A Phase 1 Study of Crizotinib in Combination With Conventional Chemotherapy for Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma
Phase: PHASE1
Conditions: Childhood Solid Neoplasm, Recurrent Childhood Anaplastic Large Cell Lymphoma, Recurrent Neuroblastoma
Sponsor: Children's Oncology Group

 
 
             
ADVL1212 
 
 
 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
ADVL1212 
 
A PHASE 1 STUDY OF CRIZOTINIB (
) IN COMBINATION WITH 
CONVENTIONAL CHEMOTHERAPY FOR RELAPSED OR REFRACTORY SOLID TUMORS 
OR ANAPLASTIC LARGE CELL LYMPHOMA 
 
Participation Limited to the COG Phase 1 Consortium 
 
 
 
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. 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
Activated: 
4/29/13 
Version Date: 
11/21/16 
Closed: 
7/14/17 
Amendment: 
    6 

 
 
                  
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For COG Phase 1/Pilot Consortium Operations Contacts See: http://members.childrensoncologygroup.org 
 
TABLE OF CONTENTS 
SECTION 
PAGE 
CHILDREN’S ONCOLOGY GROUP 
1 
TABLE OF CONTENTS 
2 
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 
12 
2.3 
Adult Studies 
14 
2.4 
Pediatric Studies 
16 
2.5 
Overview of Proposed Pediatric Study 
17 
2.6 
Amendment #3 to allow Crizotinib Formulated Capsules (FC) (February 2014) 
17 
2.7 
Amendment #4 to allow the Crizotinib Microspheres (cMS)  (2015) 
18 
2.8 
Amendment #6 to reflect requests made by CTEP and the FDA of Amendments #4 and #5 
(October 2016) 
19 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
20 
3.1 
Current Study Status 
20 
3.2 
IRB Approval 
20 
3.3 
Patient Registration in the COG Registry 
21 
3.4 
Reservation and Contact Requirements 
21 
3.5 
Informed Consent/Assent 
21 
3.6 
Screening Procedures 
21 
3.7 
Eligibility Checklist 
21 
3.8 
Institutional Pathology Report 
21 
3.9 
Study Enrollment 
21 
3.10 
Dose Assignment 
22 
4.0 
PATIENT ELIGIBILITY 
22 
4.1 
Inclusion Criteria 
22 
4.2 
Exclusion Criteria 
25 
5.0 
TREATMENT PROGRAM 
27 
5.1 
Overview of Treatment Plan 
27 
5.2 
Criteria for Starting Subsequent Cycles 
28 
5.3 
Dose Escalation Schema 
29 
5.4 
Grading of Adverse Events 
30 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
31 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
32 
6.1 
Dose Modifications for Hematological Toxicity 
32 
6.2 
Dose Modifications for Non-Hematological Toxicity 
32 

 
 
                  
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7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
34 
7.1 
Concurrent Anticancer Therapy 
34 
7.2 
Investigational Agents 
34 
7.3 
Supportive Care 
34 
7.4 
Growth Factors 
34 
7.5 
Concomitant Medications 
34 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
35 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
35 
8.2 
Radiology Studies 
37 
8.3 
Pharmacology (Required) 
38 
8.4 
Pharmacogenomic Studies 
38 
8.5 
Tumor Tissue Studies 
39 
8.6 
Correlative Studies for Patients with Neuroblastoma (Required) 
39 
8.7 
Correlative Studies for Patients with ALCL (Required) 
40 
9.0 
AGENT INFORMATION 
41 
9.1 
Crizotinib 
41 
9.2 
TOPOTECAN 
44 
9.3 
CYCLOPHOSPHAMIDE 
45 
9.4 
FILGRASTIM, TBO-FILGRASTIM, FILGRASTIM-SNDZ 
47 
9.5 
PEGFILGRASTIM 
48 
9.6 
Agent Accountability 
50 
9.7 
Agent Ordering 
50 
9.8 
Agent Inventory Records 
50 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
51 
10.1 
Criteria for Removal from Protocol Therapy 
51 
10.2 
Off Study Criteria 
51 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
52 
11.1 
Sample Size and Study Duration 
52 
11.2 
Definitions 
53 
11.3 
Dose Escalation and Determination of MTD (Parts A to D) 
53 
11.4 
Inclusion of Children, Women and Minorities 
54 
11.5 
Pharmacokinetic and Correlative Studies and Response Analysis 
54 
12.0 
EVALUATION CRITERIA 
55 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
55 
12.2 
Response Criteria for Patients with Solid Tumors 
55 
12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
60 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
60 
12.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
62 
12.6 
Response Criteria for Patients with ALCL 
63 
12.7 
Best Response 
64 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
67 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
67 
13.2 
When to Report an Event in an Expedited Manner 
70 
13.3 
Expedited Reporting Methods 
70 
13.4 
Definition of Onset and Resolution of Adverse Events 
72 
13.5 
Other Recipients of Adverse Event Reports 
72 
13.6 
Reporting Secondary AML/MDS 
73 

 
 
                  
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13.7 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
73 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
75 
14.1 
Categories of Research Records 
75 
14.2 
Access to Rave for Data Submission/ Data Reporting 
75 
14.3 
CDUS 
76 
14.4 
Data and Safety Monitoring Plan 
76 
REFERENCES 
77 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
79 
APPENDIX II: COMMON SUBSTRATES, INHIBITORS AND INDUCERS OF CYP3A4 
80 
APPENDIX III-B: CRIZOTINIB MICROSPHERE ADMINISTRATION INSTRUCTIONS 
82 
APPENDIX III-C: CRIZOTINIB MICROSPHERE PATIENT EDUCATION SHEET 
87 
APPENDIX IV-B: CRIZOTINIB NOMOGRAM FOR PATIENTS RECEIVING FORMULATED 
CAPSULES 
89 
APPENDIX IV-C: CRIZOTINIB NOMOGRAM FOR PATIENTS RECEIVING MICROSPHERES 
91 
APPENDIX V-B: CRIZOTINIB PATIENT DIARY (FORMULATED CAPSULES) 
94 
APPENDIX V-C1: CRIZOTINIB PATIENT DIARY (MICROSPHERES)-CYCLE 1 ONLY 
96 
APPENDIX V-C2: CRIZOTINIB PATIENT DIARY (MICROSPHERES)-CYCLE 2+ ONLY 
99 
APPENDIX VI: CORRELATIVE STUDIES GUIDE 
101 
APPENDIX VII: CORRELATIVE BIOLOGY STUDIES 
102 
APPENDIX VIII: PHARMACOGENOMIC STUDY FORM 
103 
APPENDIX IX:  TISSUE STUDIES FORM 
104 
APPENDIX X-1: PHARMACOKINETIC STUDY FORM (PARTS A-C) 
105 
APPENDIX X-2: PHARMACOKINETIC STUDY FORM FOR MICROSPHERES (PART D 
ONLY) 
106 
APPENDIX X-A:GUIDELINES FOR SHIPPING SAMPLES TO COVANCE-INDIANAPOLIS 
108 
APPENDIX XI: BONE MARROW STUDIES FORM (FOR PATIENTS WITH NEUROBLASTOMA 
ONLY) 
110 
APPENDIX XII: BONE MARROW AND PHERIPHERAL BLOOD STUDIES FORM (FOR 
PATIENTS WITH ALCL ONLY) 
111 
APPENDIX XIII: PREGNANCY INFORMATION FORM 
112 
APPENDIX XIV: POSSIBLE DRUG INTERACTIONS 
113 
APPENDIX XV: MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
115 
 

 
 
                  
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For COG Phase 1/Pilot Consortium Operations 
Contacts See: 
http:members.childrensoncologygroup.org  
 
AGENT NSC# AND IND#’s 
 
Investigational Agent 
 
Crizotinib (NSC# 749005, 
 
 
 
 
Commercial Agents 
 
Topotecan (NSC# 609699) 
 
Cyclophosphamide (NSC# 26271) 
 
 
The following are no longer study agents effective 
02/16/2016: 
Vincristine (NSC# 67574) 
Doxorubicin (NSC# 123127) 
Dexrazoxane (NSC# 169780) 
 
 
IND Sponsor:  COG 
 
 
 
 
 
 
 
 
 
 
 
 
SEE APPENDIX VIII, IX, X-A, XI, and XII FOR SPECIMEN SHIPPING ADDRESSES. 
 

 
 
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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 
 
Crizotinib is an orally bioavailable small molecule inhibitor of the c-Met/HGFR and ALK receptor tyrosine 
kinase (RTK) that has been studied extensively pre-clinically and is currently being investigated in early 
phase clinical trials for children with relapsed and refractory solid tumors and anaplastic large cell 
lymphoma (ALCL). C-Met/HGFR and ALK are two tyrosine kinases implicated in the development of 
multiple adult and pediatric malignancies.  The c-Met RTK is frequently altered or dysregulated in 
advanced cancers and has been implicated in tumor progression, and therefore represents an attractive novel 
therapeutic target.  It has been shown that the Met receptor plays a role in PAX3-PKHR-mediated 
transformation in rhabdomyosarcomas, and that MET can serve as a therapeutic target in this disease.  The 
anaplastic lymphoma kinase gene (ALK) is an orphan tyrosine kinase transmembrane receptor with 
homology to neurotrophin receptors and the MET oncogene.  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, 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 translocation in a fraction of non-small-cell lung cancers and in other solid 
tumors. ALK also 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.   Finally, it was previously shown that a substantial percentage of human-derived neuroblastoma cell 
lines express ALK transcripts and ALK proteins.  More recently, however activating mutations in the 
tyrosine kinase domain of the ALK oncogene were found to be the cause of hereditary neuroblastoma and 
these mutations can also be somatically acquired.  
 
This phase 1 study is conducted in several parts to evaluate crizotinib in combination with cytotoxic 
chemotherapy in patients with recurrent or refractory solid tumors and ALCL. In Part A, crizotinib oral 
solution is administered in combination with topotecan and cyclophosphamide, a cytotoxic chemotherapy 
regiment with activity against solid tumors including neuroblastoma, rhabdomyosarcoma, and Ewing 
sarcoma. In Part B, crizotinib oral solution is administered in combination with vincristine and 
doxorubicin/dexrazoxane, a cytotoxic chemotherapy with activity in most solid tumors and ALCL. Part C 
combines crizotinib formulated capsule and cyclophosphamide and topotecan and Part D combines 
crizotinib microsphere formulation in combination with cyclophosphamide and topotecan. Crizotinib will 
be administered orally twice daily at a starting dose of 165 mg/m2/dose and will be escalated in increments 
of ~30% to 280 mg/m2/dose, which is the recommended phase 2 dose in the single-agent phase 1 trial of 

 
 
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crizotinib (ADVL0912).  Topotecan and cyclophosphamide will be administered daily x 5 every 3 weeks. 
Vincristine and doxorubicin/dexrazoxane will be administered once every 21 days.  Pharmacokinetic and 
correlative biology studies will also be performed. 
 
The overarching goal of this study is to provide safety and tolerability data for the use of crizotinib in 
combination with chemotherapy in order to move forward with integrating crizotinib into upfront therapy 
for children with high-risk neuroblastoma, ALCL, and other malignancies with ALK aberrations. In 
addition, crizotinib may be beneficial in the upfront therapy for children with c-Met amplified or mutated 
tumors, such as rhabdomyosarcoma. 
 
As of February 16, 2016, Parts A and B of the study have been completed, no new patients will be enrolled 
to these cohorts, and all have been removed from the protocol. 
 
 
EXPERIMENTAL DESIGN SCHEMA 
 
Part C and D:  Crizotinib + Topotecan/Cyclophosphamide 
 
Part D- Cycle 1 Only 
Cycle Day 
1 
2 
3 
4 
5 
6 
7-21 
21 
CRIZ QD 
(PM) 
CRIZ BID 
Evaluation 
CPM 
CPM 
CPM 
CPM 
CPM 
 
 
TOPO 
TOPO 
TOPO 
TOPO 
TOPO 
 
 
 
 
 
 
 
MGF  
 
Part C# and Part D* 
Cycle Day 
1 
2 
3 
4 
5 
6 
7-21 
21 
CRIZ BID 
Evaluation 
CPM 
CPM 
CPM 
CPM 
CPM 
 
 
TOPO 
TOPO 
TOPO 
TOPO 
TOPO 
 
 
 
 
 
 
 
MGF 
 
 
CRIZ: crizotinib (PO) 
CPM: Cyclophosphamide (IV) 
TOPO: Topotecan (IV) 
MGF: Myeloid Growth Factor  (filgrastim [G-CSF] or biosimilar or PEG-filgrastim) 
# All cycles 
*Cycle 2+ for Part D 
 
Treatment with crizotinib will be discontinued on Part C or Part D if there is evidence of progressive disease 
or drug-related dose-limiting toxicity that requires removal from therapy. Therapy may otherwise continue 
for up to approximately 24 months. 
 
 

 
 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To estimate the recommended phase 2 dose (RP2D) or maximum tolerated dose 
(MTD) of crizotinib administered orally twice daily in combination with topotecan 
and cyclophosphamide in children with refractory/relapsed solid tumors or 
anaplastic large cell lymphoma (ALCL). 
 
1.1.2 
To define and describe the toxicities of crizotinib in combination with topotecan 
and cyclophosphamide administered on this schedule. 
 
1.1.3 
To characterize the pharmacokinetics of crizotinib in children with 
relapsed/refractory cancer when combined with either topotecan and 
cyclophosphamide or vincristine and doxorubicin/dexrazoxane. 
 
1.2 
Secondary Aims 
 
1.2.1 
To preliminarily define the antitumor activity of crizotinib in combination with 
either topotecan and cyclophosphamide or vincristine and doxorubicin/ 
dexrazoxane within the confines of a Phase 1 study. 
 
1.2.2 
To preliminarily examine the relationship between ALK status in patients with 
neuroblastoma or ALCL and response to crizotinib in combination with either 
topotecan and cyclophosphamide or vincristine and doxorubicin/dexrazoxane. 
 
1.2.3 
To preliminarily examine the relationship between MRD status and clinical 
response to crizotinib in combination with either topotecan and cyclophosphamide 
or vincristine and doxorubicin/dexrazoxane in patients with ALCL. 
 
1.2.4 
To examine ALK and c-Met expression, copy number and mutations status in 
archival tumor tissue from solid tumor and ALCL patients.   
 
  
1.2.5 
To use a questionnaire to gather information on the acceptability of the crizotinib 
capsule formulation.   
 
1.2.6 
To use a questionnaire to gather information on the acceptability of the crizotinib 
microsphere formulation.  
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
 
2.1.1 
Rationale For Part A Chemotherapy Backbone 
The regimen of intravenous topotecan and cyclophosphamide has been studied in 
multiple pediatric cancers.  It was initially studied in a Phase 1 clinical trial 
conducted by the Pediatric Oncology Group.  The combination was determined to 
be safe, with neutropenia being the dose limiting toxicity. Responses were seen in 
patients 
with 
Wilms’ 
tumor, 
neuroblastoma, 
rhabdomyosarcoma 
and 
osteosarcoma.1 This was followed by a Phase 2 study in children with recurrent or 

 
 
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refractory solid tumors.  Again, the therapy was found to be well tolerated with 
responses (CR+PR) in children with rhabdomyosarcoma (10/15), neuroblastoma 
(6/13) and Ewing sarcoma (6/17).  Stabilization of disease was seen in 
osteosarcoma, although objective responses were rare.1  
 
The Children’s Oncology Group (COG) conducted a randomized Phase 2 trial of 
topotecan and cyclophosphamide compared to topotecan alone in children with 
recurrent or refractory neuroblastoma and found progression free survival (PFS) 
to be significantly better for patients receiving the combination versus topotecan 
alone.2   A pilot study through COG (ANBL02P1) has demonstrated the 
feasibility/tolerable toxicity of the dose-intensive topotecan/cyclophosphamide 
administration and ability to harvest peripheral blood stem cells following this 
regimen. This combination is now embedded into the induction chemotherapy 
regimen in the COG phase III (ANBL0532) trial for treatment of patients with 
high-risk neuroblastoma.   
 
The combination of topotecan and cyclophosphamide was also studied in a Phase 
2 window trial for children with newly diagnosed metastatic rhabdomyosarcoma.  
The overall response rate (complete + partial response) to the combination was 
47%, demonstrating that it is a combination that is active against newly diagnosed 
rhabdomyosarcoma.3 While not necessarily curative, the combination of topotecan 
and cyclophosphamide induces a response in patients with a variety of tumor types, 
is well tolerated and can be administered as an outpatient.  As these agents are 
particularly active in tumors that have been shown to be affected by alterations in 
c-Met and/or ALK, it is a rational backbone to combine with crizotinib in order to 
assess toxicity. 
 
2.1.2 
Rationale For Part B Chemotherapy Backbone 
Vincristine and Doxorubicin are active agents in the treatment of most solid 
tumors, leukemias and lymphomas.   
 
Weinstein and colleagues studied 29 patients treated for large cell lymphoma with 
APO therapy.  The protocol included induction with vincristine, adriamycin and 
prednisone (APO), followed by a consolidation stage adding mercatopurine and 
asparaginase to APO and maintenance with APO plus 6-MP and Methotrexate.  
Overall survival and event free survival were 83% and 76% respectively; thus, this 
regimen was subsequently adopted as standard of care of large cell lymphoma.4 
Further studies by the Pediatric Oncology Group found that the addition of 
cyclophosphamide did not improve outcomes, whereas the addition of 
intermediate dose methotrexate and high dose cytarabine was inconclusive due to 
insufficient power in the study to detect a difference between the two arms.5  Based 
on these results, APO has been chosen as the standard of care for children with 
ALCL and ongoing studies continue to look at the addition of other conventional 
chemotherapeutic agents to this combination.  
 
Upfront therapy for solid tumors including Ewing sarcoma, neuroblastoma, 
osteosarcoma, rhabdomyosarcoma and many others includes either vincristine or 
doxorubicin, if not both.  Based on the vast amount of pediatric malignancies in 
which these two agents have activity, vincristine and doxorubicin are a logical 
combination for which to add crizotinib.  
 
 

 
 
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2.1.3 
Rationale for the use of Crizotinib 
Crizotinib is an orally bio-available, selective small molecule inhibitor of c-
Met/HGFR and ALK receptor tyrosine kinase.  In preliminary biochemical 
screens, crizotinib inhibited HGF-stimulated or constitutive total tyrosine 
phosphorylation of wild type c-Met/HGFR with a mean IC50 value of 11nm across 
a panel of human tumor cell lines.  In addition, crizotinib demonstrated potent 
activity against NPM-ALK in a human lymphoma cell line (IC50 24 nM).6 
 
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.  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. 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.7  Activating 
mutations in c-Met have been identified in multiple adult solid tumors.  In addition, 
C-Met is widely expressed in both alveolar and embryonal rhabdomyosarcoma.  
High levels of expression are associated with unfavorable clinical features and 
tumor marrow involvement.8 
 
Anaplastic lymphoma kinase (ALK) is an orphan receptor tyrosine kinase first 
identified as part of the t(2;5) chromosomal translocation associated with most 
ALCLs and a subset of T-cell non-Hodgkin lymphomas.9 ALK and its mutant 
translocation with the nucleophosmin gene (NPM-ALK) results in a constitutively 
active ALK receptor tyrosine kinase expressed in 80% of ALCLs.10 Crizotinib has 
demonstrated potent activity against NPM-ALK in both in vitro and in vivo 
models.  
 
In addition to its role in ALCL, it has recently become clear that several other 
human cancers activate ALK signaling.  This is achieved by creating unique 
oncogenic fusions of the ALK gene at chromosomal band 2p23 with a variety of 
partners through chromosomal translocation events, resulting in the generation of 
oncogenic ALK fusion genes and their encoded proteins.  These oncogenic fusion 
proteins lead to constitutive activation of the ALK kinase domain and have been 
identified in various solid tumors including myofibroblastic tumors, squamous cell 
carcinomas, and non-small cell lung cancers.10 Most notably, in a phase 1 trial of 
crizotinib in a pretreated population of patients with ALK+ NSCLC that generally 
has a 10% response rate to conventional chemotherapy, treatment with crizotinib 
yielded an overall response rate of 55% and estimated 6-month progression-free 
survival rate of 72%.11,12 
 
It has recently been discovered that germline mutations in ALK are the major cause 
of hereditary neuroblastoma and can also be somatically acquired in 8-10% of 
sporadic cases.13-16 ALK mutations are also present in a substantial subset of high-
risk neuroblastoma due to somatic mutation.  Preclinical data in neuroblastoma 
confirm the oncogenic potential of mutated ALK, and pharmacologic inhibition of 
ALK validates feasibility of a targeted approach in this tumor type.17  These data 
have also established the differential sensitivity between various mutations, with 
reduced sensitivity of F1174-expressing cells secondary to an increased affinity 
for ATP,17 providing the rationale for an increase in dosage to overcome the 
relative difference in ATP-affinity. 

 
 
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Recent studies have suggested an oncogenic role for full-length ALK in thyroid 
cancer 18 and rhabdomyosarcoma.19 It is clear that ALK is one of the few 
oncogenes activated in both hematopoietic and non-hematopoietic malignancies 
and represents a tractable target for innovative therapies on the basis of selective 
inhibition of its tyrosine kinase activity. 
 
2.2 
Preclinical Studies 
 
2.2.1 
Antitumor Activity 
Consistent with its predicted mechanism of action, crizotinib inhibits target 
dependent tumor cell proliferation or invasion, induces tumor cell apoptosis, and 
inhibits angiogenesis in preclinical tumor models. Furthermore, oral 
administration 
of 
crizotinib 
demonstrated 
efficacy, 
including 
marked 
cytoreductive antitumor activity, in several tumor models that expressed activated 
c-Met/HGFR or NPM-ALK.  
 
Preclinical in vitro and in vivo data demonstrate that crizotinib 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, 
crizotinib potently inhibited human GTL-16 gastric carcinoma cell growth, HGF-
stimulated human NCI-H441 lung carcinoma cell migration and invasion with IC50 
ranging from 6.1 to 16 nM.20  
 
In Karpas 299 ALCL, cells that express an NPM-ALK fusion protein due to a t(2;5) 
chromosomal translocation, crizotinib inhibited proliferation at an IC50 of 60 nM.  
Growth inhibition in these NPM-ALK positive lymphoma cells was associated 
with G0/G1 cell cycle arrest and induction of apoptosis.6 When investigated for 
potential anti-angiogenic activity, crizotinib inhibited HGF-mediated HUVEC 
endothelial cell survival (IC50-11nM) and matrigel invasion (IC50=35nM) as well 
as HMVEC endothelial cell tubulogenesis in fibrin gels, with IC50’s of 11nM to 
approximately 80nM.20  
 
In the Karpas 299 NPM-ALK positive human ALCL lymphoma tumor model, 
administration of crizotinib at 100 mg/kg/day resulted in complete regression of 
tumors for all mice in this dosing cohort within 15 days of the initial compound 
administration.   After 17 days, crizotinib was stopped, resulting in tumor re-
growth.  When tumors grew to a larger size (> 600 mm3), crizotinib treatment was 
re-initiated for an additional 13 days and complete regression of tumor was once 
again demonstrated.6 
 
The antitumor activity of crizotinib has also been evaluated in a variety of human 
tumor xenograft models in which dysregulation of c-Met/HGFR is implicated.  
Crizotinib 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.  It also demonstrated near complete 
tumor growth inhibition in both the U87MG glioblastoma (97% growth inhibition) 
and PC-3 prostrate carcinoma (87% growth inhibition) at 50mg/kg/day.  In models 
in which multiple dose levels were evaluated, dose-dependent inhibition of tumor 
growth correlated with inhibition of c-Met/HGFR phosphorylation.  In these 

 
 
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studies it was observed that complete inhibition of c-Met/HGFR was achieved for 
the full dosing interval at 50 mg/kg/day.20 
 
Preliminary Activity of Crizotinib in Neuroblastoma 
Mutations in the ALK proto-oncogene are the major cause of hereditary 
neuroblastoma and are also somatically acquired in sporadic primary tumors.  
Systematic re-sequencing of 1600 sporadic neuroblastoma tumors obtained at 
diagnosis and representative of the natural spectrum of this disease confirms that 
ALK is mutated in 8% of cases and mutations are distributed across the spectrum 
of phenotypes, as shown in a prior meta-analysis.21 The R1275 mutation occurs 
most frequently, as it does in the germline of patients with hereditary 
predisposition,13 and is detected in close to 50% of tumors with an ALK mutation 
followed by F1174 and F1245, with these 3 amino acid locations accounting for 
86% of all mutations and all reported to be constitutively active.17,22 Other 
predictive valuable biomarkers have been proposed for ALK tyrosine kinase 
inhibition in neuroblastoma, notably mRNA ALK expression,23 and native ALK 
protein expression measured by immunohistochemistry,24,25 suggesting that these 
are biomarkers of mutation-independent ALK activation. 
 
