and Dr. Lim at the e-mail addresses above prior to shipping samples and include 
the tracking number for the shipment. 
 
 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date 
this form below: 
 
 
Signature: ___________________________________________             Date:______________________ 
 
 
(site personnel who collected samples) 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
ADVL0912   
 
 
 
07/27/17 
 
APPENDIX XI:   CORRELATIVE STUDIES GUIDE 
 
 
 
 
Correlative  
Study 
 
 
Appendix 
Blood Volume 
 
 
Tube Type 
≤ 10 kg 
>10 kg  
Volume 
per 
sample 
Total  
Cycle 1 
Volume 
per 
sample 
Total  
Cycle 1 
Pharmacokineticsa 
V 
2 ml 
12 ml 
2 ml 
12 ml 
K+ EDTA 
Pharmacogenomics 
VI 
3 ml 
3 ml 
3 ml 
3 ml 
K+ EDTA 
Bone Marrowb 
VIII 
3-5 ml 
3-5 ml 
5 ml 
5 ml 
Preservative free heparin tubes 
Bone Marrowc 
X 
3-5 ml 
3-5 ml 
5 ml 
5 ml 
K+ EDTA 
Peripheral Bloodc 
X 
10 ml 
20 ml 
15 ml 
30 ml 
K+ EDTA 
Tumor Tissueb 
IX 
 
 
 
Total Blood Volume in Cycle 1 
- 
35 ml 
- 
45 ml 
 
Total Bone Marrow Volume 
- 
6-10 ml 
- 
10 ml 
 
a Required for all patients (Parts A, B or C) 
b Additional Studies for Patients with Neuroblastoma 
c Additional Required Studies for Patients with ALCL 
 


 
 
 
ADVL0912 
 
 
 
7/27/17 
APPENDIX XII: PF-02341066 PATIENT DIARY (CAPSULES) 
 
COG Patient ID:___________   ACC # : _____     Institution :________________________________  
Please do not write patient names on this form. 
 
Complete each day with the time and dose of PF-02341066 given. Make note of other drugs and 
supplements taken.  Add the dates to the calendar below and return the completed diary to your institution 
after each treatment cycle.  Your institution will fax this document with the corresponding shuttle sheet, to 
the COG Statistics & Data Center at (626) 447-2204 after each treatment cycle. 
 
Note:  If patients are receiving the PIC formulation, please enter 10mg, 50mg, and 100mg for the capsule 
strengths below.  If patients are receiving the formulated capsules, please enter 150mg, 200mg, and 250mg 
for the capsule strengths below. 
 
EXAMPLE (PIC formulation) 
Number of capsules taken 
Comments 
WEEK 1 
Date 
Time 
10 mg 
50 mg 
100 mg 
He felt nauseated an hour 
after taking the drug but did 
not vomit. 
Day 1 
1/15/13 
8:30 
AM 
2 
1 
0 
 
 
 
8:30 
PM 
2 
1 
0 
 
 
EXAMPLE (Formulated Capsules) 
Number of capsules taken 
Comments 
WEEK 1 
Date 
Time 
150 mg 
200 mg 
250 mg 
He felt nauseated an hour 
after taking the drug but did 
not vomit. 
Day 1 
1/15/13 
8:30 
AM 
0 
1 
0 
 
 
 
8:30 
PM 
0 
1 
0 
 
 
 
Cycle #: _____        Dose: ________   Start Date: |__/__|__/__|__/__|   End Date: |__/__|__/__|__/__| 
 
WEEK 1 
Date 
Time 
 mg 
mg 
 mg Comments 
Day 1 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 2 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 3 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 4 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 5 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 6 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 7 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
 
 
 


 
 
 
ADVL0912 
 
 
 
7/27/17 
WEEK 2 
Date 
Time 
 mg 
mg 
 mg Comments 
Day 8 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 9 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 10 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 11 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 12 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 13 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 14 
 
 
AM  
 
 
 
 
 
 
PM  
 
 
 
 
WEEK 3 
Date 
Time 
 mg 
mg 
 mg Comments 
Day 15 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 16 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 17 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 18 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 19 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 20 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 21 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
 
WEEK 4 
Date 
Time 
 mg 
mg 
 mg Comments 
Day 22 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 23 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 24 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 25 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 26 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 27 
 
 
AM  
 
 
 
 
 
 
PM 
 
 
 
 
Day 28 
 
 
AM  
 
 
 
 
 
 
PM  
 
 
 
 
 
 


 
 
 
ADVL0912 
 
 
 
7/27/17 
APPENDIX XIII: PF-02341066 PATIENT DIARY (ORAL SOLUTION) 
 
COG Patient ID:___________   ACC # : _____     Institution :________________________________  
Please do not write patient names on this form. 
 
Complete each day with the time and dose of PF-02341066 given. Make note of other drugs and 
supplements taken.  Add the dates to the calendar below and return the completed diary to your institution 
after each treatment cycle.  Your institution will fax this document with the corresponding shuttle sheet, to 
the COG Statistics & Data Center at (626) 447-2204 after each treatment cycle. 
 
EXAMPLE 
 
 
Amount of 
oral solution 
taken 
Comments 
WEEK 1 
Date 
Time 
(total mL per 
dose) 
He felt nauseated an hour after taking the drug but 
did not vomit. 
Day 1 
1/15/09 
8:30 
AM 
2 
 
8:30 
PM 
2 
 
 
 
Cycle #: _____        Dose: ________   Start Date: |__/__|__/__|__/__|   End Date: |__/__|__/__|__/__| 
 
WEEK 1 
Date 
Time 
mL 
Comments 
Day 1 
 
 
AM  
 
 
PM 
 
 
Day 2 
 
 
AM  
 
 
PM 
 
 
Day 3 
 
 
AM  
 
 
PM 
 
 
Day 4 
 
 
AM  
 
 
PM 
 
 
Day 5 
 
 
AM  
 
 
PM 
 
 
Day 6 
 
 
AM  
 
 
PM 
 
 
Day 7 
 
 
AM  
 
 
PM 
 
 
 
 
 
 
 
 
WEEK 2 
Date 
Time 
mL 
Comments 
Day 8 
 
 
AM  
 
 
PM 
 
 
Day 9 
 
 
AM  
 
 
PM 
 
 
Day 10 
 
 
AM  
 
 
PM 
 
 
Day 11 
 
 
AM  
 
 
PM 
 
 
Day 12 
 
 
AM  
 
 
PM 
 
 
Day 13 
 
 
AM  
 
 
PM 
 
 
Day 14 
 
 
AM  
 
 
PM  
 


 
 
 
ADVL0912 
 
 
 
7/27/17 
WEEK 3 
Date 
Time 
mL 
Comments 
Day 15 
 
 
AM  
 
 
PM 
 
 
Day 16 
 
 
AM  
 
 
PM 
 
 
Day 17 
 
 
AM  
 
 
PM 
 
 
Day 18 
 
 
AM  
 
 
PM 
 
 
Day 19 
 
 
AM  
 
 
PM 
 
 
Day 20 
 
 
AM  
 
 
PM 
 
 
Day 21 
 
 
AM  
 
 
PM  
 
 
 
 
 
 
 
WEEK 4 
Date 
Time 
mL 
Comments 
Day 22 
 
 
AM  
 
 
PM 
 
 
Day 23 
 
 
AM  
 
 
PM 
 
 
Day 24 
 
 
AM  
 
 
PM 
 
 
Day 25 
 
 
AM  
 
 
PM 
 
 
Day 26 
 
 
AM  
 
 
PM 
 
 
Day 27 
 
 
AM  
 
 
PM 
 
 
Day 28 
 
 
AM  
 
 
PM  
 
 
 
 


 
 
 
ADVL0912 
 
 
 
7/27/17 
APPENDIX XIV: ORAL SOLUTION ADMINISTRATION INSTRUCTIONS 
 
ADMINISTRATION INSTRUCTIONS 
 
1 
Study Site Staff should review information contained on drug label as well as dosing and administration 
instructions with patient and/or patient caregiver to ensure proper dispensing of medication.  Particular 
attention should be focused on how to accurately draw desired dose into correct oral syringe(s) and how to 
read syringe graduations to avoid patient mis-dosing. 
 
Note that oral solution will be packaged together with a press-in-bottle adaptor and re-usable dosing syringes. 
2 
Each morning and evening dose should be taken at about the same time each day, approximately 12 hours 
apart.  The dose may be taken with or without food or beverage. 
 
3 
Remove the bottle from the refrigerator and gather the appropriate oral syringe(s) and any other supplies as 
directed by Study Site Staff. 
 
Before using dosing syringes, ensure that each syringe and its components are clean and dry. The plunger 
within each syringe should be pressed all the way closed.  
 
Note once a bottle of oral solution has been opened, it should only be used for 90 days unless additional in-
use stability data has been made available. 
4 
When using a bottle for the first time, unscrew the bottle cap and insert the press in bottle adaptor (PIBA) 
into the bottle opening to help withdraw the medication.  
 