Neuroblastoma cell lines driven by an ALK mutation or amplification are sensitive 
to crizotinib. Cell lines and xenografts that express R1275Q-ALK, one of the two 
most commonly occurring mutations, are highly sensitive. By contrast, those 
expressing the F1174L-ALK are more resistant to crizotinib in vitro and in vivo. 
Biochemical analyses linked the reduced susceptibility of F1174L-mutated ALK 
to crizotinib 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.17 
 
2.2.2 
Animal Toxicology 
The primary 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 treatment at 20 mg/kg/day.  
Repeated administration of crizotinib 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 rates.  Crizotinib 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 crizotinib administration involved 
genetic toxicity findings, and other findings of uncertain risk to humans including 

 
 
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decreased cellularity in lymphoid organs, elevated liver enzymes, potential for 
phototoxicity, and effects on the salivary glands. 
 
2.2.3 
Preclinical Pharmacokinetic Studies 
The pharmacokinetics of a single oral dose of crizotinib was studied in mice at the 
dose that produced the optimal therapeutic effect in neuroblastoma xenografts (200 
mg/kg ≈ 80 mg/m2).  A one-compartmental 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 
AUC0-24h 
116 
mcg•h/mL 
AUC0-∝ 
147 
mcg•h/mL 
Steady state trough concentration (C12h) 
8.8 
mcg/mL 
Half-life (t1/2) 
12 
H 
 
One cannot directly extrapolate from the mouse model to the human given the 
marked intra-species differences in protein binding between mice and humans 
(96% versus 91%).  Once you correct for protein binding, then the free drug 
concentration is still 5-fold higher than the free drug concentration in humans. 
When these differences are taken into consideration, exposures required for 
preclinical anti-tumor activity are achievable in children. Specifically, the free 
drug exposure in mice treated at 200 mg/kg, which is equivalent to ~80 mg/m2, is 
achievable in pediatric patients.  Please refer to Section 2.4.2 for further discussion 
of the pharmacokinetics of crizotinib in children. 
 
2.3 
Adult Studies 
 
2.3.1 
Phase 1 Studies 
Crizotinib was studied in a Phase 1 clinical trial for patients with refractory solid 
tumors in order to determine toxic effects and maximum tolerated dose of single 
agent crizotinib.  This was 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, crizotinib was administered under fasting 
conditions QD or BID on a continuous schedule.   Thirty-seven patients were 
treated in the dose escalation part of the trial.  Three DLT’s were 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.  In the expanded cohort, 
patients were treated with 250 mg twice daily.  Grade 1 nausea and diarrhea were 
the most commonly reported side effects.  Nausea and emesis were independent of 
dose or duration of treatment and were effectively managed using IV or oral 
antiemetics.  Diarrhea was effectively controlled by anti-diarrheals.   In addition, 
Grade 1 visual disturbances were reported in 41% of patients consisting mainly of 
seeing shadows or streaks during changes in light.  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 
experienced Grade 3 or Grade 4 increases in ALT.  These events occurred within 
the first cycle of treatment.  Patients were asymptomatic and the ALT increases 

 
 
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were reversible upon discontinuation of study medication.  Only one patient 
discontinued treatment due to an increase in ALT levels.11    
 
In a review of safety for crizotinib, Pfizer has determined that there are 4 potential 
cases of pneumonitis in patients with NSCLC, which may be related to crizotinib. 
The frequency of non-radiation recall as of September 2012 is 1.6%. One of the 4 
cases was fatal. The 3 other patients were permanently discontinued from the study 
and fully recovered. Interpretation of the 4 non-radiation recall cases was 
complicated by the underlying non-small cell lung cancer for which patients were 
being treated. In addition, 3 cases were complicated by the co-administration of 
other drugs known to potentially cause pneumonitis and/or other pulmonary 
complications.  
 
With more than 1400 patients who have been treated with crizotinib, there are 2 
cases of fatal hepatic failure reported as serious adverse events related to crizotinib 
treatment.   
 
To date, there have been no phase 1 studies of crizotinib in combination with 
chemotherapy in adults. 
 
2.3.2 
Phase 2 Studies 
There is currently an on-going phase 2 trial of crizotinib in adults with locally 
advanced or metastatic non-small cell lung carcinoma. 
 
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.26 After oral administration of crizotinib 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. Crizotinib showed time-dependent inhibition of CYP3A isozymes in 
human liver microsomes. In order to assess the effect of crizotinib 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 crizotinib at 250 mg BID in 13 patients.26 A 
3.6-fold (90% CI: 2.7-4.9) increase in the oral midazolam AUC was observed 
following 28 days of crizotinib dosing at 250 mg BID, suggesting that crizotinib 
is a moderate inhibitor of CYP3A. 

 
 
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2.4 
Pediatric Studies 
 
2.4.1 
Prior Experience in Children  
The Children’s Oncology Group is currently conducting a Phase 1/2 study of 
crizotinib in children with relapsed/refractory solid tumors and Anaplastic Large 
Cell Lymphoma (ADVL0912). The Phase 1 dose escalation started at 100 
mg/m2/dose BID and has escalated to dose level 6 (365 mg/m2/dose). In the Phase 
1 trial, there were not any hematologic DLTs observed during the first cycle at 
100, 130, or 165 mg/m2/dose BID; at dose level 4 (215 mg/m2/dose BID), 1 subject 
experienced grade 3 dizziness, probably related to study drug, and 1 subject with 
a CNS tumor experienced grade 5 intra-tumoral CNS hemorrhage, possibly related 
to study drug. During cycle 2 of therapy, one subject at dose level 2 (130 
mg/m2/dose BID) with a CNS tumor experienced a grade 4 intra-tumoral CNS 
hemorrhage, with an attribution of unlikely related to study drug. More than 300 
adult patients with tumor metastases to the brain have been treated with crizotinib 
without experiencing an intra-tumoral hemorrhage. One subject at dose level 6 
(365 mg/m2/dose BID) experienced grade 4 ALT, AST, GGT and Alkaline 
Phosphatase, likely related to study drug; a second subject at this dose-level 
experienced grade 4 neutropenia also likely related to study drug. As a result, the 
maximum tolerated dose on the phase 1 trial of crizotinib is 280 mg/m2/dose BID. 
 
The A2 portion of the ADVL0912 phase 1 trial has enrolled patients with ALK+ 
relapsed or refractory neuroblastoma, ALCL, and other tumors activated by ALK 
or MET.  Nine patients with ALK-translocated anaplastic large cell lymphoma 
were enrolled and eight of the nine patients had measurable radiographic disease.  
Six of these patients had a complete response, one had a partial response and one 
had stable disease.  Eleven patients with neuroblastoma with known ALK 
mutations were enrolled with one patient experiencing a complete response and 
two with stable disease.  An additional 23 patients with neuroblastoma and 
unknown ALK status were treated with one patient experiencing a complete 
response and five additional patients with prolonged stable disease.27 
 
Part B, the phase 2 portion of ADVL0912 for patients with neuroblastoma and a 
known ALK aberration has been completed and results are being analyzed. 
 
2.4.2 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
Nineteen children enrolled on the pediatric phase 1 trial had adequate 
pharmacokinetic sampling after the first dose of crizotinib.   The disposition of 
crizotinib in children was highly variable (apparent clearance [CL/F] ranged from 
9 to 276 L/m2/h).  The relationship between dose and AUC of crizotinib 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 215mg/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, 

 
 
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auto-induction of metabolism may also impact the steady-state AUC.  To address 
this, the ongoing Phase 1/2 trial is performing steady state PK, which can be 
compared to the exposures in preclinical models.  Data is currently available for 
all 6 patients at dose level 5 and for 4 patients at dose level 6.  The data show peak 
crizotinib concentrations of 2 µM at the highest dose level and greater than 1.5 µM 
average concentrations.  These levels are expected to result in inhibition of growth 
in ALK driven neuroblastomas.  Preclinical data in a wide range of ALK mutated 
neuroblastoma models demonstrated that average concentrations of ≥ 1 µM are 
necessary to obtain significant anti-tumor activity.   
 
2.5 
Overview of Proposed Pediatric Study 
This will be a phase 1 study of crizotinib in combination with either topotecan and 
cyclophosphamide or vincristine and doxorubicin/dexrazoxane for children with relapsed 
or refractory solid tumors or ALCL.   The primary aim of this study will be to determine if 
these combinations are safe and tolerable.  Crizotinib will be administered orally twice 
daily with the starting dose of 165 mg/m2/dose.  We will then dose escalate to target the 
MTD of 280 mg/m2/dose BID established in the single-agent phase 1 trial of crizotinib 
(ADVL0912). 
 
Children will be enrolled on either Part A or Part B per the treating physician’s choice and 
availability of a reservation.  Children enrolled on Part A will receive topotecan 0.75 
mg/m2/dose IV x 5 days and cyclophosphamide 250 mg/m2/dose IV x 5 days every 3 weeks 
in addition to the crizotinib.  Children on Part B will receive vincristine 1.5 mg/m2/dose IV 
and doxorubicin 45 mg/m2 IV on day 1 every 3 weeks in addition to the crizotinib.  
Dexrazoxane (450 mg/m2) will be administered for children who have had an anthracycline 
exposure ≥ 350 mg/m2.  Doxorubicin will be omitted after cycle 2 for patients who have 
had a total anthracycline dose ≥ 750 mg/m2.  Patients may continue on therapy until there 
is evidence of progressive disease or drug-related dose-limiting toxicity that requires 
removal from therapy. Therapy may otherwise continue for up to 24 months. Eligibility 
will include all patients with relapsed/refractory solid tumors or ALCL.  
 
To assess potential biological correlates of efficacy, we will examine (when available) 
banked tumor DNA as well as tissue blocks from diagnosis or relapse 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.  In 
addition, IHC for ALK and c-Met expression will be performed in participating subjects 
with sarcomas. 
 
2.6 
Amendment #3 to allow Crizotinib Formulated Capsules (FC) (February 2014) 
 
As of February 2014, a total of 21 patients have been treated on ADVL1212. Ten subjects 
were enrolled on Part A and 11 subjects on Part B.   
 
On Part A, Dose Level 1 was expanded to 6 subjects after 1 subject experienced a 
hematologic DLT of Grade 3 febrile neutropenia and Grade 4 neutropenia.  There were no 
additional hematologic DLTs at this dose level and ultimately the patient with Grade 3 
febrile neutropenia and Grade 4 neutropenia was found to be inevaluable for hematologic 
DLT due to bone marrow involvement of their disease.  Additionally, following this, 
Amendment #1 was approved to exclude Grade 3 and 4 febrile neutropenia as a DLT as 
this is an expected event given the combination chemotherapy backbones.  At Dose Level 

 
 
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1, 1 of 6 patients experienced a non-hematologic DLT of Grade 3 nausea.  Given this, the 
dose was escalated.  At Dose Level 2, 1 of 3 evaluable patients thus far has experienced a 
non-hematologic DLT of Grade 3 diarrhea.  There have been no hematologic DLTs on Part 
A at Dose Level 2.  
 
On Part B, an initial cohort of 3 subjects were enrolled; however, 2 were found to be 
inevaluable for DLT as their eligibility studies were performed outside the required time 
frame, so an additional 2 subjects were enrolled.  None of the 3 evaluable subjects 
experienced a hematologic or non-hematologic DLT. Thus, Part B was escalated to Dose 
Level 2.  Again, there were no hematologic or non-hematologic DLTs at Dose Level 2.  At 
Dose Level 3, 2 out of 3 subjects experienced non-hematologic DLT of Grade 3 nausea in 
1 subject and Grade 4 QTc prolongation and Grade 3 dehydration in another subject.  The 
third subject at this dose level was found to be ineligible for the study.   
 
Due to the possibility that many of the non-hematologic DLTs observed to date on the 
study are related to the palatability of the OS rather than due to true toxicity of the 
investigational agent, Amendment #3 will only allow the administration of FCs to patients 
with a BSA of ≥ 1.07 m2 (Part C). To ensure that the non-hematologic DLTs are truly due 
to the palatability of the OS, the starting dose for Amendment #3 will be 165 mg/m2 BID, 
the same starting dose as for Parts A and B. With Amendment #3 we will no longer utilize 
the vincristine/doxorubicin/dexrazoxane chemotherapy backbone and will study the 
investigational agent in combination with topotecan and cyclophosphamide only (Part 
C).   The ongoing COG study ANHL12P1 is utilizing crizotinib at 165 mg/m2 BID in 
combination with a multi-agent chemotherapy backbone that includes doxorubicin.  The 
data regarding the safety and tolerability of crizotinib in combination with chemotherapy 
from the ANHL12P1 trial and Part C of this trial will be utilized to inform the 
recommended dosing of crizotinib for future studies. 
 
With Amendment #3, patients will no longer be accrued to Parts A and B of the study; an 
additional 29 patients to Parts C may be required to determine the MTD/ RP2D of this 
three-drug regimen (Section 11.1), assuming a 20% inevaluability rate. The study was 
expected to accrue a maximum of 50 patients. 
 
2.7 
Amendment #4 to allow the Crizotinib Microspheres (cMS)  (2015) 
With Amendment #4, the newly developed crizotinib coated microsphere sprinkle 
formulation will be studied at the MTD/ RP2D determined from Part C. Pfizer has 
developed this formulation to address the poor taste of the oral solution and eliminate this 
factor as a barrier to medication administration for children.  The microsphere sprinkles 
have a pH coated trigger membrane designed to taste neutral in the mouth (pH > 6), and to 
lose their coating and be absorbed in the stomach (pH < 5.5). The microphere sprinkles 
will be dispensed onto a dosing spoon and subsequently mixed with water for 
administration.   
 
A taste and relative bioavailability study of the coated microsphere (cMS) formulation  has 
been completed in adult healthy subjects. While the limited number of subjects (n=12) in 
this study was not designed for an bioequivalence, results showed that the cMS formulation 
almost met the bioequivalence criteria, with a relative bioavailability of 94.28% (90% CI: 
83.88%, 105.97%) in AUCinf and 90.58% (90% CI: 79.88%, 102.72%) in Cmax, compared 
with the commercial formulated capsule (FC) formulation. Based on the evaluation of taste 
sensory attributes (overall liking, mouth feel, bitterness and tongue/mouth burn) using a 
“swirl and spit” technique and oral administration, the cMS formulation performed 

 
 
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significantly better than an equivalent dose of oral solution (OS) formulation that were 
used previously   
 
Of note, at a pH ≥ 5.5, the dissolution of the cMS barrier membrane is delayed and at even 
higher pH levels will likely be shut down.  This is of significant consideration for patients 
taking agents elevating gastric pH including proton pump inhibitors (PPIs) and histamine-
2 receptor (H2) antagonists/ blockers. Therefore, patients should avoid taking PPIs and H2 
antagonists/ blockers when adiminstered with crizotinib cMS formulation.    
 
 
2.8 
Amendment #6 to reflect requests made by CTEP and the FDA of Amendments #4 
and #5 (October 2016) 
As of February 16, 2016, Part A (Crizotinib (OS) and Topotecan/Cyclophosphamide) and 
Part B (Crizotinib (OS) and Vincristine/Doxorubicin/Dexrazoxane) were completed. No 
patients are currently enrolled or receiving protocol therapy. The relevant sections have 
been removed from the protocol. Additionally, language has been revised to clarify the 
completion and closure of Parts A and B of study. 
 
 

 
 
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3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
Patient enrollment for this study will be facilitated using the Slot-Reservation System in 
conjunction with the Oncology Patient Enrollment Network (OPEN), a web-based registration 
system available on a 24/7 basis. It is integrated with the NCI Cancer Trials Support Unit (CTSU) 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient 
position in the RAVE database. 
 
Access requirements for OPEN:  
Investigators and site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account (check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >). This is the same account 
(user id and password) used for credentialing in the CTSU members' web site. To perform 
registrations in OPEN, the site user must have been assigned the 'Registrar' role on the relevant 
Group or CTSU roster. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on 
the CTSU members’ side of the website at https://www.ctsu.org. 
 
3.1 
Current Study Status  
Investigators should refer to the CTSU OPEN (Oncology Patient Enrollment Network)   
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://open.ctsu.org/open/  
2. Click the Slot Reservation Tab. The Site Patient page opens.  
3. Click the Report Tab. The Slot Reservation Report opens. Available Slots 
are detailed per study strata. 
 
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 and other required regulatory documents 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).  
 
Regulatory 
documents 
may 
be 
faxed 
(1-215-569-0206), 
emailed 
(CTSURegulatory@ctsu.coccg.org) or mailed to the CTSU Regulatory office.   
 
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. 
 
Study centers can check the status of their registration packets by querying the RSS site 
registration status page of the members’ section of the CTSU website.  (Note: Sites will 
not receive formal notification of regulatory approval from the CTSU Regulatory Office.) 
 
 

 
 
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3.3 
Patient Registration in the COG Registry 
Prior to enrollment on study, patients must be assigned a COG patient ID number. This 
number is obtained via the COG Registry system once authorization for the release of 
protected health information (PHI) has been obtained. 
 
3.4 
Reservation and Contact Requirements 
Before enrolling a patient on study, a reservation must be made in OPEN and the Study 
Chair or Vice Chair should be notified. (The patient will need a COG patient ID 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 OPEN website.  
 
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) an IRB-approved institutional screening 
protocol or b) 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 uploaded 
into RAVE immediately following enrollment.  
 
3.8 
Institutional Pathology Report 
Immediately following enrollment, the institutional pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into RAVE. The report 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. 
 
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 CTSU OPEN (Oncology Patient Enrollment Network) 
https://open.ctsu.org/open/.  For questions, please contact the CTSU OPEN helpdesk at 
https://www.ctsu.org/CTSUCOntact.aspx or the ADVL1212 COG Research Coordinator. 
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. 

 
 
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Patients must not receive any protocol therapy prior to enrollment. 
 
3.10 
Dose Assignment 
The dose level will be assigned via OPEN 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. Laboratory values used to assess eligibility must be no older 
than seven (7) days at the start of therapy.  Laboratory tests need not be repeated if therapy starts 
within seven (7) days of obtaining labs to assess eligibility.  If a post-enrollment lab value is outside 
the limits of eligibility, or laboratory values are older than 7 days, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with differential, 
bilirubin, ALT (SGPT) and serum  creatinine.  If the recheck is outside the limits of eligibility, the 
patient may not receive protocol therapy and will be considered off protocol therapy. Imaging 
studies, bone marrow aspirate and biopsy must be obtained within 14 days prior to start of protocol 
therapy (repeat the tumor imaging if necessary).  
 
 
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th.   
 
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 
Diagnosis: Patients must have had histologic verification of malignancy at original 
diagnosis or relapse. All patients with relapsed or refractory solid tumors or 
anaplastic large cell lymphoma (ALCL) are eligible except for patients with 
primary or metastatic CNS tumors or patients with primary cutaneous ALCL.  
 
4.1.3 
Disease Status: Patients must have either measurable or evaluable disease (see 
Sections 12.2 and 12.3 for definitions).  
 
4.1.4 
Therapeutic Options: Patient’s current disease state must be one for which there is 
no known curative therapy or therapy proven to prolong survival with an 
acceptable quality of life. 
  
Performance Level:  Karnofsky ≥ 60% 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. 

 
 
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4.1.5 
Prior Therapy 
4.1.5.1 Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer therapy and must meet the following minimum duration from 
prior anti-cancer directed therapy prior to enrollment. If after the required 
timeframe, the numerical eligibility criteria are met, e.g. blood count 
criteria, the patient is considered to have recovered adequately. 
 
a. Myelosuppressive chemotherapy:   
i. 
Solid Tumors: At least 21 days after the last dose of 
myelosuppressive chemotherapy (42 days if prior nitrosourea).  
ii. ALCL: 
• 
Patients with ALCL who relapse while receiving standard 
maintenance chemotherapy will not be required to have a 
waiting period before enrollment onto this study. 
• 
Patients who relapse while they are not receiving standard 
maintenance therapy, must have fully recovered from all 
acute toxic effects of prior therapy. At least 14 days must 
have elapsed after the completion of cytotoxic therapy.  
 
b. Hematopoietic growth factors: At least 14 days after the last dose of a 
long-acting growth factor (e.g. Neulasta) or 7 days for short-acting 
growth factor.  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.  
 
c. Biologic (anti-neoplastic agent):  At least 7 days after the last dose of 
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. Immunotherapy: At least 42 days after the completion of any type of 
immunotherapy, e.g. tumor vaccines. 
 
e. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be 
recovered to Grade ≤ 1. 
 
f. Corticosteroids: See Section 4.2.2.1. If used to modify immune 
adverse events related to prior therapy, ≥ 14 days must have elapsed 
since last dose of corticosteroid. 
 
g. XRT:   
i. 
Solid Tumors: At least 14 days after local palliative XRT (small 
port); ≥ 6 weeks must have elapsed since treatment with 
therapeutic doses of MIBG; At least 150 days must have elapsed 
if prior TBI, craniospinal XRT or if ≥ 50% radiation of pelvis; At 
least 42 days must have elapsed if other substantial BM radiation. 
 
ii. ALCL: At least 14 days after local palliative XRT (small port); At 

 
 
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least 84 days must have elapsed if prior TBI, craniospinal XRT or 
if ≥ 50% radiation of pelvis; At least 42 days must have elapsed if 
other substantial BM radiation. 
 
h. Stem Cell Infusion without TBI:  No evidence of active graft vs. host 
disease and at least 84 days must have elapsed after transplant and ≥ 
42 days for autologous stem cell infusion after I131-MIBG therapy. 
 
i. 
Patients must not have received prior therapy with crizotinib. 
 
4.1.6 
Organ Function Requirements 
 
4.1.6.1 Adequate Bone Marrow Function Defined as: 
 
a. For patients with solid tumors or ALCL without known bone marrow 
involvement: 
• 
Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 
• 
Platelet count ≥ 100,000/mm3 (transfusion independent, defined 
as not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
 
b. Patients with known bone marrow metastatic disease will be eligible 
for study provided they meet the blood counts in 4.1.6.1.a (may 
receive transfusions provided they are not known to be refractory to 
red cell or platelet transfusions). These patients will not be evaluable 
for hematologic toxicity. If dose-limiting hematologic toxicity is 
observed, all subsequent patients enrolled must be evaluable for 
hematologic toxicity. 
 
4.1.6.2 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 GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC. 
 
4.1.6.3 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. 
 

 
 
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4.1.6.4 Adequate Cardiac Function Defined as: 
• 
QTc ≤ 480 msec;  
 
Note: Patients should avoid concomitant medication known or suspected to 
prolong QTc interval or cause Torsades De Pointes. If possible, 
alternative agents should be considered. Patients who are receiving 
drugs that prolong the QTc are eligible if the drug is necessary and no 
alternatives are available. See Appendix XV for drugs that may 
prolong the QTc. Patients with Grade 1 prolonged QTc (450-480 
msec) at the time of study enrollment should have correctable causes 
of prolonged QTc addressed if possible (i.e., electrolytes, 
medications). 
Patients 
with 
bradyarrhythmias, 
electrolyte 
abnormalities, or who receive concomitant medications that may 
prolong the QTc should be carefully monitored. 
 
4.1.7 
Informed Consent: All patients and/or their parents or legally authorized 
representatives must sign a written informed consent. Assent, when appropriate, 
will be obtained according to institutional guidelines.  
 
4.1.8 
Body Surface Area (BSA): 
4.1.8.1 Part C: Patients must have a BSA ≥ 1.07 m2 at the time of study 
enrollment.  
4.1.8.2 Part D: Patients must have a BSA ≥ 0.43 m2 at the time of study 
enrollment. 
 
4.1.9 
Tumor tissue must be sent per Section 8.5. If tumor tissue is unavailable, the study 
chair must be notified prior to enrollment. 
 
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 may 
be fetal risks 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 during 
treatment and for 3 months after stopping treatment. 
 
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 at least 7 days prior to 
enrollment are not eligible. If used to modify immune adverse events 
related to prior therapy, ≥ 14 days must have elapsed since last dose of 
corticosteroid (See Section 4.1.5.1.f). 
 
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 are not eligible. 
 

 
 
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4.2.2.4 Anti-GVHD agents post-transplant: Patients who are receiving 
cyclosporine, tacrolimus or other agents to prevent graft-versus-host 
disease post bone marrow transplant are not eligible for this trial. 
                                  