Once inserted the press in bottle adaptor will not be taken out. 
 
5 
Open the bottle and ensure that the bottle adaptor is securely in place.  
 
6 
Select a clean, dry dosing syringe and insert the syringe tip into the bottle adaptor. 
 
7 
Pick up the bottle with one hand while holding the dosing syringe firmly in place with the other hand.  It is 
recommended that the thumb of the hand holding the dosing syringe be placed against the top of the syringe 
barrel while the fingers grip the sides of the barrel.  The dosing syringe tip should still be firmly inserted into 
the bottle adaptor. 
 
8 
Turn bottle and syringe set-up upside down so bottle is on top of syringe. 
 
Slowly pull back on the plunger to draw a small amount of solution into the syringe (about 2 mL).  Check the 
syringe for trapped air bubbles.  If air bubble(s) are present in the syringe, return the bottle to the upright 
position and then remove the dosing syringe from the adaptor. 
 
9 
Expel trapped air bubble(s) in the syringe by holding the syringe with the tip pointed upwards and gently tap 
on the side of the syringe barrel to move air bubbles into the tip of the syringe.  Slowly depress the syringe 
plunger to expel the air from the syringe tip.  Ensure that no further air bubbles are present and that the 
solution in the syringe completely fills the tip of the syringe. 
 
Note that trapped air in the syringe will cause an inaccurate volume of medication to be delivered. 
10 
Re-insert the dosing syringe tip into the bottle adaptor and invert the bottle and syringe set-up again.  
Continue to slowly pull back on the plunger and withdraw the prescribed amount of solution into the syringe. 
  
11 
When the desired amount of solution is contained within the syringe, return the bottle to the upright position 
and remove the syringe. 
 
12 
If additional dose syringes need to be prepared, repeat steps 6 -11. 
 
13 
After preparing dosing syringe(s), medication should be delivered promptly to patient. 
 


 
 
 
ADVL0912 
 
 
 
7/27/17 
If the patient cannot be dosed immediately with medication in syringes, wrap each syringe with aluminum 
foil to protect medication from light exposure and place in refrigerator.  Oral solution may be stored in 
supplied syringes for no more than 24 hours. 
 
If the patient has sensitivity to cold temperatures, then the oral solution may be held in syringes for up to 24 
hours at room temperature. As mentioned above, the syringes must be wrapped with aluminum foil to protect 
medication from light exposure. 
 
14 
To deliver the dose, place the tip of the oral dosing syringe into the patient’s mouth.  With the patient’s head 
tilted slightly back, slowly push the plunger to expel the solution. 
 
To avoid choking, be careful not to expel the dose directly into the back of the throat. 
 
15 
Recap the bottle and return it to refrigerator. 
 
16 
Complete Crizotinib Oral Solution Taste Feedback Questionnaire (see the ADVL0912 Case Report Forms) 
within 10 minutes of dosing patient.  Questionnaire is to be completed on the following schedule to capture 
patients taste responses to the oral solution after dose administration. 
• 
First administration of oral solution 
• 
Once a week during first month of administration of oral solution 
• 
Every visit to treating institution after first month of administration of oral solution 
 
17 
Wash hands. Clean the syringe by removing the plunger and rinsing the barrel and plunger with water.  
Allow the barrel and plunger to air dry or use a clean paper towel or clean cloth to dry.   
 
When dry, push the plunger back into the syringe barrel in preparation for next dose. 
 
18 
As per guidance from Study Site Staff, bring any unused medication and used syringes in a sealed plastic bag 
to your next clinic appointment for appropriate disposal.  The sealable plastic bag should be labeled as 
“waste” and kept away from the reach of children or pets. 
 
 
 
NOTE:  
• 
If the patient vomits the dose, do not repeat the dose at that time.  Wait until the next regularly 
scheduled time to administer the dose. 
• 
If a dose is missed, take a dose as soon as you remember, but never more than 6 hours after 
the time it was originally due.   
• 
If you have any questions, contact your provider.  
 
 


 
 
 
ADVL0912 
 
 
 
7/27/17 
 
APPENDIX XV: POTENTIAL DRUG INTERACTIONS 
 
The lists below do not include everything that may interact with chemotherapy. Study Subjects and/or 
their Parents should be encouraged to talk to their doctors before starting any new medications, using 
over-the-counter medicines, or herbal supplements and before making a significant change in diet. 
 
PF-02341066 (Crizotinib) 
 
Drugs that may interact with PF-02341066 (Crizotinib) 
• Antibiotics  
• Ciprofloxacin, levofloxacin, moxifloxacin, clarithromycin, erythromycin, nafcillin, 
rifabutin, rifampin, telithromycin 
• Antidepressants and antipsychotics  
• Aripiprazole, buproprion, citalopram, clozapine, escitalopram, fluvoxamine, lurasidone, 
nefazodone, quetiapine 
• Antifungals  
• Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
• Leflunomide, tofacitinib 
• Anti-rejection medications 
• Cyclosporine, sirolimus, tacrolimus 
• Antiretrovirals and antivirals  
• Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, 
indinavir, lopinavir, nelfinavir, nevirapine, rilpivirine, ritonavir, saquinavir, Stribild, 
telaprevir, tipranavir 
• Anti-seizure medications  
• Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
• Amiodarone, amlodipine, dronedenarone, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
• Aprepitant, artemether/lumefantine, deferasirox, ivacaftor, lomitapide, mifepristone, 
natalizumab, nimodipine, praziquantel, warfarin 
  
Food and supplements* that may interact with PF-02341066 (Crizotinib) 
• 
Echinacea 
• 
St. John’s Wort 
• 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided.  
 
 


 
 
 
ADVL0912 
 
 
 
7/27/17 
 
APPENDIX XVI: NON-MEMBER COLLABORATOR (NMC)  INSTITUTIONS 
 
MA036/ Dana-Farber Cancer Institute 
 
PI: Carlos Rodriguez-Galindo, MD/27475 
 
OH006/ Nationwide Children’s Hospital                                PI: Mark Anthony Ranalli, MD / 43014 
 
CO011/ Children’s Hospital Colorado     
 
PI: Kelly Maloney, MD/36571 
 
 
 
Treating Physician 
CTEP ID Treating Physician 
CTEP ID 
Treating Physician 
CTEP ID 
Prasanna  Ananth, MD 
48366 
Holcombe Grier, MD 
13310 
Steven Margossian, MD 
37140 
Daniel  Bauer, MD 
43560 
Eva Guinan, MD 
28044 
Jonathan Marron, MD 
50289 
Amy Billett, MD 
19386 
Alejandro  Gutierrez, MD 
41524 
Elizabeth Mullen, MD 
28067 
Melissa Burns, MD 
50335 
Inga Hofmann, MD 
43767 
Allison O'Neill, MD 
48196 
Susan Chi, MD 
35547 
Andrew Hong, MD 
48363 
Andrew Place, MD 
44535 
Julia Chu, MD 
50288 
Katherine Janeway 
41525 
Scott Pomeroy, MD 
28062 
Natalie Collins, MD 
48367 
Lisa Kenney, MD 
24997 
Gayle Pouliot, MD 
50122 
Brian Crompton, MD 
49046 
Jennifer Kesselheim, MD 
41865 
Charles Willard Roberts, MD 
35955 
Kimberly Davies, MD 
28026 
Mark Kieran, MD 
27594 
Stephen Sallan, MD 
9495 
Barbara Degar, MD 
33238 
Birgit Knoechel, MD 
43768 
Suzanne Shusterman, MD 
35265 
Lisa Diller, MD 
20709 
Michelle Lee, MD 
43770 
Lewis Silverman, MD 
27566 
Christine Duncan, MD 
39635 
Leslie Lehmann, MD 
27565 
Kimberly Stegmaier, MD 
33629 
Anne Frazier, MD 
28022 
Jennifer Mack, MD 
37489 
Christina Ullrich, MD 
41526 
Natasha Frederick, MD 
50151 
Peter Manley, MD 
42343 
Lynda Vrooman, MD 
41863 
Paola Friedrich, MD 
50058 
Brenton Mar, MD 
44534 
Joanne Wolfe, MD 
33724 
Rani George, MD 
35655 
Karen Marcus, MD 
30102 
Jennifer Wu, MD 
50017 
Treating Physician 
CTEP ID Treating Physician 
CTEP ID 
Treating Physician 
CTEP ID 
Rolla Abu-Arja, MD 
44498 
Terri Guinipero, MD 
47128 
Melissa Rose, MD 
43511 
Anthony Audino, MD 
50420 
Sarita Joshi, MD 
36300 
Bhuvana Setty, MD 
48357 
Jeffery Auletta, MD 
37809 
Riten Kumar, MD 
43957 
Nilay Shah, MD 
52595 
Rajinder Bajwa, MD 
40813 
Stephen Lessnick, MD 
32641 
Keri Streby, MD 
53680 
Robyn Dennis, MD 
48385 
Sarah O'Brien, MD 
48846 
Susan Vear, MD 
52596 
Amy Dunn, MD 
52975 
Randal Olshefski, MD 
43174 
Anthony Villella, MD 
37199 
Jonathan Finlay, MD 
12359 
Diana Osorio, MD 
54470 
 
 
Treating Physician 
CTEP ID Treating Physician 
CTEP ID 
Treating Physician 
CTEP ID 
Kathrin Bernt, MD 
43774 
Lia Gore, MD 
33572 
Tobias Neff, MD 
43564 
Carrye Cost, MD 
43026 
Douglas Graham, MD 
37791 
Christopher Porter, MD 
43031 
John Craddock, MD 
43521 
Brian Greffe, MD 
19670 
Lisa Reaves, MD 
43816 
Kathleen Dorris, MD 
43973 
Gerald Haase, MD 
24468 
Christopher Silliman, MD 
21481 
Nicholas Foreman, MD 
43629 
Michael Handler, MD 
44270 
Thomas Smith, MD 
21774 
Timothy Garrington, MD 
37792 
Joanne Hilden, MD 
25124 
Michael Wang, MD 
37794 
Roger Giller, MD 
13372 
Margaret Macy, MD 
43409 
 
 


 
 
 
ADVL0912 
 
 
 
7/27/17 
 
TX011/ UT Southwestern/Simmons Cancer Center-Dallas  PI:  Patrick Leavey, MD/ 36518 
 
TN008/ Vanderbilt University/Ingram Cancer Center         PI: Howard Katzenstein, MD/35354 
 
 
Treating Physician 
CTEP ID Treating Physician 
CTEP ID 
Treating Physician 
CTEP ID 
Victor Aquino, MD 
26554 
Kathleen (Wiertel) Ludwig, MD 
55619 
Martha Stegner, MD 
43019 
Daniel Bowers, MD 
43077 
Tiffany Simms-Waldrip, MD 
47408 
Gail Tomlinson, MD 
24631 
Laura Klesse, MD 
43064 
Stephen Skapek, MD 
24814 
Jonathan Wickiser, MD 
43071 
Andrew Koh, MD 
42245 
Tamra Slone, MD 
43063 
Naomi Winick, MD 
14049 
Treating Physician 
CTEP ID Treating Physician 
CTEP ID 
Treating Physician 
CTEP ID 
Scott Borinstein, MD 
42939 
Richard Ho, MD 
36287 
Devang Pastakia, MD 
49192 
Adam Esbenshade, MD 
43299 
Austin Kirschner, MD 
53988 
Emmanuel Volanakis, MD 
46599 
Debra Friedman, MD 
27336 
Heather McDaniel, MD 
48471 
 
 


 
 
 
ADVL0912 
 
 
 
7/27/17 
REFERENCES 
1. Christensen JG, Burrows J, Salgia R: c-Met as a target for human cancer and characterization of inhibitors for 
therapeutic intervention. Cancer Lett 225:1-26, 2005 
2. Taulli R, Scuoppo C, Bersani F, et al: Validation of met as a therapeutic target in alveolar and embryonal 
rhabdomyosarcoma. Cancer Res 66:4742-9, 2006 
3. Iwahara T, Fujimoto J, Wen D, et al: Molecular characterization of ALK, a receptor tyrosine kinase expressed 
specifically in the nervous system. Oncogene 14:439-49, 1997 
4. Chiarle R, Voena C, Ambrogio C, et al: The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev 
Cancer 8:11-23, 2008 
5. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-small-
cell lung cancer. Nature 448:561-6, 2007 
6. Mosse YP, Laudenslager M, Longo L, et al: Identification of ALK as a major familial neuroblastoma 
predisposition gene. Nature 455(7215):883-4, 2008 
7. McDermott U, Iafrate AJ, Gray NS, et al: Genomic alterations of anaplastic lymphoma kinase may sensitize 
tumors to anaplastic lymphoma kinase inhibitors. Cancer Res 68:3389-95, 2008 
8. Christensen JG, Zou HY, Arango ME, et al: Cytoreductive antitumor activity of PF-2341066, a novel inhibitor 
of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol 
Cancer Ther 6:3314-22, 2007 
9. Zou HY, Li Q, Lee JH, et al: An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits 
cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res 67:4408-
17, 2007 
10. Grzelinski M, Steinberg F, Martens T, et al: Enhanced antitumorigenic effects in glioblastoma on double 
targeting of pleiotrophin and its receptor ALK. Neoplasia 11:145-56, 2009 
11. Morris SW, Kirstein MN, Valentine MB, et al: Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, 
in non-Hodgkin's lymphoma. Science 263:1281-4, 1994 
12. Palmer RH, Vernersson E, Grabbe C, et al: Anaplastic lymphoma kinase: signalling in development and disease. 
Biochem J 420:345-61, 2009 
13. Pulford K, Morris SW, Turturro F: Anaplastic lymphoma kinase proteins in growth control and cancer. J Cell 
Physiol 199:330-58, 2004 
14. 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 
15. George RE, Sanda T, Hanna M, et al: Activating mutations in ALK provide a therapeutic target in 
neuroblastoma. Nature 455:975-8, 2008 
16. Chen Y, Takita J, Choi YL, et al: Oncogenic mutations of ALK kinase in neuroblastoma. Nature 455:971-4, 
2008 
17. Tan W, Wilner KD, Bang Y, et al: Pharmacokinetics (PK) of PF-02341066, a dual ALK/MET inhibitor after 
multiple oral doses to advanced cancer patients. ASCO Meeting Abstracts 28:2596, 2010 
18. Schwartz GJ, Gauthier B: A simple estimate of glomerular filtration rate in adolescent boys. J Pediatr 106:522-
6, 1985 
19. Skolnik JM, Barrett JS, Jayaraman B, et al: Shortening the timeline of pediatric phase I trials: the rolling six 
design. J Clin Oncol. 26(2):170-1, 2008 
20. Simon R: Optimal two-stage designs for phase II clinical trials.Control Clin Trials. Controlled Clinical Trials 
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21. Chang MN: Improved confidence intervals for a binomial parameter following a group sequential phase II 
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22. Diskin SJ, Li M, Hou C, et al: Adjustment of genomic waves in signal intensities from whole-genome SNP 
genotyping platforms. Nucleic Acids Res, 2008 
23. Maris JM, Mosse YP, Bradfield JP, et al: Chromosome 6p22 locus associated with clinically aggressive 
neuroblastoma. N Engl J Med 358:2585-93, 2008 
24. Jiang XR, Jimenez G, Chang E, et al: Telomerase expression in human somatic cells does not induce changes 
associated with a transformed phenotype. Nat Genet 21:111-4, 1999 
 


 
 
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Page 1 
This model informed consent form has been reviewed by the DCT/NCI and is the official consent document 
for this study.  Local IRB changes to this document are allowed.  (Institutions should attempt to use sections of 
this document, which are in bold type in their entirety.)  Editorial changes to these sections may be made as 
long as they do not change information or intent.  If the institutional IRB insists on making deletions or more 
substantive modifications to the risks or alternatives sections, they may be justified in writing by the investigator 
and approved by the IRB.  Under these circumstances, the revised language, justification and a copy of the IRB 
minutes must be filed with the COG Group Operations Center’s Regulatory Compliance Office before a patient 
may be registered on this study. 
 
SAMPLE INFORMED CONSENT / PARENTAL PERMISSION FOR 
PARTICIPATION IN RESEARCH 
[FOR PART A2 (PHASE 2 COMPONENT) OF THE STUDY ONLY]  
 
 
ADVL0912, A Phase 1/2 Study of PF-02341066, an Oral Small Molecule Inhibitor 
of Anaplastic Lymphoma Kinase (ALK) and c-MET, in Children with 
Relapsed/Refractory Solid Tumors and Anaplastic Large Cell Lymphoma 
 
When we use “you” and “I” in this consent form, we mean you or your child. 
 
This study is a clinical trial (a research study involving patients, or protocol) of an experimental new drug 
for cancer. We are asking if you want to participate in this study because there is not a standard treatment 
for your cancer at this point. Clinical trials only include patients who choose to take part. Your participation 
in this study is entirely voluntary. Please read the consent form carefully. You will be given a copy of it to 
keep if you decide to participate in this study. You may discuss your decision with your friends and family 
if you would like.  
 
This study is being carried out by the Children’s Oncology Group (COG) Phase I Consortium. COG is an 
international research group that consists of more than 200 hospitals that treat children with cancer in the 
United States, Canada, Australia, and Switzerland, and The Phase I Consortium is the group of 21 hospitals 
within COG that does phase 1/2 studies like this one.  It is common medical practice to treat children with 
cancer on research studies like this one. Participation in this study will be limited to the Consortium 
institutions and five additional hospitals within COG. 
 