4.2.2.5 CYP3A4 Substrates with Narrow Therapeutic Indices:  
As crizotinib 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. 
 
4.2.2.6 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. 
 
4.2.2.7 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. 
 
4.2.2.8 Proton Pump Inhibitors (PPIs) or H2 blockers: Patients receiving PPIs and 
H2 blockers are not eligible for Part D. 
 
4.2.3 
Infection:  Patients who have an uncontrolled infection are not eligible. 
 
4.2.4 
Patients who have received a prior solid organ transplantation are not eligible. 
 
4.2.5 
Patients who have a primary or metastatic CNS tumor at the time of study 
enrollment are not eligible.  A prior history of metastatic CNS tumor is allowed as 
long as there is no evidence of CNS disease at study enrollment. 
 
4.2.6 
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. 
 
4.2.7 
Drug Administration:  
4.2.7.1 Part C: Patients must be able to swallow intact capsules. 
 
4.2.7.2 Part D: Patients must be able to swallow liquid.  
  
 

 
 
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5.0 
TREATMENT PROGRAM 
 
5.1 
Overview of Treatment Plan 
 
Part C and Part D:  Crizotinib + Topotecan/Cyclophosphamide 
 
 
               Part D - Cycle 1 Only 
Cycle Day 
1 
2 
3 
4 
5 
6 
7-21 
21 
CRIZ QD 
(PM) 
CRIZ BID 
Evaluation 
CPM  
CPM 
CPM 
CPM 
CPM 
 
 
TOPO  
TOPO 
TOPO 
TOPO 
TOPO 
 
 
 
 
 
 
 
MGF  
 
 
               Part C# and Part D* 
Cycle Day 
1 
2 
3 
4 
5 
6 
7-21 
21 
CRIZ BID 
Evaluation 
CPM 
CPM 
CPM 
CPM 
CPM 
 
 
TOPO 
TOPO 
TOPO 
TOPO 
TOPO 
 
 
 
 
 
 
 
MGF 
 
 
CRIZ: crizotinib (PO) 
CPM: Cyclophosphamide (IV) 
TOPO: Topotecan (IV) 
MGF: Myeloid Growth Factor (filgrastim [G-CSF] or biosimilar or PEG-filgrastim) 
# All cycles 
*Cycle 2+ for Part D 
 
• 
Crizotinib will be administered orally twice daily, approximately 12 hours apart, 
except on Day 1 of Cycle 1 when crizotinib will be administered once daily in the 
evening (PART D patients only; refer to Section 5.1.2 for details).  If a patient vomits 
a dose of crizotinib, it will not be repeated. Dose escalation will occur as described in 
Section 5.3.1. Crizotinib should be administered at least one hour prior to 
chemotherapy on Day 1 through 5, except for Part D when Day 1 chemotherapy 
during Cycle 1 will be administered in the morning independent of the Day 1 
crizotinib dose.  Refer to Section 5.1.1 (FC) and Section 5.1.2 (cMS) for crizotinib 
formulation and treatment information.  
 
• 
Cyclophosphamide will be administered intravenously (250 mg/m2/dose) over 15-30 
minutes once daily x 5 days every 3 weeks. The use if Mesna is not required with low 
dose cyclophosphamide. Hydrate per institutional guidelines. 
 
• 
Topotecan will be administered intravenously (0.75 mg/m2/dose) over 30 minutes 
once daily x 5 days every 3 weeks. 
 
• 
Myeloid growth factor (filgrastim or biosimilar or pegylated filgrastim) should be 
initiated 24-48 hours after the completion of topotecan and cyclophosphamide for all 
patients.  Myeloid growth factor should continue until the post-nadir absolute 
neutrophil count is ≥ 2,000/mm3, and the administration of myeloid growth factor to 
the patient should cease at least 24 hours prior to starting Day 1 chemotherapy of 
subsequent cycles. 

 
 
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5.1.1 
Part C: For patients receiving the crizotinib capsule formulation (FC)  
 
Patients will receive the FC formulation only. Refer to the dosing nomogram (see 
Appendix IV-B).  
 
Patients should also be instructed to swallow the capsules whole and not to chew 
the capsule prior to swallowing. Patients should be instructed not to ingest 
crizotinib capsules that are broken, cracked, or otherwise not intact. 
 
Pre-Amendment #4 Part C patients should continue to receive their current 
formulation (FC). 
 
5.1.2 
Part D: For patients receiving the crizotinib microsphere formulation (cMS) 
 
• 
Cycle 1 Day 1: Crizotinib should be given in the evening with water so 
that a 12 hour trough concentration can be collected in the morning of Day 
2. 
 
• 
Cycle 1 Days 2-21 and Subsequent Cycles (Days 1-21): The dose can 
only be administered with water. After the dose has been taken, the patient 
should drink a small glass of water to ensure that the microspheres are 
rinsed from the mouth and to prevent residual taste.  
Note: On scheduled pharmacokinetic study days during Cycle 1 (Day 2 
and between Days 15 and 21) the crizotinib morning dose should be 
administered in the clinic. 
 
Patients will receive the crizotinib cMS formulation. Refer to the dosing 
nomogram in Appendix IV-C and administration guidelines in Appendices III-B 
and III-C. 
 
For All Parts of the Study 
5.1.3 
A cycle of therapy is considered to be 21 days.  A cycle may be repeated up to a 
total of 35 cycles of therapy, for a total of 24 months. 
 
5.1.4 
Drug doses should be adjusted based on the BSA calculated from height and 
weight measured within 7 days prior to the beginning of each cycle.   
 
5.2 
Criteria for Starting Subsequent Cycles 
 
A cycle may be repeated every 21 days if the patient has at least stable disease and has 
again met laboratory parameters as defined in the eligibility section, Section 4.0.  
 
 

 
 
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5.3 
Dose Escalation Schema 
 
5.3.1 
Part C: Inter-Patient Escalation (Crizotinib FC)                
The starting dose of crizotinib will be at 165 mg/m2/dose BID. The dose of 
topotecan will be fixed at 0.75 mg/m2/dose. The dose of cyclophosphamide will be 
fixed at 250 mg/m2/dose. Dose levels for subsequent groups of patients are as 
follows: 
 
Dose Level 
Crizotinib 
Cyclophosphamide 
Topotecan 
-1 
130 mg/m2/dose 
 250 mg/m2/dose 
0.75 mg/m2/dose 
   1* 
165 mg/m2/dose 
 250 mg/m2/dose 
0.75 mg/m2/dose 
          2 
215 mg/m2/dose 
 250 mg/m2/dose 
0.75 mg/m2/dose 
          3 
280 mg/m2/dose 
 250 mg/m2/dose 
0.75 mg/m2/dose 
      *Starting Dose Level 
 
There will be no escalations beyond Dose Level 3, which is the MTD established 
in the pediatric phase 1 trial of single agent crizotinib. 
 
If the MTD has been exceeded at the first dose level, then the subsequent cohort 
of patients will be treated at a dose of 130 mg/m2/dose BID (Dose Level -1). 
 
With Amendment #4, Part C patients will be treated at the recommended Phase 2 
dose (R2PD) which was determined to be Dose Level 2: 215 mg/m2/dose for 
crizotinib, 0.75 mg/m2/dose for topotecan, and 250 mg/m2/dose for 
cyclophosphamide.  
 
5.3.2 
Part D (Crizotinib cMS):  
Patients will be treated at the RP2D which was determined to be 215 mg/m2/dose 
for crizotinib, 0.75 mg/m2/dose for topotecan, and 250 mg/m2/dose for 
cyclophosphamide from Part C.  
 
Dose Level 
Crizotinib 
Cyclophosphamide 
Topotecan 
-2 
130 mg/m2/dose 
250 mg/m2/dose 
0.75 mg/m2/dose 
-1 
165 mg/m2/dose 
 250 mg/m2/dose 
0.75 mg/m2/dose 
   1* 
215 mg/m2/dose 
 250 mg/m2/dose 
0.75 mg/m2/dose 
                     *Starting Dose Level  
 
There will be no dose escalation beyond Dose Level 1.  
 
If the MTD is exceeded at Dose Level 1, then a subsequent cohort of Part D 
patients will be treated at the next lower dose level of 165 mg/m2/dose for 
crizotinib (cMS), 0.75 mg/m2/dose for topotecan, and 250 mg/m2/dose for 
cyclophosphamide (Dose Level -1).  
 
If the MTD is exceeded at Dose Level -1, then a subsequent cohort of Part D 
patients will be treated at the next lower dose level of 130 mg/m2/dose for 
crizotinib (cMS), 0.75 mg/m2/dose for topotecan, and 250 mg/m2/dose for 
cyclophosphamide (Dose Level -2). 
 
5.3.3 
Intra-Patient Escalation 
Intra-patient dose escalation is not allowed.  
 
 

 
 
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5.4 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.  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. 
 
 

 
 
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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 protocol therapy. 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 3 or 4 non-hematological toxicity with the specific exclusion of: 
o Grade 3 nausea and vomiting of less < 3 days duration 
o Grade 3 liver enzyme elevation, including ALT/AST/GGT, that return 
to levels that meet initial eligibility criteria within 7 days of study drug 
interruption. Note: For the purposes of this study the ULN for ALT is 
defined as 45 U/L. 
o Grade 3 or 4 fever < 5 days duration 
o Grade 3 infection < 5 days duration 
o Grade 3 hypophosphatemia, hypokalemia, hypocalcemia, or 
hypomagnesemia responsive to oral supplementation 
 
• 
QTc prolongation > 500 ms that persists despite correction of serum electrolyte 
abnormalities will be considered dose-limiting. 
 
• 
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. 
 
• 
Note: Allergic reactions that necessitate discontinuation of study drug will not 
be considered a dose-limiting toxicity. 
 
5.5.2 
Hematological dose limiting toxicity 
• 
Hematological dose limiting toxicity will be defined as neutropenia or 
thrombocytopenia that precludes initiation of the next cycle of therapy within 
7 days of the scheduled start date. 
 
• 
Note: Grade 3 or 4 febrile neutropenia will not be considered a dose limiting 
toxicity.  
 
 

 
 
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6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dosage modifications. 
 
Note: These dose modifications apply to all patients in all Parts of the study.  
 
6.1 
Dose Modifications for Hematological Toxicity 
 
6.1.1 
Patients who have dose-limiting hematological toxicity should receive subsequent 
cycles at the same crizotinib dose level. However, both the dexrazoxane and 
doxorubicin, or both the topotecan and cyclophosphamide doses will be reduced 
so that patients receive 75% of the full dose. 
 
6.1.2 
Patients who have dose-limiting hematological toxicity that does not resolve to 
baseline or eligibility within 21 days after the planned start of the next treatment 
cycle must be removed from protocol therapy. 
 
6.1.3 
If hematological dose-limiting toxicity recurs at the reduced dose, the patient must 
be removed from protocol therapy. 
 
6.2 
Dose Modifications for Non-Hematological Toxicity  
 
6.2.1 
Patients who have dose-limiting non-hematological toxicity (as defined in Section 
5.5.1) may continue on protocol therapy upon meeting eligibility lab requirements 
or baseline but should receive subsequent doses of crizotinib at the next lower dose 
level. In addition, the dexrazoxane, doxorubicin and vincristine or 
topotecan/cyclophosphamide doses will be reduced so that patients receive 75% of 
the full dose. 
 
6.2.1.1 For patients enrolled in Part C, if any non-hematological dose-limiting 
toxicity occurs at Dose Level -1, the patient will be removed from protocol 
therapy. 
 
6.2.1.2 For patients enrolled in Part D, if any non-hematological dose-limiting 
toxicity occurs at Dose Level -2, the patient will be removed from protocol 
therapy. 
 
6.2.2 
If any non-hematological dose-limiting toxicity recurs at the reduced dose, the 
patient must be removed from protocol therapy.   
 
6.2.3 
Patients who have a dose-limiting non-hematological toxicity that does not resolve 
to baseline or eligibility within 21 days after the planned start of the next treatment 
cycle will be removed from protocol therapy. 
 
6.2.4 
Patients with Grade 3 liver enzyme elevation, including ALT/AST/GGT, will have 
crizotinib held until levels meet initial eligibility criteria. 
• 
If levels meet initial eligibility criteria within 7 days of study drug 
interruption, this is not considered a DLT and crizotinib will be continued at 
the same dose. 
• 
If levels meet initial eligibility criteria >7 days after interruption of study 
drug, but <21 days from the planned start of the next cycle, this is a DLT and 

 
 
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the patient may continue on protocol therapy but should receive subsequent 
doses of crizotinib at the next lower dose level. In addition, the dexrazoxane, 
doxorubicin and vincristine or topotecan/cyclophosphamide doses will be 
reduced so that patients receive 75% of the full dose. 
 
6.2.4.1 For patients enrolled in Part C, if any non-hematological dose-limiting 
toxicity occurs at Dose Level -1, the patient will be removed from protocol 
therapy. 
 
6.2.4.2 For patients enrolled in Part D, if any non-hematological dose-limiting 
toxicity occurs at Dose Level -2, the patient will be removed from protocol 
therapy. 
 
6.2.5 
Patients who develop ≥ Grade 3 QTc prolongation at any time must be removed 
from protocol therapy. 
 
 

 
 
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7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY  
 
7.1 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug. If these 
treatments are administered the patient will be removed from protocol 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 7.5 for drugs that should not be used 
concomitantly due to potential interactions with crizotinib.  The use of mesna is allowed if the 
patient has had a history of hemorrhagic cystitis or develops hemorrhagic cystitis while on 
study. 
 
7.4 
Growth Factors 
Growth factors that support white cell number should be used for all patients enrolled on 
study (see Section 5.1). 
 
7.5 
Concomitant Medications 
The metabolism of crizotinib 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 crizotinib 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 crizotinib until treatment 
discontinuation (See Sections 4.2.2.6 and 4.2.2.7).  The list of potent CYP3A4 inhibitors 
and inducers in Sections 4.2.2.6 and 4.2.2.7 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 4.2.2.6 and 4.2.2.7 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 crizotinib. Please 
see Appendix II for a list of common substrates, inhibitors, and inducers of CYP3A4. 
 
Crizotinib 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 crizotinib administration at 250 mg BID, suggesting 
that crizotinib is a moderate inhibitor of CYP3A. Therefore, caution must be exercised in 
subjects receiving crizotinib in combination with drugs that are predominantly metabolized 
by CYP3A.  In particular, chronic co-administration of crizotinib with CYP3A4 substrates 
with narrow therapeutic indices must be avoided from the time of the first dose of crizotinib 
until treatment discontinuation. See Section 4.2.2.5 for the list of CYP3A4 substrates with 
narrow therapeutic indices. Crizotinib has minimal potential to inhibit other human CYP 
isoforms such as CYP1A2, 2C8, 2C9, 2C19 and 2D6.  
 
Drugs that prolong the QTc may be used only if the drug is necessary and no alternatives 
are available. See Appendix XV for drugs that may prolong the QTc. 
 
 
Additionally, the concurrent use of non-prescription drugs (excluding vitamins) or herbal 
supplements is not recommended  (see Appendix XIV). The use of PPIs and H2 blockers 
are prohibited for patients enrolled on Part D. 

 
 
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8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
(see Section 4.0) must be no older than seven (7) days at the start of therapy. Laboratory 
tests need not be repeated if therapy starts within seven (7) days of obtaining labs to assess 
eligibility. If a post-enrollment lab value is outside the limits of eligibility, or laboratory 
values are older than 7 days, then the following laboratory evaluations must be re-checked 
within 48 hours prior to initiating therapy: CBC with differential, bilirubin, ALT (SGPT) 
and serum  creatinine. If the recheck is outside the limits of eligibility, the patient may not 
receive protocol therapy and will be considered off protocol therapy. Imaging studies, bone 
marrow aspirate and biopsy must be obtained within 14 days prior to start of protocol 
therapy (repeat the tumor imaging if necessary). 
 
STUDIES TO BE OBTAINED 
Pre-
Study 
During Cycle 1 
Prior to Subsequent 
Cycles^ 
History 
X 
Weekly 
X 
Physical Exam with vital signs 
X 
Weekly 
X 
Height, weight, BSA 
X 
 
X 
Performance Status 
X 
 
 
CBC, differential, platelets3 
X 
Twice Weekly 
(every 3 to 4 days) 
Weekly 
Pharmacokinetics1 
X 
X 
 
Urinalysis 
X 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
X 
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
Albumin 
X 
 
X 
Tumor Disease Evaluation4,14 
X 
End of Cycle 1 
Every other cycle x2 
then q 3 cycles 
PET scan6 
X 
End of Cycle 1 
Every other cycle x2 
then q 3 cycles 
Bone Marrow Evaluation7, 8 
X 
End of Cycle 1 
Every other cycle x2 
then q 3 cycles 
CSF cytology9 
X 
End of Cycle 1 
As clinically indicated 
Urine HVA/VMA10 
X 
 
X 
Pregnancy Test2 
X 
 
 
Snellen Eye Chart11 
X 
 
End of Cycle 3 then q 3 
cycles 
Patient Diary5 
 
Weekly 
X 
Correlative biology studies12 
X 
X 
X 
EKG18 
X 
 
 
CNS imaging (CT or MRI)13 
X 
 
 
Tumor Tissue15 
X 
 
 
Capsule Acceptability Questionnaire 
(optional)16 
 
Day 1, then 
Weekly 
X 
Microsphere Taste Feedback 
Questionnaire (optional)17 
 
Day 1, then 
Weekly 
X 
 
^ 
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 
See Section 8.3 for timing of PK studies. 
2 
Women of childbearing potential require a negative pregnancy test prior to starting treatment; 
sexually active patients must use an acceptable method of birth control. Abstinence is an acceptable 

 
 
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method of birth control. 
3 
If patient develops Grade 4 neutropenia, then CBCs should be checked at least every 3 to 4 days 
until recovery to Grade 3 or until meeting the criteria for dose limiting toxicity. 
4 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial 
documentation of either a PR or CR.  Please note that for solid tumor patients, if the institutional 
investigator determines that the patient has progressed based on clinical or laboratory evidence, 
he/she may opt not to confirm this finding radiographically. 
5 
Patient diary (see Appendix V-B and Appendix V-C) should be reviewed and uploaded into RAVE 
weekly during Cycle 1 and then after completion of each treatment cycle. 
6 
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. 
7 
Patients with neuroblastoma or 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 
For patients with positive bone marrow involvement at time of study enrollment, evaluate at end of 
cycle 1 and then as described in the table above until negative. 
9 
For all patients with ALCL, if clinically indicated. If patients with ALCL have CSF involvement at 
the time of study enrollment, evaluate at the end of cycle one and then every other cycle until 
negative. 
10 
Neuroblastoma patients only. 
11 
Snellen eye chart should be used to assess visual acuity. If a decline in visual acuity occurs or other 
visual symptoms occur, the patient should be referred to an ophthalmologist for an examination. 
12 
See the Correlative Studies Guide in Appendix VI and see Sections 8.4, 8.5, 8.6, 8.7 and Appendix 
VII for the nature and timing of correlative biology studies. 
13 
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. 
14 
Patients with neuroblastoma must have both CT/MRI and MIBG scintigraphy prior to enrollment if 
the patient was enrolled with or has a history of having 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 and 
evaluable disease by MIBG scintigraphy or bone scan, use the same modality (MIBG scintigraphy 
or bone scan) to image and follow patients; CT/MRI are not required but may be performed as 
clinically indicated. 
15 
Archival tumor tissue should be submitted if available for all patients and extra effort should be 
expended to obtain consent for this tissue (See Section 8.5). If a patient does not have tissue 
available, the study chair must be notified. 
16 
See Capsule Acceptability Questionnaire on ADVL1212 Case Report Form. The questionnaire 
should be administered to children or adults, preferably by the clinician or the nurse at the time of 
the first dose. After that, the questionnaire should be completed as stated in the above table. 
17 
See Microsphere Taste Feedback Questionnaire on ADVL1212 Case Report Form. The 
questionnaire should be administered to consenting patients at the time of the first dose. After that, 
the questionnaire should be completed as stated in the above table. 
18 
If an initial QTc reading of > 500 msec is obtained, then a second confirmatory consecutive EKG 
must be performed. The guideline in Section 6.2.5 should be followed if a patient develops Grade 3 
QTc prolongation at any time. Patients with prolonged QTc should have correctable causes of 
prolonged QTc addressed if possible, including medications (see Appendix XV) and correction of 
electrolyte abnormalities (including Ca++ and Mg++). 

 
 
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8.2 
Radiology Studies 
 
8.2.1 
Central Radiology Review for Response:  Patients who respond (CR, PR) to 
therapy or have long term stable disease (SD) (≥ 6 cycles) on protocol therapy 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 RAVE for review by the COG 
Operations Center and for data analysis.  
 
The images are to be forwarded electronically to the Imaging Research Center at 
Children’s Hospital Los Angeles via the ImageInBox.   
 
COG institutions that are not connected to the ImageInBox can send the images on 
hard copy film, CD ROM, USB flash drive or by FTP.  Submitted imaging studies 
should be clearly marked with the COG patient ID, study number (ADVL1212) 
and date and shipped to Syed Aamer at the address below: 
 
Syed Aamer, MBBS, CRP 
Administrator, 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 
 
 

 
 
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8.3 
Pharmacology (Required) 
 
8.3.1 
Description of Studies and Assay:   
Plasma will be collected for the purpose of determining crizotinib concentrations 
for pharmacokinetic analysis. 
 
8.3.2 
Sampling Schedule 
o Part C: 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 21 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 hours.  
 
o Part D:  
• 
Days 1 and 2 of Cycle 1: Plasma samples will be obtained prior to the first 
dose of crizotinib (Day 1 pre-dose) and at 12 hours after the first dose on 
Cycle 1 Day 1 (Day 2 pre-dose). The first dose should be administered in 
the evening so that the 12 hour trough level can be drawn pre-dose on Day 
2.   
 
• 
Between Days 15 and 21 of Cycle 1: In addition, samples will be 
collected at steady state, scheduled around one dose between days 15 and 
21 of BID dosing in Cycle 1 at the following time points:  pre-dose (12 
hours after the last dose), 1 hr, 2 hr, 4 hr and 6-8 hrs.  
 
8.3.3 
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 X).   
 
Once collected, samples should be processed immediately and kept out of direct 
sunlight due to the light sensitive nature of crizotinib.  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 to -70°C 
within 1 hour of collection.   
 
Further details regarding pharmacokinetic sample processing, packaging, and 
shipping can be found in Appendix X and X-A. 
 
8.3.4 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D. (ADVL1212), and the date and time the sample was drawn.  Data should be 
recorded on the Pharmacokinetic Study Form, which must accompany the 
sample(s). 
 
8.4 
Pharmacogenomic Studies 
 
8.4.1 
Description of Studies 
Whole blood samples for pharmacogenomics will be obtained for the purpose of 
genotyping the alleles of cytochrome P450 enzymes and drug transport proteins.   
 
 

 
 
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8.4.2 
Sampling Schedule 
One peripheral blood sample (3 mL) will be collected at baseline prior to the first 
dose of crizotinib.  
 
8.4.3 
Sample Collection, Handling Instructions 
The blood sample (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 (Appendix VIII). Detailed instructions for sample 
processing and shipping can be found in Appendix VIII. 
 
8.4.4 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D. (ADVL1212), and the date and time the sample was drawn. Data should be 
recorded on the Pharmacogenomic Study Form (Appendix VIII), which must 
accompany the sample(s). 
 
8.5 
Tumor Tissue Studies 
 
8.5.1 
Description of Studies 
Tumor tissue will be evaluated for correlative biology studies assessing ALK and 
cMET expression, copy number and mutations status. Archival tumor tissue should 
be submitted for all patients and extra effort should be expended to obtain consent 
for this tissue. If a patient does not have tissue available, the study chair must 
be notified. Details are outlined in Appendix VII. 
 
8.5.2 
Sampling Schedule 
Tissue (paraffin-embedded, or fresh frozen tissue) will be collected from original 
diagnosis, relapse, or any subsequent resection or biopsy prior to treatment with 
crizotinib. 
 
8.5.3 
Sample Collection, Handling, and Shipping Instructions 
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 on the Tissue 
Studies Form (see Appendix IX).  
 
8.5.4 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D. (ADVL1212), and the date and time the sample was drawn. Data should be 
recorded on the Tissue Studies Form (Appendix IX), which must accompany the 
sample(s). 
 