This is a Phase 1/2 study of a drug called PF-02341066.  PF-02341066 is a drug that in laboratory studies 
can block or inhibit two proteins called c-met and Alk.  These proteins may be important in the growth of 
certain types of cancer cells.  PF-02341066 is considered experimental because the Food and Drug 
Administration (FDA) have not approved it.  
 
You are participating in the phase 2 portion of this trial.  In this part of the trial, we use the highest tolerable 
dose studied in the phase 1 portion to assess the anti-tumor effect of PF-02341066 in patients with an 
abnormality in the ALK gene that cannot be cured by any known standard treatment 
 
You are being asked to participate in this study because you have a recurrent or progressive tumor or 
lymphoma that cannot be cured by any known standard treatment. When a cancer comes back (recurs) or 
does not respond to therapy, your doctor may recommend other anti-cancer drugs (chemotherapy), surgery, 
or radiation therapy. For certain cancers, a combination of one or more of these approaches is considered 
standard treatment. However, for other cancers, for cancers that again come back, or for cancer for which 
therapy is no longer working, the best treatment is not known. 


 
 
ADVL0912 
 
 
07/27/17
 
 
 
 
Page 2 
Why is this study being done? 
We are testing new experimental drugs such as PF-02341066 in the hopes of finding a drug that may be 
effective against recurrent tumors or lymphoma.  
 The goals of this study are: 
 
• 
To learn what kind of side effects PF-02341066 can cause; 
• 
To learn more about the pharmacology (how your body handles the drug) of PF-02341066; 
• 
To learn more about the biology of PF-02341066; 
• 
To determine whether PF-02341066 is a beneficial treatment for your tumor. 
 
How many people will take part in the study? 
There will be up to 45 patients participating in Part A2 of this study.  About ___ will be treated at this 
hospital. 
 
 
What will happen if I take part in this research study?   
Before you begin the study … 
You will need to have the following exams, tests or procedures to find out if you can be in the study.  These 
exams, tests or procedures are part of regular cancer care and may be done even if you do not join the study.  
If you have had some of them recently, they may not need to be repeated.  This will be up to your study 
doctor.   
• 
A medical history 
• 
Physical exam 
• 
Eye exam 
• 
Vital signs (blood pressure, pulse, temperature) 
• 
Blood tests 
• 
Urine tests 
• 
Test of bone marrow (if you have lymphoma)  
• 
Pregnancy test (if you are a woman who could have children) 
• 
Plain X-ray of one or both of your lower legs 
• 
Electrocardiogram (EKG, which tests the electrical impulses of your heart) 
• 
We will also do whatever X-rays, CT scans, MRI or other tests are needed to check your 
tumor or to check whether tumor has spread to your brain since those patients may not 
participate in the study.  
During the study … 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, PF-
02341066 will be given by mouth twice a day for 28 days. This entire period is called a cycle.  You may 
continue to receive PF-02341066 unless you develop serious side effects or your tumor worsens.   
 
You will also have the following tests and procedures during the study.  They are part of regular cancer 
care. They are being done more often because you are in this study. 
• 
Physical exam 
• 
Eye exam 
• 
Blood tests 
• 
Urine tests 


 
 
ADVL0912 
 
 
07/27/17
 
 
 
 
Page 3 
• 
Tests to evaluate the status of your tumor based on your tumor type and location (e.g., CT 
or MRI scans, MIBG scans, PET scans, bone marrow aspirates and biopsies) 
 
These tests are all necessary to make sure that you are not having unsafe side effects and to see whether or 
not your tumor is responding to PF-02341066. 
 
Copies of the films used to check your child’s disease may be sent to central review centers as part of COG 
quality control.  Your name and other identifying information will be removed from these films prior to 
review. 
 
In addition, we will monitor one or both of your lower legs with a plain X-ray prior to starting treatment 
with PF-02341066.  If your bones have stopped growing, no further X-rays of the lower legs will be taken. 
If your bones are still growing, we will check your lower legs for changes at the end of Cycle 3, and then 
approximately every 6 months thereafter with a plain X-ray. Should we detect changes, we may perform 
an MRI to better describe the changes. These tests are performed, because in some growing animals that 
received PF-02341066 and other related drugs, changes in the structure of the growing bones were 
observed. 
 
You will be given a Patient Diary at the beginning of each cycle of PF-02341066. Use the diary to record 
the date and time you take the drug, side effects you experience and other medications you are taking.  This 
diary should be returned to clinic, along with the medication bottle (even if it is empty) before starting 
another cycle. This will help us to know how much of the drug you take and how it made you feel. 
 
The PF-02341066 will be given as a capsule or liquid solution by mouth. Since we do not have information 
on how well the medicine is absorbed, if you vomit the medication it should not be taken again.  
 
Questionnaire: 
If you are receiving the PF-02341066 as a liquid by mouth, we would like to ask you to fill out a short 
questionnaire at the time of the first dose, and then once per week for the first month, and then at every visit 
thereafter so we can learn more about how the drug tastes. This questionnaire will take about 20 minutes to 
fill out each time.   The study staff will collect some information from your chart about your age and what 
kind (if any) of PF-02341066 capsules or liquid you may have received in the past. The questionnaire is 
optional. The information learned would not change the way you are treated, and the results will not be 
returned to you.  
 
______/______ Yes, I agree to take part in the questionnaire. 
 
______/______ No, I do not agree to take part in the questionnaire. 
 
We would also like to do some extra tests called pharmacokinetic studies and biologic studies.  These tests 
will help us learn more about PF-02341066 and may help children who receive this drug in the future. The 
information learned would not change the way you are treated, and the results of these tests will not be 
returned to you.  The pharmacokinetic studies are required and the biology studies are optional. You do not 
have to do those tests if you do not want to.  Although these tests are a very important part of how we will 
better learn to use this drug, it is your decision as to whether or not you agree to participate in these tests. 
 
Pharmacokinetic Studies  
During the study blood samples will be collected to determine how much of the PF-02341066 is in your 
blood (pharmacokinetics).  These samples are about 2 mL (approximately ½ teaspoon) of blood each. A 


 
 
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single sample will be obtained before your first dose of the drug on Day 1 and additional samples will be 
obtained between day 15 and day 28 after you begin taking the drug in Cycle 1. These additional samples 
will be obtained before and at 1 hour, 2 hours, 4 hours, and 6-8 hours after the dose is given after 
approximately the middle of the first cycle (between day 15 and day 28).  These additional samples may 
require that a small intravenous tube (catheter or IV) be placed if you do not have a central line.  If you 
have a central line then you will not require an IV for these studies. A total of 12 mL (less than 3 teaspoons) 
of blood will be drawn for these studies.  This amount of blood is safe even for small children.  These blood 
samples are required from all participants in this study. 
 
Biology Studies 
If you consent to the biology study, one blood sample (3 ml, which is less than one teaspoon) will be 
collected before you take the first dose of PF-02341066 on Day 1 of Cycle 1.  
 
______/______ Yes, I agree to participate in the biology studies. 
 
______/______ No, I do not agree to participate in the biology studies. 
 
A total of 15 mL will be drawn (approximately 3 teaspoons) for all the pharmacokinetic and biology study 
tests described above. This amount of blood is safe to draw even from small children. 
 
 
How long will I be in the study? 
Your doctor may decide to take you off study if any of the following occur: 
 
• 
The side effects of PF-02341066 are too harmful for you 
• 
You need a treatment that is not allowed on this study 
• 
Your tumor does not improve or worsens 
• 
You are not able to follow study-related treatment instructions 
• 
New information becomes available 
• 
The study is not in your best interest 
• 
The study is stopped 
 
After you are finished taking PF-02341066, the study doctor will ask you to visit the office for follow-up 
exams as they would normally do for patients with solid tumors or lymphoma. 
 
Can I stop being in the study? 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping or decide 
to stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from PF-02341066 
can be evaluated by your doctor.  Another reason to tell your doctor that you are thinking about stopping is 
to discuss what follow-up care and testing could be most helpful for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in your best 
interest; if you do not follow the study rules; or if the study is stopped. 
 
What side effects or risks can I expect from being in the study?  
You may have side effects while on the study.  Everyone taking part in the study will be watched 
carefully for any side effects.  However, doctors don’t know all the side effects that may happen.  Side 
effects may be mild or very serious. Your health care team may give you medicines to help lessen side 


 
 
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effects. Many side effects go away soon after you stop taking the PF-02341066. In some cases, side 
effects can be serious, long lasting, may never go away, or possibly result in death.  
 
You should talk to your study doctor about any side effects that you have while taking part in the study.    
Risks and side effects related to PF-02341066 (crizotinib) include those which are: 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving PF-02341066, more than 20 and up to 100 may have: 
• Vision Changes* 
• Constipation, diarrhea, nausea, vomiting 
• Loss of appetite 
• Swelling of the body 
• Tiredness 
• Dizziness 
• Changes in taste 
• Damage to nerves that may interfere with walking or organ function which may cause 
numbness, tingling, weakness or pain in the muscles 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving PF-02341066, from 4 to 20 may have: 
• 
Anemia which may require blood transfusion 
• 
Heartburn  
• 
Sores in the mouth  
• 
Abnormal heartbeat  
• 
Change in the heart rhythm  
• 
Headache 
• 
Rash 
• 
Belly pain 
• 
Infection, especially when white blood cell count is low 
• 
Sores in the mouth 
 
RARE, AND SERIOUS 
In 100 people receiving PF-02341066, 3 or fewer may have: 
• 
Heart failure which may cause shortness of breath, swelling of ankles, and tiredness 
• 
Difficulty swallowing 
• 
Damage to the lungs which may cause shortness of breath 
• 
Liver damage which may cause yellowing of eyes and skin, swelling 
• 
Fluid collection in the kidney that may be irregular and could be benign or could become 
cancerous  
• 
A tear or hole in the stomach that may require surgery 
• 
Blood clot which may cause swelling, pain, shortness of breath 
• 
Fainting 
*Vision changes may include blurred vision, double vision, discomfort in the eyes from light, swelling and 
redness of the eyelids, impaired vision, seeing spots before the eyes (floaters), flashing lights, brightness, 
rings, shadows, and/or streaking. 
 
Some drugs or supplements may interact with your treatment plan. Talk to your doctor, pharmacist, 
or study team before starting any new prescription or over-the-counter drugs, herbals, or 
supplements and before making a significant change in your diet.  Supplements may come in many 
forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried herbs. All forms should be 


 
 
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avoided. 
 
*If you have a drop in the red blood cell count, the cells that carry oxygen around the body you may feel 
tired. If your red blood cell count drops very low you may need a blood transfusion. 
 
If you have a decrease in the white blood cell count, the cells that fight infection, you may be more likely 
to get an infection, including a serious infection that spreads through the blood stream (sepsis).  If this 
happens, you will have to come to the hospital to be treated with antibiotics.  If your white blood cell 
count is very low and you get a fever, you may have to come to the hospital to get treated with antibiotics. 
 
If you have a low platelet count, particles in the blood that help with clotting, you may have easy bruising 
or bleeding.  If the count is very low and there is bleeding, you might need platelet transfusions to help 
stop the bleeding. 
 
Transfusions may be accompanied by or followed by fever and/or reactions that can cause kidney failure, 
heart failure, anemia, hepatitis, A.I.D.S (acquired immune deficiency syndrome) and other infections. 
Reproductive risks:  You should not become pregnant or father a baby while on this study because 
the drugs in this study can affect an unborn baby.  Women should not breastfeed a baby while on 
this study.  It is important you understand that you need to use birth control while on this study.  
Check with your study doctor about what kind of birth control methods to use and how long to use them.  
Some methods might not be approved for use in this study. A pregnancy test will be obtained in female 
patients before beginning treatment with PF-02341066. 
 
We will tell you if we learn any new information that may affect your health, welfare, or decision to stay 
in this study.  
Risks of blood drawing or placing an intravenous catheter for blood drawing: 
Risks associated with drawing blood are slight, but some risks include: pain, excessive bleeding, 
fainting or feeling lightheaded, bruising, infection (a slight risk any time the skin is broken), and 
multiple punctures to locate veins. 
 
Risks of bone marrow aspirate and biopsy: 
Risks associated with having a bone marrow aspirate or biopsy include: pain, bleeding, infection, or 
bruising. 
Risks of Imaging Scans 
The following imaging scans are part of routine care for many types of cancer and are performed to assess 
the size and/or location of your tumor(s). 
 
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the study? 
The potential benefit of the treatment with PF-02341066 is that it may cause your cancer to stop growing 
or to shrink for a period of time.  It may lessen the symptoms, such as pain, that are caused by the cancer.  
Because there is not much information about the PF-02341066 effect on cancers in humans, we do not 
know if you will benefit from taking part in this study. Information learned from this study may help future 
patients with cancer. 


 
 
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What other choices do I have if I do not take part in this study? 
Your other choices may include: 
• 
Getting treatment or care for your cancer without being in a study 
• 
Taking part in another study 
• 
No further treatment, and comfort care only 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Will my medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be kept private.  
However, we cannot guarantee total privacy.  Your personal information may be given out if required by 
law.  If information from this study is published or presented at scientific meetings, your name and other 
personal information will not be used.  
 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about subjects collected during the course of our covered studies.  The 
researchers involved in the studies cannot be forced to disclose the identity or any information collected in 
the study in any legal proceedings at the federal, state, or local level, regardless of whether they are criminal, 
administrative, or legislative proceedings.  However, the subject or the researcher may choose to voluntarily 
disclose the protected information under certain circumstances.  For example, if the subject or his/her 
guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure.  Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• 
The Children’s Oncology Group 
• 
Representatives of the National Cancer Institute (NCI) and other government agencies, like 
the Food and Drug Administration (FDA), involved in overseeing research 
• 
The Institutional Review Board (IRB) of this hospital 
• 
The drug company partner (the company that makes the drug PF-02341066) and its staff 
• 
Health Canada* 
 
* -Health Canada will only be able to see and/or copy reports describing bad side effects you may experience on this 
trial.  If you are being treated at a Canadian institution, Health Canada will be able to see and/or copy all of your 
medical records.  
 
What are the costs of taking part in this study? 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of treating 
your cancer in this study.  Some health plans will not pay these costs for people taking part in studies.  
Check with your health plan or insurance company to find out what they will pay for.  Taking part in this 
study may or may not cost your insurance company more than the cost of getting regular cancer treatment.  
 
Pfizer, Inc. is supplying PF-02341066 at no cost to you.  However, you or your health plan may need to 


 
 
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pay for costs of the supplies and personnel who give you the PF-02341066. 
 
If, during the study, PF-02341066 becomes approved for use in your cancer, you and/or your health plan 
may have to pay for drug needed to complete this study. 
 
You will not be charged for the costs of the special blood studies that are being done for research purposes 
only, such as the pharmacokinetic and biology studies.  You may receive up to $100 (maximum) for the 
required pharmacokinetic studies for PF-02341066 to compensate for your inconvenience (i.e., travel, 
parking, meals reimbursement, etc). 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s 
Web site at http://cancer.gov/clinicaltrials/learning/insurance-coverage/.    You can print a copy of the 
“Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send 
you a free copy. 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel 
that you have been injured because of taking part in this study.  You can tell the doctor in person or call 
him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You and/or your 
health plan will be charged for this treatment.   The study will not pay for medical treatment.   
 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in the study.  
If you decide to take part in this study, you may leave the study at any time.   No matter what decision you 
make, there will be no penalty to you and you will not lose any of your regular benefits.  Leaving the study 
will not affect your medical care.  You can still get your medical care from our institution.    
 
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by 
signing this form.   
 
Whether you participate or not, you will continue to get the best medical care this hospital can provide. 
 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions or concerns you have about this study.  Contact your 
study doctor __________________ [name(s)] at __________________ [telephone number]. 
 
For questions about your rights while taking part in this study, call the ________________________ 
[name of center] Institutional Review Board (a group of people who review the research to protect your 
rights) at __________________ (telephone number).  [Note to Local Investigator: Contact information 
for patient representatives or other individuals in a local institution who are not on the IRB or research 
team but take calls regarding clinical trial questions can be listed here.] 
 
Where can I get more information? 
The COG Family Handbook for Children with Cancer has information about specific cancers, tests, 


 
 
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treatment side effects and their management, adjusting to cancer, and resources.  Your doctor can get you 
this Handbook, or you can get it at www.curesearch.org 
 
If you are in the United States, you may call the National Cancer Institute's Cancer Information Service at:  
1-800-4-CANCER (1-800-422-6237)  
 
A description of this clinical trial will be available at http://www.ClinicalTrials.gov, as required by U.S. 
Law. This web site will not include information that can identify you. At most, the web site will include a 
summary of the results. You can search this web site at any time. 
 
You may also visit the NCI Web site at http://cancer.gov/ 
• 
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
• 
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
You will get a copy of this form. You will be given a copy of the protocol (full study plan) upon request.  
If you want more information about this study, ask your study doctor. 
 
Signature 
 
I have been given a copy of all 10 pages of this form (including the study chart).   
I have read it or it has been read to me.  
 
I have reviewed the information and have had my questions answered.  I agree to take part in this study. 
 
Participant 
 
 
 
 
Signature of Participant / Parent (or Guardian)  
 
Date  
 
Signature of Physician or Responsible Investigator  
 
Date 


 
 
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This model informed consent form has been reviewed by the DCT/NCI and is the official consent document 
for this study.  Local IRB changes to this document are allowed.  (Institutions should attempt to use sections of 
this document, which are in bold type in their entirety.)  Editorial changes to these sections may be made as 
long as they do not change information or intent.  If the institutional IRB insists on making deletions or more 
substantive modifications to the risks or alternatives sections, they may be justified in writing by the investigator 
and approved by the IRB.  Under these circumstances, the revised language, justification and a copy of the IRB 
minutes must be filed with the COG Group Operations Center’s Regulatory Compliance Office before a patient 
may be registered on this study. 
 