8.6 
Correlative Studies for Patients with Neuroblastoma (Required) 
 
8.6.1 
Description of Studies 
Bone marrow from patients with neuroblastoma will be evaluated for correlative 
biology studies. Details of this work are outlined in Appendix VII. 
 
8.6.2 
Sampling Schedule 
A fresh bone marrow specimen will be collected prior to treatment with crizotinib 
from patients with neuroblastoma. If marrow is positive for tumor cells at time of 
study enrollment, a marrow will also be repeated every other cycle and at times of 
disease evaluations and submitted for correlative biology studies.  

 
 
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8.6.3 
Sample Collection and Handling Instructions 
Bone marrow should be sent to Dr. Yaël Mossé at room temperature by overnight 
Federal Express mail at the address listed on the Bone Marrow Studies Form for 
patients with neuroblastoma in Appendix XI.  
 
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 XI. 
 
8.6.4 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D. (ADVL1212), and the date and time the sample was drawn. Data should be 
recorded on the Correlative Study Form, which must accompany the sample(s). 
 
8.7 
Correlative Studies for Patients with ALCL (Required) 
 
8.7.1 
Description of Studies 
Minimal disease studies will be performed in patients 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. 
 
 
8.7.2 
Sampling Schedule 
 
Bone Marrow Studies 
Bone marrow samples (5 mL if >10 kg and 3-5 mL in children ≤10 kg) will be 
obtained prior to starting Cycle 1 and repeated until negative in patients with 
ALCL.   
 
Peripheral Blood Studies 
Peripheral blood samples (15 mL if >10 kg and 10 mL in children ≤10 kg) will be 
obtained at the following time points: prior to starting Cycle 1, on day 15 of Cycle 
1, and then prior to each subsequent cycle.   
 
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 XII. 
 
 
8.7.3 
Sample Handling and Labeling Instructions 
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. (ADVL1212), and the date and time the sample was drawn. Data should be 
recorded on the study form in Appendix XII, which must accompany the 
sample(s). Detailed instructions regarding sample processing, labeling, and 
shipping can be found in Appendix XII. Samples will be sent at room temperature 
to Dr. Megan S. Lim at the address listed in Appendix XII. 

 
 
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9.0 
AGENT INFORMATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

 
 
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Formulated capsule-specific information for patients and/or caregivers: 
 
 
 
 
 
 
 
 
 

 
 
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9.2 
TOPOTECAN  
 
 
 
 
 
 
 
(SKF-104864, Hycamtin®) NSC #609699 
 
 
 
(06/03/13) 
 
 
9.2.1 
Source and Pharmacology: 
Topotecan hydrochloride is a semi-synthetic derivative of camptothecin (an 
alkaloid derived from the camptothecin tree which grows widely throughout Asia) 
and 
is 
an 
anti-tumor 
drug 
with 
topoisomerase I-inhibitory 
activity. 
Topoisomerase I relieves torsional strain in DNA by inducing reversible single 
strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents 
re-ligation of these single strand breaks. The cytotoxicity of topotecan is thought 
to be due to double strand DNA damage produced during DNA synthesis, when 
replication enzymes interact with the ternary complex formed by topotecan, 
topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double 
strand breaks. Topotecan undergoes a reversible pH dependent hydrolysis of its 
lactone moiety; it is the lactone form that is pharmacologically active. At pH ≤ 4, 
the lactone is exclusively present, whereas the ring-opened hydroxy-acid form 
predominates at physiologic pH. In vitro studies in human liver microsomes 
indicate that metabolism of topotecan to an N-demethylated metabolite represents 
a 
minor 
metabolic 
pathway. 
Topotecan 
exhibits 
multi-exponential 
pharmacokinetics with a terminal half-life of 2 to 3 hours. Total exposure (AUC) 
is approximately dose-proportional. Binding of topotecan to plasma proteins is 
about 35%. 
 
In humans, about 30% of the dose is excreted in the urine and renal clearance is an 
important determinant of topotecan elimination. In patients with mild renal 
impairment (Clcr of 40 to 60 mL/min.), topotecan plasma clearance was decreased 
to about 67% of the value in patients with normal renal function. In patients with 
moderate renal impairment (Clcr of 20 to 39 mL/min.), topotecan plasma clearance 
was reduced to about 34% of the value in control patients, with an increase in half-
life. Dosage adjustment is recommended for these patients. Plasma clearance in 
patients with hepatic impairment (serum bilirubin levels between 1.7 and 
15.0 mg/dL) was decreased to about 67% of the value in patients without hepatic 
impairment. Topotecan half-life increased slightly, from 2 hours to 2.5 hours, but 
these hepatically impaired patients tolerated the usual recommended topotecan 
dosage regimen. 

 
 
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9.2.2 
Topotecan Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children  
out of every 100 
Rare 
Happens to <5 children 
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, diarrhea 
(L), constipation, fever, pain 
(abdominal, skeletal, back 
pain) 
Anorexia, headache, asthenia, rash 
(urticaria, pruritis, bullous 
eruption) (L), asymptomatic 
hypotension, dyspnea 
Anaphylaxis, 
angioedema, chest pain, 
rigors 
Prompt: 
Within 2-3 weeks, 
prior to next course 
Myelosuppression, fatigue, 
febrile neutropenia 
Stomatitis/mucositis, increased 
SGOT (AST)/SGPT 
(ALT)/alkaline phosphatase, 
sepsis 
Elevated bilirubin, 
paresthesias, myalgia, 
arthralgia, intratumoral 
bleeding 
Delayed: 
Anytime later during 
therapy 
Alopecia 
 
Microscopic hematuria, 
increased creatinine, 
proteinuria 
Unknown Frequency 
and Timing: 
Teratogenic effects of topotecan have been noted in animal models at doses ≤ to those used 
in humans. It is not known if topotecan is excreted into human breast milk.  
 (L) Toxicity may also occur later. 
 
9.2.3 
Formulation and Stability: 
Topotecan is available as a lyophilized powder for reconstitution and as a solution 
concentrate. Each vial of lyophilized powder contains topotecan hydrochloride 
equivalent to 4 mg of topotecan as free base. Inactive ingredients are mannitol 
48 mg, and tartaric acid 20 mg. Hydrochloric acid and sodium hydroxide may be 
used to adjust the pH. Topotecan concentrate solution for injection is supplied as 
a sterile, non-pyrogenic, clear, yellow to yellow-green solution at a topotecan free 
base concentration of 4 mg/4 mL (1 mg/mL) available in single use vials. Each mL 
of topotecan injection contains topotecan hydrochloride equivalent to 1 mg of 
topotecan as free base, 5 mg tartaric acid, NF and water for injection, USP. 
Hydrochloric acid and/or sodium hydroxide may be used for pH adjustment. The 
pH of the solution is approximately 2.6 to 3.2; both products must be further 
diluted prior to administration in a minimum of 50 mL of compatible fluid for 
infusion. Both types of vials should be protected from light in the original cartons 
and stored at controlled room temperature between 20° and 25°C (68° and 77°F). 
 
9.2.4 
Guidelines for Administration:  
See Treatment and Dose Modifications sections of the protocol. 
 
Reconstitute each topotecan 4 mg vial with 4 mL SWFI to concentration of 
1 mg/mL. Further dilute in 50-250 mL D5W or NS. Reconstituted vials of 
topotecan diluted for infusion are stable at approximately 20°-25°C (68°-77°F) and 
ambient lighting conditions for 24 hours. 
 
9.2.5 
Supplier:  
Commercially available. See package insert for further information. 
 
9.3 
CYCLOPHOSPHAMIDE  
 
 
 
 
 
 
(Cytoxan) NSC #26271  
 
 
 
 
 
          (03/13/13) 
 
 
 
9.3.1 
Source and Pharmacology:   
Cyclophosphamide is an alkylating agent related to nitrogen mustard. 

 
 
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Cyclophosphamide is inactive until it is metabolized by P450 isoenzymes (CYP2B6, 
CYP2C9, and CYP3A4) in the liver to active compounds. The initial product is 4-
hydroxycyclophosphamide (4-HC) which is in equilibrium with aldophosphamide 
which spontaneously releases acrolein to produce phosphoramide mustard. 
Phosphoramide mustard, which is an active bifunctional alkylating species, is 10 
times more potent in vitro than is 4-HC and has been shown to produce interstrand 
DNA cross-link analogous to those produced by mechlorethamine. Approximately 
70% of a dose of cyclophosphamide is excreted in the urine as the inactive 
carboxyphosphamide and 5-25% as unchanged drug. The plasma half-life ranges 
from 4.1 to 16 hours after IV administration.  
 
9.3.2 
Cyclophosphamide Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children  
out of every 100 
Rare 
Happens to < 5 children  
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Anorexia, nausea & vomiting 
(acute and delayed) 
Abdominal discomfort, 
diarrhea 
Transient blurred vision, nasal 
stuffiness with rapid 
administration, arrhythmias (rapid 
infusion), skin rash, anaphylaxis, 
SIADH 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Leukopenia, alopecia, immune 
suppression 
Thrombocytopenia, anemia, 
hemorrhagic cystitis (L) 
Cardiac toxicity with high dose 
(acute – CHF hemorrhagic 
myocarditis, myocardial necrosis) 
(L), hyperpigmentation, nail 
changes, impaired wound healing, 
infection secondary to immune 
suppression 
Delayed: 
Any time later 
during therapy 
Gonadal dysfunction: 
azoospermia or oligospermia 
(prolonged or permanent)1 (L) 
Amenorrhea1 
Gonadal dysfunction: ovarian 
failure1 (L), interstitial pneumonitis, 
pulmonary fibrosis2 (L)  
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy (ALL, 
ANLL, AML), bladder carcinoma 
(long term use > 2 years), bladder 
fibrosis  
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in combination with other 
antineoplastic agents) have been noted in humans. Toxicities include: chromosomal abnormalities, 
multiple anomalies, pancytopenia, and low birth weight. Cyclophosphamide is excreted into breast 
milk. Cyclophosphamide is contraindicated during breast feeding because of reported cases of 
neutropenia in breast fed infants and the potential for serious adverse effects. 
1 Dependent on dose, age, gender, and degree of pubertal development at time of treatment. 
2 Risk increased with pulmonary chest irradiation and higher doses. 
(L) Toxicity may also occur later. 
 
9.3.3 
Formulation and Stability:  
Cyclophosphamide for injection is available as powder for injection or lyophilized 
powder for injection in 500 mg, 1 g, and 2 g vials. The powder for injection 
contains 82 mg sodium bicarbonate/100 mg cyclophosphamide and the 
lyophilized 
powder 
for 
injection 
contains 
75 mg 
mannitol/100 mg 
cyclophosphamide. Storage at or below 25ºC (77ºF) is recommended. The product 
will withstand brief exposures to temperatures up to 30ºC (86ºF). 
 
9.3.4 
Guidelines for Administration 
See Treatment and Dose Modifications sections of the protocol. 

 
 
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Cyclophosphamide for Injection: If the drug will be administered as undiluted drug 
at the 20 mg/mL concentration, then reconstitute to 20 mg/mL with NS ONLY to 
avoid a hypotonic solution.  If the drug will be further diluted prior to administration, 
then first reconstitute with NS, SWFI, or Bacteriostatic Water for Injection (paraben 
preserved only) to a concentration of 20 mg/mL. Following reconstitution, 
cyclophosphamide may be further diluted in dextrose or saline containing solutions 
for IV use. 
 
9.3.5 
Supplier:   
Commercially available from various manufacturers. See package insert for further 
information 
 
9.4 
FILGRASTIM, TBO-FILGRASTIM, FILGRASTIM-SNDZ 
(Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen®, Granix®, 
Zarxio®) NSC #614629  
 
 
 
 
 
(09/09/15) 
 
 
9.4.1 
Source and Pharmacology:  
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced 
by recombinant DNA technology. Filgrastim is a 175 amino acid protein with a 
molecular weight of 18,800 daltons manufactured by recombinant DNA 
technology utilizing E coli bacteria into which has been inserted the human 
granulocyte colony stimulating factor gene. It differs from the natural protein in that 
the N- amino acid is methionine and the protein is not glycosylated. G-CSF is a 
lineage specific colony-stimulating factor, which regulates the production of 
neutrophils within the bone marrow and affects neutrophil progenitor proliferation, 
differentiation, and selected end-cell functional activation (including enhanced 
phagocytic ability, priming of the cellular metabolism associated with respiratory 
burst, antibody dependent killing, and the increased expression of some functions 
associated 
with 
cell 
surface 
antigens). 
Filgrastim 
exhibits 
nonlinear 
pharmacokinetics with clearance dependent on filgrastim concentration and 
neutrophil count. Filgrastim is cleared by the kidney. The elimination half-life is 
similar for subcutaneous and intravenous administration, approximately 3.5 hours. 
The time to peak concentration when administered subcutaneously is 2-8 hours. 
 
9.4.2 
Filgrastim Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children out of 
every 100 
Rare 
Happens to <5 children out of every 
100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Local irritation at the injection site, 
headache 
Allergic reactions (more common 
with 
IV 
administration 
than 
subq):skin (rash, urticaria, facial 
edema), 
respiratory 
(wheezing, 
dyspnea) 
and 
cardiovascular 
(hypotension, tachycardia), low grade 
fever  
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Mild 
to 
moderate 
medullary bone pain 
Increased: 
alkaline 
phosphatase, 
lactate dehydrogenase and uric acid, 
thrombocytopenia 
Splenomegaly, splenic rupture, rash 
or exacerbation of pre-existing skin 
rashes, sickle cell crises in patients 
with SCD, excessive leukocytosis, 
Sweet’s syndrome (acute febrile 
neutrophilic dermatosis) 
 
 
 
 

 
 
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Delayed: 
Anytime 
later 
during therapy 
Cutaneous vasculitis, ARDS 
Late: 
Anytime 
after 
completion 
of 
treatment 
 
 
MDS or AML (confined to patients 
with severe chronic neutropenia and 
long term administration) 
Unknown 
Frequency 
and 
Timing: 
Fetal toxicities and teratogenic effects of filgrastim in humans are unknown. Conflicting data exist in 
animal studies and filgrastim is known to pass the placental barrier. It is unknown whether the drug 
is excreted in breast milk. 
 
9.4.3 
Formulation and Stability:  
Neupogen® supplied as a clear solution of 300 mcg/mL in 1 mL or 1.6 mL vials.  
Neupogen® vials are preservative free single use vials. Discard unused portions of 
open vials. 
 
Neupogen®, Granix®, and Zarxio® are also available as single use prefilled syringes 
containing 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim for subcutaneous 
administration.  
 
Store refrigerated at 2º-8ºC (36º-46ºF). Prior to injection, filgrastim may be 
allowed to reach room temperature for a maximum of 24 hours. Avoid freezing 
and temperatures > 30ºC.  
 
For IV use, dilute filgrastim (Neupogen®) and tbo-filgrastim (Granix®) in D5W 
only to concentrations >15 mcg/mL. Filgrastim-sndz (Zarxio®) may be diluted in 
D5W to concentrations between 5 mcg/mL and 15 mcg/mL. At concentrations 
below 15 mcg/mL, human serum albumin should be added to make a final albumin 
concentration of 0.2% (2 mg/mL) in order to minimize the adsorption of filgrastim 
to plastic infusion containers and equipment for all 3 products (communication on 
file from Teva Pharmaceuticals USA). Filgrastim or filgrastim-sndz dilutions of 
5 mcg/mL or less are not recommended. Tbo-filgrastim dilutions below 2 mcg/mL 
are not recommended. Diluted filgrastim biosimilar products should be stored at 
2º-8ºC (36º-46ºF) and used within 24 hours. Do not shake. 
 
Do not dilute with saline-containing solutions at any time; precipitation will occur. 
 
 
9.4.4 
Guidelines for Administration:  
See Treatment, Dose Modifications and Supportive Care sections of the protocol. 
Filgrastim biosimilar products should not be administered within 24 hours of 
(before AND after) chemotherapy. 
 
9.4.5 
Supplier: Commercially available from various manufacturers. See package insert 
for further information. 
 
9.5 
PEGFILGRASTIM 
 
 
 
 
 
(pegylated filgrastim, PEG filgrastim, SD/01, Neulasta®) NSC #725961           (01/30/10) 
 
 
 
 
9.5.1 
Source and Pharmacology: 
Pegfilgrastim is the pegylated form of recombinant methionyl human G-CSF 
(filgrastim). Pegfilgrastim is produced by covalently binding a 20-kilodalton (kD) 

 
 
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monomethoxypolyethylene glycol molecule to the N-terminal methionyl residue 
of filgrastim. The molecular weight of pegfilgrastim is 39 kD. G-CSF is a lineage 
specific colony-stimulating factor which regulates the production of neutrophils 
within the bone marrow and affects neutrophil progenitor proliferation, 
differentiation, and selected end-cell functional activation (including enhanced 
phagocytic ability, priming of the cellular metabolism associated with respiratory 
burst, antibody dependent killing, and the increased expression of some functions 
associated with cell surface antigens). 
 
After subcutaneous injection the elimination half-life of pegfilgrastim ranges from 
15 to 80 hours and the time to peak concentration ranges from 24 to 72 hours. 
Serum levels are sustained in most patients during the neutropenic period 
postchemotherapy, and begin to decline after the start of neutrophil recovery, 
consistent 
with 
neutrophil-dependent 
elimination. 
After 
subcutaneous 
administration at 100 mcg/kg in 37 pediatric patients with sarcoma, the terminal 
elimination half-life was 30.1 (+/- 38.2) hours in patients 0 to 5 years-old, 20.2 (+/- 
11.3) hours in patients 6 to 11 years-old, and 21.2 (+/- 16) hours in children 12 to 
21 years-old. 
 
9.5.2 
Pegfilgrastim Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children out of 
every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
 
Local irritation at the injection site 
(pain, 
induration, 
and 
local 
erythema), headache 
Low 
grade 
fever, 
allergic 
reactions 
(anaphylaxis, 
angioedema, 
or 
urticaria), 
generalized 
erythema 
and 
flushing,  
Prompt: 
Within 
2-
3 weeks, prior to 
the next course 
Mild to moderate medullary 
bone pain 
Increased: alkaline phosphatase, 
lactate dehydrogenase and uric acid, 
thrombocytopenia 
Splenomegaly, splenic rupture, 
sickle cell crises in patients with 
sickle 
cell 
disease 
(SCD), 
excessive leukocytosis, Sweet's 
syndrome 
(acute 
febrile 
neutrophilic dermatosis) 
Delayed: 
Anytime 
later 
during therapy 
 
 
ARDS 
Unknown 
frequency 
and 
timing: 
Fetal toxicities and teratogenic effects of pegfilgrastim in humans are unknown. Conflicting data exist 
in animal studies. It is unknown whether the drug is excreted in breast milk. 
 
9.5.3 
Formulation and Stability: 
Supplied as a preservative-free solution containing 6 mg (0.6 mL) of pegfilgrastim 
(10 mg/mL) in a single-dose syringe with 27 g, ½ inch needle with an UltraSafe® 
Needle Guard. The needle cover of the prefilled syringe contains drug natural 
rubber (a derivative of latex). Store refrigerated at 2º-8ºC (36º-46ºF) and in the 
carton to protect from light. Prior to injection, pegfilgrastim may be allowed to 
reach room temperature protected from light for a maximum of 48 hours. Avoid 
freezing. 
 
9.5.4 
Guidelines for Administration: See Treatment and Dose Modifications sections of 
the protocol. 

 
 
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Pegfilgrastim should not be administered in the period between 2 weeks before and 
24 hours after chemotherapy. Do not shake. The manufacturer does not 
recommend use of the 6-milligram (mg) fixed-dose formulation of pegfilgrastim 
in infants, children, or adolescents under 45 kilograms. 
 
9.5.5 Supplier: Commercially available from various manufacturers. See package insert for 
further information. 
 
9.6 
Agent Accountability 
Accountability for the study drug at the trial site is the responsibility of the investigator.  
The investigator will ensure that the study drug is used only in accordance with this 
protocol.  Where allowed, the investigator may choose to assign some of the drug 
accountability responsibilities to a pharmacist or other appropriate individual.  Drug 
accountability records indicating the drug’s delivery date to the site, inventory at the site, 
and use by each patient will be maintained by the clinical site.  These records will 
adequately document that the patients were provided the doses as specified in the protocol 
and should reconcile all study drug received from Pfizer.  Accountability records will 
include dates, quantities, batch/serial numbers, expiration dates (if applicable), and patient 
numbers.   
 
 
 
To ensure adequate records, all study drug will be accounted for in the patient diary (see 
Appendix V-A, Appendix V-B, and Appendix V-C) and drug accountability inventory 
forms.  Unless otherwise authorized, at the end of the clinical trial all drug supplies 
unallocated or unused by the subjects must be disposed at the study site and documented.  
Patients must return all containers to a designated study center participant.  All containers 
of crizotinib that were sent to the investigator throughout the study must be disposed at the 
study site and documented, whether they are used or unused, and whether they are empty 
or not. 
 
All used, unused or expired study drug will be disposed of at the study site and documented.  
All material containing study drug will be treated and disposed of as hazardous waste in 
accordance with governing regulations. 
 
9.7 
Agent Ordering 
Crizotinib will be supplied by Pfizer Pharmaceuticals, Inc. Study drug can be obtained by 
following the instructions on the agent request form provided on the ADVL1212 protocol 
page of the COG website. 
 
Information on drug ordering is posted on the protocol web site. The drug supply must be 
stored in a locked limited access area. Crizotinib is for investigational use only, and is to 
be used only within the context of this study. Under no circumstances should the 
investigator or other site personnel supply study drug to other investigators, subjects, or 
clinics, or allow supplies to be used other than directed by this protocol. 
 
9.8 
Agent Inventory Records 
Patients will be required to return all bottles of study medication at the beginning of each 
cycle.  The number of capsules remaining will be documented and recorded.  Patients who 
are considered non-compliant will be withdrawn from study. 
 
 

 
 
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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 or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12.0). 
b) 
Adverse Events requiring removal from protocol therapy (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) 
Completion of 35 cycles of therapy. 
f) 
Physician determines it is not in the patient’s best interest. 
g) 
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of crizotinib (See Section 8.1). 
h) 
Study is terminated by Sponsor. 
i) 
Pregnancy 
 
Patients who are removed from protocol therapy during cycle 1 should continue to 
have the required observations in Section 8.1 until the originally planned end of the 
cycle or until all adverse events have resolved per Section 13.4.4, whichever happens 
LATER. The only exception is with documentation of the patient’s withdrawal of 
consent. Patients who are removed from protocol therapy in subsequent cycles should 
have the necessary observations to ensure adequate clinical care as outlined in Section 
10.2 (a).  
 
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 RAVE 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 required observations or data submission. 
e) 
Enrollment onto another COG therapeutic (anti-cancer) study  
 
 
 

 
 
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11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
 
There will be four parts to the study (Parts A-D). As of February 16, 2016, Parts A and B 
of the study have been completed and will no longer have patients enrolled on protocol 
therapy. The relevant sections referencing Parts A and B have been removed from the 
protocol for clarity: 
 
Part C: Crizotinib (FC) + Topotecan/Cyclophosphamide 
Part D: Crizotinib (cMS) + Topotecan/Cyclophosphamide 
  
A minimum of 3 evaluable patients will be entered at each dose level to Part C of the study 
for the determination of the MTD. Once the MTD or recommended Phase 2 dose (RP2D) 
has been defined in Part C, up to 6 additional patients with relapsed/refractory solid tumors 
or ALCL without heme restrictions may be enrolled to acquire PK data in a representative 
number of young patients (i.e. patients < 12 years old). Review of the enrollment rate into 
previous COG new agent studies indicates that 1-2 patients per month are available, which 
will permit completion of enrollment to Part C of the study within 15-30 months. An 
additional 29 patients to Part C may be required to determine the MTD, assuming a 20% 
inevaluability rate. A maximum of 50 patients is anticipated. (Fifty-one patients to Part C 
may be required if all dose levels in Part C require expansion to 12 patients per Section 
11.2.2; enrollment may require 26-51 months and a maximum of 72 patients is anticipated 
in that scenario). 
 
Part D: The starting dose level for Part D will be the RP2D determined from Part C, Dose 
Level 2: 215 mg/m2/dose for crizotinib, 0.75 mg/m2/dose for topotecan, and 250 
mg/m2/dose for cyclophosphamide. Once the MTD/RP2D has been defined for Part D, up 
to 6 additional patients with relapsed/refractory solid tumors or ALCL without restrictions 
on hematologic evaluability may be enrolled to acquire PK data in a representative number 
of young patients (e.g 6 patients < 12 years old and 6 patients ≥ 12 years old). A minimum 
of 4 patients will be required for this Part. A maximum of 22 patients would be required 
for this Part if 6 are required at both dose levels, 6 more are required for PK analysis in a 
representative number of young patients, and 20% inevaluability is observed. Part D and 
the Part C PK expansion are expected to be concluded within 11-22 months. 
 
At the time of Amendment #4, 35 patients enrolled onto the study (10 patients on Part A, 
11 patients on Part B, and 14 patients on Part C). The entire study is therefore expected to 
accrue a maximum of 65 patients within 41-52 months, accounting for the determination 
of MTD/RP2D of Part D and the PK expansion cohorts to Parts C and D. 
 
 

 
 
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11.2 
Definitions 
 
11.2.1 Evaluable For Adverse Effects 
Any patient who experiences DLT at any time during protocol therapy is 
considered evaluable for Adverse Effects. Patients without DLT who receive at 
least 85% of the prescribed dose per protocol guidelines and had the appropriate 
toxicity monitoring studies performed are also considered evaluable for Adverse 
Effects. Patients who are not evaluable for Adverse Effects at a given dose level 
during Cycle 1 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, as described in 
Section 11.3.  
 
• 
In the unlikely event that two DLTs observed out of 6 evaluable patients are 
different 
classes 
of 
Adverse 
Effects 
(e.g. 
hepatotoxicity 
and 
myelosuppression), AND all of the following conditions are met, expansion of 
the cohort to 12 patients will be considered:  
 
o One of the DLTs does not appear to be dose-related 
o The Adverse Effects are readily reversible 
o The study chair, DVL statistician, DVL committee chair or vice chair, 
and IND sponsor all agree that expansion of the cohort is acceptable 
 
Expansion will proceed according to the rules of the 3+3 design (see Section 
11.3): Three additional patients will be studied.  If none of the initial three 
additional patients experiences DLT, the dose will be escalated. If one of the 
initial three additional patients experiences DLT, expansion to a total of 12 
patients will continue. If fewer than 1/3 of patients in the expanded cohort 
experience dose-limiting toxicities, the dose escalation can proceed. 
 
• 
The DLTs observed in the pharmacokinetic (PK) expansion cohort will be 
counted towards the total number of DLTs observed at the MTD during the 
dose escalation portion of the study. If ≥1/3 of the cohort of patients at the 
MTD (during the dose escalation plus the PK expansion) experience DLT then 
the MTD will be exceeded. 
 
 
11.3 
Dose Escalation and Determination of MTD (Parts A to D) 
 
11.3.1 Three patients are studied at the first dose level. 
 
11.3.2 If none of these three patients experience DLT, then the dose is escalated                           
to the next higher level in the three subsequent patients. 
 
11.3.3 If one of three patients experiences DLT at the current dose, then up to three more 
patients are accrued at the same level. 
 
a)  If none of these three additional patients experience DLT, then the dose is 
escalated in subsequent patients. If there are no further dose escalations, then 
the RP2D has been confirmed.  
 

 
 
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b)  If one or more of these three additional patients experiences DLT, then patient 
entry at that dose level is stopped.  (See Section 11.2.2 for exception to rule).  
Up to three more patients are treated at the next lower dose (unless six patients 
have already been treated at that prior dose). 
 
11.3.4 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 (see 
Section 11.2.2 for exception to rule).  Up to three more patients are treated at the 
next lower dose (unless six or more patients have already been treated at that prior 
dose). The highest dose with less than two DLTs out of six evaluable patients will 
be the estimated MTD. 
 
11.3.5 Using this dose escalation scheme, the probability of escalating to the next dose 
level, based on the true rate of DLT at the current dose, is given by the following 
table when there are 6 evaluable patients at the current dose: 
 
 
True Adverse Effects at a Given Dose 
 
10% 
20% 
30% 
40% 
50% 
60% 
Probability of 
Escalating 
.91 
.71 
.49 
.31 
.17 
.08 
 
Thus, if the true underlying proportion of toxic events is 30% at the current dose, 
there is a 49% chance of escalating to the next dose. 
 
In addition to determination of the MTD or RP2D, a descriptive summary of all toxicities 
will be reported. 
 
11.4 
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 1 trial which will accrue a limited number of 
patients, 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. 
 
11.5 
Pharmacokinetic and Correlative Studies and Response Analysis 
A descriptive analysis of pharmacokinetic (PK) parameters of crizotinib at steady state will 
be performed and compared with data from the single agent phase 1 study of crizotinib 
(ADVL0912).  The PK parameters will be summarized with simple summary statistics, 
including means, medians, ranges, and standard deviations (if numbers and distribution 
permit).   
 
While the primary aim of this study is to evaluate the toxicity of crizotinib in combination 
with conventional chemotherapy, 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. 
 
All these analyses will be descriptive and exploratory and hypotheses generating in nature. 
 
 

 
 
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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.  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 for Patients with Solid Tumors  
See the table in Section 8.0 for the schedule of tumor evaluations. In addition to the 
scheduled scans, a confirmatory scan should be obtained 60 days following initial 
documentation of objective response. 
 
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-
247, 2009].  Key points are that 5 target lesions are identified and that changes in the largest 
diameter (unidimensional measurement) of the tumor lesions but the shortest diameter of 
malignant lymph nodes are used in the RECIST v 1.1 criteria. 
 
As outlined, patients will be assigned to one of the following categories for assessment of 
response:  a) solid tumor and measurable disease (Section 12.2); b) solid tumor and 
evaluable disease (Section 12.3); c) neuroblastoma with MIBG positive lesions (Section 
12.4); d) neuroblastoma with bone marrow involvement (Section 12.5); or e) ALCL 
(Section 12.6).   
 
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.  
 
12.2.1 Definitions 
 
12.2.1.1 Evaluable for objective response: Patients who exhibit objective 
disease progression prior to the end of cycle 1 will be considered 
evaluable for response. For all other patients, only those patients who 
have measurable disease present at baseline, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for response.  
 
12.2.1.2 Evaluable Non-Target Disease Response: Patients who have lesions 
present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for 
non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
12.2.2 Disease Parameters 
 
12.2.2.1 Measurable disease: Measurable lesions are defined as those that can 
be accurately measured in at least one dimension (longest diameter to 
be recorded) as ≥20 mm by chest x-ray, as ≥10 mm with CT scan, or 
≥10 mm with calipers by clinical exam.  All tumor measurements must 

 
 
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be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area 
might or might not be considered measurable. If the investigator 
thinks it appropriate to include them, the conditions under which 
such lesions should be considered must be defined in the 
protocol. 
 
12.2.2.2 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when 
assessed by CT scan (CT scan slice thickness no greater than 5 mm).  
At baseline and in follow-up, only the short axis will be measured and 
followed. 
 
12.2.2.3 Non-measurable disease: All other lesions (or sites of disease), 
including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 to <15 mm short axis), are considered non-
measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent 
cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, 
if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
 
12.2.2.4 Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion that can be measured reproducibly should be 
selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The 
baseline sum diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the 
disease. 
 
12.2.2.5 Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be 
identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, 

 
 
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absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
12.2.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
12.2.3.1 Clinical lesions:  Clinical lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph nodes) 
and ≥10 mm diameter as assessed using calipers (e.g., skin nodules).  In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
12.2.3.2 Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  
However, CT is preferable.  
 
12.2.3.3 Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans). Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  
 
12.2.3.4 PET-CT:  At present, the low dose or attenuation correction CT portion 
of a combined PET-CT is not always of optimal diagnostic CT quality 
for use with RECIST measurements.  However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
12.2.3.5 Tumor markers: Tumor markers alone cannot be used to assess response.  
If markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.  
 
12.2.3.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 

 
 
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Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease. 
 
12.2.3.7 FDG-PET: While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET 
scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 
 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date 
of the initial abnormal FDG-PET scan).  If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
 
 Note:  A ‘positive’ FDG-PET scan lesion means one that is FDG avid 
with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image. 
 
 
12.2.4 Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
12.2.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short 
axis to <10 mm. If immunocytology is available, 
no disease must be detected by that methodology.  
Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment (for 
patients with neuroblastoma).  
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum diameters 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new 

 
 
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lesions is also considered progressions). Note: in 
presence of SD or PR in target disease but 
unequivocal progression in non-target or non-
measurable disease, the patient has PD if there is 
an overall level of substantial worsening in non-
target disease such that the overall tumor burden 
has 
increased 
sufficiently 
to 
merit 
discontinuation of therapy 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
 
12.2.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, 
not a single lesion increase.     
 
12.2.5 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.7 from a sequence of overall response assessments. 
 
 

 
 
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12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
 
12.3.1 Evaluable Disease 
The presence of at least one lesion, with no lesion that can 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.  
 
12.3.2 Complete Response 
Disappearance of all evaluable disease. 
 
12.3.3 Partial response 
Partial responses cannot be determined in patients with evaluable disease 
 
12.3.4 Stable Disease (SD) 
That which does not qualify as Complete Response (CR), Partial Response (PR), 
or Progressive Disease. 
 
12.3.5 Progressive Disease 
The appearance of one or more new lesions or evidence of laboratory, clinical, or 
radiographic progression. 
 
12.3.6 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.7 from a sequence of overall response assessments. 
 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
12.4.1 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 28 days after radiation was completed and 
must show viable neuroblastoma. 
 
12.4.2 The following criteria will be used to report MIBG response by the treating 
institution: 
 
Complete response:  Complete resolution of all MIBG positive lesions 
Partial Response:  Resolution of at least one MIBG positive lesion, with 
persistence of other MIBG positive lesions 
Stable disease:  
No change in MIBG scan in number of positive lesions 
Progressive disease: Development of new MIBG positive lesions 
 
12.4.3 The response of MIBG lesions will be assessed on central review using the Curie 
scale14 as outlined below. Central review responses will be used to assess efficacy 
for study endpoint. See Section 8.2 for details on transferring images to the 
Imaging Research Center. 
 

 
 
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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 21 
days apart to be considered a Complete Response. 
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. 
 
 

 
 
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12.4.4 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Table 5 in Section 12.7. 
 
12.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
12.5.1 Bone Marrow Involvement  
Bone marrow obtained within 28 days prior to study enrollment with tumor cells 
seen on routine morphology (not by immunohistochemical staining only) of 
bilateral aspirate or biopsy on one bone marrow sample. 
 
Bone Marrow responses are determined by H&E Staining of bilateral bone marrow 
biopsies and aspirates. 
 
Complete Response:  
No tumor cells detectable by routine morphology on 2 
consecutive bilateral bone marrow aspirates and biopsies 
performed at least 21 days apart. Normalization of urinary 
catecholamines or other tumor markers if elevated at 
study enrollment. 
 
Progressive Disease:  
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%). 
 
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 21 days apart. 
 
Stable Disease: 
Persistence of tumor in bone marrow that does not meet 
the criteria for either complete response or progressive 
disease. 
 
12.5.2 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Section 12.7. 
 
 

 
 
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12.6 
Response Criteria for Patients with ALCL 
 
12.6.1 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. 
 
12.6.2 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).  
 
12.6.3 Partial Response 
≥50% decrease in the SPD of the lesions. No new lesions. 
 
12.6.4 No Response (Stable Disease) 
Failure to qualify for a PR. No new lesions. 
 
12.6.5 Progressive disease 
 
≥25% increase in the size of any lesions or appearance of new lesions. 
 
 
12.6.6 Overall Response Assessment 
The overall response assessment takes into account response in both target and 
non-target lesions, the appearance of new lesions and normalization of markers 
(where applicable), according to the criteria described in the table below. The 
overall response assessment is shown in the last column, and depends on the 
assessments of target, non-target, marker and new lesions in the preceding 
columns.   
 
 
Target Lesions 
 
Non-target Lesions 
 
Markers 
 
New Lesions 
 
Overall 
Response 
CR 
CR 
Normal 
No 
CR 
CR 
IR/SD 
Normal 
No 
PR 
CR  
CR, IR/SD 
Abnormal 
No 
PR 
PR 
CR, IR/SD 
Any 
No 
PR 
SD 
CR, IR/SD 
Any 
No 
SD 
PD 
Any 
Any 
Yes or No 
PD 
Any 
PD 
Any 
Yes or No 
PD 
Any 
Any 
Any 
Yes 
PD 
 

 
 
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Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.7 from a sequence of overall response assessments. 
 
12.7 
Best Response 
 
12.7.1 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
Table 1: For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>28 days Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>28 days Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once 
>28 days from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
Table 2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD 
is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised 
 
 
 

 
 
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Table 3.  Sequences of overall response assessments with corresponding best 
response 
 
1st Assessment 
2nd Assessment 
Best Response 
Progression 
 
Progressive disease 
Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
 
Table 4: 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 5: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease Only 
If patients 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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12.7.2 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
 

 
 
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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 Case Report Forms 
(CRFs) 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) whether the adverse event is considered serious; 
3) the grade (severity); and 4) 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. 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). 
 
Step 2:  Grade the adverse event using the NCI CTCAE. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
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. 
 
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 in the table 
below. Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite. 
 
 

 
 
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Table A: Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
7 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found below under the 
section entitled “Additional Instructions or Exceptions”. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
• 
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 

 
 
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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. 
 
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 clearly due 
to progressive disease 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 unless it 
is associated with hospitalization. 
 
• Grade 3 and Grade 4 febrile neutropenia (regardless of hospitalization) does not require expedited 
reporting via CTEP-AERS.  
 
• Grade 1 and 2 adverse events listed in the table below do not require expedited reporting via 
CTEP-AERS: 
 
Category 
Adverse Events 
EYE DISORDERS 
 
 
 
 
 
 
 
Eye disorders- Other (blurred 
vision, diplopia, visual 
impairment, vision brightness, 
vision field defect, 
shadows/streaking) 
Eye pain 
Flashing lights (photopsia) 
Floaters 
Photophobia 
 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
Constipation 
Diarrhea 
Nausea 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 
Fatigue 
Edema face  
Edema limbs  
Localized edema  
 

 
 
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Category 
Adverse Events 
INVESTIGATIONS 
Alanine aminotransferase 
increased 
Aspartate aminotransferase 
increased  
GGT increased 
Neutrophil count decreased 
White blood cell count decreased 
 
METABOLISM AND NUTRITION DISORDERS  
Anorexia 
 
NERVOUS SYSTEM DISORDERS  
 
Dizziness  
Dysgeusia 
Neuropathy 
 
PSYCHIATRIC DISORDERS 
Insomnia 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Periorbital edema 
 
 
As referenced in the CTEP Adverse Events 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 (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 or 7 
calendar days of learning of the event (refer to Table A). 
 
• 
Expedited AE reporting for this study must only use CTEP-AERS (CTEP Adverse 
Event 
Reporting 
System), 
accessed 
via 
the 
CTEP 
home 
page 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm. 
 
13.3 
Expedited Reporting Methods  
 
13.3.1 CTEP-AERS Reporting 
To report adverse events in an expedited fashion use the CTEP Adverse Event 
Reporting System (CTEP-AERS) that can be found at http://ctep.cancer.gov. 
 
A CTEP-AERS report must be submitted electronically via the CTEP-AERS 
Web-based application located at 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm.  

 
 
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If prompted to enter a sponsor email address, please use: 
COGCADEERS@childrensoncologygroup.org. 
 
Email supporting documentation to the ADVL1212 COG Research Coordinator. 
ALWAYS include the ticket number on all emailed documents. 
 
 

 
 
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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 course (cycle) of therapy only the 
most severe grade of the event should be reported. 
 
13.4.2 If an adverse event progresses through several grades during one course 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 
baseline or less than Grade 1, whichever level is higher (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 course to another should only be reported 
once unless the grade becomes more severe in a subsequent course. An adverse 
event which resolves and then recurs during a different course, must be reported 
each course 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 Case 
report form (CRF) 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. 
 
 

 
 
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13.6 
Reporting Secondary AML/MDS 
All cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that 
occur in patients on NCI-sponsored and non-NCI-sponsored trials following their 
chemotherapy for cancer must be reported via CTEP-AERS and included as part of the 
second malignant neoplasm reporting requirements for this protocol (see data submission 
packet).  Submit the completed CTEP-AERS report within 14 days of an AML/MDS 
diagnosis occurring after treatment for cancer on NCI-sponsored and non-NCI-sponsored 
trials.  
 
Secondary Malignancy: A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A secondary malignancy is not considered a metastasis of the initial 
neoplasm.  
All secondary malignancies that occur following treatment with an agent under an NCI 
IND/IDE or a non-NCI IND must be reported via CTEP-AERS. Three options are available 
to describe the event:  
1) Leukemia secondary to oncology chemotherapy(e.g., acute myelocytic 
leukemia [AML]),  
2) Myelodysplastic syndrome (MDS), or  
3) Treatment-related secondary malignancy.  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
Second Malignancy: A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  Second malignancies 
require ONLY routine reporting via CDUS unless otherwise specified. 
 
13.7 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal 
loss”, the Pregnancy Information Form should be completed and emailed along with any 
additional medical information to the ADVL1212 COG Research Coordinator (Appendix 
XIII). The potential risk of exposure of the fetus to the investigational agent should be 
documented in the “Description of Event” section of the CTEP-AERS report. 
 
13.7.1 Pregnancy 
• 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents which may be teratogenic. For this reason, pregnancy 
occurring on study or within 6 months following the last dose of study 
therapy should be reported in an expedited manner via CTEP-AERS as 
“Pregnancy, puerperium and perinatal conditions - Other (Pregnancy) 
under the Pregnancy, puerperium and perinatal conditions SOC and 
reported as Grade 3. 
 
• 
Pregnancy should be followed until the outcome is known. 
 
13.7.2 Fetal Death 
• 
Fetal death is defined in CTCAE as “A disorder characterized by death in 
utero; failure of the product of conception to show evidence of respiration, 
heartbeat, or definite movement of a voluntary muscle after expulsion 
from the uterus, without possibility of resuscitation.” 
 

 
 
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• 
 Any fetal death should be reported expeditiously, as Grade 4 “Pregnancy, 
puerperium and perinatal conditions - Other (pregnancy loss)” under the 
Pregnancy, puerperium and perinatal conditions SOC.  
 
• 
 A fetal death should NOT be reported as “Fetal death,” a Grade 5 event 
under the Pregnancy, puerperium and perinatal conditions SOC, as 
currently CTEP-AERS recognizes this event as a patient death. 
 
13.7.3 Death Neonatal 
• 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously. 
 
• 
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration- Other (neonatal loss)” under the General 
disorders and administration SOC. 
 
• 
Neonatal death should NOT be reported as “Death neonatal” under the 
General disorders and administration SOC, a Grade 5 event. If reported as 
such, the CTEP-AERS interprets this as a death of the patient being 
treated. 
 
Pregnancy should be followed up until the outcome of the pregnancy is known at intervals 
deemed appropriate by her physicians. The “Pregnancy Information Form” should be used 
for all follow-ups. If the baby is born with a birth defect or other anomaly, then a second 
CTEP-AERS report is required. 
 
 

 
 
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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: e.g. Roadmaps, Pathology Reports, Surgical 
Reports, and Patient Questionnaire. These forms are uploaded into RAVE. 
 
2. 
Reference Labs, Biopathology Reviews, and Imaging Center 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 RAVE with the aid of schedules and worksheets (essentially paper 
copies of the OPEN and RAVE screens) provided in the CRF packet. 
 
See separate CRF Packet, which includes submission schedule. 
 
14.2 
Access to Rave for Data Submission/ Data Reporting 
Data collection for this study will be done through the Medidata Rave clinical data 
management system.  Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support System 
(RSS).  To access Rave via iMedidata, the site user must have an active CTEP-IAM 
account (check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and the appropriate 
Rave role (Rave CRA, Read-Only, Site Investigator) on either the COG or COGC roster at 
the enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To 
accept 
the 
invitation, 
site 
users 
must 
log 
into 
the 
Select 
Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, 
and click on the “accept” link in the upper right-corner of the iMedidata page.  Please note, 
site users will not be able to access the study in Rave until all required Medidata and study 
specific trainings are completed.  Trainings will be in the form of electronic learnings 
(eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account.  Account activation instructions are located on the 
CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation 
and Study Invitation Acceptance).  Additional information on iMedidata/Rave is available 
on the CTSU members’ website under the Rave tab at www.ctsu.org/RAVE/ or by 
contacting 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
by 
e-mail 
at 
ctsucontact@westat.com, or by email to the COG Study Assigned Research Coordinator. 
 
 

 
 
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14.3 
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. 
 
14.4 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
14.4.1 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. 
 
14.4.2 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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REFERENCES 
 
 
1. 
Saylors RL, 3rd, Stine KC, Sullivan J, et al: Cyclophosphamide plus topotecan in children 
with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19:3463-
9, 2001 
 
2. 
London WB, Frantz CN, Campbell LA, et al: Phase II randomized comparison of topotecan 
plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a 
Children's Oncology Group study. J Clin Oncol 28:3808-15, 2010 
 
3. 
Walterhouse DO, Lyden ER, Breitfeld PP, et al: Efficacy of topotecan and 
cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic 
rhabdomyosarcoma: a Children's Oncology Group study. J Clin Oncol 22:1398-403, 2004 
 
4. 
Weinstein HJ, Lack EE, Cassady JR: APO therapy for malignant lymphoma of large cell 
"histiocytic" type of childhood: analysis of treatment results for 29 patients. Blood 64:422-6, 1984 
 
5. 
Laver JH, Kraveka JM, Hutchison RE, et al: Advanced-stage large-cell lymphoma in 
children and adolescents: results of a randomized trial incorporating intermediate-dose methotrexate and 
high-dose cytarabine in the maintenance phase of the APO regimen: a Pediatric Oncology Group phase III 
trial. J Clin Oncol 23:541-7, 2005 
 
6. 
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 
 
7. 
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 
 
8. 
Diomedi-Camassei F, McDowell HP, De Ioris MA, et al: Clinical significance of CXC 
chemokine receptor-4 and c-Met in childhood rhabdomyosarcoma. Clin Cancer Res 14:4119-27, 2008 
 
9. 
Mosse YP, Wood A, Maris JM: Inhibition of ALK signaling for cancer therapy. Clin 
Cancer Res 15:5609-14, 2009 
 
10. 
Pulford K, Lamant L, Espinos E, et al: The emerging normal and disease-related roles of 
anaplastic lymphoma kinase. Cell Mol Life Sci 61:2939-53, 2004 
 
11. 
Kwak EL, Bang YJ, Camidge DR, et al: Anaplastic lymphoma kinase inhibition in non-
small-cell lung cancer. N Engl J Med 363:1693-703, 2010 
 
12. 
Ou SH, Bazhenova L, Camidge DR, et al: Rapid and dramatic radiographic and clinical 
response to an ALK inhibitor (crizotinib, PF02341066) in an ALK translocation-positive patient with non-
small cell lung cancer. Journal of thoracic oncology : official publication of the International Association 
for the Study of Lung Cancer 5:2044-6, 2010 
 
13. 
Mosse YP, Laudenslager M, Longo L, et al: Identification of ALK as a major familial 
neuroblastoma predisposition gene. Nature 455:930-5, 2008 
 
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. 
Bresler SC, Wood AC, Haglund EA, et al: Differential inhibitor sensitivity of anaplastic 
lymphoma kinase variants found in neuroblastoma. Science translational medicine 3:108ra114, 2011 
 
18. 
Murugan AK, Xing M: Anaplastic thyroid cancers harbor novel oncogenic mutations of 
the ALK gene. Cancer research 71:4403-11, 2011 
 
19. 
van Gaal JC, Flucke UE, Roeffen MH, et al: Anaplastic lymphoma kinase aberrations in 
rhabdomyosarcoma: clinical and prognostic implications. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology 30:308-15, 2012 
 
20. 
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 

 
 
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mechanisms. Cancer research 67:4408-17, 2007 
 
21. 
De Brouwer S, De Preter K, Kumps C, et al: Meta-analysis of neuroblastomas reveals a 
skewed ALK mutation spectrum in tumors with MYCN amplification. Clinical cancer research : an official 
journal of the American Association for Cancer Research 16:4353-62, 2010 
 
22. 
Schonherr C, Ruuth K, Yamazaki Y, et al: Activating ALK mutations found in 
neuroblastoma are inhibited by Crizotinib and NVP-TAE684. The Biochemical journal 440:405-13, 2011 
 
23. 
Schulte JH, Bachmann HS, Brockmeyer B, et al: High ALK receptor tyrosine kinase 
expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary 
neuroblastoma. Clinical cancer research : an official journal of the American Association for Cancer 
Research 17:5082-92, 2011 
 