SAMPLE INFORMED CONSENT / PARENTAL PERMISSION FOR 
PARTICIPATION IN RESEARCH 
[FOR PARTS B OR C (PHASE 2 COMPONENT) OF THE STUDY]  
 
 
ADVL0912, A Phase 1/2 Study of PF-02341066, an Oral Small Molecule Inhibitor 
of Anaplastic Lymphoma Kinase (ALK) and c-MET, in Children with 
Relapsed/Refractory Solid Tumors and Anaplastic Large Cell Lymphoma 
 
When we use “you” and “I” in this consent form, we mean you or your child. 
 
This study is a clinical trial (a research study involving patients, or protocol) of an experimental new drug 
for cancer. We are asking if you want to participate in this study because there is not a standard treatment 
for your cancer at this point. Clinical trials only include patients who choose to take part. Your participation 
in this study is entirely voluntary. Please read the consent form carefully. You will be given a copy of it to 
keep if you decide to participate in this study. You may discuss your decision with your friends and family 
if you would like.  
 
This study is being carried out by the Children’s Oncology Group (COG) Phase I Consortium. COG is an 
international research group that consists of more than 200 hospitals that treat children with cancer in the 
United States, Canada, Australia, and Switzerland, and The Phase I Consortium is the group of 21 hospitals 
within COG that does phase 1/2 studies like this one.  It is common medical practice to treat children with 
cancer on research studies like this one. Participation in this study will be limited to the Consortium 
institutions and five additional hospitals within COG. 
 
This is a Phase 1/2 study of a drug called PF-02341066.  PF-02341066 is a drug that in laboratory studies 
can block or inhibit two proteins called c-met and ALK.  These proteins may be important in the growth of 
certain types of cancer cells.  PF-02341066 is considered experimental because the Food and Drug 
Administration (FDA) have not approved it.  
 
You are participating in the phase 2 portion of this trial.  In this part of the trial, we use the highest safe 
dose studied in the phase 1 portion to assess the anti-tumor effect of PF-02341066 in patients with 
neuroblastoma or anaplastic large cell lymphoma.  
 
You are being asked to participate in this study because you have a recurrent or progressive neuroblastoma 
or lymphoma that shows an abnormality in the ALK gene and that cannot be cured by any known standard 
treatment. When a cancer comes back (recurs) or does not respond to therapy, your doctor may recommend 
other anti-cancer drugs (chemotherapy), surgery, or radiation therapy. For certain cancers, a combination 
of one or more of these approaches is considered standard treatment. However, for other cancers, for cancers 
that again come back, or for cancer for which therapy is no longer working, the best treatment is not known. 


 
 
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Why is this study being done? 
We are testing new experimental drugs such as PF-02341066 in the hopes of finding a drug that may be 
effective against recurrent neuroblastoma or lymphoma.  
The goals of this study are: 
 
• 
To determine whether PF-02341066 is a beneficial treatment for your tumor; 
• 
To learn what kind of side effects PF-02341066 can cause; 
• 
To learn more about the pharmacology (how your body handles the drug) of PF-02341066; 
• 
To learn more about the biology of PF-02341066. 
 
How many people will take part in the study? 
There will be about 11-45 patients participating in Part B and C of this study.  About ___ will be treated at 
this hospital. 
 
 
What will happen if I take part in this research study?   
Before you begin the study …  
You will need to have the following exams, tests or procedures to find out if you can be in the study.  These 
exams, tests or procedures are part of regular cancer care and may be done even if you do not join the study.  
If you have had some of them recently, they may not need to be repeated.  This will be up to your study 
doctor.   
• 
A medical history 
• 
Physical exam 
• 
Eye exam 
• 
Vital signs (blood pressure, pulse, temperature) 
• 
Blood tests 
• 
Urine tests 
• 
Test of bone marrow (lymphoma or neuroblastoma) and spinal fluid (lymphoma)  
• 
Pregnancy test (if you are a woman who could have children) 
• 
Plain X-ray of one or both of your lower legs 
• 
Electrocardiogram (EKG, which tests the electrical impulses of your heart) 
• 
We will also do whatever X-rays, CT scans, or other tests are needed to check your tumor 
During the study …  
If the exams, tests and procedures show that you can be in the study, and you choose to take part, PF-
02341066 will be given by mouth twice a day for 28 days. This entire period is called a cycle.  You may 
continue to receive PF-02341066 unless you develop serious side effects or your tumor worsens.   
 
You will have the following tests and procedures during the study.  They are part of regular cancer care. 
They may be done more often because you are in this study. 
• 
Physical exam 
• 
Eye exam 
• 
Blood tests 
• 
Urine tests 


 
 
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• 
Tests to evaluate the status of your tumor based on your tumor type and location (e.g., CT 
or MRI scans, MIBG scans, PET scans, bone marrow aspirates and biopsies) 
 
These tests are all necessary to make sure that you are not having unsafe side effects and to see whether or 
not your tumor is responding to PF-02341066. 
 
Copies of the films used to check your child’s disease may be sent to central review centers as part of COG 
quality control. Your name and other identifying information will be removed from these films prior to 
review. 
 
In addition, we will monitor one or both of your lower legs with a plain X-ray prior to starting treatment 
with PF-02341066.  If your bones have stopped growing, no further X-rays of the lower legs will be taken. 
If your bones are still growing, we will check your lower legs for changes at the end of Cycle 3, and then 
approximately every 6 months thereafter with a plain X-ray. Should we detect changes, we may perform 
an MRI to better describe the changes. These tests are performed, because in some growing animals that 
received PF-02341066 and other related drugs, changes in the structure of the growing bones were 
observed. 
 
You will be given a Patient Diary at the beginning of each cycle of PF-02341066. Use the diary to record 
the date and time you take the drug, side effects you experience and other medications you are taking.  This 
diary should be returned to clinic, along with the medication bottle (even if it is empty) before starting 
another cycle. This will help us to know how much of the drug you take and how it made you feel. 
 
The PF-02341066 will be given as a capsule or liquid solution by mouth. Since we do not have information 
on how well the medicine is absorbed, if you vomit the medication it should not be taken again. Since this 
medicine can make you sleepy, you can take this medicine at bedtime. 
Questionnaire: 
If you are receiving the PF-02341066 as a liquid by mouth, we would like to ask you to fill out a short 
questionnaire at the time of the first dose, and then once per week for the first month, and then at every visit 
thereafter so we can learn more about how the drug tastes. This questionnaire will take about 20 minutes to 
fill out each time.   The study staff will collect some information from your chart about your age and what 
kind (if any) of PF-02341066 capsules or liquid you may have received in the past. The questionnaire is 
optional. The information learned would not change the way you are treated, and the results will not be 
returned to you.  
 
______/______ Yes, I agree to take part in the questionnaire. 
 
______/______ No, I do not agree to take part in the questionnaire. 
 
We would also like to do some extra tests called pharmacokinetic studies and biologic studies.  These tests 
will help us learn more about PF-02341066 and may help children who receive this drug in the future. The 
information learned would not change the way you are treated, and the results of these tests will not be 
returned to you.  The pharmacokinetic studies are required and the biology studies are optional, except in 
patients with ALCL in whom some specific correlative biology tests are required. You do not have to do 
these tests if you do not want to.  Although these tests are a very important part of how we will better learn 
to use this drug, it is your decision as to whether or not you agree to participate in these tests. 
 


 
 
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Pharmacokinetic Studies  
During the study blood samples will be collected to determine how much of the PF-02341066 is in your 
blood (pharmacokinetics).  These samples are about 2 mL (approximately ½ teaspoon) of blood each. A 
single sample will be obtained before your first dose of drug on Day 1 and additional samples will be 
obtained between day 15 and day 28 after you begin taking the drug in Cycle 1. These additional samples 
will be obtained before and at 1 hour, 2 hours, 4 hours, and 6-8 hours after the dose is given after 
approximately the middle of the first cycle (between day 15 and day 28).  These additional samples may 
require that a small intravenous tube (catheter or IV) be placed if you do not have a central line.  If you 
have a central line then you will not require an IV for these studies.  A total of 12 mL (less than 3 teaspoons) 
of blood will be drawn for these studies.  This amount of blood is safe even for small children. These blood 
samples are required from all participants in this study. 
 
Biology Studies 
If you consent to the biology study, one blood sample (3 ml, which is less than one teaspoon) will be 
collected before you take the first dose of PF-02341066 on Day 1 of Cycle 1.  
 
______/______ Yes, I agree to participate in the biology studies. 
 
______/______ No, I do not agree to participate in the biology studies. 
 
A total of 15 mL will be drawn (approximately 3 teaspoons) for all the pharmacokinetic and biology study 
tests described above. This amount of blood is safe to draw even from small children. 
 