24. 
Passoni L, Longo L, Collini P, et al: Mutation-independent anaplastic lymphoma kinase 
overexpression in poor prognosis neuroblastoma patients. Cancer Res 69:7338-46, 2009 
 
25. 
Duijkers FA, Gaal J, Meijerink JP, et al: Anaplastic lymphoma kinase (ALK) inhibitor 
response in neuroblastoma is highly correlated with ALK mutation status, ALK mRNA and protein levels. 
Cellular oncology 34:409-17, 2011 
 
26. 
Kwak EL, Camidge DR, Clark J, et al: Clinical activity observed in a phase I dose 
escalation trial of an oral c-met and ALK inhibitor, PF-02341066. ASCO Meeting Abstracts 27:3509, 2009 
 
27. 
Mosse YP, Lim MS, Voss SD, et al: Safety and activity of crizotinib for paediatric patients 
with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 
consortium study. Lancet Oncol 14:472-80, 2013 
 
28. 
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 
 
29. 
Maris JM, Mosse YP, Bradfield JP, et al: Chromosome 6p22 locus associated with 
clinically aggressive neuroblastoma. N Engl J Med 358:2585-93, 2008 
 
30. 
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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APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
 
 
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. Because the lists of these agents are constantly changing, it 
is important to regularly consult a frequently-updated medical references. 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 
 
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 
simvastatin 
 
Steroid 6beta-OH 
estradiol 
hydrocortisone 
progesterone 
testosterone 
 
Other 
alfentanyl 
buspirone 
cafergot 
caffeine=>TMU 
cocaine 
dapsone 
codeine-N-demethyl 
dextromethorphan 
eplerenone 
fentanyl 
finasteride 
imatinib 
haloperidol (in part) 
lidocaine 
methadone 
ondansetron* 
pimozide 
propranolol 
quinine 
salmetrerol 
sildenafil 
tamoxifen 
paclitaxel 
trazodone 
vincristine 
zaleplon 

 
 
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irinotecan 
zolpidem 
 
Inhibitors 
HIV Antivirals 
delaviridine 
indinavir 
nelfinavir 
ritonavir 
saquinavir 
 
Other 
amiodarone  
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 
*Ondansetron may be given for emesis or anti-emetic prophylaxis 
 

 
 
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APPENDIX III-B: CRIZOTINIB MICROSPHERE ADMINISTRATION INSTRUCTIONS 
 
CRIZOTINIB INSTRUCTIONS:  Please take the prescribed dose of Crizotinib microspheres twice a 
day, in the morning and evening. The only exception to this instruction is during Day 1 of Cycle 1 when 
crizotinib should be taken once during the evening (see the Patient Diary in Appendix V-C).  The dose 
can only be administered with water. After the dose has been taken, the patient should drink a small glass 
of water to ensure that the microspheres are rinsed from the mouth and to prevent residual taste. Take the 
dose at approximately the same time twice daily, except during Day 1 of Cycle 1 crizotinib should be 
taken once during the evening.    
• 
Do not swallow the capsule whole. Only take as described in the instructions below.  
• 
Administer the microspheres immediately following preparation 
• 
Do not take more than the prescribed dose at any time.   
• 
Select a clean area to prepare the dose according to the instructions below 
• 
The person preparing the dose should wash their hands before and after the dose is administered 
• 
The dosing spoon provided with the drug must be used for giving Crizotinib 
• 
Do not use the dosing spoon for any other medications 
• 
The microsphere capsules should be handled and administered with care. Any spills of coated 
microspheres during dose preparation or administration should be cleaned up with water. 
On days that you have a scheduled study visit (including on pharmacokinetic study days), do not take your 
morning dose at home.  Instead, bring your study medication bottle and the Patient Diary with you to your 
scheduled visit and await further instruction from your doctor.  
STUDY MEDICATION STORAGE:  Keep the Crizotinib microsphere capsules in the original bottle and 
store at room temperature.  Close the bottle tightly after taking a dose. Keep out of the reach of children. 
PATIENT DIARY INSTRUCTIONS (Appendix V-C):  Please record the date and time each dose is 
taken. Record any missed or extra doses as well as vomiting after a dose in the comments section.  
Remember to also include the date when these events happened. 
If you have any questions regarding how to take your study medication, please contact 
the study clinic at the telephone number provided above. 
 
 
To be completed by Study Clinic:    
 
COG Patient ID: _______                    Acc#:________                      Date Dispensed: _________   
Please do not write patient names on this form. 
 
Insititution: ______________ 
 
Study Clinic Telephone Number: ______________   Diary provided by (staff initials): ________       

 
 
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HOW TO TAKE THE MICROSPHERES USING THE DOSING SPOON PROVIDED SUPPLIES 
 
 
1 
If your dose is less than 200 mg, add 3 mL to 4 
mL of cold or room temperature water to the 
supplied dosing spoon by running the water 
down the spoon into the barrel. Do not dry the 
spoon head after adding water. The amount of 
water does not need to be exact.   
If your dose is 200 mg or more, add 5 mL to 7 
mL of cold or room temperature water to the 
supplied dosing spoon by running the water 
down the spoon into the barrel. Do not dry the 
spoon head after adding water. The amount of 
water does not need to be exact.   
 
 

 
 
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2 
Hold the dosing spoon upright to check that you have the 
correct amount of water as described in step 1. 
Place the dosing spoon with water in it onto a clean flat surface 
close by. The built-in spoon rest allows the water to stay in the 
barrel. 
(Example picture is of the 3 to 4 mL water amount) 
 
3 
Remove the capsule(s) needed for the total dose from the bottle(s) provided. 
4 
 
Hold the capsule so that the cap of the capsule is up.  
 
 
Gently tap the capsule body (smaller portion) on a clean surface 
to move the microspheres to the body of the capsule. 
 
 
6 
Hold the capsule over the center of the spoon head. 
Using both hands, gently grasp both ends of the 
capsule shell and turn the capsule cap and body in 
opposite directions to separate the two ends.  
7 
Look in the capsule cap to ensure that it is empty. If there are 
microspheres in the capsule cap, empty them onto the center of 
the spoon head by gently tapping the capsule cap while over the 
spoon head.  

 
 
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8 
Carefully pour the microspheres from the capsule body onto the 
center of the spoon head. Gently tap the capsule body with 
finger over the spoon head as needed to get the microspheres 
onto the spoon.  
 
 
 
 
 
9 
Look in the capsule body to see that it is empty. If there are still microspheres in the capsule body, 
empty them onto the center of the spoon head by gently tapping. 
Repeat steps 4 through 9 for each capsule needed for the dose. 
10 
Throw away the empty capsule shells after the microspheres have been put onto the spoon head 
and you have verified the dose. 
11 
Pick up the spoon and keep it level so the 
water 
stays in the 
barrel 
and 
the 
microspheres stay on the spoon head. In one 
pouring movement, pour the microspheres 
and water into the patient’s mouth. 
If needed for younger patients secure the 
patient’s head and gently pinch cheeks to 
pucker the mouth.  
12 
Inspect the spoon head and dosing barrel for residual microspheres. 
13 
Add cold or room temperature water to the dosing spoon again (same amount as step 1) to rinse 
any remaining microspheres on the spoon head into the barrel. 
14 
Hold the dosing spoon upright (spoon head facing up) and ensure 
that the correct amount of water has been added. The amount 
does not need to be exact.  
(Example picture is of the 3 to 4 mL water amount) 
 
 
 
 
 

 
 
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15 
With the spoon still upright, gently swirl the water to get any remaining microspheres into the 
water in the barrel. 
16 
In one pouring movement, pour the 
rinse 
water 
and 
remaining 
microspheres into the patient’s mouth. 
If needed for younger patients secure 
the patient’s head and gently pinch 
cheeks to pucker the mouth.  
17 
Look at the spoon head and dosing cylinder for 
remaining microspheres. If microspheres are still seen 
on the spoon head or barrel, perform steps 13 through 
16 again.  
 
18 
Dosing is now complete. Wash the spoon and save for future Crizotinib dosing use. 
19  
Clean the counter area where dosing was completed with water.  

 
 
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87 
 
APPENDIX III-C: CRIZOTINIB MICROSPHERE PATIENT EDUCATION SHEET 
 
Crizotinib Miscrosphere Capsules 
Please read this information before preparing 
and taking your drug.   
Please ask your doctor, nurse, or pharmacist if 
you have any questions. 
WHAT DO I NEED?  
 Crizotinib 
20 mg  #_________capsule(s) 
40 mg #_________capsule(s) 
120 mg #________capsule (s) 
 Diluents (Liquids)  
purified water ______mL 
 Supplies: 
• Crizotinib dosing spoon provided with 
the drug by your pharmacy 
• Disposable pad or paper towels  
• Disposable gloves and mask 
• Oral syringe, medicine cup, or measuring 
spoon  
• A container to collect waste (zip-top 
plastic bag or medical waste bag or 
container) 
 
HOW DO I PREPARE THE DRUG? 
If you are pregnant, could become pregnant, or 
are breast-feeding, we recommend that you 
wear appropriate safety equipment such as 
mask and gloves. 
1. 
First, choose a quiet working space away 
from food, windows, fans or heat ducts. 
2. 
Clean the working space with damp paper 
towels. 
3. 
Place a pad or paper towel on the clean 
working space. 
4. 
Next, place all needed items and drug on the 
pad or paper towel.  
5. 
Then, wash your hands with soap and water. 
6. 
Last, put on gloves (we recommend that you 
use gloves; women of childbearing should 
also use a mask) 
7. 
Finally, start making or mixing the drug as 
per instructions provided (protocol Appendix 
III-b). 
HOW DO I STORE MY MEDICATION? WHEN 
WILL MY MEDICATION EXPIRE? 
 
Keep medication in its original container and 
stored according to the labeled conditions.   
 
Store away from food and out of the reach 
of children or pets 
 
When you are finished, place all dirty gloves, 
cup, or other tools used to mix the drug, as 
well as the spoon if you are no longer 
planning to use it, in a plastic Ziploc bag or a 
special bag or container provided by your 
nurse or pharmacist.  
 
 

 
 
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88 
 
HOW DO I TAKE THE MEDICATION? 
 
My dose is: _________________ 
 
Take each dose by mouth twice a day for 
21 days in a row.   
 
During each administration, the dose 
should be taken with water. After the dose 
has been taken, drink a small glass of 
water to ensure that the microspheres are 
rinsed from the mouth and to prevent 
residual taste. Avoid grapefruit or 
grapefruit juice. 
 
Cycle 1 Day 1: Crizotinib should be given in 
the evening ONLY with water. 
 
On scheduled pharmacokinetic study 
days during Cycle 1 (Day 2 and between 
Days 15 and 21) the crizotinib morning 
dose should be administered in the clinic. 
 
On Days 1-5 of each cycle, crizotinib 
should be taken at least one (1) hour 
before chemotherapy (except on Day 1 of 
Cycle 1 when crizotinib is given in the 
evening regardless of when other 
chemotherapy drugs are given). 
 
If a dose is missed or forgotten at the due 
time, it can be taken up to (but not greater 
than) 6 hours later to help prevent missed 
doses.   
 
If you inadvertently take 1 extra dose 
during a day, do not take the next dose of 
crizotinib.  
 
If you vomit after a dose of crizotinib, that 
dose will not be repeated; wait until the 
next scheduled time to administer a dose. 
• 
When you are finished, place the dirty 
gloves, cup, and other tools used to prepare 
the drug, as well as the spoon if you are no 
longer planning to use it, in a plastic zip top 
bag or the waste container that was 
provided to you by your doctor, nurse, or 
pharmacist.  
• 
Complete the patient diary by recording the 
date and time the dose of crizotinib is given 
as well as the number of capsules taken for 
each dose. 
WHAT SHOULD I DO WITH THE  
LEFT-OVER CAPSULES? 
Throw away the leftover drug in the plastic Ziploc. 
Close the plastic bag. (Site: check all apply or insert 
your local policies) 
 Return the closed bag to the clinic at the 
next visit; or 
 ____________________________________
______________________ 
WHAT DO I DO WITH EXPIRED OR NOT USED 
DRUG (LIKE MY CAPSULES/ TABLETS)? 
Return unused and/or expired study drug to the 
clinic or hospital at your next study visit.          
WHAT PRECAUTION/SAFETY DO I NEED? 
If crizotinib gets into eyes, flush with large amount 
of water while holding eyelids open for at least 15 
minutes.  Call your study doctor or nurse 
immediately at 
________________________________ and/or 
contact the Poison Center at 1-800-222-1222. 
If you spilled the study drug on your skin, remove 
contaminated clothing.  Wash area with soap and 
large amount of water.  Call your study doctor or 
nurse about spill. 
 
 

 
 
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89 
 
APPENDIX IV-B: CRIZOTINIB NOMOGRAM FOR PATIENTS RECEIVING FORMULATED 
CAPSULES 
 
 
Note: Patients enrolled on Part C (pre-Amendment #4) must continue to receive the formulated 
capsules (FC) per below dosing nomogram. For patients receiving the crizotinib microsphere 
formulation (cMS) refer to Appendix IV-C. 
 
Crizotinib Dose Assignment: 130 mg/m2/ dose BID 
(Dose Level -1) 
 
BSA (m2) 
Total Daily Crizotinib 
Dose 
(mg/day) 
Crizotinib 
(mg PO BID) 
AM Dose  
PM Dose 
1.07-1.34 
300 
150 
150 
1.35-1.73 
400 
200 
200 
1.74-2.11 
500 
250 
250 
2.12- ≥ 2.30 
600 
300 
300 
 
 
                                             Crizotinib Dose Assignment: 165 mg/m2/ dose BID 
(Dose Level 1) 
 
BSA (m2) 
Total Daily Crizotinib 
Dose 
(mg/day) 
Crizotinib 
(mg PO BID) 
AM Dose  
PM Dose 
1.07-1.36 
400 
200 
200 
1.37-1.66 
500 
250 
250 
1.67-1.96 
600 
300 
300 
1.97-2.27 
700 
350 
350 
2.28- ≥ 2.30 
800 
400 
400 
 
 
Crizotinib Dose Assignment: 215 mg/m2/ dose BID 
(Dose Level 2) 
 
BSA (m2) 
Total Daily Crizotinib 
Dose 
(mg/day) 
Crizotinib 
(mg PO BID) 
AM Dose  
PM Dose 
1.07-1.27 
500 
250 
250 
1.28-1.51 
600 
300 
300 
1.52-1.74 
700 
350 
350 
1.75-1.97 
800 
400 
400 
1.98-2.20 
900 
450 
450 
2.21- ≥ 2.30 
1000 
500 
500 
 
 
 

 
 
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Crizotinib Dose Assignment: 280 mg/m2/ dose BID 
(Dose Level 3) 
 
BSA (m2) 
Total Daily Crizotinib 
Dose 
(mg/day) 
Crizotinib 
(mg PO BID) 
AM Dose  
PM Dose 
1.07-1.16 
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 
1.88-2.05 
1100 
550 
550 
2.06-2.23 
1200 
600 
600 
2.24- ≥ 2.30 
1300 
650 
650 
 

 
 
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APPENDIX IV-C: CRIZOTINIB NOMOGRAM FOR PATIENTS RECEIVING 
MICROSPHERES 
 
   Crizotinib Dose Assignment: 130 mg/m2/ dose  
(Dose Level -2) 
 
BSA (m2) 
Crizotinib Dose  
Cycle 1: Day 1 
ONLY 
 
BSA (m2) 
Crizotinib Dose# 
PM  Dose 
(Total Dose) 
AM Dose 
PM Dose 
0.43-0.53 
60 
0.43-0.53 
60 
60 
0.54-0.69 
80 
0.54-0.69 
80 
80 
0.70-0.84 
100 
0.70-0.84 
100 
100 
0.85-1.00 
120 
0.85-1.00 
120 
120 
1.01-1.15 
140 
1.01-1.15 
140 
140 
1.16-1.30 
160 
1.16-1.30 
160 
160 
1.31-1.46 
180 
1.31-1.46 
180 
180 
1.47-1.61 
200 
1.47-1.61 
200 
200 
1.62-1.76 
220 
1.62-1.76 
220 
220 
1.77-1.92 
240 
1.77-1.92 
240 
240 
1.93-2.07 
260 
 
1.93-2.07 
260 
260 
2.08-2.23 
280 
2.08-2.23 
280 
280 
>2.23 
300 
>2.23 
300 
300 
# BID on Days 2-21 of Cycle 1 and Days 
1-21 of Subsequent Cycles  
 

 
 
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   Crizotinib Dose Assignment: 165 mg/m2/ dose  
(Dose Level -1) 
 
BSA (m2) 
Crizotinib Dose  
Cycle 1: Day 1 
ONLY 
 
BSA (m2) 
Crizotinib Dose# 
PM  Dose 
(Total Dose) 
AM Dose 
PM Dose 
0.43-0.54 
80 
0.43-0.54 
80 
80 
0.55-0.66 
100 
0.55-0.66 
100 
100 
0.67-0.78 
120 
0.67-0.78 
120 
120 
0.79-0.90 
140 
0.79-0.90 
140 
140 
0.91-1.03 
160 
0.91-1.03 
160 
160 
1.04-1.15 
180 
1.04-1.15 
180 
180 
1.16-1.27 
200 
1.16-1.27 
200 
200 
1.28-1.39 
220 
1.28-1.39 
220 
220 
1.40-1.51 
240 
1.40-1.51 
240 
240 
1.52-1.63 
260 
1.52-1.63 
260 
260 
1.64-1.75 
280 
1.64-1.75 
280 
280 
1.76-1.87 
300 
1.76-1.87 
300 
300 
1.88-2.00 
320 
1.88-2.00 
320 
320 
2.01-2.12 
340 
2.01-2.12 
340 
340 
2.13-2.24 
360 
2.13-2.24 
360 
360 
≥2.25 
380 
≥2.25 
380 
380 
# BID on Days 2-21 of Cycle 1 and Days 
1-21 of Subsequent Cycles  
 

 
 
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Crizotinib Dose Assignment: 215 mg/m2/dose  
(Dose Level 1) 
 
BSA (m2) 
Crizotinib Dose  
Cycle 1: Day 1 ONLY 
 
BSA (m2) 
Crizotinib Dose# 
PM Dose 
(Total Dose) 
AM Dose 
PM Dose 
0.43-0.51 
100 
0.43-0.51 
100 
100 
0.52-0.60 
120 
0.52-0.60 
120 
120 
0.61-0.69 
140 
0.61-0.69 
140 
140 
0.70-0.79 
160 
0.70-0.79 
160 
160 
0.80-0.88 
180 
0.80-0.88 
180 
180 
0.89-0.97 
200 
0.89-0.97 
200 
200 
0.98-1.06 
220 
0.98-1.06 
220 
220 
1.07-1.16 
240 
1.07-1.16 
240 
240 
1.17-1.25 
260 
1.17-1.25 
260 
260 
1.26-1.34 
280 
1.26-1.34 
280 
280 
1.35-1.44 
300 
1.35-1.44 
300 
300 
1.45-1.53 
320 
1.45-1.53 
320 
320 
1.54-1.62 
340 
1.54-1.62 
340 
340 
1.63-1.72 
360 
1.63-1.72 
360 
360 
1.73-1.81 
380 
1.73-1.81 
380 
380 
1.82-1.90 
400 
1.82-1.90 
400 
400 
1.91-2.00 
420 
1.91-2.00 
420 
420 
2.01-2.09 
440 
2.01-2.09 
440 
440 
2.10-2.18 
460 
2.10-2.18 
460 
460 
2.19-2.27 
480 
2.19-2.27 
480 
480 
≥2.28 
500 
≥2.28 
500 
500 
# BID on Days 2-21 of Cycle 1 and Days 1-21 
of Subsequent Cycles 
 
 
 

 
 
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94 
 
APPENDIX V-B: CRIZOTINIB PATIENT DIARY (FORMULATED CAPSULES) 
 
COG Patient ID:___________   ACC # : _____     Institution :__________________ BSA:_____ m2 
 
Please do not write patient names on this form. 
 
Instructions: Complete the diary below by recording the date and time the dose of crizotinib is given as well as the 
number of capsules taken for each dose. Make note of other drugs and supplements taken in the Comments 
section of the diary.   
 
Crizotinib should be given twice a day, approximately 12 hours apart.  On Days 1-5, crizotinib should be taken at least 
1 hour before chemotherapy. The crizotinib capsules should be swallowed whole.  Do not open, crush, or chew the 
capsules before swallowing. If the capsule is broken and the powder gets on the skin, wash the area thoroughly with 
water.  Inform your study doctor or nurse immediately.  
 
 
If you vomit after taking crizotinib, do not take another dose. Record this event in the diary and continue on the 
normal dosing schedule. If you miss a crizotinib dose and less than 6 hours have passed since the scheduled dosing 
time, that dose should be taken immediately. If you miss a crizotinib dose and more than 6 hours have passed since 
the scheduled dosing time, skip that dose and continue on the normal dosing schedule. If you accidently take 1 extra 
dose during a day, skip the next scheduled dose of crizotinib. 
 
Return the completed diary and all study medication bottles to the study clinic at each visit (weekly during Cycle 1 
and then after each treatment cycle). The study clinic will submit this diary into an electronic system to record the 
information. 
 
EXAMPLE 
WEEK 1 
Date 
Time 
# of crizotinib capsules prescribed to take 
Comments  
(Describe any missed or extra doses, 
vomiting and/or bothersome effects.) 
150 mg 
200 mg 
250 mg 
AM#___ 
PM#___ 
AM#_2__ 
PM#_2__ 
AM#___ 
PM#___ 
# of crizotinib capsules taken  
150 mg 
200 mg 
250 mg 
Day 1 
1/7/14 
8.30 
AM 
 
2 
 
He felt nauseated an hour after taking 
the drug but did not vomit. 
8.30 
PM 
 
2 
 
 
 
Cycle #: _____    Start Date: |__/__|__/__|__/__|     
                              End Date: |__/__|__/__|__/__|              Dose Level:            mg/m2/dose          Part of Study:____                     
    
WEEK 1 
Date 
Time 
# of crizotinib capsules prescribed to take 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
150 mg 
200 mg 
250 mg 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
 
# of crizotinib capsules taken  
150 mg 
200 mg 
250 mg 
Day 1 
 
 
AM 
 
 
 
 
 
PM 
 
 
 
 
Day 2 
 
 
AM 
 
 
 
 
 
PM 
 
 
 
 
Day 3 
 
 
AM 
 
 
 
 
 
PM 
 
 
 
 
Day 4 
 
 
AM 
 
 
 
 
 
PM 
 
 
 
 
Day 5 
 
 
AM 
 
 
 
 
 
PM 
 
 
 
 
 

 
 
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COG Patient ID:___________   ACC # : _____     Institution :__________________ BSA:_____ m2 
Please do not write patient names on this form. 
 
WEEK 1 
Date 
Time 
# of crizotinib capsules prescribed to take 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
150 mg 
200 mg 
250 mg 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
 
# of crizotinib capsules taken  
150 mg 
200 mg 
250 mg 
Day 6 
 
 
AM 
 
 
 
 
 
PM 
 
 
 
 
Day 7 
 
 
AM 
 
 
 
 
 
PM 
 
 
 
 
WEEK 2 
Date 
Time 
# of crizotinib capsules taken 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
150 mg 
200 mg 
250 mg 
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 
# of crizotinib capsules taken 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
150 mg 
200 mg 
250 mg 
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 
 
 
 
 

 
 
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APPENDIX V-C1: CRIZOTINIB PATIENT DIARY (MICROSPHERES)-CYCLE 1 ONLY 
 
 
COG Patient ID:___________   ACC # : _____     Institution :__________________ BSA:_____ m2 
          Please do not write patient names on this form. 
 
 
 
NOTE: For Cycle 2+ use the Patient Diary in Appendix V-C2. 
 
Instructions: Complete the diary below by recording the date and time the dose of crizotinib is given. 
Make note of other drugs and supplements taken in the Comments section of the diary.   
 
Crizotinib should be given approximately 12 hours apart. On Day 1 of Cycle 1 crizotinib should be given 
once in the evening; on Days 2-21 of Cycle 1 crizotinib should be given twice daily. On scheduled 
study visits (including pharmacokinetic study days on Day 2 and between Days 15-21) patients should 
take their crizotinib morning dose in the clinic. On Days 2-5, the crizotinib morning dose should be 
taken at least 1 hour before chemotherapy, except on Day 1 only chemotherapy will be given in the morning 
at the clinic. If crizotinib powder gets on the skin, wash the area thoroughly with water.  Inform your study 
doctor or nurse immediately. See Appendix III-B for crizotinib handling and administration guidelines. 
 