Additional Tissue Studies to Consider for Patients with Neuroblastoma Only 
As part of your regular care, your doctor may have removed some body tissue (tumor tissue or bone 
marrow) to see if you have cancer. We would like to keep some of the tissue that is left over and test how 
much a gene called ALK can be found in the tissue. If you weigh more than 10 kg, the bone marrow sample 
is 5 mL (about 1 teaspoon). If you weigh equal to or less than 10 kg, the bone marrow sample is 3-5 mL 
(about 1 teaspoon or less). The ALK gene testing may help us learn more about how the drug, PF-02341066, 
works in the tissues in your body. If the results are positive, the bone marrow sample will be repeated with 
each disease evaluation. The tissue and/or bone marrow will be sent directly to the lab for testing and will 
not be sold. The ALK gene testing in the tumor and bone marrow is done for research and we will not 
disclose these results to you. However, if you are interested in genetic screening for neuroblastoma, you 
should talk with your doctor about a new molecular diagnostic test that is available.   
 
______/______ Yes, I agree to participate in the biology tumor tissue studies. 
 
______/______ No, I do not agree to participate in the biology tumor tissue studies. 
 
 
______/______ Yes, I agree to participate in the biology bone marrow studies. 
 
______/______ No, I do not agree to participate in the biology bone marrow studies. 
 
Additional Studies to Consider for Patients with Anaplastic Large Cell Lymphoma (ALCL) Only 
For patients with ALCL, we would like to test your blood and bone marrow before you begin therapy for 
minimal residual disease (MRD).   MRD is the presence of very small amounts of cancer in the blood and 
bone marrow and we would see if the MRD test can help us determine early signs of whether or not your 
tumor is responding to the drug. These tests are done for research and the results will not be disclosed to 
you. The bone marrow sample (5 mL, about 1 teaspoon if you weigh more than 10 kg, or 3-5 mL, about 1 


 
 
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teaspoon or less if you weigh equal to or less than 10 kg) will be drawn before your first dose of PF-
02341066. The blood samples (15 mL, about 3 teaspoons if you weigh more than 10 kg, or 10 mL, about 2 
teaspoons if you weigh equal to or less than 10 kg) will be drawn before your first dose of PF-02341066, 
on Day 15 of Cycle 1, at the beginning of Cycle 2, once in each additional cycle through Cycle 11, and then 
every 3 cycles.  These samples would be drawn at the same time as routine blood tests.  These samples will 
be sent directly to the lab for testing and will not be sold. These blood and bone marrow samples are 
required from all patients with ALCL. 
 
How long will I be in the study? 
Your doctor may decide to take you off study if any of the following occur: 
 
• 
The side effects of PF-02341066 are too harmful for you 
• 
You need a treatment that is not allowed on this study 
• 
Your tumor does not improve or worsens 
• 
You are not able to follow study-related treatment instructions 
• 
New information becomes available 
• 
The study is not in your best interest 
• 
The study is stopped 
 
After you are finished taking PF-02341066, the study doctor will ask you to visit the office for follow-up 
exams as they would normally do for patients with solid tumors or lymphoma. 
 
Can I stop being in the study? 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping or decide 
to stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from PF-02341066 
can be evaluated by your doctor.  Another reason to tell your doctor that you are thinking about stopping is 
to discuss what follow-up care and testing could be most helpful for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in your best 
interest; if you do not follow the study rules; or if the study is stopped. 
 
What side effects or risks can I expect from being in the study?  
You may have side effects while on the study.  Everyone taking part in the study will be watched 
carefully for any side effects.  However, doctors don’t know all the side effects that may happen.  Side 
effects may be mild or very serious. Your health care team may give you medicines to help lessen side 
effects. Many side effects go away soon after you stop taking the PF-02341066. In some cases, side 
effects can be serious, long lasting, may never go away, or possibly result in death.  
 
You should talk to your study doctor about any side effects that you have while taking part in the study.    
 


 
 
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Risks and side effects related to PF-02341066 (crizotinib) include those which are:  
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving PF-02341066, more than 20 may have: 
• Vision Changes* 
• Constipation, diarrhea, nausea, vomiting 
• Loss of appetite 
• Swelling of the body 
• Tiredness 
• Dizziness 
• Changes in taste 
• Damage to nerves that may interfere with walking or organ function which may cause 
numbness, tingling, weakness or pain in the muscle  
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving PF-02341066, from 4 to 20 may have: 
• 
Anemia which or may require blood transfusion 
• 
Heartburn  
• 
Sores in the mouth  
• 
Change in the heart rhythm 
• 
Headache 
• 
Rash 
• 
Belly pain 
• 
Infection, especially when white blood cell count is low 
• 
Sores in the mouth 
 
RARE, AND SERIOUS 
In 100 people receiving PF-02341066, 3 or fewer may have: 
• 
Heart failure which may cause shortness of breath, swelling of ankles, and tiredness 
• 
Difficulty swallowing 
• 
Damage to the lungs which may cause shortness of breath 
• 
Liver damage which may cause yellowing of eyes and skin, swelling 
• 
Fluid collection in the kidney that may be irregular and could be benign or could become 
cancerous  
• 
A tear or hole in the stomach that may require surgery 
• 
Blood clot which may cause swelling, pain, shortness of breath 
• 
Fainting 
 
  *Vision changes may include blurred vision, double vision, discomfort in the eyes from light, swelling 
and redness of the eyelids, impaired vision, seeing spots before the eyes (floaters), flashing lights, 
brightness, rings, shadows, and/or streaking. 
 
Some drugs or supplements may interact with your treatment plan. Talk to your doctor, pharmacist, 
or study team before starting any new prescription or over-the-counter drugs, herbals, or 
supplements and before making a significant change in your diet.  Supplements may come in many 
forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried herbs. All forms should be 
avoided. 
 
*If you have a drop in the red blood cell count, the cells that carry oxygen around the body you may feel 
tired. If your red blood cell count drops very low you may need a blood transfusion. 
 
If you have a decrease in the white blood cell count, the cells that fight infection, you may be more likely 


 
 
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to get an infection, including a serious infection that spreads through the blood stream (sepsis).  If this 
happens, you will have to come to the hospital to be treated with antibiotics.  If your white blood cell 
count is very low and you get a fever, you may have to come to the hospital to get treated with antibiotics. 
 
If you have a low platelet count, particles in the blood that help with clotting, you may have easy bruising 
or bleeding.  If the count is very low and there is bleeding, you might need platelet transfusions to help 
stop the bleeding. 
 
Transfusions may be accompanied by or followed by fever and/or reactions that can cause kidney failure, 
heart failure, anemia, hepatitis, A.I.D.S (acquired immune deficiency syndrome) and other infections. 
Reproductive risks:  You should not become pregnant or father a baby while on this study because 
the drugs in this study can affect an unborn baby.  Women should not breastfeed a baby while on 
this study.  It is important you understand that you need to use birth control while on this study.  
Check with your study doctor about what kind of birth control methods to use and how long to use them.  
Some methods might not be approved for use in this study. A pregnancy test will be obtained in female 
patients before beginning treatment with PF-02341066. 
 
We will tell you if we learn any new information that may affect your health, welfare, or decision to stay 
in this study.  
Risks of blood drawing or placing an intravenous catheter for blood drawing: 
Risks associated with drawing blood are slight, but some risks include: pain, excessive bleeding, 
fainting or feeling lightheaded, bruising, infection (a slight risk any time the skin is broken), and 
multiple punctures to locate veins. 
Risks of bone marrow aspirate and biopsy: 
Risks associated with having a bone marrow aspirate or biopsy include: pain, bleeding, infection, or 
bruising. 
Risks of spinal tap (For patients with ALCL): 
Spinal taps are part of routine care for patients with lymphoma and for some types of brain tumors. A spinal 
tap is a procedure where a special needle is inserted in the lower back through the space between the 
bones that surround the spinal canal.  This procedure has a slight risk of infection, bleeding, nerve 
damage, or headache.  Patients will be given medications to numb the pain and blur the memory 
before the test since it is painful. The pain is usually brief but occasionally may linger. Sometimes 
this procedure is done while the patient is under general anesthesia. 
Risks of Imaging Scans 
The following imaging scans are part of routine care for many types of cancer and are performed to assess 
the size and/or location of your tumor(s). 
 
Risks associated with having a PET-CT scan (For patients with ALCL): 
For the PET-CT scan you will get a radioactive sugar (FDG) by vein. This exposes your body to 
radiation like a chest X-ray or CT scan. The amount of FDG that you get depends on what you 
weigh.  The radiation exposure for the PET scan is about the same to about half that of a standard 
CT scan.  You will also get x-rays from the CT portion of the PET-CT scan. The total amount of 
radiation you get from the combined PET and CT scan will not be more than 2 to 6 times the amount 
of radiation that everyone gets in a year from natural sources like the atmosphere.  The risk from 
this amount of radiation is considered to be small when compared with other everyday risks. 