Do not swallow capsules whole. Empty capsule contents and take as directed per Crizotinib Microsphere 
Administration Instructions (Appendix III-B) and Crizotinib Microsphere Patient Education Sheet 
(Appendix III-C). 
 
If you vomit after taking crizotinib, do not take another dose. Record this event in the diary and continue 
on the normal dosing schedule. If you miss a crizotinib dose and less than 6 hours have passed since the 
scheduled dosing time, that dose should be taken immediately. If you miss a crizotinib dose and more than 
6 hours have passed since the scheduled dosing time, skip that dose and continue on the normal dosing 
schedule. If you accidently take 1 extra dose during a day, skip the next scheduled dose of crizotinib. 
 
Return the completed diary and all study medication bottles to the study clinic at each visit (weekly during 
Cycle 1). The study clinic will submit this diary into an electronic system to record the information.  
 
 
 
EXAMPLE 
WEEK 1 
Date 
Time 
# of crizotinib microsphere capsules 
prescribed to take 
Comments  
(Describe any missed or extra 
doses, vomiting and/or 
bothersome effects.) 
20 mg 
40 mg 
120 mg 
AM#___ 
PM#___ 
AM#  2 
PM#  2 
 AM#   1 
 PM#   1 
# of crizotinib microsphere capsules taken  
20 mg 
40 mg 
120 mg 
Day 1 
9/14/15 
 
AM 
AM dose should not be taken on Day 1 of Cycle 1. ONLY take the Day 1 evening 
dose. 
8.30 
PM 
 
2 
1 
He felt nauseated an hour after 
taking the drug but did not vomit. 
Day 2 
9/15/15 
8.30 
AM 
 
2 
1 
 
8.30 
PM 
 
2 
1 
 
 
Patient Diary for Cycle 1 is continued on the next couple of pages. 

 
 
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97 
 
COG Patient ID:___________   ACC # : _____     Institution :_______________ BSA:_____ m2        Cycle #: 1 
Please do not write patient names on this form. 
 
Cycle #: 1            Start Date: |__/__|__/__|__/__|      Dose Level:            mg/m2/dose                  
                              End Date: |__/__|__/__|__/__|                                                                     
    
WEEK 1 
Date 
Time 
# of crizotinib microsphere capsules 
prescribed to take 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
20 mg 
40 mg 
120 mg 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
# of crizotinib microsphere capsules taken  
20 mg 
40 mg 
120 mg 
Day 1 
 
 
AM 
AM dose should not be taken on Day 1 of Cycle 1. ONLY take the Day 1 evening 
dose. 
 
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 
# of crizotinib microsphere capsules 
prescribed to take 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
20 mg 
40 mg 
120 mg 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
# of crizotinib microsphere capsules taken 
20 mg 
40 mg 
120 mg 
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 
 
 
 
 

 
 
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COG Patient ID:___________   ACC # : _____     Institution :______________ BSA:_____ m2        Cycle #: 1 
Please do not write patient names on this form. 
 
WEEK 3 
Date 
Time 
# of crizotinib microsphere capsules 
prescribed to take 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
20 mg 
40 mg 
120 mg 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
# of crizotinib microsphere capsules taken 
20 mg 
40 mg 
120 mg 
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 
 
 
 
 
 
 
 
 

 
 
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APPENDIX V-C2: CRIZOTINIB PATIENT DIARY (MICROSPHERES)-CYCLE 2+ ONLY 
COG Patient ID:___________   ACC # : _____     Institution :__________________ BSA:_____ m2 
 
Please do not write patient names on this form. 
 
Instructions: Complete the diary below by recording the date and time the dose of crizotinib is given. Make note of 
other drugs and supplements taken in the Comments section of the diary.   
 
Crizotinib should be given twice a day, approximately 12 hours apart.  On Days 1-5, crizotinib should be taken at least 
1 hour before chemotherapy. On scheduled study visits patients should take their crizotinib morning dose in the 
clinic. See Appendix III-B for crizotinib handling and administration guidelines. If crizotinib powder gets on the skin, 
wash the area thoroughly with water.  Inform your study doctor or nurse immediately.  
 
Do not swallow capsules whole. Empty capsule contents and take as directed per Crizotinib Microsphere 
Administration Instructions (Appendix III-B) and Crizotinib Microsphere Patient Education Sheet (Appendix III-C). 
 
 
If you vomit after taking crizotinib, do not take another dose. Record this event in the diary and continue on the 
normal dosing schedule. If you miss a crizotinib dose and less than 6 hours have passed since the scheduled dosing 
time, that dose should be taken immediately. If you miss a crizotinib dose and more than 6 hours have passed since 
the scheduled dosing time, skip that dose and continue on the normal dosing schedule. If you accidently take 1 extra 
dose during a day, skip the next scheduled dose of crizotinib. 
 
Return the completed diary and all study medication bottles to the study clinic at each visit (after each treatment 
cycle). The study clinic will submit this diary into an electronic system to record the information. 
 
EXAMPLE 
WEEK 1 
Date 
Time 
# of crizotinib microsphere capsules 
prescribed to take 
Comments  
(Describe any missed or extra doses, 
vomiting and/or bothersome effects.) 
20 mg 
40 mg 
120 mg 
AM#___ 
PM#___ 
AM#_2__ 
PM#_2__ 
AM#_1__ 
   PM#_1_ 
# of crizotinib microsphere capsules taken  
20 mg 
40 mg 
120 mg 
Day 1 
9/14/15 
8.30 
AM 
 
2 
1 
He felt nauseated an hour after taking 
the drug but did not vomit. 
8.30 
PM 
 
2 
1 
 
 
Cycle #: _____    Start Date: |__/__|__/__|__/__|      Dose Level:            mg/m2/dose                  
                              End Date: |__/__|__/__|__/__|                                                                     
    
WEEK 1 
Date 
Time 
# of crizotinib microsphere capsules 
prescribed to take 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
20 mg 
40 mg 
120 mg 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
# of crizotinib microsphere capsules taken  
20 mg 
40 mg 
120 mg 
Day 1 
 
 
AM 
 
 
 
 
 
PM 
 
 
 
 
Day 2 
 
 
AM 
 
 
 
 
 
PM 
 
 
 
 
Day 3 
 
 
AM 
 
 
 
 
 
PM 
 
 
 
 
Day 4 
 
 
AM 
 
 
 
 
 
PM 
 
 
 
 
Day 5 
 
 
AM 
 
 
 
 
 
PM 
 
 
 
 

 
 
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  ADVL1212 
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100 
 
COG Patient ID:___________   ACC # : _____  Institution :______________ BSA:_____ m2   Cycle #:___ Please 
do not write patient names on this form. 
 
WEEK 1 
Date 
Time 
# of crizotinib microsphere capsules 
prescribed to take 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
20 mg 
40 mg 
120 mg 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
# of crizotinib microsphere capsules taken 
20 mg 
40 mg 
120 mg 
Day 6 
 
 
AM 
 
 
 
 
 
PM 
 
 
 
 
Day 7 
 
 
AM 
 
 
 
 
 
PM 
 
 
 
 
WEEK 2 
Date 
Time 
# of crizotinib microsphere capsules taken 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
20 mg 
40 mg 
120 mg 
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 
# of crizotinib microsphere capsules taken 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
20 mg 
40 mg 
120 mg 
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 
 
 
 
 

 
 
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ADVL1212 
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101 
 
 
APPENDIX VI: 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 
X1 and X-A 
(Parts A to C)  
2 ml 
12 ml 
2 ml 
12 ml 
K+ EDTA 
X2 and X-A 
(Part D) 
     2 ml 
14 ml 
2 ml 
14 ml 
K+ EDTA 
Pharmacogenomics 
VIII 
3 ml 
3 ml 
3 ml 
3 ml 
K+ EDTA 
Bone Marrowb 
XI 
3-5 ml 
3-5 ml 
5 ml 
5 ml 
Preservative free heparin tubes 
Bone Marrowc 
XII 
3-5 ml 
3-5 ml 
5 ml 
5 ml 
K+ EDTA 
Peripheral Bloodc 
XII 
10 ml 
20 ml 
15 ml 
30 ml 
K+ EDTA 
Tumor Tissue 
IX 
 
 
 
Total Blood Volume in Cycle 1 
 
35-37 ml 
 
45-47 ml 
 
Total Bone Marrow Volume 
 
6-10 ml 
 
10 ml 
 
a Required for all Patients  
b Additional Studies for Patients with Neuroblastoma 
c Additional Required Studies for Patients with ALCL 

 
 
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 102 
APPENDIX VII: CORRELATIVE BIOLOGY STUDIES  
 
1. COMPREHENSIVE DNA RESEQUENCING OF ALK FOR NEUROBLASTOMA  
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 crizotinib 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 FOR NEUROBLASTOMA 
We will define whole genome DNA copy number status as well as ALK allelic using the Illumina 
HH550K Single Nucleotide Polymorphism (SNP) array.13,28,29 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 FOR NEUROBLASTOMA*** 
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 IN NEUROBLASTOMA 
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.30 We will then screen 
for transformation in vitro using standard assays. 
 
5. DETERMINE THE BIOCHEMICAL CONSEQUENCES OF ALK ACTIVATION IN 
NEUROBLASTOMA 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 CRIZOTINIB AT TIME OF 
DISEASE PROGRESSION ON THIS STUDY  
We will collect bone marrow samples before and during treatment with crizotinib, 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.  
 
7. DEFINE c-Met EXPRESSION IN ALL NON-ALCL, NON-NEUROBLASTOMA TUMORS.  We 
will perform immunohistochemistry studies on all non-neuroblastoma solid tumors to determine c-Met 
expression. 

 
 
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 103 
APPENDIX VIII: PHARMACOGENOMIC STUDY FORM  
 
COG Pt ID # _______________ 
ACC # _______________          Cycle 1, Day 1 Date: __________  
Please do not write patient names on this form or on samples. 
 
Institution: ______________________________ 
 
Body Surface Area: ____ m2 
Dose Level: ________mg/m2 
 
 
Total Dose (combined am and pm dose): _______mg/day 
 
 
• 
One peripheral blood sample (3 mL) will be obtained at baseline prior to the first dose of crizotinib 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 dose is administered.  
 
 
Date 
Time 
Sample Obtained: 
|__/__|__/__|__/__| 
|___|___| : |___|___| 
Drug Administered: 
|__/__|__/__|__/__| 
|___|___| : |___|___| 
 
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. (ADVL1212), and the date and 
time the sample was drawn; please label as “pharmacogenomic sample”. 
3. Gently mix the blood with the anticoagulant by gently inverting the tube (15 times). 
4. Record the date and time of sample collection on this form.  
5. After mixing the blood with the anticoagulant, place the blood collection tube inside a cryovial storage box 
and store the blood at -70° 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 uploaded into RAVE. A second 
copy should be sent with the sample to the Mayo Clinic laboratory (see address below).  
 
Sample Shipping 
1. Ship the sample on dry ice. Shipments should be sent Monday through Wednesday only for priority 
overnight delivery. Do not ship on Thursday or Friday.  
2. Please notify Renee McGovern of a pending shipment along with the FedEx tracking number by phone at 
(507) 284-4303 or by e-mail (mcgovern.renee@mayo.edu). 
3. Ship samples to:  
 
 
 
Mayo Clinic 
Gonda 19-151 
200 First Street SW 
Rochester, MN 55905 
 
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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ADVL1212 
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 104 
APPENDIX IX:  TISSUE STUDIES FORM 
 
COG Pt ID # _______________ 
ACC # _______________          Cycle 1, Day 1 Date: __________  
Please do not write patient names on this form or on samples. 
 
Institution: _____________________________________________________ 
 
Body Surface Area: ____ m2 
Dose Level: ________mg/m2 
 
 
Total Dose (combined am and pm dose): _______mg/day 
 
Tumor Sample Labeling: 
Samples should be labeled with the following information: 
 
Protocol number: ADVL1212 
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 uploaded into RAVE.  
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) 
 

 
 
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ADVL1212 
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 105 
APPENDIX X-1: PHARMACOKINETIC STUDY FORM (PARTS A-C) 
 
COG Pt ID # _______________ 
ACC # _______________          Cycle 1, Day 1 Date: __________  
Please do not write patient names on this form or on samples. 
 
 
     Institution: ________________________   Crizotinib Formulation (tick one): □ OS   □ FC 
 
 
Body Surface Area: ____ m2 
Dose Level: ________mg/m2 
Total Dose: _______mg/day 
 
Cycle 1, Date of Steady State Sampling: __________ 
 
 
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 21 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 crizotinib dose is administered 
before the pharmacokinetic sample is drawn. Sample handling and processing instructions are described below and in 
Section 8.3.  
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. (ADVL1212), 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 crizotinib. 
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 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 a cryovial storage box and store the plasma at -20 oC to -70 
oC within 1 hour of collection until shipment. 
 
One copy of this Pharmacokinetic Study Form should be uploaded into RAVE. A second copy should be sent with the 
samples to Covance at the address listed in Appendix X-A.  See Appendix X-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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ADVL1212 
11/21/16 
 
 
 
 
 
 106 
APPENDIX X-2: PHARMACOKINETIC STUDY FORM FOR MICROSPHERES (PART D ONLY) 
 
COG Pt ID # _____________    ACC # _______________         Institution: ______________________  
Please do not write patient names on this form or on samples. 
 
       BSA: ____ m2 
         Dose Level: ________mg/m2                          Cycle 1, Day 1 Date: __________ 
 
                 Total Crizotinib Dose:    Day 1_______mg/day          Days 2-21 _______mg/day 
            
Blood samples (2 mL per timepoint) will be obtained in K2EDTA tubes during Cycle 1. Record the exact 
date and time each sample is drawn and the last crizotinib dose is administered before the pharmacokinetic 
sample is drawn. Sample handling and processing instructions are described below and in Section 8.3.  
 
Blood 
Sample 
No. 
Time Point 
Cycle 1 
Scheduled Collection Time 
Actual 
Crizotinib Dose 
Given 
Actual Date 
Sample 
Collected or 
Dose Given 
Actual Time 
Collected or  
Dose Given 
(24-hr clock) 
1 
Day 1 
Pre-Day 1 dose 
 
___/____/___ 
|__|__| : |__|__| 
Day 1 Dose 
_______mg PM 
___/____/___ 
|__|__| : |__|__| 
2 
Day 2 
12 hrs after 1st dose 
(Pre-Day 2 dose) 
 
___/____/___ 
|__|__| : |__|__| 
                                                                       Day 2 Dose* 
_______ mg AM 
___/____/___ 
|__|__| : |__|__| 
 
Last dose before Pre-Dose at Steady State# Obtained 
_______mg AM 
___/____/___ 
|__|__| : |__|__| 
_______mg  PM 
|__|__| : |__|__| 
3 
Pre-Dose at 
Steady State# 
12 hrs after the last dose 
recorded above 
 
___/____/___ 
|__|__| : |__|__| 
Steady State Dose*# 
_______mg AM 
___/____/___ 
|__|__| : |__|__| 
4 
Steady State# 
1 hr post-steady-state dose 
 
___/____/___ 
|__|__| : |__|__| 
5 
2 hrs post-steady-state dose 
 
___/____/___ 
|__|__| : |__|__| 
6 
4 hrs post-steady-state dose 
 
___/____/___ 
|__|__| : |__|__| 
7 
6-8 hrs a post-steady-state 
dose 
 
___/____/___ 
|__|__| : |__|__| 
 
*To be administered in the clinic. 
# Steady State is defined as being between Days 15 and 21 of BID dosing in Cycle 1. 
 
Sample Processing Procedures   
1. 
Label the cryovial tube with the patient’s study registration number, the study I.D. (ADVL1212), 
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 
crizotinib. 
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 labeled 
cryovial. Cap the tubes tightly.   

 
 
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ADVL1212 
11/21/16 
 
 
 
 
 
 107 
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 a cryovial storage box and store the plasma at 
-20 oC to -70 oC within 1 hour of collection until shipment. 
 
One copy of this Pharmacokinetic Study Form should be uploaded into RAVE. A second copy should be 
sent with the samples to Covance at the address listed in Appendix X-A.  See Appendix X-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) 
 
 
 
 
 
 
 

 
 
            THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
ADVL1212 
11/21/16 
 
 
 
 
 
 108 
APPENDIX X-A:GUIDELINES FOR SHIPPING SAMPLES TO COVANCE-INDIANAPOLIS 
 
REGULATORY INFORMATION 
 
Specific Federal and International Regulations define classes of “Hazardous Materials”1 and “Dangerous Goods”2.  Specimens 
transported to the Covance Indianapolis - Bioanalytical Chemistry Department should be evaluated for their Hazardous Material 
Class and categorized, packaged, labeled, documented, and transported in accordance with the applicable regulations.  Facilities 
shipping Hazardous Materials are required to maintain designated personnel trained in accordance with part 493 CFR-Subpart H 
within the last 36 months and International Air Transportation Association (IATA) regulations (if shipping by air) within the last 
24 months.  The IATA regulation manual also lists additional regulations imposed individually by a variety of Commercial Carriers 
and Airlines.   
 
The information provided here are Covance Labs guidelines to assist in the proper and safe transport of samples for assay in this 
facility.  They are not to be construed as a replacement or complete summary of applicable DOT (CFR) or IATA regulations. 
 
GUIDELINES FOR PACKAGING SAMPLES 
 
A. Please organize samples by subject where possible (i.e. bag all of subject 001 together, all of 
subject 002 together, etc) 
B. If shipping 2 or more studies in the same box, please clearly identify individual bags or boxes 
with client protocol number 
 
1. Sample container caps should be securely fastened. 
a. Samples should not be transported in glass vials.  Samples should be transferred to plastic 
tubes for transport. 
(If glass must be used, containers must be immobilized.  Note: the use of glass greatly 
increases the risk of breakage and sample loss).  
b. Use labels that will not smear or fall off under cold or moist conditions.   
 
2. Samples should be placed in a primary receptacle (insulated cooler), then into a secondary 
receptacle (sturdy cardboard box).  These primary and secondary containers are available 
commercially as combination packaging. The package contents are placed in this order: 
a. Wrap the samples in enough absorbent material to absorb at least three times the contents 
should leakage occur. 
b. Place the wrapped samples in a plastic bag and seal (heat seal or zip lock) 
c. Place the sealed bag in the bottom of the primary receptacle. 
d. Add styrofoam peanuts or equivalent (barrier to dry ice and shock stabilizer) 
e. Add a sheet of cardboard 
f. If samples are to be frozen, adequate dry ice should be included in the container to last 
the duration of the journey.  (48-72 hrs, at least 7 Kg or 15 pounds, approximately 4 
pounds per day of transit).   
g. If there is room remaining, add filler material to avoid content movement during 
transport.   
h. The primary Styrofoam container should be taped shut and placed in the secondary 
cardboard container. 
 
                                                     
1  Term used by Department of Transportation (DOT) in the Code of Federal Regulations (CFR) 
2  Similar term used by the International Air Transportation Association (IATA), will use the term Hazardous 
Material in this document  
3   Part 49 is “Hazardous Materials in Commerce” in the CFR 

 
 
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ADVL1212 
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 109 
3. Complete the Pharmacokinetic Study Form located in Appendix X-1 or Appendix X-2 of the 
ADVL1212 protocol.  Please indicate sample storage conditions on this form.   
 
4. Seal the form in a protected plastic bag.  Place the plastic bag containing the form on top of the 
secured styrofoam primary container lid so that it is immediately accessible upon opening the 
box. 
 
5. Tape the shipping box securely closed.  Use tape that is resistant to moisture and cold. 
 
6. Place Biohazard warnings on outside of box (if applicable). 
 
7. Label the box exterior in accordance with the applicable DOT CFR / IATA Regulations. 
 
8. Complete an address label and attach it to the outside of the box.   
 
****************************************************************************** 
GUIDELINES FOR SHIPPING SAMPLES 
 
Send samples to: 
 
Covance Bioanalytical Services, LLC 
8211 SciCor Drive, Suite B 
Indianapolis, Indiana 46214 
Attn:  BioA Sample Accession Mgr 
 
 
1. Samples should be shipped least 2 days prior to a USA National Holiday. 
 
2. Call the Covance Bioanalytical Services Sample Management department on the day prior to 
shipment (800-462-8887 Ext 3935 or Ext 3902), as notification of the intended shipment, OR e-
mail IndyBioSA@Covance.com with shipment information (tracking numbers and number of 
boxes sent).  
 
3. Samples to be shipped to the United States from outside the U.S.A. should be shipped using 
an International carrier.  The name of the carrier, shipping date, expected date of arrival, and 
tracking numbers should be e-mailed to IndyBioSA@Covance.com, prior to shipment. 
 
4. Any questions regarding shipping instructions may be directed to the Sample Management Group 
at 1-800-462-8887 Ext. 3957, Ext 3902, or Ext. 3935, or via  Fax 317-616-2301.  International 
phone code is 001. 
 
****************************************************************************** 
  

 
 
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 110 
APPENDIX XI: BONE MARROW STUDIES FORM (FOR PATIENTS WITH 
NEUROBLASTOMA ONLY) 
 
COG Pt ID # _______________ 
ACC # _______________          Cycle 1, Day 1 Date: __________  
Please do not write patient names on this form or on samples. 
 
Institution: _____________________________________________________ 
 
Body Surface Area: ____ m2 
Dose Level: ________mg/m2 
 
 
Total Dose (combined am and pm dose): _______mg/day 
 
• 
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 every other cycle 
at times of disease evaluation (See Section 8.1 and Section 8.6.2). 
 
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 (ADVL1212), 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) 

 
 
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ADVL1212 
11/21/16 
 
 
 
 
 
 111 
APPENDIX XII: BONE MARROW AND PHERIPHERAL BLOOD STUDIES FORM (FOR 
PATIENTS WITH ALCL ONLY)  
 
COG Pt ID # _______________ 
ACC # _______________          Cycle 1, Day 1 Date: __________  
Please do not write patient names on this form or on samples. 
 
Institution: _____________________________________________________ 
 
Body Surface Area: ____ m2 
Dose Level: ________mg/m2 
 
 
Total Dose (combined am and pm dose): _______mg/day 
 
Type of sample  
(check one) : 
 bone marrow 
 peripheral blood 
• 
Bone marrow samples (5 mL if > 10 kg and 3-5 
mL in children ≤ 10 kg) will be obtained prior to 
starting Cycle 1 and repeated until negative in 
patients with ALCL.  
 
• 
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 (ADVL1212), the type of sample (bone 
marrow or peripheral blood), 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: 
 
 
 
 
 
 
 
 
 
 
 
  
 
Email
 
when the sample is being shipped. 
 
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) 

 
 
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ADVL1212 
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 112 
APPENDIX XIII: PREGNANCY INFORMATION FORM  
 
Attach to CTEP-AERS 5-Day Report 
 
NOTE: For an initial reporting email both the Pregnancy CTEP-AERS Report and this additional Pregnancy 
Information Form. For follow-up reporting, email only this Pregnancy Information Form. See Section 13. 7. 

 
 
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ADVL1212 
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 113 
APPENDIX XIV: POSSIBLE DRUG INTERACTIONS 
 
The lists below do not include everything that may interact with crizotinib and/or chemotherapy. Study 
patients 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 the diet. 
 
Crizotinib 
 
Drugs that may interact with 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 crizotinib 
• 
Echinacea 
• 
St. John’s Wort 
• 
Grapefruit, grapefruit juice, 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.  
 
 

 
 
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ADVL1212 
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 114 
 Cyclophosphamide: 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.  
 
 
Topotecan 
 
Drugs that may interact with topotecan 
• Antibiotics and antifungals 
• Clarithromycin, erythromycin, itraconazole, ketoconazole 
• Arthritis medications  
• Leflunomide, tofacitinib 
• Anti-rejection medications 
• Cyclosporine, tacrolimus 
• Antiretrovirals and antivirals  
• Darunavir, lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir 
• Heart medications  
• Amiodarone, amlodipine, carvedilol, dronedenarone, nicardipine, propranolol, 
verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
• Atorvastatin, clozapine, dipyridamole, ivacaftor, lomitapide, natalizumab 
 
Food and supplements* that may interact with topotecan 
• Echinacea 
• Grapefruit, grapefruit juice 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided.  
 