 
 
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Risks associated with having a MIBG scan (For Patients with Neuroblastoma): 
A MIBG scan is an imaging test that involves exposure to radiation and uses a special camera to take 
pictures of specific tissues in the body after a radioactive tracer is injected in a vein in the arm. The 
risks associated with having a MIBG scan include pain at the injection site, bleeding, fainting or 
feeling lightheaded, bruising, infection (a slight risk any time the skin is broken), and multiple 
punctures to locate veins.  
 
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the study? 
The potential benefit of the treatment with PF-02341066 is that it may cause your cancer to stop growing 
or to shrink for a period of time.  It may lessen the symptoms, such as pain, that are caused by the cancer.  
Because there is not much information about the PF-02341066 effect on cancers in humans, we do not 
know if you will benefit from taking part in this study. Information learned from this study may help future 
patients with cancer. 
 
What other choices do I have if I do not take part in this study? 
Your other choices may include: 
• 
Getting treatment or care for your cancer without being in a study 
• 
Taking part in another study 
• 
No further treatment, and comfort care only 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Will my medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be kept private.  
However, we cannot guarantee total privacy.  Your personal information may be given out if required by 
law.  If information from this study is published or presented at scientific meetings, your name and other 
personal information will not be used.  
 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about subjects collected during the course of our covered studies.  The 
researchers involved in the studies cannot be forced to disclose the identity or any information collected in 
the study in any legal proceedings at the federal, state, or local level, regardless of whether they are criminal, 
administrative, or legislative proceedings.  However, the subject or the researcher may choose to voluntarily 
disclose the protected information under certain circumstances.  For example, if the subject or his/her 
guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure.  Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• 
The Children’s Oncology Group 


 
 
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• 
Representatives of the National Cancer Institute (NCI) and other government agencies, like 
the Food and Drug Administration (FDA), involved in overseeing research 
• 
The Institutional Review Board (IRB) of this hospital 
• 
The drug company partner (the company that makes the drug PF-02341066) and its staff 
• 
Health Canada* 
 
* -Health Canada will only be able to see and/or copy reports describing bad side effects you may experience on this 
trial.  If you are being treated at a Canadian institution, Health Canada will be able to see and/or copy all of your 
medical records.  
 
What are the costs of taking part in this study? 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of treating 
your cancer in this study.  Some health plans will not pay these costs for people taking part in studies.  
Check with your health plan or insurance company to find out what they will pay for.  Taking part in this 
study may or may not cost your insurance company more than the cost of getting regular cancer treatment.  
 
Pfizer, Inc. is supplying PF-02341066 at no cost to you.  However, you or your health plan may need to 
pay for costs of the supplies and personnel who give you the PF-02341066. 
 
If, during the study, PF-02341066 becomes approved for use in your cancer, you and/or your health plan 
may have to pay for drug needed to complete this study. 
 
You will not be charged for the costs of the special blood studies that are being done for research purposes 
only, such as the pharmacokinetic and biology studies.  You may receive up to $100 (maximum) for the 
required pharmacokinetic studies for PF-02341066 to compensate for your inconvenience (i.e., travel, 
parking, meals reimbursement, etc).  
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s 
Web site at http://cancer.gov/clinicaltrials/learning/insurance-coverage/.    You can print a copy of the 
“Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send 
you a free copy. 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel 
that you have been injured because of taking part in this study.  You can tell the doctor in person or call 
him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You and/or your 
health plan will be charged for this treatment.   The study will not pay for medical treatment.   
 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in the study.  
If you decide to take part in this study, you may leave the study at any time.   No matter what decision you 
make, there will be no penalty to you and you will not lose any of your regular benefits.  Leaving the study 
will not affect your medical care.  You can still get your medical care from our institution.    
 


 
 
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We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by 
signing this form.   
 
Whether you participate or not, you will continue to get the best medical care this hospital can provide. 
 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions or concerns you have about this study.  Contact your 
study doctor __________________ [name(s)] at __________________ [telephone number]. 
 
For questions about your rights while taking part in this study, call the ________________________ 
[name of center] Institutional Review Board (a group of people who review the research to protect your 
rights) at __________________ (telephone number).  [Note to Local Investigator: Contact information 
for patient representatives or other individuals in a local institution who are not on the IRB or research 
team but take calls regarding clinical trial questions can be listed here.] 
 
Where can I get more information? 
The COG Family Handbook for Children with Cancer has information about specific cancers, tests, 
treatment side effects and their management, adjusting to cancer, and resources.  Your doctor can get you 
this Handbook, or you can get it at www.curesearch.org 
 
If you are in the United States, you may call the National Cancer Institute's Cancer Information Service at:  
1-800-4-CANCER (1-800-422-6237)  
 
A description of this clinical trial will be available at http://www.ClinicalTrials.gov, as required by U.S. 
Law. This web site will not include information that can identify you. At most, the web site will include a 
summary of the results. You can search this web site at any time. 
 
You may also visit the NCI Web site at http://cancer.gov/ 
• 
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
• 
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
You will get a copy of this form. You will be given a copy of the protocol (full study plan) upon request.  
If you want more information about this study, ask your study doctor. 
 
Signature 
 
I have been given a copy of all 12 pages of this form (including the study chart).   
I have read it or it has been read to me.  
 
I have reviewed the information and have had my questions answered.  I agree to take part in this study. 
 
Participant 
 
Signature of Participant / Parent (or Guardian) 
  
Date  


 
 
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Signature of Physician or Responsible Investigator  
 
Date  


 
 
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STUDY CHART 
(FOR ALL PATIENTS ON PARTS A, B OR C OF THIS STUDY) 
 
You will receive PF-02341066 twice a day for 28 days. This 28-day period of time is called a cycle.  
The chart below shows what will happen to you during Cycle 1 and subsequent cycles. 
 
 
 
 
 
Cycle 1 
Subsequent Cycles 
DAY 
WHAT YOU DO 
DAY 
WHAT YOU DO 
Before 
starting 
study 
Come into the clinic and do the following: 
• 
Get routine blood tests 
• 
Get urine tests 
• 
Get a physical exam by your doctor 
• 
Get an eye exam by your doctor 
• 
Get CT/MRI, MIBG or PET imaging scans (if 
required) 
• 
Get a test of bone marrow (if required)  
• 
Get a test of spinal fluid (if required)  
• 
Get an EKG 
• 
Get a bone X-ray test 
• 
Get a disease evaluation that will be done by 
your doctor. Depending on the results of this 
evaluation, your doctor will tell you whether 
or not you may begin this study. 
 
Day 1 
Come into the clinic and do the following: 
• 
Get routine blood tests 
• 
Get a physical exam by your doctor 
• 
Begin taking PF-02341066 twice a day. Keep 
taking PF-02341066 for 28 days, unless told to 
stop by your health care team 
Day 1 
Come into the clinic and do the following: 
• 
Get routine blood tests 
• 
Get urine tests 
• 
Get a physical exam by your doctor 
• 
Keep taking PF-02341066 twice a day for 28 
days if you have no bad side effects and cancer 
is not getting worse.  Call the doctor at 
_____________ [insert phone number] if you 
do not know what to do. 
Days 2-28 
• 
Continue taking PF-02341066 twice a day 
until Day 28 
• 
For the required pharmacokinetic studies in 
all patients, you will need to come into the 
clinic between day 15 and day 28 to get blood 
tests done. 
Day 2-28 
• 
Continue taking PF-02341066 twice a day 
until Day 28 
Day 28 
Come into the clinic and do the following: 
• 
Return to your doctor’s office at _______ 
[insert appointment time] for your next exam 
and to begin the next cycle. 
• 
Get routine blood tests 
• 
Get a physical exam by your doctor 
• 
Get an eye exam by your doctor 
• 
Get CT/MRI, MIBG or PET imaging scans (if 
required) 
• 
Get a test of bone marrow (if required)  
• 
Get a test of spinal fluid (if required)  
• 
Get a disease evaluation that will be done by 
your doctor. Depending on the results of this 
evaluation, your doctor will tell you whether 
or not you may continue to the next cycle and 
continue to receive PF-02341066. If you 
continue, please follow the schedule listed in 
the column under “Subsequent Cycles”. 
Day 28 
Come into the clinic and do the following: 
• 
Get routine blood tests 
• 
You will get an eye exam at the end of Cycles 
3, 5 and 7 and then every 3 cycles 
• 
You will get a bone marrow and disease 
evaluation at the end of Cycles 3, 5 and 7 and 
then every 3 cycles if you are enrolled on Part 
B. 
• 
You will get a bone marrow and disease 
evaluation at the end of Cycles 3, 7, 11, 17, 23 
and then yearly thereafter if you are enrolled 
on Part C. 
• 
Get imaging scans (if required) 
• 
Get a bone X-ray test at the end of Cycle 3  
and then approximately every 6 months 
thereafter (if required) 
• 
Depending on the results of your evaluation, 
your doctor will tell you whether or not you 
may continue to the next consecutive cycle.  If 
you continue, please repeat this schedule as 
listed under “Subsequent Cycles”.