 
Drugs that may interact with cyclophosphamide 
• 
Allopurinol 
• 
Chloramphenicol 
• 
Cyclosporine 
• 
Digoxin  
• 
Etanercept  
• 
Hydrochlorothiazide 
• 
Indomethacin 
• 
Nevirapine 
 
• 
Ondansetron 
• 
Pentostatin  
• 
Tamoxifen 
• 
Trastuzumab  
• 
Warfarin 
Food and supplements* that may interact with cyclophosphamide 
• 
St John’s Wort 
• 
Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 

 
 
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ADVL1212 
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 115 
 
APPENDIX XV: MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
 
 
The use of the following medications should be avoided during protocol therapy if reasonable alternatives 
exist. This is not an inclusive list. Because the lists of these agents are constantly changing, it is important 
to regularly consult frequently updated medical references. For the most current list of medications, 
please refer to the following reference: 
Woosley, RL and Romero, KA, www.Crediblemeds.org, QTdrugs List, Accession Date March 1st, 2016, 
AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ 85755 
 
1. Medications that prolong QTc: 
Generic name 
Brand name 
 
Generic name 
Brand name 
Amiodarone 
Cordarone® 
 
Flecainide 
Tambocor® 
Anagrelide 
Agrylin® 
 
Fluconazole 
Diflucan® 
Arsenic trioxide 
Trisenox® 
 
Haloperidol 
Haldol® 
Azithromycin 
Zithromax® 
 
Ibutilide 
Corvert® 
Chloroquine 
Aralen® 
 
Methadone 
Dolophine® 
Chlorpromazine 
Thorazine® 
 
Moxifloxacin 
Avelox® 
Ciprofloxacin 
Cipro® 
 
Ondansetron 
Zofran® 
Citalopram 
Celexa® 
 
Pentamidine 
Pentam® 
Clarithromycin 
Biaxin® 
 
Pimozide 
Orap® 
Disopyramide 
Norpace® 
 
Procainamide 
Procan® 
Dofetilide 
Tikosyn® 
 
Propofol 
Diprivan® 
Domperidone 
Motilium® 
 
Quinidine  
Quinaglute® 
Droperidol 
Inapsine® 
 
Sevoflurane 
Ulane® 
Dronedarone 
Multaq® 
 
Sotalol 
Betapace® 
Erythromycin 
Erythrocin® 
 
Thioridazine  
Mellaril® 
Escitalopram 
Lexapro® 
 
Vandetanib  
Caprelsa® 
 
 
 
2. Medications that may prolong QTc: 
Generic name 
Trade name 
 
Generic name 
Trade name 
Aripiprazole 
Abilify® 
 
Lapatinib 
Tykerb® 
Bortezomib 
Velcade® 
 
Lenvatinib 
Lenvima® 
Bosutinib 
Bosulif® 
 
Leuprolide 
Leupron Depot® 
Ceritinib 
Zykadia® 
 
Mirtazapine 
Remeron® 
Clomipramine 
Anafranil® 
 
Nicardipine 
Cardene® 
Crizotinib 
Xalkori® 
 
Nilotinib 
Tasigna® 
Dabrafenib 
Tafinlar® 
 
Olanzapine 
Zyprexa® 
Dasatinib 
Sprycel® 
 
Osimertinib 
Tagrisso® 
Degarelix 
Firmagon® 
 
Pazopanib 
Votrient® 
Desipramine 
Norpramine® 
 
Promethazine 
Phenergan® 
Dolasetron 
Anzemet® 
 
Risperidone 
Risperdal® 
Eribulin mesylate 
Halaven® 
 
Sorafenib 
Nexavar® 
Famotidine 
Pepcid® 
 
Sunitinib 
Sutent® 
Foscarnet 
Foscavir® 
 
Tacrolimus 
Prograf® 
Gemifloxacin 
Factive® 
 
Vemurafenib 
Zelboraf® 
Granisetron 
Kytril® 
 
Venlafaxine 
Effexor® 
Isradipine 
Dynacirc® 
 
Vorinostat 
Zolinza® 
 

 
 
 
ADVL1212 
11/21/16 
 
 
water 
 
 
SAMPLE INFORMED CONSENT / PARENTAL PERMISSION FOR 
PARTICIPATION IN RESEARCH 
 
 
ADVL1212, A Phase 1 Study of Crizotinib (IND# 105573) in Combination with 
Conventional Chemotherapy for Relapsed or Refractory Solid Tumors or 
Anaplastic Large Cell Lymphoma 
 
If you are a parent or legal guardian of a child who may take part in this study, permission from you is 
required. The assent (agreement) of your child may also be required. When we say “you” in this consent 
form, we mean you or your child; “we” means the doctors and other staff. 
 
This study is a clinical trial (a protocol, or research study involving patients) 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 1 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. The Phase 1 Consortium is the group within COG that 
consists of 21 hospitals based in the United States and Canada, and participation in this study will be limited 
to these hospitals.  
 
This is a Phase 1 study of a drug called crizotinib in combination with chemotherapy.  Crizotinib has been 
FDA approved for use in adults with non-small cell lung cancer (NSCLC) that has spread to other parts of 
the body and is caused by a defect in a gene called ALK (anaplastic lymphoma kinase). The combination 
of crizotinib with chemotherapy is considered experimental because it has not been proven to work in a 
situation like yours. We are using crizotinib because it seems to work against cancer in test tubes and 
animals. Crizotinib has been successfully used in adults and children. This is called a Phase 1 study because 
the goal is to find the highest dose of crizotinib in combination with chemotherapy (topotecan and 
cyclophosphamide) that we can give safely to children. With Amendment #4, the recommended dose was 
determined to be Dose Level 2 from the dose escalation part of the study (Part C). 
 
 
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 
must be justified in writing by the investigator and approved by the IRB.  

 
 
 
ADVL1212 
11/21/16 
 
 
Why is this study being done? 
We are testing new experimental drugs such as crizotinib in the hopes of finding a drug that may be effective 
against tumors or lymphoma that have come back or that have not responded to standard therapy. 
 
The goals of this study are: 
 
• 
To find the highest safe dose of crizotinib that can be given in combination with standard 
chemotherapy drugs without causing severe side effects; 
• 
To learn what kind of side effects crizotinib in combination with standard chemotherapy 
drugs can cause; 
• 
To learn more about the pharmacology (how your body handles the drug) of crizotinib in 
combination with standard chemotherapy drugs; 
• 
To learn more about the biology of crizotinib in combination with standard chemotherapy 
drugs; 
• 
To determine whether crizotinib in combination with standard chemotherapy drugs is a 
beneficial treatment for your tumor. 
  
How many people will take part in the study? 
There will be about 18-64 patients participating in this study overall.  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 
• 
Bone marrow tests (if required) 
• 
Spinal tap (if you have lymphoma) 
• 
Pregnancy test (if you are a woman who could have children) 
• 
Electrocardiogram (EKG) a test that monitors the function of your heart 
• 
X-rays, CT scans, or other tests that are needed to check your tumor. 

 
 
 
ADVL1212 
11/21/16 
 
 
During the study …  
If the exams, tests and procedures show that you can be in the study, and you choose to take part, crizotinib 
will be given for 21 days.  This entire period is called a cycle.  You may continue to receive crizotinib for 
up to 35 cycles (up to 24 months) unless you develop serious side effects or your tumor worsens.     
 
The crizotinib will be given by mouth, followed by a small glass of water. Since we do not have information 
on how well the medicine is absorbed, if you vomit, the crizotinib should not be taken again. If you are 
taking the crizotinib capsules (Part C), you should not crush, open or chew the capsules; the capsules must 
be swallowed whole. If you enrolled on Part D, you will be given the crizotinib microsphere capsules; the 
microsphere capsules should be taken as instructed and should not be swallowed whole.  
 
In addition to crizotinib you also will receive topotecan and cyclophosphamide on Days 1 through 5.  
Topotecan and cyclophosphamide are both given directly into the vein through either a needle or small 
tubing inserted each treatment day or through a long-term catheter called a central line.* Approximately 24 
to 48 hours later, you will receive myeloid growth factor. 
 
*Your physician may recommend that you have a special kind of IV called a “central line.” This is a special 
kind of IV placed into a big vein in your chest that can stay in for a long time. If you get a central line, you 
will have a separate consent form for it. Potential risks of central line placement include accumulation of 
air inside the chest; bleeding; infection; blood clot development in the line; and risks from the anesthesia. 
After placement, the central line may become infected which may require hospitalization, antibiotics and 
possibly removal and replacement of the central line. 
 
Part D - Cycle 1 Only 
Cycle Day 
1 
2 
3 
4 
5 
6 
7-21 
21 
CRIZ  
(Once in 
the 
evening)  
CRIZ (Twice a day) 
Evaluation 
CPM  
CPM 
CPM 
CPM 
CPM 
 
 
TOPO  
TOPO 
TOPO 
TOPO 
TOPO 
 
 
 
 
 
 
 
MGF  
 
 
               Part C# and Part D* 
Cycle Day 
1 
2 
3 
4 
5 
6 
7-21 
21 
CRIZ (Twice a day) 
Evaluation 
CPM 
CPM 
CPM 
CPM 
CPM 
 
 
TOPO 
TOPO 
TOPO 
TOPO 
TOPO 
 
 
 
 
 
 
 
MGF 
 
 
 
CRIZ:  Crizotinib  
CPM: Cyclophosphamide 
TOPO: Topotecan 
MGF: Myeloid Growth Factor (filgrastim (G-CSF) or pegfilgrastim) 
# All cycles 
*Cycle 2+ for Part D 
 
 

 
 
 
ADVL1212 
11/21/16 
 
 
Parts C and D: If you enroll with Amendment #4, you will be treated at Dose Level 2, the recommended 
dose determined from the dose-escalation part of the study. If you have bad side effects, your dose may be 
decreased. 
 
During the study you will have tests and procedures to check for side effects and see how your tumor is 
doing. These tests are part of regular cancer care, but you may have them more often because you are on 
the study:  
* 
A medical history 
* 
Physical exam 
* 
Vital signs (blood pressure, pulse, temperature) 
* 
Eye exam  
* 
Blood tests 
* 
Bone marrow tests (if required) 
* 
Spinal tap (if you have lymphoma) 
* 
Urine tests (if you have neuroblastoma) 
* 
MRIs, X-rays, CT scans, or other tests that are needed to check your tumor 
 
Copies of the scans used to diagnose your cancer and some of the tissue already taken may be sent to a 
central review center. COG does this to double check the hospitals’ results.  
 
You will be given a Patient Diary at the beginning of each cycle of crizotinib.  Use the diary to record the 
date and time you take the drug, side effects you experience, and any other medications and supplements 
you are taking.  This diary should be returned to the clinic along with the medication bottle (even if it is 
empty) weekly during Cycle 1 and then after each treatment cycle.  This will help us to know how much of 
the drug you take and how it made you feel. 
 
Capsule Questionnaire (Part C Patients Only)             
If you are receiving the crizotinib capsules for this study, 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 well the drug can be swallowed. The questionnaire should be 
filled out within 10 minutes of taking the crizotinib capsules. It will take you about 5 minutes to fill out the 
questionnaire each time. 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. 
 
Microsphere Capsule Questionnaire (Part D Patients Only)             
If you are receiving the crizotinib microsphere capsules for this study, we would like to ask you to fill out 
a short questionnaire at the time of the first dose, and then once per week during Cycle 1, and then at every 
visit thereafter so we can learn more about how the drug tastes. The questionnaire should be filled out within 
10 minutes of taking the crizotinib microsphere capsule powder. It will take you about 5 minutes to fill out 
the questionnaire each time. 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. 
 
Research Tests 

 
 
 
ADVL1212 
11/21/16 
 
 
We would also like to do some extra tests called pharmacokinetic studies and biologic studies.  These tests 
will help us learn more about crizotinib 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 
given to you. Some of these tests are required but others are optional (you can decide whether you want to 
do them or not).  
 
Pharmacokinetic Studies (Required) 
During the study blood samples will be collected to determine how much crizotinib is in your blood.  About 
2 mL (approximately ½ teaspoon) of blood will be drawn for each sample. If you enroll on Part C, 6 blood 
samples will be obtained over 2 separate days (Day 1 and on a day between Days 15 and 21). If you enroll 
on Part D, 7 blood samples will be obtained over 3 separate days (Day 1, Day 2 and on a day between Days 
15 and 21). These 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. These 
blood samples are required from all participants in this study. 
 
If you enrolled on Part C, a total of 12 mL (about two and a half teaspoons total) will be taken for the 
pharmacokinetic tests in this study.  If  you enrolled on  Part D, a total of 14 mL (about 3 teaspoons total) 
will be taken for the pharmacokinetic tests in this study. This amount of blood is safe even for small 
children. 
 
You may be reimbursed up to $100 for inconveniences you experience as a result of your participation in 
these pharmacokinetic studies.  Your doctor will explain to you what qualifies for reimbursement (e.g. costs 
of parking). 
 
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 crizotinib 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 
As part of your regular care, your doctor may have removed some tumor tissue 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. The ALK gene testing may help us learn more about how crizotinib works in the tissues 
in your body. The tissue will be sent directly to the lab for testing.  
 
The information learned from this research will not change the way you are treated and the results of these 
tests will not be returned to you.  The research done with your tissue may help us learn more about crizotinib 
in combination with standard chemotherapy drugs and may help children who receive these drugs in the 
future. 
 
______/______ Yes, I agree to participate in the tumor tissue studies. 
 
______/______ No, I do not agree to participate in the tumor tissue studies. 
 
Additional Studies to Consider for Patients with Neuroblastoma Only 

 
 
 
ADVL1212 
11/21/16 
 
 
For patients with neuroblastoma, we would like to test your bone marrow to see how much a gene called 
ALK can be found. 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, crizotinib, works in your body. These 
samples would be drawn at the same time when bone marrow is obtained prior to treatment with crizotinib 
and then every other cycle at the time of your disease evaluations. These bone marrow samples are required 
from all patients with neuroblastoma. 
 
Additional Studies to Consider for Patients with Anaplastic Large Cell Lymphoma Only 
For patients with lymphoma, 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 teaspoon or less if you weigh equal to or less than 10 kg) will be drawn before your first dose of crizotinib. 
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 crizotinib, on Day 15 of 
Cycle 1, and once in each additional cycle.  These samples would be drawn at the same time as routine 
blood tests.  These blood and bone marrow samples are required from all patients with lymphoma. 
 
How long will I be in the study? 
You may be in the study for up to 24 months or 35 cycles of therapy. Your doctor may decide to take you 
off study if any of the following occur: 
• 
Your tumor gets worse 
• 
The side effects of crizotinib in combination with standard chemotherapy drugs are too harmful for 
you 
• 
You need a treatment that is not allowed on this study 
• 
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 
• 
If you become pregnant 
 
After you are finished taking crizotinib in combination with standard chemotherapy drugs, 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 crizotinib in 
combination with standard chemotherapy drugs can be evaluated by your doctor.  Also, your doctor can 
discuss what follow-up care and testing could be most helpful for you. 
 
What side effects or risks can I expect from being in the study?  
 
If you choose to take part in this study, there is a risk that: 

 
 
 
ADVL1212 
11/21/16 
 
 
• You may lose time at school or home and spend more time in the hospital or doctor’s office than 
usual 
• You may be asked sensitive or private questions which you normally do not discuss 
 
The crizotinib used in this study may affect how different parts of your body work such as your 
liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if 
changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drugs. 
 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are having a 
side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you. 
 
 

 
 
 
ADVL1212 
11/21/16 
 
 
Risks and side effects related to crizotinib include those which are: 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Crizotinib, more than 20 may have: 
• Vision Changes* 
• Discomfort in the eyes from light 
• Constipation, diarrhea, nausea, vomiting 
• Swelling of the body 
• Tiredness, weakness 
• Swelling and redness of the eyelids 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Crizotinib, from 4 to 20 may have: 
• Anemia which may cause tiredness, or may require blood transfusions 
• Heartburn  
• Sores in the throat or mouth which may cause difficulty swallowing 
• Abnormal heartbeat or change in the heart rhythm or abnormal heartbeat which may cause 
fainting and may be life-threatening 
• Headache 
• Rash 
• Weakness 
• Muscle spasms 
• Belly pain 
• Infection, especially when white blood cell count is low 
• Loss of appetite 
• Dizziness 
• Changes in taste 
• Damage to nerves that may interfere with walking or organ function which may cause 
numbness, tingling, weakness or pain in muscles 
 
 
 

 
 
 
ADVL1212 
11/21/16 
 
 
RARE, AND SERIOUS 
In 100 people receiving Crizotinib, 3 or fewer may have: 
• Swelling or damage of 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 
• Blood clot which may cause swelling, pain, shortness of breath 
• Change in the heart rhythm 
 
*Vision changes may include blurred vision, double vision, impaired vision, seeing spots before the eyes 
(floaters), flashing lights, brightness, rings, shadows, and/or streaking. 
 
 
Risks and side effects related to cyclophosphamide, topotecan include those which are:  
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Cyclophosphamide, Topotecan Hydrochloride,  
more than 20 and up to 100 may have: 
• Hair loss 
• Nausea, vomiting, loss of appetite 
• Sores in mouth which may cause difficulty breathing 
• Infection, especially when white blood cell count is low 
• Absence of menstrual period which may decrease the ability to have children 
• Blood in urine 
• Anemia which may require a blood transfusion 
• Constipation, diarrhea 
• Flu-like symptoms including fever, chills, body aches, muscle pain 
• Pain 
• Bruising, bleeding 
• Tiredness 
• Shortness of breath 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Cyclophosphamide, Topotecan Hydrochloride, from 4 to 20 may have: 
• Damage to the bone marrow (irreversible) which may cause infection, bleeding, may require 
transfusions 
• Loss or absence of sperm which may lead to an inability to father children 
• Stuffy nose 
• Fluid around the heart 
• Headache 
• Cough 
• Rash 
 

 
 
 
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RARE, AND SERIOUS 
In 100 people receiving Cyclophosphamide, Topotecan Hydrochloride, 3 or fewer may have: 
• Severe skin rash with blisters and peeling which can involve mouth and other parts of the 
body 
• Damage to the heart or heart failure which may cause shortness of breath, swelling of ankles, 
cough or tiredness 
• A new cancer including cancer of bone marrow (leukemia) caused by chemotherapy 
• Swelling of the body including the brain which may cause dizziness, confusion 
• Scarring of the lungs 
 
Risks and side effects related to myeloid growth factors (filgrastim (G-CSF) or pegfilgrastim) include 
those which are: 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving filgrastim or pegfilgrastim, more than 20 may have: 
• Nausea, vomiting1 
• Pain in bone 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving filgrastim or pegfilgrastim, from 4 to 20 may have: 
• Anemia which may cause tiredness, or may require transfusion 
• Damage to the lungs which may cause shortness of breath 
• Internal bleeding which may cause coughing up blood1 
• Swelling or tenderness of vessels1 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat2 
 
RARE, AND SERIOUS 
In 100 people receiving filgrastim or pegfilgrastim, 3 or fewer may have: 
• Rupture of the spleen leading to bleeding in the belly 
 
1 Reported with filgrastim  
2 Reported with pegfilgrastim 
 
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 
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 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. 

 
 
 
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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 an effective birth control method 
during the treatment and for 3 months after stopping the treatment. If a female caregiver is pregnant 
or suspects she is pregnant, she should not handle crizotinib. Check with your study doctor about what 
kind of birth control methods to use.  Some methods might not be approved for use in this study. If you 
think you/your partner might be pregnant, tell the study doctors right away. The NCI requires us to 
report the outcome of the pregnancy if you/your partner get pregnant while on this study. If your 
partner gets pregnant we will ask her permission to report the information. 
 
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. 
 
Bone Marrow Examination (if required): You may be required to take bone marrow tests for 
diagnostic purposes. If this is the case, you will be informed of the risks associated with the procedure 
and your study doctor will obtain a separate consent form. 
 
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 crizotinib in combination with standard chemotherapy 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. It is extremely unlikely that this treatment will cure your cancer. 
Because there is not much information about the effect of crizotinib in combination with standard 
chemotherapy 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 
• 
Focusing on comfort care and quality of life instead of drugs to treat the tumor 
 
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. 
 
 
 

 
 
 
ADVL1212 
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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 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 
• 
Health Canada* 
• 
The Institutional Review Board (IRB) of this hospital 
• 
The drug company partner (the company that makes crizotinib) and its staff 
* 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 crizotinib at no cost to you while you take part in the study.  However, you or your 
health plan may need to pay for costs of the supplies and personnel who give you crizotinib and the other 
standard chemotherapy drugs. If, during the study, crizotinib becomes approved for use in your cancer, you 
and/or your health plan may have to pay for drug needed to complete this study. 
 
Even though it probably won’t happen, it is possible that the manufacturer may not continue to provide 
crizotinib for some reason.  If this would occur, other possible options are: 
 
• 
You might be able to get the crizotinib from the manufacturer or pharmacy but you or your 
insurance company may have to pay for it. 
 
• 
If there is no crizotinib available at all, no one will be able to get more and the study would then 
close. 
 
If a problem with getting crizotinib occurs, your study doctor will talk to you about these options. 
 

 
 
 
ADVL1212 
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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 will not be paid for taking part in this study.  However, you may be reimbursed up to $100 (maximum) 
for inconveniences you experience as a result of your participation in the required pharmacokinetic studies 
as previously described above. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s 
Web site at http://www.cancer.gov/clinicaltrials/learningabout. 
 
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.   There are no plans for the study to pay for medical treatment 
for injuries. However, signing this form does not mean that you are giving up any legal rights to try to get 
compensation for injury. 
 
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 regular 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.   
 
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 http://www.childrensoncologygroup.org/index.php/family-handbook. 
 
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)  

 
 
 
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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 __ 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 _______________________________________ 
 
 
Physician or Responsible Investigator_______________________________________ 
 
Signature of Physician or Responsible Investigator_______________________________________ 
 
Date ______________________________________ 
 

 
 
 
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Study Chart  
You will receive crizotinib for 21 days. This 21-day period of time is called a cycle.  The chart below shows 
what will happen to you during Cycle 1 and subsequent cycles. You will also receive standard chemotherapy 
drugs (topotecan and cyclophosphamide) on Days 1 to 5 of each cycle. 
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 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 pregnancy test (for women of childbearing 
potential) 
• 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 a Patient Diary 
• Get a blood test for pharmacokinetic (PK) studies 
before taking crizotinib (All Parts) 
• Part C Only: Begin taking crizotinib twice a day. 
Keep taking crizotinib for 21 days, unless you are 
told to stop by your doctor. 
• Part D Only: Get crizotinib to take once in the 
evening on Day 1. 
• You will get chemotherapy on Day 1 through Day 5 
 
Day 1 
Come into the clinic and do the following: 
• Get a new Patient Diary 
• Get a physical exam by your doctor 
• All Parts: Keep taking crizotinib twice a day for 21 days 
if you do not have bad side effects and cancer is not 
getting worse.  Call the doctor at _____________ [insert 
phone number] if you do not know what to do. 
• Continue getting chemotherapy on Day 1 through Day 
5. 
Day 2 
Come into the clinic and do the following (Part D Only): 
• Get a blood test for PK studies before taking the 
crizotinib morning dose. 
• Begin taking crizotinib twice a day. Keep taking 
crizotinib until Day 21, unless you are told to stop by 
your doctor. 
 
Days 2-20 
Come into the clinic and do the following: 
• Get routine blood tests twice weekly 
• Return the Patient Diary at the end of each week 
• Get a physical exam by your doctor once weekly 
 
Day 2-20 
 
Come into the clinic and do the following: 
• Get routine blood tests once weekly 
 
Days 15-
21 
Come into the clinic and do the following (All Parts): 
• Come into the clinic between Day 15 and day 21 to 
get blood tests done for PK studies 
 
 
Day 21 
Come into the clinic and do the following: 
• Get routine blood tests 
• Get a physical exam by your doctor 
• Get an eye exam by your doctor 
• Get imaging scans (if required) 
• Get a test of bone marrow (if required)  
• Get a test of spinal fluid (if required)  
• Return the Patient Diary 
• Get a disease evaluation. 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 crizotinib. If you continue, please follow the 
schedule listed in the column under “Subsequent 
Cycles”. 
Day 21 
Come into the clinic and do the following: 
• Get routine blood tests 
• Get urine tests (if you have neuroblastoma) 
• Get an eye exam (end of cycle 3 and then every 3 cycles)  
• Return the Patient Diary 
• Get imaging scans (if required) (every other cycle x 2, 
then every 3 cycles) 
• Get a bone marrow test (if required) (every other cycle 
x 2, then every 3 cycles)  
• Get a disease evaluation (every other cycle x 2, then 
every 3 cycles). 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”.